Monovalent Fc receptor blockade by an anti–Fcγ receptor/albumin fusion protein ameliorates murine ITP with abrogated toxicity

Yu, Xiaojie; Menard, Melissa; Prechl, József; Bhakta, Varsha; Sheffield, William P.; Lazarus, Alan H.

doi:10.1182/blood-2015-08-664656

Cited by 24 publications

(11 citation statements)

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“…To explore the relative contribution of particular FcγRs to the function of the anti-CTLA-4 hIgG1 mAb, we utilized a panel of mAb reagents to selectively block individual FcγR-Fc interactions (Figures 4B and S4E) (Veri et al, 2007; Yu et al, 2016). Remarkably, only blockade of the FcγRIIIA-hIgG1 interaction significantly reduced anti-CTLA-4 mAb-induced T cell IL-2 responses.…”

Section: Resultsmentioning

confidence: 99%

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

et al. 2018

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SUMMARY The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.

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Section: Resultsmentioning

confidence: 99%

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

et al. 2018

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“…This finding was supported by a study using a passive ITP mouse model in which a monovalent anti-FcγRIII antibody was used. This construct which blocks immune complex-mediated engagement of FcγRIII mediated an efficient inhibition of antibody-dependent platelet removal without triggering adverse events (339). …”

Section: Autoantibody-induced Cell Lysis: Idiopathic Thrombocytopenicmentioning

confidence: 99%

Mechanisms of Autoantibody-Induced Pathology

et al. 2017

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Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

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“…The increased platelet clearance arises through diverse mechanisms, such as antiplatelet autoantibodies production, and T lymphocyte dysfunction. It was reported that receptors for the Fc fragment of IgG result in the removal of platelets coated with immunoglobulin ( 1 ) and the activation of phagocytosis in the reticuloendothelial system ( 2 ). In addition to B cell dependent autoimmune mechanisms, it is well established that cellular immune pathophysiology of ITP is associated with several T-cell abnormalities, including uncontrolled activation of T helper cells, deficiency of T regulatory cells, and increase of CD8 + T cell targeting megakaryocytes, etc.…”

Section: Introductionmentioning

confidence: 99%

Associations of Gut Microbiota and Fatty Metabolism With Immune Thrombocytopenia

Zheng

et al. 2022

Front. Med.

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ObjectiveTo determine whether gut microbiota, fatty metabolism and cytokines were associated with immune thrombocytopenia (ITP).MethodsIn total, 29 preliminarily diagnosed ITP patients and 33 healthy volunteers were enrolled. Fecal bacterial were analyzed based on 16S rRNA sequencing. Plasma cytokines and motabolites were analyzed using flow cytometry and liquid chromatography-mass spectrometry (LC-MS), respectively.ResultsBacteroides, Phascolarctobacterium, and Lactobacillus were enriched at the genus level in ITP patients, while Ruminococcaceae UCG-002, Eubacterium coprostanoligeues, Megamonas, and Lachnospiraceae NC2004 were depleted. At the phylum level, the relative abundance of Proteobacteria and Chloroflexi increased in ITP patients, while Firmicutes, Actinobacteria, and the Firmicutes/Bacteroidetes ratio decreased. Plasma levels of 5-hydroxyeicosatetraenoic acid (5-HETE), 6-trans-12-epi-leukotriene B4 (6t,12e-LTB4), and resolvin D2 (RvD2) were upregulated, and stachydrine, dowicide A, dodecanoylcarnitine were downregulated in ITP patients. Furthermore, RvD2 is positively correlated with order Bacteroidetes VC2.1 Bac22, 5-HETE is positively correlated with genus Azospirillum, and 6t,12e-LTB4 is positively correlated with genus Cupriavidus. In addition, stachydrine is positively correlated with family Planococcaceae, dowicide A is positively correlated with class MVP-15, and dodecanoylcarnitine is positively correlated with order WCHB1-41. Plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were upregulated in ITP patients.ConclusionOur study revealed a relationship between microbiota and fatty metabolism in ITP. Gut microbiota may participate in the pathogenesis of ITP through affecting cytokine secretion, interfering with fatty metabolism.

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Monovalent Fc receptor blockade by an anti–Fcγ receptor/albumin fusion protein ameliorates murine ITP with abrogated toxicity

Abstract: Key Points We generated a novel monovalent anti-FcγRIII/albumin fusion protein that ameliorates antibody-mediated murine ITP. Severe adverse events by anti-FcγR antibodies because of FcγR cross-linking are overcome by monovalent FcγR blockade.

Cited by 24 publications

References 50 publications

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

Mechanisms of Autoantibody-Induced Pathology

Associations of Gut Microbiota and Fatty Metabolism With Immune Thrombocytopenia

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