Abstract 5548: The therapeutic potential of AMV564, a novel bispecific bivalent (2x2) T-cell engager, for the treatment of CD33-expressing hematologic malignancies

Abstract

Abstract AMV564 is a novel bispecific bivalent (2x2) immunotherapy that initiates an immunological synapse between T cells and CD33-expressing cells by binding both CD33 and CD3 with strong avidity. CD33 (Siglec-3) is a clinically-validated antigen target that is broadly expressed on the surface of malignant cells in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and other hematologic malignancies, as well as on cells that potently suppress immune function, such as myeloid-derived suppressor cells (MDSC). AMV564 has been shown to eliminate MDSCs and restore hematopoiesis, induce potent cytolysis of leukemic cells in patient blood and bone marrow samples, and produce robust antitumor activity in a disseminated model of AML. In vitro studies, including cytotoxicity assays with AML patient samples, human T-cell activation assays, and cytokine-release assays, as well as animal safety studies were performed to characterize the pharmacokinetics, pharmacodynamics, and potential toxicities of AMV564. AMV564 demonstrated potent in vitro antitumor activity with EC50 values of approximately 0.7 - 3 pM. In vitro studies also demonstrated that leukemic cells are more sensitive to T-cell engagement using AMV564 than peripheral blood mononuclear cells by approximately 10-fold. In animal safety studies, AMV564 was tolerated at exposures that exceed those expected to have clinical antitumor activity by > 10-fold. Toxicological findings noted in these studies were anticipated based on the pharmacological activity of AMV564; observed findings included events related to CD3-mediated T-cell activation, cytokine release, and decreases in neutrophil and monocyte counts with rapid recovery. Results from a pharmacokinetic/pharmacodynamic model integrating the preclinical data suggest the potential for a wide therapeutic index for patients with AML. Based on the in vitro and in vivo preclinical data, AMV564 is expected to have a wide therapeutic index, with robust antitumor activity in AML and MDS at doses well below those predicted to be associated with dose-limiting toxicities, and a predictable and monitorable adverse event profile. Citation Format: Tae H. Han, Jeanmarie Guenot, William S. Denney, Eric J. Feldman. The therapeutic potential of AMV564, a novel bispecific bivalent (2x2) T-cell engager, for the treatment of CD33-expressing hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5548.