A novel monobody-drug conjugate to treat mutant KRas pancreatic cancer.

Project Summary Tezcat Biosciences is developing novel receptor-independent intracellular drug delivery technology with a unique mechanism of action to treat the most recalcitrant cancers, such as mutant RAS pancreatic cancer. Pancreatic ductal adenocarcinoma cancer (PDAC) is associated with a dismal 5-year survival rate and pancreatic cancer patients today have virtually the same therapeutic options available to patients decades ago. This dearth of effective treatments is due in part to the notorious difficulty in targeting the genetic driver of PDAC, oncogenic RAS, as well as features of the PDAC tumor microenvironment itself which obstruct drug delivery. We have observed that mutant RAS PDAC cells display high levels of macropinocytosis, a nutrient scavenging process that facilitates the bulk engulfment of extracellular fluid and its solutes. Our drug candidate, TZT-102, utilizes our proprietary macropinocytosis-selective monobody that carries an FDA-approved cytotoxic payload (MMAE). Results from our Phase I STTR project demonstrate that TZT-102 has robust anti-tumor activity in mutant RAS PDAC xenograft and orthotopic models without displaying systemic toxicity. Based on the success of our Phase I aims, we propose a Phase II SBIR program for investigators at Tezcat to advance TZT-102 through Specific Aims that will execute on bioanalytical assay validation (Aim 1) and further in vivo survival studies utilizing patient-derived xenografts, including those that are resistant to KRASG12D inhibitors (Aims 2 & 3). Tezcat has entered into a license agreement with NYU Langone Health for exclusive, worldwide rights to the technology being developed. The commercialization strategy will be based on further development through Phase II SBIR studies and towards IND status and first-in-human clinical trials through a strategic partnership. Thus, we expect this Phase II SBIR to provide additional support for pursuit of GMP protocols and IND-enabling studies to support IND submission with the FDA.