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

项目总结 目前全球有3600万艾滋病毒携带者，目前还没有疫苗可用，正在开发一种前 防止性传播的暴露预防(PREP)艾滋病毒方案仍然是全球首要健康问题 优先考虑。最近，一种封闭CCR5的单抗Leronlimab显示出极高的安全性、耐受性， 以及在多个临床试验中的抗艾滋病毒活性。鉴于艾滋病毒的性传播几乎完全是 在CCR5嗜性变异体的介导下，Leronlimab可能是一种非常有效的Prep试剂。我们确认了 每周给药一次来罗利姆单抗对猕猴CCR5嗜性直肠传播的保护作用 希夫。然而，每季度一次的在家配方将极大地提高患者的依从性。对这件事 最终，我们将开发一种新的长效Leronlimab配方，可以在家中以较低的 数量能够提供三个月的保险。在特定的目标1中，我们将确定PK和受体 这种新的Leronlimab制剂在血液和性传播组织部位的占有率。在具体目标2中， 我们将确定临床剂量的一次注射可以保护男性和女性的时间长度 猕猴对抗直肠传播。在具体目标3中，我们将确定一次注射的时间长度 临床剂量对骑行雌性猕猴具有预防阴道传播的作用。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临床上作为经性传播感染艾滋病毒的高危人群的准备。

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.