IgG Fc-binding motif-conjugated HIV-1 fusion inhibitor exhibits improved potency and in vivo half-life: Potential application in combination with broad neutralizing antibodies
IgG Fc-binding motif-conjugated HIV-1 fusion inhibitor exhibits improved potency and in vivo half-life: Potential application in combination with broad neutralizing antibodies
复制标题
IgG Fc 结合基序缀合的 HIV-1 融合抑制剂表现出改善的效力和体内半衰期：与广泛中和抗体组合的潜在应用。
DOI：
10.1371/journal.ppat.1008082
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发表时间：
2019-12-01
期刊：
影响因子：
6.7
通讯作者：
Jiang, Shibo
中科院分区：
文献类型：
--
作者：
Bi, Wenwen;Xu, Wei;Jiang, Shibo
恩夫韦肽（T20）是美国FDA批准的第一个抗HIV肽类药物。然而，由于其半衰期短和出现T20耐药的HIV毒株，其临床应用受到限制。在这里，我们开发了一种新的策略，通过将其与人IgG Fc结合肽（IBP）缀合来延长短抗HIV肽（CP 24）的半衰期。IBP-CP 24具有较强的抗HIV-1活性和较长的半衰期，有望成为一种长效抗HIV药物。有趣的是，IBP-CP 24与广泛的HIV中和抗体如N6的组合使用显示出协同抗HIV-1作用，这表明IBP-CP 24可以与N6一起用于治疗HIV-1感染，因为N6作为携带IBP-CP 24的生物质，结合gp 120进行第一次攻击，并释放结合gp 41的IBP-CP 24对HIV-1进行第二次攻击。因此，将IBP-CP 24与bNAb组合可以减少抗体和肽的剂量，从而降低治疗成本。为了克服这一限制，我们开发了一种新的策略，通过将其与人IgG Fc结合肽（IBP）融合来延长短HIV-1融合抑制肽CP 24的体内半衰期。新工程肽IBP-CP 24显示出有效和广泛的抗HIV-1活性，IC 50值范围为0.2至173.7 nM，可抑制具有不同亚型和嗜性的广谱HIV-1毒株，包括对恩夫韦肽耐药的毒株。最重要的是，其在恒河猴血浆中的半衰期为46.1小时，分别比CP 24（t（1/2）= 1.7小时）和恩夫韦肽（t（1/2）= 3小时）长约26倍和14倍。猕猴静脉注射IBP-CP 24后，未诱导出明显的IBP-CP 24特异性抗体应答，且无明显的体内外毒性。在预防性研究中，用IBP-CP 24预处理的人源化小鼠被保护免于HIV-1感染。作为一种治疗性治疗，IBP-CP 24和正常人IgG共同给药慢性HIV-1感染的人源化小鼠，导致血浆病毒血症的显着减少。IBP-CP 24与靶向gp 120中的CD 4结合位点（CD 4 bs）或gp 41中的膜近端外部区域（MPER）的广谱中和抗体（bNAb）组合显示出协同效应，导致bNAb和IBP-CP 24的剂量显著降低。这些结果表明，IBP-CP 24有潜力进一步开发为一种新的基于HIV-1融合子的长效抗HIV药物，可单独使用或与bNAb联合使用，用于治疗和预防HIV-1感染。
Author summary Enfuvirtide (T20) is the first US FDA-approved anti-HIV peptide drug. However, its clinical application is limited because of its short half-life and emergence of T20-resistant HIV strains. Here we developed a new strategy to prolong the half-life of a short anti-HIV peptide (CP24) by conjugating it with the human IgG Fc-binding peptide (IBP). IBP-CP24 exhibited potent and broad anti-HIV-1 activity and prolonged half-life, indicating its potential to be developed as a long-acting anti-HIV drug. Interestingly, combinational use of IBP-CP24 with a broad HIV neutralizing antibody, such as N6, showed synergistic anti-HIV-1 effect, suggesting that IBP-CP24 can be used together with N6 to treat HIV-1 infection because N6, as a biomissile carrying IBP-CP24, binds gp120 to make the first strike, and releases IBP-CP24 that binds gp41 to make the second strike to HIV-1. Therefore, combining IBP-CP24 with a bNAb may reduce the dose of the antibody and peptide, thus the cost of the treatment.The clinical application of conventional peptide drugs, such as the HIV-1 fusion inhibitor enfuvirtide, is limited by their short half-life in vivo. To overcome this limitation, we developed a new strategy to extend the in vivo half-life of a short HIV-1 fusion inhibitory peptide, CP24, by fusing it with the human IgG Fc-binding peptide (IBP). The newly engineered peptide IBP-CP24 exhibited potent and broad anti-HIV-1 activity with IC50 values ranging from 0.2 to 173.7 nM for inhibiting a broad spectrum of HIV-1 strains with different subtypes and tropisms, including those resistant to enfuvirtide. Most importantly, its half-life in the plasma of rhesus monkeys was 46.1 h, about 26- and 14-fold longer than that of CP24 (t(1/2) = 1.7 h) and enfuvirtide (t(1/2) = 3 h), respectively. IBP-CP24 intravenously administered in rhesus monkeys could not induce significant IBP-CP24-specific antibody response and it showed no obvious in vitro or in vivo toxicity. In the prophylactic study, humanized mice pretreated with IBP-CP24 were protected from HIV-1 infection. As a therapeutic treatment, coadministration of IBP-CP24 and normal human IgG to humanized mice with chronic HIV-1 infection resulted in a significant decrease of plasma viremia. Combining IBP-CP24 with a broad neutralizing antibody (bNAb) targeting CD4-binding site (CD4bs) in gp120 or a membrane proximal external region (MPER) in gp41 exhibited synergistic effect, resulting in significant dose-reduction of the bNAb and IBP-CP24. These results suggest that IBP-CP24 has the potential to be further developed as a new HIV-1 fusion inhibitor-based, long-acting anti-HIV drug that can be used alone or in combination with a bNAb for treatment and prevention of HIV-1 infection.