Organoids, simple, miniature versions of organs produced in vitro, are revolutionizing the way scientists study the function of cells, tissues and organs in the human body. These biological elements in 3D allow a deeper and closer knowledge of what happens inside the organism. In addition, organoids are a great help to learn more about the development of organs in the embryo/fetus.
In the field of pharmacology, the use of organoids is spreading as a more precise strategy than 2D cell cultures for evaluating the toxicity and efficacy of various treatments, before moving on to animal models. The latest breakthrough in this area has been published in the journal Nature Cancer. An international consortium of scientists, in which researchers from the Barcelona Biomedical Research Institute have participated, has discovered the MCLA-158 antibody (trade name Petosemtamab), effective against different epithelial tumors in mice, thanks to a massive screening based on a biobank composed of organoids.
The organoid biobank was created from cells from colorectal cancer patients, some of whom also suffered from metastases (invasion of cancer cells to other distant tissues) in the liver, and also from colon mucosa samples from healthy people. The advantage of these organoids with tumor cells is that they share certain characteristics with the tumors present in patients, such as their organization and structure.
The researchers used the organoid biobank for a high-throughput evaluation of the antitumor efficacy of more than 500 different antibodies. For him screening, image analyzes of the effect of each antibody on the organoids of each patient were performed: either the toxicity in healthy cells, or the decrease in the expansion of cancer cells. In this way, not only was the variability in the response due to the patient’s genetics taken into account, but also due to the genetics of the tumor. Cancer cells are characterized by presenting multiple mutations in specific genes and these mutations vary for each tumor and decisively influence their aggressiveness and their response to different treatments.
Among the hundreds of antibodies evaluated, MCLA-158 is the one that presented the most promising preclinical results. This is capable of blocking the initiation of metastasis and inhibiting the growth of colon and rectal tumors that are mutant for KRAS (an oncogene present in approximately 25% of cancers). Furthermore, in mice, MCLA-158 slows the growth of different types of human epithelial tumors (of the head and neck, stomach and esophagus). The efficacy of this molecule in organoids was superior to cetuximab, a drug frequently used in medicine as a first-line treatment for metastatic colorectal cancer.
The MCLA-159 antibody stands out for its ability to bind two different proteins simultaneously and specifically (ie, bispecific). These proteins are found on the surface of colon cancer stem cells and are involved in their survival and growth through various mechanisms. On the one hand, the antibody manages to internalize and destroy the epidermal growth factor receptor (EGFR) in cancer cells, a protein that is normally found on the surface of the cell membrane and that promotes uncontrolled growth. The destruction of this molecule only occurred in cells that expressed the LGR5 protein, which contributes to the expansion of tumors. Although LGR5 is present both in adult stem cells (from the colon, small intestine, kidneys…) and in tumor cells, this molecule barely damaged healthy colon stem cells from patients.
A phase 1 clinical trial has evaluated the safety and antitumor effect of different doses of the MCLA-158 antibody in patients with metastatic colorectal cancer. Preliminary results show good results for this molecule and the researchers are recruiting more volunteers to evaluate its effects in patients with gastric, head and neck cancer. In this way, it will take several years for the different phases of the trials to be completed and the real efficacy of the antibody to be known in detail.
Thus, the screening mass screening of anticancer drugs using organoid biobanks is presented as a more reliable option than conventional 2D cell cultures for evaluating the safety and efficacy of compounds in the laboratory. This research demonstrates the potential of this approach, which also allows a greater approach to personalized medicine, since it takes into account the variability in the response of patients and tumors with different genetic profiles.
Reference: “Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors”, Bram Herpers et al. in Nature Cancer, vol. 3, pp. 418-436, April 25, 2022.
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