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The cancer assassins: A history of immunotoxins

Cancer cells are essentially regular body cells, but with a difference: they have literally turned into freeloading parasites. How does one fight out-of-control cells that do not work as they should, but only feed and divide? Unfortunately, unlike regular parasites like bacteria or worms, they’re often too similar to normal cells to be targeted using drugs like antibiotics. Drugs capable of killing cancer cells often kill a lot of normal cells in a swathe of indiscriminate toxicity.

A recently written book chapter by Prof. Anjali Karande and her student Sudarshan Gadadhar recounts the history of a promising new approach to cancer therapy: immunotoxins, “the cancer assassins”. Immunotoxins consist of two parts – one is the target finder, an antibody specific to proteins found on cancer cells; and the second is the actual killer, a toxin that enters the cells and destroys it. The book chapter describes the history of the use of antibodies in cancer therapeutics, first as drugs themselves, and then as the targeting part of immunotoxins. It also gives a comprehensive idea of the various types of toxins from plants and bacteria that can be used or are currently in use in clinical trials as the ‘assassin’ part of immunotoxins.

Beginnings: differentiating rogue and innocent

The first few modalities used to fight cancer were radiation therapy, hormones and drugs that could suppress cancer growth. In the early 1970s, “tumour antigens” -- proteins unique to cancer cells -- were discovered. This gave scientists a method to home in on cancer cells, a way to distinguish between the rogues and the innocents in the body. At the same time, came “hybridoma technology”. Prof. Karande describes it as “an elegant way to obtain pure antibodies, of a particular specificity and at a large scale”.

After a few initial successes, antibody therapy hit one of the many hurdles it faces. Since many of the therapeutic antibodies were developed and produced from mouse cells, they were recognised as ‘foreign agents’ by the human immune system s. Immune reactions against the therapeutic antibodies reduced effectiveness of the treatment; moreover, they caused immune-related complications. This problem was partially solved by ‘humanizing’ the antibodies (making the mouse-derived antibodies more similar to human antibodies via recombinant DNA technology), and since 1997, at least 12 antibodies have been approved by the Federal Drug Authority in the United States, to treat various forms of cancer.

Transformation: Antibodies as carriers and targeting agents

Although antibodies were once dubbed ‘magic bullets’ for cancer treatment, the expected successes in curing this group of diseases were elusive. Scientists then began to consider and modify antibodies as carriers and targeting agents, rather than as drugs in themselves. One of the first major uses of antibodies as carriers was in the field of radio-immunotherapy (RIT), where tumours were targeted using antibodies attached to radioactive isotopes such as Iodine-125, Bismuth-213 and Yttrium-90. However, this method causes severe side effects. This led to the development of immunotoxins consisting of the antibodies conjugated to highly toxic plant or bacterial proteins that inhibit protein synthesis.

Toxins: the actual assassins

Proteins from various plant or bacterial sources have been considered for use as immunotoxins. The toxins are called ribosome inactivating proteins (or RIPs for short – a suitably martial acronym considering their effect on cells), and, as their name suggests, they affect the ribosomes which are the protein synthesis factories of the cells. The toxins are classified into three categories based on their structures and effects. Inhibition of protein synthesis is the main mechanism by which these proteins kill cells; some also cause cells to commit suicide in a process called ‘apoptosis’.

Immunotoxin construction and activity: more effectiveness, less non-specific toxicity

Immunotoxins are produced through chemical conjugation of antibodies to toxins, or through the creation of fusion proteins “Chemical conjugation methods are currently out-of-date, since batch-to-batch variations can be high and extensive testing is required to ascertain that each batch of constructs in of good quality. This is a waste of time and effort. It is probably much more worthwhile to design immunotoxins at the molecular level”, says Prof. Karande who believes that immunotoxins as fusion proteins are invaluable in medicine and research. The method is also useful as it allows scientists to modify the antibodies or toxins via mutations to reduce side effects such as vascular leak syndrome (a condition where blood vessels become extra-permeable and leak fluid into tissues which could lead to organ failure) or to enhance their effectiveness.

Currently there are quite a few immunotoxins in clinical trials as anti-cancer therapeutic agents. These are classified according to their use in treating either hematologic (blood-related) cancers or against solid tumours. Despite their effective use against cancers, immunotoxins are still not the panaceas they were once thought to be. Their usage as therapeutics is still riddled with several drawbacks involving low penetration (their ability to reach the cancerous cells), side effects such as vascular leaks or liver toxicity. In conclusion, despite the immense potential shown by immunotoxins in controlling cancer, many problems must be overcome before they can be effective cancer curatives.

About the authors:

Dr. Anjali Karande is a Professor at the Department of Biochemistry in the Indian Institute of Science.

Contact: Anjali@biochem.iisc.ernet.in, +91-80-22932306

Dr. Sudarshan Gadadhar is currently a Postdoctoral fellow at the Institut Curie, Orsay-Paris.