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Background: IGM-2323 is an engineered high-affinity, high-avidity bispecific anti-CD20 IgM antibody T cell engager (TCE) that is currently being studied as monotherapy in a Phase 1 clinical trial for relapsed/refractory non-Hodgkin’s lymphoma (NHL) (NCT04082936). IGM-2323 offers a novel treatment strategy in NHL through multiple mechanisms: the recruitment of T cells to kill CD20-expressing tumor cells through T cell dependent cellular cytotoxicity (TDCC), complement-dependent cytotoxicity (CDC), and enhanced immune modulation via IFNγ-dominant cytokine stimulation. Preliminary results from the first-in-human study of IGM-2323 show a 60% overall response rate at a titration dose level of 100 mg, and an excellent safety and tolerability profile up to 1000 mg with low cytokine release syndrome (CRS), no immune effector cell-associated neurotoxicity syndrome (ICANS) and limited neutropenia. Interestingly, lower response rates of IGM-2323 were observed at the highest dose levels of 600 mg and 1000 mg. Aims: An optimal bispecific antibody concentration may be required for effective synapse formation between a T lymphocyte and tumor cell. For bispecific IgG TCEs, low or excess concentrations have been described to result in impaired synapse formation and consequently reduced T cell activation in vitro. The aims of this study were to (1) characterize the concentration versus response relationship of IGM-2323 in vitro and compare with bispecific IgG TCEs, and (2) build a mechanistic binding model based on preclinical in vitro data to aid in prediction of an optimal dose of IGM-2323 in the clinic. Methods: To evaluate the dose response of IGM-2323, a concentration range that encompassed the peak and trough plasma levels up to the 1000 mg dose of IGM-2323 and equivalent concentrations of bispecific IgG TCEs were tested in preclinical in vitro assays. T cell-mediated activity was assessed using an engineered Jurkat T cell line, and in TDCC assays with primary healthy donor T cells. CDC was evaluated with human B lymphoma cell lines in the presence of normal human serum as a source of complement. Additionally, the activation status of peripheral T cells in patients that were dosed with 100 mg and 1000 mg of IGM-2323 was evaluated by flow cytometry. The in vitro data were fit to a novel mechanistic binding model of synapse formation. Results: A bell-shaped dose response was observed for IGM-2323 and bispecific IgG TCEs in the in vitro T cell activation assay, and to a lesser extent in TDCC and CDC assays. IGM-2323 exhibited peak T cell activation over a broad range of antibody concentrations which eventually declined at the highest concentrations tested. These data were well-described by the model. Interestingly, the concentration range of IGM-2323 resulting in peak activity corresponded to the peak and trough plasma levels in patients following 100 mg dose. The high concentrations associated with reduced activity are similar to plasma levels following 1000 mg dose. A trend for higher frequency of activated CD69+ peripheral T cells was detected in patients treated with 100 mg of IGM-2323 at 24 hours post dose compared to 1000 mg dose. Image:Summary/Conclusion: IGM-2323 shows a bell-shaped dose versus response relationship preclinically, with high concentrations associated with reduced T cell activity. The in vitro data support the decision to move forward with our randomized Phase 2 design testing 100 mg and 300 mg dose levels in NHL patients.
Leabman et al. (Wed,) studied this question.