New hope for HBV carriers
04 Apr 2016 NUS scientists have discovered the mechanisms of mAb mediated HBsAg clean-up, a critical step towards development of therapeutic mAbs for Hepatitis B virus (HBV) carrier treatment.
Worldwide, more than 240 million people are persistently infected by HBV, approved anti-HBV drugs, which are either interferon or nucleos(t)ide analogues, can only induce disease remission, but not effectively eradicate the virus. A team co-led by Prof Adam YUAN from the Department of Biological Sciences in NUS, in collaboration primarily with a research group from Xiamen University, has discovered a novel class of mAbs, targeting a conserved GPCK(R)TCT epitope on HBsAg, which demonstrated more profound and prolonged HBV suppression effects by efficiently preventing initial HBV infection, blocking viral spreading and facilitating the restoration of anti-HBV T-cell response in vivo testing.
The work, performed as a collaborative effort between NUS and the NUS (Suzhou) Research Institute, not only discovered a class of mAbs demonstrating potent HBV-clearance effect in vivo but also revealed the mechanisms of mAb-mediated HBsAg clean-up, henceproviding tangible strategies to elicit potential therapeutic mAbs. The research findings discovered by this group may also provide a deep understanding of antibody-mediated immunotherapy against persistent viral infection.
The superior HBsAg clearance ability displayed by this class of mAbs strongly suggests the possibilities of developing therapeutic antibodies against HBV (see Figure). The humanised mAbs derived from current research work will next be tested in the clinic alone or in combination with available anti-HBV drugs to treat chronic HBV infected patients. If successful, further development of humanised mAbs derived from this class of mAbs will provide a novel anti-HBV strategy to improve the clinical management of chronic hepatitis B (CHB).
Although mAbs have already been used as therapeutic drugs for the treatment of cancer and autoimmune disease and have showed promising therapeutic potency against HIV infection, currently available HBV mAbs only show short-term HBV viral suppression effects. The discovery of a class of novel mAbs, displaying prolonged suppression of HBV in mice by targeting an evolutionarily conserved sA epitope on HBsAg, has provided a new strategy to treat chronic HBV infection. This provides new hope for HBV carriers.
The figure shows the structural model of HBsAg in complex with therapeutic mAb recognising sA epitope on HBsAg [Image credit: Adam Yuan].
Zhang TY, Yuan Q, Zhao JH, Zhang YL, Yuan LZ, Lan Y, Lo YC, Sun CP, Wu CR, Zhang JF, Zhang Y, Cao JL, Guo XR, Liu X, Mo XB, Luo WX, Cheng T, Chen YX, Tao MH, Shih JW, Zhao QJ, Zhang J, Chen PJ, Yuan YA, Xia NS. “Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen” Gut doi:10.1136/gutjnl-2014-308964 (2015).