IGM-2323 Shows Favorable Safety Profile With Advanced B-Cell Malignancies

Results of a dose escalation study of IGM-2323, a novel anti-CD20 x anti-CD3 IgM T-cell engager (TCE), showed an excellent safety profile and tolerability in patients with relapsed or refractory (R/R) CD20+ B-cell non-Hodgkin’s lymphoma (NHL). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“IGM-2323 has 10 binding domains for CD20 and a single binding domain for CD3, and is designed to bind irreversibly to CD20-high and -low expressing cells with more physiologic stimulation to T-cells, which may mitigate cytokine release syndrome (CRS)-related toxicities,” explained Elizabeth Budde, MD, PhD, City of Hope National Medical Center, California, and co-authors.

The researchers found that the high-affinity, high-avidity bispecific IgM monoclonal antibody TCE may act by multiple mechanisms, including T-cell dependent cytotoxicity, complement dependent cytotoxicity, and enhanced immune modulation via IFNγ-dominant cytokine stimulation.

A total of 29 patients were enrolled to the trial and received IGM-2323 on days 1, 8, and 15 of 21-day cycles until disease progression or unacceptable toxicity. Out of the cohort, 12 patients were at 5 fixed dose levels (0.5, 2.5, 10, 30, 100 mg) and 17 were at 5 dose titration levels (50/100, 50/200, 50/300, 50/600, and 50/1000 mg), respectively.

NHL subtypes included 13 patients with follicular (FL), 11 with diffuse large B-cell lymphoma (DLBCL), 3 with mantle cell lymphoma (MCL), and 2 with marginal zone lymphoma (MZL).

According to Dr Budde, and co-authors, “23 patients were evaluable for efficacy, 5 had a complete response (CR), and 3 had a partial response (PR). Response kinetics varied, some with CRs at the first scan and others after biopsy-confirmed pseudo-progression or prolonged stable disease (up to 69 weeks). 7 responses were ongoing as of the data cut off.”

Further, 5 out of 11 evaluable patients in the dose titration cohorts responded (3 CR, 2 PR) with a median time to response of 6 weeks. In the titration cohort with the longest follow-up (50/100), there were 2 CR and 1 PR in 4 evaluable patients.

In nearly all patients with measurable cytokine elevations, repeatable IFNγ stimulation was detectable and polycytokine response was observed in CRS cases.

“Preliminary results from this first-in-human study of IGM-2323 show an excellent safety and tolerability profile at up to 1000 mg, with reduced CRS when IGM-2323 was given using a dose titration scheme. Response patterns included rapid responses, deepening responses, and pseudo-progression. IGM-2323 also has evidence of an IFNγ-dominant repeatable T-cell activation and preservation of T-cell function overtime. The maximum tolerable dose has not been reached. Clinical activity was observed across multiple histologies,” concluded Dr Budde, et al.—Alexa Stoia

Budde E, Gopal A, Kim W, et al. A Phase 1 Dose Escalation Study of Igm-2323, a Novel Anti-CD20 x Anti-CD3 IgM T Cell Engager (TCE) in Patients with Advanced B-Cell Malignancies. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 132.