Adimab, LLC, Lebanon, NH 03766, USA.
Adimab, LLC, Lebanon, NH 03766, USA.
Cell Rep. 2019 Sep 24;28(13):3300-3308.e4. doi: 10.1016/j.celrep.2019.08.056.
Monoclonal antibodies (mAbs) have recently emerged as one of the most promising classes of biotherapeutics. A potential advantage of B cell-derived mAbs as therapeutic agents is that they have been subjected to natural filtering mechanisms, which may enrich for B cell receptors (BCRs) with favorable biophysical properties. Here, we evaluated 400 human mAbs for polyreactivity, hydrophobicity, and thermal stability using high-throughput screening assays. Overall, mAbs derived from memory B cells and long-lived plasma cells (LLPCs) display reduced levels of polyreactivity, hydrophobicity, and thermal stability compared with naive B cell-derived mAbs. Somatic hypermutation (SHM) is inversely associated with all three biophysical properties, as well as BCR expression levels. Finally, the developability profiles of the human B cell-derived mAbs are comparable with those observed for clinical mAbs, suggesting their high therapeutic potential. The results provide insight into the biophysical consequences of affinity maturation and have implications for therapeutic antibody engineering and development.
单克隆抗体（mAbs）最近已成为最有前途的生物治疗药物之一。B 细胞衍生的 mAbs 作为治疗剂的一个潜在优势是，它们已经经过自然过滤机制的筛选，这可能会富集具有有利物理特性的 B 细胞受体（BCR）。在这里，我们使用高通量筛选检测评估了 400 个人类 mAbs 的多反应性、疏水性和热稳定性。总体而言，与初始 B 细胞衍生的 mAbs 相比，记忆 B 细胞和长寿浆细胞（LLPC）衍生的 mAbs 的多反应性、疏水性和热稳定性水平降低。体细胞高频突变（SHM）与这三种物理特性以及 BCR 表达水平呈负相关。最后，人 B 细胞衍生的 mAbs 的可开发性特征与临床 mAbs 观察到的特征相当，这表明它们具有很高的治疗潜力。这些结果提供了对亲和力成熟的物理后果的深入了解，并对治疗性抗体工程和开发具有重要意义。
