Abstract 3430: CD47 x ICAM-1 bispecific antibody represents a novel approach for treating ICAM-1 overexpressing tumors

Abstract

Abstract CD47/SIRPa axis is an important checkpoint of innate immune system, CD47 interacts with its ligand signal regulatory protein-alpha (SIRPa) on myeloid cells, conveys a “don’t eat me” signal and blocks macrophage mediated phagocytosis. Tumor cells, which express high level of CD47, exploit this mechanism to evade from immune surveillance. CD47 is considered a prominent target for cancer treatment. However, the wide expression of CD47 on normal cells could cause antigen sink and lead to safety issues, such as anemia and thrombocytopenia. ICAM-1 is constitutively present at low levels on endothelial cells, but its overexpression has been observed on various types of tumors, such as primary myeloma, lymphoma and kidney cancer. Here we describe a novel CD47 x ICAM-1 bispecific antibody, which specifically targets CD47+/ICAM-1+ tumors in preclinical studies.A novel anti-CD47 antibody and an anti-ICAM-1 antibody were used for the generation of a CD47 x ICAM-1 bispecific antibody. In vitro assays including FACS binding, FACS-based SIRPa blocking, ADCP, RBC binding and hemagglutination were performed to characterize the bispecific CD47 x ICAM-1 antibody. In vivo efficacies of CD47 x ICAM-1 bispecific antibody were evaluated in xenograft tumor models with high ICAM-1 expression.The CD47 x ICAM-1 bispecific antibody selectively exhibited potent SIRPa blocking and antibody-dependent cellular phagocytosis (ADCP) activity on CD47+/ICAM-1+ tumor cells, but not on cells lacking ICAM-1 expression. Minimal RBC binding and RBC phagocytosis were observed upon treatment with CD47 x ICAM-1 bispecific antibody. The bispecific antibody did not cause any appreciable hemagglutination with up to 1µM antibody treatment. Most importantly, the CD47 x ICAM-1 bispecific antibody demonstrated potent anti-tumor activities in in vivo CDX and PDX models that overexpress both CD47 and ICAM-1. Our findings suggest that the novel CD47 x ICAM-1 bispecific antibody selectively binds to CD47 and blocks CD47/SIRPa binding on ICAM1 overexpressing tumor cells. The bispecific antibody has minimal RBC binding compared to the bivalent CD47 monoclonal antibodies and benchmark anti-CD47 antibodies. The bispecific antibody shows potent in vivo efficacy and specificity toward ICAM-1+/CD47+ positive tumor cells and represents a novel approach for treating ICAM-1+/CD47+ tumors. Citation Format: Xinhua Wang, Oi Kwan Wong, Leonard Post, Xiaocheng Chen. CD47 x ICAM-1 bispecific antibody represents a novel approach for treating ICAM-1 overexpressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3430.