According to reports by the International Agency for Research on Cancer, an estimated 18.1 million new cancer cases are diagnosed worldwide each year and every sixth death in the world is due to cancer, making it the second leading cause of death, second only to cardiovascular disease. A small Israeli team of scientists behind Accelerated Evolution Biotechnologies Ltd. (AEBi), which was founded in 2000 in the ITEK incubator, has developed a new cancer treatment.
“We believe we will offer in a year’s time a complete cure for cancer. Our cancer cure will be effective from day one, will last a duration of a few weeks and will have no or minimal side-effects at a much lower cost than most other treatments on the market. Our solution will be both generic and personal,” said Dan Aridor, Chairman of the board of AEBi in an interview with The Times of Israel. Mr. Aridor and CEO Dr. Ilan Morad say their treatment, which they call MuTaTo (multi-target toxin) is essentially on the scale of a cancer antibiotic, a disruption technology of the highest order. AEBi is on the cusp of beginning a round of clinical trials that could be completed within a few years and would make the treatment available in specific cases. “Our results are consistent and repeatable,” Mr. Aridor added.
The potentially game-changing anti-cancer drug is based on SoAP technology, which provides functional leads to very difficult targets. It involves the introduction of DNA coding for a protein, such as an antibody, into a bacteriophage – a virus that infects bacteria. That protein is then displayed on the surface of the phage. Researchers can use these protein-displaying phages to screen for interactions with other proteins, DNA sequences and small molecules. In 2018, a team of scientists won the Nobel Prize for their work on phage display in the directed evolution of new proteins, particularly for the production of antibody therapeutics.
How the Technology is Different
AEBi is doing something similar but with peptides, compounds of two or more amino acids linked in a chain. According to Dr. Morad, peptides have several advantages over antibodies, including that they are smaller, cheaper, and easier to produce and regulate. To get started, Dr. Morad said the team had to identify why other cancer-killing drugs and treatments don’t work or eventually fail. Then, they found a way to counter that effect. He explains that most anti-cancer drugs attack a specific target on or in the cancer cell and inhibiting the target usually affects a physiological pathway that promotes cancer. Mutations in the targets or downstream in their physiological pathways could make the targets not relevant to the cancer nature of the cell, and hence the drug attacking it is rendered ineffective.
In contrast, MuTaTo combines several cancer-targeting peptides for each cancer cell at the same time, along with a strong peptide toxin that would kill cancer cells specifically. Dr. Morad said by using at least three targeting peptides on the same structure with a strong toxin “we made sure that the treatment will not be affected by mutations; cancer cells can mutate in such a way that targeted receptors are dropped by the cancer. The probability of having multiple mutations that would modify all targeted receptors simultaneously decreases dramatically with the number of targets used. Instead of attacking receptors one at a time, we attack receptors three at a time – not even cancer can mutate three receptors at the same time.”
Furthermore, many cancer cells activate detoxification mechanisms when in stress from drugs. The cells pump out the drugs or modify them to be non-functional. However, detoxification takes time: when the toxin is strong, it has a high probability of killing the cancer cell before detoxification occurs, which is what he is banking on. Many cytotoxic anticancer treatments aim at fast-growing cells, but cancer stem cells are not fast growing, and they can escape these treatments. Then, when the treatment is over, they can generate cancer again.
Dr. Morda explained that because cancer cells are born out of mutations that occur in cancer stem cells, most of the overexpressed proteins which are targeted on the cancer cell exist in the cancer stem cells. “If it does not completely annihilate the cancer, the remaining cells can start to get mutations again, and then the cancer comes back, but this time it is drug resistant,” he said, but MuTaTo’s multiple-target attack ensures that they will be destroyed as well.
Finally, some cancer tumors erect shields which create access problems to large molecules, such as antibodies. MuTaTo acts like an octopus or a piece of spaghetti and can sneak into places where other large molecules cannot reach. Morad said the peptide parts of MuTaTo are very small (12 amino acids long) and lack a rigid structure. “This should make the whole molecule non-immunogenic in most cases and would enable repeated administration of the drug,” he said.
Improvements in Treatment
Dr. Morad said their discovery could also reduce the sickening side-effects of most cancer treatments, which stem from drug treatments interacting with the wrong or additional targets, or the correct targets but on non-cancerous cells. He said MuTaTo’s having a combination of several highly specific cancer-targeting peptides on one scaffold for each type of cancer cell would increase the specificity to the cancer cell due to the avidity effect. In addition, in most cases, the non-cancer cells that have a protein in common with the cancer cells do not overexpress it. “This makes a great difference between the two kinds of cells and should decrease the side effects dramatically,” Morad said.
He equated the concept of MuTaTo to the triple drug cocktail that has helped change AIDS from being an automatic death sentence to a chronic – but often manageable – disease. Today, AIDS patients take protease inhibitors in combination with two other drugs called reverse transcriptase inhibitors. The drug combination disrupts HIV at different stages in its replication, restrains an enzyme crucial to an early stage of HIV duplication and holds back another enzyme that functions near the end of the HIV replication process.
“We used to give AIDS patients several drugs, but we would administer them one at a time,” Morad explained. “During the course of treatment, the virus mutated, and the AIDS started attacking again. Only when patients started using a cocktail, were they able to stop the disease.” Now, he said, people with AIDS are HIV carriers, but they are not sick anymore.
The MuTaTo cancer treatment will eventually be personalized. Each patient will provide a piece of his biopsy to the lab, which would then analyze it to know which receptors are overexpressed. The individual would then be administered exactly the molecule cocktail needed to cure his disease. However, unlike in the case of AIDS, where patients must take the cocktail throughout their lives, in the case of MuTaTo, the cells would be killed, and the patient could likely stop treatment after only a few weeks.
The company is now writing patents on specific peptides, which will be a large bank of targeting toxin peptides wholly owned and hard to break, said Mr. Aridor. Dr. Morad said that so far, the company has concluded its first exploratory mice experiment, which inhibited human cancer cell growth and had no effect at all on healthy mice cells, in addition to several in-vitro trials.
Karin Mayer Rubinstein, CEO of the Israel Advanced Technology Industries (IATI) has criticized their comments as irresponsible and damaging, warning, “We welcome all companies that develop breakthrough technologies [but] The things the researchers have said have damaged the image of Israel’s life sciences industry.” IATI is the umbrella organization that represents Israeli high-tech and life science companies, VCs, multinational companies operating in Israel, incubators and tech transfer arms of Israeli academia. “It is a very irresponsible statement, and we have had many people from around the world asking to clarify the subject. As we understand, there are critical stages of their research that must still be met. These kind of statements are liable to damage Israel’s life science industry, which is positioned globally as one of the most serious and professional in the world,” she said.
Dr. Morad told The Times of Israel that the reaction of the critics who have not seen the company’s results is “like criticizing a book without reading it.” He reiterated that the firm can start treating patients within clinical trials that it hopes to start “pretty quickly,” and “We are not saying that the drug will be approved in a year. Our technology is innovative and we have submitted an application for a patent on it. This application is at an advanced stage, and until now the patent lawyers have deemed our technology innovative.”
Dr. Morad said his company firm has not published its research in medical journals, as is the norm, because it “can’t afford” to do so, but that the results of its pre-clinical trials have been “very good.” He said, “We are a small company. Publishing an article takes a lot of effort and a lot of funds, and this we can’t afford. If we were a big company with a lot of funds, that would be the first thing we would do. If I have $100,000 what do I spend it on? Advancing the research and finding more and more targeting peptides, or doing many experiments to write an article? What would you do, if you had to choose?”