CD46和CD59抑制剂能增强抗CD38单克隆抗体daratumumab和isatuximab对多发性骨髓瘤和其他B细胞恶性肿瘤细胞的补体依赖性细胞毒性。

IF 4.4 4区 医学 Q2 ONCOLOGY Cancer Biology & Therapy Pub Date : 2024-12-31 Epub Date: 2024-02-15 DOI:10.1080/15384047.2024.2314322
Hongjie Wang, Theo Koob, Jonathan R Fromm, Ajay Gopal, Darrick Carter, André Lieber
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引用次数: 0

摘要

多发性骨髓瘤(MM)是一种无法治愈的B细胞系恶性肿瘤。达拉土单抗和伊沙妥昔单抗等抗CD38单克隆抗体可通过诱导补体依赖性细胞毒性(CDC)杀死骨髓瘤细胞,在治疗骨髓瘤方面取得了显著进展。我们的研究表明,达拉土单抗和伊沙妥昔单抗的补体依赖性细胞毒性(CDC)疗效受到膜补体抑制剂的限制,包括在 MM 细胞中上调的 CD46 和 CD59。我们最近开发了一种小型重组蛋白 Ad35K++,它能够瞬时清除细胞表面的 CD46。我们还生产了一种 CD59 多肽抑制剂(rILYd4)。在这项研究中,我们测试了 Ad35K++ 和 rILYd4 与达拉单抗和伊沙妥昔单抗在 MM 细胞以及其他两种 B 细胞恶性肿瘤细胞中的联合应用。我们发现,Ad35K++ 和 rILYd4 增加了达拉土单抗和伊沙妥昔单抗引发的 CDC。在体外原发性 MM 细胞以及体内小鼠异种移植 MM 模型中,这两种抑制剂的组合具有叠加效应。达拉土单抗和伊沙妥昔单抗治疗 MM 株系(不含 Ad35K++ 或 rILYd4)会导致 CD46/CD59 上调和/或 CD46 高/CD59 高的 MM 细胞存活,这些细胞逃脱了第二轮达拉土单抗和伊沙妥昔单抗的治疗。用 Ad35K++ 对细胞进行预处理可防止细胞在第二轮治疗中逃逸。总之,我们的数据表明,Ad35K++和rILYd4是达拉单抗和伊沙妥昔单抗的高效协同治疗药物,特别是在多周期治疗方案中,可用于改善多发性骨髓瘤的治疗。
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CD46 and CD59 inhibitors enhance complement-dependent cytotoxicity of anti-CD38 monoclonal antibodies daratumumab and isatuximab in multiple myeloma and other B-cell malignancy cells.

Multiple myeloma (MM) is an incurable malignancy of the B-cell lineage. Remarkable progress has been made in the treatment of MM with anti-CD38 monoclonal antibodies such as daratumumab and isatuximab, which can kill MM cells by inducing complement-dependent cytotoxicity (CDC). We showed that the CDC efficacy of daratumumab and isatuximab is limited by membrane complement inhibitors, including CD46 and CD59, which are upregulated in MM cells. We recently developed a small recombinant protein, Ad35K++, which is capable of transiently removing CD46 from the cell surface. We also produced a peptide inhibitor of CD59 (rILYd4). In this study, we tested Ad35K++ and rILYd4 in combination with daratumumab and isatuximab in MM cells as well as in cells from two other B-cell malignancies. We showed that Ad35K++ and rILYd4 increased CDC triggered by daratumumab and isatuximab. The combination of both inhibitors had an additive effect in vitro in primary MM cells as well as in vivo in a mouse xenograft model of MM. Daratumumab and isatuximab treatment of MM lines (without Ad35K++ or rILYd4) resulted in the upregulation of CD46/CD59 and/or survival of CD46high/CD59high MM cells that escaped the second round of daratumumab and isatuximab treatment. The escape in the second treatment cycle was prevented by the pretreatment of cells with Ad35K++. Overall, our data demonstrate that Ad35K++ and rILYd4 are efficient co-therapeutics of daratumumab and isatuximab, specifically in multi-cycle treatment regimens, and could be used to improve treatment of multiple myeloma.

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来源期刊
Cancer Biology & Therapy
Cancer Biology & Therapy 医学-肿瘤学
CiteScore
7.00
自引率
0.00%
发文量
60
审稿时长
2.3 months
期刊介绍: Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
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