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: 10410106
• 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/10410106
• 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.

摘要 侵袭性变异前列腺癌(AVPC)发生在第二代治疗失败的男性 抗雄激素治疗。不受雄激素受体-信号轴的驱动，有效的治疗选择不是 AVPC的存在，迫切需要新的、创新的疗法。对小说的发展至关重要 治疗是准确显示AVPC患者疾病负担的能力。一种成像设备可以 检测与AVPC相关的骨转移和内脏转移均不存在。这个项目的总体目标是 该项目是开发正电子发射断层扫描(PET)成像探测器和放射免疫治疗(RIT)试剂 通过用新的抗体结构靶向一种新发现的AVPC特有的细胞表面抗原。使用人类 抗体噬菌体展示，我们最近发现了一个单链可变区(ScFv)，它能与 跨膜蛋白CD133的多肽骨架上的糖基化非依赖性表位。经常 CD133作为一种肿瘤干细胞标记物，其在癌症中的功能尚不清楚。都是商业性的 CD133的可用抗体识别糖基化依赖的表位，这种表位在细胞和 细胞周期的不同阶段。含有这些抗体的免疫组织化学(IHC)结果不一致。 和较差的染色质量，从而导致我们对CD133的了解有限。我们的CD133单链抗体，命名为A10， 被转化为全长免疫球蛋白(IA10)，用于患者活检和组织的IHC分析 微阵列。值得注意的是，我们发现CD133只在男性的骨和内脏转移瘤中表达 开发了AVPC的人。作为一种单光子发射计算机断层成像试剂，IA10能够 图像CD133在体内的表达。在生物分布研究中，IA10和一个较小的微型身体构造版本 (MA10)均表现出较高的肿瘤摄取率和良好的药代动力学。肿瘤对肿瘤的高度摄取 A10抗体的构建是表达CD133的细胞快速内化的直接结果 它们是纵向PET成像和RIT的理想候选者。在这项提案中，我们将评估IA10的效用 AvPC细胞来源和患者来源异种移植模型中以MA10和MA10为PET探针及对CD133的评价 作为药效学生物标志物(目标1)，然后确定放射性标记的IA10的治疗潜力 单次和分次剂量下皮下和转移性异种移植中β粒子RIT的177Lu(AIM) 2)。我们的初步数据有力地表明，我们已经为AVPC开发了强大的工具，这些工具拥有 可能导致这种疾病的治疗方式发生戏剧性的变化。