Monthly Antiretroviral Therapy Using Multispecific HIV Neutralizing Antibodies

描述(申请人提供)：由每日口服的艾滋病毒小分子抑制剂组成的联合抗逆转录病毒疗法(ART)使艾滋病毒/艾滋病的治疗发生了革命性的变化；然而，在接受治疗的患者中，仍有相当一部分人继续出现治疗失败的情况，这往往是由于患者不完全遵守规定的方案。吸毒者缺乏依从性尤其严重，因此他们被发现有更高的治疗失败率。直接观察治疗(DOT)可能有助于HIV阳性药物滥用者的坚持，但每天或两次ART方案的频率、对个人自由的潜在负面影响以及每日DOT的资源密集性使得这种形式的支持既昂贵又难以维持。迫切需要新的战略来安全和有效地治疗这一人群。 我们建议开发我们认为可能是艾滋病毒治疗中的下一次革命的东西，特别是对于吸毒者：双特异性或三特异性抗体样分子，可以每月作为联合疗法使用。抗体不仅具有良好的耐受性和良好的安全性记录，而且由于与小分子相比，它们在体内的持久性和较长的半衰期，因此很少使用。这种有利的抗体特征有可能极大地提高患者对艾滋病毒治疗的依从性，从而减少治疗失败并改善临床结果。 Ibalizumab将被用作融合抗体结构的骨架，因为它在患者中的抗HIV活性和安全记录得到了很好的证明。将对ibalizumab进行重新设计，以改善其药代动力学，以便很容易实现每月低剂量治疗。最近分离出的PG9或VRC01的抗体样分子M36或ScFv将与ibalizumab的不同部分进行融合并进行经验测试，具有优异体外特征的结构将被推进到慢性感染SIV的非人灵长类动物的疗效研究中。在这些非人类灵长类动物研究中，期望的结果是将血浆病毒载量完全抑制到一年以上无法检测到的水平。 现在，第一次考虑使用单抗或类似单抗的生物分子在艾滋病毒进入过程中同时在多个地点攻击艾滋病毒是可行的。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，以尽可能地将这些风险降至最低。最后，我们只能继续前进，意识到许多决定结果的因素都不能事先确定。我们预计，在这一资助期结束时，将至少有一个三特异性抗体样分子或两个双特异性抗体样分子可作为每月联合抗逆转录病毒疗法推进到临床前开发。

DESCRIPTION (provided by applicant): 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.