CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus

CD8 + T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying CD8 + T cell dysfunction showed that interleukin-2 (IL-2)–based treatment, unlike programmed cell death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential against HBV. However, IL-2’s effectiveness is hindered by its pleiotropic nature, because its receptor is found on various immune cells, including regulatory T (T reg ) cells and natural killer (NK) cells, which can counteract antiviral responses or contribute to toxicity, respectively. To address this, we developed a cis-targeted CD8-IL2 fusion protein, aiming to selectively stimulate dysfunctional CD8 + T cells in chronic HBV. In a mouse model, CD8-IL2 boosted the number of HBV-reactive CD8 + T cells in the liver without substantially altering T reg or NK cell counts. These expanded CD8 + T cells exhibited increased interferon-γ and granzyme B production, demonstrating enhanced functionality. CD8-IL2 treatment resulted in substantial antiviral effects, evidenced by marked reductions in viremia and antigenemia and HBV core antigen–positive hepatocytes. In contrast, an untargeted CTRL-IL2 led to predominant NK cell expansion, minimal CD8 + T cell expansion, negligible changes in effector molecules, and minimal antiviral activity. Human CD8-IL2 trials in cynomolgus monkeys mirrored these results, achieving a roughly 20-fold increase in peripheral blood CD8 + T cells without affecting NK or T reg cell numbers. These data support the development of CD8-IL2 as a therapy for chronic HBV infection.