Rapamycin Enhanced Efficiency of Anti-HIV Antibodies

雷帕霉素增强抗 HIV 抗体的效率

• 批准号: 7281856
• 负责人: Antony S. Dimitrov
• 金额: $ 21.52万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7281856
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Anti-HIV Agents; Anti-HIV Therapy; Antibodies; Antiviral Agents; Antiviral Therapy; Biological Assay; Blocking Antibodies; Blood Cells; CCR5 gene; Cell Cycle; Cells; Cessation of life; Chemokine (C-C Motif) Receptor 5; Class; Clinical; Clinical Research; Clinical Trials; Collaborations; Development; Dose; Drug Combinations; Drug Formulations; Drug resistance; Drug usage; Epitopes; Evaluation; Failure; Fuzeon; Goals; Government; Growth; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV Receptors; HIV therapy; HIV-1; Highly Active Antiretroviral Therapy; Human; Human Resources; Immunoglobulin Fragments; Immunosuppressive Agents; In Vitro; Infection; Inhibitory Concentration 50; Intention; Kidney Transplantation; Licensing; Literature; Macaca; Marketing; Maryland; Mediating; Modeling; Molecular Cloning; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mutation; Numbers; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Predisposition; Preparation; Primates; Purpose; Rate; Recording of previous events; Resistance; Resistance development; Safety; Sirolimus; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Standards of Weights and Measures; System; T-20; Technology; Testing; Therapeutic; Toxic effect; Transplantation; Universities; Variant; Viral; Viral Antibodies; Viral Load result; Virus; Virus Diseases; Week; abstracting; base; concept; experience; improved; inhibitor/antagonist; mortality; mutant; neutralizing antibody; neutralizing monoclonal antibodies; novel; polyclonal antibody; prevent; research study; small molecule; success

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.

描述（由申请人提供）：本文件包含Profectus BioSciences要求不得向政府以外的人员发布的专有信息，除非用于审查和评估目的。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。在猕猴模型中的被动转移实验已经证实了它们的临床潜力。不幸的是，临床试验表明，它们与小分子抗病毒药物面临着同样的挑战-耐药病毒的快速生长。最近，发现细胞周期剂如下调CCR 5受体的雷帕霉素与进入抑制剂T20（也称为Fuzeon或Enfuvirtide）协同作用。初步实验进一步证明，体外加入雷帕霉素可防止T20抗性病毒的生长，并增强其他抗性病毒对T20的易感性。我们已经发现雷帕霉素还与scFv M9（一种有效的中和性单克隆抗体片段）协同作用。该项目的目的是评估雷帕霉素是否可以提高抑制HIV进入的单克隆抗体（mAb）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。目标1：鉴定与雷帕霉素协同作用以抑制人PBMC中病毒生长的抗HIV Env、抗CD 4和抗CCR 5抗体;目的2：证明加入雷帕霉素在体外抑制抗体介导的中和抗性病毒的生长;目的3：证明加入雷帕霉素可以恢复相应抗性病毒的抗体介导的中和。基于该I期SBIR的成功，II期SBIR将评估雷帕霉素/抗病毒mAb共制剂在灵长类动物模型中的潜力，作为开发这种治疗HIV感染方法的第一步。本文件包含Profectus BioSciences要求不得向政府以外的人员发布的专有信息，除非用于审查和评估目的。雷帕霉素（Wyeth，麦迪逊，新泽西州）是一种用于肾移植的免疫抑制药物，其下调HIV的关键受体CCR 5的表达。在体外，雷帕霉素增强了阻断HIV进入的抗体的效力。我们正在开发雷帕霉素作为抗艾滋病毒药物与这些抗病毒抗体。本SBIR I期研究的目的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。