PD-1 x CD2 cis-acting bispecific antibodies are potent PD-1 agonists that restrain human T cell responses independent of Fc-receptor engagement 4271

Abstract Description PD-1 is an inhibitory co-receptor expressed on autoreactive and chronically stimulated T cells. Organ-specific autoimmunity that emerges in cancer patients treated with PD-1 antagonists highlights the key role PD-1 plays in restraining pathogenic T cells. Furthermore, the inflammatory phenotypes of PD-1+ T cells in autoimmune patients suggests PD-1 engagement by its ligands is limiting, and that PD-1 agonizing therapies should inhibit disease progression. Several PD-1-agonist antibodies in development function by trans-ligation of PD-1 to Fc-receptors (FcRs) on antigen presenting cells (APCs), resulting in PD-1 recruitment to the immune synapse and TCR inhibition; however, other outcomes may include deletion of protective PD-1+ T cells by ADCC/ADCP and undesired proinflammatory signaling from crosslinked FcRs. FcR polymorphisms that reduce Fc binding affinities may also limit the responding patient population. Here, we describe IDP-003, an FcR-independent PD-1 agonist bispecific antibody that recruits PD-1 to the synapse by bridging it in cis to the co-stimulatory receptor CD2. Expression of the CD2 ligand CD58 on APCs, but not on T cells, is required for IDP-003 activity, which promotes PD-1 phosphorylation, T cell suppression, and attenuation of GVHD in humanized mice. As CD58 is expressed on both immune APCs and non-immune cells, IDP-003 could resolve pathology driven by autoantigens presented on both immune cells and non-immune cells in diverse autoimmune conditions. Funding Sources InduPro Topic Categories Therapeutic Approaches to Autoimmunity (THER)