De novo Antibody design against PD-۱ and PDL-۱ as critical immunecheck points involve in cancer treatment

Cancer control and treatment is an important issue in therapy, which recently have immune checkpoints considered by cancer researchers. Programmed cell death ۱ (PD-۱) is an immune checkpoint protein on T cells and it plays an important role in the interaction between tumors and T cells . The interaction of PD-۱ with its ligands PD-L۱ and PD-L۲ on cancer cells, leading to inhibition of the effector function, and apoptosis of T cells. Furthermore, blocking the interface area of the interaction PD-۱/PD-L۱ results in the normalization of antitumor response . In this study, high-specific binding antibodies have been designed using de novo method to block the immune checkpoints with the aim of cancer treatment. We used computational methods such Rosetta protein design package along with developing new codes to enhance the design process. At first, thousands of de novo designed antibodies have been generated and then the models with higher stability, a nity and shape complementarity values were selected. Then, MD simulation and MM-PBSA were used to measure the dynamics and stability as well as the binding a nity of each final design. The results obtained in this study showed that the designed antibodies bind selectively and with high potency to the PD-۱ receptor. We designed ۲۵۴۰۰ antibodies for di↵erent regions of PD-۱ and PDL-۱, docked them onto the targets, and identified %۱۹.۸۲ and %۳۰.۶ high-a nity antibodies, respectively. The PD-۱ structure has flexibility loops that adopt variable conformations by binding to antibodies, implying that these loops contribute to the binding a nity for antibodies and provide a “hotspots” region for Immune checkpoint therapy. The results demonstrated that mutation and optimization of the residues at the interface area of the CDRs, it helps the stability and high-a nity models.

کلیدواژه ها:

De Novo Design ، Antibody ، Immune checkpoints ، Protein-Protein Interactions