SBIR-STTR Award

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.

Public Health Relevance Statement:


Project narrative:
TEZCAT Laboratories LLC is an early-stage biotechnology company focused on developing innovative therapeutics to treat mutant Ras cancers. In this Phase I STTR, TEZCAT Laboratories is developing a proprietary macropinocytosis-targeting monobody-drug conjugate for the treatment of multiple myeloma.

Project Terms:
Agreement; Antibody-drug conjugates; base; Binding Proteins; Biodistribution; Biologic Characteristic; Biological; Biological Assay; Biotechnology; Bone Tissue; Bortezomib; cancer cell; Cancer Cell Growth; Cell Line; Cells; Characteristics; Clinic; Clinical Trials; clinically relevant; Colorectal Cancer; commercialization; cyanine dye 5; cytotoxic; cytotoxicity; Data; Development; Dose; drug candidate; Drug Compounding; Drug Delivery Systems; efficacy testing; Equus caballus; Evaluation; expectation; experience; Extracellular Fluid; Extracellular Protein; FDA approved; Fibronectins; first-in-human; Government; Growth; Health; Hematologic Neoplasms; Human; implantation; In Vitro; in vivo; Incidence; Injections; innovation; Knowledge; Laboratories; Lead; Liquid substance; Lytic; Magnetic Resonance Imaging; Malignant neoplasm of pancreas; Malignant Neoplasms; Marrow; Metabolic; Metabolic Clearance Rate; Microscopy; Modeling; Monitor; Morbidity - disease rate; mortality; mouse model; Multiple Myeloma; mutant; nanomolar; neoplastic cell; New York; novel; novel drug class; novel therapeutics; Nutrient; Organ; Oryctolagus cuniculus; Osteogenesis; Patients; Penetration; Permeability; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Preclinical Testing; Process; programs; Proteasome Inhibitor; Proteins; Protocols documentation; ras Oncogene; relapse patients; Research Personnel; Resistance; Resources; response; Rights; Safety; SCID Mice; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Solubility; solute; Specificity; subcutaneous; Tail; Technology; Testing; Therapeutic; therapeutic development; Tissues; Toxic effect; Toxicology; Treatment Efficacy; tumor; Tumor Burden; Universities; Validation; validation studies; Veins

Tezcat is an early-stage, biopharmaceutical company developing novel biologics with a uniquemechanism of action to treat the most recalcitrant cancers, such as mutant RAS multiplemyeloma. Multiple myeloma is an incurable hematologic malignancy with an expected mediansurvival 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 haveobserved that mutant RAS multiple myeloma cells display high levels of macropinocytosis, anutrient scavenging process that facilitates the bulk engulfment of extracellular fluid and itssolutes. Our drug candidate, TZT-102, utilizes our proprietary macropinocytosis-selectivemonobody that carries an FDA-approved cytotoxic payload. Results from our Phase I STTRproject demonstrate that TZT-102 has robust anti-tumor activity in mutant RAS MM xenograftmodels without showing toxicity issues. Based on the success of our Phase I aims, we proposea Phase II SBIR program for investigators at Tezcat to advance TZT-102 through Specific Aimsthat 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). Tezcat has entered into a licenseagreement with NYU Langone Health for exclusive, worldwide rights to the technology beingdeveloped. The commercialization strategy will be based on further development through PhaseII SBIR studies and towards IND status and first-in-human clinical trials through a strategicpartnership. Thus, we expect this Phase II SBIR to provide additional support for pursuit of GMPprotocols and GLP safety and toxicity studies to support IND submission with the FDA.

Public Health Relevance Statement:


Project narrative:
Tezcat Biosciences is an early-stage biotechnology company focused on developing innovative therapeutics to treat mutant RAS cancers. In this Phase II SBIR, Tezcat is further developing a proprietary monobody-MMAE conjugate for treatment of multiple myeloma.

Project Terms: