FC-GAMMA-RI-TARGETED FUSION PROTEINS RESULT IN EFFICIENT PRESENTATIONBY HUMAN MONOCYTES OF ANTIGENIC AND ANTAGONIST T-CELL EPITOPES

A major challenge for using native or modified T cell epitopes to indu ce or suppress immunity relates to poor localization of peptides to an tigen presenting cells (APCs) in vivo. In this study, we demonstrate e nhanced presentation of antigenic and antagonistic peptides by targeti ng them to the type I Fc receptor for IgG (Fc gamma RI, CD64) on human monocytes, A Th epitope of tetanus toroid, TT830, and the antagonisti c peptide for TT830, TT833S, were genetically grafted into the constan t region of the heavy chain of the humanized anti-CD64 mAb 22 and expr essed as monovalent fusion proteins, Fab22-TT830 and Fab22-TT833S. The se CD64-targeted peptides were up to 1,000- and 100-fold more efficien t than the parent peptides for T cell stimulation and antagonism, resp ectively, suggesting that such fusion proteins could effectively incre ase the delivery of peptides to APCs in vivo. Moreover, the Fc gamma R I-targeted antagonistic peptide inhibited proliferation of TT830-speci fic T cells even when APCs were first pulsed with native peptide, a si tuation comparable with that which would be encountered in vivo when a ttempting to ameliorate an autoimmune response, These data suggest tha t targeted presentation of antagonistic peptides could lead to promisi ng Ag-specific therapies for T cell-mediated autoimmune diseases.