Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity.
TL;DR: Overall results in this single-dose study suggest potent and sustained B cell depletion by ianalumab could provide therapeutic benefits in patients with pSS without major side effects.
Abstract: Objectives To evaluate the efficacy and safety of ianalumab (VAY736), a B cell-depleting, B cell activating factor receptor-blocking, monoclonal antibody, in patients with active primary Sjogren’s syndrome (pSS) in a double-blind, placebo-controlled, phase II, single-centre study. Methods Patients with pSS, EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) ≥6, were randomised to ianalumab single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12) or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B cell numbers had recovered. Clinical outcomes included ESSDAI, EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI), salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity. Results A similar trend showing positive therapeutic effect by ianalumab was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, Multidimensional Fatigue Inventory, Short Form-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B cell depletion of long-lasting duration occurred after a single infusion of ianalumab at either dose. Serum Ig light chains decreased, with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild to moderate infusion reactions within 24 hours of ianalumab administration. Conclusions Overall results in this single-dose study suggest potent and sustained B cell depletion by ianalumab could provide therapeutic benefits in patients with pSS without major side effects.
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TL;DR: Progress towards the ultimate goal of safely reducing disease activity and preventing damage accrual and death is reviewed, and the new classification criteria from the European League Against Rheumatism and American College of Rheumatology are discussed.
276 citations
TL;DR: The understanding of B cell biology is updated, the results of clinical trials using BCDT in autoimmune indications are reviewed, hypotheses for the mechanism of action are discussed, and evolving strategies for targeting B cells beyond depletion are speculated on.
Abstract: In the past 15 years, B cells have been rediscovered to be not merely bystanders but rather active participants in autoimmune aetiology. This has been fuelled in part by the clinical success of B cell depletion therapies (BCDTs). Originally conceived as a method of eliminating cancerous B cells, BCDTs such as those targeting CD20, CD19 and BAFF are now used to treat autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. The use of BCDTs in autoimmune disease has led to some surprises. For example, although antibody-secreting plasma cells are thought to have a negative pathogenic role in autoimmune disease, BCDT, even when it controls the disease, has limited impact on these cells and on antibody levels. In this Review, we update our understanding of B cell biology, review the results of clinical trials using BCDT in autoimmune indications, discuss hypotheses for the mechanism of action of BCDT and speculate on evolving strategies for targeting B cells beyond depletion.
209 citations
TL;DR: The utility of phage display as a powerful platform for therapeutic antibodies discovery is illustrated and all the approved mAbs derived fromphage display are described.
Abstract: Monoclonal antibodies (mAbs) have become one of the most important classes of biopharmaceutical products, and they continue to dominate the universe of biopharmaceutical markets in terms of approval and sales. They are the most profitable single product class, where they represent six of the top ten selling drugs. At the beginning of the 1990s, an in vitro antibody selection technology known as antibody phage display was developed by John McCafferty and Sir. Gregory Winter that enabled the discovery of human antibodies for diverse applications, particularly antibody-based drugs. They created combinatorial antibody libraries on filamentous phage to be utilized for generating antigen specific antibodies in a matter of weeks. Since then, more than 70 phage–derived antibodies entered clinical studies and 14 of them have been approved. These antibodies are indicated for cancer, and non-cancer medical conditions, such as inflammatory, optical, infectious, or immunological diseases. This review will illustrate the utility of phage display as a powerful platform for therapeutic antibodies discovery and describe in detail all the approved mAbs derived from phage display.
116 citations
TL;DR: The targeting of co-stimulatory molecules in autoimmune diseases is reviewed, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families, including rational combinations of immune inhibitory agents.
Abstract: Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field. Immune activating antibodies that target co-stimulatory molecules have altered the cancer therapy landscape. Here, Walker and colleagues discuss therapies — particularly those that target molecules in the same families as CTLA4 and PD1 or TNF receptor — that inhibit the immune system and are being investigated for the treatment of autoimmune diseases. They describe the future opportunities and challenges for the field, including combination approaches.
82 citations
TL;DR: The present comprehensive review of primary Sjögren’s syndrome addresses the clinical manifestations and complications of the disease, the diagnostic workup, the pathogenic mechanisms and the therapeutic approaches.
Abstract: Primary Sjogren’s syndrome (pSS) is a chronic systemic autoimmune rheumatic disease characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis, affecting 0.3–3% of the population. Women are more prone to develop pSS than men, with a sex ratio of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial cells of the salivary glands are now known to play an active role in the pathogenesis of the disease. The aetiology of the “autoimmune epithelitis” still remains unknown, but certainly involves genetic, environmental and hormonal factors. Later during the disease evolution, the subsequent chronic activation of B cells can lead to the development of systemic manifestations or non-Hodgkin’s lymphoma. The aim of the present comprehensive review is to provide the current state of knowledge on pSS. The review addresses the clinical manifestations and complications of the disease, the diagnostic workup, the pathogenic mechanisms and the therapeutic approaches.
69 citations
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TL;DR: A 36-item short-form survey designed for use in clinical practice and research, health policy evaluations, and general population surveys to survey health status in the Medical Outcomes Study is constructed.
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TL;DR: In this article, cross-sectional data from the Medical Outcomes Study (MOS) were analyzed to test the validity of the MOS 36-Item Short-Form Health Survey (SF-36) scales as measures of physical and mental health constructs.
Abstract: Cross-sectional data from the Medical Outcomes Study (MOS) were analyzed to test the validity of the MOS 36-Item Short-Form Health Survey (SF-36) scales as measures of physical and mental health constructs. Results from traditional psychometric and clinical tests of validity were compared. Principal
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TL;DR: These classification criteria for Sjögren's syndrome have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.
Abstract: Classification criteria for Sjogren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.
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TL;DR: The Multidimensional Fatigue Inventory was tested for its psychometric properties in cancer patients receiving radiotherapy, patients with the chronic fatigue syndrome, psychology students, medical students, army recruits and junior physicians, and support the validity of the MFI.
2,892 citations