PHARMACOKINETIC, PHARMACODYNAMIC, SAFETY AND TOXICOLOGICAL COMPARABILITY STUDY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本研究旨在评价两种单克隆抗体（MAB）变体TRX 1亮氨酸和TRX 1脯氨酸的体内可比性。TRX 1亮氨酸和TRX 1脯氨酸除抗体Fc区的一个氨基酸取代外均相同。 两种MAB均与在白色血细胞（淋巴细胞）上发现的CD 4分子结合，并被评价为自身免疫性疾病（慢性皮肤红斑狼疮）、器官移植（肾）的潜在治疗和目前可用治疗剂（因子VIII）有效使用的扩展。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（使其失活）。TRX 1亮氨酸和TRX 1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有医疗需求的患者有巨大的益处。在SFBR对TRX 1亮氨酸在狒狒中的安全性和有效性进行了广泛研究。已在狒狒中完成TRX 1亮氨酸单次给药、多次给药和剂量范围研究，未发生MAB相关不良事件。TRX 1脯氨酸已被选择用于继续临床开发，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应答。这两种MAB的成功比较可能减轻在狒狒中重复广泛的临床前项目以评估已研究的TRX 1亮氨酸的许多生物学参数的需要。除了通过简化从TRX 1亮氨酸到TRX 1脯氨酸的转换来限制狒狒的使用外，本研究还可以使申办者加快将这种有益治疗转移到需要医疗援助的人群中的步伐。 将对动物进行镇静，并在两周内每隔一天静脉输注TRX 1亮氨酸、TRX 1脯氨酸或生理盐水7次，每次1小时。将在输注前后的不同时间点采集血样，以评价许多参数，包括药物浓度、免疫应答、血清化学、细胞计数和细胞分型。在7次输注结束时，将处死10只给药动物，并进行完整尸检。将采集组织以检查给药对特定组织的可能影响。 处死前，在6周恢复期内监测4只动物（2只接受TRX 1脯氨酸治疗，2只接受生理盐水治疗），以评估MAB治疗的任何延长效应。

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.