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

摘要 高磷血症性家族性肿瘤钙沉积症(Hftc)是一种患者不能产生生物活性的疾病。 一种激素成纤维细胞生长因子-23(FGF23)，由骨细胞分泌，用于清除身体中的 通过作用于肾脏的磷酸盐。HfTC的特征是血磷(PI)显著升高， 会导致肌肉内大量钙化。高频结直肠癌的钙化负担可能很大， 有些矿化长到2-4磅重，变得非常疼痛，切除后复发。儿科 患者会变得虚弱，因为皮损会破坏皮肤，增加感染率，一些患者 因血管血流丧失而截肢。目前还没有FDA批准的药物或临床药物 高铁技术委员会的试验。唯一可用的治疗方法是标签外的姑息治疗，这对穷人的疗效微乎其微 坚持不懈。Hftc患者存在fgf23基因本身或与其相关的基因的失活突变。 细胞内处理/分泌具有生物活性的FGF23。怀特博士进行了最初的位置克隆 FGF23以确定常染色体显性低磷血症性软骨病的分子基础(ADHR；NAT Gen，2000)， 他的实验室鉴定了来自hftc家族的FGF23失活突变。人类的循环半衰期 FGF23为20-40分钟，使得内源性FGF23替代疗法不切实际。来填补这一空白 治疗需求，怀特博士和他的合作伙伴具有出色的商业化经验，成立了成纤维细胞生长因子 治疗学为异常磷酸盐处理疾病寻求新的治疗方法。延长…的半衰期 FGF23进入治疗范围，怀特博士开发了人源化FGF23-Fc区域融合蛋白 FGF23-稳定突变(‘FGF23-Fc1’)。哺乳动物细胞大规模分泌重组FGF23-Fc1 UP培养，在FGF23联合受体Klotho的存在下，保持了与天然FGF23一样的生物活性。此外， 在正常小鼠体内注射后24小时，人的ELISA可在纳克范围内检测到FGF23-FC1， 而内源性重组FGF23检测不到。此第一阶段提案的目标是开发 通过特定目的：1)验证和优化先导FGF23-Fc1分子用于临床研究 候选的临床前FGF23-Fc1蛋白的体外表达；2)检测FGF23-Fc1的体内生物活性 FGF23-KO hftc小鼠模型的半衰期及救治。总而言之，这项提议的主要结果是 提炼和进一步开发用于hftc替代疗法的领先候选FGF23-Fc1。跟随 成功实现这些目标后，将使用完全人性化的FGF23-FC1执行IND 第二阶段研究，以建立PK和TK。我们在世界各地与医生的联系和团队20年的经验 FGF23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.