Development of Superactive Analogs of FSH

描述(申请人提供)：大约10%的美国夫妇受到不孕症的影响，这一领域的治疗药物有一个非常巨大且快速增长的市场，特别是负责卵巢卵母细胞发育的主要激素，卵泡刺激素(FSH)。尽管现有的尿液和重组FSH产品已经相当成功，但目前对于所有不孕妇女，特别是老年患者和对当前治疗相对无效的患者，对改进的FSH类似物的治疗需求尚未得到满足。我们之前已经描述了第一个超活性的糖蛋白激素类似物，它显著增加了受体结合亲和力，以及体外和体内的生物潜力和最大疗效。在我们在Trophogen，Inc.的第一阶段支持期间，我们已经在几个体外和体内模型中确定了一些有前景的促黄体生成素和促卵泡刺激素超活性类似物，包括啮齿动物卵母细胞的数量和质量。我们现在希望在第二阶段的支持下，将我们的努力集中在进一步的体内测试上，在各种生理和治疗相关的啮齿动物和非人类灵长类动物模型中，对我们的领先的hFSH类似物和两个替代的标准重组FSH进行测试。具体地说，我们建议在啮齿动物中使用经典的Steelman Pohley试验、体外受精和胚胎发育的各种分析，在选定的情况下，将胚胎移植给代孕雌性，评估怀孕率和新生幼崽的数量和质量。这类研究将在未成熟、成熟和老化的啮齿动物以及那些具有遗传或化学诱导不孕模型的啮齿动物中进行。在非人类灵长类动物中，我们建议用模仿人类艺术的方法对模拟FSH和标准FSH进行配对研究。我们还建议用领先的FSH类似物开发更多稳定的细胞系，并进一步优化纤维床生物反应器的生产和纯化方法。此外，我们计划通过与蛋白质和碳水化合物结构相关的多种物理化学方法来表征选定的纯化类似物。

DESCRIPTION (provided by applicant): Infertility affects about 10% of American couples, and there is a very large and rapidly growing market for therapeutics in this field, particularly the primary hormone responsible for ovarian oocyte development, follicle-stimulating hormone (FSH). Although available urinary and recombinant FSH products have been quite successful, there is currently an unmet therapeutic need for improved FSH analogs for all infertile women and particularly for older patients and those relatively unresponsive to current therapies. We have previously described the first superactive analogs of glycoprotein hormones that considerably increase receptor binding affinity as well as both in vitro and in vivo biopotency and maximal efficacy. During our Phase I support at Trophogen, Inc. we have identified a number of promising LH and FSH superactive analog candidates in several in vitro and in vivo models, including rodent oocyte quantity and quality. We now wish under Phase II support to focus our efforts on further in vivo testing of our lead hFSH analog candidate and two alternates versus standard recombinant FSH in various physiologically and therapeutically relevant rodent and nonhuman primate models. Specifically, in rodents we propose to employ the classic Steelman Pohley assay, various assays of in vitro fertilization and embryo development and, in selected cases, embryo transfer to surrogate females, assessment of pregnancy rates and the quantity and quality of newborn pups. Such studies will be performed in immature, mature and aging rodents as well as in those with models of genetic or chemically induced infertility. In nonhuman primates we propose to do a paired study of analog vs standard FSH using methods emulating human ART. We also propose to develop additional stable cell lines with the lead FSH analog candidates and optimize further fibrous bed bioreactor production as well as purification methods. In addition we plan to characterize selected purified analogs by multiple physicochemical methods relating to both protein and carbohydrate structure.