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

Abstract

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-2Rα (CD25)-expressing lymphocytes that curtail anti-tumor responses. A first generation of IL-2Rβ (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.

Interleukins in cancer: from biology to therapy

“…NARA1leukin is a fusion construct that consists of human IL2 engineered into the antiIL2 antibody NARA1. NARA1 thereby permanently masks the CD25binding site of IL2 and thus abolishes the CD25 mediated T reg cell development, while mediating potent antitumour responses in a murine melanoma model 188 .…”

Role of the tumor immune microenvironment in tumor immunotherapy (Review)

“…Second-generation IL-2 based on CD122 can induce the production of NARA1 interleukin. NARA1 with longer half-life in vivo can completely avoid binding to CD25 and stimulate proliferation and activation of CD8 + T cells and NK cells more effectively ( 62 ).…”

Interleukins in the treatment of melanoma

“…These effects led to stronger antitumor responses in B16-F10 murine models, whereby NARA1leukin exceeded the efficacy of IL-2/NARA1 complexes in melanoma metastasis. [22] Collectively, these data demonstrate that engineered IL-2 variants, such as NARA1 or NARA1leukin, may reduce the toxicity and increase the efficacy of treatment in melanoma.…”