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An IgG1-like bispecific antibody targeting CD52 and CD20 for the treatment of B-cell malignancies
Methods ( IF 4.2 ) Pub Date : 2019-02-01 , DOI: 10.1016/j.ymeth.2018.08.008
Junpeng Qi , Shih-Shih Chen , Nicholas Chiorazzi , Christoph Rader

Bispecific antibodies (biAb) targeting two different antigens or two distinct epitopes on the same antigen have demonstrated broad therapeutic utility. CD52 and CD20 are co-expressed on the cell surface of malignant B cells in B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) and increased expression of both antigens is detected on dividing or recently divided cells ("proliferative fraction") in CLL. The CD52-targeting monoclonal antibody (mAb) alemtuzumab (atz) not only depletes malignant B cells but also healthy CD52+ B and T lymphocytes and monocytes, causing severe immunosuppression. Loss of CD20 can occur in CLL after treatment with rituximab (rtx) and other CD20-targeting mAbs. To broaden the benefit of atz and rtx, we engineered an IgG1-like biAb, atz × rtx scFv-Fc. The Fc fragment of the biAb facilitates purification by Protein A affinity chromatography and supports a longer circulatory half-life. While atz × rtx scFv-Fc retained both antigen binding specificities, it showed superior binding to CD52+CD20+ B cells compared to CD52+CD20- T cells. Moreover, atz × rtx scFv-Fc mediated potent complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in vitro and exhibited B-cell depleting but T-cell sparing activities in vivo in a CLL patient-derived xenograft model. B-cell depletion was more pronounced for cells of the proliferative fraction.

中文翻译:

一种靶向 CD52 和 CD20 的 IgG1 样双特异性抗体,用于治疗 B 细胞恶性肿瘤

靶向两种不同抗原或同一抗原上的两种不同表位的双特异性抗体 (biAb) 已证明具有广泛的治疗效用。CD52 和 CD20 在 B 细胞非霍奇金淋巴瘤 (B-NHL) 和慢性淋巴细胞白血病 (CLL) 的恶性 B 细胞的细胞表面共表达,并且在分裂或最近分裂的细胞上检测到两种抗原的表达增加。 CLL 中的“增殖分数”)。CD52 靶向单克隆抗体 (mAb) 阿仑单抗 (atz) 不仅会消耗恶性 B 细胞,还会消耗健康的 CD52+ B 和 T 淋巴细胞和单核细胞,导致严重的免疫抑制。在用利妥昔单抗 (rtx) 和其他 CD20 靶向单克隆抗体治疗后,CLL 可能会丢失 CD20。为了扩大 atz 和 rtx 的优势,我们设计了一种 IgG1 样 biAb,atz × rtx scFv-Fc。biAb 的 Fc 片段有助于通过蛋白 A 亲和层析进行纯化,并支持更长的循环半衰期。虽然 atz × rtx scFv-Fc 保留了两种抗原结合特异性,但与 CD52+CD20-T 细胞相比,它显示出对 CD52+CD20+B 细胞的更好结合。此外,atz × rtx scFv-Fc 在体外介导强效补体依赖性细胞毒性 (CDC) 和抗体依赖性细胞毒性 (ADCC),并在 CLL 患者来源的异种移植模型中表现出 B 细胞消耗但 T 细胞保留活性. 对于增殖部分的细胞,B 细胞耗竭更为明显。与 CD52+CD20-T 细胞相比,它显示出对 CD52+CD20+B 细胞的更好结合。此外,atz × rtx scFv-Fc 在体外介导强效补体依赖性细胞毒性 (CDC) 和抗体依赖性细胞毒性 (ADCC),并在 CLL 患者来源的异种移植模型中表现出 B 细胞消耗但 T 细胞保留活性. 对于增殖部分的细胞,B 细胞耗竭更为明显。与 CD52+CD20-T 细胞相比,它显示出对 CD52+CD20+B 细胞的更好结合。此外,atz × rtx scFv-Fc 在体外介导强效补体依赖性细胞毒性 (CDC) 和抗体依赖性细胞毒性 (ADCC),并在 CLL 患者来源的异种移植模型中表现出 B 细胞消耗但 T 细胞保留活性. 对于增殖部分的细胞,B 细胞耗竭更为明显。
更新日期:2019-02-01
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