Molecular effects of ustekinumab

To provide insight into the molecular effects of ustekinumab in ulcerative colitis (UC) patients, transcriptomic and protein analyses were performed in the first ~60% of patients who were randomised in the UNITI phase 3 induction study of ustekinumab [1]. The results demonstrated the suppression of IL-12 (IFN γ) and IL-23 (IL-17A) pathways and normalisation of the UC disease gene expression profile in response to ustekinumab.

Colonic biopsy mRNA and serum samples were analysed of patients with a history of biological therapy failure (BF) and those without (BN). Samples from healthy subjects were analysed as controls. Biopsies from UC patients had a gene expression disease profile of 4,095 probe sets, including genes involved in inflammatory response, tissue remodelling and wound healing, host-microbe interaction, intestinal permeability, and solute transport. BF and BN patients shared almost identical disease profiles.

At baseline, BF and BN patients had similar serum profiles with significantly elevated levels of IFNγ, IL-17A, IL-22, SAA, NGAL, MMPs, and TNF compared with the healthy controls. Normalisation of IFNγ, SAA, IL-17A, and IL-22 was first detected in responders to ustekinumab at week 4, and continued to improve through week 8. A trend of normalisation of MMPs, IL-10, and NGAL was observed in ustekinumab responders; this trend was weaker or absent in ustekinumab non-responders and placebo-treated patients. TNF was elevated in UC prior to treatment and was not normalised by ustekinumab induction therapy.

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   1. Li K, et al. ECCO 2019, OP13.

Posted on 9 May, 20199 April, 2024