CA2385528C - Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents - Google Patents
Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents Download PDFInfo
- Publication number
- CA2385528C CA2385528C CA2385528A CA2385528A CA2385528C CA 2385528 C CA2385528 C CA 2385528C CA 2385528 A CA2385528 A CA 2385528A CA 2385528 A CA2385528 A CA 2385528A CA 2385528 C CA2385528 C CA 2385528C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- cancer
- immunoconjugate
- chemotherapeutic agent
- maytansinoid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/04—Amoebicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
- A61P33/12—Schistosomicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention is based on the discovery that the administration of at least one immunoconjugate and at least one chemotherapeutic agent provides an unexpectedly superior treatment for cancer. The present invention is directed to compositions comprising at least one immunoconjugate and at least one chemotherapeutic agent and to methods of treating cancer using at least one immunoconjugate and at least one chemotherapeutic agent. The present invention also provides methods of modulating the growth of selected cell populations, such as cancer cells, by administering a therapeutically effective amount of at least one chemotherapeutic agent and at least one immunoconjugate.
Description
COMPOSITIONS AND METHODS FOR TREATING CANCER USING
IMMUNOCONJUGATES AND CHEMOTHERAPEUTIC AGENTS
FIELD OF THE INVENTION
The present invention is based on the discovery that the administration of at least one immunoconjugate and at least one chemotherapeutic agent provides an unexpectedly superior treatment for cancer. The present invention is directed to compositions comprising at least one immunoconjugate and at least one chemotherapeutic agent and to methods of treating cancer using a therapeutically effective amount of at least one immunoconjugate and at least one chemotherapeutic agent. The present invention is also directed to methods of modulating the growth of selected cell populations using a therapeutically effective amount of at least one chemotherapeutic agent and at least one immunoconjugate.
BACKGROUND OF THE INVENTION
Of all lung cancer cases diagnosed in the United States every year, 20-25% are small cell lung cancer (SCLC). Current treatments for small cell lung cancer include surgery, radiation treatment, and chemotherapeutic agents, such as paclitaxel or a combination of etoposide and cisplatin. Despite these treatment options, there is only a 1-5% survival rate after 5 years in patients who have clinically evident metastatic disease upon diagnosis. Glisson et al, Journal of Clinical Oncology, 17(8):2309-2315 (August 1999).
Pre-clinical studies reveal that small cell lung cancers can also be treated with an immunoconjugate comprising a monoclonal antibody and a maytansinoid. Liu et al, Proceedings of the American Association for Cancer Research, 38:29 (abstract 190) (1997). In this study, the maytansinoid was DM1, and the monoclonal antibody was humanized N901. Humanized monoclonal antibody N901 targets CD56, which is expressed on substantially all small cell lung cancers.
There is a need in the art for new and more effective methods for treating cancer. The present invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that the use of at least one chemotherapeutic agent and at least one immunoconjugate produces unexpectedly superior results in the treatment of cancer.
The present invention describes methods of treating cancer in a patient in need thereof by administering to the patient a therapeutically effective amount of at least one chemotherapeutic agent and at least one immunoconjugate. The chemotherapeutic agent can be any known in the art including, for example, taxane compounds, compounds that act via taxane mechanisms, platinum compounds, epipodophyllotoxin compounds, camptothecin compounds, or any combination thereof. The immunoconjugate can comprise a cell binding agent and at least one therapeutic agent for killing selected cell populations. The cell binding agent is preferably a monoclonal antibody or a fragment thereof, and the therapeutic agent for killing selected cell populations is preferably an anti-mitotic agent, such as a maytansinoid, a Vinca alkaloid, a dolastatin, or a cryptophycin. In particularly preferred embodiments, the immunoconjugate comprises the maytansinoid DM1 and humanized N901 monoclonal antibody. The chemotherapeutic agent and immunoconjugate can be administered separately or as components of the same composition.
The present invention also describes methods of modulating the growth of selected cell populations, such as cancer cells, by administering a therapeutically effective amount of at least one chemotherapeutic agent and at least one immunoconjugate. The chemotherapeutic agent can be any known in the art including, for example, taxane compounds, compounds that act via taxane mechanisms, platinum compounds, epipodophyllotmdn compounds, camptothecin compounds, or any combination thereof. The immunoconjugate can comprise a cell binding agent and at least one therapeutic agent for killing selected cell populations.
The cell binding agent is preferably a monoclonal antibody or a fragment thereof, and the therapeutic agent for killing selected cell populations is preferably an anti-mitotic agent, such as a maytansinoid, a Vinca alkaloid, a dolastatin, or a cryptophycin. In particularly preferred embodiments, the immunoconjugate comprises the maytansinoid DM1 and humanized N901 monoclonal antibody. The chemotherapeutic agent and immunoconjugate can be administered separately or as components of the same composition.
The present invention also describes compositions comprising at least one chemotherapeutic agent and at least one immunoconjugate. The chemotherapeutic agent can be any known in the art including, for example, taxane compounds, compounds that act via taxane mechanisms, platinum compounds, epipodophyllotoxin compounds, camptothecin compounds, or any combination thereof. The immunoconjugate can comprise a cell binding agent and at least one therapeutic agent for killing selected cell populations. The cell binding agent is preferably a monoclonal antibody or a fragment thereof, and the therapeutic agent for killing selected cell populations is preferably an anti-mitotic agent, such as a maytansinoid, a Vinca alkaloid, a dolastatin, or a cryptophycin. In particularly preferred embodiments, the immunoconjugate comprises the maytansinoid DM1 and humanized N901 monoclonal antibody. The composition can comprise a pharmaceutically acceptable carrier, exdpient or diluent.
These and other aspects of the present invention are described in detail herein.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows maytansine (1a) and maytansinol (lb).
Fig. 2 shows the synthesis of disulfide-containing derivatives of N-methyl-L-alanine.
Fig. 3 shows the synthesis of disulfide- and thiol-containing maytansinoids which can be linked to cell binding agents via a disulfide or any other sulfur-containing link such as thioether or thioester links. The synthesis starts with the intermediates of Fig. 2.
Fig. 4a shows the synthesis of disulfide- and thiol-containing derivatives of N-methyl-L-cysteine.
Fig. 4b shows the synthesis of disulfide- and thiol-containing maytansinoids from the intermediates of Fig. 4a that can be conjugated to cell binding agents via a disulfide or any other sulfur-containing link such as thioether or thioester links.
Fig. 5 is a graph comparing the anti-tumor activity of (i) a control, (ii) huN901-DM1, (iii) paclitaxel, and (iv) the combination of huN901-DM1 and paclitaxel, against small cell lung cancer xenografts in SCID mice.
Fig. 6 is a graph comparing the anti-tumor activity of (i) a control, (ii) huN901-DM1, (iii) the combination of dsplatin and etoposide, and (iv) the combination of huN901-DM1, cisplatin and etoposide, against small cell lung cancer xenografts in SCID mice.
Fig. 7 is a graph comparing the anti-tumor activity of (i) a control, (ii) huN901-DM1, (iii) docetaxel, and (iv) the combination of huN901-DM1 and docetaxel, against small cell lung cancer xenografts in SCID mice.
Fig. 8 is a graph comparing the anti-tumor activity of (i) a control, (ii) huN901-DM1, (iii) topotecan, and (iv) the combination of huN901-DM1 and topotecan, against small cell lung cancer xenografts in SCID mice.
Fig. 9 is a graph comparing the anti-tumor activity of (i) a control, (ii) huC242-DM1, (iii) paditaxel, and (iv) the combination of huC242-DM1 and paclitaxel, against human lung adenocarcinoma xenografts in SCID mice.
Fig. 10 is a graph comparing the anti-tumor activity of (i) a control, (ii) huC242-DM1, (iii) CPT-11 (also called irinotecan), and (iv) the combination of huC242-DM1 and CPT-11, against human colon cancer xenografts in SCID mice.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the unexpected discovery that the administration of at least one chemotherapeutic agent and at least one immunoconjugate produces superior results in the treatment of cancer.
Appropriate chemotherapeutic agents and immunoconjugates are described herein.
The immunoconjugates of the present invention comprise at least one therapeutic agent for killing selected cell populations linked to a cell binding agent.
The therapeutic agent for killing selected cell populations is preferably an anti-mitotic agent. Anti-mitotic agents, which are known in the art, kill cells by inhibiting tubulin polymerization and, therefore, microtubule formation. Any anti-mitotic agent known in the art can be used in the present invention, including, for example, maytansinoids, Vinca alkaloids, dolastatins, cryptophycins, and/or any other agent that kills cells by inhibiting tubulin polymerization. Preferably, the anti-mitotic agent is a maytansinoid.
Maytansinoids that can be used in the present invention, to produce the modified maytansinoid capable of being linked to a cell binding agent, are well known in the art and can be isolated from natural sources according to known methods or prepared synthetically according to known methods. Preferred maytansinoids are those described, for example, in U.S. Patent No. 5,208,020.
Suitable maytansinoids include maytansinol and maytansinol analogues.
Examples of suitable maytansinol analogues include those having a modified aromatic ring and those having modifications at other positions. Specific examples of suitable analogues of maytansinol having a modified aromatic ring include:
C-19-dechloro (U.S. Patent No. 4,256,746) (prepared by LAN reduction of ansamitocin P-2); C-20-hydroxy (or C-20-demethyl) C-19-dechloro (U.S. Patent Nos. 4,361,650 and 4,307,016) (prepared by demethylation using Streptomyces or Actinomyces or dechlorination using LAM); and C-20-demethoxy, C-20-acyloxy (-000R), +/¨ dechloro (U.S. Patent No. 4,294,757) (prepared by acylation using acyl chlorides).
Specific examples of suitable analogues of maytansinol having modifications of other positions include: C-9-SH (U.S. Patent No. 4,424,219) (prepared by the reaction of maytansinol with I-12.5 or P2S5); C-14-alkoxymethyl(demethoxy/CH2OR) (U.S. Patent No. 4,331,598); C-14-hydroxymethyl or acyloxymethyl (CH2OH or CH20Ac) (U.S. Patent No. 4,450,254) (prepared from Nocardia);
C-15-hydroxy/acyloxy (U.S. Patent No. 4,364,866) (prepared by the conversion of maytansinol by Streptomyces); C-15-methoxy (U.S. Patent Nos. 4,313,946 and 4,315,929) (isolated from Trewia nudlflora); C-18-N-demethyl (U.S. Patent Nos.
4,362,663 and 4,322,348) (prepared by the demethylation of maytansinol by Streptomyces); and 4,5-deoxy (U.S. Patent No. 4,371,533) (prepared by the titanium trichloride/LAH reduction of maytansinol).
In order to link the maytansinoid to the cell binding agent, the maytansinoid must be modified, and a linking group can be used. Suitable linking groups are known in the art and include, for example, disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups and esterase labile groups.
Preferred are disulfide groups and thioether groups.
The linking group is part of a chemical moiety that is covalently bound to the maytansinoid through conventional methods. In a preferred embodiment, the chemical moiety can be covalently bound to the maytansinoid via an ester linkage.
Many positions on maytansinoids are useful as the linkage position, depending upon the type of link. For example, for forming an ester linkage, the C-3 position having a hydroxyl group, the C-14 position modified with hydroxymethyl, the C-15 position modified with hydroxy, and the C-20 position having a hydroxy group are all expected to be useful. The C-3 position is preferred and the C-3 position of maytansinol is especially preferred. Also preferred is an N-methyl-alanine-containing C-3 ester and an N-methyl-cysteine-containing C-3 ester of maytansinol or its analogues.
The synthesis of esters of maytansinol having a linking group is described in U.S. Patent No. 5,208,020. While the synthesis of esters of maytansinol having a linking group is described herein in terms of thiol and disulfide linking groups, one of skill in the art will understand that other linking groups can also be used with the invention, as can other maytansinoids.
The synthesis of maytansinoid derivatives can be described by reference to Figs. 1, 2, 3, 4a and 4b, where disulfide-containing maytansinoid esters are prepared by condensing maytansinol lb with freshly prepared N-methyl-L-alanine or N-methyl-L-cysteine derivatives containing a disulfide group.
co-Mercapto-carboxylic acids of varying chain lengths are converted into their respective methyl-dithio, e.g., 3a-3d (where n = 1-10, including branched and cyclic aliphatics), or aryl-dithio, e.g., 4a-4b, derivatives by reacting them with methyl methanethiolsulfonate or aryldisulfides, such as diphenyldisulfide and ring substituted diphenyldisulfides and heterocyclic disulfides such as 2,2-dithiopyridine. The carboxylic acids are activated and then reacted with N-methyl-L-alanine to form the desired carboxylic acid compounds, e.g., 5a-5f, for condensation with maytansinol lb.
IMMUNOCONJUGATES AND CHEMOTHERAPEUTIC AGENTS
FIELD OF THE INVENTION
The present invention is based on the discovery that the administration of at least one immunoconjugate and at least one chemotherapeutic agent provides an unexpectedly superior treatment for cancer. The present invention is directed to compositions comprising at least one immunoconjugate and at least one chemotherapeutic agent and to methods of treating cancer using a therapeutically effective amount of at least one immunoconjugate and at least one chemotherapeutic agent. The present invention is also directed to methods of modulating the growth of selected cell populations using a therapeutically effective amount of at least one chemotherapeutic agent and at least one immunoconjugate.
BACKGROUND OF THE INVENTION
Of all lung cancer cases diagnosed in the United States every year, 20-25% are small cell lung cancer (SCLC). Current treatments for small cell lung cancer include surgery, radiation treatment, and chemotherapeutic agents, such as paclitaxel or a combination of etoposide and cisplatin. Despite these treatment options, there is only a 1-5% survival rate after 5 years in patients who have clinically evident metastatic disease upon diagnosis. Glisson et al, Journal of Clinical Oncology, 17(8):2309-2315 (August 1999).
Pre-clinical studies reveal that small cell lung cancers can also be treated with an immunoconjugate comprising a monoclonal antibody and a maytansinoid. Liu et al, Proceedings of the American Association for Cancer Research, 38:29 (abstract 190) (1997). In this study, the maytansinoid was DM1, and the monoclonal antibody was humanized N901. Humanized monoclonal antibody N901 targets CD56, which is expressed on substantially all small cell lung cancers.
There is a need in the art for new and more effective methods for treating cancer. The present invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that the use of at least one chemotherapeutic agent and at least one immunoconjugate produces unexpectedly superior results in the treatment of cancer.
The present invention describes methods of treating cancer in a patient in need thereof by administering to the patient a therapeutically effective amount of at least one chemotherapeutic agent and at least one immunoconjugate. The chemotherapeutic agent can be any known in the art including, for example, taxane compounds, compounds that act via taxane mechanisms, platinum compounds, epipodophyllotoxin compounds, camptothecin compounds, or any combination thereof. The immunoconjugate can comprise a cell binding agent and at least one therapeutic agent for killing selected cell populations. The cell binding agent is preferably a monoclonal antibody or a fragment thereof, and the therapeutic agent for killing selected cell populations is preferably an anti-mitotic agent, such as a maytansinoid, a Vinca alkaloid, a dolastatin, or a cryptophycin. In particularly preferred embodiments, the immunoconjugate comprises the maytansinoid DM1 and humanized N901 monoclonal antibody. The chemotherapeutic agent and immunoconjugate can be administered separately or as components of the same composition.
The present invention also describes methods of modulating the growth of selected cell populations, such as cancer cells, by administering a therapeutically effective amount of at least one chemotherapeutic agent and at least one immunoconjugate. The chemotherapeutic agent can be any known in the art including, for example, taxane compounds, compounds that act via taxane mechanisms, platinum compounds, epipodophyllotmdn compounds, camptothecin compounds, or any combination thereof. The immunoconjugate can comprise a cell binding agent and at least one therapeutic agent for killing selected cell populations.
The cell binding agent is preferably a monoclonal antibody or a fragment thereof, and the therapeutic agent for killing selected cell populations is preferably an anti-mitotic agent, such as a maytansinoid, a Vinca alkaloid, a dolastatin, or a cryptophycin. In particularly preferred embodiments, the immunoconjugate comprises the maytansinoid DM1 and humanized N901 monoclonal antibody. The chemotherapeutic agent and immunoconjugate can be administered separately or as components of the same composition.
The present invention also describes compositions comprising at least one chemotherapeutic agent and at least one immunoconjugate. The chemotherapeutic agent can be any known in the art including, for example, taxane compounds, compounds that act via taxane mechanisms, platinum compounds, epipodophyllotoxin compounds, camptothecin compounds, or any combination thereof. The immunoconjugate can comprise a cell binding agent and at least one therapeutic agent for killing selected cell populations. The cell binding agent is preferably a monoclonal antibody or a fragment thereof, and the therapeutic agent for killing selected cell populations is preferably an anti-mitotic agent, such as a maytansinoid, a Vinca alkaloid, a dolastatin, or a cryptophycin. In particularly preferred embodiments, the immunoconjugate comprises the maytansinoid DM1 and humanized N901 monoclonal antibody. The composition can comprise a pharmaceutically acceptable carrier, exdpient or diluent.
These and other aspects of the present invention are described in detail herein.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows maytansine (1a) and maytansinol (lb).
Fig. 2 shows the synthesis of disulfide-containing derivatives of N-methyl-L-alanine.
Fig. 3 shows the synthesis of disulfide- and thiol-containing maytansinoids which can be linked to cell binding agents via a disulfide or any other sulfur-containing link such as thioether or thioester links. The synthesis starts with the intermediates of Fig. 2.
Fig. 4a shows the synthesis of disulfide- and thiol-containing derivatives of N-methyl-L-cysteine.
Fig. 4b shows the synthesis of disulfide- and thiol-containing maytansinoids from the intermediates of Fig. 4a that can be conjugated to cell binding agents via a disulfide or any other sulfur-containing link such as thioether or thioester links.
Fig. 5 is a graph comparing the anti-tumor activity of (i) a control, (ii) huN901-DM1, (iii) paclitaxel, and (iv) the combination of huN901-DM1 and paclitaxel, against small cell lung cancer xenografts in SCID mice.
Fig. 6 is a graph comparing the anti-tumor activity of (i) a control, (ii) huN901-DM1, (iii) the combination of dsplatin and etoposide, and (iv) the combination of huN901-DM1, cisplatin and etoposide, against small cell lung cancer xenografts in SCID mice.
Fig. 7 is a graph comparing the anti-tumor activity of (i) a control, (ii) huN901-DM1, (iii) docetaxel, and (iv) the combination of huN901-DM1 and docetaxel, against small cell lung cancer xenografts in SCID mice.
Fig. 8 is a graph comparing the anti-tumor activity of (i) a control, (ii) huN901-DM1, (iii) topotecan, and (iv) the combination of huN901-DM1 and topotecan, against small cell lung cancer xenografts in SCID mice.
Fig. 9 is a graph comparing the anti-tumor activity of (i) a control, (ii) huC242-DM1, (iii) paditaxel, and (iv) the combination of huC242-DM1 and paclitaxel, against human lung adenocarcinoma xenografts in SCID mice.
Fig. 10 is a graph comparing the anti-tumor activity of (i) a control, (ii) huC242-DM1, (iii) CPT-11 (also called irinotecan), and (iv) the combination of huC242-DM1 and CPT-11, against human colon cancer xenografts in SCID mice.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the unexpected discovery that the administration of at least one chemotherapeutic agent and at least one immunoconjugate produces superior results in the treatment of cancer.
Appropriate chemotherapeutic agents and immunoconjugates are described herein.
The immunoconjugates of the present invention comprise at least one therapeutic agent for killing selected cell populations linked to a cell binding agent.
The therapeutic agent for killing selected cell populations is preferably an anti-mitotic agent. Anti-mitotic agents, which are known in the art, kill cells by inhibiting tubulin polymerization and, therefore, microtubule formation. Any anti-mitotic agent known in the art can be used in the present invention, including, for example, maytansinoids, Vinca alkaloids, dolastatins, cryptophycins, and/or any other agent that kills cells by inhibiting tubulin polymerization. Preferably, the anti-mitotic agent is a maytansinoid.
Maytansinoids that can be used in the present invention, to produce the modified maytansinoid capable of being linked to a cell binding agent, are well known in the art and can be isolated from natural sources according to known methods or prepared synthetically according to known methods. Preferred maytansinoids are those described, for example, in U.S. Patent No. 5,208,020.
Suitable maytansinoids include maytansinol and maytansinol analogues.
Examples of suitable maytansinol analogues include those having a modified aromatic ring and those having modifications at other positions. Specific examples of suitable analogues of maytansinol having a modified aromatic ring include:
C-19-dechloro (U.S. Patent No. 4,256,746) (prepared by LAN reduction of ansamitocin P-2); C-20-hydroxy (or C-20-demethyl) C-19-dechloro (U.S. Patent Nos. 4,361,650 and 4,307,016) (prepared by demethylation using Streptomyces or Actinomyces or dechlorination using LAM); and C-20-demethoxy, C-20-acyloxy (-000R), +/¨ dechloro (U.S. Patent No. 4,294,757) (prepared by acylation using acyl chlorides).
Specific examples of suitable analogues of maytansinol having modifications of other positions include: C-9-SH (U.S. Patent No. 4,424,219) (prepared by the reaction of maytansinol with I-12.5 or P2S5); C-14-alkoxymethyl(demethoxy/CH2OR) (U.S. Patent No. 4,331,598); C-14-hydroxymethyl or acyloxymethyl (CH2OH or CH20Ac) (U.S. Patent No. 4,450,254) (prepared from Nocardia);
C-15-hydroxy/acyloxy (U.S. Patent No. 4,364,866) (prepared by the conversion of maytansinol by Streptomyces); C-15-methoxy (U.S. Patent Nos. 4,313,946 and 4,315,929) (isolated from Trewia nudlflora); C-18-N-demethyl (U.S. Patent Nos.
4,362,663 and 4,322,348) (prepared by the demethylation of maytansinol by Streptomyces); and 4,5-deoxy (U.S. Patent No. 4,371,533) (prepared by the titanium trichloride/LAH reduction of maytansinol).
In order to link the maytansinoid to the cell binding agent, the maytansinoid must be modified, and a linking group can be used. Suitable linking groups are known in the art and include, for example, disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups and esterase labile groups.
Preferred are disulfide groups and thioether groups.
The linking group is part of a chemical moiety that is covalently bound to the maytansinoid through conventional methods. In a preferred embodiment, the chemical moiety can be covalently bound to the maytansinoid via an ester linkage.
Many positions on maytansinoids are useful as the linkage position, depending upon the type of link. For example, for forming an ester linkage, the C-3 position having a hydroxyl group, the C-14 position modified with hydroxymethyl, the C-15 position modified with hydroxy, and the C-20 position having a hydroxy group are all expected to be useful. The C-3 position is preferred and the C-3 position of maytansinol is especially preferred. Also preferred is an N-methyl-alanine-containing C-3 ester and an N-methyl-cysteine-containing C-3 ester of maytansinol or its analogues.
The synthesis of esters of maytansinol having a linking group is described in U.S. Patent No. 5,208,020. While the synthesis of esters of maytansinol having a linking group is described herein in terms of thiol and disulfide linking groups, one of skill in the art will understand that other linking groups can also be used with the invention, as can other maytansinoids.
The synthesis of maytansinoid derivatives can be described by reference to Figs. 1, 2, 3, 4a and 4b, where disulfide-containing maytansinoid esters are prepared by condensing maytansinol lb with freshly prepared N-methyl-L-alanine or N-methyl-L-cysteine derivatives containing a disulfide group.
co-Mercapto-carboxylic acids of varying chain lengths are converted into their respective methyl-dithio, e.g., 3a-3d (where n = 1-10, including branched and cyclic aliphatics), or aryl-dithio, e.g., 4a-4b, derivatives by reacting them with methyl methanethiolsulfonate or aryldisulfides, such as diphenyldisulfide and ring substituted diphenyldisulfides and heterocyclic disulfides such as 2,2-dithiopyridine. The carboxylic acids are activated and then reacted with N-methyl-L-alanine to form the desired carboxylic acid compounds, e.g., 5a-5f, for condensation with maytansinol lb.
Esterification of maytansinol lb or an analogue with the carboxylic acids 5a-5f gives the disulfide-containing maytansinoids 6a-6f. Cleavage of the disulfide group in 6a-6f with dithiothreitol gives the thiol-containing maytansinoids 7a-7c, which are readily linked via disulfide or thioether links to cell binding agents. N-methyl-L-alanine can be prepared as described in the literature (Fu et al, J. Amer.
Chem. Soc., 75:1953); or is obtainable commercially (Sigma Chemical Company).
In another embodiment, N-methyl-cysteine or N-methylhomocysteine can be converted to the respective disulfide derivatives 8 (n = 1 and 2, respectively) which are then acylated to yield the desired carboxylic acids 9 (n = 1 and 2, respectively).
Maytansinol is then esterified with 9 (n = 1) to give disulfide-containing ester 10.
Reduction of 10a with dithiothreitol as described for 7b produces the thiol-containing maytansinoid 11 which can be conjugated to cell binding agents.
N-methyl-cysteine can be prepared as described in Undheim et al, Acta Chem.
Scand., 23:3129-3133 (1970).
More specifically, maytansinol lb is derived from maytansine la or other esters of maytansinol by reduction such as with lithium aluminum hydride.
(Kupchan et al, J. Med. Chem., 21:31-37 (1978); U.S. Patent No. 4,360,462). It is also possible to isolate maytansinol from the microorganism Nocardia (U.S. Patent No.
4,151,042). Maytansinol is then converted to the different ester derivatives, 6a to 6f and 10, using a suitable agent such as dicyclohexylcarbodiimide (DCC) and catalytic amounts of zinc chloride (U.S. Patent Nos. 4,137,230 and 4,260,609; Kawai et al, Chem. Pharm. Bull., 32:3441-3951 (1984)). The two diastereomeric products containing the D and L-aminoacyl side chains result. The diastereomeric maytansinoid esters are readily separated by preparative TLC on silica gel.
For example, using Analtech GF plates (1000 microns) and developing with 6%
methanol in chloroform yields distinct banding: the desired bands are scraped off the plate and the products extracted with ethyl acetate (Kupchan, J. Med. Chem., 21:31-37 (1978) and U.S. Patent. No. 4,360,462).
Reduction of the disulfide-containing maytansinoids to the corresponding mercapto-maytansinoids 7a, '7b, 7c and 11, is achieved by treatment with 1-1.4 dithiothreitol (DTT) and purification by HPLC using a Waters radialpak C-18 column and eluting with a linear gradient of 55% to 80% acetonitrile in H20 over 10 minutes at a flow rate of 1.5 ml/min.
When analogues of maytansinol are used as the starting material to give analogous disulfide-containing maytansinoid esters, the analogues are prepared before reacting them with the N-methyl-L-alanine or N-methyl-L-cysteine derivatives.
One example of N-methyl-alanine-containing maytansinoid derivatives useful in the present invention is represented by formula (I):
(CH2)pSZ0 H I
may (I) wherein Zo represents H or SR, wherein R represents methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic;
p represents an integer of 1 to 10; and "may" represents a maytansinoid.
In a preferred embodiment of the compound of formula (I), Zorepresents SR, R represents methyl, and p represents an integer of 2.
Another example of N-methyl-alanine-containing maytansinoid derivatives useful in the present invention is represented by formula (II):
Chem. Soc., 75:1953); or is obtainable commercially (Sigma Chemical Company).
In another embodiment, N-methyl-cysteine or N-methylhomocysteine can be converted to the respective disulfide derivatives 8 (n = 1 and 2, respectively) which are then acylated to yield the desired carboxylic acids 9 (n = 1 and 2, respectively).
Maytansinol is then esterified with 9 (n = 1) to give disulfide-containing ester 10.
Reduction of 10a with dithiothreitol as described for 7b produces the thiol-containing maytansinoid 11 which can be conjugated to cell binding agents.
N-methyl-cysteine can be prepared as described in Undheim et al, Acta Chem.
Scand., 23:3129-3133 (1970).
More specifically, maytansinol lb is derived from maytansine la or other esters of maytansinol by reduction such as with lithium aluminum hydride.
(Kupchan et al, J. Med. Chem., 21:31-37 (1978); U.S. Patent No. 4,360,462). It is also possible to isolate maytansinol from the microorganism Nocardia (U.S. Patent No.
4,151,042). Maytansinol is then converted to the different ester derivatives, 6a to 6f and 10, using a suitable agent such as dicyclohexylcarbodiimide (DCC) and catalytic amounts of zinc chloride (U.S. Patent Nos. 4,137,230 and 4,260,609; Kawai et al, Chem. Pharm. Bull., 32:3441-3951 (1984)). The two diastereomeric products containing the D and L-aminoacyl side chains result. The diastereomeric maytansinoid esters are readily separated by preparative TLC on silica gel.
For example, using Analtech GF plates (1000 microns) and developing with 6%
methanol in chloroform yields distinct banding: the desired bands are scraped off the plate and the products extracted with ethyl acetate (Kupchan, J. Med. Chem., 21:31-37 (1978) and U.S. Patent. No. 4,360,462).
Reduction of the disulfide-containing maytansinoids to the corresponding mercapto-maytansinoids 7a, '7b, 7c and 11, is achieved by treatment with 1-1.4 dithiothreitol (DTT) and purification by HPLC using a Waters radialpak C-18 column and eluting with a linear gradient of 55% to 80% acetonitrile in H20 over 10 minutes at a flow rate of 1.5 ml/min.
When analogues of maytansinol are used as the starting material to give analogous disulfide-containing maytansinoid esters, the analogues are prepared before reacting them with the N-methyl-L-alanine or N-methyl-L-cysteine derivatives.
One example of N-methyl-alanine-containing maytansinoid derivatives useful in the present invention is represented by formula (I):
(CH2)pSZ0 H I
may (I) wherein Zo represents H or SR, wherein R represents methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic;
p represents an integer of 1 to 10; and "may" represents a maytansinoid.
In a preferred embodiment of the compound of formula (I), Zorepresents SR, R represents methyl, and p represents an integer of 2.
Another example of N-methyl-alanine-containing maytansinoid derivatives useful in the present invention is represented by formula (II):
Oyk = N CH¨CH¨(CH2),õSZI
may (1-1) wherein R, and Rõ which may be the same or different, represents H, CH, or CH,CH,;
Z, represents H or SRõ wherein R3 represents methyl, linear alkyl, branched alkyl, cydic alkyl, simple or substituted aryl, or heterocyclic:
m represents 0, 1, 2 or 3; and "may" represents a maytansinoid.
Another example of N-methyl-alanine-containing maytansinoid derivatives useful in the present invention is represented by formula (III):
( 2)n SZQ
H I
may (III) wherein:
Z, represents H or SRõ wherein R, represents methyl, linear alkyl, branched alkyl cyclic alkyl, simple or substituted aryl, or heterocyclic;
n represents an integer of 3 to 8; and "may" represents a maytansinoid.
may (1-1) wherein R, and Rõ which may be the same or different, represents H, CH, or CH,CH,;
Z, represents H or SRõ wherein R3 represents methyl, linear alkyl, branched alkyl, cydic alkyl, simple or substituted aryl, or heterocyclic:
m represents 0, 1, 2 or 3; and "may" represents a maytansinoid.
Another example of N-methyl-alanine-containing maytansinoid derivatives useful in the present invention is represented by formula (III):
( 2)n SZQ
H I
may (III) wherein:
Z, represents H or SRõ wherein R, represents methyl, linear alkyl, branched alkyl cyclic alkyl, simple or substituted aryl, or heterocyclic;
n represents an integer of 3 to 8; and "may" represents a maytansinoid.
Yet another example of N-methyl-alanine-containing maytansinoid derivatives useful in the present invention is represented by formula (IV):
\A' Tj.L(CH2)tSZO
19 \ H =
X3008 17 N 3 µCH3 1 5 µ
21l 17 ,./i 10 -_ .13 OH N'0 oCH3 (IV) wherein:
Zo represents H or SR, wherein R represents methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic:
t represents 1, 2 or 3;
Yo represents Cl or H; and X, represents H or CH,.
\A' Tj.L(CH2)tSZO
19 \ H =
X3008 17 N 3 µCH3 1 5 µ
21l 17 ,./i 10 -_ .13 OH N'0 oCH3 (IV) wherein:
Zo represents H or SR, wherein R represents methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic:
t represents 1, 2 or 3;
Yo represents Cl or H; and X, represents H or CH,.
A specific example of N-methyl-cysteine-containing maytansinoid derivatives useful in the present invention is represented by formula (V):
(CH2)o 0,A
H NI (CH2)pCH3 I
=
may (V) wherein:
Z, represents H or SIZ5, wherein R, represents methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl, or heterocyclic;
o represents 1, 2 or 3;
p represents 0 or an integer of 1 to 10; and "may" represents a maytansinoid.
Another specific example of N-methyl-cysteine-containing maytansinoid derivatives useful in the present invention is represented by formula (VI):
(CH2)o 0,A
H NI (CH2)pCH3 I
=
may (V) wherein:
Z, represents H or SIZ5, wherein R, represents methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl, or heterocyclic;
o represents 1, 2 or 3;
p represents 0 or an integer of 1 to 10; and "may" represents a maytansinoid.
Another specific example of N-methyl-cysteine-containing maytansinoid derivatives useful in the present invention is represented by formula (VI):
SZ
(CH2)0 o N (CH2)qCH3 Yo CH3 0 0 X30018 N 1 3 \CH3 //.13 F5H No (VI) wherein:
Z, represents H or SRõ wherein R, represents methyl, linear alkyl, branched alkyl, cydic alkyl, simple or substituted aryl or heterocyclic;
5 o represents 1, 2, or 3;
q represents 0 or an integer of 1 to 10;
Yo represents Cl or H; and X3 represents H or CH3.
Examples of linear alkyls include methyl, ethyl, propyl, butyl, pentyl, and 10 hexyl. Examples of branched alkyls include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and 1-ethyl-propyl. Examples of cyclic alkyls indude cydopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of simple aryls include phenyl, and naphthyl. Examples of substituted aryls include aryls such as those described above substituted with alkyl groups, with halogens, such as Cl, Br, F, nitro groups, 15 amino groups, sulfonic acid groups, carboxylic acid groups, hydroxy groups, and alkoxy groups. Examples of heterocyclics are compounds wherein the heteroatoms are selected from 0, N and S, and include pyrrollyi, pyridyl, furyl, and thiophene.
Vinca alkaloids that can be used in the present invention, to produce the modified Vinca alkaloids capable of being linked to a cell binding agent, are well known in the art. Such Vinca alkaloids include, for example, those described in Cancer Principles and Practice in Oncology, 4th Ed., DeVita et al, eds., J.B.
Lippincott Company, Philadelphia PA (1993) and by Morris et al, J. Clin. Oncol., 16:1094-(1998), Exemplary Vinca alkaloids include vincristine, vinblastine, vindesine, navelbine (vinorelbine), and the like. Other Vinca alkaloids that can be used in the present invention include those described, for example, in U.S. Patent Nos. 5,369,111, 4,952,408, 5,395,610, 4,522,750, 5,888,537, 5,891,724, 5,795,589, 4,172,077, 5,714,163, 5,436,243, 3,932,417, 5,869,620, 5,795,575, 5,780,446, 5,676,978, 5,604,237, 5,171,217, 4,831,038, 4,828,831, 4,765,972, 4,375,432, 4,309,415, 5,939,455, 5,874,402, 5,767,260, 5,763,733, 5,728,687, 5,716,928, 5,660,827, 5,541,232, 5,346,897, 5,220,016, 5,208,238, 5,190,949, 4,479,957, 4,160,767, 4,159,269, 4,096,148, RE 30,561, RE 30,560, 5,935,955, 5,922,340, 5,886,025, 5,866,679, 5,863,538, 5,855,866, 5,817,321, 5,783,178, 5,776,427, 5,767,110, 5,753,507, 5,723,625, 5,698,178, 5,686,578, 5,667,764, 5,654,287, 5,646,124, 5,635,515, 5,635,218, 5,606,017, 5,597,830, 5,595,756, 5,583,052, 5,561,136, 5,547,667, 5,543,152., 5,529,076, 5,491,285, 5,482,858, 5,455,161, 5,430,026, 5,403,574, 5,399,363, 5,397,784, 5,387,578, 5,364,843, 5,300,282, 5,182,368, 5,162,115, 5,147,294, 5,108,987, 5,100,881, 5,047,528, 5,030,620, 5,004,593, 4,946,833, 4,931,468, 4,923,876, 4,801,688, 4,737,586, 4,667,030, 4,617,305, 4,578,351, 4,476,026, 4,399,069, 4,279,817, 4,208,414, 4,199,504, 4,070,358, 4,029,663, 3,965,254, 3,954,773, 3,944,554, 3,887,565, 6,120,800, 6,071,947, 6,071,930, 6,069,146, 6,063,911, 5,994,367, 5,962,216, and 5,945,315.
The Vinca alkaloids can be linked to cell binding agents, such as antibodies, via acid-labile hydrazide links by methods described by, for example, Laguzza et al, J. Med. Chem., 32:548-555 (1989), Schrappe et al, Cancer Res., 52:3838-3844 (1992), and Apelgren et al, Cancer Res., 50:3540-3544 (1990), A preferable method is to link the Vinca alkaloids to a cell binding agent via disulfide bonds. The carboxy ester at the C-3 position of vinblastine, vincristine and navelbine can be hydrolzyed to the corresponding carboxylic acid using standard chemical methods. In vindesine, the carboxamide group at C-3 can be hydrolyzed to the free carboxy group. The free carboxy group in each of the Vinca alkaloids can be converted to an amide compound containing a terminal disulfide group by reaction with a protected cysteamine (e.g., methydithiocysteamine) in the presence of a coupling agent such as dicyclohexyl-carbodidimide (DCC) or ethyl dimethylamin-propylcarbodiimide (EDC). The resulting disulfide containing Vinca alkaloid is reduced with a reducing agent, such as dithiothreitol, to provide a thiol-containing compound. The thiol-containing Vinca alkaloid can be coupled to a cell-binding agent via disulfide exchange as described herein for the preparation of antibody-maytansinoid conjugates.
Dolastatins that can be used in the present invention, to produce the modified dolastatins capable of being linked to a cell binding agent, are well known in the art.
Such dolastatins include, for example, those described by Pitot et al, Clin.
Cancer Res., 5:525-531 (1999) and Villalona-Calero et al, J. Clin. Oncol., 16:2770-2779 (1998).
Exemplary dolastatins include dolastatin 10, dolastatin 15, and the like.
Other dolastatins that can be used in the present invention include those described, for example, in U.S. Patent Nos. 5,945,543, 5,939,527, 5,886,147, 5,886,025, 5,883,120, 5,856,324, 5,840,699, 5,831,002, 5,821,222, 5,807,984, 5,780,588, 5,767,237, 5,750,713, 5,741,892, 5,665,860, 5,663,149, 5,654,399, 5,635,483, 5,626,864, 5,599,902, 5,554,725, 5,530,097, 5,521,284, 5,504,191, 5,502,032, 5,410,024, 5,410,024, 5,378,803, 5,352,804, 5,138,036, 5,091,368, 5,076,973, 4,986,988, 4,978,744, 4,879,278, 4,816,444, 4,486,414, 4,414,205, 6,103,913, 6.103,698, 6,096,757, 6,034,065, 6,020,495, 6,017,890, 6,004,934, 5,985,837, 5,965,700, and 5,965,537.
The synthetic scheme described for dolastatin 10 by Pettit et al, J. Am. Chem.
Soc., 111:5463-5465 (1989) can be followed, with minor modification, to provide a thiol-containing dolastatin that can be linked via disulfide bonds to a cell binding agent, such as an antibody. The phenylalanine moiety in the dolphenine residue in the C-terminal of dolastatin 10 is replaced by a methyldithio-substituent containing amino acid. Thus, tyrosine can be converted into an ether by reaction with a commercially available dibromoalkane, such as 1,3-dibromobutane, using standard chemical methods. The resulting bromo compound is reacted with potassium thioacetate, followed by hydrolysis, to give a thiol-containing tyrosine. Conversion is achieved as described by Pettit, supra. The thiol-containing dolastatin can be coupled to a cell binding agent via disulfide exchange as described herein for the preparation of an antibody-maytansinoid conjugate.
Cryptophycins that can be used in the present invention, to produce the modified cryptophycins capable of being linked to a cell binding agent, are well known in the art. Such cryptophycins include, for example, those described by Smith et al, Cancer Res., 54:3779-3783 (1994), Panda et al, Proc. Natl. Acad.
Sci., 95:9313-9318 (1998), and Bai et al, Cancer Res., 56:4398-4406 (1996).
Exemplary cryptophycins include cryptophycin 52, cryptophycin 1, and the like. Other cryptophycins that can be used in the present invention include those described, for example, in Great Britain Patent No. 2220657; European Patent Nos.
870506,870501, 861838, 861839, 792875 and 870510; U.S. Patent Nos. 6,103,913, 6,046,177, 6,020,512, 6,013,626, 5,977,387, 5,955,423, 5,952,298, 5,945,315, 5,886,025, and 5,833,994; and WIPO Publication Nos. 98/38178, 98/38164, 98/08829, 98/08506, 98/08505, 97/31632, 97/08334, 97/07798, 98/09601, 97/23211, 98/46581, 98/38158, 98/09988, 98/09974, 98/08812, and 98/09955.
The aromatic methoxy group in the cryptophycins can be hydrolyzed by standard chemical or enzymatic methods to give the phenolic derivative. The phenol group can be converted into an ether by reaction with a commercially available dibromoalkane, such as 1,3-dibromobutane, using standard chemical methods. The resulting bromo compound is reacted with potassium thioacetate, followed by hydrolysis, to give a thiol-containing cryptophycin. The thiol-containing cryptophycin can be coupled to a cell binding agent via disulfide exchange as described herein for the preparation of antibody-maytansinoid conjugates.
(CH2)0 o N (CH2)qCH3 Yo CH3 0 0 X30018 N 1 3 \CH3 //.13 F5H No (VI) wherein:
Z, represents H or SRõ wherein R, represents methyl, linear alkyl, branched alkyl, cydic alkyl, simple or substituted aryl or heterocyclic;
5 o represents 1, 2, or 3;
q represents 0 or an integer of 1 to 10;
Yo represents Cl or H; and X3 represents H or CH3.
Examples of linear alkyls include methyl, ethyl, propyl, butyl, pentyl, and 10 hexyl. Examples of branched alkyls include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and 1-ethyl-propyl. Examples of cyclic alkyls indude cydopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of simple aryls include phenyl, and naphthyl. Examples of substituted aryls include aryls such as those described above substituted with alkyl groups, with halogens, such as Cl, Br, F, nitro groups, 15 amino groups, sulfonic acid groups, carboxylic acid groups, hydroxy groups, and alkoxy groups. Examples of heterocyclics are compounds wherein the heteroatoms are selected from 0, N and S, and include pyrrollyi, pyridyl, furyl, and thiophene.
Vinca alkaloids that can be used in the present invention, to produce the modified Vinca alkaloids capable of being linked to a cell binding agent, are well known in the art. Such Vinca alkaloids include, for example, those described in Cancer Principles and Practice in Oncology, 4th Ed., DeVita et al, eds., J.B.
Lippincott Company, Philadelphia PA (1993) and by Morris et al, J. Clin. Oncol., 16:1094-(1998), Exemplary Vinca alkaloids include vincristine, vinblastine, vindesine, navelbine (vinorelbine), and the like. Other Vinca alkaloids that can be used in the present invention include those described, for example, in U.S. Patent Nos. 5,369,111, 4,952,408, 5,395,610, 4,522,750, 5,888,537, 5,891,724, 5,795,589, 4,172,077, 5,714,163, 5,436,243, 3,932,417, 5,869,620, 5,795,575, 5,780,446, 5,676,978, 5,604,237, 5,171,217, 4,831,038, 4,828,831, 4,765,972, 4,375,432, 4,309,415, 5,939,455, 5,874,402, 5,767,260, 5,763,733, 5,728,687, 5,716,928, 5,660,827, 5,541,232, 5,346,897, 5,220,016, 5,208,238, 5,190,949, 4,479,957, 4,160,767, 4,159,269, 4,096,148, RE 30,561, RE 30,560, 5,935,955, 5,922,340, 5,886,025, 5,866,679, 5,863,538, 5,855,866, 5,817,321, 5,783,178, 5,776,427, 5,767,110, 5,753,507, 5,723,625, 5,698,178, 5,686,578, 5,667,764, 5,654,287, 5,646,124, 5,635,515, 5,635,218, 5,606,017, 5,597,830, 5,595,756, 5,583,052, 5,561,136, 5,547,667, 5,543,152., 5,529,076, 5,491,285, 5,482,858, 5,455,161, 5,430,026, 5,403,574, 5,399,363, 5,397,784, 5,387,578, 5,364,843, 5,300,282, 5,182,368, 5,162,115, 5,147,294, 5,108,987, 5,100,881, 5,047,528, 5,030,620, 5,004,593, 4,946,833, 4,931,468, 4,923,876, 4,801,688, 4,737,586, 4,667,030, 4,617,305, 4,578,351, 4,476,026, 4,399,069, 4,279,817, 4,208,414, 4,199,504, 4,070,358, 4,029,663, 3,965,254, 3,954,773, 3,944,554, 3,887,565, 6,120,800, 6,071,947, 6,071,930, 6,069,146, 6,063,911, 5,994,367, 5,962,216, and 5,945,315.
The Vinca alkaloids can be linked to cell binding agents, such as antibodies, via acid-labile hydrazide links by methods described by, for example, Laguzza et al, J. Med. Chem., 32:548-555 (1989), Schrappe et al, Cancer Res., 52:3838-3844 (1992), and Apelgren et al, Cancer Res., 50:3540-3544 (1990), A preferable method is to link the Vinca alkaloids to a cell binding agent via disulfide bonds. The carboxy ester at the C-3 position of vinblastine, vincristine and navelbine can be hydrolzyed to the corresponding carboxylic acid using standard chemical methods. In vindesine, the carboxamide group at C-3 can be hydrolyzed to the free carboxy group. The free carboxy group in each of the Vinca alkaloids can be converted to an amide compound containing a terminal disulfide group by reaction with a protected cysteamine (e.g., methydithiocysteamine) in the presence of a coupling agent such as dicyclohexyl-carbodidimide (DCC) or ethyl dimethylamin-propylcarbodiimide (EDC). The resulting disulfide containing Vinca alkaloid is reduced with a reducing agent, such as dithiothreitol, to provide a thiol-containing compound. The thiol-containing Vinca alkaloid can be coupled to a cell-binding agent via disulfide exchange as described herein for the preparation of antibody-maytansinoid conjugates.
Dolastatins that can be used in the present invention, to produce the modified dolastatins capable of being linked to a cell binding agent, are well known in the art.
Such dolastatins include, for example, those described by Pitot et al, Clin.
Cancer Res., 5:525-531 (1999) and Villalona-Calero et al, J. Clin. Oncol., 16:2770-2779 (1998).
Exemplary dolastatins include dolastatin 10, dolastatin 15, and the like.
Other dolastatins that can be used in the present invention include those described, for example, in U.S. Patent Nos. 5,945,543, 5,939,527, 5,886,147, 5,886,025, 5,883,120, 5,856,324, 5,840,699, 5,831,002, 5,821,222, 5,807,984, 5,780,588, 5,767,237, 5,750,713, 5,741,892, 5,665,860, 5,663,149, 5,654,399, 5,635,483, 5,626,864, 5,599,902, 5,554,725, 5,530,097, 5,521,284, 5,504,191, 5,502,032, 5,410,024, 5,410,024, 5,378,803, 5,352,804, 5,138,036, 5,091,368, 5,076,973, 4,986,988, 4,978,744, 4,879,278, 4,816,444, 4,486,414, 4,414,205, 6,103,913, 6.103,698, 6,096,757, 6,034,065, 6,020,495, 6,017,890, 6,004,934, 5,985,837, 5,965,700, and 5,965,537.
The synthetic scheme described for dolastatin 10 by Pettit et al, J. Am. Chem.
Soc., 111:5463-5465 (1989) can be followed, with minor modification, to provide a thiol-containing dolastatin that can be linked via disulfide bonds to a cell binding agent, such as an antibody. The phenylalanine moiety in the dolphenine residue in the C-terminal of dolastatin 10 is replaced by a methyldithio-substituent containing amino acid. Thus, tyrosine can be converted into an ether by reaction with a commercially available dibromoalkane, such as 1,3-dibromobutane, using standard chemical methods. The resulting bromo compound is reacted with potassium thioacetate, followed by hydrolysis, to give a thiol-containing tyrosine. Conversion is achieved as described by Pettit, supra. The thiol-containing dolastatin can be coupled to a cell binding agent via disulfide exchange as described herein for the preparation of an antibody-maytansinoid conjugate.
Cryptophycins that can be used in the present invention, to produce the modified cryptophycins capable of being linked to a cell binding agent, are well known in the art. Such cryptophycins include, for example, those described by Smith et al, Cancer Res., 54:3779-3783 (1994), Panda et al, Proc. Natl. Acad.
Sci., 95:9313-9318 (1998), and Bai et al, Cancer Res., 56:4398-4406 (1996).
Exemplary cryptophycins include cryptophycin 52, cryptophycin 1, and the like. Other cryptophycins that can be used in the present invention include those described, for example, in Great Britain Patent No. 2220657; European Patent Nos.
870506,870501, 861838, 861839, 792875 and 870510; U.S. Patent Nos. 6,103,913, 6,046,177, 6,020,512, 6,013,626, 5,977,387, 5,955,423, 5,952,298, 5,945,315, 5,886,025, and 5,833,994; and WIPO Publication Nos. 98/38178, 98/38164, 98/08829, 98/08506, 98/08505, 97/31632, 97/08334, 97/07798, 98/09601, 97/23211, 98/46581, 98/38158, 98/09988, 98/09974, 98/08812, and 98/09955.
The aromatic methoxy group in the cryptophycins can be hydrolyzed by standard chemical or enzymatic methods to give the phenolic derivative. The phenol group can be converted into an ether by reaction with a commercially available dibromoalkane, such as 1,3-dibromobutane, using standard chemical methods. The resulting bromo compound is reacted with potassium thioacetate, followed by hydrolysis, to give a thiol-containing cryptophycin. The thiol-containing cryptophycin can be coupled to a cell binding agent via disulfide exchange as described herein for the preparation of antibody-maytansinoid conjugates.
Disulfide-containing and mercapto-containing maytansinoid (or Vinca alkaloid or dolastatin or cryptophycin) drugs of the invention can be evaluated for their ability to suppress proliferation of various unwanted cell lines using in vitro methods generally accepted in the art as being predictive of in vivo activity.
For example, cell lines such as the human epidermoid carcinoma line KB, the human breast tumor line SKBR3 and the Burkitt's lymphoma line Namalwa can easily be used for the assessment of cytotoxicity of these compounds. Cells to be evaluated can be exposed to the compounds for 24 hours and the surviving fractions of cells measured in direct assays by known methods. IC,õ values can then be calculated from the results of the assays.
The effectiveness of the immunoconjugates as therapeutic agents depends on the careful selection of an appropriate cell binding agent. Cell binding agents may be of any kind presently known, or that become known, and include peptides and non-peptides. Generally, these can be antibodies (especially monoclonal antibodies), lymphokines, hormones, growth factors, nutrient-transport molecules (such as transferrin), or any other cell binding molecule or substance.
More specific examples of cell binding agents that can be used include:
monoclonal antibodies; fragments of antibodies such as Fv, Fab, Fab', and F(ab'), (Parham, J. Immunol., 131:2895-2902 (1983); Spring et al, J. Immunol., 113:470-(1974); Nisonoff et al, Arch. Biochem. Biophys., 89:230-244 (1960));
interferons (e.g., a, p, y); lymphokines such as IL2, IL3, IL-4, IL-6; hormones such as insulin, TRH
(thyrotropin releasing hormone), MSH (melanocyte-stimulating hormone), steroid hormones such as androgens and estrogens; growth factors and colony-stimulating factors such as EGF, TGF-a, G-CSF, M-CSF and GM-CSF (Burgess, Immunology Today, 5:155-158 (1984)); and transferrin (O'Keefe et al, J. Biol. Chem., 260:932-937 (1985)).
Monoclonal antibody techniques allow for the production of extremely specific cell binding agents in the form of specific monoclonal antibodies.
Particularly well known in the art are techniques for creating monoclonal antibodies produced by immunizing mice, rats, hamsters or any other mammal with the antigen of interest such as the intact target cell, antigens isolated from the target cell, whole virus, attenuated whole virus, and viral proteins such as viral coat proteins.
Sensitized human cells can also be used.
Selection of the appropriate cell binding agent is a matter of choice that depends upon the particular cell population that is to be targeted, but in general monoclonal antibodies are preferred if an appropriate one is available.
For example, the monoclonal antibody J5 is a murine IgG2a antibody that is specific for the Common Acute Lymphoblastic Leukemia Antigen (CALLA) (Ritz et al, Nature, 283:583-585 (1980)) and can be used if the target cells express CALLA such as in the disease of acute lymphoblastic leukemia. Similarly, the monoclonal antibody anti-B4 is a murine IgGi, that binds to the CD19 antigen on B cells (Nadler et al, J. Immunol., 131:244-250 (1983)) and can be used if the target cells are B cells or diseased cells that express this antigen such as in non-Hodgkin's lymphoma or chronic lymphoblastic leukemia.
Additionally, GM-CSF which binds to myeloid cells can be used as a cell binding agent to diseased cells from acute myelogenous leukemia. IL-2 which binds to activated T-cells can be used for prevention of transplant graft rejection, for therapy and prevention of graft-versus-host disease, and for treatment of acute T-cell leukemia. MSH which binds to melanocytes can be used for the treatment of melanoma.
Cancers of the breast and testes can be successfully targeted with estrogen (or estrogen analogues) or androgen (or androgen analogues), respectively, as cell binding agents.
In a preferred embodiment, the antibody or fragment thereof is one that is specific for lung cancer, preferably small cell lung cancer. An antibody or fragment thereof that is specific for small cell lung cancer can be determined by methods described in the art, such as by Doria et al, Cancer 62:1939-1945 (1988).
Preferably, the antibody or fragment thereof binds to an epitope on the CD56 antigen, which is expressed on substantially all small cell lung cancers. For example, N901 is an IgG1 murine monoclonal antibody (also called anti-N901) that is reactive with CD56, which is expressed on tumors of neuroendocrine origin, such as small cell lung cancer. See Griffin et al, J. Immunol. 130:2947-2951 (1983), and Roguska et al, Proc.
For example, cell lines such as the human epidermoid carcinoma line KB, the human breast tumor line SKBR3 and the Burkitt's lymphoma line Namalwa can easily be used for the assessment of cytotoxicity of these compounds. Cells to be evaluated can be exposed to the compounds for 24 hours and the surviving fractions of cells measured in direct assays by known methods. IC,õ values can then be calculated from the results of the assays.
The effectiveness of the immunoconjugates as therapeutic agents depends on the careful selection of an appropriate cell binding agent. Cell binding agents may be of any kind presently known, or that become known, and include peptides and non-peptides. Generally, these can be antibodies (especially monoclonal antibodies), lymphokines, hormones, growth factors, nutrient-transport molecules (such as transferrin), or any other cell binding molecule or substance.
More specific examples of cell binding agents that can be used include:
monoclonal antibodies; fragments of antibodies such as Fv, Fab, Fab', and F(ab'), (Parham, J. Immunol., 131:2895-2902 (1983); Spring et al, J. Immunol., 113:470-(1974); Nisonoff et al, Arch. Biochem. Biophys., 89:230-244 (1960));
interferons (e.g., a, p, y); lymphokines such as IL2, IL3, IL-4, IL-6; hormones such as insulin, TRH
(thyrotropin releasing hormone), MSH (melanocyte-stimulating hormone), steroid hormones such as androgens and estrogens; growth factors and colony-stimulating factors such as EGF, TGF-a, G-CSF, M-CSF and GM-CSF (Burgess, Immunology Today, 5:155-158 (1984)); and transferrin (O'Keefe et al, J. Biol. Chem., 260:932-937 (1985)).
Monoclonal antibody techniques allow for the production of extremely specific cell binding agents in the form of specific monoclonal antibodies.
Particularly well known in the art are techniques for creating monoclonal antibodies produced by immunizing mice, rats, hamsters or any other mammal with the antigen of interest such as the intact target cell, antigens isolated from the target cell, whole virus, attenuated whole virus, and viral proteins such as viral coat proteins.
Sensitized human cells can also be used.
Selection of the appropriate cell binding agent is a matter of choice that depends upon the particular cell population that is to be targeted, but in general monoclonal antibodies are preferred if an appropriate one is available.
For example, the monoclonal antibody J5 is a murine IgG2a antibody that is specific for the Common Acute Lymphoblastic Leukemia Antigen (CALLA) (Ritz et al, Nature, 283:583-585 (1980)) and can be used if the target cells express CALLA such as in the disease of acute lymphoblastic leukemia. Similarly, the monoclonal antibody anti-B4 is a murine IgGi, that binds to the CD19 antigen on B cells (Nadler et al, J. Immunol., 131:244-250 (1983)) and can be used if the target cells are B cells or diseased cells that express this antigen such as in non-Hodgkin's lymphoma or chronic lymphoblastic leukemia.
Additionally, GM-CSF which binds to myeloid cells can be used as a cell binding agent to diseased cells from acute myelogenous leukemia. IL-2 which binds to activated T-cells can be used for prevention of transplant graft rejection, for therapy and prevention of graft-versus-host disease, and for treatment of acute T-cell leukemia. MSH which binds to melanocytes can be used for the treatment of melanoma.
Cancers of the breast and testes can be successfully targeted with estrogen (or estrogen analogues) or androgen (or androgen analogues), respectively, as cell binding agents.
In a preferred embodiment, the antibody or fragment thereof is one that is specific for lung cancer, preferably small cell lung cancer. An antibody or fragment thereof that is specific for small cell lung cancer can be determined by methods described in the art, such as by Doria et al, Cancer 62:1939-1945 (1988).
Preferably, the antibody or fragment thereof binds to an epitope on the CD56 antigen, which is expressed on substantially all small cell lung cancers. For example, N901 is an IgG1 murine monoclonal antibody (also called anti-N901) that is reactive with CD56, which is expressed on tumors of neuroendocrine origin, such as small cell lung cancer. See Griffin et al, J. Immunol. 130:2947-2951 (1983), and Roguska et al, Proc.
Natl. Acad, Sci. USA, 91:969-973 (1994), Preferred antibodies or fragments thereof that are specific for small cell lung cancers include, but are not limited to, N901, NKH-1, Leu-7, anti-Leu-7, and the like (Doria et al, Cancer 62:1939-1945 (1988); Kibbelaar et al, Journal of Pathology, 159:23-28 (1989)). Other suitable antibodies or fragments thereof for use in the present invention include, for example, S-L 3-5, S-L 4-20, S-L 7-3, S-L 11-14, TFS-4, MOC-1, MOC-21, MOC-31, MOC-32, MOC-52, 123A8, 123C3, UJ13A, B10/812, SWA4, SWA20, SWA21, SWA22, SWA23, LAM-8, 534F8, 703D4704A1 and SM1, which are further described in Table I of Chapter 3 of the Proceedings of the First International Workshop on Small Cell Lung Cancer Antigens (London 1987), published in Lung Cancer, 4:15-36 (1988), In a most preferred embodiment, the antibody is N901, or a fragment thereof, that binds to an epitope on the CD56 antigen, such as Fv, Fab, Fab' and F(ab'),. The monoclonal antibody or fragment thereof can be any other antibody that binds to the CD56 antigen with the same specificity as N901. "Same specificity"
means that the antibody or fragment thereof can bind to the same antigen as demonstrated by a competitive binding assay with N901.
Another preferred antibody or fragment thereof that is useful in the present invention is C242 (commercially available from CanAg Diagnostics AB, Sweden).
C242 is also described in U.S. Patent No. 5,552,293, In other preferred embodiments, the antibodies described herein are humanized antibodies or fragments thereof because humanized antibodies or fragments thereof are not expected to elicit an immune response in humans.
Generally, antibodies can be humanized through the application of different humanization technologies described, for example, in U.S. Patent Nos.
5,225,539, 5,585,089, and 5,639,641.
The preparation of different versions of humanized N901, is described, for example, by Roguska et al Proc. Natl. Acad. Sci. USA, 91:969-973 (1994), and Roguska et al, Protein Eng., 9:895:904 (1996), To denote a humanized antibody, the letters "hu" or "h" appear before the name of the antibody. For example, humanized N901 is also referred to as huN901 or hN901.
Conjugates of the maytansinoid derivatives of the invention and a cell binding agent can be formed using any techniques presently known or later developed. The maytansinoid ester can be modified to yield a free amino group and then linked to an antibody or other cell binding agent via an acid-labile linker, or a photolabile linker. The maytansinoid ester can be condensed with a peptide and subsequently linked to a cell binding agent to produce a peptidase-labile linker. The maytansinoid ester can be treated to yield a primary hydroxyl group, which can be succinylated and linked to a cell binding agent to produce a conjugate that can be cleaved by intracellular esterases to liberate free drug. Most preferably, the maytansinoid esters are treated to create a free or protected thiol group, and then one or many disulfide or thiol-containing maytansinoid derivatives are covalently linked to the cell binding agent via disulfide bond(s).
Representational conjugates of the invention are antibody/maytansinoid derivatives, antibody fragment/maytansinoid derivatives, epidermal growth factor (EGF)/maytansinoid derivatives, melanocyte stimulating hormone (MSH)/maytansinoid derivatives, thyroid stimulating hormone (TSH)/maytansinoid derivatives, estrogen/maytansinoid derivatives, estrogen analogue/maytansinoid derivatives, androgen/maytansinoid derivatives, androgen analogue/maytansinoid derivatives.
Maytansinoid conjugates of antibodies, antibody fragments, protein hormones, protein growth factors and other proteins are made in the same way.
For example, peptides and antibodies can be modified with crosslinking reagents such as N-succinimidyl 3-(2-pyridyldithio)propionate, N-succinimidyl 4-(2-pyridyldithio)-pentanoate (SPP), 4-succinimidyl-oxycarbonyl-a-methyl-a-(2-pyridyldithio)toluene (SMPT), N-succinirnidy1-3-(2-pyridyldithio)-butyrate (SDPB), 2-iminothiolane, or acetylsuccinic anhydride by known methods (U.S. Patent No. 4,563,304; Carlsson et al, Biochem. J., 173:723-737 (1978); Blattler et al, Biochem., 24:1517-1524 (1985); Lambert et al, Biochem., 22:3913-3920 (1983); Klotz et al, Arch. Biochem. Biophys., 96:605 (1962);
means that the antibody or fragment thereof can bind to the same antigen as demonstrated by a competitive binding assay with N901.
Another preferred antibody or fragment thereof that is useful in the present invention is C242 (commercially available from CanAg Diagnostics AB, Sweden).
C242 is also described in U.S. Patent No. 5,552,293, In other preferred embodiments, the antibodies described herein are humanized antibodies or fragments thereof because humanized antibodies or fragments thereof are not expected to elicit an immune response in humans.
Generally, antibodies can be humanized through the application of different humanization technologies described, for example, in U.S. Patent Nos.
5,225,539, 5,585,089, and 5,639,641.
The preparation of different versions of humanized N901, is described, for example, by Roguska et al Proc. Natl. Acad. Sci. USA, 91:969-973 (1994), and Roguska et al, Protein Eng., 9:895:904 (1996), To denote a humanized antibody, the letters "hu" or "h" appear before the name of the antibody. For example, humanized N901 is also referred to as huN901 or hN901.
Conjugates of the maytansinoid derivatives of the invention and a cell binding agent can be formed using any techniques presently known or later developed. The maytansinoid ester can be modified to yield a free amino group and then linked to an antibody or other cell binding agent via an acid-labile linker, or a photolabile linker. The maytansinoid ester can be condensed with a peptide and subsequently linked to a cell binding agent to produce a peptidase-labile linker. The maytansinoid ester can be treated to yield a primary hydroxyl group, which can be succinylated and linked to a cell binding agent to produce a conjugate that can be cleaved by intracellular esterases to liberate free drug. Most preferably, the maytansinoid esters are treated to create a free or protected thiol group, and then one or many disulfide or thiol-containing maytansinoid derivatives are covalently linked to the cell binding agent via disulfide bond(s).
Representational conjugates of the invention are antibody/maytansinoid derivatives, antibody fragment/maytansinoid derivatives, epidermal growth factor (EGF)/maytansinoid derivatives, melanocyte stimulating hormone (MSH)/maytansinoid derivatives, thyroid stimulating hormone (TSH)/maytansinoid derivatives, estrogen/maytansinoid derivatives, estrogen analogue/maytansinoid derivatives, androgen/maytansinoid derivatives, androgen analogue/maytansinoid derivatives.
Maytansinoid conjugates of antibodies, antibody fragments, protein hormones, protein growth factors and other proteins are made in the same way.
For example, peptides and antibodies can be modified with crosslinking reagents such as N-succinimidyl 3-(2-pyridyldithio)propionate, N-succinimidyl 4-(2-pyridyldithio)-pentanoate (SPP), 4-succinimidyl-oxycarbonyl-a-methyl-a-(2-pyridyldithio)toluene (SMPT), N-succinirnidy1-3-(2-pyridyldithio)-butyrate (SDPB), 2-iminothiolane, or acetylsuccinic anhydride by known methods (U.S. Patent No. 4,563,304; Carlsson et al, Biochem. J., 173:723-737 (1978); Blattler et al, Biochem., 24:1517-1524 (1985); Lambert et al, Biochem., 22:3913-3920 (1983); Klotz et al, Arch. Biochem. Biophys., 96:605 (1962);
and Liu et al, Biochem., 18:690 (1979), Blakey and Thorpe, Antibody, Immunoconjugates and Radiopharmaceuticals, 1:1-16 (1988); Worrell et al, Anti-Cancer Drug Design, 1:179-184 (1986).
The cell binding agent containing free or protected thiol groups thus-derived is then reacted with a disulfide- or thiol-containing maytansinoid to produce conjugates. The conjugates can be purified by HPLC or by gel filtration.
Similarly, for example, estrogen and androgen cell binding agents, such as estradiol and androstenediol, can be esterified at the C-17 hydroxy group with an appropriate disulfide-containing carboxylic acid, e.g., dicydohexylcarbodiimide, as a condensing agent. Examples of such carboxylic acids that can be used are 3-(2-pyridyldithio)propanoic acid, 3-methyldithiopropanoic acid, 3-phenyldithio-propanoic acid, and 4-(2-pyridyldithio)pentanoic acid. Esterification of the C-hydroxy group can also be achieved by reaction with an appropriately protected thiol group-containing carboxylic acid chloride, such as 3-S-acetylpropanoyl chloride. Other methods of esterification can also be used as described in the literature (Haslam, Tetrahedron, 36:2400-2433 (1980)). The protected or free thiol-containing androgen or estrogen can then be reacted with a disulfide or thiol-containing maytansinoid to produce conjugates. The conjugates can be purified by column chromatography on silica gel or by HPLC.
Preferably monoclonal antibody or cell binding agent/maytansinoid conjugates are those that are joined via a disulfide bond, as discussed above, that are capable of delivering maytansinoid molecules. Such cell binding conjugates are prepared by known methods such as modifying monoclonal antibodies with succinimidyl pyridyl-dithiopropionate (SPDP) or SPP (Carlsson et al, Biochern.
J., 173:723-737 (1978)). The resulting thiopyridyl group is then displaced by treatment with thiol-containing maytansinoids to produce disulfide linked conjugates.
Alternatively, in the case of the aryldithio-maytansinoids, the formation of the cell binding conjugate is effected by direct displacement of the aryl-thiol of the maytansinoid by sulfhydryl groups previously introduced into antibody molecules.
Conjugates containing 1 to 10 maytansinoid drugs linked via a disulfide bridge are readily prepared by either method.
The cell binding agent containing free or protected thiol groups thus-derived is then reacted with a disulfide- or thiol-containing maytansinoid to produce conjugates. The conjugates can be purified by HPLC or by gel filtration.
Similarly, for example, estrogen and androgen cell binding agents, such as estradiol and androstenediol, can be esterified at the C-17 hydroxy group with an appropriate disulfide-containing carboxylic acid, e.g., dicydohexylcarbodiimide, as a condensing agent. Examples of such carboxylic acids that can be used are 3-(2-pyridyldithio)propanoic acid, 3-methyldithiopropanoic acid, 3-phenyldithio-propanoic acid, and 4-(2-pyridyldithio)pentanoic acid. Esterification of the C-hydroxy group can also be achieved by reaction with an appropriately protected thiol group-containing carboxylic acid chloride, such as 3-S-acetylpropanoyl chloride. Other methods of esterification can also be used as described in the literature (Haslam, Tetrahedron, 36:2400-2433 (1980)). The protected or free thiol-containing androgen or estrogen can then be reacted with a disulfide or thiol-containing maytansinoid to produce conjugates. The conjugates can be purified by column chromatography on silica gel or by HPLC.
Preferably monoclonal antibody or cell binding agent/maytansinoid conjugates are those that are joined via a disulfide bond, as discussed above, that are capable of delivering maytansinoid molecules. Such cell binding conjugates are prepared by known methods such as modifying monoclonal antibodies with succinimidyl pyridyl-dithiopropionate (SPDP) or SPP (Carlsson et al, Biochern.
J., 173:723-737 (1978)). The resulting thiopyridyl group is then displaced by treatment with thiol-containing maytansinoids to produce disulfide linked conjugates.
Alternatively, in the case of the aryldithio-maytansinoids, the formation of the cell binding conjugate is effected by direct displacement of the aryl-thiol of the maytansinoid by sulfhydryl groups previously introduced into antibody molecules.
Conjugates containing 1 to 10 maytansinoid drugs linked via a disulfide bridge are readily prepared by either method.
More specifically, a solution of the dithiopyridyl modified antibody at a concentration of 2.5 mg/ml in 0.05 M potassium phosphate buffer and 0.05 M
sodium chloride, at pH 6.5 containing 2 mM EDTA is treated with the thiol-containing maytansinoid (1.7 molar equivalent/dithiopyridyl group). The release of pyridine-2-thione from the modified antibody is monitored spectrophotometrically at 343 nm. The reaction is allowed to proceed up to 18 hours.
The antibody-maytansinoid conjugate is purified and freed of unreacted drug and other low molecular weight material by gel filtration through a column of Sephacryl"
S-300. The number of maytansinoids bound per antibody molecule can be determined by measuring the ratio of the absorbance at 252 nm and 280 nm. An average of 1-10 maytansinoid molecules/antibody molecule can be linked via disulfide bonds by this method.
Antibody-maytansinoid conjugates with non-cleavable links can also be prepared. The antibody can be modified with crosslinking reagents such as sucdnimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC), sulfo-SMCC, maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), sulfo-MBS or succinimidyl-iodoacetate, as described in the literature, to introduce 1-10 reactive groups (Yoshitake et al, Eur. J. Biocheni., 101:395-399 (1979); Hashida et al, J. Applied Biochern., 56-63 (1984); and Liu et al, Biochern., 18:690-697 (1979)). The modified antibody is then reacted with the thiol-containing maytansinoid derivative to produce a conjugate. The conjugate can be purified by gel filtration through a =rm Sephacryl S-300 column.
The modified antibodies are treated with the thiol-containing maytansinoid (1.25 molar equivalent/maleimido group). The mixtures are incubated overnight at about 4 C. The antibody-maytansinoid conjugates are purified by gel filtration through a SephadeT1G-25 column. Typically, an average of 1-10 maytansinoids per antibody are linked.
A preferred method is to modify antibodies with succinimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC) to introduce maleimido groups followed by reaction of the modified antibody with a thiol-containing maytansinoid to give a thioether-linked conjugate. Again conjugates with 1 to drug molecules per antibody molecule result.
As described herein, the present invention is based on the unexpected discovery that the use of at least one immunoconjugate and at least one chemotherapeutic agent produces superior results in treating cancer. Any chemotherapeutic agent known in the art can be used in combination with the immunoconjugate of the present invention to achieve the unexpectedly superior results described and demonstrated herein. Preferably, the chemotherapeutic agent is a taxane compound, a compound that acts via a taxane mechanism, a platinum compound, an epidophyllotoxin compound, a camptothecin compound, and/or any combination thereof. As is known in the art, platinum compounds and epidophyllotoxin compounds are generally used together for treating cancer.
In one embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate and at least one taxane compound.
In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate and at least one compound that acts via a taxane mechanism. In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, and at least one platinum compound. In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one platinum compound, and at least one epidophyllotoxin compound. In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate and at least one camptothecin compound. In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate and at least one compound that is capable of inhibiting DNA topoisomerase I. In yet another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one taxane compound, and at least one platinum compound. In yet another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one taxane compound, at least one platinum compound, and, optionally, at least one epidophyllotoxin compound. In yet another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one camptothecin compound, at least one platinum compound and, optionally, at least one epidophyllotoxin compound. In yet another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one compound that acts via a taxane mechanism and at least one camptothecin compound. One skilled in the art will appreciate that the methods described in the present invention encompass administering at least one immunoconjugate with one or more chemotherapeutic agents selected from the group consisting of taxane compounds, compounds that act through a taxane mechanism, platinum compounds, epidophyllotoxin compounds, camptothecin compounds and compounds that can inhibit DNA topoisomerase I. In the methods of the present invention, the immunoconjugate and chemotherapeutic agent can be administered simultaneously, about the same time, or at different times, or can be components of a single composition.
Taxane compounds prevent the growth of cancer cells by affecting cell structures called microtubules, which play an important role in cell functions. In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. Taxane compounds stop the microtubules from breaking down, such that the cancer cells become clogged with microtubules so that they cannot grow and divide.
sodium chloride, at pH 6.5 containing 2 mM EDTA is treated with the thiol-containing maytansinoid (1.7 molar equivalent/dithiopyridyl group). The release of pyridine-2-thione from the modified antibody is monitored spectrophotometrically at 343 nm. The reaction is allowed to proceed up to 18 hours.
The antibody-maytansinoid conjugate is purified and freed of unreacted drug and other low molecular weight material by gel filtration through a column of Sephacryl"
S-300. The number of maytansinoids bound per antibody molecule can be determined by measuring the ratio of the absorbance at 252 nm and 280 nm. An average of 1-10 maytansinoid molecules/antibody molecule can be linked via disulfide bonds by this method.
Antibody-maytansinoid conjugates with non-cleavable links can also be prepared. The antibody can be modified with crosslinking reagents such as sucdnimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC), sulfo-SMCC, maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), sulfo-MBS or succinimidyl-iodoacetate, as described in the literature, to introduce 1-10 reactive groups (Yoshitake et al, Eur. J. Biocheni., 101:395-399 (1979); Hashida et al, J. Applied Biochern., 56-63 (1984); and Liu et al, Biochern., 18:690-697 (1979)). The modified antibody is then reacted with the thiol-containing maytansinoid derivative to produce a conjugate. The conjugate can be purified by gel filtration through a =rm Sephacryl S-300 column.
The modified antibodies are treated with the thiol-containing maytansinoid (1.25 molar equivalent/maleimido group). The mixtures are incubated overnight at about 4 C. The antibody-maytansinoid conjugates are purified by gel filtration through a SephadeT1G-25 column. Typically, an average of 1-10 maytansinoids per antibody are linked.
A preferred method is to modify antibodies with succinimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC) to introduce maleimido groups followed by reaction of the modified antibody with a thiol-containing maytansinoid to give a thioether-linked conjugate. Again conjugates with 1 to drug molecules per antibody molecule result.
As described herein, the present invention is based on the unexpected discovery that the use of at least one immunoconjugate and at least one chemotherapeutic agent produces superior results in treating cancer. Any chemotherapeutic agent known in the art can be used in combination with the immunoconjugate of the present invention to achieve the unexpectedly superior results described and demonstrated herein. Preferably, the chemotherapeutic agent is a taxane compound, a compound that acts via a taxane mechanism, a platinum compound, an epidophyllotoxin compound, a camptothecin compound, and/or any combination thereof. As is known in the art, platinum compounds and epidophyllotoxin compounds are generally used together for treating cancer.
In one embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate and at least one taxane compound.
In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate and at least one compound that acts via a taxane mechanism. In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, and at least one platinum compound. In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one platinum compound, and at least one epidophyllotoxin compound. In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate and at least one camptothecin compound. In another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate and at least one compound that is capable of inhibiting DNA topoisomerase I. In yet another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one taxane compound, and at least one platinum compound. In yet another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one taxane compound, at least one platinum compound, and, optionally, at least one epidophyllotoxin compound. In yet another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one camptothecin compound, at least one platinum compound and, optionally, at least one epidophyllotoxin compound. In yet another embodiment, the present invention provides methods of treating cancer and/or modulating the growth of selected cell populations (e.g., cancer cells) by administering at least one immunoconjugate, at least one compound that acts via a taxane mechanism and at least one camptothecin compound. One skilled in the art will appreciate that the methods described in the present invention encompass administering at least one immunoconjugate with one or more chemotherapeutic agents selected from the group consisting of taxane compounds, compounds that act through a taxane mechanism, platinum compounds, epidophyllotoxin compounds, camptothecin compounds and compounds that can inhibit DNA topoisomerase I. In the methods of the present invention, the immunoconjugate and chemotherapeutic agent can be administered simultaneously, about the same time, or at different times, or can be components of a single composition.
Taxane compounds prevent the growth of cancer cells by affecting cell structures called microtubules, which play an important role in cell functions. In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. Taxane compounds stop the microtubules from breaking down, such that the cancer cells become clogged with microtubules so that they cannot grow and divide.
Taxane compounds are known in the art and include, for example, paclitaxel (available as TAXOL from Bristol-Myers Squibb, Princeton, NJ), docetaxel (available as TA)(OTERE from Aventis), and the like. Other taxane compounds that become approved by the U.S. Food and Drug Administration (FDA) or foreign counterparts thereof are also preferred for use in the methods and compositions of the present invention. Other taxane compounds that can be used in the present invention include those described, for example, in 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, page 100, Nos. 382 and 383 (June 16-19, 1998); and U.S. Patent Nos. 4,814,470, 5,721,268, 5,714,513, 5,739,362, 5,728,850, 5,728,725, 5,710,287, 5,637,484, 5,629,433, 5,580,899, 5,549,830, 5,523,219, 5,281,727, 5,939,567, 5,703,117, 5,480,639, 5,250,683, 5,700,669, 5,665,576, 5,618,538, 5,279,953, 5,243,045, 5,654,447, 5,527,702, 5,415,869, 5,279,949, 5,739,016, 5,698,582, 5,478,736, 5,227,400, 5,516,676, 5,489,601, 5,908,759, 5,760,251, 5,578,739, 5,547,981, 5,547,866, 5,344,775, 5,338,872, 5,717,115, 5,620,875, 5,284,865, 5,284,864, 5,254,703, 5,202,448, 5,723,634, 5,654,448, 5,466,834, 5,430,160, 5,407,816, 5,283,253, 5,719,177, 5,670,663, 5,616,330, 5,561,055, 5,449,790, 5,405,972, 5,380,916, 5,912,263, 8,808,113, 5,703,247, 5,618,952, 5,367,086, 5,200,534, 5,763,628, 5,705,508, 5,622,986, 5,476,954, 5,475,120, 5,412,116, 5,916,783, 5,879,929, 5,861,515, 5,795,909, 5,760,252, 5,637,732, 5,614,645, 5,599,820, 5,310,672, RE 34,277, 5,877,205, 5,808,102, 5,766,635, 5,760,219, 5,750,561, 5,637,723, 5,475,011, 5,256,801, 5,900,367, 5,869,680, 5,728,687, 5,565,478, 5,411,984, 5,334,732, 5,919,815, 5,912,264, 5,773,464, 5,670,673, 5,635,531, 5,508,447, 5,919,816, 5,908,835, 5,902,822, 5,880,131, 5,861,302, 5,850,032, 5,824,701, 5,817,867, 5,811,292, 5,763,477, 5,756,776, 5,686,623, 5,646,176, 5,621,121, 5,616,739, 5,602,272, 5,587,489, 5,567,614, 5,498,738, 5,438,072, 5,403,858, 5,356,928, 5,274,137, 5,019,504, 5,917,062, 5,892,063, 5,840,930, 5,840,900, 5,821,263, 5,756,301, 5,750,738, 5,750,562, 5,726,318, 5,714,512, 5,686,298, 5,684,168, 5,681,970, 5,679,807, 5,648,505, 5,641,803, 5,606,083, 5,599,942, 5,420,337, 5,407,674, 5,399,726, 5,322,779, 4,924,011, 5,939,566, 5,939,561, 5,935,955, 5,919,455, 5,854,278, 5,854,178, 5,840,929, 5,840,748, 5,821,363, 5,817,321, 5,814,658, 5,807,888, 5,792,877, 5,780,653, 5,770,745, 5,767,282, 5,739,359, 5,726,346, 5,717,103, 5,710,099, 5,698,712, 5,683,715, 5,677,462, 5,670,653, 5,665,761, 5,654,328, 5,643,575, 5,621,001, 5,608,102, 5,606,068, 5,587,493, 5,580,998, 5,580,997, 5,576,450, 5,574,156, 5,571,917, 5,556,878, 5,550,261, 5,539,103, 5,532,388, 5,470,866, 5,453,520, 5,384,399, 5,364,947, 5,350,866, 5,336,684, 5,296,506, 5,290,957, 5,274,124, 5,264,591, 5,250,722, 5,229,526, 5,175,315, 5,136,060, 5,015,744, 4,924,012, 6,118,011, 6,114,365, 6,107,332, 6,072,060, 6,066,749, 6,066,747, 6,051,724, 6,051,600, 6,048,990, 6,040,330, 6,030,818, 6,028,205, 6,025,516, 6,025,385, 6,018,073, 6,017,935, 6,011,056, 6,005,138, 6,005,138, 6,005,120, 6,002,023, 5,998,656, 5,994,576, 5,981,564, 5,977,386, 5,977,163, 5,965,739, 5,955,489, 5,939,567, 5,939,566, 5,919,815, 5,912,264, 5,912,263, 5,908,835, and 5,902,822.
Other compounds that can be used in the invention are those that act through a taxane mechanism. Compounds that act through a taxane mechanism include compounds that have the ability to exert microtubule-stabilizing effects and cytotoxic activity against rapidly proliferating cells, such as tumor cells or other hyperproliferative cellular diseases. Such compounds include, for example, epothilone compounds, such as, for example, epothilone A, B, C, D, E and F, and derivatives thereof. Other compounds that act through a taxane mechanism (e.g., epothilone compounds) that become approved by the FDA or foreign counterparts thereof are also preferred for use in the methods and compositions of the present invention. Epothilone compounds and derivatives thereof are known in the art and are described, for example, in U.S. Patent Nos. 6,121,029, 6,117,659, 6,096,757, 6,043,372,5,969,145, and 5,886,026; and WO 97/19086, WO 98/08849, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02514, WO 99/03848, WO
99/07692, WO 99/27890, and WO 99/28324, Other compounds that can be used in the invention include platinum compounds such as, for example, dsplatin (available as PLATINOL from Bristol-Myers Squibb, Princeton, NJ), carboplatin (available as PARAPLATINO from Bristol-Myers Squibb, Princeton, NJ), oxaliplatin (available as ELOXATINE from Sanofi, France), iproplatin, ormaplatin, tetraplatin, and the like. Other platinum compounds that become approved by the FDA or foreign counterparts thereof are also preferred for use in the methods and compositions of the present invention. Platinum compounds that are useful in treating cancer are known in the art and are described, for example in U.S. Patent Nos. 4,994,591, 4,906,646, 5,902,610, 5,053,226, 5,789,000, 5,871,710, 5,561,042, 5,604,095, 5,849,790, 5,705,334, 4,863,902, 4,767,611, 5,670,621, 5,384,127, 5,084,002, 4,937,262, 5,882,941, 5,879,917, 5,434,256, 5,393,909, 5,117,022, 5,041,578, 5,843,475, 5,633,243, 5,178,876, 5,866,169, 5,846,725, 5,646,011, 5,527,905, 5,844,001, 5,832,931, 5,676,978, 5,604,112, 5,562,925, 5,541,232, 5,426,203, 5,288,887, 5,041,581, 5,002,755, 4,946,954, 4,921,963, 4,895,936, 4,686,104, 4,594,238, 4,581,224, 4,250,189, 5,829,448, 5,690,905, 5,665,771, 5,648,384, 5,633,016, 5,460,785, 5,395,947, 5,256,653, 5,132,323, 5,130,308, 5,106,974, 5,059,591, 5,026,694, 4,992,553, 4,956,459, 4,956,454, 4,952,676, 4,895,935, 4,892,735, 4,843,161, 4,760,156, 4,739,087, 4,720,504, 4,544,759, 4,515,954, 4,466,924, 4,462,998, 4,457,926, 4,428,943, 4,325,950, 4,291,027, 4,291,023, 4,284,579, 4,271,085, 4,234,500, 4,234,499, 4,200,583, 4,175,133, 4,169,846, 5,922,741, 5,922,674, 5,922,302, 5,919,126, 5,910,102, 5,876,693, 5,871,923, 5,866,617, 5,866,615, 5,866,593, 5,864,024, 5,861,139, 5,859,034, 5,855,867, 5,855,748, 5,849,770, 5,843,993, 5,824,664, 5,821,453, 5,811,119, 5,798,373, 5,786,354, 5,780,478, 5,780,477, 5,776,925, 5,770,593, 5,770,222, 5,747,534, 5,739,144, 5,738,838, 5,736,156, 5,736,119, 5,723,460, 5,697,902, 5,693,659, 5,688,773, 5,674,880, 5,670,627, 5,665,343, 5,654,287, 5,648,362, 5,646,124, 5,641,627, 5,635,218, 5,633,257, 5,632,982, 5,622,977, 5,622,686, 5,618,393, 5,616,613, 5,612,019, 5,608,070, 5,595,878, 5,585,112, 5,580,888, 5,580,575, 5,578,590, 5,575,749, 5,573,761, 5,571,153, 5,563,132, 5,561,136, 5,556,609, 5,552,156, 5,547,982, 5,542,935, 5,525,338, 5,519,155, 5,498,227, 5,491,147, 5,482,698, 5,469,854, 5,455,270, 5,443,816, 5,415,869, 5,409,915, 5,409,893, 5,409,677, 5,399,694, 5,399,363, 5,380,897, 5,340,565, 5,324,591, 5,318,962, 5,302,587, 5,292,497, 5,272,056, 5,258,376, 5,238,955, 5,237,064, 5,213,788, 5,204,107, 5,194,645, 5,182,368, 5,130,145, 5,116,831, 5,106,858, 5,100,877, 5,087,712, 5,087,618, 5,078,137, 5,057,302, 5,049,396, 5,034,552, 5,028,726, 5,011,846, 5,010,103, 4,985,416, 4,970,324, 4,936,465, 4,931,553, 4,927,966, 4,912,072, 4,906,755, 4,897,384, 4,880,832, 4,871,528, 4,822,892, 4,783,452, 4,767,874, 4,760,155, 4,687,780, 4,671,958, 4,665,210, 4,645,661, 4,599,352, 4,594,418, 4,593,034, 4,587,331, 4,575,550, 4,562,275, 4,550,169, 4,482,569, 4,431,666, 4,419,351, 4,407,300, 4,394,319, 4,335,087, 4,329,299, 4,322,391, 4,302,446, 4,287,187, 4,278,660, 4,273,755, 4,255,417, 4,255,347, 4,248,840, 4,225,529, 4,207,416, 4,203,912, 4,177,263, 4,151,185, 4,140,707, 4,137,248, 4,115,418, 4,079,121, 4,075,307, 3,983,118, 3,870,719, RE 33,071, 6,087,392, 6,077,864, 5,998,648, and 5,902,610.
As is known in the art, platinum compounds are preferably used in Other compounds that can be used in the present invention include camptothecin compounds. Camptothecin compounds are capable of inhibiting DNA
topoisomerase I. Camptothecin compounds include camptothecin, derivatives of be used in the present invention include those described in, for example, J.
Med.
Chem, 29:2358-2363 (1986); J. Med. Chem., 23:554 (1980); J. Med. Chem., 30:1774 (1987);
European Patent Application Nos. 0 418 099, 0 088 642, and 0 074 770; and U.S.
Patent Nos. 5,633,016, 5,004,758, 4,604,463, 4,473,692, 4,545,880, 4,513,138, 4,399,276, 6,121,451, 6,121,278, 6,121,277, 6,121,275, 6,121,263, 6,107,486, 6,100,273, 6,096,336, 6,093,721, 6,063,801, 6,046,209, 6,040,313, 6,034,243, 6,028,078, 5,998,426, 5,990,120, 5,985,888, 5,981,542, 5,972,955, 5,968,943, 5,958,937, 5,955,467, 5,948,797, 5,935,967, 5,932,709, 5,932,588, 5,922,877, 5,916,897, 5,916,896, 5,910,491, 5,900,419, 5,892,043, 5,889,017, 5,880,133, 5,859,023, 5,859,022, 5,856,333, 5,843,954, 5,840,899, 5,837,673, 5,834,012, 5,807,874, 5,801,167, 5,786,344, 5,773,522, 5,767,142, 5,744,605, 5,734,056, 5,731,316, 5,726,181, 5,677,286, 5,674,874, 5,674,873, 5,670,500, 5,633,177, 5,652,244, 5,646,159, 5,633,260, 5,614,628, 5,604,233, 5,602,141, 5,597,829, 5,559,235, 5,552,154, 5,541,327, 5,525,731, 5,496,952, 5,475,108, 5,468,859, 5,468,754, 5,459,269, 5,447,936, 5,446,047, 5,401,747, 5,391,745, 5,364,858, 5,340,817, 5,244,903, 5,227,380, 5,200,524, 5,191,082, 5,180,722, 5,162,532, 5,122,606, 5,122,526, 5,106,742, 5,061,800, 5,053,512, 5,049,668, 5,004,758, 4,981,968, 4,943,579, 4,939,255, 4,914,205, 4,894,456, RE 32,518, 4,604,463, 4,513,138, 4,473,692, 4,399,282, 4,399,276, and 4,031,098, the disclosures of which are incorporated by reference herein in their entirety.
The immunoconjugates and chemotherapeutic agents of the present invention can be administered in vitro, in vivo and/or ex vivo to treat patients and/or to modulate the growth of selected cell populations induding, for example, cancer of the lung, breast, colon, prostate, kidney, pancreas, brain, bones, ovary, testes, and lymphatic organs; autoimmune diseases, such as systemic lupus, rheumatoid arthritis, and multiple sclerosis; graft rejections, such as renal transplant rejection, liver transplant rejection, lung transplant rejection, cardiac transplant rejection, and bone marrow transplant rejection; graft versus host disease; viral infections, such as CMV infection, HIV infection, and AIDS; and parasite infections, such as giardiasis, amoebiasis, schistosomiasis, and the like. Preferably, the immunoconjugates and chemotherapeutic agents of the invention are administered in vitro, in vivo and/or ex vivo to treat cancer in a patient and/or to modulate the growth of cancer cells, including, for example, cancer of the lung, breast, colon, prostate, kidney, pancreas, brain, bones, ovary, testes, and lymphatic organs; more preferably lung cancer or colon cancer. In a most preferred embodiment, the lung cancer is small cell lung cancer (SCLC).
"Modulating the growth of selected cell populations" includes inhibiting the proliferation of selected cell populations (e.g., SCLC cells, NCI N417 cells, SW-2 cells, NCI-H441 cells, HT-29 cells, and the like) from dividing to produce more cells;
reducing the rate of increase in cell division as compared, for example, to untreated cells; killing selected cell populations; and/or preventing selected cell populations (such as cancer cells) from metastasizing. The growth of selected cell populations can be modulated in vitro, in vivo or ex vivo.
In the methods of the present invention, the immunoconjugates and chemotherapeutic agents can be administered in vitro, in vivo, or ex vivo separately or as components of the same composition. The immunoconjugates and chemotherapeutic agents can be used with suitable pharmaceutically acceptable carriers, diluents, and/or excipients, which are well known, and can be determined by one of sldll in the art as the clinical situation warrants. Examples of suitable carriers, diluents and/or excipients include: (1) Dulbecco's phosphate buffered saline, pH about 6.5, which would contain about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v NaCl), and (3) 5% (w/v) dextrose.
The compounds and compositions described herein may be administered in appropriate form, preferably parenterally, more preferably intravenously. For parenteral administration, the compounds or compositions can be aqueous or nonaqueous sterile solutions, suspensions or emulsions. Propylene glycol, vegetable oils and injectable organic esters, such as ethyl oleate, can be used as the solvent or vehicle. The compositions can also contain adjuvants, emulsifiers or dispersants.
The compositions can also be in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or any other injectable sterile medium.
The "therapeutically effective amount" of the chemotherapeutic agents and immunoconjugates described herein refers to the dosage regimen for inhibiting the proliferation of selected cell populations and/or treating a patient's disease, and is selected in accordance with a variety of factors, including the age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, and pharmacological considerations, such as the activity, efficacy, pharmacoldnetic and toxicology profiles of the particular compound used. The "therapeutically effective amount" can also be determined by reference to standard medical texts, such as the Physicians Desk Reference 1999 (53rd Ed.), The patient is preferably an animal, more preferably a mammal, most preferably a human. The patient can be male or female, and can be an infant, child or adult.
Examples of suitable protocols of immunoconjugate administration are as follows. Immurtoconjugates can be given daily for about 5 days either as an i.v.
bolus each day for about 5 days, or as a continuous infusion for about 5 days.
Alternatively, they can be administered once a week for six weeks or longer.
As another alternative, they can be administered once every two or three weeks.
Bolus doses are given in about 50 to about 400 ml of normal saline to which about 5 to about 10 ml of human serum albumin can be added. Continuous infusions are given in about 250 to about 500 ml of normal saline, to which about 25 to about 50 ml of human serum albumin can be added, per 24 hour period. Dosages will be about 10 -p.g to about 1000 mg/kg per person, i.v. (range of about 100 ng to about 10 mg/kg).
About one to about four weeks after treatment, the patient can receive a second course of treatment. Specific clinical protocols with regard to route of administration, excipients, diluents, dosages, and times can be determined by the skilled artisan as the clinical situation warrants.
The present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and/or compositions of the present invention, including, one or more immunoconjugates and one or more chemotherapeutic agents. Such kits can also include, for example, other compounds and/or compositions, a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products.
Other compounds that can be used in the invention are those that act through a taxane mechanism. Compounds that act through a taxane mechanism include compounds that have the ability to exert microtubule-stabilizing effects and cytotoxic activity against rapidly proliferating cells, such as tumor cells or other hyperproliferative cellular diseases. Such compounds include, for example, epothilone compounds, such as, for example, epothilone A, B, C, D, E and F, and derivatives thereof. Other compounds that act through a taxane mechanism (e.g., epothilone compounds) that become approved by the FDA or foreign counterparts thereof are also preferred for use in the methods and compositions of the present invention. Epothilone compounds and derivatives thereof are known in the art and are described, for example, in U.S. Patent Nos. 6,121,029, 6,117,659, 6,096,757, 6,043,372,5,969,145, and 5,886,026; and WO 97/19086, WO 98/08849, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02514, WO 99/03848, WO
99/07692, WO 99/27890, and WO 99/28324, Other compounds that can be used in the invention include platinum compounds such as, for example, dsplatin (available as PLATINOL from Bristol-Myers Squibb, Princeton, NJ), carboplatin (available as PARAPLATINO from Bristol-Myers Squibb, Princeton, NJ), oxaliplatin (available as ELOXATINE from Sanofi, France), iproplatin, ormaplatin, tetraplatin, and the like. Other platinum compounds that become approved by the FDA or foreign counterparts thereof are also preferred for use in the methods and compositions of the present invention. Platinum compounds that are useful in treating cancer are known in the art and are described, for example in U.S. Patent Nos. 4,994,591, 4,906,646, 5,902,610, 5,053,226, 5,789,000, 5,871,710, 5,561,042, 5,604,095, 5,849,790, 5,705,334, 4,863,902, 4,767,611, 5,670,621, 5,384,127, 5,084,002, 4,937,262, 5,882,941, 5,879,917, 5,434,256, 5,393,909, 5,117,022, 5,041,578, 5,843,475, 5,633,243, 5,178,876, 5,866,169, 5,846,725, 5,646,011, 5,527,905, 5,844,001, 5,832,931, 5,676,978, 5,604,112, 5,562,925, 5,541,232, 5,426,203, 5,288,887, 5,041,581, 5,002,755, 4,946,954, 4,921,963, 4,895,936, 4,686,104, 4,594,238, 4,581,224, 4,250,189, 5,829,448, 5,690,905, 5,665,771, 5,648,384, 5,633,016, 5,460,785, 5,395,947, 5,256,653, 5,132,323, 5,130,308, 5,106,974, 5,059,591, 5,026,694, 4,992,553, 4,956,459, 4,956,454, 4,952,676, 4,895,935, 4,892,735, 4,843,161, 4,760,156, 4,739,087, 4,720,504, 4,544,759, 4,515,954, 4,466,924, 4,462,998, 4,457,926, 4,428,943, 4,325,950, 4,291,027, 4,291,023, 4,284,579, 4,271,085, 4,234,500, 4,234,499, 4,200,583, 4,175,133, 4,169,846, 5,922,741, 5,922,674, 5,922,302, 5,919,126, 5,910,102, 5,876,693, 5,871,923, 5,866,617, 5,866,615, 5,866,593, 5,864,024, 5,861,139, 5,859,034, 5,855,867, 5,855,748, 5,849,770, 5,843,993, 5,824,664, 5,821,453, 5,811,119, 5,798,373, 5,786,354, 5,780,478, 5,780,477, 5,776,925, 5,770,593, 5,770,222, 5,747,534, 5,739,144, 5,738,838, 5,736,156, 5,736,119, 5,723,460, 5,697,902, 5,693,659, 5,688,773, 5,674,880, 5,670,627, 5,665,343, 5,654,287, 5,648,362, 5,646,124, 5,641,627, 5,635,218, 5,633,257, 5,632,982, 5,622,977, 5,622,686, 5,618,393, 5,616,613, 5,612,019, 5,608,070, 5,595,878, 5,585,112, 5,580,888, 5,580,575, 5,578,590, 5,575,749, 5,573,761, 5,571,153, 5,563,132, 5,561,136, 5,556,609, 5,552,156, 5,547,982, 5,542,935, 5,525,338, 5,519,155, 5,498,227, 5,491,147, 5,482,698, 5,469,854, 5,455,270, 5,443,816, 5,415,869, 5,409,915, 5,409,893, 5,409,677, 5,399,694, 5,399,363, 5,380,897, 5,340,565, 5,324,591, 5,318,962, 5,302,587, 5,292,497, 5,272,056, 5,258,376, 5,238,955, 5,237,064, 5,213,788, 5,204,107, 5,194,645, 5,182,368, 5,130,145, 5,116,831, 5,106,858, 5,100,877, 5,087,712, 5,087,618, 5,078,137, 5,057,302, 5,049,396, 5,034,552, 5,028,726, 5,011,846, 5,010,103, 4,985,416, 4,970,324, 4,936,465, 4,931,553, 4,927,966, 4,912,072, 4,906,755, 4,897,384, 4,880,832, 4,871,528, 4,822,892, 4,783,452, 4,767,874, 4,760,155, 4,687,780, 4,671,958, 4,665,210, 4,645,661, 4,599,352, 4,594,418, 4,593,034, 4,587,331, 4,575,550, 4,562,275, 4,550,169, 4,482,569, 4,431,666, 4,419,351, 4,407,300, 4,394,319, 4,335,087, 4,329,299, 4,322,391, 4,302,446, 4,287,187, 4,278,660, 4,273,755, 4,255,417, 4,255,347, 4,248,840, 4,225,529, 4,207,416, 4,203,912, 4,177,263, 4,151,185, 4,140,707, 4,137,248, 4,115,418, 4,079,121, 4,075,307, 3,983,118, 3,870,719, RE 33,071, 6,087,392, 6,077,864, 5,998,648, and 5,902,610.
As is known in the art, platinum compounds are preferably used in Other compounds that can be used in the present invention include camptothecin compounds. Camptothecin compounds are capable of inhibiting DNA
topoisomerase I. Camptothecin compounds include camptothecin, derivatives of be used in the present invention include those described in, for example, J.
Med.
Chem, 29:2358-2363 (1986); J. Med. Chem., 23:554 (1980); J. Med. Chem., 30:1774 (1987);
European Patent Application Nos. 0 418 099, 0 088 642, and 0 074 770; and U.S.
Patent Nos. 5,633,016, 5,004,758, 4,604,463, 4,473,692, 4,545,880, 4,513,138, 4,399,276, 6,121,451, 6,121,278, 6,121,277, 6,121,275, 6,121,263, 6,107,486, 6,100,273, 6,096,336, 6,093,721, 6,063,801, 6,046,209, 6,040,313, 6,034,243, 6,028,078, 5,998,426, 5,990,120, 5,985,888, 5,981,542, 5,972,955, 5,968,943, 5,958,937, 5,955,467, 5,948,797, 5,935,967, 5,932,709, 5,932,588, 5,922,877, 5,916,897, 5,916,896, 5,910,491, 5,900,419, 5,892,043, 5,889,017, 5,880,133, 5,859,023, 5,859,022, 5,856,333, 5,843,954, 5,840,899, 5,837,673, 5,834,012, 5,807,874, 5,801,167, 5,786,344, 5,773,522, 5,767,142, 5,744,605, 5,734,056, 5,731,316, 5,726,181, 5,677,286, 5,674,874, 5,674,873, 5,670,500, 5,633,177, 5,652,244, 5,646,159, 5,633,260, 5,614,628, 5,604,233, 5,602,141, 5,597,829, 5,559,235, 5,552,154, 5,541,327, 5,525,731, 5,496,952, 5,475,108, 5,468,859, 5,468,754, 5,459,269, 5,447,936, 5,446,047, 5,401,747, 5,391,745, 5,364,858, 5,340,817, 5,244,903, 5,227,380, 5,200,524, 5,191,082, 5,180,722, 5,162,532, 5,122,606, 5,122,526, 5,106,742, 5,061,800, 5,053,512, 5,049,668, 5,004,758, 4,981,968, 4,943,579, 4,939,255, 4,914,205, 4,894,456, RE 32,518, 4,604,463, 4,513,138, 4,473,692, 4,399,282, 4,399,276, and 4,031,098, the disclosures of which are incorporated by reference herein in their entirety.
The immunoconjugates and chemotherapeutic agents of the present invention can be administered in vitro, in vivo and/or ex vivo to treat patients and/or to modulate the growth of selected cell populations induding, for example, cancer of the lung, breast, colon, prostate, kidney, pancreas, brain, bones, ovary, testes, and lymphatic organs; autoimmune diseases, such as systemic lupus, rheumatoid arthritis, and multiple sclerosis; graft rejections, such as renal transplant rejection, liver transplant rejection, lung transplant rejection, cardiac transplant rejection, and bone marrow transplant rejection; graft versus host disease; viral infections, such as CMV infection, HIV infection, and AIDS; and parasite infections, such as giardiasis, amoebiasis, schistosomiasis, and the like. Preferably, the immunoconjugates and chemotherapeutic agents of the invention are administered in vitro, in vivo and/or ex vivo to treat cancer in a patient and/or to modulate the growth of cancer cells, including, for example, cancer of the lung, breast, colon, prostate, kidney, pancreas, brain, bones, ovary, testes, and lymphatic organs; more preferably lung cancer or colon cancer. In a most preferred embodiment, the lung cancer is small cell lung cancer (SCLC).
"Modulating the growth of selected cell populations" includes inhibiting the proliferation of selected cell populations (e.g., SCLC cells, NCI N417 cells, SW-2 cells, NCI-H441 cells, HT-29 cells, and the like) from dividing to produce more cells;
reducing the rate of increase in cell division as compared, for example, to untreated cells; killing selected cell populations; and/or preventing selected cell populations (such as cancer cells) from metastasizing. The growth of selected cell populations can be modulated in vitro, in vivo or ex vivo.
In the methods of the present invention, the immunoconjugates and chemotherapeutic agents can be administered in vitro, in vivo, or ex vivo separately or as components of the same composition. The immunoconjugates and chemotherapeutic agents can be used with suitable pharmaceutically acceptable carriers, diluents, and/or excipients, which are well known, and can be determined by one of sldll in the art as the clinical situation warrants. Examples of suitable carriers, diluents and/or excipients include: (1) Dulbecco's phosphate buffered saline, pH about 6.5, which would contain about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v NaCl), and (3) 5% (w/v) dextrose.
The compounds and compositions described herein may be administered in appropriate form, preferably parenterally, more preferably intravenously. For parenteral administration, the compounds or compositions can be aqueous or nonaqueous sterile solutions, suspensions or emulsions. Propylene glycol, vegetable oils and injectable organic esters, such as ethyl oleate, can be used as the solvent or vehicle. The compositions can also contain adjuvants, emulsifiers or dispersants.
The compositions can also be in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or any other injectable sterile medium.
The "therapeutically effective amount" of the chemotherapeutic agents and immunoconjugates described herein refers to the dosage regimen for inhibiting the proliferation of selected cell populations and/or treating a patient's disease, and is selected in accordance with a variety of factors, including the age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, and pharmacological considerations, such as the activity, efficacy, pharmacoldnetic and toxicology profiles of the particular compound used. The "therapeutically effective amount" can also be determined by reference to standard medical texts, such as the Physicians Desk Reference 1999 (53rd Ed.), The patient is preferably an animal, more preferably a mammal, most preferably a human. The patient can be male or female, and can be an infant, child or adult.
Examples of suitable protocols of immunoconjugate administration are as follows. Immurtoconjugates can be given daily for about 5 days either as an i.v.
bolus each day for about 5 days, or as a continuous infusion for about 5 days.
Alternatively, they can be administered once a week for six weeks or longer.
As another alternative, they can be administered once every two or three weeks.
Bolus doses are given in about 50 to about 400 ml of normal saline to which about 5 to about 10 ml of human serum albumin can be added. Continuous infusions are given in about 250 to about 500 ml of normal saline, to which about 25 to about 50 ml of human serum albumin can be added, per 24 hour period. Dosages will be about 10 -p.g to about 1000 mg/kg per person, i.v. (range of about 100 ng to about 10 mg/kg).
About one to about four weeks after treatment, the patient can receive a second course of treatment. Specific clinical protocols with regard to route of administration, excipients, diluents, dosages, and times can be determined by the skilled artisan as the clinical situation warrants.
The present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and/or compositions of the present invention, including, one or more immunoconjugates and one or more chemotherapeutic agents. Such kits can also include, for example, other compounds and/or compositions, a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products.
EXAMPLES
The following examples are for purposes of illustration only, and are not intended to limit the scope of the invention or claims.
Example 1 The maytansinoid DM1 was conjugated to the humanized monoclonal antibody N901.
TM
Ansamitocin P-3, provided by Takeda (Osaka, Japan) was converted to the disulfide-containing maytansinoid DM1, as described herein and in U.S. Patent No.
5,208,020.
y.CHMe2 CIH 113C\ 0 0 = fl H3C0 =
_ 0 .., . .
.3 ,. . ,_..
OH N, 7. H
Ansamitocin P-3 1><.... ru31, 0 0µ.0 I
a n3c 0 0 1111 \ H =
C = %CH 3 ,,.
' 3;.11 NO
r_ H
DM1: R = CH3 huN901-DM1: R = huN901 Humanized N901 is an antibody that binds to the CD56 antigen expressed on all human small cell lung cancer (SCLC) tissues, neuroblastomas and carcinoid tumors (Doria et al, Cancer 62:1839-1845 (1988); Kibbelaar et al, Eur. J.
Cancer, 27:431-435 (1991);Rygaard et al, Br. J. Cancer, 65:573-577 (1992)).
Humanized N901 was modified with N-succinimidy1-442-pyridyldithiol-pentanoate (SPP) to introduce dithiopyridyl groups. Alternatively, N-succinimidyl-3-[2-pyridyldithio]-propanoate (SPDP) can be used. The antibody (8 mg/mL) in iiiM potassium phosphate buffer, pH 6.5, containing NaC1 (50 mM) and EDTA (2 mM) was treated with SPP (5.6 molar equivalents in ethanol). The final ethanol concentration was 5% (v/v). After 90 minutes at ambient temperature, the reaction mixture was gel filtered through a Sephadex G25 column equilibrated in the above buffer. Antibody-containing fractions were pooled and the degree of modification was determined by treating a sample with dithiothreitol and measuring the change in absorbance at 343 nm (release of 2-mercaptopyridine with Ã343. = 8,080 M-1).
Recovery of the antibody was typically 90%, with 4.8 pyridyldithio groups linked per antibody molecule.
The modified antibody was diluted with 50 mM potassium phosphate buffer, 6.5, containing NaC1 (50 mM) and EDTA (2 mM) to a final concentration of 2.5 mg/mL. DM1 (1.7 eq.) in dimethylacetamide (DMA, 3% v/v in final reaction mixture) was then added to the modified antibody solution. The reaction proceeded at ambient temperature under argon for 20 hours.
The reaction mixture was then loaded on to a Sephacryl S300 gel filtration column equilibrated with phosphate-buffered saline (PBS, pH 6.5). The major peak comprised monomeric hu901-DM1. The number of DM1 drug molecules linked per antibody molecule was determined by measuring the absorbance at 252 nm and 280 nm and found to be 3.9 DM1 molecules per antibody molecule.
Example 2 In this experiment, a low, non-curative dose of huN901-DM1 was used with an optimal does of paclitaxel (Sigma Chemical Co., St. Louis, MO). SCID mice (7 animals per group) were inoculated subcutaneously with NCI N417 cells (8 x 106 cells/animal). After the tumors were well-established (average tumor size was approximately 100 mrn3), one group of animals was treated with huN901-DM1 at a DM1 dose of 75 pg/kg/d x 5, administered i.v. everyday. A second group of animals was treated with paclitaxel at a dose of 10 mg/kg/d x 5, administered by i.p. everyday. A third group of animals was treated with huN901-DM1 and paclitaxel using the same dose and schedule used for the individual agents. A
fourth, control group of animals was left untreated. Tumor size was measured as described by Liu et al, Proc. Natl. Acad. Sci., 93:8618-8623 (1996). Animals were also monitored for weight loss as an indicator of signs of toxicity.
The results of the experiment are shown in Fig. 5. In the control group of animals, the tumors grew rapidly to a size of about 900 mire by Day 28 post-tumor inoculation. In animals treated with either huN901-DM1 or paclitaxel, there was a modest anti-tumor effect with a tumor growth delay of 4 days in each case. In the animals treated with huN901-DM1 and paclitaxel, the tumors disappeared with complete regression lasting 58 days. Importantly, there was no evidence of toxicity in the animals. These data demonstrate that treatment with huN901-DM1 and paclitaxel has an unexpectedly superior (e.g., synergistic) anti-tumor effect.
The following examples are for purposes of illustration only, and are not intended to limit the scope of the invention or claims.
Example 1 The maytansinoid DM1 was conjugated to the humanized monoclonal antibody N901.
TM
Ansamitocin P-3, provided by Takeda (Osaka, Japan) was converted to the disulfide-containing maytansinoid DM1, as described herein and in U.S. Patent No.
5,208,020.
y.CHMe2 CIH 113C\ 0 0 = fl H3C0 =
_ 0 .., . .
.3 ,. . ,_..
OH N, 7. H
Ansamitocin P-3 1><.... ru31, 0 0µ.0 I
a n3c 0 0 1111 \ H =
C = %CH 3 ,,.
' 3;.11 NO
r_ H
DM1: R = CH3 huN901-DM1: R = huN901 Humanized N901 is an antibody that binds to the CD56 antigen expressed on all human small cell lung cancer (SCLC) tissues, neuroblastomas and carcinoid tumors (Doria et al, Cancer 62:1839-1845 (1988); Kibbelaar et al, Eur. J.
Cancer, 27:431-435 (1991);Rygaard et al, Br. J. Cancer, 65:573-577 (1992)).
Humanized N901 was modified with N-succinimidy1-442-pyridyldithiol-pentanoate (SPP) to introduce dithiopyridyl groups. Alternatively, N-succinimidyl-3-[2-pyridyldithio]-propanoate (SPDP) can be used. The antibody (8 mg/mL) in iiiM potassium phosphate buffer, pH 6.5, containing NaC1 (50 mM) and EDTA (2 mM) was treated with SPP (5.6 molar equivalents in ethanol). The final ethanol concentration was 5% (v/v). After 90 minutes at ambient temperature, the reaction mixture was gel filtered through a Sephadex G25 column equilibrated in the above buffer. Antibody-containing fractions were pooled and the degree of modification was determined by treating a sample with dithiothreitol and measuring the change in absorbance at 343 nm (release of 2-mercaptopyridine with Ã343. = 8,080 M-1).
Recovery of the antibody was typically 90%, with 4.8 pyridyldithio groups linked per antibody molecule.
The modified antibody was diluted with 50 mM potassium phosphate buffer, 6.5, containing NaC1 (50 mM) and EDTA (2 mM) to a final concentration of 2.5 mg/mL. DM1 (1.7 eq.) in dimethylacetamide (DMA, 3% v/v in final reaction mixture) was then added to the modified antibody solution. The reaction proceeded at ambient temperature under argon for 20 hours.
The reaction mixture was then loaded on to a Sephacryl S300 gel filtration column equilibrated with phosphate-buffered saline (PBS, pH 6.5). The major peak comprised monomeric hu901-DM1. The number of DM1 drug molecules linked per antibody molecule was determined by measuring the absorbance at 252 nm and 280 nm and found to be 3.9 DM1 molecules per antibody molecule.
Example 2 In this experiment, a low, non-curative dose of huN901-DM1 was used with an optimal does of paclitaxel (Sigma Chemical Co., St. Louis, MO). SCID mice (7 animals per group) were inoculated subcutaneously with NCI N417 cells (8 x 106 cells/animal). After the tumors were well-established (average tumor size was approximately 100 mrn3), one group of animals was treated with huN901-DM1 at a DM1 dose of 75 pg/kg/d x 5, administered i.v. everyday. A second group of animals was treated with paclitaxel at a dose of 10 mg/kg/d x 5, administered by i.p. everyday. A third group of animals was treated with huN901-DM1 and paclitaxel using the same dose and schedule used for the individual agents. A
fourth, control group of animals was left untreated. Tumor size was measured as described by Liu et al, Proc. Natl. Acad. Sci., 93:8618-8623 (1996). Animals were also monitored for weight loss as an indicator of signs of toxicity.
The results of the experiment are shown in Fig. 5. In the control group of animals, the tumors grew rapidly to a size of about 900 mire by Day 28 post-tumor inoculation. In animals treated with either huN901-DM1 or paclitaxel, there was a modest anti-tumor effect with a tumor growth delay of 4 days in each case. In the animals treated with huN901-DM1 and paclitaxel, the tumors disappeared with complete regression lasting 58 days. Importantly, there was no evidence of toxicity in the animals. These data demonstrate that treatment with huN901-DM1 and paclitaxel has an unexpectedly superior (e.g., synergistic) anti-tumor effect.
Example 3 In this experiment, a low, non-curative dose of huN901-DM1 was used with an optimal dose of cisplatin (Sigma Chemical Co., St. Louis, MO) and etoposide (Sigma Chemical Co., St. Louis, MO). SCID mice (7 animals per group) were inoculated subcutaneously with NCI N417 cells (8 x 106 cells/animal). After the tumors were well-established (average tumor size was approximately 100 mm3), one group of animals was treated with huN901-DM1 at a DM1 dose of 75 pg/kg/d x 5, administered i.v. everyday. A second group of animals was treated with cisplatin (at a dose of 2 mg/kg/d x 3, administered by i.v. ever other day) and etoposide (at a dose of 8 mg/kg/d x 3, administered every other day). A third group of animals was treated with huN901-DM1, cisplatin and etoposide using the same dose and schedule used for the individual agents. A fourth, control group of animals was left untreated. Tumor size was measured as described by Liu et al, Proc. Natl.
Acad. Sci., 93:8618-8623 (1996). Animals were also monitored for weight loss as an indicator of signs of toxicity.
The results of the experiment are shown in Fig. 6. In the control group of animals, the tumors grew rapidly to a size of about 900 mn-eby Day 28 post-tumor inoculation. In animals treated with either huN901-DM1 or cisplatin and etoposide, there was a modest anti-tumor effect with a tumor growth delay of 4 days in each case. In the animals treated with huN901-DM1, cisplatin and etoposide, there was a tumor growth delay of 12 days, which is 50% longer than what one would expect for an additive anti-tumor effect of the individual compounds. Importantly, there was no evidence of toxicity in the animals. These data demonstrate that treatment with huN901-DM1, cisplatin, and etoposide has an unexpectedly superior (e.g., synergistic) anti-tumor effect.
Example 4 The anti-tumor effect of a combination of a low dose of huN901-DM1 and docetaxel (available as TAXOTEREO from Aventis) was evaluated in an established subcutaneous xenograft model of small cell lung cancer. SCID mice (24 animals) were inoculated with human small cell lung cancer SW-2 cells (8 x 106 cells/animal) injected subcutaneously into the right flank of the mice. When the tumors reached about 100 mm3 in size (10 days after tumor cell inoculation), the mice were randomly divided into four groups (6 animals per group). The first group of mice was treated with docetaxel (5 mg/kg x 5, q2d) administered i.v. A second group of animals was treated with huN901-DM1 (DM1 dose of 75 lig/kg x 5, qd) administered i.v. The third group of mice received a combination of docetaxel and huN901-DM1, using the same doses and schedules as in groups 1 and 2. A control group of animals received phosphate-buffered saline (PBS) using the same schedule as the animals in group 2. Tumor growth was monitored by measuring tumor size twice per week.
Tumor size was calculated with the formula: length x width x height x 1/2.
The change in tumor size is shown in Fig. 7. In the control group of animals, tumors grew rapidly to about 1000 mm3 in 26 days. Treatment with docetaxel alone, or a low dose of huN901-DM1 alone, resulted in tumor growth delays of 8 days and days, respectively. In contrast, treatment with the combination of docetaxel and huN901-DM1 showed a remarkable anti-tumor effect resulting in complete tumor 15 regression in all the treated animals. In 3 out of 6 animals in this treatment group, the tumor was eradicated -- resulting in cures lasting greater than 200 days.
In the remaining 3 animals in this group, there was a tumor growth delay of 52 days, which is 24 days longer than the calculated additive effect. Thus, the combination of docetaxel and huN901-DM1 shows an unexpectedly superior (e.g., synergistic) anti-20 tumor effect in this human SCLC xenograft model.
Example 5 The anti-tumor effect of a combination of a low dose of huN901-DM1 and topotecan (available as HYCAMTIN from SmithKline Beecham Pharmaceuticals), one of the approved drugs for the treatment of small cell lung cancer (SCLC) in humans, was evaluated in an established subcutaneous xenograft model of SCLC.
SCID mice (24 animals) were inoculated with human small cell lung cancer SW-2 cells (8 x 106 cells/animal) injected subcutaneously into the right flank of the mice.
When the tumors reached about 80 mm3 in size, the mice were randomly divided into four groups (6 animals per group). The first group of mice was treated with topotecan (1.4 mg/kg x 5, qd) administered i.v. A second group of animals was treated with huN901-DM1 (DM1 dose of 100 p.,g/kg x 5, qd) administered i.v.
The third group of mice received a combination of topotecan and huN901-DM1, using the same doses and schedules as in groups 1 and 2. A control group of animals received phosphate-buffered saline (PBS) using the same schedule as the animals in group 2. Tumor growth was monitored by measuring tumor size twice per week.
Tumor size was calculated using the formula: length x width x height x 1/2.
The change in tumor size is shown in Fig. 8. In the control group of animals, tumors grew to about 800 mm3 in 44 days. Treatment with topotecan alone resulted in tumor growth delays of 12 days. Treatment with a low dose of huN901-DM1 alone resulted in a tumor-growth delay of 34 days in 3 out of 6 animals. The remaining 3 animals in this group had complete tumor regressions. Treatment with the combination of topotecan and huN901-DM1 showed a remarkable anti-tumor effect resulting in complete tumor regression in 5 out of the 6 treated animals. These animals were tumor-free on day 78, the last measurement point. Thus, the combination of topotecan and huN901-DM1 is unexpectedly superior (e.g., synergistic) when compared to the single agents in this human SCLC xenograft model.
Example 6 The anti-tumor effect of a combination of a low dose of huC242-DM1 (manufactured by ImmunoGen, Inc. following the procedures described in U.S.
Patent No. 5,208,020 and also described in Example 1) and paditaxel (Sigma Chemical Co., St.
Louis, MO) was evaluated in an established subcutaneous xenograft model of non-small cell lung cancer. SCID mice (24 animals) were inoculated with human lung adenocardnoma NCI-H441 cells (8 x 106 cells/animal), injected subcutaneously into the right flank of the mice. When the tumors reached about 125 mm3 in size (4 days after tumor cell inoculation), the mice were randomly divided into four groups (6 animals per group). The first group of mice was treated with paditaxel (15 mg/kg x 5, q2d) administered i.p. A second group of animals was treated with huC242-(DM1 dose of 75 p.g/kg x 5, qd) administered i.v. The third group of mice received a combination of paditaxel and huC242-DM1, using the same doses and schedules as in groups 1 and 2. In the combination group, the huC242-DM1 conjugate was administered 2 hours after the paclitaxel. A control group of animals received phosphate-buffered saline (PBS) using the same schedule as the animals in group 2.
Tumor growth was monitored by measuring tumor size twice per week. Tumor size was calculated using the formula: length x width x height x 1/2.
The change in tumor size is shown in Fig. 9. In the control group of animals, tumors grew rapidly to about 1000 mm3 in 32 days. Treatment with paclitaxel alone, resulted in a small tumor growth delay of 4 days. Treatment with huC242-DM1 resulted in shrinkage of the tumor, but none of the 6 treated animals showed complete tumor regression. Treatment with a combination of paclitaxel and huC242-DM1 showed a greater anti-tumor effect resulting in complete tumor regression, with 3 out of the 6 animals showing no evidence of tumor. The remaining 3 animals in this group showed a significant shrinkage in the tumor. Thus, the combination of paclitaxel and huC242-DM1 is unexpectedly superior (e.g., synergistic) in this human SCLC lung adenocarcinoma xenograft model.
Example 7 The anti-tumor effect of a combination of a low dose of huC242-DM1 (manufactured by ImmunoGen, Inc. following the methods described in U.S.
Patent No. 5,208,020 and also described in Example 1) and paclitaxel (Sigma Chemical Co., St.
Louis, MO) was evaluated in an established subcutaneous xenograft model of non-small cell lung cancer. SCID mice (32 animals) were inoculated with human colon cancer HT-29 cells (8 x 106 cells/animal), injected subcutaneously into the right flank of the mice. When the tumors reached about 80 mm3 in size, the mice were randomly divided into four groups (8 animals per group). The first group of mice was treated with CPT-11 (50 mg/kg x 2, q3d) administered i.v. The second group of animals was treated with murine C242-DM1 (DM1 dose of 75 g/kg x 5, qd) administered i.v. The third group of mice received a combination of CPT-11 and C242-DM1, using the same doses and schedules as in groups 1 and 2. A control group of animals received phosphate-buffered saline (PBS) using the same schedule as the animals in group 2. Tumor growth was monitored by measuring tumor size twice per week. Tumor size was calculated using the formula: length x width x height x 1/2.
The change in tumor size is shown in Fig. 10. In the control group of animals, tumors grew rapidly to about 1000 mm3 in 31 days. Treatment with CPT41 alone -- resulted in a small tumor growth delay of 6 days. Treatment with C242-DM1 resulted in a delay in tumor growth of 22 days. Treatment with a combination of CPT-11 and C242-DM1 showed an unexpectedly superior anti-tumor effect resulting in a tumor growth delay of 38 days, which is 10 days longer than the calculated additive effect. Thus, the combination of CPT-11 and C242-DM1 is unexpectedly -- superior (e.g., synergistic) in this human colon cancer xenograft model.
Various modifications of the invention, in addition to those described herein, will be apparent to one skilled in the art from the foregoing description.
Such -- modifications are intended to fall within the scope of the appended claims.
Acad. Sci., 93:8618-8623 (1996). Animals were also monitored for weight loss as an indicator of signs of toxicity.
The results of the experiment are shown in Fig. 6. In the control group of animals, the tumors grew rapidly to a size of about 900 mn-eby Day 28 post-tumor inoculation. In animals treated with either huN901-DM1 or cisplatin and etoposide, there was a modest anti-tumor effect with a tumor growth delay of 4 days in each case. In the animals treated with huN901-DM1, cisplatin and etoposide, there was a tumor growth delay of 12 days, which is 50% longer than what one would expect for an additive anti-tumor effect of the individual compounds. Importantly, there was no evidence of toxicity in the animals. These data demonstrate that treatment with huN901-DM1, cisplatin, and etoposide has an unexpectedly superior (e.g., synergistic) anti-tumor effect.
Example 4 The anti-tumor effect of a combination of a low dose of huN901-DM1 and docetaxel (available as TAXOTEREO from Aventis) was evaluated in an established subcutaneous xenograft model of small cell lung cancer. SCID mice (24 animals) were inoculated with human small cell lung cancer SW-2 cells (8 x 106 cells/animal) injected subcutaneously into the right flank of the mice. When the tumors reached about 100 mm3 in size (10 days after tumor cell inoculation), the mice were randomly divided into four groups (6 animals per group). The first group of mice was treated with docetaxel (5 mg/kg x 5, q2d) administered i.v. A second group of animals was treated with huN901-DM1 (DM1 dose of 75 lig/kg x 5, qd) administered i.v. The third group of mice received a combination of docetaxel and huN901-DM1, using the same doses and schedules as in groups 1 and 2. A control group of animals received phosphate-buffered saline (PBS) using the same schedule as the animals in group 2. Tumor growth was monitored by measuring tumor size twice per week.
Tumor size was calculated with the formula: length x width x height x 1/2.
The change in tumor size is shown in Fig. 7. In the control group of animals, tumors grew rapidly to about 1000 mm3 in 26 days. Treatment with docetaxel alone, or a low dose of huN901-DM1 alone, resulted in tumor growth delays of 8 days and days, respectively. In contrast, treatment with the combination of docetaxel and huN901-DM1 showed a remarkable anti-tumor effect resulting in complete tumor 15 regression in all the treated animals. In 3 out of 6 animals in this treatment group, the tumor was eradicated -- resulting in cures lasting greater than 200 days.
In the remaining 3 animals in this group, there was a tumor growth delay of 52 days, which is 24 days longer than the calculated additive effect. Thus, the combination of docetaxel and huN901-DM1 shows an unexpectedly superior (e.g., synergistic) anti-20 tumor effect in this human SCLC xenograft model.
Example 5 The anti-tumor effect of a combination of a low dose of huN901-DM1 and topotecan (available as HYCAMTIN from SmithKline Beecham Pharmaceuticals), one of the approved drugs for the treatment of small cell lung cancer (SCLC) in humans, was evaluated in an established subcutaneous xenograft model of SCLC.
SCID mice (24 animals) were inoculated with human small cell lung cancer SW-2 cells (8 x 106 cells/animal) injected subcutaneously into the right flank of the mice.
When the tumors reached about 80 mm3 in size, the mice were randomly divided into four groups (6 animals per group). The first group of mice was treated with topotecan (1.4 mg/kg x 5, qd) administered i.v. A second group of animals was treated with huN901-DM1 (DM1 dose of 100 p.,g/kg x 5, qd) administered i.v.
The third group of mice received a combination of topotecan and huN901-DM1, using the same doses and schedules as in groups 1 and 2. A control group of animals received phosphate-buffered saline (PBS) using the same schedule as the animals in group 2. Tumor growth was monitored by measuring tumor size twice per week.
Tumor size was calculated using the formula: length x width x height x 1/2.
The change in tumor size is shown in Fig. 8. In the control group of animals, tumors grew to about 800 mm3 in 44 days. Treatment with topotecan alone resulted in tumor growth delays of 12 days. Treatment with a low dose of huN901-DM1 alone resulted in a tumor-growth delay of 34 days in 3 out of 6 animals. The remaining 3 animals in this group had complete tumor regressions. Treatment with the combination of topotecan and huN901-DM1 showed a remarkable anti-tumor effect resulting in complete tumor regression in 5 out of the 6 treated animals. These animals were tumor-free on day 78, the last measurement point. Thus, the combination of topotecan and huN901-DM1 is unexpectedly superior (e.g., synergistic) when compared to the single agents in this human SCLC xenograft model.
Example 6 The anti-tumor effect of a combination of a low dose of huC242-DM1 (manufactured by ImmunoGen, Inc. following the procedures described in U.S.
Patent No. 5,208,020 and also described in Example 1) and paditaxel (Sigma Chemical Co., St.
Louis, MO) was evaluated in an established subcutaneous xenograft model of non-small cell lung cancer. SCID mice (24 animals) were inoculated with human lung adenocardnoma NCI-H441 cells (8 x 106 cells/animal), injected subcutaneously into the right flank of the mice. When the tumors reached about 125 mm3 in size (4 days after tumor cell inoculation), the mice were randomly divided into four groups (6 animals per group). The first group of mice was treated with paditaxel (15 mg/kg x 5, q2d) administered i.p. A second group of animals was treated with huC242-(DM1 dose of 75 p.g/kg x 5, qd) administered i.v. The third group of mice received a combination of paditaxel and huC242-DM1, using the same doses and schedules as in groups 1 and 2. In the combination group, the huC242-DM1 conjugate was administered 2 hours after the paclitaxel. A control group of animals received phosphate-buffered saline (PBS) using the same schedule as the animals in group 2.
Tumor growth was monitored by measuring tumor size twice per week. Tumor size was calculated using the formula: length x width x height x 1/2.
The change in tumor size is shown in Fig. 9. In the control group of animals, tumors grew rapidly to about 1000 mm3 in 32 days. Treatment with paclitaxel alone, resulted in a small tumor growth delay of 4 days. Treatment with huC242-DM1 resulted in shrinkage of the tumor, but none of the 6 treated animals showed complete tumor regression. Treatment with a combination of paclitaxel and huC242-DM1 showed a greater anti-tumor effect resulting in complete tumor regression, with 3 out of the 6 animals showing no evidence of tumor. The remaining 3 animals in this group showed a significant shrinkage in the tumor. Thus, the combination of paclitaxel and huC242-DM1 is unexpectedly superior (e.g., synergistic) in this human SCLC lung adenocarcinoma xenograft model.
Example 7 The anti-tumor effect of a combination of a low dose of huC242-DM1 (manufactured by ImmunoGen, Inc. following the methods described in U.S.
Patent No. 5,208,020 and also described in Example 1) and paclitaxel (Sigma Chemical Co., St.
Louis, MO) was evaluated in an established subcutaneous xenograft model of non-small cell lung cancer. SCID mice (32 animals) were inoculated with human colon cancer HT-29 cells (8 x 106 cells/animal), injected subcutaneously into the right flank of the mice. When the tumors reached about 80 mm3 in size, the mice were randomly divided into four groups (8 animals per group). The first group of mice was treated with CPT-11 (50 mg/kg x 2, q3d) administered i.v. The second group of animals was treated with murine C242-DM1 (DM1 dose of 75 g/kg x 5, qd) administered i.v. The third group of mice received a combination of CPT-11 and C242-DM1, using the same doses and schedules as in groups 1 and 2. A control group of animals received phosphate-buffered saline (PBS) using the same schedule as the animals in group 2. Tumor growth was monitored by measuring tumor size twice per week. Tumor size was calculated using the formula: length x width x height x 1/2.
The change in tumor size is shown in Fig. 10. In the control group of animals, tumors grew rapidly to about 1000 mm3 in 31 days. Treatment with CPT41 alone -- resulted in a small tumor growth delay of 6 days. Treatment with C242-DM1 resulted in a delay in tumor growth of 22 days. Treatment with a combination of CPT-11 and C242-DM1 showed an unexpectedly superior anti-tumor effect resulting in a tumor growth delay of 38 days, which is 10 days longer than the calculated additive effect. Thus, the combination of CPT-11 and C242-DM1 is unexpectedly -- superior (e.g., synergistic) in this human colon cancer xenograft model.
Various modifications of the invention, in addition to those described herein, will be apparent to one skilled in the art from the foregoing description.
Such -- modifications are intended to fall within the scope of the appended claims.
Claims (43)
1. Use of a therapeutically effective amount of a synergistic combination of at least one chemotherapeutic agent and at least one immunoconjugate, wherein the immunoconjugate comprises at least one cell binding agent and at least one maytansinoid compound, wherein the cell binding agent is a monoclonal antibody or an epitope-binding fragment thereof that binds to an antigen expressed by a cancer cell and wherein the chemotherapeutic agent is a taxane compound, an epothilone compound, a platinum compound, an epipodophyllotoxin compound, a camptothecin compound, or a mixture of two or more thereof, for treating cancer in a patient in need thereof.
2. The use of claim 1, wherein the cancer is a cancer of the breast, colon, lung, prostate, kidney, pancreas, brain, bones, ovary, testes or a lymphatic organ.
3. The use of claim 1, wherein the cancer is lung cancer.
4. The use of claim 3, wherein the lung cancer is a small cell lung cancer.
5. The use of claim 1, wherein the cancer is colon cancer.
6. The use of claim 1, wherein the maytansinoid is DM1.
7. The use of claim 1, wherein the monoclonal antibody or epitope-binding fragment thereof is a humanized monoclonal antibody or epitope-binding fragment thereof.
8. The use of claim 1, wherein the monoclonal antibody or epitope-binding fragment thereof binds to the CanAg antigen or the CD19 antigen.
9. The use of claim 1, wherein the monoclonal antibody or epitope-binding fragment thereof binds to a CD56 antigen.
10. The use of claim 1, wherein the monoclonal antibody or epitope-binding fragment thereof is a humanized anti-B4 antibody, a humanized N901 antibody or a humanized C242 antibody.
11. The use of claim 1, wherein the monoclonal antibody or epitope-binding fragment thereof is Fv, Fab, Fab' or F(ab')2.
12. The use of claim 1, wherein the chemotherapeutic agent is a taxane compound.
13. The use of claim 12, wherein the taxane compound is paclitaxel or docetaxel.
14. The use of claim 1, wherein the chemotherapeutic agent is an epothilone compound.
15. The use of claim 14, wherein the epothilone compound is epothilone A, epothilone B, epothilone C, epothilone D, epothilone E or epothilone F.
16. The use of claim 1, wherein the chemotherapeutic agent is a platinum compound.
17. The use of claim 16, wherein the platinum compound is cisplatin, carboplatin, oxaliplatin, iproplatin, ormaplatin, or tetraplatin.
18. The use of claim 16, wherein the chemotherapeutic agent further comprises at least one epipodophyllotoxin compound.
19. The use of claim 18, wherein the epipodophyllotoxin compound is etoposide or teniposide.
20. The use of claim 1, wherein the chemotherapeutic agent is a camptothecin compound.
21. The use of claim 20, wherein the camptothecin compound is camptothecin, topotecan, irinotecan or 9-aminocamptothecin.
22. The use of claim 1, wherein the therapeutically effective amount is about 100 ng to about mg/kg body weight once per week.
23. The use of claim 1, wherein the immunoconjugate and chemotherapeutic agent are in separate compositions.
24. The use of claim 1, wherein the immunoconjugate and chemotherapeutic agent are components of a single composition.
25. The use of claim 1, wherein the immunoconjugate and chemotherapeutic agent are in a parental formulation.
26. The use of claim 25, wherein the immunoconjugate and chemotherapeutic agent are in an intravenous formulation.
27. Use of a therapeutically effective amount of a synergistic combination of at least one chemotherapeutic agent and at least one immunoconjugate, wherein the immunoconjugate comprises at least one cell binding agent and at least one maytansinoid compound, wherein the cell binding agent is a monoclonal antibody or an epitope-binding fragment thereof that binds to an antigen expressed by a cancer cell, and wherein the chemotherapeutic agent is a taxane compound, an epothilone compound, a platinum compound, an epipodophyllotoxin compound, a camptothecin compound, or a mixture of two or more thereof, for modulating growth of cancer cells.
28. The use of claim 27, wherein modulating the growth of cancer cells modulates the growth of cancer cells selected from cancer of the breast, colon, lung, prostate, kidney, pancreas, brain, bones, ovary, testes and a lymphatic organ.
29. The use of claim 27, wherein modulating the growth of cancer cells comprises inhibiting the proliferation of cancer cells.
30. The use of claim 27, wherein modulating the growth of cancer cells comprises reducing the rate of cell division of the cancer cells as compared to the rate of cell division in untreated cancer cells.
31. The use of claim 27, wherein modulating the growth of cancer cells comprises killing cancer cells.
32. The use of claim 27, wherein modulating the growth of cancer cells comprises preventing metastasis of the cancer cells.
33. A composition comprising a synergistic combination of at least one chemotherapeutic agent and at least one immunoconjugate, wherein the immunoconjugate comprises at least one cell binding agent and at least one maytansinoid compound, wherein the cell binding agent is a monoclonal antibody or an epitope-binding fragment thereof that binds to an antigen expressed by a cancer cell, and wherein the chemotherapeutic agent is a taxane compound, an epothilone compound, a platinum compound, an epipodophyllotoxin compound, a camptothecin compound, or a mixture of two or more thereof.
34. A kit comprising a synergistic combination of at least one chemotherapeutic agent and at least one immunoconjugate, wherein the immunoconjugate comprises at least one cell binding agent and at least one maytansinoid compound, wherein the cell binding agent is a monoclonal antibody or an epitope-binding fragment thereof that binds to an antigen expressed by a cancer cell, and wherein the chemotherapeutic agent is a taxane compound, an epothilone compound, a platinum compound, an epipodophyllotoxin compound, a camptothecin compound, or a mixture of two or more thereof.
35. The use of claim 1, wherein the cancer is cancer of the breast.
36. The use of claim 1, wherein the therapeutically effective amount is about 100 ng to about mg/kg body weight once every two weeks.
37. The use of claim 1, wherein the therapeutically effective amount is 100 ng to about 10 mg/kg body weight once every three weeks.
38. The composition of claim 33, wherein the maytansinoid is DM1.
39. An immunoconjugate comprising a cell binding agent and a maytansinoid, wherein the cell binding agent is conjugated to the maytansinoid using N-succinimidyl-4- [2-pyridyldithio]-pentanoate (SPP), and wherein the cell binding agent is a humanized N901 monoclonal antibody or an epitope binding fragment thereof.
40. The immunoconjugate of claim 39, wherein the cell binding agent is a humanized N901 monoclonal antibody.
41. The immunoconjugate of claim 39, wherein the cell binding agent is an Fv, Fab, Fab', or F(ab')2 fragment of a humanized N901 monoclonal antibody.
42. The immunoconjugate of claim 39, wherein the maytansinoid is DM1.
43. A pharmaceutical composition comprising the immunoconjugate of claim 39 and a pharmaceutically acceptable carrier.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15705199P | 1999-10-01 | 1999-10-01 | |
US60/157,051 | 1999-10-01 | ||
PCT/US2000/026800 WO2001024763A2 (en) | 1999-10-01 | 2000-09-29 | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2385528A1 CA2385528A1 (en) | 2001-04-12 |
CA2385528C true CA2385528C (en) | 2013-12-10 |
Family
ID=22562160
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2385528A Expired - Fee Related CA2385528C (en) | 1999-10-01 | 2000-09-29 | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
Country Status (7)
Country | Link |
---|---|
US (3) | US7601354B2 (en) |
EP (3) | EP2289549A3 (en) |
JP (3) | JP4776843B2 (en) |
AU (1) | AU775373B2 (en) |
CA (1) | CA2385528C (en) |
HK (1) | HK1049787B (en) |
WO (1) | WO2001024763A2 (en) |
Families Citing this family (184)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US6333410B1 (en) * | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
WO2002092771A2 (en) | 2001-05-11 | 2002-11-21 | Ludwig Institute For Cancer Research | Specific binding proteins and uses thereof |
US20100056762A1 (en) | 2001-05-11 | 2010-03-04 | Old Lloyd J | Specific binding proteins and uses thereof |
PT1392313E (en) * | 2001-05-16 | 2007-07-17 | Novartis Ag | Combination comprising n- 5- 4-(4-methyl-piperazino-methyl)-benzoylamido |
EP1258255A1 (en) * | 2001-05-18 | 2002-11-20 | Boehringer Ingelheim International GmbH | Conjugates of an antibody to CD44 and a maytansinoid |
US20030103985A1 (en) | 2001-05-18 | 2003-06-05 | Boehringer Ingelheim International Gmbh | Cytotoxic CD44 antibody immunoconjugates |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
JP2005532258A (en) * | 2002-01-03 | 2005-10-27 | スミスクライン・ビーチャム・コーポレイション | Method for preparing immunoconjugate |
US8435529B2 (en) | 2002-06-14 | 2013-05-07 | Immunomedics, Inc. | Combining radioimmunotherapy and antibody-drug conjugates for improved cancer therapy |
US8877901B2 (en) | 2002-12-13 | 2014-11-04 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US7591994B2 (en) | 2002-12-13 | 2009-09-22 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US9770517B2 (en) | 2002-03-01 | 2017-09-26 | Immunomedics, Inc. | Anti-Trop-2 antibody-drug conjugates and uses thereof |
EP1340498A1 (en) * | 2002-03-01 | 2003-09-03 | Schering Aktiengesellschaft | Use of epothilones in the treatment of brain diseases associated with proliferative processes |
AU2003247686A1 (en) * | 2002-07-02 | 2004-01-23 | Smithkline Beecham Corporation | A novel stable formulation |
ES2361739T3 (en) * | 2002-08-16 | 2011-06-21 | Immunogen, Inc. | RETICULANTS WITH HIGH REACTIVITY AND SOLUBILITY AND ITS USE IN THE PREPARATION OF CONJUGATES FOR THE DIRECTED SUPPLY OF DRUGS OF SMALL MOLECULE. |
EP1391213A1 (en) * | 2002-08-21 | 2004-02-25 | Boehringer Ingelheim International GmbH | Compositions and methods for treating cancer using maytansinoid CD44 antibody immunoconjugates and chemotherapeutic agents |
AU2003288467A1 (en) | 2002-12-13 | 2004-07-09 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US8088387B2 (en) * | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
WO2004110498A2 (en) | 2003-05-14 | 2004-12-23 | Immunogen, Inc. | Drug conjugate composition |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
BRPI0410748B8 (en) * | 2003-05-20 | 2021-05-25 | Immunogen Inc | maytansinoid compounds, their pharmaceutical compositions, methods of esterification of maytansinoids, as well as methods for their production, and maytansinoid-cell binding agent conjugate |
EP2457586A1 (en) | 2003-06-27 | 2012-05-30 | Amgen Fremont Inc. | Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof |
CN101087611B (en) * | 2003-10-10 | 2019-04-23 | 伊缪诺金公司 | With method, the conjugate and the method for preparing the conjugate of the cell binding agent maytansinoid conjugate targeting specific cells group through not cleavable connector connection |
US9523231B2 (en) | 2003-11-10 | 2016-12-20 | Strattec Power Access Llc | Attachment assembly and drive unit having same |
MXPA06014065A (en) | 2004-06-01 | 2007-01-31 | Genentech Inc | Antibody drug conjugates and methods. |
US7541330B2 (en) | 2004-06-15 | 2009-06-02 | Kosan Biosciences Incorporated | Conjugates with reduced adverse systemic effects |
CN101065151B (en) | 2004-09-23 | 2014-12-10 | 健泰科生物技术公司 | Cysteine engineered antibodies and conjugates |
EP1640004A1 (en) * | 2004-09-24 | 2006-03-29 | Schering Aktiengesellschaft | Use of epothilones in the treatment of bone metastases and bone tumors or cancers |
CA2590431A1 (en) * | 2004-12-13 | 2006-06-22 | F. Hoffmann-La Roche Ag | Novel pharmaceutical composition containing at least one dolastatin 10 derivative |
US20110166319A1 (en) * | 2005-02-11 | 2011-07-07 | Immunogen, Inc. | Process for preparing purified drug conjugates |
AU2006213662B2 (en) * | 2005-02-11 | 2010-08-05 | Immunogen, Inc. | Process for preparing stable drug conjugates |
EP1695717A1 (en) * | 2005-02-23 | 2006-08-30 | Ludwig-Maximilians-Universität | Transport of nano-and macromolecular structures into cytoplasm and nucleus of cells |
US9707302B2 (en) | 2013-07-23 | 2017-07-18 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
US10058621B2 (en) | 2015-06-25 | 2018-08-28 | Immunomedics, Inc. | Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers |
JP2006316040A (en) | 2005-05-13 | 2006-11-24 | Genentech Inc | Herceptin(r) adjuvant treatment |
CA2615122A1 (en) | 2005-08-03 | 2007-02-15 | Immunogen, Inc. | Immunoconjugate formulations |
NZ609752A (en) | 2005-08-24 | 2014-08-29 | Immunogen Inc | Process for preparing maytansinoid antibody conjugates |
EP2126127B1 (en) | 2007-01-25 | 2016-09-28 | Dana-Farber Cancer Institute, Inc. | Use of anti-egfr antibodies in treatment of egfr mutant mediated disease |
AU2008227123B2 (en) | 2007-03-15 | 2014-03-27 | Ludwig Institute For Cancer Research Ltd. | Treatment method using EGFR antibodies and src inhibitors and related formulations |
EP2641618A3 (en) | 2007-07-16 | 2013-10-23 | Genentech, Inc. | Humanized anti-CD79B antibodies and immunoconjugates and methods of use |
SG183023A1 (en) | 2007-07-16 | 2012-08-30 | Genentech Inc | Anti-cd79b antibodies and immunoconjugates and methods of use |
EP2188311B1 (en) | 2007-08-14 | 2016-10-05 | Ludwig Institute for Cancer Research Ltd. | Monoclonal antibody 175 targeting the egf receptor and derivatives and uses thereof |
IL295449A (en) | 2008-01-31 | 2022-10-01 | Genentech Inc | Cycteine engineering anti-cd79b antibodies and antibody-drug conjugates |
EP2644204B1 (en) | 2008-03-18 | 2017-04-19 | Genentech, Inc. | Combinations of an Anti-HER2 antibody-drug conjugate and pertuzumab |
NZ589880A (en) * | 2008-06-16 | 2012-10-26 | Immunogen Inc | Use of synergistic anti-cancer compositions comprising lenalidomide, at least one corticosteroid and at least one immunoconjugate |
DK3912643T3 (en) | 2009-02-13 | 2022-10-17 | Immunomedics Inc | IMMUNOCONJUGATES WITH AN INTRACELLULAR-CLEAVABLE BOND |
WO2010096394A2 (en) | 2009-02-17 | 2010-08-26 | Redwood Biosciences, Inc. | Aldehyde-tagged protein-based drug carriers and methods of use |
AR076284A1 (en) | 2009-04-29 | 2011-06-01 | Bayer Schering Pharma Ag | IMMUNOCONJUGADOS OF ANTIMESOTELINA AND USES OF THE SAME |
CA2761120A1 (en) | 2009-05-06 | 2010-11-11 | Biotest Ag | Uses of immunoconjugates targeting cd138 |
LT2437790T (en) | 2009-06-03 | 2019-06-10 | Immunogen, Inc. | Conjugation methods |
PL2437785T3 (en) | 2009-06-04 | 2015-08-31 | Novartis Ag | METHODS FOR IDENTIFICATION OF SITES FOR IgG CONJUGATION |
WO2011028952A1 (en) | 2009-09-02 | 2011-03-10 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
US20110097345A1 (en) * | 2009-10-21 | 2011-04-28 | Immunogen Inc. | Novel dosing regimen and method of treatment |
KR20120123299A (en) | 2009-12-04 | 2012-11-08 | 제넨테크, 인크. | Multispecific antibodies, antibody analogs, compositions, and methods |
US8765432B2 (en) | 2009-12-18 | 2014-07-01 | Oligasis, Llc | Targeted drug phosphorylcholine polymer conjugates |
RU2012131663A (en) * | 2010-01-21 | 2014-02-27 | Иммьюноджен, Инк. | COMPOSITIONS AND METHODS FOR TREATING OVARIAN CANCER |
JP5841072B2 (en) | 2010-02-10 | 2016-01-06 | イミュノジェン・インコーポレーテッド | CD20 antibody and use thereof |
AR080243A1 (en) * | 2010-02-23 | 2012-03-21 | Genentech Inc | COMPOSITIONS AND METHODS FOR DIAGNOSIS AND TUMOR TREATMENT |
BR112012023010A8 (en) | 2010-03-12 | 2017-12-26 | Immunogen Inc | ANTIBODY OR ANTIGEN-BINDING FRAGMENT OF THE SAME THAT SPECIFICALLY BINDS TO CD37, IMMUNOCONJUGATE COMPRISING THE SAME, USE OF THE SAID ANTIBODY, FRAGMENT AND IMMUNOCONJUGATE, COMPOSITION COMPRISING THE SAME, KIT, ISOLATED CELL, AS WELL AS IN VITRO METHOD TO INHIBIT GROWTH MENT OF A CELL THAT EXPRESSES CD37 |
KR102416359B1 (en) | 2010-04-15 | 2022-07-01 | 코디악 사이언시스 인코포레이티드 | High molecular weight zwitterion-containing polymers |
KR101839163B1 (en) | 2010-06-08 | 2018-03-15 | 제넨테크, 인크. | Cysteine engineered antibodies and conjugates |
DK3029066T3 (en) | 2010-07-29 | 2019-05-20 | Xencor Inc | ANTIBODIES WITH MODIFIED ISOELECTRIC ITEMS |
EP2621954A1 (en) | 2010-10-01 | 2013-08-07 | Oxford Biotherapeutics Ltd. | Anti-rori antibodies |
EP2632490A4 (en) | 2010-10-29 | 2014-10-22 | Immunogen Inc | Novel egfr-binding molecules and immunoconjugates thereof |
JOP20210044A1 (en) | 2010-12-30 | 2017-06-16 | Takeda Pharmaceuticals Co | Anti-cd38 antibodies |
EP2663647A4 (en) | 2011-01-14 | 2015-08-19 | Redwood Bioscience Inc | Aldehyde-tagged immunoglobulin polypeptides and method of use thereof |
KR20220009505A (en) | 2011-03-29 | 2022-01-24 | 이뮤노젠 아이엔씨 | Preparation of maytansinoid antibody conjugates by a one-step process |
EA201391342A1 (en) | 2011-04-01 | 2014-11-28 | Иммьюноджен, Инк. | CD37-BINDING MOLECULES AND THEIR IMMUNOCONJUGATES |
JP5926374B2 (en) | 2011-06-10 | 2016-05-25 | メルサナ セラピューティクス,インコーポレイティド | Protein-polymer-drug conjugate |
AU2015224535B2 (en) * | 2011-06-21 | 2017-07-20 | Immunogen, Inc. | Novel maytansinoid derivatives with peptide linker and conjugates thereof |
KR20140037208A (en) * | 2011-06-21 | 2014-03-26 | 이뮤노젠 아이엔씨 | Novel maytansinoid derivatives with peptide linker and conjugates thereof |
WO2013022855A1 (en) | 2011-08-05 | 2013-02-14 | Xencor, Inc. | Antibodies with modified isoelectric points and immunofiltering |
AU2012323287B2 (en) | 2011-10-10 | 2018-02-01 | Xencor, Inc. | A method for purifying antibodies |
US10851178B2 (en) | 2011-10-10 | 2020-12-01 | Xencor, Inc. | Heterodimeric human IgG1 polypeptides with isoelectric point modifications |
US9233171B2 (en) | 2011-11-21 | 2016-01-12 | Immunogen, Inc. | Method of treatment of tumors that are resistant to EGFR antibody therapies by EGFR antibody cytotoxic agent conjugate |
US10117932B2 (en) | 2011-12-08 | 2018-11-06 | Biotest Ag | Uses of immunoconjugates targeting CD138 |
WO2013130093A1 (en) | 2012-03-02 | 2013-09-06 | Genentech, Inc. | Biomarkers for treatment with anti-tubulin chemotherapeutic compounds |
AR090549A1 (en) | 2012-03-30 | 2014-11-19 | Genentech Inc | ANTI-LGR5 AND IMMUNOCATE PLAYERS |
AR090903A1 (en) | 2012-05-01 | 2014-12-17 | Genentech Inc | ANTI-PMEL ANTIBODIES AND IMMUNOCADES17 |
CN104540519B (en) | 2012-05-21 | 2018-06-01 | 基因泰克公司 | Anti- Ly6E antibody and immunoconjugates and application method |
RU2015106946A (en) | 2012-08-02 | 2016-09-27 | Дженентек, Инк. | ANTIBODIES TO TYPE B ENDOTHELIN RECEPTOR (ETBR) AND THEIR IMMUNO CONJUGATES |
EP2879708A4 (en) | 2012-08-02 | 2016-03-16 | Genentech Inc | Anti-etbr antibodies and immunoconjugates |
US9382329B2 (en) | 2012-08-14 | 2016-07-05 | Ibc Pharmaceuticals, Inc. | Disease therapy by inducing immune response to Trop-2 expressing cells |
NZ739573A (en) * | 2012-09-26 | 2019-11-29 | Immunogen Inc | Improved methods for the acylation of maytansinol |
IN2015DN03202A (en) | 2012-10-04 | 2015-10-02 | Immunogen Inc | |
US9353150B2 (en) | 2012-12-04 | 2016-05-31 | Massachusetts Institute Of Technology | Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]-indole-1,4-diones for cancer treatment |
JP6334553B2 (en) | 2012-12-10 | 2018-05-30 | メルサナ セラピューティクス,インコーポレイティド | Protein-polymer-drug conjugate |
US9872918B2 (en) | 2012-12-12 | 2018-01-23 | Mersana Therapeutics, Inc. | Hydroxyl-polymer-drug-protein conjugates |
US9492566B2 (en) | 2012-12-13 | 2016-11-15 | Immunomedics, Inc. | Antibody-drug conjugates and uses thereof |
US10137196B2 (en) | 2012-12-13 | 2018-11-27 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity |
PT2900277T (en) | 2012-12-13 | 2022-05-25 | Immunomedics Inc | Dosages of immunoconjugates of antibodies and sn-38 for improved efficacy and decreased toxicity |
ES2819573T3 (en) | 2012-12-13 | 2021-04-16 | Immunomedics Inc | Method for Producing Antibody-SN-38 Immunoconjugates with a CL2A Linker |
US9931417B2 (en) | 2012-12-13 | 2018-04-03 | Immunomedics, Inc. | Antibody-SN-38 immunoconjugates with a CL2A linker |
US10744129B2 (en) | 2012-12-13 | 2020-08-18 | Immunomedics, Inc. | Therapy of small-cell lung cancer (SCLC) with a topoisomerase-I inhibiting antibody-drug conjugate (ADC) targeting Trop-2 |
US10413539B2 (en) | 2012-12-13 | 2019-09-17 | Immunomedics, Inc. | Therapy for metastatic urothelial cancer with the antibody-drug conjugate, sacituzumab govitecan (IMMU-132) |
US10206918B2 (en) | 2012-12-13 | 2019-02-19 | Immunomedics, Inc. | Efficacy of anti-HLA-DR antiboddy drug conjugate IMMU-140 (hL243-CL2A-SN-38) in HLA-DR positive cancers |
WO2014110601A1 (en) | 2013-01-14 | 2014-07-17 | Xencor, Inc. | Novel heterodimeric proteins |
US10968276B2 (en) | 2013-03-12 | 2021-04-06 | Xencor, Inc. | Optimized anti-CD3 variable regions |
US11053316B2 (en) | 2013-01-14 | 2021-07-06 | Xencor, Inc. | Optimized antibody variable regions |
US9605084B2 (en) | 2013-03-15 | 2017-03-28 | Xencor, Inc. | Heterodimeric proteins |
US10487155B2 (en) | 2013-01-14 | 2019-11-26 | Xencor, Inc. | Heterodimeric proteins |
US10131710B2 (en) | 2013-01-14 | 2018-11-20 | Xencor, Inc. | Optimized antibody variable regions |
US9701759B2 (en) | 2013-01-14 | 2017-07-11 | Xencor, Inc. | Heterodimeric proteins |
US9738722B2 (en) | 2013-01-15 | 2017-08-22 | Xencor, Inc. | Rapid clearance of antigen complexes using novel antibodies |
US10106624B2 (en) | 2013-03-15 | 2018-10-23 | Xencor, Inc. | Heterodimeric proteins |
EP3421495A3 (en) | 2013-03-15 | 2019-05-15 | Xencor, Inc. | Modulation of t cells with bispecific antibodies and fc fusions |
US10858417B2 (en) | 2013-03-15 | 2020-12-08 | Xencor, Inc. | Heterodimeric proteins |
US10519242B2 (en) | 2013-03-15 | 2019-12-31 | Xencor, Inc. | Targeting regulatory T cells with heterodimeric proteins |
EP3587448B1 (en) | 2013-03-15 | 2021-05-19 | Xencor, Inc. | Heterodimeric proteins |
CA2910945A1 (en) | 2013-05-08 | 2014-11-13 | Zymeworks Inc. | Bispecific her2 and her3 antigen binding constructs |
US10208125B2 (en) | 2013-07-15 | 2019-02-19 | University of Pittsburgh—of the Commonwealth System of Higher Education | Anti-mucin 1 binding agents and uses thereof |
US11253606B2 (en) | 2013-07-23 | 2022-02-22 | Immunomedics, Inc. | Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
JP2016537399A (en) | 2013-09-17 | 2016-12-01 | ジェネンテック, インコーポレイテッド | Method using anti-LGR5 antibody |
ES2726850T3 (en) | 2013-10-11 | 2019-10-09 | Mersana Therapeutics Inc | Protein-polymer-drug conjugates |
EP3055331B1 (en) | 2013-10-11 | 2021-02-17 | Oxford Bio Therapeutics Limited | Conjugated antibodies against ly75 for the treatment of cancer |
CN105813655B (en) | 2013-10-11 | 2022-03-15 | 阿萨纳生物科技有限责任公司 | Protein-polymer-drug conjugates |
US9290578B2 (en) | 2013-10-21 | 2016-03-22 | Genentech, Inc. | Anti-Ly6E antibodies and methods of use |
MX2016006301A (en) | 2013-11-13 | 2016-12-16 | Zymeworks Inc | Monovalent antigen binding constructs targeting egfr and/or her2 and uses thereof. |
CR20160506A (en) | 2014-03-28 | 2017-03-10 | Xencor Inc | Bispecific Antibodies that bind to CD38 and CD3 |
AU2015292326A1 (en) | 2014-07-24 | 2017-02-23 | Xencor, Inc. | Rapid clearance of antigen complexes using novel antibodies |
EP3191521A2 (en) | 2014-09-12 | 2017-07-19 | F. Hoffmann-La Roche AG | Cysteine engineered antibodies and conjugates |
ES2796903T3 (en) | 2014-09-23 | 2020-11-30 | Hoffmann La Roche | Procedure for the use of anti-CD79b immunoconjugates |
CA2968878A1 (en) | 2014-11-26 | 2016-06-02 | Xencor, Inc. | Heterodimeric antibodies that bind cd3 and cd38 |
US10259887B2 (en) | 2014-11-26 | 2019-04-16 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and tumor antigens |
DK3223845T3 (en) | 2014-11-26 | 2021-08-16 | Xencor Inc | HETERODIMERING ANTIBODIES BINDING CD3 AND CD20 |
WO2016090157A1 (en) | 2014-12-04 | 2016-06-09 | Celgene Corporation | Biomolecule conjugates |
EP3237449A2 (en) | 2014-12-22 | 2017-11-01 | Xencor, Inc. | Trispecific antibodies |
US10227411B2 (en) | 2015-03-05 | 2019-03-12 | Xencor, Inc. | Modulation of T cells with bispecific antibodies and FC fusions |
CA2981543A1 (en) | 2015-04-22 | 2016-10-27 | Immunomedics, Inc. | Isolation, detection, diagnosis and/or characterization of circulating trop-2-positive cancer cells |
CA2986437A1 (en) | 2015-06-08 | 2016-12-15 | Debiopharm International, S.A. | Anti-cd37 immunoconjugate and anti-cd20 antibody combinations |
US10195175B2 (en) | 2015-06-25 | 2019-02-05 | Immunomedics, Inc. | Synergistic effect of anti-Trop-2 antibody-drug conjugate in combination therapy for triple-negative breast cancer when used with microtubule inhibitors or PARP inhibitors |
EA201890347A1 (en) | 2015-08-28 | 2018-09-28 | Дебиофарм Интернэшнл, С.А. | ANTIBODIES AND RESEARCH FOR DETECTION CD37 |
CN108699136B (en) | 2015-12-07 | 2022-03-18 | Xencor股份有限公司 | Heterodimeric antibodies that bind CD3 and PSMA |
CA3011372A1 (en) | 2016-02-10 | 2017-08-17 | Immunomedics, Inc. | Combination of abcg2 inhibitors with sacituzumab govitecan (immu-132) overcomes resistance to sn-38 in trop-2 expressing cancers |
JP2019515677A (en) | 2016-04-26 | 2019-06-13 | アール.ピー.シェーラー テクノロジーズ エルエルシー | Antibody conjugates and methods of making and using the same |
CN109310385A (en) | 2016-04-27 | 2019-02-05 | 免疫医疗公司 | Anti- TROP-2-SN-38 antibody drug conjugate is used for the effect of checkpoint inhibitor recurrence/refractory tumors therapy |
WO2017197045A1 (en) | 2016-05-11 | 2017-11-16 | Movassaghi Mohammad | Convergent and enantioselective total synthesis of communesin analogs |
WO2017218707A2 (en) | 2016-06-14 | 2017-12-21 | Xencor, Inc. | Bispecific checkpoint inhibitor antibodies |
US11617799B2 (en) | 2016-06-27 | 2023-04-04 | Tagworks Pharmaceuticals B.V. | Cleavable tetrazine used in bio-orthogonal drug activation |
CN116063545A (en) | 2016-06-28 | 2023-05-05 | Xencor股份有限公司 | Heterodimeric antibodies that bind somatostatin receptor 2 |
US10793632B2 (en) | 2016-08-30 | 2020-10-06 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
EP3526241A1 (en) | 2016-10-14 | 2019-08-21 | Xencor, Inc. | Il15/il15r heterodimeric fc-fusion proteins |
JP2020510608A (en) | 2016-11-02 | 2020-04-09 | デビオファーム インターナショナル, エス. アー. | Method for improving anti-CD37 immunoconjugate therapy |
US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
GB201703876D0 (en) | 2017-03-10 | 2017-04-26 | Berlin-Chemie Ag | Pharmaceutical combinations |
EP3600283A4 (en) | 2017-03-27 | 2020-12-16 | Immunomedics, Inc. | Treatment of trop-2 expressing triple negative breast cancer with sacituzumab govitecan and a rad51 inhibitor |
CN110352201A (en) | 2017-04-03 | 2019-10-18 | 免疫医疗公司 | The subcutaneous administration of antibody drug conjugate for cancer therapy |
WO2018209239A1 (en) | 2017-05-11 | 2018-11-15 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
AU2018290330A1 (en) | 2017-06-22 | 2020-01-02 | Mersana Therapeutics, Inc. | Methods of producing drug-carrying polymer scaffolds and protein-polymer-drug conjugates |
CN111132733A (en) | 2017-06-30 | 2020-05-08 | Xencor股份有限公司 | Targeted heterodimeric Fc fusion proteins containing IL-15/IL-15R α and an antigen binding domain |
CN107488231B (en) * | 2017-09-15 | 2020-10-30 | 四川大学 | anti-CD 56 antibodies and uses thereof |
US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
US10981992B2 (en) | 2017-11-08 | 2021-04-20 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
US11312770B2 (en) | 2017-11-08 | 2022-04-26 | Xencor, Inc. | Bispecific and monospecific antibodies using novel anti-PD-1 sequences |
CA3086199A1 (en) | 2017-12-19 | 2019-06-27 | Xencor, Inc. | Engineered il-2 fc fusion proteins |
US10982006B2 (en) | 2018-04-04 | 2021-04-20 | Xencor, Inc. | Heterodimeric antibodies that bind fibroblast activation protein |
KR20210010862A (en) | 2018-04-18 | 2021-01-28 | 젠코어 인코포레이티드 | IL-15/IL-15Rα Fc-fusion protein and PD-1 targeting heterodimer fusion protein containing PD-1 antigen binding domain and uses thereof |
WO2019204655A1 (en) | 2018-04-18 | 2019-10-24 | Xencor, Inc. | Tim-3 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and tim-3 antigen binding domains |
CA3099419A1 (en) | 2018-05-04 | 2019-11-07 | Tagworks Pharmaceuticals B.V. | Tetrazines for high click conjugation yield in vivo and high click release yield |
CA3099421A1 (en) | 2018-05-04 | 2019-11-07 | Tagworks Pharmaceuticals B.V. | Compounds comprising a linker for increasing transcyclooctene stability |
GB201809746D0 (en) | 2018-06-14 | 2018-08-01 | Berlin Chemie Ag | Pharmaceutical combinations |
TW202019473A (en) | 2018-07-02 | 2020-06-01 | 美商安進公司 | Anti-steap1 antigen-binding protein |
JP2022503959A (en) | 2018-10-03 | 2022-01-12 | ゼンコア インコーポレイテッド | IL-12 heterodimer FC-fusion protein |
KR20210084546A (en) | 2018-10-29 | 2021-07-07 | 메르사나 테라퓨틱스, 인코포레이티드 | Cysteine Engineered Antibody-Drug Conjugates with Peptide-Containing Linkers |
EP3930850A1 (en) | 2019-03-01 | 2022-01-05 | Xencor, Inc. | Heterodimeric antibodies that bind enpp3 and cd3 |
US11535634B2 (en) | 2019-06-05 | 2022-12-27 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
IL289094A (en) | 2019-06-17 | 2022-02-01 | Tagworks Pharmaceuticals B V | Tetrazines for high click release speed and yield |
EP3983363B1 (en) | 2019-06-17 | 2024-04-10 | Tagworks Pharmaceuticals B.V. | Compounds for fast and efficient click release |
EP4041312A4 (en) | 2019-10-10 | 2023-12-20 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
US11919956B2 (en) | 2020-05-14 | 2024-03-05 | Xencor, Inc. | Heterodimeric antibodies that bind prostate specific membrane antigen (PSMA) and CD3 |
US20210402001A1 (en) * | 2020-06-30 | 2021-12-30 | David I. Cohen | Zinc Porters, and their Monoclonal Antibody Conjugates, for the Prevention and Treatment of COVID-19 (SARS-CoV-2), Other Infections, and Cancers |
US20230256114A1 (en) | 2020-07-07 | 2023-08-17 | Bionecure Therapeutics, Inc. | Novel maytansinoids as adc payloads and their use for the treatment of cancer |
AU2021329378A1 (en) | 2020-08-19 | 2023-03-23 | Xencor, Inc. | Anti-CD28 compositions |
CN117157319A (en) | 2021-03-09 | 2023-12-01 | Xencor股份有限公司 | Heterodimeric antibodies that bind CD3 and CLDN6 |
WO2022192586A1 (en) | 2021-03-10 | 2022-09-15 | Xencor, Inc. | Heterodimeric antibodies that bind cd3 and gpc3 |
WO2023031445A2 (en) | 2021-09-06 | 2023-03-09 | Veraxa Biotech Gmbh | Novel aminoacyl-trna synthetase variants for genetic code expansion in eukaryotes |
WO2023089314A1 (en) | 2021-11-18 | 2023-05-25 | Oxford Biotherapeutics Limited | Pharmaceutical combinations |
EP4186529A1 (en) | 2021-11-25 | 2023-05-31 | Veraxa Biotech GmbH | Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion |
WO2023094525A1 (en) | 2021-11-25 | 2023-06-01 | Veraxa Biotech Gmbh | Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion |
WO2023104941A1 (en) | 2021-12-08 | 2023-06-15 | European Molecular Biology Laboratory | Hydrophilic tetrazine-functionalized payloads for preparation of targeting conjugates |
WO2023158305A1 (en) | 2022-02-15 | 2023-08-24 | Tagworks Pharmaceuticals B.V. | Masked il12 protein |
WO2024013724A1 (en) | 2022-07-15 | 2024-01-18 | Pheon Therapeutics Ltd | Antibody-drug conjugates |
WO2024080872A1 (en) | 2022-10-12 | 2024-04-18 | Tagworks Pharmaceuticals B.V. | Strained bicyclononenes |
Family Cites Families (785)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US506333A (en) | 1893-10-10 | norwell | ||
US171217A (en) | 1875-12-21 | Improvement in convertible revolving harrows | ||
NL6613143A (en) | 1965-09-21 | 1967-03-22 | ||
US4177263A (en) | 1972-02-28 | 1979-12-04 | Research Corporation | Anti-animal tumor method |
US5562925A (en) | 1970-04-20 | 1996-10-08 | Research Corporation Tech. Inc. | Anti-tumor method |
CH605550A5 (en) | 1972-06-08 | 1978-09-29 | Research Corp | |
US3870719A (en) | 1972-06-16 | 1975-03-11 | Us Health | Synthesis of n-5-methyltetrahydrohomofolic acid and related reduced derivatives of homofolic acid |
US3896111A (en) | 1973-02-20 | 1975-07-22 | Research Corp | Ansa macrolides |
US4479957A (en) | 1973-04-02 | 1984-10-30 | Eli Lilly And Company | Use of vindesine in treating acute lymphatic leukemia and _other susceptible neoplasms |
US3965254A (en) | 1973-05-23 | 1976-06-22 | The Procter & Gamble Company | Compositions for the treatment of calcific tumors |
US3932417A (en) | 1973-10-24 | 1976-01-13 | Eli Lilly And Company | Dimeric indole alkaloid purification process |
US3887565A (en) | 1974-05-06 | 1975-06-03 | Lilly Co Eli | Vincadioline |
US4207416A (en) | 1974-09-05 | 1980-06-10 | Engelhard Minerals & Chemicals Corporation | Ethylenediamineplatinum(II) 2,4-dioxopyrimidine complexes |
US3954773A (en) | 1974-11-21 | 1976-05-04 | Eli Lilly And Company | 4-Desacetoxyvinblastine |
US4079121A (en) | 1974-12-13 | 1978-03-14 | Mobil Oil Corporation | Complexes of beta platinum chloride and ammonia |
FR2296418B1 (en) | 1974-12-30 | 1978-07-21 | Anvar | |
US3944554A (en) | 1975-01-09 | 1976-03-16 | Eli Lilly And Company | 4-Desacetoxy-3-hydroxyvinblastine |
JPS5198300A (en) | 1975-02-20 | 1976-08-30 | Kanputoteshin oyobi sonoruijitaino seizoho | |
US4279817A (en) | 1975-05-30 | 1981-07-21 | The United States Of America As Represented By The Department Of Health & Human Services | Method for producing dimer alkaloids |
US4029663A (en) | 1975-07-10 | 1977-06-14 | Eli Lilly And Company | Dimeric anhydro-vinca derivatives |
HU172708B (en) | 1975-10-28 | 1978-11-28 | Richter Gedeon Vegyeszet | New process for the separation of diindole alkaloids |
US4255417A (en) | 1976-08-04 | 1981-03-10 | Johnson Matthey, Inc. | Platinum compounds for the irradication of skin blemishes |
US4115418A (en) | 1976-09-02 | 1978-09-19 | Government Of The United States Of America | 1,2-diaminocyclohexane platinum (ii) complexes having antineoplastic activity |
JPS6041077B2 (en) | 1976-09-06 | 1985-09-13 | 喜徳 喜谷 | Cis platinum(2) complex of 1,2-diaminocyclohexane isomer |
USRE30560E (en) | 1976-12-06 | 1981-03-31 | Eli Lilly And Company | Oxazolidinedione derivatives of Vinca alkaloids |
US4096148A (en) | 1976-12-06 | 1978-06-20 | Eli Lilly And Company | Oxazolidinedione derivatives of Vinca alkaloids |
US4160767A (en) | 1976-12-06 | 1979-07-10 | Eli Lilly And Company | Vinca alkaloid intermediates |
USRE30561E (en) | 1976-12-06 | 1981-03-31 | Eli Lilly And Company | Vinca alkaloid intermediates |
US4175133A (en) | 1977-02-18 | 1979-11-20 | United States Of America | 1,2-Diaminocyclohexane platinum (II) complexes having antineoplastic activity against L1210 leukemia |
US4151042A (en) | 1977-03-31 | 1979-04-24 | Takeda Chemical Industries, Ltd. | Method for producing maytansinol and its derivatives |
US4162940A (en) | 1977-03-31 | 1979-07-31 | Takeda Chemical Industries, Ltd. | Method for producing Antibiotic C-15003 by culturing nocardia |
US4151185A (en) | 1977-05-02 | 1979-04-24 | Research Corporation | Complex or salt of a platinum (II) compound and a nitrogen containing polymer |
US4278660A (en) | 1977-05-02 | 1981-07-14 | Research Corporation | Complex or salt of a platinum (II) compound and a nitrogen containing polymer |
HU178084B (en) | 1977-05-31 | 1982-03-28 | Richter Gedeon Vegyeszet | New process for the extraction of native vindoline,catharantine,3',4'-anhydrovinblastine,leurosine and,if desired,of other diinodle alkaloids from vinca rosea l.drogue |
US4260609A (en) | 1977-06-01 | 1981-04-07 | Merck & Co., Inc. | Di- and tri- substituted thiazoles |
US4419351A (en) | 1977-06-03 | 1983-12-06 | Research Corporation | Platinum-dioxopyrimidine complexes |
US4137248A (en) | 1977-08-29 | 1979-01-30 | The United States Of America As Represented By The Department Of Health, Education And Welfare | Compound, 4-carboxyphthalato(1,2-diaminocyclohexane)-platinum(II) and alkali metal salts thereof |
JPS5829957B2 (en) | 1977-09-12 | 1983-06-25 | 喜徳 喜谷 | Novel platinum complex |
US4225529A (en) | 1977-10-19 | 1980-09-30 | Johnson, Matthey & Co., Limited | Compositions containing platinum |
US4203912A (en) | 1977-10-19 | 1980-05-20 | Johnson, Matthey & Co., Limited | Compositions containing platinum |
US4137230A (en) | 1977-11-14 | 1979-01-30 | Takeda Chemical Industries, Ltd. | Method for the production of maytansinoids |
US4159269A (en) | 1978-03-03 | 1979-06-26 | Eli Lilly And Company | Preparation of oxazolidinedione derivatives of Vinca alkaloids |
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
US4265814A (en) | 1978-03-24 | 1981-05-05 | Takeda Chemical Industries | Matansinol 3-n-hexadecanoate |
DE2967049D1 (en) | 1978-04-11 | 1984-07-19 | Efamol Ltd | Pharmaceutical and dietary composition comprising gamma-linolenic acids |
SE7903361L (en) | 1978-04-20 | 1979-10-21 | Johnson Matthey Co Ltd | COMPOSITIONS CONTAINING PLATINUM |
US4199504A (en) | 1978-05-15 | 1980-04-22 | Eli Lilly And Company | Bridged cathranthus alkaloid dimers |
US4208414A (en) | 1978-06-05 | 1980-06-17 | Eli Lilly And Company | Vinblastine in rheumatoid arthritis |
JPS6034958B2 (en) | 1978-09-02 | 1985-08-12 | 喜徳 喜谷 | New platinum complex |
JPS5562090A (en) | 1978-10-27 | 1980-05-10 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS5566585A (en) | 1978-11-14 | 1980-05-20 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164687A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
JPS55102583A (en) | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
US4291027A (en) | 1979-03-07 | 1981-09-22 | Engelhard Minerals & Chemicals Corp. | Method for treating tumors with ethylenediamine platinum (II) and 1,2-diaminocyclohexane-platinum (II) pyrophosphate complexes |
US4291023A (en) | 1979-03-07 | 1981-09-22 | Engelhard Minerals & Chemicals Corp. | Method for treating tumors using cis-diammineplatinum (II) organophosphate complexes |
US4234499A (en) | 1979-03-07 | 1980-11-18 | Engelhard Minerals & Chemicals Corporation | Cis-diammireplatinum(II) organophosphate complexes |
US4287187A (en) | 1979-03-07 | 1981-09-01 | Engelhard Minerals & Chemicals Corporation | Method for treating tumors with cis-diammineplatinum(II) orthophosphate complexes |
US4234500A (en) | 1979-03-07 | 1980-11-18 | Engelhard Minerals & Chemicals Corporation | Ethylenediamine platinum(II) and 1,2-diamino-cyclohexane platinum(II) pyrophosphate complexes |
US4248840A (en) | 1979-03-07 | 1981-02-03 | Engelhard Minerals And Chemicals Corporation | Cis-diammineplatinum(II) orthophosphate complexes |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS55164685A (en) | 1979-06-08 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
JPS55164686A (en) | 1979-06-11 | 1980-12-22 | Takeda Chem Ind Ltd | Novel maytansinoid compound and its preparation |
US4457926A (en) | 1979-06-20 | 1984-07-03 | Engelhard Corporation | Cis-Platinum(II) amine ascorbate complexes |
US4462998A (en) | 1979-06-20 | 1984-07-31 | Engelhard Corporation | Method of using a cis-platinum(II) amine ascorbate |
US4271085A (en) | 1979-06-20 | 1981-06-02 | Engelhard Minerals & Chemicals Corporation | Cis-platinum (II) amine lactate complexes |
US4399282A (en) | 1979-07-10 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives |
US4284579A (en) | 1979-07-17 | 1981-08-18 | The United States Of America As Represented By The Of The Department Of Health & Human Services | (N-Phosphonacetyl-L-aspartato)(1,2-diaminocyclchexane)platinum(II) or alkali metal salt |
US4309428A (en) | 1979-07-30 | 1982-01-05 | Takeda Chemical Industries, Ltd. | Maytansinoids |
US4273755A (en) | 1979-08-16 | 1981-06-16 | Mpd Technology Corporation | Preparation of platinum complexes |
US4335087A (en) | 1979-08-16 | 1982-06-15 | Mpd Technology Corporation | Process for preparing cis-Pt(NH3)2 Cl2 |
ZA805101B (en) | 1979-08-23 | 1981-08-26 | Johnson Matthey Co Ltd | Compositions containing platinium |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
EP0028683A1 (en) | 1979-09-21 | 1981-05-20 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PHO and production thereof |
JPS5645485A (en) | 1979-09-21 | 1981-04-25 | Takeda Chem Ind Ltd | Production of c-15003pnd |
US4302446A (en) | 1979-10-02 | 1981-11-24 | Bristol-Myers Company | Pharmaceutical compositions |
NL181434C (en) | 1980-01-03 | 1987-08-17 | Tno | PLATINUM (IV) DIAMINE COMPLEXES, AND THEIR PREPARATION AND APPLICATION. |
US4325950A (en) | 1980-02-19 | 1982-04-20 | The Research Corporation Of The University Of Hawaii | Platinum caffeine chloride anion complex and method |
US4428943A (en) | 1980-06-09 | 1984-01-31 | The United States Of America As Represented By The Department Of Health And Human Services | (N-Phosphonacetyl-L-aspartato) (1,2-diaminocyclohexane)platinum(II) or alkali metal salt |
US4407300A (en) | 1980-07-14 | 1983-10-04 | Davis Robert E | Potentiometric diagnosis of cancer in vivo |
US4594238A (en) | 1980-08-08 | 1986-06-10 | Regents Of University Of Minnesota | Inhibition of undesired effect of platinum compounds |
US4581224A (en) | 1980-08-08 | 1986-04-08 | Regents Of The University Of Minnesota | Inhibition of undesired effect of platinum compounds |
GR75317B (en) | 1980-09-03 | 1984-07-13 | Johnson Matthey Plc | |
WO1982001188A1 (en) | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
HU183234B (en) | 1980-10-17 | 1984-04-28 | Richter Gedeon Vegyeszet | Process for the enantioselective synthesis of optically active cys-14-oxo-e-homo-eburnan |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4399276A (en) | 1981-01-09 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | 7-Substituted camptothecin derivatives |
JPS57123198A (en) | 1981-01-23 | 1982-07-31 | Shionogi & Co Ltd | Novel platinum complex |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4563304A (en) | 1981-02-27 | 1986-01-07 | Pharmacia Fine Chemicals Ab | Pyridine compounds modifying proteins, polypeptides or polysaccharides |
NL8101026A (en) | 1981-03-03 | 1982-10-01 | Tno | PLATINADIAMINE COMPLEXES, A METHOD FOR PREPARING THE SAME, A METHOD FOR PREPARING A MEDICINAL PRODUCT USING SUCH PLATINADIAMINE COMPLEX FOR THE TREATMENT OF CANCER AND CONTAINED IN SUCH FORM. |
DE3269549D1 (en) | 1981-04-02 | 1986-04-10 | Atomic Energy Authority Uk | Improvements in or relating to the production of chemical compounds |
US4375432A (en) | 1981-05-12 | 1983-03-01 | Eli Lilly And Company | Method of preparing vincristine |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US4515954A (en) | 1981-08-24 | 1985-05-07 | American Cyanamid Company | Metal chelates of anthracene-9,10-bis-carbonylhydrazones |
US4414205A (en) | 1981-08-28 | 1983-11-08 | University Patents, Inc. | Cell growth inhibitory substances |
JPS5839685A (en) | 1981-09-04 | 1983-03-08 | Yakult Honsha Co Ltd | Novel camptothecin derivative and its preparation |
US4473692A (en) | 1981-09-04 | 1984-09-25 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
US5108987A (en) | 1982-02-25 | 1992-04-28 | Faulk Ward P | Conjugates of proteins with anti-tumor agents |
US4671958A (en) | 1982-03-09 | 1987-06-09 | Cytogen Corporation | Antibody conjugates for the delivery of compounds to target sites |
JPS58154582A (en) | 1982-03-10 | 1983-09-14 | Yakult Honsha Co Ltd | Novel camptothecin derivative and its preparation |
JPS58167592A (en) | 1982-03-26 | 1983-10-03 | Takeda Chem Ind Ltd | Novel maytansinoid |
US5087618A (en) | 1982-05-18 | 1992-02-11 | University Of Florida | Redox carriers for brain-specific drug delivery |
LU84664A1 (en) | 1983-02-25 | 1984-11-08 | Onmichem S A | ALKYL-4-INDOLONAPHTYRIDINES AND THEIR THERAPEUTIC APPLICATION |
US4486414A (en) | 1983-03-21 | 1984-12-04 | Arizona Board Of Reagents | Dolastatins A and B cell growth inhibitory substances |
US4476026A (en) | 1983-03-21 | 1984-10-09 | The Perkin-Elmer Corporation | Apparatus useful in identifying a solute |
USRE33071E (en) | 1983-03-28 | 1989-09-26 | Platinum bound to transferrin for use in the treatment of breast tumors | |
US4906646A (en) | 1983-03-31 | 1990-03-06 | Board Of Governors Of Wayne State University | Method and composition for the treatment of tumors by administering a platinum coordination compound and a calcium channel blocker compound of the dihydropyridine class |
US4720504A (en) | 1983-05-10 | 1988-01-19 | Andrulis Research Corporation | Use of bis-platinum complexes as antitumor agents |
US5059591B1 (en) | 1983-05-26 | 2000-04-25 | Liposome Co Inc | Drug preparations of reduced toxicity |
CA1237670A (en) | 1983-05-26 | 1988-06-07 | Andrew S. Janoff | Drug preparations of reduced toxicity |
JPS6019790A (en) | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | Novel camptothecin derivative |
US4544759A (en) | 1983-07-29 | 1985-10-01 | American Cyanamid Company | Platinum complexes of antitumor agents |
JPS6032799A (en) | 1983-07-29 | 1985-02-19 | Microbial Chem Res Found | Novel 4'-demethyl-4-epipodophyllotoxin derivative |
US4550169A (en) | 1983-11-21 | 1985-10-29 | American Cyanamid Company | Platinum chelates of 2-hydrazino-azoles |
US4567253A (en) | 1984-02-03 | 1986-01-28 | Tony Durst | 2-Substituted derivatives of podophyllotoxin and etoposide |
US4522750A (en) | 1984-02-21 | 1985-06-11 | Eli Lilly And Company | Cytotoxic compositions of transferrin coupled to vinca alkaloids |
IL74449A (en) | 1984-03-01 | 1988-07-31 | Us Commerce | Tetrahalo-1,2-cyclohexane-diamino platinum complexes and anti-neoplastic compositions comprising them |
US4562275A (en) | 1984-03-23 | 1985-12-31 | Bristol-Myers Co. | Antitumor platinum complexes |
US4593034A (en) | 1984-04-06 | 1986-06-03 | A. H. Robins Company, Inc. | 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides |
US4843161A (en) | 1984-06-01 | 1989-06-27 | Massachusetts Institute Of Technology | Platinum-intercalative complexes for the treatment of cancer |
GB8416048D0 (en) | 1984-06-22 | 1984-07-25 | Johnson Matthey Plc | Anti-tumour compounds of platinum |
EP0169645A1 (en) | 1984-06-27 | 1986-01-29 | Johnson Matthey Public Limited Company | Platinum co-ordination compounds |
US4952676A (en) | 1984-06-27 | 1990-08-28 | Johnson Matthey Plc | Monoclonal antibody-platinum co-ordination compound complex |
ATE63919T1 (en) | 1984-06-27 | 1991-06-15 | Johnson Matthey Plc | PLATINUM COORDINATION CONNECTIONS. |
US4956454A (en) | 1984-06-27 | 1990-09-11 | Johnson Matthey Plc | Monoclonal antibody - platinum co-ordination compound complex |
US4645661A (en) | 1984-06-29 | 1987-02-24 | St. Jude Children's Research Hospital | Method for alleviating cisplatin-induced nephrotoxicity and dithiocarbamate compounds for effecting same |
US4767611A (en) | 1984-07-03 | 1988-08-30 | Gordon Robert T | Method for affecting intracellular and extracellular electric and magnetic dipoles |
HU193809B (en) | 1984-09-12 | 1987-12-28 | Chugai Pharmaceutical Co Ltd | Process for producing new platinum complexes |
US4665210A (en) | 1984-12-17 | 1987-05-12 | American Cyanamid Company | Platinum complexes of aliphatic tricarboxylic acids |
US4587331A (en) | 1984-12-17 | 1986-05-06 | American Cyanamid Company | Platinum complexes of polyhydroxylated alkylamines and 2-polyhydroxylated alkyl-1,2-diaminoethanes |
US4739087A (en) | 1985-01-10 | 1988-04-19 | Bristol-Myers Company | Antineoplastic platinum complexes |
JPS61227590A (en) | 1985-04-02 | 1986-10-09 | Microbial Chem Res Found | Novel 4'-epopodophyllotoxin derivative |
US5086182A (en) | 1985-04-12 | 1992-02-04 | Bristol-Myers Company | Intermediates for the production of epipodophyllotoxin and related compounds and processes for the preparation and use thereof |
US4795819A (en) | 1985-04-12 | 1989-01-03 | Bristol-Myers Company | Intermediates for the production of epipodophyllotoxin and related compounds and processes for the preparation and use thereof |
US4644072A (en) | 1985-04-12 | 1987-02-17 | Bristol-Myers Company | Intermediates for the production of epipodophyllotoxin and related compounds and processes for the preparation and use thereof |
US4728740A (en) | 1985-04-12 | 1988-03-01 | Bristol-Myers Company | Intermediates for the production of epipodophylotoxin and related compounds and processes for the preparation and use thereof |
US5011948A (en) | 1985-04-12 | 1991-04-30 | Bristol-Myers Company | Intermediates for the production of epipodophyllotoxin and related compounds and processes for the preparation and use thereof |
US4866189A (en) | 1985-04-12 | 1989-09-12 | Bristol-Myers Company | Intermediates for the production of epipodophyllotoxin and related compounds and processes for the preparation and use thereof |
US5120862A (en) | 1985-04-12 | 1992-06-09 | Bristol-Myers Company | Intermediates for the production of epipodophyllotoxin and related compounds and processes for the preparation and use thereof |
US4686104A (en) | 1985-04-30 | 1987-08-11 | Sloan-Kettering Institute For Cancer Research | Methods of treating bone disorders |
US4895727A (en) | 1985-05-03 | 1990-01-23 | Chemex Pharmaceuticals, Inc. | Pharmaceutical vehicles for exhancing penetration and retention in the skin |
US4667030A (en) | 1985-06-17 | 1987-05-19 | Eli Lilly And Company | Hydrazide succinimide derivatives of antineoplastic indole-dihydroindole alkaloids |
US5776093A (en) | 1985-07-05 | 1998-07-07 | Immunomedics, Inc. | Method for imaging and treating organs and tissues |
US5525338A (en) | 1992-08-21 | 1996-06-11 | Immunomedics, Inc. | Detection and therapy of lesions with biotin/avidin conjugates |
JPH0665648B2 (en) | 1985-09-25 | 1994-08-24 | 塩野義製薬株式会社 | Stable freeze-drying formulation of platinum anticancer substance |
US5041581A (en) | 1985-10-18 | 1991-08-20 | The University Of Texas System Board Of Regents | Hydrophobic cis-platinum complexes efficiently incorporated into liposomes |
US5117022A (en) | 1985-10-18 | 1992-05-26 | The Board Of Regents, The University Of Texas System | Hydrophobic cis-platinum complexes efficiently incorporated into liposomes |
GB8525689D0 (en) | 1985-10-18 | 1985-11-20 | Johnson Mathey Plc | Platinum coordination compounds |
US5384127A (en) | 1985-10-18 | 1995-01-24 | Board Of Regents, The University Of Texas System | Stable liposomal formulations of lipophilic platinum compounds |
CA1275922C (en) | 1985-11-28 | 1990-11-06 | Harunobu Amagase | Treatment of cancer |
EP0232693A3 (en) | 1985-12-16 | 1988-04-06 | La Region Wallonne | Conjugates of vinblastine and its derivatives, process for their preparation and pharmaceutical compositions containing them |
IL77334A (en) | 1985-12-16 | 1991-04-15 | Univ Bar Ilan | Synthesis of 9-epipodophyllotoxin glucoside derivatives and some novel intermediates therefor |
LU86212A1 (en) | 1985-12-16 | 1987-07-24 | Omnichem Sa | NOVEL CONJUGATES OF VINBLASTINE AND DERIVATIVES THEREOF, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US4970324A (en) | 1985-12-24 | 1990-11-13 | Hoeschele James D | Aminoalkyl-substituted azetidine platinum(II) complexes |
US5116831A (en) | 1985-12-24 | 1992-05-26 | Warner-Lambert Company | Aminoalkyl-substituted cycloalkylamine platinum (II) complexes |
EP0233101A1 (en) | 1986-01-13 | 1987-08-19 | Ire-Celltarg S.A. | Vinblastine derivatives and pharmaceutical compositions containing them |
IL81264A (en) | 1986-01-30 | 1990-11-05 | Takeda Chemical Industries Ltd | Quinone derivatives,their production and pharmaceutical compositions containing them |
US7838216B1 (en) | 1986-03-05 | 2010-11-23 | The United States Of America, As Represented By The Department Of Health And Human Services | Human gene related to but distinct from EGF receptor gene |
US5395924A (en) | 1986-03-20 | 1995-03-07 | Dana-Farber Cancer Institute, Inc. | Blocked lectins; methods and affinity support for making the same using affinity ligands; and method of killing selected cell populations having reduced non-selective cytotoxicity |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4765972A (en) | 1986-04-03 | 1988-08-23 | The United States Of America As Represented By The Department Of Health And Human Services | Vinca alkaloid photoactive analogs and their uses |
US5078137A (en) | 1986-05-05 | 1992-01-07 | Massachusetts Institute Of Technology | Apparatus for measuring oxygen partial pressure and temperature, in living tissue |
US5100877A (en) | 1986-05-21 | 1992-03-31 | Kuraray Co., Ltd. | Platinum containing pullulan derivatives and pharmaceutical compositions comprising the same |
US4801688A (en) | 1986-05-27 | 1989-01-31 | Eli Lilly And Company | Hydrazone immunoglobulin conjugates |
US5182368A (en) | 1986-06-13 | 1993-01-26 | Ledbetter Jeffrey A | Ligands and methods for augmenting B-cell proliferation |
FR2601675B1 (en) | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | TAXOL DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
GB8620917D0 (en) | 1986-08-29 | 1986-10-08 | Davidson B C | Platinum derivatives & cancer treatments |
US5869620A (en) | 1986-09-02 | 1999-02-09 | Enzon, Inc. | Multivalent antigen-binding proteins |
ATE53217T1 (en) | 1986-10-03 | 1990-06-15 | Asta Pharma Ag | DIAMININE-PLATINUM (II) COMPLEX COMPOUNDS WITH A HYDROXYLATED 2-PHENYL-INDOLE RING. |
KR950013762B1 (en) | 1986-10-07 | 1995-11-15 | Boehringer Mannheim Italia | Pharmaceutical compositions having antineoplastic activity |
US4906755A (en) | 1986-11-03 | 1990-03-06 | Merrell Dow Pharmaceuticals Inc. | Esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one and related compounds |
US5011959A (en) | 1986-11-17 | 1991-04-30 | The Board Of Regents, The University Of Texas System | 1,2-diaminocyclohexane-platinum complexes with antitumor activity |
US4968603A (en) | 1986-12-31 | 1990-11-06 | The Regents Of The University Of California | Determination of status in neoplastic disease |
US4916217A (en) | 1987-01-08 | 1990-04-10 | Bristol-Myers Company | Phosphorus containing derivatives of epipodophyllotoxin |
US5047528A (en) | 1987-01-22 | 1991-09-10 | University Of Bristish Columbia | Process of synthesis of vinblastine and vincristine |
US5057302A (en) | 1987-02-13 | 1991-10-15 | Abbott Laboratories | Bifunctional chelating agents |
US5256653A (en) | 1987-02-19 | 1993-10-26 | Henkel Kommanditgesellschaft Auf Aktien | Pharmaceutical preparations containing platinum complexes/phosphonic acid liquid and processes for their use |
MX9203808A (en) | 1987-03-05 | 1992-07-01 | Liposome Co Inc | HIGH DRUG CONTENT FORMULATIONS: LIPID, FROM LIPOSOMIC-ANTINEOPLASTIC AGENTS. |
EP0281463A3 (en) | 1987-03-06 | 1989-01-25 | Sumitomo Pharmaceuticals Company, Limited | Platinum complex, process for its preparation and pharmaceutical composition including such a complex |
US5079600A (en) | 1987-03-06 | 1992-01-07 | Schnur Joel M | High resolution patterning on solid substrates |
US4981968A (en) | 1987-03-31 | 1991-01-01 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
US5364858A (en) | 1987-03-31 | 1994-11-15 | Research Triangle Institute | Camptothecin analogs as potent inhibitors of topoisomerase I |
US5053512A (en) | 1987-04-14 | 1991-10-01 | Research Triangle Institute | Total synthesis of 20(S) and 20(R)-camptothecin and compthothecin derivatives |
US5244903A (en) | 1987-03-31 | 1993-09-14 | Research Triangle Institute | Camptothecin analogs as potent inhibitors of topoisomerase I |
US5106742A (en) | 1987-03-31 | 1992-04-21 | Wall Monroe E | Camptothecin analogs as potent inhibitors of topoisomerase I |
US4894456A (en) | 1987-03-31 | 1990-01-16 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
US5122526A (en) | 1987-03-31 | 1992-06-16 | Research Triangle Institute | Camptothecin and analogs thereof and pharmaceutical compositions and method using them |
US5227380A (en) | 1987-03-31 | 1993-07-13 | Research Triangle Institute | Pharmaceutical compositions and methods employing camptothecins |
US4921963A (en) | 1987-04-13 | 1990-05-01 | British Columbia Cancer Foundation | Platinum complexes with one radiosensitizing ligand |
US5026694A (en) | 1987-04-13 | 1991-06-25 | The British Columbia Cancer Foundation | Platinum complexes with one radiosensitizing ligand |
US5180722A (en) | 1987-04-14 | 1993-01-19 | Research Triangle Institute | 10,11-methylenedioxy-20(RS)-camptothecin and 10,11-methylenedioxy-20(S)-camptothecin analogs |
US5122606A (en) | 1987-04-14 | 1992-06-16 | Research Triangle Institute | 10,11-methylenedioxy camptothecins |
US5340817A (en) | 1987-04-14 | 1994-08-23 | Research Triangle Institute | Method of treating tumors with anti-tumor effective camptothecin compounds |
US5049668A (en) | 1989-09-15 | 1991-09-17 | Research Triangle Institute | 10,11-methylenedioxy-20(RS)-camptothecin analogs |
ES2061646T3 (en) | 1987-05-08 | 1994-12-16 | Sankyo Co | ANTITUMORAL PLATINUM COMPLEXES, THEIR PREPARATION AND USE IN THERAPEUTICS. |
US4853467A (en) | 1987-05-19 | 1989-08-01 | Bristol-Myers Company | Nitrogen containing derivatives of epipodophyllotoxin glucosides |
US5811119A (en) | 1987-05-19 | 1998-09-22 | Board Of Regents, The University Of Texas | Formulation and use of carotenoids in treatment of cancer |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
US4927966A (en) | 1987-06-04 | 1990-05-22 | The Research Foundation Of State University Of New York | 2-mercaptomethylglutaric acid derivatives |
US5010103A (en) | 1987-06-04 | 1991-04-23 | The Research Foundation Of State University Of N.Y. | Compositions and methods comprising 2-mercaptomethylglutaric acid derivatives |
US4939255A (en) | 1987-06-24 | 1990-07-03 | Daiichi Pharmaceutical Co., Ltd. | Hexa-cyclic camptothecin derivatives |
CA1332413C (en) | 1987-06-25 | 1994-10-11 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
US4874851A (en) | 1987-07-01 | 1989-10-17 | Bristol-Meyers Company | 3',4'-dinitrogen substituted epipodophyllotoxin glucoside derivatives |
US4816444A (en) | 1987-07-10 | 1989-03-28 | Arizona Board Of Regents, Arizona State University | Cell growth inhibitory substance |
US5053226A (en) | 1987-07-15 | 1991-10-01 | Board Of Regents, The University Of Texas System | Monoclonal antibodies binding platinum complexes |
US4895936A (en) | 1987-07-17 | 1990-01-23 | Georgetown University | Platinum pharmaceuticals |
US4956459A (en) | 1987-07-17 | 1990-09-11 | Georgetown University | Platinum compounds suitable for use as pharmaceuticals |
US4895935A (en) | 1987-07-17 | 1990-01-23 | Georgetown University | Platinum pharmaceuticals |
US4904768A (en) | 1987-08-04 | 1990-02-27 | Bristol-Myers Company | Epipodophyllotoxin glucoside 4'-phosphate derivatives |
ZA885929B (en) | 1987-08-25 | 1989-04-26 | Oxi Gene Inc | Agents for use in tumor or cancer cell killing therapy |
US4888419A (en) | 1987-08-31 | 1989-12-19 | Bristol-Myers Company | 3'-demethoxyepipodophyllotoxin glucoside derivatives |
US4981979A (en) | 1987-09-10 | 1991-01-01 | Neorx Corporation | Immunoconjugates joined by thioether bonds having reduced toxicity and improved selectivity |
US4943579A (en) | 1987-10-06 | 1990-07-24 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Water soluble prodrugs of camptothecin |
FR2623504B1 (en) | 1987-11-25 | 1990-03-09 | Adir | NOVEL N- (VINBLASTINOYL-23) DERIVATIVES OF 1-AMINO METHYLPHOSPHONIC ACID, PROCESSES FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US5824311A (en) | 1987-11-30 | 1998-10-20 | Trustees Of The University Of Pennsylvania | Treatment of tumors with monoclonal antibodies against oncogene antigens |
US5004758A (en) | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
US4936465A (en) | 1987-12-07 | 1990-06-26 | Zoeld Tibor | Method and apparatus for fast, reliable, and environmentally safe dispensing of fluids, gases and individual particles of a suspension through pressure control at well defined parts of a closed flow-through system |
US5378803A (en) | 1987-12-11 | 1995-01-03 | Sterling Winthrop Inc. | Azole-fused peptides and processes for preparation thereof |
US4935504A (en) | 1987-12-18 | 1990-06-19 | Bristol-Myers Company | Epipodophyllotoxin glucoside 4'-acyl derivatives |
US5292497A (en) | 1987-12-22 | 1994-03-08 | U.S. Bioscience, Inc. | Method of reducing chemotherapy toxicity using (methylaminopropylamino)propyl dihydrogen phosphorothioate |
US5720937A (en) | 1988-01-12 | 1998-02-24 | Genentech, Inc. | In vivo tumor detection assay |
WO1989006692A1 (en) | 1988-01-12 | 1989-07-27 | Genentech, Inc. | Method of treating tumor cells by inhibiting growth factor receptor function |
JPH0615547B2 (en) | 1988-01-20 | 1994-03-02 | 株式会社ヤクルト本社 | Novel camptothecin derivative |
US4958010A (en) | 1988-02-16 | 1990-09-18 | Bristol-Myers Company | Epipodophyllotoxin glucoside lactam derivatives |
US5002755A (en) | 1988-02-18 | 1991-03-26 | Vanderbilt University | Method of controlling nephrotoxicity of anti-tumor plaintum compounds |
US5011846A (en) | 1988-02-23 | 1991-04-30 | Merrell Dow Pharmaceuticals Inc. | Medicament compositions derived from quinolizine and quinolizinone and methods of use thereof |
GB8806224D0 (en) | 1988-03-16 | 1988-04-13 | Johnson Matthey Plc | Platinum chemotherapeutic product |
NO169490C (en) | 1988-03-24 | 1992-07-01 | Takeda Chemical Industries Ltd | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PYRROLOPYRIMIDINE DERIVATIVES |
USRE34277E (en) | 1988-04-06 | 1993-06-08 | Centre National De La Recherche Scientifique | Process for preparing taxol |
FR2629818B1 (en) | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF TAXOL |
FR2629819B1 (en) | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF BACCATIN III AND DESACETYL-10 BACCATIN III DERIVATIVES |
US4923876A (en) | 1988-04-18 | 1990-05-08 | Cetus Corporation | Vinca alkaloid pharmaceutical compositions |
GB8810173D0 (en) | 1988-04-29 | 1988-06-02 | Norsk Hydro As | Pharmaceutical compositions with anti-cancer activity & method for treatment of cancer |
JP3038339B2 (en) | 1988-05-02 | 2000-05-08 | ザイナクシス・テクノロジーズ・インコーポレーテッド | Compounds that bind bioaffecting substances to the surface membrane of bioparticles |
US4931553A (en) | 1988-05-11 | 1990-06-05 | Gill Devinder S | Platinum-polymer complexes and their use as antitumor agents |
US4952408A (en) | 1988-05-23 | 1990-08-28 | Georgetown University | Liposome-encapsulated vinca alkaloids and their use in combatting tumors |
US4946835A (en) | 1988-07-15 | 1990-08-07 | Merck & Co., Inc. | Antifungal fermentation product and method |
US5084002A (en) | 1988-08-04 | 1992-01-28 | Omnitron International, Inc. | Ultra-thin high dose iridium source for remote afterloader |
DE3827974A1 (en) | 1988-08-18 | 1990-02-22 | Boehringer Mannheim Gmbh | COMBINATION PREPARATIONS OF PROTEINKINASE-C INHIBITORS WITH LIPIDS, LIPID ANALOGS, CYTOSTATICA OR INHIBITORS OF PHOSPHOLIPASES |
US4912204A (en) | 1988-09-06 | 1990-03-27 | Bristol-Myers Company | Fluoro-substituted epipodophyllotoxin glucosides |
US5705334A (en) | 1988-09-22 | 1998-01-06 | Massachusetts Institute Of Technology | Uses for DNA structure-specific recognition protein |
US5359047A (en) | 1988-09-22 | 1994-10-25 | Massachusetts Institute Of Technology | Nucleic acids encoding DNA structure-specific recognition protein and uses therefor |
US5213788A (en) | 1988-09-29 | 1993-05-25 | Ranney David F | Physically and chemically stabilized polyatomic clusters for magnetic resonance image and spectral enhancement |
US4912072A (en) | 1988-10-21 | 1990-03-27 | Gas Research Institute | Method for selective internal platinization of porous aluminosilicates |
US5076973A (en) | 1988-10-24 | 1991-12-31 | Arizona Board Of Regents | Synthesis of dolastatin 3 |
US5041578A (en) | 1988-11-22 | 1991-08-20 | Board Of Regents, The University Of Texas System | Water soluble 1,2-diaminocyclohexane platinum (IV) complexes as antitumor agents |
US5434256A (en) | 1988-11-22 | 1995-07-18 | Board Of Regents, The University Of Texas System | Diamine platinum complexes as antitumor agents |
US5393909A (en) | 1988-11-22 | 1995-02-28 | Board Of Regents, The University Of Texas System | Diamine platinum complexes as antitumor agents |
US5612019A (en) | 1988-12-19 | 1997-03-18 | Gordon, Deceased; David | Diagnosis and treatment of HIV viral infection using magnetic metal transferrin particles |
US5242824A (en) | 1988-12-22 | 1993-09-07 | Oncogen | Monoclonal antibody to human carcinomas |
US5217713A (en) | 1988-12-27 | 1993-06-08 | Takeda Chemical Industries, Ltd. | Cytotoxic bispecific monoclonal antibody, its production and use |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US4946954A (en) | 1989-01-17 | 1990-08-07 | Georgetown University | Platinum pharmaceutical agents |
US4978744A (en) | 1989-01-27 | 1990-12-18 | Arizona Board Of Regents | Synthesis of dolastatin 10 |
JPH04502162A (en) | 1989-02-01 | 1992-04-16 | インスチツート、フジチェスコイ、ヒミー、イメーニ、エル、ベー、ピサルゼフスコボ、アカデミー、ナウク、ウクラインスコイ、エスエスエル | Platinum 2 derivative with polymethylsiloxane, its production method and antitumor agent based thereon |
US5676978A (en) | 1989-02-14 | 1997-10-14 | Amira, Inc. | Methods of inhibiting undesirable cell growth using a combination of a cyclocreatine compound and a hyperplastic inhibitory agent |
US5300500A (en) | 1989-02-23 | 1994-04-05 | The University Of North Carolina At Chapel Hill | 4 beta-amino podophyllotoxin analog compounds and methods |
US4985416A (en) | 1989-03-13 | 1991-01-15 | Dana Farber Cancer Institute, Inc. | Platinum complexes of azodiazonium dyes as anti-tumor agents |
US5019504A (en) | 1989-03-23 | 1991-05-28 | The United States Of America As Represented By The Secretary Of Agriculture | Production of taxol or taxol-like compounds in cell culture |
US5004593A (en) | 1989-04-17 | 1991-04-02 | Mayo Foundation For Medical Education And Research | Hexamethylmelamine formulation exhibiting reduced neurotoxicity |
IT1230145B (en) | 1989-05-05 | 1991-10-14 | Boehringer Biochemia Srl | RUTHENIUM (III) COMPLEXES AS ANTINEOPLASTIC AGENTS. |
US5162115A (en) | 1989-05-09 | 1992-11-10 | Pietronigro Dennis D | Antineoplastic solution and method for treating neoplasms |
US4879278A (en) | 1989-05-16 | 1989-11-07 | Arizona Board Of Regents | Isolation and structural elucidation of the cytostatic linear depsipeptide dolastatin 15 |
US4986988A (en) | 1989-05-18 | 1991-01-22 | Arizona Board Of Regents | Isolation and structural elucidation of the cytostatic linear depsipeptides dolastatin 13 and dehydrodolastatin 13 |
US4965348A (en) | 1989-05-19 | 1990-10-23 | Bristol-Myers Company | Dimeric epipodophyllotoxin glucoside derivatives |
US5175315A (en) | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
MY110249A (en) | 1989-05-31 | 1998-03-31 | Univ Florida State | Method for preparation of taxol using beta lactam |
US4994591A (en) | 1989-06-02 | 1991-02-19 | The Research Foundation Of State University Of Ny | Platinum complexes derived from b-silyamines |
US5036055A (en) | 1989-06-07 | 1991-07-30 | Bristol-Myers Company | Acylated derivatives of etoposide |
GB8914061D0 (en) | 1989-06-19 | 1989-08-09 | Wellcome Found | Agents for potentiating the effects of antitumour agents and combating multiple drug resistance |
US5208238A (en) | 1989-06-19 | 1993-05-04 | Burroughs Wellcome Company | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
GB8914060D0 (en) | 1989-06-19 | 1989-08-09 | Wellcome Found | Agents for potentiating the effects of antitumour agents and combating multiple drug resistance |
GB8914040D0 (en) | 1989-06-19 | 1989-08-09 | Wellcome Found | Agents for potentiating the effects of antitumour agents and combating multiple drug resistance |
US5705157A (en) | 1989-07-27 | 1998-01-06 | The Trustees Of The University Of Pennsylvania | Methods of treating cancerous cells with anti-receptor antibodies |
FR2651348B1 (en) | 1989-08-04 | 1993-01-22 | Adir | |
US5443816A (en) | 1990-08-08 | 1995-08-22 | Rhomed Incorporated | Peptide-metal ion pharmaceutical preparation and method |
US5460785A (en) | 1989-08-09 | 1995-10-24 | Rhomed Incorporated | Direct labeling of antibodies and other protein with metal ions |
US5066645A (en) | 1989-09-01 | 1991-11-19 | Bristol-Myers Company | Epipodophyllotoxin altroside derivatives |
ATE211142T1 (en) | 1989-09-15 | 2002-01-15 | Res Triangle Inst | METHOD FOR PRODUCING 10,11-METHYLENEDIOXY-20(RS)-CAMPTOTHECINE AND 10,11-METHYLENEDIOXY-20(S)-CAMPTOTHECIN ANALOG |
CA2026147C (en) * | 1989-10-25 | 2006-02-07 | Ravi J. Chari | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5208020A (en) * | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5552154A (en) | 1989-11-06 | 1996-09-03 | The Stehlin Foundation For Cancer Research | Method for treating cancer with water-insoluble s-camptothecin of the closed lactone ring form and derivatives thereof |
HU204995B (en) | 1989-11-07 | 1992-03-30 | Richter Gedeon Vegyeszet | Process for producing pharmaceutical composition comprising alkaloid with bis-indole skeleton, with antitumour activity and suitable fr parenteral purposes |
US5138036A (en) | 1989-11-13 | 1992-08-11 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Isolation and structural elucidation of the cytostatic cyclodepsipeptide dolastatin 14 |
US5015744A (en) | 1989-11-14 | 1991-05-14 | Florida State University | Method for preparation of taxol using an oxazinone |
US5136060A (en) | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
US5034380A (en) | 1989-11-20 | 1991-07-23 | Bristol-Myers Squibb Company | Alkoxymethylidene epipodophyllotoxin glucosides |
US5258376A (en) | 1989-11-22 | 1993-11-02 | Bernstein Lawrence R | Pharmaceutical compositions of gallium complexes of 3-hydroxy-4-pyrones |
US5183884A (en) | 1989-12-01 | 1993-02-02 | United States Of America | Dna segment encoding a gene for a receptor related to the epidermal growth factor receptor |
AU639804B2 (en) | 1989-12-12 | 1993-08-05 | Toray Industries, Inc. | Novel platinum (ii) complex and drug for treating malignant tumor |
US5580575A (en) | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
US5542935A (en) | 1989-12-22 | 1996-08-06 | Imarx Pharmaceutical Corp. | Therapeutic delivery systems related applications |
US5469854A (en) | 1989-12-22 | 1995-11-28 | Imarx Pharmaceutical Corp. | Methods of preparing gas-filled liposomes |
US5585112A (en) | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
KR910014122A (en) | 1990-01-19 | 1991-08-31 | 디께다 가즈히꼬 | Lyophilized Formulation of Etoposide-2-dimethylamino Compound |
US5028726A (en) | 1990-02-07 | 1991-07-02 | The University Of Vermont And State Agricultural College | Platinum amine sulfoxide complexes |
WO1991015124A1 (en) | 1990-04-10 | 1991-10-17 | The University Of Vermont | Modulator agent and use thereof |
US5238955A (en) | 1990-04-10 | 1993-08-24 | Asta Pharma Ag | Ethylene-substituted phenylalkylethylenediamine-platinum (II or IV) derivatives and phenylalkylethylenediamines |
US5081234A (en) | 1990-04-30 | 1992-01-14 | Bristol-Myers Squibb Co. | 4'-demethylepipodophyllotoxin glycosides |
FR2662440B1 (en) | 1990-05-22 | 1992-07-31 | Rhone Poulenc Sante | PROCESS FOR THE STEREOSELECTIVE PREPARATION OF PHENYLISOSERIN DERIVATIVES. |
US4997931A (en) | 1990-06-11 | 1991-03-05 | Bristol-Myers Squibb Company | Epipodophyllotoxin glycosides |
GB9017024D0 (en) | 1990-08-03 | 1990-09-19 | Erba Carlo Spa | New linker for bioactive agents |
US5091368A (en) | 1990-08-08 | 1992-02-25 | Harbor Branch Oceanographic Institution, Inc. | Biologically active compounds from blue-green algae |
WO1992005785A1 (en) | 1990-09-28 | 1992-04-16 | Smithkline Beecham Corporation | Water soluble camptothecin analogues, processes and methods |
US5147294A (en) | 1990-10-01 | 1992-09-15 | Trustees Of Boston University | Therapeutic method for reducing chronic pain in a living subject |
US5475120A (en) | 1990-11-02 | 1995-12-12 | University Of Florida | Method for the isolation and purification of taxol and its natural analogues |
US5380916A (en) | 1990-11-02 | 1995-01-10 | University Of Florida | Method for the isolation and purification of taxane derivatives |
JPH04185601A (en) | 1990-11-20 | 1992-07-02 | Unitika Ltd | Sustained release preparation containing platinum anticancer drug |
MX9102128A (en) | 1990-11-23 | 1992-07-08 | Rhone Poulenc Rorer Sa | DERIVATIVES OF TAXANE, PROCEDURE FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION THAT CONTAINS THEM |
US5561136A (en) | 1990-12-13 | 1996-10-01 | Merrell Pharmaceuticals Inc. | Method of treating cancer by conjunctive therapy with N,N'-bis[ethylamino)propyl]-1,7-heptanediamine and a cytotoxic agent |
US5191082A (en) | 1990-12-20 | 1993-03-02 | North Carolina State University | Camptothecin intermediate and method of making camptothecin intermediates |
US5200524A (en) | 1990-12-20 | 1993-04-06 | North Carolina State University | Camptothecin intermediates and method of making same |
US5162532A (en) | 1990-12-20 | 1992-11-10 | North Carolina State University | Intermediates and method of making camptothecin and camptothecin analogs |
US5272056A (en) | 1991-01-03 | 1993-12-21 | The Research Foundation Of State University Of New York | Modification of DNA and oligonucleotides using metal complexes of polyaza ligands |
KR100220538B1 (en) | 1991-01-11 | 1999-09-15 | 뮈쉘 쥐르밀 | Acridine derivatives |
US5684168A (en) | 1991-01-17 | 1997-11-04 | Rhone-Poulenc Rorer S.A. | β-phenylisoserine-(2R,3S), salts, preparation and use thereof |
TW221441B (en) | 1991-01-25 | 1994-03-01 | Taiho Pharmaceutical Co Ltd | |
US5399363A (en) | 1991-01-25 | 1995-03-21 | Eastman Kodak Company | Surface modified anticancer nanoparticles |
JPH06505991A (en) | 1991-02-25 | 1994-07-07 | デビオファルム ソシエテ アノニム | Drugs to suppress multidrug resistance in cancer |
US5171217A (en) | 1991-02-28 | 1992-12-15 | Indiana University Foundation | Method for delivery of smooth muscle cell inhibitors |
GB9105037D0 (en) | 1991-03-09 | 1991-04-24 | Johnson Matthey Plc | Improvements in chemical compounds |
US5194635A (en) | 1991-03-18 | 1993-03-16 | Virginia Tech Intellectual Properties, Inc. | Rearranged taxol compounds and method of using in testing of in vivo activity |
AU654990B2 (en) | 1991-03-23 | 1994-12-01 | Sunkyong Industries Ltd. | Novel platinum(II) complex and processes for preparing the same |
DE69229267T2 (en) | 1991-04-19 | 1999-12-16 | Univ Mississippi University | METHOD AND PREPARATIONS FOR INSULATING TAXANES |
IL101943A0 (en) | 1991-05-24 | 1992-12-30 | Genentech Inc | Structure,production and use of heregulin |
WO1994004679A1 (en) | 1991-06-14 | 1994-03-03 | Genentech, Inc. | Method for making humanized antibodies |
DE122004000008I1 (en) | 1991-06-14 | 2005-06-09 | Genentech Inc | Humanized heregulin antibody. |
US5407653A (en) | 1991-06-26 | 1995-04-18 | Brigham And Women's Hospital | Evaluation of the multidrug resistance phenotype |
US5766635A (en) | 1991-06-28 | 1998-06-16 | Rhone-Poulenc Rorer S.A. | Process for preparing nanoparticles |
SE9102074D0 (en) | 1991-07-03 | 1991-07-03 | Kabi Pharmacia Ab | TOMOUR ANTIGEN SPECIFIC ANTIBODY |
US5714512A (en) | 1991-07-08 | 1998-02-03 | Rhone-Poulenc Rorer, S.A. | Compositions containing taxane derivatives |
US5750561A (en) | 1991-07-08 | 1998-05-12 | Rhone-Poulenc Rorer, S.A. | Compositions containing taxane derivatives |
FR2678833B1 (en) | 1991-07-08 | 1995-04-07 | Rhone Poulenc Rorer Sa | NEW PHARMACEUTICAL COMPOSITIONS BASED ON DERIVATIVES OF THE TAXANE CLASS. |
US5698582A (en) | 1991-07-08 | 1997-12-16 | Rhone-Poulenc Rorer S.A. | Compositions containing taxane derivatives |
FR2678930B1 (en) | 1991-07-10 | 1995-01-13 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF DERIVATIVES OF BACCATIN III AND DESACETYL-10 BACCATIN III. |
US5220016A (en) | 1991-07-29 | 1993-06-15 | Board Of Regents, The University Of Texas System | Synthesis of navelbine analogs |
KR0185440B1 (en) | 1991-08-09 | 1999-04-01 | 야마구찌 다까시 | Tetrapeptide derivative having antitumor activity |
ATE176328T1 (en) | 1991-08-22 | 1999-02-15 | Becton Dickinson Co | METHODS AND COMPOSITIONS OF CANCER THERAPY AND PREDICTABILITY OF RESPONSE TO THIS TREATMENT |
US5571153A (en) | 1991-09-20 | 1996-11-05 | Wallst+E,Acu E+Ee N; Hans I. | Device for hyperthermia treatment |
US6011056A (en) | 1991-09-23 | 2000-01-04 | Florida State University | C9 taxane derivatives and pharmaceutical compositions containing them |
US5998656A (en) | 1991-09-23 | 1999-12-07 | Florida State University | C10 tricyclic taxanes |
US5739362A (en) | 1991-09-23 | 1998-04-14 | Florida State University | Taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
US5274124A (en) | 1991-09-23 | 1993-12-28 | Florida State University | Metal alkoxides |
SG46582A1 (en) | 1991-09-23 | 1998-02-20 | Univ Florida State | 10-Desacetoxytaxol derivatives |
US5284865A (en) | 1991-09-23 | 1994-02-08 | Holton Robert A | Cyclohexyl substituted taxanes and pharmaceutical compositions containing them |
US5229526A (en) | 1991-09-23 | 1993-07-20 | Florida State University | Metal alkoxides |
US5399726A (en) | 1993-01-29 | 1995-03-21 | Florida State University | Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups |
US6028205A (en) | 1991-09-23 | 2000-02-22 | Florida State University | C2 tricyclic taxanes |
US5728725A (en) | 1991-09-23 | 1998-03-17 | Florida State University | C2 taxane derivaties and pharmaceutical compositions containing them |
US6018073A (en) | 1991-09-23 | 2000-01-25 | Florida State University | Tricyclic taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
US5714513A (en) | 1991-09-23 | 1998-02-03 | Florida State University | C10 taxane derivatives and pharmaceutical compositions |
US6005138A (en) | 1991-09-23 | 1999-12-21 | Florida State University | Tricyclic taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
US5250683A (en) | 1991-09-23 | 1993-10-05 | Florida State University | Certain substituted taxanes and pharmaceutical compositions containing them |
US5243045A (en) | 1991-09-23 | 1993-09-07 | Florida State University | Certain alkoxy substituted taxanes and pharmaceutical compositions containing them |
US5283253A (en) | 1991-09-23 | 1994-02-01 | Florida State University | Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them |
US5430160A (en) | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US5227400A (en) | 1991-09-23 | 1993-07-13 | Florida State University | Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them |
US5728850A (en) | 1991-09-23 | 1998-03-17 | Florida State University | Taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
US5710287A (en) | 1991-09-23 | 1998-01-20 | Florida State University | Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them |
US5721268A (en) | 1991-09-23 | 1998-02-24 | Florida State University | C7 taxane derivatives and pharmaceutical compositions containing them |
US5654447A (en) | 1991-09-23 | 1997-08-05 | Florida State University | Process for the preparation of 10-desacetoxybaccatin III |
US5338872A (en) | 1993-01-15 | 1994-08-16 | Florida State University | Process for the preparation of 10-desacetoxybaccatin III and 10-desacetoxytaxol and derivatives thereof |
US5489601A (en) | 1991-09-23 | 1996-02-06 | Florida State University | Taxanes having a pyridyl substituted side-chain and pharmaceutical compositions containing them |
FR2682110B1 (en) | 1991-10-02 | 1995-05-24 | Atta | PERFLUOROALKYL AMPHIPHILIC LIGANDS, THEIR METAL COMPLEXES AND THEIR USES IN PREPARATIONS FOR THERAPEUTIC USE. |
US6022541A (en) | 1991-10-18 | 2000-02-08 | Beth Israel Deaconess Medical Center | Immunological preparation for concurrent specific binding to spatially exposed regions of vascular permeability factor bound in-vivo to a tumor associated blood vessel |
US5559235A (en) | 1991-10-29 | 1996-09-24 | Glaxo Wellcome Inc. | Water soluble camptothecin derivatives |
WO1993009782A1 (en) | 1991-11-15 | 1993-05-27 | Smithkline Beecham Corporation | Combination chemotherapy |
US5344775A (en) | 1991-11-15 | 1994-09-06 | Escagenetics Corporation | Synthesis of taxanes in culture using pseudocalluscells |
US5556609A (en) | 1992-02-20 | 1996-09-17 | Rhomed Incorporated | YIGSR peptide radiopharmaceutical applications |
US5738838A (en) | 1992-02-20 | 1998-04-14 | Rhomed Incorporated | IKVAV peptide radiopharmaceutical applications |
ES2230790T3 (en) | 1992-01-15 | 2005-05-01 | E.R. SQUIBB & SONS, INC. | ENZYMATIC PROCEDURES FOR THE RESOLUTION OF ENANTIOMERIC BLENDS OF USEFUL COMPOUNDS AS INTERMEDIATES IN THE PREPARATION OF TAXANES. |
US5622929A (en) | 1992-01-23 | 1997-04-22 | Bristol-Myers Squibb Company | Thioether conjugates |
ATE295420T1 (en) | 1992-02-06 | 2005-05-15 | Chiron Corp | MARKER FOR CANCER AND BIOSYNTHETIC BINDING PROTEIN FOR IT |
FR2687145B1 (en) | 1992-02-07 | 1994-03-25 | Rhone Poulenc Rorer Sa | NEW ANHYDRIDES OF ACIDS, THEIR PREPARATION AND THEIR PACKAGE AND |
US5407816A (en) | 1992-02-20 | 1995-04-18 | Phyton Catalytic, Inc. | Enhanced production of taxol and taxanes by cell cultures of taxus species |
DK0627940T3 (en) | 1992-03-05 | 2003-09-01 | Univ Texas | Use of immunoconjugates for diagnosis and / or therapy of vascularized tumors |
US5776427A (en) | 1992-03-05 | 1998-07-07 | Board Of Regents, The University Of Texas System | Methods for targeting the vasculature of solid tumors |
US5965132A (en) | 1992-03-05 | 1999-10-12 | Board Of Regents, The University Of Texas System | Methods and compositions for targeting the vasculature of solid tumors |
IT1254517B (en) | 1992-03-06 | 1995-09-25 | Indena Spa | 14-BETA IDROSSI-10-DEACETIL-BACCATINA III, ITS DERIVATIVES, THEIR PREPATION AND THERAPEUTIC USE |
US5698712A (en) | 1992-03-06 | 1997-12-16 | Indena S.P.A. | Baccatine III derivatives |
IT1254515B (en) | 1992-03-06 | 1995-09-25 | Indena Spa | TASSANI OF ONCOLOGICAL INTEREST, THEIR METHOD OF PREPARATION AND USE |
US5939561A (en) | 1992-03-10 | 1999-08-17 | Rhone-Poulence Rorer S.A. | Process for the preparation of β-phenylisoserine and β-lactam and their analogues |
FR2688499B1 (en) | 1992-03-10 | 1994-05-06 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF BETA-PHENYLISOSERINE AND ITS ANALOGS. |
US5200534A (en) | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
DK0563475T3 (en) * | 1992-03-25 | 2000-09-18 | Immunogen Inc | Conjugates of Cell Binding Agents and Derivatives of CC-1065 |
CA2131532A1 (en) | 1992-04-01 | 1993-10-14 | Steven R. Wann | Induction of somatic embryogenesis in taxus, and the production of taxane-ring containing alkaloids therefrom |
US5850032A (en) | 1992-04-01 | 1998-12-15 | Union Camp Corporation | Method for production of plant biological products in precocious neomorphic embryoids |
US5254703A (en) | 1992-04-06 | 1993-10-19 | Florida State University | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones |
CA2092849C (en) | 1992-04-07 | 2003-11-18 | Paul M. Cino | Callus cell induction and the preparation of taxanes |
AU4025193A (en) | 1992-04-08 | 1993-11-18 | Cetus Oncology Corporation | Humanized C-erbB-2 specific antibodies |
US5622960A (en) | 1992-04-14 | 1997-04-22 | The United States Of America As Represented By The Department Of Health And Human Services | Topoisomerase II inhibitors and therapeutic uses therefor |
US5322779A (en) | 1992-04-16 | 1994-06-21 | The Research And Development Institute, Inc. At Montana State University | Taxol production by taxomyces andreanae |
US5831002A (en) | 1992-05-20 | 1998-11-03 | Basf Aktiengesellschaft | Antitumor peptides |
US5237064A (en) | 1992-05-20 | 1993-08-17 | Merck & Co., Inc. | Process for producing 7β-substituted-aza-5αandrostan-3-ones |
DE4317458A1 (en) | 1992-06-11 | 1993-12-16 | Bayer Ag | Use of cyclic depsipeptides with 18 ring atoms for the control of endoparasites, new cyclic depsipeptides with 18 ring atoms and process for their preparation |
US5459269A (en) | 1992-06-18 | 1995-10-17 | North Carolina State University | 14-halo-camptothecins |
YU43193A (en) | 1992-06-22 | 1997-01-08 | Eli Lilly And Company | 2'-DEOXY-2 ', 2'-DIFLUORO (4-SUBSTITUTED) PYRIMIDINE NUCLEOSIDS OF ANTIVIRUS AND ANTICANCEROGENIC ACTIVITY AND INTERMEDIATES |
US5274137A (en) | 1992-06-23 | 1993-12-28 | Nicolaou K C | Intermediates for preparation of taxols |
US5279953A (en) | 1992-06-24 | 1994-01-18 | Esca Genetics Corporation | In vivo production of taxanes |
AU687346B2 (en) | 1992-06-30 | 1998-02-26 | Oncologix, Inc. | A combination of anti-erbB-2 monoclonal antibodies and method of using |
US5334732A (en) | 1992-07-02 | 1994-08-02 | Hauser Chemical Research, Inc. | Oxidation of cephalomannine with ozone in the presence of taxol |
US5792877A (en) | 1992-07-02 | 1998-08-11 | Hauser Chemical Research, Inc. | Girard derivatives of taxanes |
US5364947A (en) | 1992-07-02 | 1994-11-15 | Hauser Chemical Research, Inc. | Process for separating cephalomannine from taxol using ozone and water-soluble hydrazines or hydrazides |
US5354331A (en) | 1992-07-15 | 1994-10-11 | Schachar Ronald A | Treatment of presbyopia and other eye disorders |
US5446047A (en) | 1992-07-23 | 1995-08-29 | Sloan-Kettering Institute For Cancer Research | Camptothecin analogues |
IL102617A (en) | 1992-07-23 | 1996-01-19 | Technion Res & Dev Foundation | Method for assessing clinical sensitivity and resistance to multiple anticancer drugs of mammalian cells |
US5391745A (en) | 1992-07-23 | 1995-02-21 | Sloan-Kettering Institute For Cancer Research | Methods of preparation of camptothecin analogs |
CA2086874E (en) | 1992-08-03 | 2000-01-04 | Renzo Mauro Canetta | Methods for administration of taxol |
US5202448A (en) | 1992-08-14 | 1993-04-13 | Napro Biotherapeutics, Inc. | Processes of converting taxanes into baccatin III |
US5256801A (en) | 1992-08-14 | 1993-10-26 | Napro Biotherapeutics, Inc. | Processes of converting taxanes into 10-deacetylbaccatin III |
US5470866A (en) | 1992-08-18 | 1995-11-28 | Virginia Polytechnic Institute And State University | Method for the conversion of cephalomannine to taxol and for the preparation of n-acyl analogs of taxol |
US5871710A (en) | 1992-09-04 | 1999-02-16 | The General Hospital Corporation | Graft co-polymer adducts of platinum (II) compounds |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
US5922340A (en) | 1992-09-10 | 1999-07-13 | Children's Medical Center Corporation | High load formulations and methods for providing prolonged local anesthesia |
FR2696464B1 (en) | 1992-10-05 | 1994-11-10 | Rhone Poulenc Rorer Sa | New esterification process for baccatin III and 10-deacetyl baccatin III. |
FR2696459B1 (en) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
FR2696454B1 (en) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for the stereoselective preparation of a beta-phenylisoserine derivative and its use for the preparation of Taxane derivatives. |
FR2696458B1 (en) | 1992-10-05 | 1994-11-10 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
FR2696460B1 (en) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
US5817321A (en) | 1992-10-08 | 1998-10-06 | Supratek Pharma, Inc. | Biological agent compositions |
US5411984A (en) | 1992-10-16 | 1995-05-02 | Virginia Tech Intellectual Properties, Inc. | Water soluble analogs and prodrugs of taxol |
US5552156A (en) | 1992-10-23 | 1996-09-03 | Ohio State University | Liposomal and micellular stabilization of camptothecin drugs |
GB9222253D0 (en) | 1992-10-23 | 1992-12-09 | Celltech Ltd | Chemical compounds |
US5891724A (en) | 1992-10-27 | 1999-04-06 | Queen's University At Kingston | Methods for conferring multidrug resistance on a cell |
FR2697522B1 (en) | 1992-10-30 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
US5356928A (en) | 1992-11-06 | 1994-10-18 | Hauser Chemical Research, Inc. | Cytotoxic agents |
US5412116A (en) | 1992-11-06 | 1995-05-02 | Hauser Chemical Research, Inc. | Oxidation of glycoside substituted taxanes to taxol or taxol precursors and new taxane compounds formed as intermediates |
FR2697752B1 (en) | 1992-11-10 | 1995-04-14 | Rhone Poulenc Rorer Sa | Antitumor compositions containing taxane derivatives. |
AP9300587A0 (en) | 1992-11-12 | 1995-05-05 | Glaxo Inc | Water soluble camptothecin derivatives. |
US5420337A (en) | 1992-11-12 | 1995-05-30 | E. R. Squibb & Sons, Inc. | Enzymatic reduction method for the preparation of compounds useful for preparing taxanes |
FR2698363B1 (en) | 1992-11-23 | 1994-12-30 | Rhone Poulenc Rorer Sa | New taxane derivatives, their preparation and the compositions containing them. |
EP0675754A4 (en) | 1992-11-27 | 1996-01-10 | Napro Biotherapeutics Inc | Processing taxane solutes using membranes. |
US5281727A (en) | 1992-11-27 | 1994-01-25 | Napro Biotherapeutics, Inc. | Method of using ion exchange media to increase taxane yields |
FR2698543B1 (en) | 1992-12-02 | 1994-12-30 | Rhone Poulenc Rorer Sa | New taxoid-based compositions. |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
US6034065A (en) | 1992-12-03 | 2000-03-07 | Arizona Board Of Regents | Elucidation and synthesis of antineoplastic tetrapeptide phenethylamides of dolastatin 10 |
EP0627010A4 (en) | 1992-12-07 | 1995-05-03 | Univ Michigan | PROCESS FOR THE ISOLATION AND PURIFICATION OF TAXOL AND TAXANES FROM -i(TAXUS) spp. |
US5279949A (en) | 1992-12-07 | 1994-01-18 | Board Of Trustees Operating Michigan State University | Process for the isolation and purification of taxol and taxanes from Taxus spp |
FR2698871B1 (en) | 1992-12-09 | 1995-02-24 | Rhone Poulenc Rorer Sa | New taxoids, their preparation and the pharmaceutical compositions containing them. |
US5814658A (en) | 1992-12-09 | 1998-09-29 | Rhone-Poulenc Rorer S.A. | Taxoids, their preparation and pharmaceutical compositions containing them |
AU679479B2 (en) | 1992-12-16 | 1997-07-03 | Basf Aktiengesellschaft | Dolostatin analog |
FR2699535B1 (en) | 1992-12-22 | 1995-03-17 | Pf Medicament | Etoposide derivatives, process for their preparation, their use as medicaments and their use for the preparation of a medicament intended for anticancer treatment. |
US5622977A (en) | 1992-12-23 | 1997-04-22 | Celltech Therapeutics Limited | Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same |
US5973160A (en) | 1992-12-23 | 1999-10-26 | Poss; Michael A. | Methods for the preparation of novel sidechain-bearing taxanes |
GB9226830D0 (en) | 1992-12-23 | 1993-02-17 | Celltech Ltd | Chemical compounds |
US5646176A (en) | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
US5352804A (en) | 1993-01-19 | 1994-10-04 | Arizona Board Of Regents, A Body Corporate, Acting On Behalf Of Arizona State University | Isolation and structure of Halistatin 2 |
US5410024A (en) | 1993-01-21 | 1995-04-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide amides |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
EP0682660B1 (en) | 1993-02-05 | 2003-11-05 | Bryn Mawr College | Synthesis of taxol, analogs and intermediates with variable a-ring side chains |
DE4305003A1 (en) | 1993-02-18 | 1994-08-25 | Knoll Ag | Process for the preparation of colloidal aqueous solutions of poorly soluble active substances |
US5527913A (en) | 1993-02-25 | 1996-06-18 | The Stehlin Foundation For Cancer Research | Methods for purifying camptothecin compounds |
US5604112A (en) | 1993-02-26 | 1997-02-18 | The Dupont Merck Pharmaceutical Company | Method for detecting the cardiotoxicity of compounds |
US5844001A (en) | 1993-02-26 | 1998-12-01 | Research Development Foundation | Combination platinum chemotherapeutic/antiestrogen therapy for human cancers |
US5756301A (en) | 1993-03-03 | 1998-05-26 | The Trustees Of Columbia University In The City Of New York | Endogenous taxol-like substance in human serum, monoclonal antibodies directed thereto and methods of assaying therefor |
ATE232854T1 (en) | 1993-03-05 | 2003-03-15 | Univ Florida State | METHOD FOR PRODUCING 9-DESOXOTAXANES |
US5547981A (en) | 1993-03-09 | 1996-08-20 | Enzon, Inc. | Taxol-7-carbazates |
GB9304920D0 (en) | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
GB9304919D0 (en) | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
US5703247A (en) | 1993-03-11 | 1997-12-30 | Virginia Tech Intellectual Properties, Inc. | 2-Debenzoyl-2-acyl taxol derivatives and methods for making same |
US5824664A (en) | 1993-03-26 | 1998-10-20 | U.S. Bioscience, Inc. | Suppression of HIV expression by organic thiophosphate |
US5475011A (en) | 1993-03-26 | 1995-12-12 | The Research Foundation Of State University Of New York | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
FR2703353B1 (en) | 1993-03-29 | 1995-05-05 | Rhone Poulenc Rorer Sa | Process for the preparation of beta-phenylisoserine derivatives. |
WO1994022478A1 (en) | 1993-03-30 | 1994-10-13 | The Trustees Of The University Of Pennsylvania | PREVENTION OF TUMORS WITH MONOCLONAL ANTIBODIES AGAINST $i(NEU) |
US5482698A (en) | 1993-04-22 | 1996-01-09 | Immunomedics, Inc. | Detection and therapy of lesions with biotin/avidin polymer conjugates |
US5336684A (en) | 1993-04-26 | 1994-08-09 | Hauser Chemical Research, Inc. | Oxidation products of cephalomannine |
KR100220864B1 (en) | 1993-05-17 | 1999-09-15 | 오트리브 데이비스 더블유 | Improved detection and therapy of lesions with biotin/avidin-metal chelating protein conjugates |
AU6833994A (en) | 1993-05-17 | 1994-12-12 | Liposome Company, Inc., The | Incorporation of taxol into liposomes and gels |
IT1261667B (en) | 1993-05-20 | 1996-05-29 | TAX FOR ANTI-CANCER ACTIVITIES. | |
US5380897A (en) | 1993-05-25 | 1995-01-10 | Hoeschele; James D. | Tri(platinum) complexes |
US5405963A (en) | 1993-06-10 | 1995-04-11 | Smithkline Beecham Corporation | Process for asymmetric total synthesis of camptothecin analogues |
AU7138894A (en) | 1993-06-11 | 1995-01-03 | Pharmacia & Upjohn Company | Delta 6,7--taxols antineoplastic use and pharmaceutical compositions containing them |
US5516676A (en) | 1993-06-15 | 1996-05-14 | Bristol-Myers Squibb Company | Preparation of C-13 hydroxyl-bearing taxanes using nocardioides or a hydrolase isolated therefrom |
US5523219A (en) | 1993-06-15 | 1996-06-04 | Bristol-Myers Squibb Company | Enzymatic hydrolysis method for the preparation of C-10 hydroxyl-bearing taxanes and enzymatic esterification method for the preparation of C-10 acyloxy-bearing |
US5409690A (en) | 1993-06-23 | 1995-04-25 | Chemex Pharmaceuticals, Inc. | Treatment of multidrug resistant diseases in cancer cell by potentiating with masoprocol |
US5744605A (en) | 1993-06-30 | 1998-04-28 | University Of Pittsburgh | Intermediates in the synthesis of (+) camptothecin and related compounds and synthesis thereof |
TW397866B (en) | 1993-07-14 | 2000-07-11 | Bristol Myers Squibb Co | Enzymatic processes for the resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes |
US5716981A (en) | 1993-07-19 | 1998-02-10 | Angiogenesis Technologies, Inc. | Anti-angiogenic compositions and methods of use |
US5405972A (en) | 1993-07-20 | 1995-04-11 | Florida State University | Synthetic process for the preparation of taxol and other tricyclic and tetracyclic taxanes |
US6005120A (en) | 1993-07-20 | 1999-12-21 | Florida State University | Tricyclic and tetracyclic taxanes |
JP3161490B2 (en) | 1993-07-30 | 2001-04-25 | 松下電器産業株式会社 | Mold equipment |
US5455270A (en) | 1993-08-11 | 1995-10-03 | Bristol-Myers Squibb Co. | Stabilized solutions of platinum(II) antitumor agents |
US5409677A (en) | 1993-08-26 | 1995-04-25 | The Curators Of The University Of Missouri | Process for separating a radionuclide from solution |
US5475108A (en) | 1993-08-31 | 1995-12-12 | North Carolina State University | Camptothecin intermediates and method of making camptothecin and comptothecin analogs |
US5409915A (en) | 1993-09-14 | 1995-04-25 | The University Of Vermont And State Agricultural College | Bis-platinum (IV) complexes as chemotherapeutic agents |
US5498227A (en) | 1993-09-15 | 1996-03-12 | Mawad; Michel E. | Retrievable, shielded radiotherapy implant |
US5484612A (en) | 1993-09-22 | 1996-01-16 | The Board Of Trustees Of The Leland Stanford Junior University | Method of treating a mammal having a solid tumor susceptible to treatment with cisplatin |
GB9319944D0 (en) | 1993-09-28 | 1993-11-17 | Erba Carlo Spa | Process for the preparation of 9-amino camptothecin |
DE69434136T2 (en) | 1993-10-01 | 2005-12-01 | Teikoku Hormone Mfg. Co., Ltd. | Dolastatin DERIVATIVES |
US5648384A (en) | 1993-10-04 | 1997-07-15 | Tanaka Kikinzoku Kogyo K.K. | Anti-tumor platinum (IV) complex |
GB9320781D0 (en) | 1993-10-08 | 1993-12-01 | Erba Carlo Spa | Polymer-bound camptothecin derivatives |
KR970010594B1 (en) | 1993-10-16 | 1997-06-28 | 한국과학기술연구원 | Platinum complexes of malonic acid derivatives and process for the preparation thereof |
JPH09504033A (en) | 1993-10-20 | 1997-04-22 | エンゾン,インコーポレーテッド | 2'- and / or 7-substituted taxoids |
US5824701A (en) | 1993-10-20 | 1998-10-20 | Enzon, Inc. | Taxane-based prodrugs |
US5840900A (en) | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5880131A (en) | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
JPH09504176A (en) | 1993-10-25 | 1997-04-28 | ライボジーン、インコーポレイテッド | Antifungal selection method |
US5919455A (en) | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5643575A (en) | 1993-10-27 | 1997-07-01 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5459248A (en) | 1993-11-04 | 1995-10-17 | Bristol-Myers Squibb Company | Process of preparing etoposide phosphate and etoposide |
US5633177A (en) | 1993-11-08 | 1997-05-27 | Advanced Micro Devices, Inc. | Method for producing a semiconductor gate conductor having an impurity migration barrier |
US5821453A (en) | 1993-11-12 | 1998-10-13 | The Ohio State University Research Foundation | Molecular based magnets comprising vanadium tetracyanoethylene complexes for shielding electromagnetic fields |
US5415869A (en) | 1993-11-12 | 1995-05-16 | The Research Foundation Of State University Of New York | Taxol formulation |
WO1995014103A1 (en) | 1993-11-15 | 1995-05-26 | Mitsui Petrochemical Industries, Ltd. | Process for producing taxane diterpene and method of harvesting cultred cell capable of producing taxane diterpene in high yield |
US5436243A (en) | 1993-11-17 | 1995-07-25 | Research Triangle Institute Duke University | Aminoanthraquinone derivatives to combat multidrug resistance |
US5855748A (en) | 1993-11-22 | 1999-01-05 | E. I. Du Pont De Nemours And Company | Electrochemical cell having a mass flow field made of glassy carbon |
US6063911A (en) | 1993-12-01 | 2000-05-16 | Marine Polymer Technologies, Inc. | Methods and compositions for treatment of cell proliferative disorders |
US5952298A (en) | 1993-12-21 | 1999-09-14 | The University Of Hawaii | Cryptophycins |
EP0735819B1 (en) | 1993-12-21 | 2001-07-11 | University Of Hawaii | Cryptophycins |
US5955423A (en) | 1993-12-21 | 1999-09-21 | The University Of Hawaii | Cryptophycins |
US5595756A (en) | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
GB9326173D0 (en) | 1993-12-22 | 1994-02-23 | Celltech Ltd | Chemical compounds and process |
US5447936A (en) | 1993-12-22 | 1995-09-05 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of 10-hydroxy 7-ethyl camptothecin and methods for uses thereof |
WO1995017399A1 (en) | 1993-12-22 | 1995-06-29 | Celltech Therapeutics Limited | Trisubstituted phenyl derivatives, processes for their preparation and their use as phosphodiesterase (type iv) inhibitors |
US5476939A (en) | 1993-12-30 | 1995-12-19 | Abbott Laboratories | Certain pyridyl and isoquinolyl carbinolamine derivatives |
IL112061A (en) | 1994-01-13 | 1999-10-28 | Bristol Myers Squibb Co | Methods for the preparation of taxanes |
US5491285A (en) | 1994-01-21 | 1996-02-13 | Goldsmith Seeds Inc. | Phytophthora resistance gene of catharanthus and its use |
IL127597A (en) | 1994-01-28 | 2003-07-31 | Upjohn Co | Iso-taxol analogs |
AT400950B (en) | 1994-02-04 | 1996-04-25 | Immodal Pharmaka Gmbh | METHOD FOR THE TECHNICAL PRODUCTION OF DEFINED ISOMERIC MIXTURES FROM COMPOUNDS WITH SPIROCYCLIC - AMINOCARBOXYL AND / OR SPIROCYCLIC - AMINOCARBONYL SYSTEMS |
GB9402934D0 (en) | 1994-02-16 | 1994-04-06 | Erba Carlo Spa | Camptothecin derivatives and process for their preparation |
US5565478A (en) | 1994-03-14 | 1996-10-15 | The United States Of America As Represented By The Department Of Health & Human Services | Combination therapy using signal transduction inhibitors with paclitaxel and other taxane analogs |
FR2718135B1 (en) | 1994-04-05 | 1996-04-26 | Rhone Poulenc Rorer Sa | Process for the preparation of hydroxy-7 taxanes. |
US5449790A (en) | 1994-04-06 | 1995-09-12 | Hauser Chemical Research, Inc. | Preparation of 10-deacetylbaccatin III and 7-protected-10-deacetylbaccatin III derivatives from 10-deacetyl taxol A, 10-deacetyl taxol B, and 10-deacetyl taxol C |
US5646011A (en) | 1994-04-08 | 1997-07-08 | Yokoyama; Shiro | Cisplatin resistance gene and uses therefor |
DE4415263C1 (en) | 1994-04-15 | 1995-11-30 | Asta Medica Ag | Cis- [trans-1,2-cyclobutane bis (methylamine) -N, N '] - [(2S) -lactato-O · 1 ·, O · 2 ·] -platinum (II) trihydrate (lobaplatin trihydrate), its manufacture and medicinal use |
US5616613A (en) | 1994-04-19 | 1997-04-01 | Toray Industries, Inc. | Platinum(II) complex and malignant tumor treatment agent |
US5468754A (en) | 1994-04-19 | 1995-11-21 | Bionumerik Pharmaceuticals, Inc. | 11,7 substituted camptothecin derivatives and formulations of 11,7 substituted camptothecin derivatives and methods for uses thereof |
GB9408218D0 (en) | 1994-04-26 | 1994-06-15 | Johnson Matthey Plc | Improvements in platinum complexes |
US5604233A (en) | 1994-04-28 | 1997-02-18 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of 7-ethyl camptothecin and methods for uses thereof |
US5597829A (en) | 1994-05-09 | 1997-01-28 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of camptothecin and methods for uses thereof |
US5882941A (en) | 1994-05-04 | 1999-03-16 | Massachusette Institute Of Technology | Programmable genotoxic agents and uses therefor |
DE4415998A1 (en) | 1994-05-06 | 1995-11-09 | Basf Ag | New tetrapeptides, their production use |
IT1269634B (en) | 1994-05-06 | 1997-04-08 | Indena Spa | TOPICAL MEDICATION WITH CICATRIZING ACTIVITY |
ES2119446T3 (en) | 1994-05-23 | 1998-10-01 | Liposome Co Inc | FORMULATION PREPARATION DEVICE. |
US5508447A (en) | 1994-05-24 | 1996-04-16 | Board Of Regents, The University Of Texas System | Short synthetic route to taxol and taxol derivatives |
GB9410388D0 (en) | 1994-05-24 | 1994-07-13 | Erba Carlo Spa | Method for the preparation of 9-amino camptothecin |
US5632982A (en) | 1994-06-07 | 1997-05-27 | The Board Of Trustees Of The Leland Stanford Junior University | Cytotoxic enhancement of TNF with copper |
US5605826A (en) | 1994-06-10 | 1997-02-25 | Panorama Research, Inc. | 24 kilodalton cytoplasmic protease activating DNA fragmentation in apoptosis |
US5543152A (en) | 1994-06-20 | 1996-08-06 | Inex Pharmaceuticals Corporation | Sphingosomes for enhanced drug delivery |
US5786354A (en) | 1994-06-21 | 1998-07-28 | Celltech Therapeutics, Limited | Tri-substituted phenyl derivatives and processes for their preparation |
US5602272A (en) | 1994-06-21 | 1997-02-11 | Bristol-Myers Squibb Company | Reduction and resolution methods for the preparation of compounds useful as intemediates for preparing taxanes |
US5563132A (en) | 1994-06-21 | 1996-10-08 | Bodaness; Richard S. | Two-step cancer treatment method |
GB9412571D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
GB9412573D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
GB9412672D0 (en) | 1994-06-23 | 1994-08-10 | Celltech Ltd | Chemical compounds |
US5714163A (en) | 1994-06-27 | 1998-02-03 | Nexstar Pharmaceuticals, Inc. | Vinca alkaloid vesicles with enhanced efficacy and tumor targeting properties |
US5498738A (en) | 1994-06-28 | 1996-03-12 | Karvinen; Esko | Method for the preparation of a novel a-ring precursor for taxoids and novel intermediates |
US5648505A (en) | 1994-06-28 | 1997-07-15 | Xia; Zhi-Qiang | Method for the preparation of a novel C-ring precursor for taxoids and novel intermediates |
US5866679A (en) | 1994-06-28 | 1999-02-02 | Merck & Co., Inc. | Peptides |
US5786344A (en) | 1994-07-05 | 1998-07-28 | Arch Development Corporation | Camptothecin drug combinations and methods with reduced side effects |
US5864024A (en) | 1994-07-11 | 1999-01-26 | Glinskii; Guennadi Victor | Synthetic glycoamines and methods for their use that affect cell adhesion, inhibit cancer cell metastasis, and induce apoptosis |
US5629433A (en) | 1994-07-18 | 1997-05-13 | Hauser, Inc. | Selective process for the deacylation and deacetylation of taxol and taxanes |
US5616330A (en) | 1994-07-19 | 1997-04-01 | Hemagen/Pfc | Stable oil-in-water emulsions incorporating a taxine (taxol) and method of making same |
US5646159A (en) | 1994-07-20 | 1997-07-08 | Research Triangle Institute | Water-soluble esters of camptothecin compounds |
US5547866A (en) | 1994-07-20 | 1996-08-20 | The Regents Of The University Of California | Taxane production in haploid-derived cell cultures |
US5604095A (en) | 1994-07-22 | 1997-02-18 | Cancer Therapy & Research Center | Unsymmetrically linked bisnaphthalimides as antitumor agents |
US5763477A (en) | 1994-07-22 | 1998-06-09 | Dr. Reddy's Research Foundation | Taxane derivatives from 14-β-hydroxy-10 deacetylbaccatin III |
US5561042A (en) | 1994-07-22 | 1996-10-01 | Cancer Therapy And Research Center | Diamine platinum naphthalimide complexes as antitumor agents |
RU2134688C1 (en) | 1994-07-26 | 1999-08-20 | Индена С.П.А. | Semisynthetic taxane, intermediate compounds, methods of synthesis and pharmaceutical composition |
US5530097A (en) | 1994-08-01 | 1996-06-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory peptide amides |
US5521284A (en) | 1994-08-01 | 1996-05-28 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide amides and esters |
US5504191A (en) | 1994-08-01 | 1996-04-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide methyl esters |
US5686578A (en) | 1994-08-05 | 1997-11-11 | Immunomedics, Inc. | Polyspecific immunoconjugates and antibody composites for targeting the multidrug resistant phenotype |
US5688773A (en) | 1994-08-17 | 1997-11-18 | The General Hospital Corporation | Method of selectively destroying neoplastic cells |
JP4157600B2 (en) | 1994-08-19 | 2008-10-01 | ラ レフィオン バロンネ | COMPOUND, COMPOSITION FOR PREPARATION, DIAGNOSTIC DEVICE CONTAINING THEM, AND USE THEREOF |
US5479648A (en) * | 1994-08-30 | 1995-12-26 | Stratus Computer, Inc. | Method and apparatus for switching clock signals in a fault-tolerant computer system |
JPH0873461A (en) | 1994-09-06 | 1996-03-19 | Yakult Honsha Co Ltd | Novel camptothecin derivative, method for producing the same and antitumor agent |
US5554725A (en) | 1994-09-14 | 1996-09-10 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Synthesis of dolastatin 15 |
US5763733A (en) | 1994-10-13 | 1998-06-09 | Enzon, Inc. | Antigen-binding fusion proteins |
FR2725990B1 (en) | 1994-10-21 | 1997-01-10 | Pf Medicament | WATER-SOLUBLE DERIVATIVES OF EPIPODOPHYLLOTOXIN, PROCESS FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, AND THEIR USE FOR CANCER TREATMENTS |
US5719177A (en) | 1994-11-04 | 1998-02-17 | Pharmacia S.P.A. | Taxane derivatives |
DE4440193A1 (en) | 1994-11-10 | 1996-05-15 | Bayer Ag | Use of dioxomorpholines to control endoparasites, new dioxomorpholines and processes for their production |
US5599902A (en) | 1994-11-10 | 1997-02-04 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Cancer inhibitory peptides |
US5919816A (en) | 1994-11-14 | 1999-07-06 | Bionumerik Pharmaceuticals, Inc. | Formulations and methods of reducing toxicity of antineoplastic agents |
GB9422947D0 (en) | 1994-11-14 | 1995-01-04 | Univ Salamanca | Immunosuppressive cyclolignan derivatives |
US5789000A (en) | 1994-11-14 | 1998-08-04 | Bionumerik Pharmaceuticals, Inc. | Sterile aqueous parenteral formulations of cis-diammine dichloro platinum |
CA2162086A1 (en) | 1994-11-15 | 1996-05-16 | Michihito Ise | Agent for reducing nephrotoxicity due to medicine |
US5783178A (en) | 1994-11-18 | 1998-07-21 | Supratek Pharma. Inc. | Polymer linked biological agents |
RU2182598C2 (en) | 1994-11-21 | 2002-05-20 | Новартис Аг | Modified proteinase inhibitors |
US5679648A (en) * | 1994-11-30 | 1997-10-21 | The University Hospital | Methods for the treatment and prevention of fungal infections by administration of 3'-deoxypurine nucleosides |
US5663149A (en) | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
US5654328A (en) | 1994-12-15 | 1997-08-05 | Sredni; Benjamin | Method and composition for reducing tumor development with a combination of platinum and tellurium or selenium compounds |
US5597830A (en) | 1994-12-20 | 1997-01-28 | Warner-Lambert Company | Combination chemotherapy |
GB9426090D0 (en) | 1994-12-23 | 1995-02-22 | Xenova Ltd | Pharmaceutical compounds |
US5580899A (en) | 1995-01-09 | 1996-12-03 | The Liposome Company, Inc. | Hydrophobic taxane derivatives |
US5679807A (en) | 1995-01-30 | 1997-10-21 | Hauser, Inc. | Preparation of taxol and docetaxel through primary amines |
US5496952A (en) | 1995-02-07 | 1996-03-05 | North Carolina State University | Method of making asymmetric DE ring intermediates for the synthesis of camptothecin and camptothecin analogs |
GB9502799D0 (en) | 1995-02-14 | 1995-04-05 | Johnson Matthey Plc | Improvements in platinum complexes |
US5620875A (en) | 1995-02-17 | 1997-04-15 | University Of Portland | Transfer of taxol from yew tree cuttings into a culture medium over time |
US5547982A (en) | 1995-02-27 | 1996-08-20 | Johnson Matthey, Inc. | Anti-tumor platinum complexes |
EP0815096A4 (en) | 1995-03-10 | 1998-07-08 | Hauser Chemical Res Inc | Cephalomannine epoxide, its analogues and a method for preparing the same |
IT1275936B1 (en) | 1995-03-17 | 1997-10-24 | Indena Spa | DERIVATIVES OF 10-DEACETYLBACCATIN III AND OF 10-DEACETYL-14B- HYDROXYBACCATIN III THEIR METHOD OF PREPARATION AND FORMULATIONS |
US5736156A (en) | 1995-03-22 | 1998-04-07 | The Ohio State University | Liposomal anf micellular stabilization of camptothecin drugs |
US5855867A (en) | 1995-03-29 | 1999-01-05 | The Curators Of The University Of Missouri | Hydroxymethyl phosphine compounds for use as diagnostic and therapeutic pharmaceuticals and method of making same |
CA2215833A1 (en) | 1995-03-29 | 1996-10-03 | Alan R. Ketring | Hydroxyalkyl phosphine compounds for use as diagnostic and therapeutic pharmaceuticals and method of making same |
IL117684A (en) | 1995-04-07 | 2002-02-10 | Pharmacia & Upjohn Inc | Intermediates and process for the manufacture of camptothesin derivatives (cpt-11) and related compounds |
US5840929A (en) | 1995-04-14 | 1998-11-24 | Bristol-Myers Squibb Company | C4 methoxy ether derivatives of paclitaxel |
DK0831100T3 (en) | 1995-04-21 | 2001-01-02 | Teikoku Hormone Mfg Co Ltd | New peptide derivatives |
US5677286A (en) | 1995-04-27 | 1997-10-14 | The University Of Michigan | Glycosylated analogs of camptothecin |
CN1166780C (en) | 1995-04-29 | 2004-09-15 | (株)三养吉尼克斯 | Method for mass production of taxol from taxus genus plant |
US5834012A (en) | 1995-05-03 | 1998-11-10 | Roman Perez-Soler | Lipid complexed topoisomerase I inhibitors |
US5561055A (en) | 1995-05-05 | 1996-10-01 | Bcm Developpement Inc. | Bacterial mass production of taxanes with Erwinia |
US5807874A (en) | 1995-05-17 | 1998-09-15 | Rutgers, The State University Of New Jersey | Trisbenzimidazoles useful as topoisomerase I inhibitors |
US5767142A (en) | 1996-03-20 | 1998-06-16 | Rutgers, The State University Of New Jersey | Trisbenzimidazoles useful as topoisomerase I inhibitors |
GB9510716D0 (en) | 1995-05-26 | 1995-07-19 | Pharmacia Spa | Substituted camptothecin derivatives and process for their preparation |
US5670500A (en) | 1995-05-31 | 1997-09-23 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
US5595878A (en) | 1995-06-02 | 1997-01-21 | Boron Biologicals, Inc. | Detection of biopolymers and biooligomers with boron hydride labels |
US5726181A (en) | 1995-06-05 | 1998-03-10 | Bionumerik Pharmaceuticals, Inc. | Formulations and compositions of poorly water soluble camptothecin derivatives |
US5935967A (en) | 1995-06-05 | 1999-08-10 | Bionumerik Pharmaceuticals, Inc. | Pharmaceutical formulations of highly lipophilic camptothecin derivatives |
US5972955A (en) | 1995-06-06 | 1999-10-26 | Dr. Reddy's Research Foundation | Water soluble C-ring analogues of 20(S)-camptothecin |
EP0846107A1 (en) | 1995-06-06 | 1998-06-10 | Pharmeco Laboratories, Inc. | Stereoselective method for synthesizing dolaphenine |
US5837234A (en) | 1995-06-07 | 1998-11-17 | Cytotherapeutics, Inc. | Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane |
US5716928A (en) | 1995-06-07 | 1998-02-10 | Avmax, Inc. | Use of essential oils to increase bioavailability of oral pharmaceutical compounds |
US5780653A (en) | 1995-06-07 | 1998-07-14 | Vivorx Pharmaceuticals, Inc. | Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers |
WO1997000271A1 (en) | 1995-06-14 | 1997-01-03 | The Regents Of The University Of California | Novel high affinity human antibodies to tumor antigens |
GB9512471D0 (en) | 1995-06-20 | 1995-08-23 | Pharmacia Spa | Method for the preparation of taxol and its derivatives |
GB9512670D0 (en) | 1995-06-21 | 1995-08-23 | Sod Conseils Rech Applic | Camptothecin analogues |
WO1997004801A1 (en) | 1995-07-27 | 1997-02-13 | Genentech, Inc. | Stabile isotonic lyophilized protein formulation |
DE19527574A1 (en) | 1995-07-28 | 1997-01-30 | Basf Ag | Process for the preparation of - (N, N-dialkyl) aminocaarboxamides |
DE19527575A1 (en) | 1995-07-28 | 1997-01-30 | Basf Ag | Process for the preparation of peptide active ingredients |
SG50747A1 (en) | 1995-08-02 | 1998-07-20 | Tanabe Seiyaku Co | Comptothecin derivatives |
US5760251A (en) | 1995-08-11 | 1998-06-02 | Sepracor, Inc. | Taxol process and compounds |
AU709828B2 (en) | 1995-08-30 | 1999-09-09 | University Of Hawaii | Cryptophycins from aberrant biosynthesis |
US6107332A (en) | 1995-09-12 | 2000-08-22 | The Liposome Company, Inc. | Hydrolysis-promoting hydrophobic taxane derivatives |
DE69620802T2 (en) | 1995-09-12 | 2002-10-10 | Liposome Co Inc | HYDROLYZABLE HYDROPHOBIC TAXAN DERIVATIVES |
US6051600A (en) | 1995-09-12 | 2000-04-18 | Mayhew; Eric | Liposomal hydrolysis-promoting hydrophobic taxane derivatives |
US5753507A (en) | 1995-09-22 | 1998-05-19 | Novartis Finance Corporation | Plant geraniol/nerol 10-hydroxylase and DNA coding therefor |
KR0164460B1 (en) | 1995-10-02 | 1999-03-20 | 김은영 | Polymer-pt coordination compound process for preparation and the anti-cancers using it |
US5840748A (en) | 1995-10-02 | 1998-11-24 | Xechem International, Inc. | Dihalocephalomannine and methods of use therefor |
US5807888A (en) | 1995-12-13 | 1998-09-15 | Xechem International, Inc. | Preparation of brominated paclitaxel analogues and their use as effective antitumor agents |
US5654448A (en) | 1995-10-02 | 1997-08-05 | Xechem International, Inc. | Isolation and purification of paclitaxel from organic matter containing paclitaxel, cephalomannine and other related taxanes |
US5854278A (en) | 1995-12-13 | 1998-12-29 | Xechem International, Inc. | Preparation of chlorinated paclitaxel analogues and use thereof as antitumor agents |
JP2907781B2 (en) | 1995-11-06 | 1999-06-21 | エフ・ホフマン−ラ ロシユ アーゲー | Novel method for producing (4,5) -trans-oxazolidine |
US5807984A (en) | 1995-11-09 | 1998-09-15 | Basf Aktienegesellschaft | Oligopeptides, the preparation and use thereof |
EP1440973A3 (en) | 1995-11-17 | 2004-10-20 | Gesellschaft für biotechnologische Forschung mbH (GBF) | Epothilone derivatives, preparation and use |
US5849790A (en) | 1995-11-17 | 1998-12-15 | The University Of South Florida | (Mono) ethylenediaminenitroplatinum (IV) complexes with ligands of oxides of nitrogen as possible anti-tumor agents |
AU7732996A (en) | 1995-11-22 | 1997-06-11 | Research Triangle Institute | Camptothecin compounds with combined topoisomerase i inhibition and dna alkylation properties |
ES2191733T3 (en) | 1995-12-04 | 2003-09-16 | Nippon Kayaku Kk | PROCEDURE TO PRODUCE ETOPOSIDE. |
US5783186A (en) | 1995-12-05 | 1998-07-21 | Amgen Inc. | Antibody-induced apoptosis |
GB9526246D0 (en) | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
GB9526245D0 (en) | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
JP2000502351A (en) | 1995-12-22 | 2000-02-29 | イーライ・リリー・アンド・カンパニー | Pharmaceutical compounds |
CA2192725C (en) | 1995-12-28 | 2004-04-20 | Kenji Tsujihara | Camptothecin derivatives |
GB9600438D0 (en) | 1996-01-10 | 1996-03-13 | Pharmacia Spa | Hexacyclic camptothecin analogues, and process for preparing them |
US5776925A (en) | 1996-01-25 | 1998-07-07 | Pharmacyclics, Inc. | Methods for cancer chemosensitization |
GB9601779D0 (en) | 1996-01-30 | 1996-04-03 | Pharmacia Spa | 9, 10 Disubstituted camptothecin derivatives |
US6096336A (en) | 1996-01-30 | 2000-08-01 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
US5731316A (en) | 1996-01-30 | 1998-03-24 | The Stehlin Foundation For Cancer Research | Derivatives of camptothecin and methods of treating cancer using these derivatives |
US5670663A (en) | 1996-02-14 | 1997-09-23 | Regents Of The University Of California | Recovery of taxanes from conifers |
EP0904074A4 (en) | 1996-02-21 | 2006-01-11 | Intarcia Therapeutics Inc | Use of cell membrane permeants in the treatment of cellular proliferative diseases |
US5710099A (en) | 1996-02-27 | 1998-01-20 | The United States Of America As Represented By The Secretary Of Agriculture | Bioactive compounds |
AU2058197A (en) | 1996-02-27 | 1997-09-16 | Eli Lilly And Company | Pharmaceutical compounds |
AU735900B2 (en) | 1996-03-12 | 2001-07-19 | Pg-Txl Company, L.P. | Water soluble paclitaxel prodrugs |
GB9608435D0 (en) | 1996-04-24 | 1996-06-26 | Celltech Therapeutics Ltd | Chemical compounds |
IT1283633B1 (en) | 1996-05-10 | 1998-04-23 | Indena Spa | TAXANIC DERIVATIVES THEIR SUMMARY AND FORMULATIONS CONTAINING THEM |
IT1283635B1 (en) | 1996-05-10 | 1998-04-23 | Indena Spa | CAMPTOTECIN SKELETON COMPOUNDS ISOLATED FROM MAPPIA FOETIDA AND THEIR USE AS SYNTONES FOR DRUGS OR ACTIVE INGREDIENTS |
US5919815A (en) | 1996-05-22 | 1999-07-06 | Neuromedica, Inc. | Taxane compounds and compositions |
US5795909A (en) | 1996-05-22 | 1998-08-18 | Neuromedica, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
US5968517A (en) | 1996-05-23 | 1999-10-19 | Duncan; Kelvin Winston | Process for extraction of proanthocyanidins from botanical material |
US5883120A (en) | 1997-06-16 | 1999-03-16 | Arizona Board Of Regents, A Body Corporate, Acting On Behalf Of Arizona State University | Antifungal activity of the spongistatins |
US5877205A (en) | 1996-06-28 | 1999-03-02 | Board Of Regents, The University Of Texas System | Parenteral paclitaxel in a stable non-toxic formulation |
US5635531A (en) | 1996-07-08 | 1997-06-03 | Bristol-Myers Squibb Company | 3'-aminocarbonyloxy paclitaxels |
US5780446A (en) | 1996-07-09 | 1998-07-14 | Baylor College Of Medicine | Formulations of vesicant drugs and methods of use thereof |
US5922845A (en) | 1996-07-11 | 1999-07-13 | Medarex, Inc. | Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies |
EP0930309A4 (en) | 1996-07-15 | 2001-09-26 | Yakult Honsha Kk | Taxane derivatives and drugs containing the same |
US5939527A (en) | 1996-07-30 | 1999-08-17 | Basf Aktiengesellschaft | Tetrapeptides as antitumor agents |
US5741892A (en) | 1996-07-30 | 1998-04-21 | Basf Aktiengesellschaft | Pentapeptides as antitumor agents |
EP0925301B1 (en) | 1996-08-19 | 2004-03-17 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic camptothecin derivatives |
WO1998008833A1 (en) | 1996-08-26 | 1998-03-05 | Bristol-Myers Squibb Company | Sulfenamide taxane derivatives |
WO1998008506A1 (en) | 1996-08-30 | 1998-03-05 | Eli Lilly And Company | Pharmaceutical compounds |
US5977387A (en) | 1996-08-30 | 1999-11-02 | Eli Lilly And Company | Process for preparing pharmaceutical compounds |
WO1998008849A1 (en) | 1996-08-30 | 1998-03-05 | Novartis Aktiengesellschaft | Method for producing epothilones, and intermediate products obtained during the production process |
AU4169897A (en) | 1996-08-30 | 1998-03-19 | Eli Lilly And Company | Pharmaceutical compounds |
DE69736067T9 (en) | 1996-08-30 | 2007-10-31 | University Of Hawaii, Honolulu | NEW CRYPTOPHYCIN DERIVATIVES AS ANTINEOPLASTICS |
US5969145A (en) | 1996-08-30 | 1999-10-19 | Novartis Ag | Process for the production of epothilones and intermediate products within the process |
JP4849700B2 (en) * | 1996-09-03 | 2012-01-11 | 中外製薬株式会社 | Anti-integrin α3 antibody complex |
WO1998009974A1 (en) | 1996-09-06 | 1998-03-12 | Eli Lilly And Company | Process and novel intermediates |
JP2001500128A (en) | 1996-09-06 | 2001-01-09 | イーライ・リリー・アンド・カンパニー | Method for producing a medicinal composition |
KR20010029474A (en) | 1996-09-06 | 2001-04-06 | 피터 지. 스트링거 | Process to Prepare Pharmaceutical Compounds |
CA2263764A1 (en) | 1996-09-06 | 1998-03-12 | Michael John Martinelli | Process and novel intermediates |
US20020052309A1 (en) | 1996-09-11 | 2002-05-02 | Athanasius A. Anagnostou | Method of treating endothelial injury |
US5773464A (en) | 1996-09-30 | 1998-06-30 | Bristol-Myers Squibb Company | C-10 epoxy taxanes |
KR20060079258A (en) | 1996-10-18 | 2006-07-05 | 제넨테크, 인크. | Anti-erbb2 antibodies |
US5832931A (en) | 1996-10-30 | 1998-11-10 | Photogen, Inc. | Method for improved selectivity in photo-activation and detection of molecular diagnostic agents |
US5829448A (en) | 1996-10-30 | 1998-11-03 | Photogen, Inc. | Method for improved selectivity in photo-activation of molecular agents |
EP0941227B2 (en) | 1996-11-18 | 2009-10-14 | Gesellschaft für biotechnologische Forschung mbH (GBF) | Epothilone d, production process, and its use as cytostatic as well as phytosanitary agent |
US6242469B1 (en) | 1996-12-03 | 2001-06-05 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
GB9625184D0 (en) | 1996-12-04 | 1997-01-22 | Celltech Therapeutics Ltd | Chemical compounds |
US5843475A (en) | 1996-12-06 | 1998-12-01 | Board Of Regents, The University Of Texas System | Delivery and activation through liposome incorporation of diaminocyclohexane platinum (II) complexes |
WO1998025974A1 (en) | 1996-12-12 | 1998-06-18 | E.I. Du Pont De Nemours And Company | Improved packaging composition |
US6441186B1 (en) | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
US5977386A (en) | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
ATE272640T1 (en) | 1997-01-06 | 2004-08-15 | Pfizer | CYCLIC SULFONE DERIVATIVES |
US5833994A (en) | 1997-01-08 | 1998-11-10 | Paracelsian, Inc. | Use of the AH receptor and AH receptor ligands to treat or prevent cytopathicity of viral infection |
US5910102A (en) | 1997-01-10 | 1999-06-08 | Scimed Life Systems, Inc. | Conversion of beta radiation to gamma radiation for intravascular radiation therapy |
US5739359A (en) | 1997-01-24 | 1998-04-14 | Virginia Tech Intellectual Properties, Inc. | Methods for preparing 1-deoxy paclitaxels |
DK0975638T3 (en) | 1997-02-25 | 2002-11-18 | Biotechnolog Forschung Gmbh | Side-chain modified epothilones |
AU6338698A (en) | 1997-02-26 | 1998-09-18 | Eli Lilly And Company | Tripeptide and tetrapeptide pharmaceutical compounds |
AU738999B2 (en) | 1997-02-26 | 2001-10-04 | Eli Lilly And Company | Selective epoxidation process for preparing pharmaceutical compounds |
US5902822A (en) | 1997-02-28 | 1999-05-11 | Bristol-Myers Squibb Company | 7-methylthiooxomethyl and 7-methylthiodioxomethyl paclitaxels |
US5912264A (en) | 1997-03-03 | 1999-06-15 | Bristol-Myers Squibb Company | 6-halo-or nitrate-substituted paclitaxels |
US5886025A (en) | 1997-03-06 | 1999-03-23 | Baylor University | Anti-mitotic agents which inhibit tubulin polymerization |
US5994367A (en) | 1997-03-07 | 1999-11-30 | The University Of North Carolina At Chapel Hill | Method for treating tumors using 2-aryl-naphthyridin-4-ones |
US5965537A (en) | 1997-03-10 | 1999-10-12 | Basf Aktiengesellschaft | Dolastatin 15 derivatives with carbonyl and heterocyclic functionalities at the C-terminus |
US5939455A (en) | 1997-03-11 | 1999-08-17 | Beacon Laboratories, Inc. | Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives |
GB9705035D0 (en) | 1997-03-11 | 1997-04-30 | Pharmacia & Upjohn Spa | Indolyl-pyrrolydenemethylpyrrole derivatives and process for their preparation |
US6103698A (en) | 1997-03-13 | 2000-08-15 | Basf Aktiengesellschaft | Dolastatin-15 derivatives in combination with taxanes |
US5843993A (en) | 1997-03-14 | 1998-12-01 | The Curators Of The University Of Missouri | Hydroxyalkyl phosphine gold complexes for use as diagnostic and therapeutic pharmaceuticals and method of making same |
EP0870501A1 (en) | 1997-04-11 | 1998-10-14 | Eli Lilly And Company | Use of specific cryptophycin derivatives for the manufacture of a medicament in the treatment of fungal infections |
EP0870506A1 (en) | 1997-04-11 | 1998-10-14 | Eli Lilly And Company | Compositions comprising a cryptophycin compound in combination with a synchronizing or activating agent for treating cancer |
EP0870510A3 (en) | 1997-04-11 | 1999-09-15 | Eli Lilly And Company | Synergistic combination comprising cryptophycin derivatives and microtubule synergizing agents |
US6017935A (en) | 1997-04-24 | 2000-01-25 | Bristol-Myers Squibb Company | 7-sulfur substituted paclitaxels |
US6117659A (en) | 1997-04-30 | 2000-09-12 | Kosan Biosciences, Inc. | Recombinant narbonolide polyketide synthase |
US6046177A (en) | 1997-05-05 | 2000-04-04 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations |
US6046209A (en) | 1997-05-27 | 2000-04-04 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
US5919126A (en) | 1997-07-07 | 1999-07-06 | Implant Sciences Corporation | Coronary stent with a radioactive, radiopaque coating |
US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
PT1001951E (en) | 1997-07-16 | 2003-02-28 | Schering Ag | TIAZOLO DERIVATIVES, PROCESS FOR THEIR PREPARATION AND USE |
GB9715821D0 (en) | 1997-07-25 | 1997-10-01 | Pharmacia & Upjohn Spa | Amidino-camptothecin derivatives |
US5922877A (en) | 1997-08-05 | 1999-07-13 | The Stehlin Foundation For Cancer Research | Methods of preparing and purifying 9-nitro-20-camptothecin |
DK1005465T3 (en) | 1997-08-09 | 2007-11-05 | Bayer Schering Pharma Ag | New epothilone derivatives, processes for their preparation and their pharmaceutical use |
US6121278A (en) | 1997-09-03 | 2000-09-19 | Guilford Pharmaceuticals, Inc. | Di-n-heterocyclic compounds, methods, and compositions for inhibiting parp activity |
US6120800A (en) | 1997-09-25 | 2000-09-19 | Nexstar Pharmaceuticals, Inc. | Vinca-alkaloid vesicles with enhanced efficacy and tumor targeting properties |
US5917062A (en) | 1997-11-21 | 1999-06-29 | Indena S.P.A | Intermediates and methods useful in the semisynthesis of paclitaxel and analogs |
US6365749B1 (en) | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
WO1999028324A1 (en) | 1997-12-04 | 1999-06-10 | Bristol-Myers Squibb Company | A process for the reduction of oxiranyl epothilones to olefinic epothilones |
US6020495A (en) | 1997-12-08 | 2000-02-01 | Pharm-Eco Laboratories, Inc. | Stereoselective method for synthesizing dolaphenine |
ZA9811162B (en) | 1997-12-12 | 2000-06-07 | Genentech Inc | Treatment with anti-ERBB2 antibodies. |
US6030818A (en) | 1997-12-22 | 2000-02-29 | Bcm Developpement, Inc. | Bacterial mass production of taxanes and paclitaxel |
US6096757A (en) | 1998-12-21 | 2000-08-01 | Schering Corporation | Method for treating proliferative diseases |
KR100246722B1 (en) | 1997-12-30 | 2000-04-01 | 박호군 | Oral platium(iv) antitumor agents and their preparation method |
US6063801A (en) | 1998-02-12 | 2000-05-16 | Rutgers, The State University Of New Jersey | Heterocyclic topoisomerase poisons |
US6017890A (en) | 1998-02-19 | 2000-01-25 | Ortho-Mcneil Pharmaceutical, Inc. | Azole peptidomimetics as thrombin receptor antagonists |
US6069146A (en) | 1998-03-25 | 2000-05-30 | The Regents Of The University Of California | Halimide, a cytotoxic marine natural product, and derivatives thereof |
PA8469501A1 (en) | 1998-04-10 | 2000-09-29 | Pfizer Prod Inc | HYDROXAMIDES OF THE ACID (4-ARILSULFONILAMINO) -TETRAHIDROPIRAN-4-CARBOXILICO |
US6048990A (en) | 1998-05-01 | 2000-04-11 | Napro Biotherapeutics, Inc. | Method for selective acylation of C-2'-O-protected-10-hydroxy-taxol at the C-10 position |
US6066749A (en) | 1998-05-01 | 2000-05-23 | Napro Biotherapeutics, Inc. | Method for conversion of C-2'-O-protected-10-hydroxy taxol to c-2'-O-protected taxol:useful intermediates in paclitaxel synthesis |
WO2002016429A2 (en) | 2000-08-24 | 2002-02-28 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US6121029A (en) | 1998-06-18 | 2000-09-19 | Novartis Ag | Genes for the biosynthesis of epothilones |
US5981564A (en) | 1998-07-01 | 1999-11-09 | Universite Laval | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
US5985837A (en) | 1998-07-08 | 1999-11-16 | Basf Aktiengesellschaft | Dolastatin 15 derivatives |
AU5963699A (en) | 1998-10-02 | 2000-04-26 | Mcmaster University | Spliced form of (erb)b-2/neu oncogene |
US6025516A (en) | 1998-10-14 | 2000-02-15 | Chiragene, Inc. | Resolution of 2-hydroxy-3-amino-3-phenylpropionamide and its conversion to C-13 sidechain of taxanes |
US6103913A (en) | 1998-10-16 | 2000-08-15 | Eli Lilly And Company | Process for preparing enollactone derivatives |
US6040330A (en) | 1999-01-08 | 2000-03-21 | Bionumerik Pharmaceuticals, Inc. | Pharmaceutical formulations of taxanes |
ES2333400T3 (en) | 1999-04-01 | 2010-02-22 | Hana Biosciences, Inc. | COMPOSITIONS AND PROCEDURES TO TREAT LYMPHONES. |
US6342221B1 (en) | 1999-04-28 | 2002-01-29 | Board Of Regents, The University Of Texas System | Antibody conjugate compositions for selectively inhibiting VEGF |
JP5623681B2 (en) | 1999-05-14 | 2014-11-12 | ジェネンテック, インコーポレイテッド | Treatment with anti-ErbB2 antibody |
EP1189634B1 (en) | 1999-06-25 | 2007-02-28 | Genentech, Inc. | Treating prostate cancer with anti-erbb2 antibodies |
US6949245B1 (en) | 1999-06-25 | 2005-09-27 | Genentech, Inc. | Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies |
US20030086924A1 (en) | 1999-06-25 | 2003-05-08 | Genentech, Inc. | Treatment with anti-ErbB2 antibodies |
CN100340575C (en) | 1999-06-25 | 2007-10-03 | 杰南技术公司 | Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies |
DK2283866T3 (en) * | 1999-06-25 | 2015-05-18 | Genentech Inc | METHODS OF TREATMENT USING ANTI-ERBB ANTIBODY-MAYTANSINOID CONJUGATES |
US20040013667A1 (en) | 1999-06-25 | 2004-01-22 | Genentech, Inc. | Treatment with anti-ErbB2 antibodies |
US6362342B1 (en) | 1999-06-29 | 2002-03-26 | Lion Bioscience Ag | Triazole compounds and methods of making same |
US6531131B1 (en) | 1999-08-10 | 2003-03-11 | The United States Of America As Represented By The Department Of Health And Human Services | Conjugate vaccine for Neisseria meningitidis |
US6114365A (en) | 1999-08-12 | 2000-09-05 | Pharmacia & Upjohn S.P.A. | Arylmethyl-carbonylamino-thiazole derivatives, process for their preparation, and their use as antitumor agents |
US6635677B2 (en) | 1999-08-13 | 2003-10-21 | Case Western Reserve University | Methoxyamine combinations in the treatment of cancer |
DE60042693D1 (en) | 1999-08-27 | 2009-09-17 | Genentech Inc | DOSAGE FOR TREATMENT WITH ANTI ERBB2 ANTIBODIES |
US7030231B1 (en) | 1999-09-30 | 2006-04-18 | Catalyst Biosciences, Inc. | Membrane type serine protease 1 (MT-SP1) and uses thereof |
US7303749B1 (en) | 1999-10-01 | 2007-12-04 | Immunogen Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
DE60032633T2 (en) | 1999-11-24 | 2007-10-04 | Immunogen Inc., Cambridge | CYTOTOXIC AGENTS CONTAINING TAXANE AND ITS THERAPEUTIC APPLICATION |
US6632979B2 (en) | 2000-03-16 | 2003-10-14 | Genentech, Inc. | Rodent HER2 tumor model |
US7097840B2 (en) | 2000-03-16 | 2006-08-29 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
KR100788092B1 (en) | 2001-06-20 | 2007-12-21 | 제넨테크, 인크. | Compositions and Methods for the Diagnosis and Treatment of Tumor |
US20040235068A1 (en) | 2001-09-05 | 2004-11-25 | Levinson Arthur D. | Methods for the identification of polypeptide antigens associated with disorders involving aberrant cell proliferation and compositions useful for the treatment of such disorders |
US20080085283A1 (en) | 2001-09-05 | 2008-04-10 | Levinson Arthur D | Methods for the identification of polypeptide antigens associated with disorders involving aberrant cell proliferation and compositions useful for the treatment of such disorders |
DE60238143D1 (en) | 2001-09-18 | 2010-12-09 | Genentech Inc | COMPOSITIONS AND METHODS FOR THE DIAGNOSIS OF TUMORS |
US20050238650A1 (en) | 2002-04-17 | 2005-10-27 | Genentech, Inc. | Compositions and methods for the treatment of tumor of hematopoietic origin |
JP2006502110A (en) | 2002-07-03 | 2006-01-19 | イミュノジェン・インコーポレーテッド | Antibodies against non-released Muc1 and Muc16 and uses thereof |
EP1578371A4 (en) | 2002-08-19 | 2009-05-20 | Genentech Inc | Compositions and methods for the diagnosis and treatment of tumor |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
WO2004110498A2 (en) | 2003-05-14 | 2004-12-23 | Immunogen, Inc. | Drug conjugate composition |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
US7754441B2 (en) | 2003-11-17 | 2010-07-13 | Genentech, Inc. | Compositions and methods for the treatment of tumor of hematopoietic origin |
JP3991983B2 (en) | 2003-12-19 | 2007-10-17 | 日産自動車株式会社 | Vehicle drive control device |
JP4658967B2 (en) | 2003-12-24 | 2011-03-23 | ジェネンテック, インコーポレイテッド | Compositions and methods for the treatment of tumors of hematopoietic origin |
EP1718667B1 (en) | 2004-02-23 | 2013-01-09 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
MXPA06014065A (en) | 2004-06-01 | 2007-01-31 | Genentech Inc | Antibody drug conjugates and methods. |
CN101065151B (en) | 2004-09-23 | 2014-12-10 | 健泰科生物技术公司 | Cysteine engineered antibodies and conjugates |
-
2000
- 2000-09-29 CA CA2385528A patent/CA2385528C/en not_active Expired - Fee Related
- 2000-09-29 EP EP10185092A patent/EP2289549A3/en not_active Withdrawn
- 2000-09-29 EP EP00970516.1A patent/EP1229934B1/en not_active Expired - Lifetime
- 2000-09-29 JP JP2001527762A patent/JP4776843B2/en not_active Expired - Fee Related
- 2000-09-29 AU AU79885/00A patent/AU775373B2/en not_active Ceased
- 2000-09-29 EP EP10184672A patent/EP2266607A3/en not_active Withdrawn
- 2000-09-29 WO PCT/US2000/026800 patent/WO2001024763A2/en active IP Right Grant
-
2003
- 2003-01-29 HK HK03100743.7A patent/HK1049787B/en not_active IP Right Cessation
-
2006
- 2006-06-15 US US11/453,008 patent/US7601354B2/en not_active Expired - Lifetime
-
2007
- 2007-11-01 JP JP2007284684A patent/JP5530060B2/en not_active Expired - Fee Related
-
2011
- 2011-04-27 JP JP2011099295A patent/JP2011148826A/en active Pending
-
2012
- 2012-01-12 US US13/349,078 patent/USRE43899E1/en not_active Expired - Lifetime
- 2012-09-13 US US13/613,743 patent/USRE44704E1/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JP2003528034A (en) | 2003-09-24 |
JP4776843B2 (en) | 2011-09-21 |
HK1049787A1 (en) | 2003-05-30 |
EP1229934A2 (en) | 2002-08-14 |
EP1229934A4 (en) | 2004-11-24 |
JP5530060B2 (en) | 2014-06-25 |
WO2001024763A3 (en) | 2001-10-11 |
AU775373B2 (en) | 2004-07-29 |
EP2266607A3 (en) | 2011-04-20 |
EP1229934B1 (en) | 2014-03-05 |
EP2289549A2 (en) | 2011-03-02 |
EP2266607A2 (en) | 2010-12-29 |
JP2008074863A (en) | 2008-04-03 |
US7601354B2 (en) | 2009-10-13 |
US20060233811A1 (en) | 2006-10-19 |
AU7988500A (en) | 2001-05-10 |
CA2385528A1 (en) | 2001-04-12 |
USRE43899E1 (en) | 2013-01-01 |
JP2011148826A (en) | 2011-08-04 |
HK1049787B (en) | 2014-07-25 |
USRE44704E1 (en) | 2014-01-14 |
EP2289549A3 (en) | 2011-06-15 |
WO2001024763A2 (en) | 2001-04-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2385528C (en) | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents | |
US7303749B1 (en) | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents | |
AU2006236489B2 (en) | Elimination of heterogeneous or mixed cell population in tumors | |
AU765588C (en) | Cytotoxic agents comprising taxanes and their therapeutic use | |
AU2004282491C1 (en) | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates | |
WO2010126552A1 (en) | Potent cell-binding agent drug conjugates | |
JP2024059792A (en) | Methods for targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via non-cleavable linkers, said conjugates, and methods for making said conjugates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKLA | Lapsed |
Effective date: 20150929 |