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
Year: 2025
Type: article
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)
Source: The Journal of Immunology
Authors: Marc A. Gavin, Christie-Lynn Mortales, Mikaela Rusnak, Tsadik Habtetsion, Aniruddh Saxena, Lauren Webb, Jing Song, Hayley Ma, Sophia Romero, Ben Setter, Brian Woodruff, Zach Caldwell, Carina Xu, Heath Klock, Jason Misurelli, Payam Farahani, Robert Gene, Kendal Johnson, Noah Dephoure, Rob Oslund, Niyi Fadeyi, Ertan Eryilmaz, Scott Lesley, Pam Holland
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416446196
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