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

• Published in: Nature biotechnology 2011-07, Vol.29 (7), p.615-624
• Main Authors: Benson, Jacqueline M, Sachs, Clifford W, Treacy, George, Zhou, Honghui, Pendley, Charles E, Brodmerkel, Carrie M, Shankar, Gopi, Mascelli, Mary A
• Format: Article
• Language: English
• Subjects: 631/337; 631/61/24; 692/699/249; 692/700/565/251; Agriculture; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antigens; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Crohn's disease; Cytokines; Drug Delivery Systems - methods; Drug dosages; Drug therapy; Fundamental and applied biological sciences. Psychology; Health. Pharmaceutical industry; Humans; Immunoglobulins; Immunomodulators; Industrial applications and implications. Economical aspects; Interleukin-12; Interleukin-12 - antagonists & inhibitors; Interleukin-23 - antagonists & inhibitors; Life Sciences; Medical sciences; Monoclonal antibodies; perspective; Pharmacology. Drug treatments; Physiological aspects; Production of active biomolecules; Proteins; Psoriasis; Psoriatic arthritis; R&D; Research & development; Signal Transduction - drug effects; Signal Transduction - physiology; Skin diseases; T cells; Transcription factors; Transgenic animals; Ustekinumab
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt.1903

Preclinical and clinical studies conducted in the mid-1990s reported strong association and causality between the T-cell helper (T H ) 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 T H 17 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.