Targeting CD133 for imaging and therapy in prostate cancer

靶向 CD133 用于前列腺癌的成像和治疗

基本信息

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
项目类别：
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

项目摘要

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.

抽象的侵略性变体前列腺癌（AVPC）出现在第二代治疗失败的男性中抗雄激素治疗。不是由雄激素受体信号轴驱动的，有效的治疗选择不会迫切需要使用AVPC和新的创新疗法。对于新颖的发展至关重要治疗方法是能够准确地对AVPC患者进行疾病负担的能力。一个可以的成像方式不存在与AVPC相关的骨骼和内脏转移。总体目标项目将开发正电子发射断层扫描（PET）成像探针和放射免疫疗法（RIT）剂通过靶向具有新型抗体构建体的新近鉴定的细胞表面抗原。使用人抗体噬菌体显示，我们最近确定了一个单链变量片段（SCFV），该片段特别结合到跨膜蛋白CD133的肽骨架上的糖基化非依赖性表位。经常 CD133在癌症中的功能是癌症干细胞标记的特征，尚不清楚。全部商业 CD133的可用抗体识别糖基化依赖性表位，在细胞和在细胞周期的不同阶段。具有这些抗体的免疫组织化学（IHC）产生不一致的结果和染色质量不佳；因此有助于我们对CD133的有限了解。我们用于CD133的SCFV，称为A10，被转化为全长免疫球蛋白（IA10），以分析患者活检和组织微阵列。值得注意的是，我们发现CD133仅在男性的骨骼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剂，IA10能够图像CD133体内表达。在生物分布研究中，IA10和较小的小型构建版本（MA10）均表现出高肿瘤的吸收和有利的药代动力学。肿瘤的高肿瘤吸收 A10抗体构建体是表达CD133的细胞快速内在化的直接结果他们是纵向宠物成像和RIT的理想候选人。在此提案中，我们将评估IA10的效用 MA10作为PET探针在细胞系衍生和患者衍生的异种移植模型中，并评估CD133 作为药效生物标志物（AIM 1），然后确定IA10辐射标记的治疗潜力 177LU使用单剂量和分离剂量，在皮下和转移性异种移植物中的β粒子RIT（目标） 2）。我们的初步数据强烈表明，我们已经为拥有的AVPC开发了有效的工具可能导致疾病的治疗方式发生巨大变化。