Bispecific Antibody Targeting IL-33 and TSLP for Treating Asthma and COPD
Hao Ran (New York, United States of America), Jingwei Huang (New York, United States of America), Huili Li (New York, United States of America), Liguo Dong (New York, United States of America), Chenpeng Su (New York, United States of America), Dandan Liu (New York, United States of America), Yifei Zhou (New York, United States of America), Chuan Chen (New York, United States of America), Xiaoou Xu (New York, United States of America), Xiaoqian Chen (New York, United States of America), Liang Tian (New York, United States of America), Jian Peng (New York, United States of America), Zhenping Zhu (New Yor, United States of America)
Background

Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway disorders marked by obstructive airflow limitation, creating a significant burden on patients and healthcare systems. Alarmins IL-33 and TSLP have emerged as key therapeutic targets for both conditions. Importantly, IL-33 and TSLP are the only targets that have shown clinical efficacy in non-Th2 asthma cases. To address this, we have engineered HXN-1013, a bispecific antibody (bsAb) that concurrently targets both TSLP and IL-33, with the goal of enhancing clinical outcomes for asthma and COPD patients.

Method

Anti-TSLP antibodies were developed, characterized, and selected through a range of in vitro assays, including TSLPR-STAT5-Luc reporter assays, TSLP-induced Baf3 proliferation, and CCL17 release from PBMCs. IL-33 antibodies were generated and evaluated using an IL-33 reporter assay and an IL-33-induced PBMC activation assay. The synergistic effects of dual targeting were assessed by measuring IL-5 and IL-13 release in human PBMCs co-stimulated with TSLP and IL-33.

Results

Multiple high-potency anti-TSLP antibodies were generated, targeting different binding epitopes, including Site I (TSLPR binding site), Site II (IL-7Rα binding site), and biparatopic antibodies that simultaneously target both Sites I and II. These antibodies demonstrated significantly enhanced activity compared to Tezepelumab in functional assays. Additionally, a series of anti-IL-33 antibodies were developed with superior potency relative to Itepekimab, as shown by IL-33 reporter assays and PBMC activation assays. Based on these building blocks, we engineered the bispecific antibody HXN-1013, which is capable of binding simultaneously to both TSLP and IL-33, blocking their interactions with their respective receptors. Each arm of the bispecific antibody exhibited biological activity comparable to the individual parent antibodies. In the PBMC activation assay, co-induced by both TSLP and IL-33, HXN-1013 demonstrated superior activity compared to either of the parent antibodies alone.

Conclusion

HXN-1013 is a bsAb designed to simultaneously block both TSLP and IL-33, with each arm exhibiting activity comparable to the parent antibodies. HXN-1013 has the potential to deliver more robust therapeutic effects, offering significant promise for improving clinical efficacy in the treatment of asthma and COPD.