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

Research output: Contribution to journal/periodicalArticleScientificpeer-review

54 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 languageEnglish
Pages (from-to)418-436
Number of pages19
JournalNature cancer
Volume3
Issue number4
DOIs
Publication statusPublished - 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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