LitCovid-sentences  

PMC:7228307 / 49161-54061 JSONTXT 19 Projects

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Id Subject Object Predicate Lexical cue
T282 0-54 Sentence denotes Attenuating and ablating FcγR‐related functions of IgG
T283 55-163 Sentence denotes There are circumstances where binding to FcγR is unnecessary or undesirable in the MOA of a therapeutic mAb.
T284 164-501 Sentence denotes Unmodified IgG irrespective of its subclass or intended therapeutic effect has the potential to engage an FcγR which may lead to suboptimal therapeutic performance or to unexpected and catastrophic consequences.57, 59 Clearly reducing or eliminating FcγR interactions, when they are not required for therapeutic effect, may be desirable.
T285 502-594 Sentence denotes Indeed, this had been addressed by the choice of IgG subclass or by modifying the Fc region.
T286 595-756 Sentence denotes Indeed, most efforts in Fc engineering mAbs that have translated to an approved drug have focused on the reduction or elimination of FcγR interactions (Table 4).
T287 757-1024 Sentence denotes One approach to minimize interactions with the activating FcγR has been the use of IgG4 or IgG2 backbones, which show a more restricted specificity for the activating FcγR and consequently have been traditionally, and simplistically, viewed as “inert” IgG subclasses.
T288 1025-1206 Sentence denotes Notwithstanding the unexpected, and FcγR‐dependent, severe adverse reaction induced by the IgG4 TGN1412 mAb, the IgG4 or IgG2 backbones have been successfully used in many settings.
T289 1207-1441 Sentence denotes Indeed, checkpoint inhibitors, such as mAbs targeting CTLA‐4 or the PD‐L1/PD‐1 interaction for the suppression of inhibitory signals that contribute to immune tolerance in the tumor microenvironment, are formatted on an IgG4 backbone.
T290 1442-1666 Sentence denotes Pembrolizumab, nivolumab and cemiplimab are all anti‐PD‐1 antibodies currently used for cancer therapy and have been formatted on an IgG4 backbone95, 96, 97 with a stabilized core hinge (S228P) to prevent half‐IgG4 exchange.
T291 1667-1823 Sentence denotes Similarly, the checkpoint inhibitor tremelimumab is an anti‐CTLA‐4 antibody formatted on an IgG2 backbone to avoid potential ADCC killing of target cells.98
T292 1824-1895 Sentence denotes However, the use of IgG2 and IgG4 as “inert” subclasses is problematic.
T293 1896-2291 Sentence denotes Both bind to the activating receptors FcγRIIa‐H131 and FcγRI, respectively (Table 2), and initiate effector functions such as neutrophil activation and apoptosis induction.75, 99 Interestingly, in experimental systems, cross‐linking of anti‐PD‐1 IgG4‐based mAb by FcγRI switched its activity from blocking to activatory.10 Moreover, IgG4 binds to FcγRIIb, which may scaffold the therapeutic mAb.
T294 2292-2609 Sentence denotes Although scaffolding may be beneficial in some contexts, for example, in immune agonism,43 it can be disastrous and unexpected in others as it was for the anti‐CD28 TGN1412 mAb.59 Thus, the IgG2 and IgG4 subclasses are not the optimum choice for “FcR‐inactive” mAbs, and so modifying the Fc is a more direct approach.
T295 2610-2904 Sentence denotes The complete removal of the heavy‐chain N‐linked glycan is well known to ablate all FcγR binding by dramatically altering the Fc conformation.36, 67, 101, 102 Atezolizumab, an IgG1 anti‐PD‐L1 checkpoint inhibitor mAb, utilizes this strategy and eliminates FcγR and also complement activation.13
T296 2905-3016 Sentence denotes Modification to the Fc amino acid sequence of the FcγR‐contact regions can also be used to reduce FcγR binding.
T297 3017-3172 Sentence denotes A widely used modification of IgG1 is the substitution of leucine 234 and 235 in the lower hinge sequence (L234 L235 G236 G237) with alanine (L234A L235A).
T298 3173-3341 Sentence denotes It is often referred to as the “LALA mutation” and effectively eliminates FcγR binding by more than 100 fold104, 105 and is used in teplizumab and spesolimab (Table 4).
T299 3342-3546 Sentence denotes A separate strategy has used combinations of amino acid residues from the FcγR‐binding regions of IgG2 and IgG4, which have restricted FcγR specificity, together with other binding‐inactivating mutations.
T300 3547-3725 Sentence denotes The lower hinge amino acids of the IgG1 mAbs durvalumab (anti‐PD‐L1) and anifrolumab (anti‐interferon‐α receptor; Table 4) were modified to mimic the lower hinge of IgG4 (L234F).
T301 3726-3943 Sentence denotes They additionally incorporated L235E in the lower hinge and P331S in the F/G loop of the CH2 domain to ablate FcγR binding by disrupting two major FcγR contact sites7 and also coincidently decreasing C1q activation.16
T302 3944-4039 Sentence denotes IgG4 mAbs have been similarly engineered to eliminate their interaction with FcγRI and FcγRIIb.
T303 4040-4314 Sentence denotes The IgG4 anti‐PD‐1 antibody tislelizumab has had its FcγR contact residues in the lower hinge E233, F234, L235 substituted with the equivalent residues of IgG2 P, V, A (E233P, F234V, L235A) as well as the additional D265A mutation which disrupts a major FcγR contact in CH2.
T304 4315-4532 Sentence denotes It also has substitutions in the core hinge S228P and the CH3 L309V and R409K to stabilize the H‐chain disulfides and CH3 interactions, respectively, thereby preventing half‐Ig exchange characteristic of natural IgG4.
T305 4533-4637 Sentence denotes Collectively, these modifications create a stable IgG4 with no FcγR binding nor complement activation.17
T306 4638-4900 Sentence denotes Thus, Fc engineering is an effective way to remove FcγR effector functions and may be preferable to using unmodified IgG2 or IgG4 backbones that have a more restricted repertoire of FcγR interactions but which are still able to induce certain effector functions.