Identification of a High Affinity Fc gamma RIIA-binding Peptide That Distinguishes Fc gamma RIIA from Fc gamma RIIB and Exploits Fc gamma RIIA-mediated Phagocytosis and Degradation

Abstract

FcγRIIA is a key activating receptor linking immune complex formation with cellular effector functions. FcγRIIA has 93% identity with an inhibitory receptor, FcγRIIB, which negatively regulates FcγRIIA. FcγRIIA is important in the therapeutic action of several monoclonal antibodies. Binding molecules that discriminate FcγRIIA from FcγRIIB may optimize receptor activity and serve as a lead for development of therapeutics with FcγRIIA as a key target. Here we report the use of phage display libraries to select short peptides with distinct FcγRIIA binding properties. An 11-mer peptide (WAWVWLTETAV) was characterized that bound FcγRIIA with a Kd of 500 nm. It mediated cell internalization and degradation of a model antigen. The peptide-binding site on FcγRIIA was shown to involve Phe163 and the IgG binding amino acids Trp90 and Trp113. It is thus overlapping but not identical to that of IgG. Neither activating receptors FcγRI and FcγRIII, nor FcγRIIB, all of which lack Phe163, bound the peptide. This research was originally published in: Journal of Biological Chemistry. © the American Society for Biochemistry and Molecular Biology.