Anti-interleukin-6 agents are a class of therapeutics.

Interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...

is a

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) 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 autocrin ...

relevant to many inflammatory diseases and many cancers. Hence, anti-IL6 agents have been sought. In

rheumatoid arthritis 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 involv ...

they can help patients unresponsive to

TNF inhibitor 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, ...

s. The first approved medication in this class,

tocilizumab Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID19. It is a hu ...

(Actemra), is an antibody directed against the IL6-receptor. The second,

siltuximab Siltuximab ( INN, trade name Sylvant; also known as CNTO 328, anti-IL-6 chimeric monoclonal antibody or cCLB8) is a chimeric (made from human and mouse proteins) monoclonal antibody. It binds to interleukin-6. Siltuximab has been investigated fo ...

(Sylvant), is directed against IL-6 itself.

Siltuximab Siltuximab ( INN, trade name Sylvant; also known as CNTO 328, anti-IL-6 chimeric monoclonal antibody or cCLB8) is a chimeric (made from human and mouse proteins) monoclonal antibody. It binds to interleukin-6. Siltuximab has been investigated fo ...

is approved for treatment of human immunodeficiency virus-negative and

HHV-8 Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesviru ...

-negative patients with multicentric

Castleman's disease Castleman disease (CD) describes a group of rare lymphoproliferative disorders that involve enlarged lymph nodes, and a broad range of inflammatory symptoms and laboratory abnormalities. Whether Castleman disease should be considered an autoimmun ...

. Siltuximab was also tested in the phase I/II study for therapy of patients with metastatic castration-associated

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

in combination with

docetaxel Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-ce ...

and in

renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...

; phase II trials in

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

resulted in 39% of patients showed disease stabilization via IL-6-regulated downregulation of

CCL2 ''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.'' The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL ...

CXCL12 The stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is a chemokine protein that in humans is encoded by the ''CXCL12'' gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types. Str ...

and

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

Tocilizumab Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID19. It is a hu ...

was first used in

large-cell lung carcinoma Large-cell carcinoma (LCC, LCLC) is a heterogeneous group of undifferentiated malignant neoplasms that lack the cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation. LCC is categorized as a type of ...

. In phase I/II trial of tocilizumab in

EGFR pathway upregulation was observed and after inhibition of this pathway by

gefitinib Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targe ...

tumor growth was decreased both ''in vitro'' and ''in vivo''.

Sarilumab Sarilumab, sold under the brand name Kevzara, is a human monoclonal antibody medication against the interleukin-6 receptor. Regeneron Pharmaceuticals and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it rece ...

was approved by

US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

in 2017 for rheumatoid arthritis. Several agents are in clinical trials: olokizumab (CDP6038)

elsilimomab Elsilimomab (also known as B-E8) is a mouse monoclonal antibody. B-E8 was developed by Diaclone, a French company which produces many mouse monoclonal antibodies. It (OPR-003) targets (and blocks) Interleukin-6. It has undergone a number of early ...

clazakizumab Clazakizumab (formerly ALD518 and BMS-945429), an investigational drug, is an aglycosylated, humanized rabbit monoclonal antibody against interleukin-6. Clazakizumab was developed by Bristol Myers Squib and Alder Biopharmaceuticals. A prelimina ...

(BMS-945429, ALD518), sirukumab (CNTO 136), levilimab (BCD-089), and CPSI-2364 an apparent macrophage-specific inhibitor of the

p38 mitogen-activated protein kinase p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell different ...

pathway. ALX-0061. e.g. for rheumatoid arthritis : clazakizumab, olokizumab, sarilumab and sirukumab have all reported encouraging phase 2 results. Sirukumab is in multiple phase 3 trials. Agents in pre-clinical development include ARGX-109, FE301, and FM101.

Anti-IL-6 Receptor antibodies: Treatment of Coronavirus-associated pulmonary pathology

During the

COVID-19 pandemic The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identif ...

, antagonistic antibodies against the IL-6 receptors were tested in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s to assess their use in treating or preventing severe pneumonia in critically ill

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...

patients. Such antibodies include

and

sarilumab Sarilumab, sold under the brand name Kevzara, is a human monoclonal antibody medication against the interleukin-6 receptor. Regeneron Pharmaceuticals and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it rece ...

. Antibodies against IL-6 itself, such as

, were also investigated. Also: Levilimab.

Exercise induced IL-6

New research has found IL-6 to be an anti-inflammatory cytokine with multiple beneficial effects when released by contracting muscle as a

myokine A myokine is one of several hundred cytokines or other small proteins (~5–20 kDa) and proteoglycan peptides that are produced and released by skeletal muscle cells (muscle fibers) in response to muscular contractions. They have autocrine, paracr ...

. IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage. However, it has become evident that

eccentric exercises Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as ...

are not associated with a larger increase in plasma IL-6 than exercise involving concentric “nondamaging” muscle contractions. This finding demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. In fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery. Anti-IL-6 therapies should therefore take into consideration the (beneficial) anti-inflammatory effects of

s generally, including the now-established multiple benefits of muscle-derived

IL6 and asthma

Obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

is a known risk factor in the development of severe

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...

, and work has suggested that IL-6 plays a role in regulating disease severity in obesity-related asthma.

Luteolin Luteolin is a flavone, a type of flavonoid, with a yellow crystalline appearance. Luteolin is the principal yellow dye compound that is obtained from the plant ''Reseda luteola'', which has been used as a source of the dye since at least the fir ...

reduces IL-6 production in some neurons.

References

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