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

Background: 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.

Objectives: 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.

Methods: 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).

Results: 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.

Conclusion: 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.