Anti-CD20 monoclonal antibody in rheumatoid arthritis and systemic lupus erythematosus

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheumatic diseases. In the last few years, evolution in the understanding of RA and SLE pathogenesis and underlying molecular mechanisms has resulted in development and availability of novel therapies. In particular, the recent acknowledgement of a more significant role for B cells in the pathogenesis of RA, in contrast to the view that it was predominantly a T cell disorder, provided rationale for trials of B cell depletion therapy with the chimeric anti-CD20 monoclonal antibody rituximab. The efficacy and favourable safety profile of rituximab have resulted in the recent approval by the European Medicines Agency for its usage in patients with RA unresponsive to conventional therapies. The salient features from the pivotal open and randomised controlled trials are reviewed in this chapter. Given the recognition of B cell dysfunction as central to SLE pathogenesis, the use of anti-CD20 antibody therapy for this patient group has also been established. Results of the open trials have been encouraging, particularly in patients not responding to usual therapies, and a randomised controlled trial is underway.     

Anti B cell therapy (rituximab) in the treatment of autoimmune diseases

B cells play an important role in the pathogenesis of many autoimmune diseases. Selective targeting of these cells has been recently achieved using a chimeric monoclonal antibody against the pan B cell surface marker CD20 (rituximab). This antibody was originally developed for the treatment of non-Hodgkin's lymphoma. It was found to be effective, well tolerated and had a very good safety profile. Recent studies have demonstrated the efficacy of rituximab in several refractory autoimmune disorders including rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenic purpura, chronic cold agglutinin disease, IgM-mediated neuropathies and mixed cryoglobulinemia.     

利妥昔单抗治疗类风湿关节炎的临床研究进展

利妥昔单抗是一种特异性针对CD20分子的基因工程抗体,能与B淋巴细胞表面的CD20结合,并通过补体介导的细胞毒作用等机制对B淋巴细胞进行特异性清除,从而达到治疗作用.利妥昔单抗最初作为抗淋巴瘤药物首先获得美国FDA认证,近年来被应用于类风湿关节炎等自身免疫病的治疗,取得了较好的疗效.现对其治疗类风湿关节炎的作用机制、临床应用和研究进展做一综述.     

Anti‐CD20 Antibody Rituximab in the Treatment of Rheumatoid Arthritis

Abstract: Rheumatoid arthritis (RA) is a chronic, autoimmune reaction‐driven systemic inflammatory disease that affects joints and several other organs. Although anti‐TNF therapy and combination therapy with traditional anti‐rheumatic drugs have improved the treatment of RA, still quite a significant proportion of patients do not reach adequate anti‐rheumatic response. The understanding of the pathogenesis of RA has developed markedly during the last two decades, and this has brought up new targets for anti‐rheumatic therapy. B cells have been found to have a pivotal role in the development of arthritis both in experimental models and in humans. Rituximab, an anti‐CD20 antibody that depletes B cells, has been introduced in the treatment of RA, and it has proven to be safe and efficacious in RA. This review gives an overview on the mechanism of action of rituximab in RA and summarizes the published clinical data of rituximab in the treatment of RA.     

Rituximab: novel B-cell depletion therapy for the treatment of rheumatoid arthritis

Significant numbers of patients with rheumatoid arthritis (RA) suffer from disease that is refractory to both conventional therapy and newer biological agents such as TNF-α inhibitors. These patients may respond insufficiently, lose an effective response, develop toxicity or carry contraindications to such agents. Rituximab, a chimeric monoclonal antibody against CD20 that effectively depletes B cells in peripheral blood, has been licensed for the treatment of certain haematological malignancies for almost 10 years. B cells are now known to have multiple key roles in the pathogenesis of RA. Data is now available that indicates efficacy and safety of B-cell depletion with rituximab in the treatment of RA in a variety of patient groups. The clinical outcomes from these studies, together with its safety profile, have led to rituximab being licensed for the treatment of patients with RA who have failed to obtain benefit from anti-TNF-α agents.     

B-cell-targeted therapy for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex disease characterised by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis of this disease has more recently gained prominence as a result of research in both mice and humans. Both antibody-dependent and -independent mechanisms of B cells are important in SLE. Autoantibodies contribute to autoimmunity by multiple mechanisms, including immune complex-mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines such as interferon-alpha, tumour necrosis factor and interleukin-1. Suggested autoantibody-independent B-cell functions include antigen presentation, T-cell activation and polarisation, and dendritic-cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines, chemokines and lymphangiogenic growth factors, and by their critical contribution to lymphoid tissue development and organisation, including the development of ectopic tertiary lymphoid tissue. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, a recent therapeutic focus has been to develop interventions that target the B-cell compartment by multiple mechanisms.Rituximab, a mouse-human chimeric monoclonal antibody against CD20 that specifically depletes B cells, has been studied the most extensively. Although promising open-label data await confirmation in ongoing multicentre placebo-controlled trials, a number of preliminary conclusions can be drawn. The adequacy of peripheral B-cell depletion depends on achieving high and sustained serum rituximab concentrations, pharmacokinetics that can be varied with treatment dose and factors that may affect drug clearance, such as human anti-chimeric antibodies. In SLE patients with effective B-cell depletion, the clinical response can be significant, with favourable responses observed in a diverse array of disease manifestations. Moreover, rituximab appears to have the potential to induce clinical remission in severe, refractory disease. B-cell depletion has the potential to induce disease amelioration by inhibiting autoantibody production and/or by interfering with other B-cell pathogenic functions. The fact that clinical improvement correlates with B-cell depletion and precedes by several months any decline in serum levels of relevant autoantibodies suggests a predominant effect of autoantibody-independent functions of B cells, although the subset of patients with disease remission ultimately also experience autoantibody normalisation. Significant questions remain about rituximab therapy in SLE, including the immunological determinants of treatment response and remission, the role of combination therapy, and the safety of repeated courses of rituximab. In addition, the efficacy and role of other B-cell-depleting approaches, such as humanised anti-CD20 antibodies and anti-CD22, remain to be defined.Another B-cell-targeted therapeutic approach is to block costimulatory interactions between T and B cells. Blockade of the CD40-CD40 ligand pathway has met with variable clinical benefit and unfortunate thromboembolic complications, although inhibition of the B7 pathway with cytotoxic T-lymphocyte antigen-4Ig is currently under early investigation in SLE clinical trials. Preliminary data on the treatment of SLE with belimumab, a fully human monoclonal antibody that specifically binds to and neutralises the B-lymphocyte stimulator (BLyS or B-cell-activating factor [BAFF]), are now available. In a phase II double-blind, placebo-controlled trial of the safety and efficacy of three different doses administered in addition to standard therapy, belimumab was well tolerated but reportedly did not meet primary efficacy endpoints. Blockade of BAFF is still viewed as a promising therapeutic approach and additional agents that interfere with the BAFF pathway are under study.Overall, therapies targeting B cells appear to be promising in the treatment of SLE, provide additional evidence for the importance of B cells to disease pathogenesis, and will continue to elucidate the diverse roles of B cells in this disease.     

Belimumab Human Genome Sciences/Cambridge Antibody Technology/GlaxoSmithKline

Belimumab, the lead in a series of human monoclonal antibodies against the human protein B-lymphocyte stimulator (BLyS), is under development by Human Genome Sciences, Cambridge Antibody Technology and GlaxoSmithKline for the potential treatment of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). By January 2006, belimumab had completed phase II clinical trials in SLE and RA; a phase III clinical SLE trial is scheduled to begin later this year.     

Rituximab: novel B-cell depletion therapy for the treatment of rheumatoid arthritis

Significant numbers of patients with rheumatoid arthritis (RA) suffer from disease that is refractory to both conventional therapy and newer biological agents such as TNF-alpha inhibitors. These patients may respond insufficiently, lose an effective response, develop toxicity or carry contraindications to such agents. Rituximab, a chimeric monoclonal antibody against CD20 that effectively depletes B cells in peripheral blood, has been licensed for the treatment of certain haematological malignancies for almost 10 years. B cells are now known to have multiple key roles in the pathogenesis of RA. Data is now available that indicates efficacy and safety of B-cell depletion with rituximab in the treatment of RA in a variety of patient groups. The clinical outcomes from these studies, together with its safety profile, have led to rituximab being licensed for the treatment of patients with RA who have failed to obtain benefit from anti-TNF-alpha agents.     

Belimumab: anti-BLyS human monoclonal antibody, anti-BLyS monoclonal antibody, BmAb, human monoclonal antibody to B-lymphocyte stimulator

Belimumab is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS. Belimumab is in phase III trials for the treatment of systemic lupus erythematosus (SLE) and has completed a phase II trial in rheumatoid arthritis (RA); the product may also have potential in the treatment of other autoimmune disorders. In May 2001, Cambridge Antibody Technology (now MedImmune) completed its discovery programme and Human Genome Sciences identified belimumab as a candidate for clinical development. More than 1000 distinct human antibodies specific to BLyS were characterized by the collaboration.B-lymphocyte stimulator is a naturally occurring protein discovered by Human Genome Sciences that stimulates B-lymphocytes to develop into mature B cells. Laboratory studies have indicated that higher than normal levels of B-lymphocyte stimulator may contribute to the pathogenesis of autoimmune diseases, such as SLE and RA. Human Genome Sciences (HGS) and Cambridge Antibody Technology signed a collaborative agreement in August 1999 to study the B-lymphocyte stimulator as a human protein target. HGS is also developing other BLyS products. In March 2000, HGS and Cambridge Antibody Technology expanded their agreement into a 10-year collaboration and product development alliance, providing Human Genome Sciences with the right to use the antibody technology of Cambridge Antibody Technology to fully develop human antibodies for therapeutic and diagnostic purposes. Cambridge Antibody Technology will receive royalty payments on product sales from HGS, as well as the development and milestone payments it has already received. Belimumab will be manufactured in Human Genome Sciences' manufacturing facility, located in Rockville, MD, USA. HGS holds commercial rights to the drug. In July 2005, GlaxoSmithKline (GSK) exercised its co-development and co-promotion option to belimumab. In an agreement made in June 1996, HGS had granted a 50/50 co-development and co-promotion option to GSK for certain therapies that complete phase IIa trials successfully. The companies subsequently entered into a definite worldwide, co-development and commercialization agreement in August 2006, under which HGS will be responsible for conducting phase III trials of the product, with assistance from GSK. The companies will share equally phase III/IV development costs, sales and marketing expenses, and profits. In October 2007, Cambridge Antibody Technology was integrated into MedImmune. Both companies were previously independent subsidiaries of AstraZeneca. MedImmune is now the operationally independent biologics business unit of AstraZeneca. Human Genome Sciences intends to initiate a phase II trial of subcutaneous belimumab by mid-2008. Results from a phase II trial in 449 patients with SLE demonstrated that belimumab improved or stabilized SLE over 2.5 years. The phase II trial was a double-blind, placebo-controlled, multicentre study that evaluated the safety, optimal dosing, and preliminary efficacy of belimumab in patients with active SLE over 52 weeks initially, followed by a continuation phase for a total of 2.5 years. Belimumab has received fast-track designation for the treatment of SLE from the US FDA and has also been selected for inclusion in the agency's continuous Marketing Application Pilot 2 programme.     

Belimumab, a BLyS-specific inhibitor for the treatment of systemic lupus erythematosus

As B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), therapies targeting them may provide a valuable treatment for patients with SLE. One of the therapeutic strategies for B-cell targeting is through the inhibition of factors involved in the survival or differentiation of B cells. B-cell-activating factor (BAFF) or B-lymphocyte stimulator (BlyS; trademark of Human Genome Sciences, Rockville, MD, USA) has proven to be a key factor in the selection and survival of B cells. Belimumab is a fully human monoclonal antibody (immunoglobulin G1) that binds to soluble BAFF and inhibits it from binding to its receptors. To date, two phase III trials have demonstrated that belimumab in combination with standard of care significantly reduced SLE disease activity and SLE flare rates in patients with active SLE. In addition, it was generally well tolerated. This article reviews the immune mechanisms induced by the inhibition of BAFF/BLyS and the evidence-based clinical effectiveness of belimumab in SLE patients.     

Ofatumumab,a second-generation anti-CD20 monoclonal antibody,for the treatment of lymphoproliferative and autoimmune disorders

Background: Lymphoproliferative and autoimmune disorders share monoclonal dysregulation and survival advantage of B-lymphocytes. Thus, therapies directed towards eliminating B-cells will play an important role as CD20 is exclusively expressed in B-lymphocytes and its modulation by monoclonal antibodies such as rituximab has improved outcomes in lymphoproliferative and autoimmune disorders. Ofatumumab is a new, fully human anti-CD20 antibody and has been shown to be effective and safe, but its role in these conditions is still unclear. Objectives: To describe the preclinical and clinical data available on ofatumumab for the treatment of lymphoproliferative and autoimmune disorders. Methods: An extensive search of published articles and abstracts on preclinical and clinical studies with ofatumumab was undertaken. Conclusions: Ofatumumab is a second-generation anti-CD20 antibody that has been demonstrated to be safe and efficacious in patients with lymphoproliferative and autoimmune disorders. Ofatumumab is fully human, attaches to a newly identified epitope and shows lower off-rates and improved complement-dependent cytotoxicity. Initial data present ofatumumab as an attractive agent with lower rates of infusion-related events than rituximab. Ongoing Phase III trials in patients with follicular lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis are ongoing, and Phase II trials in patients with aggressive lymphoma and multiple sclerosis are also under development.     

Targeting BLyS in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic disabling autoimmune disease that significantly impacts the quality of life of patients, and can associate with several complications including end-stage renal disease and shortened lifespan. A central component in the pathogenesis of SLE is the B-cell production of autoantibodies to multiple self-antigens. Since, B lymphocyte stimulator (BLyS) plays a key role in the selection, differentiation and survival of most B cells, it has been studied as a therapeutic target in SLE. After a gap of more than fifty years without new drugs being approved for this disease, the human neutralizing anti-BLyS monoclonal antibody belimumab has recently been approved by the FDA for SLE therapy. This review provides an overview on the targeting of BLyS in lupus animal models, the use of belimumab in human SLE, and relevant patents.     

Anti-interleukin-6 receptor antibody therapy in rheumatic diseases

In the treatment of rheumatic diseases such as rheumatoid arthritis (RA) or systemic onset juvenile idiopathic arthritis (soJIA), new therapies targeting pro-inflammatory cytokines have been developed. IL-6 is a pleiotropic cytokine with a wide range of biological activities including a pro-inflammatory mediator activity. Overproduction of IL-6 has been reported to be pathologically involved in the rheumatic diseases and, therefore, blockade of IL-6 actions may improve the disease. Tocilizumab, a humanized monoclonal antibody against human interleukin-6 receptor (IL-6R), inhibits IL-6 binding to IL-6R and specifically interferes with IL-6 actions. Castleman's disease is an atypical lymphoproliferative disorder caused by the overproduction of IL-6. Tocilizumab therapy improves immunological and hematological abnormalities as well as systemic inflammatory symptoms including wasting. This translational study also confirmed the pathological significance of IL-6 in the disease. RA is a representative autoimmune inflammatory disease characterized by bone and cartilage destruction in multiple joints. Since IL-6 also plays pathological roles in RA, tocilizumab therapy has been introduced to the patients with refractory disease and has shown a strong therapeutic effect. Besides Castleman's disease and RA, tocilizumab has been shown to be effective for patients with soJIA and Crohn's disease. Tocilizumab treatment is generally well tolerated and safe. Therefore, tocilizumab can be a promising therapeutic agent for the rheumatic diseases in which IL-6 overproduction is pathologically involved.     

Treatment of rheumatoid arthritis.

PURPOSE: Current and investigational treatments of rheumatoid arthritis (RA) are described. SUMMARY: The current therapies used to treat RA include nonsteroidal antiinflammatory drugs (NSAIDs), used for the management of pain and inflammation; disease-modifying antirheumatic drugs (DMARDs), used as first-line therapy for all newly diagnosed cases of RA; and biological-response modifiers, targeted agents that selectively inhibit specific molecules of the immune system. Glucocorticoids and other antirheumatic drugs are also used to treat RA. DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. NSAIDs and glucocorticoids are effective in controlling the pain, inflammation, and stiffness related to RA. Unlike NSAIDs, they slow clinical and radiographic progression of RA. The biological-response modifiers include infliximab, etanercept, and adalimumab (inhibitors of tumor necrosis factor [TNF]-alpha); anakinra, a recombinant inhibitor of interleukin-1; abatacept, the first costimulation blocker; and rituximab, a chimeric anti-CD20 monoclonal antibody. Investigational therapies for RA include anti-interleukin-6-receptor monoclonal antibodies, new TNF-alpha inhibitors (including one for oral administration), and antibodies against proteins critical for B-cell function and survival. Data accumulated in the past decade favor early aggressive therapy for patients suspected of having RA, including early referral to a rheumatologist, new diagnostic techniques, and aggressive therapy with DMARDs, glucocorticoids, and biological agents. The benefits of this approach have been demonstrated in clinical trials. CONCLUSION: Pharmacologic treatments of RA include NSAIDs, glucocorticoids, DMARDs, and biological agents. With an improved understanding of the pathophysiology of RA and the evidence from various clinical trials with the agents, early aggressive therapy with a combination of drugs or biological agents may be warranted for the effective treatment of RA.     

New prospects for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a common inflammatory and destructive arthropathy. Current therapies fail to stop joint damage and reduce long-term disability. Greater understanding of disease pathogenesis has identified many inflammatory mediators as possible therapeutic targets. Novel therapeutic agents, such as monoclonal antibodies (mAbs), cytokine receptor-human immunoglobulin constructs, recombinant human proteins and antisense oligodeoxynucleotides targeting these inflammatory mediators have been tested in rheumatoid arthritis with some success. In particular, inflammation can be effectively suppressed using anticytokine therapies. However, the ideal treatment for RA, one that is immunomodulatory and induces prolonged disease remission after a single course of therapy, still eludes us. Strategies aiming to achieve this include TCR peptide vaccination and anti-CD4 mAbs, currently in clinical trials in RA.     

The use of TNF-alpha blocking agents in rheumatoid arthritis: an overview

TNF-alpha has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis (RA). The overexpression of TNF-alpha in RA synovium, the data from in vitro synovial cell cultures with the use of anti-TNF-alpha antibody and the results from TNF-alpha blockade in animal models of arthritis argued for the importance of this cytokine in RA. Drugs targeting TNF-alpha have been developed to neutralise the deleterious effects of this inflammatory cytokine. There are currently three drugs available in the treatment of RA patients with active disease, which was refractory to conventional treatments including methotrexate, infliximab (a chimeric mouse/human monoclonal antibody), etanercept (a fusion protein combining 2 p75 TNF receptors with a Fc fragment of human IgG (1)) and adalimumab (a fully human monoclonal antibody). These three drugs have proved to be effective and safe in appropriate and well conducted clinical trials and showed effectiveness in slowing and even arresting the progression of radiographic damage. With the long-term surveillance of these drugs serious adverse events were described, particularly intracellular organism infections such as tuberculosis. Other drugs targeting TNF-alpha are in development and include monoclonal antibody (CDP571), pegylated molecules (CDP870 and PEG-r-Hu-sTNF-RI) or soluble p55 TNF receptor construct (lenercept). These new biological therapies blocking TNF-alpha undoubtedly constitute a considerable advance in the management of RA, but careful evaluation at the initiation of the treatment and long-term surveillance of the patients receiving such drugs remains necessary.     

Rituximab: new indication. In rheumatoid arthritis: for a few patients, with close monitoring

(1) Methotrexate is often used as a first-line treatment for severe and worsening rheumatoid arthritis. TNF alpha antagonists (etanercept, infliximab and adalimumab) are second-line options. (2) Rituximab, a monoclonal antibody first used to treat lymphoma, is now also approved for the treatment of rheumatoid arthritis when at least one TNF alpha antagonist has failed. (3) There are three available comparative trials including about 1150 rheumatoid arthritis patients. The results indicate that rituximab is no more effective than methotrexate; a combination of rituximab + methotrexate is more effective than methotrexate alone (although only about half the patients meet the ACR 20% response criterion); and adding a steroid fails to improve effectiveness. (4) The adverse effect profile of rituximab in arthritis seems similar to that observed in lymphoma. In the short term, the main adverse effects are infusion hypersensitivity reactions, which are more frequent during the first infusion and can be partly prevented by premedication with a steroid. The other known risks are mainly infectious and cardiovascular. Follow-up is too short to rule out a possible increase in the risk of cancer. Gastrointestinal perforations have occurred in some lymphoma patients treated with rituximab. (5) In practice, when standard treatment fails, adding rituximab to methotrexate can be beneficial but requires close patient monitoring.     

Treatment of systemic lupus erythematosus with epratuzumab

Systemic lupus erythematosus is a prototypic autoimmune disease characterized by abnormalities in the activity of B-cells and T-cells. A novel specific treatment for autoimmune diseases is B-cell depletion with monoclonal antibodies. Epratuzumab is a monoclonal antibody that targets CD22 antigen on B-cells. Initial phase II and two terminated early phase III studies suggest that treatment of systemic lupus erythematosus with this immunomodulatory agent is effective, well tolerated and significantly improves the patient's quality of life. In vitro studies and clinical trials with non-Hodgkin lymphoma patients indicate epratuzumab can potentially serve as a complementary drug in combination therapy with another inhibitor of B-cell activity, rituximab, which is a monoclonal anti-CD20 antibody.     

Rituximab

Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule on the B-cell surface. It is the first antibody of its kind to be licensed for the treatment of non-Hodgkin's lymphoma. Rituximab was found to be effective, well-tolerated and has a good safety profile, though its precise cellular effects are still not well understood. Rituximab has been shown to be of therapeutic benefit in various autoimmune diseases in which B lymphocytes play a role. This article summarizes the current literature regarding the use of rituximab in lymphoma, rheumatoid arthritis, systemic lupus erythematosus and other selected autoimmune diseases.     

Pharmacological profile of MEDI-551, a novel anti-CD19 antibody,in human CD19 transgenic mice

B cell depletion therapy is beneficial for patients with B cell malignancies and autoimmune diseases. CD19, a transmembrane protein, is expressed on a vast majority of normal and neoplastic B cells, making it a suitable target for monoclonal antibody (MAb) mediated immunotherapy. We have developed MEDI-551, an affinity optimized and afucosylated IgG1 MAb targeting human CD19 for B cell depletion. MEDI-551 is currently under investigation in multiple clinical trials. Because MEDI-551 does not cross react with rodent and non-human primate CD19, the pharmacological characteristics of the MAb were evaluated in human CD19 transgenic mice (hCD19 Tg). Here we show that MEDI-551 potently depletes tissue and circulating B cells in hCD19 Tg mice and is more efficacious than the anti-CD19 MAb with intact fucose. The length of B cell depletion depends on MEDI-551 dose; and, B cell recovery in the circulation follows stepwise phenotypic maturation. Furthermore, intravenous (IV) and subcutaneous (SC) administration of MEDI-551 results in comparable efficacy. Lastly, the combination of MEDI-551 with the anti-CD20 MAb, rituximab, further prolongs the duration of B cell depletion. In summary, the pharmacological profile of MEDI-551 presented in hCD19 Tg mice supports further testing of MEDI-551 in clinical trials involving B cell malignancies and autoimmune diseases.