Monoclonal antibodies targeting surface exposed epitopes of Candida albicans cell wall proteins confer in vivo protection in an infection model
Monoclonal antibodies targeting surface exposed epitopes of Candida albicans cell wall proteins confer in vivo protection in an infection model
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针对白色念珠菌细胞壁蛋白表面暴露表位的单克隆抗体在感染模型中提供体内保护
DOI：
10.1101/2021.09.29.462385
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Palliyil S
中科院分区：
文献类型：
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作者：
Palliyil S
针对全身性和深部真菌感染的基于单克隆抗体（mAb）的免疫疗法仍处于早期开发阶段，目前尚无许可的抗真菌mAb可用于风险患者。白色念珠菌的细胞壁糖蛋白由于其细胞外位置和在真菌发病机制中的关键参与而作为治疗性抗体产生的潜在靶标特别令人感兴趣。在这里，我们描述了特异性靶向两个关键细胞壁蛋白（CWP）的重组人抗体在C。白色念珠菌：Utr 2和Pga 31。这些抗体是从噬菌体展示抗体库中分离的，使用肽抗原代表体内感染期间以升高水平表达的CWP的表面暴露区域。重组人-鼠嵌合单抗优先识别C.与酵母细胞相比，白色念珠菌菌丝形成，并且当细胞在抗真菌剂卡泊芬净存在下生长时，观察到增加的结合。在J774.1巨噬细胞相互作用试验中，mAb预处理导致C.白色念珠菌细胞，提示在吞噬细胞募集过程中CWP抗体作为调理剂的作用。最后，在一系列全身性念珠菌病的临床预测小鼠模型中，我们的领先mAb实现了生存率的提高（83%）和肾脏真菌负荷的对数减少，与杀真菌药物卡泊芬净的水平相似，并且上级优于迄今报道的任何抗念珠菌单抗的治疗效果。
Monoclonal antibody (mAb)-based immunotherapies targeting systemic and deep-seated fungal infections are still in their early stages of development, with no licensed antifungal mAbs currently being available for patients at risk. The cell wall glycoproteins of Candida albicans are of particular interest as potential targets for therapeutic antibody generation due to their extracellular location and key involvement in fungal pathogenesis. Here, we describe the generation of recombinant human antibodies specifically targeting two key cell wall proteins (CWPs) in C. albicans: Utr2 and Pga31. These antibodies were isolated from a phage display antibody library using peptide antigens representing the surface-exposed regions of CWPs expressed at elevated levels duringin vivoinfection. Reformatted human-mouse chimeric mAbs preferentially recognized C. albicans hyphal forms compared to yeast cells, and increased binding was observed when the cells were grown in the presence of the antifungal agent caspofungin. In J774.1 macrophage interaction assays, mAb pretreatment resulted in the faster engulfment of C. albicans cells, suggesting a role of the CWP antibodies as opsonizing agents during phagocyte recruitment. Finally, in a series of clinically predictive mouse models of systemic candidiasis, our lead mAb achieved improved survival (83%) and a several-log reduction of the fungal burden in the kidneys, similar to the levels achieved for the fungicidal drug caspofungin and superior to the therapeutic efficacy of any anti-CandidamAb reported to date.