MCLA-158, the first drug candidate targeting solid tumor cancer stem cells

An international consortium and the biotech company Merus reveal preclinical data leading to the discovery of MCLA-158 and its mechanism of action.

Published in Nature Cancer.

Scientists from an international consortium led by Dr. Eduard Batlle, head of the Colorectal Cancer laboratory, ICREA researcher and group leader at CIBER Cancer (CIBERONC), together with the Dutch company Merus N.V., reveal the preclinical data that lead to the discovery of MCLA-158 and its mechanism of action on cancer stem cells.

Under the trade name of Petosemtamab, the MCLA-158 antibody blocks the appearance of metastases (that is, the spread of cancer to other vital organs) and slows the growth of primary tumors 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 carried out by pharmaceutical companies.

Organoids are patient-derived samples that can be cultured and reproduce certain aspects of the tumor compartment in the laboratory. Until now, its usefulness in personalized cancer medicine was being explored, that is, for its role in making 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 was used to discriminate among hundreds of new antibodies which one was more effective and suitable for most patients.

In October 2021, Merus published preliminary data corresponding to the analysis of the efficacy of the antibody, based on its (ongoing) phase 1 dose expansion clinical trial. This clinical trial investigates the safety, tolerability, and antitumor activity of MCLA-158 monotherapy in head and neck squamous cell carcinomas (HNSCC).

In the trial, three of seven patients with HNSCC achieved partial remissions, with one achieving a complete remission after the data cutoff date of August 2021. Tumor shrinkage was seen in all seven patients.

“It is a great satisfaction to see that our discoveries are helping patients. We started researching cancer stem cells 15 years ago. The path to get here has been exciting, but also very complex, and has required a large investment of resources, as well as the efforts of many researchers. This study and the collaboration with Merus N.V. illustrates IRB Barcelona’s leitmotif: "The medicine of the future starts here", explains Dr. Batlle.

MCLA-158: an antibody with two action fronts

Antibodies are proteins that our body produces naturally to recognize infectious agents or altered cells, so that they can be eliminated by the lymphocytes of the immune system (white blood cells). The antibody that we describe in this work, Petosemtamab (“Peto”, MCLA-158: LGR5 x EGFR Biclonics®), is a bispecific antibody that recognizes two different proteins on the surface of cancer stem cells, which are EGFR and the LGR5.

EGFR activity promotes uncontrolled cell growth, while LGR5 marks the surface of cancer stem cells, which are responsible for tumor expansion.

Dr. Eduard Batlle’s laboratory is recognized worldwide for its work in the identification and characterization of colorectal cancer stem cells, and has led research not only in the development of MCLA-158/Petosemtamab, but also in the characterization of its mechanism of action.

Specifically, MCLA-158/Petosemtamab degrades the EGFR protein in cancer stem cells that display 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 proper tissue function.

The MCLA-158 antibody shows a potent growth inhibition of colorectal cancer organoids, blocks the initiation of metastasis, as well as cancer growth in different preclinical models, such as tumors of the head and neck, esophagus and stomach.

An organoid biobank for drug discovery

For the development and characterization of this antibody, HUB Organoids researchers constructed a biobank that features organoids derived from colon cancer patients, organoids from colon cancer metastases in the liver, and organoids from normal, non-cancerous tissue.

Incorporating organoids in the earliest phases of drug generation (in this case, therapeutic antibodies) makes it possible to identify those that are effective for most patients or even for tumors carrying a particular mutation.

Another advantage is the possibility of identifying unwanted side effects of drugs on our organs, using organoids from healthy tissue. This has made it possible to assess the harmful effects of the drug on healthy cells and thus eliminate the most toxic antibodies in the earliest phases of the study.

In the coming months, the Merus company plans to publish new data on ongoing clinical trials with Petosemtamab. "We hope that the antitumor activity published in the preliminary data will be confirmed," says Dr. Batlle.

The 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 various international research institutions; IRB Barcelona, the Hubrecht Institute and the Sanger Institute and the companies –Merus NV and Ocello BV/Crown Bioscience. The Vall d’Hebron Institute of Oncology (VHIO), the Catalan Institute of Oncology (ICO), the Bellvitge Biomedical Research Institute (IDIBELL) and the company Xenopat also collaborated in this publication, which demonstrated the effectiveness of MCLA-158 in the inhibition of metastasis after implantation of tumor cells from colon cancer patients in mice.

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