Background 23ME-00610 is a first-in-class monoclonal antibody that binds to CD200R1, an immune-oncology target identified from the 23andMe database, and restores T cell activity thereby killing CD200-expressing tumor cells.¹ Preclinical pharmacology data and monkey pharmacokinetics (PK) were used to select doses for the Phase 1/2a study (NCT05199272).

Methods In Phase 1, participants with locally advanced (unresectable) or metastatic solid malignancies received ascending intravenous (IV) doses of 23ME-00610 from 2 to 1400mg Q3W. Doses were selected by integrating allometrically scaled monkey PK with in vitro CD200R1 binding, CD200-CD200R1 blocking, and functional data from CD200R1-expressing primary immune cells fitted to an E_max model. The MABEL starting dose was based on the in vitro tumor cell-killing assay, nonclinical safety, and predicted Cycle 1 (C1) C_max. Intensive PK was collected in C1 and C4, PD samples were collected every cycle, and safety was assessed throughout. Dose proportionality was assessed using the power model. Accumulation was evaluated by comparing the exposure in C4 to C1. T-cell and neutrophil receptor occupancy (RO), and free and total soluble CD200R1 were evaluated. PK, PD, and safety data were used to select the recommended phase 2 dose (RP2D).

Results 23ME-00610 enhanced tumor cell-killing in vitro with an EC₅₀ of 0.3 µg/mL and had a half-life in monkeys of 10–13 days, or ~17 days when scaled to humans. The MABEL of EC₆₅ in the tumor-killing assay at the C1 C_max, equivalent to ~92% predicted RO and ≥30-fold margin relative to the 23ME-00610 concentration with no cytokine release, corresponded to 2 mg 23ME-00610 starting dose. Based on the E_max model, peripheral saturation (i.e., C1 C_trough ≥ 99% RO) was expected at doses ≥ 60 mg and anticancer activity (i.e., C1 tumor C_trough > EC₉₀) at doses ≥ 600 mg, assuming a 10% serum-to-tumor partition.^{2 3}

Linear PK and saturation of peripheral target engagement were observed for doses ≥ 60 mg. 23ME-00610 had a median C1 half-life of 11–13 days, and accumulation for Q3W dosing was ~2-fold for C_max and AUC. Predicted C1 tumor C_trough was > EC₉₀ for 1400 mg. As of May 15, 2023, there were no dose limiting toxicities or treatment-related serious adverse events.

Conclusions Human PK and peripheral PD was consistent with projections. Doses in the linear PK range demonstrated sustained peripheral target engagement and 23ME-00610 had a manageable safety profile. The clinical PK, PD, safety, and translational data support evaluation of 23ME-00610 1400 mg Q3W in the ongoing Phase 2a.

Acknowledgements Trial participants and investigators, 23andMe colleagues, and Dr. Rong Deng, Dr. Steve Smith, and Dr. Kristin Follman for clinical pharmacology support.

Trial Registration NCT05199272

References 1. Fenaux J, Fang X, Huang YM, et al. 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function. Oncoimmunology. 2023;12(1):2217737. Published 2023 Jun 5.

2. Bensch F, van der Veen EL, Lub-de Hooge MN, et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018;24(12):1852–1858.

3. Li TR, Chatterjee M, Lala M, et al. Pivotal dose of pembrolizumab: a dose-finding strategy for immuno-oncology. Clin Pharmacol Ther. 2021;110(1):200–209.

Ethics Approval The study obtained approval from Advarra IRB (Pro00062976), Salus IRB (START2021.35), MD Anderson OHRP IRB (2021–0888), Oregon Health & Science University IRB (STUDY00023966) and Ontario Cancer Research Ethics Board (3953). All study participants provided informed consent for the study.