Therapeutic antibody engineering for efficient targeted degradation of membrane proteins in lysosomes.

Autor: Gauthier C; NanoMedSyn, Montpellier, France; Institut des Biomolécules Max Mousseron (IBMM), University of Montpellier, CNRS, ENSCM, Montpellier, France., Daurat M; NanoMedSyn, Montpellier, France., Ali LMA; Institut des Biomolécules Max Mousseron (IBMM), University of Montpellier, CNRS, ENSCM, Montpellier, France; Department of Biochemistry, Medical Research Institute, University of Alexandria, Alexandria 21561, Egypt., El Cheikh K; NanoMedSyn, Montpellier, France., El Bahlagui I; NanoMedSyn, Montpellier, France., Taliercio C; NanoMedSyn, Montpellier, France., Morère E; NanoMedSyn, Montpellier, France; Institut des Biomolécules Max Mousseron (IBMM), University of Montpellier, CNRS, ENSCM, Montpellier, France., Gary-Bobo M; Institut des Biomolécules Max Mousseron (IBMM), University of Montpellier, CNRS, ENSCM, Montpellier, France., Morère A; Institut des Biomolécules Max Mousseron (IBMM), University of Montpellier, CNRS, ENSCM, Montpellier, France., Garcia M; NanoMedSyn, Montpellier, France., Maynadier M; NanoMedSyn, Montpellier, France., Basile I; NanoMedSyn, Montpellier, France. Electronic address: i.basile@nanomedsyn.com.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Jun; Vol. 175, pp. 116707. Date of Electronic Publication: 2024 May 12.
DOI: 10.1016/j.biopha.2024.116707
Abstrakt: Targeted degradation of pathological proteins is a promising approach to enhance the effectiveness of therapeutic monoclonal antibodies (mAbs) in cancer therapy. In this study, we demonstrate that this objective can be efficiently achieved by the grafting of mannose 6-phosphate analogues called AMFAs 2 onto the therapeutic antibodies trastuzumab and cetuximab, both directed against membrane antigens. The grafting of AMFAs confers to these antibodies the novel property of being internalized via the mannose 6-phosphate receptor (M6PR) pathway. AMFA conjugation to these mAbs significantly increases their cellular uptake and leads to enhanced degradation of the target antigens in cancer cells. This results in a drastic inhibition of cancer cell proliferation compared to unconjugated mAbs, as demonstrated in various cancer cell lines, and an increased therapeutic efficacy in mouse and zebrafish xenografted models. These findings highlight the potential of this technology to improve therapeutic outcomes in cancer treatment.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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