Abstract 2139: Determination of first in human dose of the T cell-redirecting bispecific antibody CT-95 targeting mesothelin

Abstract CT-95 is a mesothelin (MSLN) x CD3 bispecific T cell-redirecting antibody that is entering phase 1 clinical development. It is affinity tuned to avoid the soluble MSLN sink that has interfered with earlier MSLN-targeting programs. The first-in-human dose of CT-95 was determined using the minimal anticipated biological effect level (MABEL) approach, as required for immune agonist drugs. This is the dose level expected to lead to a minimal biological effect level in humans. The most sensitive and pharmacologically relevant measure of CT-95 activity was determined to be induction of CD25 expression on human T cells using a panel of six human MSLN expressing tumor cell lines. The median EC50 for this panel was 9.94 pM and resulted in an estimated target serum concentration of 1.98 ng/mL. Based on nonclinical PK data, the predicted volume of distribution is 123.5 mL/kg, which suggests a starting dose of 0.24 μg/kg. An additional safety factor was applied to obtain a proposed starting dose of 0.1 μg/kg. From the results of the GLP monkey study, the highest non-severely toxic dose (HNSTD) was considered to be 0.01 mg/kg, and the no-observed-adverse-effect level (NOAEL) was 0.003 mg/kg. Relative to doses in the one-month repeat dose GLP-compliant toxicology study, the proposed starting dose for CT-95 (0.1 μg/kg) is 30-fold lower than the NOAEL (3 μg/kg) and 100-fold lower than the HNSTD (10 μg/kg). The weight of evidence of these data supports the safety of the proposed clinical starting dose of 0.1 μg/kg for CT-95. Citation Format: Stanley A. Roberts, Kelly Byrnes-Blake, Eric Butz. Determination of first in human dose of the T cell-redirecting bispecific antibody CT-95 targeting mesothelin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2139.