# Development of Human Asparaginase for Cancer Therapy

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2020 · —

## Abstract

Project Summary:
This application will address the unmet need for superior treatment outcomes for adults with acute
lymphoblastic leukemia (ALL), and will develop the tools needed for personalized treatment to allow a more
expanded use of the unique anti-cancer drug called L-asparaginase. Unlike pediatric ALL, a disease with a
cure rate of >90%, the cure rate of adult ALL is <40%. One significant difference between the treatment of
pediatric and adult ALL patients is that only the pediatric regimen always includes the drug L-asparaginase.
Indeed, it was shown that cure rates are highly dependent on using this drug, and for the patient being able to
complete the full course of treatment. Unfortunately, the side effects of L-asparaginase treatment often require
prematurely stopping use of this drug.
These L-asparaginase side effects can be traced directly to the bacterial origin and properties of all current
FDA-approved L-asparaginases (and not to the anti-cancer asparagine depletion effect of drug). Being
bacterial enzymes, currently approved drugs are highly immunogenic. Although a portion of this clinical
problem has recently been addressed by pegylating the enzyme, the other source of side effects, the L-
glutaminase co-activity of these bacterial enzymes, still remains. We propose a strategy that would address
both the immunogenic and L-glutaminase-related side effects, in which the bacterial enzymes are replaced by
human-like L-asparaginases that are devoid of L-glutaminase co-activity.
The more similar a biologic is to a human sequence, the less likely it would be immunogenic. In our work to
date, we identified a mammalian L-asparaginase (referred to as gpASNas1) that is 70% identical to the human
enzyme (as compared to the mere 25% identity of the bacterial enzymes), and we have increased that
percentage identity to 85% by employing a genetic screen and structural information. In our proposed work
here, we have identified a path that will increase this percent identity to >95%. As importantly, gpASNase1 is
devoid of the toxicity-causing L-glutaminase activity, so as a drug, it will also lack those side effects that are
caused by glutamine depletion. Critically, in a mouse xenograft model of human T-ALL and B-ALL, we
observed a potent anti-cancer effect of these human-like L-asparaginase drugs, which serves to demonstrate
that the L-glutaminase activity is not required for killing the cancer cells. Moreover, as compared to the L-
glutaminase containing FDA drug, our L-asparaginase version without this co-activity has exhibited reduced
toxicity. Thus, the L-asparaginase variant that will be developed by the proposed work will have a high impact
on ALL therapy, especially for adults, and thus with special relevance for veterans.
In addition to impacting ALL treatment, our vision is to expand the use of L-asparaginases to other
malignancies. A main factor that currently prevents the expanded use of L-asparaginases (in addition to
aforementione...

## Key facts

- **NIH application ID:** 9932285
- **Project number:** 5I01BX001919-08
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** ARNON LAVIE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932285

## Citation

> US National Institutes of Health, RePORTER application 9932285, Development of Human Asparaginase for Cancer Therapy (5I01BX001919-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932285. Licensed CC0.

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