Durable Vaginal Protection from HIV via mRNA expression of BNABS

项目总结 尽管在开发有效的抗艾滋病毒药物方面取得了重大进展，但目前约有200万新药物 全世界每年仍有感染病例，超过95%是通过异性性接触。在采取预防措施时 已取得进展，如PrEP，这些措施经常被忽视、误用或往往没有 女性合伙人可以商量。因此，为预防由女性控制的感染提供了选择 在遏制全球新感染率的斗争中将是一笔财富。随着最近广泛的爆炸性增长 来自艾滋病毒感染者的中和抗体(BNAbs)，其中几种已被用于证明预防 病毒感染的可能性，即使是在暴露后给药。不幸的是，到目前为止，疫苗还不够 诱导bNAbs，尽管局部递送的bNAbs已显示出保护作用，但这种保护迄今仍显示出 耐用性有限。为此，一种新的表达抗体的方法，具有惊人的长动力学，在 女性生殖道(FRT)是最近被证实通过合成的mRNA来实现的。交付是通过以下方式实现的 将FRT上皮直接、快速、气溶胶暴露于水中裸露的mRNA。抗体的持久性是 通过将GPI连接物结合到重链中来实现。在恒河猴身上，有能力 保护猕猴FRT外植体免受希沃克病毒的体外感染已被证明。我们的长远目标是发展 一种经济有效的基于mRNA的方法在FRT中表达bNAbs，提供了一个新的范式 在入境的粘膜口岸(S)产生抗感染屏障。短期目标是优化 BNAbs的传递、寿命和对SIV感染猕猴的保护效果：1)优化 给药方法和方案，使我们能够有效地转染阴道和宫颈上皮， 2)优化抗体连接子策略以促进猕猴的长期表达，以及3)检测 单一抗体和组合，包括双特异性抗体。优化的效果将是 在猕猴模型的真正挑战研究中进行了测试。如果成功，设计信息对于制定适当的 将提供向人类FRT传递mRNA的设备，并提供足够的临床前数据来支持 FDA未来的IND申请。

Project summary In spite of the major advances in the development of effective anti-HIV drugs, currently some 2 million new infections still occur annually worldwide and over 95% via heterosexual contact. While prevention measures have made progress, such as PrEP, these measures are frequently either ignored, misused, or often non- negotiable for the female partner. Thus, providing choices for prevention of infection that are female controlled will be an asset in the fight to curb the rate of new infections worldwide. With the recent explosion of broadly neutralizing antibodies (bnAbs) from HIV infected patients, several have been used to demonstrate prevention of virus acquisition, even when administered post exposure. Unfortunately, vaccines have so far fallen short of inducing bnAbs, and though topically delivered bnAbs have shown protection, such protection has to date shown limited durability. To that end, a novel approach for expressing antibodies, with surprisingly long kinetics, in the female reproductive tract (FRT) via synthetic mRNA was recently demonstrated. Delivery was achieved through direct, rapid, aerosol exposure of the FRT epithelium to naked mRNA in water. Persistence of the antibody was achieved through the incorporation of a GPI-linker into the heavy chain. In rhesus macaques, the ability to protect macaque FRT explants from SHIV infection ex vivo has been shown. The long-term goal is to develop a cost-effective mRNA-based approach for expressing bnAbs in the FRT, providing a new paradigm for generating anti-infection barriers at the mucosal port(s) of entry. The short-term goals are to optimize the delivery, longevity and protective efficacy of bnAbs against SHIV infections of rhesus macaques by: 1) optimizing the delivery approach and protocol such that we have efficient transfection of the vaginal and cervical epithelium, 2) optimization of the antibody linker strategy to promote long-term expression in macaques, and 3) testing of single antibodies and combinations, including bi-specific antibodies. The efficacy of the optimization will be tested in a true challenge study in the macaque model. If successful, design information vital for making a proper device for delivering mRNA to the FRT in humans will be provided, and sufficient pre-clinical data in support of a future FDA IND application.