Abstract A138: Preclinical pharmacokinetic-pharmacodynamic modeling guides setting of the human starting dose of DS-1471a, a novel anti-CD147 antibody

Abstract

Abstract Background: CD147 is a member of the immunoglobulin superfamily that is highly expressed in various cancers and is involved in growth, metastasis, and activation of inflammatory signals in cancer cells. DS-1471a is a novel humanized anti-human CD147 monoclonal antibody under development as an anticancer agent. In this study, pharmacokinetic (PK)-pharmacodynamic (PD) analysis of DS-1471a was conducted to set the dose and dosing regimen for first-in-human (FIH) study. The safety profile of DS-1471a was also assessed in cynomolgus monkeys. Methods: Preclinical pharmacological study was conducted in xenograft model mice transplanted with MIA PaCa-2 cells by intravenous (IV) administration of DS-1471a, and receptor occupancy (RO) of CD147 in tumor was measured. Monkey PK and RO in blood were measured after the IV administration of DS-1471a. The expression levels of CD147 in hepatocytes and erythrocytes in monkeys and humans were measured to estimate the species differences. Using monkey PK, RO, and CD147 expression data, a minimal physiologically based pharmacokinetic (PBPK) model was constructed. Subsequently, PK and RO profiles in humans were predicted by replacing physiological parameters and CD147 expression levels with human values. For the safety assessment, DS-1471a was intravenously administered to monkeys every 2 weeks for 1 month. Results: In xenograft model mice, DS-1471a exhibited partial and potent antitumor activity at 1 and 3 mg/kg, respectively. At those doses, RO in tumor the day after dosing was 18% (1 mg/kg) and 89% (3 mg/kg). In monkeys, non-linear PK was observed, owing to high expression of CD147 in erythrocytes, resulting in target-mediated drug disposition. Compared to the findings in monkeys, the human expression level of CD147 was lower in erythrocytes and higher in hepatocytes. PBPK modeling, incorporating species differences in CD147 expression levels, projected that RO in tumor after the IV administration of DS-1471a to humans would reach 20%, 50%, and 90% at 2 day after injection at 0.3, 1, and 3 mg/kg, respectively. In the monkey toxicity study, DS-1471a was well tolerated at up to 158.4 mg/kg (human equivalent dose of 51 mg/kg). Conclusions: Based on preclinical PK-PD analysis and safety study of DS-1471a, the starting dose in FIH study was set to 1 mg/kg as a safe and efficacious dose. Citation Format: Miki Yokoyama, Masataka Oitate, Ken Sakurai, Takuma Iguchi, Katja Damme, Kayoko Nanai, Keisuke Fukuchi. Preclinical pharmacokinetic-pharmacodynamic modeling guides setting of the human starting dose of DS-1471a, a novel anti-CD147 antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A138.