7U6M

Albumin binding domain fused to a mutant of the Erwinia asparaginase

7U6M の概要

• エントリーDOI: 10.2210/pdb7u6m/pdb
• 分子名称: L-asparaginase, ASPARTIC ACID (3 entities in total)
• 機能のキーワード: asparaginase, albumin binding domain, hydrolase
• 由来する生物種: Dickeya chrysanthemi
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 150900.24

構造登録者

Lavie, A.,Nguyen, H.A. (登録日: 2022-03-04, 公開日: 2022-08-31, 最終更新日: 2024-10-23)

主引用文献

Van Trimpont, M.,Schalk, A.M.,De Visser, Y.,Nguyen, H.A.,Reunes, L.,Vandemeulebroecke, K.,Peeters, E.,Su, Y.,Lee, H.,Lorenzi, P.L.,Chan, W.K.,Mondelaers, V.,De Moerloose, B.,Lammens, T.,Goossens, S.,Van Vlierberghe, P.,Lavie, A.
In vivo stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia.
Haematologica, 108:409-419, 2023

PubMed Abstract: 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.

PubMed: 35979719
DOI: 10.3324/haematol.2022.281390

実験手法

X-RAY DIFFRACTION (1.75 Å)