Regulatory-Driven Pharmacokinetic and Immunogenicity Study of Siltartoxatug, a Recombinant Native Human Monoclonal Antibody Against Tetanus Toxin, in Cynomolgus Monkeys.

Abstract

Siltartoxatug-developed by Trinomab Pharmaceutical Co., Ltd., using its proprietary HitmAb® platform-is the first-in-class recombinant monoclonal antibody drug for urgent prophylaxis of tetanus approved by China National Medical Products Administration in February 2025, which addresses the critical unmet need to substitute blood-derived passive immunization preparations for prevention of tetanus. The nonclinical pharmacokinetic and immunogenicity study of siltartoxatug was designed and conducted in strict compliance with global regulatory guidelines for initiating the first-in-human clinical trials. Herein, we report the comprehensive findings from this study. Twenty-four naive cynomolgus monkeys (Macaca fascicularis) were randomly assigned to four groups each with 6 animals. Monkeys in Group 1 received intravenous infusion of siltartoxatug at 1 mg/kg. Monkeys in Groups 2, 3, and 4 received intramuscular injection of siltartoxatug at dose of either 1 mg/kg, 3 mg/kg, or 10 mg/kg. Blood samples were collected over 57 days post-administration, and serum drug concentrations and anti-drug antibody levels were determined with validated methods. Results showed that intramuscular administration of siltartoxatug exhibited favorable pharmacokinetic characteristics: primarily systemic distribution with high bioavailability (88.0% at 1 mg/kg) and low apparent volume of distribution (58.7-69.4 mL/kg), prolonged elimination half-life (11.7-12.4 days), short mean time to maximum concentration (1.2-2.7 days), and dose-dependent systemic exposure without significant sex differences. Additionally, minimal anti-drug antibody responses were observed. These findings underpinned greater predictability for its clinical translation and informed its first-in-human development.