LitCovid-sentences  

PMC:7228307 / 2471-9469 JSONTXT 23 Projects

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Id Subject Object Predicate Lexical cue
T17 0-12 Sentence denotes Introduction
T18 13-148 Sentence denotes The regulatory approval of the first therapeutic monoclonal antibodies (mAbs) in the 1980s ushered in the modern era of immune therapy.
T19 149-274 Sentence denotes Since then, mAbs have become one of the most clinically successful therapeutic modalities across a diverse array of diseases.
T20 275-728 Sentence denotes They have revolutionized the treatment of chronic inflammatory diseases and of some cancers including otherwise incurable malignancies.1 They are commercially important and in 2017, five mAbs collectively grossed $45.6 billion in sales, placing them in the top ten drugs globally.2 MAb development is expanding rapidly with over 100 mAbs approved for clinical use or in late‐stage clinical trials and over 600 in various stages of clinical development.1
T21 729-1103 Sentence denotes The therapeutic actions of mAbs can take many forms—neutralization of the target such as cytokines in autoimmune disease, clearance of the target such as virus in infection or immunoglobulin (Ig)E in allergy, induction of innate effector cell activation that leads to target destruction by direct killing or the induction of apoptosis and the induction of adaptive immunity.
T22 1104-1496 Sentence denotes Most therapeutic mAbs are IgG in origin and the heavy‐chain subclass determines many of their biological properties including their long plasma half‐life3; complement activation, which is important in the action of some cytotoxic mAbs4, 5, 6 and importantly engagement by their fragment crystallizable (Fc) region with specific cell surface receptors, called FcγR, the subject of this review.
T23 1497-1830 Sentence denotes In normal homeostatic immunity, there is a balance between IgG immune complex activation of proinflammatory responses through the activating‐type FcγRs—which leads to the destruction of opsonized pathogens—and of the modulation of these destructive effector responses by the inhibitory‐type FcγR, thereby avoiding injury to the host.
T24 1831-2019 Sentence denotes Thus, therapeutic mAbs powerfully exploit these opposing activities, making them versatile drugs whose therapeutic potency can be improved by specific engineering of Fc–FcγR interactions.7
T25 2020-2183 Sentence denotes Many therapeutic mAbs depend, to varying degrees, on FcγR function (Figure 1, Table 1) for their mechanism of action (MOA) and/or their pharmacokinetic properties.
T26 2184-2436 Sentence denotes For some mAbs interaction with FcγR is central to their MOA, such as the destruction of a target cell by antibody‐dependent cell‐mediated cytotoxicity (ADCC; Figure 1a) or antibody‐dependent cell‐mediated phagocytosis (phagocytosis or ADCP; Figure 1b).
T27 2437-2655 Sentence denotes This also includes mAbs that may harness the inhibitory action of FcγRIIb to modulate the proinflammatory responses of immunoreceptor tyrosine activation motif (ITAM)‐dependent receptor signaling complexes (Figure 1c).
T28 2656-2982 Sentence denotes For other mAbs, FcγR may play a secondary role, such as the removal or “sweeping” of all immune complexes formed by cytokine or virus‐specific neutralizing antibodies or of opsonized fragments of lysed target cells which in antigen‐presenting cells may also feed the antigen into the antigen‐presentation pathways (Figure 1d).
T29 2983-3275 Sentence denotes In addition, FcγRs, particularly FcγRIIb (Figure 1e), are also key participants in the MOA of immune‐stimulating agonistic mAbs or apoptotic mAbs by acting as a scaffold for the additional cross‐linking of mAbs already bound to a cellular target, thereby inducing a signal in the target cell.
T30 3276-3601 Sentence denotes Figure 1 Graphical representation of the FcγR effector functions. (a) Natural killer cell antibody‐dependent cell‐mediated cytotoxicity via FcγRIIIa. (b) Antibody‐dependent cell‐mediated phagocytosis, and/or trogocytosis of large immune complexes, by professional phagocytes via activating FcγR such as FcγRIIIa and FcγRIIa.
T31 3602-3816 Sentence denotes Biological sequelae include the destruction of the ingested complexes which may also feed antigen into antigen‐presentation pathways of antigen‐presenting cells (APCs). (c) Inhibition of cell activation by FcγRIIb.
T32 3817-4117 Sentence denotes The immunoreceptor tyrosine activation motif (ITAM)‐mediated signaling of B‐cell antigen receptors (left) or of activating FcγR (right) on innate immune cells such as macrophages and basophils is inhibited by IgG Fc‐mediated co‐cross‐linking of these activating receptors with the inhibitory FcγRIIb.
T33 4118-4529 Sentence denotes This leads to phosphorylation of the FcγRIIb immunoreceptor tyrosine‐based inhibitory motif (ITIM) and consequently recruits the phosphatases that modulate the ITAM‐driven signaling responses leading to diminished cell responses. (d) Sweeping or internalization of small immune complexes leading to their removal and, in APC, to enhanced immune responses. (e) Scaffolding in which the FcγRs play a passive role.
T34 4530-4848 Sentence denotes Typically involving FcγRIIb, no signal is generated in the effector cell but “super‐cross‐linking” of the opsonizing antibody by the FcγR on one cell generates a signal in the conjugated target cell, for example, induction of apoptosis or activation in agonistic expansion of cells and/or their secretion of cytokines.
T35 4849-4913 Sentence denotes In extreme cases, this leads to life‐threatening cytokine storm.
T36 4914-5041 Sentence denotes ADCC, antibody‐dependent cell‐mediated cytotoxicity; Ag, antigen; BCR, B‐cell receptor; Ig, immunoglobulin; NK, natural killer.
T37 5042-5119 Sentence denotes Table 1 FcγR responses relevant to therapeutic monoclonal antibodies (mAbs).
T38 5120-5200 Sentence denotes FcγR‐mediated mechanism of action Effector responses Action Dominant receptor
T39 5201-5299 Sentence denotes Activation Antibody‐dependent cell‐mediated cytotoxicity Direct killing of target cell FcγRIIIa
T40 5300-5416 Sentence denotes Antibody‐dependent cell‐mediated phagocytosis, trogocytosis Direct killing of target cell FcγRIIIa, FcγRIIa, FcγRI
T41 5417-5503 Sentence denotes Antigen presentation Vaccine‐like immunity post‐mAb therapy FcγRIIa, FcγRI, FcγRIIIa
T42 5504-5688 Sentence denotes Inhibition Reduce B‐cell proliferation or innate cell activation by antibody complexes Inhibition of ITAM cell activation (i.e. BCR) or activating‐type FcR (i.e. FcγR, FcεRI, FcαRI).
T43 5689-5769 Sentence denotes Note that the FcγRIIb must be co‐cross‐linked with the ITAM activating receptor.
T44 5771-5778 Sentence denotes FcγRIIb
T45 5779-5850 Sentence denotes Sweeping Internalization Removal of small immune complexes FcγRIIb a
T46 5851-6045 Sentence denotes Scaffolding Target agonism or apoptosis Passive “super‐cross‐linking” of mAb on opsonized target cell, for example, CD40, CD28, CD20, by FcγR on an adjacent cell FcγRIIb; also FcγRIIa, FcγRI?
T47 6046-6115 Sentence denotes BCR, B‐cell receptor; ITAM, immunoreceptor tyrosine activation motif.
T48 6116-6179 Sentence denotes a Activating FcγR can also contribute to removal of complexes.
T49 6180-6327 Sentence denotes John Wiley & Sons, Ltd This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response.
T50 6328-6510 Sentence denotes It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
T51 6511-6998 Sentence denotes This review focuses on the cell‐based effector functions that arise from the interaction of IgG with the classical human leukocyte FcγR.7 Although beyond the scope of this review, it should be noted that the IgG‐Fc portion dictates other aspects of an antibody’s biology, including its serum half‐life mediated by the neonatal FcR (FcRn), 3 the activation of complement C1,8 antiviral protection via the intracellular receptor TRIM219 and interactions with the Fc receptor‐like family.10