Novel Radioimmunotherapy Strategies for Prostate Cancer

前列腺癌的新型放射免疫治疗策略

• 批准号: 10650786
• 负责人: Aaron Matthew LeBeau
• 金额: $ 33.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10650786
• 关键词: Androgen Receptor; Antiandrogen Therapy; Antibodies; Antigens; Binding; Biodistribution; Biopsy; Blood; Cell Cycle Stage; Cell Line; Cell Surface Proteins; Cells; Clinic; Clinical; Data; Disease; Dose; Drug Kinetics; Effectiveness; Engineering; Epitopes; Fractionation; Future; Generations; Goals; Human; Image; Immunoglobulin G; Immunoglobulins; Immunohistochemistry; In Vitro; Innovative Therapy; Integral Membrane Protein; Knowledge; Label; Length; Libraries; Malignant Neoplasms; Malignant neoplasm of prostate; Membrane; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modality; Modeling; Neoplasm Metastasis; Organoids; Patients; Peptides; Phage Display; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Property; Radiation therapy; Radiation-Sensitizing Agents; Radioimmunotherapy; Radiolabeled; Radiosensitization; Receptor Signaling; Research; Resistance; Solid Neoplasm; Stains; Surface Antigens; Techniques; Technology; Testing; Therapeutic; Therapeutic Index; Tissue Microarray; Treatment Efficacy; Tumor Antigens; Tumor-Derived; Ultraviolet Rays; Variant; Vertebral column; Xenograft Model; Xenograft procedure; androgen deprivation therapy; cancer cell; cancer radioimmunotherapy; cancer stem cell; clinically relevant; combat; curative treatments; design; effective therapy; glycosylation; imaging agent; in vitro Model; in vivo; innovation; men; novel; nuclear imaging; overexpression; patient derived xenograft model; pre-clinical; public health relevance; scaffold; small molecule; soft tissue; stem cell biomarkers; subcutaneous; success; systemic toxicity; targeted agent; targeted treatment; therapeutic evaluation; therapy development; tissue fixing; tool; tumor; uptake

ABSTRACT Aggressive variant prostate cancer (AVPC) is a highly lethal form of prostate cancer (PCa) that 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. Radioimmunotherapy agents targeting the cell-surface protein prostate cancer-specific membrane antigen (PSMA) have shown promise in treating patients with certain subsets of PCa. PSMA is not expressed in AVPC and there is a dire need to identify targetable antigens specific to AVPC for RIT. The overall goal of this project is to create clinically relevant radioimmunotherapy strategies for AVPC by targeting newly identified cell- surface antigens unique to the disease with novel antibody constructs and by using radiosensitizing small- molecule drugs to increase the effectiveness of RIT. Recently, we identified a novel single chain variable fragment (scFv) from a human antibody phage display library that specifically bound to a glycosylation- independent epitope on the peptide backbone of the transmembrane protein CD133. Commonly identified 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 yields 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 soft tissue and bone metastases of men who failed second-generation anti- androgen therapy and developed AVPC. As a nuclear 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 (RIT). In this proposal, we will investigate the therapeutic potential of IA10 and MA10 as RIT agents labeled with 177Lu in cell line-derived and patient-derived xenograft models of AVPC (Aim 1), evaluate the ability of the poly(ADP- ribose) polymerase inhibitor olaparib to act as a radiosensitizing agent to increase the therapeutic efficacy of RIT agents (Aim 2), and identify novel antigen-antibody combinations for RIT from AVPC tumor-derived organoid models using antibody phage display (Aim 3). Our preliminary data strongly suggest that we have developed potent RIT tools for AVPC that possess the potential to result in a dramatic shift in how the disease is treated.

摘要 侵袭性变异型前列腺癌(AVPC)是一种发生在男性的高度致命的前列腺癌(PCA) 他们用第二代抗雄激素疗法治疗失败。不是由雄激素受体驱动的- 信号轴心，AVPC尚不存在有效的治疗选择，迫切需要新的创新疗法 需要的。靶向细胞表面蛋白前列腺癌特异性膜的放射免疫治疗药物 抗原(PSMA)在治疗某些PCa亚型患者方面显示出很好的前景。PSMA未用来表示 AvPC和迫切需要识别针对AvPC的靶向抗原用于RIT。这个项目的总体目标是 该项目是通过靶向新发现的细胞来为AVPC创建临床相关的放射免疫治疗策略- 这种疾病特有的表面抗原具有新的抗体结构，并通过使用放射增敏的小分子 提高RIT疗效的分子药物。最近，我们发现了一种新的单链变量 人抗体噬菌体展示文库中与糖基化特异结合的片段(ScFv)- 跨膜蛋白CD133的多肽骨架上的独立表位。通常被标识为 肿瘤干细胞标记物CD133在肿瘤中的作用尚不清楚。所有商业上可获得的抗体 CD133识别糖基化依赖的表位，这些表位在不同的细胞和不同的细胞阶段有所不同 周而复始。用这些抗体进行免疫组织化学(IHC)结果不一致，染色质量较差； 因此，我们对CD133的了解有限。我们的CD133单链抗体，命名为A10，被转换为完整的- 长度免疫球蛋白(IA10)，用于患者活检和组织微阵列的IHC分析。值得注意的是，我们发现 CD133仅在第二代抗-HBs失败的男性软组织和骨转移瘤中表达 雄激素治疗和开发动静脉曲张。作为核显像剂，IA10能够对CD133的表达进行成像 在活体内。在生物分布研究中，IA10和较小的迷你体构造版本(MA10)都显示出高 肿瘤摄取和良好的药代动力学。A10抗体构建体对肿瘤的高摄取率是 CD133表达的细胞快速内化的直接结果使它们成为RIT的理想候选者。在……里面 在这项建议中，我们将研究IA10和MA10作为177Lu标记的RIT制剂的治疗潜力 细胞来源和患者来源的AVPC异种移植模型(AIM 1)，评估聚(ADP-1) 核糖)聚合酶抑制剂奥拉帕利作为放射增敏剂提高RIT的疗效 试剂(目标2)，并从AVPC肿瘤衍生有机体内鉴定用于RIT的新的抗原-抗体组合 使用抗体噬菌体展示的模型(目标3)。我们的初步数据有力地表明，我们已经发展出 用于AVPC的强大的RIT工具，具有导致疾病治疗方式的戏剧性转变的潜力。