Development of monoclonal catalytic antibodies for HIV immunotherapy

描述(由申请人提供)：我们已经将小鼠单抗(MAb)提升到gp120(CD4bs)的CD4结合部位的保守区域，以中和遗传多样性的HIV毒株。单抗有一种新的作用机制。它们能降解gp120的多个分子，从而赋予单抗更高的生物学效力。大约10%的艾滋病毒感染者对目前可用的药物方案产生抗药性，并且没有其他治疗选择。我们的单抗旨在满足这一未得到满足的医疗需求。在目前的第一阶段提案中，我们将进行制备治疗级单抗所需的分子工程和初步功能研究。我们将：(A)通过将小鼠的催化可变区与人的免疫球蛋白恒定区融合，克隆两个免疫原性降低的嵌合单抗(CMAb)；(B)确定cMAb表现出与亲本单抗相当的催化和表位特异性；(C)确定cMAb中和遗传多样性的HIV毒株的效力作为初始疗效指标；以及(D)确认CMAB不与宿主人类蛋白发生交叉反应，这是设计用于人类临床的单抗的要求。如果cMAb达到第一阶段的里程碑，我们将寻求第二阶段的支持，以进行动物模型疗效测试、毒性分析和药代动力学研究，以便进行人体测试。 与公共卫生相关：对抗逆转录病毒药物产生抗药性的艾滋病毒感染者没有适当的治疗方法。我们将研究开发可降解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.