An IL-2-grafted antibody immunotherapy with potent efficacy against metastatic cancer

Modified interleukin-2 (IL-2) formulations are being tested in cancer patients. However, IL-2 immunotherapy damages IL-2 receptor (IL-2R)-positive endothelial cells and stimulates IL-2R alpha (CD25)-expressing lymphocytes that curtail anti-tumor responses. A first generation of IL-2R beta (CD122)-biased IL-2s addressed some of these drawbacks. Here, we present a second-generation CD122-biased IL-2, developed by splitting and permanently grafting unmutated human IL-2 (hIL-2) to its antigen-binding groove on the anti-hIL-2 monoclonal antibody NARA1, thereby generating NARA1leukin. In comparison to hIL-2/NARA1 complexes, NARA1leukin shows a longer in vivo half-life, completely avoids association with CD25, and more potently stimulates CD8(+) T and natural killer cells. These effects result in strong anti-tumor responses in various pre-clinical cancer models, whereby NARA1leukin consistently surpasses the efficacy of hIL-2/NARA1 complexes in controlling metastatic disease. Collectively, NARA1leukin is a CD122-biased single-molecule construct based on unmutated hIL-2 with potent efficacy against advanced malignancies. IL-2/anti-IL-2 complexes have been proposed to curtail the severe adverse effects associated with IL-2 immunotherapy. Here, the authors, by integrating unmutated human IL-2 in the antigen binding groove of an anti-IL-2 monoclonal antibody, generate a CD122-biased fusion protein that prevents binding of IL-2 to CD25 and promotes anti-tumor immune response in several preclinical metastatic cancer models.