Biological therapy for inflammatory bowel disease

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The anti-TNF-a monoclonal antibody infliximab is a major biological therapy for inflammatory bowel disease Infliximab structure2.jpg
The anti-TNF-α monoclonal antibody infliximab is a major biological therapy for inflammatory bowel disease

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel 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]

Contents

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 (such as TNF inhibitors and interleukin antagonists) have been developed for the treatment of these diseases. Although the use of antibodies to treat diseases can be dated back to the 1800s, biologic therapy as we know it today is a relatively new concept for the treatment of inflammatory bowel disease. [9] The previous treatment options had many shortcomings, and the introduction of biological therapy changed the way physicians treat Crohn's disease and ulcerative colitis. [5] [6] Even so, biologic therapy still has its faults such as high cost and risk of side effects. A lot of research is being done in fields like biosimilars and oral delivery to address these concerns. [10] [11]

History

The use of antibodies to treat diseases can be traced all the way back to the late 1800s with the advent of diphtheria antitoxin for the treatment of diphtheria. It wasn't until the 1900s 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. 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. [12] They started the field of monoclonal antibody development and won the Nobel Prize for Medicine in 1984 for their work. [13] Soon after, muromonab-CD3 became the first fully licensed monoclonal antibody in 1986 for its use in treating kidney transplant rejection. [14] Since then, over 70 monoclonal antibodies have been approved by the FDA. [15]

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. [10] 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. [16] 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 categories of biologics that treat IBD are integrin receptor antagonists such as vedolizumab and natalizumab and interleukin antagonists like ustekinumab. [11]

Rationale for biological therapy

Cytokines involved in IBD Cytokines in IBD.jpg
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. [7] 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. [17] 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. [17] Patients with Crohn's disease that developed complications, including fistulae (= abnormal connections to the bowel) were treated with surgery. [18] Patients with ulcerative colitis who do not respond to medications are still treated with colectomy (= removal of the colon).

However, basic science research showed that many cytokines were elevated in both Crohn's disease and ulcerative colitis. [19] Crohn's disease cytokines are of the type 1 (Th1) cytokines, which include TNF-α, interleukin-2, and interferon γ. [20] Ulcerative colitis was less conclusively linked to the production of Th2 cytokines. [21]

TNF inhibiting biological therapies were initially used in IBD patients who weren't responding to conventional therapy. [17] 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. [22] 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. [17]

TNF inhibitors

Schematic demonstrating infliximab structure Infliximab structure.jpg
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. [23]

Infliximab

The monoclonal antibody infliximab is a mouse-human chimeric antibody to TNF-α. The FDA approved it in 1998, making it the first approved TNF inhibitor. Infliximab has shown significant success in treating both Crohn's disease and ulcerative colitis, but it is also approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. [11]

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. [11] Adalimumab showed effectiveness in patients with Crohn's disease, but less than that of infliximab. [24] It was the best selling drug in 2017 with sales upwards of $18 billion. [25]

Certolizumab pegol

Certolizumab pegol is a recombinant antigen-binding fragment antibody that is attached to a 40kDa polyethylene glycol. [11] The addition of polyethylene glycol, or PEGylation, increases bioavailability, drug stability, and plasma half-life. [26] It was found to have efficacy over placebo medications for 10 weeks in the treatment of moderate to severe Crohn's disease in one large trial. [27] It is not used in the treatment of ulcerative colitis, but it is used in the treatment of rheumatoid arthritis, active psoriatic arthropathy, and ankylosing spondylitis. [11]

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. [11]

Integrin receptor antagonists

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. [23]

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. [11] It was approved for the treatment of multiple sclerosis as well, but there have been concerns due to reports of progressive multifocal leukoencephalopathy. [23]

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. [23]

Interleukin antagonists

Interleukins are a cytokine that play a major role in the immune system. IL-12 and IL-23 help with the activation and differentiation of natural killer cells and CD4+ T lymphocyte, both of which contribute to inflammation. Interleukin antagonists, the most recent class of biologics available for use in IBD, inhibit the action of IL-12 and IL-23 by binding to the p40 protein subunit that is found on both of these cytokines. [23]

Ustekinumab

Ustekinumab was approved by the FDA in 2009 for the treatment of plaque psoriasis, making it the first and so far the only approved interleukin antagonist. It is also used for the treatment of Crohn's disease and psoriatic arthritis. Studies suggest that the blocking of IL-23, rather than IL-12, has the greatest effect on the therapeutic benefits of ustekinumab. [23]

Biosimilars

When the patent period of a drug ends, a generic version is usually made. With conventional small-molecule drugs, it is possible to create a generic that is exactly the same as the original because small-molecule drugs can be characterized down to a single atom. However, the structure of biologics is far more complex and can't be fully characterized with current analytical techniques. [11] Also, the cell-based manufacturing process of biologics results in undefinable post-translational modifications. Thus, it is impossible to prove whether two biologics are exactly the same in every aspect. [23] There are no generic versions of biologics. Instead there are biosimilars. Biosimilars are defined by the FDA as, "a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product." [28] Currently, the only two biologic treatments for IBD that have approved biosimilars are adalimumab and infliximab. [11]

Side effects and concerns

Biologics are known to sometimes cause harsh side effects. Currently, Biologics are only delivered systemically. They can't be delivered orally because the harsh environment of the gastrointestinal tract would breakdown the drug before it could reach the diseased tissue. Because systemic administration results in blockading the same pathway in both healthy and diseased tissue, pharmacology is exaggerated leading to many side effects such as lymphoma, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, injection site reactions, and additional systemic side effects. [10]

Patients often wait until after other treatment options have failed to begin biological therapy because biologics are extremely expensive. One study modeled that, in the US, the average yearly cost of biological therapy for inflammatory bowel disease was around $36,000. [29] The treatment of inflammatory bowel diseases, with an estimated direct cost of $5.9 billion annually, poses a significant economic burden on the health care system. Recently, the primary treatment cost has shifted from hospitalization to medication. The shift is due to the rising use of these expensive biologics as well as their ability to reduce the need for hospitalization. [10]

Overtime, patients can lose response to biologics even after an initial positive response. Because biologics are foreign substances to the body, they can prompt an immunological response causing the development of anti-drug antibodies. Anti-drug antibodies can cause negative side effects, accelerate the rate of drug clearance, and reduce the therapeutic effects of the biologic. [23] In clinical practice, less than 50% of patients who showed an initial positive response to biological therapy were in remission after one year. [10] The development of anti-drug antibodies can be reduced by limiting any times when there is no biologic present in the body and by taking other immunosuppressants (such as thiopurines or methotrexate) in combination. [23]

Research

New biologic therapies that target both existing cellular targets (including IL-12 and IL-23) and new cellular targets are being developed. Brazikumab and risankizumab are both IL-23 specific antagonists, opposed to ustekinumab which targets both IL-12 and IL-23, that have shown efficacy in phase 2 trials for Crohn's disease. Etrolizumab is an integrin receptor antagonist that targets beta 7 integrins. Etrolizumab has shown efficacy in phase 2 trials as well. The hope is that etrolizumab can show similar efficacy to natalizumab while avoiding the specific cellular target that is believed to have caused the instances of progressive multifocal leukoencephalopathy. [23]

Another area of research is focusing on the personalization of biological therapy. The idea is to use a specific patient's biochemical or genetic profile to predict how a patient will respond to a biological therapy. The information could help inform which class of biologics to use first. Personalized medicine is already being used in practice in the oncology field. [23]

A lot of research is being done to develop a biologic that can be delivered orally to address the many drawbacks associated with systemic administration. The general consensus in the field is that oral delivery of biologics directly to the diseased tissue could greatly reduce side effects, the development of anti-drug antibodies, and the cost of treatment. [10]

See also

Related Research Articles

<span class="mw-page-title-main">Crohn's disease</span> Type of inflammatory bowel disease

Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue. The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum. Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer.

<span class="mw-page-title-main">Ulcerative colitis</span> Inflammatory bowel disease that causes ulcers in the colon

Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon (megacolon), inflammation of the eye, joints, or liver, and colon cancer.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Infliximab</span> Biopharmaceutical drug for autoimmune disorders

Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.

<span class="mw-page-title-main">Inflammatory bowel disease</span> Medical condition

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus, whereas UC primarily affects the colon and the rectum.

Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. It is administered by subcutaneous injection. It works by inactivating tumor necrosis factor-alpha (TNFα).

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

Management of Crohn's disease involves first treating the acute symptoms of the disease, then maintaining remission. Since Crohn's disease is an immune system condition, it cannot be cured by medication or surgery. Treatment initially involves the use of medications to eliminate infections and reduce inflammation. Surgery may be required for complications such as obstructions, fistulae, abscesses, or if the disease does not respond to drugs within a reasonable time. However, surgery cannot cure Crohn's disease. It involves removing the diseased part of the intestine and rejoining the healthy ends, but the disease tends to recur after surgery.

Management of ulcerative colitis involves first treating the acute symptoms of the disease, then maintaining remission. Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset which often leads to anaemia. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine.

Biological response modifiers (BRMs) are substances that modify immune responses. They can be endogenous or exogenous, and they can either enhance an immune response or suppress it. Some of these substances arouse the body's response to an infection, and others can keep the response from becoming excessive. Thus they serve as immunomodulators in immunotherapy, which can be helpful in treating cancer and in treating autoimmune diseases, such as some kinds of arthritis and dermatitis. Most BRMs are biopharmaceuticals (biologics), including monoclonal antibodies, interleukin 2, interferons, and various types of colony-stimulating factors. "Immunotherapy makes use of BRMs to enhance the activity of the immune system to increase the body's natural defense mechanisms against cancer", whereas BRMs for rheumatoid arthritis aim to reduce inflammation.

Ustekinumab, sold under the brand name Stelara among others, is a monoclonal antibody medication developed by Janssen Pharmaceuticals, for the treatment of Crohn's disease, ulcerative colitis, plaque psoriasis and psoriatic arthritis, targeting both IL-12 and IL-23.

Cedelizumab is a monoclonal antibody acting on the immune system. Possible indications include the prevention of organ transplant rejections and the treatment of autoimmune diseases.

Vedolizumab, sold under the brand name Entyvio, is a monoclonal antibody medication developed by Takeda Oncology for the treatment of ulcerative colitis and Crohn's disease. It binds to integrin α4β7, blocking the α4β7 integrin results in gut-selective anti-inflammatory activity.

<span class="mw-page-title-main">Enteropathic arthropathy</span> Medical condition

Enteropathic arthropathy commonly referred to as enteropathic arthritis, is a type of arthritis linked to Crohn's disease, ulcerative colitis, and chronic inflammatory bowel diseases.

Etrolizumab is a biopharmaceutical drug candidate being developed for the treatment of ulcerative colitis and Crohn's disease. It is a humanized monoclonal antibody against the β7 subunit of integrins α4β7 and αEβ7. Etrolizumab was developed by Genentech by engineering the FIB504 antibody to include human IgGl-heavy chain and κ-light chain frameworks; it is manufactured in CHO cells.

Celltrion, Inc. is a biopharmaceutical company headquartered in Incheon, South Korea. Celltrion Healthcare conducts worldwide marketing, sales, and distribution of biological medicines developed by Celltrion. Celltrion's founder, Seo Jung-jin, is the richest person in South Korea.

Otilimab is a fully human antibody which has been developed by the biotechnology company MorphoSys. It can also be referred to as HuCAL antibody, HuCAL standing for Human Combinatorial Antibody Library and being a technology used to generate monoclonal antibodies. Otilimab is directed against the granulocyte-macrophage colony stimulating factor (GM-CSF), a monomeric glycoprotein functioning as a cytokine promoting both proliferation and activation of macrophages and neutrophils.

<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

Shomron Ben-Horin is an Israeli physician, a co-founder & Chief Medical Officer of Evinature, and professor of medicine at the Tel-Aviv University.

Integrin α4β7 is an integrin heterodimer composed of CD49d (alpha-4) subunit and beta-7 subunit noncovalently linked. LPAM-1 is expressed on the cell surface of leukocytes. This receptor is involved in lymphocyte trafficking pathway to site of inflammation in intestinal tissues.

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