TOXICITY AND SAFETY STUDY OF DB4C7 ANTIBODY IN BABOONS

DB4C7抗体在狒狒体内的毒性及安全性研究

• 批准号: 7957935
• 负责人: Krishna K Murthy
• 金额: $ 18.53万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-06 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957935
• 关键词: Acquired Immunodeficiency Syndrome; Adverse reactions; Affect; Animals; Antibodies; Binding; Binding Sites; CD4 Positive T Lymphocytes; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Dose; Drops; Drug Delivery Systems; Drug Kinetics; Funding; Grant; HIV; HIV Entry Inhibitors; HIV Infections; HIV Receptors; HIV-1; Human; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Infection prevention; Infusion procedures; Injection of therapeutic agent; Institution; Monoclonal Antibodies; Multi-Drug Resistance; Mus; Pan Genus; Papio; Patients; Plan B; Plasma; Primates; Research; Research Personnel; Resources; Retroviridae; Safety; Source; Toxic effect; Toxicology; United States National Institutes of Health; Virus; Virus Receptors; immunotoxicity; receptor binding; safety study

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 此前，我们已经制备了一种小鼠单克隆抗体 B4，特异性针对 CD4 阳性 T 淋巴细胞上的 HIV 受体。在用 HIV-1 分离物攻击黑猩猩之前，向黑猩猩注射 B4 抗体可预防感染；在第二项研究中，与未经抗体治疗的病毒血症动物相比，向先前感染的黑猩猩注射 B4 抗体，血浆中的 HIV-1 水平立即降至接近基线。 HIV-1 是一种导致人类艾滋病（获得性免疫缺陷综合症）的逆转录病毒。由于多次施用小鼠 B4 抗体对于治疗 AIDS 患者是禁忌的，因此我们对这种抗体 (dB4C7) 进行了人源化，以使其抗原性/过敏性降低，因此作为治疗人类 HIV 感染的免疫治疗剂是安全的。现在，我们需要在将dB4C7抗体用于人体临床试验之前证明，该抗体(1)在输注给狒狒时不会引起不良反应，(2)由于其预期与HIV受体结合位点结合，因此不会对T淋巴细胞CD4+子集的正常功能产生不利影响。这些是 FDA 定义的免疫治疗抗体 IND 毒理学研究的安全标准。拟议的研究有两个具体目标，如 N 部分所述。研究计划 A 将评估 30 天期间的药代动力学和安全性。研究计划 B 将包括重复剂量的符合 GLP 标准的毒理学研究，涉及每周施用 8 剂抗体。总的来说，这项研究将评估狒狒中 dB4C7 抗体的安全性、耐受性和免疫毒性。我们预计 dB4C7 抗体将是安全且耐受性良好的，它将为 HN 感染个体提供免疫治疗选择，无论是单独使用还是与药物（针对病毒）或其他 HIV 进入抑制剂药物（针对病毒受体）联合使用，或者为感染多重耐药 HIV 的患者提供免疫治疗选择。