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Engineered Antibody Fc Variants with Enhanced Effector Function
Greg A. Lazar, Wei Dang, Sher Karki, Omid Vafa, Judy S. Peng, Linus Hyun, Cheryl Chan, Helen S. Chung, Araz Eivazi, Sean C. Yoder, Jost Vielmetter, David F. Carmichael, Robert J. Hayes and Bassil I. Dahiyat
Proceedings of the National Academy of Sciences of the United States of America
Vol. 103, No. 11 (Mar. 14, 2006), pp. 4005-4010
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/30048873
Page Count: 6
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Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcγ receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fcγ receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.
Proceedings of the National Academy of Sciences of the United States of America © 2006 National Academy of Sciences