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

项目总结 我们已经开发出一种类似抗体的HIV-1进入抑制剂eCD4-Ig，它由前两个结构域组成 CD4与抗体Fc结构域和酪氨酸硫化的CCR5模拟短肽融合。ECD4-Ig有 这些特性使其成为抗击艾滋病毒-1大流行的极具前景的工具。 具体地说，它比任何广谱中和抗体(BNAb)都要广泛，至少在 中和和抗体依赖的细胞介导的细胞毒(ADCC)，更难逃脱，更少 免疫原性，并独特地能够放大非中和抗体的ADCC活性 病人血清。当腺相关病毒(AAV)载体表达时，它可以保护恒河猴 来自SIV和SIV的猕猴比任何传统疫苗策略都更有效地挑战，而且， 正如我们在这里展示的，在联合抗逆转录病毒治疗停止后，它可以抑制病毒反弹。 (购物车)。简而言之，优化eCD4-Ig的理由很充分。在这里，我们描述了一系列细胞培养和 动物研究将进一步延长eCD4-Ig的半衰期，提高其效力，并降低其 免疫原性。这些改进将增加eCD4-Ig作为输液的安全性和有效性 蛋白质和AAV表达的转基因，并使我们更接近持续无毒艾滋病毒的目标- 1针对艾滋病毒-1感染的缓解和有效的长期预防。

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.