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）：我们的主要兴趣是基于与F-18标记的肽结合使用的双特异性抗体（BSMAB）的成像方法。这种方法将根据BSMAB对肿瘤抗原或其他标记的反应性提高PET成像的特异性。这种成像方法将利用BSMAB预定的PET和高肿瘤与非肿瘤比率的极好的敏感性。我们先前已经描述了一种基于针对组胺 - 辛基 - 甘氨酸（HSG）的抗体的触觉结合特异性（HSG）的新型BSMAB预构图系统。使用该系统，可以使用各种放射性同位素进行成像和治疗。该有预量的系统在注射肽的1-3小时内具有出色的肿瘤吸收和高肿瘤/非肿瘤比率，并且肾脏吸收要比直接放射标记的抗体片段（例如Fab'或SCFV）少得多。鉴于该预先目标的成功成功，该II期应用的主要目标是检查将最常用的放射性核素固定在PET成像F-18上的方法。第一年的主要重点是进一步开发将F-18附加到I阶段报告中披露的肽的新方法。该方法的几种修改将在易于使用，产品产量，特定活动，稳定性和纯化性方面进行检查。靶肽将携带两种HSG触觉，以稳定肿瘤细胞表面的结合（11）。大多数临床前工作都是用与结合结肠直肠肿瘤标记癌症抗原和HSG结合的BSMAB完成的。这项工作的主要证明将使用靶向人类胰腺肿瘤抗原，MUC1和HSG的BSMAB（TF10）测试。目的是帮助改善胰腺癌的早期检测和诊断，并确定疾病的程度。公共卫生相关性：这项工作的第一个目标是开发一种将PET成像同位素F-18附加到肽的一般，简单的方法。这项工作的第二个目标是通过首先管理一种新型的，具有基因工程的，三价的双特异性抗体，将F-18标记的肽特异性地传递给肿瘤，同时向正常组织提供最小的活性，该抗体特异性地结合了与特异性结合的感兴趣（在这种情况下为胰腺癌），使未结合的抗体从血液中清除（天），然后注入F-18标记的肽，其中包含两组与靶向抗体结合的组。注射的肽迅速定位于双特异性抗体在肿瘤表面和不与肿瘤结合的肽的一部分中迅速从血液中清除（分钟），从而最大程度地减少了正常组织的摄取，从而增加了肿瘤与正常的对比度组织。

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.