Durable vaginal protection from HIV via mRNA expression of bnAbs

项目摘要 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200万新的 全世界每年仍有感染发生，95%以上是通过异性性接触感染的。虽然预防措施 已经取得了进展，如PrEP，这些措施经常被忽视，滥用，或经常不 对女性合伙人来说可以商量因此，提供由女性控制的预防感染的选择， 将成为遏制全球新感染率的一笔财富。随着最近大规模的 中和抗体（bnAbs）从HIV感染的患者，几个已被用来证明预防 即使是在接触后给药，不幸的是，迄今为止， 诱导bnAb，并且尽管局部递送的bnAb已经显示出保护作用，但是这种保护作用迄今为止已经显示出 有限的耐久性。为此目的，一种用于在大肠杆菌中表达抗体的新方法，具有令人惊讶的长动力学， 女性生殖道（FRT）通过合成mRNA最近被证明。交付是通过 FRT上皮细胞直接、快速、气溶胶暴露于水中的裸mRNA。抗体的持久性是 通过将GPI-接头掺入重链中实现。在恒河猴中， 保护猕猴FRT外植体免受离体SHIV感染。长期目标是发展 在FRT中表达bnAb的基于mRNA的成本有效的方法，提供了一种新的范式， 在粘膜入口处产生抗感染屏障。短期目标是优化 针对恒河猴的SHIV感染的bnAb的递送、寿命和保护功效，通过：1）优化 递送方法和方案使得我们能够有效转染阴道和宫颈上皮， 2)优化抗体接头策略以促进猕猴中的长期表达，和3）测试 单一抗体和组合，包括双特异性抗体。优化的功效将是 在猕猴模型中进行了真正的挑战研究。如果成功，设计信息至关重要， 将提供用于将mRNA递送至人类FRT的装置，并提供足够的临床前数据以支持 FDA 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.