Identification of a High Affinity FcγRIIA-binding Peptide That Distinguishes FcγRIIA from FcγRIIB and Exploits FcγRIIA-mediated Phagocytosis and Degradation

Berntzen, Gøril; Andersen, Jan Terje; Ustgård, Kristine; Michaelsen, T. E.; Mousavi, Seyed Ali; Qian, Julie Dee; Kristiansen, Per Eugen; Lauvrak, Vigdis; Sandlie, Inger

doi:10.1074/jbc.m803584200

Cited by 9 publications

(5 citation statements)

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“…In fact, regulatory agencies such as the FDA and EMA insist on such measurements being performed. Several publications have referenced the use of NS0-derived Fcγ receptors for use in SPR studies of antibody binding affinity. ,,,− It is worth noting that in many cases these analyses are performed without a detailed knowledge of the glycosylation of the recombinant receptors used in the assays, and this is one of the main reasons why the work described here was performed. Interestingly, recent studies evaluating the biological activity of afucosylated anti-CD20 antibody with FcγRIIIa has shown that specific glycan sites on the receptor significantly affect the binding of antibodies.…”

Section: Discussionmentioning

confidence: 99%

N-Linked Glycan Structures of the Human Fcγ Receptors Produced in NS0 Cells

et al. 2013

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Immune recognition of nonself is coordinated through complex mechanisms involving both innate and adaptive responses. Circulating antibodies communicate with effector cells of the innate immune system through surface receptors known as Fcγ receptors (FcγRs). The FcγRs are single-pass transmembrane glycoproteins responsible for regulating innate effector responses toward antigenic material. Although immunoglobulin G (IgG) antibodies bind to a range of receptors, including complement receptors and C-type lectins, we have focused on the Fcγ receptors. A total of five functional FcγRs are broadly classified into three families (FcγRI, FcγRII, and FcγRIII) and together aid in controlling both inflammatory and anti-inflammatory responses of the innate immune system. Due to the continued success of monoclonal antibodies in treating cancer and autoimmune disorders, research is typically directed toward improving the interaction of antibodies with the FcγRs through manipulation of IgG properties such as N-linked glycosylation. Biochemical studies using recombinant forms of the FcγRs are often used to quantitate changes in binding affinity, a key indicator of a likely biological outcome. However, analysis of the FcγRs themselves is imperative as recombinant FcγRs differ greatly from those observed in humans. In particular, the N-linked glycan composition is significantly important due to its function in the IgG-FcγR interaction. Here, we present data for the N-linked glycans present on FcγRs produced in NS0 cells, namely, FcγRIa, FcγRIIa, FcγRIIB, FcγRIIIa, and FcγRIIIb. Importantly, these FcγRs demonstrate typical murine glycosylation in the form of α-galactose epitopes, N-glycolylneuraminic acid, and other key glycan properties that are generally expressed in murine cell lines and therefore are not typically observed in humans.

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Section: Discussionmentioning

confidence: 99%

N-Linked Glycan Structures of the Human Fcγ Receptors Produced in NS0 Cells

et al. 2013

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“…Besides affording efficacy, therapeutic targeting of Fc gamma receptors, whether by blocking antibodies or Fc-engineering, must be safe and associated with therapeutically relevant pharmacokinetics. In addition to its high expression on B cells and certain macrophage/dendritic cells, FcγRIIB has been reported to be highly expressed in mouse and rat liver sinusoidal endothelial cells (LSEC) (107), where they have been implicated in removal of circulating small immune complexes (108). These observations raise potential safety concerns of undesirably cytotoxic activity with therapeutic antibodies targeting FcγRIIB.…”

Section: Antibody Checkpoints Determine Anti-cancer Antibody Efficacymentioning

confidence: 99%

Targeting the Antibody Checkpoints to Enhance Cancer Immunotherapy–Focus on FcγRIIB

2019

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Immunotherapy with therapeutic antibodies has increased survival for patients with hematologic and solid cancers. Still, a significant fraction of patients fails to respond to therapy or acquire resistance. Understanding and overcoming mechanisms of resistance to antibody drugs, and in particular those common to antibody drugs as a class, is therefore highly warranted and holds promise to improve response rates, duration of response and potentially overall survival. Activating and inhibitory Fc gamma receptors (FcγR) are known to coordinately regulate therapeutic activity of tumor direct-targeting antibodies. Similar, but also divergent, roles for FcγRs in controlling efficacy of immune modulatory antibodies e.g., checkpoint inhibitors have been indicated from mouse studies, and were recently implicated in contributing to efficacy in the human clinical setting. Here we discuss evidence and mechanisms by which Fc gamma receptors–the “antibody checkpoints”–regulate antibody-induced antitumor immunity. We further discuss how targeted blockade of the sole known inhibitory antibody checkpoint FcγRIIB may help overcome resistance and boost activity of clinically validated and emerging antibodies in cancer immunotherapy.

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“…Dendritic cells fall into the category of leukocytes, or white blood cells, which comprise a category consisting of several other cell types. Several peptides have been isolated against other types of leukocytes, including the leukocyte-binding peptide WAWVWLTETAV isolated against the FcγRIIA receptor expressed by neutrophils and mononuclear phagocytes . Importantly, this peptide bound primary mononuclear (PMN) cells and monocytes isolated from human peripheral blood.…”

Section: Isolation Of Disease-specific or Organ-specific Peptidesmentioning

confidence: 99%