Seidler Clarissa A, Spanke Vera A, Gamper Jakob, Bujotzek Alexander, Georges Guy, Liedl Klaus R
Department of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria.
Roche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany.
MAbs. 2025 Dec;17(1):2507950. doi: 10.1080/19420862.2025.2507950. Epub 2025 May 25.
The Observed Antibody Space provides the most abundant collection of annotated paired antibody variable domain sequences, thus offering a unique platform for the systematic investigation of the factors governing the pairing of antibody heavy and light chains. By examining a range of characteristics, including amino acid conservation, structural features, charge distribution, and interface residue identity, we challenge the prevailing assumption that pairing is random. Our findings indicate that specific physicochemical properties of single amino acid residues may influence the compatibility and affinity of heavy and light chain combinations. Further structural analyses based on antibody Fv fragments deposited in the Protein Data Bank (PDB) provide insights into the underlying structural features driving these pairing preferences, including a novel definition for the residues constituting the V-V interface, based on a collection of over 3500 structures. These results have significant implications for understanding antibody assembly and may guide the rational design of therapeutic antibodies with desired properties. Moreover, we provide a complete description and reference characterizing the various human germlines.
观察到的抗体空间提供了注释配对抗体可变结构域序列最丰富的集合，从而为系统研究控制抗体重链和轻链配对的因素提供了一个独特的平台。通过研究一系列特征，包括氨基酸保守性、结构特征、电荷分布和界面残基同一性，我们对配对是随机的这一普遍假设提出了挑战。我们的研究结果表明，单个氨基酸残基的特定物理化学性质可能会影响重链和轻链组合的兼容性和亲和力。基于蛋白质数据库（PDB）中 deposited 的抗体 Fv 片段进行的进一步结构分析，深入了解了驱动这些配对偏好的潜在结构特征，包括基于 3500 多个结构的集合对构成 V-V 界面的残基的新定义。这些结果对理解抗体组装具有重要意义，并可能指导具有所需特性的治疗性抗体的合理设计。此外，我们提供了对各种人类种系的完整描述和参考特征。
