CA1309340C - Cationized antibodies for delivery through the blood-brain barrier - Google Patents
Cationized antibodies for delivery through the blood-brain barrierInfo
- Publication number
- CA1309340C CA1309340C CA000574859A CA574859A CA1309340C CA 1309340 C CA1309340 C CA 1309340C CA 000574859 A CA000574859 A CA 000574859A CA 574859 A CA574859 A CA 574859A CA 1309340 C CA1309340 C CA 1309340C
- Authority
- CA
- Canada
- Prior art keywords
- antibodies
- antibody
- cationized
- blood
- antigen
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
CATIONIZED ANTIBODIES FOR DELIVERY
THROUGH THE BLOOD BRAIN BARRIER
Abstract of the Disclosure The rate of trancytosis of antibodies across the blood-brain barrier is increased by cationizing the antibodies to provide cationized antibodies having an isoelectric point of between about 8.0 to 11Ø The increased rates of transport across the blood-brain barrier makes such cationized antibodies useful for both neurodiagnostic and neuropharmaceutical purposes.
Methods for preparing such cationized antibodies are disclosed.
THROUGH THE BLOOD BRAIN BARRIER
Abstract of the Disclosure The rate of trancytosis of antibodies across the blood-brain barrier is increased by cationizing the antibodies to provide cationized antibodies having an isoelectric point of between about 8.0 to 11Ø The increased rates of transport across the blood-brain barrier makes such cationized antibodies useful for both neurodiagnostic and neuropharmaceutical purposes.
Methods for preparing such cationized antibodies are disclosed.
Description
q ~ 4 0 CATIONIZED ANTIBODIES FOR
DELIVERY THROUGH THE BLOOD-BRAIN BARRIER
Backqround of the Invention The present invention relates generally to the use of antibodies for treatment and diagnosis of neurologi-cal diseases. More particularly, the present invention deals with the modification of antibodies so that they can be delivered through the blood-brain barrier by transcytosis.
This invention was made with Government support under Grant No.: DK 25744 with the National Institutes of Health and the University of California. The Government has certain rights in this invention.
Antibodies in general, and especially monoclonal antibodies, are widely used in diagnostic tests as a means for detecting the presence of specific antigens.
Enzyme linked immunoassay and radioimmunoassay are common diagnostic techniques which utilize antibodies and detect antigens in vivo. Antigens may also be detected in vitro by administering radiolabe~led antibodies to a living subject followed by external detection of radiolabelled antibody sequestered by a particular organ bearing the respective antigen.
Antibodies have also been used widely in the treatment of viral infections and other diseases. However, the use of antibodies in either the treatment or diagnosis of neurological diseases has been very limited because most antibodies are not capable of traversing the blood-brain barrier (BBB) and entering the brain.
1 3n,9340 The vertebrate brain has a unique capillary system which is unlike that in any other organ in the body.
The unique capillary system has morphologic character-istics which make up the blood-brain barrier. The 5blood-brain barrier acts as a system wide cellular membrane which separates the brain interstitial space from the blood. The unique morphologic characteristics of the brain capillaries which make up the blood-brain barrier are: (a) epithelial-like high resistance tight 10junctions which literally cement all endothelia of brain capillaries together, and (b) scanty pinocytosis or transendothelial channels, which are abundant in endothelia of peripheral organs. Due to the unique characteristics of the blood-brain barrier, antibodies 15that readily gain access to other tissues in the body are barred from entry into the brain or their rates of entry are very low.
Few strategies have been developed for introducing these antibodies into the brain which otherwise would 20not cross the blood-brain barrier. The most commonly used strategy involves an invasive procedure where the antibody is delivered directly into the brain. The most common procedure is the implantation of a catheter into the ventricular system to bypass the blood-brain barrier 25and deliver the antibody directIy to the brain. Such a procedure has been used in treating echovirus en-cephalitis (Erlendsson et al., Successful Reversal of Echovirus Encephalitis in X-linked Hypogammablobulinemia by Intraventricular Administration of Immunoglobulin.
301985. New England Journal of Medicine. Vol. 312, No.
6. pages 351-353).
Although invasive procedures, such as the one described above, for the direct delivery of antibodies to the brain ventricles have experienced some success, 35they are not entirely satisfactory because they do not deliver the antibodies to the structures deep within the -- l3f~s34n brain. Further, the invasive procedures are potentially harmful to the patient. Accordingly, there presently is a need to provide an improved method for delivering antibodies across the blood-brain barrier and into the brain for both diagnostic and therapeutic purposes.
SummarY of the Invention According to one aspect of the present lnvention there is provided in a diagnostic composition comprising one or more antibodies for administration to an individual for neurodiagnostic purposes, said antibodies having a relatively low transfer rate across the blood-brain barrier, wherein the improvement comprises cationizing said antibodies to provide cationized antibodies having an isoelectric point of between about 8.0 and 11.0, said cationized antibodies having increased rates of transfer across said blood-brain barrier.
According to one aspect of the present invention there is provided in a neuropharmaceutical composition comprising one or more antibodies for administration to an individual for neurotherapeutic purposes, said antibodies having a relatively low transfer rate across the blood-brain barrier, wherein the improvement comprises cationizing said antibodies to provide cationized antibodies having an isoelectric point of between about 8.0 and 11.0, said cationized antibodies having increased rates of transfer across said blood-brain barrier.
According to another aspect of the present invention there is provided a method for preparing an antibody having an increased transfer rate across the blood-brain barrier comprising : the step of treating said antibody with an effective amount of a - 1 3('J9340 - 3a - 62196-513 cationization agent to form a catlonized antibody havlng an isoelectric point of between about 8.0 to 11Ø
In accordance with the present invention, a method is provided for introducing antibodies directly across the blood-brain barrier by transcytosis. The invention is based upon the discovery that cationized antibodies cross the blood-brain barrier at much higher rates than normal non-cationized antibodies.
The effectiveness of antibodies for both neurodiagnostic and neuropharmaceutical purposes is increased by catlonizing the antibodies to provide cationized antibodies having an isoelectric point (pI) of between about 8.0 to 11Ø These highly basic antibodies cross the blood-brain barrier at rates which are much higher than the tanscytosis rates for normal acid and neutral antibodies which typically have isoelectric points in the range of 5 to 6. This provides an effective means for delivering antibodies into the brain by trancytosis rather than by the previously used direct invasive methods.
The cationized antibodies in accordance with the present invention are prepared by treating a given monoclonal or polyclonal antibody with a cationization agent such as hexamethylenediamine. The cationization agent replaces surface carboxyl groups on the antibody with a more basic group, such as a primary amine group in the case of hexamethylenediamine and related amine compounds. The amount of cationization agent and reaction conditions are controlled so that the resulting cationized antibody has an isoelectric point of between about 8.0 to 11.0 and preferably between about 8.0 to _4_ -- l 3n~q 3Q o 9 . O .
As one feature of the present invention, the immunoreactivity of the antibodies is preserved during cationization by first reacting the antibody with an excess of a corresponding antigen to block the immu-noreactive sites on the antibody. These blocked immunoreactive sites are unreactive during the subse-quent cationization steps. The antigens are then decoupled from the cationized antibodies after the cationization step to thereby reactivate the blocked immunoreactive sites.
The cationization of antibodies in accordance with the present invention is useful whenever it is necessary to introduce an antibody into the brain. Both neuro-diagnostic and neurotherapeutic uses for antibodies iscontemplated. Particular diagnostic uses include diagnosis of Alzheimer's disease, brain tumors or any other diagnostic use where a labeled or tagged antibody is introduced into the brain for reaction with and detection of specific antigens. Therapeutic uses include treatment of viral infections of the brain or other diseased conditions where introduction of an antibody into the brain is re~uired to treat the disease.
The above discussed and many other features and attendant advantages of the present invention will become apparent as the invention becomes better under-stood by reference to the following detailed descrip-tion.
Brief Description of the Drawings Figure l is a graph showing the increase in uptake of cationized IgG by brain capillaries at both 4C and 37C. The results are expressed as percent uptake of IgG per milligram of IgG.
Figure 2 is a graph which also shows the increase ~ l ~rJq~4~) ln uptake of catlonlzed IgG by braln caplllarles. The results are expressed as percent uptake of IgG versus amount of braln capll-larles.
F'lgure 3 is a graph showlng the uptake of catlonlzed IgG
plotted versus the concentratlon of elther natlve IgG or catlon-lzed IgG.
Detalled DescriPtlon of the Inventlon The present lnventlon lnvolves the transport of antl-bodles through the braln caplllary wall, ie. the blood-braln barrler (B8B). The nature of the blood-braln barrler and problems assoclated wlth transport of peptldes and protelns therethrough ls set forth ln "Receptor-~edlated Peptide Transport through the Blood-Braln Barrler~' (W.M. Pardrldge, Endocrlne Revlews, Vol. 7, No. 3, August 1986, pages 314-330).
The present lnventlon has wlde appllcatlon to any antl-body whlch ls useful ln diagnosing or treatlng braln dlsorders.
Antlbodles ln general do not readily cross the blood-braln barrler. Thls ls due to the acldlc or neutral character of antl-bodles. It was dlscovered that the uptake or transport of antl-bodles lnto tne braln can be greatly lncreased by catlonlzlng theantlbodles to form catlonlzed antlbodles havlng an lsoelectrlc polnt of between about 8.0 to 11Ø
Antlbodles are protelns whlch have both posltlve and negatlve charges wlth the number of each dependlng upon the pH of the antlbody solutlon. The pH at whlch the posltlve and negatlve charges are equal ls called the "lsoelectrlc polnt" (pI). Technl-ques for measurlng the pI of a glven antlbody or proteln are well ,~
-- 1 3'`1q340 Sa 62196-513 known and generally lnvolve isoelectrlc focuslng accordlng to conventlonal electrophoresls procedure. As previously mentloned, most antlbodles have an lsoelectrlc polnt of between about 5 to 6.
/
1 ~"iq3~
The relatively low isoelectric point of antibodies is due to the presence of carboxyl groups on the surface of the antibodies. The present invention involves substituting basic groups in place of a sufficient number of surface carboxyl groups to increase the pI of the antibody to between about 8.0 to 11Ø Isoelectric points of between about 8.0 to 9.0 are preferred with isoelectric points of around 8.5 being especially preferred. The degree of cationization should be as high as possible without causing the antibody to form into aggregates. Higher pI's are preferred because the rate of transport of the antibody across the blood-brain barrier increases with increasing pI. However, this must be offset by the increasing possibility of antibody aggregate formation at higher levels of cationization.
Cationization of the antibody can be carried out according to any of the known procedures for displacing surface carboxyl groups on proteins with basic cations.
Preferred cationization agents include amine compounds such as hexamethlyenediamine and related amine com-pounds. Hexamethylenediamine is the preferred cationi-zation agent because it is widely available and the techniques for its use in cationizing proteins are well known. The amount of cationizing agent and the condi-tions for reaction with the antibody can be varied so long as the final cationized antibody has a pI within the above-mentioned range required for blood-brain barrier transport.
The particular antibodies which can be used are virtually unlimited, provided that they have some diagnostic or therapeutic use in connection with the brain. Monoclonal antibodies are preferred because of their increased diagnostic or therapeutic potential.
Typical antibodies which can be cationized for blood-brain barrier transcytosis are antibodies to one or more - 1 3r~9~40 of the antigenic portions of peptides specific to Alz-heimer's disease (Pardridge, W.M. et al., Amyloid Angiopathy of Alzheimer's Disease: Amino Acid Composi-tion and Partial Sequence of a 4,200 - Dalton Peptide Isolated from Cortical Microvessels, Journal of Neuro-chemistry, 1987, pages 001 - 008). Antibodies to such specific peptides can be tagged with a radioactive tracer or other identifier and then cationized to a pI
of 8.5 with hexamethylenediamine. The resulting tagged and cationized antibody can then be administered intravenously to the patient using a suitable phar-maceutically acceptable carrier solution. The tagged and cationized antibody will cross the blood-brain barrier and enter the brain where it will bind to any of the peptides which are unique to Alzheimer's disease.
Detection of the bond tagged and cationized antibody which is bound to the specific peptides is then per-formed by convention of neuroimaging techniques, such as external detection nuclide counting.
Other diagnostic antibodies which can be cationized to provide entry into the brain include antibodies for use in detecting various types of brain tumors. For example, monoclonal antibodies to tumor specific proteins such as glial fibrillary acidic protein (GFAP) can be prepared by conventional and well known tech-niques for monoclonal antibody preparation. Antibodies to human DR antigen and human immunodeficiency virus HIV
antigen are other examples.
The resulting monoclonal antibodies are treated with hexamethylenediamine or other cationization agents to increase the pI of the antibody to between about 8.0 to 11Ø The antibody can be tagged with a radioactive tracer prior to or after the cationization process. The resulting tumor specific cationized and tagged antibody is then administered to the patient intravenously for transport across the blood-brain barrier and binding to - 1 3"q340 any tumor specific antigen. Detection of bound antibody is again accomplished by convention radionuclide scanning techniques.
Cationized antibodies for use in treating viral diseases such as AIDS or other disorders of the brain can also be prepared as set forth above. Once an antibody (preferably monoclonal) is prepared for a specific neurotropic virus or other infectious agent, the antibody is cationized to increase its pI to between about 8.0 to 11Ø The antibody is then administered intramuscularly or intravenously to the patient. The antibody is typically administered as a solution of antibody in a suitable pharmaceutical carrier such as saline buffer. The doses of cationized antibody administered for either diagnostic or therapeutic purposes will parallel the dosage levels established for non-cationized antibodies. Typical dosages range from 0.01 mg to 1 mg for diagnostic purposes and from 1 mg to 100 mg for therapeutic purposes.
Preferred antibodies include chimeric human antibody molecules designed to have reduced antigeneity, such as those antibodies having mouse antigen-binding domains with human constant region domains. Such chimeric antibodies have been disclosed by S. L.
Morrison et al. (Chimeric Human Antibody Molecules:
Mouse Antigen-binding Domains with Human Constant Region Domains, Proc. Nat'l. Acad. Sci. USA, November 1984, Vol. 81, pages 6851 - 6855).
Although hexamethylenediamine is the preferred compound for use in cationizing antibodies, other cationizing agents are possible. For example, ethylene diamine, N,N-dimethyl-1,3-propanediamine, or polylysine may be used. Cationization is catalyzed by carboxyl activation using N-ethyl,N1(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDAC) using the method described by Hoare and Koshland (A Method for the 1 3'~9340 Quantitative Modification and Estimation of Carboxylic Acid Groups in Proteins. 1967. J. Biol. Chem. 342:2447-2453)-In order to prevent reductions in the immunore-activity of an antibody during cationization, it ispreferred that the antibody be pre-bound to the antigen of interest prior to cationization. This pre-binding with antigen effectively blocks the immunoreactive sites on the antibody and prevents them from being cationized.
After cationization is complete and the pI of the antibody has been raised to the desired level between about 8.0 to 11.0, the cationized antibody is then treated to unbind the antigen from the antibody. The unbinding is accomplished according to well known procedures where the antibody-antigen complex is treated with an acid to break the antibody-antigen bond. The antibody is then recovered by column chromatography or other conventional separation and recovery technique.
As an example of practice, bovine IgG was cation-ized and tested against native bovine IgG as follows:
One gram of bovine immunoglobulin G was dissolvedin 10 ml of water followed by dialysis at 4C overnight against water. To this was added slowly 67 ml of 2 M
hexamethylenediamine while stirring, and the pH was kept 2S at 7.8. Thirty minutes later, 1 g of EDAC was added and the pH was maintained at 7.8 and the solution was stirred at room temperature for 3-4 hours. The material was then dialyzed against 40 liters of water overnight at 4C followed by evaporation to dryness the following day.
The cationized antibody and native bovine antibody were then radiolabelled with 3H-sodium borohydride using standard methods which have been described previously by Pardridge et al. (Absence of Albumin Receptor on Brain Cappillaries In Vivo or In Vitro. 1985, Am. J. Phvsiol.
249:E264-E267; Chimeric Peptides as a Vehicle for - 1 3'1934a Peptide Pharmaceutical Delivery through the Blood-Brain Barrier. 1987, Biochem. Biophys. Res. Commun. 146:307-315). Bovine brain capillaries were isolated from fresh bovine brain and used as in vitro model system of the blood-brain barrier as reviewed by Pardridge, W.M.
(Receptor-Mediated Peptide Transport through the Blood-Brain Barrier. 1986, Endocrine Reviews 7:314-330).
The results of the above tests with bovine IgG are set forth in Figures l, 2 and 3. In Figure 1, the percent uptake per milligram protein of (l25I) cation-ized IgG or (125I) native IgG at either 37C or 4C is plotted versus incubation time. The labeled cationized or native IgG was incubated with isolated bovine brain capillaries, which are used as an in vitro model system of blood-brain barrier transport. The results show that the cationization procedure increases the uptake of the IgG by nearly 50-fold, and that this is partially inhibited by cold temperatures. In Figure 2, the percent uptake of (l25I) cationized IgG or (l25I) native IgG is plotted versus the amount of bovine brain capill&-y protein content in micrograms per tube. There is approximately a 25-fold increase in the uptake of the IgG following cationization.
In Figure 3, the percent uptake of (l25I) cation-ized IgG per milligram protein of isolated bovine braincapillary is plotted versus the concentration of unlabeled cationized IgG or native IgG. The data show that the uptake of (l25I) cationized IgG is completely independent of concentration of native IgG through three log orders of magnitude in concentration. However, the presence of unlabeled cationized IgG stimulates the uptake in low concentrations and greatly depresses the uptake in high concentrations. The concentration of cationized IgG which causes 50~ inhibition is approx-imately 2.5 mg/ml or approximately 15 uM cationized ~G.
1 ;~"9 ~4'~
Further examples of practice are:
A monoclonal antibody may be prepared against asynthetic peptide corresponding to the 4200 Dalton amyloid peptide of Alzheimer's disease amyloid angio-pathy (see Pardridge et al, Amyloid angiopathy of Alzheimer's disease: amino acid composition and partial sequence of a 4,200-Dalton peptide isolated from cortical microvessels, 1987 J. Neurochem 49.) This amyloid is deposited on the brain side of the BBB and, thus, a monoclonal antibody to the amyloid peptide cannot be used as a neuroimaging device unless the monoclonal antibody is transportable through the BBB.
The monoclonal antibody to the synthetic amyloid peptide may be cationized using hexamethylenediamine and EDAC, in the presence of saturated concentrations of synthetic amyloid peptide (to protect the active antigen binding sites on the antibody), to an isoelectric point of between 8 - 11. The cationized antibody may then be separated from the antigen by gel filtration in the presence of 0.1 M glycine (pH = 2.5). The high mole-cular weight peak containing the cationized antibody is then neutralized to pH = 7.4 and is now suitable for radiolabelling using standard radionuclides such as technetium 99m or iodine-I131.
A monoclonal antibody to human GFAP may be prepared by isolating GFAP from human autopsy brain using standard techniques or by isolating recombinant human GFAP from either a bacterial or a eukaryotic expressing system. The monoclonal antibody to GFAP may then be cationized using hexamethylenediamine and EDAC
in the presence of high concentrations of GFAP, followed by separation of cationized antibody from antigen as described above. The cationized monoclonal antibody to human GFAP may then be radiolabelled with technetium 99m or iodine-I131 or other conventional radionuclides. The final preparation is a radiolabelled antibody to GFAP
that is transportable through the BBB and may be used as a neuroi~aging device for early detection of brain glial tumors.
Another example is the preparation of mouse-human 5 chimeric antibody directed against the human DR-antigen.
This mouse-human chimeric antibody may be cationized using hexamethylenediamine and EDAC in the presence of saturating concentrations of recombinant DR-antigen followed by separation of cationized antibody from the 10 free DR-antigen. The cationized human-mouse chimeric monoclonal antibody to the human DR-antigen may then be administered subcutaneously to subjects with demyeli-nating diseases, such as multiple sclerosis, that have an immune basis, and the pathogenesis of which may be 15 ameliorated by the adminstration of antibody against the DR-antigen. For example, Sriram and Steinman (Anti I-A
Antibody Suppresses Active Encephalomyelitis: Treatment Model for Diseases Linked to IR Genes. 1983, J. Exp.
Med. 158:1362-1367) have provided evidence that immune 20 linked demyelinating diseases may be treated by ad-ministration of antibody against the class II histocom-patibility antigen.
Having thus described exemplary embodiments of the present invention, it should be noted by those skilled 25 in the art that the within disclosures are exemplary only and that various other alternatives, adaptations and modifications may be made within the scope of the present invention. Accordingly the present invention is not limited to the specific embodiments as illustrated 30 herein, but is only limited by the following claims.
DELIVERY THROUGH THE BLOOD-BRAIN BARRIER
Backqround of the Invention The present invention relates generally to the use of antibodies for treatment and diagnosis of neurologi-cal diseases. More particularly, the present invention deals with the modification of antibodies so that they can be delivered through the blood-brain barrier by transcytosis.
This invention was made with Government support under Grant No.: DK 25744 with the National Institutes of Health and the University of California. The Government has certain rights in this invention.
Antibodies in general, and especially monoclonal antibodies, are widely used in diagnostic tests as a means for detecting the presence of specific antigens.
Enzyme linked immunoassay and radioimmunoassay are common diagnostic techniques which utilize antibodies and detect antigens in vivo. Antigens may also be detected in vitro by administering radiolabe~led antibodies to a living subject followed by external detection of radiolabelled antibody sequestered by a particular organ bearing the respective antigen.
Antibodies have also been used widely in the treatment of viral infections and other diseases. However, the use of antibodies in either the treatment or diagnosis of neurological diseases has been very limited because most antibodies are not capable of traversing the blood-brain barrier (BBB) and entering the brain.
1 3n,9340 The vertebrate brain has a unique capillary system which is unlike that in any other organ in the body.
The unique capillary system has morphologic character-istics which make up the blood-brain barrier. The 5blood-brain barrier acts as a system wide cellular membrane which separates the brain interstitial space from the blood. The unique morphologic characteristics of the brain capillaries which make up the blood-brain barrier are: (a) epithelial-like high resistance tight 10junctions which literally cement all endothelia of brain capillaries together, and (b) scanty pinocytosis or transendothelial channels, which are abundant in endothelia of peripheral organs. Due to the unique characteristics of the blood-brain barrier, antibodies 15that readily gain access to other tissues in the body are barred from entry into the brain or their rates of entry are very low.
Few strategies have been developed for introducing these antibodies into the brain which otherwise would 20not cross the blood-brain barrier. The most commonly used strategy involves an invasive procedure where the antibody is delivered directly into the brain. The most common procedure is the implantation of a catheter into the ventricular system to bypass the blood-brain barrier 25and deliver the antibody directIy to the brain. Such a procedure has been used in treating echovirus en-cephalitis (Erlendsson et al., Successful Reversal of Echovirus Encephalitis in X-linked Hypogammablobulinemia by Intraventricular Administration of Immunoglobulin.
301985. New England Journal of Medicine. Vol. 312, No.
6. pages 351-353).
Although invasive procedures, such as the one described above, for the direct delivery of antibodies to the brain ventricles have experienced some success, 35they are not entirely satisfactory because they do not deliver the antibodies to the structures deep within the -- l3f~s34n brain. Further, the invasive procedures are potentially harmful to the patient. Accordingly, there presently is a need to provide an improved method for delivering antibodies across the blood-brain barrier and into the brain for both diagnostic and therapeutic purposes.
SummarY of the Invention According to one aspect of the present lnvention there is provided in a diagnostic composition comprising one or more antibodies for administration to an individual for neurodiagnostic purposes, said antibodies having a relatively low transfer rate across the blood-brain barrier, wherein the improvement comprises cationizing said antibodies to provide cationized antibodies having an isoelectric point of between about 8.0 and 11.0, said cationized antibodies having increased rates of transfer across said blood-brain barrier.
According to one aspect of the present invention there is provided in a neuropharmaceutical composition comprising one or more antibodies for administration to an individual for neurotherapeutic purposes, said antibodies having a relatively low transfer rate across the blood-brain barrier, wherein the improvement comprises cationizing said antibodies to provide cationized antibodies having an isoelectric point of between about 8.0 and 11.0, said cationized antibodies having increased rates of transfer across said blood-brain barrier.
According to another aspect of the present invention there is provided a method for preparing an antibody having an increased transfer rate across the blood-brain barrier comprising : the step of treating said antibody with an effective amount of a - 1 3('J9340 - 3a - 62196-513 cationization agent to form a catlonized antibody havlng an isoelectric point of between about 8.0 to 11Ø
In accordance with the present invention, a method is provided for introducing antibodies directly across the blood-brain barrier by transcytosis. The invention is based upon the discovery that cationized antibodies cross the blood-brain barrier at much higher rates than normal non-cationized antibodies.
The effectiveness of antibodies for both neurodiagnostic and neuropharmaceutical purposes is increased by catlonizing the antibodies to provide cationized antibodies having an isoelectric point (pI) of between about 8.0 to 11Ø These highly basic antibodies cross the blood-brain barrier at rates which are much higher than the tanscytosis rates for normal acid and neutral antibodies which typically have isoelectric points in the range of 5 to 6. This provides an effective means for delivering antibodies into the brain by trancytosis rather than by the previously used direct invasive methods.
The cationized antibodies in accordance with the present invention are prepared by treating a given monoclonal or polyclonal antibody with a cationization agent such as hexamethylenediamine. The cationization agent replaces surface carboxyl groups on the antibody with a more basic group, such as a primary amine group in the case of hexamethylenediamine and related amine compounds. The amount of cationization agent and reaction conditions are controlled so that the resulting cationized antibody has an isoelectric point of between about 8.0 to 11.0 and preferably between about 8.0 to _4_ -- l 3n~q 3Q o 9 . O .
As one feature of the present invention, the immunoreactivity of the antibodies is preserved during cationization by first reacting the antibody with an excess of a corresponding antigen to block the immu-noreactive sites on the antibody. These blocked immunoreactive sites are unreactive during the subse-quent cationization steps. The antigens are then decoupled from the cationized antibodies after the cationization step to thereby reactivate the blocked immunoreactive sites.
The cationization of antibodies in accordance with the present invention is useful whenever it is necessary to introduce an antibody into the brain. Both neuro-diagnostic and neurotherapeutic uses for antibodies iscontemplated. Particular diagnostic uses include diagnosis of Alzheimer's disease, brain tumors or any other diagnostic use where a labeled or tagged antibody is introduced into the brain for reaction with and detection of specific antigens. Therapeutic uses include treatment of viral infections of the brain or other diseased conditions where introduction of an antibody into the brain is re~uired to treat the disease.
The above discussed and many other features and attendant advantages of the present invention will become apparent as the invention becomes better under-stood by reference to the following detailed descrip-tion.
Brief Description of the Drawings Figure l is a graph showing the increase in uptake of cationized IgG by brain capillaries at both 4C and 37C. The results are expressed as percent uptake of IgG per milligram of IgG.
Figure 2 is a graph which also shows the increase ~ l ~rJq~4~) ln uptake of catlonlzed IgG by braln caplllarles. The results are expressed as percent uptake of IgG versus amount of braln capll-larles.
F'lgure 3 is a graph showlng the uptake of catlonlzed IgG
plotted versus the concentratlon of elther natlve IgG or catlon-lzed IgG.
Detalled DescriPtlon of the Inventlon The present lnventlon lnvolves the transport of antl-bodles through the braln caplllary wall, ie. the blood-braln barrler (B8B). The nature of the blood-braln barrler and problems assoclated wlth transport of peptldes and protelns therethrough ls set forth ln "Receptor-~edlated Peptide Transport through the Blood-Braln Barrler~' (W.M. Pardrldge, Endocrlne Revlews, Vol. 7, No. 3, August 1986, pages 314-330).
The present lnventlon has wlde appllcatlon to any antl-body whlch ls useful ln diagnosing or treatlng braln dlsorders.
Antlbodles ln general do not readily cross the blood-braln barrler. Thls ls due to the acldlc or neutral character of antl-bodles. It was dlscovered that the uptake or transport of antl-bodles lnto tne braln can be greatly lncreased by catlonlzlng theantlbodles to form catlonlzed antlbodles havlng an lsoelectrlc polnt of between about 8.0 to 11Ø
Antlbodles are protelns whlch have both posltlve and negatlve charges wlth the number of each dependlng upon the pH of the antlbody solutlon. The pH at whlch the posltlve and negatlve charges are equal ls called the "lsoelectrlc polnt" (pI). Technl-ques for measurlng the pI of a glven antlbody or proteln are well ,~
-- 1 3'`1q340 Sa 62196-513 known and generally lnvolve isoelectrlc focuslng accordlng to conventlonal electrophoresls procedure. As previously mentloned, most antlbodles have an lsoelectrlc polnt of between about 5 to 6.
/
1 ~"iq3~
The relatively low isoelectric point of antibodies is due to the presence of carboxyl groups on the surface of the antibodies. The present invention involves substituting basic groups in place of a sufficient number of surface carboxyl groups to increase the pI of the antibody to between about 8.0 to 11Ø Isoelectric points of between about 8.0 to 9.0 are preferred with isoelectric points of around 8.5 being especially preferred. The degree of cationization should be as high as possible without causing the antibody to form into aggregates. Higher pI's are preferred because the rate of transport of the antibody across the blood-brain barrier increases with increasing pI. However, this must be offset by the increasing possibility of antibody aggregate formation at higher levels of cationization.
Cationization of the antibody can be carried out according to any of the known procedures for displacing surface carboxyl groups on proteins with basic cations.
Preferred cationization agents include amine compounds such as hexamethlyenediamine and related amine com-pounds. Hexamethylenediamine is the preferred cationi-zation agent because it is widely available and the techniques for its use in cationizing proteins are well known. The amount of cationizing agent and the condi-tions for reaction with the antibody can be varied so long as the final cationized antibody has a pI within the above-mentioned range required for blood-brain barrier transport.
The particular antibodies which can be used are virtually unlimited, provided that they have some diagnostic or therapeutic use in connection with the brain. Monoclonal antibodies are preferred because of their increased diagnostic or therapeutic potential.
Typical antibodies which can be cationized for blood-brain barrier transcytosis are antibodies to one or more - 1 3r~9~40 of the antigenic portions of peptides specific to Alz-heimer's disease (Pardridge, W.M. et al., Amyloid Angiopathy of Alzheimer's Disease: Amino Acid Composi-tion and Partial Sequence of a 4,200 - Dalton Peptide Isolated from Cortical Microvessels, Journal of Neuro-chemistry, 1987, pages 001 - 008). Antibodies to such specific peptides can be tagged with a radioactive tracer or other identifier and then cationized to a pI
of 8.5 with hexamethylenediamine. The resulting tagged and cationized antibody can then be administered intravenously to the patient using a suitable phar-maceutically acceptable carrier solution. The tagged and cationized antibody will cross the blood-brain barrier and enter the brain where it will bind to any of the peptides which are unique to Alzheimer's disease.
Detection of the bond tagged and cationized antibody which is bound to the specific peptides is then per-formed by convention of neuroimaging techniques, such as external detection nuclide counting.
Other diagnostic antibodies which can be cationized to provide entry into the brain include antibodies for use in detecting various types of brain tumors. For example, monoclonal antibodies to tumor specific proteins such as glial fibrillary acidic protein (GFAP) can be prepared by conventional and well known tech-niques for monoclonal antibody preparation. Antibodies to human DR antigen and human immunodeficiency virus HIV
antigen are other examples.
The resulting monoclonal antibodies are treated with hexamethylenediamine or other cationization agents to increase the pI of the antibody to between about 8.0 to 11Ø The antibody can be tagged with a radioactive tracer prior to or after the cationization process. The resulting tumor specific cationized and tagged antibody is then administered to the patient intravenously for transport across the blood-brain barrier and binding to - 1 3"q340 any tumor specific antigen. Detection of bound antibody is again accomplished by convention radionuclide scanning techniques.
Cationized antibodies for use in treating viral diseases such as AIDS or other disorders of the brain can also be prepared as set forth above. Once an antibody (preferably monoclonal) is prepared for a specific neurotropic virus or other infectious agent, the antibody is cationized to increase its pI to between about 8.0 to 11Ø The antibody is then administered intramuscularly or intravenously to the patient. The antibody is typically administered as a solution of antibody in a suitable pharmaceutical carrier such as saline buffer. The doses of cationized antibody administered for either diagnostic or therapeutic purposes will parallel the dosage levels established for non-cationized antibodies. Typical dosages range from 0.01 mg to 1 mg for diagnostic purposes and from 1 mg to 100 mg for therapeutic purposes.
Preferred antibodies include chimeric human antibody molecules designed to have reduced antigeneity, such as those antibodies having mouse antigen-binding domains with human constant region domains. Such chimeric antibodies have been disclosed by S. L.
Morrison et al. (Chimeric Human Antibody Molecules:
Mouse Antigen-binding Domains with Human Constant Region Domains, Proc. Nat'l. Acad. Sci. USA, November 1984, Vol. 81, pages 6851 - 6855).
Although hexamethylenediamine is the preferred compound for use in cationizing antibodies, other cationizing agents are possible. For example, ethylene diamine, N,N-dimethyl-1,3-propanediamine, or polylysine may be used. Cationization is catalyzed by carboxyl activation using N-ethyl,N1(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDAC) using the method described by Hoare and Koshland (A Method for the 1 3'~9340 Quantitative Modification and Estimation of Carboxylic Acid Groups in Proteins. 1967. J. Biol. Chem. 342:2447-2453)-In order to prevent reductions in the immunore-activity of an antibody during cationization, it ispreferred that the antibody be pre-bound to the antigen of interest prior to cationization. This pre-binding with antigen effectively blocks the immunoreactive sites on the antibody and prevents them from being cationized.
After cationization is complete and the pI of the antibody has been raised to the desired level between about 8.0 to 11.0, the cationized antibody is then treated to unbind the antigen from the antibody. The unbinding is accomplished according to well known procedures where the antibody-antigen complex is treated with an acid to break the antibody-antigen bond. The antibody is then recovered by column chromatography or other conventional separation and recovery technique.
As an example of practice, bovine IgG was cation-ized and tested against native bovine IgG as follows:
One gram of bovine immunoglobulin G was dissolvedin 10 ml of water followed by dialysis at 4C overnight against water. To this was added slowly 67 ml of 2 M
hexamethylenediamine while stirring, and the pH was kept 2S at 7.8. Thirty minutes later, 1 g of EDAC was added and the pH was maintained at 7.8 and the solution was stirred at room temperature for 3-4 hours. The material was then dialyzed against 40 liters of water overnight at 4C followed by evaporation to dryness the following day.
The cationized antibody and native bovine antibody were then radiolabelled with 3H-sodium borohydride using standard methods which have been described previously by Pardridge et al. (Absence of Albumin Receptor on Brain Cappillaries In Vivo or In Vitro. 1985, Am. J. Phvsiol.
249:E264-E267; Chimeric Peptides as a Vehicle for - 1 3'1934a Peptide Pharmaceutical Delivery through the Blood-Brain Barrier. 1987, Biochem. Biophys. Res. Commun. 146:307-315). Bovine brain capillaries were isolated from fresh bovine brain and used as in vitro model system of the blood-brain barrier as reviewed by Pardridge, W.M.
(Receptor-Mediated Peptide Transport through the Blood-Brain Barrier. 1986, Endocrine Reviews 7:314-330).
The results of the above tests with bovine IgG are set forth in Figures l, 2 and 3. In Figure 1, the percent uptake per milligram protein of (l25I) cation-ized IgG or (125I) native IgG at either 37C or 4C is plotted versus incubation time. The labeled cationized or native IgG was incubated with isolated bovine brain capillaries, which are used as an in vitro model system of blood-brain barrier transport. The results show that the cationization procedure increases the uptake of the IgG by nearly 50-fold, and that this is partially inhibited by cold temperatures. In Figure 2, the percent uptake of (l25I) cationized IgG or (l25I) native IgG is plotted versus the amount of bovine brain capill&-y protein content in micrograms per tube. There is approximately a 25-fold increase in the uptake of the IgG following cationization.
In Figure 3, the percent uptake of (l25I) cation-ized IgG per milligram protein of isolated bovine braincapillary is plotted versus the concentration of unlabeled cationized IgG or native IgG. The data show that the uptake of (l25I) cationized IgG is completely independent of concentration of native IgG through three log orders of magnitude in concentration. However, the presence of unlabeled cationized IgG stimulates the uptake in low concentrations and greatly depresses the uptake in high concentrations. The concentration of cationized IgG which causes 50~ inhibition is approx-imately 2.5 mg/ml or approximately 15 uM cationized ~G.
1 ;~"9 ~4'~
Further examples of practice are:
A monoclonal antibody may be prepared against asynthetic peptide corresponding to the 4200 Dalton amyloid peptide of Alzheimer's disease amyloid angio-pathy (see Pardridge et al, Amyloid angiopathy of Alzheimer's disease: amino acid composition and partial sequence of a 4,200-Dalton peptide isolated from cortical microvessels, 1987 J. Neurochem 49.) This amyloid is deposited on the brain side of the BBB and, thus, a monoclonal antibody to the amyloid peptide cannot be used as a neuroimaging device unless the monoclonal antibody is transportable through the BBB.
The monoclonal antibody to the synthetic amyloid peptide may be cationized using hexamethylenediamine and EDAC, in the presence of saturated concentrations of synthetic amyloid peptide (to protect the active antigen binding sites on the antibody), to an isoelectric point of between 8 - 11. The cationized antibody may then be separated from the antigen by gel filtration in the presence of 0.1 M glycine (pH = 2.5). The high mole-cular weight peak containing the cationized antibody is then neutralized to pH = 7.4 and is now suitable for radiolabelling using standard radionuclides such as technetium 99m or iodine-I131.
A monoclonal antibody to human GFAP may be prepared by isolating GFAP from human autopsy brain using standard techniques or by isolating recombinant human GFAP from either a bacterial or a eukaryotic expressing system. The monoclonal antibody to GFAP may then be cationized using hexamethylenediamine and EDAC
in the presence of high concentrations of GFAP, followed by separation of cationized antibody from antigen as described above. The cationized monoclonal antibody to human GFAP may then be radiolabelled with technetium 99m or iodine-I131 or other conventional radionuclides. The final preparation is a radiolabelled antibody to GFAP
that is transportable through the BBB and may be used as a neuroi~aging device for early detection of brain glial tumors.
Another example is the preparation of mouse-human 5 chimeric antibody directed against the human DR-antigen.
This mouse-human chimeric antibody may be cationized using hexamethylenediamine and EDAC in the presence of saturating concentrations of recombinant DR-antigen followed by separation of cationized antibody from the 10 free DR-antigen. The cationized human-mouse chimeric monoclonal antibody to the human DR-antigen may then be administered subcutaneously to subjects with demyeli-nating diseases, such as multiple sclerosis, that have an immune basis, and the pathogenesis of which may be 15 ameliorated by the adminstration of antibody against the DR-antigen. For example, Sriram and Steinman (Anti I-A
Antibody Suppresses Active Encephalomyelitis: Treatment Model for Diseases Linked to IR Genes. 1983, J. Exp.
Med. 158:1362-1367) have provided evidence that immune 20 linked demyelinating diseases may be treated by ad-ministration of antibody against the class II histocom-patibility antigen.
Having thus described exemplary embodiments of the present invention, it should be noted by those skilled 25 in the art that the within disclosures are exemplary only and that various other alternatives, adaptations and modifications may be made within the scope of the present invention. Accordingly the present invention is not limited to the specific embodiments as illustrated 30 herein, but is only limited by the following claims.
Claims (20)
1. In a diagnostic composition comprising one or more antibodies for administration to an individual for neurodiagnostic purposes, said antibodies having a relatively low transfer rate across the blood-brain barrier, wherein the improvement comprises cationizing said antibodies to provide cationized antibodies having an isoelectric point of between about 8.0 and 11.0, said cationized antibodies having increased rates of transfer across said blood-brain barrier.
2. A diagnostic composition according to claim 1, wherein said antibodies are monoclonal antibodies.
3. A diagnostic composition according to claim 2 wherein the isoelectric point of said cationized antibodies is between about 8.0 to 9Ø
4. A diagnostic composition according to claim 1 wherein said antibody is an antibody to an Alzheimer's disease amyloid peptide.
5. A diagnostic composition according to claim 1 wherein said antibody is an antibody to one or more antigens present in GFAP protein.
6. In a neuropharmaceutical composition compri-sing one or more antibodies for administration to an individual for neurotherapeutic purposes, said anti-bodies having a relatively low transfer rate across the blood-brain barrier, wherein the improvement comprises cationizing said antibodies to provide cationized antibodies having an isoelectric point of between about 8.0 and 11.0, said cationized antibodies having in-creased rates of transfer across said blood-brain barrier.
7. A neuropharmaceutical composition according to claim 6 wherein said antibodies are monoclonal anti-bodies.
8. A neuropharmaceutical composition according to claim 7 wherein the isoelectric point of said cationized antibodies is between about 8.0 to 9Ø
9. A neuropharmaceutical composition according to claim 6 wherein said antibody is an antibody to an antigen selected from the group consisting of amyloid peptide of Alzheimer's disease, human GFAP, human DR-antigen, or the human immunodeficiency virus (HIV).
10. A method for preparing an antibody having an increased transfer rate across the blood-brain barrier comprising the step of treating said antibody with an effective amount of a cationization agent to form a cationized antibody having an isoelectric point of between about 8.0 to 11Ø
11. A method according to claim 10 wherein said antibody is a monoclonal antibody.
12. A method according to claim 10 including the additional steps of:
reacting said antibody with an antigen for said antibody to form an antibody having immunoreactive sites blocked by said antigen prior to cationization of said antibody; and treating the cationized antibody to remove said antigens therefrom to provide a cationized antibody having unblocked immunoreactive sites.
reacting said antibody with an antigen for said antibody to form an antibody having immunoreactive sites blocked by said antigen prior to cationization of said antibody; and treating the cationized antibody to remove said antigens therefrom to provide a cationized antibody having unblocked immunoreactive sites.
13. A method according to claim 10 wherein said cationization agent is an amine cationization agent.
14. A method according to claim 13 wherein said amine cationization agent is hexamethylenediamine.
15. A method according to claim 10 wherein cationized antibodies having an isoelectric point of between about 8.0 to 9.0 are formed.
16. A method according to claim 14 wherein cationized antibodies having an isoelectric point of about 8.5 are formed.
17. A method according to claim 10 wherein said antibodies are antibodies for diagnostic uses.
18. A method according to claim 10 wherein said antibodies are antibodies for therapeutic uses.
19. A method according to claim 17 wherein said antibodies are selected from the group consisting of antibodies to Alzheimer's disease amyloid peptide, GFAP
protein, DR-antigen and HIV antigen.
protein, DR-antigen and HIV antigen.
20. A method according to claim 18 wherein said antibody is an antibody to an antigen selected from the group consisting of Alzheimer's disease amyloid peptide, GFAP protein, DR-antigen and HIV antigen.
U68103PA.02I
U68103PA.02I
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/085,627 US5004697A (en) | 1987-08-17 | 1987-08-17 | Cationized antibodies for delivery through the blood-brain barrier |
US085,627 | 1987-08-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1309340C true CA1309340C (en) | 1992-10-27 |
Family
ID=22192873
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000574859A Expired - Fee Related CA1309340C (en) | 1987-08-17 | 1988-08-16 | Cationized antibodies for delivery through the blood-brain barrier |
Country Status (8)
Country | Link |
---|---|
US (1) | US5004697A (en) |
EP (1) | EP0557270B1 (en) |
JP (1) | JPH03500644A (en) |
AT (1) | ATE123227T1 (en) |
AU (1) | AU628299B2 (en) |
CA (1) | CA1309340C (en) |
DE (1) | DE3853923T2 (en) |
WO (1) | WO1989001343A1 (en) |
Families Citing this family (404)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5234814A (en) * | 1989-06-01 | 1993-08-10 | Du Pont Merck Pharmaceutical Company | Diagnostic assay for alzheimer's disease |
US5652214A (en) * | 1989-06-05 | 1997-07-29 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factors and analogs |
US6723699B1 (en) | 1989-06-05 | 2004-04-20 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factors and analogs |
US5093317A (en) * | 1989-06-05 | 1992-03-03 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factor |
US6693076B1 (en) | 1989-06-05 | 2004-02-17 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factors and analogs |
US5672683A (en) * | 1989-09-07 | 1997-09-30 | Alkermes, Inc. | Transferrin neuropharmaceutical agent fusion protein |
US5527527A (en) * | 1989-09-07 | 1996-06-18 | Alkermes, Inc. | Transferrin receptor specific antibody-neuropharmaceutical agent conjugates |
US5182107A (en) * | 1989-09-07 | 1993-01-26 | Alkermes, Inc. | Transferrin receptor specific antibody-neuropharmaceutical or diagnostic agent conjugates |
US6329508B1 (en) | 1989-09-07 | 2001-12-11 | Alkermes, Inc. | Transferrin receptor reactive chimeric antibodies |
US5977307A (en) * | 1989-09-07 | 1999-11-02 | Alkermes, Inc. | Transferrin receptor specific ligand-neuropharmaceutical agent fusion proteins |
AU6909091A (en) * | 1989-12-05 | 1991-06-26 | Ramsey Foundation | Neurologic agents for nasal administration to the brain |
US5624898A (en) | 1989-12-05 | 1997-04-29 | Ramsey Foundation | Method for administering neurologic agents to the brain |
US6407061B1 (en) | 1989-12-05 | 2002-06-18 | Chiron Corporation | Method for administering insulin-like growth factor to the brain |
US5130129A (en) * | 1990-03-06 | 1992-07-14 | The Regents Of The University Of California | Method for enhancing antibody transport through capillary barriers |
WO1992019971A1 (en) | 1991-04-30 | 1992-11-12 | Alkermes, Inc. | Cationized antibodies against intracellular proteins |
AU1947395A (en) * | 1994-02-28 | 1995-09-11 | Medinova Medical Consulting Gmbh | Drug targeting system, method for preparing same and its use |
US5639940A (en) | 1994-03-03 | 1997-06-17 | Pharmaceutical Proteins Ltd. | Production of fibrinogen in transgenic animals |
US6709653B1 (en) * | 1994-09-16 | 2004-03-23 | Human Genome Sciences, Inc. | Antibodies specific for human inositol monophosphatase H1 |
GB9509620D0 (en) | 1995-05-12 | 1995-07-05 | Nat Blood Authority | Transepithelial transport of molecular species |
US6015555A (en) * | 1995-05-19 | 2000-01-18 | Alkermes, Inc. | Transferrin receptor specific antibody-neuropharmaceutical or diagnostic agent conjugates |
CA2277519A1 (en) | 1997-01-10 | 1998-07-16 | Massachusetts Institute Of Technology | Treatments for neurotoxicity in alzheimer's disease by .beta.-amyloid peptides |
US6942963B1 (en) | 1997-01-10 | 2005-09-13 | Massachusetts Institute Of Technology | Methods for identifying treatments for neurotoxicity in Alzheimer's disease caused by β-amyloid peptides |
US20080050367A1 (en) * | 1998-04-07 | 2008-02-28 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
US6710226B1 (en) | 1997-12-02 | 2004-03-23 | Neuralab Limited | Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics |
US6761888B1 (en) * | 2000-05-26 | 2004-07-13 | Neuralab Limited | Passive immunization treatment of Alzheimer's disease |
US7179892B2 (en) * | 2000-12-06 | 2007-02-20 | Neuralab Limited | Humanized antibodies that recognize beta amyloid peptide |
US6905686B1 (en) | 1997-12-02 | 2005-06-14 | Neuralab Limited | Active immunization for treatment of alzheimer's disease |
US6787523B1 (en) | 1997-12-02 | 2004-09-07 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
US6923964B1 (en) | 1997-12-02 | 2005-08-02 | Neuralab Limited | Active immunization of AScr for prion disorders |
TWI239847B (en) * | 1997-12-02 | 2005-09-21 | Elan Pharm Inc | N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease |
US7964192B1 (en) * | 1997-12-02 | 2011-06-21 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidgenic disease |
US7588766B1 (en) | 2000-05-26 | 2009-09-15 | Elan Pharma International Limited | Treatment of amyloidogenic disease |
US6750324B1 (en) | 1997-12-02 | 2004-06-15 | Neuralab Limited | Humanized and chimeric N-terminal amyloid beta-antibodies |
US7790856B2 (en) * | 1998-04-07 | 2010-09-07 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
US6913745B1 (en) | 1997-12-02 | 2005-07-05 | Neuralab Limited | Passive immunization of Alzheimer's disease |
US20050059802A1 (en) * | 1998-04-07 | 2005-03-17 | Neuralab Ltd | Prevention and treatment of amyloidogenic disease |
US20030147882A1 (en) * | 1998-05-21 | 2003-08-07 | Alan Solomon | Methods for amyloid removal using anti-amyloid antibodies |
ES2345746T3 (en) * | 1998-05-21 | 2010-09-30 | University Of Tennessee Research Foundation | METHODS FOR THE ELIMINATION OF AMYLOID USING ANTIAMILOID ANTIBODIES. |
US7273618B2 (en) | 1998-12-09 | 2007-09-25 | Chiron Corporation | Method for administering agents to the central nervous system |
US6787637B1 (en) | 1999-05-28 | 2004-09-07 | Neuralab Limited | N-Terminal amyloid-β antibodies |
UA81216C2 (en) * | 1999-06-01 | 2007-12-25 | Prevention and treatment of amyloid disease | |
AUPQ180499A0 (en) * | 1999-07-23 | 1999-08-19 | Biomolecular Research Institute Limited | Beta-amyloid peptide inhibitors |
EP1257584B2 (en) * | 2000-02-24 | 2013-03-06 | Washington University St. Louis | Humanized antibodies that sequester amyloid beta peptide |
AU2001287550B2 (en) | 2000-09-13 | 2007-03-22 | Novo Nordisk Health Care Ag | Human coagulation factor VII variants |
US7067550B2 (en) * | 2000-11-03 | 2006-06-27 | Massachusetts Institute Of Technology | Treatments for neurotoxicity in Alzheimer's Disease |
EP1341548A4 (en) * | 2000-11-03 | 2006-06-14 | Massachusetts Inst Technology | METHODS FOR IDENTIFYING TREATMENTS FOR NEUROTOXICITY IN ALZHEIMER'S DISEASE CAUSED BY $g(b)-AMYLOID PEPTIDES |
PE20020574A1 (en) * | 2000-12-06 | 2002-07-02 | Wyeth Corp | HUMANIZED ANTIBODIES THAT RECOGNIZE THE AMYLOID PEPTIDE BETA |
US7700751B2 (en) | 2000-12-06 | 2010-04-20 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize β-amyloid peptide |
CZ20032454A3 (en) | 2001-03-22 | 2004-03-17 | Novo Nordisk Health Care Ag | Coagulation factor vii derivative |
US20020172676A1 (en) * | 2001-05-16 | 2002-11-21 | George Jackowski | Method of treatment of alzheimer's disease and device therefor |
DE60232880D1 (en) | 2001-05-24 | 2009-08-20 | Neuren Pharmaceuticals Ltd | GPE ANALOGUE AND PEPTIDOMIMETICS |
US7714020B2 (en) | 2001-05-24 | 2010-05-11 | Neuren Pharmaceuticals Limited | Treatment of non-convulsive seizures in brain injury using G-2-methyl-prolyl glutamate |
US7605177B2 (en) | 2001-05-24 | 2009-10-20 | Neuren Pharmaceuticals Limited | Effects of glycyl-2 methyl prolyl glutamate on neurodegeneration |
US20030096748A1 (en) * | 2001-06-04 | 2003-05-22 | The Regents Of The University Of Michigan | Methods and compositions for the treatment of diseases associated with signal transduction aberrations |
US7771722B2 (en) * | 2001-08-17 | 2010-08-10 | Eli Lilly And Company | Assay method for alzheimer's disease |
US20030082191A1 (en) * | 2001-08-29 | 2003-05-01 | Poduslo Joseph F. | Treatment for central nervous system disorders |
MY139983A (en) * | 2002-03-12 | 2009-11-30 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
US7074893B2 (en) * | 2002-06-03 | 2006-07-11 | Regents Of The University Of Michigan | Methods and compositions for the treatment of diseases associated with signal transduction aberrations |
DE10303974A1 (en) | 2003-01-31 | 2004-08-05 | Abbott Gmbh & Co. Kg | Amyloid β (1-42) oligomers, process for their preparation and their use |
RU2390350C2 (en) * | 2003-02-01 | 2010-05-27 | Ньюралаб Лимитед | Active immunisation for creating soluble a-beta antibodies |
DE602004027348D1 (en) | 2003-02-10 | 2010-07-08 | Applied Molecular Evolution | ABETA-BINDING MOLECULES |
CN1780637A (en) | 2003-03-18 | 2006-05-31 | 诺和诺德医疗保健公司 | Liquid, aqueous, pharmaceutical compositions of factor VII polypeptides |
TWI374893B (en) | 2003-05-30 | 2012-10-21 | Janssen Alzheimer Immunotherap | Humanized antibodies that recognize beta amyloid peptide |
ATE547519T1 (en) | 2003-09-09 | 2012-03-15 | Novo Nordisk Healthcare Ag | CLOTTING FACTOR VII POLYPEPTIDES |
ES2343965T3 (en) | 2003-11-25 | 2010-08-13 | The Government Of The United States, As Represented By The Secretary Of Health And Human Services | ANTI-CD22 ANTIBODIES AND MUTED IMMUNOCONGUJADOS. |
US20050272722A1 (en) * | 2004-03-18 | 2005-12-08 | The Brigham And Women's Hospital, Inc. | Methods for the treatment of synucleinopathies |
US20050288298A1 (en) * | 2004-03-18 | 2005-12-29 | The Brigham And Women's Hospital, Inc. | Methods for the treatment of synucleinopathies |
US20070293539A1 (en) * | 2004-03-18 | 2007-12-20 | Lansbury Peter T | Methods for the treatment of synucleinopathies |
JP2007538004A (en) * | 2004-03-18 | 2007-12-27 | ザ ブライハム アンド ウイメンズ ホスピタル, インコーポレイテッド | How to treat synucleinopathy |
WO2005089518A2 (en) * | 2004-03-18 | 2005-09-29 | The Brigham And Women's Hospital, Inc. | Uch-l1 expression and cancer therapy |
WO2005089502A2 (en) * | 2004-03-18 | 2005-09-29 | The Brigham And Women's Hospital, Inc. | Methods for the treatment of synucleinopathies |
CA2590337C (en) * | 2004-12-15 | 2017-07-11 | Neuralab Limited | Humanized amyloid beta antibodies for use in improving cognition |
AR051800A1 (en) * | 2004-12-15 | 2007-02-07 | Wyeth Corp | BETA ANTIBODIES USED TO IMPROVE COGNITION |
US7625560B2 (en) * | 2004-12-15 | 2009-12-01 | Janssen Alzheimer Immunotherapy | Humanized antibodies that recognize beta amyloid peptide |
US20060194821A1 (en) * | 2005-02-18 | 2006-08-31 | The Brigham And Women's Hospital, Inc. | Compounds inhibiting the aggregation of superoxide dismutase-1 |
AU2006232287B2 (en) | 2005-03-31 | 2011-10-06 | Chugai Seiyaku Kabushiki Kaisha | Methods for producing polypeptides by regulating polypeptide association |
CU23317A1 (en) | 2005-07-22 | 2008-10-22 | Ct De Investigacia N Y Desarro | NASAL EPORH FORMULATIONS WITH LOW SYLICAL ACID CONTENT FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISEASES |
ES2410783T3 (en) | 2005-07-29 | 2013-07-03 | The Government Of The United States Of America, As Represented By The Secretary Of Health And Human Services | Exotoxins of mutated pseudomonas with reduced antigenicity |
ES2423663T3 (en) | 2005-08-08 | 2013-09-23 | Oregon Health And Science University | Inactivation of pathogens with hydrogen peroxide for vaccine production |
WO2007027559A2 (en) | 2005-08-29 | 2007-03-08 | Shashoua Victor E | Neuroprotective and neurorestorative methods and compositions |
US20100130425A1 (en) | 2005-09-09 | 2010-05-27 | Oregon Health & Science University | Use of toll-like receptor ligands in treating excitotoxic injury, ischemia and/or hypoxia |
WO2007031559A2 (en) | 2005-09-14 | 2007-03-22 | Novo Nordisk Health Care Ag | Human coagulation factor vii polypeptides |
KR20180058863A (en) | 2005-11-30 | 2018-06-01 | 애브비 인코포레이티드 | Monoclonal antibodies against amyloid beta protein and uses thereof |
US8691224B2 (en) | 2005-11-30 | 2014-04-08 | Abbvie Inc. | Anti-Aβ globulomer 5F7 antibodies |
ES2535856T3 (en) | 2005-12-15 | 2015-05-18 | Genentech, Inc. | Methods and compositions for targeting polyubiquitin |
EP2545919A1 (en) | 2005-12-23 | 2013-01-16 | Link Medicine Corporation | Treatment of synucleinopathies |
EP1994409A2 (en) | 2006-03-14 | 2008-11-26 | Oregon Health and Science University | Methods for producing an immune response to tuberculosis |
EP4342995A2 (en) | 2006-03-31 | 2024-03-27 | Chugai Seiyaku Kabushiki Kaisha | Methods for controlling blood pharmacokinetics of antibodies |
JP5144499B2 (en) | 2006-03-31 | 2013-02-13 | 中外製薬株式会社 | Antibody modification method for purifying bispecific antibodies |
US8784810B2 (en) * | 2006-04-18 | 2014-07-22 | Janssen Alzheimer Immunotherapy | Treatment of amyloidogenic diseases |
WO2009017467A1 (en) | 2007-07-27 | 2009-02-05 | Elan Pharma International Limited | Treatment of amyloidogenic diseases |
EP2016097A2 (en) | 2006-05-04 | 2009-01-21 | Genentech, Inc. | Methods and compositions relating to zpa polypeptides |
TWI608014B (en) | 2006-07-14 | 2017-12-11 | Ac免疫公司 | Anti-beta-amyloid antibodies or antigen-binding fragments thereof, the use and method of use thereof |
PL2046833T3 (en) | 2006-07-14 | 2014-01-31 | Ac Immune Sa | Humanized antibody against amyloid beta |
CA3163418A1 (en) | 2006-10-06 | 2008-05-22 | Jeffrey S. Isenberg | Prevention of tissue ischemia, related methods and compositions |
US8455626B2 (en) | 2006-11-30 | 2013-06-04 | Abbott Laboratories | Aβ conformer selective anti-aβ globulomer monoclonal antibodies |
UA95996C2 (en) * | 2007-01-18 | 2011-09-26 | Эли Лилли Энд Компани | Pegylated fab antibody fragment that specifically binds human a-beta peptide |
US20080200441A1 (en) * | 2007-02-14 | 2008-08-21 | University Of Southern California | Estrogen receptor modulators associated pharmaceutical compositions and methods of use |
US20100311767A1 (en) | 2007-02-27 | 2010-12-09 | Abbott Gmbh & Co. Kg | Method for the treatment of amyloidoses |
AU2008221383B2 (en) | 2007-02-28 | 2012-09-13 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Brachyury polypeptides and methods for use |
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
US20090004213A1 (en) * | 2007-03-26 | 2009-01-01 | Immatics Biotechnologies Gmbh | Combination therapy using active immunotherapy |
CN101970000A (en) * | 2007-04-18 | 2011-02-09 | 杨森阿尔茨海默氏症免疫治疗公司 | Prevention and treatment of cerebral amyloid angiopathy |
US8003097B2 (en) * | 2007-04-18 | 2011-08-23 | Janssen Alzheimer Immunotherapy | Treatment of cerebral amyloid angiopathy |
JP2010526636A (en) * | 2007-05-16 | 2010-08-05 | イェダ リサーチ アンド デベロップメント カンパニー リミテッド | Evaluation of blood-brain barrier disruption |
CA2690434C (en) | 2007-06-12 | 2018-05-22 | Ac Immune S.A. | Monoclonal anti beta amyloid antibody |
AU2008267038B2 (en) | 2007-06-12 | 2014-08-07 | Ac Immune S.A. | Humanized antibodies to amyloid beta |
EP2008666A1 (en) * | 2007-06-29 | 2008-12-31 | Institut Pasteur | Use of VHH antibodies for the preparation of peptide vectors for delivering a substance of interest and their applications |
EP2197903B9 (en) * | 2007-09-04 | 2015-04-22 | The Government of the United States of America as represented by the Secretary of the Department of Health and Human Services | Deletions in domain ii of pseudomonas exotoxin a that reduce non-specific toxicity |
MX2010003450A (en) | 2007-09-26 | 2010-04-27 | Chugai Pharmaceutical Co Ltd | Modified antibody constant region. |
EP3127921A1 (en) * | 2007-09-26 | 2017-02-08 | Chugai Seiyaku Kabushiki Kaisha | Method of modifying isoelectric point of antibody via amino acid substition in cdr |
SG178809A1 (en) | 2007-10-05 | 2012-03-29 | Genentech Inc | Use of anti-amyloid beta antibody in ocular diseases |
JO3076B1 (en) * | 2007-10-17 | 2017-03-15 | Janssen Alzheimer Immunotherap | Immunotherapy regimes dependent on apoe status |
TWI468417B (en) | 2007-11-30 | 2015-01-11 | Genentech Inc | Anti-vegf antibodies |
CN101514335B (en) | 2008-02-22 | 2013-04-17 | 中国科学院生物物理研究所 | Expression and purification of influenza virus polymerase PA and crystal structure of complex of polypeptides at amino terminal of PA, carboxyl terminal of PA and amino terminal of PB1 |
WO2009151683A2 (en) * | 2008-03-12 | 2009-12-17 | Link Medicine Corporation | Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications |
EP2143735A1 (en) * | 2008-07-10 | 2010-01-13 | Institut Pasteur | Variable domains of camelid heavy-chain antibodies directed against glial fibrillary acidic proteins |
WO2010009271A2 (en) | 2008-07-15 | 2010-01-21 | Academia Sinica | Glycan arrays on ptfe-like aluminum coated glass slides and related methods |
TWI440469B (en) | 2008-09-26 | 2014-06-11 | Chugai Pharmaceutical Co Ltd | Improved antibody molecules |
JP5913980B2 (en) | 2008-10-14 | 2016-05-11 | ジェネンテック, インコーポレイテッド | Immunoglobulin variants and uses thereof |
JP5836125B2 (en) | 2008-10-16 | 2015-12-24 | ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション | Fully human antibodies against high molecular weight melanoma-related antigens and uses thereof |
EP2340040B1 (en) | 2008-10-22 | 2019-01-16 | F.Hoffmann-La Roche Ag | Modulation of axon degeneration |
US9067981B1 (en) | 2008-10-30 | 2015-06-30 | Janssen Sciences Ireland Uc | Hybrid amyloid-beta antibodies |
US20110060005A1 (en) * | 2008-11-13 | 2011-03-10 | Link Medicine Corporation | Treatment of mitochondrial disorders using a farnesyl transferase inhibitor |
WO2010057006A1 (en) * | 2008-11-13 | 2010-05-20 | Link Medicine Corporation | Azaquinolinone derivatives and uses thereof |
US20100331363A1 (en) * | 2008-11-13 | 2010-12-30 | Link Medicine Corporation | Treatment of mitochondrial disorders using a farnesyl transferase inhibitor |
WO2010059241A2 (en) | 2008-11-20 | 2010-05-27 | Cambria Pharmaceuticals, Inc. | Treatment of amyotrophic lateral sclerosis |
WO2010075548A2 (en) | 2008-12-23 | 2010-07-01 | Genentech, Inc. | Immunoglobulin variants with altered binding to protein a |
WO2010085607A1 (en) * | 2009-01-23 | 2010-07-29 | Surmodics Pharmaceuticals, Inc. | Continuous double emulsion process for making microparticles |
CN101792745B (en) | 2009-02-04 | 2014-09-17 | 中国科学院生物物理研究所 | Expression and purification of influenza virus polymerase PA N-terminal polypeptide and crystal structure thereof |
US8664183B2 (en) | 2009-02-27 | 2014-03-04 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | SPANX-B polypeptides and their use |
CN106432493B (en) | 2009-03-10 | 2020-01-31 | 贝勒研究院 | anti-CD40 antibodies and uses thereof |
CA2754906C (en) * | 2009-03-10 | 2021-02-09 | Baylor Research Institute | Antigen presenting cell targeted fusion proteins comprising a linker for increased stability |
CN105884903B (en) * | 2009-03-10 | 2019-12-06 | 贝勒研究院 | Antigen presenting cell targeted vaccines |
TWI646193B (en) | 2009-03-19 | 2019-01-01 | 中外製藥股份有限公司 | Antibody constant region alteration |
US20120046309A1 (en) | 2009-05-05 | 2012-02-23 | Northwestern University | Pyrimidine-2,4,6-triones for use in the treatment of amyotrophic lateral sclerosis |
SG176628A1 (en) | 2009-06-05 | 2012-01-30 | Link Medicine Corp | Aminopyrrolidinone derivatives and uses thereof |
AU2010272483B2 (en) | 2009-07-17 | 2016-07-21 | Omeros Corporation | MASP isoforms as inhibitors of complement activation |
JP2013502263A (en) | 2009-08-18 | 2013-01-24 | ベン‐グリオン ユニバーシティ オブ ザ ネゲヴ リサーチ アンド デベロップメント オーソリティ | System and method for analyzing imaging data |
WO2011031441A1 (en) | 2009-08-28 | 2011-03-17 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Therapy with a chimeric molecule and a pro-apoptotic agent |
JP5887270B2 (en) | 2009-09-02 | 2016-03-16 | ジェネンテック, インコーポレイテッド | Mutant SMOOTHENED AND METHOD OF USING THE SAME |
EP2475398B1 (en) | 2009-09-11 | 2015-05-20 | The Government of the United States of America as represented by The Secretary of the Department of Health and Human Services | Improved pseudomonas exotoxin a with reduced immunogenicity |
US9175070B2 (en) | 2009-09-25 | 2015-11-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to HIV-1 and their use |
US9181306B2 (en) | 2009-10-16 | 2015-11-10 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Insertion of foreign genes in rubella virus and their stable expression in a live, attenuated viral vaccine |
EP3011970A3 (en) | 2009-10-22 | 2016-06-08 | F. Hoffmann-La Roche AG | Modulation of axon degeneration |
US8961989B2 (en) | 2009-11-20 | 2015-02-24 | Oregon Health & Science University | Methods for producing an immune response to tuberculosis |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
EP2509626B1 (en) | 2009-12-11 | 2016-02-10 | F.Hoffmann-La Roche Ag | Anti-vegf-c antibodies and methods using same |
ES2585350T3 (en) | 2009-12-23 | 2016-10-05 | F. Hoffmann-La Roche Ag | Anti Bv8 antibodies and uses thereof |
WO2011100455A1 (en) | 2010-02-12 | 2011-08-18 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Inhibition of antibody responses to foreign proteins |
US10435458B2 (en) | 2010-03-04 | 2019-10-08 | Chugai Seiyaku Kabushiki Kaisha | Antibody constant region variants with reduced Fcgammar binding |
CA2791841C (en) | 2010-03-05 | 2023-01-03 | Rigshospitalet | Chimeric inhibitor molecules of complement activation |
WO2011112599A2 (en) | 2010-03-12 | 2011-09-15 | The United States Of America, As Represented By The Secretary. Department Of Health & Human Services | Immunogenic pote peptides and methods of use |
CA2793959C (en) | 2010-03-25 | 2019-06-04 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
WO2011130332A1 (en) | 2010-04-12 | 2011-10-20 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
US8987419B2 (en) | 2010-04-15 | 2015-03-24 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
DK2568976T3 (en) | 2010-05-10 | 2016-01-11 | Academia Sinica | Zanamivir-phosphonate congener with the anti-influenza activity, and determining the sensitivity oseltamivir in influenza viruses |
ES2611479T3 (en) | 2010-06-16 | 2017-05-09 | University Of Pittsburgh- Of The Commonwealth System Of Higher Education | Endoplasmin antibodies and their use |
MY164579A (en) | 2010-07-30 | 2018-01-15 | Ac Immune Sa | Safe and functional humanized antibodies |
WO2012020124A1 (en) | 2010-08-12 | 2012-02-16 | Ac Immune S.A. | Vaccine engineering |
CN103298833B (en) | 2010-08-14 | 2015-12-16 | Abbvie公司 | Amyloid beta associated proteins |
EP2625197B1 (en) | 2010-10-05 | 2016-06-29 | Genentech, Inc. | Mutant smoothened and methods of using the same |
WO2012045882A2 (en) | 2010-10-07 | 2012-04-12 | Ac Immune S.A. | Pharmaceutical composition |
AR083561A1 (en) | 2010-10-26 | 2013-03-06 | Ac Immune Sa | PREPARATION OF AN ANTIGENIC CONSTRUCTION |
MX355060B (en) | 2010-11-17 | 2018-04-03 | Chugai Pharmaceutical Co Ltd | Multi-specific antigen-binding molecule having alternative function to function of blood coagulation factor viii. |
KR102147548B1 (en) | 2011-02-25 | 2020-08-24 | 추가이 세이야쿠 가부시키가이샤 | FcγRIIb-specific Fc antibody |
TW201300418A (en) | 2011-03-25 | 2013-01-01 | Baylor Res Inst | Compositions and methods to immunize against hepatitis C virus |
US9150644B2 (en) | 2011-04-12 | 2015-10-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibodies that bind insulin-like growth factor (IGF) I and II |
EP2998320B1 (en) | 2011-04-19 | 2018-07-18 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Human monoclonal antibodies specific for glypican-3 and use thereof |
RU2600067C2 (en) | 2011-05-06 | 2016-10-20 | Дзе Гавермент Оф Дзе Юнайтед Стейтс Оф Америка Эз Репрезентед Бай Дзе Секретари Оф Дзе Депармент Оф Хелс Энд Хьюман Сёрвисез | Recombinant immunotoxin aimed at mesothelin |
AU2012267786B2 (en) | 2011-06-10 | 2017-08-03 | Oregon Health & Science University | CMV glycoproteins and recombinant vectors |
JP6061922B2 (en) | 2011-06-22 | 2017-01-18 | ザ ジェネラル ホスピタル コーポレイション | How to treat proteinopathy |
ES2855110T3 (en) | 2011-07-18 | 2021-09-23 | The Us Secretary Department Of Health And Human Services National Institutes Of Health | Methods and compositions for the inhibition of a disease associated with polyomavirus |
WO2013039792A1 (en) | 2011-09-12 | 2013-03-21 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Immunogens based on an hiv-1 gp120 v1v2 epitope |
WO2013039916A1 (en) | 2011-09-12 | 2013-03-21 | The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services | Compositions for and methods of treatment and enhanced detection of non-pituitary tumors |
AU2012216792A1 (en) | 2011-09-12 | 2013-03-28 | International Aids Vaccine Initiative | Immunoselection of recombinant vesicular stomatitis virus expressing HIV-1 proteins by broadly neutralizing antibodies |
EP3939996A1 (en) | 2011-09-30 | 2022-01-19 | Chugai Seiyaku Kabushiki Kaisha | Antigen-binding molecule promoting disappearance of antigens having plurality of biological activities |
TW201817744A (en) | 2011-09-30 | 2018-05-16 | 日商中外製藥股份有限公司 | Therapeutic antigen-binding molecule with a FcRn-binding domain that promotes antigen clearance |
EP3275902A1 (en) | 2011-10-04 | 2018-01-31 | IGEM Therapeutics Limited | Ige anti-hmw-maa antibody |
KR101981351B1 (en) | 2011-10-07 | 2019-09-02 | 에이씨 이뮨 에스.에이. | Phosphospecific antibodies recognising tau |
EP2768386B1 (en) | 2011-10-19 | 2024-04-03 | Tel HaShomer Medical Research Infrastructure and Services Ltd. | Magnetic resonance maps for analyzing tissue |
US9402894B2 (en) | 2011-10-27 | 2016-08-02 | International Aids Vaccine Initiative | Viral particles derived from an enveloped virus |
PL2812024T3 (en) | 2012-02-09 | 2018-09-28 | Var2 Pharmaceuticals Aps | Targeting of chondroitin sulfate glycans |
CN104271772A (en) | 2012-03-29 | 2015-01-07 | 科罗拉多州立大学董事会,公司实体 | Click nucleic acids |
AU2013243861A1 (en) | 2012-04-05 | 2014-10-23 | Ac Immune S.A. | Humanized Tau antibody |
US9566329B2 (en) | 2012-04-06 | 2017-02-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Live, attenuated rubella vector to express vaccine antigens |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
JP6267193B2 (en) | 2012-05-22 | 2018-01-24 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Substituted dipyridylamines and their use |
IN2014MN02574A (en) | 2012-05-22 | 2015-07-24 | Genentech Inc | |
WO2013181543A1 (en) | 2012-06-01 | 2013-12-05 | The United States Of America, As Represented By The Secretary, Dept. Of Health And Human Services | High-affinity monoclonal antibodies to glypican-3 and use thereof |
EP2679596B1 (en) | 2012-06-27 | 2017-04-12 | International Aids Vaccine Initiative | HIV-1 env glycoprotein variant |
WO2014008458A2 (en) | 2012-07-06 | 2014-01-09 | Genentech, Inc. | N-substituted benzamides and methods of use thereof |
JP6302909B2 (en) | 2012-08-18 | 2018-03-28 | アカデミア シニカAcademia Sinica | Cell-permeable probes for sialidase identification and imaging |
CA2883168A1 (en) | 2012-08-21 | 2014-02-27 | Academia Sinica | Benzocyclooctyne compounds and uses thereof |
WO2014031476A1 (en) | 2012-08-21 | 2014-02-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mesothelin domain-specific monoclonal antibodies and use thereof |
WO2014043518A1 (en) | 2012-09-14 | 2014-03-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Brachyury protein, non-poxvirus non-yeast vectors encoding brachyury protein, and their use |
WO2014049047A1 (en) | 2012-09-27 | 2014-04-03 | F. Hoffmann-La Roche Ag | Substituted sulfonamide compounds |
ES2666131T3 (en) | 2012-09-27 | 2018-05-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mesothelin antibodies and methods to cause potent antitumor activity |
US20150307865A1 (en) | 2012-10-15 | 2015-10-29 | Novo Nordisk Health Care Ag | Coagulation factor vii polypeptides |
CA2888367A1 (en) | 2012-10-19 | 2014-04-24 | Bavarian Nordic, Inc. | Methods and compositions for the treatment of cancer |
WO2014093702A1 (en) | 2012-12-12 | 2014-06-19 | The Usa, As Represented By The Secretary, Department Of Health And Human Services | Hiv therapeutics and methods of making and using same |
EP3530284B1 (en) | 2012-12-26 | 2023-10-25 | OncoSynergy, Inc. | Anti-integrin beta1 antibody compositions and methods of use thereof |
JP6199991B2 (en) | 2013-01-18 | 2017-09-20 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Trisubstituted pyrazoles and use as DLK inhibitors |
EP2956169B1 (en) | 2013-02-12 | 2018-04-11 | THE UNITED STATES OF AMERICA, represented by the S | Monoclonal antibodies that neutralize norovirus |
EP2968536B1 (en) | 2013-03-13 | 2023-06-28 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Methods for modulating chemotherapeutic cytotoxicity |
BR112015022488A2 (en) | 2013-03-14 | 2017-07-18 | Genentech Inc | substituted triazolopyridines and methods of use thereof |
US9598485B2 (en) | 2013-03-15 | 2017-03-21 | Ac Immune S.A. | Anti-tau antibodies and methods of use |
JP6526627B2 (en) | 2013-04-24 | 2019-06-05 | テル ハショメール メディカル リサーチ インフラストラクチャー アンド サービシズ リミテッド | Magnetic resonance map for tissue analysis |
WO2014177524A1 (en) | 2013-05-01 | 2014-11-06 | F. Hoffmann-La Roche Ag | C-linked heterocycloalkyl substituted pyrimidines and their uses |
TWI622587B (en) | 2013-05-01 | 2018-05-01 | 赫孚孟拉羅股份公司 | Biheteroaryl compounds and uses thereof |
WO2014182532A1 (en) | 2013-05-07 | 2014-11-13 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Mesothelin-specific immunocytokine and use thereof |
EP2994163B1 (en) | 2013-05-09 | 2019-08-28 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Single-domain vhh antibodies directed to norovirus gi.1 and gii.4 and their use |
US10086054B2 (en) | 2013-06-26 | 2018-10-02 | Academia Sinica | RM2 antigens and use thereof |
WO2014210564A1 (en) | 2013-06-27 | 2014-12-31 | Academia Sinica | Glycan conjugates and use thereof |
PL3019532T3 (en) | 2013-07-09 | 2019-10-31 | Univ Duke | Human bispecific egfrviii antibody engaging molecules |
EP2848937A1 (en) | 2013-09-05 | 2015-03-18 | International Aids Vaccine Initiative | Methods of identifying novel HIV-1 immunogens |
CA2923579C (en) | 2013-09-06 | 2023-09-05 | Academia Sinica | Human inkt cell activation using glycolipids with altered glycosyl groups |
AU2014318748B2 (en) | 2013-09-11 | 2019-02-28 | Duquesne University Of The Holy Ghost | Novel anthranilic amides and the use thereof |
JP6534615B2 (en) | 2013-09-27 | 2019-06-26 | 中外製薬株式会社 | Method for producing polypeptide heteromultimer |
US10058604B2 (en) | 2013-10-07 | 2018-08-28 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
LT3055302T (en) | 2013-10-11 | 2019-03-12 | F. Hoffmann-La Roche Ag | Substituted heterocyclic sulfonamide compounds useful as trpa1 modulators |
CA2925393C (en) | 2013-10-11 | 2023-03-07 | Dimiter Dimitrov | Tem8 antibodies and their use |
EP3062808B1 (en) | 2013-10-28 | 2021-09-29 | The Regents of the University of California | Treatment of metastatic prostate cancer |
EP3066118B1 (en) | 2013-11-06 | 2020-01-08 | The U.S.A. as represented by the Secretary, Department of Health and Human Services | Alk antibodies, conjugates, and chimeric antigen receptors, and their use |
WO2015095770A1 (en) | 2013-12-20 | 2015-06-25 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Immunogenic jc polyomavirus compositions and methods of use |
MX2016008110A (en) | 2013-12-20 | 2016-08-19 | Hoffmann La Roche | Pyrazole derivatives and uses thereof as inhibitors of dlk. |
WO2015103549A1 (en) | 2014-01-03 | 2015-07-09 | The United States Of America, As Represented By The Secretary Department Of Health And Human Services | Neutralizing antibodies to hiv-1 env and their use |
WO2015106003A1 (en) | 2014-01-08 | 2015-07-16 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Ras pathways as markers of protection against hiv and methods to improve vaccine efficacy |
JP7037884B2 (en) | 2014-01-13 | 2022-03-17 | ベイラー リサーチ インスティテュート | New vaccines for HPV and HPV-related diseases |
WO2015108998A2 (en) | 2014-01-15 | 2015-07-23 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Cartilage targeting agents and their use |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2016114819A1 (en) | 2015-01-16 | 2016-07-21 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
CA2937123A1 (en) | 2014-01-16 | 2015-07-23 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
CA2937539A1 (en) | 2014-02-04 | 2015-08-13 | Genentech, Inc. | Mutant smoothened and methods of using the same |
CN106415244B (en) | 2014-03-27 | 2020-04-24 | 中央研究院 | Reactive marker compounds and uses thereof |
WO2015175704A1 (en) | 2014-05-14 | 2015-11-19 | The Regents Of The University Of California | Inhibitors of bacterial dna gyrase with efficacy against gram-negative bacteria |
EP3149036A4 (en) | 2014-05-27 | 2017-12-27 | Academia Sinica | Anti-cd20 glycoantibodies and uses thereof |
EP4116329A1 (en) | 2014-05-27 | 2023-01-11 | Academia Sinica | Anti-her2 glycoantibodies and uses thereof |
TWI717319B (en) | 2014-05-27 | 2021-02-01 | 中央研究院 | Fucosidase from bacteroides and methods using the same |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
TWI732738B (en) | 2014-05-28 | 2021-07-11 | 中央研究院 | Anti-tnf-alpha glycoantibodies and uses thereof |
WO2016007534A1 (en) | 2014-07-07 | 2016-01-14 | Genentech, Inc. | Therapeutic compounds and methods of use thereof |
US9683017B2 (en) | 2014-07-17 | 2017-06-20 | University Tennessee Research Foundation | Inhibitory peptides of viral infection |
ES2848857T3 (en) | 2014-07-31 | 2021-08-12 | Us Gov Health & Human Services | Human monoclonal antibodies against EphA4 and their use |
CA2956820A1 (en) | 2014-08-26 | 2016-03-03 | University Of Tennessee Research Foundation | Targeting immunotherapy for amyloidosis |
EP3189067B1 (en) | 2014-09-04 | 2021-05-19 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Recombinant hiv-1 envelope proteins and their use |
CA2960712A1 (en) | 2014-09-08 | 2016-03-17 | Academia Sinica | Human inkt cell activation using glycolipids |
MA40764A (en) | 2014-09-26 | 2017-08-01 | Chugai Pharmaceutical Co Ltd | THERAPEUTIC AGENT INDUCING CYTOTOXICITY |
US20170267784A1 (en) | 2014-10-23 | 2017-09-21 | Singh Molecular Medicine, Llc | Single domain antibodies directed against intracellular antigens |
LT3590962T (en) | 2014-10-23 | 2021-12-27 | Singh Molecular Medicine, Llc | Single domain antibodies directed against intracellular antigens |
EP3218397B8 (en) | 2014-11-14 | 2021-04-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to ebola virus glycoprotein and their use |
EP3221349B1 (en) | 2014-11-19 | 2020-11-04 | Axon Neuroscience SE | Humanized tau antibodies in alzheimer's disease |
US10072070B2 (en) | 2014-12-05 | 2018-09-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Potent anti-influenza A neuraminidase subtype N1 antibody |
EP3233921B1 (en) | 2014-12-19 | 2021-09-29 | Chugai Seiyaku Kabushiki Kaisha | Anti-c5 antibodies and methods of use |
MA41294A (en) | 2014-12-19 | 2017-11-08 | Chugai Pharmaceutical Co Ltd | ANTI-MYOSTATIN ANTIBODIES, POLYPEPTIDES CONTAINING FC REGION VARIANTS, AND METHODS OF USE |
US10420834B2 (en) | 2014-12-24 | 2019-09-24 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Recombinant metapneumovirus F proteins and their use |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
TWI710571B (en) | 2015-01-24 | 2020-11-21 | 中央研究院 | Cancer markers and methods of use thereof |
CA2972072A1 (en) | 2015-01-24 | 2016-07-28 | Academia Sinica | Novel glycan conjugates and methods of use thereof |
CA2973886A1 (en) | 2015-01-30 | 2016-08-04 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
CA2975875A1 (en) | 2015-02-04 | 2016-08-11 | Genentech, Inc. | Mutant smoothened and methods of using the same |
CN114773470A (en) | 2015-02-05 | 2022-07-22 | 中外制药株式会社 | Antibodies comprising an ion concentration-dependent antigen-binding domain, FC region variants, IL-8-binding antibodies and uses thereof |
KR20170140180A (en) | 2015-02-24 | 2017-12-20 | 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 | Middle east respiratory syndrome coronavirus immunogens, antibodies, and their use |
CA2972393A1 (en) | 2015-02-27 | 2016-09-01 | Chugai Seiyaku Kabushiki Kaisha | Composition for treating il-6-related diseases |
CN107406462B (en) | 2015-03-09 | 2020-11-10 | 豪夫迈·罗氏有限公司 | Tricyclic DLK inhibitors and uses thereof |
EP3268087A4 (en) | 2015-03-12 | 2018-08-29 | The Regents of the University of California | METHODS FOR TREATING CANCER WITH RORgamma INHIBITORS |
US10174292B2 (en) | 2015-03-20 | 2019-01-08 | International Aids Vaccine Initiative | Soluble HIV-1 envelope glycoprotein trimers |
PL3271389T3 (en) | 2015-03-20 | 2020-08-10 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to gp120 and their use |
EP3072901A1 (en) | 2015-03-23 | 2016-09-28 | International Aids Vaccine Initiative | Soluble hiv-1 envelope glycoprotein trimers |
US11142587B2 (en) | 2015-04-01 | 2021-10-12 | Chugai Seiyaku Kabushiki Kaisha | Method for producing polypeptide hetero-oligomer |
NZ737536A (en) | 2015-05-22 | 2019-04-26 | Genentech Inc | Substituted benzamides and methods of use thereof |
WO2016196975A1 (en) | 2015-06-03 | 2016-12-08 | The United States Of America, As Represented By The Secretary Department Of Health & Human Services | Neutralizing antibodies to hiv-1 env and their use |
ES2961346T3 (en) | 2015-06-12 | 2024-03-11 | Lentigen Tech Inc | Procedure to treat cancer with genetically modified T cells |
EP3341353A1 (en) | 2015-08-27 | 2018-07-04 | Genentech, Inc. | Therapeutic compounds and methods of use thereof |
AR105910A1 (en) | 2015-09-04 | 2017-11-22 | Obi Pharma Inc | GLICAN MATRICES AND METHOD OF USE |
US11028155B2 (en) * | 2015-09-11 | 2021-06-08 | Nascent Biotech, Inc. | Enhanced delivery of drugs to the brain |
CA2997809A1 (en) | 2015-10-07 | 2017-04-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Il-7r-alpha specific antibodies for treating acute lymphoblastic leukemia |
AU2016335848B2 (en) | 2015-10-09 | 2020-12-17 | Miltenyi Biotec Technology, Inc. | Chimeric antigen receptors and methods of use |
TWI746473B (en) | 2015-11-02 | 2021-11-21 | 美商辛分子醫藥有限公司 | Single domain antibodies directed against intracellular antigens |
WO2017079479A1 (en) | 2015-11-03 | 2017-05-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human | Neutralizing antibodies to hiv-1 gp41 and their use |
WO2017091592A1 (en) | 2015-11-25 | 2017-06-01 | Genentech, Inc. | Substituted benzamides useful as sodium channel blockers |
JP7141336B2 (en) | 2015-12-25 | 2022-09-22 | 中外製薬株式会社 | Anti-myostatin antibodies and methods of use |
SG11201803989WA (en) | 2015-12-28 | 2018-06-28 | Chugai Pharmaceutical Co Ltd | Method for promoting efficiency of purification of fc region-containing polypeptide |
JP2019509721A (en) | 2016-02-04 | 2019-04-11 | キュリス,インコーポレイテッド | Mutant smoothened and method of using the same |
CA3016170A1 (en) | 2016-03-08 | 2017-09-14 | Academia Sinica | Methods for modular synthesis of n-glycans and arrays thereof |
US11072666B2 (en) | 2016-03-14 | 2021-07-27 | Chugai Seiyaku Kabushiki Kaisha | Cell injury inducing therapeutic drug for use in cancer therapy |
WO2017160599A1 (en) | 2016-03-14 | 2017-09-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Use of cd300b antagonists to treat sepsis and septic shock |
TWI780045B (en) | 2016-03-29 | 2022-10-11 | 台灣浩鼎生技股份有限公司 | Antibodies, pharmaceutical compositions and methods |
US10980894B2 (en) | 2016-03-29 | 2021-04-20 | Obi Pharma, Inc. | Antibodies, pharmaceutical compositions and methods |
EP3854782A1 (en) | 2016-03-30 | 2021-07-28 | Genentech, Inc. | Substituted benzamides and methods of use thereof |
KR20230110820A (en) | 2016-04-22 | 2023-07-25 | 오비아이 파머 인코퍼레이티드 | Cancer immunotherapy by immune activation or immune modulation via globo series antigens |
WO2017192589A1 (en) | 2016-05-02 | 2017-11-09 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to influenza ha and their use and identification |
JP6843970B2 (en) | 2016-05-10 | 2021-03-17 | ナジット テクノロジーズ, インコーポレイテッド | Using a double-oxidation process to inactivate pathogens to produce a highly immunogenic inactivated vaccine |
WO2017196847A1 (en) | 2016-05-10 | 2017-11-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Variable new antigen receptor (vnar) antibodies and antibody conjugates targeting tumor and viral antigens |
WO2017214182A1 (en) | 2016-06-07 | 2017-12-14 | The United States Of America. As Represented By The Secretary, Department Of Health & Human Services | Fully human antibody targeting pdi for cancer immunotherapy |
WO2018015411A1 (en) | 2016-07-20 | 2018-01-25 | F. Hoffmann-La Roche Ag | Sulfonylcycloalkyl carboxamide compounds as trpa1 modulators |
EP3487853B1 (en) | 2016-07-20 | 2022-06-08 | F. Hoffmann-La Roche AG | Bicyclic proline compounds |
CA3032049C (en) | 2016-07-27 | 2023-11-07 | Obi Pharma, Inc. | Immunogenic/therapeutic glycan compositions and uses thereof |
EP3491026A4 (en) | 2016-07-29 | 2020-07-29 | OBI Pharma, Inc. | Human antibodies, pharmaceutical compositions and methods |
US11066479B2 (en) | 2016-08-02 | 2021-07-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies targeting glypican-2 (GPC2) and use thereof |
CN116271014A (en) | 2016-08-05 | 2023-06-23 | 中外制药株式会社 | Compositions for preventing or treating IL-8 related diseases |
WO2018029288A1 (en) | 2016-08-12 | 2018-02-15 | F. Hoffmann-La Roche Ag | Sulfonyl pyridyl trp inhibitors |
CA3034057A1 (en) | 2016-08-22 | 2018-03-01 | CHO Pharma Inc. | Antibodies, binding fragments, and methods of use |
EP3507304B1 (en) | 2016-09-02 | 2024-04-03 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with duocars |
US10702589B2 (en) | 2016-10-04 | 2020-07-07 | Ann And Robert H. Lurie Children's Hospital Of Chicago | Compositions and methods of treating neurological disorder and stress-induced conditions |
WO2018071576A1 (en) | 2016-10-14 | 2018-04-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Treatment of tumors by inhibition of cd300f |
EP3526219B1 (en) | 2016-10-17 | 2021-12-15 | F. Hoffmann-La Roche AG | Bicyclic pyridone lactams and methods of use thereof |
EP3541414A4 (en) | 2016-11-21 | 2020-11-11 | OBI Pharma, Inc. | Conjugated biological molecules, pharmaceutical compositions and methods |
JP7171567B2 (en) | 2016-11-28 | 2022-11-15 | エフ.ホフマン-ラ ロシュ アーゲー | Oxadiazolones as transient receptor voltage-gated channel inhibitors |
AR110282A1 (en) | 2016-12-02 | 2019-03-13 | Hoffmann La Roche | BICYCLIC AMIDA COMPOUNDS AND USE OF THESE IN THE TREATMENT OF DISEASES MEDIATED BY RIP1 |
MX2019006349A (en) | 2016-12-16 | 2019-08-22 | Inst Res Biomedicine | Novel recombinant prefusion rsv f proteins and uses thereof. |
US11072607B2 (en) | 2016-12-16 | 2021-07-27 | Genentech, Inc. | Inhibitors of RIP1 kinase and methods of use thereof |
US11236171B2 (en) | 2016-12-21 | 2022-02-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibodies specific for FLT3 and uses thereof |
EP4183798A1 (en) | 2017-01-09 | 2023-05-24 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-mesothelin immunotherapy |
WO2018148660A1 (en) | 2017-02-10 | 2018-08-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use |
CN114874209A (en) | 2017-03-07 | 2022-08-09 | 豪夫迈·罗氏有限公司 | Oxadiazole transient receptor potential channel inhibitors |
EP3601356A1 (en) | 2017-03-24 | 2020-02-05 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd33 immunotherapy |
EP3601273B1 (en) | 2017-03-24 | 2021-12-01 | Genentech, Inc. | 4-piperidin-n-(pyrimidin-4-yl)chroman-7-sulfonamide derivatives as sodium channel inhibitors |
CA3058457A1 (en) | 2017-03-31 | 2018-10-04 | Seattle Genetics, Inc. | Combinations of chk1- and wee1 - inhibitors |
KR20200014298A (en) | 2017-04-28 | 2020-02-10 | 시애틀 지네틱스, 인크. | Treatment of HER2-positive cancer |
US11851486B2 (en) | 2017-05-02 | 2023-12-26 | National Center Of Neurology And Psychiatry | Method for predicting and evaluating therapeutic effect in diseases related to IL-6 and neutrophils |
US11389480B2 (en) | 2017-05-19 | 2022-07-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibody targeting TNFR2 for cancer immunotherapy |
WO2019006280A1 (en) | 2017-06-30 | 2019-01-03 | Lentigen Technology, Inc. | Human monoclonal antibodies specific for cd33 and methods of their use |
WO2019005208A1 (en) | 2017-06-30 | 2019-01-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human mesothelin antibodies and uses in cancer therapy |
MA49560A (en) | 2017-07-14 | 2020-05-20 | Hoffmann La Roche | BICYCLIC KETONIC COMPOUNDS AND PROCESSES FOR USE |
EP3661964A1 (en) | 2017-07-31 | 2020-06-10 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd19/cd20 immunotherapy |
GB201712952D0 (en) | 2017-08-11 | 2017-09-27 | Univ Edinburgh | Immunomodulatory agent |
CA3075915A1 (en) | 2017-09-15 | 2019-03-21 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd19 immunotherapy |
US10610585B2 (en) | 2017-09-26 | 2020-04-07 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and compositions for treating and preventing HIV |
RU2020114670A (en) | 2017-10-11 | 2021-11-12 | Ф. Хоффманн-Ля Рош Аг | BICYCLIC COMPOUNDS FOR USE AS RIP1 KINASE INHIBITORS |
AU2018352245A1 (en) | 2017-10-16 | 2020-04-30 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-CD22 immunotherapy |
SG11202002877RA (en) | 2017-10-31 | 2020-04-29 | Hoffmann La Roche | Bicyclic sulfones and sulfoxides and methods of use thereof |
EP3703745B1 (en) | 2017-11-04 | 2024-04-10 | Nevada Research & Innovation Corporation | Immunogenic conjugates and methods of use thereof |
TWI805653B (en) | 2017-11-30 | 2023-06-21 | 韓商韓美藥品股份有限公司 | Salts of 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide, and crystalline forms thereof |
EP3728307A4 (en) | 2017-12-20 | 2021-05-19 | Lentigen Technology, Inc. | Compositions and methods for treating hiv/aids with immunotherapy |
EP3724223A1 (en) | 2018-01-02 | 2020-10-21 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Neutralizing antibodies to ebola virus glycoprotein and their use |
WO2019164778A1 (en) | 2018-02-20 | 2019-08-29 | Genentech, Inc. | Process for preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide transient receptor potential channel antagonist compounds and crystalline forms thereof |
CN111971299A (en) | 2018-02-21 | 2020-11-20 | 美国政府(由卫生和人类服务部的部长所代表) | Neutralizing antibodies to HIV-1Env and uses thereof |
EP3759098A1 (en) | 2018-02-26 | 2021-01-06 | Genentech, Inc. | Pyridine-sulfonamide compounds and their use against pain and related conditions |
US10710994B2 (en) | 2018-03-19 | 2020-07-14 | Genentech, Inc. | Oxadiazole transient receptor potential channel inhibitors |
JP2021519788A (en) | 2018-03-30 | 2021-08-12 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Condensation ring hydropyrido compound as a sodium channel inhibitor |
CN112074519A (en) | 2018-04-20 | 2020-12-11 | 豪夫迈·罗氏有限公司 | N- [ 4-oxo-2, 3-dihydro-1, 5-benzoxazepin-3-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole-2-carboxamide derivatives and related compounds as RIP1 kinase inhibitors for the treatment of e.g. Irritable Bowel Syndrome (IBS) |
TW202003490A (en) | 2018-05-22 | 2020-01-16 | 瑞士商赫孚孟拉羅股份公司 | Therapeutic compounds and methods of use thereof |
WO2019236590A1 (en) | 2018-06-04 | 2019-12-12 | University Of Maryland, Baltimore | Methods for preventing acute kidney injury |
WO2020006176A1 (en) | 2018-06-27 | 2020-01-02 | Obi Pharma, Inc. | Glycosynthase variants for glycoprotein engineering and methods of use |
WO2020014482A1 (en) | 2018-07-12 | 2020-01-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Affinity matured cd22-specific monoclonal antibody and uses thereof |
US20210278406A1 (en) | 2018-07-13 | 2021-09-09 | Varct Diagnostic Aps | Isolation of circulating cells of fetal origin using recombinant malaria protein var2csa |
CN112585163A (en) | 2018-08-08 | 2021-03-30 | 美国政府(由卫生和人类服务部的部长所代表) | High-affinity monoclonal antibody targeting glypican-2 and application thereof |
EP3847154A1 (en) | 2018-09-03 | 2021-07-14 | F. Hoffmann-La Roche AG | Carboxamide and sulfonamide derivatives useful as tead modulators |
CA3113058A1 (en) | 2018-09-20 | 2020-03-26 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd123 immunotherapy |
CA3114349A1 (en) | 2018-09-26 | 2020-04-02 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd19/cd22 immunotherapy |
WO2020113108A1 (en) | 2018-11-30 | 2020-06-04 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-cd38 immunotherapy |
EP3891170A4 (en) | 2018-12-04 | 2022-12-07 | The Rockefeller University | Hiv vaccine immunogens |
EP3883609A2 (en) | 2018-12-20 | 2021-09-29 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Ebola virus glycoprotein-specific monoclonal antibodies and uses thereof |
US20220064324A1 (en) | 2019-01-08 | 2022-03-03 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Cross species single domain antibodies targeting mesothelin for treating solid tumors |
WO2020146615A1 (en) | 2019-01-11 | 2020-07-16 | Genentech, Inc. | Bicyclic pyrrolotriazolr ketone compounds and methods of use thereof |
AU2020212534A1 (en) | 2019-01-22 | 2021-07-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | High affinity monoclonal antibodies targeting glypican-1 and methods of use |
TW202042820A (en) | 2019-01-28 | 2020-12-01 | 美商西雅圖遺傳學股份有限公司 | Methods of treating breast cancer with tucatinib |
CN113924103A (en) | 2019-03-06 | 2022-01-11 | 莱蒂恩技术公司 | Compositions and methods for treating cancer with self-driven chimeric antigen receptors |
CA3140102A1 (en) | 2019-05-30 | 2020-12-03 | Dina SCHNEIDER | Compositions and methods for treating cancer with anti-bcma immunotherapy |
CN114269783B (en) | 2019-07-02 | 2024-03-26 | 美国政府(由卫生和人类服务部的部长所代表) | Monoclonal antibody binding to EGFRVIII and application thereof |
CN114746094A (en) | 2019-10-21 | 2022-07-12 | 思进公司 | Methods of treating HER2 positive breast cancer with tucaninib in combination with capecitabine and trastuzumab |
JP2022552875A (en) | 2019-10-22 | 2022-12-20 | ザ ユナイテッド ステイツ オブ アメリカ, アズ リプレゼンテッド バイ ザ セクレタリー, デパートメント オブ ヘルス アンド ヒューマン サービシーズ | High-affinity Nanobodies Targeting B7H3 (CD276) for Treating Various Solid Tumors |
TW202130618A (en) | 2019-11-13 | 2021-08-16 | 美商建南德克公司 | Therapeutic compounds and methods of use |
CA3159770A1 (en) | 2019-11-15 | 2021-05-20 | Seagen Inc. | Methods of treating her2 positive breast cancer with tucatinib in combination with an anti-her2 antibody-drug conjugate |
CA3159964A1 (en) | 2019-12-04 | 2021-06-10 | Ac Immune Sa | Novel molecules for therapy and diagnosis |
EP4041769A1 (en) | 2019-12-12 | 2022-08-17 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Antibody-drug conjugates specific for cd276 and uses thereof |
US20230057461A1 (en) | 2020-01-27 | 2023-02-23 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Rab13 and net1 antisense oligonucleotides to treat metastatic cancer |
EP4093762A1 (en) | 2020-02-20 | 2022-11-30 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Epstein-barr virus monoclonal antibodies and uses thereof |
US20230136203A1 (en) | 2020-03-11 | 2023-05-04 | Seagen Inc. | Methods of treating her2 mutant cancers with tucatinib |
US11497770B2 (en) | 2020-06-22 | 2022-11-15 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with TSLPR-CD19 or TSLPR-CD22 immunotherapy |
US11787775B2 (en) | 2020-07-24 | 2023-10-17 | Genentech, Inc. | Therapeutic compounds and methods of use |
WO2022034228A1 (en) | 2020-08-14 | 2022-02-17 | Ac Immune Sa | Humanized anti-tdp-43 binding molecules and uses thereof |
AU2021349384A1 (en) | 2020-09-28 | 2023-05-25 | Seagen Inc. | Methods of treating solid tumors driven by her2 alterations with tucatinib in combination with an anti-her2 antibody |
IL301266A (en) | 2020-10-02 | 2023-05-01 | Genentech Inc | Process for the preparation of biheteroaryl compounds and crystal forms thereof |
EP4229082A1 (en) | 2020-10-16 | 2023-08-23 | AC Immune SA | Antibodies binding to alpha-synuclein for therapy and diagnosis |
WO2022093745A1 (en) | 2020-10-26 | 2022-05-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies targeting sars coronavirus spike protein and uses thereof |
CN116801898A (en) | 2020-11-05 | 2023-09-22 | 莱蒂恩技术公司 | Compositions and methods for treating cancer with anti-CD 19/CD22 immunotherapy |
JP2023549581A (en) | 2020-11-17 | 2023-11-27 | シージェン インコーポレイテッド | Method of treating cancer with a combination of tucatinib and anti-PD-1/anti-PD-L1 antibodies |
TW202237638A (en) | 2020-12-09 | 2022-10-01 | 日商武田藥品工業股份有限公司 | Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof |
CA3208365A1 (en) | 2021-02-15 | 2022-08-18 | Chantal KUHN | Cell therapy compositions and methods for modulating tgf-b signaling |
AU2022230408A1 (en) | 2021-03-03 | 2023-09-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | La protien as a novel regulator of osteoclastogenesis |
WO2022232612A1 (en) | 2021-04-29 | 2022-11-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Lassa virus-specific nanobodies and methods of their use |
WO2022261017A1 (en) | 2021-06-09 | 2022-12-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Cross species single domain antibodies targeting pd-l1 for treating solid tumors |
WO2023281097A1 (en) | 2021-07-09 | 2023-01-12 | Immunic Ag | Methods for treating cancer |
WO2023028077A1 (en) | 2021-08-24 | 2023-03-02 | Genentech, Inc. | Sodium channel inhibitors and methods of designing same |
WO2023028056A1 (en) | 2021-08-24 | 2023-03-02 | Genentech, Inc. | 3-amino piperidyl sodium channel inhibitors |
WO2023076881A1 (en) | 2021-10-26 | 2023-05-04 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies targeting the s2 subunit of sars-cov-2 spike protein |
US11492394B1 (en) | 2021-10-29 | 2022-11-08 | Nascent Biotech, Inc. | Kits and containers for treating vimentin expressing tumors |
WO2023097194A2 (en) | 2021-11-24 | 2023-06-01 | Genentech, Inc. | Therapeutic compounds and methods of use |
TW202332429A (en) | 2021-11-24 | 2023-08-16 | 美商建南德克公司 | Therapeutic compounds and methods of use |
WO2023156549A1 (en) | 2022-02-16 | 2023-08-24 | Ac Immune Sa | Humanized anti-tdp-43 binding molecules and uses thereof |
US20230338424A1 (en) | 2022-03-02 | 2023-10-26 | Lentigen Technology, Inc. | Compositions and Methods for Treating Cancer with Anti-CD123 Immunotherapy |
WO2023192827A1 (en) | 2022-03-26 | 2023-10-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Bispecific antibodies to hiv-1 env and their use |
WO2023192881A1 (en) | 2022-03-28 | 2023-10-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Neutralizing antibodies to hiv-1 env and their use |
WO2023194565A1 (en) | 2022-04-08 | 2023-10-12 | Ac Immune Sa | Anti-tdp-43 binding molecules |
WO2023201333A1 (en) | 2022-04-14 | 2023-10-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Bispecific antibodies to ebola virus glycoprotein and their use |
WO2023230429A1 (en) | 2022-05-22 | 2023-11-30 | Seagen Inc. | Methods of treating colorectal cancer with tucatinib in combination with an anti-her2 antibody |
WO2024026107A2 (en) | 2022-07-28 | 2024-02-01 | Lentigen Technology, Inc. | Chimeric antigen receptor therapies for treating solid tumors |
WO2024030829A1 (en) | 2022-08-01 | 2024-02-08 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies that bind to the underside of influenza viral neuraminidase |
US20240075142A1 (en) | 2022-08-26 | 2024-03-07 | Lentigen Technology, Inc. | Compositions and Methods for Treating Cancer with Fully Human Anti-CD20/CD19 Immunotherapy |
WO2024050399A1 (en) | 2022-09-01 | 2024-03-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies targeting hpv e6/e7 oncogenic peptide/mhc complexes |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2442655C3 (en) * | 1974-09-06 | 1979-09-20 | Behringwerke Ag, 3550 Marburg | Amidated immunoglobulins and their use for intravenous administration |
US4118379A (en) * | 1974-09-06 | 1978-10-03 | Behringwerke Aktiengesellschaft | Amidated immune globulins and process for preparing them |
-
1987
- 1987-08-17 US US07/085,627 patent/US5004697A/en not_active Expired - Lifetime
-
1988
- 1988-08-15 WO PCT/US1988/002760 patent/WO1989001343A1/en active IP Right Grant
- 1988-08-15 AU AU23870/88A patent/AU628299B2/en not_active Ceased
- 1988-08-15 JP JP63507415A patent/JPH03500644A/en active Pending
- 1988-08-15 AT AT88907980T patent/ATE123227T1/en not_active IP Right Cessation
- 1988-08-15 EP EP88907980A patent/EP0557270B1/en not_active Expired - Lifetime
- 1988-08-15 DE DE3853923T patent/DE3853923T2/en not_active Expired - Fee Related
- 1988-08-16 CA CA000574859A patent/CA1309340C/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
EP0557270A1 (en) | 1993-09-01 |
ATE123227T1 (en) | 1995-06-15 |
DE3853923T2 (en) | 1995-11-16 |
US5004697A (en) | 1991-04-02 |
AU2387088A (en) | 1989-03-09 |
AU628299B2 (en) | 1992-09-17 |
DE3853923D1 (en) | 1995-07-06 |
JPH03500644A (en) | 1991-02-14 |
EP0557270B1 (en) | 1995-05-31 |
WO1989001343A1 (en) | 1989-02-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1309340C (en) | Cationized antibodies for delivery through the blood-brain barrier | |
CA2077670C (en) | Method for enhancing antibody transport through capillary barriers | |
AU649079B2 (en) | Modified antibodies with controlled clearance time | |
JP4153560B2 (en) | Treatment of allergic asthma | |
Boyd et al. | The production of high-titre antibody against free angiotensin II | |
JPH05500944A (en) | Transferrin receptor-specific antibody-nerve drug conjugate | |
CA2174501A1 (en) | Method of binding material to the .beta.-amyloid peptide | |
CA2283295C (en) | Concurrent in-vivo immunoconjugate binding to multiple epitopes of vascular permeability factor on tumor-associated blood vessels | |
JP2012131808A (en) | Antibody having reduced net positive charge | |
AU616161B2 (en) | Methods for improved targeting of antibody, antibody fragments, hormones and other targeting agents, and conjugates thereof | |
US20060182683A1 (en) | Methods for reduced renal uptake of protein conjugates | |
CA2066031C (en) | Methods for reducing non-target retention of immunoconjugates and metabolites thereof | |
Koyama et al. | Effect of chemical cationization of antigen on glomerular localization of immune complexes in active models of serum sickness nephritis in rabbits. | |
AU2003217467B2 (en) | Avidin dimers effective in increasing the concentration of radioactive biotin in pretargeted radioimmunotherapy | |
Goldman et al. | Pharmacokinetics and biodistribution of a monoclonal antibody to Cryptococcus neoformans capsular polysaccharide antigen in a rat model of cryptococcal meningitis: implications for passive immunotherapy | |
EP0090025A1 (en) | Specific mammary gland labelling | |
JPS6045598A (en) | Immunoassey by thymosin beta 4 tritium | |
Choi et al. | Dynamics of streptococcus histone retention by mouse kidneys | |
Louw et al. | Species and immunoglobulin preparation related effects on the biodistribution of technetium-99m-labelled immunoglobulin G in a baboon model | |
EP0412920B1 (en) | Diagnostic or therapeutic composition, especially for cancer | |
EP0338436A2 (en) | Monoclonal antibody against neuropeptide Y, method for its preparation as well as its use | |
Lan et al. | Preclinical Evaluation of SPECT Imaging with 131∣–Labeled Monoclonal Antibody SZ39 in Nude Mice Bearing Human Glioma Xenografts | |
JPH06507641A (en) | Endothelial cell ligand recognition antibody for leukocyte CR3 | |
Bloch et al. | Interaction of circulating radiolabelled IgG antibody and fed protein antigen in the rat | |
WO2000014537A2 (en) | Immunoconjugate for diagnosis of multidrug resistance |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKLA | Lapsed |