An engineered bispecific human monoclonal antibody against SARS-CoV-2

• Published in: Nature immunology Vol. 23; no. 3; pp. 423 - 430
• Main Authors: Li, Zhaohui, Li, Shihua, Zhang, Gen, Peng, Weiyu, Chang, Zhen, Zhang, Xue, Fan, Zheng, Chai, Yan, Wang, Feiran, Zhao, Xin, Li, Dedong, Zhang, Rong, He, Zhanlong, Zou, Weiwei, Xu, Ke, Lei, Wenwen, Liu, Peipei, Hao, Junfeng, Zhang, Jingjing, Sun, Litao, Wu, Guizhen, Tan, Shuguang, Gao, George Fu, Gao, Feng, Wu, Yan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2022
• Subjects: 631/250/255/2514; 631/326/596/4130; 692/420/2780/2152/2153/1291; Biomedical and Life Sciences; Biomedicine; Immunology; Infectious Diseases
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-022-01138-w

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19. Although COVID-19 vaccines are proving to be generally effective, new therapeutics to neutralize SARS-CoV-2 are required. Here, the authors engineer bispecific antibodies from ACE2-blocking B38 and H4 SARS-CoV-2 neutralizing antibodies and demonstrate their superiority in mice and nonhuman primates.