Development of Superactive Analogs of Follice Stimulating Hormone (FSH)

不孕症影响约10%的美国夫妇，并且该领域的治疗药物市场非常大且增长迅速，特别是负责卵巢卵母细胞发育的主要激素，卵泡刺激素（FSH）。虽然可用的尿和重组FSH产品已经相当成功，但目前对所有不孕妇女，特别是老年患者和对当前疗法相对无反应的患者的改良FSH类似物的治疗需求尚未得到满足。我们先前已经描述了糖蛋白激素的第一个超活性类似物，其显著增加受体结合亲和力以及体外和体内生物效价和最大功效。在Trophogen，Inc.的第一阶段支持期间，我们已经在包括啮齿动物卵母细胞数量和质量在内的几种体外和体内模型中鉴定了许多有希望的LH和FSH超活性类似物候选物。我们现在希望在II期支持下，将我们的努力集中在我们的主要hFSH类似物候选物和两种替代物与标准重组FSH在各种生理和治疗相关的啮齿动物和非人灵长类动物模型中的进一步体内测试上。具体而言，在啮齿类动物中，我们建议采用经典的Steelman Pohley试验，体外受精和胚胎发育的各种试验，并在选定的情况下，胚胎移植到代孕女性，评估妊娠率和新生幼崽的数量和质量。这些研究将在未成熟、成熟和衰老的啮齿动物以及遗传或化学诱导的不育模型中进行。在非人灵长类动物中，我们建议使用模拟人类ART的方法进行类似物与标准FSH的配对研究。我们还建议使用主要FSH类似物候选物开发其他稳定的细胞系，并优化进一步的纤维床生物反应器生产以及纯化方法。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所选的纯化类似物。

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.