A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B-cell lymphoma.

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m , rituximab 375 mg/m (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT.

Outlook of IL-6 signaling blockade for COVID-19 pneumonia.

In this review article, it is highlighted the implications of pleiotropic functions of interleukin-6 (IL-6) for one of the therapeutic options targeting for COVID-19. Moreover, it is discussed how real-world data and trials with IL-6 signaling blockade will be crucial in informing the development of new treatment for COVID-19 pneumonia. Given physiological roles of IL-6 in inflammatory conditions and the data from real world, IL-6 signal inhibitors, along with standard of care (SOC) treatment, might provide efficacy, offering the potential to treat COVID-19 in hospitalized populations more effectively than current SOC alone.

Translating IL-6 biology into effective treatments.

In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome.

Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD.

Graft-versus-host disease (GVHD) induces pathological damage in peripheral target organs leading to well-characterized, organ-specific clinical manifestations. Patients with GVHD, however, can also have behavioral alterations that affect overall cognitive function, but the extent to which GVHD alters inflammatory and biochemical pathways in the brain remain poorly understood. In the current study, we employed complementary murine GVHD models to demonstrate that alloreactive donor T cells accumulate in the brain and affect a proinflammatory cytokine milieu that is associated with specific behavioral abnormalities.

Baseline Serum Osteopontin Levels Predict the Clinical Effectiveness of Tocilizumab but Not Infliximab in Biologic-Naïve Patients with Rheumatoid Arthritis: A Single-Center Prospective Study at 1 Year (the Keio First-Bio Cohort Study).

Objective: To explore the baseline predictors of clinical effectiveness after tocilizumab or infliximab treatment in biologic-naïve rheumatoid arthritis patients.

Methods: Consecutive biologic-naïve patients with rheumatoid arthritis initiating infliximab (n = 57) or tocilizumab (n = 70) treatment were included in our prospective cohort study. Our cohort started in February 2010, and the patients observed for at least 1 year as of April 2013 were analysed.

IL-6 as a target in inflammation.

Interleukin-6 (IL-6) has a unique feature of its own signaling pathway. IL-6 can act on various types of cells because there are abundant amounts of soluble IL-6 receptor in peripheral blood and can mediate signaling into cells. IL-6 participates in a broad spectrum of biological events, such as immune responses, hematopoiesis, and acute-phase reactions.

Peripheral blood CD4(+)CD25(+)CD127(low) regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response.

Introduction: Tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, is clinically effective against rheumatoid arthritis (RA), and several reports have indicated how TCZ influences a number of mechanisms underlying RA pathogenesis. However, it is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. We evaluated associations between proportions of subsets of peripheral immune cells and clinical response in patients with RA treated with TCZ.

Tocilizumab, a humanized anti-IL-6R antibody, as an emerging therapeutic option for rheumatoid arthritis: molecular and cellular mechanistic insights.

Pro-inflammatory cytokines play a major role in the initiation and maintenance of joint inflammation and destruction in rheumatoid arthritis (RA). The therapeutic success of biologics targeting tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin (IL)-6 receptor (IL-6R) has broadened the treatment options for RA. These agents have potential overlapping and discriminating biologic effects, as well as different pharmacological features.

Anti-interleukin-6 receptor antibody prevents systemic bone mass loss via reducing the number of osteoclast precursors in bone marrow in a collagen-induced arthritis model.

Systemic bone loss is a hallmark of rheumatoid arthritis (RA). Inflammatory cytokines such as interleukin (IL)-6 promote bone resorption by osteoclasts. Sphingosine-1-phosphate (S1P) controls the migration of osteoclast precursor cells (OCPs) between the blood and bone marrow, in part via S1P receptors (S1PR1 and S1PR2) expressed on the surface of OCPs.

Blockade of IL-6 and TNF-α inhibited oxLDL-induced production of MCP-1 via scavenger receptor induction.

In chronic inflammatory diseases, cardiovascular disease risk is increased and is the main cause of increased mortality. Oxidized LDL (oxLDL) and scavenger receptors participate in atherogenesis. Using human arterial endothelial cells (HAECs), we evaluated the effect of IL-6 and TNF-α on the expression of scavenger receptors.

Interleukin-6 regulates anti-arthritic effect of methotrexate via reduction of SLC19A1 expression in a mouse arthritis model.

Introduction: Methotrexate (MTX) enters cells via the reduced folate carrier SLC19A1, suggesting that SLC19A1 is associated with the efficacy of MTX. We here examined the relationship between the efficacy of MTX and the expression of SLC19A1 in glucose 6-phosphate isomerase (GPI)-induced arthritis. We found that interleukin-6 (IL-6) regulated the expression of SLC19A1, so we studied the effect of a combination of MTX and anti-mouse IL-6 receptor antibody (MR16-1).

Atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors.

Patients with chronic inflammatory disorders such as rheumatoid arthritis (RA) have a high risk of developing cardiovascular disease. We evaluated the effects of TNF-α and IL-6 on foam cell formation, a pivotal process in atherogenesis. Accumulation of intracellular oxidized LDL (oxLDL) was induced when THP-1/macrophages were stimulated with TNF-α or IL-6.

The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis.

Several clinical studies have demonstrated that the humanized anti-interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) improves clinical symptoms and prevents progression of joint destruction in rheumatoid arthritis (RA). However, the precise mechanism by which IL-6 blockade leads to the improvement of RA is not well understood. IL-6 promotes synovitis by inducing neovascularization, infiltration of inflammatory cells, and synovial hyperplasia.

IL-6/IL-6 receptor system and its role in physiological and pathological conditions.

IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, haemopoiesis, the acute phase response and inflammation. IL-6 is produced by various types of cell and influences various cell types, and has multiple biological activities through its unique receptor system. IL-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor) and gp130.

IL-6 plays an essential role in neutrophilia under inflammation.

In the present study, we explored the involvement of interleukin-6 (IL-6) in neutrophilia under inflammatory conditions. The neutrophil count in the peripheral blood was high in arthritic monkeys, and anti-IL-6 receptor antibody reduced neutrophil counts to normal levels. IL-6 injection into normal monkeys significantly increased neutrophil counts in the blood 3h after injection.

High molecular weight hyaluronic acid inhibits IL-6-induced MMP production from human chondrocytes by up-regulating the ERK inhibitor, MKP-1.

To investigate the mechanism of the inhibitory action of high molecular weight hyaluronic acid (HA) on production of matrix metalloproteinases (MMPs) induced by IL-6 in human chondrocyte. Human chondrocyte were stimulated by interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) with or without HA for 24h and the productions of MMP-1, MMP-3 and MMP-13 were measured. Phosphorylations of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase kinase (MEK) in IL-6+sIL-6R-treated chondrocytes were detected by western blotting.

IL-6 blockade preferentially inhibits Th17 differentiation in collagen-induced arthritis.

We examined the time course of cytokine production by CD4 T cells from mice with collagen-induced arthritis (CIA), and we determined the influence of interleukin-6 (IL-6) blockade on cytokine production. CD4 T cells purified from spleen were cultured with both collagen and anti-CD28 antibody for 48 h and the production of interferon-γ (IFN-γ), IL-4, and IL-17 by the cells, secreted into the supernatants, was measured at various time intervals. The production of all these cytokines started 7 days after the first immunization.

Induction of high-dose tolerance to the rat anti-mouse IL-6 receptor antibody in NZB/NZW F1 mice.

MR16-1 is a monoclonal antibody to mouse IL-6 receptor (IL-6R) and a good tool to investigate the involvement of IL-6 in mouse disease models. However, long-term administration of MR16-1 induced anti-MR16-1 antibody that inhibited IL-6 blocking activity of MR16-1. In this study, we treated NZB/NZW F1 (BWF1) mice with MR16-1 (0.

Striking species difference in the contribution of concentrative nucleoside transporter 2 to nucleoside uptake between mouse and rat hepatocytes.

Concentrative nucleoside transporter 2 (CNT2) (encoded by the SLC28A2 gene) transports various antiviral or antitumor purine nucleoside analogs to be involved in their pharmacokinetics and pharmacological actions. The results of our study showed that mouse hepatocytes hardly expressed CNT2 mRNA and no CNT2-dependent nucleoside uptake was observed, while rat hepatocytes exhibited high CNT2-dependent nucleoside uptake activity levels with abundant CNT2 mRNA expression. We concluded that CNT2 contributes considerably to nucleoside uptake in rat hepatocytes but not in mouse hepatocytes.

High molecular weight hyaluronic acid relieved joint pain and prevented the progression of cartilage degeneration in a rabbit osteoarthritis model after onset of arthritis.

We examined the therapeutic effect of high molecular weight hyaluronic acid (HA) on the progression of joint pain and cartilage degeneration in a rabbit osteoarthritis (OA) model. The OA model was induced by partial meniscectomy. In the time course study, cartilage degeneration was assessed at 3, 7 and 14 days after operation.

IL-6 and IL-1 synergistically enhanced the production of MMPs from synovial cells by up-regulating IL-6 production and IL-1 receptor I expression.

In the present study, we investigated potential synergism between IL-6 and IL-1 for the production of matrix metalloproteinases (MMPs) by the synovial cell line SW982. Cells were cultured with different combinations of IL-6, soluble IL-6 receptor (sIL-6R) and IL-1beta for 24h and production of MMPs was then measured. IL-6+sIL-6R, but not IL-6 alone, induced MMP-13 and MMP-3 production.