Preclinical evaluation of ISH0339, a tetravalent broadly neutralizing bispecific antibody against SARS-CoV-2 with long-term protection

Huabing Yang; Yuxin Chen; Dongcheng Jiang; Xiaoli Feng; Ying Xu; Jiayu Wei; Qingcui Zou; Qiaojiang Yang; Jihong Chen; Xiaoling Jiang; Chunling Qin; Zhenzhen Huang; Chongbing Wu; Ying Zhou; Minghua Li; Liusong Yin

doi:10.1093/abt/tbad003

Preclinical evaluation of ISH0339, a tetravalent broadly neutralizing bispecific antibody against SARS-CoV-2 with long-term protection

Antib Ther. 2023 Mar 6;6(2):97-107. doi: 10.1093/abt/tbad003. eCollection 2023 Apr.

Authors

Affiliations

¹ SunHo (China) BioPharmaceutical Co., Ltd., No.5 Xingjian Road, Economic and Technological Development Zone, Nanjing 210046, Jiangsu, China.
² Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, Jiangsu, China.
³ Kunming National High-level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650107, Yunnan, China.
⁴ College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China.

Abstract

Background: Ending the global COVID-19 pandemic requires efficacious therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nevertheless, the emerging Omicron sublineages largely escaped the neutralization of current authorized monoclonal antibody therapies. Here we report a tetravalent bispecific antibody ISH0339, as a potential candidate for long-term and broad protection against COVID-19.

Methods: We report here the making of ISH0339, a novel tetravalent bispecific antibody composed of a pair of non-competing neutralizing antibodies that binds specifically to two different neutralizing epitopes of SARS-CoV-2 receptor-binding domain (RBD) and contains an engineered Fc region for prolonged antibody half-life. We describe the preclinical characterization of ISH0339 and discuss its potential as a novel agent for both prophylactic and therapeutic purposes against SARS-CoV-2 infection.

Results: ISH0339 bound to SARS-CoV-2 RBD specifically with high affinity and potently blocked the binding of RBD to the host receptor hACE2. ISH0339 demonstrated greater binding, blocking and neutralizing efficiency than its parental monoclonal antibodies, and retained neutralizing ability to all tested SARS-CoV-2 variants of concern. Single dosing of ISH0339 showed potent neutralizing activity for treatment via intravenous injection and for prophylaxis via nasal spray. Preclinical studies following single dosing of ISH0339 showed favorable pharmacokinetics and well-tolerated toxicology profile.

Conclusion: ISH0339 has demonstrated a favorable safety profile and potent anti-SARS-CoV-2 activities against all current variants of concern. Furthermore, prophylactic and therapeutic application of ISH0339 significantly reduced the viral titer in lungs. Investigational New Drug studies to evaluate the safety, tolerability and preliminary efficacy of ISH0339 for both prophylactic and therapeutic purposes against SARS-CoV-2 infection have been filed.

Keywords: COVID-19; ISH0339; SARS-CoV-2; bispecific; long-protection; neutralizing; omicron; tetravalent.