Base-Edited Hematopoietic Stem and Progenitor Cells To Enable Safe Use Of Highly Potent CD33-Targeted Radioimmunotherapy

碱基编辑造血干细胞和祖细胞可安全使用高效 CD33 靶向放射免疫疗法

基本信息

  • 批准号:
    10647646
  • 负责人:
  • 金额:
    $ 72.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT Antigen-specific therapies have long been pursued to improve outcomes in acute myeloid leukemia (AML). So far most exploited are monoclonal antibodies (mAbs) targeting CD33, a glycoprotein displayed on the cell surface of leukemic blasts in almost all cases and possibly leukemia stem cells in some. Longer survival of some patients treated with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this approach, but GO is often ineffective, prompting efforts to develop improved, more potent CD33-directed therapeutics. Because AML cells are exquisitely sensitive to radiation in a dose-dependent fashion, radionuclides are ideal to arm anti- CD33 mAbs. Indeed, early phase clinical trials demonstrated substantial anti-AML efficacy of the anti-CD33 mAb lintuzumab (HuM195, SGN-33) when coupled with the a-emitter actinium-225 (225Ac). a-emitters deliver a very high amount of radiation over just a few cell diameters, thereby enabling precise and efficient target cell kill, rendering them particularly interesting for specific targeting of AML with radioimmunoconjugates (“RIT”). However, even with 225Ac-lintuzumab, an important shortcoming is CD33 expression on normal myeloid cells, which leads to “on-target, off-tumor cell” toxicities that manifest as severe and prolonged myelosuppression with life-threatening sequelae (e.g. infection). Thus, clinical use of CD33-directed RIT without immediate stem cell rescue is currently limited to suboptimal drug doses. We have recently demonstrated in mice and nonhuman primates that CRISPR/Cas9 nuclease-based editing of CD33 results in functionally normal hematopoiesis that expresses reduced levels of CD33 and is protected from GO and CD33-directed T cell-engaging therapeutics. We hypothesize CD33-edited normal hematopoietic stem and progenitor cells (HSPCs) will resist CD33-directed RIT with a-particle-emitting radionuclides and enable their safe use at maximally effective drug doses. However, the CRISPR/Cas9-based CD33 gene editing strategy suffers from significant off-target activity, and DNA double strand breaks (DSBs) can generate larger deletions and complex chromosomal rearrangements and cause TP53-dependent DNA damage response and cell cycle arrest. To address this limitation, we will optimize and characterize a novel gene-editing strategy to protect normal hematopoiesis from highly potent CD33-directed RIT by utilizing the recently described base editor (BE) technology. BEs induce precise nucleotide modifications without intentional introduction of DSBs, making them an attractive strategy to generate CD33null “normal” hematopoietic cells. We have assembled a multidisciplinary team of investigators with complementary expertise in CD33-directed therapies, preclinical optimization of RIT, and radiopharmaceutics to conduct well-controlled preclinical IND-enabling studies to develop BE-based CD33 engineering of normal human HSPCs for clinical use with a-emitter CD33-directed RIT for patients with AML and other CD33-expressing disorders.
抽象的 长期以来一直在追求抗原特异性疗法,以改善急性髓样白血病(AML)的结局。 探索最多的是靶向CD33的单克隆抗体(mAb),这是一种在细胞表面上显示的糖蛋白 在几乎所有情况下,白血病爆炸,有些情况下可能存在白血病干细胞。某些患者的生存时间更长 用CD33抗体 - 药物结合物gemtuzumab ozogamicin(GO)验证了这种方法,但请GO 通常是无效的,促使人们努力开发改进的,更多潜在的CD33导向疗法。因为 AML细胞以剂量依赖性的方式对辐射完全敏感,放射线非常适合手臂抗 CD33 mabs。实际上,早期临床试验表明抗CD33 mAb的大量抗AML效率 lintuzumab(HUM195,SGN-33)与A-Emitter Actinium-225(225AC)结合使用。 a-emitters提供了一个非常 仅在几个细胞直径上大量辐射,从而实现了精确有效的靶细胞杀伤 对于用放射免疫缀合物(“ RIT”)将AML的特定靶向特别有趣。 然而,即使有225Ac-lintuzumab,一个重要的缺点是在正常髓样细胞上的CD33表达, 这导致“靶向,肿瘤细胞的焦虑”毒性,表现为严重且长时间的骨髓抑制作用 威胁生命的后遗症(例如感染)。那是CD33定向RIT的临床使用,而无需立即干细胞 救援目前仅限于次优剂量。我们最近在小鼠和非人类中证明了 基于CRISPR/CAS9基于CD33的编辑的灵长类动物会导致功能正常的造血作用 表达CD33的水平降低,并受到GO和CD33定向的T细胞启动疗法的保护。 我们假设CD33编辑的正常造血茎和祖细胞(HSPC)将抵抗以CD33为导向的 带有A颗粒发射放射线的RIT,并在最大有效的药物剂量下进行安全使用。然而, 基于CRISPR/CAS9的CD33基因编辑策略遭受重大脱靶活动,DNA双重 链断裂(DSB)可以产生更大的缺失和复杂的染色体重排,并导致 TP53依赖性DNA损伤反应和细胞周期停滞。为了解决此限制,我们将优化和 表征一种新型的基因编辑策略,以保护正常造血免受高度潜在的CD33导向 使用最近描述的基本编辑器(BE)技术的RIT。 BES诱导精确的核苷酸修饰 无故意引入DSB,使其成为产生CD33NULL“正常”的吸引力策略 造血细胞。我们已经组建了一个具有完整专业知识的研究人员的多学科团队 在CD33导向的疗法中,RIT的临床前优化和放射性药物进行了良好的控制 临床前的临床前研究研究是基于正常人HSPC的基于CD33的CD33工程 与A-Emitter CD33指导的RIT一起使用,可用于AML和其他表达CD33的患者。

项目成果

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Roland Bruno Walter其他文献

Roland Bruno Walter的其他文献

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{{ truncateString('Roland Bruno Walter', 18)}}的其他基金

Base-Edited Hematopoietic Stem and Progenitor Cells To Enable Safe Use Of Highly Potent CD33-Targeted Radioimmunotherapy
碱基编辑造血干细胞和祖细胞可安全使用高效 CD33 靶向放射免疫疗法
  • 批准号:
    10346735
  • 财政年份:
    2022
  • 资助金额:
    $ 72.48万
  • 项目类别:
CD117-Targeted Radioimmunotherapy with Astatine-211 for Acute Myeloid Leukemia and Myelodysplastic Syndrome
CD117 靶向放射免疫治疗砹 211 治疗急性髓系白血病和骨髓增生异常综合征
  • 批准号:
    10670383
  • 财政年份:
    2022
  • 资助金额:
    $ 72.48万
  • 项目类别:
Optimizing NK Cell-Engaging Bispecific Antibody Therapy Targeting CD33
优化靶向 CD33 的 NK 细胞双特异性抗体疗法
  • 批准号:
    10403976
  • 财政年份:
    2021
  • 资助金额:
    $ 72.48万
  • 项目类别:
Optimizing NK Cell-Engaging Bispecific Antibody Therapy Targeting CD33
优化靶向 CD33 的 NK 细胞双特异性抗体疗法
  • 批准号:
    10601351
  • 财政年份:
    2021
  • 资助金额:
    $ 72.48万
  • 项目类别:
Optimizing NK Cell-Engaging Bispecific Antibody Therapy Targeting CD33
优化靶向 CD33 的 NK 细胞双特异性抗体疗法
  • 批准号:
    10197394
  • 财政年份:
    2021
  • 资助金额:
    $ 72.48万
  • 项目类别:
Optimization of Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders
针对嗜酸性粒细胞和肥大细胞疾病的 Siglec-8 定向免疫疗法的优化
  • 批准号:
    10641465
  • 财政年份:
    2020
  • 资助金额:
    $ 72.48万
  • 项目类别:
Novel Approaches to CD33-Directed Radioimmunotherapy
CD33 定向放射免疫治疗的新方法
  • 批准号:
    10318979
  • 财政年份:
    2019
  • 资助金额:
    $ 72.48万
  • 项目类别:
Novel Approaches to CD33-Directed Radioimmunotherapy
CD33 定向放射免疫治疗的新方法
  • 批准号:
    10601434
  • 财政年份:
    2019
  • 资助金额:
    $ 72.48万
  • 项目类别:
CAR T-Cell Therapy Targeting the Membrane-Proximal C2-Set Domain of CD33 for Treatment of Acute Myeloid Leukemia and Other CD33-Expressing Hematopoietic Neoplasms
靶向 CD33 近膜 C2 组结构域的 CAR T 细胞疗法用于治疗急性髓系白血病和其他表达 CD33 的造血肿瘤
  • 批准号:
    10603015
  • 财政年份:
    2019
  • 资助金额:
    $ 72.48万
  • 项目类别:
Novel Approaches to CD33-Directed Radioimmunotherapy
CD33 定向放射免疫治疗的新方法
  • 批准号:
    10523534
  • 财政年份:
    2019
  • 资助金额:
    $ 72.48万
  • 项目类别:

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Base-Edited Hematopoietic Stem and Progenitor Cells To Enable Safe Use Of Highly Potent CD33-Targeted Radioimmunotherapy
碱基编辑造血干细胞和祖细胞可安全使用高效 CD33 靶向放射免疫疗法
  • 批准号:
    10346735
  • 财政年份:
    2022
  • 资助金额:
    $ 72.48万
  • 项目类别:
Iomab-ACT: A phase I/II study of 131-I apamistamab targeted lymphodepletion followed by CD19-targeted CAR T-cell therapy for patients with relapsed or refractory B-ALL or DLBCL
Iomab-ACT:针对复发或难治性 B-ALL 或 DLBCL 患者进行 131-I apamistamab 靶向淋巴细胞清除随后进行 CD19 靶向 CAR T 细胞治疗的 I/II 期研究
  • 批准号:
    10471038
  • 财政年份:
    2020
  • 资助金额:
    $ 72.48万
  • 项目类别:
Iomab-ACT: A phase I/II study of 131-I apamistamab targeted lymphodepletion followed by CD19-targeted CAR T-cell therapy for patients with relapsed or refractory B-ALL or DLBCL
Iomab-ACT:针对复发或难治性 B-ALL 或 DLBCL 患者进行 131-I apamistamab 靶向淋巴细胞清除随后进行 CD19 靶向 CAR T 细胞治疗的 I/II 期研究
  • 批准号:
    10081925
  • 财政年份:
    2020
  • 资助金额:
    $ 72.48万
  • 项目类别:
Novel Approaches to CD33-Directed Radioimmunotherapy
CD33 定向放射免疫治疗的新方法
  • 批准号:
    10318979
  • 财政年份:
    2019
  • 资助金额:
    $ 72.48万
  • 项目类别:
Novel Approaches to CD33-Directed Radioimmunotherapy
CD33 定向放射免疫治疗的新方法
  • 批准号:
    10601434
  • 财政年份:
    2019
  • 资助金额:
    $ 72.48万
  • 项目类别:
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