Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, Krakow, 30-387, Poland.
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, Wrocław, 50-370, Poland.
Mol Cancer. 2023 Sep 7;22(1):150. doi: 10.1186/s12943-023-01853-4.
Recent advances in immuno-oncology have opened up new and impressive treatment options for cancer. Notwithstanding, overcoming the limitations of the current FDA-approved therapies with monoclonal antibodies (mAbs) that block the PD-1/PD-L1 pathway continues to lead to the testing of multiple approaches and optimizations. Recently, a series of macrocyclic peptides have been developed that exhibit binding strengths to PD-L1 ranging from sub-micromolar to micromolar. In this study, we present the most potent non-antibody-based PD-1/PD-L1 interaction inhibitor reported to date. The structural and biological characterization of this macrocyclic PD-L1 targeting peptide provides the rationale for inhibition of both PD-1/PD-L1 and CD80/PD-L1 complexes. The IC and EC values obtained in PD-L1 binding assays indicate that the pAC65 peptide has potency equivalent to the current FDA-approved mAbs and may have similar activity to the BMS986189 peptide, which entered the clinical trial and has favorable safety and pharmacokinetic data. The data presented here delineate the generation of similar peptides with improved biological activities and applications not only in the field of cancer immunotherapy but also in other disorders related to the immune system.
免疫肿瘤学的最新进展为癌症治疗开辟了新的、令人印象深刻的选择。尽管如此，为了克服当前 FDA 批准的单克隆抗体（mAbs）阻断 PD-1/PD-L1 通路的治疗方法的局限性，仍在不断尝试多种方法和优化方案。最近，已经开发出一系列对 PD-L1 具有亚毫摩尔至毫摩尔结合强度的大环肽。在这项研究中，我们报告了迄今为止报道的最有效的非抗体 PD-1/PD-L1 相互作用抑制剂。这种大环 PD-L1 靶向肽的结构和生物学特性为抑制 PD-1/PD-L1 和 CD80/PD-L1 复合物提供了依据。在 PD-L1 结合测定中获得的 IC 和 EC 值表明，pAC65 肽具有与当前 FDA 批准的 mAbs 相当的效力，并且可能与 BMS986189 肽具有相似的活性，后者已进入临床试验，具有良好的安全性和药代动力学数据。这里提供的数据描述了具有改进的生物学活性的类似肽的产生，不仅在癌症免疫治疗领域，而且在与免疫系统相关的其他疾病领域都具有应用前景。
