肿瘤细胞治疗研究
英文原题：Revisiting the Ofatumumab Epitope on CD20 through Integrative Molecular Dynamics and Flow Cytometry Analyses.
奥法木单抗是一种全人源抗CD20抗体，用于B细胞恶性肿瘤和自身免疫性疾病，但其精确的表位识别仍未完全明确。
Ofatumumab是一种全人源抗CD20抗体，用于B细胞恶性肿瘤和自身免疫性疾病，但其精确的表位识别仍未完全明确。本研究结合分子动力学模拟、结合自由能分析和流式细胞术，阐明了CD20结合的结构基础。单链可变区识别一个主要集中于胞外环2b/胞外螺旋2的近膜表位，该表位由涉及Y105-Y107-Y169簇和Arg228的疏水及静电相互作用所稳定，而Asp99和Tyr107的突变破坏了互补决定区稳定性并显著降低了细胞结合。这些结果完善了ofatumumab单链可变区-CD20识别的分子模型，并提供了原子水平的见解，可能有助于下一代抗CD20和CAR-T 细胞疗法的设计。
Ofatumumab is a fully human anti-CD20 antibody used in B-cell malignancies and autoimmune disorders, yet its precise epitope recognition remains incompletely defined. Here, molecular dynamics simulations, binding free-energy analyses, and flow cytometry were combined to elucidate the structural basis of CD20 binding. The single-chain variable fragment recognizes a membrane-proximal epitope primarily centered on extracellular loop 2b/extracellular helix 2, stabilized by hydrophobic and electrostatic interactions involving the Y105-Y107-Y169 cluster and Arg228, while mutations at Asp99 and Tyr107 disrupted paratope stability and markedly reduced cellular binding. These results refine the molecular model of ofatumumab single-chain variable fragment-CD20 recognition and provide atomic-level insights that may assist the design of next-generation anti-CD20 and chimeric antigen receptor T-cell therapeutics.
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