Immune‐Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B–Infected Cells

Abstract

Background and Aims Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV‐specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity‐enhanced T Cell receptor with an anti‐CD3 T Cell‐activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus‐derived peptides presented by human leukocyte antigen (HLA). Approach and Results ImmTAV molecules specific for HLA‐A*02:01‐restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV‐Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging‐based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV‐Env can redirect T cells from healthy and HBV‐infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV‐Env redirection of T cells induced cytolysis of antigen‐positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA. Conclusions The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non‐HBV‐specific T cells, bypassing exhausted HBV‐specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.

Immune classifier-based signatures provide good prognostic stratification and predict the clinical benefits of immune-based therapies for hepatocellular carcinoma

“…HLA molecules are also crucial for T cell-mediated immune surveillance in HCC patients, and HLA-mediated immunomodulatory functions have been observed in numerous pathological conditions, including cancer [ 35 ]. HLA-G has shown both prognostic potential and diagnostic value in HCC patients, and HLA molecules have been reported to play crucial roles in the pathogenesis of HCC [ 53 ]; therefore, they may be useful as part of an overall immunotherapy strategy against HCC [ 54 ]. Accordingly, we found that the subgroups with high immune scores and Group 4 (with high levels of immune cell infiltration) may have better immunotherapy responses.…”

Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure

“…ImmTAV molecules are bispecific molecules that combine a TCR with increased affinity that targets HBV-specific human leukocyte antigen (HLA)-limited epitopes and a recombinant anti-CD3 antibody that triggers T-cell activation. ImmTAV molecules designed for HLA-A*02:01-restricted HBV antigen epitopes generated T cells that specifically lyse in vitro HCC cells containing integrated HBV DNA and HBV-infected cells[ 150 ]. A phase II study is currently evaluating the safety, antiviral activity, and pharmacokinetics of the ImmTAV molecule IMC-I109V in HLA-A*02:01-positive patients with CHB (EudraCT 2019-004212-64).…”

Novel Antivirals in Clinical Development for Chronic Hepatitis B Infection

“…In vitro study has confirmed that ImmTAV-Env (ImmTAV molecules that are specific for HLA-A*02:01-restricted HBV epitopes derived from the viral envelope proteins) can redirect T cells from healthy and HBV-infected donors toward HCC cells containing integrated DNA. The induced cytokine release was suppressible by corticosteroid, and the redirected T-cells induced cytolysis of HBV-infected cells and antigen-positive HCC cells, leading to reduction of HBeAg and loss of cells expressing viral RNA [ 73 ]. IMC-I109V is currently in phase 1/2 clinical trial, involving mainly non-cirrhotic and virally suppressed HBeAg-negative CHB patients.…”