TRX1 LEUCINE AND TRX1 PROLINE MABS GIVEN IV: PK, SAFETY, AND TOX

IV 给予 TRX1 亮氨酸和 TRX1 脯氨酸 MABS：PK、安全性和毒性

• 批准号: 7562456
• 负责人: KATHLEEN M BRASKY
• 金额: $ 1.07万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562456
• 关键词: Adverse event; Amino Acid Substitution; Animals; Antibodies; Autopsy; Binding; Biological; Blood specimen; CD4 Antigens; Cell Count; Chemistry; Clinic; Clinical; Computer Retrieval of Information on Scientific Projects Database; Condition; Development; Discoid Lupus Erythematosus; Disease; Dose; Factor VIII; Funding; Grant; Hour; Human body; Immune response; Infusion procedures; Institution; Investigation; Kidney; Leucine; Leukocytes; Lymphocyte; MLL gene; Medical; Medical Assistance; Monitor; Monoclonal Antibodies; Numbers; Organ Transplantation; Papio; Patients; Pharmaceutical Preparations; Phase; Population; Proline; Proteins; Purpose; Range; Recovery; Research; Research Personnel; Resources; Safety; Saline; Serum; Source; Therapeutic Agents; Time; Tissues; United States National Institutes of Health; Variant; Week; cell type; chronic autoimmune disease; day; in vivo; intravenous administration; pre-clinical; prevent; programs; response

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. The purpose of this study is to evaluate the in vivo comparability of two monoclonal antibody (MAB) variants, TRX1 Leucine and TRX1 Proline. TRX1 Leucine and TRX1 Proline are identical except for one amino acid substitution in the Fc region of the antibody. Both MABs bind to the CD4 molecule found on white blood cells (lymphocytes) and are being evaluated as a potential treatment of autoimmune diseases (Chronic cutaneous lupus erythematosus), organ transplantation (kidney) and the extension of the effective use of currently available therapeutic agents (Factor VIII). In these conditions, the human body is rejecting its own protein (causing tissue damage) or a given treatment (rendering it inactive). TRX1 Leucine and TRX1 Proline are both believed to prevent or delay this response and therefore may have an enormous benefit to patients with these diseases or medical needs. Extensive investigation into safety and efficacy has occurred with TRX1 Leucine in baboons at SFBR. TRX1 Leucine single dose, multiple dose and dose ranging studies have been completed in baboons with no MAB related adverse events. TRX1 Proline has been selected for continued clinical development as it is more representative of a naturally occurring antibody and is believed to elicit less of an immune response in vivo. A successful comparison of these two MABs may alleviate the need to repeat an extensive preclinical program in baboons to assess many biological parameters already investigated with regards to TRX1 Leucine. In addition to limiting the use of baboons by streamlining the transition from TRX1 Leucine to TRX1 Proline in the clinic, this study may enable the sponsor to accelerate the pace of moving this beneficial treatment to the populations in need of medical assistance. The animals will be sedated and given seven 1 hour intravenous infusions of either TRX1 Leucine, TRX1 Proline, or saline every other day over a two-week period. Blood samples will be collected at various time points before and after infusions in order to evaluate a number of parameters including drug concentrations, immune response, serum chemistries, cell counts and cell typing. At the end of the seven infusions, 10 treated animals will be sacrificed and a complete necropsy performed. Tissues will be collected to examine possible effects on specific tissues due to drug administration. Prior to sacrifice, four animals, two treated with TRX1 Proline and two treated with saline, will be monitored during a six week recovery phase to assess any prolonged effect of MAB treatment.

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。 本研究的目的是评估两种单克隆抗体 (MAB) 变体 TRX1 亮氨酸和 TRX1 脯氨酸的体内可比性。 TRX1 亮氨酸和 TRX1 脯氨酸相同，只是抗体 Fc 区有一个氨基酸取代。 两种 MAB 均与白细胞（淋巴细胞）上发现的 CD4 分子结合，并正在被评估为自身免疫性疾病（慢性皮肤红斑狼疮）、器官移植（肾脏）和扩展现有治疗药物（因子 VIII）的有效使用的潜在治疗方法。 在这些情况下，人体会排斥自身的蛋白质（导致组织损伤）或特定的治疗（使其失去活性）。 TRX1 亮氨酸和 TRX1 脯氨酸都被认为可以预防或延迟这种反应，因此可能对患有这些疾病或医疗需求的患者带来巨大的好处。 SFBR 对狒狒中 TRX1 亮氨酸的安全性和有效性进行了广泛的研究。 TRX1 亮氨酸单剂量、多剂量和剂量范围研究已在狒狒身上完成，未出现 MAB 相关不良事件。 TRX1 脯氨酸已被选择进行持续的临床开发，因为它更能代表天然存在的抗体，并且被认为在体内引起较少的免疫反应。 这两种 MAB 的成功比较可能会减少在狒狒身上重复进行广泛的临床前计划的需要，以评估已经研究的有关 TRX1 亮氨酸的许多生物参数。 除了通过简化临床中从 TRX1 亮氨酸到 TRX1 脯氨酸的过渡来限制狒狒的使用外，这项研究还可以使申办者加快将这种有益治疗方法推广到需要医疗援助的人群的步伐。 这些动物将被注射镇静剂，并在两周内每隔一天静脉输注 7 次 TRX1 亮氨酸、TRX1 脯氨酸或盐水，每次 1 小时。 将在输注前后的不同时间点收集血样，以评估许多参数，包括药物浓度、免疫反应、血清化学、细胞计数和细胞分型。 在七次输注结束时，将处死 10 只接受治疗的动物并进行完整的尸检。 将收集组织以检查给药对特定组织可能产生的影响。 在处死之前，将在六周的恢复阶段对四只动物（其中两只用 TRX1 脯氨酸处理，两只用盐水处理）进行监测，以评估 MAB 治疗的任何长期效果。