# Pharmacological and toxicological testing of a novel L-asparaginase

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

## Abstract

Project Summary: The goal of this proposal is to perform IND-enabling studies of a significantly safer variant
of the anti-cancer biologic drug L-asparaginase. L-asparaginases are enzyme drugs that act to deplete the
amino acid asparagine from the blood. Due to toxicity, which is especially pronounced in adults, L-
asparaginase treatment is limited to acute lymphoblastic leukemia (ALL), a cancer of white blood cells. One
source of toxicity of L-asparaginases is due to their bacterial origin (either from E. coli (Elspar) or Erwinia
chrysanthemi (Erwinaze)), making the naked drugs highly immunogenic. The current standard of care is a
PEGylated version of Elspar called Oncaspar. While PEGylation reduces, but does not eliminate the
immunological challenge of using these drugs, the other toxicity-causing factor remains - this being their L-
glutaminase coactivity. Therefore, Oncaspar is limited to ALL, where even its use to treat adult ALL patients is
highly limited. Of note, L-asparaginase-associated side effects prevent the use of this unique cancer drug in
other hematological malignancies (e.g. acute myeloid leukemia) and in solid tumors (e.g. pancreatic cancer),
despite strong evidence that L-asparaginases would be effective in treating those cancers. Hence, there is a
clear unmet need for an L-asparaginase with reduced immunogenicity and that lacks L-glutaminase
coactivity. Recently, we characterized a guinea pig L-asparaginase (GpA) that possesses the required low
KM property for clinical efficacy and that exhibits in vivo tumor cell-killing. Notably, we also discovered that GpA
is devoid of the toxicity-causing L-glutaminase co-activity. With ~70% sequence identity to human L-
asparaginase, GpA should be less immunogenic compared to the bacterial enzymes that share only ~25%
sequence identity with the human enzyme. We recently identified the lead biologic GpA369 which is a stable
and active C-terminal truncation of GpA comprising the catalytic domain. Here we will perform the required
studies required to bring this novel enzyme drug to patients. In Aim 1 we will increase its sequence identity to
the human homolog using a structure-guided approach and identify the optimal PEGylation strategy. Aim 2 will
determine the pharmacokinetic properties of the top 3 optimized leads from Aim 1, as well as confirm their anti-
cancer efficacy in a human ALL mouse model. In Aim 3, the top variant (optimal combination of PK and anti-
cancer efficacy) will proceed to toxicity studies, first in mice, followed by more extensive studies in rats and
dogs. Finally, Aim 4 will evaluate the immunogenicity of our enzyme drug in a novel mouse model that has a
reconstituted human immune system, and compare our drug to Oncaspar. Together, these studies will bring us
to the cusp of submitting an IND application for testing this novel L-asparaginase in patients. Impact is
predicted to extend beyond ALL, since the improved safety profile of our L-asparaginase variant would e...

## Key facts

- **NIH application ID:** 9898149
- **Project number:** 5I01BX004589-02
- **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:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898149

## Citation

> US National Institutes of Health, RePORTER application 9898149, Pharmacological and toxicological testing of a novel L-asparaginase (5I01BX004589-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9898149. Licensed CC0.

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