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

改善 eCD4-Ig 的药代动力学、效力和免疫原性

基本信息

批准号：
10394340
负责人：
MICHAEL DAVID ALPERT
金额：
$ 90.74万
依托单位：
EMMUNE, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-19 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394340
关键词：
Address Animals Antibodies C-terminal CCR5 gene Cell Culture Techniques Data Dependovirus Disease remission Dose Drug Kinetics Epitopes Exhibits Fc domain Generations Goals HIV-1 HIV-2 Half-Life Human Immunoglobulin G Individual Infection Lead Light Macaca Macaca mulatta Mutation Patients Peptides Persons Pharmaceutical Preparations Phase Production Property Prophylactic treatment Proteins Proteome Residual state Resistance Rodent Model SIV Safety Series Serum Testing Therapeutic Toxic effect Toxicology Transgenes Variant Viral Viral reservoir Virus adeno-associated viral vector antibody-dependent cell cytotoxicity antiretroviral therapy cost fight against fitness immunogenic immunogenicity improved in vivo inhibitor lead candidate mimetics neutralizing antibody pandemic disease peptidomimetics prevent receptor screening simian human immunodeficiency virus synergism tool tyrosine O-sulfate vaccine strategy viral rebound

项目摘要

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.

项目摘要我们已经开发了一种类似抗体的HIV-1进入抑制剂ECD4-Ig，该抑制剂由前两个域组成 CD4与抗体FC结构域和短酪氨酸硫化的CCR5模拟肽融合。 ECD4-Ig具有使其成为与HIV-1大流行作斗争的异常有希望的工具的特性。具体而言，它比任何广泛中和抗体（BNAB）更广泛，至少在谈判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，并且能够放大非中和抗体的ADCC活性患者血清。当由腺相关病毒（AAV）载体表达时，它可以保护恒河猴 SHIV和SIV的猕猴比任何常规疫苗策略都更有效地挑战，并且正如我们在这里显示的那样，它可以抑制抗逆转录病毒疗法的停止后的病毒反弹（大车）。简而言之，优化ECD4-IG的情况很强。在这里，我们描述了一系列细胞培养和动物研究将进一步扩大ECD4-IG的半衰期，提高其效力并降低其效力免疫原性。这些改进将提高ECD4-Ig作为感染的安全性和效率蛋白质和一种表达AAV的转换，使我们更接近我们持续无毒的HIV的目标 1针对HIV-1感染的缓解和有效的长期预防。