Translational and phase I evaluation of AZD0292, a novel, half-life extended anti-Pseudomonal Psl-PcrV bispecific monoclonal antibody

Abstract Background Chronic Pseudomonas aeruginosa airway colonization in bronchiectasis (BE) is associated with frequent exacerbations. Bispecific antibody AZD0292, targeting P. aeruginosa Psl and PcrV, was engineered from gremubamab with a Fc N3Y substitution to extend half-life and is being developed to reduce exacerbations in BE with chronic P. aeruginosa colonization. Methods Preclinical studies assessed opsonophagocytic killing and anti-cytotoxicity assays, repeat-dose toxicology with ex vivo pharmacodynamic analyses in cynomolgus monkeys, and pharmacokinetics in human FcRn transgenic mice. In Phase I, healthy adults were randomized to receive a single dose of AZD0292 (n =24) or placebo (n = 8) in 4 cohorts (100-2,000 mg) and followed for 61 days or 161 days in cohort 4. Endpoints included safety, pharmacokinetics, immunogenicity, and exploratory cytokine/complement assessments. Results AZD0292 demonstrated comparable functional activity to gremubamab, an approximately 55% lower clearance in transgenic mice, and retained anti-P. aeruginosa activity in cynomolgus monkey serum after repeated dosing. In Phase I, AZD0292 was generally well tolerated. Mild/moderate infusion-related reactions occurred only at higher doses and were managed with routine clinical measures. Transient cytokine increases were observed after dosing, with no meaningful complement activation. Pharmacokinetics were approximately dose-dependent but slightly less than dose-proportional across 100-2,000 mg. Geometric mean half-life ranged from 24 to 47 days, though estimates are provisional given small cohort sizes and limited follow-up. No treatment-emergent anti-drug antibodies were detected. Conclusions These results support further clinical development of AZD0292 for reduction of exacerbations in BE with chronic P. aeruginosa colonization, with pharmacokinetics requiring confirmation in the target patient population.