Lupus clinical development: will belimumab's approval catalyse a new paradigm for SLE drug development?

INTRODUCTION: Systemic lupus erythematosus (SLE) is a diverse autoimmune disease affecting many different organ systems. Although disease manifestations are varied across the lupus population, the widespread presence of autoantibodies indicates that SLE immunopathology involves B-cell dysregulation. Belimumab, a human anti-B-cell activating factor (BLyS) monoclonal antibody, was invented by Human Genome Sciences and co-developed with GlaxoSmithKline and became, in 2011, the first new therapy approved for SLE patients in over 50 years. AREAS COVERED: Belimumab approval represents a milestone as a new treatment for a subset of SLE patients and also a window onto the continued unmet need for many patients suffering from this diverse disease. This paper analyses the drugs and clinical trials of industry-sponsored development programs to profile the current SLE landscape and to consider how belimumab is shaping the future of SLE drug development. EXPERT OPINION: Our analysis demonstrates that the belimumab clinical program created a model for improvements in study designs that is reflected in ongoing clinical trials sponsored by a broad range of companies. Additional BLyS inhibitors, with distinctive targeting characteristics, are now in late stage development. A broad range of drugs with other mechanisms of action are also under investigation in Phase II - III trials, some of which are focused on the underserved lupus nephritis population.

TWEAK/Fn14 pathway: a nonredundant role in intestinal damage in mice through a TWEAK/intestinal epithelial cell axis.

BACKGROUND AND AIMS: Tumor necrosis factor (TNF) superfamily members have attracted attention as new therapeutic targets for treating inflammatory disease. TNF-like weak inducer of apoptosis (TWEAK) is a unique, multifunctional TNF family cytokine that signals through its receptor, fibroblast growth factor-inducible molecule 14 (Fn14). The role of this pathway in the intestine has not been previously reported. METHODS: The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model was conducted in TWEAK- or Fn14-deficient mice or in normal mice treated with a TWEAK-blocking monoclonal antibody, and clinical severity, histopathology, immunohistochemistry for cell infiltrates, TWEAK and Fn14, gene expression profiling in the colon, and systemic adaptive immunity were assessed. The effect of TWEAK on colon epithelial cell production of inflammatory mediators was analyzed in vitro. The gamma-irradiation injury model was conducted in TWEAK- or Fn14-deficient mice, and crypt epithelial death was assessed. RESULTS: Colitis severity and histologic scores were significantly reduced by TWEAK pathway deficiency or TWEAK-blocking monoclonal antibody. Neutrophil and macrophage infiltrates, chemokines, cytokines, and matrix metalloproteinase expression were reduced in the TWEAK-deficient colon after TNBS administration; however, systemic adaptive immune responses to trinitrophenyl were not altered. Fn14 is expressed on colon epithelial cells in TNBS colitis, and TWEAK induces epithelial production of pathogenic mediators. TWEAK also regulates intestinal epithelial turnover, as evidenced by reduced epithelial cell death after gamma-irradiation injury in TWEAK and Fn14 knockout mice. CONCLUSIONS: Our studies elucidate a nonredundant TWEAK-intestinal epithelial cell axis and suggest that blocking TWEAK may dampen chronic intestinal inflammation and allow normal epithelial repair.

TNF superfamily member TWEAK exacerbates inflammation and demyelination in the cuprizone-induced model.

Inflammatory cytokines have been implicated in the pathology of multiple neurologic diseases, including multiple sclerosis. We examined the role of the TNF family member TWEAK in neuroinflammation. Cuprizone-fed mice undergo neuroinflammation and demyelination in the brain, but upon removal of cuprizone from the diet, inflammation is resolved and remyelination occurs. Using this model, we demonstrate that mice lacking TWEAK exhibit a significant delay in demyelination and microglial infiltration. During remyelination, mice lacking the TWEAK gene demonstrate only a marginal delay in remyelination. Thus, this study identifies a primary role of TWEAK in promoting neuroinflammation and exacerbating demyelination during cuprizone-induced damage.

IFN-alpha2 induces leukocyte integrin redistribution, increased adhesion, and migration.

The human type I Interferon (IFN) family includes 14 closely related cytokines that are produced in response to viral and bacterial infections and mediate the progress of innate immune responses to adaptive immune protection, bind to a common receptor, and have qualitatively similar biologic activities. We have shown previously that IFN-alpha2 can induce human T cell chemotaxis, suggesting that type I IFNs may contribute to the development of an inflammatory environment. We here report that, in addition to promoting T cell chemotaxis, IFN-alpha2 enhances T cell adhesion to integrin ligands, which is associated with integrin clustering on the T cell surface and enhanced conjugate formation with dendritic cells. These effects were prevented by inhibition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). As type I IFN receptor is ubiquitously expressed, this analysis was extended to other human leukocyte populations, including granulocytes and B cells. All leukocyte populations analyzed displayed increased chemotaxis, integrin clustering, and increased integrin-mediated adhesion following exposure to IFN-alpha2, revealing a broad-spectrum proinflammatory activity. These findings have obvious implications for the role of type I IFNs in the development of inflammatory responses leading to the initiation of adaptive immunity.

TWEAK is a novel arthritogenic mediator.

TNF-like weak inducer of apoptosis (TWEAK) is a TNF family member with pleiotropic effects on a variety of cell types, one of which is the induction of proinflammatory cytokines by synovial fibroblasts derived from rheumatoid arthritis (RA) patients. In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA. Histological analyses also revealed that TWEAK inhibition diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Anti-TWEAK treatment proved efficacious when administered just before the disease onset but not during the priming phase of CIA. Consistent with this, TWEAK inhibition did not affect either cellular or humoral responses to collagen. In contrast, TWEAK inhibition significantly reduced serum levels of a panel of arthritogenic mediators, including chemokines such as MIP-1beta (CCL-4), lymphotactin (XCL-1), IFN-gamma-inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), as well as the matrix metalloprotease-9. Exploring the possible role of the TWEAK/Fn14 pathway in human RA pathogenesis, we showed that TWEAK can target human primary chondrocytes and osteoblast-like cells, in addition to synovial fibroblasts. We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models. These results provide evidence for a novel cytokine pathway that contributes to joint tissue inflammation, angiogenesis, and damage, as well as may inhibit endogenous repair, suggesting that TWEAK may be a new therapeutic target for human RA.