New Immunotherapy Approach Targets Immune System to Treat Chronic Hepatitis B

Hepatitis B virus

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Researchers have identified a potential new immunotherapeutic approach for chronic Hepatitis B (HBV) infection, which is often driven by T cell dysfunction. Chronic HBV infection is linked to elevated levels of the hepatitis B surface antigen (HBsAg), a protein that impairs T-cell responses. This study published in Nature focuses on a non-polymorphic molecule called HLA-E, which may offer a universal target for treating chronic infections like HBV.¹

The team characterized three variants of an HLA-E-binding peptide from the HBV envelope protein (Env371-379) using bioinformatics and laboratory assays. Among these, the Env371-379 L6I variant stood out as the most stable and capable of activating functional T-cells. Using a T-cell receptor (TCR)-anti-CD3 bispecific molecule, the researchers demonstrated that Env371-379 L6I could stimulate polyclonal T-cells when co-cultured with cells expressing HBsAg.¹

To further refine this approach, the team developed the a09b08 ImmTAV molecule, which specifically targets all three HLA-E-presented HBV Env371-379 peptide variants, “The a09b08 ImmTAV molecule specifically and potently targeted all three HLA-E-presented HBV Env371-379 peptide variants in T-cell redirection assays with HBV Env-positive targets. These desirable characteristics were achieved by introducing multiple sequence modifications in the TCR CDR regions during the engineering process, thereby generating novel interactions with both the peptide and HLA-E, as shown by structural analyses of the trimolecular peptide–HLA-E-TCR complexes,” investigators said.¹

Additionally, CD8+ T-cells specific to the HLA-E-Env371-379 L6I complex were detected in HBV-naive individuals and patients with chronic HBV after in vitro priming. The investigators note, “We detected HBV Env371-379 (L6I) HLA-E-restricted CD8+ T-cells in the PBMC of people with chronic HBV and HBV-naïve individuals after in vitro expansion with Env371-379 (L6I)-pHLA-E complexes. Although ex vivo identification of HLA-E-restricted CD8+ T-cells in people with chronic HBV proved elusive, a possible explanation could be the limited frequency of these cells in the blood, because of tissue residency.”¹

A key limitation of this study is the absence of evaluation of the a09b08 ImmTAV molecule in HBV-infected primary human hepatocytes (PHH). Since HLA-E is expressed on most PHH and remains present on HBV-infected cells, it is possible that, in an inflammatory liver environment, HLA-E expression could be further upregulated, enhancing recognition by the ImmTAV molecule.¹

What You Need To Know

The study explores HLA-E as a potential universal target for activating immune responses in chronic HBV by addressing T cell dysfunction.

Researchers identified the Env371-379 L6I variant as a highly stable peptide capable of activating T cells against HBV-infected cells.

The a09b08 ImmTAV molecule effectively redirects T cells to target HBV-infected cells by binding to HLA-E-presented peptides, enhancing immune responses.

This HLA-E-targeting strategy aligns with other recent efforts in HBV immunotherapy, such as another study we recently covered by Arbutus Biopharma’s, which also aims to enhance immune responses in chronic HBV. Both strategies focus on overcoming T-cell dysfunction, a major challenge in treating chronic HBV infection.²

In the case of Arbutus’ therapy, described in the IM-PROVE I trial,, imdusiran (AB-729) uses RNA interference (RNAi) to reduce HBsAg levels, which alleviates the immune suppression caused by this protein. This reduction in HBsAg is crucial for restoring T-cell function and priming the immune system to better recognize and clear the virus. Additionally, imdusiran has been shown to activate the immune system, particularly T-cells, making treatments like interferon more effective.²

In contrast, the HLA-E-targeting strategy seeks to activate CD8+ T-cells directly through a novel immune redirection approach. By using engineered molecules like ImmTAV, this method directs T-cells toward HBV-infected cells via the HLA-E-Env371-379 peptide complex.¹ Unlike imdusiran, which works by reducing surface antigen levels to alleviate immune suppression², the HLA-E strategy focuses on stimulating the immune system to recognize and target HBV-infected cells more effectively.¹

Overall, this study underscores the potential of HLA-E as a target for immune-based therapies and highlights the significant role of viral mutations in affecting the stability and effectiveness of immune responses. While both therapeutic approaches aim to enhance T-cell responses against chronic infection, they operate through distinct mechanisms: imdusiran works by reducing viral antigens to decrease immune tolerance, whereas the HLA-E strategy actively re-engages the immune system to target the virus. Together, these therapies represent complementary approaches in the evolving field of immune-based treatments for chronic HBV.