Monoclonal Antibodies: What are they?
The Immune System: Invaders and Defenders
We are surrounded by billions of bacteria and viruses which try to invade our bodies and reproduce. We call these invaders antigens and pathogens. When we receive a cut and invaders enter the body, cells are destroyed. The dying cells trigger an automatic response called inflammation, which includes dilated blood vessels and increased blood flow. Inflammation is the body's equivalent to a burglar alarm. Once it goes off, it draws defensive cells to the damaged area in great numbers.
The defensive cells, our immune cells, are white blood cells produced in huge quantities in the bone marrow. There are a wide variety of immune cells, each with its own strengths and weaknesses. Some seek out and devour invading organisms, while others destroy infected or mutated body cells. Yet another type has the ability to release special proteins called antibodies that mark intruders for destruction by other cells.
But the really cool thing about the immune system is that it has the ability to "remember" enemies that it has fought in the past. If the immune system detects a "registered" invader, it will strike much more quickly and more fiercely against it. As a result, an invader that tries to attack the body a second time will most likely be wiped out before there are any symptoms of disease. When this happens, we say that the body has become immune.
The Immune System in MS: T-Cells and B-Cells
Multiple sclerosis is an inflammatory, autoimmune disease of the central nervous system involving a class of white blood cells called lymphocytes, a normal part of our defense system against infections and cancer. In an autoimmune disease, our defensive cells begin to attack normal body cells rather than invaders and can cause lots of damage in the process. In the case of MS, it is our myelin sheath (protective covering around nerves) which is attacked leaving damaged oligodendrocytes in the wake and exposing axons.
Lymphocytes are divided into two main classes--T-lymphocytes and B-lymphocytes (also called T-cells and B-cells for short). Traveling on those lymphocytes are protein molecules called antibodies (or immunoglobulins) which bind to foreign antigens expressed on cells. It is the B-cells that manufacture, display, and secrete antibodies. Both type of lymphocytes, T-cells and B-cells, seem to have a role in mediating the damage in MS that results in loss of myelin and axonal injury in the brain and spinal cord.
A wonderful primer on the immune system, including the army of T-cells and B-cells, is available on the website of The Nobel Foundation.
What are monoclonal antibodies?
Monoclonal antibodies (MABs) are a type of biological therapy which have an ability to bind to selective molecules found on the cell surface of lymphocytes. (‘Monoclonal’ just means all one type.) Monoclonal antibody therapy uses antibodies that are made in the lab rather than by a person's own immune system. This type of treatment is used in inflammatory conditions such as MS, rheumatoid arthritis, or malignant diseases such as leukemia and lymphoma.
The first monoclonal antibodies (MABs) were made entirely from mouse cells. One problem with this is that the human immune system will see these antibodies as foreign (because they're from a different species) and then will mount an immune response against them. In the short term, this can sometimes cause allergic-type reactions. In the long term, it means that the antibodies may only work the first time they are given; after that, the body's immune system is primed to destroy them before they can be helpful.
Has monoclonal antibody production been improved?
Over time, researchers have learned how to replace some parts of these mouse antibody proteins with human parts. Depending on how much of the MAB is human, these are called chimeric or humanized antibodies. Some MABs are now fully human, which means they are likely to be even safer and may be more effective than older monoclonal antibodies.
The following are MABs which are being (have been) studied in use for MS:
- Humanized MABs (90% human components and 10% mouse structure) include natalizumab (Tysabri), alemtuzumab (Campath), and daclizumab (Zenapax) and ocrelizumab.
- Chimeric MABs (~66% human and ~34% mouse structures) include rituximab (Rituxan) and basiliximab (Simulect).
- Fully human MABs include ofatumumab (Arzerra), adalimumab (Humira), ustekinumab (Stelara), and ch5D12.
In the next post, we will take a closer look at specific monoclonal antibodies and their use in multiple sclerosis.
Monoclonal Antibodies: A New Way to Treat MS. Denise Campagnolo, MD, MS Director, Clinical MS Research, Barrow Neurological Institute, Phoenix, Arizona. United Spinal’s MS Scene (2008).
Monoclonal Antibody Treatment in MS. John Rose, MD, Chief of Neurology, VA Medical Center, Salt Lake City, UT. Multiple Sclerosis Center of Excellence website.
The Immune System - In More Detail. The Nobel Foundation website.
For More (Technical) Information:
Monoclonal Antibodies in Multiple Sclerosis Treatment: Current and Future Steps. Helliwell CL, Coles AJ. Therapeutic Advances in Neurological Disorders 2009;2(4):195-203.
Treating Multiple Sclerosis With Monoclonal Antibodies. Buttman M, Rieckmann P, et al. Expert Review Neurotherapeutics 2008;8(3):433-455.
Recent developments in multiple sclerosis therapeutics. Spain RI, Cameron MH and Bourdette D. BMC Medicine 2009;7:74 (regarding alemtuzumab)