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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：
10653106
负责人：
Aaron Matthew LeBeau
金额：
$ 34.86万
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/10653106
关键词：
Androgen Receptor Antiandrogen Therapy Antibodies Beta Particle Binding 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 bone bone imaging burden of illness cancer stem cell chemotherapy clinical translation clinically relevant combat 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 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.

摘要