Abstract B-cell activating factor receptor (BAFF-R) is a mature B-cell survival receptor, which is highly expressed in a wide variety of B-cell malignancies but with minimal expression in immature B cells. These properties make BAFF-R an attractive target for therapy of B-cell lymphomas. We generated a novel humanized anti BAFF-R monoclonal antibody (mAb) with high specificity and potent in vitro and in vivo activity against B-cell lymphomas and leukemias. The humanized variants of an original chimeric BAFF-R mAb retained BAFF-R binding affinity and antibody-dependent cellular cytotoxicity (ADCC) against a panel of human cell lines and primary lymphoma samples. Furthermore, 1 humanized BAFF-R mAb clone and its afucosylated version, glycoengineered to optimize the primary mechanism of action, prolonged survival of immunodeficient mice bearing human tumor cell lines or patient-derived lymphoma xenografts in 3 separate models, compared with controls. Finally, the tissue specificity of this humanized mAb was confirmed against a broad panel of normal human tissues. Taken together, we have identified a robust lead-candidate BAFF-R mAb for clinical development.

中文翻译：

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产生具有广泛抗人 B 细胞恶性肿瘤活性的人源化无岩藻糖基化 BAFF-R 抗体


摘要B 细胞激活因子受体 (BAFF-R) 是一种成熟的 B 细胞存活受体，在多种 B 细胞恶性肿瘤中高表达，但在未成熟 B 细胞中表达极少。这些特性使 BAFF-R 成为 B 细胞淋巴瘤治疗的有吸引力的靶点。我们产生了一种新型人源化抗 BAFF-R 单克隆抗体 (mAb)，具有高特异性和有效的体外和体内抗 B 细胞淋巴瘤和白血病活性。原始嵌合 BAFF-R mAb 的人源化变体保留了针对一组人类细胞系和原发性淋巴瘤样本的 BAFF-R 结合亲和力和抗体依赖性细胞毒性 (ADCC)。此外，1 个人源化 BAFF-R mAb 克隆及其无岩藻糖基化版本经过糖基化改造，优化了主要作用机制，与对照相比，在 3 个不同的模型中延长了携带人类肿瘤细胞系或患者来源的淋巴瘤异种移植物的免疫缺陷小鼠的生存期。最后，这种人源化单克隆抗体针对广泛的正常人体组织的组织特异性得到了证实。总而言之，我们已经确定了一种用于临床开发的强大的候选 BAFF-R mAb。