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زهره ابراهیمی، علیرضا جلیانی

Background: Cancer is considered a serious health challenge, which is the second cause of death in the world. To date, various approaches have been used to suppress tumor cell growth. Recently, cancer immunotherapy has been developed as an effective approach for cancer treatment, in which monoclonal antibodies inhibit immune checkpoints, thereby inhibiting the proliferation of cancer cells. Monoclonal antibodies (mAbs) have demonstrated significant efficacy in cancer immunotherapy due to their high specificity and affinity in binding to their target antigens. Atezolizumab is a monoclonal antibody that blocks PD-1/PD-L1 axis, which are one of key immune checkpoints, leading to enhanced anti-tumor immune responses. Introducing specific amino acid substitutions within the complementarity-determining region 3 (CDR3) of monoclonal antibodies, can significantly enhance their binding affinity to the target antigens. We hypothesized that strategically chosen amino acid substitutions can enhance binding affinity and potentially improve therapeutic outcomes. Methods: In this study, site-directed mutagenesis was performed on Atezolizumab antibody by targeting Proline 102, replacing it with Glutamine to introduce novel interactions. The impact of this substitution on antibody-antigen interactions was evaluated through structural analysis using PyMOL software and HADDOCK server. Results: Introduction of Glutamine substitution resulted in the formation of novel interactions with the PD-L1 antigen, as indicated by newly formed bonds of 2.7 Å and 3.4 Å. These findings suggest that introducing specific charged amino acid in the CDR3 region of monoclonal antibodies (mAbs) can potentially enhance antigen recognition. Conclusions: This study highlights the potential of amino acid substitution in the CDR3 region of antibodies through site-directed mutagenesis as a strategy to enhance PD-L1 targeting. Further investigations are necessary to fully understand the functional implications of these novel interactions and assess their potential for therapeutic applications.

PD-L1, Atezolizumab, site-directed mutagenesis, antibodies, amino acid substitution

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ابراهیمی، زهره، جلیانی، علیرضا، 1404، In-silico investigation of affinity maturation of Atezolizumab antibody using site-directed mutagenesis، کنگره بین المللی زیست پزشکی سرطان و سلولهای بنیادی، http://conf.sums.ac.ir/fa/archive_index.php?c=HN-icsbc1&aid=1514236