Anti-CD38 targeted alpha emitter radioimmunotherapy to eliminate multiple myeloma

抗 CD38 靶向 α 发射体放射免疫疗法消除多发性骨髓瘤

• 批准号: 10548806
• 负责人: Damian J. Green
• 金额: $ 41.32万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-08 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548806
• 关键词: Address; Antibodies; Antigen Targeting; Apoptosis; Applications Grants; Autologous Stem Cell Transplantation; Avidity; Behavior Therapy; Biological Models; Biotechnology; Bone Marrow; Cell Death; Cells; Characteristics; Chromosome abnormality; Clinical; Clinical Trials; Clinical Trials Design; Clone Cells; Coupled; DNA Damage; DNA Double Strand Break; Deposition; Detection of Minimal Residual Disease; Diameter; Disease; Disease Progression; Dose; Dose Limiting; Eligibility Determination; Flow Cytometry; Fred Hutchinson Cancer Research Center; Goals; Health; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Heterogeneity; High Dose Chemotherapy; Human; In complete remission; Individual; Investigational New Drug Application; Label; Length; MEL Gene; Maintenance; Malignant - descriptor; Malignant Bone Marrow Neoplasm; Malignant Neoplasms; Maximum Tolerated Dose; Measurement; Measures; Melphalan; Minority; Modeling; Modification; Monoclonal Antibodies; Multiple Myeloma; Outcome; Parents; Patients; Phase; Phase II Clinical Trials; Plasma Cells; Positioning Attribute; Preparation; Prognosis; Progressive Disease; Proteins; Radiation induced damage; Radioactive; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiolabeled; Reagent; Recording of previous events; Recovery; Regimen; Relapse; Research; Research Personnel; Residual Neoplasm; SCID-hu Mice; Sampling; Site; Stem cell transplant; Surface; Sweden; Testing; Therapeutic Index; Tissues; Toxic effect; Transplantation Conditioning; United States Food and Drug Administration; Universities; Washington; chemotherapy; conditioning; design; ds-DNA; efficacy evaluation; experience; high risk; immunoreactivity; improved; innovation; mutational status; neoplastic cell; neovascularization; next generation sequencing; novel; novel strategies; patient subsets; permissiveness; pre-clinical; prevent; repaired; response; skills; standard of care; targeted imaging; treatment response; virtual

PROJECT SUMMARY/ABSTRACT The majority of patients with multiple myeloma (MM) ultimately die of progressive disease despite high rates of initial response to novel agents. While complete response (CR) is achievable in a significant subset of patients, most of these individuals relapse as a consequence of minimal residual disease (MRD) defined by occult foci of treatment insensitive tumor cells clones. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves response, but relapse remains virtually inevitable. No modification to high dose melphalan chemotherapy conditioning regimens has further augmented the impact of ASCT on outcome over the past two decades. Unmodified CD38 monoclonal antibodies (MAbs) have demonstrated anti-MM tumor cell responses and CD38 antigen targeting with β-emitter radioimmunotherapy (RIT) can eliminate disease in pre-clinical MM models. In clinical settings however, β-emitter RIT has been associated with dose limiting toxicity that can prevent dose escalation to levels necessary for elimination of MRD in a substantial proportion of patients. Based on the physical characteristics of α-emitting radionuclides and new opportunities to harness their potential, there is a compelling rationale for employing α-emitter RIT to treat MM. The α-emitter 211At deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double strand DNA breaks that overwhelm cellular repair mechanisms. We anticipate that this combination of high energy and short path length will confer a unique capacity to kill individual targeted MM cells and eliminate MRD with minimal radiation damage to surrounding tissues. This proposal will use 211At to functionalize an anti-CD38 monoclonal antibody ([211At]OKT10-B10) as part of a novel approach to ASCT conditioning. The goal of this project is to address three hypotheses: 1). [211At]OKT10-B10 will eliminate MRD by selectively targeting all malignant plasma cells irrespective of mutational status, 2). [211At]OKT10-B10 will disrupt the disease permissive milieu found in the bone marrow microenvironment of MM patients and 3) [211At]OKT10-B10 will demonstrate a therapeutic index sufficient to safely sterilize all occult sites of disease. First, we will generate clinical grade [211At]OKT10-B10 necessary to perform patient studies. Second, we will conduct a clinical trial to a) demonstrate that [211At]OKT10-B10 localizes to MM target cells as confirmed by direct measurement of 211At in the bone marrow and alpha camera images of target tissue; and b) evaluate the safely of [211At]OKT10-B10 dose escalation in combination with high dose melphalan. Third, we will assess the impact of [211At]OKT10-B10 on a) stringent complete response rates, b) MRD detected by high throughput next generation sequencing and multi-parameter high sensitivity flow cytometry, c) the bone marrow microenvironment, d) MM cell repopulating potential in a SCID-hu model, and e) double strand DNA injury in target cells. The successful elimination of MRD through the incorporation of [211At]OKT10-B10 into ASCT conditioning could lead to significant improvements in MM patient survival and potentially eradicate disease.

项目摘要/摘要 大多数多发性骨髓瘤（MM）的患者最终死于进行性疾病目的地的高率 对新型代理的最初反应。虽然完全反应（CR）在大量患者中成功，但 这些个体中的大多数是由神秘灶​​定义的最小残留疾病（MRD）的结果 治疗不敏感的肿瘤细胞克隆。高剂量化疗，然后是自体干细胞 移植（ASCT）改善了反应，但接力实际上是不可避免的。没有对高的修改 剂量Melphalan化学疗法调节方案已进一步增强了ASCT对结果的影响 在过去的二十年中。未修饰的CD38单克隆抗体（mAb）已证明抗MM 肿瘤细胞反应和用β发射体放射免疫疗法（RIT）靶向CD38抗原靶向可以消除 临床前MM模型中的疾病。然而，在临床环境中，βemitter RIT与剂量有关 限制毒性，以防止剂量升级达到消除MRD所必需的水平 患者比例。基于发射α的放射线和新机会的物理特征 为了利用它们的潜力，使用α-发射极RIT来治疗MM有一个令人信服的理由。 α-Emitter 211AT在几个细胞直径（50-90μm）中沉积了大量的能量（〜100 keV/μm），导致 无法弥补的双链DNA破坏了淹没细胞修复机制。我们预料到了 高能量和短路径长度的结合将赋予杀死单个目标MM的独特能力 细胞并消除对周围组织的辐射损害最小的MRD。该提议将使用211at 将抗CD38单克隆抗体（[211AT] OKT10-B10）官能化，作为新型ASCT方法的一部分 调理。该项目的目的是解决三个假设：1）。 [211AT] OKT10-B10将消除MRD 通过选择性靶向所有恶性血浆细胞，无论突变状态如何，2）。 [211AT] OKT10-B10 Will 破坏在MM患者的骨髓微环境中发现的允许环境和3） [211AT] OKT10-B10将展示一个足以安全立体的治疗指数。 首先，我们将生成进行患者研究所需的临床级[211AT] OKT10-B10。第二，我们会的 对a）进行临床试验，证明[211AT] OKT10-B10定位于MM靶细胞，证实 直接测量目标组织的骨髓和α相机图像中的211AT； b）评估 安全的[211AT] OKT10-B10剂量升级与高剂量Melphalan结合使用。第三，我们将评估 [211AT] OKT10-B10对A）严格的完整响应率的影响，B）高通量检测到MRD 下一代测序和多参数高灵敏度流式细胞术，c）骨髓 微环境，D）MM细胞在SCID-HU模型中的重新流动电势，E）双链DNA损伤 靶细胞。 MRD通过[211AT] OKT10-B10的保险成功演变为ASCT 调理可能会导致MM患者生存和潜在的放射性疾病的显着改善。