Igm-2644, a Novel CD38xCD3 Bispecific IgM T Cell Engager Demonstrates Potent Efficacy on Myeloma Cells with an Improved Preclinical Safety Profile

Abstract

Multiple myeloma (MM) is a cancer of plasma cells affecting > 30,000 new patients every year in the United States. Despite improved treatment options, including anti-CD38 monospecific IgG antibodies such as daratumumab and isatuximab in combination with chemotherapies, resistance eventually develops in most patients. Several bispecific (CD38xCD3) or trispecific (CD38xCD3xCD28) T cell engager antibody therapies are currently in development to further improve upon the efficacy of CD38 targeted therapies by leveraging T cell dependent cellular cytotoxicity (TDCC) of MM cells. However, a unique challenge for anti-CD38 T cell engagers is to potently kill myeloma cells without depleting CD38+ immune cells, including activated cytotoxic T cells (i.e., fratricide), while also avoiding dangerous cytokine release syndrome associated with T cell engaging therapies. Encouraged by the favorable safety and tolerability profile of imvotamab (IGM-2323), our CD20xCD3 IgM T cell engager, we have developed a novel CD38xCD3 bispecific IgM T cell engager, IGM-2644. It has 10 binding sites for human CD38, and a single anti-CD3 scFv fused to the joining (J) chain. Here, we have evaluated the potency and potential safety profile of IGM-2644 in a panel of in vitro immunoassays and in vivo models. IGM-2644 demonstrated significantly improved complement-dependent cytotoxicity (CDC) activity compared to daratumumab and isatuximab, with over 30-fold increased potency on MM cell lines, and depletion of these cells was further enhanced when PBMCs were used as effector cells. IGM-2644 was able to achieve TDCC activities similar to bispecific CD38xCD3 IgGs on low CD38 expressing cell lines that are resistant to daratumumab, while showing much lower levels of cytokine release than bispecific IgGs. In a short-term in vitro colony forming unit (CFU) assay, IGM-2644 was able to reduce MM colonies using primary MM patient bone marrow samples containing autologous T cells and myeloma cells, while no effect was observed on the colony formation of erythroid, granulocyte and macrophage using bone marrow samples from normal donors. IGM-2644 was able to show in vivo efficacy and suppress CD38+ NCI-H929 (myeloma) and Raji (lymphoma) xenograft tumor growth in humanized mouse models. Importantly, IGM-2644 also demonstrated reduced T cell fratricide compared to bispecific IgGs both in vitro and in vivo. Taken together, our data demonstrates IGM-2644 is a potent molecule with both CDC and TDCC activities, and the potential to be active in daratumumab resistant tumors. It has an improved preclinical safety profile compared to other CD38xCD3 bispecific T cell engagers due to lower cytokine release and reduced T cell fratricide. A Phase I clinical study evaluating the activity and safety of IGM-2644 is planned.