Department of Immunology, University Hospital Zurich, CH-8091, Zurich, Switzerland.
Institute of Physiology, University of Zurich, CH-8057, Zurich, Switzerland.
Nat Commun. 2020 Dec 22;11(1):6440. doi: 10.1038/s41467-020-20220-1.
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.
正在癌症患者中测试改良的白细胞介素-2 (IL-2) 制剂。然而，IL-2 免疫疗法会损害 IL-2 受体 (IL-2R) 阳性的内皮细胞，并刺激表达 IL-2Rα (CD25) 的淋巴细胞，从而抑制抗肿瘤反应。第一代 IL-2Rβ (CD122)-偏向性的 IL-2 解决了其中的一些缺点。在这里，我们介绍了第二代 CD122-偏向性的 IL-2，它是通过将未突变的人白细胞介素-2 (hIL-2) 分裂并永久嫁接在抗 hIL-2 单克隆抗体 NARA1 的抗原结合槽上而开发的，从而产生了 NARA1leukin。与 hIL-2/NARA1 复合物相比，NARA1leukin 在体内的半衰期更长，完全避免与 CD25 结合，并且更有效地刺激 CD8 T 细胞和自然杀伤细胞。这些作用导致在各种临床前癌症模型中产生强烈的抗肿瘤反应，其中 NARA1leukin 始终优于 hIL-2/NARA1 复合物控制转移性疾病的疗效。总的来说，NARA1leukin 是一种基于未突变 hIL-2 的 CD122-偏向性单分子构建体，对晚期恶性肿瘤具有强大的疗效。
