Novel Radioimmunotherapy Strategies for Prostate Cancer

前列腺癌的新型放射免疫治疗策略

基本信息

批准号：
10411260
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
项目类别：
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/10411260
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/antagonist 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

项目摘要

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.

抽象的侵略性变体前列腺癌（AVPC）是一种高度致命的前列腺癌（PCA），在男性中产生第二代抗雄激素疗法治疗失败的人。不是由雄激素受体驱动的信号轴，AVPC不存在有效的治疗方案，而新的，创新的疗法则是需要。靶向细胞表面蛋白前列腺癌特异性膜的放射免疫疗法抗原（PSMA）在治疗某些PCA子集的患者方面表现出了希望。 PSMA未在 AVPC，并且需要识别针对RIT的AVPC特定的可靶向抗原。总体目标项目是通过针对新鉴定的细胞来为AVPC创建临床相关的放射免疫疗法策略表面抗原具有新型抗体构建体并使用放射敏感的小型抗原分子药物提高RIT的有效性。最近，我们确定了一个新颖的单链变量来自人类抗体噬菌体显示库的片段（SCFV），该文库特别结合到糖基化 - 跨膜蛋白CD133的肽骨架上的独立表位。通常被确定为癌症干细胞标记，CD133在癌症中的功能尚不清楚。所有市售的抗体 CD133识别细胞和细胞不同阶段之间变化的糖基化依赖性表位循环。具有这些抗体的免疫组织化学（IHC）产生不一致的结果，染色质量差；因此有助于我们对CD133的有限了解。我们的CD133的SCFV称为A10，被转换为一个完整的用于患者活检和组织微阵列的IHC分析的IHC分析的长度免疫球蛋白（IA10）。值得注意的是，我们发现该CD133仅在第二代抗 - 雄激素疗法并开发了AVPC。作为核成像剂，IA10能够成像CD133表达体内。在生物分布研究中，IA10和较小的小型构建版本（MA10）都表现出很高的肿瘤摄取和有利的药代动力学。 A10抗体构建体的高肿瘤吸收是表达CD133的细胞快速内在化的直接结果，使其成为（RIT）的理想候选者。在这项提议，我们将研究IA10和MA10的治疗潜力，称为177LU标记的RIT代理 AVPC的细胞系衍生和患者衍生的异种移植模型（AIM 1），评估聚（ADP-）的能力（ADP- 核糖）聚合酶抑制剂Olaparib充当放射敏化剂，以提高RIT的治疗疗效代理（AIM 2），并鉴定来自AVPC肿瘤衍生的器官的RIT的新型抗原抗体组合使用抗体噬菌体显示器模型（AIM 3）。我们的初步数据强烈表明我们已经开发了有效的AVPC的RIT工具具有可能导致疾病治疗方式发生巨大变化。