Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR x 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.; van de Wetering, Marc; Bartelink-Clements, Carina; Zondag-van der Zande, Vanessa; Mateos, Jara García; Yan, Kuan; Salinaro, Lucia; Basmeleh, Abdul; Fatrai, Szabolcs; Maussang, David; Lammerts van Bueren, Jeroen J.; Chicote, Irene; Serna, Garazi; Cabellos, Laia; Ramírez, Lorena; Nuciforo, Paolo; Salazar, Ramon; Santos, Cristina; Villanueva, Alberto; Stephan-Otto Attolini, Camille; Sancho, Elena; Palmer, Hector G.; Tabernero, Josep; Stratton, Michael R.; de Kruif, John; Logtenberg, Ton; Clevers, Hans; Price, Leo S.; Vries, Robert G.J.; Batlle, Eduard; Throsby, Mark
(2022) Nature Cancer, volume 3, issue 4, pp. 418 - 436
(Article)
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
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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.
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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, Oncology, Cancer Research, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2662-1347
Publisher: Nature Research
Note: Funding Information: We thank all patients for donating materials to the organoid biobank and all employees of U-PORT UMC Utrecht, as well as O. Kranenburg at UMC Utrecht and E. Wink van Gestel and N. van Scharrenburg at Meander Medisch Centrum for their assistance with patient inclusion and tissue acquisition. We thank J. Blokker, R. Korporaal and T. Mehraban for their contributions to building the CRC organoid biobank. We also thank R. Fong from Integral Molecular for performing the alanine scanning; L. Kaldenberg for graphically displaying the structural models; H. van der Maaden and W. Bartelink for technical assistance; M. Sevillano, A. Berenguer and staff at IRB facilities for excellent support with flow cytometry, functional genomics and histopathology. This study was funded by the European Union under the Seventh Framework Programme (FP7-HEALTH-2013-INNOVATION-2, SUPPRESSTEM, grant agreement no. 601876). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from the Spanish Ministry of Economy and Competitiveness and E.B. received support from AGAUR 2017-SGR-698 (Generalitat de Catalunya). A.V. was supported by grant from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III FEDER (PI19/01320). A.C.-S. held an FPU predoctoral fellowship from the Spanish Ministry of Economy and Competitiveness. Funding Information: We thank all patients for donating materials to the organoid biobank and all employees of U-PORT UMC Utrecht, as well as O. Kranenburg at UMC Utrecht and E. Wink van Gestel and N. van Scharrenburg at Meander Medisch Centrum for their assistance with patient inclusion and tissue acquisition. We thank J. Blokker, R. Korporaal and T. Mehraban for their contributions to building the CRC organoid biobank. We also thank R. Fong from Integral Molecular for performing the alanine scanning; L. Kaldenberg for graphically displaying the structural models; H. van der Maaden and W. Bartelink for technical assistance; M. Sevillano, A. Berenguer and staff at IRB facilities for excellent support with flow cytometry, functional genomics and histopathology. This study was funded by the European Union under the Seventh Framework Programme (FP7-HEALTH-2013-INNOVATION-2, SUPPRESSTEM, grant agreement no. 601876). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from the Spanish Ministry of Economy and Competitiveness and E.B. received support from AGAUR 2017-SGR-698 (Generalitat de Catalunya). A.V. was supported by grant from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III FEDER (PI19/01320). A.C.-S. held an FPU predoctoral fellowship from the Spanish Ministry of Economy and Competitiveness. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc. © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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