History of Remicade
Originally in search of an immunotherapy drug to combat cancer, Dr. Jan Vilcek and a team of researches made a remarkable discovery of a promising protein, tumor necrosis factor alpha. TNF-α,is a cytokine secreted by macrophages to elicit inflammation. Vilcek initially discovered the protein while studying the growth of tumors in transplantable animals, such as murine mice. It was found that this protein could not only block the growth of such tumors, but could even rid the mice completely of cancerous cells. This left many hopeful that TNF could also be employed as a therapeutic agent to fight cancers in humans.
Beginning human trials, Vilcek and his team caught the attention of several drug companies, especially Centocor. Their hope was to have discovered a means of treating cancer using the body’s own immune system. However, within a few years of trials having been underway, this was not case. Rather, the extraordinary protein they had discovered in 1993 was highly toxic, even at low doses. Although, the study did not result in the desired outcome, the team further researched the use of TNF for other clinical applications.
Using the knowledge of TNF-as a pro-inflammatory cytokine, Vilcek started exploring the generation of antibodies for the protein. Murine mice were used as a model organism to develop the first monoclonal antibody, A2. This antibody was found to bind to TNF-thus causing the reduction of inflammation in systemic immune responses. The use of TNF inhibitors to treat diseases that were known to induce excessive inflammation, would be the foundation of Remicade. This was an engineered chimeric antibody, created by the combination of mouse and human TNF that allowed for a higher specificity and affinity to the TNF receptor. With the collaborative efforts of Centocor, Remicade became the first drug of its kind on the market.
Structure
Remicade (Infliximab) is a chimeric IgG1 monoclonal antibody consisting of 597 amino acids, weighing 149,000 Daltons. A chimeric monoclonal antibody is produced when the variable regions of a murine antibody (25%) are combined with the constant regions of a human antibody (75%) at the hinge region. Within the hinge region, intramolecular disulfide bonds stabilize the two fragment antigen binding regions (Fab) to the fragment crystallizable region (Fc). The Fab regions are comprised of both a heavy and light chain, while the Fc region consist of only a heavy chain. Located in the folded Vh and Ch domains of the heavy chain, amino acid residues Glu-1 to Thr-226 are found. In addition, the light chains is composed of residues Asp-1 to Cys-214 that fold into the Vl and Cl domain. The heavy and light chain at the N-terminus form the variable region that functions as a receptor binding site.
After intravenously injecting Infliximab, the p55 and p75 receptors on TNF-α are neutralized when bound to the drugs high affinity receptor binding sites. The complex formed is stabilized through the vast array of weak interactions between the two proteins, such as hydrogen bonds, salt bridges, and Van der Waal forces. Specifically, TNF-α contributes to the stability by creating a large hydrophobic interface through its . This interface is formed primarily by the C-D and E-F loop residues connecting the antiparallel 8-stranded Beta sheets. Results of in vitro binding assays revealed the antibody and loops to be interacting through a molecular network.
Function
Upon the injection of Remicade into the body, the drug is dispersed throughout the bloodstream and to the tissues. Depending on the patient’s body surface index, the dosage of the drug administered will vary. In determining the proper amount of how much of the drug should be injected, Remicade is able to sufficiently block TNF-α from interacting with the TNF receptors (TNFR) on the target cell, thus inhibiting the induction of IL-1 and IL-6, both of which are pro-inflammatory cytokines. When this occurs, Remicade acts as a competitive inhibitor to TNF-R. If an adequate amount is introduced, the interface will be obstructed, thus preventing TNF-α from participating further in diseases.
Once the complex forms, it is stabilized by the amino acid residues Gln67–His73 and Gln102–Lys112 of the C-D and E-F loops. Particularly, the weak interactions between the loops and side chains, allows for a stronger binding affinity. (ASK ABOUT ACIDIC CHAIN SUBSTITUTIONS) The strongest interaction between the two proteins is best seen in the peak region in Figure.... This arises when TNF-α is in its active form and exists as a trimer. Although, research has offered some insight into the mechanisms of how Remicade effectively inhibits TNF-α, studies have not shown a clear understanding of the extensive underlying network. Thus, more research into this matter should be pursued.
Diseases
Rheumatoid Arthritis:
Rheumatoid Arthritis is a chronic inflammatory disease that affects the joints of the body, especially those in the hands and feet. Patients with this disease experience severe swelling in the joints that could eventually lead to bone erosion and joint deformity. With the use of Remicade, signs and symptoms can be reduced and the further progression of joint damage can be halted. This ultimately improves physical function and movement in patients enduring moderate to severe active Rheumatoid Arthritis. Often, methotrexate (a chemotherapy drug) is used in addition as part of the treatment plan.
Crohn’s Disease:
Crohn’s disease, also called ileitis, is a chronic inflammatory bowel disease that affects the lining and layers of the digestive tract. Disease activity can be assessed by measuring the levels of TNF-α in stool samples from patients. In the hope of reducing signs and symptoms, patients are prescribed Remicade if they have not responded well to other therapies. Remicade has the ability to reduce the influx of inflammatory cytokines and TNF-α production in the inflamed parts of the intestine. Following treatment, patients exhibit decreased levels of the pro-inflammatory cytokine, IL-6.
Ulcerative Colitis:
Similar to Crohn’s disease, Ulcerative Colitis is a chronic inflammatory bowel disease that causes inflammation in the digestive tract, particularly the sigmoid colon of the large intestine and rectum. Levels of TNF-α in stool samples is a technique used to assess the level of the disease in patients. To promote intestinal healing, Remicade is a drug that can be prescribed to prevent the use of steroids in adults with moderate to severe symptoms.
Ankylosing Spondylitis:
Ankylosing Spondylitis is an inflammatory disease affecting the spine and large joints in the body. Symptoms typically begin to appear in early adulthood causing reduced flexibility, eventually leading to a hunched-forward posture. With Remicade, signs and symptoms can be lessened in patients who are experiencing active Ankylosing Spondylitis by inhibiting TNF-α.
Plaque Psoriasis:
Plaque psoriasis is the most common form of the disease, appearing as raised, red patches covered with a off-white buildup of dead skin cells. These plaques typically appear on the scalp, knees, elbows and lower back. Remicade has been FDA approved for the treatment of adult patients expressing severe, chronic symptoms. The severity of the disease is ultimately assessed by a physician to determine if Remicade is the right course of action in consideration with other possible therapies.
Psoriatic Arthritis:
Psoriatic arthritis is a form of arthritis infecting people who usually have the skin condition plaque psoriasis. This disease cannot be cured but treatment can help with the symptoms. When Remicade is prescribed, symptoms are reduced and further joint damage is prevented. Patients also experience improvement in physical functions.
Structural highlights
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