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      Immune complex disease in a chronic monkey study with a humanised, therapeutic antibody against CCL20 is associated with complement-containing drug aggregates

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          Abstract

          Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002—a humanized IgG1 monoclonal antibody against human CCL20—was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of GSK3050002, that was not predicted by in vitro assays. The aggregates also contained complement components. These findings support the hypothesis that immune complexes of drug aggregates, not necessarily including anti-drug antibodies, can fix complement, accumulate over time, and trigger immune complex disease. A situation which may have increased clinical relevance than typical anti-drug antibody-associated immune complex disease in monkeys administered human antibody proteins.

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          Most cited references 26

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          Phenotypic and functional features of human Th17 cells

          T helper (Th) 17 cells represent a novel subset of CD4+ T cells that are protective against extracellular microbes, but are responsible for autoimmune disorders in mice. However, their properties in humans are only partially known. We demonstrate the presence of Th17 cells, some of which produce both interleukin (IL)-17 and interferon (IFN)-γ (Th17/Th1), in the gut of patients with Crohn's disease. Both Th17 and Th17/Th1 clones showed selective expression of IL-23R, CCR6, and the transcription factor RORγt, and they exhibited similar functional features, such as the ability to help B cells, low cytotoxicity, and poor susceptibility to regulation by autologous regulatory T cells. Interestingly, these subsets also expressed the Th1-transcription factor T-bet, and stimulation of these cells in the presence of IL-12 down-regulated the expression of RORγt and the production of IL-17, but induced IFN-γ. These effects were partially inhibited in presence of IL-23. Similar receptor expression and functional capabilities were observed in freshly derived IL-17–producing peripheral blood and tonsillar CD4+ T cells. The demonstration of selective markers for human Th17 cells may help us to understand their pathogenic role. Moreover, the identification of a subset of cells sharing features of both Th1 and Th17, which can arise from the modulation of Th17 cells by IL-12, may raise new issues concerning developmental and/or functional relationships between Th17 and Th1.
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            Complement is activated by IgG hexamers assembled at the cell surface.

            Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.
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              The CC chemokine CCL20 and its receptor CCR6.

              CCL20, alternatively named liver and activation-regulated chemokine (LARC), macrophage inflammatory protein-3alpha (MIP-3alpha) or Exodus-1, is the only chemokine known to interact with CC chemokine receptor 6 (CCR6), a property shared with the antimicrobial beta-defensins. The ligand-receptor pair CCL20-CCR6 is responsible for the chemoattraction of immature dendritic cells (DC), effector/memory T-cells and B-cells and plays a role at skin and mucosal surfaces under homeostatic and inflammatory conditions, as well as in pathology, including cancer and rheumatoid arthritis. In this review, the discovery, the gene and protein structure, the in vitro biological activities, the cell and inducer specific expression and the tissue distribution of CCL20 and CCR6 are discussed.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: Writing – original draft
                Role: InvestigationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: Investigation
                Role: Formal analysis
                Role: Formal analysis
                Role: InvestigationRole: Methodology
                Role: Formal analysisRole: Writing – review & editing
                Role: InvestigationRole: Methodology
                Role: ConceptualizationRole: Writing – original draft
                Role: ConceptualizationRole: Writing – original draft
                Role: ConceptualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 April 2020
                2020
                : 15
                : 4
                Affiliations
                [1 ] In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
                [2 ] Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
                [3 ] Pathology, IVIVT, R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
                [4 ] Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, United Kingdom
                [5 ] Charles River Laboratories, Inc., Frederick, Maryland, United States of America
                [6 ] Envigo CRS, Inc., Princeton, New Jersey, United States of America
                [7 ] Biopharm Molecular Discovery, R&D Platform Technology and Science, GlaxoSmithKline, Stevenage, United Kingdom
                [8 ] Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline, Stevenage, United Kingdom
                Emory University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: Funding for this study was provided by GlaxoSmithKline and Morphotek, Inc. (NCT01984047). JR is an employee of Charles River Laboratories and principal investigator of the immunohistochemistry analysis. TR is an employee of Covance CRS, LLC (formerly Envigo CRS) and study director of the 26-week monkey toxicity study. LP was an employee of Envigo CRS for the duration of the study. All other listed authors were employees of GlaxoSmithKline (GSK) during the conduct of the study, hold GSK stock or stock options, and meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                [¤a]

                Current address: Pathology, Preclinical Safety AbbVie, North Chicago, Illinois, United States of America

                [¤b]

                Current address: Global Early Development, Covance CRS LLC, Somerset, New Jersey, United States of America

                [¤c]

                Current address: Confluence Pathology, LLC, Oakland, New Jersey, United States of America

                Article
                PONE-D-19-35001
                10.1371/journal.pone.0231655
                7180069
                32325480
                © 2020 Laffan et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 3, Tables: 1, Pages: 18
                Product
                Funding
                Funding for this study was provided by GlaxoSmithKline and Morphotek, Inc. (NCT01984047). JR is an employee of Charles River Laboratories and principal investigator of the immunohistochemistry analysis. TR is an employee of Covance CRS, LLC (formerly Envigo CRS) and study director of the 26-week monkey toxicity study. LP was an employee of Envigo CRS for the duration of the study. All other listed authors were employees of GlaxoSmithKline (GSK) during the conduct of the study, hold GSK stock or stock options, and meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Listed authors from GlaxoSmithKline designed the studies and were involved in data collection and analysis, decision to publish and preparation of the manuscript.
                Categories
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