Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors

Bram Herpers; Berina Eppink; Mark I James; Carme Cortina; Adrià Cañellas-Socias; Sylvia F Boj; Xavier Hernando-Momblona; Dominik Glodzik; Rob C Roovers; Marc van de Wetering; Carina Bartelink-Clements; Vanessa Zondag-van der Zande; Jara García Mateos; Kuan Yan; Lucia Salinaro; Abdul Basmeleh; Szabolcs Fatrai; David Maussang; Jeroen J Lammerts van Bueren; Irene Chicote; Garazi Serna; Laia Cabellos; Lorena Ramírez; Paolo Nuciforo; Ramon Salazar; Cristina Santos; Alberto Villanueva; Camille Stephan-Otto Attolini; Elena Sancho; Hector G Palmer; Josep Tabernero; Michael R Stratton; John de Kruif; Ton Logtenberg; Hans Clevers; Leo S Price; Robert G J Vries; Eduard Batlle; Mark Throsby

doi:10.1038/s43018-022-00359-0

Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors

Bram Herpers, Berina Eppink, Mark I James, Carme Cortina, Adrià Cañellas-Socias, Sylvia F Boj, Xavier Hernando-Momblona, Dominik Glodzik, Rob C Roovers, Marc van de Wetering, Carina Bartelink-Clements, Vanessa Zondag-van der Zande, Jara García Mateos, Kuan Yan, Lucia Salinaro, Abdul Basmeleh, Szabolcs Fatrai, David Maussang, Jeroen J Lammerts van Bueren, Irene ChicoteGarazi Serna, Laia Cabellos, Lorena Ramírez, Paolo Nuciforo, Ramon Salazar, Cristina Santos, Alberto Villanueva, Camille Stephan-Otto Attolini, Elena Sancho, Hector G Palmer, Josep Tabernero, Michael R Stratton, John de Kruif, Ton Logtenberg, Hans Clevers, Leo S Price, Robert G J Vries, Eduard Batlle, Mark Throsby

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

70 Citations (Scopus)

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.

Original language	English
Pages (from-to)	418-436
Number of pages	19
Journal	Nature cancer
Volume	3
Issue number	4
DOIs	https://doi.org/10.1038/s43018-022-00359-0
Publication status	Published - Apr 2022

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

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Herpers, B., Eppink, B., James, M. I., Cortina, C., Cañellas-Socias, A., Boj, S. F., Hernando-Momblona, X., Glodzik, D., Roovers, R. C., van de Wetering, M., Bartelink-Clements, C., Zondag-van der Zande, V., Mateos, J. G., Yan, K., Salinaro, L., Basmeleh, A., Fatrai, S., Maussang, D., Lammerts van Bueren, J. J., ... Throsby, M. (2022). Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. Nature cancer, 3(4), 418-436. https://doi.org/10.1038/s43018-022-00359-0

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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",

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Herpers, B, Eppink, B, James, MI, Cortina, C, Cañellas-Socias, A, Boj, SF, Hernando-Momblona, X, Glodzik, D, Roovers, RC, van de Wetering, M, Bartelink-Clements, C, Zondag-van der Zande, V, Mateos, JG, Yan, K, Salinaro, L, Basmeleh, A, Fatrai, S, Maussang, D, Lammerts van Bueren, JJ, Chicote, I, Serna, G, Cabellos, L, Ramírez, L, Nuciforo, P, Salazar, R, Santos, C, Villanueva, A, Stephan-Otto Attolini, C, Sancho, E, Palmer, HG, Tabernero, J, Stratton, MR, de Kruif, J, Logtenberg, T, Clevers, H, Price, LS, Vries, RGJ, Batlle, E & Throsby, M 2022, 'Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors', Nature cancer, vol. 3, no. 4, pp. 418-436. https://doi.org/10.1038/s43018-022-00359-0

TY - JOUR

T1 - Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × 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

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

U2 - 10.1038/s43018-022-00359-0

DO - 10.1038/s43018-022-00359-0

M3 - Article

C2 - 35469014

SN - 2662-1347

VL - 3

SP - 418

EP - 436

JO - Nature cancer

JF - Nature cancer

IS - 4

ER -

Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors

Abstract

Keywords

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