James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA; Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA; Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
Mol Ther. 2019 Nov 6;27(11):2038-2052. doi: 10.1016/j.ymthe.2019.07.021. Epub 2019 Aug 9.
High-mannose-type glycans (HMGs) are aberrantly enriched on HIV envelope glycoproteins. However, there is currently no drug selectively targeting HIV-associated HMGs. Here, we describe a novel HMG-targeting "lectibody," a recombinant Fc-fusion protein comprising human IgG1 Fc and a novel actinohivin lectin variant (Avaren) obtained by structure-guided modifications for improved overall surface charge properties (AvFc). AvFc was engineered and produced using a rapid and scalable plant-based transient overexpression system. The lectibody exhibited potent antiviral activity against HIV-1 groups M and O primary viruses, as well as HIV-2 and simian immunodeficiency virus (SIV) strains, without affecting normal human blood cells. Furthermore, the lectibody induced Fc-mediated cell killing activity against HIV-1-infected cells and selectively recognized SIVmac239-infected macaque mesenteric lymph node cells in vitro. AvFc showed an extended serum half-life in rats and rhesus macaques, while no discernible toxicity was observed upon repeated systemic dosing in mice. These results highlight AvFc's potential as a biotherapeutic targeting HIV-associated HMGs of cell-free virions, as well as productively infected cells, providing a foundation for new anti-HIV strategies. Efficient and cost-effective bioproduction in greenhouse facilities may open unique possibilities for further development of AvFc.
高甘露糖型聚糖 (HMGs) 在 HIV 包膜糖蛋白上异常富集。然而，目前尚无专门针对与 HIV 相关的 HMGs 的药物。在这里，我们描述了一种新型的 HMG 靶向“lectibody”，它是一种由人 IgG1 Fc 和一种通过结构指导修饰获得的新型肌动蛋白 HIV 素 lectin 变体 (Avaren) 组成的重组 Fc 融合蛋白，用于改善整体表面电荷特性（AvFc）。AvFc 是使用快速且可扩展的植物瞬时过表达系统进行工程设计和生产的。该 lectibody 对 HIV-1 组 M 和 O 原发性病毒以及 HIV-2 和猴免疫缺陷病毒 (SIV) 株表现出强大的抗病毒活性，而不会影响正常的人类血细胞。此外，该 lectibody 在体外诱导针对 HIV-1 感染细胞的 Fc 介导的细胞杀伤活性，并选择性识别 SIVmac239 感染的猕猴肠系膜淋巴结细胞。AvFc 在大鼠和恒河猴中表现出延长的血清半衰期，而在小鼠中重复全身给药时未观察到明显的毒性。这些结果突出了 AvFc 作为一种针对无细胞病毒和感染性细胞中 HIV 相关 HMGs 的生物治疗药物的潜力，为新的抗 HIV 策略提供了基础。在温室设施中高效且具有成本效益的生物生产可能为进一步开发 AvFc 开辟独特的可能性。
