DOCSLIB.ORG

Targeting BAFF and APRIL in Systemic Lupus Erythemathosis a Comparison of Trials of Three BAFF/APRIL Inhibitors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Targeting BAFF and APRIL in Systemic Lupus Erythemathosis a Comparison of Trials of Three BAFF/APRIL Inhibitors Targeting BAFF and APRIL in Systemic Lupus Erythemathosis A comparison of trials of three BAFF/APRIL inhibitors Figure 1: B-cell targeting therapies to treat systemic lupus erythemathosis (1) Abstract: Systemic Lupus Erythemathosis (SLE) is a complex autoimmune disease. Diagnosis and prognosis are difficult and have a lot of confounders. Progress of the disease is thus followed by a number of measures, such as damage indices like SELENA/SLEDAI and BILAG, B-cell numbers, immunoglobulin levels, in particular autoantibodies such as anti-dsDNA antibodies, and complement C3 and C4 levels. B-cell proliferation and activation are overstimulated in SLE, particularly through the BAFF/APRIL stimulated pathways. A number of BAFF/APRIL targeting biologicals have been approved for use in treatment of SLE or are currently in clinical trials. Three of these are highlighted here: Belimumab, Blisibimod and Atacicept. Belimumab, a fully humanized anti-BAFF antibody, is already approved by the USFDA. In clinical studies it has been show to lower the damage index, B-cell numbers and immunoglobulin levels, it increases complement levels and may reduce the need for steroids. Blisibimod, a synthetic peptibody, is in stage II trials. Like Belimumab, Blisbimod lowers the damage index and B-cell numbers, increases complement levels and may reduce the need for steroids. Ataticept, a fusion protein, is in stage III trials. Atacicept also lowers the damage index, B-cell numbers and immunoglobulin levels, increases complement and may reduce the need for steroids. The differences are relatively small and to determine the most promising of these treatments close attention has to be paid to the data from trials. So far, the fully human antibody Belimumab seems to retain the advantage over biologicals like Blisibimod and Atacicept. Introduction: Lupus: Systemic Lupus Erythemathosis (SLE) is a complex and heterogeneous autoimmune disease. The pathology is so complex that it can be seen as a complex of immune diseases. The symptoms such as general malaise, fever, lethargy, renal and pulmonary problems as well as cardiac, nervous and hematopoietic manifestations are common. Because of the combination of symptoms patients have it is often hard to recognize lupus (2). Prevalence of SLE is 20-150 per 100.000 persons. Women with lupus outnumber men by ten to one, and the disease is more prevalent in Africa and Asia than it is in Europe. The reason for the differences between these groups is unclear. Diagnosis of SLE is difficult, and a large number of tests need to be done to ensure proper diagnosis. In addition to broad symptoms like rashes, arthritis, seizures, periods of lethargy and nephritis, the diagnosis has to be confirmed with laboratory tests. As has been popularized in the American hit TV series House, the main manifestations of lupus are not unique to SLE, in fact SLE shares manifestations with more common afflictions such as depression, fibromyalgia, infection, and many connective tissue diseases. From a list of eleven symptoms, a patient needs to present at least four, before laboratory tests can add to the conclusions. Immunological measures for SLE includes high levels of Anti-Nuclear Antibodies (ANA), Anti double-stranded DNA antibodies (Anti-dsDNA), low C3 and C4 complement levels, anti-smith antibodies and antiphospholipid antibodies (3). Progress of disease is followed using a number of indexes that score damage to organs, such as the SLICC/ACR damage index (SDI) (4), the SELENA/SLEDAI and British Isles Lupus Assessment Group (BILAG). These indexes measure progress of disease by scoring a number of symptoms, with each type of symptom weighted to indicate how important the symptom is for the prognosis. Examples of symptoms include a specific headache, evidence of proteinuria indicating renal damage , and evidence of chronic inflammation like rashes, arthritis and vasculitis (3). Measurements taken for the damage index include, among others, platelet count, complement count and leukocyte count in combination with assessment of pain, psychoses and sensory abnormalities. These measurements for damage indexes measure damage already present. While types of damage can be indicative for prognosis, the measurements do not detect what is happening with the immune system in a direct way. Immunological measurement, such as the complement levels, can show activity of the disease. Activity of SLE can be important for monitoring medication. Highly active disease sometimes requires suppression of acute inflammations. A burst of particularly active SLE is called a ‘flare’, though how exactly a flare is defined is still a matter of debate (5), though many adhere to a temporary increase of the SLEDAI score by four or more points. Treatment: In the short term patients with SLE can be treated with non-steroidal anti-inflammatory drugs (NSAIDs). These drugs only counter acute inflammation and have no long term immunosuppressive properties. NSAIDs need to be used only for short periods of time for reduction of symptoms, as prolonged use strongly increases risk of strokes, ulcers and renal failure (6). Main therapy in treating SLE is relatively short courses of corticosteroids which are immunosuppressant but cause osteoporotic fractures, avascular necrosis and cataract formation when used in high doses (7). In addition to being immunosuppressive in the long term, they are anti- inflammatory in the short term, making them efficient in heading off minor flares in serologically active disease. Corticosteroid therapy can be supplemented with antimalarials such as hydroxychloroquine (6,8). Other antimalarials are used but they have strong side effects. Hydroxychloroquine is immunosuppressive and additionally is known to have cardioprotective properties. In acute situations, corticosteroid use can be reduced or supplemented by lymphocytes inhibitors such as azathioprine and cyclophosphamide, both of which come with severe side effects. Supplementary drugs and alternatives are aimed at reducing immediate anti-inflammatory drugs, and the risk anti-inflammatory drugs come with. So far all therapies come with their own risks and require low doses. Pathogenesis Over 200 genes are involved with the aetiology of SLE, and the disease is thought to be triggered by a combination of hereditary factors and environmental triggers such as UV exposure and exposure to certain drugs, such as penicillamine. The nature of the genes involved in SLE and their contribution to pathogenesis of SLE is varied (9). Among the list are genes involved in nucleic acid sensing and interferon production, T-cell activation and B-cell activation. During normal inflammation, debris remains from apoptotic lymphocytes. In SLE patients this debris is insufficiently cleared. Faulty nucleic acid sensing may lead to exaggerated activation of the adaptive immune system, sometimes exacerbated by high interferon production. Activation of T and B-cells through antigen receptors is altered, leading to increased activation and longevity of active T and B-cells (10). T-cells are aberrantly activated when the intracellular domain of CD3 binds the spleen tyrosine kinase instead of the canonical CD3-ζ associated protein ZAP70 (11), leading to increased activation of B-cells, depleting the population of naïve B-cells and increasing the number of plasma cells (12). The resulting glut of peripheral blood mononuclear cells goes into apoptosis, and the debris is insufficiently cleared (13). This debris, including nuclear components, as well as the contribution of B- cells in general, may trigger production of auto-antibodies. The auto-antibodies then activate the immune system to attack healthy tissue. As a further consequence, complement is depleted by continuous activation. Tissue damage is mediated by combinations of auto-antibody-antigen immune complex deposition and apoptosis of tissue cells induced by cytokines. Large amounts of auto-antibodies and other inflammatory molecules cause plaques and chronic inflammation. B-cells: One of the major hallmarks in autoimmunity is presence of autoantibodies, such as antibodies directed against double stranded DNA. These antibodies are produced in mature B cells, thus mature B cells are a target for novel therapies to partially replace or supplement corticosteroid treatment. During inflammation, inactive CD19+/CD20+ B-cells (immature, figure 2) are activated and express CD27 and IgD. These CD27+/IgD+ B-cells mature (Mature, figure 2) and one subset becomes IgD+/CD27+ memory B-cells, while other subsets switch class to IgD+/CD27- or IgD-/CG27- (plasma, figure 2) and secrete immunoglobulins (14). In SLE, the population of B-cells that is affected most is CD19/CD20+ naïve B-cells. They are activated and subsequently undergo apoptosis and aberrantly undergo necroptosis, leaving debris in their wake (12,15). Levels of immunoglobulins can be used as a measure of B-cell activity, but not as a measure of SLE disease activity. Lymphoid Pro-B Pre-B Immature Mature Plasma CD10 CD19 CD20 CD21 CD22 CD23 CD27 CD38 CD138 Figure 2: Maturation of B-cells with associated cell markers. Immature B-cells are recognized by expression of CD19 and CD20 and lack CD27. B-cells gain CD27 when maturing and becoming memory cells. Plasma cells have lost their CD27 (1). Several promising new therapies aim to modulate the function of B-cells. Antibodies like Rituximab and Epratuzumab target receptors like CD20 and CD22 to affect B-cells. Targeting of CD20 results in activation of apoptotic pathways as well as attraction of effector T-cells which induce apoptosis (16). CD22 has a more complicated web of interactions and is involved in B-cell function and CD19 mediated B-cell survival (17). Trials with rituximab targeting CD20 however showed little benefit to patients. Targeting of CD22 with epratuzumab showed more promise. The most promising target for the treatment of SLE through manipulating B cells is the BAFF/APRIL axis. Rather than targeting total B-cell populations, activation of B-cells is target. B-cell Activating Factor (BAFF) and A PRoliferation Inducing Ligand (APRIL) are essential factors for B-cell survival and maturation (18). The BAFF/APRIL axis is part of a cascade of immune cell activation.
Load more

Recommended publications
  • BAFF-Neutralizing Interaction of Belimumab Related to Its Therapeutic Efficacy for Treating Systemic Lupus Erythematosus
    ARTICLE DOI: 10.1038/s41467-018-03620-2 OPEN BAFF-neutralizing interaction of belimumab related to its therapeutic efficacy for treating systemic lupus erythematosus Woori Shin1, Hyun Tae Lee1, Heejin Lim1, Sang Hyung Lee1, Ji Young Son1, Jee Un Lee1, Ki-Young Yoo1, Seong Eon Ryu2, Jaejun Rhie1, Ju Yeon Lee1 & Yong-Seok Heo1 1234567890():,; BAFF, a member of the TNF superfamily, has been recognized as a good target for auto- immune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF–belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF–receptor interaction, but also disrupting the for- mation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a similar manner as endogenous BAFF receptors. Our data thus provides insights for the design of new drugs targeting BAFF for the treatment of autoimmune diseases. 1 Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea. 2 Department of Bio Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea. These authors contributed equally: Woori Shin, Hyun Tae Lee, Heejin Lim, Sang Hyung Lee.
    [Show full text]
  • BCMA-Targeted Immunotherapy for Multiple Myeloma Bo Yu1, Tianbo Jiang2 and Delong Liu2*
    Yu et al. Journal of Hematology & Oncology (2020) 13:125 https://doi.org/10.1186/s13045-020-00962-7 REVIEW Open Access BCMA-targeted immunotherapy for multiple myeloma Bo Yu1, Tianbo Jiang2 and Delong Liu2* Abstract B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development. Keywords: B cell maturation antigen, BCMA, Belantamab mafodotin, CAR-T, Antibody-drug conjugate, Bispecific T cell engager Introduction B cell maturation antigen (BCMA) Recent advances in novel therapeutics such as prote- BCMA is encoded by a 2.92-kb TNFRSF17 gene located asome inhibitors (PI) and immunomodulatory drugs on the short arm of chromosome 16 (16p13.13) and (IMiD) have significantly improved the treatment out- composed of 3 exons separated by 2 introns (Fig. 1). comes in patients with multiple myeloma (MM) [1–8]. BCMA is a 184 amino acid and 20.2-kDa type III trans- However, most MM patients eventually relapse due to membrane glycoprotein, with the extracellular N the development of drug resistance [9]. In addition, terminus containing a conserved motif of 6 cysteines many of the current popular target antigens, such as [18–21].
    [Show full text]
  • An Update on the Current State of Management and Clinical Trials for Iga Nephropathy
    Journal of Clinical Medicine Review An Update on the Current State of Management and Clinical Trials for IgA Nephropathy Chee Kay Cheung 1,2 , Arun Rajasekaran 3 , Jonathan Barratt 1,2,† and Dana V. Rizk 3,*,† 1 Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK; [email protected] (C.K.C.); [email protected] (J.B.) 2 John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester LE5 4PW, UK 3 Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, ZRB 614, 1720 2nd Avenue South, Birmingham, AL 35294, USA; [email protected] * Correspondence: [email protected] † Both authors contributed equally to this work. Abstract: IgA nephropathy remains the most common primary glomerular disease worldwide. It affects children and adults of all ages, and is a leading cause of end-stage kidney disease, making it a considerable public health issue in many countries. Despite being initially described over 50 years ago, there are still no disease specific treatments, with current management for most patients being focused on lifestyle measures and renin-angiotensin-aldosterone system blockade. However, significant advances in the understanding of its pathogenesis have been made particularly over the past decade, leading to great interest in developing new therapeutic strategies, and a significant rise in the number of interventional clinical trials being performed. In this review, we will summarise the current state of management of IgAN, and then describe major areas of interest where new therapies are at their most advanced stages of development, that include the gut mucosal immune system, B cell signalling, the complement system and non-immune modulators.
    [Show full text]
  • The Future of B-Cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus
    pISSN: 2093-940X, eISSN: 2233-4718 Journal of Rheumatic Diseases Vol. 24, No. 2, April, 2017 https://doi.org/10.4078/jrd.2017.24.2.65 Review Article The Future of B-cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus William Stohl Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA To review B-cell activating factor (BAFF)-antagonist therapy in systemic lupus erythematosus (SLE), literature was searched us- ing the search words and phrases, “BAFF”, “B lymphocyte stimulator (BLyS)”, “a proliferation-inducing ligand (APRIL)”, “B-cell maturation antigen (BCMA)”, “transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI)”, “BLyS receptor 3 (BR3)”, “belimumab”, “atacicept”, “blisibimod”, “tabalumab”, and “lupus clinical trial”. In addition, papers from the author’s personal library were searched. BAFF-antagonist therapy in SLE has a checkered past, with four late-stage clin- ical trials meeting their primary endpoints and four failing to do so. Additional late-stage clinical trials are enrolling subjects to address some of the remaining unresolved questions, and novel approaches are proposed to improve results. The BAFF-centric pathway is a proven therapeutic target in SLE. As the only pathway in the past 50+ years to have yielded an United States Food and Drug Administration-approved drug for SLE, it occupies a unique place in the armamentarium of the practicing rheumatologist. The challenges facing clinicians and investigators are how to better tweak the BAFF-centric pathway and im- prove on the successes realized. (J Rheum Dis 2017;24:65-73) Key Words.
    [Show full text]
  • BAFF Suppresses IL-15 Expression in B Cells
    BAFF Suppresses IL-15 Expression in B Cells Ning Ma, Chen Xing, He Xiao, Youdi He, Gencheng Han, Guojiang Chen, Chunmei Hou, Bernadette Marrero, Yujuan Wang, Shengquan Zhang, Beifen Shen, Yan Li and Renxi This information is current as Wang of September 28, 2021. J Immunol 2014; 192:4192-4201; Prepublished online 26 March 2014; doi: 10.4049/jimmunol.1302132 http://www.jimmunol.org/content/192/9/4192 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/03/26/jimmunol.130213 Material 2.DCSupplemental http://www.jimmunol.org/ References This article cites 39 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/192/9/4192.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology BAFF Suppresses IL-15 Expression in B Cells Ning Ma,*,†,1 Chen Xing,*,1 He Xiao,*,1 Youdi He,‡ Gencheng Han,* Guojiang Chen,* Chunmei Hou,* Bernadette Marrero,x Yujuan Wang,{ Shengquan Zhang,‖ Beifen Shen,* Yan Li,* and Renxi Wang* Clinical trials have shown that BAFF inhibitors do not reduce memory B cell levels but can reduce the number of mature B cells.
    [Show full text]
  • By Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia
    cancers Article Neutralization of B-Cell Activating Factor (BAFF) by Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia 1, 1, 1 1 1 Claudia Tandler y, Moritz Schmidt y, Jonas S. Heitmann , Julia Hierold , Jonas Schmidt , Pascal Schneider 2, Daniela Dörfel 1, Juliane Walz 1,3 and Helmut R. Salih 1,3,* 1 Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Department of Internal Medicine, University Hospital Tuebingen, 72076 Tuebingen, Germany; [email protected] (C.T.); [email protected] (M.S.); [email protected] (J.S.H.); [email protected] (J.H.); [email protected] (J.S.); [email protected] (D.D.); [email protected] (J.W.) 2 Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland; [email protected] 3 DFG Cluster of Excellence 2180 ‘Image-Guided and Functional Instructed Tumor Therapy’ (iFIT), Eberhard Karls University, 72076 Tuebingen, Germany * Correspondence: [email protected]; Tel.: +49-7071/29-83275 These authors contributed equally to this work. y Received: 29 August 2020; Accepted: 21 September 2020; Published: 23 September 2020 Simple Summary: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries. Despite the substantial progress achieved by the recent introduction of the novel small molecule inhibitors idelalisib, ibrutinib and venetoclax in CLL treatment, therapy resistance occurs frequently and the disease so far remains incurable. In the present study we report that BAFF, a member of the TNF protein family, protects CLL cells from treatment-induced cell death.
    [Show full text]
  • NDA/BLA Multi-Disciplinary Review and Evaluation
    BLA 125370/s-064 and BLA 761043/s-007 Multi-disciplinary Review and Evalaution Benlysta® (belimumab) for Intravenous Infusion in Children 5 to 17 Years of Age with SLE NDA/BLA Multi-Disciplinary Review and Evaluation Application Type Postmarketing Required Pediatric Study Application Number(s) sBLA 125370/s-064 and BLA 761043/s-007 Priority or Standard Priority Submit Date(s) October 26, 2018 Received Date(s) October 26, 2018 PDUFA Goal Date April 26, 2019 Division/Office Division of Pulmonary, Allergy and Rheumatology Products (DPARP)/ODE2 Review Completion Date See Electronic Stamp Date Established/Proper Name Belimumab (Proposed) Trade Name BENLYSTA Pharmacologic Class Monoclonal Anti-BLyS Antibody Code name N/A Applicant Human Genome Sciences Dosage form 10 mg/kg via Intravenous Infusion Applicant proposed Dosing 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week Regimen intervals thereafter Applicant Proposed Treatment of patients aged 5 years and older with active, Indication(s)/Population(s) autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy Recommendation on Approval Regulatory Action Recommended Treatment of patients aged 5 years and older with active, Indication(s)/Population(s) autoantibody-positive, systemic lupus erythematosus (SLE) who (if applicable) are receiving standard therapy Recommended Dosing 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week Regimen intervals thereafter 1 Version date: October 12, 2018 Reference ID: 4424800 BLA 125370/s-064 and BLA 761043/s-007 Multi-disciplinary Review and Evalaution Benlysta® (belimumab) for Intravenous Infusion in Children 5 to 17 Years of Age with SLE Table of Contents Table of Tables ...............................................................................................................................
    [Show full text]
  • Effects of Sex and Aging on the Immune Cell Landscape As Assessed by Single-Cell Transcriptomic Analysis
    Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis Zhaohao Huanga,1, Binyao Chena,1, Xiuxing Liua,1,HeLia,1, Lihui Xiea,1, Yuehan Gaoa,1, Runping Duana, Zhaohuai Lia, Jian Zhangb, Yingfeng Zhenga,2, and Wenru Sua,2 aState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China; and bDepartment of Clinical Research Center, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved June 22, 2021 (received for review November 19, 2020) Sex and aging influence the human immune system, resulting in the immune system integrates numerous interconnected compo- disparate responses to infection, autoimmunity, and cancer. How- nents, pathways, and cell types in sex and aging. ever, the impact of sex and aging on the immune system is not yet To this end, we profiled the transcriptomes of peripheral im- fully elucidated. Using small conditional RNA sequencing, we mune cells sampled from men and women of two distinct age found that females had a lower percentage of natural killer (NK) groups. Then, we investigated sex- and age-related differences in cells and a higher percentage of plasma cells in peripheral blood PBMC immune cell composition, molecular programs, and com- compared with males. Bioinformatics revealed that young females munication network. Extensive differences in all of these aspects exhibited an overrepresentation of pathways that relate to T and were observed between sexes, particularly in aging. Compared – B cell activation. Moreover, cell cell communication analysis revealed with males, females exhibited a higher expression of T cell (TC)– evidence of increased activity of the BAFF/APRIL systems in females.
    [Show full text]
  • BCMA) As a Target for New Drug Development in Relapsed And/Or Refractory Multiple Myeloma
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 3 July 2020 doi:10.20944/preprints202007.0016.v1 Peer-reviewed version available at Int. J. Mol. Sci. 2020, 21, 5192; doi:10.3390/ijms21155192 B-Cell Maturation Antigen (BCMA) As a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma Hanley N. Abramson1 1Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202 Abstract: During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T- cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ- 68284528.
    [Show full text]
  • European Journal of Neurology Accepted (14:10:2019) Version
    1 European Journal of Neurology Accepted (14:10:2019) version Failed B cell survival factor trials support the importance of memory B cells in multiple sclerosis. David Baker1, Gareth Pryce1, Louisa K. James1, Klaus Schmierer1,2,*, Gavin Giovannoni1,2,* 1. Blizard Institute, Queen Mary University of London, United Kingdom. 2. Clinical Board:Medicine [Neuroscience], Barts Health NHS Trust, London * Joint senior authors Running Title: Failed trials implicate memory B cells Keywords: A proliferating ligand, B cell activating factor, memory B cells, multiple sclerosis, trial, Corresponding author: David Baker; Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT. Tel:+442078822485; Fax:+442078822180; Email:[email protected] Disclosure of Conflict of Interest: None considered relevant. However, DB has received honoraria for consultant activities have been received from Canbex therapeutics, Japan tobacco, Merck Serono, Roche and Sanofi-Genzyme. GP and LKJ have nothing to declare, KS has been a principal investigator of trials sponsored by Medday, Novartis, Roche and Teva and has received speaker fees, honoraria for advisory board activities and meeting support from Biogen, Lipomed, Merck, Novartis, Roche and Teva. GG has received fees for participation in advisory board from AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Japan tobacco, Novartis, Merck, Roche, Sanofi-Genzyme, Synthon, Teva and Vertex; speaker fees from AbbVie, Biogen, Bayer HealthCare, Celgene, Sanofi-Genzyme and Teva. Research support from Biogen, Sanofi-Genzyme, Ironwood, Merck, Novartis and Takeda. 2 ABSTRACT BACKGROUND: Clinical trials are probably the most informative experiments to help understanding of multiple sclerosis (MS) biology. Recent successes with CD20-depleting antibodies have focussed attention towards B cell subsets as important mediators in MS.
    [Show full text]
  • Merck Kgaa, Darmstadt, Germany, Announces Out-Licensing Agreement for Investigational Atacicept with Vera Therapeutics 09.11.202
    Your Contact News Release Media Relations [email protected] Phone: +49 6151 72-9591 Investor Relations [email protected] Phone: +49 6151 72-3321 November 9, 2020 Merck KGaA, Darmstadt, Germany, Announces Out- Licensing Agreement for Investigational Atacicept with Vera Therapeutics • Merck KGaA, Darmstadt, Germany, out-licenses Phase IIb-ready atacicept to Vera Therapeutics • Phase IIa trial conducted by Merck KGaA, Darmstadt, Germany, shows promising results in IgA nephropathy (IgAN), also known as “Berger’s disease” • Out-licencing deal includes 10% equity in Vera Therapeutics and up to € 605 million in development and commercial milestones, plus royalties on any future net sales Darmstadt, Germany, November 9, 2020– Merck KGaA, Darmstadt, Germany, a leading science and technology company, today announced that it, through its subsidiary Ares Trading S.A., has entered into an out-licensing agreement with biotechnology company Vera Therapeutics, South San Francisco, USA, for the f urther development of investigational therapy atacicept. Vera Therapeutics will f irst prioritize to take atacicept into a Phase IIb study in IgA nephropathy (IgAN), an autoimmune kidney disease also known as “Berger’s disease”. “The positive results from our Phase IIa study in IgA nephropathy reinforce the potential of this compound, and we are pleased to see Vera Therapeutics take it into the next phase of development,” says Andreas Stickler, Chief Financial Officer and Page 1 of 4 Frankfurter Strasse 250 Head of Media Relations -6328 64293 Darmstadt · Ge rm a ny Spokesperson: -9591 / -8908 / -45946 / -55707 Hotline +49 6151 72-5000 www.emdgroup.com News Release Head of Strategy, Business Development and Portfolio Management of the healthcare business sector of Merck KGaA, Darmstadt, Germany.
    [Show full text]
  • BAFF- and APRIL-Targeted Therapy in Systemic Autoimmune Diseases Shingo Nakayamada and Yoshiya Tanaka*
    Nakayamada and Tanaka Inflammation and Regeneration (2016) 36:6 Inflammation and Regeneration DOI 10.1186/s41232-016-0015-4 REVIEW Open Access BAFF- and APRIL-targeted therapy in systemic autoimmune diseases Shingo Nakayamada and Yoshiya Tanaka* Abstract B cells play a pivotal role in autoimmunity not only by producing pathogenic autoantibodies but also by modulating immune responses via the production of cytokines and chemokines. The B cell-activating factor/a proliferation-inducing ligand (BAFF/APRIL) system promotes B cell survival and differentiation and thus plays a prominent role in the pathogenesis of autoimmune diseases. Currently, BAFF and APRIL inhibitors are in clinical trials for systemic lupus erythematosus with significant efficacy. However, several studies have demonstrated the efficacy of the BAFF/APRIL blockade which showed considerable variability in the response to B cell-targeted therapy. This may indicate substantial heterogeneity in the pathogenesis of autoimmune diseases. Therefore, objective markers that can predict the effect of BAFF/APRIL-blocking agents could be valuable to the precision medicine linked clinically and to cost-effective therapy. Keywords: BAFF, APRIL, B cells, Tfh cells, Autoimmune diseases Background CD20-expressing pre-B and mature B cells through Systemic autoimmune diseases are pathologically charac- antibody- and complement-dependent cytotoxic activ- terized by immune complexes consisting of antigens, the ities [3]. In Japan, rituximab is approved for clinical activation of dendritic cells and autoreactive T cells, and use in childhood refractory nephrotic syndrome and the overproduction of autoantibodies secreted from AAVsuchasgranulomatosiswithpolyangiitis(GPA) activated B cells, which cause severe inflammation in and microscopic polyangiitis (MPA). Despite expectations, various organs [1].
    [Show full text]