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The anti-TNF-α monoclonal antibody infliximab is a major biological therapy for inflammatory bowel disease

Biological therapy refers to the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease.[1] Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy; many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer,[2][3] autoimmune diseases,[4] and diseases of unknown cause that result in symptoms due to immune related mechanisms.[5][6]

Inflammatory bowel disease (IBD), a collection of systemic diseases involving inflammation of the gastrointestinal tract,[7] includes two (or three) diseases of unknown causation: ulcerative colitis, which affects only the large bowel; Crohn's disease, which can affect the entire gastrointestinal tract; and indeterminate colitis, which consists of large bowel inflammation that shows elements of both Crohn's disease and ulcerative colitis.[8]

Although the causes of these diseases are unknown, genetic, environmental, immune, and other mechanisms have been proposed. Of these, the immune system plays a large role in the development of symptoms.[8] Given this, a variety of biological therapies has been developed for the treatment of these diseases. These have changed the way physicians treat Crohn's disease and ulcerative colitis.[5][6]

History

[edit]

The use of antibodies to treat diseases can be traced all the way back to the late 1800s with the advent of diptheria antitoxin for the treatment of diptheria, but it wasn't until the 1900's that the newly emerging class of naturally derived medications such as sera, vaccines, and antitoxins began to be referred to as biologics. The definition for biologics and biological therapy has changed a lot since, and the development of recombinant DNA technology in the 1970s shaped the modern understanding of what constitutes as biological therapy, which often does not include traditional biological substances like vaccines. Today, biological therapy most commonly refers to the use of proteins, such as monoclonal antibodies, to regulate the immune system in the treatment of disease.[9]

In 1975, Georges J. F. Köhler and César Milstein generated the first monoclonal antibodies using their own hybridoma technology.[10] They started the field of monoclonal antibody development and won the Nobel Prize for Medicine in 1984 for their work.[11] Soon after, muromonab-CD3 became the first fully licensed monoclonal antibody in 1986 for its use in treating kidney transplant rejection.[12] Since then, over 70 monoclonal antibodies have been approved by the FDA.[13]

The advancements in biological therapy greatly changed how IBD is treated. Patients with Crohn's disease and ulcerative colitis show an increase in proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-23, and TNF.[14] In 1988, a monoclonal antibody called infliximab was discovered at New York University's School of Medicine. Infliximab works by binding to TNF, stopping its inflammatory effects. It was initially used for the treatment of Crohn's disease and it became the first FDA approved TNF inhibitor in 1998.[15] Infliximab as well as other TNF inhibitors like adalimumab, certolizumab, and golimumab are currently the most common biologics used in the treatment of both Crohn's disease and ulcerative colitis. The other main category of biologics that treat IBD are integrin receptor antagonists such as vedolizumab and natalizumab.[16]

Rationale for biological therapy

[edit]
Cytokines involved in IBD

Prior to the development of biological therapy as a modality to treat IBD, other medications that modulate the immune system—including 5-aminosalicylates, steroids, azathioprine, and other immunosuppressants—were primarily used in treatment.[17] Corticosteroids are effective in inducing clinical remission in patients with active IBD, but they can't be used long term due to the risk of steroid-dependence and harsh side effects.[18] The other medications like 5-aminosalicylates and azathioprine are often used to reduce steroid use while maintaining remission, but their actual effect on the state of the disease and the need for surgery remains unknown.[18] Patients with Crohn's disease that developed complications, including fistulae (= abnormal connections to the bowel) were treated with surgery.[19] Patients with ulcerative colitis who do not respond to medications are still treated with colectomy (= removal of the colon).

TNF inhibiting biological therapies were initially used in IBD patients who weren't responding to conventional therapy.[18] They proved to be very effective in some patients, shifting treatment goals from simply improving symptoms to actually changing the course of the disease by reversing mucosal inflammation and preventing long-term complications and surgery.[20] Although there are strong initial responses in some patients, biologic therapies also have their downsides, and there is still a debate as to what the most effective treatment strategy is.[18]

TNF inhibitors

[edit]
Schematic demonstrating infliximab structure

TNF inhibitors are commonly the first drug prescribed when a patient begins biologic therapy. They have the most extensive history of clinical evidence because they have been available the longest, are the most accessible, and are often the least expensive. Initially, it was thought that TNF inhibitors inactivate the proinflammatory cytokine by direct neutralization, but TNF signaling is a very complex process. Many recent studies suggest that TNF inhibitors may act with a more complex mechanism than simple blockade. They are all administered systemically either subcutaneously or intravenously. [21]

Infliximab

[edit]
Main article: Infliximab

The monoclonal antibody infliximab is a mouse-human chimeric antibody to TNF. The FDA approved it in 1998, making it the first approved TNF inhibitor. It was initially used to treat Crohn's disease, but it is also used in the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.[22][23] Infliximab has shown significant success in treating Crohn's disease and ulcerative colitis.[24]

Adalimumab

[edit]
Main article: Adalimumab

Adalimumab was approved by the FDA in 2002, becoming the first fully human monoclonal antibody to be approved. It was initially used in the treatment of rheumatoid arthritis, but it is now also used in patients with moderate-to-severe Crohn's disease and ulcerative colitis who don't respond well to conventional treatment.[16] It was the best selling drug in 2017 with sales upwards of $18 billion.[25]

Certolizumab pegol

[edit]
Main article: Certolizumab pegol

Certolizumab pegol is a recombinant antigen-binding fragment antibody that is attached to a 40kDa polyethylene glycol.[16] The addition of polyethylene glycol, or PEGylation, increases bioavailability, drug stability, and plasma half-life.[26] It is not used in the treatment of ulcerative colitis, but it is used in the treatment of Crohn's disease, rheumatoid arthritis, active psoriatic arthropathy, and ankylosing spondylitis.[16]

Golimumab

[edit]
Main article: Golimumab

Golimumab is a fully human IgG1 monoclonal antibody that was first approved by the FDA in 2009 to treat rheumatoid arthritis. Since, it has been approved to also treat psoriatic arthritis, ankylosing spondylitis, and moderately to severely active ulcerative colitis. [16]

Integrin receptor antagonists

[edit]

Integrin receptor antagonists are different than TNF inhibitors because they block transmembrane receptors called integrins instead of cytokines like TNF. Integrins mediate adhesion, signaling, and migration in many different types of cells. During active periods of disease, cell adhesion molecules on the vascular endothelium increase in response to various proinflammatory cytokines. The alpha 4 integrin on inflammatory cells interacts with these adhesion molecules to allow for migration. Integrin receptor antagonists block the interaction and prevent the migration of inflammatory cells to disease sites. [21]

Natalizumab

[edit]
Main article: Natalizumab

Natalizumab is a humanized IgG4 monoclonal antibody that inhibits the alpha 4 integrin. It was the first integrin receptor antagonist, receiving FDA approval in 2004 for the treatment of Crohn's disease. [16]

Vedolizumab

[edit]
Main article: Vedolizumab

Vedolizumab is very similar to natalizumab in that it is a humanized IgG monoclonal antibody, but vedolizumab is an IgG1 that specifically blocks the alpha 4 beta 7 integrin that is located primarily on cells in the gastrointestinal tract. It is promoted as being gut specific due to the localization of alpha 4 beta 7 integrin in the gastrointestinal tract and was the first biologic to be made specifically for inflammatory bowel disease. [21]

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