An agonistic anti-signal regulatory protein α antibody for chronic inflammatory diseases

Markus M Xie; Bingbing Dai; Jason A Hackney; Tianhe Sun; Juan Zhang; Janet K Jackman; Surinder Jeet; Ricardo A Irizarry-Caro; Yongyao Fu; Yuxin Liang; Hannah Bender; Eliah R Shamir; Mary E Keir; Jack Bevers; Gerald Nakamura; Michael J Townsend; David A Fox; Alexis Scherl; Wyne P Lee; Flavius Martin; Paul J Godowski; Rajita Pappu; Tangsheng Yi

doi:10.1016/j.xcrm.2023.101130

An agonistic anti-signal regulatory protein α antibody for chronic inflammatory diseases

Cell Rep Med. 2023 Aug 15;4(8):101130. doi: 10.1016/j.xcrm.2023.101130. Epub 2023 Jul 24.

Authors

Markus M Xie¹, Bingbing Dai¹, Jason A Hackney², Tianhe Sun¹, Juan Zhang³, Janet K Jackman¹, Surinder Jeet³, Ricardo A Irizarry-Caro⁴, Yongyao Fu⁵, Yuxin Liang⁶, Hannah Bender⁷, Eliah R Shamir⁷, Mary E Keir⁸, Jack Bevers⁹, Gerald Nakamura⁹, Michael J Townsend⁸, David A Fox¹⁰, Alexis Scherl⁷, Wyne P Lee³, Flavius Martin¹, Paul J Godowski¹¹, Rajita Pappu¹², Tangsheng Yi¹³

Affiliations

¹ Department of Immunology Discovery, Genentech, Inc., South San Francisco, CA, USA.
² Department of OMNI Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
³ Department of Translational Immunology, Genentech, Inc., South San Francisco, CA, USA.
⁴ Department of Immunology Discovery, Genentech, Inc., South San Francisco, CA, USA; Department of Human Pathobiology and OMNI Reverse Translation, Genentech, Inc., South San Francisco, CA, USA.
⁵ Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA, USA.
⁶ Department of Microchemistry, Proteomics, and Lipidomics and Next Generation Sequencing, Genentech, Inc., South San Francisco, CA, USA.
⁷ Department of Pathology, Genentech, Inc., South San Francisco, CA, USA.
⁸ Department of Human Pathobiology and OMNI Reverse Translation, Genentech, Inc., South San Francisco, CA, USA.
⁹ Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA.
¹⁰ Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, USA.
¹¹ Department of Immunology Discovery, Genentech, Inc., South San Francisco, CA, USA. Electronic address: godowski89@gmail.com.
¹² Department of Immunology Discovery, Genentech, Inc., South San Francisco, CA, USA. Electronic address: Pappu.Rajita@gene.com.
¹³ Department of Immunology Discovery, Genentech, Inc., South San Francisco, CA, USA. Electronic address: tangshengy@gmail.com.

Abstract

Signal regulatory protein (SIRPα) is an immune inhibitory receptor expressed by myeloid cells to inhibit immune cell phagocytosis, migration, and activation. Despite the progress of SIRPα and CD47 antagonist antibodies to promote anti-cancer immunity, it is not yet known whether SIRPα receptor agonism could restrain excessive autoimmune tissue inflammation. Here, we report that neutrophil- and monocyte-associated genes including SIRPA are increased in inflamed tissue biopsies from patients with rheumatoid arthritis and inflammatory bowel diseases, and elevated SIRPA is associated with treatment-refractory ulcerative colitis. We next identify an agonistic anti-SIRPα antibody that exhibits potent anti-inflammatory effects in reducing neutrophil and monocyte chemotaxis and tissue infiltration. In preclinical models of arthritis and colitis, anti-SIRPα agonistic antibody ameliorates autoimmune joint inflammation and inflammatory colitis by reducing neutrophils and monocytes in tissues. Our work provides a proof of concept for SIRPα receptor agonism for suppressing excessive innate immune activation and chronic inflammatory disease treatment.

Keywords: SIRPα; agonistic antibody; arthritis; autoimmune inflammation; colitis; monocyte; neutrophil.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colitis* / metabolism
Humans
Inflammation / pathology
Neoplasms* / drug therapy
Neutrophils / metabolism
Phagocytosis