Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006, Paris, France.
Commun Biol. 2021 Mar 23;4(1):391. doi: 10.1038/s42003-021-01931-7.
Immunoglobulin repertoires contain a fraction of antibodies that recognize low molecular weight compounds, including some enzymes' cofactors, such as heme. Here, by using a set of 113 samples with variable region sequences matching clinical-stage antibodies, we demonstrated that a considerable number of these antibodies interact with heme. Antibodies that interact with heme possess specific sequence traits of their antigen-binding regions. Moreover they manifest particular physicochemical and functional qualities i.e. increased hydrophobicity, higher propensity of self-binding, higher intrinsic polyreactivity and reduced expression yields. Thus, interaction with heme is a strong predictor of different molecular and functional qualities of antibodies. Notably, these qualities are of high importance for therapeutic antibodies, as their presence was associated with failure of drug candidates to reach clinic. Our study reveled an important facet of information about relationship sequence-function in antibodies. It also offers a convenient tool for detection of liabilities of therapeutic antibodies.
免疫球蛋白库中包含一部分能够识别小分子化合物的抗体，包括一些酶的辅因子，如血红素。在这里，我们使用了一组 113 个具有匹配临床阶段抗体可变区序列的样本，证明了相当数量的这些抗体与血红素相互作用。与血红素相互作用的抗体具有其抗原结合区域的特定序列特征。此外，它们表现出特殊的物理化学和功能特性，即增加疏水性、更高的自结合倾向、更高的固有多反应性和降低表达产量。因此，与血红素的相互作用是抗体不同分子和功能特性的强有力预测因子。值得注意的是，这些特性对于治疗性抗体非常重要，因为它们的存在与候选药物未能进入临床阶段有关。我们的研究揭示了抗体中序列-功能关系信息的一个重要方面。它还为检测治疗性抗体的缺陷提供了一个方便的工具。
