@article{06b7bea9adb444dc9013631489b16e6a,
title = "Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors",
abstract = "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.",
keywords = "Antibodies, Bispecific/pharmacology, ErbB Receptors/metabolism, Humans, Imidazoles, Neoplasms, Glandular and Epithelial/metabolism, Neoplastic Stem Cells/metabolism, Organoids, Pyrazines, Receptors, G-Protein-Coupled/metabolism",
author = "Bram Herpers and Berina Eppink and James, {Mark I} and Carme Cortina and Adri{\`a} Ca{\~n}ellas-Socias and Boj, {Sylvia F} and Xavier Hernando-Momblona and Dominik Glodzik and Roovers, {Rob C} and {van de Wetering}, Marc and Carina Bartelink-Clements and {Zondag-van der Zande}, Vanessa and Mateos, {Jara Garc{\'i}a} and Kuan Yan and Lucia Salinaro and Abdul Basmeleh and Szabolcs Fatrai and David Maussang and {Lammerts van Bueren}, {Jeroen J} and Irene Chicote and Garazi Serna and Laia Cabellos and Lorena Ram{\'i}rez and Paolo Nuciforo and Ramon Salazar and Cristina Santos and Alberto Villanueva and {Stephan-Otto Attolini}, Camille and Elena Sancho and Palmer, {Hector G} and Josep Tabernero and Stratton, {Michael R} and {de Kruif}, John and Ton Logtenberg and Hans Clevers and Price, {Leo S} and Vries, {Robert G J} and Eduard Batlle and Mark Throsby",
note = "{\textcopyright} 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = apr,
doi = "10.1038/s43018-022-00359-0",
language = "English",
volume = "3",
pages = "418--436",
journal = "Nature cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "4",
}