MC001：一种用于治疗表达叶酸受体α的胰腺癌的新型化学免疫治疗抗体药物偶联物

Background: The prognosis for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains dismal, even with intensive multi-agent chemotherapy. Many patients are also unable to tolerate these regimens due to systemic toxicity. Folate receptor alpha (FRalpha), overexpressed in up to 80% of PDAC cases, is associated with poor clinical outcomes and represents a promising therapeutic target. MC001 is a novel chemoimmunotherapy antibody-drug conjugate (ADC) designed to target FRalpha and to harness both payload-mediated and antibody-mediated cytotoxic mechanisms. Here, we evaluated the preclinical efficacy and safety of MC001 in FRalpha-expressing PDAC models. Methods: A high-affinity FRalpha-specific antibody was isolated from a human v-gene phage display library and engineered into a dimeric, tetravalent IgG1 antibody (ADoBind) through a disulfide bond generated by an S444C mutation. MC001 was synthesized by lysine-based conjugation of the ADoBind antibody to monomethyl auristatin E (MMAE) via an enzyme-cleavable linker, achieving an average drug-to-antibody ratio of 6. Results: The tetravalent ADoBind antibody demonstrated higher avidity to FRalpha than its monomeric counterpart and mediated robust antibody-dependent cellular cytotoxicity (ADCC) against FRalpha-positive SU.86.86 human pancreatic cancer cells using human peripheral blood mononuclear cells (PBMCs), while complement-dependent cytotoxicity was not detected. In a SCID mouse xenograft model co-administered with human PBMCs, ADoBind antibodies induced potent ADCC in vivo and achieved significant tumor growth inhibition. In a single-dose PDAC xenograft study, ADoBind-MMAE ADC (MC001) produced approximately fivefold greater tumor inhibition than its monomeric ADC counterpart at equivalent molar dosing. Tumor suppression was durable, persisting beyond 30 days after a single injection, and resulted in improved overall survival. Single-dose toxicology studies in SD rats and cynomolgus monkeys showed that MC001 was well tolerated, with no significant systemic toxicities. Only transient, mild neutropenia was observed at the highest dose level (12 mg/kg). The serum half-life of MC001 was 5.4 days following a single 3 mg/kg dose, supporting favorable pharmacokinetics for intermittent dosing. Conclusions: Up to 40% of ADC payloads may be released extracellularly before cellular internalization, revealing an opportunity to exploit the intrinsic antitumor activity of the antibody moiety. By combining antibody-mediated immune cytotoxicity with targeted delivery of a payload, MC001 represents a next-generation chemoimmunotherapy ADC capable of killing both proliferating and quiescent (G₀-phase) tumor cells. These results in preclinical models support advancement of MC001 and the ADoBind platform, which are currently progressing through IND-enabling development.