Scientists from an international consortium led by Eduardo Batalhaboss of Colorectal Cancer Laboratory from IRB Barcelona, ​​researcher at ICREA and leader of the Cancer CIBER group (CYBERON), together with the Dutch company Merus NVrevealed the preclinical data that led to the discovery of MCLA-158 and its mechanism of action in cancer stem cells.

under the trade name of petosemtabthe MCLA-158 antibody blocks the appearance of metastasis (ie, the spread of cancer to other vital organs) and slows the growth of primary tumors in experimental cancer models.

The study, published in Nature Cancer, lays the groundwork for incorporating the use of organoids in the drug discovery process carried out by pharmaceutical companies.

The MCLA-158 antibody blocks the onset of metastases and slows the growth of primary tumors in experimental cancer models

Organoids are patient-derived samples that can be cultured and reproduce certain aspects of the tumor compartment in the laboratory. Until now, its usefulness was being explored in the personalized cancer medicinethat 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 most effective and suitable for the most patients.

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

In the study, three of the seven patients with HNSCC achieved partial remissionsand one of them got one complete remission after the August 2021 data cut-off date. Tumor shrinkage was observed in all seven patients.

“It is a great satisfaction to see that our findings are helping patients. We started researching cancer stem cells 15 years ago. The way to get here was exciting, but also very complex. It has required a large investment of resources, as well as the effort of many researchers”, explains Batlle.

Patient-derived organoids to find new anticancer drugs. /Muriel Arimon/IRB Barcelona

MCLA-158: an antibody with two fronts of action

Antibodies are proteins that our body naturally produces to recognize infectious agents or altered cells so that they can be eliminated by the body. lymphocytes of the immune system (white blood cells). The petosemtab It is a bispecific antibody that recognizes two different proteins on the surface of the cancer stem cellswhich are EGFR and LGR5.

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

Batlle’s laboratory is recognized worldwide for its work in the identification and characterization of stem cells from the Colorectal cancerand led research not only in the development of MCLA-158/ petosemtabbut also in the characterization of its mechanism of action.

This antibody does not interfere with the functioning of healthy stem cells in the body

Specifically, MCLA-158/ petosemtab degrades the EGFR protein in cancer stem cells that display the LGR5 marker. Thus, blocks growth and survival pathways in cells that initiate 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 tissues.

MCLA-158 antibody shows potent inhibition of colorectal cancer organoid growth, blocks the onset of metastasis as well as cancer growth in different preclinical models such as head tumors s neck, esophagus s stomach.

An organoid biobank for drug discovery

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

Incorporating organoids in the early stages of drug generation makes it possible to identify those that are effective for the majority of patients.

The incorporation of organoids in the first stages of drug generation (in this case, therapeutic antibodies) allows us to identify those that are effective for the majority of patients or even for tumors carrying a particular mutation.

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

In the coming months, the company Merus plans to publish new data on ongoing clinical trials with petosemtab. “We hope that the antitumor activity published in the preliminary data will be confirmed”, concludes Batlle.

Reference:

Herpes and others. “Functional screening on patient-derived organoids identifies a bispecific therapeutic antibody that triggers EGFR degradation in LGR5+ tumor cells” Nature Cancer (2022)

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