PUBLICATION
Therapeutic antibody engineering for efficient targeted degradation of membrane proteins in lysosomes
- Authors
- Gauthier, C., Daurat, M., Ali, L.M.A., El Cheikh, K., El Bahlagui, I., Taliercio, C., Morère, E., Gary-Bobo, M., Morère, A., Garcia, M., Maynadier, M., Basile, I.
- ID
- ZDB-PUB-240514-8
- Date
- 2024
- Source
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 175: 116707116707 (Journal)
- Registered Authors
- Keywords
- AMFA, Antibody engineering, Lysosome, Mannose 6-phosphate receptor, Mannose 6-phosphonate, Targeted protein degradation
- MeSH Terms
-
- Trastuzumab*/pharmacology
- Antineoplastic Agents, Immunological/pharmacology
- Animals
- Lysosomes*/drug effects
- Lysosomes*/metabolism
- Protein Engineering/methods
- Antibodies, Monoclonal/pharmacology
- Cell Proliferation/drug effects
- Cetuximab/pharmacology
- Humans
- Mice, Nude
- Cell Line, Tumor
- Neoplasms/drug therapy
- Neoplasms/metabolism
- Xenograft Model Antitumor Assays*
- Female
- Zebrafish*
- Membrane Proteins*/metabolism
- Mice
- PubMed
- 38739989 Full text @ Biomed. Pharmacother.
Citation
Gauthier, C., Daurat, M., Ali, L.M.A., El Cheikh, K., El Bahlagui, I., Taliercio, C., Morère, E., Gary-Bobo, M., Morère, A., Garcia, M., Maynadier, M., Basile, I. (2024) Therapeutic antibody engineering for efficient targeted degradation of membrane proteins in lysosomes. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 175:116707116707.
Abstract
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 AMFAs2 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping