The MCLA-158 antibody, dubbed Petosemtamab, was developed through experiments performed on tumor organoids derived from patients; these “mini-tumors”, which perfectly reproduce the architecture and behavior of a true tumor, allow the medical profession to test various anti-cancer treatments. Researchers set out to use a heterogeneous biobank of organoids derived from colorectal cancer patients to determine which antibody – out of hundreds – was most effective and suitable for most cases. MCLA-158 quickly differed from the others.
A double-targeted monoclonal antibody
Antibodies are proteins that are naturally produced by our body to detect and neutralize pathogens or damaged cells; they bind to these unwanted elements (called antigens) so that they can be eliminated by other cells in the immune system. The monoclonal antibody described in this new study was selected after a large-scale functional screening of double-targeted bispecific antibodies; the scientists thus assessed the reaction of the organoids under the influence of more than 500 antibodies.
MCLA-158 recognizes two proteins (EGFR and LGR5) on the surface of cancer stem cells. The role of the epidermal growth factor receptor (or EGFR, for Epidermal growth factor receptor) is to send a growth signal to the cell nucleus. Similarly, the LGR5 cursor (Leucine-rich repeat-containing G-protein coupled receptor 5) promotes the spread of cancer cells in the body.
Schematic representation of the MCLA-158 antibody showing the monovalent affinities of the Fab fragments for EGFR (Fab232) and LGR5 (Fab072). © B. Herpers et al., Nature Cancer (2022)
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Merus NV had already conducted a Phase 1 clinical trial last year to assess the safety, tolerability and antitumor activity of MCLA-158 as monotherapy in the case of advanced squamous cell carcinoma of the head and neck. This experiment, performed on seven patients, had given quite encouraging results: a reduction in the tumor was observed in all the patients; three obtained a partial response during the trial, while one patient obtained a complete response after the cut-off date.
In this new study, published in the journal Natural cancer, the researchers were able to better understand the mechanism of action of this antibody: MCLA-158 specifically triggers the degradation of the EGFR protein in cancer stem cells that possess the LGR5 marker – thus blocking the growth and survival pathways in the cells that initiate and spread cancer . Furthermore, the antibody has “minimal toxicity” to healthy colon stem cells, which also have the LGR5 marker – ensuring that it does not interfere with the function of these cells, which is essential for the proper functioning of the drugs.
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“Mini-organs” essential to medical research
The researchers report that MCLA-158 is a potent growth inhibitor of colorectal cancer organoids and has been shown to be equally effective in several preclinical cancer models, including head and neck tumors, esophagus and stomach. ” MCLA-158 exhibits therapeutic properties such as growth inhibition of mutant colorectal cancer Of type KRAS, blockade of metastasis initiation and suppression of tumor growth in preclinical models for several types of epithelial cancer “, The researchers conclude in Natural cancer.
Mutations in the RAS gene (KRAS and NRAS) are common in colorectal cancers and generally lead to activation of the EGFR signaling pathway; these mutations thus result in the ineffectiveness of current treatments specifically targeting EGFR. However, MCLA-158 remains effective even in the presence of KRAS mutations, which affect more than one-third of people with colon cancer.
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In addition to the therapeutic interest of MCLA-158 / Petosemtamab, this study highlights the interest in organoids derived from patients (cancer and non-cancer) for medical research. The use of these mini-organs from the early stages of the development of new drugs makes it possible to identify as early as possible which ones are most effective for the largest number of patients. Organoids grown from healthy tissue, on the other hand, make it possible to quickly identify unwanted side effects and ensure that the substance will not harm healthy cells.
New clinical trials with MCLA-158 / Petosemtamab are underway and Merus NV expects to publish the first results in the coming months. ” We hope the antitumor activity reported in the preliminary data will be confirmed. said Dr. Batlle in a statement.