Novel monkey mAbs induced by a therapeutic vaccine targeting the hepatitis B surface antigen effectively suppress hepatitis B virus in mice. (29th September 2021)

• Record Type: Journal Article
• Authors: Chen, Yuanzhi; Xiang, Xinchu; Qi, Ruoyao; Wang, Yiwen; Huang, Yang; You, Min; Xian, Yangfei; Wu, Yangtao; Fu, Rao; Kang, Ciming; Tang, Jixian; Yu, Hai; Zhang, Tianying; Yuan, Quan; Luo, Wenxin; Xia, Ningshao
• Is Part Of: Antibody therapeutics. Volume 4:Number 4(2021)
• Page Start: 197
• Page End: 207
• Publication Date: 2021-09-29
• Subjects: chronic hepatitis B infection -- hepatitis B surface antigen -- B cell culture -- cynomolgus monkey antibody -- antibody-mediated HBV suppression; Immunoglobulins -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Therapeutic use -- Periodicals; Immunotechnology -- Periodicals; 616.0798
• DOI: 10.1093/abt/tbab020
• Languages: English
• ISSNs: 2516-4236

Abstract

ABSTRACT: Background: We have previously obtained a mouse anti-hepatitis B surface antigen (HBsAg) antibody E6F6 with long-lasting serum HBsAg clearance effects. The E6F6 epitope-based protein CR-T3-SEQ13 (HBsAg aa 113-135) vaccination therapy in cynomolgus monkeys induced long-term polyclonal antibodies-mediated clearance of HBsAg in the HBV transgenic (HBV-Tg) mice. Methods: We isolated monoclonal antibodies from CR-T3-SEQ13 vaccinated cynomolgus monkeys, compared their therapeutic effects with E6F6, identified their epitopes on HBsAg, determined the pharmacokinetics and studied their physical property. Results: A panel of anti-HBsAg mAbs was generated through memory B cell stimulatory culture. Two lead monkey-human chimeric antibodies, C1-23 and C3-23, effectively suppressed HBsAg and HBV DNA in HBV-Tg mice. The humanized antibodies and humanized-mouse reverse chimeric antibodies of two antibodies exhibited comparable HBsAg clearance and viral suppression efficacy as those versions of E6F6 in HBV-Tg mice. Humanized antibody hu1-23 exhibited more efficacy HBsAg-suppressing effects than huE6F6-1 and hu3-23 in HBV-Tg mice at dose levels of 10 and 20 mg/kg. Evaluation of the binding sites indicates that the epitope recognized by hu1-23 is located in HBsAg aa 118-125 and 121-125 for hu3-23. Physical property study revealed that hu1-23 and hu3-23 are stable enough for further development as a drug candidate. Conclusions: Our data suggest that the CR-T3-SEQ13 protein is a promising HBV therapeutic vaccine candidate, and hu1-23 and hu3-23 are therapeutic candidates for the treatment of chronic hepatitis b. Moreover, the generation of antibodies from the epitope-based vaccinated subjects may be an alternative approach for novel antibody drug discovery.