TY - JOUR
T1 - Immune-Mobilizing Monoclonal T Cell Receptors Mediate Specific and Rapid Elimination of Hepatitis B–Infected Cells
AU - Fergusson, Joannah R.
AU - Wallace, Zoë
AU - Connolly, Mary M.
AU - Woon, Amanda P.
AU - Suckling, Richard J.
AU - Hine, Dominic W.
AU - Barber, Claire
AU - Bunjobpol, Wilawan
AU - Choi, Beak San
AU - Crespillo, Sara
AU - Dembek, Marcin
AU - Dieckmann, Nele
AU - Donoso, Jose
AU - Godinho, Luis F.
AU - Grant, Tressan
AU - Howe, Dawn
AU - McCully, Michelle L.
AU - Perot, Carole
AU - Sarkar, Anshuk
AU - Seifert, Florian U.
AU - Singh, Praveen K.
AU - Stegmann, Kerstin A.
AU - Turner, Bethany
AU - Verma, Anil
AU - Walker, Andrew
AU - Leonard, Sarah
AU - Maini, Mala K.
AU - Wiederhold, Katrin
AU - Dorrell, Lucy
AU - Simmons, Ruth
AU - Knox, Andrew
N1 - Publisher Copyright:
© 2020 Immunocore Ltd. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85095411280&partnerID=8YFLogxK
U2 - 10.1002/hep.31503
DO - 10.1002/hep.31503
M3 - Article
C2 - 32770836
AN - SCOPUS:85095411280
SN - 0270-9139
VL - 72
SP - 1528
EP - 1540
JO - Hepatology
JF - Hepatology
IS - 5
ER -
