A Solid-Phase, Long-Acting CCR5 Monoclonal Antibody for HIV Transmission

针对 HIV 传播的固相长效 CCR5 单克隆抗体

• 批准号: 10650749
• 负责人: Jonah B. Sacha
• 金额: $ 97.59万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-23 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650749
• 关键词: Adherence; Anti-Retroviral Agents; Antibodies; Biopsy; Blocking Antibodies; Blood; CCR5 gene; CXCR4 gene; Chemistry; Clinical; Clinical Trials; Collaborations; Data; Development; Dose; Dose Limiting; Drug Interactions; Drug Kinetics; Epidemic; Female; Formulation; Foundations; HIV; HIV Antibodies; HIV Infections; HIV-1; Half-Life; Health Priorities; Home; Homozygote; Individual; Infection; Injectable; Injections; Length; Macaca; Measurement; Measures; Mediating; Modality; Modeling; Monitor; Monoclonal Antibodies; Mucous Membrane; Oral; PRO 140; Parents; Patients; Persons; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Plasma; Preventive vaccine; Reagent; Recording of previous events; Rectum; Regimen; Resistance; Reverse Transcriptase Inhibitors; Safety; Schedule; Self Administration; Serum; Sexual Transmission; Site; Solid; Techniques; Tenofovir; Testing; Therapeutic; Time; Tissues; Toxic effect; Vaccines; Vagina; Vaginal Ring; Variant; Virus; antiretroviral therapy; compliance behavior; emtricitabine; fighting; global health; high risk; industry partner; male; novel; nucleoside analog; particle; pre-exposure prophylaxis; prevent; prophylactic; receptor; rectal; rectal HIV transmission; sexual HIV transmission; side effect; simian human immunodeficiency virus; subcutaneous; success; transmission process; user-friendly; vaginal transmission; viral resistance; viral transmission; weapons

PROJECT SUMMARY With 36 million people currently living with HIV worldwide and no vaccine currently available, developing a pre- exposure prophylactic (PREP) HIV regimen that protects against sexual transmission remains a top global health priority. Recently, a CCR5 blocking monoclonal antibody, Leronlimab, has shown exceptional safety, tolerability, and anti-HIV activity in multiple clinical trials. Given that sexual transmission of HIV is almost exclusively mediated by CCR5-tropic variants, Leronlimab may be extremely effective as a PREP reagent. We confirmed the ability of once-weekly administered Leronlimab to protect macaques from rectal transmission of CCR5-tropic SHIV. However, a once-quarterly at home formulation would dramatically increase patient adherence. To this end we will develop a novel formulation of long-acting Leronlimab that can be administered at home in a low volume able to provide coverage for three months. In specific aim 1, we will determine the pK and receptor occupancy of this new Leronlimab formulation in blood and tissue sites of sexual transmission. In specific aim 2, we will determine the length of time a single injection at the clinical dose can protect both male and female macaques against rectal transmission. In specific aim 3, we will determine the length of time a single injection of the clinical dose can protect against vaginal transmission in cycling female macaques. These studies will determine the optimal clinical dosing of long-acting Leronlimab and lay the foundation for testing long-acting Leronlimab clinically as PREP in individuals at high-risk of acquiring HIV via sexual transmission.

项目摘要 目前有3600万人在全球享有艾滋病毒艾滋病毒，目前没有疫苗，开发 防止性传播的预防性暴露预防（PREP）HIV方案仍然是全球最佳健康 优先事项。最近，CCR5阻断单克隆抗体Leronlimab表现出了出色的安全性，耐受性， 和在多个临床试验中的抗HIV活性。鉴于艾滋病毒的性传播几乎完全是 Leronlimab通过CCR5循环变体介导，作为PREP试剂可能非常有效。我们确认 每周一次管理的Leronlimab保护猕猴免受CCR5-Tropic直肠传播的能力 湿婆。但是，在家中曾经四分之一的公式将大大提高患者的依从性。对此 最后，我们将开发一种长效leronlimab的新颖配方，可以在家中进行管理 能够提供三个月的覆盖范围。在特定目标1中，我们将确定PK和受体 这种新的Leronlimab表述在性传播的血液和组织部位的占用。在特定的目标2中， 我们将确定临床剂量的单个注射的时间长度可以保护男性和女性 猕猴针对直肠传输。在特定的目标3中，我们将确定单个注入的时间长度 临床剂量可以预防骑自行车猕猴中的阴道传播。这些研究会 确定长效Leronlimab的最佳临床剂量，并为长效测试奠定基础 Leronlimab在临床上作为通过性传播获得艾滋病毒的高风险的人的临床准备。