Role of N-Glycosylation in FcγRIIIa interaction with IgG

Coillie, Julie Van; Schultz, Morten A.; Bentlage, Arthur E. H.; Haan, Noortje de; Ye, Zilu; Geerdes, Dionne M; Esch, Wim J. E. van; Hafkenscheid, Lise; Miller, Rebecca L.; Narimatsu, Yoshiki; Vakhrushev, Sergey Y.; Yang, Zifeng; Vidarsson, Gestur; Clausen, Henrik

doi:10.3389/fimmu.2022.987151

Cited by 24 publications

(13 citation statements)

References 79 publications

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“…This N162 glycan can only be sterically accommodated in the IgG-Fc in the absence of the core fucose ( 17 , 19 , 49 ). Interestingly, marked differences in the glycosylation of FcγRs in vivo have recently been reported ( 50 , 51 ), which have a slight modifying effect on the affinity towards IgG glycoforms ( 51 , 52 ).…”

Section: Discussionmentioning

confidence: 99%

Cellular surface plasmon resonance-based detection of anti-HPA-1a antibody glycosylation in fetal and neonatal alloimmune thrombocytopenia

Szittner,

Bentlage,

Temming

et al. 2023

Front. Immunol.

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Fetal and neonatal alloimmune thrombocytopenia (FNAIT) can occur due to maternal IgG antibodies targeting platelet antigens, causing life-threatening bleeding in the neonate. However, the disease manifests itself in only a fraction of pregnancies, most commonly with anti-HPA-1a antibodies. We found that in particular, the core fucosylation in the IgG-Fc tail is highly variable in anti-HPA-1a IgG, which strongly influences the binding to leukocyte IgG-Fc receptors IIIa/b (FcγRIIIa/b). Currently, gold-standard IgG-glycoanalytics rely on complicated methods (e.g., mass spectrometry (MS)) that are not suited for diagnostic purposes. Our aim was to provide a simplified method to quantify the biological activity of IgG antibodies targeting cells. We developed a cellular surface plasmon resonance imaging (cSPRi) technique based on FcγRIII-binding to IgG-opsonized cells and compared the results with MS. The strength of platelet binding to FcγR was monitored under flow using both WT FcγRIIIa (sensitive to Fc glycosylation status) and mutant FcγRIIIa-N162A (insensitive to Fc glycosylation status). The quality of the anti-HPA-1a glycosylation was monitored as the ratio of binding signals from the WT versus FcγRIIIa-N162A, using glycoengineered recombinant anti-platelet HPA-1a as a standard. The method was validated with 143 plasma samples with anti-HPA-1a antibodies analyzed by MS with known clinical outcomes and tested for validation of the method. The ratio of patient signal from the WT versus FcγRIIIa-N162A correlated with the fucosylation of the HPA-1a antibodies measured by MS (r=-0.52). Significantly, FNAIT disease severity based on Buchanan bleeding score was similarly discriminated against by MS and cSPRi. In conclusion, the use of IgG receptors, in this case, FcγRIIIa, on SPR chips can yield quantitative and qualitative information on platelet-bound anti-HPA-1a antibodies. Using opsonized cells in this manner circumvents the need for purification of specific antibodies and laborious MS analysis to obtain qualitative antibody traits such as IgG fucosylation, for which no clinical test is currently available.

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Section: Discussionmentioning

confidence: 99%

Cellular surface plasmon resonance-based detection of anti-HPA-1a antibody glycosylation in fetal and neonatal alloimmune thrombocytopenia

Szittner,

Bentlage,

Temming

et al. 2023

Front. Immunol.

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“…Glycosylation is among the most common PTM that can induce tremendous effects on the physicochemical properties, structure, and function of mAbs therapeutic efficiency 17 . The glycoprofile can affect the absorption distribution metabolization elimination (ADME) properties and the biosimilarity of the glycoprotein-based drugs by altering the PK profile 18 , receptor binding, and antibody dependent cell cytotoxicity (ADCC) 19 . Currently, MS-based techniques are widely used for the analysis of mAb heterogeneity of glycosylation 20,21 .…”

Section: Glycoprofiles and Post Translational Modifications (Ptms)mentioning

confidence: 99%

Clinical validation of pneumatic transportation systems for monoclonal antibodies

Coliat

Erb

Diemer

et al. 2023

Preprint

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Pneumatic transportation systems (PTS) were recently proposed as a method to carry ready-for-injection diluted monoclonal antibodies (mAbs) from the pharmacy to the bedside of patients. This method reduces transportation time and improves the efficiency of drug distribution process. However, mAbs are highly sensitive molecules for which subtle alterations may lead to deleterious clinical effects. These alterations can be caused by various external factors such as temperature, pH, pressure, and mechanical forces that may occur during transportation. Hence, it is essential to ensure that the mAbs transported by PTS remain stable and active throughout the transportation process. This study aims to determine the safety profile of PTS to transport 11 routinely used mAbs in a clinical setting through assessment of critical quality attributes (CQA) and orthogonal analysis. Hence, we performed aggregation/degradation profiling, post-translational modifications identification using complementary mass spectrometry-based methods, along with visible and subvisible particle formation determination by light absorbance and dynamic light scattering measurements. Altogether, these results highlight that PTS can be safely used for this purpose when air is removed from the bags during preparation.

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“…The activation of NK cells is tightly regulated by the balance of signals from inhibitory and activating receptors, which is controlled by multiple lineage-encoded receptors that enable these cells to sense and respond rapidly to changes in their environment ( 49 , 50 ). N-Glycosylation of FcγRIII also affects receptor interactions with IgG, which has led to studies of antibody engineering with greatly improved ADCC activities ( 51 ). Recombinant cytokines, agonists that promote activation receptors, and antibodies that block inhibitory receptors can be used to enhance ADCC ( 52 , 53 ).…”

Section: Regulatory Mechanisms and Research Strategies Of Nk Cells An...mentioning

confidence: 99%

Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

Liu

2022

Front. Immunol.

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Human epidermal growth factor receptor 2 (HER2)-positive breast cancer has a high metastatic potential. Monoclonal antibodies (mAbs) that target HER2, such as trastuzumab and pertuzumab, are the cornerstone of adjuvant therapy for HER2-positive breast cancer. A growing body of preclinical and clinical evidence points to the importance of innate immunity mediated by antibody-dependent cellular cytotoxicity (ADCC) in the clinical effect of mAbs on the resulting anti-tumor response. In this review, we provide an overview of the role of natural killer (NK) cells and ADCC in targeted therapy of HER2-positive breast cancer, including the biological functions of NK cells and the role of NK cells and ADCC in anti-HER2 targeted drugs. We then discuss regulatory mechanisms and recent strategies to leverage our knowledge of NK cells and ADCC as an immunotherapy approach for HER2-positive breast cancer.

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Role of N-Glycosylation in FcγRIIIa interaction with IgG

Cited by 24 publications

References 79 publications

Cellular surface plasmon resonance-based detection of anti-HPA-1a antibody glycosylation in fetal and neonatal alloimmune thrombocytopenia

Cellular surface plasmon resonance-based detection of anti-HPA-1a antibody glycosylation in fetal and neonatal alloimmune thrombocytopenia

Clinical validation of pneumatic transportation systems for monoclonal antibodies

Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

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