Taltz® (Ixekizumab)

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What is the mechanism of action of ixekizumab?

Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that binds with high affinity (<3pM) and specificity to interleukin (IL)-17A, a proinflammatory cytokine and inhibits its interaction with the IL-17 receptor.

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How Ixekizumab Works, Ixekizumab Structure and Pharmacology

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Ixekizumab is a humanized IgG4 monoclonal antibody that binds with high affinity (<3 pM) and specificity to IL-17A, a proinflammatory cytokine and inhibits its interaction with the IL-17 receptor.1,2

Ixekizumab Structure and Pharmacology

Ixekizumab is a humanized immunoglobulin G subclass 4 monoclonal antibody that selectively binds with the interleukin (IL)-17A cytokine and inhibits its interaction with the IL-17 receptor. Interleukin-17A is a naturally occurring cytokine involved in normal inflammatory and immune responses. By inhibiting IL-17A, ixekizumab inhibits the release of proinflammatory cytokines and chemokines.1,3

Interleukin-17A is a proinflammatory cytokine by virtue of its ability to activate and recruit neutrophils. As shown in Production of IL-17A, IL-17A can be produced by many cell types.4-6

Elevated levels of IL-17A have been implicated in the pathogenesis of a variety of autoimmune diseases.6

Production of IL-17A5-8

Left: Various cytokines produced by Th17 cells. Th17 cells also produce chemokines.
Right: Various cell types that produce IL-17A.
Abbreviations: CCL20 = chemokine (C-C motif) ligand 20; CD8+ = cluster of differentiation 8; GM-CSF = granulocyte macrophage colony-stimulating factor, IL = interleukin; ILC = innate lymphoid cells; LTi = lymphoid tissue inducer; NK cells = natural killer cells; NKT cells = natural killer T cells; Th17 = T-helper type 17.

Interleukin-17A Family Members

Ixekizumab selectively binds to IL-17A, without cross-reactivity to other IL-17 family members.1,9,10 Ixekizumab does not bind to ligands IL-17B, IL-17C, IL-17D, IL-17E, or IL-17F.10

The IL-17A cytokine can be composed of either IL-17A homodimers or IL-17A-IL-17F heterodimers. Interleukin-17A binds to receptor interleukin-17 receptor-A (IL-17RA) which consists of 2 IL-17RA subunits and 1 IL-17RC subunit.9 Interleukin-17A belongs to a broader family, which includes IL-17A, IL-17B, IL-17C, IL-17D, and IL-17E (Interleukin-17 Cytokine Family and Receptors).

Interleukin-17 Cytokine Family and Receptors11

Abbreviation: IL = interleukin.

References

1Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021.

2Liu L, Lu J, Allan BW, et al. Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A. J Inflamm Res. 2016;9:39-50. http://dx.doi.org/10.2147/JIR.S100940

3Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010;10(7):479-489. http://dx.doi.org/10.1038/nri2800

5Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009;9(8):556-567. http://dx.doi.org/10.1038/nri2586

6Lin AM, Rubin CJ, Khandpur R, et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 2011;187(1):490-500. http://dx.doi.org/10.4049/jimmunol.1100123

7Krueger JG, Fretzin S, Suárez-Fariñas M, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol. 2012;130(1):145-154.e9. http://dx.doi.org/10.1016/j.jaci.2012.04.024

8Maddur MS, Miossec P, Kaveri SV, Bayry J. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol. 2012;181(1):8-18. http://dx.doi.org/10.1016/j.ajpath.2012.03.044

9Chiricozzi A, Krueger JG. IL-17 targeted therapies for psoriasis. Expert Opin Investig Drugs. 2013;22(8):993-1005. http://dx.doi.org/10.1517/13543784.2013.806483

10Tham LS, Tang CC, Choi SL, et al. Population exposure–response model to support dosing evaluation of ixekizumab in patients with chronic plaque psoriasis. J Clin Pharmacol. 2014;54(10):1117-1124. http://dx.doi.org/10.1002/jcph.312

11Martin DA, Towne JE, Kricorian G, et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol. 2013;133(1):17-26. http://dx.doi.org/10.1038/jid.2012.194

Fecha de la última revisión: 2021 M07 22


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