A recombinant antibody fragment directed to the thymic stromal lymphopoietin receptor (CRLF2) efficiently targets pediatric Philadelphia chromosome-like acute lymphoblastic leukemia.

Autor: Mohamed SMA; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia.; University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt., Wohlmann A; Institute of Biochemistry II, Jena University Hospital, Jena, Germany., Schofield P; Garvan Institute of Medical Research, Sydney, NSW, Australia; St.Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia., Sia KCS; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia.; University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia., McCalmont H; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia.; University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia., Savvides SN; VIB-UGent Centre for Inflammation Research, Ghent, Belgium., Verstraete K; VIB-UGent Centre for Inflammation Research, Ghent, Belgium., Kavallaris M; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia.; University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia; Australian Centre for Nanomedicine, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Sydney, Sydney, NSW, Australia., Christ D; Garvan Institute of Medical Research, Sydney, NSW, Australia; St.Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia., Friedrich KH; Institute of Biochemistry II, Jena University Hospital, Jena, Germany., Bayat N; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia.; University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia., Lock RB; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia.; University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia. Electronic address: rlock@ccia.unsw.edu.au.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2021 Nov 01; Vol. 190, pp. 214-223. Date of Electronic Publication: 2021 Sep 02.
DOI: 10.1016/j.ijbiomac.2021.08.194
Abstrakt: Antibody fragments are promising building blocks for developing targeted therapeutics, thus improving treatment efficacy while minimising off-target toxicity. Despite recent advances in targeted therapeutics, patients with Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL), a high-risk malignancy, lack specific and effective targeted treatments. Cytokine receptor-like factor 2 (CRLF2) is overexpressed in 50% of Ph-like ALL cases, conferring the survival of leukemia blasts through activation of the JAK/STAT signalling pathway. Targeting such a vital cell-surface protein could result in potent anti-leukaemic efficacy and reduce the likelihood of relapse associated with antigen loss. Herein, we developed a novel single-chain variable fragment (scFv) against CRLF2 based on a monoclonal antibody raised against the recombinant extracellular domain of human TSLPRα chain. The scFv fragment demonstrated excellent binding affinity with CRLF2 protein in the nanomolar range. Cellular association studies in vitro using an inducible CRLF2 knockdown cell line and ex vivo using patient-derived xenografts revealed the selective association of the scFv with CRLF2. The fragment exhibited significant receptor antagonistic effects on STAT5 signalling, suggesting possible therapeutic implications in vivo. This study is the first to describe the potential use of a novel scFv for targeting Ph-like ALL.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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