Biological response modifiers

Last updated March 14, 2019

Biological response modifiers (BRMs) are substances that modify immune responses. They can be both endogenous (produced naturally within the body) and exogenous (as pharmaceutical drugs), 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 (therapy that makes use of immune responses), which can be helpful in treating cancer (where targeted therapy often relies on the immune system being used to attack cancer cells) and in treating autoimmune diseases (in which the immune system attacks the self), 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 (e.g., CSF, GM-CSF, G-CSF). "Immunotherapy makes use of BRMs to enhance the activity of the immune system to increase the body's natural defense mechanisms against cancer",^[1] whereas BRMs for rheumatoid arthritis aim to reduce inflammation.

A chemical substance is a form of matter having constant chemical composition and characteristic properties. It cannot be separated into components by physical separation methods, i.e., without breaking chemical bonds. Chemical substances can be simple substances, chemical compounds, or alloys. Chemical elements may or may not be included in the definition, depending on expert viewpoint.

The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. In many species, the immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity. In humans, the blood–brain barrier, blood–cerebrospinal fluid barrier, and similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain.

Endogenous substances and processes are those that originate from within an organism, tissue, or cell.

Some of the effects of BRMs include nausea and vomiting, diarrhea, loss of appetite, fever and chills, muscle aches, weakness, skin rash, an increased tendency to bleed, or swelling.^{[ citation needed ]} For example, patients with Systemic Lupus Erythematosus (SLE) who are treated with standard of care, including biologic response modifiers, experience a higher risk of mortality and opportunistic infection compared to the general population^[2].

Nausea is an unpleasant, diffuse sensation of unease and discomfort, often perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged, and has been described as placing discomfort on the chest, upper abdomen, or back of the throat.

Diarrhea is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin with loss of the normal stretchiness of the skin and irritable behaviour. This can progress to decreased urination, loss of skin color, a fast heart rate, and a decrease in responsiveness as it becomes more severe. Loose but non-watery stools in babies who are exclusively breastfed, however, are normal.

Abciximab

Mechanism of action: A monoclonal antibody that binds to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Clinical use: Acute coronary syndromes, percutaneous transluminal coronary angioplasty. Toxicity: Bleeding, thrombocytopenia.

In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there. Drugs that do not bind to receptors produce their corresponding therapeutic effect by simply interacting with chemical or physical properties in the body. Common examples of drugs that work in this way are antacids and laxatives.

Monoclonal antibody monospecific antibody that is made by identical immune cells that are all clones of a unique parent cell

Monoclonal antibodies are antibodies that are made by identical immune cells that are all clones of a unique parent cell. Monoclonal antibodies can have monovalent affinity, in that they bind to the same epitope. In contrast, polyclonal antibodies bind to multiple epitopes and are usually made by several different plasma cell lineages. Bispecific monoclonal antibodies can also be engineered, by increasing the therapeutic targets of one single monoclonal antibody to two epitopes.

Acute coronary syndrome (ACS) is a syndrome due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is chest pain, often radiating to the left shoulder or angle of the jaw, crushing, central and associated with nausea and sweating. Many people with acute coronary syndromes present with symptoms other than chest pain, particularly, women, older patients, and patients with diabetes mellitus.

Anakinra (Kineret)

Mechanism of action: A recombinant version of the Interleukin 1 receptor antagonist. Clinical use: Rheumatoid arthritis. Toxicity: Allergic response & neutropenia.

The interleukin-1 receptor antagonist (IL-1RA) is a protein that in humans is encoded by the IL1RN gene.

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell (cytotoxicity) or an organ such as the liver (hepatotoxicity). By extension, the word may be metaphorically used to describe toxic effects on larger and more complex groups, such as the family unit or society at large. Sometimes the word is more or less synonymous with poisoning in everyday usage.

Etanercept (Enbrel)

Mechanism of action: Recombinant form of human TNF receptor that binds TNF. Clinical use: Rheumatoid arthritis, psoriasis, ankylosing spondylitis.

Psoriasis is a long-lasting autoimmune disease characterized by patches of abnormal skin. These skin patches are typically red, dry, itchy, and scaly. On people with darker skin the patches may be purple in colour. Psoriasis varies in severity from small, localized patches to complete body coverage. Injury to the skin can trigger psoriatic skin changes at that spot, which is known as the Koebner phenomenon.

Ankylosing spondylitis (AS) is a type of arthritis in which there is long term inflammation of the joints of the spine. Typically the joints where the spine joins the pelvis are also affected. Occasionally other joints such as the shoulders or hips are involved. Eye and bowel problems may also occur. Back pain is a characteristic symptom of AS, and it often comes and goes. Stiffness of the affected joints generally worsens over time.

Infliximab (Remicade)

Mechanism of action: A monoclonal antibody to TNF, proinflammatory cytokine. Clinical use: Crohn's disease, rheumatoid arthritis, ankylosing spondylitis. Toxicity: Respiratory infection, fever, hypotension. Predisposes to infections (reactivation of latent TB).

Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any part of the gastrointestinal tract from mouth to anus. Signs and symptoms often include abdominal pain, diarrhea, fever, and weight loss. Other complications may occur outside the gastrointestinal tract and include anemia, skin rashes, arthritis, inflammation of the eye, and tiredness. 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 bowel cancer.

Infection invasion of a host by disease-causing organisms

Infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to the infectious agents and the toxins they produce. Infectious disease, also known as transmissible disease or communicable disease, is illness resulting from an infection.

Fever, also known as pyrexia and febrile response, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using values between 37.5 and 38.3 °C. The increase in set point triggers increased muscle contractions and causes a feeling of cold. This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat. Rarely a fever may trigger a febrile seizure. This is more common in young children. Fevers do not typically go higher than 41 to 42 °C.

Rituximab (Rituxan)

Mechanism of action: A monoclonal antibody to CD20 surface immunoglobulin. Clinical use: Lymphoma and a variety of autoimmune diseases, although it may be ineffective in treating IgA-mediated diseases.^[3]

Trastuzumab (Herceptin)

Mechanism of action: A monoclonal antibody against HER2/neu (erb-B2). Helps kill breast cancer cells that overexpress HER-2, possibly through antibody-dependent cytotoxicity. Clinical use: Metastatic breast cancer. Toxicity: Cardiotoxicity.

Natural BRMs

Extracts from some medicinal mushrooms are natural biological response modifiers.^[4]

Related Research Articles

Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues. Any disease that results from such an aberrant immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, sarcoidosis, systemic lupus erythematosus (SLE), Sjögren's syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM) and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

Rheumatology is a branch of medicine devoted to the diagnosis and therapy of rheumatic diseases. Physicians who have undergone formal training in rheumatology are called rheumatologists. Rheumatologists deal mainly with immune-mediated disorders of the musculoskeletal system, soft tissues, autoimmune diseases, vasculitides, and heritable connective tissue disorders.

Immunosuppressive drug Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting dna synthesis. Others may act through activation of t-cells or by inhibiting the activation of helper cells. While

Immunosuppressive drugs or immunosuppressive agents or antirejection medications are drugs that inhibit or prevent activity of the immune system.

Infliximab is a chimeric monoclonal antibody biologic drug that works against tumor necrosis factor alpha (TNF-α) and is used to treat autoimmune diseases. Infliximab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. It is used off-label outside its FDA approval for Behçet's disease and other conditions. Infliximab is administered by intravenous infusion, typically at six- to eight-week intervals. It cannot be given by mouth because the digestive system would destroy the drug.

Etanercept is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.

Cancer immunotherapy is the artificial stimulation of the immune system to treat cancer, improving on the system's natural ability to fight cancer. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology. It exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can be detected by the antibody proteins of the immune system, binding to them. The tumor antigens are often proteins or other macromolecules. Normal antibodies bind to external pathogens, but the modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill.

Adalimumab, sold under the trade name Humira among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, chronic psoriasis, hidradenitis suppurativa, juvenile idiopathic arthritis, and uveitis. In rheumatoid arthritis, adalimumab has a response rate similar to methotrexate, and in combination, it nearly doubles the response rate of methotrexate alone.

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.

Certolizumab pegol is a biologic medication for the treatment of Crohn's disease, rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. It is a fragment of a monoclonal antibody specific to tumor necrosis factor alpha (TNF-α) and is manufactured by UCB.

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. 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, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. More recently antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

Golimumab is a human monoclonal antibody which is used as an immunosuppressive drug and marketed under the brand name Simponi. Golimumab targets tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory molecule and hence is a TNF inhibitor. Profound reduction in C-reactive protein (CRP) levels, interleukin (IL)-6, intercellaular adhesion molecules (ICAM)-1, matrix metalloproteinase (MMP)-3, and vascular endothelial growth factor (VEGF) demonstrates golimumab as an effective modulator of inflammatory markers and bone metabolism.

Abatacept is a drug used to treat autoimmune diseases like rheumatoid arthritis, by interfering with the immune activity of T cells. It is a modified antibody.

Sir Marc Feldmann,, is an Australian immunologist, and a professor at the University of Oxford.

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R).

Secukinumab, trade name Cosentyx, is a human IgG1κ monoclonal antibody that binds to the protein interleukin (IL)-17A, and is marketed by Novartis for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis.

Sarilumab is a human monoclonal antibody against the interleukin-6 receptor. Regeneron and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it received US FDA approval on 22 May 2017 and European Medicines Agency approval on 23 June 2017.

Celltrion is a biopharmaceutical company headquartered in Incheon, South Korea. Celltrion Healthcare conducts worldwide marketing, sales, and distribution of biological medicines developed by Celltrion.

An immune checkpoint regulator is a modulator of the immune system, that allows initiation of a productive immune response and prevents the onset of autoimmunity. Examples of such a molecule are cytotoxic T-lymphocyte antigen 4, which is an inhibitory receptor found on immune cells and programmed cell death 1 (CD279), which has an important role in down-regulating the immune system by preventing the activation of T-cells.

MOR103 is a so-called 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. MOR103 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.

References

↑ "Biological Response Modifiers (BRM)".
↑ Shamliyan, Tatyana A.; Dospinescu, Paula (July 2017). "Additional Improvements in Clinical Response From Adjuvant Biologic Response Modifiers in Adults With Moderate to Severe Systemic Lupus Erythematosus Despite Immunosuppressive Agents: A Systematic Review and Meta-analysis". Clinical Therapeutics. 39 (7): 1479–1506.e45. doi:10.1016/j.clinthera.2017.05.359. ISSN 1879-114X. PMID 28673504.
↑ He Y, Shimoda M, Ono Y, Villalobos IB, Mitra A, Konia T, Grando SA, Zone JJ, Maverakis E (2015). "Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab". JAMA Dermatol. 151 (6): 646–50. doi:10.1001/jamadermatol.2015.59. PMID 25901938.
↑ Tzianabos AO (2000). "Polysaccharide immunomodulators as therapeutic agents: structural aspects and biologic function". Clin Microbiol Rev. 13 (4): 523–33. doi:10.1128/CMR.13.4.523-533.2000. PMC 88946 . PMID 11023954.

Biological Response Modifier
Deepak A. Rao; Le, Tao; Bhushan, Vikas. First Aid for the USMLE Step 1 2008 (First Aid for the Usmle Step 1). McGraw-Hill Medical. ISBN 0-07-149868-0.

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[1] "Biological Response Modifiers (BRM)".

[2] Shamliyan, Tatyana A.; Dospinescu, Paula (July 2017). "Additional Improvements in Clinical Response From Adjuvant Biologic Response Modifiers in Adults With Moderate to Severe Systemic Lupus Erythematosus Despite Immunosuppressive Agents: A Systematic Review and Meta-analysis". Clinical Therapeutics. 39 (7): 1479–1506.e45. doi:10.1016/j.clinthera.2017.05.359. ISSN 1879-114X. PMID 28673504.

[3] He Y, Shimoda M, Ono Y, Villalobos IB, Mitra A, Konia T, Grando SA, Zone JJ, Maverakis E (2015). "Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab". JAMA Dermatol. 151 (6): 646–50. doi:10.1001/jamadermatol.2015.59. PMID 25901938.

[pmid11023954-4] Tzianabos AO (2000). "Polysaccharide immunomodulators as therapeutic agents: structural aspects and biologic function". Clin Microbiol Rev. 13 (4): 523–33. doi:10.1128/CMR.13.4.523-533.2000. PMC 88946 . PMID 11023954.