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      Monoklonale Antikörper zur antiinfektiven Therapie Translated title: Monoclonal antibodies for anti-infective therapy

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          Abstract

          Ein Jahrhundert lang wurde die Serumtherapie von Seren tierischen Ursprungs und Hyperimmunglobulinen dominiert. Obwohl seit Ende der Achtzigerjahre des letzten Jahrhunderts zahlreiche monoklonale Antikörper (MAB) insbesondere zur Behandlung von immunologischen und onkologischen Erkrankungen entwickelt wurden, sollte es noch 20 Jahre bis zur Zulassung des ersten antiinfektiven MAB in der Europäischen Union dauern. In den folgenden 2 Dekaden kamen nur 2 weitere antiinfektive MAB hinzu. Interessanterweise werden zurzeit zur Bekämpfung der COVID-19-Pandemie zahlreiche MAB, die insbesondere in immunologischer Indikation zugelassen sind, zur Behandlung der Folgen der SARS-CoV-2-Infektion, wie Pneumonie oder Hyperimmunreaktion, eingesetzt.

          Im Folgenden werden die zugelassenen monoklonalen Antikörper zur Behandlung von Infektionskrankheiten vorgestellt. Darüber hinaus wird eine Übersicht über die aktuellen Entwicklungen, insbesondere bei der Therapie der SARS-CoV-2-Infektion, gegeben.

          Translated abstract

          Sera of animal origin and hyperimmunoglobulins have dominated serum therapy for a century. Although numerous monoclonal antibodies (MABs) have been developed since the end of the 1980s, particularly for the treatment of immunological and oncological diseases, it will take 20 years before the first anti-infective MAB is approved in the European Union. Interestingly, to combat the COVID-19 pandemic, numerous MABs, which are approved in particular for immunological indications, are currently being used to treat the consequences of SARS-CoV‑2 infection, such as pneumonia or hyperimmune reactions.

          The approved monoclonal antibodies for the treatment of infectious diseases are presented here. In addition, an overview of the current developments, in particular in the treatment of SARS-CoV‑2 infection, is provided.

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          Most cited references38

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            Effective treatment of severe COVID-19 patients with tocilizumab

            Significance In patients with coronavirus disease 2019, a large number of T lymphocytes and mononuclear macrophages are activated, producing cytokines such as interleukin-6 (IL-6), which bind to the IL-6 receptor on the target cells, causing the cytokine storm and severe inflammatory responses in lungs and other tissues and organs. Tocilizumab, as a recombinant humanized anti-human IL-6 receptor monoclonal antibody, can bind to the IL-6 receptor with high affinity, thus preventing IL-6 itself from binding to its receptor, rendering it incapable of immune damage to target cells, and alleviating the inflammatory responses.
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              The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

              Highlights • Pathogenesis of cytokine release syndrome in severe COVID-19 patients • The key role of IL-6 in cytokine release syndrome • Propose possible drugs IL-6R antagonist Tocilizumab for severe COVID-19
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                Author and article information

                Contributors
                Bettina.Klug@pei.de
                Journal
                Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz
                Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz
                Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1436-9990
                1437-1588
                9 October 2020
                9 October 2020
                : 1-7
                Affiliations
                [1 ]GRID grid.425396.f, ISNI 0000 0001 1019 0926, Paul-Ehrlich-Institut, ; Paul-Ehrlich-Straße 51–59, 63225 Langen, Deutschland
                [2 ]GRID grid.13652.33, ISNI 0000 0001 0940 3744, Robert Koch-Institut, ; Berlin, Deutschland
                Article
                3229
                10.1007/s00103-020-03229-1
                7545799
                33034695
                e7b01a56-0e2a-4dac-84ad-bcb534f48565
                © The Author(s) 2020

                Open Access. Dieser Artikel wird unter der Creative Commons Namensnennung 4.0 International Lizenz veröffentlicht, welche die Nutzung, Vervielfältigung, Bearbeitung, Verbreitung und Wiedergabe in jeglichem Medium und Format erlaubt, sofern Sie den/die ursprünglichen Autor(en) und die Quelle ordnungsgemäß nennen, einen Link zur Creative Commons Lizenz beifügen und angeben, ob Änderungen vorgenommen wurden.

                Die in diesem Artikel enthaltenen Bilder und sonstiges Drittmaterial unterliegen ebenfalls der genannten Creative Commons Lizenz, sofern sich aus der Abbildungslegende nichts anderes ergibt. Sofern das betreffende Material nicht unter der genannten Creative Commons Lizenz steht und die betreffende Handlung nicht nach gesetzlichen Vorschriften erlaubt ist, ist für die oben aufgeführten Weiterverwendungen des Materials die Einwilligung des jeweiligen Rechteinhabers einzuholen.

                Weitere Details zur Lizenz entnehmen Sie bitte der Lizenzinformation auf http://creativecommons.org/licenses/by/4.0/deed.de.

                History
                : 27 May 2020
                : 21 September 2020
                Funding
                Funded by: Paul-Ehrlich-Institut - Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel (4253)
                Categories
                Leitthema

                immuntherapie,anti-virale monoklonale antikörper,anti-bakterielle monoklonale antikörper,symptomatische behandlung,sars-cov-2,immunetherapy,anti-viral monoclonal antibodies,anti-bacterial monoclonal antibodie,symptomatic treatment

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