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The Journal of Immunology, 1998, 161: 3862-3869.
Copyright © 1998 by The American Association of Immunologists

Therapy with Monoclonal Antibodies. II. The Contribution of Fc{gamma} Receptor Binding and the Influence of CH1 and CH3 Domains on In Vivo Effector Function1

John D. Isaacs2, Judith Greenwood3 and Herman Waldmann4

Department of Pathology, Immunology Division, University of Cambridge, Cambridge, United Kingdom

An in vivo model is used to define Fc motifs engaged by mAbs to deplete target cells. Human IgG1 and human IgG4 were very potent, and mutations within a motif critical for Fc{gamma}R binding (glutamate 233 to proline, leucine/phenylalanine 234 to valine, and leucine 235 to alanine) completely prevented depletion. Mouse IgG2b was also potent, and mutations to prevent complement activation did not impair depletion with this isotype, as previously shown for human IgG1. In contrast, a mutation that impaired binding to mouse Fc{gamma}RII (glutamate 318 to alanine) eliminated effector function of mouse IgG2b and also reduced the potency of human IgG4. To reveal potential contributions of domains other than CH2, domain switch mutants were created between human IgG1 and rat IgG2a. Two hybrid mAbs were generated with potencies exceeding anything previously seen in this model. While their mechanism of depletion was not defined, their activity appeared dependent upon interdomain interactions in the Fc region.




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