Dual Neutralization Research Articles

Dual neutralization of influenza virus hemagglutinin and neuraminidase by a bispecific antibody leads to improved antiviral activity

Targeting multiple viral proteins is pivotal for sustained suppression of highly mutable viruses. In recent years, broadly neutralizing antibodies that target the influenza virus hemagglutinin and neuraminidase glycoproteins have been developed, and antibody monotherapy has been tested in preclinical and clinical studies to treat or prevent influenza virus infection. However, the impact of dual neutralization of the hemagglutinin and neuraminidase on the course of infection, as well as its therapeutic potential, has not been thoroughly tested. For this purpose, we generated a bispecific antibody that neutralizes both the hemagglutinin and the neuraminidase of influenza viruses. We demonstrated that this bispecific antibody has a dual antiviral activity as it blocks infection and prevents the release of progeny viruses from the infected cells. We show that dual neutralization of the hemagglutinin and the neuraminidase by a bispecific antibody is advantageous over monoclonal antibody combination as it resulted an improved neutralization capacity and augmented the antibody effector functions. Notably, the bispecific antibody showed enhanced antiviral activity in influenza virus-infected mice, reduced mice mortality and limited the virus mutation profile upon antibody administration. Thus, dual neutralization of the hemagglutinin and neuraminidase could be effective in controlling influenza virus infection.

CO2-generated amorphous metal organic frameworks for efficient CO2 conversion

Amorphous CO2-based MOFs are directly synthesized and utilized for CO2 cycloaddition, providing an avenue for dual carbon neutralization. The amorphous MOFs show superior catalytic performance compared with crystalline ones (yield >99%, TON >2600).

Impact of dual neutralization of TNF-α and IL-1β along with Gentamicin treatment on the functions of blood and splenic neutrophils and its role on improvement of S. aureus induced septic arthritis

Researches of recent past years have emphasized potential of antibiotics to improve septic arthritis but as multi-drug resistant strains like MRSA are emerging fast, new alternative therapeutic advances are high in demand. This study aims to figure out the role of neutrophils in regulating inflammatory responses of S. aureus induced septic arthritis while using TNF-α Ab or IL-1β Ab along with antibiotic gentamicin or both in combination. In this study, role of anti-oxidant enzymes were investigated and correlated with generated ROS level. While expression of TLR2, TNFR2, MMP2, RANKL, SAPK/JNK in the spleen were evaluated through western blot. Serum activity of IL-8, IL-10, IL-12, OPG, OPN, CRP was assessed using ELISA. Flow cytometry study evaluated inflamed neutrophil population. Results have shown TNF-α neutralization along with gentamicin was able to reduce arthritic swelling prominently. While combination therapy effectively reduced blood neutrophil ROS activity, arginase activity, MPO activity along with spleen bacterial burden. Serum OPG, CRP, IL-10 level got reduced while serum OPN, IL-8 and IL-12 level enhanced in treatment groups, showing mitigation of inflammatory damage. Overall, it is a novel work that observed how antibiotic and antibody therapy enhanced neutrophil function positively to combat sepsis. This study may not be fully applicable in clinical trials as it is performed with animal model. Clinical trials include crystalline and inflammatory arthritides, trauma, neoplasm. Interdisciplinary collaboration between radiology, orthopaedic surgery and knowledge of animal system responses may give better idea to find proper therapeutic approach in future research works.

A Discussion on CO2 Sequestration in the UCG Space Based upon the Review of the UCG Residue Physicochemical Properties

The strategic goal of “carbon peaking and carbon neutrality” has promoted further reform of the global energy system. Additionally, coal is still the dominate form of energy consumption. Underground coal gasification, which changes the method of coal utilization, is an important way to execute clean coal development and clean utilization, and is also an effective method for the development of deep coal resources, belonging to the technical category of clean energy resources. Compared with the traditional method of coal mining surface gasification, it has obvious advantages of being economical, safe and environmentally friendly. After high-temperature gasification, the physicochemical properties of the residues in the three reaction zones of UCG are significantly different from those of the raw coal. Therefore, this paper summarizes the transformation characteristics and the evolution of organic matter and minerals during UCG. Moreover, the paper analyzes the transformation of pore structure caused by UCG and its influencing mechanism, and discusses the possible utilization of UCG residue based on its physicochemical properties. The results show that: (1) after the UCG, the gasification center residue was mainly composed of acidic and alkaline oxides, accompanied by glassy silica that wrapped the carbon residue, which was located far from the gasification center. Due to the weakening of the oxygen supply, the chemical reaction changed from oxidation to reduction, and the influence of baking on the pyrolysis of coal and minerals gradually weakened. Furthermore, the organic carbon content in the residue gradually increased, whereas the inorganic mineral content decreased. Additionally, the thermal decomposition declined. In the boundary between the dry distillation zone and the raw coal, the organic skeleton of coal and inorganic minerals remained basically unchanged. (2) It is suitable for carbonation to sequestrate CO2 for the oxidation residue after the oxidation process because the residue was composed of slag, whereas the baked roof rock fell off. It is suitable for high-pressure adsorption to sequestrate CO2 in the reduction coal due to the porous and high specific surface of the pyrolysis coal. Some pyrolytic minerals were conducive to mineralization to sequestrate CO2. The dry distillated coal had higher specific surface area and volume of pores in the dry distillation zone than those of the raw coal, whereas the values were lower than those of the reduction zone. The pyrolysis of minerals was not obvious, and the carbonation of CO2 was relatively low. The study points out that CO2 sequestration in the UCG space is an important way to reduce greenhouse gas emissions under the dual carbon peak and neutralization targets. The use of UCG cavities for CO2 sequestration is important for achieving the strategic goal of carbon neutrality. However, the current research on CO2 sequestration using UCG cavities is at the theoretical stage, further field tests are lacking and the commercialization process of CO2 sequestration has not yet been realized.

Generation and characterization of QLS22001, a humanized monoclonal antibody that neutralizes IL-17A and IL-17F with an extended half-life.

Therapeutic intervention to block IL-17A signaling has proven to be an effective treatment for numerous autoimmune diseases, including psoriasis, psoriatic arthritis, and axial spondylarthritis. Among the IL-17 family members, IL-17F, which shares 55% sequence homology with IL-17A, has been reported to functionally overlap with IL-17A in many inflammatory diseases. In this study, we describe the generation and characterization of QLS22001, a humanized monoclonal IgG1 antibody with an extended half-life and high affinity for both IL-17A and IL-17F. QLS22001 effectively blocks IL-17A and IL-17F mediated signaling pathways both in vitro and in vivo. Briefly, the YTE (M225Y/S254T/T256E) modification was introduced into the Fc fragment of QLS22001 WT Fc to prolong its half-life, and the resulting construct was named QLS22001. Functionally, it significantly inhibits IL-17A- and IL-17F-stimulated signaling in cell-based IL-6 release and reporter assays. The dual neutralization of the endogenous IL-17A and IL-17F produced by Th17 cells, as opposed to the selective blockade of IL-17A alone, results in a greater suppression of inflammatory cytokine secretion, according to in vitro blockade assays. Furthermore, in an in vivo mouse pharmacodynamic study, QLS22001 blocked human IL-17A-induced mouse keratinocyte chemoattractant (KC) release. In cynomolgus monkey pharmacokinetics evaluation, QLS22001 showed linear pharmacokinetic characteristics with a mean half-life of 31.2days, while its parent antibody, QLS22001 WT Fc, had a mean half-life of 17.2days. In addition, QLS22001 does not induce cytokine release in a human whole-blood assay. Collectively, these data provide a comprehensive preclinical characterization of QLS22001 and support its clinical development.

Simultaneous neutralization of TGF-β and IL-6 attenuates Staphylococcus aureus-induced arthritic inflammation through differential modulation of splenic and synovial macrophages.

Septic arthritis is a joint disease caused by Staphylococcus aureus. Different macrophage populations contribute in various ways to control blood-borne infections and induce inflammatory responses. Macrophage tissue-resident niche is necessary for the suppression of chronic inflammation and may contribute to the pathogenesis of septic arthritis. Thus, to obtain a resolution of the disease and restoration of synovial homeostasis, it needs the activation of macrophages that further regulate the inflammatory consequences. The aim of this study was to find out the mechanism by which neutralization of transforming growth factor-beta (TGF-β) and/or interleukin (IL)-6 after induction of septic arthritis could alter the specific macrophage responses in spleen and synovial joints via different cytokines (osteoprotegerin (OPG), osteopontin (OPN), IL-10, IL-12 and CXCL8) cross-talking, and how the response could be modulated by reactive oxygen species vs antioxidant enzyme activities. Dual neutralization of TGF-β and IL-6 is notably effective in eliciting splenic and synovial tissue-resident macrophage responses. Synovial macrophage-derived IL-10 can elicit protection against septic arthritis via regulating receptor-activated nuclear factor Kappa-B ligand (RANKL)/OPG interaction. They also reduced oxidative stress by increasing the activity of antioxidant enzymes including SOD and catalase. Histopathological analysis revealed that dual neutralization of TGF-β and IL-6 prevented bone destruction and osteoclastic activity in septic arthritis by promoting the differential functional response of the splenic and synovial macrophages. Additionally, the macrophage-derived IL-10 can elicit protection against S.aureus-induced septic arthritis via regulating RANKL/OPG interaction. Further studies on STAT3 and STAT4 are needed for the understanding of such cross-talking in resident macrophages of arthritic mice.

Endogenous neutralization of TGF-β and IL-6 ameliorates septic arthritis by altering RANKL/OPG interaction in lymphocytes

Septic arthritis is an inflammatory joint disease caused by S. aureus. Hematogenous entry of the bacteria to the synovium produces pro-inflammatory cytokines TGF-β and IL-6, which alter the Th17/Treg balance. Hence, targeting TGF-β and IL-6 could be beneficial in ameliorating arthritis. Antibody neutralization of TGF-β and IL-6 to modulate Th17/Treg homeostasis and RANKL/OPG ratio are not investigated so far in S. aureus-induced septic arthritis. Contribution of synovial lymphocyte-derived cytokines IL-10, IL-12, and CXCL-8; along with OPN, OPG, CRP, cellular ROS, antioxidant enzymes, and the expressions of RANKL, SAPK-JNK, MMP2, SOD, CAT, GPx, TGF-β and IL-6 were studied in lymphocytes of blood, spleen and synovial tissues of mice treated with antibody against of TGF-β and IL-6 after induction of septic arthritis. Dual neutralization of TGF-β and IL-6 is effective in shifting the Th17 cell into immunosuppressive Treg cell of the arthritic mice and enhances the RANKL/OPG interaction leading to the down-regulation of osteoclastic activity and reduces the production of OPN, IL-12, CXCL-8, and CRP. Additionally, it reduces oxidative stress via enhancing the activities of antioxidant enzymes including SOD, catalase, and GPx in lymphocytes. Thus it can be concluded that dual endogenous neutralization of TGF-β and IL-6 may be chosen as an alternative therapeutic approach for controlling the severity of septic arthritis through Treg-derived IL-10 that could ameliorate the inflammatory consequences of septic arthritis via influencing RANKL/OPG interaction in lymphocytes.

Promising Treatment Options for Axial Spondyloarthritis: An Overview of Experimental Pharmacological Agents.

Axial spondyloarthritis (axSpA) is a chronic inflammatory condition that predominantly affects the axial skeleton. All patients receive conservative management measures which include physiotherapy, patient education and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Those with significant active disease will require escalation of their treatment with the use of biologics. Currently, there are five approved TNF inhibitors and two approved IL-17 inhibitors for use in axSpA. However, despite this up to 40% of patients do not respond or are intolerant to current available treatment. This leaves a significant number of patients with uncontrolled disease and unmet need for additional therapies. Though many drug classes have been trialed for axSpA they show poor efficacy; however, over the last few years there are three which demonstrate much greater promise as novel therapies for axSpA, these include dual neutralization of IL-17A and IL-17F, Janus kinase (JAK) inhibitors, and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors. This article reviews the evidence for these novel emerging therapeutic options for axSpA.

Out of the shadow of interleukin-17A: the role of interleukin-17F and other interleukin-17 family cytokines in spondyloarthritis.

Purpose of reviewThe last decade has witnessed tremendous advances in revealing an important role for the interleukin (IL)-17 cytokine family in the pathogenesis of spondyloarthritis (SpA). Although most attention has been focused on IL-17A, a potential role of other IL-17 family members in inflammation and tissue remodelling is emerging. Herein, I review recent studies covering the role of IL-17B-F cytokines in the pathogenesis of SpA.Recent findingsSeveral recent studies provided new insights into the cellular source, regulation and function of IL-17F. IL-17F/IL-17A expression ratio is higher in psoriatic skin compared to SpA synovitis. IL-17F-expressing T cells produce different proinflammatory mediators than IL-17A-expressing cells, and IL-17F and IL-17A signal through different receptor complex. Dual IL-17A and IL-17F neutralization resulted in greater suppression of downstream inflammatory and tissue remodelling responses. Furthermore, there is additional evidence of IL-23-independent IL-17 production. In contrast to IL-17A, IL-17F and IL-17C, which play proinflammatory roles in skin and joint inflammation, an anti-inflammatory function is proposed for IL-17D. An increase in IL-17E is associated with subclinical gut microbiome alterations after anti-IL-17A therapy in SpA patients.SummaryIL-17 family cytokines may act as agonists or antagonists to IL-17A contributing in concert to local inflammatory responses. Understanding their function and identifying their cellular sources, and molecular mechanisms driving their expression will be the key to designing rational therapies in SpA.

Modulating inflammation through the neutralization of Interleukin-6 and tumor necrosis factor-α by biofunctionalized nanoparticles

Biological agents that neutralize the activity of pro-inflammatory cytokines are revolutionizing the treatment of inflammatory conditions. However, the antibodies (Abs) short half-life and off-target distribution critically limit their efficacy and safety. Therefore, this work proposes the immobilization of anti-TNF-α and anti-IL-6 Abs at the surface of polymeric nanoparticles (NPs) in order to extend and increase the Abs therapeutic efficacy, owing to the protection from degradation that the NPs provide, and to avoid off-target side effects through local administration. In an in vitro model of inflammation, biofunctionalized NPs were able to reduce the harmful effects on human chondrocytes provided by inflammatory macrophages, being demonstrated the additive effects of the dual neutralization. Significantly, biofunctionalized NPs ameliorated inflammation more efficiently than soluble Abs in an in vivo experimental model of inflammation, exhibiting a safe profile, a prolonged action, and a stronger efficacy. Hence, as this strategy is able to increase the therapeutic efficacy of the currently available treatments, it is a promising potential therapeutic option for inflammatory conditions.

Interleukin (IL)-12 and IL-18 Synergize to Promote MAIT Cell IL-17A and IL-17F Production Independently of IL-23 Signaling.

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

Bimekizumab, a Novel Humanized IgG1 Antibody That Neutralizes Both IL-17A and IL-17F

Interleukin (IL)-17A is a key driver of inflammation and the principal target of anti-IL-17 therapeutic monoclonal antibodies. IL-17A, and its structurally similar family member IL-17F, have been shown to be functionally dysregulated in certain human immune-mediated inflammatory diseases such as psoriasis, psoriatic arthritis, and axial spondyloarthritis. Given the overlapping biology of these two cytokines, we postulated that dual neutralization of IL-17A and IL-17F may provide a greater depth of clinical response in IL-17-mediated diseases than IL-17A inhibition alone. We identified 496.g1, a humanized antibody with strong affinity for IL-17A but poor affinity for IL-17F. Affinity maturation of 496.g1 to 496.g3 greatly enhanced the affinity of the Fab fragment for IL-17F while retaining strong binding to IL-17A. As an IgG1, the affinity for IL-17A and IL-17F was 3.2 pM and 23 pM, respectively. Comparison of 496.g3 IgG1 with the commercially available anti-IL-17A monoclonal antibodies ixekizumab and secukinumab, by surface plasmon resonance and in a human in vitro IL-17A functional assay, showed that 496.g3 and ixekizumab display equivalent affinity for IL-17A, and that both antibodies are markedly more potent than secukinumab. In contrast to ixekizumab and secukinumab, 496.g3 exhibited the unique feature of also being able to neutralize the biological activity of IL-17F. Therefore, antibody 496.g3 was selected for clinical development for its ability to neutralize the biologic function of both IL-17A and IL-17F and was renamed bimekizumab (formerly UCB4940). Early clinical data in patients with psoriasis, in those with psoriatic arthritis, and from the Phase 2 studies in psoriasis, psoriatic arthritis, and ankylosing spondylitis, are encouraging and support the targeted approach of dual neutralization of IL-17A and IL-17F. Taken together, these findings provide the rationale for the continued clinical evaluation of bimekizumab in patients with immune-mediated inflammatory diseases.

Neutralization of TNF-α and IL-1β Regulates CXCL8 Production through CXCL8/CXCR1 Axis in Macrophages during Staphylococcus aureus Infection

ABSTRACT Anti-cytokine therapy is widely acknowledged as an anti-inflammatory technique to treat varied infectious diseases. TNF-α and IL-1β are major cytokines that regulate every aspect of the inflammatory process. However, the effects of single or dual cytokine neutralization on S. aureus mediated CXCL8 secretion and CXCR1 expression in murine peritoneal macrophages remained noninvestigated. Thus we aimed to explore the effects of kinetic-dose dependent neutralization of TNF-α and IL-1β using specific anti-cytokine antibodies and its influential impact on the CXCL8/CXCR1 axis at different stages of S. aureus (30, 60, and 90 min) infection. The murine peritoneal macrophages were isolated and infected with viable S. aureus followed by subsequent addition of anti-TNF-α and anti-IL-1β into the medium. The treated cells were centrifuged and lysate and supernatant collected for various experiments. The ROS generation was measured and cytokine production was estimated by ELISA. The expression of TNFR1, IL-1R, CXCR1, signaling molecules (NF-κB and JNK) were evaluated by Western blot. The role of single or dual cytokine neutralization on intracellular bacterial phagocytosis had also been analyzed by confocal microscopy. Dual cytokine neutralization significantly suppressed ROS, cytokines, CXCL8 secretion, and intracellular bacterial count compared to single cytokine neutralization and it was more apparent at 90 min post S. aureus infection. There was a drastic reduction in TNFR1, IL-1R, and CXCR1 expression on macrophage surface due to reduced expression of downstream signaling molecules, NF-κB and JNK. Hence dual cytokine neutralization was more effectual compared to single cytokine neutralization in the downregulation of S. aureus induced CXCR1 expression.

Bimekizumab for patients with moderate to severe plaque psoriasis: 60-week results from BE ABLE 2, a randomized, double-blinded, placebo-controlled, phase 2b extension study

Dual neutralization of both interleukin 17A and 17F with the monoclonal antibody bimekizumab may have greater efficacy in psoriasis than neutralization of interleukin 17A alone. To provide longer-term efficacy and safety data for bimekizumab from a phase 2b extension study in patients with moderate to severe psoriasis (BE ABLE 2). After the 12-week initial study (BE ABLE 1), patients who had a 90% improvement in Psoriasis Area and Severity Index (PASI 90) at week 12 received bimekizumab 64, 160, or 320mg for an additional 48weeks (60weeks in total). The primary objective was safety. Across all dose groups (N=217), initial PASI 90 responders generally maintained high levels of efficacy through week 60: PASI 90, 80% to 100%; 100% improvement in PASI, 69% to 83%; Investigator's Global Assessment score 0 or 1, 78% to 100% (all nonresponder imputation). Incidence of serious treatment-emergent adverse events was 15/217 (6.9%). No cases of inflammatory bowel disease, major adverse cardiovascular events, or suicidal ideation or behavior were reported. Low numbers in the bimekizumab 64 mg group (n=15). The majority of 60-week data reported here are primarily for the week 12 PASI 90 responders only. Bimekizumab response rates were maintained through week 60. A substantial proportion of patients achieved complete skin clearance. Bimekizumab was generally well tolerated.

Dual neutralization of IL-17A and IL-17F with bimekizumab in patients with active ankylosing spondylitis (AS): 12-week results from a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study

Dual neutralization of IL-17A and IL-17F with bimekizumab in patients with active ankylosing spondylitis (AS): 12-week results from a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study

Dual neutralization of IL-17A and IL-17F with bimekizumab in patients with active PsA: Overall and TNF-inhibitor-naïve population results from a 48-week Phase 2b randomized study

Dual neutralization of IL-17A and IL-17F with bimekizumab in patients with active PsA: Overall and TNF-inhibitor-naïve population results from a 48-week Phase 2b randomized study

Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling.

Disseminated intravascular coagulation is a frequent manifestation during bacterial infections and is associated with negative clinical outcomes. Imbalanced expression and activity of intravascular tissue factor (TF) is central to the development of infection-associated coagulopathies. Recently, we showed that anthrax peptidoglycan (PGN) induces disseminated intravascular coagulation in a nonhuman primate model of anthrax sepsis. We hypothesized that immune recognition of PGN by monocytes is critical for procoagulant responses to PGN and investigated whether and how PGN induces TF expression in primary human monocytes. We found that PGN induced monocyte TF expression in a large cohort of healthy volunteers similar to lipopolysaccharide stimulation. Both immune and procoagulant responses to PGN involve intracellular recognition after PGN internalization, as well as surface signaling through immune Fcγ receptors (FcγRs). In line with our hypothesis, blocking immune receptor function, both signaling and FcγR-mediated phagocytosis, significantly reduced but did not abolish PGN-induced monocyte TF expression, indicating that FcγR-independent internalization contributes to intracellular recognition of PGN. Conversely, when intracellular PGN recognition is abolished, TF expression was sensitive to inhibitors of FcγR signaling, indicating that surface engagement of monocyte immune receptors can promote TF expression. The primary procoagulant responses to PGN were further amplified by proinflammatory cytokines through paracrine and autocrine signaling. Despite intersubject variability in the study cohort, dual neutralization of tumor necrosis factor-α and interleukin-1β provided the most robust inhibition of the procoagulant amplification loop and may prove useful for reducing coagulopathies in gram-positive sepsis.

Dual neutralization of IL-17A and IL-17F with bimekizumab improves quality of life in patients withmoderate-to-severe plaque psoriasis: results from a Phase 2b study and correlation with clinical response

Abstract not available. Disclosures: Study sponsored by UCB Pharma.Copyright 2018 SKIN

Inhibition of CRTH2-mediated Th2 activation attenuates pulmonary hypertension in mice.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2+/+ bone marrow reconstitution and CRTH2+/+ CD4+ T cell adoptive transfer deteriorated hypoxia + ovalbumin-induced PAH in CRTH2-/- mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH.

Dual neutralization of both interleukin 17A and interleukin 17F with bimekizumab in patients with psoriasis: Results from BE ABLE 1, a 12-week randomized, double-blinded, placebo-controlled phase 2b trial

Neutralizing interleukin (IL) 17F in addition to IL-17A might provide a more complete and specific approach to inhibiting inflammation. Assess the efficacy and safety of bimekizumab, a monoclonal antibody that potently and selectively neutralizes IL-17A and IL-17F, in patients with moderate-to-severe plaque psoriasis. Double-blinded, placebo-controlled phase 2b study (NCT02905006). Patients (randomized 1:1:1:1:1:1) received subcutaneous bimekizumab every 4weeks at doses of 64mg, 160mg, 160mg with 320mg loading dose, 320mg, 480mg, or placebo. Primary endpoint was ≥90% reduction in Psoriasis Area Severity Index (PASI90) at week 12. There was a significant (P<.0001) dose-dependent response for PASI90 (week 12); more patients achieved PASI90 in the bimekizumab groups (46.2%-79.1%) than patients in the placebo group (0%; P<.0001 all doses). Across all doses, there were significant improvements from baseline for all secondary endpoints (PASI90week 8, PASI75week 12, PASI100week 12, and Investigators Global Assessment clear or almost clear weeks 8 and 12; P≤.0003) compared with placebo. More bimekizumab-treated patients than placebo-treated patients achieved PASI100 (week 12) (27.9%-60.0% vs 0%; P≤.0002 all doses). Treatment-emergent adverse events were reported by 126 of 208 (61%) bimekizumab-treated patients and 15 of 42 (36%) placebo-treated patients. No active comparator. Dual neutralization of IL-17A and IL-17F with bimekizumab provided rapid and substantial clinical improvements in patients with psoriasis, with no unexpected or dose-related safety findings.