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

描述（由申请人提供）：我们的主要兴趣是开发基于与F-18标记肽组合使用的双特异性抗体（bsMAb）预靶向的成像方法。这种方法将基于bsMAb与肿瘤抗原或其他标志物的反应性来提高PET成像的特异性。这种成像方法将利用PET的优异灵敏度和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，可以用各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的1-3小时内具有优异的肿瘤摄取和高肿瘤/非肿瘤比率，并且具有比直接放射性标记的抗体片段（例如，Fab'或scFv）。鉴于这种预靶向系统已被证明是成功的，该第二阶段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连接到肽上的方法。第一年的主要重点将是进一步开发将F-18连接到第一阶段报告中公开的肽上的新方法。将对该方法的几种改进进行检查，以便于使用，产品收率，比活性，稳定性和易于纯化。靶向肽将携带两个HSG半抗原以稳定在肿瘤细胞表面上的结合（11）。大多数临床前工作都是用与结肠直肠肿瘤标志物癌胚抗原和HSG结合的bsMab完成的。将使用靶向人胰腺肿瘤抗原MUC 1和HSG的bsMAb（TF 10）检测本工作的主要证据。目的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连接到肽上的通用简单方法。这项工作的第二个目标是通过首先施用一种特异性结合靶组织的新型基因工程三价双特异性抗体，将F-18标记的肽特异性递送至肿瘤，同时向正常组织递送最低活性。感兴趣（在这种情况下是胰腺癌），允许未结合的抗体从血液中清除（天），然后注射F-18标记的肽，其含有两个与靶向抗体结合的基团。注射的肽快速定位于肿瘤表面上的双特异性抗体，并且不与肿瘤结合的肽部分快速（几分钟）从血液中清除，使正常组织中的摄取最小化，从而增加肿瘤和正常组织之间的对比度。

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.