Red pulp macrophages in the human spleen are a distinct cell population with a unique expression of Fc-γ receptors

Nagelkerke, Sietse Q.; Bruggeman, Christine W.; Haan, Joke M. M. den; Mul, Erik; Berg, Timo K. van den; Bruggen, Robin van; Kuijpers, Taco W.

doi:10.1182/bloodadvances.2017015008

Cited by 62 publications

(60 citation statements)

References 37 publications

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“…ADCP activity is known to be triggered by FcγRIIa intracellular signaling (Fig. 1b) [20][21][22] , which has been shown by glycoengineered antibodies to exhibit enhanced affinity toward FcγRIIa, resulting in increased ADCP activity 21,23 . However, the existence of other human Fc-glycoengineered antibodies that do not affect FcγRIIa binding 24 but improve ADCP 20 also indicates the possibility that FcγRIIIa contributes downstream signaling to phagocytic activity 25 .…”

Section: Fc Receptors: Fcγ Receptors (Fcγrs) and Neonatal Fc Receptormentioning

confidence: 99%

Boosting therapeutic potency of antibodies by taming Fc domain functions

2019

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Monoclonal antibodies (mAbs) are one of the most widely used drug platforms for infectious diseases or cancer therapeutics because they selectively target pathogens, infectious cells, cancerous cells, and even immune cells. In this way, they mediate the elimination of target molecules and cells with fewer side effects than other therapeutic modalities. In particular, cancer therapeutic mAbs can recognize cell-surface proteins on target cells and then kill the targeted cells by multiple mechanisms that are dependent upon a fragment crystallizable (Fc) domain interacting with effector Fc gamma receptors, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellmediated phagocytosis. Extensive engineering efforts have been made toward tuning Fc functions by either reinforcing (e.g. for targeted therapy) or disabling (e.g. for immune checkpoint blockade therapy) effector functions and prolonging the serum half-lives of antibodies, as necessary. In this report, we review Fc engineering efforts to improve therapeutic potency, and propose future antibody engineering directions that can fulfill unmet medical needs.

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Section: Fc Receptors: Fcγ Receptors (Fcγrs) and Neonatal Fc Receptormentioning

confidence: 99%

Boosting therapeutic potency of antibodies by taming Fc domain functions

2019

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“…Together with well-known functions of macrophages in tumor phagocytic activity [86], these results indicate that ADCP activity is critical in therapeutic efficacy against cancer. The ADCP activity of macrophages is triggered by FcγRIIa intracellular signaling [87][88][89]; however, anti-CD20 or anti-Her2 antibodies with engineered Fcs that only bind to FcγRIIIa triggered not only ADCC, but also ADCP using human NK cells and macrophages in vitro, which is an unknown function of FcγRIIIa [90]. This study again highlights a clinical ramification of FcγRIIIa in cancer therapeutics.…”

Section: Recent Findings Of Fc Receptor Functions For Treating Malignmentioning

confidence: 76%

Reprogramming the Constant Region of Immunoglobulin G Subclasses for Enhanced Therapeutic Potency against Cancer

Kang

Jung

2020

Biomolecules

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The constant region of immunoglobulin (Ig) G antibodies is responsible for their effector immune mechanism and prolongs serum half-life, while the fragment variable (Fv) region is responsible for cellular or tissue targeting. Therefore, antibody engineering for cancer therapeutics focuses on both functional efficacy of the constant region and tissue- or cell-specificity of the Fv region. In the functional aspect of therapeutic purposes, antibody engineers in both academia and industry have capitalized on the constant region of different IgG subclasses and engineered the constant region to enhance therapeutic efficacy against cancer, leading to a number of successes for cancer patients in clinical settings. In this article, we review IgG subclasses for cancer therapeutics, including (i) IgG1, (ii) IgG2, 3, and 4, (iii) recent findings on Fc receptor functions, and (iv) future directions of reprogramming the constant region of IgG to maximize the efficacy of antibody drug molecules in cancer patients.

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“…In vitro, phagocytosis of anti-D opsonised RBC by monocytes is mediated by FcγRI, with the extent of phagocytosis proportional to anti-D coverage on RBCs 50 . FcγRI is also present on splenic red pulp macrophages and although at low expression compared to FcγRIIIa, it gives a major contribution to phagocytosis 75 . This may be due to upregulation of surface expression of FcγRI after stimulation of FcγRIIIa by binding opsonised RBC or by inflammation 75 .…”

Section: Discussionmentioning

confidence: 99%

“…FcγRI is also present on splenic red pulp macrophages and although at low expression compared to FcγRIIIa, it gives a major contribution to phagocytosis 75 . This may be due to upregulation of surface expression of FcγRI after stimulation of FcγRIIIa by binding opsonised RBC or by inflammation 75 . Thus in vivo, it is likely that opsonised RBC are selected and captured by splenic macrophages through FcγRIIIa binding afucosylated anti-D followed by FcγRI-mediated internalisation.…”

Section: Discussionmentioning

confidence: 99%

Anti-D monoclonal antibodies from 23 human and rodent cell lines display diverse IgG Fc-glycosylation profiles that determine their clinical efficacy

Kumpel

Saldova

Koeleman

et al. 2020

Sci Rep

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Anti-D immunoglobulin (Anti-D Ig) prophylaxis prevents haemolytic disease of the fetus and newborn. Monoclonal IgG anti-Ds (mAb-Ds) would enable unlimited supplies but have differed in efficacy in fcγRIIIa-mediated ADCC assays and clinical trials. Structural variations of the oligosaccharide chains of mAb-Ds are hypothesised to be responsible. Quantitative data on 12 Fc-glycosylation features of 23 mAb-Ds (12 clones, 5 produced from multiple cell lines) and one blood donor-derived anti-D Ig were obtained by HPLC and mass spectrometry using 3 methods. Glycosylation of mAb-Ds from human B-lymphoblastoid cell lines (B) was similar to anti-D Ig although fucosylation varied, affecting ADcc activity. In vivo, two B mAb-Ds with 77-81% fucosylation cleared red cells and prevented D-immunisation but less effectively than anti-D Ig. High fucosylation (>89%) of mouse-human heterohybridoma (HH) and Chinese hamster ovary (CHO) mAb-Ds blocked ADCC and clearance. Rat YB2/0 mAb-Ds with <50% fucosylation mediated more efficient ADCC and clearance than anti-D Ig. Galactosylation of B mAb-Ds was 57-83% but 15-58% for rodent mAb-Ds. HH mAb-Ds had non-human sugars. These data reveal high galactosylation like anti-D Ig (>60%) together with lower fucosylation (<60%) as safe features of mAb-Ds for mediating rapid red cell clearance at low doses, to enable effective, inexpensive prophylaxis.

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Red pulp macrophages in the human spleen are a distinct cell population with a unique expression of Fc-γ receptors

Abstract: Key Points• Human red pulp macrophages are distinct from monocytes and monocyte-derived macrophages in the expression of FcgRs and other surface markers.• Red pulp macrophages phagocytose IgGopsonized blood cells by activating FcgRs and are sensitive to IV immunoglobulin blocking

Cited by 62 publications

References 37 publications

Boosting therapeutic potency of antibodies by taming Fc domain functions

Boosting therapeutic potency of antibodies by taming Fc domain functions

Reprogramming the Constant Region of Immunoglobulin G Subclasses for Enhanced Therapeutic Potency against Cancer

Anti-D monoclonal antibodies from 23 human and rodent cell lines display diverse IgG Fc-glycosylation profiles that determine their clinical efficacy

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