Pharmacodynamics and Biomarker Correlates of Imvotamab (IGM-2323), the First-in-Class CD20xCD3 Bispecific IgM Antibody with Dual Mechanisms of Action, in Patients with Advanced B Cell Malignancies

Introduction: Imvotamab (IGM-2323) is a novel CD20xCD3 bispecific T cell engager utilizing an engineered IgM antibody platform, with 10 high-affinity CD20 binding domains and a single anti-CD3 scFv fused through the recombinant J-chain. Its high avidity enables irreversible target cell binding even at low CD20 levels and results in T cell dependent (TDCC) and complement dependent (CDC) mechanisms of cytotoxicity, with minimal cytokine release. Imvotamab is also designed to induce more physiologic T cell activation in order to prevent overstimulation and subsequent downregulation of immune function. The first-in-human Phase 1/2 study of imvotamab (NCT04082936) is ongoing, and preliminary results show single agent activity with durable complete responses as well as favorable safety and tolerability profile up to 1000 mg (Budde et al. ASH 2021). Here we present biomarker data highlighting pharmacodynamic effects and immune correlates that demonstrate mechanisms of action (MOA), inform optimal dose/schedule selection, and identify potential predictors of response.

Methods: Data to date were obtained from patients on dose escalation cohorts that received 0.5-1000 mg under fixed or dose titration schemes (n=40). Immune profiling of peripheral blood was performed by flow cytometry. Plasma biomarker evaluation included measurement of cytokines by MSD, complement activation markers by ELISA, and ctDNA-MRD by PhasED-Seq (Foresight Dx). Tumor biomarkers were assessed in baseline and on-treatment tissue through immunohistochemistry.

Results: Imvotamab biologic activity was observed starting at the 10 mg dose, as evidenced by transient elevations in plasma cytokines, which occurred over multiple sequential infusions, peaking within 2-12 hours post-infusion and returning to baseline by 24 hours. Maximal cytokine levels were observed after Cycle 1 Day 1 in the majority of patients, including those that received dose titration. In contrast to bispecific IgG T cell engagers, imvotamab induced consistently higher levels of IFNγ relative to inflammatory cytokines such as IL-6 and TNFα. However, patients with cytokine release syndrome (CRS) exhibited a poly-cytokine profile, where elevated levels of multiple cytokines in addition to IFNγ were also observed. The timing of poly-cytokine response corresponded with the onset and duration of CRS.

Complement activation factors Bb, C3a, C4a, and sC5b9 transiently increased ~2-5 fold on average in plasma of nearly all patients tested, with peak values detected immediately after the first dose. Circulating B cells were depleted by the end of Cycle 1 in majority of patients with measurable B cells at baseline. In peripheral blood, imvotamab infusion resulted in rapid and transient T cell activation that coincided with T cell margination. There was a trend for higher frequency of activated CD69+ T cells and greater margination at 24 hours following intermediate 100 and 300 mg vs. higher 600 and 1000 mg plateau doses. Notably, patients with progressive disease did not show significant T cell activation. Patients with complete response had marked elevations of T cells at later cycles; these patients also had higher baseline T cell counts vs. others (median: 910 vs. 590 cells/ul). The proportion of PD1+ T cells on-treatment was ~2-fold lower in responders vs. non-responders.

Paired tumor biopsies showed increase of intratumoral CD3+ T cells on-treatment regardless of response. At baseline, some complete responders had low CD20 expression, as indicated by CD20 H-scores < 30. Finally, ctDNA analysis in a subset of patients showed greater depth of decrease in responders vs. non-responders, with sustained MRD responses seen in samples > 1 year from patients with complete response.

Conclusions: Acute pharmacodynamic changes confirm TDCC and CDC MOA for imvotamab in patients. The repeatable IFNγ-dominant cytokine profile is consistent with its ability to induce a more physiologic stimulation that can preserve or strengthen T cell effector function, without overstimulating undesired inflammatory cytokines related to CRS. Overall, the data support the use of dose titration as a safe and efficacious drug administration scheme and suggest a model whereby an optimal number of sufficiently activated and functional T cells may be required to elicit strong and durable clinical responses. Updated analyses will be presented at the meeting.

Hernandez:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1; Teiko Bio: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. So:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Logronio:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1. Kotturi:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1. Armand:GenMab: Consultancy; Tessa Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kite Pharma: Research Funding; IGM Biosciences: Research Funding; Roche/Genentech: Consultancy, Research Funding; Adaptive Biotechnologies: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy, Honoraria, Research Funding; C4 Therapeutics: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy. Cheah:Novartis: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Eli Lilly and Company: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck Sharp & Dohme: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Gopal:Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab: Research Funding; Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi: Consultancy, Honoraria. Flinn:Rhizen Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Xencor: Consultancy; Infinity Pharmaceuticals: Research Funding; Genmab: Consultancy; Hutchison MediPharma: Consultancy; Myeloid Therapeutics: Research Funding; CALGB: Research Funding; BeiGene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Seattle Genetics: Research Funding; Biopath: Research Funding; Trillium Therapeutics: Research Funding; InnoCare Pharma: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Curis: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Century Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; IGM Biosciences: Research Funding; Incyte: Research Funding; Takeda: Consultancy; TG Therapeutics: Consultancy, Research Funding; Forty Seven: Research Funding; Iksuda Therapeutics: Consultancy; Loxo@Lilly: Research Funding; Secura Bio: Consultancy; CALIBR: Research Funding; Forma Therapeutics: Research Funding; Agios: Research Funding; Merck: Research Funding; AstraZeneca: Consultancy, Research Funding; Nurix Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; ArQule: Research Funding; Celgene: Research Funding; Unum Therapeutics: Research Funding; Acerta Pharma: Research Funding; Servier Pharmaceuticals: Consultancy; City of Hope National Medical Center: Research Funding; Verastem: Consultancy, Research Funding; Vincerx Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; CTI Biopharma: Research Funding; Epizyme: Research Funding; Fate Therapeutics: Research Funding; Millenium Pharmaceuticals: Research Funding; Tessa Therapeutics: Research Funding; TCR2 Therapeutics: Research Funding; Triphase Research & Development Corp: Research Funding; 2seventy bio: Research Funding. Gregory:Roche, BMS: Honoraria; Roche: Speakers Bureau; BeiGene, Merck, AbbVie, Janssen: Research Funding; Roche, Novartis: Other: Travel/ Accommodations/ Expenses; Janssen: Other: Expert testimony; Roche, Novartis, BMS, Janssen: Consultancy. Matasar:Karyopharm: Consultancy; Rocket Medical: Consultancy, Research Funding; Merck: Consultancy, Current equity holder in private company; TG Therapeutics: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; AstraZeneca: Consultancy; Teva: Consultancy; Takeda: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; IMV Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding. Nastoupil:BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Genmab, Janssen, IGM Biosciences, Novartis, Takeda: Research Funding; ADC Therapeutics, BMS, Caribou Biosciences, Epizyme, Genentech/Roche, Gilead/Kite, Genmab, Janssen, MEI, Morphosys, Novartis, Takeda: Honoraria; Genentech/Roche, MEI, Takeda: Other: DSMC. Diefenbach:Kite: Consultancy; Incyte: Research Funding; IMAB: Consultancy; Gilead: Current equity holder in publicly-traded company; Genmab: Consultancy; Genentech/Roche: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI Pharma: Research Funding; MorphoSys: Consultancy, Research Funding; Seattle Genetics: Research Funding. Yoon:Amgen: Consultancy; Novartis: Consultancy; Kyowa Kirin: Research Funding; Yuhan Pharmaceutical: Research Funding; Tikaros: Consultancy; Roche-Genetech: Research Funding; Chugai Pharmaceutical: Consultancy; Janssen Pharmaceutical: Consultancy; Celgene: Consultancy; Astellas Pharma: Consultancy; Takeda: Consultancy. Ku:Genor BioPharma: Consultancy; Roche: Consultancy; St Vincent's Hospital: Current Employment; Antengene: Consultancy. Qazi:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Leabman:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Sison:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1. Keyt:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Takimoto:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Manley:IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Budde:Genentech: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board; Merck: Research Funding; AstraZeneca: Research Funding; Amgen Inc: Research Funding; Ziopharm Oncology Inc: Other: DMSC member for a phase 1 clinical trial.