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

Sara M A Mohamed; Peter Schofield; Hannah McCalmont; Ernest Moles; Karl-Heinz Friedrich; Maria Kavallaris; Daniel Christ; Narges Bayat; Richard B Lock

doi:10.1016/j.ijbiomac.2023.127596

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

Int J Biol Macromol. 2024 Jan;254(Pt 1):127596. doi: 10.1016/j.ijbiomac.2023.127596. Epub 2023 Oct 26.

Authors

Sara M A Mohamed¹, Peter Schofield², Hannah McCalmont³, Ernest Moles⁴, Karl-Heinz Friedrich⁵, Maria Kavallaris⁴, Daniel Christ², Narges Bayat⁶, Richard B Lock⁷

Affiliations

¹ 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.
² Garvan Institute of Medical Research, Sydney, NSW, Australia; St.Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.
³ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
⁴ 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.
⁵ Institute of Biochemistry II, Jena University Hospital, Jena, Germany.
⁶ 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.
⁷ 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.

PMID: 37898250
DOI: 10.1016/j.ijbiomac.2023.127596

Abstract

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.

Keywords: Cell apoptotic assay; Cytotoxicity; Internalization; Patient-derived xenografts; scFv-Fc.

MeSH terms

Animals
Disease Models, Animal
Humans
Immunoconjugates* / pharmacology
Immunoglobulin Fragments
Liposomes / therapeutic use
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
Recurrence

Substances

Immunoglobulin Fragments
Liposomes
Immunoconjugates