Rapamycin Enhanced Efficiency of Anti-HIV Antibodies

描述(由申请人提供)：本文件包含Proectus BioSciences要求不得向政府以外的人发布的专有信息，除非是出于审查和评估的目的。摘要多克隆和单克隆抗体制剂是最早发现的阻断HIV进入靶细胞的药物之一。猕猴模型的被动移植实验已经肯定了它们的临床潜力。不幸的是，临床试验表明，它们面临着与小分子抗病毒药物相同的挑战之一--耐药病毒的快速生长。最近，下调CCR5受体的细胞周期药物，如雷帕霉素，被发现与进入抑制剂T20有协同作用，也称为Fuzeon或Enfuvide。初步实验进一步证明，在体外添加雷帕霉素可以防止T20耐药病毒的生长，并增强其他耐药病毒对T20的敏感性。我们发现雷帕霉素还与单链抗体M9有协同作用，单链抗体是一种有效的中和性单抗片段。该项目的目的是评估雷帕霉素是否可以提高抑制HIV进入的单抗的治疗潜力。我们建议通过实现以下三个目标来实现这一目标。目的1：鉴定与雷帕霉素协同抑制病毒生长的抗HIV Env、抗CD4和抗CCR5抗体；目的2：证明加入雷帕霉素可在体外抑制抗体介导的中和耐药病毒的生长；目的3：证明加入雷帕霉素可恢复相应耐药病毒的抗体介导的中和作用。在第一阶段SBIR成功的基础上，第二阶段SBIR将在灵长类动物模型中评估雷帕霉素/抗病毒mAb共制剂的潜力，作为开发这种治疗艾滋病毒感染的方法的第一步。本文件包含Proectus BioSciences要求不得向政府以外的人发布的专有信息，除非是出于审查和评估的目的。项目简介雷帕霉素(惠氏，麦迪逊，新泽西州)是一种用于肾移植的免疫抑制药物，它下调艾滋病毒的关键受体CCR5的表达。在体外，雷帕霉素增强了阻止艾滋病毒进入的抗体的效力。我们正在开发雷帕霉素作为一种与这些抗病毒抗体结合使用的抗艾滋病毒药物。这项第一阶段SBIR建议的目标是确定雷帕霉素和抗病毒抗体的潜在组合，这些组合可能具有临床潜力。

DESCRIPTION (provided by applicant): This document contains proprietary information that Profectus BioSciences requests not be released to persons outside the Government, except for purposes of review and evaluation. Abstract Polyclonal and monoclonal antibody preparations were among the first agents identified that block HIV entry into target cells. Passive transfer experiments in macaque models have affirmed their clinical potential. Unfortunately, clinical trials have demonstrated that they suffer from one of the same challenges as small molecule antivirals - that of the rapid outgrowth of resistant virus. Recently, cell cycle agents such as rapamycin that downregulate the CCR5 receptor, were found to synergize with the entry inhibitor T20, know also as Fuzeon or Enfuvirtide. Preliminary experiments further demonstrate that the addition of rapamycin in vitro prevents the outgrowth of T20 resistant viruses and enhances the susceptibility to T20 of otherwise resistant viruses. We have found that rapamycin also synergizes with scFv M9, a potent neutralizing monoclonal antibody fragment. The objective of this project is to evaluate whether rapamycin can improve the therapeutic potential of monoclonal antibodies (mAbs) that inhibit HIV entry. We propose to pursue this objective by fulfilling the following 3 aims. Aim 1: Identify anti-HIV Env, anti-CD4 and anti-CCR5 antibodies that synergize with rapamycin to inhibit viral growth in human PBMCs; Aim 2: Demonstrate that the addition of rapamycin inhibits the outgrowth of antibody-mediated neutralization resistant viruses in vitro; Aim 3: Demonstrate that the addition of rapamycin can recover antibody-mediated neutralization of the corresponding resistant viruses. Based on the success of this phase I SBIR, a phase II SBIR will evaluate the potential of rapamycin/antiviral mAb coformulations in a primate model as the first step towards developing this approach to treat HIV infection. This document contains proprietary information that Profectus BioSciences requests not be released to persons outside the Government, except for purposes of review and evaluation. Project Narrative Rapamycin (Wyeth, Madison, NJ) is an immunosuppressant drug used in kidney transplantation that downregulates the expression of CCR5, a key receptor for HIV. In vitro, rapamycin enhances the efficacy of antibodies that block HIV entry. We are developing Rapamycin as an anti-HIV drug in conjunction with these antiviral antibodies. The objective of this Phase I SBIR proposal is to identify potential combinations of rapamycin and antiviral antibodies that may have clinical potential.