IgGA: A 'Cross-Isotype' Engineered Human Fc Antibody Domain that Displays Both IgG-like and IgA-like Effector Functions

摘要

All clinically approved antibodies are of the IgG isotype and mediate the clearance of target cells via binding to Fc gamma receptors and complement (C1q). Even though IgA can elicit powerful cytotoxic action via Fc alpha RI receptor binding, IgA antibodies have not been amenable to therapeutic development. Here, we report the engineering of a "cross-isotype" antibody, IgGA, which combines the effector functions of both IgG and IgA. IgGA binds to Fc alpha RI with an affinity comparable to that of IgA, and to the activating Fc gamma receptors, Fc gamma RI and Fc gamma RIIa, with high affinity, and displays increased binding to C1q compared to IgG. Unlike trastuzumab-IgG, trastuzumab-IgGA potently activates both neutrophils and macrophages to kill Her2(+) cancer cells. Furthermore, IgGA mediates greater complement-dependent cytotoxicity than IgG1 or IgA antibodies. The multitude of IgGA effector functions could be important for therapeutic purposes and highlights the concept of engineering antibodies that combine effector functions from multiple antibody isotypes.