A novel inhalable nanobody targeting IL-4Rα for the treatment of asthma - 13/07/24

Doi : 10.1016/j.jaci.2024.05.027

Min Zhu, MS ^a,^{^{∗
These authors contributed equally to this work as co-first authors.}}, Linlin Ma, PhD ^b,^{^{∗
These authors contributed equally to this work as co-first authors.}}, Peiyu Zhong, PhD ^c,^{^{∗
These authors contributed equally to this work as co-first authors.}}, Jing Huang, MS ^a,^{^{∗
These authors contributed equally to this work as co-first authors.}}, Junwei Gai, MS ^a, Guanghui Li, MS ^a, Yanfei Li, PhD ^b, Peng Qiao, MS ^a, Huaiyu Gu, BS ^a, Xiaofei Li, MS ^a, Yong Yin, PhD ^d,^e,^f, Lei Zhang, PhD ^d, Zhenzhen Deng, MS ^a, Baihe Sun, MS ^b, Zhihong Chen, PhD ^g,^⁎,^{^{‡
These authors contributed equally to this work as co-senior authors.}} , Yu Ding, PhD ^c,^⁎,^{^{‡
These authors contributed equally to this work as co-senior authors.}} , Yakun Wan, PhD ^a,^{^{‡
These authors contributed equally to this work as co-senior authors.},}^⁎
^a Shanghai Novamab Biopharmaceuticals Co, Ltd, Shanghai, China
^b School of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
^c State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
^d Department of Respiratory Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
^e Shanghai Children’s Medical Center Pediatric Medical Complex (Pudong), Shanghai, China
^f Pediatric AI Clinical Application and Research Center, Shanghai Children’s Medical Center, Shanghai, China
^g Department of Respiratory and Critical Care Medicine of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, Shanghai, China

^∗Corresponding author: Yakun Wan, PhD, Shanghai Novamab Biopharmaceuticals Co, Ltd, Shanghai 201318, China.Shanghai Novamab Biopharmaceuticals Co, LtdShanghai201318China^∗Yu Ding, PhD, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.State Key Laboratory of Genetic EngineeringSchool of Life SciencesFudan UniversityShanghai200438China^∗Zhihong Chen, PhD, Department of Respiratory and Critical Care Medicine of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, Shanghai 200032, China.Department of Respiratory and Critical Care Medicine of Zhongshan HospitalShanghai Institute of Respiratory DiseaseFudan UniversityShanghai200032China

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 13 July 2024

Graphical abstract

Le texte complet de cet article est disponible en PDF.

Abstract

Background

Inhalable biologics represent a promising approach to improve the efficacy and safety of asthma treatment. Although several mAbs targeting IL-4 receptor α chain (IL-4Rα) have been approved or are undergoing clinical trials, the development of inhalable mAbs targeting IL-4Rα presents significant challenges.

Objective

Capitalizing on the distinctive advantages of nanobodies (Nbs) in maintaining efficacy during storage and administration, we sought to develop a novel inhalable IL-4Rα Nb for effectively treating asthma.

Methods

Three IL-4Rα immunized Nb libraries were used to generate specific and functional IL-4Rα Nbs. LQ036, a bivalent Nb comprising 2 HuNb103 units, was constructed with a high affinity and specificity for human IL-4Rα. The efficacy, pharmacokinetics, and safety of inhaled LQ036 were evaluated in B-hIL4/hIL4RA humanized mice.

Results

LQ036 inhibited secreted embryonic alkaline phosphatase reporter activity, inhibited TF-1 cell proliferation, and suppressed phosphorylated signal transducer and activator of transduction 6 in T cells from patients with asthma. Crystal structure analysis revealed a binding region similar to dupilumab but with higher affinity, leading to better efficacy in blocking the signaling pathway. HuNb103 competed with IL-4 and IL-13 for IL-4Rα binding. Additionally, LQ036 significantly inhibited ovalbumin-specific IgE levels in serum, CCL17 levels in bronchoalveolar lavage fluid, bronchial mucous cell hyperplasia, and airway goblet cell hyperplasia in B-hIL4/hIL4RA humanized mice. Inhaled LQ036 exhibited favorable pharmacokinetics, safety, and tissue distribution, with higher concentrations observed in the lungs and bronchi.

Conclusions

These findings from preclinical studies establish the safety and efficacy of inhaled LQ036, underscoring its potential as a pioneering inhalable biologic therapy for asthma.

Le texte complet de cet article est disponible en PDF.

Key words : IL-4Rα, nanobody, inhalable, asthma

Abbreviations used : BALF, CDR, IC₅₀, IL-4Rα, hIL, Nb, OVA, PAS, PDB, SEAP, STAT6