ENHANCEMENT OF THE IMMUNE RESPOSE BY FC MODIFICATION

DESCRIPTION (provided by applicant): Passive and active humoral immune responses are mediated by the interaction of immunoglobulins and the low affinity Fc receptors, FcRIIB and FcRIIIA, present on the surface of effector cells. Recent proof-of-principle experiments in xenograft and syngenic tumor models indicate that the interaction between the Fc and the activation receptor, FcRIIIA, triggers a cytotoxic response in the presence of an anti-tumor antibody and that the inhibiting receptor, FcRIlB, restricts the cytotoxic response. Thus novel Fc domains that have increased affinity for FcRIIIA and a reduced affinity for FcRIIB have the potential to improve the efficacy of monoclonal therapeutic antibodies. We propose to identify high affinity Fc alleles by directed protein evolution of the human Fc using yeast surface display. Yeast display provides a unique platform that expresses and displays eukaryotic peptides efficiently and allows screening >107 independent Fc mutants. Successful identification of Fc alleles with a high affinity for FcRIIIA and a low affinity for FcRIIB will be pursued.