Single-dose serum PK and peripheral target engagement for 23ME-00610 in patients with cancer by dose level. Sample size for participants with evaluable data by dose cohorts: 1,400 mg (N = 8), 600 mg (N = 8), 200 mg (N = 3),60 mg (N = 4), 20 mg (N = 3), 6 mg (N = 1), and 2 mg (N = 1). A, Geometric mean and geometric SD for cycle 1 serum 23ME-00610 concentration–time data by dose level. Below limit of quantitation (BLQ) values were set to missing, and data were plotted only if more than half of the evaluable data was quantifiable [greater than the lower limit of quantitation (LLOQ)] and not missing. EC90 in tumor PK target (dotted reference line) based on in vitro tumor-killing assay and 10% tumor-to-serum partition. B, Median RO by dose level for cycle 1. The RO assay is qualitative and measures 23ME-00610 bound to the target receptor CD200R1 on the target cell of interest. At least 60% RO (shaded in green) is considered saturated, in which less than 60% RO is considered not saturated. C, Median-free soluble CD200R1 by dose level from cycle 1 day 1 predose to cycle 4 day 1 predose (63 study days). The assay lower limit of detection (following a 20-fold minimum required dilution) is 312 pg/mL (dotted reference line). BLQ values were plotted at the LLOQ. All patients for dose levels ≥60 mg were BLQ at day 21 and day 63. D, Median total soluble CD200R1 (sum of free soluble CD200R1 and 23ME-00610–bound soluble CD200R1) by dose level from cycle 1 day 1 predose to cycle 4 day 1 predose (63 study days). The assay lower limit of detection (following a 20-fold minimum required dilution) is 312 pg/mL (dotted reference line).
ARTICLE ABSTRACT
In this phase 1 portion of a first-in-human phase 1/2a study (NCT05199272), 23ME-00610 was evaluated in participants with advanced solid malignancies to determine its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Exploratory biomarkers were evaluated to examine potential correlates of efficacy and safety.
Eligible participants (≥18 years) were administered 23ME-00610 intravenously every 3 weeks (Q3W) using an accelerated titration design followed by a traditional 3 + 3 design, with an initial dose level of 2 mg.
Twenty-eight participants were enrolled across seven cohorts and received a median of four cycles of 23ME-00610. No treatment-related serious adverse events (AE) were observed, and the maximum tolerated dose was not reached. Overall, the PK of 23ME-00610 was linear and dose proportional for doses ≥60 mg, with a median terminal half-life of 13 days at 1,400 mg. Peripheral saturation of CD200R1 was observed for doses ≥60 mg. Immune-related AEs, including rash, pruritus, and hypothyroidism, were predicted by phenome-wide association studies and observed for doses ≥60 mg. A confirmed partial response was observed in a participant with well-differentiated pancreatic neuroendocrine cancer whose tumor was among those with the highest tumor CD200 expression.
23ME-00610 has mild-to-moderate on-target AEs and PK/PD consistent with tumor target saturation and dosing every 3 weeks. The trend for clinical benefit in participants with tumor CD200 expression suggests that 23ME-00610 inhibits CD200R1 signaling and may reverse CD200-mediated immune evasion. Based on PK/PD, safety, and preliminary antitumor activity, 1,400 mg Q3W was selected as the dose for further study.
Genome-wide association studies (GWAS) of the 23andMe genetic database identified CD200R1 as a promising therapeutic target for cancer. This phase 1 study of 23ME-00610, a CD200R1 antagonist IgG1, showed acceptable safety and tolerability, PK supporting Q3W dosing, and PD and preliminary clinical activity supporting an initial recommended phase 2 dose of 1,400 mg.
