Nektar Therapeutics, San Francisco, California 94103, USA; email:
Annu Rev Med. 2021 Jan 27;72:281-311. doi: 10.1146/annurev-med-073118-011031. Epub 2020 Nov 6.
Interleukin-2 (IL-2) is integral to immune system regulation. Its opposing immunostimulatory and immunosuppressive actions make it an attractive therapeutic target for cancer and autoimmune diseases. A challenge in developing IL-2-directed anticancer therapies has been how to stimulate effector T cells (Teffs) without inducing regulatory T cells (Tregs) in the tumor microenvironment; conversely, IL-2 therapy for autoimmune diseases requires Treg induction without further stimulation of Teffs. High-dose IL-2 is approved for melanoma and renal cell carcinoma, but its therapeutic value is limited by a need for frequent dosing at specialist centers, its short half-life, severe toxicity, and a lack of efficacy in most patients. Re-engineered IL-2 therapeutics are designed to have longer in vivo half-lives, target specific IL-2 receptor conformations to stimulate specific T cell subsets, or localize to target tissues to optimize efficacy and reduce toxicity. We discuss recent studies that elucidate the potential of newly engineered IL-2-based therapeutics for cancer and autoimmune diseases.
白细胞介素-2（IL-2）是免疫系统调节的重要组成部分。它具有免疫刺激和免疫抑制的双重作用，使其成为癌症和自身免疫性疾病的有吸引力的治疗靶点。在开发针对白细胞介素-2 的抗癌疗法方面的一个挑战是如何在肿瘤微环境中刺激效应 T 细胞（Teffs）而不诱导调节性 T 细胞（Tregs）；相反，IL-2 治疗自身免疫性疾病需要诱导 Treg，而不进一步刺激 Teffs。高剂量的白细胞介素-2 已被批准用于治疗黑色素瘤和肾细胞癌，但由于需要在专科中心频繁给药、半衰期短、毒性严重以及大多数患者疗效不佳，其治疗价值有限。经过重新设计的白细胞介素-2 治疗药物旨在具有更长的体内半衰期，针对特定的白细胞介素-2 受体构象以刺激特定的 T 细胞亚群，或定位到靶组织以优化疗效并降低毒性。我们讨论了最近的研究，这些研究阐明了新型工程化基于白细胞介素-2 的治疗药物在癌症和自身免疫性疾病中的潜力。
