短 FcRn 结合肽能够挽救和转胞吞 scFv 抗体片段,ACS Chemical Biology

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短 FcRn 结合肽能够挽救和转胞吞 scFv 抗体片段
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2022-01-20 , DOI: 10.1021/acschembio.1c00862
Vince W Kelly ₁ , Shannon J Sirk _{1,

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Affiliation

治疗性抗体由于其独特的抗原特异性和针对多种疾病靶标进行工程改造的能力，已成为使用最广泛的生物治疗药物之一。利用截短的抗体片段作为治疗剂引起了人们的极大兴趣，因为它们的小尺寸提供了有利的特性，例如增加了肿瘤渗透以及利用低成本原核生产方法的能力。然而，它们的小尺寸和简单的结构也会导致快速的血液清除，从而限制了这些潜在强大疗法的功效。规避这些限制的一种常见方法是启用延长半衰期的新生儿 Fc 受体 (FcRn)。这通常是通过与大的 Fc 结构域融合来实现的，这抵消了抗体片段小尺寸的好处。在这项工作中，我们展示了用模拟天然 IgG 与 FcRn 结合的短 FcRn 结合肽结构域修饰抗体片段能够在基于细胞的测定中实现结合和 FcRn 介导的再循环和跨膜转胞吞作用。此外，我们表明肽序列的合理的单氨基酸突变对受体介导的功能具有显着影响，并使用计算模型研究了这种影响的潜在结构基础。最后，我们报告了从人血清白蛋白中鉴定出一种短肽，当移植到单链可变片段 (scFv) 支架上时，它能够实现 FcRn 介导的功能，

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Short FcRn-Binding Peptides Enable Salvage and Transcytosis of scFv Antibody Fragments

Therapeutic antibodies have become one of the most widely used classes of biotherapeutics due to their unique antigen specificity and their ability to be engineered against diverse disease targets. There is significant interest in utilizing truncated antibody fragments as therapeutics, as their small size affords favorable properties such as increased tumor penetration as well as the ability to utilize lower-cost prokaryotic production methods. Their small size and simple architecture, however, also lead to rapid blood clearance, limiting the efficacy of these potentially powerful therapeutics. A common approach to circumvent these limitations is to enable engagement with the half-life extending neonatal Fc receptor (FcRn). This is usually achieved via fusion with a large Fc domain, which negates the benefits of the antibody fragment’s small size. In this work, we show that modifying antibody fragments with short FcRn-binding peptide domains that mimic native IgG engagement with FcRn enables binding and FcRn-mediated recycling and transmembrane transcytosis in cell-based assays. Further, we show that rational, single amino acid mutations to the peptide sequence have a significant impact on the receptor-mediated function and investigate the underlying structural basis for this effect using computational modeling. Finally, we report the identification of a short peptide from human serum albumin that enables FcRn-mediated function when grafted onto a single-chain variable fragment (scFv) scaffold, establishing an approach for the rational selection of short-peptide domains from full-length proteins that could enable the transfer of non-native functions to small recombinant proteins without significantly impacting their size or structure.

更新日期：2022-01-20

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