TOXICITY AND SAFETY STUDY OF DB4C7 ANTIBODY IN BABOONS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在此之前，我们已经制备了一种小鼠单克隆抗体B4，其特异性针对CD 4阳性T淋巴细胞上的HIV受体。在用HIV-1分离株攻击黑猩猩之前，将B4抗体注射到黑猩猩体内可预防感染;在第二项研究中，与未接受抗体治疗的病毒血症动物相比，将B4抗体注射到先前感染的黑猩猩体内，血浆中的HIV-1水平立即下降到接近基线。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。由于小鼠B4抗体的多次给药禁忌用于治疗艾滋病患者，因此我们对该抗体（dB 4C 7）进行了人源化，使其抗原性/过敏性降低，因此作为治疗人类HIV感染的免疫抑制剂是安全的。现在，我们需要在dB 4C 7抗体用于人类临床试验之前证明抗体（1）在输注到狒狒中时不会引起不良反应，以及（2）由于其预期与HIV受体结合位点结合，不会对T淋巴细胞的CD 4+亚群的正常功能产生不利影响。这些是FDA定义的免疫缺陷抗体的IND使能毒理学研究的安全性标准。建议的研究有两个具体目标，详见第N部分。研究计划A将评估30天内的药代动力学和安全性。研究计划B将包括一项重复给药GLP投诉毒理学研究，涉及以每周一次的间隔给予8剂抗体。总体而言，本研究将评估dB 4C 7抗体在狒狒中的安全性、耐受性和免疫毒性。我们预计dB 4C 7抗体将是安全的，耐受性良好，它将为HN感染的个体提供免疫治疗选择，无论是单独使用还是与药物（靶向病毒）或其他HIV进入抑制剂药物（靶向病毒受体）联合使用，或感染多重耐药HIV的患者。

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.