Project Summary: Multiple myeloma is an incurable hematologic malignancy with an expected median survival of 7-8 years. The proteasome inhibitors, bortezomib, carfilzomib and the recently approved ixazomib, are a mainstay of current myeloma treatment. Despite an initial response rate approaching 90% to proteasome inhibitor-containing combinations, all patients relapse and eventually become resistant to any treatments. Approximately 50% of these patients harbor mutant NRas or KRas. 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. Harnessing this metabolic adaptation, we have created macropinocytosis-targeting monobodies that carry an FDA-approved cytotoxic payload (vc- MMAE). In vitro proliferation assays demonstrate that the monobody-drug conjugates show selectivity for macropinocytosis-positive cancer cells, and maintain potency in the low nanomolar range. Monobody-based technologies display fast clearance rates in humans (1-2hr), but maintain beneficial characteristics of biologics such as tumor accumulation through enhanced permeability and retention (EPR) effect. Thus, we hypothesize that our novel macropinocytosis-targeting monobody-drug conjugates will reduce on-target and off-target effects often seen with traditional antibody-drug conjugates, and fill a void of therapeutic options for patients with mutant Ras multiple myeloma. We propose a Phase I STTR program for investigators at TEZCAT Laboratories and New York University Langone Health to advance this lead through Specific Aims that evaluate the lead drug candidate in controlling human cancer cell growth in vitro (Aim 1) and in a clinically-relevant mouse model of multiple myeloma (Aim 2 & 3). TEZCAT Laboratories has entered into an Option Agreement with NYU for exclusive rights to the technology being developed. The commercialization strategy will be based on establishing initial efficacy and nontoxicity of the lead compound in relation to cellular macropinocytosis levels in Phase I STTR studies, further development towards IND status in Phase II SBIR studies, and then first-in-human clinical trials. Thus, we expect Phase I STTR to provide the basis for pursuit of additional data in Phase II aimed at GMP protocols and further non-GLP and GLP safety and toxicity studies.