A novel monobody-drug conjugate to treat mutant Ras multiple myeloma

Project Summary: Tezcat is an early-stage biopharmaceutical company developing novel biologics with a unique mechanism of action to treat the most recalcitrant cancers, such as mutant RAS multiple myeloma. Multiple myeloma is an incurable hematologic malignancy with an expected median survival of 7-8 years. Despite an initial response rate approaching 90% to proteasome inhibitor-containing combinations, all patients relapse and eventually become resistant to any treatments. Approximately 70% of these relapse/refractory patients harbor a mutation in RAS. We have observed that mutant RAS multiple myeloma 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. Results from our Phase I STTR project demonstrate that TZT-102 has robust anti-tumor activity in mutant RAS MM xenograft models without showing toxicity issues. Based on the success of our Phase I aims, we have proposed a Phase II SBIR program for investigators at Tezcat to advance TZT- 102 through Specific Aims that will pursue bioanalytical assay development (Aim 1) and non-GLP toxicology studies in rats (Aim 2) to prepare for a pre-IND meeting with the FDA (Aim 3). We further propose to use an Administrative Supplement to initiate bioanalytical assay validation efforts for the detection of the full TZT-102 conjugate and the free drug payload in rat plasma, that will subsequently be used for IND-enabling toxicology studies. 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 the ong- going Phase II SBIR studies and towards IND status and first-in-human clinical trials via a strategic partnership. Thus, we expect this Phase II SBIR and the Administrative Supplement to provide additional support for pursuit of GMP protocols and GLP safety and toxicity studies to support IND submission with the FDA.