Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
Proc Natl Acad Sci U S A. 2022 Jan 25;119(4). doi: 10.1073/pnas.2112887119.
Deep mining of B cell repertoires of HIV-1-infected individuals has resulted in the isolation of dozens of HIV-1 broadly neutralizing antibodies (bNAbs). Yet, it remains uncertain whether any such bNAbs alone are sufficiently broad and potent to deploy therapeutically. Here, we engineered HIV-1 bNAbs for their combination on a single multispecific and avid molecule via direct genetic fusion of their Fab fragments to the human apoferritin light chain. The resulting molecule demonstrated a remarkable median IC value of 0.0009 µg/mL and 100% neutralization coverage of a broad HIV-1 pseudovirus panel (118 isolates) at a 4 µg/mL cutoff-a 32-fold enhancement in viral neutralization potency compared to a mixture of the corresponding HIV-1 bNAbs. Importantly, Fc incorporation on the molecule and engineering to modulate Fc receptor binding resulted in IgG-like bioavailability in vivo. This robust plug-and-play antibody design is relevant against indications where multispecificity and avidity are leveraged simultaneously to mediate optimal biological activity.
对 HIV-1 感染者的 B 细胞 repertoire 进行深入挖掘，已经分离出数十种 HIV-1 广谱中和抗体（bNAbs）。然而，目前仍不确定是否有任何此类 bNAbs 具有足够的广谱性和效力，可用于治疗。在这里，我们通过 Fab 片段与人脱铁铁蛋白轻链的直接基因融合，对 HIV-1 bNAbs 进行工程改造，使其在单个多特异性和高亲和力分子上组合。结果表明，该分子在 4 µg/mL 截点下对广泛的 HIV-1 假病毒面板（118 个分离株）的中位 IC 值为 0.0009 µg/mL，中和率达到 100%，与相应的 HIV-1 bNAbs 混合物相比，病毒中和效力提高了 32 倍。重要的是，该分子上的 Fc 结合和工程改造以调节 Fc 受体结合，导致 IgG 样体内生物利用度。这种强大的即插即用抗体设计与需要同时利用多特异性和亲和力来介导最佳生物学活性的适应症相关。
