Exceptionally Potent and Broadly Cross-Reactive, Bispecific Multivalent HIV-1 Inhibitors Based on Single Human CD4 and Antibody Domains
Exceptionally Potent and Broadly Cross-Reactive, Bispecific Multivalent HIV-1 Inhibitors Based on Single Human CD4 and Antibody Domains
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DOI：
10.1128/jvi.02566-13
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发表时间：
2014-01-01
影响因子：
5.4
通讯作者：
Dimitrov, Dimiter S.
中科院分区：
文献类型：
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作者：
Chen, Weizao;Feng, Yang;Dimitrov, Dimiter S.
人类免疫缺陷病毒 1 型 (HIV-1) 主要受体 CD4（可溶性 CD4 [sCD4]）的可溶形式在四分之一个世纪以来已被广泛描述为有前途的 HIV-1 抑制剂，但它们尚未在临床上取得成功。通过结合蛋白质空腔填充策略和库技术的力量，我们鉴定了一种工程化空腔改变的单域 sCD4 (mD1.22)，它具有独特的优异特性组合，包括广泛而有效的中和活性、高特异性、稳定性、溶解度和对 HIV-1 包膜糖蛋白 gp120 的亲和力，以及小分子尺寸。为了进一步提高其中和效力和广度，我们生成了 mD1.22 与另一种有效的 HIV-1 抑制剂（针对 gp120 上的辅助受体结合位点的抗体结构域 (m36.4)）的双特异性多价融合蛋白。这些融合蛋白可中和所有测试的 HIV-1 分离株，其效力分别比广泛中和抗体 VRC01、美国 FDA 批准的肽抑制剂 T20 和临床测试的 sCD4-Fc 融合蛋白 CD4-Ig 高约 10 倍、50 倍和 200 倍。此外，它们比 CD4-Ig 表现出更高的稳定性和特异性以及更低的聚集倾向。因此，mD1.22 和相关融合蛋白可用于 HIV-1 的预防和治疗，包括根除该病毒。
Soluble forms of the human immunodeficiency virus type 1 (HIV-1) primary receptor CD4 (soluble CD4 [sCD4]) have been extensively characterized for a quarter of a century as promising HIV-1 inhibitors, but they have not been clinically successful. By combining a protein cavity-filling strategy and the power of library technology, we identified an engineered cavity-altered single-domain sCD4 (mD1.22) with a unique combination of excellent properties, including broad and potent neutralizing activity, high specificity, stability, solubility, and affinity for the HIV-1 envelope glycoprotein gp120, and small molecular size. To further improve its neutralizing potency and breadth, we generated bispecific multivalent fusion proteins of mD1.22 with another potent HIV-1 inhibitor, an antibody domain (m36.4) that targets the coreceptor-binding site on gp120. The fusion proteins neutralized all HIV-1 isolates tested, with potencies about 10-, 50-, and 200-fold higher than those of the broadly neutralizing antibody VRC01, the U. S. FDA-approved peptide inhibitor T20, and the clinically tested sCD4-Fc fusion protein CD4-Ig, respectively. In addition, they exhibited higher stability and specificity and a lower aggregation propensity than CD4-Ig. Therefore, mD1.22 and related fusion proteins could be useful for HIV-1 prevention and therapy, including eradication of the virus.