Fc Receptors in Immune Responses

Mancardi, David A.; Daëron, Marc

doi:10.1016/b978-0-12-801238-3.00119-7

Cited by 18 publications

(13 citation statements)

References 204 publications

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“…FcγRI is a high affinity receptor for IgG and as such is largely considered to be saturated by IgG in the circulation [ 10 ]. Despite evidence suggesting that it is capable of mediating anti-tumor immunotherapy in certain B16 mouse models, it is still considered a minor player in immunotherapy [ 11 ]. As such there has been comparatively little effort to engineer antibodies with altered binding to FcγRI.…”

Section: Introductionmentioning

confidence: 99%

Fc-Engineering for Modulated Effector Functions—Improving Antibodies for Cancer Treatment

et al. 2020

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The majority of monoclonal antibody (mAb) therapeutics possess the ability to engage innate immune effectors through interactions mediated by their fragment crystallizable (Fc) domain. By delivering Fc-Fc gamma receptor (FcγR) and Fc-C1q interactions, mAb are able to link exquisite specificity to powerful cellular and complement-mediated effector functions. Fc interactions can also facilitate enhanced target clustering to evoke potent receptor signaling. These observations have driven decades-long research to delineate the properties within the Fc that elicit these various activities, identifying key amino acid residues and elucidating the important role of glycosylation. They have also fostered a growing interest in Fc-engineering whereby this knowledge is exploited to modulate Fc effector function to suit specific mechanisms of action and therapeutic purposes. In this review, we document the insight that has been generated through the study of the Fc domain; revealing the underpinning structure-function relationships and how the Fc has been engineered to produce an increasing number of antibodies that are appearing in the clinic with augmented abilities to treat cancer.

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Section: Introductionmentioning

confidence: 99%

Fc-Engineering for Modulated Effector Functions—Improving Antibodies for Cancer Treatment

et al. 2020

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“…MAbs exert their anticancer activities through a combination of immune‐mediated and nonimmune‐mediated mechanisms such as direct receptor inhibition, antibody‐dependent cell‐mediated cytotoxicity (ADCC), antibody‐mediated phagocytosis and complement‐mediated cell lysis. The initiation of inflammatory responses by antibodies is largely dependent on the binding and activation of Fcγ receptors (FcγRs), which are differentially expressed in several immune cell types, in particular natural killer (NK) cells, neutrophils, macrophages and monocytes (Mancardi and Daëron, 2014 ). Binding of the Fc region of an antibody to the activating FcγRs (FcγRI, FcγRIIa and FcγRIIIa) results in the generation of signalling cascades through intracellular ITAM domains, leading to cellular activation, degranulation or phagocytosis in a cell type‐specific manner (Vidarsson et al ., 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Impact of glycoengineering and antidrug antibodies on the anticancer activity of a plant‐made lectin‐Fc fusion protein

Dent

Mayer

Garcia

et al. 2022

Plant Biotechnology Journal

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Plants are an efficient production platform for manufacturing glycoengineered monoclonal antibodies and antibody-like molecules. Avaren-Fc (AvFc) is a lectin-Fc fusion protein or lectibody produced in Nicotiana benthamiana, which selectively recognizes cancer-associated high-mannose glycans. In this study, we report the generation of a glycovariant of AvFc that is devoid of plant glycans, including the core a1,3-fucose and b1,2-xylose residues. The successful removal of these glycans was confirmed by glycan analysis using HPLC. This variant, AvFc DXF , has significantly higher affinity for Fc gamma receptors and induces higher levels of luciferase expression in an antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay against B16F10 murine melanoma cells without inducing apoptosis or inhibiting proliferation. In the B16F10 flank tumour mouse model, we found that systemic administration of AvFc DXF , but not an aglycosylated AvFc variant lacking affinity for Fc receptors, significantly delayed the growth of tumours, suggesting that Fc-mediated effector functions were integral. AvFc DXF treatment also significantly reduced lung metastasis of B16F10 upon intravenous challenge whereas a sugar-binding-deficient mutant failed to show efficacy. Lastly, we determined the impact of antidrug antibodies (ADAs) on drug activity in vivo by pretreating animals with AvFc DXF before implanting tumours. Despite a significant ADA response induced by the pretreatment, we found that the activity of AvFc DXF was unaffected by the presence of these antibodies. These results demonstrate that glycoengineering is a powerful strategy to enhance AvFc's antitumor activity.

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“…MAbs exert their anti-cancer activities through a combination of immune-mediated and non-immune-mediated mechanisms such as direct receptor inhibition, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-mediated phagocytosis, and complement-mediated cell lysis. The initiation of inflammatory responses by antibodies is largely dependent on the binding and activation of Fcγ receptors (FcγRs), which are differentially expressed in several immune cell types, in particular natural killer (NK) cells, neutrophils, macrophages, and monocytes (Mancardi and Daёron, 2014). Binding of the Fc region of an antibody to the activating FcγRs (FcγRI, FcγRIIa, FcγRIIIa) results in the generation of signaling cascades through intracellular ITAM domains, leading to cellular activation, degranulation, or phagocytosis in a cell type-specific manner (Vidarsson et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Impact of glycoengineering and immunogenicity on the anti-cancer activity of a plant-made lectin-Fc fusion protein

Dent

Mayer

Garcia

et al. 2022

Preprint

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Plants are an efficient production platform for manufacturing glycoengineered monoclonal antibodies and antibody-like molecules. Avaren-Fc (AvFc) is a lectin-Fc fusion protein or lectibody produced in Nicotiana benthamiana, which selectively recognizes cancer-associated high-mannose glycans. In this study, we report the generation of a glycovariant of AvFc that is devoid of plant glycans, including the core α1,3-fucose and β1,2-xylose residues. The successful removal of these glycans was confirmed by glycan analysis using HPLC. This variant, AvFcΔXF, has significantly higher affinity for Fc gamma receptors and induces higher levels of luciferase expression in an antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay against B16F10 murine melanoma cells without inducing apoptosis or inhibiting proliferation. In the B16F10 flank tumor mouse model, we found that systemic administration of AvFcΔXF, but not an aglycosylated AvFc variant lacking affinity for Fc receptors, significantly delayed the growth of tumors, suggesting that Fc-mediated effector functions were integral. AvFcΔXF treatment also significantly reduced lung metastasis of B16F10 upon intravenous challenge whereas a sugar-binding-deficient mutant failed to show efficacy. Lastly, we determined the impact of anti-drug antibodies (ADAs) on drug activity in vivo by pretreating animals with AvFcΔXF before implanting tumors. Despite a significant ADA response induced by the pretreatment, we found that the activity of AvFcΔXF was unaffected by the presence of these antibodies. These results demonstrate that glycoengineering is a powerful strategy to enhance AvFc′s antitumor activity.

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Fc Receptors in Immune Responses

Cited by 18 publications

References 204 publications

Fc-Engineering for Modulated Effector Functions—Improving Antibodies for Cancer Treatment

Fc-Engineering for Modulated Effector Functions—Improving Antibodies for Cancer Treatment

Impact of glycoengineering and antidrug antibodies on the anticancer activity of a plant‐made lectin‐Fc fusion protein

Impact of glycoengineering and immunogenicity on the anti-cancer activity of a plant-made lectin-Fc fusion protein

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