CA2012993C - Monoclonal antibodies (mabs) against tumor-associated antigens, the preparation and use thereof - Google Patents

Monoclonal antibodies (mabs) against tumor-associated antigens, the preparation and use thereof Download PDF

Info

Publication number
CA2012993C
CA2012993C CA002012993A CA2012993A CA2012993C CA 2012993 C CA2012993 C CA 2012993C CA 002012993 A CA002012993 A CA 002012993A CA 2012993 A CA2012993 A CA 2012993A CA 2012993 C CA2012993 C CA 2012993C
Authority
CA
Canada
Prior art keywords
mab
monoclonal antibody
mabs
variable domain
carcinomas
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 - Lifetime
Application number
CA002012993A
Other languages
French (fr)
Other versions
CA2012993A1 (en
Inventor
Bernhard Auerbach
Gerhard Seemann
Hans H. Sedlacek
Klaus Bosslet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Siemens Healthcare Diagnostics GmbH Germany
Original Assignee
Behringwerke AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Behringwerke AG filed Critical Behringwerke AG
Publication of CA2012993A1 publication Critical patent/CA2012993A1/en
Application granted granted Critical
Publication of CA2012993C publication Critical patent/CA2012993C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3076—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
    • C07K16/3084—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6815—Enzymes
    • 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
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • 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
    • A61K47/6851—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 determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The invention relates to marine monoclonal anti-bodies (MAbs), A, B, C and D, which are directed against tumor-associated antigens. The nearly complete nucleotide sequences of the v genes of these MAbs are described, so that the relevant variable domains can be put together to give chimeric MAbs, or "humanized" MAbs are obtained by inserting the hypervariable regions (complementarity determining regions = CDR) into a human MAb framework.
Antibody constructs of this type can be employed in human therapy and in vivo diagnosis without the disadvantages observed with marine MAbs.

Description

2012gg3.

Monoclonal Antibodies (MAbs) against Tumor-associated antigens, the pr~aration and use thereof Field of the Invention The invention relates to monoclonal antibodies (MAbs), A, B, C, and D, which are directed against tumor-associated antigens and to the preparation and uses thereof.
Summary of the Invention In an embodiment, the present invention provides an epitope which is bound by monoclonal antibodies (blabs) A
or B, where blabs A and B have the variable domains shown in Figures 3 and 4, respectively and monoclonal antibodies directed against the epitope.
In another embodiment, the invention provides monoclonal antibodies which contain a variable domain as shown in Figures 3 or 4. In one embodiment, the monoclonal antibodies of the invention contain a human or murine , but preferably human, antibody framework outside the variable domain. In yet another embodiment, the variable domains outside the antigen-binding sequences are of human origin.
In one embodiment, the invention provides a therapeutic composition containing a monoclonal antibody of the invention and an inert vehicle. In another embodiment, the monoclonal antibodies can be a pharmaceutical and/or a diagnostic aid.
In yet another embodiment, the invention provides molecular constructs containing monoclonal antibodies of the invention or reactive parts thereof. The molecular constructs can be coupled to enzymes or radioactive labels; toxins, catalytic antibodies, combinations of various V-gene specificities, MHC class I or class II
antigens or cytolytic components.
G

20 ~ 2993 - 1a -Brief Description of the Drawings Figure 1 is a plot of absorbance values which are indicative of concentration of antigens) in the samples defined by the specific binding of MAb C in serum samples of healthy blood donors (NS), patients with acute pancreatitis (AP), patients with chromic pancreatitin (CP), and patients with carcinoma of the pancreas (Pan-Ca).
Figure 2 is a graph showing absorbance levels of respective samples of control, Mab 19-9, with and without MAb C , MAb C 50 as described in Example 5.
Figure 3 shows the nucleotide and protein sequences of the (a) VH and (b)VK gene of Mab A.
Figure 4 shows the nucleotide and protein sequences of the (a) VH and (b)VK gene of Mab B.
Figure 5 is shows the nucleotide and protein sequences of the (a) VH and (b)VK gene of Mab C.
Figure 6 is shows the nucleotide and protein sequences of the (a) VH and (b)VK gene of Mab D.
Description The invention relates to murine monoclonal antibodies (MAbs), A, B, C and D, which are directed against tumor-associated antigens. The nearly complete nucleotide sequences of the V genes of these MAbs are described, so that the relevant variable domains can be put together to give chimeric MAbs, or "humanized" MAbs are obtained by inserting the hypervariable regions (complementarity determining regions = CDR) into a human MAb framework. Antibody constructs of this type can be employed in human therapy and in vivo diagnosis without the disadvantages observed with murine MAbs.
MAb A reacts with antigen 2, MAb B reacts with antigen 11 and MAb C reacts with antigen 7, all of which are described in EP-A2 0,141,079 and are membrane associated antigens on permanent human tumor cells lines such as the CaLu-1, Chago, Oat 75, PaTuII and Bewo cell - 1b -line. MAb D is directed against a Vibrio cholerae neur-aminidase (VCN)-sensitive epitope on the ganalioside GD2 which is exposed on human melanoma cell lines.
MAbs A to D were generated as described in EP-A2 0,141,079 and isolated by standard methods.
MAb A binds to cells of the granulocyte compartment and to carcinomas of the colon, pancreas and some of the lung and breast, as shown in Tab. 1.
i 2~~~~~

Tab.l: Binding characteristics of MAb A
Malignant tissue samples Number of Total investigated positives number colorectal carcinomas:
primary carcinomas 6 6 liver metastases 15 16 carcinomas of the pancreas 6 8 carcinomas of the lung:
small-cell 1 2 adeno 9 10 squamous cell 3 4 large-cell 1 2 carcinoma of the breast 1 3 MAb B binds to virtually all carcinomas of the gastro-intestinal tract and to some ovarian carcinomas and adenocarcinomas of the lung, whereas it does not react with most normal human tissues or reacts only with secretion-containing sites thereon. The binding charac-teristics are summarized in Tab. 2.

- 2~~~9~3 Tab.2: Binding characteristics of MAb B
Malignant tissue samples Number of Total investigated positives number colorectal carcinomas:
primary 6 6 liver metastases 9 10 carcinomas of the pancreas 5 6 carcinomas of the stomach 4 4 carcinomas of the lung:
small-cell 2 11 adeno 9 10 squamous cell 2 12 large-cell 4* 12 carcinoma of the breast 2 9 ovarian carcinomas (secretion-containing sites) 4 6 carcinomas of the kidneys 1 12 weak, heterogeneous reaction MAb C shows a distinct reaction with 70-80% of stage I
and II primary tumors of carcinoma of the pancreas (11/14). Like the primary tumors, most grade I and II
metastases of carcinoma of the pancreas appear to have a positive reaction (3/4). The type of reaction on these positive tissues indicates that the epitope recognized by MAb C is located in the cytoplasm, on the membrane and in the intercellular space.

~(~~.~993 Grade III carcinomas of the pancreas do not express the epitope (primary tumor 0/2, metastases 0/5). However, since grade I and II carcinomas of the pancreas comprise up to 95% of carcinomas of the pancreas, MAb C ought to react with 60-70% of all carcinomas of the pancreas.
Another important property of MAb C is its reactivity with the duct system in the chronically inflamed pancreas (pancreatitis 10/13), whereas there is no detectable binding to healthy exocrine and endocrine pancreatic tissue (0/8). Only a minority of the investigated primary tumors of carcinoma of the colon was reactive (4/14), whereas most of the liver metastases of carcinoma of the colon showed distinct binding (7/10).
Cross-reactivities of MAb C are confined to the mucus-producing goblet cells of the colonic mucosa and of the stomach. All the other normal tissue tested, including peripheral blood leukocytes and bone marrow, do not express the mucus-associated epitope recognized by MAb C
(see Tab. 3). *) see end of page 5!
Tab.
Summary of the formaldehyde-fixed, paraffin-embedded human tissue investigated (indirect immunoperoxidase) with MAb C.
Pancreatic tumors Grade I/II Grade III
primary carcinoma 11/14 0/2 liver metastases of carcinoma 3/4 0/5 papillary carcinoma 1/2 cystadenoma 0/1 Pancreatic tissue ducts with changes due to pancreatitis 10/13 - 5 - 2~9..~~~~
Tab. 3 continued Grade I/II Grade III
normal exo- and endocrine pancreas 0/8 Carcinomas of the colon primary tumors 4/14 liver metastases 7/10 Normal colonic tissue goblet cells of the mucosa, luminal part 9/10 part of the mucosa facing the muscularis 3/10 muscularis mucosae 0/7 tunica muscularis 0/7 submucosa 0/7 Carcinomas of the lunq 8/18 (a few twnor cells) Carcinomas of the breast 0/3 Other normal tissue investigated lung 0/3 liver 0/5 breast 0/1 Stomach muscle 0/2 mucus-prod. cells 3/3 kidney 0/5 lymph nodes 0/4 spleen 0/2 bone marrow 0/1 peripheral blood leukocytes 0/2 connective tissue 0/2 muscles 0/10 *) MAK C recognizes an epitope located on a tumor associated antigen which can be detected at increased levels of patients with gastrointestinal tumors e. g. carcinomas of the pancreas and thus may be used as a tumor marker.

MAb D recognizes a VCN-sensitive epitope on the ganglio-side GD2 which does not occur on other bovine cerebral gangliosides, including GD3, GM3, GM1, GTla. GDlb. GDla and GM4. Using MAb D it was possible to stain all gliomas, meningiomas and neurilemmomas in normal human cerebral tissue. Tab. 4 summarizes the binding properties of MAb D
with respect to intracranial tumors.
Tab. 4 Number of tumors Positive Total number Type of tumor well-differentiated gliomas, grade I-II 6 6 malignant gliomas, grade III-IV 10 10 meningiomas il 11 neurilemmomas 4 4 pineal adenomas 0 5 metastases of carcinomas 0 1 The epitope defined by MAb D is also present on neuro-blastomas, ganglioneuroblastomas and ganglioneuromas.
Tab. 5 shows a summary.

- ~~~~993 Tab. 5 Reactivity of MAb D with neuroblastomas and small round-cell tumors in children Number of tumors Neuroblastomas Positive Total number Grade I 1 1 Grade II 6 6 Grade III 4 4 ganglioneuroblastomas 3'°' 3 Ewing sarcomas 0 2 rhabdomyosarcomas 0 1 non-Hodgkin lymphomas 2'°°' 5 x Hughes classification xx ganglion cells xxx some positive tumor cells Thus, MAb D is suitable for differential diagnosis of neuroblastomas and small round-cell tumors in children.
The specificity of MAb D for two other tumors derived from the neuroectoderm, namely melanomas and small-cell carcinomas of the lung (SCLC) and for unrelated tumors is shown in Tab. 6.

-8- 2012gg3 Tab. 6 Number of tumors Positive Total number melanoma 4' 10 SCLC 2' 11 carcinomas of the colon 0 3 carcinomas of the breast 0 3 non-SCLC:

adenocarcinomas 0 3 squamous cell carcinomas of the lung 0 3 large-cell carcinomas 0 3 " Weak and heterogeneous staining of a few tumor cells The immunoglobulin V genes of MAb A to MAb D were iso-lated using the methods detailed in the Examples.
The nucleotide and protein sequences are shown in Figure 3 (V gene of MAb A), Figure 4 (V gene of MAb B), Figure 5 (V gene of MAb C) and Figure 6 (V gene of MAb D). The CDRs can be identified therein as described by Kabat and Wu (loc. cit., see Examples p. 9).
Accordingly, the invention relates to the epitopes specified by MAbs A, B, C and D, monoclonal antibodies against these epitopes, with MAbs A, B, C and D being particularly preferred, and monoclonal antibodies which contain the V genes specified above, or parts thereof (complementarity determining regions), with a human antibody framework or framework parts being preferred.
The invention furthermore relates to constructs which contain these V genes or parts thereof together with enzymes or radioactive labels or toxins or catalytic antibodies or combinations of various V-gene specifici-' ties or MFiC class I or class II antigens or cytolytic 2L~~.~~~~
- g _ components. :'finally the invention relates to pharmaceuti-cals containing the MAb's specified above anti the use cf said MAb's or in vivo or in vitro diagnosis.
'the invention is furthermore contained in the Examples and the patent claims.
Examples:
The polymerase chain reaction (PCR) described by Saiki et al., Science 230, 1350-1354 (1985) was employed herein-after for the cloning and expression of the variable domain of murine immunoglobulins (Ig).
1. Identification of the conserved regions at the 5' and 3' end of the murine heavy Ig chain (VH) and the light Ig chain (VK).
The mutually aligned sequences of the variable regions were taken from the data file of Rabat et al. Sequences of Proteins of Immunological Interest, US Dept. of Health and Human Services, US Government Printing Office (1987).
The nucleotide sequences start there at the amino ter-minus of the mature protein and do not include the signal sequences. Computer screening (DBUTIL, R. Staden (1986) Nucleic Acids Res. 14, 217-231) was used to find suitable primers for cDNA synthesis and amplimers for use in the PCR:
OliQOnucleotide I:
Bst EII VH1FORWARD
5' TGA GGA GAC GGT GAC CGT GGT CCC TTG GCC CCA 3' OliQOnucleotide II:
CKl 5' TGC AGC ATC AGCC 3' Olicronucleotide III:
5' AG GTC CAG CTG CAG GAG TCT GG 3' G A A C A
PstI

OliQOnucleotide IV:
5' GAC ATT CAG CTG ACC CAG TCT CCA 3' PvuII

Oliaonucleotide V:

5' GTT AGA TCT CCA GCT TGG TCC C 3' Bgl II
2. cDNA synthesis RNA was prepared from about 3 x 108 cells of the par-ticular hybridomas which secrete MAb A, B, C or D, and poly A+ mRNA was enriched from the latter using oligo dT
Sepharose . The poly A+ mRNA was used for the cDNA syn-thesis. The first strands of cDNA were synthesized using oligonucleotide primers which hybridize in the J region of the V8 nucleotide sequences (oligonucleotide I) and at the 5' end of the kappa C gene nucleotide sequences (oligonucleotide II).
The RNA is then decomposed by NaOH treatment. The second strands of cDNA were synthesized using oligonucleotide primers which hybridize at the 5' ends of the V8 (oligo-nucleotide III) and of the Vkap~ (oligonucleotide IV) nucleotide sequences.
3. Amplification of the synthesized cDNA and sequencing of the variable domains The DNA generated as described in 2. was amplified using oligonucleotides I, III, IV and V (oligonucleotide V
hybridizes in the J region of the V,~p~, nucleotide sequences) and the Taq DNA polymerase from Thermophilus aquatius. A typical mixture contained in 50 11 total volume 5 11 of ds DNA (prepared in 2.), 25 pmol of amplimers, and was 250 1M in each of dATP, dTTP, dCTP and dGTP, 67 mM tris-HC1 pH 8.8, 17 mM (NHa)ZS04, 10 mM MgCl2, 200 1g/ml gelatin and 2 units of Taq polymerase. A layer of liquid paraffin was placed on the mixture and then 25 cycles each of 1 min at 95°C (for denaturation), 1 min at 30°C (hybridization) and 2 min at 72°C (DNA synthesis) were carried out using a Techne PHC-1 programmable heating block.
The oligonucleotides used for the cDNA cloning and amplification contain restriction cleavage sites. The cDNA cloning and the amplification resulted in these restriction cleavage sites being introduced at the 5' end and at the 3' end of the V$ and V,~p~ nucleotide sequences (Pst I and BstEII in Ve and PvuII and BglII in V~p~).
These restriction cleavage sites were then used to clone V$ and VR cDNA fragments in M13 vectors (Lys 19, Lys 17) (Verhoyen et al. Science 239, (1988), 1534-1536).
Finally, the nucleotide sequences of the particular VH and V,~ppa cDNA fragments were determined using the method of Sanger (PNAS, iJSA, 74, 5463-5467, ( 1977 ) ) from the Lys 19 and Lys 17 vectors (see Figures 3, 4, 5, 6).

Examples 4 and 5 shall explain the use of the MAb C
described using MAb C:
Euample 4:
Mab C was fixed to the wells of microtitration plates (Nunc) by adsorption. Into these wells 20 ~C1 sample plus 100 ~1 buffer-solution (OSND, Behringwerke AG) each was pipetted and 2 respective 3 hours incubated. After threefold washing with diluted EnzygnostR washing solu-tion (OSEN, Behringwerke AG) 100 ~1 conjugate-solution was filled into each well. Used here were conjugates of peroxidase with lectin (e. g. wheat germ agglutinin '--WGA) or with other antibodies recognizing different epitopes of the tumor-associated antigens defined by MAb C. The following two or three hours incubation step at 37°C was terminated by 3 wash cycles. For the third incubation step at room temperature 100 ~1 each of a buffer/substrate-chromogene solution (OUVG/OUSF Behring-werke AG) was filled into the wells and the enzyme reaction was terminated after 30 min. with 100 ~1 of stopping solution EnzygnostR (OSFA, Behringwerke AG).
Absorbance of the samples was measured at 450 mm.
result:
The absorbance values determined as shown above correspond to the concentration of the antigens) in the samples. The concentration of the antigen defined by the specific binding of MAb C, in serum or plasma of tumor patients is significantly elevated as compared to said concentration of healthy control persons or patients with benign disease. This is especially true for patients with carcinoma of the pancreas (Fig. 1). In Figure 1 NS signifies serum samples o healthy blood donors (n=141); AP means serum samples of patients with acute pancreatitis (n=56). CP means serum samples of patients which chromic pancreatitin (n=40) and Pan-Ca means patients with carcinome of the pancreas (n-82). A means asorance.
Significantly elevated concentrations were also determined in serum or plasma of patients with carcinoma of the stomach, colon or rectum. Equally good results were obtained irrespective of the conjugate system (antibody-peroxidase or WGA-peroxidase). With the use of MAb C as specific binding-component a sensitive test for tumor markers of especially gastrointestinal tumor disease can be made.
Exaa:pl. 5:
5 ~tg each of MAb C or MAb C 50 as control (Pharmacia;
Holmgren et al. (1984) British Med. J. 288, 1479) were pipeted in 50 ~1 phosphate-buffered-saline (PBS) into a CA 19-9 Test (CA 19-9 EIA "Roche"). The highest standard (100 U/ml) was added before start of the incubation. The tests were perfonaed according to the instructions of the test-kit above and the absorbances of the respective samples were determined.
~tesult:
The additional dilution of the standard-antigen after addition of the PBS-solution reduces the signal of the highest standard even without addition of MAb. No further reduction of the signal results by the presence of MAb C
in the assay. In contrast hereto the signal formation is totally inhibited by MAb C 50, which as is known binds among others specifically to the epitope "sialosyl Lea"
recognized also by MAb 19-9: From the above one may conclude that MAb C recognizes a different epitope as MAb 19-9. (See Fig. 2).

-- 13 a -Table 7 vH
MAb A
Q V Q L Q E S G G G L V Q P G G S L R L
CAGGTCCAACTGCAGGAGTCTGGP:GGAGGCTTGGTACAGCCTGGGGGTTCTCTGAGACTC

S C A T S G F S D Y Y M N W V R Q P P G
TCCTGCGCAACTTCTGGGTTCAGTGATTACTACATGAACTGGGTCCGCCAGCCTCCAGGA

K A L E W L G F I S N K P N G H T T E Y
AAAGCACTTGAGTGGTTGGGTTTTATTTCAAACAAACCTAATGGTCACACAACAGAGTAC

S A S V K G R F T I S R D N S Q S I L Y
AGTGCATCTGTGAAGGGTCGGTTCACCATCTCCAGAGATAATTCCCAAAGCATCCTCTAT

L Q M N T L R A E D S A T Y Y C A R D K
CTTCAAATGAACACCCTGAGAGCTGAGGACAGTGCCACTTATTATTGTGCAAGAGATAAG

G I R W Y F D V W G Q G T T V T V S S
GGAATACGATGGTACTTCGATGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA

VK
MAb A
A I L S A S P G E K V T M T C R A S S S
AGCAATCCTGTCTGCATCTCCAG~GTCACAATGACTTGCAGGGCCAGCTCAAG

V S Y M H W Y Q Q K P G S S P K P W I Y
TGTAAGTTACATGCACTGGTACCAGCAGAAGCCAGGATCCTCCCCCAAACCCTGGATTTA

A T S N L A S G V P A R F S G S G S G T
TGCCACATCCAACCTGGCTTCTGGAGTCCCTGCTCGCTTCAGTGGCAGTGGGTCTGGGAC
130 140 lso lso 170 lao S Y S L T I I R V E A E D A A T Y Y C Q
CTCTTACTCTCTCACAATCATCAGAGT~TGAAGATGCTGCCACTTATTACTGCCA

Q W S S N P L T F G A G T K L E I
GCAGTGGAGTAGTAACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGATC

Table 8 MAb B
VH
L Q E S G P D L V K P S Q S L S L T C T
CTGCAGGAGTCAGGACCTGACCTGGTGAAACCTTCTCAGTCACTTTCACTCACCTGCACT

V T G Y S I T S G Y S W H W I R Q F P G
GTCACTGGCTACTCCATCACCAGTGGTTATAGCTGGCACTGGATCCGGCAGTTTCCAGGA

N K L E W M G Y I Q Y S G I T N Y N P S
AAC~P.AACTGGAATGGATGGGCTACATACAGTACAGTGGTATCACTAACTACAACCCCTCT

L K S R I S I T R D T S K N Q F F L Q L
CTCAAA.AGTCGAATCTCTATCACTCGAGACACATCCAAGAACCAGTTCTTCCTGCAGTTG

N S V T T E D T A T Y Y C A R, E D Y D Y
AATTCAGTGACTACTGAGGACACAGCCACATATTACTGTGCAAGAGAAGACTATGATTAC

H W Y F D V W G A G T T V T V S S
CACTGGTACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCA

MAb B
VK
L T Q S P A I M S A S L G E E I T L T C
CTGACCCAGTCTCCAGCAATCATGTCTGCATCTCTAGGGGAGGAGATCACCCTAACCTGC

S T S S S V S Y M H W Y Q Q K S G T S P
AGTACCAGCTCGAGTGTAAGTTACATGCACTGGTACCAGCAGAAGTCAGGCACTTCTCCC

K L L I Y S T S N L A S G V P S R F S G
AAACTCTTGATTTATAGCACATCCAACCTGGCTTCTGGAGTCCCTTCTCGCTTCAGTGGC

S G S G T F Y S L T I S S V E A E D A A
AGTGGGTCTGGGACCTTTTATTCTCTCACAATCAGCAGTGTGGAGGCTGAAGATGCTGCC

D Y Y C H Q W S S Y P T F G G G T K L E
GATTATTACTGCCATCAGTGGAGTAGTTATCCCACGTTCGG1~~~GGGGGACCAAGCTGGAG

Table 9 MAb C
VH
Q V Q L Q Q S G P E L V K P G A S V K M
CAGGTCCAACTGCAGCAGTCTGGACCTGAGCTGGTAAAGCCTGGGGCTTCAGTGAAGATG

S C K A S G Y T F T Y Y V I H W V K Q K
TCCTGCAAGGCTTCTGGATACACATTCACTTACTATGTTATTCACTGGGTGAAACAGAAG

P G Q G L E W I G Y I H P Y N A G T E Y
CCTGGGCAGGGCCTTGAGTGGATTGGATACATTCATCCTTACAATGCTGGTACTGAGTAC

N E K F K G K A T L T S D K S S S T A Y
AATGAGAAGTTCAAAGGCAAGGCCACACTGACTTCAGACP.AATCCTCCAGCACAGCCTAC

M E L S S L T S E D S A V Y Y C S M G R
ATGGAGCTCAGCAGCCTGACCTCTGAGGACTCTGCGGTCTATTACTGTTCAATGGGACGA

G G D Y W G Q G T T V T V S S
GGGGGTGACTACTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA

MAb C
vx L T Q S P A I M S A S P G E K V T M T C
CTGACCCAGTCTCCAGCAATTATGTCTGCATCTCCTGGGGAGAAGGTCACCATGACCTGC

S A S S S V S Y M H W Y Q Q K S G T S P
AGTGCCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGTCAGGCACCTCCCCC
7o ao 90 loo ll0 120 K R W I Y D T S K L A S G V P A R F S G
AAAAGATGGATTTATGACACATCCAAACTGGCTTCTGGAGTCCCTGCTCGCTTCAGTGGC

S G S G T S Y S L T I S S M E A E D A A
AGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGCATGGAGGCTGAAGATGCTGCC

T Y Y C Q Q W S S N P F T F G A G T K L
ACTTATTACTGCCAGCAGTGGAGTAGTAACCCATTCACGTTCGGCGCGGGGACCAAGCTG

E I
GAGATC

- 16 - i~~~.i~~~~
Table 10 MAb D
A E S G P G L V R L T S L S I T C T V S
GCAGAGTCAGGGCCTGGCCTGGTGCGCCTCACGAGCCTGTCCATCACTTGCACTGTCTCT

G F S L I S Y G V H W V R Q P P G K G L
GGCTTTTCATTAATTAGTTATGGTGTACACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTG

E W L G V I W A G G S T N Y N S A L M S
GAGTGGCTGGGAGTAATATGGGCAGGTGGAAGCACAAATTATAATTCGGCTCTCATGTCC

R L S I S K D N S K S Q V F L K M N S L
AGACTGAGCATCAGCAAAGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTG

Q T G D T A I Y Y C A R G G D D Y D G F
CAAACTGGTGACACAGCCATATACTACTGTGCCAGAGGGGGGGATGATTACGATGGGTTT

A Y W G Q G T T V T V S S G E S
GCTTACTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGGTGAGTCC

VK
MAb D
L A Q S T K R K N Y L A W Y Q Q K P G Q
TCTGGCTCAGAGTp~C:AAAGC~TACTTGGCTTGGTACCAGCAGAAACCAGGTCA

S P K L L I Y W A S T R E S G V P D R F
GTCTCCTAAACTACTGATCTACTGGGCATCCACTCGGGAPrTCTGGGGTCCCTGATCGCTT

T G S G S G T D F T L T I S S V Q A E D
CACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGA

L A V Y Y C K Q S Y N L R A F G G G T K
CCTGGCAGTTTATTACTGCAAACAATCTTATAATCTTCGGGCGTTCGGTG~C~AGGCACCAA

L E I K
GCTGGAGATCAAA

Claims (11)

1. A monoclonal antibody directed against an epitope taken from carcinogenic tissue wherein the monoclonal antibody is MAb A having a variable domain having an amino acid sequence shown in Figure 3 or MAb B having a variable domain having an amino acid sequence shown in Figure 4.
2. A monoclonal antibody which contains a variable domain as shown in Figure 3 or 4.
3. A monoclonal antibody as claimed in claim 1 or 2, which contains a human antibody framework outside the variable domain.
4. A monoclonal antibody as claimed in claim 3, wherein the variable domain outside the antigen-binding sequence is of human origin.
5. A monoclonal antibody as claimed in claim 3, which contains a murine antibody framework outside the variable domain.
6. A pharmaceutical composition comprising a monoclonal antibody as claimed in any one of claims 1, 2, 3, 4, 5 or 6 and an inert carrier.
7. A diagnostic aid comprising a monoclonal antibody as claimed in anyone of claims 1, 2, 3, 4, 5 or 6.
8. A therapeutic composition containing a monoclonal antibody as claimed in any one of claims 1, 2, 3, 4, 5 or 6 and an inert vehicle.
9. A molecular construct containing as portion monoclonal antibodies or reactive parts thereof as claimed in any one of claims 1, 2, 3, 4, 5 or 6.
10. A molecular construct as claimed in claim 9, wherein enzymes or radioactive labels are coupled.
11. A molecular construct as claimed in claim 9, wherein toxins or catalytic antibodies or combination of various V-gene specificities or MHC
class I or class II antigens or cytolytic components are coupled.
CA002012993A 1989-03-24 1990-03-23 Monoclonal antibodies (mabs) against tumor-associated antigens, the preparation and use thereof Expired - Lifetime CA2012993C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3909799A DE3909799A1 (en) 1989-03-24 1989-03-24 MONOCLONAL ANTIBODIES (MAK) AGAINST TUMOR ASSOCIATED ANTIGENS, THEIR PRODUCTION AND USE
DEP3909799.4 1989-03-24

Publications (2)

Publication Number Publication Date
CA2012993A1 CA2012993A1 (en) 1990-09-24
CA2012993C true CA2012993C (en) 2001-07-03

Family

ID=6377161

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002012993A Expired - Lifetime CA2012993C (en) 1989-03-24 1990-03-23 Monoclonal antibodies (mabs) against tumor-associated antigens, the preparation and use thereof

Country Status (12)

Country Link
US (3) US6926896B2 (en)
EP (3) EP0727435B1 (en)
JP (1) JP3043772B2 (en)
KR (1) KR100189046B1 (en)
AT (3) ATE140486T1 (en)
AU (1) AU628948B2 (en)
CA (1) CA2012993C (en)
DE (4) DE3909799A1 (en)
DK (3) DK0727436T3 (en)
ES (3) ES2116790T3 (en)
GR (1) GR3020610T3 (en)
PT (1) PT93536B (en)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ229159A (en) * 1988-05-17 1992-11-25 Soldano Ferrone Anti-idiotype antibodies which bind to the idiotype of murine antibody 225.28
DE3909799A1 (en) * 1989-03-24 1990-09-27 Behringwerke Ag MONOCLONAL ANTIBODIES (MAK) AGAINST TUMOR ASSOCIATED ANTIGENS, THEIR PRODUCTION AND USE
DE3920358A1 (en) 1989-06-22 1991-01-17 Behringwerke Ag BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE
DE4106389A1 (en) * 1991-02-28 1992-09-03 Behringwerke Ag FUSION PROTEINS FOR PRODRUG ACTIVATION, THEIR PRODUCTION AND USE
US6610299B1 (en) 1989-10-19 2003-08-26 Aventis Pharma Deutschland Gmbh Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates
US7241595B2 (en) 1989-10-20 2007-07-10 Sanofi-Aventis Pharma Deutschland Gmbh Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates
DE4033120A1 (en) * 1990-10-18 1992-04-23 Boehringer Mannheim Gmbh Genomic DNA fragment encoding antibody variable region prodn. - by attaching primers to hybridoma DNA then subjecting to polymerase chain reaction, for constructing genes encoding chimeric antibodies
DE4133791A1 (en) * 1991-10-11 1993-04-15 Behringwerke Ag MONOCLONAL ANTIBODIES AGAINST TUMOR ASSOCIATED ANTIGENS, METHOD FOR THEIR PRODUCTION AND THEIR USE
DE4225853A1 (en) * 1992-08-05 1994-02-10 Behringwerke Ag Granulocyte-binding antibody fragments, their production and use
US6030797A (en) * 1992-10-08 2000-02-29 Dade Behring Marburg Gmbh Monoclonal antibodies against tumor-associated antigens, processes for the preparation thereof and the use thereof
GB9525180D0 (en) * 1995-12-08 1996-02-07 Univ Mcgill Design of hormone-like antibodies with agonistic and antagonistic fuctions
US5905027A (en) * 1995-12-27 1999-05-18 Uab Research Foundation Method of diagnosing and treating gliomas
MA24512A1 (en) * 1996-01-17 1998-12-31 Univ Vermont And State Agrienl PROCESS FOR THE PREPARATION OF ANTICOAGULATING AGENTS USEFUL IN THE TREATMENT OF THROMBOSIS
CA2420193A1 (en) * 2000-08-24 2002-02-28 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
US20060088899A1 (en) * 2002-05-31 2006-04-27 Alvarez Vernon L Combination chemotherapy with chlorotoxin
AU2009246142A1 (en) 2008-05-15 2009-11-19 Transmolecular, Inc. Treatment of metastatic tumors
CA2774260C (en) * 2009-09-16 2018-10-09 Immunomedics, Inc. Class i anti-cea antibodies and uses thereof
US9018347B2 (en) 2010-02-04 2015-04-28 Morphotek, Inc. Chlorotoxin polypeptides and conjugates and uses thereof
KR101972173B1 (en) 2010-05-11 2019-04-24 프레드 헛친슨 켄서 리서치 센터 Chlorotoxin variants, conjugates, and methods for their use
WO2011144744A1 (en) 2010-05-20 2011-11-24 Therapharm Gmbh Targeted radioactive compound for human cd66 for the treatment of disorders
US20140179560A1 (en) 2012-12-10 2014-06-26 Fred Hutchinson Cancer Research Center Drug discovery methods and platforms
US11559580B1 (en) 2013-09-17 2023-01-24 Blaze Bioscience, Inc. Tissue-homing peptide conjugates and methods of use thereof
EP3351271A1 (en) 2017-01-23 2018-07-25 TheraPharm GmbH Radioimmunoconjugate for use in treating bone marrow associated diseases

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1193378A (en) 1967-04-11 1970-05-28 Rand Dev Corp Cancer Antigen Complexes
US3862925A (en) 1973-07-05 1975-01-28 American Home Prod Preparation of somatotropin release inhibiting factor and intermediates therefor
US4349528A (en) 1979-11-21 1982-09-14 The Wistar Institute Monocolonal hybridoma antibody specific for high molecular weight carcinoembryonic antigen
US4331647A (en) 1980-03-03 1982-05-25 Goldenberg Milton David Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers
US4444744A (en) 1980-03-03 1984-04-24 Goldenberg Milton David Tumor localization and therapy with labeled antibodies to cell surface antigens
US4460561A (en) 1980-03-03 1984-07-17 Goldenberg M David Tumor localization and therapy with labeled antibodies specific to intracellular tumor-associated markers
US4582797A (en) 1980-09-25 1986-04-15 The Salk Institute For Biological Studies Monoclonal antibodies specific for human hematopoietic cell surface glycoproteins
US4446240A (en) 1981-01-30 1984-05-01 Nerenberg Samuel T Pancreas specific protein systems
US4522918A (en) 1981-12-15 1985-06-11 Jeffery Schlom Process for producing monoclonal antibodies reactive with human breast cancer
US4612282A (en) 1981-12-15 1986-09-16 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Monoclonal antibodies reactive with human breast cancer
JPH0811075B2 (en) 1982-06-30 1996-02-07 雄治 松岡 Monoclonal anti-CEA antibody
US4485093A (en) 1982-08-13 1984-11-27 Runge Richard G Immunotoxin conjugate which comprises arsanilic acid, useful for treating malignant tumors, particularly pancreatic cancer
CA1215331A (en) 1983-03-04 1986-12-16 Tsann M. Chu Monoclonal antibodies to human breast carcinoma cells and their use in diagnosis and therapy
US4579827A (en) 1983-03-11 1986-04-01 Sloan-Kettering Institute For Cancer Research Monoclonal antibodies to human gastrointestinal cancers and hybridoma method of production of the monoclonal antibodies
US4569788A (en) 1983-05-18 1986-02-11 The United States Of America As Represented By The Department Of Health And Human Services Monoclonal antibodies against non small cell lung cancer
US4677058A (en) 1983-05-19 1987-06-30 Karl Tryggvason Detecting malignant cells with monoclonal antibodies specific to type IV collagenase enzyme
DE3416774A1 (en) 1984-05-07 1985-11-14 Behringwerke Ag, 3550 Marburg MONOCLONAL ANTIBODIES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE
DE3531301A1 (en) 1985-09-02 1987-03-05 Behringwerke Ag MONOCLONAL ANTIBODIES AGAINST TUMOR ASSOCIATED GLYCOPROTEINS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE
US6294172B1 (en) * 1983-08-12 2001-09-25 Dade Behring Marburg Gmbh Monoclonal antibodies with specificity for membrane-associated antigens
DE3329184A1 (en) 1983-08-12 1985-02-21 Behringwerke Ag, 3550 Marburg MONOCLONAL ANTIBODIES WITH SPECIFICITY FOR MEMBRANE-ASSOCIATED ANTIGENS
EP0145373B1 (en) * 1983-11-23 1992-03-25 The Ohio State University Research Foundation Purification of cancer-associated protein and preparation of antibody thereto
US4585742A (en) 1983-12-14 1986-04-29 Dana-Farber Cancer Institute, Inc. Monoclonal antibody with specificity to human small cell carcinoma and use thereof
NZ210867A (en) 1984-01-31 1989-01-06 Litton Bionetics Inc Tumour-specific monoclonal antibodies, production thereof and use
US4753894A (en) 1984-02-08 1988-06-28 Cetus Corporation Monoclonal anti-human breast cancer antibodies
US4645828A (en) 1984-03-23 1987-02-24 Oncogen Platelet related growth regulator
EP0160446B1 (en) 1984-05-01 1992-06-17 Ciba Corning Diagnostics Corp. Breast tumor-associated antigen and monoclonal antibodies specific thereto
US4683200A (en) 1984-05-17 1987-07-28 Setsuo Hirohashi Monoclonal antibody to human cancer antigen and method for producing same
JPS6144900A (en) * 1984-08-08 1986-03-04 Green Cross Corp:The Monoclonal antibody and reagent for detecting cancer antigen
US4590071A (en) * 1984-09-25 1986-05-20 Xoma Corporation Human melanoma specific immunotoxins
CA1339798C (en) 1985-02-01 1998-04-07 Alan N. Houghton Method for treatment of neuroectodermal malignancies and epithelial carcinomas in humans
US5169939A (en) * 1985-05-21 1992-12-08 Massachusetts Institute Of Technology & Pres. & Fellows Of Harvard College Chimeric antibodies
AU617652B2 (en) * 1986-09-19 1991-12-05 Scripps Clinic And Research Foundation Monoclonal paratopic molecule directed to human ganglioside gd2
IL84285A (en) * 1986-10-27 1993-03-15 Int Genetic Engineering Chimeric antibody with specificity to human tumor antigen
DK554886A (en) * 1986-11-19 1988-07-18 Novo Industri As ANTIBODIES
US4810781A (en) * 1987-01-15 1989-03-07 The George Washington University Methods of preparing epitopes of tumor associated antigens
US5204244A (en) * 1987-10-27 1993-04-20 Oncogen Production of chimeric antibodies by homologous recombination
EP0365209A3 (en) * 1988-10-17 1990-07-25 Becton, Dickinson and Company Anti-leu 3a amino acid sequence
JP2919890B2 (en) * 1988-11-11 1999-07-19 メディカル リサーチ カウンスル Single domain ligand, receptor consisting of the ligand, method for producing the same, and use of the ligand and the receptor
DE3909799A1 (en) * 1989-03-24 1990-09-27 Behringwerke Ag MONOCLONAL ANTIBODIES (MAK) AGAINST TUMOR ASSOCIATED ANTIGENS, THEIR PRODUCTION AND USE
US5580774A (en) * 1989-07-31 1996-12-03 Eli Lilly And Company Chimeric antibodies directed against a human glycoprotein antigen

Also Published As

Publication number Publication date
ATE166883T1 (en) 1998-06-15
ES2090052T3 (en) 1996-10-16
CA2012993A1 (en) 1990-09-24
US20020068056A1 (en) 2002-06-06
DK0727435T3 (en) 1999-02-01
AU5215090A (en) 1990-11-08
JPH032200A (en) 1991-01-08
KR100189046B1 (en) 1999-06-01
DE59010418D1 (en) 1996-08-22
US7662383B2 (en) 2010-02-16
DE3909799A1 (en) 1990-09-27
ATE140486T1 (en) 1996-08-15
US6926896B2 (en) 2005-08-09
ES2116790T3 (en) 1998-07-16
ATE166882T1 (en) 1998-06-15
US20090246132A1 (en) 2009-10-01
PT93536A (en) 1990-11-07
AU628948B2 (en) 1992-09-24
EP0727435B1 (en) 1998-06-03
GR3020610T3 (en) 1996-10-31
EP0727436A1 (en) 1996-08-21
DE59010826D1 (en) 1998-07-09
JP3043772B2 (en) 2000-05-22
US20060159682A1 (en) 2006-07-20
EP0388914A1 (en) 1990-09-26
PT93536B (en) 1996-03-29
KR900013986A (en) 1990-10-22
DK0727436T3 (en) 1999-02-01
ES2116789T3 (en) 1998-07-16
DK0388914T3 (en) 1996-11-04
EP0727435A1 (en) 1996-08-21
EP0388914B1 (en) 1996-07-17
EP0727436B1 (en) 1998-06-03
DE59010825D1 (en) 1998-07-09

Similar Documents

Publication Publication Date Title
CA2012993C (en) Monoclonal antibodies (mabs) against tumor-associated antigens, the preparation and use thereof
EP0783313B1 (en) Cdr-grafted type iii anti-cea humanized mouse monoclonal antibodies
WO2004081051A1 (en) Bispecific antibodies
US20200255536A1 (en) Target for b-cell disorders
WO1998012227A1 (en) Recombinant single chain antibodies directed against the gp54 cancer marker, composition comprising same and use thereof
JP2016540826A (en) Anti-EFNA4 antibody-drug conjugate
Krishnan et al. Chimerization of mu‐9: A colon‐specific antigen‐p antibody reactive with gastrointestinal carcinomas
US20230085269A1 (en) Anti- muc1-sea antibodies
OA20958A (en) Anti- MUC1-sea antibodies
AU689331C (en) CDR-grafted type III anti-CEA humanized mouse monoclonal antibodies
AU2002361885B2 (en) Methods for using anti-MUC18 antibodies
Colnaghi et al. Monoclonal Antibodies in Diagnosis, Prognosis, and Therapy of Human Carcinomas: Clinical Impact 20 Years Later

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry