Anti–Tumor Necrosis Factor With a Glyco-Engineered Fc-Region Has Increased Efficacy in Mice With Colitis

Bloemendaal, Felicia M.; Levin, Alon D.; Wildenberg, Manon E.; Koelink, Pim J.; McRae, Bradford L.; Salfeld, Jochen; Lum, Jenifer K.; Kolfschoten, Marijn van der Neut; Claassens, Jill; Visser, Remco; Bentlage, Arthur E. H.; D’Haens, Geert R.; Verbeek, J. Sjef; Vidarsson, Gestur; Brink, Gijs R. van den

doi:10.1053/j.gastro.2017.07.021

Cited by 27 publications

(43 citation statements)

References 44 publications

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“…We have previously shown that full monoclonal antibodies (mAbs) against TNF engage Fcγ receptors (FcγRs) and that this Fc–FcγR interaction is necessary for the therapeutic efficacy of anti-TNF in a preclinical model of IBD. Mice without activating FcγRs completely lost response to anti-TNF therapy in the T-cell transfer colitis model, and conversely, a hypofucosylated anti-TNF antibody with increased Fc-binding affinity showed improved efficacy 15 16. Additionally, we have shown that anti-TNF skews human monocytes towards CD206+ regulatory macrophages in an Fc-dependent manner in vitro17 and in vivo,16 and that the response to anti-TNF therapy in both mice and humans was accompanied by the formation of these CD206+ regulatory macrophages in the intestine 16 18.…”

Section: Introductionmentioning

confidence: 76%

“…Mice without activating FcγRs completely lost response to anti-TNF therapy in the T-cell transfer colitis model, and conversely, a hypofucosylated anti-TNF antibody with increased Fc-binding affinity showed improved efficacy 15 16. Additionally, we have shown that anti-TNF skews human monocytes towards CD206+ regulatory macrophages in an Fc-dependent manner in vitro17 and in vivo,16 and that the response to anti-TNF therapy in both mice and humans was accompanied by the formation of these CD206+ regulatory macrophages in the intestine 16 18. However, the exact signalling mechanism of the induction of these macrophages and their precise role in the resolution of intestinal inflammation on anti-TNF therapy are currently unknown.…”

Section: Introductionmentioning

confidence: 76%

“…Interestingly, it has previously been shown that FcγR signalling in macrophages increases the secretion of IL-10 19–21. Given the crucial role of macrophage IL-10 signalling in specifying an M2-like CD206+ regulatory macrophage phenotype to prevent intestinal inflammation,12 13 the dependence of response to anti-TNF on FcγR signalling16 and the observation that IL-10 mutant mice are refractory to anti-TNF, we decided to examine the role of IL-10 signalling in the therapeutic response to anti-TNF.…”

Section: Introductionmentioning

confidence: 99%

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Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling

Koelink¹,

Bloemendaal²,

et al. 2019

Gut

148

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ObjectiveMacrophage interleukin (IL)-10 signalling plays a critical role in the maintenance of a regulatory phenotype that prevents the development of IBD. We have previously found that anti-tumour necrosis factor (TNF) monoclonal antibodies act through Fcγ-receptor (FcγR) signalling to promote repolarisation of proinflammatory intestinal macrophages to a CD206+ regulatory phenotype. The role of IL-10 in anti-TNF-induced macrophage repolarisation has not been examined.DesignWe used human peripheral blood monocytes and mouse bone marrow-derived macrophages to study IL-10 production and CD206+ regulatory macrophage differentiation. To determine whether the efficacy of anti-TNF was dependent on IL-10 signalling in vivo and in which cell type, we used the CD4+CD45Rbhigh T-cell transfer model in combination with several genetic mouse models.ResultsAnti-TNF therapy increased macrophage IL-10 production in an FcγR-dependent manner, which caused differentiation of macrophages to a more regulatory CD206+ phenotype in vitro. Pharmacological blockade of IL-10 signalling prevented the induction of these CD206+ regulatory macrophages and diminished the therapeutic efficacy of anti-TNF therapy in the CD4+CD45Rbhigh T-cell transfer model of IBD. Using cell type-specific IL-10 receptor mutant mice, we found that IL-10 signalling in macrophages but not T cells was critical for the induction of CD206+ regulatory macrophages and therapeutic response to anti-TNF.ConclusionThe therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.

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Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling

Koelink¹,

Bloemendaal²,

et al. 2019

Gut

148

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“…In IBD patients, mucosal healing is not obtained in 50% of the patients treated with anti-TNF biologics, and therapeutic efficacy is shown to be dependent on the interaction between the Fc region of the anti-TNF IgG and the cellular FcγR. Recently, a hypo-fucosylated form of adalimumab was designed and was found to have improved mucosal healing properties thanks to its higher affinity to FcγRIII and induction of CD206 + macrophages [272]. Consequently, some studies correlated the low-affinity FcγRIIIa allotype in IBD patients with lower changes to respond to therapies with IgG1 Ab infliximab and reduced mucosal healing [283].…”

Section: Clinical Responsementioning

confidence: 99%

“…In IBD, also the interplay between the IgG1-Fc domain of the anti-TNF antibodies and the Fcγreceptors (FcγR) on macrophages accounts for the efficacy of the anti-TNF antibodies by increasing the number of regulatory CD206 + macrophages upon activation. This M2-type macrophage subset expresses specific membrane markers and inhibits T cell proliferation [272]. Alternatively, adalimumab promotes the interaction between monocytes and Tregs via TNFR2 in RA.…”

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confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

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FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer

et al. 2022

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Low-affinity immunoglobulin gamma Fc region receptor III-A (FccRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FccRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FccRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FccRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FccRIIIa expression, suggesting that FccRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FccRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Ka), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FccRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FccRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FccRIIIa protein expression. Similarly, inhibition of PIP5K1a decreased FccRIIIa expression Abbreviations ALDH, aldehyde dehydrogenases; AR, androgen receptor; ARE-Luc vector, androgen-responsive element luciferase vector; BPH, benign prostate hyperplasia; BRFS, biochemical recurrence-free survival; CRPC, castration-resistant prostate cancer; DHT, dihydrotestosterone; FccRIIIa, low-affinity immunoglobulin gamma Fc region receptor III-A; GDPR, The General Data Protection Regulation; PCa, prostate cancer; PIP2, phosphatidylinositol-4,5-P 2 ; PIP5K1a, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha.

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Anti–Tumor Necrosis Factor With a Glyco-Engineered Fc-Region Has Increased Efficacy in Mice With Colitis

Cited by 27 publications

References 44 publications

Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling

Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling

A New Venue of TNF Targeting

FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer

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