Induction of immunogenicity of monoclonal antibodies by conjugation with drugs

Human anti-mouse antibody has been a nearly consistent result of human clinical trials utilizing murine antibodies. It is generally anticipated that the problem of human anti-mouse antibody will be reduced as genetically engineered, more human ("humanized") antibodies become available. It...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1991-10, Vol.51 (20), p.5774-5776
Main Authors: JOHNSON, D. A, BARTON, R. L, FIX, D. V, SCOTT, W. L, GUTOWSKI, M. C
Format: Article
Language:English
Subjects:
Alanine - immunology
Animals
Antibodies, Monoclonal - immunology
Antineoplastic agents
Biological and medical sciences
Chemotherapy
Ether - immunology
Immunotoxins - immunology
Medical sciences
Pharmacology. Drug treatments
Pyrroles - immunology
Receptor, Epidermal Growth Factor - immunology
Vinblastine - analogs & derivatives
Vinblastine - immunology
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Summary:Human anti-mouse antibody has been a nearly consistent result of human clinical trials utilizing murine antibodies. It is generally anticipated that the problem of human anti-mouse antibody will be reduced as genetically engineered, more human ("humanized") antibodies become available. It is not clear, however, what effect chemical modification of such "humanized" antibodies will have on their immunogenicity. The present studies utilize a mouse antibody and rat host model to explore aspects of this question. Rats injected with unmodified mouse monoclonal antibodies failed to mount anti-mouse immune responses, presumably due to their phylogenetic relatedness. In contrast, rats injected with a Vinca immunoconjugate mounted strong anticonjugate antibody responses that were directed primarily against the linker portion of the conjugate. The in vivo serum pharmacokinetics of 125I-labeled antibody and conjugates were evaluated in rats with existing anticonjugate antibody. The peak serum level attained was inversely correlated with the level of reactivity of the anticonjugate antibody with the injected compound. This model provides a potentially useful tool for exploration of the immunogenicity of drug, toxin, or radionuclide monoclonal antibody conjugates.
ISSN:0008-5472
1538-7445