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

目前，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，用于改进并首次通过加速到发情时代在猪和牛身上进行完全合乎道德的繁殖，估计每年的市场价值超过2亿美元，一个潜在的兽医产品“重磅炸弹”！目前使用的动物产品-怀孕母马血清促性腺激素(PMSG)-通过越来越多的人认识到高贵怀孕母马的非人道出血而获得的极具争议的产品，引起了动物权利活动家、监管和政治机构越来越多的关注，他们已经或即将计划禁止销售PMSG。我们之前的第一阶段心电SBIR达到了25分的显著影响分数，并在第一次提交时得到了NICHD的资助。目前这份第二阶段SBIR提案最显著的方面是，首先，我们提供了令人信服的数据，这些数据不仅实现了，而且大大超过了我们第一阶段心电模拟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默克动物健康公司达成了一项非常有利的商业化协议，默克动物健康公司是目前领先的PMSG产品的制造商，该公司非常希望用这种经过极大改进的重组模拟药物来取代其天然的心电。我们的目标是：第一年目标1：提高其生物反应器的表达、糖基化和主要的商业规模；以及方法：A.贴壁CHO细胞悬浮的最先进的渗透微球；B.第一阶段开发的更大的纤维床生物反应器；C.贴壁CHO细胞在悬浮培养中直接生长的可能性；目标2：在啮齿动物身上进行广泛的PK研究，以建立体内生物检测的最佳剂量范围和注射数量。第2年目标1：在GMP条件下开发CHO细胞主细胞库，无论是贴壁细胞还是悬浮细胞，适合转移到默克动物健康商业生物反应堆设施；目标2：在适合向FDA-CVM提交INAD的GLP条件下，同时在猪和奶牛中测试心电的多种商业用途，并开始监管讨论，以快速批准对人和动物的安全和对马的伦理治疗：a.在母猪和母猪中同步和加速发情；b.在小母牛和奶牛中同步和加速发情；c.牛的超排；目的3：检测默克PG 600中人CG成分的假定免疫原性：A.单次和重复使用hCG和心电图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Zoetis合作将其第一个兽用牛FSH类似物商业化方面取得了显著成功，现在，第二个是由排名第三的动物制药公司默克动物健康公司提供的其心电类似物，我们认为这项第二阶段的提议非常值得加快批准。

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.