When we get infected with a pathogen or develop a disease, our body defends itself by generating antibodies, proteins that are capable of recognizing infectious agents or defective cells so that the lymphocytes of the immune system (white blood cells) can eliminate them. Now, a team of scientists from an international consortium with Spanish participation has identified the first antibody (MCLA-158 – whose trade name is Petosemtamab – that attacks cancer stem cells, stops tumor growth and prevents metastasis or spread of the disease to other areas of the patient’s body.
The study in which this antibody and its mechanisms of action on cancer stem cells have been discovered has been led by Dr. Eduard Batlle, head of the Colorectal Cancer Laboratory at IRB Barcelona, ICREA researcher and group leader at the CIBER de Cancer (CIBERONC), together with the Dutch company Merus NV, and its results have been published in Nature Cancer.
How the MCLA-158/Petosemtamab Antibody Works Against Cancer
Petosemtamab (“Peto”, MCLA-158: LGR5 x EGFR Biclonics®) is a bispecific antibody that recognizes two different proteins on the surface of cancer stem cells, namely EGFR and LGR5. EGFR acts by facilitating uncontrolled cell growth, while LGR5 marks the surface of cancer stem cells, which are responsible for the expansion of tumors.
MCLA-158/Petosemtamab blocks the initiation of metastasis and cancer growth in different preclinical models, such as tumors of the head and neck, esophagus and stomach
The mechanism of action of MCLA-158/Petosemtamab consists of degrading the EGFR protein in cancer stem cells that present the LGR5 marker. This blocks the growth and survival pathways in the cells that start cancer and spread it. This antibody, however, does not interfere with the functioning of the body’s healthy stem cells, which are key to the proper functioning of tissues.
This antibody shows 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.
Use of organoids to test drugs that cure diseases
In this research, organoids have been used to verify that the MCLA-158 antibody was effective in preventing the appearance of metastases and slowing down the growth of primary tumors in experimental models of cancer, and also demonstrates the advantages offered by the use of organoids to discover and develop new drugs.
Organoids are samples from patients that can be grown in the laboratory and that reproduce certain aspects of the tumor compartment. To find MCLA-158, a biobank of organoids from patients with colon cancer, organoids from colon cancer metastases in the liver, and organoids from normal non-cancerous tissue were used for the first time, to identify the most effective antibody. and suitable for most patients, choosing from hundreds of new antibodies.
Using organoids in the early stages of drug generation (in this case, therapeutic antibodies) makes it possible to determine which ones are effective for the majority of patients, or even for tumors that have a particular mutation. In addition, using organoids from healthy tissue, it is also possible to detect adverse side effects of drugs on healthy cells and rule out the most toxic antibodies from the start.
“The medicine of the future starts here”, explains Dr. Batlle
In October 2021, Merus published preliminary data on the efficacy analysis 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). Three of the seven HNSCC patients who participated in the trial experienced partial remissions, with one achieving a complete remission after the data cutoff date of August 2021. Tumor shrinkage was observed 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 road 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 NV illustrates IRB Barcelona’s leitmotif: “The medicine of the future starts here”, explains Dr. Batlle.
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