Novel Radioimmunotherapy Strategies for Prostate Cancer

前列腺癌的新型放射免疫治疗策略

• 批准号: 10470949
• 负责人: Aaron Matthew LeBeau
• 金额: $ 34.24万
• 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/10470949
• 关键词: Androgen Receptor; Antiandrogen Therapy; Antibodies; Antigen Targeting; Antigens; 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; Immunoglobulins; Immunohistochemistry; In Vitro; Innovative Therapy; Integral Membrane Protein; Knowledge; Label; Lead; 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) 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; Tissues; Treatment Efficacy; Tumor Antigens; Tumor-Derived; Ultraviolet Rays; Variant; Vertebral column; Xenograft Model; Xenograft procedure; androgen deprivation therapy; base; cancer cell; cancer radioimmunotherapy; cancer stem cell; clinically relevant; combat; curative treatments; design; effective therapy; glycosylation; imaging agent; in vitro Model; in vivo; inhibitor; 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; 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）是一种高致死性的前列腺癌（PCa），发生于男性 第二代抗雄激素治疗失败的患者。不是由雄激素受体驱动的- 信号轴，有效的治疗方案并不存在AVPC和新的，创新的治疗方法是迫切的。 needed.靶向细胞表面蛋白前列腺癌特异性膜的放射免疫治疗剂 前列腺特异性抗原（PSMA）在治疗具有某些PCa亚群的患者中显示出前景。PSMA不表达于 因此，迫切需要鉴定对AVPC特异性的靶向抗原用于RIT。总的目标是 该项目旨在通过靶向新发现的细胞， 用新的抗体构建体和通过使用放射增敏的小- 分子药物，以增加RIT的有效性。最近，我们发现了一个新的单链可变区， 来自人抗体噬菌体展示文库的特异性结合至糖基化- 跨膜蛋白CD 133的肽骨架上的独立表位。通常被认为是 作为癌症干细胞标志物，CD 133在癌症中的功能尚不清楚。所有市售抗体 CD 133识别糖基化依赖性表位，这些表位在细胞之间和细胞的不同阶段变化 周期使用这些抗体的免疫组织化学（IHC）产生不一致的结果和较差的染色质量; 这也是我们对CD 133认识有限的原因。我们的针对CD 133的scFv，称为A10，被转化为完整的 长度的免疫球蛋白（IA 10），用于对患者活检和组织微阵列进行IHC分析。值得注意的是，我们发现 CD 133仅在第二代抗-CD 133治疗失败的男性的软组织和骨转移中表达。 雄激素治疗和发展AVPC。作为核显像剂，IA 10能够对CD 133表达进行显像 in vivo.在生物分布研究中，IA 10和较小的微抗体构建体形式（MA 10）都显示出高的生物分布。 肿瘤摄取和有利的药代动力学。A10抗体构建体的高肿瘤摄取是 这是它们被表达CD 133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 在本研究中，我们将研究IA 10和MA 10作为177 Lu标记的RIT试剂在治疗糖尿病中的治疗潜力。 细胞系来源的和患者来源的AVPC异种移植物模型（目的1），评价聚（ADP- 核糖）聚合酶抑制剂奥拉帕尼作为放射增敏剂以增加RIT的治疗功效 试剂（目的2），并从AVPC肿瘤衍生的类器官中鉴定用于RIT的新型抗原-抗体组合 模型使用抗体噬菌体展示（Aim 3）。我们的初步数据有力地表明，我们已经开发了 AVPC的有效RIT工具，有可能导致疾病治疗方式的巨大转变。