Elizabeth Budde, MD Ph.D. of the City of Hope discusses the ASH 2020 abstract – 1142 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.
Introducing:
In treating B-cell malignancies, bispecific antibodies that bridge lymphoma cells to T-cells have shown promise. However, toxicity, especially cytokine release syndrome (CRS), which can restrict dose intensity and efficacy, is associated with established T cell engaging antibodies. CRS results from T cell overstimulation, which can also result in subsequent downregulation of the function of T cells. IGM-2323 is a novel type of bispecific antibody with a recombinant J-chain fused to an anti-CD3 scfv, based on an engineered pentameric IgM structure. For CD20 and one binding domain for CD3, the resulting build has 10 high-affinity binding domains. IGM-2323 has been shown to bind irreversibly to CD20-expressing cells in preclinical studies and deplete them in human PBMC cell cultures with the minimal secretion of cytokines. In order to evaluate the efficacy, tolerability, biomarkers, and preliminary anti-tumor activity of IGM-2323 in adults with B-cell malignancies, this first-in-human Phase 1, open-label, multicenter, dose-escalation study was planned.
Methodology:
Qualified for enrollment are patients with relapsed or refractory CD20-positive B-cell NHL who obtained >= 2 prior systemic therapies, appropriate organ function, and ECOG 0-1. On days 1, 8, and 15 of the 21-day period, IGM-2323 is administered as an IV infusion for up to 8 cycles, or longer if proof of clinical benefit exists. The study used an accelerated titration model for the first two dose levels with single patient cohorts, followed by the conventional 3+3 template with additional dose levels. The primary goals are to assess the safety and tolerability of IGM-2323 and to evaluate the recommended dosage and schedule for phase 2.
Outcomes:
Eight patients were treated at 4 dose levels as of 12 June 2020 (0.5, 2.5, 10, and 30 mg).
3 follicular lymphoma (FL), 2 mantle cell lymphoma, 2 marginal zone lymphoma, and 1 diffuse large B-cell lymphoma are subtypes of NHL. The median age is 65 (range 47-81), while the median number of previous treatments is 4 (range 2-6). Prior autologous transplantation in 2 patients (ASCT).
All 8 patients have undergone at least one period and can be tested for protection and dose-restricting toxicity (DLT). At the time of the database cutoff, 6/8 patients were on active therapy. Two patients were discontinued at 25 and 7 weeks because of the decision of the patient and the investigator. At 37, 27, 18, 9, 6, and 5 weeks, six patients are still in the study. The median dose count is 14. No DLT and no SAE related to drugs were observed. Grade 3-4 treatment-emergent transient neutropenia adverse effects (0.5 mg cohort G4 <3 days on day 76; 30 mg cohort G3 <7 days on day 8) were experienced in two patients. Neither experienced fever nor required treatment with antibiotics. No patient stopped due to toxicity and no patient required a reduction in the dosage.
In the 30 mg cohort, two patients experienced intermittent low-grade fever (one grade 1, one grade 2), with neither requiring steroid treatment. Pharmacodynamic biomarker analysis shows measurable levels of circulating B cells at baseline in 1/8 of the patients who underwent treatment with B cell depletion. In addition, there is evidence of cytokine secretion consistent with repeatable T cell responses in the 10 mg and 30 mg cohorts over successive doses. They were transient when cytokines were detectable after dosing and were mostly gone in less than 6-12 hours. The primary cytokine observed was Interferon-gamma (IFNg), with large levels of IL-6 found in only one patient.
Findings:
IGM-2323 is the first high-affinity high-avidity bispecific IgM monoclonal antibody to be studied in the clinic and is intended to bind to CD20-expressing cells irreversibly while supplying T cells with further physiological stimulation. Improved protection and tolerability profile at higher doses is shown by preliminary findings from this first human T-cell engaging antibody analysis. Compared to other T cell engaging antibodies, there is also evidence of a novel mechanism of action based on repeatable T cell activation and T cell function preservation. The research continues to recruit dose-escalation patients. The meeting will present updated safety, pharmacokinetic, biomarker, and efficacy data. This research is registered with NCT04082936, the clinicaltrials.gov identifier.