TOXICITY AND SAFETY STUDY OF DB4C7 ANTIBODY IN BABOONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 此前，我们已经研制出抗HIV受体的小鼠单抗B4，定位于CD4阳性的T淋巴细胞上。在用HIV-1分离株攻击之前向黑猩猩注射B4抗体可以防止感染；在第二项研究中，与没有接受抗体治疗的病毒感染动物相比，在先前感染的黑猩猩中注射B4抗体立即将血浆中的HIV-1水平降低到接近基线水平。HIV-1是导致人类艾滋病(获得性免疫缺陷综合征)的逆转录病毒。由于多次注射小鼠B4抗体是治疗艾滋病患者的禁忌，我们将其人源化，使其抗原性/过敏性较低，因此作为治疗人类艾滋病毒感染的免疫治疗剂是安全的。现在，在DB4C7抗体用于人类临床试验之前，我们需要证明：(1)该抗体(L)在注射到狒狒体内时不会引起不良反应；(2)由于预期会与HLV受体结合部位，因此不会对T淋巴细胞亚群的正常功能产生不利影响。这些是FDA定义的启用LND的免疫治疗性抗体毒理学研究的安全标准。这项拟议的研究有两个具体目标，如N部分所述。研究计划A将在30天内评估药物动力学和安全性。B研究计划将包括一项重复剂量的GLP抵抗毒理学研究，包括每周间隔注射8剂抗体。总体而言，这项研究将评估dB4C7抗体在狒狒中的安全性、耐受性和免疫毒性。我们预计dB4C7抗体将是安全和耐受性良好的，它将为单独感染HN的个人或与药物(针对病毒)或其他艾滋病毒进入抑制药物(针对病毒受体)或感染多重耐药艾滋病毒的患者提供一种免疫治疗选择。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previously, we have made a mouse monoclonal antibody, B4, specific against HIV receptor on CD4-positive T-lymphocytes. Injection ofB4 antibody into chimpanzees before challenge with a HIV-1 isolate prevented infection; in a second study, injection of B4 antibody in previously infected chimpanzees immediately dropped the HIV-1 leve1s in plasma to near baseline when compared to viremic animals without antibody treatment. HIV-1 is the retrovirus that causes AIDS (Acquired Immunodeficiency Syndrome) in humans. Since multiple administrations of the mouse B4 antibody is contraindicated for treatment of patients with AIDS, we have humanized thus antibody (dB4C7) to make it less antigenic/allergeric, and therefore safe as a immunotherapeutic agent for treatment of HIV infection in humans. Now, we need to show before dB4C7 antibody is used in human clinical trials, that the antibody (l) does not cause adverse reactions upon infusion into baboons and (2) does not adversely affect the normal function of CD4+ subset of T-Iymphocytes due to its anticipated binding to the HlV receptor binding site. These are safety criteria for the FDA-defined lND-enabling toxicology study of an immunotherapeutic antibody. The proposed study has two specific objectives as described in Part N. Study Plan A will assess the pharmacokinetics and safety over a 30 day period. Study Plan B will consist of a repeat dose GLP-complaint toxicology study involving 8 doses of antibody administered at weekly intervals. Overall this study will assess safety, tolerability and immunotoxicity of the dB4C7 antibody in baboons. We anticipate that dB4C7 antibody will be safe and well tolerated and it will provide an immunotherapy option for individuals with HN infection either alone or in combination with drugs (targeting the virus) or other HIV entry inhibitor drugs (targeting for virus receptor) or for patients infected with multiple' drug resistant HIV.