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

(2023) HAEMATOLOGICA. 108(2). p.409-419
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Abstract
Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase (ASNS). Acute lymphoblastic leukemia (ALL) cells do not or minimally express ASNS 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 a 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 anti-cancer 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 a very short half-life 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 anti-leukemic effect between the standard-of-care PEG-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.
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Hematology

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MLA
Van Trimpont, Maaike, et al. “In Vivo Stabilization of a Less Toxic Asparaginase Variant Leads to a Durable Anti-Tumor Response in Acute Leukemia.” HAEMATOLOGICA, vol. 108, no. 2, 2023, pp. 409–19, doi:10.3324/haematol.2022.281390.
APA
Van Trimpont, M., Schalk, A. M., De Visser, Y., Nguyen, H. A., Reunes, L., Vandemeulebroecke, K., … Lavie, A. (2023). In vivo stabilization of a less toxic asparaginase variant leads to a durable anti-tumor response in acute leukemia. HAEMATOLOGICA, 108(2), 409–419. https://doi.org/10.3324/haematol.2022.281390
Chicago author-date
Van Trimpont, Maaike, Amanda M. Schalk, Yanti De Visser, Hien Anh Nguyen, Lindy Reunes, Katrien Vandemeulebroecke, Evelien Peeters, et al. 2023. “In Vivo Stabilization of a Less Toxic Asparaginase Variant Leads to a Durable Anti-Tumor Response in Acute Leukemia.” HAEMATOLOGICA 108 (2): 409–19. https://doi.org/10.3324/haematol.2022.281390.
Chicago author-date (all authors)
Van Trimpont, Maaike, Amanda M. Schalk, Yanti De Visser, Hien Anh Nguyen, Lindy Reunes, Katrien Vandemeulebroecke, Evelien Peeters, Ying Su, Hyun Lee, Philip L. Lorenzi, Wai-Kin Chan, Veerle Mondelaers, Barbara De Moerloose, Tim Lammens, Steven Goossens, Pieter Van Vlierberghe, and Arnon Lavie. 2023. “In Vivo Stabilization of a Less Toxic Asparaginase Variant Leads to a Durable Anti-Tumor Response in Acute Leukemia.” HAEMATOLOGICA 108 (2): 409–419. doi:10.3324/haematol.2022.281390.
Vancouver
1.
Van Trimpont M, Schalk AM, De Visser Y, Nguyen HA, Reunes L, Vandemeulebroecke K, et al. In vivo stabilization of a less toxic asparaginase variant leads to a durable anti-tumor response in acute leukemia. HAEMATOLOGICA. 2023;108(2):409–19.
IEEE
[1]
M. Van Trimpont et al., “In vivo stabilization of a less toxic asparaginase variant leads to a durable anti-tumor response in acute leukemia,” HAEMATOLOGICA, vol. 108, no. 2, pp. 409–419, 2023.
@article{8764123,
  abstract     = {{Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase (ASNS). Acute lymphoblastic leukemia (ALL) cells do not or minimally express ASNS 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 a 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 anti-cancer 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 a very short half-life 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 anti-leukemic effect between the standard-of-care PEG-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.}},
  author       = {{Van Trimpont, Maaike and Schalk, Amanda M. and De Visser, Yanti and Nguyen, Hien Anh and Reunes, Lindy and Vandemeulebroecke, Katrien and Peeters, Evelien and Su, Ying and Lee, Hyun and Lorenzi, Philip L. and Chan, Wai-Kin and Mondelaers, Veerle and De Moerloose, Barbara and Lammens, Tim and Goossens, Steven and Van Vlierberghe, Pieter and Lavie, Arnon}},
  issn         = {{0390-6078}},
  journal      = {{HAEMATOLOGICA}},
  keywords     = {{Hematology}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{409--419}},
  title        = {{In vivo stabilization of a less toxic asparaginase variant leads to a durable anti-tumor response in acute leukemia}},
  url          = {{http://doi.org/10.3324/haematol.2022.281390}},
  volume       = {{108}},
  year         = {{2023}},
}

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