DEVELOPMENT OF ANTICO RECEPTOR MABS FOR HIV THERAPY

描述：（改编自P.I.的摘要）。艾滋病研究的一个主要目标是 开发针对不同阶段的新的抗病毒剂， 病毒复制周期最近，HIV-1与宿主细胞膜的融合已经成为一种新的研究热点。 已经证明需要某些属于人的“辅助受体”分子， 趋化因子受体7跨膜家族（7-TM），G 蛋白偶联受体这些分子提供了很好的靶点， 目前，大部分的药品。这个项目的总体目标是 项目是确定是否抗共受体单克隆抗体（mAb）， 单独使用或与其他抗病毒药物联合使用， 体外抑制HIV-1复制和体内抗感染 最好的系统可用。 在I期项目中，产生了针对CCR 5共受体的mAb， 有效抑制HIV-1进入而不影响正常的CCR 5活性。在 II期项目，将产生HIV-1抑制剂mAb， 趋化因子受体分子已知支持进入广泛的 病毒分离物。将对mAb的生物学特性进行广泛评价 以及它们的抗病毒活性的广度、效力和机制。的潜在 HIV-1通过改变其辅助受体的使用模式而产生耐药性 将在一系列广泛的体外研究中进行探索。具体 抗共受体mAb和其它抗病毒剂的组合将被 检查在预防HIV-1感染中可能的协同活性， 抗药突变体的发展。MAb和组合提供 在体外对HIV-1的最广泛、有效和持续的抑制将 在HIV-1的hu-PBL-SCID和SHIV-猕猴模型中进行体内评价 感染在这里，将测试特定方案的保护能力， 动物抵抗来自不同HIV-1分离株的病毒感染。如果 如果成功，该项目将指导我们选择人源化的mAb， 作为新型治疗药物进入临床开发， 预防HIV-1感染。 拟议商业应用：不可用

DESCRIPTION: (Adapted from P.I.'s abstract). A major goal of HIV research is the development of new antiviral agents that target distinct stages of the viral replicative cycle. Recently, fusion of HIV-1 with host cell membranes has been shown to require certain human "co-receptor" molecules that belong to the chemokine receptor family of seven transmembrane-spanning (7-TM), G protein-coupled receptors. These molecules provide excellent targets for the majority of currently licensed pharmaceuticals. The overall goal of this project is to determine whether anti-co-receptor monoclonal antibodies (mAbs), used alone or in combination with other antiviral agents, can effectively inhibit HIV-1 replication in vitro and protect against infection in vivo using the best systems available. In the Phase I project, mAbs to the CCR5 co-receptor were generated that potently inhibit HIV-1 entry without affecting normal CCR5 activity. In the Phase II project, HIV-1 inhibitor mAbs will be generated to additional chemokine receptor molecules known to support the entry of a wide range of viral isolates. The mAbs will be extensively evaluated for biologic properties and their breadth, potency and mechanism of antiviral activity. The potential for HIV-1 to develop resistance by altering its patterns of co-receptor usage will be explored in an extensive series of in vitro studies. Specific combinations of anti-co-receptor mAbs and other antiviral agents will be examined for possible synergistic activity in preventing HIV-1 infection and the development of drug resistant mutants. MAbs and combinations that provide the most broad, potent, and sustained inhibition of HIV-1 in vitro will evaluated in vivo in the hu-PBL-SCID and SHIV-macaque models of HIV-1 infection. Here specific regimens will be tested for the ability to protect animals against infection by viruses derived from diverse HIV-1 isolates. If successful, this project would guide our selection of mAbs to be humanized and advanced into clinical development as novel agents for the treatment and prophylaxis of HIV-1 infection. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE