Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator
Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator
复制标题
DOI：
10.1002/art.11299
复制
发表时间：
2003-11-01
影响因子：
--
通讯作者：
Albert, VR
中科院分区：
文献类型：
--
作者：
Baker, KP;Edwards, BM;Albert, VR
Objective.鉴定和表征一种针对B淋巴细胞刺激因子（BLyS）的全人源抗体，BLyS是一种在调节B细胞成熟和发育中起关键作用的肿瘤坏死因子相关细胞因子。BLyS水平升高与自身免疫性疾病的发病机制有关。筛选针对人BLyS的抗体的人噬菌体展示文库。通过文库筛选和随后的亲和优化诱变，获得了对人BLyS具有特异性的人单克隆抗体，PhosphoStat-B。在体外和体内鼠模型中测试抗体对人BLyS的抑制。此外，通过向食蟹猴施用PhosphoStat-B在体内测试BLyS抑制的结果。PhosphoStat-B以高亲和力结合人BLyS，并抑制BLyS与其3种受体TACI、BCMA和BLyS受体3/BAFF-R的结合。PhosphoStat-B在体外有效抑制BLyS诱导的B细胞增殖，并且对小鼠施用PhosphoStat-B可防止人BLyS诱导的脾B细胞数量和伊加滴度增加。在食蟹猴中，给予PhosphoStat-B导致脾脏和肠系膜淋巴结中的B细胞表达减少。已分离出一种完全人源单克隆抗体，其以高亲和力结合BLyS并在体外和体内中和人BLyS生物活性。对食蟹猴给予该抗体导致脾脏和淋巴结中的B细胞耗竭。该抗体可证明在治疗人类自身免疫性疾病中具有治疗用途。
Objective. To identify and characterize a fully human antibody directed against B lymphocyte stimulator (BLyS), a tumor necrosis factor-related cytokine that plays a critical role in the regulation of B cell maturation and development. Elevated levels of BLyS have been implicated in the pathogenesis of autoimmune diseases.Methods. A human phage display library was screened for antibodies against human BLyS. A human monoclonal antibody, LymphoStat-B, specific for human BLyS was obtained from the library screening and subsequent affinity optimization mutagenesis. The antibody was tested for inhibition of human BLyS in vitro and in an in vivo murine model. Additionally, the consequences of BLyS inhibition were tested in vivo by administration of LymphoStat-B to cynomolgus monkeys.Results. LymphoStat-B bound with high affinity to human BLyS and inhibited the binding of BLyS to its 3 receptors, TACI, BCMA, and BLyS receptor 3/BAFF-R. LymphoStat-B potently inhibited BLyS-induced proliferation of B cells in vitro, and administration of LymphoStat-B to mice prevented human BLyS-induced increases in splenic B cell numbers and IgA titers. In cynomolgus monkeys, administration of LymphoStat-B resulted in decreased B cell representation in both spleen and mesenteric lymph nodes.Conclusion. A fully human monoclonal antibody has been isolated that binds to BLyS with high affinity and neutralizes human BLyS bioactivity in vitro and in vivo. Administration of this antibody to cynomolgus monkeys resulted in B cell depletion in spleen and lymph node. This antibody may prove therapeutically useful in the treatment of autoimmune diseases in humans.