Wang Xiaojuan, Liu Peng, Jiang Yuanying, Han Bing, Yan Lan
School of Pharmacy, Naval Medical University, Shanghai, China.
Department of Pharmacy, Minhang Hospital, Fudan University, Shanghai, China.
Front Microbiol. 2022 Aug 23;13:992275. doi: 10.3389/fmicb.2022.992275. eCollection 2022.
() is the most prevalent opportunistic human pathogen, accounting for approximately half of all clinical cases of candidemia. Resistance to the existing antifungal drugs is a major challenge in clinical therapy, necessitating the development and identification of novel therapeutic agents and potential treatment strategies. Monoclonal antibody-based immunotherapy represents a promising therapeutic strategy against disseminated candidiasis. Protein mannosyltransferase (Pmt4) encodes mannosyltransferases initiating O-mannosylation of secretory proteins and is essential for cell wall composition and virulence of . Therefore, the Pmt4 protein of is an attractive target for the discovery of alternative antibody agents against invasive infections. In the present study, we found that monoclonal antibodies (mAbs) C12 and C346 specifically targeted the recombinant protein mannosyltransferase 4 (rPmt4p) of . These mAbs were produced and secreted by hybridoma cells isolated from the spleen of mice that were initially immunized with the purified rPmt4p to generate IgG antibodies. The mAbs C12 and C346 exhibited high affinity to whole cells. Remarkably, these mAbs reduced the fungal burden, alleviated inflammation in the kidneys, and prolonged the survival rate significantly in the murine model of systemic candidiasis. Moreover, they could activate macrophage opsonophagocytic killing and neutrophil killing of strain . These results suggested that anti-rPmt4p mAbs may provide immunotherapeutic interventions against disseminated candidiasis opsonophagocytosis and opsonic killing activity. Our findings provide evidence for mAbs as a therapeutic option for the treatment of invasive candidiasis.
（某真菌名称）是最常见的人类机会性病原菌，约占所有念珠菌血症临床病例的一半。对现有抗真菌药物的耐药性是临床治疗中的一项重大挑战，因此需要开发和鉴定新型治疗药物及潜在治疗策略。基于单克隆抗体的免疫疗法是一种针对播散性念珠菌病的有前景的治疗策略。蛋白质甘露糖基转移酶（Pmt4）编码启动分泌蛋白O-甘露糖基化的甘露糖基转移酶，对（某真菌名称）的细胞壁组成和毒力至关重要。因此，（某真菌名称）的Pmt4蛋白是发现针对侵袭性（某真菌名称）感染的替代抗体药物的一个有吸引力的靶点。在本研究中，我们发现单克隆抗体（mAbs）C12和C346特异性靶向（某真菌名称）的重组蛋白甘露糖基转移酶4（rPmt4p）。这些单克隆抗体由从最初用纯化的rPmt4p免疫以产生IgG抗体的小鼠脾脏中分离的杂交瘤细胞产生和分泌。单克隆抗体C12和C346对（某真菌名称）全细胞表现出高亲和力。值得注意的是，这些单克隆抗体降低了真菌负荷，减轻了肾脏炎症，并在系统性念珠菌病小鼠模型中显著延长了存活率。此外，它们可以激活巨噬细胞调理吞噬杀伤作用和中性粒细胞对（某真菌名称）菌株的杀伤作用。这些结果表明，抗rPmt4p单克隆抗体可能通过调理吞噬作用和调理杀伤活性为播散性念珠菌病提供免疫治疗干预。我们的研究结果为单克隆抗体作为治疗侵袭性念珠菌病的一种治疗选择提供了证据。
