Therapeutic antibody engineering for efficient targeted degradation of membrane proteins in lysosomes.
Biomed Pharmacother
; 175: 116707, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38739989
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peixe-Zebra
/
Ensaios Antitumorais Modelo de Xenoenxerto
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Trastuzumab
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Lisossomos
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Proteínas de Membrana
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Biomed Pharmacother
/
Biomed. pharmacother
/
Biomedicine & pharmacotherapy
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
França