Interleukin antagonists

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Dr. med. Raphael Gruber

All authors of this article

Last updated on: 29.10.2020

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cytokine antagonists; Interleukin antagonists; Interleukin antibodies; Interleukin antibody; Interleukin blockers; Interleukin inhibitors

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The inhibition of interleukins or their receptors is an effective therapeutic principle of numerous drugs that intervene at different levels with different effects. Interleukin antagonists are antibodies that induce selective inhibition of cytokine effects.

General information
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Interleukins (IL) mediate their effect by binding to specific high-affinity receptors on the target cells. They play an important role in the differentiation of B and T lymphocytes from haematopoietic stem cells. IL-3, for example, supports the differentiation of haematopoietic stem cells. IL-7, which is produced by the stromal cells of the bone marrow, is involved in the recombination of gene elements on the DNA level. The immune reactions mediated by T-helper (Th) lymphocytes are also controlled by different interleukins. In addition to interferon-gamma, interleukins 12 and 18 also play an important role in the development of Th1 cells. IL-4 is responsible for the differentiation of Th2 cells.

Numerous cytokines act as mediators in inflammatory reactions. Thus, infectious agents activate the formation of cytokines from their inactive precursors. Proinflammatory cytokines include IL-1, IL-6 and tumor necrosis factor-alpha; they can enhance or maintain inflammation. IL-1beta plays a central role as the "master cytokine". IL-1beta can initiate the synthesis of the other cytokines. In tissue, IL-1 and TNF-alpha, but also IL-6 stimulate the synthesis and release of inflammatory mediators such as reactive oxygen species, nitric oxide, enzymes, prostaglandins or leukotrienes, essential factors in inflammatory tissue reactions.

Inhibition of the IL-1 effect is used therapeutically in RA patients. Anakinra, a human IL-1 receptor antagonist, inhibits the inflammatory cascade triggered by IL-1. Other IL-1 antagonists are canakinumab (Ilaris®) and tocilizumab (RoActemra®) a human IL-1 receptor antagonist.

Interleukin-6 is also an important therapeutic target cytokine.IL-6 is significantly involved in the regulation of humoral and cell-mediated immune defence. It promotes the differentiation of CD4+ lymphocytes into Th17 cells. Furthermore, IL-6 causes the differentiation of B-lymphocytes and macrophages as well as the maturation of megakaryocytes and osteoclasts. The cytokine stimulates the synthesis of the immunoglobulins G and M, the "oxidative burst" in monocytes and in neutrophilic granulocytes.

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Interleukin-6 induces the secretion of acute phase proteins in the liver (C-reactive protein, ferritin, serum amyloid A) as well as the production of other cytokines. Several compounds that inhibit this cytokine are available with different indications: Basiliximab (Simulect®) a humanized anti-IL-6 receptor, Clazakizumab (not yet approved) an IL-6 antibody, Sarilumab (Kevzara®) an IL-6 receptor antibody, Olokizumab (not yet approved) a human IgG4-anti IL-6 receptor antibody, Siltuximab (Sylvant®) an anti-IL-6-AK. Siltuximab inhibits the pro-angiogenetic effect of IL-6 in the vicinity of solid tumours.

Another target cytokine that significantly influences inflammatory processes is IL-17, which plays a central role in the pathogenesis of psoriasis, psoriatic arthritis and rheumatoid arthritis. As antipsoriatic and/or antirheumatic drugs there are 3 preparations available: Ixekizumab (Taltz®) a monoclonal IgG4 antibody that binds to interleukin-17A. Secukinumab (Cosentyx®) a human monoclonal antibody and Brodalumab (Kyntheum®) a monoclonal antibody that binds to the IL-17 receptor.

With interleukin-23 (IL-23) another "master cytokine" can be attacked therapeutically. IL-23 plays an important role in the inflammatory process in psoriasis. Interleukin-23 (IL-23) is a heterodimeric, pleiotropic cytokine that belongs to the Interleukin-12 family. The cytokine is composed of two subunits: the IL-12B subunit (identical to IL-12p40 of an interleukin-12 subunit) and the IL23A subunit (IL-23p19). Interleukin-23 activates the proliferation of T cells (T-helper cells, Th-17 cells), NK cells and possibly macrophages and osteoclasts. After binding to its receptor, it activates the JAK/STAT signalling cascade and triggers the phosphoinositid-3-kinase (PI3K) of RAC-alpha serine/threonine kinase (AKT) and NF-kappaB. IL23 is jointly responsible for inflammatory processes in autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn's disease, etc. Furthermore, IL-23 plays a pathogenetic role in allergic bronchial asthma. With Guselkumab (Tremfya®) a monoclonal anti-Il-23 antibody, Risankizumab (Skyrizi® approval expected soon) also a monoclonal anti-Il-23 antibody and Tildakizumab (Ilumetri®) a monoclonal antibody that selectively binds to the p19-subunit of interleukin 23, 3 effective cytokine antagonists are available.

The physiological antagonist: IL-10 occupies a special position. Interleukin-10 inhibits the action of activated T-cells and thus slows down the production of interferon-gamma. The cytokine acts (comparable to interleukin-4, -11 and TGF-beta) as a so-called anti-inflammatory cytokine by inhibiting macrophage function and thus preventing excessive inflammatory reactions. In TH1 cells, but not in TH2 cells, it inhibits the cytokine synthesis, e.g. of interferon gamma, interleukin-2, TNF-beta and the chemokine CCL20, so interleukin-10 inhibits the formation of cytokines of the Th1 response. Furthermore, interleukin-10 together with interleukin -2, interleukin-4 and interleukin -7 stimulates the growth of thymocytes and promotes the differentiation of cytotoxic T-lymphocytes (CD8+T cells). This feedback mechanism ensures that an inflammation does not perpetuate itself unchecked and that it regresses after the pathogen or noxious agent has been eliminated.

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The most frequent ADRs of anti-interleukin therapies can be explained by the protein structure and the immunosuppressive mechanism of action. Since these proteins are foreign to the body, hypersensitivity reactions can occur within 24 hours or even a few days after administration. Characteristic are urticarial exanthema, pruritus, angioedema, dyspnoea, bronchospasm or circulatory problems. Rare are anaphylactic reactions of varying severity (up to anaphylactic shock).

Neutralizing antibodies: It is possible to form neutralizing antibodies against the interleukin antagonists. The proportion of these "seropositive" patients is usually < 5%. Neutralizing antibodies can weaken the effectiveness.

Increased risk of infection: The immunosuppressive properties of interleukin antagonists result in an increased risk of infection. Latent infections like tuberculosis, hepatitis B or opportunistic infections can be reactivated. Thus, for the interleukin antagonists, these infections are a criterion for exclusion or a reason to discontinue treatment.

Risk of malignant tumours: Immunosuppressive drugs potentially increase the risk of malignant tumours. This complication cannot yet be assessed with certainty, the study periods are too short for a final evaluation.

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  • Tocilizumab (RoActemra®) human IL-6 receptor antagonist that selectively binds to the IL-1 receptor. Approved indications: rheumatoid arthritis, in combination with methotrexate
  • Anakinra (Kineret®) human interleukin-1 receptor antagonist for the treatment of rheumatoid arthritis in combination with methotrexate.
  • Canakinumab (Ilaris®) human anti-IL-1beta MAK; approved indications: CAPS, gouty arthritis
  • Basiliximab (Simulect®) murine/human chimeric anti-IL-2 receptor antibody that binds to the α subunit of the human IL-2 receptor on activated T cells. Basiliximab thus prevents the docking of its ligand and thus the IL-2 mediated proliferation of T cells. Approved indications: Prophylaxis of acute graft rejection after kidney transplantation
  • Clazakizumab (not yet approved) anti-IL-6 antibody Indication: prophylaxis of transplant rejection after kidney transplantation
  • Sarilumab (Kevzara®) binds to the IL-6 receptor: human monoclonal antibody that selectively targets the interleukin (IL)-6 receptor and interrupts IL-6 mediated signal transduction. Indication: Rheumatoid arthritis.
  • Sirukumab (approval withdrawn) antibody directed against IL-6 receptor Indication: rheumatoid arthritis
  • Olokizumab (not yet approved) human IgG4-anti IL-6 receptor antibody. Indication: Rheumatoid arthritis
  • Siltuximab (Sylvant®) Anti-IL-6-AK; inhibits the pro-angiogenetic effect of IL-6 in the microenvironment of solid tumors. Indication: in adult patients with Multicentric Castleman's Disease (MCD) who are HIV (human immunodeficiency virus) negative and HHV-8 (human herpesvirus-8) negative.
  • Ustekinumab (Stelara®) human anti-IL-12/23 MAK; indications: plaque psoriasis, psoriatic arthritis
  • Ixekizumab (Taltz®) monoclonal IgG4 antibody that binds to interleukin-17A. Indication Plaque psoriasis in adults, active psoriatic arthritis.
  • Secukinumab (Cosentyx®) human monoclonal antibody Indication: human monoclonal antibody that binds to interleukin 17. Indication: uveitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis.
  • Brodalumab (Kyntheum®) monoclonal antibody which binds to the IL-17 receptor. Indication: moderate to severe plaque psoriasis.
  • Guselkumab (Tremfya®) anti-Il-23 monoclonal antibody: Approved indication: moderate to severe plaque psoriasis.
  • Risankizumab (Skyrizi® approval expected shortly) anti-Il-23 monoclonal antibody: Indication: moderate to severe plaque psoriasis.
  • Tildakizumab (Ilumetri®): monoclonal antibody that selectively binds to the p19-lower p19 of interleukin 23. Indication: moderate to severe plaque psoriasis.

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However, the temporary blockage of cytokines or their receptors does not eliminate the cause of the respective inflammation. An interruption of the medication usually leads to recurrence.

It is known that IL-6 and IL-1 suppress the formation of hepatic cytochrome P450 enzymes (CYP450). Under therapy with interleukin antibodies such as tocilizumab or canakinumab the enzyme expression normalized. If patients take additional drugs that are metabolised by CYP 3A4, 1A2 or 2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin or benzodiazepines), underdoses may occur.

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Last updated on: 29.10.2020