Young Patricia A, Morrison Sherie L, Timmerman John M
Division of Hematology & Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA.
Semin Oncol. 2014 Oct;41(5):623-36. doi: 10.1053/j.seminoncol.2014.08.002. Epub 2014 Aug 12.
The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing interleukin (IL)-2, IL-12, IL-21, tumor necrosis factor (TNF)α, and interferons (IFNs) α, β, and γ have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results.
由于剂量限制性全身毒性，无法将最佳浓度的细胞因子输送到肿瘤部位，这限制了细胞因子疗法在癌症治疗中的真正潜力。为了使细胞因子疗法的疗效最大化，多个研究小组构建了重组抗体-细胞因子融合蛋白，以利用单克隆抗体的肿瘤靶向能力。目的是将细胞因子特异性地引导至肿瘤部位，在那里它们可能刺激更理想的抗肿瘤免疫反应，同时避免游离细胞因子疗法的全身毒性。含有白细胞介素（IL）-2、IL-12、IL-21、肿瘤坏死因子（TNF）α以及干扰素（IFN）α、β和γ的抗体-细胞因子融合蛋白已被构建出来，并在临床前和早期临床研究中显示出抗肿瘤活性。该技术未来的发展重点包括优化肿瘤靶向、融合细胞因子的生物活性以及选择合适的联合治疗药物。本综述旨在作为构建理想抗体-细胞因子融合蛋白的框架，重点关注先前开发的构建体及其临床试验结果。
