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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要目前全球有 3600 万人感染艾滋病毒，且目前尚无疫苗可用，因此正在开发一种预防止性传播的艾滋病毒暴露预防 (PREP) 治疗方案仍然是全球最重要的健康方案优先事项。最近，一种 CCR5 阻断单克隆抗体 Leronlimab 显示出卓越的安全性、耐受性、以及多项临床试验中的抗 HIV 活性。鉴于艾滋病毒几乎完全通过性传播由 CCR5-tropic 变体介导，Leronlimab 作为 PREP 试剂可能非常有效。我们确认每周一次 Leronlimab 能够保护猕猴免受 CCR5-tropic 直肠传播艾滋病毒。然而，每季度一次的家庭配方将显着提高患者的依从性。对此最后，我们将开发一种长效 Leronlimab 的新型配方，可以在家中以较低的剂量给药容量能够提供三个月的覆盖范围。在具体目标 1 中，我们将确定 pK 和受体这种新的 Leronlimab 制剂在性传播的血液和组织部位中的占据。在具体目标 2 中，我们将确定临床剂量下单次注射可以保护男性和女性的时间长度猕猴抵抗直肠传播。在具体目标3中，我们将确定单次注射的时间长度临床剂量可以防止骑自行车的雌性猕猴的阴道传播。这些研究将确定长效Leronlimab的最佳临床剂量，为长效试验奠定基础 Leronlimab 临床上可作为通过性传播感染艾滋病毒高风险个体的 PREP。