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的第二个兽药产品，第一个更有效和长效的重组马绒毛膜促性腺激素（reCG）激动剂的当前提案，用于通过加速发情时间来改善猪和牛的繁殖，首次完全符合伦理道德，估计每年市场超过2亿美元，这是一个潜在的兽药产品“重磅炸弹”！目前使用的动物产品，怀孕的母马血清促性腺激素（PMSG），越来越多地被认为是不人道的出血的高贵怀孕的母马是非常有争议的，引起了越来越多的关注，动物权利活动家，监管和政治机构已经或即将计划禁止销售的PMSG。我们之前的第一阶段eCG SBIR取得了25分的显著影响力得分，并在首次提交时得到了NICHD的资助。目前第2阶段SBIR提交的最值得注意的方面是，首先，我们提供了令人信服的数据，我们不仅实现了而且大大超过了我们第1阶段eCG模拟SBIR提案的所有目标。其次，值得注意的是，我们已经在第一阶段与Merck Animal Health建立了非常有利的商业化协议，Merck Animal Health是目前领先的PMSG产品的制造商，该产品非常希望用这种大大改进的重组类似物取代其天然eCG。我们的目标是：第一年目标1：提高表达、糖基化及其生物反应器生产和纯化方法的大规模商业化：A.现有技术水平的具有悬浮的粘附CHO细胞的可渗透珠; 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中的直接生长;目的2：在啮齿动物中进行广泛的PK研究，以模拟体内生物测定的优化剂量范围和注射次数。第二年目标1：在GMP条件下开发适合转移至Merck Animal Health商业生物反应器设施的贴壁或悬浮细胞的CHO细胞主细胞库;目的2：在适合向FDA提交INAD的GLP条件下，与Merck Animal Health平行在猪和牛中检测eCG的多种商业用途-CVM和开始关于人类和动物安全以及马匹伦理治疗的快速通道批准的监管讨论：小母猪和母猪的同期发情和加速发情; B.小母牛和母牛的同期发情和加速发情;牛的超数排卵;目的3：检测Merck PG 600：A中人CG成分的假定免疫原性。单次和重复使用hCG和eCG的血清免疫原性研究; B。重复使用可能减弱临床反应。鉴于PI在与世界领先的动物制药公司硕腾公司（Zoetis）将其第一个兽用牛FSH类似物产品商业化方面取得了显著成功，现在，第二个是由第三大动物制药公司默克动物保健公司（Merck Animal Health）将其eCG类似物商业化，我们认为该II期提案非常值得加快批准。