First-in-human, phase 1 study of CM512, a TSLP/IL-13 bispecific antibody, in healthy volunteers: safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity.

Purpose: Type 2 chronic inflammatory diseases (e.g., atopic dermatitis and allergic rhinitis) impose a substantial global burden with unmet medical needs. Thymic stromal lymphopoietin (TSLP) and interleukin-13 (IL-13) are key pathogenic drivers, and bispecific antibodies targeting both cytokines may offer synergistic clinical benefits. CM512 is a novel recombinant bispecific antibody targeting both TSLP and IL-13 with high affinity. This first-in-human, randomized, double-blind, placebo-controlled phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of single (SAD) and multiple ascending doses (MAD) of subcutaneous CM512 in healthy adults. Methods: The SAD phase enrolled 40 healthy participants across four sequential cohorts (150, 450, 900, and 1200 mg), randomized 4:1 to receive subcutaneous CM512 or placebo per cohort. The MAD phase enrolled 24 participants across two sequential cohorts (150 and 600 mg biweekly), randomized 2:1 per cohort. The primary endpoint was safety and tolerability; secondary endpoints included PK, PD, and immunogenicity. Results: CM512 was well tolerated. Treatment-emergent adverse events (TEAEs) occurred in 71.9% (23/32) and 68.8% (11/16) of CM512 recipients in the SAD and MAD phases, with incidence comparable to placebo. All treatment-related TEAEs were mild or moderate. No serious adverse events, TEAEs leading to withdrawal, or deaths were reported. In the SAD phase, CM512 displayed linear, dose-proportional PK from 150-1200 mg, accompanied by a long terminal half-life (mean range: 58.7-73.6 days). In the MAD phase, biweekly administration resulted in accumulation (mean accumulation ratio: 2.50-3.17), consistent with its long half-life. CM512 significantly reduced free TSLP and IL-13, and sustainedly lowered blood eosinophils, IgE, and thymus activation-regulated chemokine (TARC) levels versus placebo. The incidence of treatment-emergent anti-drug antibodies in healthy participants receiving CM512 was low, at 3.1% (1/32) in the SAD phase and 0% (0/16) in the MAD phase, respectively. Conclusion: CM512 demonstrated favorable safety, linear PK, and low immunogenicity in healthy participants. It significantly reduced free target cytokines and type 2 inflammation biomarkers, supporting further clinical investigation for type 2 inflammatory diseases. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT06553209.