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

项目摘要 目前全世界有3600万人感染艾滋病毒，而且目前还没有疫苗可用，因此开发一种预防艾滋病毒感染的疫苗是必要的。 预防性接触（PREP）艾滋病毒方案，防止性传播仍然是全球最重要的健康 要务最近，一种CCR 5阻断单克隆抗体Leronlimab已经显示出优异的安全性、耐受性， 和抗艾滋病毒活性。鉴于艾滋病毒的性传播几乎完全是 通过CCR 5嗜性变体介导，Leronlimab作为PREP试剂可能非常有效。我们证实 每周一次给予Leronlimab保护猕猴免受CCR 5-嗜性直肠传播的能力 SIV.然而，一个季度一次的家庭配方将显着增加患者的依从性。本 最后，我们将开发一种新的长效Leronlimab制剂，可以在家中以较低的剂量给药。 量能够提供三个月的覆盖面。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的占有率。在具体目标2中， 我们将确定临床剂量的单次注射可以保护男性和女性的时间长度 防止直肠传播。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，并为测试长效Leronlimab奠定基础。 Leronlimab在临床上作为PREP用于通过性传播获得HIV的高风险个体。

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.