PHARMACOKINETIC, PHARMACODYNAMIC, SAFETY AND TOXICOLOGICAL COMPARABILITY STUDY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。本研究的目的是评价两种单抗(MAB)变异体TRX1亮氨酸和TRX1 Pro的体内可比性。TRX1亮氨酸和TRX1 Pro除了在抗体的Fc区有一个氨基酸替换外，其余均相同。这两种单抗都与白细胞(淋巴细胞)上发现的CD4分子结合，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)和扩大目前可用的治疗剂的有效使用(第八因子)的潜在治疗方法。在这些情况下，人体排斥自己的蛋白质(导致组织损伤)或特定的治疗(使其处于不活动状态)。TRX1亮氨酸和TRX1 Pro都被认为可以防止或推迟这种反应，因此可能对患有这些疾病或有医疗需求的患者有巨大的好处。在SFBR，已经对使用TRX1亮氨酸的狒狒的安全性和有效性进行了广泛的调查。TRX1亮氨酸的单剂量、多剂量和剂量范围的研究已经在无MAB相关不良事件的狒狒身上完成。TRX1 Proline被选择用于继续临床开发，因为它更能代表一种自然产生的抗体，被认为在体内引起的免疫反应较少。这两个MAB的成功比较可能会减轻在狒狒身上重复广泛的临床前计划以评估与TRX1亮氨酸相关的许多生物学参数的需要。除了通过简化临床上从TRX1亮氨酸到TRX1 Pro的过渡来限制狒狒的使用外，这项研究还可能使赞助商加快将这种有益的治疗转移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给予七次1小时的TRX1亮氨酸、TRX1 Pro或生理盐水静脉输注。在输液前后的不同时间点将采集血液样本，以评估一系列参数，包括药物浓度、免疫反应、血清化学、细胞计数和细胞分类。在七次输液结束时，10只经过处理的动物将被处死，并进行全面的尸检。将收集组织以检查药物给药对特定组织可能产生的影响。在牺牲前，将在六周的恢复期内监测四只动物，其中两只接受TRX1 Proline治疗，两只接受生理盐水治疗，以评估MAB治疗的任何长期效果。

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.