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

Published: April 2022


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.

Full Access Link: Nature Cancer