A phase I/IIa dose escalation and expansion study of 23ME-01473, an anti-ULBP6/2/5 antibody, for patients with advanced solid malignancies

BackgroundULBP6 is a stress-induced, high affinity NKG2D ligand that can be shed by tumors into a soluble form to attenuate NK and T cell activity, and was identified as a promising immuno-oncology drug target based upon genetic associations from the 23andMe database. 23ME-01473, a humanized monoclonal antibody, was developed to bind ULBP6/2/5 to restore NK and T cell activation by blocking soluble ULBP6/2/5 from binding NKG2D. Furthermore, 23ME-01473 binds cell surface ULBP6/2/5 to induce ADCC through its enhanced affinity for FcγRIIIa on NK cells. The dual activation of NKG2D and FcγRIIIa is synergistic in enhancing NK cell-mediated anti-tumor immunity, and may restore immune surveillance, especially in tumors resistant to immune-checkpoint inhibitors due to the loss of neoantigen presentation.Trial designThe safety and preliminary anti-tumor activity of 23ME-01473 are being evaluated in a Phase 1/2a dose escalation and expansion study in adults with locally advanced unresectable or metastatic solid malignancies that have progressed on standard therapies with ECOG 0-1; adolescents 12 years of age or older will be included in the expansion phase. 23ME-01473 is administered intravenously every 3 weeks until disease progression or unacceptable toxicity in a dose escalation consisting of accelerated titration followed by a 3+3 design and a PK/PD cohort at the highest dose levels. The primary objectives are determination of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety, and tolerability, as measured by the incidence and severity of dose-limiting toxicities, treatment-emergent adverse events (AEs), and withdrawals due to AEs. Secondary objectives include pharmacokinetics, immunogenicity, and preliminary anti-tumor activity of 23ME-01473. The target engagement and immunomodulatory profile of 23ME-01473, baseline tumor characteristics, and germline genotype are being evaluated and used to correlate with safety and efficacy outcomes. 23ME-01473 will be evaluated in multiple cohorts of immunologically active cancers with high ULBP6/2/5 expression in the expansion phase, with a primary objective of objective response rate based on RECIST 1.1.Clinical trial identificationNCT06290388; March 4, 2024.Legal entity responsible for the study23andMe, Inc.Funding23andMe, Inc.DisclosureM.R. Sharma: Financial Interests, Personal, Stocks or ownership: Abbott Laboratories, AbbVie, Amgen, Bristol Myers Squibb, Gilead Sciences, Johnson & Johnson/Janssen, Lilly, Merck, Moderna Therapeutics, Pfizer, Regeneron, Vertex, West Pharmaceutical; Financial Interests, Personal, Advisory Role: Pliant; Financial Interests, Personal, Research Funding: AbbVie, Adcentrx Therapeutics, Agenus, Alkermes, Alpine Immune Sciences, ALX Oncology, Artios, Astellas Pharma, AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, Bolt Biotherapeutics, Boundless Bio Therapeutics, Bristol Myers Squibb, Celgene. D. Rasco: Financial Interests, Institutional, Research Funding: 23andMe, Inc, AbbVie, Arcus Biosciences, Ascentage Pharma, Astex Pharmaceuticals, Boehringer Ingelheim, Bolt Biotherapeutics, Compugen, Constellation Pharmaceuticals, Coordination Therapeutics, Cullinan Oncology, Eisai, GSK, Gossamer Bio, Kronos, Merck, Molecular Templates, PureTech, Seven and Eight BioPharmaceuticals, Surface Oncology, Takeda, TD2; Financial Interests, Research Funding: Celgene. S. Kummar: Financial Interests, Personal, Stocks or ownership: PathomIQ, Arxeon; Financial Interests, Personal, Advisory Role: Bayer, Boehringer Ingelheim, Mundipharma, Harbour Biomed, Springworks Therapeutics, Gilead Biosciences, Mirati Therapeutics, Oxford Biotherapeutics, Genome & Company, SeaGen, BPGBio, Inc, Cadila Pharmaceuticals. D. Maslyar, D. Strahs: Financial Interests, Institutional, Financially compensated role: 23andMe, Inc. D.M. Glatt, K. Gerrick: Financial Interests, Institutional, Full or part-time Employment: 23andMe, Inc; Financial Interests, Institutional, Stocks/Shares: 23andMe, Inc.