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Anti-Siglec-3 mAb as immune checkpoint inhibitor to combat Hepatitis B infection

Hepatitis B virus (HBV) infection is a worldwide health problem. According to WHO’s report, there are over 257 million peoples globally infected by hepatitis B virus. HBV infection is prevalent in China, Taiwan, and Southeast Asia countries. Approximately 887,000 individuals die each year from HBV-related liver diseases or liver cancer.

Vertical transmission (mother-to-child) of virus during delivery is the most common route of HBV transmission in childern. In adults, HBV can are transmitted via contaminated syringes and tattooing. Unlike hepatitis C virus infection, patients suffered with chronic hepatitis B virus (CHB) infection need to take nucleotides/nucleosides analogs life long to suppress virus replicaion, and CHB patients have higher risk to progress liver cirrhosis and hepatocellular carcinoma.

Unlike other viruses, hepatitis B virus DNA is permanently integrated into the genomic DNA of infected hepatocytes to form cccDNA DNA in CHB patients. Moreover, HBV produces large amounts of viral particles and HBsAg-containing subviral particles. It has been speculated that HBV viral particles and subviral particles can attenuate host immune responses, thus patients’ immune system cannot effectively clear HBV and lead to chronic and persistent liver inflammation, cirrhosis, and hepatocellular carcinoma. However, current oral nucleot(s)ide analogues for HBV treatment are rarely able to clean up of the cccDNA in the nucleus, and high concentration of HBsAg still circulating in CHB patients’ peripheral blood.

The team led by Dr. Shie-Liang Hsieh in the Genomics Research Center (GRC) has found a novel strategy to treat chronic hepatitis B virus infection. They found that the sialyglycans on HBsAg interact with immune checkpoint receptor Siglec-3 (CD33) to inhibit host immunity. In collaboration with Dr. An-Suei Yang, they identified antagonistic anti-Siglec-3 mAb to block SIGLEC-3-HBV interaction and reactivate host immunity against HBV. Because antibodies against immune checkpoint receptor PD-1 have been shown to reactivate host immunity to suppress cancer cell growth, or even clear all the cacer cells in patients, identification of CD33 as HBV immune checkpoint receptor unveils a new direction for hepatitis B treatment. This work is published in the Journal of Clinical Investigation in June 1, 2021.

 

 

The first author Tsung-Yu Tsai, a clinician in the Department of Digestive Medicine in China Medical University Hospital, was enrolled into the Translational Medicine PhD program and joined Dr. Hsieh’s team to invesitgate the mechanism of HBV-mediated immunosuppression. He found that the anti-Siglec-3 mAb (clone 10C8) is able to block the interaction between biantennary sialoglycan on HBsAg and Sig-lec-3, thereby reactivates host immune response to upregulate the expression of proinflammatory cytokines and molecules involved in antigen presention. It is interesting to note that HBV produced in transgenic mice does not express the sialyglycan at Asn146 in HBsAg, and is unable to bind the CD33 immune checkpoint receptor. This observation may explain the discrepancy between mouse models and humans. The application of anti-Siglec-3 mAb (10C8) has been filed for patent.

This work is completed with the assistance of GRC colleagues Dr. An-Suei Yang, Dr. Chung-Yi Wu, Dr. Hwai-I Yang, Dr. Jung-Lee Lin (MASS core laboratory), Dr. Ying-Ta Wu (BLI assay), as well as Dr. Mi-Hua Tao from Institute of Biomedicine science) and We-Chao Chagn (Taipei Medical Univeersity). Special thanks go to Dr. Ding-Shinn Chen and Dr. Pei-Jer Chen for all the inspiriang discussions for this work. The financial support for this work is from the Biotechnology Research Park Translation Project (BRPT), Academia Sinica.

Tsai TY, Huang MT, Sung PS, Peng CY, Tao MH, Yang HI, Chang WC, Yang AS, Yu CM, Lin YP, et al. SIGLEC-3 (CD33) serves as an immune checkpoint receptor for HBV infection. J Clin Invest. 2021;131(11):e141965

Full paper can be found in the following website: https://doi.org/10.1172/JCI141965

Video: https://youtu.be/mk_nowE-U-8

 

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