A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer

Mellor, James Dan; Brown, Michael P.; Irving, Helen Ruth; Zalcberg, John; Dobrovic, Alexander

doi:10.1186/1756-8722-6-1

Cited by 312 publications

(290 citation statements)

References 49 publications

(74 reference statements)

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“…Whether the frequency of NKG2C bright NK cells, not appreciated through genetic analysis, could explain the controversial data in studies addressing the impact of those polymorphisms in clinical contexts such as Ab-based anticancer therapies deserves attention (54).…”

Section: Differentiation Of Nkg2c Bright Nk Cells As Cytokine Producementioning

confidence: 99%

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Costa‐García

Vera

Moraru³

et al. 2015

The Journal of Immunology

103

108

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Human CMV (HCMV) infection promotes a variable and persistent expansion of functionally mature NKG2Cbright NK cells. We analyzed NKG2Cbright NK cell responses triggered by Abs from HCMV+ sera against HCMV-infected MRC5 fibroblasts. Specific Abs promoted the degranulation (i.e., CD107a expression) and the production of cytokines (TNF-α and IFN-γ) by a significant fraction of NK cells, exceeding the low natural cytotoxicity against HCMV-infected targets. NK cell–mediated Ab-dependent cell-mediated cytotoxicity was limited by viral Ag availability and HLA class I expression on infected cells early postinfection and increased at late stages, overcoming viral immunoevasion strategies. Moreover, the presence of specific IgG triggered the activation of NK cells against Ab-opsonized cell-free HCMV virions. As compared with NKG2A+ NK cells, a significant proportion of NKG2Cbright NK cells was FcεR γ-chain defective and highly responsive to Ab-driven activation, being particularly efficient in the production of antiviral cytokines, mainly TNF-α. Remarkably, the expansion of NKG2Cbright NK cells in HCMV+ subjects was related to the overall magnitude of TNF-α and IFN-γ cytokine secretion upon Ab-dependent and -independent activation. We show the power and sensitivity of the anti-HCMV response resulting from the cooperation between specific Abs and the NKG2Cbright NK-cell subset. Furthermore, we disclose the proinflammatory potential of NKG2Cbright NK cells, a variable that could influence the individual responses to other pathogens and tumors.

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Section: Differentiation Of Nkg2c Bright Nk Cells As Cytokine Producementioning

confidence: 99%

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Costa‐García

Vera

Moraru³

et al. 2015

The Journal of Immunology

103

108

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“…4), cetuximab (anti-EGFR; ref. 5), or trastuzumab (anti-HER2; ref. 5) therapy in lymphoma, colorectal, and breast cancer patients, respectively, suggesting that Fcg receptor-mediated effector functions play an important role in cancer treatment.…”

Section: Most Clinically Used Mabs Belong To the Igg Subclass And Thementioning

confidence: 99%

Pegfilgrastim Enhances the Antitumor Effect of Therapeutic Monoclonal Antibodies

Cornet

Mathé

Chettab

et al. 2016

Molecular Cancer Therapeutics

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Therapeutic mAbs exert antitumor activity through various mechanisms, including apoptotic signalization, complementdependent cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP). G-CSF and GM-CSF have been reported to increase the activity of antibodies in preclinical models and in clinical trials. To determine the potential role of pegfilgrastim as an enhancer of anticancer antibodies, we performed a comparative study of filgrastim and pegfilgrastim. We found that pegfilgrastim was significantly more potent than filgrastim in murine xenograft models treated with mAbs. This was observed with rituximab in CD20 þ models and with trastuzumab in HER2 þ models. Stimulation with pegfilgrastim was associated with significant enhancement of leukocyte content in spleen as well as mobilization of activated monocytes/ granulocytes from the spleen to the tumor bed. These results suggest that pegfilgrastim could constitute a potent adjuvant for immunotherapy with mAbs possessing ADCC/ADCP properties.

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“…Interactions of IgGs with effector cells through fragment crystallizable γ (Fcγ) receptors are often considered a mode of action of therapeutic antibodies 2, 3, 4. Fcγ receptors are cell surface receptors that can be found on innate immune effector cells such as natural killer cells and macrophages.…”

mentioning

confidence: 99%

Rapid screening of IgG quality attributes – effects on Fc receptor binding

Geuijen¹,

Oppers-Tiemissen

Egging

et al. 2017

FEBS Open Bio

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The interactions of therapeutic antibodies with fragment crystallizable γ (Fcγ) receptors and neonatal Fc receptors (FcRn) are measured in vitro as indicators of antibody functional performance. Antibodies are anchored to immune cells through the Fc tail, and these interactions are important for the efficacy and safety of therapeutic antibodies. High‐throughput binding studies on each of the human Fcγ receptor classes (FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb) as well as FcRn have been developed and performed with human IgG after stress‐induced modifications to identify potential impact in vivo. Interestingly, we found that asparagine deamidation (D‐N) reduced the binding of IgG to the low‐affinity Fcγ receptors (FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb), while FcγRI and FcRn binding was not impacted. Deglycosylation completely inhibited binding to all Fcγ receptors, but showed no impact on binding to FcRn. On the other hand, afucosylation only impacted binding to FcγRIIIa and FcγRIIIb. Methionine oxidation at levels below 7%, multiple freeze/thaw cycles and short‐term thermal/shake stress did not influence binding to any of the Fc receptors. The presence of high molecular weight species, or aggregates, disturbed measurements in these binding assays; up to 5% of aggregates in IgG samples changed the binding and kinetics to each of the Fc receptors. Overall, the screening assays described in this manuscript prove that rapid and multiplexed binding assays may be a valuable tool for lead optimization, process development, in‐process controls, and biosimilarity assessment of IgGs during development and manufacturing of therapeutic IgGs.

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A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer

Cited by 312 publications

References 49 publications

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Pegfilgrastim Enhances the Antitumor Effect of Therapeutic Monoclonal Antibodies

Rapid screening of IgG quality attributes – effects on Fc receptor binding

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