Celestine antibodies, the fourth branch of cancer immunotherapy

The 1984 Nobel Prize in Medicine went to three researchers for antibodies , the most famous proteins of the pandemic. Two of them, Kohler and Milstein , received him for developing the hybridoma , a technology that allowed them to be manufactured in a generous and specific way. This technique, which fused a lymphocyte with an immortal tumor cell, revolutionized research, multiplied the possibilities of diagnoses and opened the door to numerous treatments, such as those directed at many types of cancer .

These antibodies are natural: they come from selecting and amplifying an existing one. But now the techniques allow to play more and more with the forms and, like a mechanic of nature, to invent and add new functions to them. Among them, for example, joining at its other end to a killer T lymphocyte , activating it and directing it towards a target chosen to eliminate it. For example, a tumor cell . They are celestine antibodies because they take them to the tumor and present it to them, causing a fatal love.

They are a new immunotherapy in which research is accumulating and that many see close to hatching.

Strength and sensitivity

Actually, these artificial antibodies are called bispecific , because they bind to two targets instead of one alone, as the natives do. And, as they stimulate our own defenses, “they can be considered without any doubt a form of immunotherapy,” says Luis Álvarez Vallina , head of the Cancer Immunotherapy Unit at Hospital 12 October, in Madrid.

The three classic branches of cancer immunotherapy are drugs that release the brakes of defenses, vaccines and cells CAR-T , which are modified in the laboratory to attack the tumor. Traditional antibodies often act without being related to our defenses, so they cannot always be considered as such. Since matchmakers do, they can be assigned the fourth branch.

“The concept is terrific,” says Josep Tabernero , head of the Oncology Department of the Vall d´Hebron Hospital, in Barcelona, ​​and former president of the European Society of Medical Oncology. It combines the sensitivity of antibodies with the strength of T lymphocytes, “but there are a number of obstacles that must be overcome.”

If we look at the number of ongoing clinical trials and the market forecasts , it would seem that there is confidence in achieving this.

Big Pharma is on it

The concept may be good, but it is not entirely new, and many trials have failed along the way. Right now there are only three approved products of this type , and only one is exactly a celestine antibody against cancer, specifically against a type of leukemia that does not respond or that it has stopped responding to other treatments. The other two are used against a very particular subtype of lung cancer and to treat hemophilia A , but they do not bind to other defense cells, but instead take advantage of their ability to bind to two different targets to block the tumor or to bind two clotting factors.

“The main problem we have encountered has been toxicity,” acknowledges Tabernero. “Somehow they work by adding gasoline to a fire that is initially small”, visualizes Vallina, “but the response may be too powerful”. If that sleeping lion is awakened but not controlled, it can end up causing a cytokine storm very similar to that which occurs in the most serious cases of covid and which is sometimes difficult to control.

The main problem is toxicity. Somehow they work by adding gasoline to a fire that is initially small, but the response may be too powerful

Luis Álvarez Vallina, head of the Cancer Immunotherapy Unit of the Hospital 12 de Octubre

Despite this, at the moment there are about 150 clinical trials in progress to test more than 100 different types of these antibodies – many of the celestine type – against the most varied types of tumors. . And a quick search of Google news yields a whole showcase of market promises, million-dollar investments, and expected returns. Therapies are mixed in the salmon pages and, if the bets are oriented towards the results, it is striking that “all the big pharmaceutical companies are in it,” says Vallina. “Knowledge of biology has been improving and, with it, expectations.”

Work better in liquid tumors

Celestine antibodies have several advantages over treatments with CAR-T cells , with which they are often compared, since both try to put T lymphocytes to work. In general, CAR-T must be manufactured from patient cells, which requires waiting a while and having special infrastructures. These antibodies, however, could be available from the outset in stock .

Although it could be more or less chronic treatments, this would allow better adaptation to side effects. And, although they will not be cheap, their prices are not expected to reach the 300,000 euros that a treatment with CAR-T cells usually costs when it has not been developed from the public .

In what they do resemble is that it is easier to make them work against blood tumors than against the rest, the so-called solid. Not only is it easier to get them to reach them, but “the targets we can target are much cleaner,” explains Tabernero. That is, they are exclusive to those cells, which limits their action against others and, therefore, side effects.

Not by chance, one of the diseases with the most tests is multiple myeloma , a tumor of antibody-producing cells. It is no coincidence because, in addition to cleaning the targets, it is easier to live without antibodies than without T lymphocytes, although the former have made headlines in the pandemic. Up to seven antibodies from different companies are now being tested : a race that promises millionaire earnings to whoever gets their first pass – not expecting large differences in efficacy, the position advantage skyrockets [ 19459006] -.

So-called solid tumors present more problems. Access is more difficult and they can also carve out an environment in which they hide, in which they put brakes on defenses. Even immunotherapies that seek to release these brakes are often not effective, because either because of the environment or because there are not too many mutations or a combination of all of this, not enough defense cells arrive. “They are tumors that we call cold”, explains Tabernero. Celestine antibodies look for “the flame to rise”, for the T lymphocytes to come and for the cold to turn into heat.

The problem for this is the fact that they have fewer specific targets and that these may also be in normal cells. “Even if they are in smaller quantities, this can trigger secondary effects,” explains Tabernero. This is what happened with the project involving his own team against colon cancer . It was presented as very promising at a major international congress in 2017 , just when the name “matchmaker” began to become known. But after a while he had to stop. “It was very effective, but too toxic,” he acknowledges.

The challenge is to adjust the designs to overcome the problems. Despite the obstacles, for Tabernero “the general concept is still valid”. Proof of optimism is that numerous trials are still underway against solid tumors of many types, not only of the colon but also of the lung, prostate, brain or skin.

Masked Celestines

If more celestine antibodies start to be approved it will most likely be against blood tumors first. If they demonstrate efficacy and safety, they would be administered first to the most advanced forms of the disease, those that no longer respond to other treatments. But the prices of those already approved “are around 100,000 euros, which can lead to situations of injustice depending on the resources,” says Vallina.

As with other therapies, it is logical that in many cases they lead to partial responses and then the tumor learns to resist them. “That is something we will see over time,” says Vallina. The good news is that there are theoretical ways to improve them, such as through “drug combinations,” he adds. For example, with those who release the brakes: if the side effects are controlled, it is tempting to release them while at the same time a matchstick steps on the accelerator.

In the medium term there are also many ideas to improve these Celestinas: one idea that is being worked on is to “take them masked and that they are only released when they find the tumor,” explains Tabernero. Another, according to Vallina, “is to manage to regulate them, to incorporate a kind of switch”. And Vallina’s own team is working on modifying cells so that they themselves produce the celestinas. They are STAb cells (“stab”).

Perhaps the more distant future has also begun to glimpse. This year, two articles in the journal Science have taken a step towards achieving an old dream of the anti-tumor fight .

A showcase inside the tumor

The Kohler and Milstein antibodies were a revolution and allowed the development of many treatments against various tumors. But these antibodies act on their own, they do not call on T lymphocytes, and in general they need their target to be highly present on the cell surface. That limits the possibilities.

The fantasy of many researchers is to attack the heart of many types of cancer, the altered proteins that usually serve as their motor. Two of them are p53 , the so-called “guardian of the genome” and RAS , who could informally be nicknamed the “genome killer”. When your genes mutate, one fails to protect the cell and another makes it uncontrollable. Antibodies do not work against them, because they do not go outside. Rather, they hardly come out.

The so-called HLA is a showcase that cells have to show what they hide. If there is something strange, the T lymphocytes – and not the antibodies – can recognize and attack it. This is how they work against infections. But the alterations of p53 or RAS are very small for some T lymphocytes that are not so sensitive. And each cell only shows a couple of copies. It is as if they are in an almost invisible corner of the shop window.

This year, two investigations led by Shibin Zhou , from Johns Hopkins University, have achieved a great conceptual step. They have developed celestine antibodies that do two things impossible for natives: they recognize the storefront on the one hand and attract a T lymphocyte to the store on the other. One work is directed at the guardian and is published by in the journal Science , the other targets the murderer, and can be read in Science Immunology . The studies are only in mice and the results are notably better in the case of the first, but its importance lies in the paradigm shift.

“For the first time a therapy of this type would be seeing the inside of the cell,” explains Vallina. “The design is impressive,” adds Tabernero, because “it would allow attacking targets that in this case are completely specific to the tumor and not to normal cells.” The fine print includes that shop windows are not the same in all people, that efficacy should be proven in humans and that tumors sometimes also defend themselves by not expressing HLA, lowering the blind on the shop window. And that “it would be necessary to spin a fine thread to guarantee security,” says Tabernero.

This is what Zhou himself thinks, for whom “it will take several years to translate all this development into clinical trials because we need to optimize the antibodies and make sure they are safe in humans”.

In a comment based on these works , the researchers Ivano Amelio , Gerry Melino and Arnold J. Levine [19459003 ] ended in a way that seems appropriate for this entire article in general: “We must learn to arm the immune system so that it actually eliminates tumors or, better yet, prevents them from occurring. (…) Despite the long list of difficulties, we must continue to achieve a deeper understanding of the complexities of our defense system ”.

The title was somewhat more optimistic. It said: “Specific antibodies come to the aid of immunotherapy against cancer.”