IE910697A1 - Human monoclonal antibodies against rabies viruses, the¹production and the use thereof - Google Patents
Human monoclonal antibodies against rabies viruses, the¹production and the use thereofInfo
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- IE910697A1 IE910697A1 IE069791A IE69791A IE910697A1 IE 910697 A1 IE910697 A1 IE 910697A1 IE 069791 A IE069791 A IE 069791A IE 69791 A IE69791 A IE 69791A IE 910697 A1 IE910697 A1 IE 910697A1
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- rabies
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/205—Rhabdoviridae, e.g. rabies virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/20011—Rhabdoviridae
- C12N2760/20111—Lyssavirus, e.g. rabies virus
- C12N2760/20122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
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- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Mycology (AREA)
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- Tropical Medicine & Parasitology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract
The present patent application relates to human monoclonal antibodies against rabies viruses and to the use thereof in diagnosis, prophylaxis and therapy. Antibodies against the epitope, which is defined by human monoclonal antibody TW-1, on the 67 kD glycoprotein of the virus coat provide better protection against development of rabies after infection has taken place than do commercial human immunoglobulin preparations.
Description
BEHRINGWERKE AKTIENGESELLSCHAFT HOE 90/B 010 - Ma 809 Dr. Lp/rd Description Human monoclonal antibodies against rabies viruses, the 5 production and the use thereof The present patent application relates to human monoclonal antibodies against rabies viruses, and the use thereof in diagnosis, prevention and therapy. Antibodies against the epitope, defined by the human monoclonal antibody TW-1, on the 67 kD glycoprotein of the virus envelope give a better protection against the outbreak of rabies, after infection has taken place, than commercial preparations of human immunoglobulins.
Rabies is an encephalomyelitis having a lethal course, which is caused by rabies virus, a member of the Rhabdoviridae family. Especially in less developed countries, the disease is a big problem and, for example, in India more than 20,000 deaths per year are ascribed to rabies according to cautious estimates. The infection often takes place via a bite by infected animals (Canidae, Chiroptera). The first target cell for the virus seems to be muscle cells at the place of entry. After entry into peripheral nerves, the virus migrates from the infection site by retrograde axoplasmatic transport to the central nervous system and the spinal cord. After viral replication in the central nervous system, the virus migrates via the nerve paths to various target tissues in the body, e.g. salivary glands.
Owing to the long incubation time, in relation to other viral infections, of about 30 to 90 days until rabiesspecific symptoms appear, post-exposure vaccination is possible. In order to achieve fast protection until the active immunization is effective, a passive immunization IE 91697 with homologous or heterologous serum preparations together with the active immunization is urgently recommended by the WHO. In underdeveloped countries, especially preparations from horse sera are used, anaphylac5 tic reactions being a serious problem.
In contrast to polyclonal preparations, monoclonal antibodies have the advantage of unchanging specificity. Human monoclonal antibodies (HUMAB) moreover avoid undesired immunoreactions of the recipient against heterologous monoclonal antibodies of murine origin, and appear to have a longer circulation time in the body.
The rabies virus is enveloped and of bullet-shaped morphology. The single stranded RNA of the virus is associated with a 55 kD nucleoprotein, the 190 kD large transcriptase molecule and the 38 kD nonstructural protein. The viral envelope contains a 26 kD matrix protein and a 67 kD glycoprotein. This glycoprotein is an important binding site for antibodies neutralizing the virus (D. L. Lodmell, J. Virol., 61, 10: 3314-3318, 1987). The mechanism of neutralization is presumed to be an inhibition of the intraendosomal fusion step, i.e. an uncoating of the virus is prevented. Dietzschold et al. (Virology, 161: 29-36, (1987)) describe the neutralization of a rabies virus by murine MAB against the 67 kD glycoprotein. Whilst a technique which has been established for a long time (G. Kohler and C. Mil stein, Nature, 256, 495-497, 1975) allows murine monoclonal antibodies against certain antigens such as the glycoprotein of rabies virus to be established in a relatively simple way (D. L. Lodmell, loc. cit.), it is extremely difficult to obtain human monoclonal antibodies for therapeutic use. Moreover it was not known whether such human monoclonal antibodies not only bind to the glycoprotein but can also neutralize infectious rabies virus and protect, in vivo, from the outbreak of the disease.
To obtain the human monoclonal antibody TW-1 against rabies virus, which is described here, human peripheral blood lymphocytes of a healthy serum-positive donor were incubated with Epstein-Barr Virus (EBV). Supernatants of growing B-lymphocytes transformed by EBV were tested for rabies-specific antibodies in an ELISA. Specifically producing B-cell lines were fused with the mouse myeloma cell line SP2/0 in order to stabilize the antibody production. The resulting hybridoma were cloned several times and tested for specific production of antibodies of the IgG class . The process was modified by a known method (D. Kozbor & J. C. Roder, Immunol. Today, 4:72-79, 1983) and carried out as described in a different publication (J. Hilfenhaus et al., Behring Inst. Mitt., 80:31-41, 1986). The selection of antibody-producing cells was, in the present case, carried out by testing the supernatants of the cultures in an ELISA on coating material containing rabies virus. The ELISA used is illustrated in more detail in Example 1.
It has been found that the human monoclonal antibody against rabies virus, TW-1, which is described here, reacts specifically with rabies-containing coating material (carried out with the Pitman-Moore, Fluri-LEP, CVS strains) but not with control material free of rabies virus in an ELISA. It has likewise been found that TW-1 does not bind to coating material containing control viruses, such as VZV, CMV, rubella, HSV or measles. TW-1 binds to fixed chicken fibroblasts infected with rabies virus but not to non-infected ones, since, after incubation of TW-1 with these cells and subsequent incubation with FITC-coupled antiserum against human immunoglobulin, it is possible to detect the fluorescence typical of rabies only on infected cells. Furthermore it has been found that TW-1 belongs to the IgGl immunoglobulin class (lambda). After SDS gel electrophoresis of rabies antigen reduced by means of dithiothreitol (DTT) (carried out with the Pitman-Moore and Fluri-LEP strains), it was possible to find TW-1 reacting with a band around 67 kD in Western blots. It is possible to conclude from comparisons of own data found and data in the literature (W. H. Wunner et al., Reviews of Infectious Diseases, 10, 4:771-784, 1988) that the protein recognized by TW-1 is the glycoprotein of rabies virus. This is confirmed by the observation that, after digesting the rabies antigen by means of endoglycosidase F before fractionating the antigen in the SDS gel, a reduction of the molecular weight of the protein marked by TW-1 can be observed in Western blots. Since endoglycosidase F cleaves off N10 glycosidically linked sugar residues from proteins, it is possible to conclude from the data obtained that the band marked by TW-1 in Western blots is the glycoprotein of rabies virus. The cross-reaction of TW-1 with the rabies virus strains tested, Pitman-Moore, Fluri-LEP and CVS, indicate binding to a relatively conserved epitope within the glycoprotein.
The testing of whether TW-1 has the capability of neutralizing rabies virus was carried out by two different methods which are known per se. An in vitro fluores20 cence neutralization test was carried out as the first type of test. Antibody dilutions were mixed with active rabies viruses. After adding cells susceptible to rabies virus, the mixture was incubated for 24 hours then incubated with FITC-coupled antiserum specific for rabies and evaluated in a fluorescence invertoscope. Cultures which exhibit rabies-specific fluorescence are counted as positive. Since negative cultures only occur when rabies viruses are completely neutralized by added antibodies it is possible to examine an antibody for rabies-specific neutralizing activity by suitable dilutions and comparing with rabies-specific standard serum of known activity by means of this test. As the second neutralization test method, an experiment was carried out, in which, after mixing the antibody dilutions with infectious rabies virus and an incubation in vitro, the mixture was administered intracerebral ly to NMRI mice (P. Atanasiu, Laboratory Techn. in Rabies, 3rd Edition, Editors Μ. M. Kaplan and H. Koprowski, WHO (1973) 314-318). If active rabies viruses are completely neutralized by added antibodies, the proportion of animals contracting the disease is smaller in this group than in the case of giving pure virus without previous admixture of antibody.
It has been found that rabies virus (CVS strain) is neutralized by TW-1 both in the fluorescence neutralization test and in the neutralization test involving the administration to mice.
In order to demonstrate that giving TW-1 antibody can 10 inhibit or prevent the outbreak of the disease in vivo in the case of an infection with rabies virus, protection experiments were carried out in NMRI mice. It has been found that TW-1 antibody can protect NMRI mice from the outbreak of the disease even 2 hours after the infection with rabies viruses. In comparison with a preparation from human sera containing antibodies against rabies (commercially available Berirab*, Behringwerke AG) significantly less protein is needed for the same neutralizing and protecting effect when giving TW-1. This is a significant advantage of TW-1.
In addition to the use as immunoprophylactic, the antibody, bound to a suitable carrier material, can also be used for the purification of rabies viruses or rabies virus glycoprotein by means of affinity chromatography processes. Apart from this, the antibody is suitable for validating the glycoprotein proportion in vaccine preparations since rabies virus glycoprotein can be detected specifically, as is described in principle in the examples.
The invention therefore relates to an epitope on the 67 kD glycoprotein of rabies virus which is defined by the monoclonal antibody TW-1, and to polyclonal or preferably human monoclonal antibodies against the abovementioned epitope, very preferably TW-1 antibody.
The invention likewise comprises the use of IE 91697 abovementioned antibodies for the preparation of passive vaccines, for diagnoses, for the purification of rabies viruses or rabies virus glycoprotein and for the validation of vaccine preparations. The invention is finally contained in the examples and the patent claims.
The hybridoma secreting the human monoclonal antibody TW-1 was deposited at the European Collection of Animal Cell Cultures (ECACC), Porton Down, Salisbury, UK on 26 February, 1990 with the No. 90022604 in accordance with the Budapest Convention.
Examples t The examples below are intended to illustrate the invention in more detail but do not restrict the invention. For the experiments described in the examples, antibodies purified by affinity chromatography were used.
Example 1: Specificity of TW-1 antibodies in ELISA. 96-well ELISA plates were coated with concentrates, which have been purified by sucrose gradient centrifugation and inactivated by means of β-propiolactone, of culture supernatants of infected MRC-5 cells (Pitman-Moore strain) or infected chicken fibroblasts (Fluri-LEP strain), or with preparations of the corresponding noninf ected cells as control, at room temperature for 24 hours. Dilutions of the antibody samples were incubated on the plate for 1 hour and unbound antibody was removed by washing. Bound antibodies were marked by incubating with a peroxidase-conjugated antibody (rabbit anti-human IgG, Behringwerke) for 1 hour. It was possible to detect human antibodies with a specificity for rabies virus via a peroxidase-catalyzed color reaction. In Fig. 1, the titration of TW-1 and BerirabR on the applied rabies antigens and the corresponding control antigens is shown. If varicella zoster virus, cytomegalo virus, rubella viruses, herpes simplex virusl or measles viruses are used for the coating, no reaction takes place. For this reason, it can be assumed that TW-1 binds to rabies virus with a high specificity. Since the binding curves of TW-1 against the rabies strains used have a very similar course, an approximately equal binding affinity of TW-1 against Fluri-LEP and Pitman-Moore can be assumed.
Example 2: Characterization of the binding epitope of TW-1 antibody in Western blots Purified rabies virus (Pitman-Moore strain) was frac10 tionated in a 10% polyacrylamide gel according to Laemmli containing 1% SDS/50 mM DTT. After the separated antigen had been transferred onto nitrocellulose, incubation with TW-1 antibody, rabies-positive and rabies-negative human serum was carried out. The detection was carried out by biotin-coupled sheep anti-human immunoglobulin (Amersham), subsequent incubation with streptavidinperoxidase (Amersham) and developing with chloronaphtol (Merck). TW-1 antibody reacts with a band around 67 kD in Western blots (Fig. 2). It can be concluded from litera20 ture data (W. Wunner et al., loc. cit.) that this is the glycoprotein of rabies virus. This is confirmed by digesting the rabies proteins with endoglycosidase F (Boehringer Mannheim) before applying them to the SDS gel. The digestion was carried out according to the manufacturer's instructions. It was intended to observe a reduction of the molecular weight due to cleaving off of sugar residues from the glycoprotein. Such a reduction can be clearly seen for the 67 kD band in comparison with the original antigen in Western blots after TW-1 an30 tibodies have reacted, and this indicates a glycosylation of the protein recognized by TW-1 antibody. TW-1 antibody did not react with control antigens such as CMV, bovine serum albumin or human serum albumin.
Example 3: In vitro fluorescence neutralization test (RFFIT) The test was carried out in vitro by the method of Smith et al., (J. S. Smith et al., Laboratory Techn. in Rabies, 3rd Edition, Editors Μ. M. Kaplan and H. Koprowsky, WHO (1973), 354-357) as microtest in microtiter plates (E. Zalan, J. of Biol. Stand., 7:213-220, (1979)). Sample dilutions (antibody or PBS for the virus control) were mixed with infectious rabies virus. It was possible to deduce from the tests carried out (Fig. 2) that TW-1 antibody exhibits a neutralizing effect on the amount of virus used even at a concentration of about 0.14 lg/ml in this test. About 13.88 lg/ml of the reference serum used (horse) are required for the same effect. A human mono15 clonal antibody against Varizella zoster (VZV-6) of the same isotype which was used as a control did, in a comparable concentration, not have any effect on the infectiousness of the virus.
Example 4: In vitro neutralization test with inocula20 tion of the antibody/antigen mixture into susceptible NMRI mice The test was carried out according to Atanasiu (loc. cit.). NMRI mice with a weight of 20 g were used for the experiment. For the straining with virus, 60 LD50 per mouse were used. In an analogous way to Example 3, sample dilutions (antibody or controls) were initially mixed with active rabies virus in vitro and incubated. In order to monitor the neutralization, the mixture was then administered to NMRI mice intracerebrally. The mice were checked daily for 14 days and the number of surviving animals compared for TW-1 antibody, rabies-specific control serum, a VZV-specific humAb and the administration of pure virus. The corresponding data after an incubation time of 14 days are shown in Fig. 3. This makes clear that TW-1 antibody exhibits a clear neutralization of rabies virus even at the low concentration of 0.08 pg/ml used, while the same concentration of VZV-6 does not have any neutralizing effect.
Example 5: Protection experiment The protection test was carried out using NMRI mice (weight: 20 g) susceptible to rabies virus. For the virus strain, 150 LD50 were administered i.m. (CVS strain). Dilutions of TW-1 antibody, commercially available Berirab® or of VZV-6 were administered i.v. 2 hours before or 2 hours after administration of active rabies virus. In the experiment shown in Fig. 4, the same protection was achieved using 2.5 pg/ml IgG TW-1 antibody as when using 1.5 mg/ml polyclonal BerirabR. As control, VZV-6 was employed at double the concentration of TW-1 antibody. The effect of VZV-6 was in the region of the virus control without administration of antibodies.
Legend for Fig. 1 (Example Is Specificity of TW-1 antibody in ELISA μg/ml TW-1 antibody and 100 pg/ml IgG Berirab (Behringwerke) were used as starting concentration. Extinction was measured at 492 nm. The ELISA plates were coated with 0.4 IE/ml. A is extinction and Cone, is the concentration of the antibodies used.
+ TW-1 on rabies antigen * TW-1 on control antigen o Berirab® on rabies antigen - Berirab® on control antigen Legend for Fig. 2 (Example 3): In vitro neutralization test with fluorescence evaluation 4.4 pg/ml TW-1 antibody ( = 1:100), 111.1 pg/ml ( = 1:100) standard serum and 3.8 pg/ml VZV-6 (= 1:100) were used as starting concentrations.
I.C. is infected cultures The antibody dilution (Dil.) is plotted on the abscissa + TW-1 o rabies standard 5 * VZV-6 Legend for Fig. 3 (Example 5): In vitro neutralization test, evaluation in vivo 0.7 pg/ml TW-1 antibody ( = 1:600), 18.5 /xg/rnl BerirabR (Behringwerke AG) and 0.6 pg/ml VZV-6 (= 1:600) were used as starting concentrations.
S.A. is surviving animals The antibody dilution (DIL.) is plotted on the abscissa + TW-1 o rabies standard * VZV-6 Legend for Fig. 4: Protection experiments in vivo Fig. 4 A: administration of the antibodies 2 hours before administering the virus. Fig. 4 B: administration of the antibodies 2 hours after administering the virus. 2.5 pg/ml TW-1 antibody, 1.5 mg/ml IgG Berirab* and 5 pg/ml VZV-6 were used.
S.A. see above d.p.a. is days past administration
Claims (9)
1. An epitope on the 67 kD glycoprotein of rabies virus, wherein the human monoclonal antibody secreted by the hybridoma TW-1 having the deposit No. 5 90022604 at the European Collection of Animal Cell Cultures (ECACC) reacts therewith.
2. A polyclonal or monoclonal antibody against the epitope as claimed in claim 1.
3. The human monoclonal antibody as claimed in claim 2, 10 secreted by the hybridoma having the deposit No. 90022604 at the ECACC.
4. A process for the preparation of immunoprophylactics, comprising antibodies as claimed in claim 2 or 3 being used. 15 5. A process for detecting a rabies virus infection comprising antibodies as claimed in claim 2 or 3 being used. 6. A process for validating immunoprophylactics, comprising antibodies as claimed in claim 2 or 3 being 20 used. 7. A process for purifying rabies virus antigen, comprising antibodies as claimed in claim 2 or 3 being used. 8. A cell line or another expression system which 25 produces antibody molecules as claimed in claim 2 or parts of these antibodies. 9. A cell line as claimed in claim 8, which results from transformation of human lymphocytes by EpsteinBarr virus and subsequent fusion with a myeloma 30 cell. 10. 10. 11. 11.
5. 12. 5 12. 13. 13. 14. 14. 15. 15. 1
6. 16. 1
7. 17. 1
8. 18. 1
9. 19. The cell line TW-1 having the deposit No. 90022604 at the ECACC. A polyclonal or monoclonal antibody as claimed in claim 2 or 3 as immunoprophylactic or diagnostic. The use of antibodies as claimed in claim 2 or 3 for purifying rabies virus antigen, for diagnosis or for immunoprophylaxis. An epitope according to claim 1, substantially as hereinbefore described and exemplified. A polyclonal or monoclonal antibody according to claim 2, substantially as hereinbefore described and exemplified. A process according to claim 4 for the preparation of immunoprophylactics, substantially as hereinbefore described and exemplified. An immunoprophylactic whenever prepared by a process claimed in claim 4 or 15. A process according to any one of claims 5-7, substantially as hereinbefore described and exemplified. A cell line or another expression system according to claim 8, substantially as hereinbefore described. Use according to claim 12, substantially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4006630A DE4006630A1 (en) | 1990-03-03 | 1990-03-03 | HUMANE MONOCLONAL ANTIBODIES AGAINST RABBIT VIRUSES, THEIR PRODUCTION AND USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE910697A1 true IE910697A1 (en) | 1991-09-11 |
Family
ID=6401309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE069791A IE910697A1 (en) | 1990-03-03 | 1991-03-01 | Human monoclonal antibodies against rabies viruses, the¹production and the use thereof |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0445625A1 (en) |
| JP (1) | JPH05301894A (en) |
| KR (1) | KR910016346A (en) |
| AU (1) | AU634030B2 (en) |
| CA (1) | CA2037446A1 (en) |
| DE (1) | DE4006630A1 (en) |
| IE (1) | IE910697A1 (en) |
| PT (1) | PT96908A (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2344208A1 (en) | 2001-04-30 | 2002-10-30 | Oxford Biomedica (Uk) Limited | Method |
| CN1665528B (en) | 2002-07-05 | 2013-05-15 | 弗利亚生物技术公司 | Adjuvant viral particle |
| US8101189B2 (en) | 2002-07-05 | 2012-01-24 | Folia Biotech Inc. | Vaccines and immunopotentiating compositions and methods for making and using them |
| USRE47770E1 (en) | 2002-07-18 | 2019-12-17 | Merus N.V. | Recombinant production of mixtures of antibodies |
| PT2314629E (en) | 2002-07-18 | 2014-01-22 | Merus B V | Recombinant production of mixtures of antibodies |
| US20100069614A1 (en) | 2008-06-27 | 2010-03-18 | Merus B.V. | Antibody producing non-human mammals |
| ES2408582T3 (en) | 2003-05-30 | 2013-06-21 | Merus B.V. | Fab library for the preparation of a mixture of antibodies |
| JP5912211B2 (en) | 2004-01-20 | 2016-04-27 | メルス ビー．ヴィー． | Mixture of binding proteins |
| DK1749029T3 (en) * | 2004-05-27 | 2011-06-06 | Crucell Holland Bv | Binding molecules that can neutralize rabies virus and its uses |
| GB0526210D0 (en) | 2005-12-22 | 2006-02-01 | Oxford Biomedica Ltd | Vectors |
| EA031202B1 (en) | 2006-06-06 | 2018-11-30 | Янссен Вэксинс Энд Превеншн Б.В. | Human antibody having phagocytic activity against staphylococci and use thereof |
| MX2009005414A (en) | 2006-12-05 | 2009-06-01 | Crucell Holland Bv | Liquid anti-rabies antibody formulations. |
| EP3192874B1 (en) | 2008-06-18 | 2019-10-16 | Oxford BioMedica (UK) Limited | Virus purification |
| JP2010085126A (en) * | 2008-09-29 | 2010-04-15 | Adtec Kk | Determination instrument for determining neutralizing antibody titer of rabies virus, and method for measuring neutralizing antibody titer of rabies virus |
| CN102946907A (en) | 2010-05-28 | 2013-02-27 | 牛津生物医学（英国）有限公司 | Delivery of lentiviral vectors to the brain |
| GB201118636D0 (en) | 2011-10-28 | 2011-12-07 | Oxford Biomedica Ltd | Nucleotide sequence |
| NZ772318A (en) | 2012-04-20 | 2023-06-30 | Merus Nv | Methods and means for the production of ig-like molecules |
| CN103954777A (en) * | 2014-05-20 | 2014-07-30 | 北京凯思百奥科技发展有限公司 | Rabies virus monoclonal antibody and application thereof |
| WO2019227039A1 (en) * | 2018-05-24 | 2019-11-28 | Lankenau Institute For Medical Research | Compositions comprising antibodies to rabies virus and the uses thereof |
| CA3133188A1 (en) | 2019-03-10 | 2020-09-17 | Oxford Biomedica (Uk) Limited | Gene therapy compositions and methods for treating parkinson's disease |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6054687A (en) * | 1983-07-19 | 1985-03-29 | スロ−ン−ケツタリング インステイテユ−ト フオ− キヤンサ− リサ−チ | Production of monoclone antibody |
| AU3432389A (en) * | 1988-04-07 | 1989-11-03 | Farmitalia Carlo Erba S.R.L. | Human monoclonal antibodies against rabies virus |
| DE69005908T2 (en) * | 1989-06-08 | 1994-04-28 | Wistar Inst Philadelphia | Monoclonal antibodies for treatment after contact with rabies virus. |
-
1990
- 1990-03-03 DE DE4006630A patent/DE4006630A1/en not_active Withdrawn
-
1991
- 1991-02-26 EP EP91102804A patent/EP0445625A1/en not_active Withdrawn
- 1991-02-28 PT PT96908A patent/PT96908A/en not_active Application Discontinuation
- 1991-03-01 CA CA002037446A patent/CA2037446A1/en not_active Abandoned
- 1991-03-01 AU AU71982/91A patent/AU634030B2/en not_active Ceased
- 1991-03-01 IE IE069791A patent/IE910697A1/en unknown
- 1991-03-02 JP JP3061286A patent/JPH05301894A/en active Pending
- 1991-03-02 KR KR1019910003427A patent/KR910016346A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2037446A1 (en) | 1991-09-04 |
| KR910016346A (en) | 1991-11-05 |
| EP0445625A1 (en) | 1991-09-11 |
| AU7198291A (en) | 1991-09-05 |
| AU634030B2 (en) | 1993-02-11 |
| DE4006630A1 (en) | 1991-09-12 |
| PT96908A (en) | 1991-10-31 |
| JPH05301894A (en) | 1993-11-16 |
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