In vivo stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia

Journal Article · Thu Aug 18 00:00:00 EDT 2022 · Haematologica (Pavia)

DOI:https://doi.org/10.3324/haematol.2022.281390· OSTI ID:2423253

Van Trimpont, Maaike ^[1]; Schalk, Amanda M. ^[2]; De Visser, Yanti ^[3]; Nguyen, Hien Anh ^[2]; Reunes, Lindy ^[1]; Vandemeulebroecke, Katrien ^[4]; Peeters, Evelien ^[1]; Su, Ying ^[2]; Lee, Hyun ^[2]; Lorenzi, Philip L. ^[5]; Chan, Wai-Kin ^[5]; Mondelaers, Veerle ^[6]; De Moerloose, Barbara ^[4]; Lammens, Tim ^[4]; Goossens, Steven ^[1]; Van Vlierberghe, Pieter ^[1]; Lavie, Arnon ^[7]

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1. Cancer Research Institute Ghent (CRIG), Ghent (Belgium); Ghent Univ. (Belgium)
2. Univ. of Illinois, Chicago, IL (United States)
3. Cancer Research Institute Ghent (CRIG), Ghent (Belgium); Ghent Univ. (Belgium); Katholieke Univ. Leuven, Heverlee (Belgium)
4. Cancer Research Institute Ghent (CRIG), Ghent (Belgium); Ghent University Hospital (Belgium); Ghent Univ. (Belgium)
5. Univ. of Texas, Houston, TX (United States)
6. Cancer Research Institute Ghent (CRIG), Ghent (Belgium); Ghent University Hospital (Belgium)
7. Univ. of Illinois, Chicago, IL (United States); Jesse Brown VA Medical Center, Chicago, IL (United States)

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE
• Grant/Contract Number: AC02-06CH11357
• OSTI ID: 2423253
• Journal Information: Haematologica (Pavia), Journal Name: Haematologica (Pavia) Journal Issue: 2 Vol. 108; ISSN 0390-6078
• Publisher: Ferrata-Storti Foundation
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
Hematology