Division of Monoclonal Antibody Products, National Institutes for Food and Drug Control, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Beijing, China.
Department of Molecular Biology, Beijing Wisdomab Biotechnology Co., Ltd., Beijing, China.
J Med Virol. 2023 Aug;95(8):e29016. doi: 10.1002/jmv.29016.
Rabies is a zoonotic viral disease characterized by an almost 100% fatality rate once symptoms appear. However, it can be prevented through timely postexposure prophylaxis (PEP). Currently, there is a growing trend to replace polyclonal rabies immune globulin (RIG) with monoclonal antibodies (mAbs) in rabies PEP. In this study, we developed a human bispecific antibody, GR1801, by combining two mAbs, A2 and B353, which target distinct epitopes. GR1801 is an asymmetric immunoglobulin G1 molecule, with one arm (A2 targeting epitope III) in fragment antigen-binding (Fab) form and the other arm (B353 targeting epitope I) in single-chain variable fragment (scFv) form, constructed using Knobs-into-Holes technology. GR1801 demonstrated the ability to neutralize 90 naturally occurring rabies virus (RABV) glycoprotein antigenic variants, 21 pseudotyped, and 18 live street RABVs, exhibiting broad-spectrum neutralizing activity. In vivo, GR1801 provided protection equivalent to that of human RIG in golden hamsters challenged with lethal RABV. In conclusion, these findings demonstrate the neutralization potency and breadth of GR1801, which can be a promising candidate drug for rabies PEP, and a comprehensive testing against a broad spectrum of Chinese prevalent RABVs will be investigated in great detail in the future for the in vitro and in vivo studies.
狂犬病是一种由动物传播的病毒性疾病，一旦出现症状，死亡率几乎达到 100%。然而，它可以通过及时的暴露后预防（PEP）来预防。目前，在狂犬病 PEP 中，用单克隆抗体（mAbs）替代多克隆狂犬病免疫球蛋白（RIG）的趋势日益增长。在这项研究中，我们通过结合两种针对不同表位的 mAbs（A2 和 B353），开发了一种人源双特异性抗体 GR1801。GR1801 是一种不对称的 IgG1 分子，其中一个臂（靶向表位 III 的 A2）为 Fab 形式，另一个臂（靶向表位 I 的 B353）为单链可变片段（scFv）形式，使用 Knobs-into-Holes 技术构建。GR1801 表现出中和 90 种天然狂犬病病毒（RABV）糖蛋白抗原变异体、21 种假型和 18 种活街 RABV 的能力，显示出广谱中和活性。在体内，GR1801 在受致死性 RABV 攻击的金黄地鼠中提供的保护与人类 RIG 相当。总之，这些发现表明了 GR1801 的中和效力和广度，它可能是狂犬病 PEP 的一种有前途的候选药物，未来将对广泛的中国流行 RABV 进行全面测试，以详细研究其体外和体内研究。
