In today’s world cancer is responsible for approximately 8.2 million deaths per year globally and is considered the second most frequently diagnosed deadly disease. Currently, the most common form of treatment for cancer is chemotherapy, surgery or radiation, with novel techniques like stem cell therapy, hyperthermia, photo-dynamic therapy laser treatment etc., filling in where conventional one’s fail. Scientists throughout the world are trying to find different ways of treating this disease with a focus on reducing severe side effects in patients.
Cancer is a very challenging disease as the cause can vary from person to person. Cancer is a mystery disease, although we think we know a lot about it, there’s still a substantial chunk of information that evades us and this lack of understanding manifests as the difficulties in treatment. Although chemotherapy is used readily for cancer treatment, it is not a targeted treatment option. This means that anticancer drugs not only kill cancer cells, but also adversely impact healthy cells – which causes side effects, ranging from extrinsic implications like baldness, to more serious intrinsic complications. This treatment is also highly toxic and is usually used as a combination therapy.
The major focus of cancer research therefore is on making the treatment more targeted, thus reducing or eliminating chances of severe side effects in patients. One of the techniques that is now being explored is known as antibody drug conjugation therapy (ADC), which aims at reducing side effects by conjugating different types of highly potent un-targeted drugs used in chemotherapy to a monoclonal (produced from the same ancestral cell) antibody (mAb). Too complex? Before diving into how ADCs work, it would be informative to recollect the how our immune system works, and then move to understand monoclonal antibodies.
The human immune system is like an army of soldiers ready to attack if any foreign body crosses the border. It’s an intriguing system comprising of a range of specialised cells such as natural killer cells (NKCs), B-cells, T-cells, macrophages, etc. Each of these cells plays a different role in maintaining the defence system of the human body. Antibodies, also known as immunoglobulin (Ig), are a protective protein produced by the B-cells during an immune response against a foreign substance – aka, an antigen (these includes microorganisms, viruses or toxins, etc).
These proteins are large, Y-shaped, and function by recognising the antigen using the unique manner in which the antibody attaches to the antigen. This is known as the ‘fragment antigen-binding’ (Fab) variable region. Each tip of the “Y” of an antibody contains a structure that is unique to every antigen, allowing these two structures to bind together with precision, much like a lock and key, where only the correct combination allows the antibody to function. This mechanism allows the antibody to tag the antigen, or the abnormal cell, for attack by other parts of the immune system. Such a tag serves two purposes:
Every new tag is memorized by our body, so when the same antigen attacks again, our body knows which lock and key combination to use. This is the functional principle behind vaccination where a mild antigen of a disease is introduced in the body for our immune system to practice; and more importantly,
The tagging allows other parts of the immune system – which actually kill the antigen – to differentiate between the cells of our body and the antigen. This prevents unnecessary side-effects on the patients.
Now, ideally, we should be able to develop an antibody that finds the correct lock and key combination to tag cancer cells. However, the glitch is that cancer cells are essentially regular cells that have become infected and unhealthy. As this happens, a series of chemical reactions in these cells mask them from the immune system, making it difficult to differentiate between normal body cells and cancer cells and causing complications in antibiotic action. This is where Antibody Durg Conjugation Therapy comes into the picture.
To produce ADCs, monoclonal antibodies (mAb) are created in the lab from a single cloned immune cell. These immune cells are genetically identical, so the antibodies that they produce are also identical, resulting in high specificity. Simply put, the antibodies can bind to a specific antigen. To produce these antibodies that can bind to cancer cells, mice are first vaccinated with the target antigen, stimulating their bodies to create B cells in response. These B cells then start to produce antibodies specific to the target antigen (the cancer cell). These B-cells are then isolated, and fused with tumour cells (also known as the hybridoma cell) because while B-cells lack the ability to divide, tumor cells can divide quite rapidly. The division of the hybridoma cells (now fused with B cells) results in the cloning of the B-cells that results in the production of identical antibodies in vast quantities. The monoclonal antibodies are then collected and purified for use in ADC production.
Antibody drug conjugates comprise of three components i.e. monoclonal antibody (mAb), a linker and the cytotoxic payload (or the anti-cancer drug). The mAb targets a specific antigen displayed by the tumour cells, the linkers role is to connect mAb and the drug; forming a specific targeting component. This composition mainstay preserves the cytotoxicity of the drug (lethal effect on cancer cells), targeting characteristics, and stability of ADCs, as they circulate in the body. The selection of the right combination is of utmost importance for ADC therapy to be effective. To achieve specific delivery of a cytotoxic payload, the target antigen must be highly expressed on the surface of the tumour cells rather than the normal cells. By conjugating a mAb to a highly potent cytotoxic payloads allows for site-specific delivery of the payload to the target cells, thus minimizing the chances of off target cytotoxicity. Once the antibody binds to the specific antigen, the antibody gets absorbed releasing the cytotoxic drug inside the cell.
So far only four types of ACDs have been approved for clinical trials and have shown some promising results in breast cancer and different form on leukaemia (blood cancer). In theory, this therapy sounds very promising, but a range of technical challenges are encountered while developing the conjugates. A large amount of pharmaceutical research is now being focussed on ACD development and finding different combination of mAb, linker and the drug. In coming years, this treatment could revolutionize the direction of cancer treatment by providing a more targeted therapy with limited/reduced side effects.
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About the Author
Shalini Guleria is currently pursuing her Masters in Tissue Engineering where her research is focused on developing better treatment and detection techniques for Cancer. She is presently associated with Scion Research, New Zealand and holds a Bachelor's Degree in Chemical and Biological Engineering from the University of Waikato, New Zealand. Shalini has won two consecutive national awards at the prestigious Sir Paul Callaghan Eureka Awards for engineers and scientists. Apart from sciences, she is also a highly talented artist.