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

DT-EGF 毒性融合蛋白用于治疗膀胱癌

• 批准号: 10261493
• 负责人: Mike Glode
• 金额: $ 100万
• 依托单位: AURORA ONCOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261493
• 关键词: Address; Antibodies; Applications Grants; Bacillus Calmette-Guerin Therapy; Binding; Biological Models; Bladder; Blood; Cancer Etiology; Cancer Patient; Canis familiaris; Cell Adhesion Molecules; Cells; Cessation of life; Chimeric Proteins; Clinical; Clinical Data; Complement; Cystectomy; Cystoscopy; Data; Development; Diphtheria Toxin; Dose; Drug Kinetics; Drug Targeting; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cells; Excipients; Excision; Formulation; Fusion Toxin; Goals; Grant; Human; Immunotoxins; In complete remission; Individual; Intravenous; Intravesical Administration; Intravesical Instillation; Life; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Membrane; Methods; Mus; Names; Nude Mice; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Positioning Attribute; Prognosis; Proteins; Pseudomonas aeruginosa toxA protein; Receptor Cell; Recurrence; Reporting; Rodent Model; Role; Route; Safety; Sampling; Side; Small Business Innovation Research Grant; Specificity; Survival Rate; System; Targeted Toxins; Temperature; Testing; Time; Tissues; Toxic effect; Toxin; Treatment Protocols; Urine; Urothelial Cell; Validation; Work; Xenograft procedure; aggressive therapy; cancer cell; cell killing; conditioning; design; drug efficacy; high risk; improved outcome; in vivo; in vivo Model; intravesical; manufacture; mortality risk; new therapeutic target; novel; novel strategies; novel therapeutics; overexpression; pre-Investigational New Drug meeting; pre-clinical; receptor binding; research clinical testing; safety study; standard of care; success; targeted treatment

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.

项目总结/摘要 膀胱癌每年导致全球超过165，000人死亡，其中70，000例新发病例和16，000例死亡 报道在美国。通过切除和BCG施用治疗浅表性膀胱癌， 40%的复发病例不成功，最终需要环磷酰胺或其他积极治疗; 需要新的疗法。表皮生长因子受体在膀胱癌中的作用 其发病机制已得到很好的确立，其在泌尿上皮细胞腔侧的病理表达 为膀胱内靶向治疗提供了理想的靶点。之前我们已经证实 DTEGF-一种单链蛋白，编码已取代B链的修饰白喉毒素（DT） 序列通常使细胞进入与表皮生长因子-是有效的，在一个同源的， 在膀胱癌的啮齿动物模型中，以及在人膀胱癌的许多异种移植外植体中， 裸鼠在这些小鼠研究中未观察到毒性，在犬的初步研究中也未观察到毒性 膀胱内DTEGF在远高于功效所需的浓度下耐受良好。IND使能 DTEGF进入临床测试需要进行研究。虽然我们有临床前概念验证， 另一家公司DTEGF已经展示了EpCAM-毒素A融合的II期临床概念验证- 在浅表性膀胱癌患者中显示40%的完全反应。他们的工作提供了一个 我们的EGFR靶向毒素的成熟发展路径。目前的拨款申请建议优化 膀胱内给药，随后完成IND支持安全性研究，举行IND前会议 完成IND申请。完成这项工作将使我们的代理人成为一个具有很高声誉的代理人。 成功的可能性为临床测试做好准备。我们预计DTEGF将满足以下未满足的需求： BCG失败（40%）和EGFR过度表达（70%）的患者，最终成为一线治疗， 可能与EpCAM靶向治疗和其他治疗一起工作，使大多数患者受益。