Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Patent
1994-08-16
1999-01-26
Caputa, Anthony C.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
4241351, 4241411, 4241451, 4241521, 4241721, 530350, 5303871, 5303873, 53038823, A61K 39395, A61K 3940, C07K 1600, C12P 2108
Patent
active
058635378
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Human interleukin-4 (IL-4) was first cloned and characterized by Yokota et lymphokine which affects many different components of the immune system. It has T cell growth factor (TCGF) activity, and B cell growth factor activity. It is capable of potentiating the TCGF activity of interleukin-2 (IL-2) and the colony-forming activity of granulocyte-macrophage colony stimulating factor (GM-CSF).
It induces the preferential production of IgG.sub.1 and IgE, induces the low affinity receptor for IgE (CD23), and induces the expression of human leukocyte class II DR antigens.
These activities suggest several possible therapeutic uses for IL-4, e.g., agent for IL-2 anticancer therapy, as a potentiating agent for GM-CSF-stimulated bone marrow regeneration, or as an agent to treat bare Touraine et al., Human Immunology 2:147 (1981); and Sullivan et al., J. Clin. Invest. 76:75 (1985)!. IL-4 and IL-4 agonists are thus potentially useful therapeutic agents.
The IgE- and CD23-inducing activity of IL-4 could have important consequences for persons suffering from allergic diseases. The availability of IL-4 antagonists could provide an alternative to the use of glucocorticoid steroids, which have many deleterious side effects, Basis of Therapeutics, 6th Ed. (MacMillan Publishing Company, New York, 1980)!.
Strongly blocking monoclonal antibodies specific for human IL-4 provide a means for constructing agonists or antagonists by generating anti-idiotype al., J. Immunol. Meth. 102:259 (1987); PCT patent applications WO 86/00991 and WO 86/06487!. Because most monoclonal antibodies are of rodent cell origin, however, there is a possibility that they would be immunogenic if used therapeutically in a human being, particularly if used over a long period of time. To avoid this possibility, it would be desirable to have human antibodies, or "humanized" antibodies, against human IL-4.
Initial efforts to reduce the immunogenicity of rodent antibodies involved the production of chimeric antibodies, in which mouse variable regions USA 84:3439 (1987)!. It has been shown, however, that mice injected with hybrids of human variable regions and mouse constant regions develop a strong anti-antibody response directed against the human variable region. This suggests that in the human system, retention of the entire rodent Fv region in such chimeric antibodies may still give rise to human anti-mouse antibodies.
It is generally believed that CDR loops of variable domains comprise the binding site of antibody molecules, the grafting of rodent CDR loops onto human frameworks (i.e., humanization) was attempted to further minimize (1991)! have shown that framework residues of antibody variable domains are involved in CDR loop support.
It has also been found that changes in framework support residues in humanized antibodies may be required to preserve antigen binding affinity. The use of CDR grafting and framework residue preservation in a number of humanized antibody constructs has been reported, e.g., by Queen et al. Exact sequence information has been reported for only a few humanized constructs.
From the foregoing, it is evident that there is a need for monoclonal antibodies specific for IL-4 that can be used therapeutically. Preferably, these antibodies should be humanized antibodies.
SUMMARY OF THE INVENTION
The present invention fills this need by providing monoclonal antibodies and compositions that are useful for the treatment of IL-4-related diseases, and intermediates for making such materials.
More particularly, this invention provides a monoclonal antibody produced by a hybridoma having the identifying characteristics of a cell line deposited under American Type Culture Collection Accession No. ATCC HB 9809, and the hybridoma itself.
This invention further provides polypeptides comprising heavy or light chain variable regions of a monoclonal antibody which have amino acid sequences defined by SEQ ID NO: 1, SEQ ID NO: 2, or subsequences thereof.
The present invention still further provides isolated DNAs which e
REFERENCES:
patent: 5041381 (1991-08-01), Abrams et al.
patent: 5585089 (1996-12-01), Queen et al.
Casali et al., Science 234:476 (1986).
Jameson et al., Nature 341:465 (1989).
Kabat et al.. Sequences of Proteins of Immunological Interest, 4h Edition, U.S. Dept. of Health and Human Services, National Institutes of Health (1987), pp. vii-xliv.
Lewis et al., Gene 101:297 (1991).
Queen et al., Proc. Natl. Acad. Sci. USA 86:10029 (1989).
Riechmann et al., Nature 332:323 (1988).
Saiki et al., Science 239:487 (1988).
Bird et al., 1988, Science 242:423-426.
Bird and Walker, 1991, Tibtech 9:132-137.
Lazar et al (Molecular & Cellular Biology vol. 8 Mar. 1988 pp. 1247-1252).
Burgess et al (J. of Cell Biology vol. 111 Nov. 1990 pp. 2129-2138).
Dalie Barbara
Le Hung V.
Miller Kenneth
Murgolo Nicholas J.
Nguyen Hanh
Caputa Anthony C.
Dulak Norman C.
Foulke Cynthia L.
Navarro Mark
Schering Corporation
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