DT-EGF Toxic Fusion Protein for the Treatment of Bladder Cancer

项目摘要/摘要 膀胱癌每年导致全球超过16.5万人死亡，新增7万例，死亡1.6万人 据报道在美国。浅表性膀胱癌切除加卡介苗治疗 40%的复发病例不成功，最终需要膀胱切除术或其他积极治疗； 需要新的治疗方法。表皮生长因子受体在膀胱癌中的作用 发病机制已确定，其病理表达在尿路上皮细胞的管腔侧 70%的患者为膀胱内靶向治疗提供了理想的靶点。我们之前已经演示过 DTEGF-一种单链蛋白，编码已取代B链的修饰白喉毒素(DT) 正常情况下能够与表皮生长因子一起进入细胞的序列-在同基因移植中有效 人膀胱癌啮齿动物模型以及人膀胱癌异种移植瘤的研究 裸鼠。在这些小鼠研究中没有观察到毒性，在狗身上的初步研究也没有观察到毒性。 膀胱内注射DTEGF的浓度远高于疗效所需的浓度，耐受性良好。启用IND-Enabling DTEGF需要进行研究才能进入临床试验。虽然我们有临床前的概念验证 DTEGF，另一家公司已经展示了EPCAM-毒素A融合的第二阶段临床概念验证- 毒素在浅表性膀胱癌患者中显示40%完全应答。他们的工作提供了一种 我们的EGFR靶向毒素已被证明是一条发展道路。目前的赠款申请建议优化 膀胱内给药并随后完成启用IND的安全研究，举行IND前会议 并完成IND申请。这项工作的完成将使我们的代理商成为一名具有非常高 成功的可能性为临床测试做好准备。我们期待DTEGF解决未得到满足的需求 卡介苗失败(40%)和过度表达EGFR(70%)的患者最终成为一线治疗，将 可能与EpCAM靶向和其他疗法合作，使大多数患者受益。

Project Summary/Abstract Bladder cancer causes over 165,000 annual deaths worldwide with 70,000 new cases and 16,000 deaths reported in the US. Treatment of superficial bladder cancer by resection and BCG administration is unsuccessful in 40% of cases with recurrences eventually requiring cystectomy or other aggressive therapy; new therapies are needed. The role of Epidermal Growth Factor Receptor (EGFR) in bladder cancer pathogenesis has been well established and its pathologic expression on the luminal side of uroepithelial cells in 70% of patients provides an ideal target for intravesical targeted therapy. We have previously demonstrated DTEGF—a single chain protein, encoding modified diphtheria toxin (DT) that has replaced the B-chain sequence normally enabling cell entry with that of Epidermal Growth Factor—was efficacious in a syngeneic rodent model of bladder cancer, as well as in a number of xenograph explants of human bladder cancer in nude mice. Toxicity was not observed in these murine studies, nor in a pilot study in dogs demonstrated intravesical DTEGF was well tolerated at concentrations well above those needed for efficacy. IND-enabling studies are needed for DTEGF to move into the clinical testing. While we have preclinical proof-of-concept with DTEGF, another company has demonstrated Phase II clinical proof-of-concept with an EpCAM-toxinA fusion- toxin demonstrating 40% complete response in superficial bladder cancer patients. Their work provides a proven developmental path for our EGFR targeted toxin. The present grant application proposes to optimize intravesical administration and subsequently complete IND-enabling safety studies, hold a pre-IND meeting and complete an IND application. Completion of this work would position our agent as one with a very high likelihood success to be ready for clinically testing. We anticipate DTEGF to address the unmet need of patients that fail BCG (40%) and over express EGFR (70%) and eventually become a first line therapy that will likely work with EpCAM-targeted and other therapies to benefit the majority of patients.