The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody.
The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody.
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DOI：
10.1371/journal.pone.0253487
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Hanson BJ
中科院分区：
文献类型：
--
作者：
Chan CEZ;Seah SGK;Chye H;Massey S;Torres M;Lim APC;Wong SKK;Neo JJY;Wong PS;Lim JH;Loh GSL;Wang D;Boyd-Kirkup JD;Guan S;Thakkar D;Teo GH;Purushotorman K;Hutchinson PE;Young BE;Low JG;MacAry PA;Hentze H;Prativadibhayankara VS;Ethirajulu K;Comer JE;Tseng CK;Barrett ADT;Ingram PJ;Brasel T;Hanson BJ
尽管SARS-CoV-2中和抗体是对抗COVID-19的有希望的治疗剂，但对其作用机制或有效剂量窗口知之甚少。我们报告的生成和发展的SC 31，一个强大的SARS-CoV-2中和抗体，从康复期患者分离。抗体介导的中和通过SARS-CoV-2刺突蛋白的受体结合结构域内的表位发生。SC 31在多种动物模型中显示出有效的抗SARS-CoV-2活性。在SARS-CoV-2感染的K18-人ACE 2转基因小鼠中，SC 31治疗大大降低了病毒载量，并减弱了与COVID-19严重程度相关的促炎反应。重要的是，SC 31及其Fc-无效LALA变体的功效的比较揭示，除了其中和能力之外，SC 31的最佳治疗功效还需要促进IFNγ驱动的抗病毒免疫应答的Fc-介导的效应子功能。当在病毒诱导的肺部炎症反应之前给药时，观察到SC 31的剂量依赖性功效低至5 mg/kg。此外，即使用亚治疗剂量的SC 31治疗感染小鼠，也没有观察到抗体依赖性增强。在SARS-CoV-2感染的仓鼠中，SC 31治疗显著防止了体重减轻，降低了病毒载量，并减弱了肺部的组织病理学。在恒河猴中，SC 31的治疗潜力通过将上呼吸道和下呼吸道中的病毒载量降低至不可检测的水平而得到证明。总之，我们的临床前研究结果证明了SC 31在三种不同模型中的治疗效果及其作为COVID-19治疗候选药物的潜力。
Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID-19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated pro-inflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2-infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.
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