Novel Therapy for Tumor-induced Osteomalacia

描述（由申请方提供）：肿瘤诱导的骨软化症（TIO，或致癌性骨软化症）是一种由过量的成纤维细胞生长因子23（FGF 23）引起的磷酸盐和维生素D代谢异常的潜伏性、进行性、副肿瘤性疾病。由于对这种疾病的存在缺乏认识，以及症状通常发作缓慢，TIO的患病率很可能被低估。慢性升高的FGF 23导致肾磷酸盐消耗，从而导致低磷酸盐血症和磷酸盐尿、低维生素D和骨软化症，伴有频繁骨折。FGF 23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）左心室肥大（Tomasello，2008）。FGF 23的蛋白水解裂解产生C-末端肽（FGF 23 c），其作为全长、生物活性形式的FGF 23的内源性抑制剂，以减轻FGF 23介导的肾磷酸盐消耗（Goetz，2010）。为了开发基于这种抑制剂的最佳治疗方法，我们将创建一种蛋白水解抗体，FGF 23- abzyme！iFGF 23-abzl. iFGF 23-abz是二元武器：a）直接结合并中和FGF 23，和B）释放抑制性FGF 23 c以减弱FGF 23介导的信号传导并恢复稳态。基于我们小组（Sharma，2009）和其他人（Hifumi，2012; Treweek，2012）最近成功设计蛋白水解抗体，iFGF 23-abz携带重链以结合FGF 23的氨基末端结构域，和蛋白水解Ab轻链以释放FGF 23 c。预期iFGF 23-abz比常规抑制性Ab或FGF 23 c融合蛋白更有效地恢复体内平衡。在I期，将产生常规人抗FGF 23抗体、FGF 23 c和iFGF 23-abz，并使用体外测定进行比较。基于这些研究的结果，最好的分子将在II期进一步开发。II期将支持使用肾磷酸盐消耗模型、PK/PD、毒理学和生产优化的扩展动物研究，以支持该孤儿适应症的IND提交。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）和骨纤维异常增殖症。

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.