Taltz® (ixekizumab): Verkningsmekanism

How Ixekizumab Works, Ixekizumab Structure and Pharmacology

• Ixekizumab is an IgG4 monoclonal antibody that binds with high affinity (< 3 pM) and specificity to interleukin 17A (both IL‑17A and IL‑17A/F).¹

• Elevated concentrations of IL‑17A have been implicated in the pathogenesis of

  • psoriasis by promoting keratinocyte proliferation and activation,

  • psoriatic arthritis and axial spondyloarthritis by driving inflammation leading to erosive bone damage and pathological new bone formation. ¹

• Neutralisation of IL‑17A by ixekizumab inhibits these actions.¹ 

• Ixekizumab does not bind to ligands IL‑17B, IL‑17C, IL‑17D, IL‑17E or IL‑17F.¹ 

• In vitro binding assays confirmed that ixekizumab does not bind to human Fcγ receptors I, IIa, and IIIa or to complement component C1q.¹

• IL-17A is a proinflammatory cytokine by virtue of its ability to activate and recruit neutrophils. As depicted in Figure 1, IL-17A can be produced by many cell types.^2-4

• Elevated levels of IL-17A have been implicated in the pathogenesis of a variety of autoimmune diseases.⁴

• The IL-17A cytokine can be composed of either IL-17A homodimers or IL-17A—IL-17F heterodimers. IL-17A binds to receptor IL-17RA which consists of 2 IL-17RA subunits and 1 IL-17RC subunit.⁵ IL-17A belongs to a broader family, which includes IL-17A, IL-17B, IL-17C, IL-17D, and IL-17E (Figure 2).

• Ixekizumab selectively binds to IL-17A, without cross-reactivity to other IL-17 family members.^5,6

Figure 1. Production of IL-17A^3,4,7,8

Left: Various cytokines produced by Th17 cells. Th17 cells also produce chemokines.
Right: Various cell types that produce IL-17A.
Abbreviations: CCL20 = IL-22 and chemokine (C-C motif) ligand 20; GM-CSF = granulocyte macrophage colony-stimulating factor, IL = interleukin; LTi = lymphoid tissue inducer; NK cells = natural killer cells; NKT = natural killer T cells; Th17 = T-helper type 17.

Figure 2. Interleukin-17 Cytokine Family and Receptors⁹

Abbreviation: IL = interleukin.

Pharmacodynamic effects

• Ixekizumab modulates biological responses that are induced or regulated by IL‑17A.¹

• Based on psoriatic skin biopsy data from a phase I study, there was a dose-related trend towards

  • decreased epidermal thickness,

  • number of proliferating keratinocytes,

  • T cells, and dendritic cells, as well as

  • reductions in local inflammatory markers from baseline to day 43.¹

• As a direct consequence treatment with ixekizumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.¹

• Ixekizumab has been shown to lower (within 1 week of treatment) levels of C-reactive protein, which is a marker of inflammation.¹

References

1. Taltz [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Cua 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

3. Gaffen 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

4. Lin 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

5. Chiricozzi 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

6. Tham 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

7. Krueger 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

8. Maddur 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

9. Martin 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

Glossary

IgG4 = immunoglobulin G subclass 4

IL-17 = interleukin-17

mAb(s) = monoclonal antibody