Development of monoclonal catalytic antibodies for HIV immunotherapy

描述（由申请人提供）：我们已经产生了针对gp 120（CD 4 bs）的CD 4结合位点保守区域的鼠单克隆抗体（MAbs），其中和遗传多样性HIV毒株。MAb具有新颖的作用机制。它们水解多个gp 120分子，从而赋予单克隆抗体增加的生物学功效。大约10%的HIV感染者对目前可用的药物方案产生耐药性，并且没有其他治疗选择。我们的MAb旨在满足这一未满足的医疗需求。在目前的I期计划中，我们将进行制备治疗级单克隆抗体所需的分子工程和初步功能研究。我们将：（a）通过将鼠催化可变结构域与人IgG恒定结构域融合，克隆两种免疫原性降低的嵌合MAb（cMAb）;（B）确定cMAb表达与亲本MAb相当的催化和表位特异性性质;（c）确定cMAb中和遗传多样性HIV株的效力作为初始效力指标;和（d）确认cMAb与宿主人蛋白质没有交叉反应，这是设计用于人类临床的MAb的要求。如果cMAb达到I期里程碑，我们将寻求II期支持，用于动物模型功效测试，毒性分析和药代动力学研究，以实现人体测试。 公共卫生相关性：对抗逆转录病毒药物产生耐药性的艾滋病毒感染患者没有适当的治疗方法。我们将研究开发降解HIV外壳蛋白的抗体用于治疗此类患者的可行性。

DESCRIPTION (provided by applicant): We have raised murine monoclonal antibodies (MAbs) to a conserved region of the CD4 binding site of gp120 (CD4bs) that neutralize genetically diverse HIV strains. The MAbs have a novel mechanism of action. They hydrolyze multiple molecules of gp120, thereby imparting MAb increased biological efficacy. About 10% of HIV infected subjects develop resistance to currently available drug regimens and have no other treatment options. Our MAbs are intended to fulfill this unmet medical need. In the present Phase I proposal, we will conduct molecular engineering and initial functional studies necessary to preparing therapy-grade MAbs. We will: (a) clone two chimeric MAbs (cMAbs) with reduced immunogenicity by fusing the murine catalytic variable domains to human IgG constant domains; (b) establish that the cMAbs express catalytic and epitope specificity properties comparable to the parent MAbs; (c) determine the potency with which the cMAbs neutralize genetically diverse HIV strains as the initial efficacy indicator; and (d) confirm the absence of cMAb cross-reaction with host human proteins, a requirement for a MAb designed for clinical use in humans. If the cMAbs meet the Phase I milestones, we will seek Phase II support for animal model efficacy tests, toxicity analysis and pharmacokinetic studies to enable human testing. PUBLIC HEALTH RELEVANCE: No adequate therapies are available for HIV infected patients who develop resistance to antiretroviral drugs. We will examine the feasibility of developing antibodies that degrade the coat protein of HIV for treatment of such patients.