Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors.

Antibodies, Bispecific / pharmacology ErbB Receptors / metabolism Humans Imidazoles Neoplasms, Glandular and Epithelial / metabolism Neoplastic Stem Cells / metabolism Organoids Pyrazines Receptors, G-Protein-Coupled / metabolism

Journal

Nature cancer

ISSN: 2662-1347

Titre abrégé: Nat Cancer

Pays: England

ID NLM: 101761119

Informations de publication

Date de publication:
04 2022

Historique:

received: 10 08 2020

accepted: 04 03 2022

pubmed: 27 4 2022

medline: 30 4 2022

entrez: 26 4 2022

Statut: ppublish

Résumé

Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses. Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.

Identifiants

DOI: 10.1038/s43018-022-00359-0 PMID: 35469014

pubmed: 35469014

doi: 10.1038/s43018-022-00359-0

pii: 10.1038/s43018-022-00359-0

doi:

Substances chimiques

Antibodies, Bispecific 0

Imidazoles 0

LGR5 protein, human 0

Pyrazines 0

Receptors, G-Protein-Coupled 0

2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo(1,2-alpha)pyrazin-3-one 118877-07-9

EGFR protein, human EC 2.7.10.1

ErbB Receptors EC 2.7.10.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

418-436

Commentaires et corrections

Type : CommentIn

Informations de copyright

Références

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