Missense variants in the TNFA epitopes and their effects on interaction with therapeutic antibodies-in silico...

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. 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.

The binding affinities of CZP and ADA to corresponding epitopes appear to be reduced by four (TNFA^R131Q, TNFA^E135G, TNFA^R138Q, and TNFA^R138W) and two (TNFA^G66C and TNFA^G66S) variants, respectively. The binding of GLM and IFX appears to be affected by TNFA^R141S and TNFA^R138W, respectively. TNFA^G66C and TNFA^G66S may be associated with autoimmune diseases, whereas TNFA^E135G, TNFA^R138W, and TNFA^R141S may be pathogenic per se.

These 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.