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

Award Number: R41CA250616
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2022

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	TEZCAT LABORATORIES LLC	5 W 16TH ST	NEW YORK	NY	10011	NEW YORK	USA	Cancer Treatment Research	000	1	9/15/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $399,877 )
2020	2020	TEZCAT LABORATORIES LLC	5 W 16TH ST APT 12	NEW YORK	NY	10011	NEW YORK	USA	Cancer Treatment Research	000	1	7/15/2020	NEW	$399,877
														Subtotal = $399,877

Grand Total All Awards = $399,877

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

Award Number: R41CA250616

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2022

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