Specificity is one of the most important and complex properties that is central to both natural antibody function and therapeutic antibody efficacy. However, it has proven extremely challenging to define robust guidelines for predicting antibody specificity. Here we evaluated the physicochemical determinants of antibody specificity for multiple panels of antibodies, including >100 clinical-stage antibodies. Surprisingly, we find that the theoretical net charge of the complementarity-determining regions (CDRs) is a strong predictor of antibody specificity. Antibodies with positively charged CDRs have a much higher risk of low specificity than antibodies with negatively charged CDRs. Moreover, the charge of the entire set of six CDRs is a much better predictor of antibody specificity than the charge of individual CDRs, variable domains (VH or VL) or the entire variable fragment (Fv). The best indicators of antibody specificity in terms of CDR amino acid composition are reduced levels of arginine and lysine and increased levels of aspartic and glutamic acid. Interestingly, clinical-stage antibodies with negatively charged CDRs also have a lower risk for poor biophysical properties in general, including a reduced risk for high levels of self-association. These findings provide powerful guidelines for predicting antibody specificity and for identifying safe and potent antibody therapeutics.

中文翻译：

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抗体互补决定区的净电荷是特异性的关键指标。

特异性是最重要和最复杂的特性之一，它对天然抗体功能和治疗性抗体功效均至关重要。然而，事实证明，定义用于预测抗体特异性的可靠指南非常具有挑战性。在这里，我们评估了多种抗体（包括> 100种临床阶段抗体）的抗体特异性的理化决定因素。令人惊讶地，我们发现互补决定区（CDR）的理论净电荷是抗体特异性的强预测剂。带负电荷的CDR的抗体比带负电荷的CDR的抗体具有更低的低特异性风险。此外，整个六个CDR的电荷比单个CDR的电荷更好地预测了抗体的特异性，可变域（VH或VL）或整个可变片段（Fv）。就CDR氨基酸组成而言，抗体特异性的最佳指标是精氨酸和赖氨酸水平降低以及天冬氨酸和谷氨酸水平升高。有趣的是，带有负电荷CDR的临床阶段抗体通常也具有较低的生物物理特性差的风险，包括降低的高水平自我缔合风险。这些发现为预测抗体特异性和鉴定安全有效的抗体疗法提供了有力的指导。通常，带有带负电荷CDR的临床阶段抗体通常具有较低的生物物理特性差的风险，包括降低了高水平自我缔合的风险。这些发现为预测抗体特异性和鉴定安全有效的抗体疗法提供了有力的指导。通常，带有带负电荷CDR的临床阶段抗体通常具有较低的生物物理特性差的风险，包括降低了高水平自我缔合的风险。这些发现为预测抗体特异性和鉴定安全有效的抗体疗法提供了有力的指导。