LitCovid-sentences  

PMC:7228307 / 21315-33795 JSONTXT 23 Projects

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Id Subject Object Predicate Lexical cue
T130 0-33 Sentence denotes FcγR‐Dependent Effector Responses
T131 35-126 Sentence denotes Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency
T132 127-422 Sentence denotes To understand the immunobiology of FcγR effector responses particularly in the therapeutic mAb context, it is important to appreciate that the quality and potency of such effector responses is greatly affected by the nature of the IgG immune complex and/or the state of potential effector cells.
T133 423-566 Sentence denotes First, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response.
T134 567-1241 Sentence denotes Although it is the IgG Fc that interacts with and clusters the FcγR to induce a response, the nature of the Fab interaction with its epitope can strongly influence the likelihood or potency of FcγR effector responses by influencing the density of appropriately presented Fc portions.35 and also the size of the immune complex.36 Furthermore, the display/orientation and geometry of the Fc portions, as a consequence of the fragment antigen‐binding (Fab) interaction with the target epitope, can result in effector responses such as ADCC that differ substantially in potency, presumably because the orientation of the Fc makes FcγR engagement more, or less, accessible.37, 38
T135 1242-1597 Sentence denotes Second, in innate effector cells at rest, the largely linear actin cytoskeleton and the extracellular glycosaminoglycan glycocalyx regulate function by interacting with large glycoproteins, such as CD44, arranging these into ordered “picket” fences.39, 40 These corral receptors, including the FcγRs, and sterically inhibit their interaction with ligands.
T136 1598-2296 Sentence denotes Upon cell activation, cytoskeletal remodeling is associated with the loss of the receptor corrals, allowing FcγRs and other receptors to freely diffuse, engage ligand, cluster and signal.39 The influence of such surface constraints on receptors and effector cell function helps explain some of the observed epitope distance requirements for optimal mAb function,39, 41 which were apparent in a comparative study of ADCC and ADCP.42 ADCC was optimal when the epitope was displayed close, 0.3 nm “flush” or 1.5 nm, to the target membrane where close conjugation of effector and target by the mAb presumably facilitates the delivery of pore‐forming proteins to the target membrane as required by ADCC.
T137 2297-2442 Sentence denotes Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints.
T138 2443-2736 Sentence denotes By contrast, ADCP was poor  when targeting epitopes displayed close or "flush" to the target cell membrane (within ~0.3 nm) but ADCP activity was restored when the epitope was displayed 1.5 nm off the membrane, demonstrating different optimal epitope distance requirements for ADCC and ADCP.42
T139 2737-2932 Sentence denotes Although the action of agonistic/antagonistic mAbs is mechanistically distinct to those eliciting cytotoxicity and ADCP, the distance segregation between target and FcγR+ cells is also important.
T140 2933-3064 Sentence denotes Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44
T141 3065-3309 Sentence denotes Clearly, the effects of immune complex valency, Fc density, presentation and geometry together with FcγR organization in the cell membrane suggest that the development of mAbs to certain targets will be heavily influenced by the context of use.
T142 3310-3426 Sentence denotes Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone.
T143 3427-3647 Sentence denotes A more function‐oriented approach early in mAb selection and development by, for example, application of rapid screening technologies that select for effector potency,34 followed by Fc engineering may be more productive.
T144 3649-3670 Sentence denotes ADCC and phagocytosis
T145 3671-3882 Sentence denotes ADCC and ADCP are the most widely appreciated FcγR‐dependent effector functions (Figure 1a, b) and are, respectively, mediated primarily via  FcγRIIIa on NK cells and professional phagocytes such as macrophages.
T146 3883-4036 Sentence denotes These effector functions, particularly NK cell ADCC, are believed to be major components of the MOA of cytotoxic therapeutic mAbs used in cancer therapy.
T147 4037-4210 Sentence denotes In addition, ADCP can also occur via FcγRIIa and FcγRI,45 but the extent to which cytotoxic anticancer therapeutic mAbs depend on these for their MOA in patients is unclear.
T148 4211-4482 Sentence denotes The improvement in clinical utility of mAbs engineered for selectively increased FcγRIII binding suggests that FcγRIIa and FcγRI may be less important in vivo in cell killing effects but perhaps are more important in other aspects of therapeutic efficacy—discussed later.
T149 4484-4524 Sentence denotes Inhibition of cell activation by FcγRIIb
T150 4525-4649 Sentence denotes FcγRIIb is an immune checkpoint46, 47 and its splice variants are potent modulators of ITAM‐dependent signaling (Figure 1c).
T151 4650-4748 Sentence denotes This modulatory function occurs only when FcγRIIb is coaggregated with an ITAM signaling receptor.
T152 4749-5162 Sentence denotes Thus, B‐cell activation by the binding of the antigen in the immune complex to the BCR is regulated by the simultaneous binding of the Fcs of the immune complex to FcγRIIb1 on the same cell. In innate leukocytes, the activating‐type FcR (i.e. FcγRI, FcγRIIa, FcγRIIc, FcγRIII) and the high‐affinity IgE receptor, FcεRI, and the IgA receptor, FcαRI, are all modulated by immune complex co‐engagement with FcγRIIb2.
T153 5163-5368 Sentence denotes The inhibitory function contributes to the MOA of therapeutic antibodies that target cell‐activating molecules where the target cells also express the inhibitory FcγRIIbs such as the BCR (discussed later).
T154 5369-5567 Sentence denotes Thus, B‐cell activation is modulated by the simulatenous binding of the antigen in the immune complex to the BCR and the binding of the Fcs, also in the immune complex, to FcγRIIB1 on the same cell.
T155 5569-5614 Sentence denotes Sweeping: clearance of small immune complexes
T156 5615-5742 Sentence denotes The removal of immune complexes in humans depends primarily on the complement receptor pathway and to a lesser degree the FcγR.
T157 5743-5880 Sentence denotes Among the FcγRs, it has been widely believed that immune complex removal only occurs by phagocytosis/endocytosis of activating‐type FcγR.
T158 5881-6201 Sentence denotes Surprisingly, the inhibitory FcγRIIb, which lacks intrinsic activating function, plays a major role in clearance, and rapidly “sweeps” away small complexes from the circulation (Figure 1d).48, 49 A major tissue involved in the clearance is likely to be the LSEC, where FcγRIIb is expressed abundantly in mice and humans.
T159 6202-6453 Sentence denotes This role is potentially important in resistance to viruses and toxins but may also be key to optimal performance of therapeutic IgG mAbs whose primary MOA is believed to be only neutralization of soluble macromolecules, for example, cytokines or IgE.
T160 6455-6529 Sentence denotes FcγR uptake of antigen: antibody complexes and shaping the immune response
T161 6530-6592 Sentence denotes Monoclonal antibody therapy is a form of passive immunization.
T162 6593-6914 Sentence denotes Indeed, longer‐term vaccine‐like or vaccinal immunity has been demonstrated in anti‐CD20‐treated mice via FcγRIIa50, 51 and in vitro recall memory responses from CD20‐treated patients.52 Although this is dependent on FcγR and anti‐CD20, the mechanism by which long‐term anti‐tumor response is established remains unclear.
T163 6915-7616 Sentence denotes Nonetheless, the active involvement of FcγR in the enhancement of antigen‐specific immunity by uptake of immune complexes through FcγR is historically well documented in experimental systems where FcγRs bind immune complexes and thereby feed antigens into the antigen‐presentation pathways.53 This has been demonstrated in vivo for small immune complexes via human FcγRI on human antigen‐presenting cells54 and in mice.19 Similarly, the capacity of FcγRIIbs to bind and rapidly internalize antigen–antibody complexes suggests that it too may significantly influence feeding antigens into professional antigen‐presenting cells of hematopoietic origin such as dendritic cells and possibly B lymphocytes.
T164 7617-7901 Sentence denotes Although not a classical major histocompatibility complex‐dependent antigen presentation, FcγRIIb on the stroma‐derived follicular dendritic cells influences antibody immunity by recycling antigen–antibody complexes to the cell surface for presentation of intact antigen to B cells.55
T165 7902-8124 Sentence denotes Although somewhat speculative, FcγRIIb’s rapid internalization/sweeping of complexes by the abundant LSEC, which interact with lymphocytes and can present antigen,56 may have a significant role in shaping immune responses.
T166 8126-8171 Sentence denotes Scaffolding of cell‐bound mAbs by FcγR+ cells
T167 8172-8273 Sentence denotes FcγR‐expressing cells can be critical, but passive, participants in the MOA of some mAbs (Figure 1e).
T168 8274-8486 Sentence denotes In FcγR scaffolding, IgG mAb molecules that have opsonized the cell surface of a target cell are additionally cross‐linked by their Fc portions engaging the FcγRs that are arrayed on the surface of a second cell.
T169 8487-8699 Sentence denotes This “super‐cross‐linking” of the target‐bound mAb by the FcγR lattice or “scaffold” on the adjacent cell greatly exceeds the target cross‐linking by the mAb alone, thereby inducing a response in the target cell.
T170 8700-9293 Sentence denotes Scaffolding was originally identified as the basis of T‐cell mitogenesis induced by anti‐CD3 mAb.57, 58 The CD3 mAbs alone were poor mitogens but the “super‐cross‐linking” of the T‐cell‐bound CD3 mAb by the membrane FcγR on adjacent cells, particularly by monocytes, induced rapid T‐cell expansion and cytokine secretion but did not require activation of FcγR‐expressing cells.57 Regrettably, FcγR scaffolding came to prominence and clinical relevance because of its causal role in the catastrophic adverse events resulting from the administration of anti‐CD357 and anti‐CD28 (TGN1412)59 mAbs.
T171 9294-9429 Sentence denotes Nonetheless, FcγR scaffold‐based induction of intracellular responses in a target cell can also lead to beneficial therapeutic effects.
T172 9430-9652 Sentence denotes Such examples are the induction of apoptotic death in a target cell, which is likely part of the MOA of daratumumab in multiple myeloma60 or the controlled agonistic expansion of cells, for example, via CD40 mAb agonism.43
T173 9654-9703 Sentence denotes IgG subclasses: specificity and affinity for FcγR
T174 9704-9927 Sentence denotes Most FcγRs (Table 2) are weak, low‐affinity receptors (affinities in the micromolar range) for IgG‐Fc, irrespective of whether the IgG is uncomplexed, monomeric or when it is complexed with antigen (i.e. an immune complex).
T175 9928-10169 Sentence denotes The very avid binding of immune complexes to an effector cell surface that displays an array of FcγR molecules is the result of the collective contributions of the low‐affinity interactions of each Fc of the IgGs in the complex with an FcγR.
T176 10170-10322 Sentence denotes This avidity effect is necessary as the FcγRs operate in vivo in environments of high concentrations of uncomplexed monomeric IgG (normally 3–12 g L–1).
T177 10323-10413 Sentence denotes Thus, the avid multivalent binding of the complex out competes uncomplexed, monomeric IgG.
T178 10414-10467 Sentence denotes The notable exception to this is the enigmatic FcγRI.
T179 10468-10644 Sentence denotes This receptor shows high, nanomolar affinity for uncomplexed monomeric IgG and thus would be expected to be constantly occupied in vivo by the normal circulating monomeric IgG.
T180 10645-10712 Sentence denotes However, IgG dissociation permits engagement with immune complexes.
T181 10713-10879 Sentence denotes Furthermore, FcγRI is not expressed or expressed poorly on resting cells, requiring interferon‐γ for induction of its expression, presumably at sites of inflammation.
T182 10880-11061 Sentence denotes Although the human IgG heavy‐chain constant domains have greater than 90% identity, key amino acid differences confer each subclass with unique structural and functional properties.
T183 11062-11133 Sentence denotes IgG1 and IgG3 are “universal” ligands, that is, they bind to all FcγRs.
T184 11134-11456 Sentence denotes Formal measurement of the weak, micromolar KD interactions of the low‐affinity receptors with monomeric IgG1 also revealed differing affinities between the low‐affinity FcγRs, with inhibitory FcγRIIb generally having the lowest affinity and FcγRIII the higher, sometimes referred to as a “moderate” affinity receptor.7, 61
T185 11457-11620 Sentence denotes The strength of IgG1 interaction can also be affected by FcγR polymorphism and in the context of therapeutic mAbs, variation in FcγRIIIa is particularly important.
T186 11621-11832 Sentence denotes The most common and possibly clinically significant polymorphism is phenylalanine/valine variation at position 158 in the IgG‐binding site, wherein FcγRIIIa‐F158 binds IgG1 less well than the FcγRIIIa‐V158 form.
T187 11833-11885 Sentence denotes IgG4 and IgG2 have more restricted FcγR specificity.
T188 11886-12023 Sentence denotes IgG4 has low affinity (KA = ~2 × 105 m –1) for the inhibitory FcγRIIb, but is also a high‐affinity ligand for FcγRI (KA = ~4 × 108 m –1).
T189 12024-12269 Sentence denotes IgG2 exhibits a highly restricted specificity, showing functional activity with only one polymorphic form of FcγRIIa (binding affinity KA = ~4.5 × 105 m –1) which is permitted by the presence of histidine at position 131 of its IgG‐binding site.
T190 12270-12480 Sentence denotes This FcγRIIa–H131 form is expressed in approximately 70% of the population, whereas IgG2 has no functional activity on the other common allelic form, FcγRIIa‐R131, which contains arginine at position 131.11, 61