![]() | This article may have been created or edited in return for undisclosed payments, a violation of Wikipedia's terms of use. It may require cleanup to comply with Wikipedia's content policies, particularly neutral point of view. (November 2019) |
Monoclonal antibody | |
---|---|
Type | ? |
Clinical data | |
Other names | GSK3196165; MOR103 |
Legal status | |
Legal status |
|
Identifiers | |
CAS Number | |
UNII | |
KEGG |
Otilimab (development codes MOR103 and GSK3196165) is a fully human antibody which has been developed by the biotechnology company MorphoSys. [1] 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.
Otilimab, as its monoclonal antibody, specifically binds to GM-CSF which is consequently neutralised and incapable of binding its targeted inflammatory cells as it should in order to allow their proliferation and activation. There is no following induction of inflammation (through cytokines e.g. TNF-α, IL-1, IL-6), chemotaxis (via chemokines e.g. IL-8), tissue degradation (caused by e.g. MMPs, H2O2) or T and B cell response (following up-regulated MHC II level).
Beyond its role in natural immune pathways, GM-CSF has been shown to be involved in autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) in which cases GM-CSF levels are elevated and mediate an increased production of pro-inflammatory elements (cytokines, chemokines, proteases). The factor is also known to be involved in osteoarthritis of the hand. Research has thus been working on it as a molecular target for the treatment of such disorders, notably through immunotherapy such as monoclonal antibody therapy which is known to be efficient against autoimmune diseases.
There already exist treatments of rheumatoid arthritis through monoclonal antibodies (i.e. infliximab, adalimumab). These drugs are not targeting GM-CSF but TNF-α which is another cytokine involved in the disease. However, the major involvement of TNF-α in immunity makes its suppression delicate: it diminishes the immune defenses of treated patients against potential new infections and may allow the reactivation of latent ones such as hepatitis B and tuberculosis. The number of reported cases of severe side effects, including fatal ones, has led the FDA to instruct tight monitoring of patients before and during a treatment by TNF-inhibiting drugs. Nevertheless, another way to circumvent such outcomes may be to target an alternate cytokine.
In multiple sclerosis (MS), GM-CSF is produced by T helper cells (Th1 and Th17). It is able to cross the blood-brain barrier (BBB) and bind to CD52 on macrophages surface. Along with other pro-inflammatory events, this will participate in the central nervous system (CNS) inflammation process typically occurring in MS.
There are numerous existing monoclonal antibodies used in the treatment of multiple sclerosis: natalizumab (targets α4-integrin), daclizumab and alemtuzumab (both binding to CD25, the α-subunit of IL-2 receptor on the surface of mature lymphocytes), ocrelizumab (against CD20 marker on B-cells). [2] However, the frequent adverse effects notified, including secondary autoimmune phenomena, [3] suggest that the uncovering of a new molecular target for monoclonal antibody therapy would be welcomed in the research for an improved treatment against MS.
Otilimab is currently undergoing clinical trials to determine whether it could be used as treatment and has so far shown to be generally well tolerated by both relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS) patients. Indeed, most TEAEs (treatment-emergent adverse events) which were observed were mild to moderate. There isn't evidence of immunogenecity either: no anti-otilimab antibodies were detected in patients following treatment. These results provide Class I evidence in regards to acceptable tolerance in MS patients and reveal that otilimab remains a fitted candidate for the treatment of multiple sclerosis [4]
Cytokines are a broad and loose category of small proteins important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system.
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.
Cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.
Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with rodents and is widely studied as an animal model of the human CNS demyelinating diseases, including multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). EAE is also the prototype for T-cell-mediated autoimmune disease in general.
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.
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.
Biological response modifiers (BRMs) are substances that modify immune responses. They can be both endogenous and 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.
CCL17 is a powerful chemokine produced in the thymus and by antigen-presenting cells like dendritic cells, macrophages, and monocytes. CCL17 plays a complex role in cancer. It attracts T-regulatory cells allowing for some cancers to evade an immune response. However, in other cancers, such as melanoma, an increase in CCL17 is linked to an improved outcome. CCL17 has also been linked to autoimmune and allergic diseases.
Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.
The following outline is provided as an overview of and topical guide to immunology:
An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.
MorphoSys AG is a biopharmaceutical company founded in 1992. The company is headquartered near Munich, Germany and has a wholly owned subsidiary, MorphoSys US Inc., in Boston MA in the US. The company has various antibody, protein and peptide technologies that it uses to discover and develop both proprietary and partnered drug candidates. The company has more than 100 drugs in its wider pipeline that are being investigated for a variety of diseases. While many of these are being developed in partnership with pharma and biotech companies, MorphoSys also has a proprietary pipeline with a focus on cancer and autoimmune diseases.
Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents. In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.
TOL101, is a murine-monoclonal antibody specific for the human αβ T cell receptor. In 2010 it was an Investigational New Drug under development by Tolera Therapeutics, Inc.
Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit and an IL-23A (IL-23p19) subunit. IL-23 is part of the IL-12 family of cytokines. The functional receptor for IL-23 consists of a heterodimer between IL-12Rβ1 and IL-23R.
Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier.
Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases. It must provide absence of specific antibodies for exactly that antigenes.
Lenzilumab is a humanized monoclonal antibody that targets colony stimulating factor 2 (CSF2)/granulocyte-macrophage colony stimulating factor (GM-CSF).