Novel Recombinant High-Affinity, Long- and Dual-Acting Equine CG Analogs for Improved and More Ethical Reproduction in Pigs and Cattle

新型重组高亲和力、长效和双效马 CG 类似物，可改善猪和牛的繁殖并使其更加合乎道德

• 批准号: 9898401
• 负责人: MARIUSZ W SZKUDLINSKI
• 金额: $ 72.76万
• 依托单位: TROPHOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898401
• 关键词: Acceleration; Achievement; Affinity; Agonist; Agreement; Animal Rights; Animals; Beds; Bioreactors; Cattle; Cells; Chinese Hamster Ovary Cell; Chorionic Gonadotropin; Clinical; Country; Data; Development; Diagnosis; Dose; Equus caballus; Estrus; Ethics; Family suidae; Funding; Generations; Glycoproteins; Goals; Growth; Health; Hemorrhage; Hormones; Human; Human Chorionic Gonadotropin; Human Follicle Stimulating Hormone; Infertility; Injections; Licensing; Livestock; Malignant neoplasm of thyroid; Manufacturer Name; Methods; Modeling; National Institute of Child Health and Human Development; PMSG (Gonadotropins); Permeability; Phase; Politics; Production; Recombinants; Recording of previous events; Reproduction; Research; Risk; Rodent; Sales; Serum; Small Business Innovation Research Grant; Study Section; Superovulation; Suspension Culture; Suspensions; Testing; Time; United States National Institutes of Health; Work; analog; animal safety; attenuation; cell bank; commercial application; commercialization; egg; experience; glycosylation; hormone analog; immunogenicity; improved; in vivo Bioassay; novel; pregnant; response; scale up; success

The current proposal of the PI’s second veterinary product, the first more potent and long acting recombinant equine chorionic gonadotropin (reCG) agonist for improved and, for the first time, totally ethical reproduction in pigs and cattle by acceleration to the times of estrus is estimated to be $ 200 M + annual market, a potential veterinary product “blockbuster”! The currently used animal product, pregnant mare serum gonadotropin (PMSG) obtained by increasingly recognized inhumane bleeding of noble pregnant mares is highly controversial, has raised increasing concerns among animal rights activists, regulatory and political bodies which have already or soon plan to ban the sale of PMSG. Our previous Phase 1 eCG SBIR achieved a remarkable impact score of 25 and was funded by NICHD in its first submission. The most remarkable aspects of this current Phase 2 SBIR submission is that, first, we provide compelling data that we have not only achieved but have greatly exceeded all aims of our Phase 1 eCG analog SBIR proposal. Secondly and remarkably, we have already established an extraordinarily advantageous commercialization agreement in Phase 1 with Merck Animal Health, the manufacturer of the leading current PMSG product which vitally wishes to replace its natural eCG with this greatly improved recombinant analog. Our aims are: YEAR 1 Aim 1: Improve expression, glycosylation and a major commercial scale up of its bioreactor production and purification methods: A. State of the art permeable beads with adherent CHO cells in suspension; B. Larger fibrous bed bioreactor as developed in Phase 1; C. Possible adaptation of adherent CHO cells to direct growth in suspension culture; Aim 2: Extensive PK studies in rodents to model optimized dose ranging amount and injection number of in vivo bioassays. YEAR 2 Aim 1: Development of CHO Cell Master Cell Bank under GMP conditions of either adherent or suspension cells suitable for transfer to a Merck Animal Health Commercial Bioreactor Facility; Aim 2: Testing of multiple commercial uses of the eCG in both pigs and cows in parallel with Merck Animal Health under GLP conditions suitable to submit an INAD to FDA-CVM and begin regulatory discussions for Fast Track Approval for human and animal safety and ethical treatment of horses: A. Synchronization and acceleration to estrus in gilts and sows; B. Synchronization and acceleration to estrus in heifers and cows; C. Superovulation of cattle; Aim 3: Testing for presumed immunogenicity of the human CG component within Merck’s PG 600: A. Serum immunogenicity studies to hCG and eCG on single and repeated use; B. Possible attenuation of clinical response in repeated use. In view of the PI’s remarkable success in commercializing its very first veterinary bovine FSH analog product with world leader animal pharma Zoetis and now, secondly, for its eCG analog by number 3 animal pharma, Merck Animal Health, we believe this Phase 2 proposal strongly merits expedited approval.

PI 目前提出的第二种兽药产品是第一种更有效、更长效的重组马绒毛膜促性腺激素 (reCG) 激动剂，用于通过加速发情时间来改善猪和牛的繁殖，并且首次实现完全合乎道德的繁殖。年市场规模达2亿美元+，潜在兽药产品“重磅炸弹” 目前使用的动物产品，孕马血清促性腺激素（PMSG）越来越多的人认识到，通过高贵怀孕母马的不人道放血而获得的物质存在很大争议，引起了动物权利活动人士、监管机构和政治机构越来越多的关注，他们已经或很快计划禁止销售 PMSG。我们之前的第一阶段 eCG SBIR 取得了显着的影响。得分为 25，并在首次提交中得到了 NICHD 的资助，当前第 2 阶段 SBIR 提交的最引人注目的方面是，首先，我们提供了令人信服的数据，这些数据不仅实现了，而且远远超出了我们第 1 阶段 eCG 的所有目标。特别且不寻常的是，我们已经在第一阶段与默克动物健康公司（Merck Animal Health）建立了一项非常有利的商业化协议，默克动物健康公司是当前领先的 PMSG 产品的制造商，该公司非常希望用这种大大改进的重组类似物取代其天然心电图。第 1 年目标 1：改善表达、糖基化以及生物反应器生产和纯化方法的主要商业规模扩大： A. 最先进的具有贴壁 CHO 细胞的渗透性珠子B. 第一阶段开发的更大的纤维床生物反应器；C. 贴壁 CHO 细胞可能适应悬浮培养的直接生长；目标 2：在啮齿动物中进行广泛的 PK 研究，以模拟第 2 年体内生物测定的最佳剂量范围和注射次数目标 1：在 GMP 条件下开发适合转移至默克动物健康商业生物反应器设施的 CHO 细胞主细胞库； 2：与默克动物健康公司在适合向 FDA-CVM 提交 INAD 的 GLP 条件下，对猪和牛的 eCG 的多种商业用途进行测试，并开始针对人类和动物安全和伦理治疗的快速审批进行监管讨论马： A. 后备母猪和母猪发情的同步和加速； B. 小母牛和母牛发情的同步和加速； C. 牛的超数排卵；对于默克 PG 600 中人类 CG 成分的假定免疫原性：A. 单次和重复使用时对 hCG 和 eCG 的血清免疫原性研究；B. 重复使用时临床反应可能减弱，因为 PI 在商业化方面取得了巨大成功。世界领先的动物制药公司硕腾 (Zoetis) 推出首款兽用牛 FSH 类似物产品，现在，第三大动物制药公司默克动物公司 (Merck Animal) 推出心电图类似物产品健康，我们相信这个第二阶段提案非常值得加速批准。