Improving the pharmacokinetics, potency, and immunogenicity of eCD4-Ig

项目摘要 我们已经开发了一种抗体样HIV-1进入抑制剂eCD 4-IG，由以下结构域组成： CD 4融合到抗体Fc结构域和短的酪氨酸硫酸化的CCR 5模拟肽。eCD 4-IG具有 这些特性使其成为抗击HIV-1流行病的非常有前途的工具。 具体地说，它比任何广泛中和抗体（bNAb）更广泛，至少在 中和和抗体依赖性细胞介导的细胞毒性（ADCC），更难逃脱，更少 免疫原性的，并且独特地能够扩增非中和抗体的ADCC活性， 患者血清。当通过腺相关病毒（AAV）载体表达时，它可以保护恒河猴 来自SHIV和SIV的猕猴的挑战比任何常规疫苗策略更有效，并且， 正如我们在这里所展示的，它可以抑制联合抗逆转录病毒疗法停止后的病毒反弹。 （cART）。简而言之，优化eCD 4-IG的理由很充分。在这里，我们描述了一系列的细胞培养， 动物研究将进一步延长eCD 4-IG的半衰期，提高其效力，并降低其毒性。 免疫原性这些改进将增加eCD 4-IG作为输注药物的安全性和有效性。 蛋白质和作为AAV表达的转基因，并使我们更接近我们的目标，持续无毒艾滋病毒- 1缓解和有效的长期预防HIV-1感染。

PROJECT SUMMARY We have developed an antibody-like HIV-1 entry inhibitor, eCD4-Ig, composed of the first two domains of CD4 fused to an antibody Fc domain and a short tyrosine-sulfated CCR5-mimetic peptide. eCD4-Ig has properties that make it an exceptionally promising tool in the fight against the HIV-1 pandemic. Specifically, it is broader than any broadly neutralizing antibody (bNAb), at least as potent at neutralization and antibody-dependent cell-mediated cytotoxicity (ADCC), more difficult to escape, less immunogenic, and uniquely capable of amplifying the ADCC activity of non-neutralizing antibodies in patient sera. When expressed by an adeno-associated virus (AAV) vector, it can protect rhesus macaques from SHIV and SIV challenges more effectively than any conventional vaccine strategy, and, as we show here, it can suppress viral rebound after cessation of combined antiretroviral therapies (cART). In short, the case for optimizing eCD4-Ig is strong. Here we describe a series of cell-culture and animal studies that will further extend eCD4-Ig’s half-life, improve its potency, and reduce its immunogenicity. These improvements will increase the safety and efficacy of eCD4-Ig as an infused protein and as an AAV-expressed transgene, and bring us closer to our goals of sustained drug-free HIV- 1 remission and effective long-term prophylaxis against HIV-1 infection.