Novel Therapy for Tumor-induced Osteomalacia

描述（由申请人提供）：肿瘤诱导骨软化症（TIO，或癌性骨软化症）是一种隐匿的、进行性的副肿瘤疾病，由过量的成纤维细胞生长因子23 （FGF23）引起的磷酸盐和维生素D代谢异常。由于缺乏对这种疾病存在的认识，以及通常症状发作缓慢，TIO的患病率很可能被低估。长期升高的FGF23导致肾磷消耗，导致低磷血症和磷尿症，低维生素D和骨软化，并经常骨折。FGF23升高也可能导致a)继发性甲状旁腺功能亢进（SHPT）， b)肾性骨营养不良，c)骨骼外钙化，d)左心室肥厚（Tomasello, 2008）。FGF23的蛋白水解裂解产生c端肽（FGF23c），作为FGF23全长生物活性形式的内源性抑制剂，减轻FGF23介导的肾磷酸盐消耗（Goetz, 2010）。为了开发基于该抑制剂的最佳治疗方法，我们将创建一种蛋白水解抗体，FGF23- abzyme ！iFGF23-abz是一种双重武器：a)直接结合并中和FGF23， b)释放抑制性FGF23c以减弱FGF23介导的信号传导并恢复体内平衡。根据我们小组（Sharma, 2009）和其他人（Hifumi, 2012; Treweek, 2012）最近设计蛋白水解抗体的成功经验，iFGF23-abz携带一条重链来结合FGF23的氨基末端结构域，以及一条蛋白水解Ab轻链来释放FGF23c。iFGF23-abz有望比传统的抑制性Ab或FGF23c融合蛋白更有效地恢复体内平衡。在I期，将生成一种传统的人抗fgf23抗体，FGF23c和iFGF23-abz，并使用体外检测进行比较。基于这些研究的结果，最佳分子将在II期进一步开发。II期将支持扩大动物研究，使用肾磷酸盐消耗模型、PK/PD、毒理学和生产优化，以支持该孤儿症适应症的IND申请。该疗法的其他孤儿适应症可能包括x连锁低磷血症（XLH）、常染色体显性低磷血症佝偻病（ADHR）、常染色体隐性低磷血症佝偻病（ARHR）和骨纤维性发育不良。

DESCRIPTION (provided by applicant): Tumor-induced osteomalacia (TIO, or oncogenic osteomalacia) is an insidious, progressive, paraneoplastic disorder of abnormal phosphate and vitamin D metabolism caused by excessive fibroblast growth factor 23 (FGF23). Due to a lack of appreciation of the existence of this disease, as well as a typically slow onset of symptoms, the prevalence of TIO is most likely under-estimated. Chronically elevated FGF23 leads to renal phosphate wasting with resultant hypophosphatemia and phosphaturia, low vitamin D, and osteomalacia, with frequent fractures. Elevated FGF23 may also lead to a) secondary hyperparathyroidism (SHPT), b) renal osteodystrophy, c) extra-skeletal calcification, and d) left ventricular hypertrophy (Tomasello, 2008). Proteolytic cleavage of FGF23 produces a C-terminal peptide (FGF23c) that acts as an endogenous inhibitor of the fulllength, bioactive form of FGF23 to alleviate FGF23-mediated renal phosphate wasting (Goetz, 2010). To develop a best-in-class therapeutic based on this inhibitor, we will create a proteolytic antibody, FGF23- abzyme !iFGF23-abzl. iFGF23-abz is a binary weapon: a) directly binding and neutralizing FGF23, and b) releasing the inhibitory FGF23c to attenuate FGF23-mediated signaling and restore homeostasis. Based on recent successes of our group (Sharma, 2009) and others (Hifumi, 2012; Treweek, 2012) with design of proteolytic antibodies, iFGF23-abz carries a heavy chain to bind the amino-terminal domain of FGF23, and a proteolytic Ab light chain to release FGF23c. iFGF23-abz is expected to more efficiently restore homeostasis than a conventional inhibitory Ab or an FGF23c fusion protein. In Phase I, a conventional human anti-FGF23 antibody, FGF23c, and iFGF23-abz will be generated and compared using in vitro assays. Based on the outcome of these studies, the best molecule will be further developed in Phase II. Phase II will support expanded animal studies using renal phosphate wasting models, PK/PD, toxicology, and production optimization to support submission of an IND for this orphan indication. Other orphan indications of this therapy might include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), and fibrous dysplasia of bone.