2026-04-13T01:59:14Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1910892025-12-04T19:30:49Zcom_2072_1057col_2072_478916col_2072_478908col_2072_478917

00925njm 22002777a 4500 dc Herpers, Bram author Eppink, Berina author James, Mark I. author Cortina, Carme author Cañellas Socias, Adrià author Boj, Sylvia F. author Hernando Momblona, Xavier author Glodzik, Dominik author Roovers, Rob C. author Wetering, Marc van de author Bartelink Clements, Carina author Zondag van der Zande, Vanessa author García Mateos, Jara author Yan, Kuan author Salinaro, Lucia author Basmeleh, Abdoul author Fatrai, Szabolc author Maussang, David author Lammerts van Bueren, Jeroen J. author Chicote, Irene author Serna, Garazi author Cabellos, Laia author Ramírez, Lorena author Nuciforo, Paolo author Salazar Soler, Ramón author Santos, Cristina author Villanueva Garatachea, Alberto author Attolini, Stephan-Otto author Sancho, Elena author Palmer, Héctor G. author Tabernero Caturla, Josep author Stratton, Michael R. author Kruif, John de author Logtenberg, Ton author Clevers, Hans author Price, Leo S. author Vries, Robert author Batlle, Eduard author Throsby, Mark author 2022-11-24T09:30:25Z 2022-11-24T09:30:25Z 2022-11-24 2022-11-23T12:27:35Z 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.© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc. Càncer colorectal Desenvolupament de medicaments Colorectal cancer Drug development Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors