Abstract 1906: UNO-A001 (A001), a clinical candidate CD38 x CD3 bispecific with a novel structure, potently kills multiple myeloma cells <i>in vitro</i> and is highly effective <i>in vivo</i>
Authors: Mark Anderson, Yan Ling, Mark L. Chiu, Peter Cheung
Journal: Cancer Research (2024)

Abstract CD38 is a validated target for the treatment of multiple myeloma (MM) as evidenced by the important clinical activity of CD38 targeting monoclonal antibodies. Bispecific T Cell Engagers (TCEs) kill cancer cells by distinct mechanisms as compared to standard format antibody therapeutics and several TCEs have demonstrated impressive clinical activity, and have been approved for clinical use, in hematologic malignancies. Here we describe a novel bispecific leveraging the potent killing mechanism of TCEs to target CD38 bearing cancer cells. UNO-A001 is a TCE binding the cell surface receptor CD38 on target human cancer cells and CD3 on T cells. The molecule has a differentiated format, binding CD38 with a high affinity humanized camelid VHH moiety and CD3 on T cells through a unique antibody Fab arm. The affinities of each arm were optimized so that the CD38 arm bound with high affinity and the CD3 arm with much lower relative binding affinity. This configuration was designed to engage CD38 bearing target cells with multiple TCE molecules at lower doses and concentrations while minimizing T cell binding in the periphery, and in the absence of cell surface CD38. A001 potently and specifically killed human CD38 bearing multiple myeloma cell lines in T cell killing assays in vitro with EC50s in the 2.7-6.6 pM range. This potency, despite the designed lower affinity to CD3, may be due to the unique structure of A001 enabling a productive immunologic synapse between T cells and the target cancer cells, and an optimal TAA/CD3 binding affinity ratio. A001 was also highly effective in inhibiting tumor growth in H929 xenograft models. In a flank model of H929 tumor growth A001 dose dependently inhibited tumor growth with complete growth inhibition of established tumors at the highest dose level tested. In a systemic disease model with NCI-H929-luc cells A001 was also highly effective and improved survival relative to control treated animals. In preparation for clinical studies a robust and high yield production cell line was created and characterized. It achieved high expression levels of quality monodisperse UNO-A001 product that was stable in all relevant storage conditions. A001 has similar affinities for human and cynomolgus macaque CD38 and CD3. Dose ranging studies in cynomolgus macaques demonstrated tolerability consistent with clinically approved TCEs, and the expected dose dependent pharmacodynamic effects on CD38 expressing myeloid and lymphoid cell populations. These data support planned clinical testing of A001 in multiple myeloma and other CD38 bearing hematologic malignancies, including mantle cell lymphoma, T cell lymphoma, and acute myelogenous leukemia. Citation Format: Mark Anderson, Yan Ling, Mark L. Chiu, Peter Cheung. UNO-A001 (A001), a clinical candidate CD38 x CD3 bispecific with a novel structure, potently kills multiple myeloma cells in vitro and is highly effective in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1906.