Identification of a High Affinity FcγRIIA-binding Peptide That Distinguishes FcγRIIA from FcγRIIB and Exploits FcγRIIA-mediated Phagocytosis and Degradation

Fc gamma RIIA is a key activating receptor linking immune complex formation with cellular effector functions. Fc gamma RIIA has 93% identity with an inhibitory receptor, Fc gamma RIIB, which negatively regulates Fc gamma RIIA. Fc gamma RIIA is important in the therapeutic action of several monoclonal antibodies. Binding molecules that discriminate Fc gamma RIIA from Fc gamma RIIB may optimize receptor activity and serve as a lead for development of therapeutics with Fc gamma RIIA as a key target. Here we report the use of phage display libraries to select short peptides with distinct Fc gamma RIIA binding properties. An 11-mer peptide (WAWVWLTETAV) was characterized that bound Fc gamma RIIA with a K-d of 500 nM. It mediated cell internalization and degradation of a model antigen. The peptide-binding site on Fc gamma RIIA was shown to involve Phe(163) and the IgG binding amino acids Trp(90) and Trp(113). It is thus overlapping but not identical to that of IgG. Neither activating receptors Fc gamma RI and Fc gamma RIII, nor Fc gamma RIIB, all of which lack Phe(163), bound the peptide.