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Research Articles: Therapeutics, Targets, and Development

Optimization of antibody binding to FcRIIa enhances macrophage phagocytosis of tumor cells

Xencor, Inc., Monrovia, California

Requests for reprints: John R. Desjarlais, Xencor, 111 West Lemon Avenue, Monrovia, CA 91016. Phone: 626-737-8077; Fax: 626-737-8098. E-mail: jrd{at}xencor.com

Abstract

The contribution of Fc-mediated effector functions to the therapeutic efficacy of some monoclonal antibodies has motivated efforts to enhance interactions with Fc receptors (FcR). Although an early goal has been enhanced FcRIIIa binding and natural killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), other relevant cell types such as macrophages are dependent on additional activating receptors such as FcRIIa. Here, we describe a set of engineered Fc variants with diverse FcR affinities, including a novel substitution G236A that provides selectively enhanced binding to FcRIIa relative to FcRIIb. Variants containing this substitution have up to 70-fold greater FcRIIa affinity and 15-fold improvement in FcRIIa/FcRIIb ratio and mediate enhanced phagocytosis of antibody-coated target cells by macrophages. Specific double and triple combination variants with this substitution are simultaneously capable of exhibiting high NK-mediated ADCC and high macrophage phagocytosis. In addition, we have used this unique set of variants to quantitatively probe the relative contributions of individual FcR to effector functions mediated by NK cells and macrophages. These experiments show that FcRIIa plays the most influential role for macrophages and, surprisingly, that the inhibitory receptor FcRIIb has little effect on effector function. The enhancements in phagocytosis described here provide the potential to improve the performance of therapeutic antibodies targeting cancers. [Mol Cancer Ther 2008;7(8):2517–27]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Unpublished results.

² Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/28/08; revised 4/11/08; accepted 4/24/08.

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