Preliminary Results of a Phase 1 Dose Escalation Study of the First-in-Class IgM Based Bispecific Antibody Igm-2323 (anti-CD20 x anti-CD3) in Patients with Advanced B-Cell Malignancies

Introduction: Bispecific antibodies that bridge lymphoma cells to T-cells have shown promise in treating B-cell malignancies. However, existing T cell engaging antibodies are associated with toxicity, especially cytokine release syndrome (CRS), which may limit dose intensity and efficacy. CRS results from overstimulation of T cells, which can also lead to subsequent downregulation of T cell function. IGM-2323 is a novel type of bispecific antibody, based on an engineered pentameric IgM framework, with a recombinant J-chain that is fused to an anti-CD3 scfv. The resulting construct has 10 high-affinity binding domains for CD20 and one binding domain for CD3. In preclinical studies, IGM-2323 has been shown to bind irreversibly to CD20-expressing cells and deplete them in human PBMC cell cultures with limited cytokine secretion. This first-in-human Phase 1, open-label, multicenter, dose escalation study was designed to evaluate the safety, tolerability, biomarkers and preliminary anti-tumor activity of IGM-2323 in adults with B- cell malignancies. Methods: Patients with relapsed or refractory CD20-positive B-cell NHL who had received >= 2 prior systemic therapies, acceptable organ function and ECOG 0-1 are eligible for enrollment. IGM-2323 is administered as an IV infusion on Days 1, 8, and 15 of a 21-day cycle, for up to 8 cycles, or longer if there is evidence of clinical benefit. The study utilized an accelerated titration design, with single patient cohorts for the first two dose levels, followed by traditional 3+3 design with further dose levels. The primary objectives are to evaluate the safety and tolerability of IGM-2323, and to determine a recommended phase 2 dose and schedule. Results: As of June 12, 2020, 8 patients have been treated at 4 dose levels (0.5, 2.5, 10, and 30 mg). NHL subtypes include 3 follicular lymphoma (FL), 2 mantle cell lymphoma, 2 marginal zone lymphoma, and 1 diffuse large B-cell lymphoma. Median age is 65 (range 47-81), median number of prior therapies is 4 (range 2-6). 2 patients had prior autologous transplant (ASCT). All 8 patients have completed at least one cycle and are evaluable for safety and dose limiting toxicities (DLT). 6/8 patients remain on active treatment at the time of the database cutoff. Two patients have discontinued at 25 and 7 weeks, due to patient and investigator decision. Six patients remain on study at 37, 27, 18, 9, 6, and 5 weeks ongoing. Median number of doses is 14. There were no DLT observed and