The Cytotoxic Effects of Certolizumab Pegol and Golimumab Mediated by Transmembrane Tumor Necrosis Factor α

Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF α‐related immunological diseases. Other than neutralizing TNF α, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand‐binding interaction of these mAbs used in TNF α‐related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen‐binding fragment (Fab) portions of infliximab, complexed with TNF α (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype Fcγ RIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcγ RIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab‐TNF α interactions, we found that in the absence of fucosylation the Fc–mAb domain and Fcγ RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcγ RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.

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“…Golimumab, however, shows a minor apoptosis activity as compared to adalimumab and infliximab (Ueda et al. 2013; Urbano et al. 2014).…”

Section: Discussionmentioning

confidence: 99%

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Pierri

Bossis

Punzi

et al. 2016

Pharmacology Res & Perspec

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“…In both settings, etanercept binding was shown to be low. The more recently approved anti-TNF antibody golimumab induced both CDC and ADCC to a similar extent as infliximab and adalimumab[77]. …”

Section: Antibody-dependent Cellular Cytotoxicity and Complement-depementioning

confidence: 99%

Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

Billmeier

Dieterich

Neurath

et al. 2016

WJG

167

156

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Anti-tumor necrosis factor (TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases (IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn’s disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each anti-TNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membrane-bound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with anti-TNF antibodies in chronic intestinal inflammation, by predicting response to therapy.

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“…35 Evidence exists that infliximab, adalimumab, and golimumab can cause antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). 36 In vitro examination of cells overexpressing mTNF has demonstrated that infliximab and adalimumab induce CDC and ADCC but both processes are reduced upon etanercept administration, which is unable to bind C3, and abrogated under certolizumab pegol administration, which does not have an Fc portion. 37 The efficacy of certolizumab in treatment despite its inability to cause apoptosis calls into question the significance of apoptosis in anti-TNF treatment of IBD, though this is still up for debate.…”

Section: Currently Available Therapiesmentioning

confidence: 99%

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

et al. 2018

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The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.

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The Cytotoxic Effects of Certolizumab Pegol and Golimumab Mediated by Transmembrane Tumor Necrosis Factor α

Cited by 54 publications

References 28 publications

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

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