State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China.
Biomolecules. 2024 Jan 15;14(1):106. doi: 10.3390/biom14010106.
Acute T-lymphoblastic leukemia (T-ALL) is a type of leukemia that can occur in both pediatric and adult populations. Compared to acute B-cell lymphoblastic leukemia (B-ALL), patients with T-cell T-ALL have a poorer therapeutic efficacy. In this study, a novel anti-CD7 antibody-drug conjugate (ADC, J87-Dxd) was successfully generated and used for T-ALL treatment. Firstly, to obtain anti-CD7 mAbs, we expressed and purified the CD7 protein extracellular domain. Utilizing hybridoma technology, we obtained three anti-CD7 mAbs (J87, G73 and A15) with a high affinity for CD7. Both the results of immunofluorescence and Biacore assay indicated that J87 (KD = 1.54 × 10 M) had the highest affinity among the three anti-CD7 mAbs. In addition, an internalization assay showed the internalization level of J87 to be higher than that of the other two mAbs. Next, we successfully generated the anti-CD7 ADC (J87-Dxd) by conjugating DXd to J87 via a cleavable maleimide-GGFG peptide linker. J87-Dxd also possessed the ability to recognize and bind CD7. Using J87-Dxd to treat T-ALL cells (Jurkat and CCRF-CEM), we observed that J87-Dxd bound to CD7 was internalized into T-ALL cells. Moreover, J87-Dxd treatment significantly induced the apoptosis of Jurkat and CCRF-CEM cells. The IC50 (half-maximal inhibitory concentration) value of J87-Dxd against CCRF-CEM obtained by CCK-8 assay was 6.3 nM. Finally, to assess the antitumor efficacy of a J87-Dxd in vivo, we established T-ALL mouse models and treated mice with J87-Dxd or J87. The results showed that on day 24 after tumor inoculation, all mice treated with J87 or PBS died, whereas the survival rate of mice treated with J87-Dxd was 80%. H&E staining showed no significant organic changes in the heart, liver, spleen, lungs and kidneys of all mice. In summary, we demonstrated that the novel anti-CD7 ADC (J87-Dxd) had a potent and selective effect against CD7-expressing T-All cells both in vitro and in vivo, and could thus be expected to be further developed as a new drug for the treatment of T-ALL or other CD7-expression tumors.
急性 T 淋巴细胞白血病（T-ALL）是一种可发生于儿童和成人的白血病。与急性 B 细胞淋巴细胞白血病（B-ALL）相比，T 细胞 T-ALL 患者的治疗效果较差。在这项研究中，成功地生成了一种新型的抗 CD7 抗体药物偶联物（ADC，J87-Dxd），并将其用于 T-ALL 治疗。首先，为了获得抗 CD7 mAbs，我们表达和纯化了 CD7 蛋白胞外结构域。利用杂交瘤技术，我们获得了三种高亲和力抗 CD7 mAbs（J87、G73 和 A15）。免疫荧光和 Biacore 分析结果均表明，J87（KD=1.54×10-9 M）在三种抗 CD7 mAbs 中具有最高的亲和力。此外，内化实验表明 J87 的内化水平高于其他两种 mAbs。接下来，我们通过将 DXd 与 J87 通过可切割的马来酰亚胺-GGFG 肽接头连接，成功地生成了抗 CD7 ADC（J87-Dxd）。J87-Dxd 也具有识别和结合 CD7 的能力。用 J87-Dxd 治疗 T-ALL 细胞（Jurkat 和 CCRF-CEM），我们观察到与 CD7 结合的 J87-Dxd 被内化到 T-ALL 细胞中。此外，J87-Dxd 处理显著诱导 Jurkat 和 CCRF-CEM 细胞凋亡。CCK-8 测定法得到的 J87-Dxd 对 CCRF-CEM 的 IC50（半最大抑制浓度）值为 6.3 nM。最后，为了评估 J87-Dxd 在体内的抗肿瘤疗效，我们建立了 T-ALL 小鼠模型，并使用 J87-Dxd 或 J87 处理小鼠。结果表明，在肿瘤接种后第 24 天，用 J87 或 PBS 处理的所有小鼠均死亡，而用 J87-Dxd 处理的小鼠的存活率为 80%。H&E 染色显示所有小鼠的心脏、肝脏、脾脏、肺和肾脏均无明显器质性变化。总之，我们证明了新型抗 CD7 ADC（J87-Dxd）在体外和体内均对表达 CD7 的 T-ALL 细胞具有强大且选择性的作用，因此有望进一步开发为治疗 T-ALL 或其他 CD7 表达肿瘤的新药。
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