CM512, a potentially novel IgG1-based bispecific antibody dual-targeting TSLP and IL-13, for the suppression of type 2 inflammation

BACKGROUND: CM512, a novel IgG1-based 1 + 1 bispecific antibody designed with one arm targeting thymic stromal lymphopoietin (TSLP) and the other targeting interleukin-13 (IL-13), is currently under phase 2 clinical investigation for multiple autoimmune diseases. Here, we reported for the first time the translational pharmacology of CM512. METHODS: We measured the binding affinity of CM512 to each cytokine and tested its ability to block TSLP- or IL-13-mediated biological activity. CM512 was also evaluated in an OVA-induced mouse asthma model to assess its therapeutic effects on type 2 inflammation. Pharmacokinetics were characterized in cynomolgus monkeys to test its half-life. RESULTS: CM512 bound both TSLP and IL-13 with high affinity and effectively prevented their receptor engagement. In vitro bioassays demonstrated that CM512 potently inhibited the activation of downstream signaling pathways, cell proliferation, and the release of inflammatory factors induced by either TSLP or IL-13. Moreover, CM512 showed greater inhibition of type 2 inflammatory responses compared with single-target antibodies against TSLP or IL-13. An in vivo study further confirmed that CM512 robustly inhibited type 2 inflammatory responses and alleviated disease symptoms. Pharmacokinetic analyses revealed a circulating half-life of approximately 396 to 557 h in cynomolgus monkeys. CONCLUSIONS: Our study establishes that dual TSLP/IL-13 inhibition achieves broad suppression of type 2 inflammatory pathways, overcoming limitations of single-cytokine therapies and demonstrating greater inhibition than single blockade efficacy in type 2-driven diseases. These findings provide the first translational evidence supporting the potential of dual cytokine blockade for treating refractory type 2 inflammatory conditions.