- The new antibody, MCLA-158, targets both epidermal growth factor receptor (EGFR) and protein LGR5 and has been shown to be significantly more active than the monospecific antibody combination.
- A novel contribution to the development of this new bispecific antibody is the use of a biobank of organoids derived from tumour cells in patients with colorectal cancer to address the efficacy of a battery of candidate antibodies on cancer stem cells.
- The researchers at the Vall d’Hebron Institute of Oncology (VHIO), part of the Vall d’Hebron Campus, later confirmed that the drug selected, MCLA-158, was effective in animal models of patients derived xenografts or PDX.
Barcelona, April 25 , 2022– Scientists from an international consortium, led by Dr. Eduard Batlle, head of the colorectal cancer laboratory at IRB Barcelona, ICREA researcher and group head at CIBERONC, alongside the Dutch company Merus NV, have released preclinical data leading to the discovery of MCLA-158 and its mechanism of action on cancer stem cells. The Vall d’Hebron Institute of Oncology (VHIO) has also participated in this consortium. This antibody blocks the development of metastases – that is, the spread of cancer to other vital organs – and slows the growth of primary tumours in experimental models of cancer.
The study, published today in Nature Cancer, lays the foundation for incorporating the use of organoids into the drug discovery process conducted by pharmaceutical companies. Organoids are samples derived from patients that can be grown and that reproduce certain aspects of the behaviour of the tumour in the laboratory. Until now, their usefulness in personalized cancer medicine was being explored, that is, to help make decisions about the best treatment for each patient. However, for the discovery of MCLA-158, for the first time a biobank of organoids from cancer patients has been used to discriminate among hundreds of new antibodies which of them was most effective and suitable for most patients.
Once the most promising antibody was selected thanks to the organoid bank, what are known as PDX models – in which cells from human patients are implanted in mice – were used to validate its functionality and demonstrate that it blocked the formation of metastases. This part of the study was carried out by the Vall d’Hebron Institute of Oncology (VHIO). “We have used a computed tomography or CT scan in PDX, as used in human patients, to image the growth of the tumour within the gut of mice, and we have seen that the antibody worked,” explains Dr. Héctor G. Palmer, head of the VHIO Stem Cells and Cancer Group and one of the researchers who participated in the study.
Dr. Héctor G. Palmer was not the only member of this research team; many other VHIO professionals have also participated, among them Dr. Paolo Nucyforum, head of the VHIO Molecular Oncology Group. This is a fact highlighted by Dr. Josep Tabernero, director of the VHIO, head of the Medical Oncology Department of the Vall d’Hebron University Hospital and also author of this article: “This collaborative work demonstrates how important the multidisciplinary and transversal work carried out in our centre is. As a result, it is possible to develop new drugs as sophisticated as this new antibody, which require the involvement of professionals with experience in very different fields of research.”
MCLA-158: An antibody with two action fronts
Antibodies are proteins that our body naturally produces to recognize infectious agents or altered cells, so that they can be eliminated by the immune system’s lymphocytes (white blood cells). The antibody described in this paper, MCLA-158, is a bispecific antibody that recognizes two distinct proteins on the surface of cancer stem cells, EGFR and LGR5.
EGFR activity promotes uncontrolled cell growth, while LGR5 labels the surface of cancer stem cells, which are responsible for tumour expansion. Specifically, MCLA-158 degrades the EGFR protein in cancer stem cells with the LGR5 marker. In this way, it blocks growth and survival pathways in cells that start and spread cancer. This antibody, however, does not interfere with the functioning of the body’s healthy stem cells, which are essential for the proper functioning of tissue.
The antibody MCLA-158 shows a potent inhibition of the growth of colorectal cancer organoids, blocks the onset of metastasis, as well as the growth of cancer in different preclinical models, such as head and neck, oesophagus and stomach tumours.
An organoid biobank for drug discovery
For the development and characterization of this antibody, researchers at HUB Organoids constructed a biobank comprising organoids derived from patients with colon cancer, organoids from colon cancer metastases in the liver, and organoids from normal non-cancerous tissue.
The incorporation of organoids at the earliest stages of drug generation, in this case therapeutic antibodies, allows identification of those that are effective for most patients or even against tumours carrying a particular mutation. Another additional advantage is the possibility of identifying unwanted side effects of drugs on our organs, using organoids from healthy tissue. This has enabled the harmful effects of the drug on healthy cells to be assessed and thereby the most toxic antibodies were eliminated in the earlier stages of the study.
This preclinical research published today in Nature Cancer includes work carried out within the framework of the EU-funded suppresSTEM consortium and with the collaborative work of several international research institutions; IRB Barcelona, The Hubrecht Institute and the Sanger Institute and companies such as Merus N.V. and Ocello B.V./Crown Bioscience. The Vall d’Hebron Institute of Oncology (VHIO), the Catalan Institute of Oncology (ICO) and the company Xenopad also collaborated in this publication.
Bram Herpers, Berina Eppink, Mark I. James, Carme Cortina, Adrià Cañellas, 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 Vries, Eduard Batlle & Mark Throsby. “Functional screening on patient-derived organoids identifies a therapeutic bispecific antibody that triggers EGFR degradation in LGR5+ tumor cells”. Nature Cancer (2022) DOI: 10.1038/s43018-022-00359-0