Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Anti-idiotypic
Patent
1996-05-22
1999-02-02
Chan, Christina
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Anti-idiotypic
4241331, 435810, 435 723, 5303872, 5303873, A61K 39395, C07K 1642, C12P 2108, G01N 33574
Patent
active
058661247
DESCRIPTION:
BRIEF SUMMARY
The invention concerns antiidiotypic monoclonal antibodies comprising human constant regions, and variable regions bearing the internal image of human high molecular weight-melanoma associated antigen (HMW-MAA), and derivatives of said antibodies. The antibodies of the invention and their derivatives are useful for diagnostic, prophylactic and therapeutic purposes, such as the immune therapy of melanoma.
BACKGROUND OF THE INVENTION
Melanomas are tumors of the skin, less frequently of mucous membranes, some of which are benign. Malignant melanomas are carcinomas of neuroectodermal origin generally derived from melanocytes (pigment-producing cells), sometimes from mucous membranes, the chorioid coat or the meninges. There are several types of malignant melanoma which differ in localization, way of spreading and production of metastases.
Conventional treatment of melanoma includes surgery, radio- or chemotherapy, and the application of biological response modifiers. However, these methods have proved to be insufficient to combat the illness, e.g. to prevent tumor recurrence, and are complicated by a large number of severe side effects. Therefore, it is desirable to develop therapeutic approaches which overcome these drawbacks and can replace or be used in combination with conventional treatment.
Since the immune system seems to be heavily involved in the pathogenesis of this disease, the most suitable treatment would be a method of active immunotherapy, for example based on the application of specific antiidiotypic antibodies. Of special interest for therapeutic application are antiidiotypic antibodies of the internal image type which mimic the initial antigen and can substitute for it.
For tumor therapy, suitable antiidiotypic antibodies are those which are raised against antibodies specific for tumor associated antigens. In melanoma, one of the associated antigens (MAA) identified so far is the high molecular weight-melanoma associated antigen (HMW-MAA) with a molecular weight of >1,000,000. Murine antiidiotypic monoclonal antibodies raised against an antibody to HMW-MAA have been disclosed in European Patent Application No. 428 485.
However, a major limitation in the use of said murine-derived antiidiotypic monoclonal antibodies as diagnostic and therapeutic agents is their immunogenicity as foreign proteins, their rather long persistence in the circulation, and the formation of damaging immune complexes. On the other hand, the treatment with human monoclonal antibodies is also limited since human hybridoma cell lines are hard to prepare, generally unstable, and do not produce monoclonal antibodies of appropriate specificity in sufficient quantities and at reasonable costs.
Accordingly, there is a need for antiidiotypic antibodies the application of which inheres a reduced risk of eliciting an undesired anti-murine immunoglobulin immune response, while e.g. the idiotypic immune response and thus the production of endogenous anti-antiidiotypic antibodies should not be affected.
OBJECT OF THE INVENTION
It is an object of the invention to provide such antibodies and methods for the production therof. The antibodies of the invention are antibodies which are obtainable by "humanizing" murine antiidiotypic monoclonal antibodies bearing the internal image of HMW-MAA.
The antibodies of the invention can be used for diagnostic, prophylactic and therapeutic purposes, e.g. for monitoring, control, prevention and treatment of melanoma. The anti-bodies of the invention have immunregulatory functions such as the stimulation of humoral and cellular immunity.
It is another object of the present invention to provide recombinant DNA molecules encoding the antibodies according to the invention, and methods for the production thereof.
Moreover the invention relates to expression systems suitable for the expression of such recombinant DNA molecules.
DESCRIPTION OF THE INVENTION
Due to the fact that the variable region and each of the constant region domains of immunoglobulin molecules are encoded in separate exons
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Hardman Norman
Murray Brendan
Pluschke Gerd
Chan Christina
Novartis Corporation
Pfeiffer Hesna J.
VanderVegt F. Pierre
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