Monthly Antiretroviral Therapy Using Multispecific HIV Neutralizing Antibodies

联合抗逆转录病毒治疗（ART），包括口服小分子HIV抑制剂 每天服用的药物已经彻底改变了艾滋病毒/艾滋病的治疗;然而，治疗失败仍在继续发生， 治疗的患者中有很大一部分，通常是由于患者不完全遵守规定的方案。 药物滥用者不遵守规定的情况尤其严重，因此， 治疗失败率较高。直接观察治疗（DOT）可以支持艾滋病毒感染者的依从性- 阳性药物滥用者，然而，每日或每日两次ART方案的频率，潜在的阴性 对个人自由影响，以及日常DOT的资源密集性质，使得这种形式的支持 成本高，难以维持。安全有效地治疗这一人群的新策略是绝望的 needed. 我们建议开发我们认为可能是艾滋病治疗的下一次革命，特别是药物治疗。 使用者：可以每月联合给药的双特异性或三特异性抗体样分子 疗法抗体不仅耐受性好，具有良好的安全记录， 由于它们在体内的持久性和长的半衰期，与小剂量给药相比， 分子。这种有利的抗体谱有可能大大增加患者的依从性 艾滋病毒治疗，导致减少治疗失败和更好的临床结果。 Ibalizumab将被用作融合抗体构建体的骨架，因为其具有良好的文献记载。 患者的抗HIV活性和安全性记录。将对ibalizumab进行重新设计， 因此，低剂量的每月治疗将很容易实现。最近融合的 制备针对ibalizumab不同部分的PG 9或VRC 01的分离的抗体样分子m36或scFv 并进行了经验性测试，具有上级体外特征的构建体将进入有效性研究， 慢性感染SHIV的非人灵长类动物。在这些非人灵长类动物身上所期望的结果 研究的目的是将血浆病毒载量完全抑制到不可检测的水平超过一年。 这是第一次，考虑使用单克隆抗体或类似单克隆抗体的生物分子来攻击艾滋病毒是可行的。 在进入过程中同时在多个地点。这种雄心勃勃的项目并非没有风险， 但我们相信，我们已经概述了必要的实验，以尽量减少这些风险， 可能最后，我们只能继续前进，意识到许多结果的决定因素不能 先确定。我们预计，在本供资期结束时，至少将有一个 三特异性抗体样分子或两个双特异性抗体样分子，其可以被推进到 作为每月联合抗逆转录病毒疗法的临床前开发。

Combination antiretroviral therapy (ART) consisting of orally-administered small-molecule inhibitors of HIV taken daily has revolutionized the treatment of HIV/AIDS; however, treatment failures continue to occur in a significant fraction of those treated, often due to incomplete patient adherence to the prescribed regimen. Lack of compliance is particularly severe among drug abusers, who consequently are found to have a higher rate of treatment failure. Directly observed treatment (DOT) may support adherence among HIV- positive drug abusers, however the frequency of daily or twice daily ART regimens, potential negative impact on individual freedom, and resource-intensive nature of daily DOT makes this form of support both costly and difficult to sustain. New strategies to treat this population safely and effectively are desperately needed. We propose developing what we believe could be the next revolution in HIV therapy, particularly for drug users: bi-specific or tri-specific antibody-like molecules that could be administered monthly as combination therapy. Antibodies are not only well tolerated and have an excellent safety record, but are also administered infrequently because of their in vivo persistence and long half-life as compared to small molecules. This favorable profile of antibodies has the potential to dramatically increase patient adherence to HIV therapy, leading to decreased treatment failures and better clinical outcomes. Ibalizumab will be used as the backbone of the fusion-antibody constructs because of its well-documented anti-HIV activity and safety record in patients. Re-engineering of ibalizumab will be undertaken to improve on its pharmacokinetics so that low-dose monthly therapy will be readily achievable. Fusion of the recently isolated antibody-like molecules m36 or scFv of PG9 or VRC01 to various parts of ibalizumab will be made and tested empirically, and constructs with superior in vitro profiles will be advanced into efficacy studies in nonhuman primates chronically infected with SHIV. The desired outcome in these nonhuman primate studies is the complete suppression of plasma viral load to non-detectable levels for longer than a year. It is now feasible, for the first time, to think about using mAbs or mAb-like biological molecules to attack HIV at multiple sites simultaneously during its entry process. An ambitious project of this sort is not without risk, but we believe that we have outlined the necessary experiments to minimize these risks as much as possible. In the end, we could only push ahead, realizing that many of the determinants of outcome cannot be determined a priori. It is our expectation that, at the end of this funding period, there will be at least one tri-specific antibody-like molecule or two bi-specific antibody-like molecules that could be advanced into preclinical development as monthly combination antiretroviral therapy.