Ahsan Tamim, Sajib Abu Ashfaqur
Molecular Biotechnology Division, National Institute of Biotechnology, Dhaka, 1349, Bangladesh.
Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, 1000, Bangladesh.
J Genet Eng Biotechnol. 2022 Jan 10;20(1):7. doi: 10.1186/s43141-021-00288-y.
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, TNFA, TNFA, and TNFA) and two (TNFA and TNFA) variants, respectively. The binding of GLM and IFX appears to be affected by TNFA and TNFA, respectively. TNFA and TNFA may be associated with autoimmune diseases, whereas TNFA, TNFA, and TNFA 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.
肿瘤坏死因子α（TNFA）是一种影响多种生物学过程的重要细胞因子。它是急性和慢性全身炎症反应的关键介质之一，在多种自身免疫性疾病中起核心作用。一些已获批的单克隆抗体（mAb）被广泛用于缓解这些自身免疫性疾病。然而，这些mAb治疗的无反应率很高。因此，在给药前能够以个体化方式预测患者对这些治疗性抗体的反应非常重要。在本研究中，我们使用计算机工具来探究四种治疗性抗TNFA mAb（阿达木单抗（ADA）、聚乙二醇化赛妥珠单抗（CZP）、戈利木单抗（GLM）和英夫利昔单抗（IFX））各自表位中的错义变体对其与TNFA相互作用的影响。
CZP和ADA与相应表位的结合亲和力似乎分别因四种变体（TNFA、TNFA、TNFA和TNFA）和两种变体（TNFA和TNFA）而降低。GLM和IFX的结合似乎分别受TNFA和TNFA影响。TNFA和TNFA可能与自身免疫性疾病有关，而TNFA、TNFA和TNFA本身可能具有致病性。
这些变体可能导致观察到的抗TNFA mAb治疗个体间反应差异，并可作为预测反应的标志物，从而优化对患者的治疗效果。
