Engineering and characterization of Hu3A4: A novel humanized antibody with potential as a therapeutic agent against myeloid lineage leukemias.

IF 6.3 2区医学 Q1 ONCOLOGY

Neoplasia Pub Date : 2024-11-20 DOI:10.1016/j.neo.2024.101084

Sisi Li, Zhujun Wang, Xiaoping Guo, Yongmin Tang

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引用次数: 0

Abstract

Leukemia stem cells (LSCs) play a critical role in the initiation, recurrence, and resistance to treatment of leukemia. Eradicating LSCs is crucial for the complete elimination of the disease. CD45RA is identified as an important marker for LSC subsets in acute myeloid leukemia (AML), providing a strategic target for therapy. In this report, we introduce Hu3A4, an innovative humanized CD45RA antibody devised to target LSCs expressing this antigen. Hu3A4 retains the antigen-recognition ability of its parental antibody while removing sequences from the variable region that could elicit human anti-mouse immune reactions. The modified variable regions of the heavy and light chains were intricately fused with the constant regions of human IgG1 heavy and light chains, respectively, producing a humanized antibody that emulates the structure of natural IgG. Hu3A4 was produced through recombinant expression in Chinese Hamster Ovary (CHO) cells, which ensured stable gene integration. In vitro tests revealed that Hu3A4 could effectively target and lyse the cells. Further, in vivo studies highlighted Hu3A4's substantial anti-leukemic activity, significantly prolonging survival times in treated animal models compared to controls (P < 0.01). To summarize, Hu3A4 exhibits remarkable bioactivity and offers a promising therapeutic potential for the treatment of leukemia patients. Progressing Hu3A4 through additional preclinical and clinical studies is crucial to validate its efficacy as a therapeutic agent for leukemia.

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Hu3A4的工程设计和特征描述：一种新型人源化抗体，具有治疗髓系白血病的潜力。

白血病干细胞（LSCs）在白血病的发病、复发和抗药性方面起着至关重要的作用。根除白血病干细胞对彻底治愈白血病至关重要。CD45RA 被确定为急性髓性白血病（AML）中 LSC 亚群的重要标志物，为治疗提供了战略目标。在本报告中，我们介绍了一种创新的人源化 CD45RA 抗体 Hu3A4，该抗体专为靶向表达该抗原的 LSCs 而设计。Hu3A4 保留了亲代抗体的抗原识别能力，同时去除了可变区中可能引起人类抗小鼠免疫反应的序列。经过修饰的重链和轻链的可变区分别与人 IgG1 重链和轻链的恒定区进行了复杂的融合，从而产生了仿天然 IgG 结构的人源化抗体。Hu3A4 在中国仓鼠卵巢（CHO）细胞中重组表达，确保了基因整合的稳定性。体外测试表明，Hu3A4 能有效靶向并裂解细胞。此外，体内研究强调了 Hu3A4 的抗白血病活性，与对照组相比，治疗后动物模型的存活时间明显延长（P < 0.01）。总之，Hu3A4 具有显著的生物活性，为治疗白血病患者提供了广阔的治疗前景。要验证 Hu3A4 作为白血病治疗药物的疗效，通过更多的临床前和临床研究取得进展至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neoplasia ONCOLOGY-

自引率

2.10%

发文量

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.