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

FcyRIIA is a key activating receptor linking immune complex formation with cellular effector functions. FcyRIIA has 93% identity with an inhibitory receptor, FCγRIIB, which negatively regulates FcyRIIA. FcyRIIA is important in the therapeutic action of several monoclonal antibodies. Binding molecules that discriminate FcyRIIA from FcyRIIB may optimize receptor activity and serve as a lead for development of therapeutics with FcyRIIA as a key target. Here we report the use of phage display libraries to select short peptides with distinct FcyRIIA binding properties. An 11-mer peptide (WAWVWLTETAV) was characterized that bound FcyRIIA with a K d of 500 nM. It mediated cell internalization and degradation of a model antigen. The peptide-binding site on FcγRIIA 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 FcyRI and FcyRIII, nor FθγRIIB, all of which lack Phe 163 , bound the peptide.