We have applied a suite of structure-based protein engineering tools to optimize multiple properties of antibodies. Beginning with the constant Fc domain of antibodies, we designed specific amino acid substitutions to promote high affinity and selective interactions with various Fc gamma receptors to enhance cell-mediated cytotoxicity of tumor cells. These substitutions dramatically enhanced in vitro and in vivo cytotoxicity in mouse and monkey models of disease. Substitutions in a different region of the Fc domain were designed to promote higher affinity for FcRn, leading to markedly enhanced pharmacokinetics properties in mouse and monkey models. Finally, we have introduced a new paradigm for humanization of the antibody variable domain and a novel set of computational tools to reduce the immunogenic potential of antibodies.

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