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225Ac 标记的 CD33 靶向抗体逆转急性髓系白血病模型中对 Bcl-2 抑制剂 venetoclax 的耐药性。

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models.

机构信息

University of Saskatchewan, Saskatoon, Canada.

Actinium Pharmaceuticals Inc, New York, USA.

出版信息

Cancer Med. 2021 Feb;10(3):1128-1140. doi: 10.1002/cam4.3665. Epub 2020 Dec 21.

DOI:10.1002/cam4.3665
PMID:33347715
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7897952/
Abstract

PURPOSE

Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low-dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. Actinium-lintuzumab ( Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single-agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer.

EXPERIMENTAL DESIGN

Here we investigated the potential for Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML.

RESULTS

We demonstrated that Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models.

CONCLUSIONS

There results suggest that the combination of Ac-lintuzumab with venetoclax is a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML. Clinical trial of this combination therapy (NCT03867682) is currently ongoing.

摘要

目的

尽管有新的药物可用，但许多急性髓系白血病 (AML) 患者无法缓解，预后仍然较差。 Venetoclax 是一种有前途的新型疗法，已获准与低剂量阿糖胞苷联合用于治疗新诊断的年龄较大的 AML 患者或不适合强化化疗的患者。 Actinium-lintuzumab (Ac-lintuzumab) 是一种针对 CD33 的临床阶段放射免疫疗法，在复发性/难治性 AML 中已显示出单药活性的证据。 MCL-1 的过度表达是 Venetoclax 耐药性的介质。

实验设计

在这里，我们研究了 Ac-lintuzumab 靶向 DNA 损伤抑制 MCL-1 水平的潜力，作为逆转 Venetoclax 在两种 AML 临床前体内模型中耐药性的可能机制。

结果

我们证明，与单独使用任何一种药物相比，Ac-lintuzumab 联合 Venetoclax 在 Venetoclax 耐药的 AML 细胞系中通过诱导双链 DNA 断裂 (DSB) 和耗尽 MCL-1 蛋白水平，协同增加肿瘤细胞杀伤。此外，这种联合治疗在 Venetoclax 耐药的体内 AML 模型中导致显著的肿瘤生长控制和延长的生存获益。

结论

这些结果表明，Ac-lintuzumab 与 Venetoclax 的联合是治疗 Venetoclax 耐药 AML 患者的一种很有前途的治疗策略。该联合治疗的临床试验（NCT03867682）目前正在进行中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf5c/7897952/05a82399e3c8/CAM4-10-1128-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf5c/7897952/b1f2220fe063/CAM4-10-1128-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf5c/7897952/d365b147a1eb/CAM4-10-1128-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf5c/7897952/9770d248dfb1/CAM4-10-1128-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf5c/7897952/05a82399e3c8/CAM4-10-1128-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf5c/7897952/b1f2220fe063/CAM4-10-1128-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf5c/7897952/4444c58d4e8f/CAM4-10-1128-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf5c/7897952/05a82399e3c8/CAM4-10-1128-g007.jpg

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