Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials.

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown.

Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis.

Design, Setting, And Participants: Two phase 3 randomized clinical trials were conducted.

Risankizumab: Mechanism of action, clinical and translational science.

Risankizumab is a high-affinity neutralizing anti-interleukin (IL)-23 monoclonal antibody marketed in over 40 countries across the globe to treat several inflammatory diseases, such as plaque psoriasis (PsO), psoriatic arthritis (PsA), and Crohn's disease (CD). This paper reviews the regulatory approval, mechanism of action, pharmacokinetics (PKs)/pharmacodynamics, immunogenicity, and clinical efficacy and safety data for risankizumab, focusing on the three main approved indications. Risankizumab binds to the p19 subunit of IL-23 and inhibits IL-23 from interacting with the IL-23 receptor and subsequent signaling.

Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.

Background: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

Background: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease.

Methods: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8.

Mechanisms and regulation of IL-22-mediated intestinal epithelial homeostasis and repair.

Aims: Ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease (IBD), are chronic inflammatory disorders of the intestine for which key elements in disease initiation and perpetuation are defects in epithelial barrier integrity. Achieving mucosal healing is essential to ameliorate disease outcome and so new therapies leading to epithelial homeostasis and repair are under investigation. This study was designed to determine the mechanisms by which IL-22 regulates intestinal epithelial cell function.

A population of proinflammatory T cells coexpresses αβ and γδ T cell receptors in mice and humans.

T cells are classically recognized as distinct subsets that express αβ or γδ TCRs. We identify a novel population of T cells that coexpress αβ and γδ TCRs in mice and humans. These hybrid αβ-γδ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αβ TCR-mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs.

Mechanistic study of classical translocation-dead SpoIIIE36 reveals the functional importance of the hinge within the SpoIIIE motor.

SpoIIIE/FtsK ATPases are central players in bacterial chromosome segregation. It remains unclear how these DNA translocases harness chemical energy (ATP turnover) to perform mechanical work (DNA movement). Bacillus subtilis sporulation provides a dramatic example of intercompartmental DNA transport, in which SpoIIIE moves 70% of the chromosome across the division plane.

SpoIIIE protein achieves directional DNA translocation through allosteric regulation of ATPase activity by an accessory domain.

Bacterial chromosome segregation utilizes highly conserved directional translocases of the SpoIIIE/FtsK family. These proteins employ an accessory DNA-binding domain (γ) to dictate directionality of DNA transport. It remains unclear how the interaction of γ with specific recognition sequences coordinates directional DNA translocation.

Enabling structure-based drug design of Tyk2 through co-crystallization with a stabilizing aminoindazole inhibitor.

Background: Structure-based drug design (SBDD) can accelerate inhibitor lead design and optimization, and efficient methods including protein purification, characterization, crystallization, and high-resolution diffraction are all needed for rapid, iterative structure determination. Janus kinases are important targets that are amenable to structure-based drug design. Here we present the first mouse Tyk2 crystal structures, which are complexed to 3-aminoindazole compounds.

The transmembrane segment of a tail-anchored protein determines its degradative fate through dislocation from the endoplasmic reticulum.

Terminally misfolded proteins that accumulate in the endoplasmic reticulum (ER) are dislocated and targeted for ubiquitin-dependent destruction by the proteasome. UBC6e is a tail-anchored E2 ubiquitin-conjugating enzyme that is part of a dislocation complex nucleated by the ER-resident protein SEL1L. Little is known about the turnover of tail-anchored ER proteins.