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

> **NIH NIH R41** · TEZCAT LABORATORIES LLC · 2020 · $399,877

## Abstract

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.

## Key facts

- **NIH application ID:** 10080987
- **Project number:** 1R41CA250616-01A1
- **Recipient organization:** TEZCAT LABORATORIES LLC
- **Principal Investigator:** DAFNA BAR-SAGI
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,877
- **Award type:** 1
- **Project period:** 2020-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10080987

## Citation

> US National Institutes of Health, RePORTER application 10080987, A novel monobody-drug conjugate to treat mutant Ras multiple myeloma (1R41CA250616-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10080987. Licensed CC0.

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