LitCovid-sample-sentences  

PMC:7228307 / 40050-49159 JSONTXT 25 Projects

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Id Subject Object Predicate Lexical cue
T225 0-51 Sentence denotes Fc engineering for enhanced anticancer therapeutics
T226 52-231 Sentence denotes IgG1 is the predominant subclass used in the development of cytotoxic mAbs where induction of an activation‐type response, ADCC or phagocytosis, is considered desirable.45, 76, 77
T227 232-324 Sentence denotes Cytotoxic mAb cancer therapeutics can control disease progression by one or more mechanisms.
T228 325-481 Sentence denotes Their MOAs include direct induction of apoptotic cell death of the cancer cell (anti‐CD20, anti‐CD52) or blocking receptor signaling (anti‐HER2, anti‐EGFR).
T229 482-894 Sentence denotes They may also harness FcγR effector functions, including ADCC in the tumor microenvironment.78 The approved mAbs, rituximab (anti‐CD20), trastuzumab (anti‐HER2) and cetuximab (anti‐EGFR), are formatted on a human IgG1 backbone and all require activating‐type FcγR engagement for optimal therapeutic activity.79, 80 This presents an example where context of therapeutic use is critical for therapeutic mAb design.
T230 895-984 Sentence denotes IgG1 antibodies bind both the activating FcγR (e.g. FcγRIIIa) and the inhibitory FcγRIIb.
T231 985-1134 Sentence denotes In some environments effector cells will coexpress FcγRIIb together with FcγRI, FcγRIIa and FcγIIIa, as may occur on a tumor‐infiltrating macrophage.
T232 1135-1391 Sentence denotes Therapy with an IgG1 anti‐cancer cell mAb may then be compromised by the inhibitory action of FcγRIIb upon the ITAM signaling of the activating FcγR as both types of receptor would be coengaged on  such an effector cell by the mAb bound to the target cell.
T233 1392-1438 Sentence denotes This leads to reduced therapeutic mAb potency.
T234 1439-1888 Sentence denotes Thus, the relative contributions of the activating (A) and inhibitory (I) FcγR to the response by an effector cell, the A‐to‐I ratio, may be an important determinant in clinical outcome of therapeutic mAb activity,76, 81, 82 that is, the higher the A‐to‐I ratio, the greater the proinflammatory response induced by the therapeutic mAb or conversely the lower the A‐to‐I ratio, the greater the inhibition or dampening of the proinflammatory response.
T235 1889-2000 Sentence denotes Thus, the challenge for the development of more potent FcγR effector mAbs is to overcome three major obstacles.
T236 2001-2193 Sentence denotes First, improving activation potency by selectively enhancing interaction with activating‐type FcγR, particularly FcγRIIIa owing to its predominant role in ADCC‐mediated killing of tumor cells.
T237 2194-2260 Sentence denotes Second, reducing binding interactions with the inhibitory FcγRIIb.
T238 2261-2335 Sentence denotes These two approaches improve the FcγR A‐to‐I ratio of cytotoxic IgG1 mAbs.
T239 2336-2606 Sentence denotes Third, overcoming the significant affinity difference in the interaction with the main FcγRIII allelic forms of FcγRIIIa‐V158 and FcγRIIIa‐F158 76, 83, 84 which appears to be an important source of patient variability in responses to therapeutic mAb treatment of cancer.
T240 2607-2692 Sentence denotes At the time of writing, some mAbs with improved potency are coming into clinical use.
T241 2693-2825 Sentence denotes Their improved action has been achieved by modifying the N‐linked glycan or the amino acid sequence of the heavy‐chain Fc (Table 4).
T242 2826-2932 Sentence denotes Table 4 Fc or hinge‐engineered monoclonal antibodies (mAbs) approved or in advanced clinical development.
T243 2933-3042 Sentence denotes mAb name Target IgG backbone Fc modification Effect on mAb Therapy area Most advanced development stage
T244 3043-3147 Sentence denotes Andecaliximab Matrix Metalloproteinase 9 (MMP9) IgG4 S228P Stabilize core hinge Oncology Phase III
T245 3148-3308 Sentence denotes Anifrolumab Interferon alpha/beta receptor 1 IgG1 L234F; L235E; P331S Mimic IgG4 hinge and its CH2/F/G loop; plus ablate FcγR binding Immunology Phase III
T246 3309-3398 Sentence denotes Atezolizumab PD‐L1 IgG1 Aglycosylated (N297A) Ablate FcγR binding Oncology Marketed
T247 3399-3592 Sentence denotes Benralizumab Interleukin 5 IgG1 Afucosylated Selectively enhance FcγRIII interaction Respiratory dermatology; ear nose throat disorders; gastrointestinal; hematology; immunology; Marketed
T248 3593-3722 Sentence denotes Durvalumab PD‐L1 IgG1 L234F; L235E; P331S Mimic IgG4 hinge and its CH2 F/G loop; plus ablate FcγR binding Oncology Marketed
T249 3723-3832 Sentence denotes Evinacumab Angiopoietin‐related protein 3 IgG4 S228P Stabilize core hinge Metabolic disorders Phase III
T250 3833-3957 Sentence denotes Inebilizumab CD19 IgG1 Afucosylated Selectively enhance FcγRIII interaction Central nervous system; oncology Phase III
T251 3958-4082 Sentence denotes Ixekizumab Interleukin 17A IgG4 S228P Stabilize core hinge Dermatology; immunology; musculoskeletal disorders Marketed
T252 4083-4204 Sentence denotes Margetuximab HER2 IgG1 F243L; L235V; R292P; Y300L; P396L Selectively enhance FcγRIII interaction Oncology Phase III
T253 4205-4361 Sentence denotes Mogamulizumab C–C chemokine receptor type 4 (CCR4) IgG1 Afucosylated Selectively enhance FcγRIII interaction Central nervous system; oncology Marketed
T254 4362-4480 Sentence denotes Tafasitamab (MOR208 XmAb 5574) CD19 IgG1 S239D; I332E Selectively enhance FcγRIII interaction Oncology Phase III
T255 4481-4571 Sentence denotes Nivolumab PD‐1 IgG4 S228P Stabilize core hinge Infectious disease; oncology Marketed
T256 4572-4683 Sentence denotes Obinutuzumab CD20 IgG1 Afucosylated Selectively enhance FcγRIII interaction Immunology; oncology Marketed
T257 4684-4784 Sentence denotes Ocaratuzumab CD20 IgG1 P247I; A339Q Selectively enhance FcγRIII interaction Oncology Phase III
T258 4785-4870 Sentence denotes Pembrolizumab PD‐1 IgG4 S228P Stabilize core hinge Infection; oncology Marketed
T259 4871-4987 Sentence denotes Roledumab Rhesus D IgG1 Afucosylated Selectively enhance FcγRIII interaction Hematological disorders Phase III
T260 4988-5100 Sentence denotes Spesolimab (BI‐655130) IL‐36R IgG1 L234A; L235A Ablate FcγR binding Gastrointestinal; immunology Phase III
T261 5101-5188 Sentence denotes Teplizumab CD3 IgG1 L234A; L235A Ablate FcγR binding Metabolic disorders Phase II
T262 5189-5409 Sentence denotes Tislelizumab PD‐1 IgG4 S228P; E233P; F234V; L235A; D265A; L309V; R409K Stabilize core hinge; mimic IgG2 lower hinge for restricted FcγR specificity; ablate FcγR binding; stabilize CH3 interaction Oncology Phase III
T263 5410-5492 Sentence denotes Toripalimab (JS 001) PD‐1 IgG4 S228P Stabilize core hinge Oncology Phase III
T264 5493-5616 Sentence denotes Ublituximab CD20 IgG1 Afucosylated Selectively enhance FcγRIII interaction Central nervous system; oncology Phase III
T265 5617-5636 Sentence denotes Ig, immunoglobulin.
T266 5637-5784 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.
T267 5785-5967 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.
T268 5969-5998 Sentence denotes Modification of the Fc glycan
T269 5999-6279 Sentence denotes The typical complex N‐linked glycan attached to N297 of the heavy chain includes a core fucose.85 Antibodies that lack this fucose have approximately 50‐fold improved binding to FcγRIIIa and FcγRIIIb and importantly retain the weak, low‐affinity binding to the inhibitory FcγRIIb.
T270 6280-6654 Sentence denotes Furthermore, this glycoengineering increased binding affinity of the modified IgG1 mAb for both FcγRIIIa V158 and F158 allelotypes.86, 87, 88 Afucosyl versions of the tumor targeting mAbs such as anti‐HER2, anti‐EGFR and anti‐CD20 had greater antitumor effects and increased survival,68, 88, 89 which is a reflection of the greatly increased, and selective, FcγRIII binding.
T271 6655-6980 Sentence denotes Compared with their unmodified counterparts, the afucosyl mAbs showed dramatic improvement of FcγRIII‐related effector responses such as stronger NK cell‐mediated ADCC, or enhanced neutrophil‐mediated phagocytosis through FcγRIIIb and/or FcγRIIIa.23 However, certain neutrophil functions via FcγRIIa may be compromised.90, 91
T272 6981-7085 Sentence denotes There are six afucosylated antibodies in late‐stage clinical trials or approved for treatment (Table 4).
T273 7086-7436 Sentence denotes Notable is obinutuzumab, an afucosyl anti‐CD20 mAb which nearly doubles progression‐free survival in chronic lymphocytic leukemia patients as compared with the fucose‐containing rituximab.68 This dramatic improvement in clinical utility reinforces the value of glycan engineering specifically and of Fc engineering generally in anticancer treatments.
T274 7438-7468 Sentence denotes Mutation of the Fc amino acids
T275 7469-7581 Sentence denotes Alteration of the amino acids in the heavy‐chain Fc can alter IgG specificity and affinity for activating FcγRs.
T276 7582-7862 Sentence denotes The anti‐CD19 antibody MOR208 (XmAb 5574) is currently in phase III trials for the treatment of chronic lymphocytic leukemia.92 It contains two mutations in its IgG1 Fc, S329D and I332E, which increases affinity to FcγRIIIa, particularly the “lower‐affinity” FcγRIIIa F158 allele.
T277 7863-7980 Sentence denotes The mAb shows increased FcγRIII‐mediated ADCC and phagocytosis in vitro, and reduced lymphoma growth in mouse models.
T278 7981-8360 Sentence denotes Margetuximab is an ADCC‐enhanced IgG1 Fc‐engineered variant of the approved anti‐HER2 mAb trastuzumab in phase III for HER2‐expressing cancers.66, 93 Alteration of five amino acids (L235V, F243L, R292P, Y300L and P396L) enhanced binding to FcγRIIIa which also had the additional effect of decreasing binding to the inhibitory FcγRIIb, and thereby increased its A‐to‐I FcγR ratio.
T279 8361-8575 Sentence denotes This was apparent when compared with unmodified trastuzumab the  margetuximab showed enhanced ADCC against HER2+ cells in vitro and demonstrated superior antitumor effects in an HER2‐expressing tumor model in mice.
T280 8576-8947 Sentence denotes The anti‐CD20 ocaratuzumab is an Fc‐engineered IgG1 mAb in late‐stage clinical trials for the treatment of a range of cancers, including non‐Hodgkin lymphoma and chronic lymphocytic leukemia.94 Two Fc mutations, P247I and A339Q, conferred about 20‐fold increase in binding to both major allelic variants of FcγRIIIa and elicited sixfold greater ADCC than unmodified IgG1.
T281 8948-9109 Sentence denotes Thus, the engineering of the Fc domain or glycan for improved FcγRIIIa binding is a powerful tool to create more potent and clinically effective anticancer mAbs.