Novel Therapy for Hyperphosphatemic Familial Tumoral Calcinosis (hfTC) and Generalized Hyperphosphatemia

摘要 高磷血症家族性肿瘤性钙质沉着症（hfTC）是一种患者不能产生生物活性物质的疾病， 成纤维细胞生长因子23（FGF 23）是一种激素，由骨细胞分泌，用于清除体内的 磷酸盐作用于肾脏。hfTC的特征是血清磷酸盐（Pi）显著升高， 导致肌肉内出现大量钙化hfTC的钙化负担可能很大， 一些矿化生长到2-4磅重，变得非常痛苦，切除后复发。儿科 患者会变得虚弱，因为病变会破坏皮肤，增加感染率， 由于血管血流不足而截肢。目前没有FDA批准的药物或临床 对HFTC的试验。唯一可用的治疗方法是适应症外姑息治疗， 坚持。hfTC患者在FGF 23基因本身或与hfTC相关的基因中存在失活突变， 生物活性FGF 23的细胞内加工/分泌。白色博士进行了最初的位置克隆 FGF 23，以确定常染色体显性遗传性低磷酸盐血症性佝偻病的分子基础（ADHR; Nat Gen，2000）， 他的实验室鉴定了来自hfTC家族的FGF 23失活突变。人体循环半衰期 FGF 23是20-40分钟，使得内源性FGF 23替代疗法不切实际。为了填补这一空缺 白色博士和他的合作伙伴具有出色的商业化经验，形成了FGF 寻求磷酸盐处理异常疾病的新疗法。为了延长 为了将FGF 23纳入治疗范围，白色博士开发了一种人源化FGF 23-Fc区融合蛋白， FGF 23稳定突变（“FGF 23-Fc 1”）。重组FGF 23-Fc 1由哺乳动物细胞大规模分泌 在培养物中，并且在FGF 23共受体Klotho存在下，保留了与天然FGF 23一样的生物活性。此外，本发明还 FGF 23-Fc 1在正常小鼠中注射后24小时可以通过人ELISA检测到纳克范围， 而内源性重组FGF 23检测不到。第一阶段提案的目标是开发 一种用于临床研究的先导FGF 23-Fc 1分子，其具体目的是：1）验证和优化 体外候选临床前FGF 23-Fc 1蛋白;和2）测试FGF 23-Fc 1的体内生物活性，以延长FGF 23-Fc 1的体内生物活性。 Fgf 23-K 0 hfTC小鼠模型的半衰期和挽救。总而言之，这项建议的主要成果是 用于hfTC替代疗法的先导FGF 23-Fc 1候选物的改进和进一步开发。以下 为了成功实现这些目标，完全人源化的FGF 23-Fc 1将用于进行IND使能性治疗。 II期研究，以确定PK和TK。我们与医生和团队的全球联系>20年 FGF 23领域的经验将支持这些未来的研究。

Abstract Hyperphosphatemic familial tumoral calcinosis (hfTC) is a disease in which patients cannot produce the bioactive form of the hormone Fibroblast growth factor-23 (FGF23), which is secreted by osteocytes to rid the body of phosphate by acting on the kidney. hfTC is characterized by markedly elevated serum phosphate (Pi) which causes large intramuscular calcifications to develop. The calcification burden in hfTC can be substantial, with some mineralizations growing to weigh 2-4 pounds, becoming very painful and recur after resection. Pediatric patients can become debilitated, as the lesions can break the skin to increase infection rates, and some patients have had amputations due to loss of vascular blood flow. Currently there are no FDA-approved agents or clinical trials for hfTC. The only available treatments are off-label palliative care, which is minimally effective with poor adherence. Patients with hfTC have inactivating mutations in the FGF23 gene itself or in genes associated with the intracellular processing/secretion of bioactive FGF23. Dr. White carried out the original positional cloning of FGF23 to identify the molecular basis of autosomal dominant hypophosphatemic rickets (ADHR; Nat Gen, 2000), and his lab characterized FGF23 inactivating mutations from hfTC families. The circulating half-life of human FGF23 is 20-40 minutes, making endogenous FGF23 replacement therapy impractical. To fill this unmet therapeutic need, Dr. White and his partners with outstanding commercialization experience formed FGF Therapeutics to pursue novel therapies for diseases of aberrant phosphate handling. To extend the half-life of FGF23 into a therapeutic range, Dr. White developed a humanized FGF23-Fc region fusion protein harboring FGF23-stabilizing mutations (‘FGF23-Fc1’). Recombinant FGF23-Fc1 is secreted by mammalian cells in scale up cultures, and in the presence of the FGF23 co-receptor Klotho, retains bioactivity like native FGF23. Further, FGF23-Fc1 can be detected by human ELISAs in the nanogram range 24 h after injection in normal mice, whereas endogenous recombinant FGF23 was undetectable. The objective of this Phase I proposal is to develop a lead FGF23-Fc1 molecule for clinical investigation through the specific aims: 1) Verify and optimize the candidate pre-clinical FGF23-Fc1 protein in vitro; and 2) Test the in vivo bioactivity of FGF23-Fc1 for extended half-life and rescue of the Fgf23-KO hfTC mouse model. In sum, the primary outcome of this proposal is refinement and further development of a lead FGF23-Fc1 candidate for hfTC replacement therapy. Following successful accomplishment of these aims, the fully humanized FGF23-Fc1 will be used to perform IND-enabling studies in Phase II to establish PK and TK. Our worldwide connections with physicians and the team’s >20 year experience in the FGF23 field will support these future studies.