IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells.

IF 29.5 1区 医学 Q1 HEMATOLOGY
Yi Zhang, Miso Park, Lucy Y Ghoda, Dandan Zhao, Melissa Valerio, Ebtesam Nafie, Asaul Gonzalez, Kevin Ly, Bea Parcutela, Hyeran Choi, Xubo Gong, Fang Chen, Kaito Harada, Zhenhua Chen, Le Xuan Truong Nguyen, Flavia Pichiorri, Jianjun Chen, Joo Song, Stephen J Forman, Idoroenyi Amanam, Bin Zhang, Jie Jin, John C Williams, Guido Marcucci
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引用次数: 0

Abstract

Background: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML.

Methods: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples.

Results: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002).

Conclusions: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

IL1RAP 特异性 T 细胞吸引器可消耗急性髓性白血病干细胞。
背景:白细胞介素-1受体附属蛋白(IL1RAP)在急性髓性白血病(AML)散粒细胞和白血病干细胞(LSCs)上高表达,但在正常造血干细胞(HSCs)上不表达,这为靶向治疗和消除疾病提供了机会,同时也保护了正常造血。在此,我们报告了新型抗IL1RAP/CD3 T细胞诱导剂(TCE)BIF002在AML中的活性:方法:通过光电定位和单细胞测序从免疫小鼠的 CD138+ B 细胞中分离出 IL1RAP 抗体。在此基础上,我们利用Fab臂交换法生成了抗人IL1RAP/CD3 TCE抗体BIF002。我们在人类 IgG1 Fc 中引入了突变,以减少 FcγR 的结合。利用多种细胞系和来自急性髓细胞性白血病患者的样本对 BIF002 的体外和体内抗白血病活性进行了鉴定:结果发现,IL1RAP在大多数人类急性髓细胞白血病细胞系和原发性爆炸细胞(包括来自新发和复发/难治性(R/R)白血病患者的CD34+造血干细胞富集亚群)上高表达,但在正常造血干细胞上不表达。在来自健康供体的T细胞与IL1RAP高的AML细胞系和原发性白血病细胞的共培养中,BIF002能在亚纳摩尔浓度下诱导剂量和效应目标(E:T)比依赖性的T细胞活化和白血病细胞裂解。与对照组相比,BIF002 与人类 T 细胞一起静脉注射可消耗白血病细胞,并显著延长 IL1RAP 高的 MOLM13 或 AML 患者衍生异种移植物的存活时间,且无脱靶副作用。值得注意的是,BiF002能有效地重新定向T细胞以消除LSCs,这一点从BIF002+T细胞处理供体骨髓(BM)的二次受体(未达到中位生存期;所有受体的生存期均大于200天)与接受车辆处理供体骨髓(中位生存期:26天;p = 0.0004)或同型对照抗体+T细胞处理供体骨髓(26天;p = 0.0002)的受体相比没有出现疾病开始即可看出:结论:新型抗IL1RAP/CD3 TCE(BIF002)可消灭LSCs并显著延长急性髓细胞性白血病异种移植的存活时间,是治疗急性髓细胞性白血病的一种前景广阔的新型疗法。
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来源期刊
CiteScore
48.10
自引率
2.10%
发文量
169
审稿时长
6-12 weeks
期刊介绍: The Journal of Hematology & Oncology, an open-access journal, publishes high-quality research covering all aspects of hematology and oncology, including reviews and research highlights on "hot topics" by leading experts. Given the close relationship and rapid evolution of hematology and oncology, the journal aims to meet the demand for a dedicated platform for publishing discoveries from both fields. It serves as an international platform for sharing laboratory and clinical findings among laboratory scientists, physician scientists, hematologists, and oncologists in an open-access format. With a rapid turnaround time from submission to publication, the journal facilitates real-time sharing of knowledge and new successes.
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