Preclinical and phase I randomized study of a potent inhalable nanobody targeting TSLP for the treatment of airway inflammation.

Abstract

TSLP, a cytokine derived from epithelial cells at barrier surfaces, has been extensively studied as a pivotal regulator of type 2 and non-type-2 immune responses, implicated in inflammatory airway diseases. Although mAb therapy targeting TSLP has shown significant therapeutic effects, there is still no approved TSLP-targeting inhaled formulation. Leveraging the distinct advantages of nanobodies (Nbs) in maintaining efficacy during storage and administration, our objective is to develop a novel inhalable TSLP Nb for effectively treating airway inflammation. Four TSLP-immunized Nb libraries were screened to generate specific and functional TSLP Nbs. LQ043, a bivalent Nb comprising 2 humanized Nb13 units, was constructed. The efficacy, pharmacokinetics, and safety of inhaled LQ043 were evaluated in mice and nonhuman primates, followed by a randomized, double-blind phase I clinical study. The clinical trial was registered with the Chinese Clinical Trial Registry (CTR20230092). LQ043 exhibited high affinity and specificity for human TSLP, coupled with a favorable inhibitory effect on TSLP/TSLP receptor interaction. Furthermore, inhaled LQ043 significantly attenuated ovalbumin-induced allergic inflammation in mice and demonstrated excellent safety, pharmacokinetic characteristics, and tissue distribution in nonhuman primate models, with high concentrations observed in the respiratory system. Notably, phase I clinical trial results demonstrated dose-proportional pharmacokinetics, safety, and good tolerability for LQ043. In addition, LQ043 can be produced on a large scale at low cost in yeast cells, thereby substantially alleviating the economic burden associated with inhaled biopharmaceuticals. These preclinical and clinical studies robustly establish the safety and efficacy of inhaled LQ043, underscoring its potential as a pioneering inhalation therapy for airway inflammation.