Using phage display, we generated a panel of optimized neutralizing antibodies against the human and mouse receptors for interleukin 21 (IL-21), a cytokine that is implicated in the pathogenesis of many types of autoimmune disease. Two antibodies, Ab-01 and Ab-02, which differed by only four amino acids in V_L CDR3, showed potent inhibition of human and mouse IL-21R in cell-based assays and were evaluated for their pharmacological and pharmacodynamic properties. Ab-01, but not Ab-02, significantly reduced a biomarker of disease (anti-dsDNA antibodies) and IgG deposits in the kidney in the MRL-Fas^lpr mouse model of lupus, suggesting that anti-IL-21R antibodies may prove useful in the treatment of lupus. Ab-01 also had a consistently higher exposure (AUC0_-∞) than Ab-02 following a single dose in rodents or cynomolgus monkeys (2-3-fold or 4-7-fold, respectively). Our data demonstrate that small differences in CDR3 sequences of optimized antibodies can lead to profound differences in in vitro and in vivo properties, including differences in pharmacological activity and pharmacokinetic profiles. The lack of persistent activity of Ab-02 in the MRL-Fas^lpr mouse lupus model may have been a consequence of faster elimination, reduced potency in blocking the effects of mouse IL-21R, and more potent/earlier onset of the anti-product response relative to Ab-01.

使用噬菌体展示，我们生成了一组针对人类和小鼠白细胞介素 21 (IL-21) 受体的优化中和抗体，IL-21 是一种与多种类型自身免疫疾病的发病机制有关的细胞因子。两种抗体 Ab-01 和 Ab-02 在 V _L CDR3 中仅相差四个氨基酸，在基于细胞的测定中显示出对人和小鼠 IL-21R 的有效抑制，并评估了它们的药理学和药效学特性。在 MRL- Fas ^lpr狼疮小鼠模型中，Ab-01（而非 Ab-02）显着降低了疾病的生物标志物（抗 dsDNA 抗体）和肾脏 IgG 沉积，表明抗 IL-21R 抗体可能有用在狼疮的治疗中。Ab-01 的暴露量也一直较高（AUC0 _-∞) 在啮齿动物或食蟹猴中单次给药后的 Ab-02 (分别为 2-3 倍或 4-7 倍)。我们的数据表明，优化抗体的 CDR3 序列的微小差异会导致体外和体内特性的巨大差异，包括药理活性和药代动力学特征的差异。在 MRL- Fas ^lpr小鼠狼疮模型中缺乏 Ab-02 的持续活性可能是由于更快的消除、阻断小鼠 IL-21R 作用的效力降低以及抗产品更有效/更早起效的结果相对于 Ab-01 的反应。