BIOSYNTHESIS, GLYCOSYLATION, AND ACTION OF THYROTROPIN--CLINICAL TRIALS OF TSH

重组促甲状腺激素已经通过瞬时或间接的新方法产生 α-和HTSH-β微型基因在中国仓鼠中的稳定表达 卵巢细胞。利用大型生物反应器生产的产品作为 作为一个中空纤维生物反应器，我们已经能够提纯几个 百毫克这种产品。一般来说，重组产品是 比标准的脑下垂体促甲状腺激素更稀疏，由至少7 主要在唾液酸含量上不同的异构体。越是被唾弃 形式具有较少的体外生物活性，但代谢较长 清除率和体内生物活性增强。不同的类比 TSH也是通过修改Beta的不同区域而产生的 促甲状腺激素亚单位。这些类似物在体外似乎具有不同的 体内生物活性。特定碳水化合物链在体内的作用 TSH的作用是通过顺序酶促脱糖作用研究的。 重组TSH的体内外特性研究 生物检测。 通过与Genzyme的合作研究和开发协议 波士顿公司的重组人促甲状腺激素正在用于临床 对甲状腺癌患者的研究。这款产品预计将 促进放射性碘的摄取，用于诊断和治疗 目的并消除在以下方面进行摄取研究的需要 甲状腺功能减退的病人。一项调查性的新药申请已经完成 经美国食品和药物管理局批准，一期和二期临床 美国国立卫生研究院和其他四个医疗中心已经完成了试验，显示 19例患者的初步疗效和安全性。第三阶段试验是 目前正在计划中。

Recombinant thyrotropin has been produced by novel methods of transient or stable transfection of alpha and hTSH beta minigenes into Chinese hamster ovary cells. Utilizing products produced in a large scale bioreactor as well as a hollow fiber bioreactor, we have been able to purify several hundred milligrams of this product. In general, the recombinant product is more sialylated than standard pituitary TSH and consists of at least 7 isoforms differing primarily in sialic acid content. The more sialylated forms have less in vitro biologic activity, but a longer metabolic clearance rate and enhanced in vivo biologic activity. Various analogs of TSH have also been produced by modifying various regions of the beta subunit of TSH. Such analogs appear to have different in vitro as well as in vivo biologic activity. The role of specific carbohydrate chains in the action of TSH has been studied by sequential enzymatic deglycosylation of recombinant TSH followed by characterization in in vitro and in vivo bioassays. Through a Cooperative Research and Development Agreement with the Genzyme Corporation (Boston), recombinant human TSH is being used for clinical studies in patients with thyroid cancer. This product is expected to stimulate uptake of radioactive iodine for both diagnostic and therapeutic purposes and to obviate the need for performing uptake studies in hypothyroid patients. An Investigational New Drug Application has been approved by the Food and Drug Administration and phase I and II clinical trials have been completed at NIH and 4 other medical centers showing preliminary efficacy and safety in 19 patients. Phase III trials are currently being planned.