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F-18 Labeled Peptides for Pretargeted PET Imaging of Pancreatic Cancer

用于胰腺癌预靶向 PET 成像的 F-18 标记肽

基本信息

批准号：
7936956
负责人：
William John McBride
金额：
$ 51.72万
依托单位：
IMMUNOMEDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-24 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7936956
关键词：
Acute Aluminum Animal Testing Antibodies Antibody Specificity Antigen Targeting Binding Biodistribution Biological Assay Bioreactors Bispecific Antibodies Bispecific Monoclonal Antibodies Blood Blood Cells Buffers CA-15-3 Antigen Cancer Patient Carcinoembryonic Antigen Cell Line Cell surface Cells Clinical Clinical Research Complex Cyclic GMP Development Diagnosis Disease Dose Drug Formulations Early Diagnosis Engineering Epitopes Evaluation Excision Exclusion Excretory function Flow Cytometry Funding Glycine Goals Government Grant Guidelines Haptens High Pressure Liquid Chromatography Histamine Hour Human Image Imagery Immunoglobulin Fragments In Vitro Infection Injection of therapeutic agent Ion Exchange Resins Isotopes Kidney Kinetics Label Ligand Binding Ligands Malignant neoplasm of pancreas Methodology Methods Modification Mucin-1 Staining Method Mus Normal tissue morphology Nude Mice Oryctolagus cuniculus Peptide Receptor Peptides Performance Persons Phase Phase I Clinical Trials Positron-Emission Tomography Preparation Procedures Process Production Productivity Progress Reports Proteins Radioimmunoconjugate Radioisotopes Radiolabeled Reaction Time Recombinant Fusion Proteins Rectal Tumors Reporting Scheme Screening procedure Serum Site Small Business Innovation Research Grant Specificity Staging Sterility Surface System Techniques Temperature Testing Time Tissues Toxic effect Tumor Antigens Tumor Markers Tumor Tissue Viral Work base cGMP production cell bank human tissue imaging modality immunoreactivity improved in vivo interest neoplastic cell novel pancreas xenograft pancreatic neoplasm pre-clinical preclinical study public health relevance radiotracer research clinical testing scale up success tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Our primary interest is to develop an imaging method based on bispecific antibody (bsMAb) pretargeting used in combination with F-18 labeled peptides. Such a method would improve the specificity for PET imaging based on the bsMAb's reactivity with either tumor antigens or other markers. This imaging method would take advantage of excellent sensitivity of PET and the high tumor to non-tumor ratios provided by bsMab pretargeting. We have previously described a novel bsMAb pretargeting system based on the hapten binding specificity of an antibody directed to histamine-succinyl-glycine (HSG). Using this system, radiolabeled peptides can be prepared with a variety of radioisotopes for use in imaging and therapy. This pretargeting system has excellent tumor uptake and high tumor/nontumor ratios within 1-3 hours of the peptide injection, and has substantially less renal uptake than directly radiolabeled antibody fragments (e.g., Fab' or scFv). Given the proven success of this pretargeting system, the primary goal of this Phase II application is to examine methods of attaching the most commonly used radionuclide for PET imaging, F-18, to a peptide. The main focus in the first year will be to further develop the novel method of attaching F-18 to a peptide that was disclosed in the Phase I report. Several modifications of the method will be examined with respect to the facile use, yield of product, specific activity, stability and ease of purification. The targeting peptide will carry two HSG haptens to stabilize binding on the tumor cell surface (11). Most of the preclinical work has been done with a bsMab that binds to the colo-rectal tumor marker carcinoembryonic antigen and HSG. The proof of principal for this work will be tested using a bsMAb (TF10) that targets the human pancreatic tumor antigen, MUC1 and HSG. The goal is to help improve the early detection and diagnosis of pancreatic cancer as well as determine the extent of the disease. PUBLIC HEALTH RELEVANCE: The first goal of this work is to develop a general, simple method of attaching the PET imaging isotope, F-18, to peptides. The second goal of this work is to deliver the F-18 labeled peptide specifically to a tumor while at the same time delivering minimal activity to normal tissues by first administering a novel, genetically engineered, trivalent bispecific antibody that binds specifically to the target tissue of interest (in this case pancreatic cancer), allowing the unbound antibody to clear from the blood (days) and then injecting the F-18 labeled peptide, which contains two groups that bind to the targeted antibody. The injected peptide rapidly localizes to the bispecific antibody on the tumor surface and the portion of the peptide that does not bind to the tumor is rapidly (minutes) cleared from the blood, minimizing uptake in normal tissues thus increasing the contrast between the tumor and normal tissues.

描述（由申请人提供）：我们的主要兴趣是开发一种基于双特异性抗体 (bsMAb) 预靶向与 F-18 标记肽结合使用的成像方法。这种方法将提高基于 bsMAb 与肿瘤抗原或其他标记物的反应性的 PET 成像的特异性。该成像方法将利用 PET 的出色灵敏度以及 bsMab 预靶向提供的高肿瘤与非肿瘤比率。我们之前描述了一种新型 bsMAb 预靶向系统，该系统基于针对组胺-琥珀酰-甘氨酸 (HSG) 的抗体的半抗原结合特异性。使用该系统，可以用多种放射性同位素制备放射性标记的肽，用于成像和治疗。该预靶向系统在肽注射后 1-3 小时内具有出色的肿瘤摄取和高肿瘤/非肿瘤比率，并且比直接放射性标记的抗体片段（例如 Fab' 或 scFv）具有显着更少的肾脏摄取。鉴于该预靶向系统已被证明是成功的，该 II 期应用的主要目标是检查将 PET 成像最常用的放射性核素 F-18 附着到肽上的方法。第一年的主要重点将是进一步开发第一阶段报告中披露的将 F-18 附着到肽上的新方法。将在使用方便、产物收率、比活性、稳定性和纯化容易性方面对该方法进行一些修改。靶向肽将携带两个 HSG 半抗原以稳定肿瘤细胞表面的结合 (11)。大部分临床前工作都是通过与结肠直肠肿瘤标志物癌胚抗原和 HSG 结合的 bsMab 完成的。这项工作的原理证明将使用针对人类胰腺肿瘤抗原 MUC1 和 HSG 的 bsMAb (TF10) 进行测试。目标是帮助改善胰腺癌的早期检测和诊断以及确定疾病的程度。公共健康相关性：这项工作的首要目标是开发一种通用、简单的方法，将 PET 成像同位素 F-18 附着到肽上。这项工作的第二个目标是将 F-18 标记的肽特异性地递送至肿瘤，同时向正常组织递送最小的活性，方法是首先施用一种新颖的基因工程三价双特异性抗体，该抗体特异性地结合到感兴趣的靶组织（在本例中为胰腺癌），使未结合的抗体从血液中清除（数天），然后注射 F-18 标记的肽肽，包含两个与目标抗体结合的基团。注射的肽迅速定位到肿瘤表面的双特异性抗体，并且不与肿瘤结合的肽部分迅速（几分钟）从血液中清除，最大限度地减少正常组织的摄取，从而增加肿瘤和正常组织之间的对比度。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New lyophilized kit for rapid radiofluorination of peptides.

DOI：
10.1021/bc200608e
发表时间：
2012-03-21
期刊：
BIOCONJUGATE CHEMISTRY
影响因子：
4.7
作者：
McBride, William J.;D'Souza, Christopher A.;Karacay, Habibe;Sharkey, Robert M.;Goldenberg, David M.
通讯作者：
Goldenberg, David M.

Optimized labeling of NOTA-conjugated octreotide with F-18.

DOI：
10.1007/s13277-011-0250-x
发表时间：
2012-04
期刊：
TUMOR BIOLOGY
影响因子：
0
作者：
Laverman, Peter;D'Souza, Christopher A.;Eek, Annemarie;McBride, William J.;Sharkey, Robert M.;Oyen, Wim J. G.;Goldenberg, David M.;Boerman, Otto C.
通讯作者：
Boerman, Otto C.

The radiolabeling of proteins by the [18F]AlF method.

DOI：
10.1016/j.apradiso.2011.08.013
发表时间：
2012-01
期刊：
APPLIED RADIATION AND ISOTOPES
影响因子：
1.6
作者：
McBride, William J.;D'Souza, Christopher A.;Sharkey, Robert M.;Goldenberg, David M.
通讯作者：
Goldenberg, David M.

High-yielding aqueous 18F-labeling of peptides via Al18F chelation.

DOI：
10.1021/bc200175c
发表时间：
2011-09-21
期刊：
BIOCONJUGATE CHEMISTRY
影响因子：
4.7
作者：
D'Souza, Christopher A.;McBride, William J.;Sharkey, Robert M.;Todaro, Louis J.;Goldenberg, David M.
通讯作者：
Goldenberg, David M.

Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide.

DOI：
10.1002/cmmi.1523
发表时间：
2013-05
期刊：
CONTRAST MEDIA & MOLECULAR IMAGING
影响因子：
0
作者：
Dijkgraaf, Ingrid;Terry, Samantha Y. A.;McBride, William J.;Goldenberg, David M.;Laverman, Peter;Franssen, Gerben M.;Oyen, Wim J. G.;Boerman, Otto C.
通讯作者：
Boerman, Otto C.