Laddha Kapil, Sobhia M Elizabeth
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Mohali, Punjab, 160062, India.
Mol Divers. 2025 Jan 20. doi: 10.1007/s11030-024-11037-x.
CD47, a cell surface protein, serves as a "don't eat me" signal that prevents immune cells from engulfing healthy cells upon its interaction with SIRPα. Cancer cells exploit this mechanism by overexpressing CD47 to evade immune destruction. Blocking the interaction between CD47 and its receptor, SIRPα, is a promising therapeutic strategy. Targeting the interactions between these surface proteins with small molecules is quite challenging, and on the other hand, antibodies offer potential. However, the interactions between antigen (CD47) and antibody (B6H12.2) play a crucial role in this scenario, and increasing the affinity by mutating the interacting residues might impact the inclination and effectiveness of the antibody towards antigen. Thus, this study focuses on designing antibodies with increased affinity and stability towards the antigen compared to the wild-type. Residual scanning calculations were performed to mutate the interacting as well as the hydrophobic residues of the antibody and affinity was assessed. Computational approaches, including antigen-antibody docking studies and molecular dynamics simulations, were employed to evaluate the affinity, stability and therapeutic potential of these modified antibodies.
CD47是一种细胞表面蛋白，作为一种“别吃我”信号，当其与信号调节蛋白α（SIRPα）相互作用时，可防止免疫细胞吞噬健康细胞。癌细胞通过过度表达CD47来利用这一机制逃避免疫破坏。阻断CD47与其受体SIRPα之间的相互作用是一种很有前景的治疗策略。用小分子靶向这些表面蛋白之间的相互作用颇具挑战性，而抗体则具有潜力。然而，抗原（CD47）与抗体（B6H12.2）之间的相互作用在这种情况下起着关键作用，通过突变相互作用残基来提高亲和力可能会影响抗体对抗原的倾向性和有效性。因此，本研究的重点是设计出与野生型相比对抗原具有更高亲和力和稳定性的抗体。进行了残基扫描计算，以突变抗体的相互作用残基和疏水残基，并评估亲和力。采用包括抗原-抗体对接研究和分子动力学模拟在内的计算方法，评估这些修饰抗体的亲和力、稳定性和治疗潜力。
