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Antibodies for treating prostate cancer

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Researchers have successfully made an antibody to target prostate cancer. This antibody binds a protein called PSMA, found on the surface of prostate cancer cells. It is a “biological tool”, with the potential to be part of a new therapy targeting prostate cancer. This week’s blog explains what an antibody is, and how they are revolutionising cancer therapies.

Antibodies are part of our immune system

Our bodies are under constant threat from infectious diseases. We come in contact with viruses, bacteria, parasites and other organisms on a daily basis. It’s the job of our immune system to protect us from these diseases. White blood cells are an important part of our immune system. There are many different types of immune responses carried out by white blood cells to kill invading organisms. One of their jobs is to produce antibodies.

Antibodies are biological molecules. They are like the watchdogs of the immune system.  Their role is to recognise infectious organisms such as bacteria, viruses, parasites, moulds or fungus. When an antibody binds to one of these organisms, it alerts the immune system to the presence of something foreign, and possibly dangerous. Antibodies also play a role in immune response. They take part in the processes that protect us from the invading organisms.

How are antibodies made?

Antibodies tell our immune system when they see something that is foreign to the body. The way that this happens is an amazing and complicated process. Millions of different types of antibodies are produced by the body. Most of each antibody molecule is the same. But at the end of their long “molecular arms”, are parts that vary a lot. These variable regions are the ones that recognise and bind to the invading organisms. By having millions of different types, the immune system aims to recognise every different biological molecule that it comes into contact with.

We don’t want an immune response directed at normal cells in our bodies. When this happens, it causes autoimmune diseases. So the immune system has a process for deleting the antibodies that recognise anything that is part of our body. Antibodies are produced by white blood cells that develop in the bone marrow. During their development, the cells producing antibodies are killed if they produce an antibody that recognises any part of the body. So the white blood cells that are released from the bone marrow into the blood, only make antibodies that recognise foreign molecules.

What do antibodies do?

As watchdogs, antibodies alert us to invading organisms. They recognise foreign molecules and bind to them. Sometimes, just binding to these organisms is enough to stop them from infecting the body. For instance, an antibody that binds to a virus can stop the virus entering cells, stopping infection. But often, a more complicated immune response is needed. An antibody binding to bacteria doesn’t stop them from growing in the body. But it brings other immune cells to the bacteria to kill them.

What our antibodies don’t do is recognise normal cells. So we can’t rely on our body’s antibodies to recognise and kill cancer cells. This is because cancer cells look very similar, if not identical, to normal cells, as far as antibodies are concerned.

Antibodies made in laboratories

Although the body doesn’t produce antibodies that effectively fight off cancers, antibodies can be a useful component of cancer treatments. This is possible for two reasons:

-  we don’t need to rely on antibodies made by our bodies. We can make custom-designed antibodies in laboratories.

- antibodies don’t just recognise infectious diseases, we can make antibodies to recognise almost any biological molecule.

Early in the days of laboratory experiments, antibodies could only be made in animals. Animals such as mice and rabbits were inoculated with proteins that researchers wanted to target. The animal’s immune cells made the antibodies, which were collected from blood samples. Scientists developed methods isolate and grow the antibody-producing cells from the animals. This allowed these animal antibodies to be mass produced in the laboratory. Antibodies have been extremely useful for scientists in making discoveries in the laboratory. Further technical breakthroughs were necessary to make them useful as therapies. Researchers can now convert animal antibodies into the equivalent human antibodies. This allows them to be used in humans. It’s now possible to bypass the animal steps completely, using laboratories techniques to discover and develop new antibodies.

Antibodies as therapies

Antibodies can be very effective therapies. There are many examples of antibodies being used to treat a variety of conditions. For instance, antibodies that target a protein called TNFa are used to treat rheumatoid arthritis, psoriasis, Crohn’s disease and other inflammatory conditions. These antibodies bind to TNFa proteins, which are signals that control inflammation. The antibodies stop TNFa from interacting with cells via receptors on the cell surface. This reduces inflammation around joints, reducing the symptoms of rheumatoid arthritis.

For cancers, antibodies only work well as therapies if there is an appropriate target. An antibody can be made to recognise a cancer cell. But the challenge is that we need to only kills those cells, not normal cells in the body. Since cancer cells are so similar to normal cells, it can be difficult to find a target that recognises only the cancer cell.

One way to target cancer cells is to stop their access to growth factors. Growth factors are often proteins or hormones that circulate via the blood stream. When cells meet up with growth factors, they bind to the matching receptors on the cell surface. This tells the cells to divide and grow. Some cancers are reliant on growth factors. So stopping this process with an antibody can stop their growth. Prostate cancer is often reliant on testosterone to signal growth. Stopping prostate cancer cells from access to testosterone has been a good strategy to slow tumour growth, although this isn’t done with antibodies at the moment.

Another way to target a cancer is by antibodies that target molecules present on the outside of the cancer cells. These antibodies can be linked with a toxin, sometimes referred to as a “magic bullet”. Fortunately, there is a reasonably good target molecule for prostate cancer. PSMA is a protein that is present on the outside of prostate cells but not many other places in the body. There is a lot more PSMA present on prostate cancer cells than normal prostate cells. By making an antibody that binds to PSMA, prostate cancer cells can be targeted. This would be a way of bringing a toxin, stuck to the antibody, specifically to the prostate cancer cells.  

A new antibody for prostate cancer

Researchers from the Fourth Military Medical University in Xi’an in China have made a new antibody to target prostate cancer. Their results have recently been published in the journal Molecular Cancer Therapeutics.

The antibody made in China has many important features that make it a good fit as part of a prostate cancer therapy. It’s a human antibody, rather than one made in a mouse or rabbit. It binds very strongly to PSMA, but not to other molecules. It also has good thermostability – meaning that it’s likely to be stable and not break down easily.

The researchers used mouse studies to demonstrate that their antibodies specifically recognise prostate tumours. Human prostate cancer cell lines were injected into mice, leading to growth of human prostate cancer cells in the mice. The new PSMA antibody, attached to a fluorescent marker, was then injected intravenously into the mice. The fluorescent antibody showed the positions in the mice where tumours were growing. The researchers also showed that PSMA antibody treatment could slow tumour growth in the mice. They predicted that the antibody was able to bring other immune cells to the prostate tumours, killing the prostate cancer cells. Importantly, no obvious side effects affected the mice when they were treated with PSMA antibodies.

Targeting prostate cancer via PSMA in humans

PSMA is a good target for prostate cancer, but it’s not perfect. PSMA is found on the surface of prostate gland cells. There is more PSMA on the surface of prostate cancer cells, and even more again on metastatic prostate cancer cells. But PSMA is also found at lower levels in some other regions of the body, such as salivary glands, kidneys and intestine. So targeting PSMA with antibodies or toxins might also affect other regions of the body.

One treatment that seems to successfully use PSMA as a target is lutetium-PSMA. During this treatment, a radioactive lutetium is attached to a molecule that binds to PMSA. It brings the toxic radioactive component close to cells that have PSMA on their surface. Although clinical trials are ongoing, early case series studies indicate that this treatment is very promising. Lutetium-PSMA didn’t use an antibody to target PSMA, and I’m unsure why. It could be that the existing PSMA antibodies were not good enough at the time, or unavailable due to being owned by pharmaceutical companies.

The authors of the Chinese study comment that existing PSMA antibodies are limited, and that theirs appears to be a much better one. Theirs is a human antibody, whereas previous ones had regions of mouse protein. They have also demonstrated that their antibody is capable of bringing other immune cells in to kill a target cell – but we don’t yet know if this will happen in humans.

There is considerable research necessary before this antibody can be made part of a new treatment for prostate cancer. But having a better antibody means that we have better building blocks with which to make these new treatments. This research is a great example of the essential groundwork, done in laboratories and mouse studies, that drives the production of new treatments for prostate cancer.

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