Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody
Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody
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DOI：
10.1371/journal.pbio.3000323
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发表时间：
2019-06-01
期刊：
影响因子：
9.8
通讯作者：
Ram, Sanjay
中科院分区：
文献类型：
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作者：
Gulati, Sunita;Beurskens, Frank J.;Ram, Sanjay
多重耐药淋病奈瑟菌是一个全球性的健康问题。单克隆抗体 (mAb) 2C7 可识别淋球菌脂寡糖表位，超过 95% 的临床分离株均表达该表位，并可加速小鼠中淋球菌阴道清除。具有 E430G Fc 修饰的嵌合 mAb 2C7（人免疫球蛋白 G1 [IgG1]）可增强表面靶点结合后的 Fc:Fc 相互作用和六聚化，并增加补体激活（HexaBody 技术），与具有野生型 Fc 的 mAb 2C7 相比，C1q 结合以及 C4 和 C3 沉积显着增强。与 Fc 未修饰的嵌合 2C7 相比，2C7-E430G Fc 更大的补体激活转化为体外杀菌活性增加，因此增强了小鼠的功效。淋球菌以人类特异性方式结合补体抑制剂 H 因子 (FH) 和 C4b 结合蛋白 (C4BP)，从而抑制抗体 (Ab) 介导的补体依赖性杀伤。变体2C7-E430G Fc克服了这些抑制剂在人FH/C4BP转基因小鼠中造成的障碍，单次1μg静脉注射剂量即可清除已建立的感染。衣原体经常与淋病共存并加剧淋病； 2C7-E430G Fc 还被证明对淋病/衣原体共感染小鼠的淋病有效。补体激活对于 2C7 功能来说是必要且充分的，事实证明：(1) 与 Fc gamma 受体 (Fc gamma R) 结合的补体失活 Fc 修饰使 2C7 无效； (2)当C5功能被阻断时，2C7在C1q(-/-)小鼠或C9(-/-)小鼠中失去功能； (3) 2C7 在中性粒细胞耗尽的小鼠和用 C5a 受体 (C5aR1) 抑制剂 PMX205 治疗的小鼠中仍然有效。我们强调补体激活对于生殖道抗淋球菌抗体功能的重要性。阐明淋病保护的相关性将为基于抗体的淋球菌疫苗和免疫治疗的开发提供信息。
Multidrug-resistant Neisseria gonorrhoeae is a global health problem. Monoclonal antibody (mAb) 2C7 recognizes a gonococcal lipooligosaccharide epitope that is expressed by >95% of clinical isolates and hastens gonococcal vaginal clearance in mice. Chimeric mAb 2C7 (human immunoglobulin G1 [IgG1]) with an E430G Fc modification that enhances Fc:Fc interactions and hexamerization following surface-target binding and increases complement activation (HexaBody technology) showed significantly greater C1q engagement and C4 and C3 deposition compared to mAb 2C7 with wild-type Fc. Greater complement activation by 2C7-E430G Fc translated to increased bactericidal activity in vitro and, consequently, enhanced efficacy in mice, compared with Fc-unmodified chimeric 2C7. Gonococci bind the complement inhibitors factor H (FH) and C4b-binding protein (C4BP) in a human-specific manner, which dampens antibody (Ab)-mediated complement-dependent killing. The variant 2C7-E430G Fc overcame the barrier posed by these inhibitors in human FH/C4BP transgenic mice, for which a single 1 mu g intravenous dose cleared established infection. Chlamydia frequently coexists with and exacerbates gonorrhea; 2C7-E430G Fc also proved effective against gonorrhea in gonorrhea/chlamydia-coinfected mice. Complement activation alone was necessary and sufficient for 2C7 function, evidenced by the fact that (1) complement-inactive Fc modifications that engaged Fc gamma receptor (Fc gamma R) rendered 2C7 ineffective, nonetheless; (2) 2C7 was nonfunctional in C1q(-/-) mice, when C5 function was blocked, or in C9(-/-) mice; and (3) 2C7 remained effective in neutrophil-depleted mice and in mice treated with PMX205, a C5a receptor (C5aR1) inhibitor. We highlight the importance of complement activation for antigonococcal Ab function in the genital tract. Elucidating the correlates of protection against gonorrhea will inform the development of Ab-based gonococcal vaccines and immunotherapeutics.