Abstract 954: AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma

Abstract

Overexpression of CD47 by tumor cells exploits an immune checkpoint that prevents tumor recognition and destruction by innate immune cells. Binding of tumor CD47 to SIRPα on macrophages and dendritic cells triggers a “don9t eat me” signal that inhibits phagocytosis enabling escape from innate immune surveillance. Blockade of the CD47/SIRPα axis enables immune recognition and phagocytic clearance of tumor cells. We have developed a clinical stage CD47 targeting antibody AO-176, that is highly differentiated among agents in this class. AO-176 not only blocks the CD47/SIRPα interaction to induce tumor cell phagocytosis, but also: a) directly induces solid and hematologic tumor cell cytotoxicity and damage-associated molecular patterns (DAMPs); b) preferentially binds tumor versus normal cells, which is correlated with β1-integrin expression and localization; c) negligibly binds RBC; and d) exhibits improved binding at acidic pH as found in tumor microenvironments.Previously we have shown that AO-176 is efficacious in a variety of solid tumor xenograft models as well as in models of multiple myeloma and AML. Here, we show the therapeutic potential of AO-176 in pre-clinical models of lymphoma where CD47 is upregulated and associated with poor prognosis. Using a variety of cell based and in vivo models we show that AO-176 demonstrates increased binding to lymphoma cells at an acidic versus physiologic pH and that this binding and blocking of the do not eat me signal leads to enhanced phagocytosis of lymphoma cells either alone or in combination with rituximab. In addition, we show that AO-176 induces annexin V positivity in lymphoma cells as well as inducing a variety of DAMPs that ultimately may aid in inducing immunogenic cell death of the lymphoma cells. We also demonstrate that AO-176 is a potent tumor growth inhibitor in lymphoma xenograft models and appears to induce immune infiltrates as well as inflammatory cytokines.Taken together, these data show that AO-176 has strong therapeutic potential in lymphoma. AO-176 is currently being evaluated in clinical trials of select solid tumors (NCT03834948) and multiple myeloma (NCT04445701). Citation Format: Benjamin J. Capoccia, Michael J. Donio, John O. Richards, Ronald R. Hiebsch, Robyn J. Puro, Arun K. Kashyap, Daniel S. Pereira. AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 954.