P815: high valency of igm-2644, a cd38xcd3 igm bispecific t cell engager, displaces daratumumab binding and induces potent multiple myeloma cell killing

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Multiple myeloma (MM) is a common hematologic malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow. CD38 is a uniformly highly expressed cell surface glycoprotein on neoplastic plasma cells and is the target of approved anti-CD38 monoclonal antibodies, such as daratumumab. Unfortunately, most patients develop resistance to these antibody therapies, especially in advanced stage MM, which leads to disease relapse and progression. Importantly, CD38 expression is still maintained on resistant plasma cells. IGM-2644 is an engineered high-affinity, high-avidity bispecific anti-CD38 IgM antibody T cell engager being developed for the treatment of relapsed/refractory (r/r) MM. IGM-2644 kills CD38 expressing tumor cells through T cell-dependent cellular cytotoxicity (TDCC) and complement-dependent cytotoxicity (CDC). Given the high valency of IGM-2644, it demonstrates robust killing activity against cell lines that are resistant to daratumumab with low CD38 expression. Aims: Daratumumab can persist in MM patients for up to 9 months after treatment discontinuation and binds to an epitope on CD38 overlapping that of IGM-2644. We hypothesized that with its high valency, IGM-2644 could displace daratumumab, thus enabling potent tumor killing by IGM-2644 even in the presence of high concentrations of daratumumab. The aims of this study were to (1) evaluate the in vitro activity of IGM-2644, and (2) assess in a mouse model the in vivo anti-tumor activity of IGM-2644 in the presence of daratumumab at clinically relevant doses. Methods: To evaluate the activity of IGM-2644 in the presence of daratumumab, a concentration range that encompassed the projected serum concentrations of daratumumab at ~6 weeks to 6 months post the last treatment in MM patients was tested with IGM-2644 in vitro. The competition binding potential of IGM-2644 to human CD38 in the presence of daratumumab was evaluated by two independent methods, including binding to recombinant human CD38 by Bio-Layer Interferometry and binding to human CD38-expressing MM cell lines by flow cytometry. CDC was evaluated with human MM cell lines in the presence of normal human serum as a source of complement. T cell-mediated activity was assessed in TDCC assays with primary immune cells. In vivo anti-tumor activity of IGM-2644 in the presence of daratumumab was evaluated in a human CD38-expressing tumor xenograft mouse model with engrafted human PBMCs. Results: IGM-2644 bound to recombinant human CD38 in the presence of daratumumab, while an anti-CD38 bivalent IgG antibody that recognizes the same epitope as IGM-2644 did not. IGM-2644 also displaced daratumumab binding on human MM cell lines with a range of CD38 expression levels. The CDC of IGM-2644 showed minimal inhibition by daratumumab across multiple human CD38-expressing MM cell lines. In TDCC assays with primary immune cells, modest inhibition of IGM-2644 activity can only be observed when pre-treating with high concentrations of daratumumab. Furthermore, pre-treatment with daratumumab did not negatively impact the anti-tumor activity of IGM-2644 in vivo. Summary/Conclusion: Our preclinical data indicate that IGM-2644 maintains activity in the presence of daratumumab. A Phase 1 clinical trial in r/r MM is being planned to evaluate the safety and pharmacokinetics of IGM-2644. The clinical study will evaluate these preclinical findings, including the treatment of patients with circulating serum levels of daratumumab.Keywords: Bispecific, CD38, Multiple myeloma