Matteo Bianchi, Christian Reichen, Amelie Croset, Stefanie Fischer, Aline Eggenschwiler, Yvonne Grübler, Rajlakshmi Marpakwar, Thamar Looser, Patricia Spitzli, Christel Herzog, Denis Villemagne, Dieter Schiegg, Liridon Abduli, Chloé Iss, Alexandra Neculcea, Marco Franchini, Tamara Lekishvili, Simone Ragusa, Christof Zitt, Yvonne Kaufmann, Alienor Auge, Martin Hänggi, Waleed Ali, Teresa M. Frasconi, Stephan Wullschleger, Iris Schlegel, Mirela Matzner, Ursina Lüthi, Bernd Schlereth, Keith M. Dawson, Vladimir Kirkin, Adrian F. Ochsenbein, Sebastian Grimm, Nina Reschke, Carsten Riether, Daniel Steiner, Nicolas Leupin, Anne Goubier
{"title":"The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell–Mediated Killing of AML Leukemic Stem Cells","authors":"Matteo Bianchi, Christian Reichen, Amelie Croset, Stefanie Fischer, Aline Eggenschwiler, Yvonne Grübler, Rajlakshmi Marpakwar, Thamar Looser, Patricia Spitzli, Christel Herzog, Denis Villemagne, Dieter Schiegg, Liridon Abduli, Chloé Iss, Alexandra Neculcea, Marco Franchini, Tamara Lekishvili, Simone Ragusa, Christof Zitt, Yvonne Kaufmann, Alienor Auge, Martin Hänggi, Waleed Ali, Teresa M. Frasconi, Stephan Wullschleger, Iris Schlegel, Mirela Matzner, Ursina Lüthi, Bernd Schlereth, Keith M. Dawson, Vladimir Kirkin, Adrian F. Ochsenbein, Sebastian Grimm, Nina Reschke, Carsten Riether, Daniel Steiner, Nicolas Leupin, Anne Goubier","doi":"10.1158/2326-6066.cir-23-0692","DOIUrl":null,"url":null,"abstract":"The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging DARPin (designed ankyrin repeat protein) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell–mediated killing of AML cells co-expressing at least two of the antigens. In vitro, MP0533 induced selective T cell–mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen–targeting T-cell engagers. In xenograft AML mouse models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity towards LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"2010 1","pages":""},"PeriodicalIF":8.1000,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer immunology research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2326-6066.cir-23-0692","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging DARPin (designed ankyrin repeat protein) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell–mediated killing of AML cells co-expressing at least two of the antigens. In vitro, MP0533 induced selective T cell–mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen–targeting T-cell engagers. In xenograft AML mouse models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity towards LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).
急性髓性白血病(AML)患者的预后有限,尤其是老年患者或不适合接受造血干细胞(HSC)移植的患者。这种疾病由白血病干细胞(LSC)驱动,其特点是克隆异质性和对传统疗法的抗药性。因此,这些细胞被认为是导致病情恶化和复发的主要原因。我们设计了一种多特异性 CD3 结合 DARPin(设计的碱基重复蛋白)MP0533,它能同时与 AML 细胞上的三种抗原(CD33、CD123 和 CD70)结合,目的是实现由 T 细胞介导的对同时表达至少两种抗原的 AML 细胞的亲和性杀伤。在体外,MP0533 能诱导 T 细胞介导的选择性杀伤表达两种或两种以上靶抗原的急性髓细胞系以及患者来源的急性髓细胞凋亡细胞和 LSCs,而不损伤健康的造血干细胞、血液和内皮细胞。与单抗原靶向 T 细胞吞噬细胞相比,更高的选择性也使正常人血液中细胞因子的释放水平明显降低。在异种移植急性髓细胞性白血病小鼠模型中,MP0533 能诱导肿瘤定位的 T 细胞活化和细胞因子释放,从而彻底消除肿瘤,同时不会产生全身不良反应。这些研究表明,MP0533 采用的多特异性靶向策略有望提高对 LSCs 的选择性和对克隆异质性的疗效,从而有可能为这类需求尚未得到满足的患者带来新的治疗选择。MP0533目前正在复发或难治性急性髓细胞性白血病患者中进行剂量递增1期研究(NCT05673057)。
期刊介绍:
Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes.
Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.