Fc Receptor-mediated Effector Function Contributes to the Therapeutic Response of Anti-TNF Monoclonal Antibodies in a Mouse Model of Inflammatory Bowel Disease

McRae, Bradford L.; Levin, Alon D.; Wildenberg, Manon E.; Koelink, Pim J.; Bousquet, Peter F.; Mikaelian, Igor; Sterman, Annette Schwartz; Bryant, Shaughn; D’Haens, Geert; Kamath, Rajesh V.; Salfeld, Jochen; Brink, Gijs R. van den

doi:10.1093/ecco-jcc/jjv179

Cited by 32 publications

(32 citation statements)

References 33 publications

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“…The anti-IL-10Rα diminished the therapeutic efficacy of anti-TNF, indicated by the absence of a significant improvement of the endoscopy score (figure 2A,B), the histology score (figure 2C,D) and colon density (figure 2E). Interestingly, it did not affect the effect of the anti-TNF on body weight loss (figure 2F), indicating that body weight loss is dependent on the well-established cachectic effects of circulating TNF, which we have seen before,15 that are less dependent on IL-10. There was an increase in intestinal Il10 expression on treatment with anti-TNF, especially when Il10 levels were expressed relative to levels of key proinflammatory cytokines, such as Ifng or Il1b (figure 2G).…”

Section: Resultsmentioning

confidence: 55%

“…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: 80%

“…In previous studies, we have shown that FcγR interaction is crucial for the therapeutic efficacy of anti-TNF in IBD, presumably through the induction of regulatory macrophages 15–17. As FcγR ligation is a potent inducer of IL-10 in macrophages,19–21 we investigated Il10 expression in the T-cell transfer model in FcgR KO /Rag1 KO animals that are refractory to anti-TNF therapy 16.…”

Section: Resultsmentioning

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

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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: Resultsmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 80%

Section: Resultsmentioning

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

Self Cite

148

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“…The commonly used dose of anti-TNF in murine models ranges around 100–300 µg/mouse twice weekly. This dose results in near complete disease remission after 4 weeks of treatment, 14 negating the possibility of testing drugs that potentiate the effect of anti-TNF. We therefore first titrated the anti-mouse TNF to identify a dose that could be considered suboptimal.…”

Section: Resultsmentioning

confidence: 99%

Benzimidazoles Promote Anti-TNF Mediated Induction of Regulatory Macrophages and Enhance Therapeutic Efficacy in a Murine Model

Wildenberg

Levin

Ceroni

et al. 2017

Journal of Crohn's and Colitis

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Background and AimsRegulatory macrophages play a critical role in tissue repair, and we have previously shown that anti-tumour necrosis factor [TNF] antibodies induce these macrophages in vitro and in vivo in IBD patients. The induction of regulatory macrophages can be potentiated using the combination of anti-TNF and thiopurines, consistent with the enhanced efficacy of this combination therapy described in clinical trials. As thiopurines are unfortunately associated with significant side effects, we here aimed to identify alternatives for combination therapy with anti-TNF, using the macrophage induction model as a screening tool.MethodsMixed lymphocyte reactions were treated with anti-TNF and a library of 1600 drug compounds. Induction of CD14+CD206+ macrophages was analysed by flow cytometry. Positive hits were validated in vitro and in the T cell transfer model of colitis.ResultsAmong the 98 compounds potentiating the induction of regulatory macrophages by anti-TNF were six benzimidazoles, including albendazole. Albendazole treatment in the presence of anti-TNF resulted in alterations in the tubulin skeleton and signalling though AMPK, which was required for the enhanced induction. Combination therapy also increased expression levels of the immunoregulatory cytokine IL-10. In vivo, albendazole plus anti-TNF combination therapy was superior to monotherapy in a model of colitis, in terms of both induction of regulatory macrophages and improvement of clinical symptoms.ConclusionsAlbendazole enhances the induction of regulatory macrophages by anti-TNF and potentiates clinical efficacy in murine colitis. Given its favourable safety profile, these data indicate that the repurposing of albendazole may be a novel option for anti-TNF combination therapy in IBD.

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“…37 It may also partly explain why an anti-TNF immunoglobulin (Ig) G1 construct with reduced Fc binding did not ameliorate murine colitis. 38 For biosimilars, data on this possible anti-TNF mechanism of action in IBD are relatively scant, although comparable induction of regulatory macrophages and wound healing in an intestinal cell model was observed for CT-P13 and infliximab RP ( Table 2).…”

Section: Comparing Mechanisms Of Action Across Indicationsmentioning

confidence: 99%

Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation

Ben‐Horin

Casteele

Schreiber

et al. 2016

Clinical Gastroenterology and Hepatology

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Biologic drugs such as infliximab and other anti-tumor necrosis factor monoclonal antibodies have transformed the treatment of immune-mediated inflammatory conditions such as Crohn's disease and ulcerative colitis (collectively known as inflammatory bowel disease [IBD]). However, the complex manufacturing processes involved in producing these drugs mean their use in clinical practice is expensive. Recent or impending expiration of patents for several biologics has led to development of biosimilar versions of these drugs, with the aim of providing substantial cost savings and increased accessibility to treatment. Biosimilars undergo an expedited regulatory process. This involves proving structural, functional, and biological biosimilarity to the reference product (RP). It is also expected that clinical equivalency/comparability will be demonstrated in a clinical trial in one (or more) sensitive population. Once these requirements are fulfilled, extrapolation of biosimilar approval to other indications for which the RP is approved is permitted without the need for further clinical trials, as long as this is scientifically justifiable. However, such justification requires that the mechanism(s) of action of the RP in question should be similar across indications and also comparable between the RP and the biosimilar in the clinically tested population(s). Likewise, the pharmacokinetics, immunogenicity, and safety of the RP should be similar across indications and comparable between the RP and biosimilar in the clinically tested population(s). To date, most anti-tumor necrosis factor biosimilars have been tested in trials recruiting patients with rheumatoid arthritis. Concerns have been raised regarding extrapolation of clinical data obtained in rheumatologic populations to IBD indications. In this review, we discuss the issues surrounding indication extrapolation, with a focus on extrapolation to IBD.

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Fc Receptor-mediated Effector Function Contributes to the Therapeutic Response of Anti-TNF Monoclonal Antibodies in a Mouse Model of Inflammatory Bowel Disease

Cited by 32 publications

References 33 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

Benzimidazoles Promote Anti-TNF Mediated Induction of Regulatory Macrophages and Enhance Therapeutic Efficacy in a Murine Model

Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation

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