2026-04-13T07:05:55Zhttps://recercat.cat/oai/request

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

urn:hdl:2445/191089 Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors Herpers, Bram Eppink, Berina James, Mark I. Cortina, Carme Cañellas Socias, Adrià Boj, Sylvia F. Hernando Momblona, Xavier Glodzik, Dominik Roovers, Rob C. Wetering, Marc van de Bartelink Clements, Carina Zondag van der Zande, Vanessa García Mateos, Jara Yan, Kuan Salinaro, Lucia Basmeleh, Abdoul Fatrai, Szabolc Maussang, David Lammerts van Bueren, Jeroen J. Chicote, Irene Serna, Garazi Cabellos, Laia Ramírez, Lorena Nuciforo, Paolo Salazar Soler, Ramón Santos, Cristina Villanueva Garatachea, Alberto Attolini, Stephan-Otto Sancho, Elena Palmer, Héctor G. Tabernero Caturla, Josep Stratton, Michael R. Kruif, John de Logtenberg, Ton Clevers, Hans Price, Leo S. Vries, Robert Batlle, Eduard Throsby, Mark Càncer colorectal Desenvolupament de medicaments Colorectal cancer Drug development 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. 2022-11-24T09:30:25Z 2022-11-24T09:30:25Z 2022-11-24 2022-11-23T12:27:35Z info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Postprint del document publicat a: https://doi.org/10.1038/s43018-022-00359-0 Nature Cancer, 2022, num. 3, p. 418–436 https://doi.org/10.1038/s43018-022-00359-0 (c) Herpers, Bram, 2022 info:eu-repo/semantics/openAccess Springer Nature Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))