What do the latest promises against the lupus and Alzheimer’s, medications for viral infections such as bronchiolitis and SARS-CoV-2 and the therapies that have changed the prognosis of cancers such as melanoma? They are all monoclonal antibodies and none would exist without the altruism of the creators of this technology..
“The medicine of the 21st century cannot be understood without monoclonal antibodies”. That’s how blunt it shows Marcos Lopez Hoyos, President of the Spanish Society of Immunology, SEI. At first glance, the relationship with the immune system of lupus, infections and even cancer can be understood, but it may be a little more difficult to discern how they might work against dementia, as lecanemab demonstrated this week after being Know your results in Alzheimer’sbut also against osteoporosis or migraine.
“The immune response, that is, inflammation, is present in all pathologies and affects all organs,” explains the also head of the Immunology service at the Marqués de Valdecilla University Hospital, in Santander. He proudly notes: “Immunology is the clearest example, in biology, of globalizationand each time we know better its mechanisms”.
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Thus, these antibodies synthesized in the laboratory (monoclonal means that it is directed at a single target) are capable of mediating the immune response but also of blocking certain cells to prevent them from carrying out a specific function. Hence the reason for its success: “They are bullets, very well aimed missiles“.
That is why they are also used for diagnosis, to detect very specific proteins within the body that provide information to healthcare providers about which drugs will be used to treat a specific condition.
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Although it was not until the late 1990s that they began to proliferate, the history of monoclonal antibodies dates back to the second half of the 1970s, years that will mark medicine in the 21st century: it is then that the possibilities of genetics and to devise the first biological medicines.
The Argentinian Chemist Cesar Milsteinwho had fled his country in the 1960s due to the military dictatorship, had met the young German Georges Kohler and, impressed by his talent, he signed him to work in his molecular biology laboratory at the University of Cambridge, in the United Kingdom.
With effort and ingenuity they were able to unite a B cell, which produces antibodies, with another from a myeloma, a plasma cell cancer. The particularity of cancer cells, which can multiply indefinitely, and the specificity of the antibodies produced by the B cell (whose main handicap is that it is finite) together generated infinite possibilities.
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Milstein and Kohler would be recognized, along with the Danish Niels K. Ironwith the Nobel Prize for Medicine in 1984. They decided not to patent their finding –other versions say that it was the patent office that denied it for not seeing an immediate application– and, in this way, research into all kinds of antibodies was able to proliferate monoclonal.
The first of these appeared in 1986, muromonab, indicated to prevent rejection in solid organ transplants. It took more than a decade for those who would change the course of diseases to arrive: rituximab in lymphoma, trastuzumab in breast cancer and infliximab in inflammatory bowel disease.
At the beginning of the 21st century, the monoclonal antibody market was growing in double digits, already accounting for $5.4 billion in revenue. Before the end of the decade they were close to quadrupling that figure. In 2018, biologic drugs (the vast majority of which are monoclonal antibodies) already accounted for more than half of total drug sales. In 2021, five of the ten drugs that generate the most revenue were of this typeaccording to the specialized consultancy Evaluate Pharma.
Because, while they benefited from the non-proprietary technology, monoclonal antibodies are expensive drugs. “They are expensive for all the development of knowledge and clinical studies behind them,” says Marcos López Hoyos. And although many of them already have biosimilars (versions that other laboratories make after the release of the patent for a specific drug), their price remains at hundreds or thousands of euros.
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However, there are pathologies that account for almost all available treatments. “In rheumatoid arthritis it does not reach 100% but it is a very high number, and it has been shown that its early administration greatly improves the prognosis of these patients”, comments the immunologist.
Rodrigo Sánchez-Bayonaan oncologist at Hospital Universitario 12 de Octubre, estimates that cancer patients who can take advantage of treatment with monoclonal antibodies at some point during their disease account for between 25 and 30% of the total.
“They have brought about a paradigm shift in the way we treat cancer. Chemotherapy is an effective treatment but very little selective in terms of knowing that no two tumors are the same, and yet chemotherapy is the same for everyone.”
Instead, these drugs are able to recognize which tumors express certain proteins and attack them. Some recent drugs combine the destructive effect of chemotherapy and the specificity of monoclonal antibodies into highly effective therapies.
a gigantic size
Sánchez-Bayona, who is also scientific secretary of the Spanish Society of Medical Oncology, considers that there are still steps to be taken to better identify which patients can benefit from these treatments, improve their side effect profile and, above all, “integrate these drugs, which usually have a high cost, in a way that is sustainable for the system. It is the other toxicity, sometimes called financial toxicity”.
The pharmaceutical Piedad Lopeza member of the group of immune-mediated diseases of the Spanish Society of Hospital Pharmacy, adds a piece of information that helps to understand the complexity of these drugs: a monoclonal antibody is 10,000 times larger than a molecule of a product developed by chemical synthesis, such as aspirin.
It also opens the complexity of these drugs to another field: the route of administration. In general, they have always been intravenously – “we are never going to take them orally” – which forced the patient to go to the day hospital from time to time to have it administered.
But now intramuscular and even subcutaneous forms are emerging, with single-use pre-filled pens. “The patient has to learn to handle these medications even if they are not knowledgeable in the matter,” he acknowledges.
Its complexity and, he does not deny it, its price, is also forcing a change in the way of measuring the results of medicines. Today, the process of entering a drug of this type into public health is more complicated because the Administration has to ensure that it works for the patient to whom it is given. If it doesn’t work, the pharmaceutical company will not be paid full price.