Humira® (adalimumab) is a recombinant human IgG1 monoclonal antibody (mAb). Monoclonal antibodies are man-made antibodies that are highly specific for a single epitope of an antigen. These antibodies are mass produced in various ways, often using animal models/single B cell clone, by introducing an antigen (harmful substances that the host recognizes as being foreign) of interest to a mouse. For example, polyclonal B cells from the mouse’s spleen can then be fused to myeloma cells. This fusion results in forming hybridoma cells which are then cultured and allowed to continue to produce antibodies to the antigen. Generating monoclonal antibodies are useful because they have high affinity to only one epitope of your antigen of interest and can be produced from almost any substance. Also, since these monoclonal antibodies are produced from a single clone of B cells, all molecules in a preparation will have the same constant and variable regions and, thus, the same functional characteristics and specificity. These monocolonal antibodies can later be developed into immunoassays that detect or purify that antigen of interest. Therefore, there are significant biomedical value, including use in medications. Non-proprietary drug names end in the suffix -mab. Also, sometimes the monoclonal antibodies used need to be made more “human” in order to improve their therapeutic effectiveness. This is accomplished using recombinant DNA techniques that function to replace most of the animal-derived antibody molecule with human equivalents. When this happens it creates what is called a rhuMAb (recombinant humanized monoclonal antibody). The therapeutic value of these drugs are improved in humans because rhuMAbs have a longer half-life than standard monoclonal antibodies and the human immune system is less likely to destroy them. Non-proprietary medications composed of rhuMAbs have names ending in -zumab.
The FDA-approved the monoclonal antibody drugs adalimumab (Humira, Amjevita) in 2002 which is specific for human tumor necrosis factor (TNF). Humira is made by joining together DNA molecules and is thus recognized as a biologic. Because Humira is an immune supressant drug, patients typically must have an inadequate response to conventional medications to be considered. Humira is a tumor necrosis factor-α blocker, meaning that it blocks the inflammatory effects of tumor necrosis factor alpha (TNF-alpha) in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and Crohn ‘s disease of the intestine and ulcerative colitis. As part of the inflammatory response mechanism of the immune system, a protein called tumor necrosis factor, also known as TNF, is naturally produced by the body’s immune system. Humira works by binding to TNF-alpha molecules and blocking them from attaching to and attacking healthy cells. When TNF-alpha concentrations are high it can be very damaging to the body so blocking those cytokines helps reduce the damaging effects of excess TNF.
Inflammation is not all bad, it is the body’s reaction to injury and it is a necessary process for the repair of that injury. Consequently, TNF-alpha is a cytokine that is produced by macrophages, monocytes, endothelial cells, neutrophils, smooth muscle cells, activated lymphocytes, astrocytes, and adipocytes in the body. TNF-alpha has many functions, such as mediating expression of genes responsible for making growth factors, cytokines, transcription factors, and receptors. When TNF is secreted by the body, it promotes inflammation and results in various signs, such as in the case of arthritis, include pain, fever, tenderness, and joint swelling. For example, the inflammation in Crohn’s disease can result in perforations or narrowing in the intestine. By blocking TNF-alpha, the consequences in the joints and intestine are reduced/slowed or prevented.
Inflammation plays an essential role in shaping the ensuing adaptive immune responses. One of the consequences of blocking TNF-alpha and reducing its prolonged inflammatory response is that it can lower the ability of your immune system to fight infections. Therefore, people being treated with HUMIRA have an increased chance of developing serious infections, hospitalization or even death. Additionally, patients may experience serious adverse events such as increase the chance of getting lymphoma, skin or other cancers. I think that’s why HUMIRA is a last resort drug because there have been cases of unusual cancers in children, teenagers, and young adults using TNF blockers. In fact, some people have developed a rare type of cancer called hepatosplenic T-cell lymphoma which can often results in death.
Although there can be serious consequences to taking a TNF blocker, typical side effects include headache, rash, nausea, stomach upset. Also, adalimumab also has been associated with serious infections such as tuberculosis and sepsis (bacteria in the blood) and fungal infection. In some cases people have developed active tuberculosis (TB), including reactivation of latent TB. Latent TB can become active again in cases of weakened immune system so these patients have frequently presented with disseminated or extrapulmonary disease. Since adalimumab suppresses the immune system, it can be associated with minor infections of the urinary tract, respiratory tract, and sinuses, hypersensitivity reactions (including anaphylaxis ), reduced levels in the blood of platelets and red cells (aplastic anemia ), and may increase the risk of reactivating hepatitis B virus in chronic disease. Therefore, I think that TNF-alpha can be a double-edged sword. In the initial inflammatory response it can be invaluable in responding to and repairing wounds and infection but prolonged inflammation due to elevated levels of TNF-alpha can lead to damaging of healthy tissue and the inflammatory devastation seen in the earlier mentioned diseases. Severe side effects include heart failure, liver problems/failure and nervous system weakness.
I am very impressed that our body’s are so well equipped to protect us from invading pathogens and substances it recognizes as being foreign. However, too much of a good thing can lead to serious consequences to the homeostasis that our body needs. In this case we see how inflammation is a useful defense of our immune system but too high levels of inflammatory cytokines can lead to damage to normal tissue and result in disease. In the case of HUMIRA, patient’s and clinicians have to balance the pros and cons of risk/benefit assessments and can have positive results under careful and well monitored treatment.
Microbiology and You 