2 research outputs found
Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B-Infected Cells
Background and Aims:
Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBVâspecific 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 affinityâenhanced T Cell receptor with an antiâCD3 T Cellâactivating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virusâderived peptides presented by human leukocyte antigen (HLA).
Approach and Results:
ImmTAV molecules specific for HLAâA*02:01ârestricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAVâEnv to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imagingâbased 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 ImmTAVâEnv can redirect T cells from healthy and HBVâinfected 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, ImmTAVâEnv redirection of T cells induced cytolysis of antigenâpositive 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 nonâHBVâspecific T cells, bypassing exhausted HBVâspecific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials
ImmuneâMobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis BâInfected Cells
Background and Aims:
Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBVâspecific 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 affinityâenhanced T Cell receptor with an antiâCD3 T Cellâactivating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virusâderived peptides presented by human leukocyte antigen (HLA).
Approach and Results:
ImmTAV molecules specific for HLAâA*02:01ârestricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAVâEnv to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imagingâbased 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 ImmTAVâEnv can redirect T cells from healthy and HBVâinfected 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, ImmTAVâEnv redirection of T cells induced cytolysis of antigenâpositive 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 nonâHBVâspecific T cells, bypassing exhausted HBVâspecific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials