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Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab

Abstract

Preclinical and clinical studies conducted in the mid-1990s reported strong association and causality between the T-cell helper (TH) 1 inductor cytokine interleukin (IL)-12 and numerous immune-mediated disorders, which spurred the development of therapeutic agents targeting IL-12 function. One of the first to enter the clinic, ustekinumab, is a human monoclonal antibody (mAb) that binds to the p40 subunit of IL-12. Subsequent to the generation of ustekinumab, it was discovered that IL-23 also contains the p40 subunit. Thus, although ustekinumab was designed to target IL-12, it also modulates IL-23, a cytokine important to the development and/or maintenance of TH17 cells. Clinical observations established that IL-12/23p40 is integral to the pathologies of psoriasis, psoriatic arthritis and Crohn's disease. The molecular and cellular evaluations conducted in ustekinumab clinical programs have provided numerous insights into the pathologic processes of these disorders, illustrating how a novel molecular entity can contribute to our understanding of disease. The individual contributions of these cytokines to specific pathologies require investigation and clinical evaluation of the role of IL-12– and IL-23–specific inhibitors.

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Figure 1: Timeline of important TH and ustekinumab milestones.
Figure 2: Ustekinumab and its target.
Figure 3: Diagram of ustekinumab pharmacokinetic/pharmacodynamic model for patients with psoriasis.
Figure 4: Generation of IL-12/23 and their effector functions in the development and maintenance of psoriasis.

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Acknowledgements

The authors want to thank M. Curran and M. Whitman for their critical review and insightful comments on manuscript content, and B. Loux for graphic development.

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Correspondence to Jacqueline M Benson.

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M.M. is an independent biopharmaceutical consultant under contract with Centocor/Orthobiotech – the developers of ustekinumab.

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Benson, J., Sachs, C., Treacy, G. et al. Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab. Nat Biotechnol 29, 615–624 (2011). https://doi.org/10.1038/nbt.1903

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