Capsule-intravaginal ring for sustained release of antibodies for non-hormonal contraception and vaginal protection against HIV

总结 迫切需要改进避孕和预防艾滋病毒的方法。近一半 在美国，所有的怀孕都是意外的，全球有超过8500万的意外怀孕， 每年新增艾滋病毒感染者100万人。毫不奇怪，意外怀孕最常发生在女性身上 不使用避孕措施的妇女：许多妇女由于真实的和 副作用，并经常停止激素避孕。这强调了需要一个 非激素避孕方法，不需要性交时间的行动，也不需要日常干预。我们 我相信，在艾滋病预防方法中加入避孕措施也会大大提高使用者的依从性，因为 很少有夫妇自认为有感染艾滋病毒的风险，而几乎所有夫妇都自认为有怀孕的风险。 灵感来自于自然界，在那里一些不孕妇女表达抗体，结合表面抗原的精子 并阻止精子穿透宫颈粘液，我们已经研究了一种完全的人类单克隆抗体， 一种抗体（mAb），可以快速结合仅存在于人类精子表面的独特抗原;我们参考 人避孕抗体（human contraceptive antibody，HCA）。重要的是，HCA凝集>90%的精子， 在所有100个新鲜精液样本中，来自不同人口统计学特征的男性的精液样本中，一种类似的mAb， 在高生育力兔模型中，结合兔精子使卵子受精减少约95%。了重大进展 通过发现和测试针对艾滋病毒的广泛中和mAb（bnAb），包括针对艾滋病毒的保护作用 阴道艾滋病毒传播。事实上，我们团队的成员领导了第一次阴道分娩的VRC 01临床试验。 为了实现基于mAb的MPT产品的愿景，我们开发的下一步是（i）配制 将mAb导入递送系统，该递送系统维持mAb在雌性生殖道中的有效水平，以及（ii） 进一步验证在大型动物模型中的功效。因此，在此快速通道申请的第一阶段，我们将 配制包封mAb混合物的持续释放聚合物胶囊（HCA和VRC 01 +N6， 艾滋病毒预防），并可以嵌入阴道环（IVR）中。我们的目标是证明， 暴露时，mAb将保持足够的稳定性和活性（中和/捕获HIV和凝集/捕获精子） 并在35天内释放到人宫颈阴道分泌物中。在成功完成 I期里程碑，我们将进行重复的低剂量阴道SHIV激发，以确认mAb是否从 工程聚合物胶囊可有效地减少阴道传播。如果成功，我们的建议 这项工作将有力地支持我们的避孕和艾滋病毒预防组合MPT-IVR的临床开发 可以解决市场上一个主要的未满足的需求。

Summary There is a critical need for improved methods for both contraception and HIV prevention. Nearly half of all pregnancies in the U.S. are unintended, and globally there are >85 million unintended pregnancies and 2 million new HIV infections each year. Not surprisingly, unintended pregnancies occur most often in women who are non-users of contraception: many women are averse to using exogenous hormones due to real and perceived side effects, and frequently discontinue hormonal contraception. This underscores the need for a non-hormonal contraceptive method that does not require coitally-timed actions, nor daily intervention. We believe adding contraception to an HIV prevention method would also strongly improve user adherence, since few couples self-identify as at risk of HIV, while nearly all self-identify as at risk of pregnancy. Inspired by nature, where some infertile women express antibodies that bind surface antigens on sperm and block sperm penetration through their cervical mucus, we have investigated a fully human monoclonal antibody (mAb) that can quickly bind a unique antigen present only on the surface of human sperm; we refer to this mAb as human contraceptive antibody (HCA). Importantly, HCA agglutinated >90% of sperm within seconds in all 100 fresh semen samples tested from men spanning diverse demographics. A similiar mAb that binds rabbit sperm reduced egg fertilization by ~95% in the highly fertile rabbit model. Major strides have been made with discovering and testing broadly neutralizing mAb (bnAb) against HIV, including protection against vaginal HIV transmission. Indeed, members of our team led the first clinical trial of VRC01 delivered vaginally. To realize the vision of a mAb-based MPT product, the next step in our development is to (i) formulate mAb into a delivery system that maintains effective levels of mAb in the female reproductive tract, and (ii) further validate efficacy in large animal models. Thus, during Phase I of this Fast-Track application, we will formulate sustained release polymeric capsules encapsulating a cocktail of mAbs (HCA and VRC01+N6 for HIV prevention), and can be embedded into intravaginal rings (IVR). The goal is to demonstrate that loaded mAbs will remain sufficiently stable and active (neutralize/trap HIV and agglutinate/trap sperm) when exposed and released into human cervicovaginal secretions over a 35 day period. Pending successful completion of Phase I milestone, we will perform repeated low-dose vaginal SHIV challenges to confirm if mAb released from the engineered polymeric capsules can effectively reduce vaginal transmission. If successful, our proposed work will strongly support clinical development of our combination contraceptive and HIV-prevention MPT-IVR that could address a major unmet need in the marketplace.