Hepatitis B virus (HBV) infection is a major global health issue, driven by high levels of immunosuppressive viral antigens, the host immune system's failure to effectively control the virus, and the immunosuppressive environment of the liver. Existing therapies have limited effectiveness in eliminating the hepatitis B surface antigen (HBsAg). Antibody-based treatments have shown promise in neutralizing the virus and clearing HBsAg, but achieving effective virologic control often requires high doses or frequent administration.
Effect of HBV infection on immune responses. DOI:10.3389/fimmu.2019.02290
Currently, several different antibody drug types are being developed. This week, the HBV antibody GIGA-2339 was cleared for phase I clinical trials, following a recent FDA approval of the GigaGen’s investigational new drug (IND) application. GIGA-2339 is the first recombinant human polyclonal antibody treatment for HBV. The drug consists of over 1,000 anti-HBV antibodies developed in the laboratory by capturing and then reproducing the natural antibody response from donors who have been vaccinated against HBV. It is more than 2,000 times more potent than plasma-derived HBV drugs and covers the large diversity of circulating HBV variants.
Meanwhile in the research space, a team at Xiamen University have introduced an immune-stimulating ADC made up of a TLR7/8 agonist small molecule compound IMDQ linked to an anti-HBsAg antibody 129G1. Preliminary results of this dual-targeting antibody-drug conjugate (ADC) demonstrated robust and sustained anti-HBsAg specific reactions with short-term administration, and a strong and lasting anti-HBsAg immune response after short-term treatment in AAV/HBV mice.
Furthermore, researchers from Ospedale San Raffaele found that CD8-IL2 treatment exhibited antiviral activity in a preclinical model of chronic HBV, reducing viremia; further data in human cells and cynomolgus monkeys supported the specificity and safety of this molecule. The team developed and tested a CD8 cis-targeted IL-2 (CD8-IL2) that selectively activates CD8+ T cells without affecting regulatory T cells or natural killer cells, since traditional IL-2–based therapies are plagued by toxicities and unintended activation of other immune cell populations. Their results support further development of CD8-IL2 for chronic HBV.
However, a mini-review discusses how HBV reactivation poses a significant clinical challenge, especially in patients undergoing immunosuppressive therapies, including monoclonal antibodies. HBV reactivation is a potentially fatal complication after immunosuppressive biological or targeted therapy. Reports from the literature demonstrate that this is more frequent in patients treated with anti-CD20 or anti-TNF. However, there are some case reports of other mAbs causing this adverse event. Many unanswered questions remain about the risk of HBV reactivation associated with recently introduced mAbs. These questions provide an opportunity for monitoring and research.
