Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1995-07-31
1999-07-20
Eisenschenk, Frank C.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
4241601, 5303913, 5303917, 4353391, C07K 1600, A61K 3942, C12P 2108, C12N 500
Patent
active
059257415
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention concerns novel antigenic epitopes which become substantially more accessible after binding of two members of a binding couple, e.g. ligand-receptor binding, antibody-antigen binding, etc. These novel antigenic epitopes will be referred to herein at times as "binding" associated epitopes (BAE). A specific aspect of the present invention concerns BAE which are revealed after virus-receptor interaction, e.g. HIV-CD4 interaction.
The present invention further concerns antibodies, particularly monoclonal antibodies, directed against BAEs, and further concerns the use of such antibodies or BAEs in diagnostics and treatment.
BACKGROUND OF THE INVENTION AND PRIOR ART
Binding of two members of a binding couple, e.g. a virus to its receptor on a cell membrane, is a complex interaction which may involve, inter alia, a conformational change in the receptor and likely also in the viral receptor-binding protein. The study of such conformational changes may have various important therapeutic implications.
A virus-receptor interaction which has been studies extensively in recent years is that of the HIV (Human Immunodeficiency Virus) to the CD4 protein which is expressed by and present on membranes of T lymphocytes, some macrophages and likely also on several other kinds of cells. An HIV protein, gp120, which has a binding affinity to the CD4 receptor was discovered, and the receptor recognition sites in this protein have been at least partially identified. Seeing that the binding between the HIV virus or its gp120 protein to the CD4 receptor and the occurrences following such interaction are critical phases in the infection process, it is believed that agents which will interfere with these infection stages will likely be useful as drugs in treating AIDS and particularly in inhibiting the progress of the HIV infection. It has been proposed to use antibodies which recognize either the CD4 receptor, the gp120 protein or the complex which is formed following binding, as it was believed that such antibodies may form useful agents in inhibiting the infection process. Monoclonal antibodies (mAbs) useful for this purpose have been proposed, amongst others, by Celada et al. 1990 (J. Exp. Med., 172, 1143-1150), Celada, 1992 (WO 92/05799) and Healey et al., 1990 (J. Exp. Med., 172, 1223-1242). These references disclosed antibodies directed against CD4 which were shown to prevent syncytium formation without interfering with the gp120/CD4 complex formation. However, all the antibodies described to date were not found to be useful in treatment since they either bind well to CD4 receptors and thus may interfere with the normal function of non-infected CD4 bearing cells or, where the antibodies were directed to an epitope in the virus and specifically in the gp120 protein, they were as a rule found to be strain and even isolate-specific.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide antigenic epitopes associated with binding of two members of a binding couple to one another (BAE).
It is another object of the present invention to provide binding associated antibodies capable of binding to a complex consisting of two members of a binding couple, with a higher affinity than to each member by itself.
It is another object of the present invention to provide medicinal and diagnostic uses of such epitopes or antibodies.
The remaining objects of the present invention will be revealed in the following description and claims.
GENERAL DESCRIPTION OF THE INVENTION
The present invention is based on the surprising finding that upon binding of two members of a binding couple, certain novel antigenic epitopes are revealed or exposed and as a result become accessible to antibodies. When a complex of the two members is injected to an animal, an immune reaction is elicited and some of the produced antibodies are such which bind to the complex with a substantially higher affinity than to either of the two members individually.
Hybridomas producing such antibodies can be
REFERENCES:
The Faseb Journal, vol. 7, No. 12, issued Sep. 1993, Gershoni et al., "HIV binding to its receptor creates specific epitopes for the CD4/gp 120 complex," pp. 1185-1187.
Journal Of Experimental Medicine, vol. 172, issued Oct. 1990, Caleda et al., "Antibody raised against soluble CD4-rgp 120 complex recognizes the CD4 moiety and blocks membrane fusion without inhibiting CD4-gp 120 binding," pp. 1143-1150.
Parasitology, vol. 88, issued 1984, Ortega et al., The occurrence of antibodies to hidden and exposed determinants of surface antigens of Trichinella spiralis, pp. 359-369.
Abstract 586686, Journal of Laboratory Clinical Medicine, vol. 86, No. 5, issued 1975, Javid et al., "The modification of hemoglobin antihemiglobin reaction by haptoglobin," pp. 777-784.
Abstract 6538081, British Journal of Haematology, vol. 68, No. 3, issued 1988, Nordfang et al., "Radioimmunoassay afor quantitative measurement of Factor VIII-heavy chain," pp. 307-312.
Abstract 207470, Scandinavian Journal of Immunology, vol. 3, No. 2, issued 1974, Lind et al., Immunochemical study of the interaction between staphylococcal protein A, rabbit antistaphyloccoccal sera, and selected sera from nonimmunized animals, pp. 147-156.
Abstract 407661, Scandinavian Journal of Immunology, vol. 3, No. 6, issued 1974, Lind., I., "The formation of antibodies against hidden determinants of autologous IgG during immunization of rabbits with Staphylococcus aureus," pp. 689-696.
Abstract 359023, International Journal of Parasitology, vol. 4, No. 6, issued 1974, Boreham et al., "Autoimmunity in trypansome infections II. Anti fibrin/fibrinogen (anti-F) autoantibody in Trypanosoma (Trypanozoon) brucei infections of the rabbit, " pp. 601-607.
Abstract 9626985, Journal of Immunology, vol. 149, No. 6, issued 1992, Callahan et al., "Analysis of HIV induced autoantibodies to cryptic epitopes on human CD4," pp. 2194-2202.
Eisenschenk Frank C.
Park Hankyel T.
Ramot University Authority for Applied Research and Industrial
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