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

• 批准号: 7669049
• 负责人: William John McBride
• 金额: $ 60.57万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669049
• 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

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(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)预靶向结合F-18标记多肽的成像方法。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。这种成像方法将利用PET良好的敏感性和bsMab预靶向提供的高肿瘤与非肿瘤比率。我们之前已经描述了一种新的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。利用这个系统，可以用各种放射性同位素制备放射性标记的多肽，用于成像和治疗。这种前靶向系统在注射多肽后1-3小时内具有良好的肿瘤摄取和高肿瘤/非肿瘤比率，并且与直接放射性标记的抗体片段(例如Fab‘或ScFv)相比，肾脏摄取显著减少。鉴于这种预靶向系统已被证明是成功的，这一第二阶段应用的主要目标是研究将最常用的用于PET成像的放射性核素F-18固定在多肽上的方法。第一年的主要重点将是进一步开发将F-18结合到第一阶段报告中披露的多肽上的新方法。该方法的几个改进将从易用性、产品产率、比活性、稳定性和易提纯等方面进行考察。靶向多肽将携带两个HSG半抗原，以稳定结合在肿瘤细胞表面(11)。大多数临床前工作都是通过结合结直肠癌标记物癌胚抗原和HSG的bsMab来完成的。这项工作的原理证明将使用针对人胰腺肿瘤抗原MUC1和HSG的bsMAb(TF10)进行测试。其目标是帮助改善胰腺癌的早期发现和诊断，以及确定疾病的程度。与公众健康相关：这项工作的第一个目标是开发一种通用、简单的方法，将PET成像同位素F-18连接到多肽上。这项工作的第二个目标是将F-18标记的多肽特异性地传递到肿瘤，同时通过首先给予一种新型的、基因工程的、与感兴趣的目标组织(在这种情况下是胰腺癌)特异结合的三价双特异性抗体，允许未结合的抗体从血液中清除(Days)，然后注射F-18标记的多肽，该多肽包含两个结合目标抗体的基团。注射的多肽迅速定位于肿瘤表面的双特异性抗体，未与肿瘤结合的多肽部分迅速(几分钟)从血液中清除，使正常组织的摄取降至最低，从而增加了肿瘤与正常组织之间的对比度。