<br>通过 CDC 介导的机制增强 P29 蛋白靶向单克隆抗体在治疗肺泡包虫病中的治疗潜力,PLoS Pathogens

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通过 CDC 介导的机制增强 P29 蛋白靶向单克隆抗体在治疗肺泡包虫病中的治疗潜力
PLoS Pathogens ( IF 5.5 ) Pub Date : 2024-08-23 , DOI: 10.1371/journal.ppat.1012479
Cuiying Zhang _{1,

2} , Tao Li ₃ , Siyu Hou _{1,

2} , Jing Tang _{1,

2} , Rou Wen _{1,

2} , Chan Wang _{1,

2} , Shiqin Yuan _{1,

2,

4} , Zihua Li ₁ , Wei Zhao _{1,

2}

Affiliation

肺泡包虫病 (AE) 是一种高度致命的蠕虫感染。目前针对 AE 的化疗策略主要涉及使用苯并咪唑 (BZ)，例如甲苯咪唑 (MDZ) 和阿苯达唑 (ABZ)，其疗效有限。在之前的一项研究中，重组细粒棘球绦虫 P29 (rEgP29) 疫苗对小鼠和绵羊均表现出显着的针对细粒棘球绦虫的免疫保护作用。在本研究中，我们利用杂交瘤技术产生了五种针对P29的单克隆抗体（mAb），其中4G10F4 mAb表现出最高的抗原特异性结合能力。选择该 mAb 来进一步研究体内和体外的抗 AE 疗法。在体外，4G10F4 通过补体依赖性细胞毒性 (CDC) 机制抑制了对多房 E. multilularis 原头节和原代细胞活力的显着抑制。在体内，进行了两个实验。在第一个实验中，小鼠腹腔注射Em原头节，随后在感染后12周用4G10F4 mAb（2.5/5/10 mg/kg）通过尾静脉注射每周一次，共8次。与同种型mAb治疗的对照小鼠(2.21±1.30g)相比，仅以5mg/kg剂量用4G10F4mAb治疗的小鼠表现出显着较低的平均寄生虫负荷(0.89±0.97g)。第二个实验中，小鼠经肝门静脉感染，术后一周用4G10F4 mAb（5mg/kg）治疗，每周一次，共8次。 4G10F4治疗组的肝后睾丸病变数量明显低于同种型对照组。病理分析显示，在两个实验中，后绦虫的内部结构都受到严重破坏，特别是影响生发层和层压层，导致在用4G10F4处理后转变为不育囊泡。此外，通过评估小鼠体重以及肝肾功能评估，证实了4G10F4用于AE治疗的安全性。这项研究提出了抗原特异性单克隆抗体免疫疗法作为针对多房阿米巴诱导的 AE 的一种有前途的治疗方法。

"点击查看英文标题和摘要"

Enhancing the therapeutic potential of P29 protein-targeted monoclonal antibodies in the management of alveolar echinococcosis through CDC-mediated mechanisms

Alveolar echinococcosis (AE) is a highly lethal helminth infection. Current chemotherapeutic strategies for AE primarily involve the use of benzimidazoles (BZs) such as mebendazole (MDZ) and albendazole (ABZ), which exhibit limited efficacy. In a previous study, the vaccine of recombinant Echinococcus granulosus P29 (rEgP29) showed significant immunoprotection against E. granulosus in both mice and sheep. In the current study, we utilized hybridoma technology to generate five monoclonal antibodies (mAbs) against P29, among which 4G10F4 mAb exhibited the highest antigen-specific binding capacity. This mAb was selected for further investigation of anti-AE therapy, both in vivo and in vitro. In vitro, 4G10F4 inhibited a noteworthy inhibition of E. multilocularis protoscoleces and primary cells viability through complement-dependent cytotoxicity (CDC) mechanism. In vivo, two experiments were conducted. In the first experiment, mice were intraperitoneally injected with Em protoscoleces, and subsequently treated with 4G10F4 mAb (2.5/5/10 mg/kg) at 12 weeks postinfection once per week for 8 times via tail vein injection. Mice that were treated with 4G10F4 mAb only in dosage of 5mg/kg exhibited a significant lower mean parasite burden (0.89±0.97 g) compared to isotype mAb treated control mice (2.21±1.30 g). In the second experiment, mice were infected through hepatic portal vein and treated with 4G10F4 mAb (5mg/kg) at one week after surgery once per week for 8 times. The numbers of hepatic metacestode lesions of the 4G10F4 treatment group were significantly lower in comparison to the isotype control group. Pathological analysis revealed severe disruption of the inner structure of the metacestode in both experiments, particularly affecting the germinal and laminated layers, resulting in the transformation into infertile vesicles after treatment with 4G10F4. In addition, the safety of 4G10F4 for AE treatment was confirmed through assessment of mouse weight and evaluation of liver and kidney function. This study presents antigen-specific monoclonal antibody immunotherapy as a promising therapeutic approach against E. multilocularis induced AE.

更新日期：2024-08-23

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