Exploring Multivalency in the Development of Anti-PD-L1 Peptides for Cancer Immunotherapy.

IF 3.5 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Pharmaceutical Research Pub Date : 2024-12-17 DOI:10.1007/s11095-024-03803-1

Umar-Farouk Mamani, Mohammed Nurudeen Ibrahim, Yanli Liu, John Fetse, Chien-Yu Lin, Sashi Kandel, Maryam Nakhjiri, Sushil Koirala, Yuhan Guo, Mohammed Alahmari, Kun Cheng

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引用次数: 0

Abstract

Purpose: The PD-1/PD-L1 pathway is one of the most effective immune checkpoint pathways utilized for cancer immunotherapy. Despite the success of anti-PD-1/PD-L1 mAbs, there is growing interest in developing low molecular weight anti-PD-1/PD-1 agents, such as peptides, because of their improved tumor penetration. We recently developed a small anti-PD-L1 peptide and demonstrated its promising anti-tumor activity. In this study, we investigate multivalency as a strategy to increase the binding avidity and blocking efficiency of the anti-PD-L1 peptide.

Methods: Multivalent peptide inhibitors are designed with multiple copies of a peptide inhibitor in a single molecule. We synthesized peptides with different valences and examined their activity. We also investigated how spacer length affects the activity of these multivalent peptides.

Results: Using this strategy, we developed a multivalent peptide that demonstrated approximately 40 times higher blocking efficiency and improved stability compared to the original peptide. Increasing the valency enhanced the peptide's specificity, which is essential for minimizing side effects.

Conclusions: Multivalency approach represents a promising platform for improving the efficacy of peptide-based checkpoint inhibitors.

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目的：PD-1/PD-L1 通路是癌症免疫疗法中最有效的免疫检查点通路之一。尽管抗PD-1/PD-L1 mAbs取得了成功，但人们对开发低分子量抗PD-1/PD-1制剂（如多肽）的兴趣与日俱增，因为它们的肿瘤穿透力更强。我们最近开发了一种小型抗 PD-L1 肽，并证明了其具有良好的抗肿瘤活性。在本研究中，我们将多价作为一种策略来提高抗 PD-L1 肽的结合活性和阻断效率：多价肽抑制剂是在单个分子中设计多个拷贝的肽抑制剂。我们合成了不同价位的多肽，并检测了它们的活性。我们还研究了间隔长度如何影响这些多价肽的活性：结果：利用这种策略，我们开发出了一种多价肽，与原始肽相比，它的阻断效率提高了约 40 倍，稳定性也得到了改善。提高多价肽的特异性对减少副作用至关重要：多价方法是提高基于多肽的检查点抑制剂疗效的一个前景广阔的平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.