Anti-CD38 targeted alpha emitter radioimmunotherapy to eliminate multiple myeloma

项目概要/摘要 大多数多发性骨髓瘤（MM）患者最终死于疾病进展，尽管其高发病率。 对新药物的初步反应。虽然在相当一部分患者中可实现完全缓解（CR）， 这些患者中的大多数由于隐匿性病灶定义的微小残留病（MRD）而复发 对治疗不敏感的肿瘤细胞克隆。大剂量化疗后自体干细胞移植 移植（ASCT）改善了反应，但复发仍然几乎不可避免。未修改为高 剂量美法仑化疗预处理方案进一步增强了ASCT对结局的影响 在过去的二十年里。未修饰的CD 38单克隆抗体（MAb）已证明抗MM 肿瘤细胞应答和β-发射体放射免疫治疗（RIT）靶向CD 38抗原可以消除 临床前MM模型中的疾病。然而，在临床环境中，β发射体RIT与剂量相关 限制毒性，可以防止剂量递增至消除MRD所需的水平， 患者比例。基于α放射性核素的物理特性和新的机遇 为了利用它们的潜力，采用α-发射体RIT治疗MM有一个令人信服的理由。 211 At在几个细胞直径（50-90 μm）内沉积非常大的能量（~100 keV/μm），导致 无法修复的双链DNA断裂，压倒了细胞修复机制。我们预计， 高能量和短路径长度的组合将赋予杀死单个目标MM的独特能力 细胞和消除MRD，对周围组织的辐射损伤最小。该提案将使用211 At来 功能化抗CD 38单克隆抗体（[211 At] OKT 10-B10）作为ASCT新方法的一部分 条件反射本项目的目标是解决三个假设：1）。[211 At] OKT 10-B10将消除MRD 通过选择性地靶向所有恶性浆细胞而不管突变状态，2）。[211 At] OKT 10-B10将 破坏MM患者骨髓微环境中发现的疾病容许环境，以及3） [211 At] OKT 10-B10将显示出足以安全地对所有隐匿性疾病部位进行灭菌的治疗指数。 首先，我们将生成进行患者研究所需的临床级[211 At] OKT 10-B10。二是 进行临床试验，以a）证明[211 At] OKT 10-B10定位于MM靶细胞，如通过 直接测量骨髓中的211 At和靶组织的α照相机图像;和B）评估 [211 At] OKT 10-B10剂量递增联合高剂量美法仑的安全性。第三，我们将评估 [211 At] OKT 10-B10对a）严格完全应答率，B）通过高通量检测的MRD 下一代测序和多参数高灵敏度流式细胞术， d）SCID-hu模型中的MM细胞再增殖潜力，和e）SCID-hu模型中的双链DNA损伤。 靶细胞通过将[211 At] OKT 10-B10掺入ASCT成功消除MRD 预处理可能导致MM患者存活率的显著改善并可能根除疾病。

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.