609 Phase 1/2a dose selection of 23ME-00610, a first-in-class anti-CD200R1 antibody, in patients with advanced solid malignancies
Bibliographic record
Abstract
<h3>Background</h3> 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.<sup>1</sup> Preclinical pharmacology data and monkey pharmacokinetics (PK) were used to select doses for the Phase 1/2a study (NCT05199272). <h3>Methods</h3> 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<sub>max</sub> model. The MABEL starting dose was based on the in vitro tumor cell-killing assay, nonclinical safety, and predicted Cycle 1 (C1) C<sub>max</sub>. 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). <h3>Results</h3> 23ME-00610 enhanced tumor cell-killing in vitro with an EC<sub>50</sub> 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 EC<sub>65</sub> in the tumor-killing assay at the C1 C<sub>max</sub>, 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<sub>max</sub> model, peripheral saturation (i.e., C1 C<sub>trough</sub> ≥ 99% RO) was expected at doses ≥ 60 mg and anticancer activity (i.e., C1 tumor C<sub>trough</sub> > EC<sub>90</sub>) at doses ≥ 600 mg, assuming a 10% serum-to-tumor partition.<sup>2 3</sup> 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<sub>max</sub> and AUC. Predicted C1 tumor C<sub>trough</sub> was > EC<sub>90</sub> for 1400 mg. As of May 15, 2023, there were no dose limiting toxicities or treatment-related serious adverse events. <h3>Conclusions</h3> 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. <h3>Acknowledgements</h3> Trial participants and investigators, 23andMe colleagues, and Dr. Rong Deng, Dr. Steve Smith, and Dr. Kristin Follman for clinical pharmacology support. <h3>Trial Registration</h3> NCT05199272 <h3>References</h3> 1. Fenaux J, Fang X, Huang YM, <i>et al</i>. 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function. <i>Oncoimmunology</i>. 2023;<b>12</b>(1):2217737. Published 2023 Jun 5. 2. Bensch F, van der Veen EL, Lub-de Hooge MN, <i>et al</i>. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. <i>Nat Med</i>. 2018;<b>24</b>(12):1852–1858. 3. Li TR, Chatterjee M, Lala M, <i>et al</i>. Pivotal dose of pembrolizumab: a dose-finding strategy for immuno-oncology. <i>Clin Pharmacol Ther.</i> 2021;<b>110</b>(1):200–209. <h3>Ethics Approval</h3> 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".