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LitCovid-PubTator

LitCovid-PD-FMA-UBERON

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T15","span":{"begin":2196,"end":2200},"obj":"Body_part"},{"id":"T16","span":{"begin":2331,"end":2335},"obj":"Body_part"}],"attributes":[{"id":"A15","pred":"uberon_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/UBERON_0008915"},{"id":"A16","pred":"uberon_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/UBERON_0008915"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-sample-PD-IDO

{"project":"LitCovid-sample-PD-IDO","denotations":[{"id":"T132","span":{"begin":235,"end":242},"obj":"http://purl.obolibrary.org/obo/BFO_0000019"},{"id":"T133","span":{"begin":381,"end":386},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T134","span":{"begin":1234,"end":1239},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T135","span":{"begin":1347,"end":1355},"obj":"http://purl.obolibrary.org/obo/BFO_0000034"},{"id":"T136","span":{"begin":1568,"end":1572},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T137","span":{"begin":1821,"end":1825},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T138","span":{"begin":1826,"end":1834},"obj":"http://purl.obolibrary.org/obo/BFO_0000034"},{"id":"T139","span":{"begin":1916,"end":1924},"obj":"http://purl.obolibrary.org/obo/BFO_0000034"},{"id":"T140","span":{"begin":2501,"end":2505},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T141","span":{"begin":2873,"end":2878},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T142","span":{"begin":2981,"end":2989},"obj":"http://purl.obolibrary.org/obo/BFO_0000034"},{"id":"T143","span":{"begin":3135,"end":3147},"obj":"http://purl.obolibrary.org/obo/OBI_0100026"},{"id":"T144","span":{"begin":3155,"end":3159},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T145","span":{"begin":3399,"end":3407},"obj":"http://purl.obolibrary.org/obo/BFO_0000034"},{"id":"T146","span":{"begin":3601,"end":3611},"obj":"http://purl.obolibrary.org/obo/IDO_0000607"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-sample-CHEBI

{"project":"LitCovid-sample-CHEBI","denotations":[{"id":"T23","span":{"begin":1309,"end":1326},"obj":"Chemical"},{"id":"T24","span":{"begin":1382,"end":1395},"obj":"Chemical"},{"id":"T25","span":{"begin":2209,"end":2217},"obj":"Chemical"},{"id":"T26","span":{"begin":2344,"end":2352},"obj":"Chemical"},{"id":"T27","span":{"begin":3359,"end":3370},"obj":"Chemical"}],"attributes":[{"id":"A23","pred":"chebi_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/CHEBI_18085"},{"id":"A24","pred":"chebi_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/CHEBI_17089"},{"id":"A25","pred":"chebi_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A26","pred":"chebi_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A27","pred":"chebi_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/CHEBI_15841"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-sample-Pubtator

LitCovid-sample-sentences

{"project":"LitCovid-sample-sentences","denotations":[{"id":"T131","span":{"begin":0,"end":91},"obj":"Sentence"},{"id":"T132","span":{"begin":92,"end":387},"obj":"Sentence"},{"id":"T133","span":{"begin":388,"end":531},"obj":"Sentence"},{"id":"T134","span":{"begin":532,"end":1206},"obj":"Sentence"},{"id":"T135","span":{"begin":1207,"end":1562},"obj":"Sentence"},{"id":"T136","span":{"begin":1563,"end":2261},"obj":"Sentence"},{"id":"T137","span":{"begin":2262,"end":2407},"obj":"Sentence"},{"id":"T138","span":{"begin":2408,"end":2701},"obj":"Sentence"},{"id":"T139","span":{"begin":2702,"end":2897},"obj":"Sentence"},{"id":"T140","span":{"begin":2898,"end":3029},"obj":"Sentence"},{"id":"T141","span":{"begin":3030,"end":3274},"obj":"Sentence"},{"id":"T142","span":{"begin":3275,"end":3391},"obj":"Sentence"},{"id":"T143","span":{"begin":3392,"end":3612},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-sample-PD-UBERON

{"project":"LitCovid-sample-PD-UBERON","denotations":[{"id":"T15","span":{"begin":2196,"end":2200},"obj":"Body_part"},{"id":"T16","span":{"begin":2331,"end":2335},"obj":"Body_part"}],"attributes":[{"id":"A15","pred":"uberon_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/UBERON_0008915"},{"id":"A16","pred":"uberon_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/UBERON_0008915"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-sample-UniProt

LitCovid-sample-PD-FMA

LitCovid-sample-PD-MAT

{"project":"LitCovid-sample-PD-MAT","denotations":[{"id":"T10","span":{"begin":2919,"end":2927},"obj":"http://purl.obolibrary.org/obo/MAT_0000491"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-sample-PD-GO-BP-0

{"project":"LitCovid-sample-PD-GO-BP-0","denotations":[{"id":"T53","span":{"begin":395,"end":407},"obj":"http://purl.obolibrary.org/obo/GO_0008228"},{"id":"T54","span":{"begin":1064,"end":1068},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T55","span":{"begin":1568,"end":1583},"obj":"http://purl.obolibrary.org/obo/GO_0001775"},{"id":"T56","span":{"begin":1723,"end":1738},"obj":"http://purl.obolibrary.org/obo/GO_1990256"},{"id":"T57","span":{"begin":1978,"end":1982},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T58","span":{"begin":1995,"end":1999},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T59","span":{"begin":2111,"end":2122},"obj":"http://purl.obolibrary.org/obo/GO_0000746"},{"id":"T60","span":{"begin":2256,"end":2260},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T61","span":{"begin":2277,"end":2310},"obj":"http://purl.obolibrary.org/obo/GO_0097278"},{"id":"T62","span":{"begin":2685,"end":2689},"obj":"http://purl.obolibrary.org/obo/GO_0001788"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-sample-GO-BP

{"project":"LitCovid-sample-GO-BP","denotations":[{"id":"T53","span":{"begin":395,"end":407},"obj":"http://purl.obolibrary.org/obo/GO_0008228"},{"id":"T54","span":{"begin":1064,"end":1068},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T55","span":{"begin":1568,"end":1583},"obj":"http://purl.obolibrary.org/obo/GO_0001775"},{"id":"T56","span":{"begin":1723,"end":1738},"obj":"http://purl.obolibrary.org/obo/GO_1990256"},{"id":"T57","span":{"begin":1978,"end":1982},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T58","span":{"begin":1995,"end":1999},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T59","span":{"begin":2111,"end":2122},"obj":"http://purl.obolibrary.org/obo/GO_0000746"},{"id":"T60","span":{"begin":2256,"end":2260},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T61","span":{"begin":2277,"end":2310},"obj":"http://purl.obolibrary.org/obo/GO_0097278"},{"id":"T62","span":{"begin":2685,"end":2689},"obj":"http://purl.obolibrary.org/obo/GO_0001788"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T53","span":{"begin":395,"end":407},"obj":"http://purl.obolibrary.org/obo/GO_0008228"},{"id":"T54","span":{"begin":1064,"end":1068},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T55","span":{"begin":1568,"end":1583},"obj":"http://purl.obolibrary.org/obo/GO_0001775"},{"id":"T56","span":{"begin":1723,"end":1738},"obj":"http://purl.obolibrary.org/obo/GO_1990256"},{"id":"T57","span":{"begin":1978,"end":1982},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T58","span":{"begin":1995,"end":1999},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T59","span":{"begin":2111,"end":2122},"obj":"http://purl.obolibrary.org/obo/GO_0000746"},{"id":"T60","span":{"begin":2256,"end":2260},"obj":"http://purl.obolibrary.org/obo/GO_0001788"},{"id":"T61","span":{"begin":2277,"end":2310},"obj":"http://purl.obolibrary.org/obo/GO_0097278"},{"id":"T62","span":{"begin":2685,"end":2689},"obj":"http://purl.obolibrary.org/obo/GO_0001788"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

LitCovid-sentences

{"project":"LitCovid-sentences","denotations":[{"id":"T131","span":{"begin":0,"end":91},"obj":"Sentence"},{"id":"T132","span":{"begin":92,"end":387},"obj":"Sentence"},{"id":"T133","span":{"begin":388,"end":531},"obj":"Sentence"},{"id":"T134","span":{"begin":532,"end":1206},"obj":"Sentence"},{"id":"T135","span":{"begin":1207,"end":1562},"obj":"Sentence"},{"id":"T136","span":{"begin":1563,"end":2261},"obj":"Sentence"},{"id":"T137","span":{"begin":2262,"end":2407},"obj":"Sentence"},{"id":"T138","span":{"begin":2408,"end":2701},"obj":"Sentence"},{"id":"T139","span":{"begin":2702,"end":2897},"obj":"Sentence"},{"id":"T140","span":{"begin":2898,"end":3029},"obj":"Sentence"},{"id":"T141","span":{"begin":3030,"end":3274},"obj":"Sentence"},{"id":"T142","span":{"begin":3275,"end":3391},"obj":"Sentence"},{"id":"T143","span":{"begin":3392,"end":3612},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Not all opsonized targets are equal: size, distance, valency and Fc geometry affect potency\nTo 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.\nFirst, opsonization, per se, of a target is not necessarily sufficient to ensure FcγR interaction in a way that initiates an effector response. 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\nSecond, 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. 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. Interestingly, complement‐dependent cytotoxicity which also utilizes pore‐forming proteins for its cytotoxicity has similar distance constraints. 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\nAlthough 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. Indeed, the membrane proximal epitopes of CD28 and CD40 are important for the FcγR function in the complex MOA of these mAbs.43, 44\nClearly, 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. Thus, improved mAb potency may not necessarily be achieved by engineering of the Fc polypeptide or its glycan alone. 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."}

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