Manetta Joseph, Bina Holly, Ryan Paul, Fox Niles, Witcher Derrick R, Kikly Kristine
Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
J Inflamm Res. 2014 Aug 20;7:121-31. doi: 10.2147/JIR.S67751. eCollection 2014.
B-cell activating factor (BAFF) is a B-cell survival factor with a key role in B-cell homeostasis and tolerance. Dysregulated BAFF expression may contribute to autoimmune diseases or B-cell malignancies via effects on abnormal B-lymphocyte activation, proliferation, survival, and immunoglobulin secretion. Monoclonal antibodies were generated against human BAFF, characterized for species specificity and affinity, and screened for the ability to neutralize both membrane-bound and soluble BAFF. In addition, studies were undertaken to determine the relative potency of membrane-bound and soluble BAFF. Tabalumab has a high affinity for human, cynomolgus monkey, and rabbit BAFF. No binding to mouse BAFF was detected. Tabalumab was able to neutralize soluble human, cynomolgus monkey, or rabbit BAFF with equal potency. Our data demonstrate that membrane-bound BAFF can be a more potent stimulus for B-cells than soluble BAFF, and tabalumab also neutralized membrane-bound BAFF. Tabalumab prevented BAFF from binding to BAFF receptors and demonstrated pharmacodynamic effects in human BAFF transgenic mice. Tabalumab is a high-affinity human antibody with neutralizing activity against membrane-bound and soluble BAFF. Given our findings that membrane-bound BAFF can have greater in vitro potency than soluble BAFF, neutralization of both forms of BAFF is likely to be important for optimal therapeutic effect.
B细胞活化因子（BAFF）是一种B细胞存活因子，在B细胞稳态和耐受性中起关键作用。BAFF表达失调可能通过影响异常B淋巴细胞的活化、增殖、存活和免疫球蛋白分泌，导致自身免疫性疾病或B细胞恶性肿瘤。制备了针对人BAFF的单克隆抗体，对其物种特异性和亲和力进行了表征，并筛选了中和膜结合型和可溶性BAFF的能力。此外，还进行了研究以确定膜结合型和可溶性BAFF的相对效力。他巴鲁单抗对人、食蟹猴和兔BAFF具有高亲和力。未检测到与小鼠BAFF的结合。他巴鲁单抗能够以同等效力中和可溶性人、食蟹猴或兔BAFF。我们的数据表明，膜结合型BAFF对B细胞的刺激作用可能比可溶性BAFF更强，并且他巴鲁单抗也能中和膜结合型BAFF。他巴鲁单抗可阻止BAFF与BAFF受体结合，并在人BAFF转基因小鼠中显示出药效学作用。他巴鲁单抗是一种具有中和膜结合型和可溶性BAFF活性的高亲和力人源抗体。鉴于我们发现膜结合型BAFF在体外可能比可溶性BAFF具有更强的效力，中和两种形式的BAFF可能对于获得最佳治疗效果很重要。
