Mucosal immunity is dominated by secretory IgA and IgM, although these are less favorable compared to IgG molecules for therapeutic development. Polymeric IgA and IgM are actively transported across the epithelial barrier via engagement of the polymeric Ig receptor (pIgR), but IgG molecules lack a lumen-targeted active transport mechanism, resulting in poor biodistribution of IgG therapeutics in mucosal tissues. In this work, we describe the discovery and characterization of single-domain antibodies (VHH) that engage pIgR and undergo transepithelial transport across the mucosal epithelium. The anti-pIgR VHH panel displayed a broad range of biophysical characteristics, epitope diversity, IgA competition profiles and transcytosis activity in cell and human primary lung tissue models. Making use of this diverse VHH panel, we studied the relationship between biophysical and functional properties of anti-pIgR binders targeting different domains and epitopes of pIgR. These VHH molecules will serve as excellent tools for studying pIgR-mediated transport of biologics and for delivering multispecific IgG antibodies into mucosal lumen, where they can target and neutralize mucosal antigens.

中文翻译：

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单域抗体的发现和表征，该单域抗体可用于生物制品的聚合Ig受体介导的粘膜递送。

粘膜免疫主要由分泌型IgA和IgM决定，尽管与IgG分子相比，它们对治疗的发展不利。聚合的IgA和IgM通过聚合的Ig受体（pIgR）的结合被主动转运穿过上皮屏障，但是IgG分子缺乏以腔为目标的主动转运机制，导致IgG治疗剂在粘膜组织中的生物分布较差。在这项工作中，我们描述了单域抗体（VHH）的发现和表征，这些抗体与pIgR结合并经历跨粘膜上皮的上皮运输。抗pIgR VHH面板在细胞和人原发性肺组织模型中显示出广泛的生物物理特征，表位多样性，IgA竞争概况和转胞吞活性。利用这种多样化的VHH面板，我们研究了针对不同域和pIgR表位的抗pIgR结合物的生物物理和功能特性之间的关系。这些VHH分子将成为研究pIgR介导的生物制剂运输以及将多特异性IgG抗体递送至粘膜腔的有效工具，在那里它们可以靶向并中和粘膜抗原。