Missense variants in the TNFA epitopes and their effects on interaction with therapeutic antibodies—in silico analysis

Tamim Ahsan,Abu Ashfaqur Sajib

doi:10.1186/s43141-021-00288-y

Abstract

BackgroundTumor necrosis factor alpha (TNFA) is an important cytokine that influences multiple biological processes. It is one of the key mediators of acute and chronic systemic inflammatory reactions and plays a central role in several autoimmune diseases. A number of approved monoclonal antibodies (mAbs) are widely used to subside these autoimmune diseases. However, there is a high rate of non-responsiveness to treatments with these mAbs. Therefore, it is important to be able to predict responses of the patients in an individualistic manner to these therapeutic antibodies before administration. In the present study, we used in silico tools to explore the effects of missense variants in the respective epitopes of four therapeutic anti-TNFA mAbs—adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM), and infliximab (IFX)—on their interactions with TNFA. ResultsThe binding affinities of CZP and ADA to corresponding epitopes appear to be reduced by four (TNFAR131Q, TNFAE135G, TNFAR138Q, and TNFAR138W) and two (TNFAG66C and TNFAG66S) variants, respectively. The binding of GLM and IFX appears to be affected by TNFAR141S and TNFAR138W, respectively. TNFAG66C and TNFAG66S may be associated with autoimmune diseases, whereas TNFAE135G, TNFAR138W, and TNFAR141S may be pathogenic per se. ConclusionThese variants may contribute to the observed inter-individual variability in response to anti-TNFA mAbs treatments and be used as markers to predict responses, and thus optimize therapeutic benefits to the patients.

Highlights

Tumor necrosis factor alpha (TNFA) is an important cytokine that influences multiple biological processes
We investigated the interactions of ADA, certolizumab pegol (CZP), GLM, and IFX Monoclonal antibody (mAb) with their respective epitopic variants in TNFA using in silico tools
Missense variants in the epitopes of anti‐TNFA monoclonal antibodies Amino acid residues that constitute the epitopes of TNFA for ADA [20], CZP [21], GLM [22], and IFX [23] were retrieved through literature survey (Table 1)

Summary

Introduction

Tumor necrosis factor alpha (TNFA) is an important cytokine that influences multiple biological processes It is one of the key mediators of acute and chronic systemic inflammatory reactions and plays a central role in several autoimmune diseases. Tumor necrosis factor alpha (TNFA) is a cytokine that mediates pleotropic influences on a myriad of cellular processes including cell proliferation and differentiation, immune responses, apoptosis, necroptosis, etc [1, 2]. Several FDA-approved anti-TNFA monoclonal antibodies (mAbs) such as adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM), and infliximab (IFX) are commercially available and widely used to treat such diseases [15]

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