Abstract A137: Pharmacokinetics and pharmacodynamics of IGM-8444, a first-in-class engineered pentameric DR5-targeting agonist IgM monoclonal antibody, in patients with R/R and newly diagnosed cancers
Authors: Hernandez Genevive , Bilic Sanela , Guan Yinghui , So John , Bhattacharya Sabya , Wang Beatrice , Kotturi Maya , Oyasu Miho , Desbois Melanie , Cao Yuan , Humke Eric , Ahern Sean , Sinclair Angus , Ulahannan Susanna , Subbiah Vivek , Pelster Merideth , Lorusso Patricia , Falchook Gerald , Wang Judy , Barve Minal , Grewal Jaspreet , Chow Warren , Henry Jason , Cecchini Michael , Takimoto Chris , Leabman Maya 
Published: December 2023

Abstract
Introduction: IGM-8444 is an engineered DR5 agonist IgM antibody with 10 binding sites that efficiently multimerizes DR5 to induce tumor cell apoptosis. The first-in-human Phase 1a/1b study of IGM-8444 (NCT04553692) is ongoing, and preliminary results show that IGM-8444 is well-tolerated as a single agent (SA) and in combination with chemotherapeutic and targeted agents. Encouraging efficacy is also observed with IGM-8444 combined with FOLFIRI +/- bevacizumab (bev) in patients with relapsed/refractory mCRC. Here we present pharmacokinetic (PK) and pharmacodynamic biomarker data from Phase 1a participants treated with IGM-8444 as SA or in combination at doses of 0.15 to 5 mg/kg given weekly (QW) or 0.3 to 10 mg/kg given every 2 weeks (Q2W).
Methods: Blood samples for PK and biomarker analysis were collected at multiple timepoints during cycles 1 and 2. Sparse sampling was utilized at later cycles. Plasma biomarker evaluation included measurement of M30 by ELISA and total caspase-3 (casp-3) by MSD. Tumor biomarkers were assessed in baseline and on-treatment tissue through immunohistochemistry for DR5 and cleaved caspase-3 (CC3). Initial population PK modeling was conducted to assess the PK characteristics of IGM-8444 as SA and in combination, and to enable simulations of different doses and dosing regimen scenarios.
Results: Treatment-related increases in plasma levels of apoptotic markers casp-3 (up to 25-fold) and M30 (up to 6-fold) were observed across dose levels. These changes occurred independently of any ALT or AST fluctuations, suggesting tumor-specific apoptosis induction. Dose-dependent increases in casp-3 and CC3 were observed in blood and tumor, respectively, indicating activation of DR5 pathway. At 3 mg/kg, on-treatment tumor CC3 levels were up to 10-fold higher in FOLFIRI combo, signifying enhanced apoptosis when IGM-8444 is combined with chemotherapy. Population PK analysis indicates that IGM-8444 PK is best described by a two-compartment model with parallel linear and nonlinear clearance. Terminal half-life at 10 mg/kg Q2W was &gt;2 days. PK simulations suggest that IGM-8444 administered at 3 or 10 mg/kg Q2W sustains average concentrations within the range as those observed at efficacious doses of IGM-8444 in preclinical mouse tumor models, where SA IGM-8444 exhibits dose-dependent efficacy with no evidence of a bell-shaped response. To date, ADAs have been detected in ~25% of participants. ADA titers in confirmed ADA-positive participants remain relatively low and the available data do not indicate a significant effect of ADAs on the PK of IGM-8444.
Conclusions: Pharmacodynamic changes in blood and tissue confirm the biologic activity of IGM-8444 and demonstrates that targeted therapy with an engineered IgM antibody can result in tumor penetration and target engagement within tumor tissue. Taken together, the biomarker and PK data support the use of IGM-8444 at a dose of 3 mg/kg or above for combination studies. The randomized Phase 1b is underway and evaluates the activity of FOLFIRI+bev +/- IGM-8444 in 2L mCRC.
Citation Format: Genevive Hernandez, Sanela Bilic, Yinghui Guan, John So, Sabya Bhattacharya, Beatrice Wang, Maya Kotturi, Miho Oyasu, Melanie Desbois, Yuan Cao, Eric Humke, Sean Ahern, Angus Sinclair, Susanna Ulahannan, Vivek Subbiah, Merideth Pelster, Patricia Lorusso, Gerald Falchook, Judy Wang, Minal Barve, Jaspreet Grewal, Warren Chow, Jason Henry, Michael Cecchini, Chris Takimoto, Maya Leabman. Pharmacokinetics and pharmacodynamics of IGM-8444, a first-in-class engineered pentameric DR5-targeting agonist IgM monoclonal antibody, in patients with R/R and newly diagnosed cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A137.