Abstract 5385: Multiple modes of action of the CD38 x ICAM-1 bispecific antibody

Abstract

Abstract The cluster of differentiation 38 (CD38) is a well validated target for treating multiple myeloma. Although the anti-CD38 monoclonal antibody treatment has resulted in outstanding responses in patients with multiple myeloma, a significant portion of patients still failed to respond and nearly all patients eventually relapsed. The mechanism of resistance has been partially associated with downregulation of CD38 expression. In addition, CD38 is broadly expressed on normal lymphoid, myeloid, as well as red blood cells (RBCs). To effectively target CD38 on tumor cells, we hypothesize that a bispecific antibody against a tumor associated guide antigen (TAG) and CD38 could achieve tumor specificity and improve potency. ICAM-1, an Ig-like cell adhesion molecule, is highly expressed in multiple myeloma, lymphoma and a subset of solid tumors. Antibody against ICAM-1, bersanlimab (BI505, BioInvent), was well-tolerated, but only showed limited clinical efficacy in MM patients. We generated bispecific CD38 x ICAM-1 antibodies with different formats and geometries and compared their in-vitro activities on ICAM1high tumor cells with low to medium CD38 expression. Our results showed that the asymmetric 1+1 format has potent ADCC and ADCP activities on ICAM-1+CD38medium or ICAM-1+CD38low cells. Fc modifications further improved ADCC activities of the bispecific antibody. To further understand the impact of antigen densities, we tested ADCC activities on a selected set of myeloma and lymphoma cell lines with a range of CD38 and ICAM-1 expressions. We observed superior ADCC activity on cells with extremely low CD38 expression. Moreover, we showed that the bispecific antibody reduced NK fratricide and RBC binding comparing to the bivalent CD38 antibody. Most importantly, the CD38 x ICAM1 bispecific antibody demonstrated potent tumor inhibition activities in in-vivo myeloma and lymphoma models. These studies suggested that CD38 x ICAM-1 bispecific antibody has multiple modes of action for treating lymphoma and multiple myeloma. Citation Format: Xiaocheng Chen, Oi Kwan Wong, Leonard Post. Multiple modes of action of the CD38 x ICAM-1 bispecific antibody [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 5385.