Clinical pharmacokinetics and immunogenicity evaluation of a trophoblast cell surface antigen 2-targeted antibody-drug conjugate, FDA018, in patients with epithelial malignant solid tumors.

FDA018, a novel trophoblast cell surface antigen 2-targeted antibody-drug conjugate, is designed for treating trophoblast cell surface antigen 2-positive solid tumors, including triple-negative breast cancer, lung cancer, and gastric cancer. In this study, a single-center, open-label, dose-escalation clinical study was conducted to evaluate the pharmacokinetics (PK) and immunogenicity of FDA018 injection in patients with advanced or metastatic epithelial malignant solid tumors, using an "accelerated titration" design and a standard "3+3" design across 6 dose cohorts (2.5, 5, 7.5, 10, 12 and 15 mg/kg). PK profiles were investigated for a topoisomerase I inhibitor (SN-38)-conjugated antibody, total antibody, unconjugated SN-38, a glucuronate metabolite of SN-38 (SN-38G), and total SN-38. To evaluate the impact of immunogenicity on PK profiles of FDA018, immunogenicity was assessed with an electrochemiluminescence-based bridging immunoassay. PK results showed that the exposure of the SN-38-conjugated antibody increased linearly with dose escalation. The terminal half-life of the SN-38-conjugated antibody (about 30 hours) was significantly shorter than that of the total antibody (about 85 hours). The terminal half-life of the SN-38-conjugated antibody and total antibody appeared to be prolonged after multiple administrations. The exposure of unconjugated SN-38 accounted for approximately 1% of total SN-38, indicating that most SN-38 remained conjugated to the monoclonal antibody in the systemic circulation, and the off-target toxicity was controllable. The accumulation analysis results showed that total antibody accumulated after multiple administrations. For immunogenicity assessment, among 20 patients receiving doses from 7.5 to 15 mg/kg, 15% tested positive for anti-drug antibodies. Anti-drug antibody-positive results did not significantly affect the PK profiles of FDA018. In conclusion, FDA018 demonstrated promising PK and immunogenicity profiles and laid a solid foundation for further clinical research. SIGNIFICANCE STATEMENT: This study comprehensively evaluated the clinical pharmacokinetic and immunogenicity of the trophoblast cell surface antigen 2-targeted antibody-drug conjugate, FDA018, for the first time, to the authors' knowledge. Compared with the commercially available trophoblast cell surface antigen 2-targeted antibody-drug conjugate sacituzumab govitecan, FDA018 showed promising pharmacokinetic properties with higher exposure of conjugated antibody and lower exposure of unconjugated SN-38 in vivo, implying better efficacy and lower off-target toxicity.