Development of a synthetic antibody based on the HIV receptor and co-receptor that is optimized for highly efficient killing of HIV-infected cells by ADCC

开发基于 HIV 受体和辅助受体的合成抗体，该抗体经过优化，可通过 ADCC 高效杀死 HIV 感染细胞

• 批准号: 8992832
• 负责人: MICHAEL DAVID ALPERT
• 金额: $ 22.39万
• 依托单位: EMMUNE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992832
• 关键词: Affect; Antibodies; Antibody Response; Antigenic Diversity; Binding; Binding Sites; Biological Assay; CCR5 gene; CD4 Positive T Lymphocytes; Cell Line; Cells; Collaborations; Development; Effectiveness; Enhancing Antibodies; Epitopes; Evaluation; Exposure to; FCGR3B gene; Fc Receptor; Goals; HIV; HIV Envelope Protein gp120; HIV Receptors; HIV vaccine; HIV-1; IgG1; IgG3; Immune response; Immunoglobulin Genes; Infection; Laboratories; Lead; Letters; Macaca mulatta; Measures; Mucous Membrane; Natural Killer Cells; Nature; Neutralization Tests; Patients; Performance; Phase; Plasma; Property; Public Health; Resistance; Route; SIV; Stimulus; Surface; Systemic infection; Testing; Therapeutic; Vaccination; Vaccines; Variant; Viral; Virus; Virus Receptors; antibody-dependent cell cytotoxicity; base; crosslink; density; design; env Glycoproteins; gene therapy; improved; in vivo; killings; neutralizing antibody; pandemic disease; prevent; public health relevance; receptor; simian human immunodeficiency virus

 DESCRIPTION (provided by applicant): Eliciting antibodies that neutralize human immunodeficiency virus type-1 (HIV-1) by vaccination is a daunting challenge, due to features of the HIV-1 envelope glycoprotein (Env) that render it inherently resistant to antibody responses, and the extraordinary antigenic diversity that has accrued since the beginning of the HIV-1 pandemic. To circumvent these formidable obstacles, we are pursuing durable in vivo expression of a synthetic neutralizing antibody by gene therapy as an alternative to conventional vaccine approaches. This synthetic antibody (eCD4-Ig) is based on the Env-binding determinants of the viral receptor (CD4) and the viral coreceptor (CCR5). Consequently, eCD4-Ig neutralizes 100% of strains of HIV-1 and simian immunodeficiency virus (SIV) tested thus far, protects rhesus macaques from infection with simian-human immunodeficiency virus (SHIV), and is itself a poor target for host immune responses. Antibody functions in addition to virus neutralization, including antibody-dependent cell-mediated cytotoxicity (ADCC), may substantially augment the ability of eCD4-Ig to prevent systemic infection following exposure to HIV-1. The goal of this project is to maximize the capacity of eCD4-Ig to direct the elimination of virus-infected cells by ADCC. The resulting ADCC-optimized version of eCD4-Ig may confer greater protection against HIV-1 infection, reduce the concentration of eCD4-Ig that must be sustained in plasma and the mucosa to reliably prevent HIV-1 infection, and may increase its effectiveness as a therapeutic in people already infected with HIV-1.

 描述（由申请方提供）：由于HIV-1包膜糖蛋白（Env）的特性使其固有地对抗体应答具有抗性，以及自HIV-1大流行开始以来积累的非凡抗原多样性，通过接种疫苗激发中和人类免疫缺陷病毒1型（HIV-1）的抗体是一项艰巨的挑战。为了克服这些巨大的障碍，我们正在寻求通过基因治疗在体内持久表达合成的中和抗体，作为传统疫苗方法的替代方案。该合成抗体（eCD 4-IG）基于病毒受体（CD 4）和病毒辅助受体（CCR 5）的Env结合决定簇。因此，eCD 4-IG中和迄今为止测试的100%的HIV-1和猿猴免疫缺陷病毒（SIV）菌株，保护恒河猴免受猿猴-人类免疫缺陷病毒（SHIV）感染，并且其本身是宿主免疫应答的不良靶标。除病毒中和作用外，抗体功能（包括抗体依赖性细胞介导的细胞毒性（ADCC））可显著增强eCD 4-IG预防暴露于HIV-1后全身感染的能力。本项目的目标是最大限度地发挥eCD 4-IG的能力， 病毒感染的细胞通过ADCC。所得到的eCD 4-IG的ADCC优化版本可以赋予针对HIV-1感染的更大保护，降低必须维持在血浆和粘膜中以可靠地预防HIV-1感染的eCD 4-IG的浓度，并且可以增加其作为已经感染HIV-1的人的治疗剂的有效性。