Targeting CD133 for imaging and therapy in prostate cancer

靶向 CD133 用于前列腺癌的成像和治疗

• 批准号: 10470959
• 负责人: Aaron Matthew LeBeau
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470959
• 关键词: Androgen Receptor; Antiandrogen Therapy; Antibodies; Beta Particle; Biodistribution; Biopsy; Blood; Cancer Model; Cancer Patient; Cell Cycle Stage; Cell Line; Cells; Clinical; Data; Development; Disease; Dose; Drug Kinetics; Engineering; Epitopes; Generations; Goals; Human; Image; Immunoglobulins; Immunohistochemistry; Innovative Therapy; Integral Membrane Protein; Knowledge; Label; Lead; Length; Libraries; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modality; Modeling; Monitor; Neoplasm Metastasis; Oryctolagus cuniculus; Patients; Peptides; Phage Display; Positron-Emission Tomography; Property; Radiation therapy; Radioimmunotherapy; Radiolabeled; Receptor Signaling; Research; Resistance; Safety; Stains; Study models; Surface; Surface Antigens; Testing; Therapeutic; Tissue Microarray; Treatment Efficacy; Validation; Variant; Vertebral column; Viscera; Visceral metastasis; Xenograft Model; Xenograft procedure; androgen deprivation therapy; antibody engineering; base; bone; bone imaging; burden of illness; cancer stem cell; chemotherapy; clinical translation; clinically relevant; combat; density; disorder subtype; dosimetry; effective therapy; glycosylation; imaging agent; imaging modality; imaging probe; imaging study; in vitro Model; in vivo; innovation; longitudinal positron emission tomography; men; mouse model; novel; novel therapeutics; overexpression; patient derived xenograft model; patient response; pharmacodynamic biomarker; public health relevance; single photon emission computed tomography; standard of care; stem cell biomarkers; subcutaneous; targeted agent; therapeutic evaluation; therapeutically effective; therapy development; tool; treatment response; tumor; uptake

ABSTRACT Aggressive variant prostate cancer (AVPC) arises in men who have failed treatment with second-generation anti-androgen therapy. Not driven by the androgen receptor-signaling axis, effective treatment options do not exist for AVPC and new, innovative therapies are urgently needed. Critical to the development of novel therapeutics is the ability to accurately image disease burden in AVPC patients. An imaging modality that can detect both the bone and visceral metastases associated with AVPC does not exist. The overall goal of this project is to develop positron emission tomography (PET) imaging probes and radioimmunotherapy (RIT) agents by targeting a newly identified cell-surface antigen unique to AVPC with novel antibody constructs. Using human antibody phage display, we recently identified a single chain variable fragment (scFv) that specifically bound to a glycosylation-independent epitope on the peptide backbone of the transmembrane protein CD133. Often characterized as a cancer stem cell marker, the function of CD133 in cancer is unknown. All commercially available antibodies for CD133 recognize glycosylation-dependent epitopes that vary between cells and at different stages of the cell cycle. Immunohistochemistry (IHC) with these antibodies yield inconsistent results and poor staining quality; thus contributing to our limited knowledge of CD133. Our scFv for CD133, termed A10, was converted into a full-length immunoglobulin (IA10) for IHC analysis on patient biopsies and tissue microarrays. Remarkably, we found that CD133 was only expressed in bone and visceral metastases of men who had developed AVPC. As a single-photon emission computed tomography imaging agent, IA10 was able to image CD133 expression in vivo. In biodistribution studies, IA10 and a smaller minibody construct version (MA10) both demonstrated high tumor uptake and favorable pharmacokinetics. The high tumor uptake of the A10 antibody constructs was the direct result of their rapid internalization by CD133-expressing cells making them ideal candidates for longitudinal PET imaging and RIT. In this proposal, we will evaluate the utility of IA10 and MA10 as PET probes in cell line-derived and patient-derived xenograft models of AVPC and evaluate CD133 as a pharmacodynamic biomarker (Aim 1) then determine the therapeutic potential of IA10 radiolabeled with 177Lu for beta particle RIT in subcutaneous and metastatic xenografts using single and fractionated doses (Aim 2). Our preliminary data strongly suggest that we have developed potent tools for AVPC that possess the potential to result in a dramatic shift in how the disease is treated.

抽象的 侵袭性变异前列腺癌 (AVPC) 发生在第二代治疗失败的男性中 抗雄激素治疗。不受雄激素受体信号轴驱动，有效的治疗方案不会 AVPC 存在新的、创新的疗法。对小说的发展至关重要 治疗是准确地了解 AVPC 患者疾病负担的能力。一种成像方式可以 检测到与AVPC相关的骨和内脏转移均不存在。本次活动的总体目标 项目是开发正电子发射断层扫描（PET）成像探针和放射免疫治疗（RIT）药剂 通过使用新型抗体结构靶向新鉴定的 AVPC 特有的细胞表面抗原。利用人类 抗体噬菌体展示，我们最近鉴定了一个单链可变片段（scFv），它特异性结合 跨膜蛋白 CD133 肽骨架上的糖基化独立表位。经常 CD133 作为癌症干细胞标记物，在癌症中的功能尚不清楚。全部商业化 CD133 的可用抗体可识别糖基化依赖性表位，这些表位在细胞之间和时间点上有所不同 细胞周期的不同阶段。使用这些抗体进行免疫组织化学 (IHC) 会产生不一致的结果 染色质量差；从而加深了我们对 CD133 的有限了解。我们的 CD133 scFv，称为 A10， 转化为全长免疫球蛋白 (IA10)，用于对患者活检和组织进行 IHC 分析 微阵列。值得注意的是，我们发现 CD133 仅在男性的骨和内脏转移中表达 谁开发了 AVPC。作为单光子发射计算机断层扫描成像剂，IA10 能够 体内CD133表达图像。在生物分布研究中，IA10 和更小的微型抗体构建版本 (MA10) 均表现出高肿瘤摄取和良好的药代动力学。肿瘤的高摄取 A10 抗体构建体是 CD133 表达细胞快速内化的直接结果 它们是纵向 PET 成像和 RIT 的理想选择。在本提案中，我们将评估 IA10 的效用 和 MA10 作为 AVPC 细胞系来源和患者来源异种移植模型中的 PET 探针并评估 CD133 作为药效生物标志物（目标 1），然后确定 IA10 放射性标记的治疗潜力 177Lu 用于皮下和转移性异种移植物中的 β 粒子 RIT，使用单剂量和分次剂量（目标 2）。我们的初步数据强烈表明，我们已经为 AVPC 开发了强大的工具，具有 可能会导致疾病治疗方式发生巨大转变。