Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques.
Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques.
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DOI：
10.1371/journal.pntd.0005637
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发表时间：
2017-06
影响因子：
3.8
通讯作者：
Streblow DN
中科院分区：
文献类型：
--
作者：
Broeckel R;Fox JM;Haese N;Kreklywich CN;Sukulpovi-Petty S;Legasse A;Smith PP;Denton M;Corvey C;Krishnan S;Colgin LMA;Ducore RM;Lewis AD;Axthelm MK;Mandron M;Cortez P;Rothblatt J;Rao E;Focken I;Carter K;Sapparapau G;Crowe JE Jr;Diamond MS;Streblow DN
基孔肯雅病毒（CHIKV）是一种蚊媒病毒，可引起人类发热综合征，伴有急性和慢性使人衰弱的关节和肌肉疼痛。目前没有获得许可的疫苗或疗法可用于预防或治疗CHIKV感染。我们最近分离了一组强中和的人单克隆抗体（mab），其中一种（4N12）在免疫功能低下的小鼠中表现出对CHIKV的预防和暴露后治疗活性。在这里，我们描述了一种工程的CHIKV单抗的开发，命名为SVIR001，具有与其亲本4N12相似的抗原结合和中和谱。由于在免疫功能正常的小鼠中治疗性给予SVIR001可显著降低关节组织中的病毒载量，因此我们在恒河猴CHIKV感染模型中评估了其疗效。与用SVIR002（一种同型对照单抗）治疗的恒河猴相比，用SVIR001治疗后的恒河猴表现出病毒血症的快速消除，关节浸润和疾病的严重程度较轻。SVIR001降低了感染部位和远处部位的病毒负担，也减少了激活的先天免疫细胞的数量和促炎细胞因子和趋化因子的水平。SVIR001疗法;然而，并没有实质性地减少对chikv特异性B细胞或T细胞反应的诱导。总的来说，这些结果表明人类抗CHIKV单抗在恒河猴中具有良好的治疗活性，并为其可能用于人类治疗活动性CHIKV感染提供了原理证明。基孔肯雅病毒（CHIKV）引起发烧、皮疹以及急性和慢性关节痛。目前还没有批准的治疗方法或疫苗来预防人类感染CHIKV病毒。在这项研究中，我们设计了SVIR001，一种重组的全人源单克隆抗体（mAb），可以消除病毒血症，降低感染部位的病毒载量，并在感染后在恒河猴体内减少向远处靶组织的传播。SVIR001治疗减少了关节炎症和疾病，而不损害适应性免疫反应的诱导。这些结果证明了单克隆抗体治疗降低CHIKV疾病严重程度的有效性。
Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections. Chikungunya virus (CHIKV) causes fever, rash, and acute and chronic arthralgia. Currently there are no approved therapies to treat or vaccines to prevent CHIKV infection in humans. In this study, we engineered SVIR001, a recombinant fully human monoclonal antibody (mAb) that eliminated viremia, reduced viral load at the site of infection, and diminished spread to distant target tissues in rhesus macaques when administered after infection. SVIR001 treatment reduced joint inflammation and disease without impairing the induction of the adaptive immune response. These results demonstrate the efficacy of mAb therapy to reduce the severity of CHIKV disease.