Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
Medical Research Council (MRC) Antibody Immunity Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Front Immunol. 2021 Sep 16;12:734110. doi: 10.3389/fimmu.2021.734110. eCollection 2021.
Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitates vector-driven gene expression. We have previously shown that scFv of bNAbs individually retain significant breadth and potency. Here we tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface) and 10E8v4 (MPER). Either two or three scFv were combined in equimolar amounts and tested in the TZM-bl neutralization assay against a multiclade panel of 17 viruses. Experimental IC and IC data were compared to predicted neutralization titers based on single scFv titers using the Loewe additive and the Bliss-Hill model. Like full-sized antibodies, combinations of scFv showed significantly improved potency and breadth compared to single scFv. Combinations of two or three scFv generally followed an independent action model for breadth and potency with no significant synergy or antagonism observed overall although some exceptions were noted. The Loewe model underestimated potency for some dual and triple combinations while the Bliss-Hill model was better at predicting IC titers of triple combinations. Given this, we used the Bliss-Hill model to predict the coverage of scFv against a 45-virus panel at concentrations that correlated with protection in the AMP trials. Using IC titers and concentrations of 1μg/mL, there was 93% coverage for one dual scFv combination (3BNC117+10E8v4), and 96% coverage for two of the triple combinations (CAP256.25+3BNC117+10E8v4 and PGT121+3BNC117+10E8v4). Combinations of scFv, therefore, show significantly improved breadth and potency over individual scFv and given their size advantage, have potential for use in passive immunization.
广谱中和抗体（bnAb）目前正在临床试验中评估其预防 HIV 感染的能力。bnAb 的单链可变片段（scFv）比完整抗体具有优势，因为其较小的尺寸允许更好地扩散到黏膜组织，并促进载体驱动的基因表达。我们之前已经表明，bnAb 的 scFv 单独保留了显著的广度和效力。在这里，我们测试了来自 bnAb CAP256-VRC26.25（V2-尖端）、PGT121（N332-超站点）、3BNC117（CD4bs）、8ANC195（gp120-gp41 界面）和 10E8v4（MPER）的五个 scFv 的组合。以等摩尔量组合两个或三个 scFv，并在 TZM-bl 中和测定中针对多谱系 17 种病毒的面板进行测试。实验 IC 和 IC 数据与基于单个 scFv 滴度使用 Loewe 加性和 Bliss-Hill 模型预测的中和效价进行了比较。与完整抗体一样，scFv 的组合显示出与单个 scFv 相比，效力和广度显著提高。两个或三个 scFv 的组合通常遵循独立作用模型，无论是在广度还是效力方面，都没有观察到明显的协同作用或拮抗作用，尽管有一些例外。Loewe 模型低估了一些双重和三重组合的效力，而 Bliss-Hill 模型在预测三重组合的 IC 滴度方面更好。有鉴于此，我们使用 Bliss-Hill 模型来预测 scFv 在浓度与 AMP 试验中保护相关的 45 种病毒面板上的覆盖率。使用 IC 滴度和 1μg/mL 的浓度，一种双重 scFv 组合（3BNC117+10E8v4）的覆盖率为 93%，两种三重组合（CAP256.25+3BNC117+10E8v4 和 PGT121+3BNC117+10E8v4）的覆盖率为 96%。因此，scFv 的组合在广度和效力方面明显优于单个 scFv，并且由于其尺寸优势，具有被动免疫的潜力。
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