Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Patent
1996-09-06
1998-01-06
Feisee, Lila
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
4241311, 4241391, 4241411, 4241421, 4241451, 5303871, 5303872, 5303879, 53038823, A61K 39395, C07K 1624, C07K 1642, C07H 2104
Patent
active
057051542
DESCRIPTION:
BRIEF SUMMARY
This is a U.S. national application corresponding to International application No. PCT/US95/02400, filed Mar. 8, 1995, which Application is a continuation-in-part of application Ser. No. 08/208,886, filed Mar. 10, 1994, now U.S. Pat. No. 5,597,710.
This invention relates to polypeptides comprising variable regions of a humanized monoclonal antibody that specifically binds human IL-4, monoclonal antibodies and binding fragments comprising the polypeptides, and pharmaceutical compositions comprising the polypeptides, antibodies and binding fragments. This invention also relates to nucleic acids and recombinant vectors encoding the foregoing, and to methods for making the polypeptides and antibodies.
BACKGROUND OF THE INVENTION
Human interleukin-4 (IL-4) is a highly pleiotropic 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 also induces (a) the preferential production of IgG.sub.1 and IgE, (b) the low affinity receptor for IgE (CD23), and (c) the expression of human leukocyte class It 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 at., 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.
On the other hand, the IgE- and CD23-inducing activity of IL-4 may have important adverse 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, especially with prolonged usage.
Monoclonal antibodies specific for blocking human IL-4 biological activity provide a means for constructing agonists or antagonists by generating anti-idiotype antibodies (U.S. Pat. No. 4,731,237) or by mimotope 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 over a long period of time.
To avoid this possibility, it is desirable to have human antibodies, or "humanized" antibodies, against human IL-4. The preparation of humanized antibodies against IL-4 has in fact been disclosed in International Patent Application Publication No. WO 93/17106. The disclosed antibodies while useful, however, do not have binding affinities equal to that of the starting rodent monoclonal antibody upon which they were based.
It would be desirable to have a humanized antibody against human IL-4 which would possess a binding affinity comparable to that of the rodent antibody. It cannot be predicted from the present state of the art, however, whether or how such an antibody could be produced.
SUMMARY OF THE INVENTION
The present invention provides such a high-affinity monoclonal antibody, methods and compositions useful for the treatment of IL-4-related diseases, and intermediates for making such materials.
More particularly, this invention provides polypeptides comprising light or heavy chain variable regions of a humanized monoclonal antibody against human IL-4 which have amino acid sequences shown in SEQ ID NO: 70 and SEQ ID NO: 79, respectively, or subsequences of such sequences. In one embodiment, such polypeptides comprise a complete humanized monoclonal antibody. In other embodiments they comprise IL-4-binding and/or antigenic fragments of the humanized monoclonal antibody.
The present invention further provides isolated DNAs that encode polypeptides comprising light or heavy chain variable regions of a humanized monoclonal antibody against human IL-4 which have amino acid sequences shown
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Dalie Barbara
Miller Kenneth
Murgolo Nicholas
Tindall Stephen
Dulak Norman C.
Feisee Lila
Foulke Cynthia L.
Lucas John
Schering Corporation
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