TY - JOUR
T1 - Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR x LGR5 bispecific antibody with efficacy in epithelial tumors
AU - Herpers, Bram
AU - Eppink, Berina
AU - James, Mark I.
AU - Cortina, Carme
AU - Cañellas-Socias, Adrià
AU - Boj, Sylvia F.
AU - Hernando-Momblona, Xavier
AU - Glodzik, Dominik
AU - Roovers, Rob C.
AU - van de Wetering, Marc
AU - Bartelink-Clements, Carina
AU - Zondag-van der Zande, Vanessa
AU - Mateos, Jara García
AU - Yan, Kuan
AU - Salinaro, Lucia
AU - Basmeleh, Abdul
AU - Fatrai, Szabolcs
AU - Maussang, David
AU - Lammerts van Bueren, Jeroen J.
AU - Chicote, Irene
AU - Serna, Garazi
AU - Cabellos, Laia
AU - Ramírez, Lorena
AU - Nuciforo, Paolo
AU - Salazar, Ramon
AU - Santos, Cristina
AU - Villanueva, Alberto
AU - Stephan-Otto Attolini, Camille
AU - Sancho, Elena
AU - Palmer, Hector G.
AU - Tabernero, Josep
AU - Stratton, Michael R.
AU - de Kruif, John
AU - Logtenberg, Ton
AU - Clevers, Hans
AU - Price, Leo S.
AU - Vries, Robert G.J.
AU - Batlle, Eduard
AU - Throsby, Mark
N1 - 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.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - Antibodies, Bispecific/pharmacology
KW - ErbB Receptors/metabolism
KW - Humans
KW - Imidazoles
KW - Neoplasms, Glandular and Epithelial/metabolism
KW - Neoplastic Stem Cells/metabolism
KW - Organoids
KW - Pyrazines
KW - Receptors, G-Protein-Coupled/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85128777957&partnerID=8YFLogxK
U2 - 10.1038/s43018-022-00359-0
DO - 10.1038/s43018-022-00359-0
M3 - Article
C2 - 35469014
AN - SCOPUS:85128777957
VL - 3
SP - 418
EP - 436
JO - Nature Cancer
JF - Nature Cancer
IS - 4
ER -