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Contains fulltext : 153713.pdf (Publisher’s version ) (Closed access) PURPOSE: Pretargeting with bispecific antibodies and radiolabeled hapten-peptides could be used to specifically target tumors with high target-to-background ratios. TF12 is a trivalent bispecific antibody that consists of two anti-TROP-2 Fab fragments and one anti-HSG (histamine-succinyl-glycine) Fab fragment. The TROP-2 antigen is expressed in many epithelial cancers, including prostate cancer (PC), and therefore, this bispecific antibody can be used for pretargeting of PC. In this study, the potential for pretargeted radioimmunoPET with TF12 and the (68)Ga-labeled di-HSG peptide IMP288 in mice with human PC xenografts was investigated using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) as a reference. PROCEDURES: The potential of pretargeted immunoPET with TF12 and the (68)Ga-labeled di-HSG hapten-peptide, IMP288, was studied in mice with subcutaneous PC3 tumors using [(18)F]FDG as a reference. Furthermore, the use of this pretargeting system for imaging PC lesions was evaluated in mice with intraperitoneally growing tumors with [(18)F]FDG as a reference. RESULTS: [(68)Ga]lMP288 showed rapid accumulation in the TF12 pretargeted subcutaneous tumor (7.2 +/- 1.1 % ID/g) with low uptake in the kidneys (1.8 +/- 0.5 % ID/g) and high tumor-to-blood ratios (17.4 +/- 11.2) at 1 h p.i. Accumulation of [(18)F]FDG in the s.c. tumors was significantly lower (3.4 +/- 0.9 % ID/g, P = 0.008), with lower tumor-to-blood ratios (3.0 +/- 1.9, P = 0.011). ImmunoPET/CT images clearly visualized both subcutaneous and intraperitoneal tumors as small as 5 mm(3) with low blood levels and kidney uptake as early as 1 h p.i. CONCLUSION: Pretargeted immunoPET with TF12 in combination with a (68)Ga-labeled hapten-peptide is an efficient system for rapid, sensitive, and specific imaging of prostate cancer.

TF12 is a trivalent bispecific antibody that consists of two anti-TROP-2 Fab fragments and one anti-histamine-succinyl-glycine (HSG) Fab fragment. The TROP-2 antigen is found in many epithelial cancers, including prostate cancer (PC), and therefore this bispecific antibody could be suitable for pretargeting in this cancer. In this study, the characteristics and the potential for pretargeted radioimmunoimaging and radioimmunotherapy with TF12 and the radiolabeled di-HSG peptide IMP288 in mice with human PC were investigated.The optimal TF12 protein dose, IMP288 peptide dose, and dose interval for PC targeting were assessed in nude mice with s.c. PC3 xenografts. Immuno-positron emission tomography (PET)/CT was performed using TF12/⁶⁸Ga-IMP288 at optimized conditions. The potential of pretargeted radioimmunotherapy (PRIT) using the TF12 pretargeted ¹⁷⁷Lu-IMP288 was determined.TF12 and ¹¹¹In-IMP288 showed high and fast accumulation in the tumor [20.4 ± 0.6%ID/g at 1 h post-injection (p.i.)] at optimized conditions, despite the internalizing properties of TF12. The potential for PRIT was shown by retention of 50% of the ¹¹¹In-IMP288 in the tumor at 48 h p.i. One cycle of treatment with TF12 and ¹⁷⁷Lu-IMP288 showed significant improvement of survival compared to treatment with ¹⁷⁷Lu-IMP288 alone (90 vs. 67 days, p0.0001) with no renal or hematological toxicity.TROP-2-expressing PC can be pretargeted efficiently with TF12, with very rapid uptake of the radiolabeled hapten-peptide, IMP288, sensitive immuno-PET, and effective therapy.

Item does not contain fulltext RS7 is an internalizing anti-Trop-2 pancarcinoma antibody capable of targeting most epithelial cancers. Because pretargeting strategies could improve the tumor localization of radionuclides, a new anti-Trop-2 x antihapten bispecific antibody for pretargeting, based on humanized RS7, was prepared and evaluated with a radiolabeled hapten-peptide in vitro and in vivo to determine whether its internalization properties would interfere with pretargeting. METHODS: The anti-Trop-2 x antihapten bispecific antibody, TF12, was prepared using the modular dock-and-lock method. TF12 and humanized RS7 binding was assessed by cell binding assays and fluorescence-activated cell sorting analysis in a variety of human carcinoma cell lines. The internalization of TF12 was evaluated in vitro using a fluorescent TF12 conjugate or hapten-peptide and (111)In-labeled TF12 and RS7. The biodistribution of TF12 and its use as a pretargeting agent with an (111)In-labeled hapten-peptide were assessed in several human epithelial cancer xenografts. Dose optimization was examined in 2 tumor models. RESULTS: TF12 internalizes, but a substantial fraction remained accessible on the tumor surface. Fluorescence-activated cell sorting analysis showed only a minor change in fluorescent signal when the tumor was probed with a fluorescent hapten-peptide over 4 h, and microscopy showed substantial membrane staining when reassessed at 24 h after TF12 exposure. Only 40.1% of (111)In-TF12 was internalized after 24 h. In vivo, excellent tumor localization of the (111)In-labeled peptide was observed in several tumor models. CONCLUSION: TF12 was retained sufficiently on the cell surface in several epithelial cancers, thereby making it suitable for pretargeted imaging and therapy of various Trop-2-expressing carcinomas.

Objective The objectives of the study were to develop a population pharmacokinetic model for 11C-flumazenil at tracer concentrations, to assess the effects of patient-related covariates and to derive an optimal sampling protocol for clinical use. Methods A population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM) with data obtained from 51 patients with either depression or epilepsy. Each patient received ∼370 MBq (1–4 µg) of 11C-flumazenil. The effects of selected covariates (gender, weight, type of disease and age) were investigated. The model was validated using a bootstrap method. Finally, an optimal sampling design was established. Results The population pharmacokinetics of tracer quantities of 11C-flumazenil were best described by a two compartment model. Type of disease and weight were identified as significant covariates (P

Radical removal of malignant lesions may be improved using tumor-targeted dual-modality probes that contain both a radiotracer and a fluorescent label to allow for enhanced intraoperative delineation of tumor resection margins. Because pretargeting strategies yield high signal-to-background ratios, we evaluated the feasibility of a pretargeting strategy for intraoperative imaging in prostate cancer using an anti–TROP-2 x anti-HSG bispecific antibody (TF12) in conjunction with the dual-labeled diHSG peptide (RDC018) equipped with both a DOTA chelate for radiolabeling purposes and a fluorophore (IRdye800CW) to allow near-infrared optical imaging. Nude mice implanted s.c. with TROP-2–expressing PC3 human prostate tumor cells or with PC3 metastases in the scapular and suprarenal region were injected i.v. with 1 mg of TF12 and, after 16 hours of tumor accumulation and blood clearance, were subsequently injected with 10 MBq, 0.2 nmol/mouse of either 111In-RDC018 or 111In-IMP288 as a control. Two hours after injection, both microSPECT/CT and fluorescence images were acquired, both before and after resection of the tumor nodules. After image acquisition, the biodistribution of 111In-RDC018 and 111In-IMP288 was determined and tumors were analyzed immunohistochemically. The biodistribution of the dual-label RDC018 showed specific accumulation in the TROP-2–expressing PC3 tumors (12.4 ± 3.7% ID/g at 2 hours postinjection), comparable with 111In-IMP288 (9.1 ± 2.8% ID/g at 2 hours postinjection). MicroSPECT/CT and near-infrared fluorescence (NIRF) imaging confirmed this TROP-2–specific uptake of the dual-label 111In-RDC018 in both the s.c. and metastatic growing tumor model. In addition, PC3 metastases could be visualized preoperatively with SPECT/CT and could subsequently be resected by image-guided surgery using intraoperative NIRF imaging, showing the preclinical feasibility of pretargeted dual-modality imaging approach in prostate cancer. Cancer Res; 74(21); 6216–23. ©2014 AACR.

Boron neutron capture therapy (BNCT) is a promising technique for highly targeted tumor therapy.[1][1],[2][2] BNCT relies on the high cross-section of the nonradioactive isotope boron-10 to capture thermal neutrons, leading to the reaction 10B(n,α)7Li. This capture reaction first results in the

Contains fulltext : 97008.pdf (Publisher’s version ) (Closed access) hRS7 is a humanized IgG1 monoclonal antibody directed against the epithelial glycoprotein-1 (EGP-1; also known as TROP2). This antigen is found in many epithelial cancers, including prostate cancer, and therefore this antibody could be suitable for targeting this cancer. In this study, the characteristics of hRS7 for targeting prostate cancer were examined. The potential for immuno-PET with (89)Zr-hRS7 and immuno-SPECT with (111)In-hRS7 was assessed using nude mice with human prostate cancer xenografts. METHODS: EGP-1 expression was assessed by immunohistology in human primary and metastatic prostate cancer samples and in PC3 xenografts. The optimal antibody protein dose for prostate cancer targeting was examined in nude mice with subcutaneous PC3 xenografts, and then the biodistribution of (111)In-, (125)I-, and (89)Zr-labeled hRS7 was determined in subcutaneous PC3 xenografts at 1, 3, and 7 d after injection. Immuno-PET and immuno-SPECT were performed with (89)Zr-hRS7 and (111)In-hRS7 in mice with subcutaneous and intraprostatic PC3 xenografts, respectively. RESULTS: Immunohistochemical analysis showed abundant EGP-1 expression in human primary and metastatic prostate cancers and in PC3 xenografts. (111)In-hRS7 and (89)Zr-hRS7 preferentially and specifically accumulated in PC3 xenografts, with tumor uptake as high as 60% injected dose per gram at a protein dose of 0.1 mug per mouse. PC3 tumors in nude mice were clearly visualized with both tracers with immuno-PET and immuno-SPECT. CONCLUSION: hRS7 shows excellent in vivo tumor targeting in human prostate cancer xenografts. Therefore, hRS7 is a potential vehicle for targeting prostate cancer.

Aim: Glioblastoma multiforme (GBM) is an incurable disease that can only be managed in a palliative way. The GBM accounts for approximately half of all newly diagnosed primary brain tumors with an incidence of 2–3 cases per 100,000 people each year. Surgery and radiation are the standard options for palliation, and whether there is a place for chemotherapy is still discussed. Boron neutron capture therapy (BNCT) is a promising and possibly curative method of treating GBM. The purpose of this article is to provide an updated review on the current management and future possibilities of treating GBM with BNCT. Method: Use was made of computerized searches and of checking cross-references of articles and book chapters. Results: The principle of BNCT uses the high ability of 10B to capture thermal neutrons and to disintegrate immediately into a He nucleus (α-particle) and a Li nucleus. To reach a sufficient concentration of 10B in the malignant cells compared to the surrounding healthy tissue, 10B-carriers must be highly tumor-selective. At present, the 10B carriers boronophenylalanine (BPA) and sodium borocaptate (BSH) are used in clinical trials to perform BNCT. Conclusion: The BNCT is a promising and possibly curative method of treating GBM, but at present this procedure is far from perfect. Because of the lack of selectivity of the boron carriers, it appears so far that radiation toxicity limits the radiation dose, so that tumor damage is modest. Current investigations and developments are aimed at targeting the boron carriers to the tumor, in order to limit the damage to the healthy, surrounding tissue.