SBIR-STTR Award

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.

Project Terms:
Address; aggressive therapy; Antibodies; Applications Grants; Bacillus Calmette-Guerin Therapy; base; Binding; Biological Models; Bladder; Blood; cancer cell; Cancer Etiology; Cancer Patient; Canis familiaris; Cell Adhesion Molecules; cell killing; Cells; Cessation of life; Chimeric Proteins; Clinical; Clinical Data; Complement; conditioning; Cystectomy; Cystoscopy; Data; design; Development; Diphtheria Toxin; Dose; drug efficacy; Drug Kinetics; Drug Targeting; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cells; Excipients; Excision; Formulation; Fusion Toxin; Goals; Grant; high risk; Human; Immunotoxins; improved outcome; In complete remission; in vivo; in vivo Model; Individual; Intravenous; intravesical; Intravesical Administration; Intravesical Instillation; Life; Malignant neoplasm of urinary bladder; Malignant Neoplasms; meetings; Membrane; method development; Methods; Mus; Names; new therapeutic target; novel; novel strategies; novel therapeutics; Nude Mice; outcome forecast; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Positioning Attribute; pre-clinical; Preparation; Proteins; Pseudomonas aeruginosa toxA protein; receptor binding; Recurrence; Reporting; research clinical testing; Rodent Model; Role; Route; Safety; safety study; Sampling; Side; Small Business Innovation Research Grant; Specificity; standard of care; success; Survival Rate; System; TACSTD1 gene; Targeted Toxins; targeted treatment; Temperature; Testing; Time; Tissues; Toxic effect; Toxin; Treatment Protocols; Urine; Urothelial Cell; Validation; Work; Xenograft procedure;

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.

Public Health Relevance Statement:
Project Narrative Annually in the US, 70,000 new cases and 16,000 deaths are due to bladder cancer. This project will complete the work needed for a new therapy—that targets the Epidermal Growth Factor Receptor present on bladder cancer cells—to be ready for testing in bladder cancer patients.

Project Terms:
Address; aggressive therapy; Antibodies; Applications Grants; Bacillus Calmette-Guerin Therapy; base; Binding; Biological Models; Bladder; Blood; cancer cell; Cancer Etiology; Cancer Patient; Canis familiaris; Cell Adhesion Molecules; cell killing; Cells; Cessation of life; Chimeric Proteins; Clinical; Clinical Data; Complement; conditioning; Cystectomy; Cystoscopy; Data; design; Development; Diphtheria Toxin; Dose; drug efficacy; Drug Kinetics; Drug Targeting; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cells; Excipients; Excision; Formulation; Fusion Toxin; Goals; Grant; high risk; Human; Immunotoxins; improved outcome; In complete remission; in vivo; in vivo Model; Individual; Intravenous; intravesical; Intravesical Administration; Intravesical Instillation; Life; Malignant neoplasm of urinary bladder; Malignant Neoplasms; meetings; Membrane; Methods; mortality risk; Mus; Names; new therapeutic target; novel; novel strategies; novel therapeutics; Nude Mice; outcome forecast; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Positioning Attribute; pre-clinical; Proteins; Pseudomonas aeruginosa toxA protein; receptor binding; Recurrence; Reporting; research clinical testing; Rodent Model; Role; Route; Safety; safety study; Sampling; Side; Small Business Innovation Research Grant; Specificity; standard of care; success; Survival Rate; System; TACSTD1 gene; Targeted Toxins; targeted treatment; Temperature; Testing; Time; Tissues; Toxic effect; Toxin; Treatment Protocols; Urine; Urothelial Cell; Validation; Work; Xenograft procedure