Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Microbiology-Immunology, Albert Einstein College of Medicine, New York, New York, USA.
J Clin Invest. 2023 Feb 1;133(3):e161968. doi: 10.1172/JCI161968.
There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2-vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo-electron microscopic structure of the Fab-glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.
目前，临床上急需能够预防或辅助治疗单纯疱疹病毒（HSV）疾病的单克隆抗体（mAbs）。大多数疫苗和 mAb 研究都集中在中和抗体上，但对于 HSV，这种策略已被证明无效。候选 HSV 疫苗株 ΔgD-2 的临床前研究表明，能够激活 Fcγ 受体（FcγRs）从而介导抗体依赖性细胞毒性（ADCC）的非中和抗体，可提供针对 HSV-1 和 HSV-2 的主动和被动保护。我们假设该疫苗为鉴定和表征保护性 mAbs 提供了一种工具。我们从 ΔgD-2 疫苗接种小鼠的生发中心和记忆 B 细胞以及骨髓浆细胞中分离出 HSV 特异性 mAbs，并评估了这些 mAbs 的结合、中和和 FcγR 激活活性，以及在小鼠中的保护效力。最有效的保护性 mAb BMPC-23 不具有中和作用，但能激活小鼠 FcγRIV，这是 ADCC 的生物标志物。Fab-糖蛋白 B（gB）复合物的低温电子显微镜结构确定了 gB 的结构域 IV 为抗原表位。在病毒攻击前 24 小时或后 24 小时给予单次剂量的 BMPC-23，以鼠 IgG2c 形式给药时具有显著的保护作用，当设计为人 IgG1 并在表达人 FcγRIII 的小鼠中时也具有保护作用。这些结果强调了 FcR 激活抗体在预防 HSV 中的重要性。
