An antibody fragment-decorated liposomal conjugate targets Philadelphia-like acute lymphoblastic leukemia.

Cell apoptotic assay Cytotoxicity Internalization Patient-derived xenografts scFv-Fc

Journal

International journal of biological macromolecules
ISSN: 1879-0003
Titre abrégé: Int J Biol Macromol
Pays: Netherlands
ID NLM: 7909578

Informations de publication

Date de publication:
26 Oct 2023
Historique:
received: 15 02 2023
revised: 28 08 2023
accepted: 19 10 2023
pubmed: 29 10 2023
medline: 29 10 2023
entrez: 28 10 2023
Statut: aheadofprint

Résumé

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is an aggressive B-ALL malignancy associated with high rates of relapse and inferior survival rate. While targeted treatments against the cell surface proteins CD22 or CD19 have been transformative in the treatment of refractory B-ALL, patients may relapse due to antigen loss, necessitating targeting alternative antigens. Cytokine receptor-like factor 2 (CRLF2) is overexpressed in half of Ph-like ALL cases conferring chemoresistance and enhancement of leukemia cell survival. Therefore, targeting CRLF2 may reduce the likelihood of relapse associated with antigen loss. We developed a CRLF2-targeting single-chain variable fragment modified by the fragment crystallizable region (CRLF2 scFv-Fc) conjugated to a drug maytansinoid 1 (DM1)-DOPC liposomal conjugate, creating homogeneous CRLF2-targeted liposomes (CRLF2-DM1 LIP). Cellular association and internalization studies in a Ph-like ALL cell line, MHH-CALL-4, compared to its lentivirally transduced CRLF2-knockdown counterpart (KD-CALL-4) revealed excellent CRLF2-targeting efficiency of CRLF2-DM1 LIP. Moreover, CRLF2-DM1 LIP showed selective association and internalization ex vivo using Ph-like ALL patient-derived xenograft (PDX) cells with minimal reactivity with non-target cells. Cell apoptosis assays demonstrated the CRLF2-dependent potency of CRLF2-DM1 LIP in Ph-like ALL cell lines. This study is the first to highlight the therapeutic potential of a CRLF2-directed scFv-Fc-liposomal conjugate for targeting Ph-like ALL.

Identifiants

DOI: 10.1016/j.ijbiomac.2023.127596 PMID: 37898250
pubmed: 37898250
pii: S0141-8130(23)04494-X
doi: 10.1016/j.ijbiomac.2023.127596
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

127596

Informations de copyright

Copyright © 2023 Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest Authors disclose no conflict of interest.

Auteurs

Sara M A Mohamed (SMA)

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Peter Schofield (P)

Garvan Institute of Medical Research, Sydney, NSW, Australia; St.Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.

Hannah McCalmont (H)

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.

Ernest Moles (E)

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia; Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW, Australia; UNSW RNA Institute, UNSW Sydney, NSW, Australia.

Karl-Heinz Friedrich (KH)

Institute of Biochemistry II, Jena University Hospital, Jena, Germany.

Maria Kavallaris (M)

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia; Australian Centre for Nanomedicine, UNSW Sydney, Sydney, NSW, Australia; UNSW RNA Institute, UNSW Sydney, NSW, Australia.

Daniel Christ (D)

Garvan Institute of Medical Research, Sydney, NSW, Australia; St.Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.

Narges Bayat (N)

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.

Richard B Lock (RB)

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia. Electronic address: rlock@ccia.unsw.edu.au.

Classifications MeSH