Anti-IL17F Monoclonal antibody, clone 29G2029G20 [PE]

AIMS To assess safety, pharmacokinetics (PK) and clinical efficacy of bimekizumab (formerly UCB4940), a novel humanized monoclonal antibody and dual inhibitor of interleukin (IL)-17A and IL-17F, in subjects with mild plaque psoriasis. METHODS Randomized, double-blind, first-in-human study of bimekizumab in 39 subjects who received single-dose intravenous bimekizumab (8-640 mg) or placebo (NCT02529956). RESULTS Bimekizumab demonstrated dose-proportional linear PK and was tolerated across the dose range assessed. No subject discontinued due to treatment-emergent adverse events and no severe adverse events were reported. Bimekizumab demonstrated fast onset of clinically-meaningful effects on skin of patients with mild psoriasis as early asWeek 2. Maximal improvements (100% or near 100% reductions from baseline) in all measures of disease activity were observed between Weeks 8-12 in subjects receiving 160-640 mg bimekizumab. The duration of effect at doses >= 160mg was evident up toWeeks 12-20 after a single intravenous dose, dependent on endpoint. CONCLUSIONS This is the first study to demonstrate the safety, tolerability and clinical efficacy of a dual IL-17A and IL-17F inhibitor, in subjects with mild psoriasis. Bimekizumab showed fast onset of clinically-meaningful efficacy by Week 2, with a maximal or near-maximal magnitude of response that was maintained up to studyWeeks 12-20. These findings support the continued clinical development of bimekizumab for diseases mediated by both IL-17A and IL-17F, including psoriasis.

Background: Transcriptional regulation of Smads that modulate T helper (Th) cell differentiation is not well understood. Results: Active form of vitamin D (1,25(OH)(2)D-3) leads to VDR-RXR-Smad3-HDAC2 repressive complex on VDRE-Smad7 promoter. 1,25(OH)(2)D-3 activates ERK. Conclusion: 1,25(OH)(2)D-3-VDR represses Smad7 and activates ERK leading to inhibition of inflammatory T cells and EAE. Significance: TGF Smad and non-Smad MAPK are involved in 1,25(OH)(2)D-3-VDR mediated inhibition of EAE. The ability of the active form of vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), to transcriptionally modulate Smads to inhibit Th17 differentiation and experimental autoimmune encephalomyelitis (EAE) has not been adequately studied. This study reports modulation of Smad signaling by the specific binding of the VDR along with its heterodimeric partner RXR to the negative vitamin D response element on the promoter of Smad7, which leads to Smad7 gene repression. The vitamin D receptor-mediated increase in Smad3 expression partially explains the IL10 augmentation seen in Th17 cells. Furthermore, the VDR axis also modulates non-Smad signaling by activating ERK during differentiation of Th17 cells, which inhibits the Th17-specific genes il17a, il17f, il22, and il23r. In vivo EAE experiments revealed that, 1,25(OH)(2)D-3 suppression of EAE correlates with the Smad7 expression in the spleen and lymph nodes. Furthermore, Smad7 expression also correlates well with IL17 and IFN expression in CNS infiltered inflammatory T cells. We also observed similar gene repression of Smad7 in in vitro differentiated Th1 cells when cultured in presence of 1,25(OH)(2)D-3. The above canonical and non-canonical pathways in part address the ability of 1,25(OH)(2)D-3-VDR to inhibit EAE.