Pretargeted radioimmunoscintigraphy in patients with primary colorectal cancer using a bispecific anticarcinoembryonic antigen CEA X anti‐di‐diethylenetriaminepentaacetic acid F(ab′)₂ antibody

Abstract

BACKGROUND: Antibody-based imaging agents are available commercially, but their success has been limited, mainly because of low contrast and the emergence of 2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) scanning. In pretargeting, administration of the radionuclide is separated from the antibody, thereby enhancing image contrast and allowing detection at earlier time points after injection. METHODS: The authors conducted an open-label, single-arm trial that assessed a pretargeting procedure in which an anticarcinoembryonic antigen x (anti-CEA x) anti-diethylenetriaminepentaacetic acid (anti-DTPA)-indum (In) antibody was used in combination with a 111 In-labeled di-DTPA peptide for the diagnostic imaging of CEA-expressing colorectal cancer. Three patients received the 111 In peptide alone to investigate tumor targeting, organ distribution, and clearance of the peptide. Thereafter, 11 patients received the bispecific antibody (bsAb) (5 mg) to pretarget the tumor. After 3 to 5 days, patients were injected with 185 megabecquerels of 111 In-labeled peptide to assess the optimal interval for best image quality. RESULTS: Fourteen patients with primary colorectal cancer were enrolled. One of 3 patients who received 111 In peptide alone had low-level tumor uptake. In 9 of 11 other patients, tumors were observed. In 1 patient, FDG-PET-positive lymph nodes were observed clearly with pretargeted immunoscintigraphy. Peptide pharmacokinetics revealed enhanced circulating levels of 111 In-labeled peptide in patients in the 3-day interval cohort compared with the other cohorts. Tumor-to-background ratios ranged from 3.5 to 6.4 in the 3-day interval group, from 5.1 to 14.2 in the 4-day interval group, and from 3.5 to 3.9 in the 5-day interval group. The best images were acquired with a 4-day interval at 24 hours after injection of the radiolabeled peptide. Grade 1 adverse events were observed in 2 patients. CONCLUSIONS: Imaging of colorectal cancer using a 2-step, pretargeting system produced the best imaging results 24 hours after peptide administration using a 4-day interval between injection of the bsAb and the peptide. Cancer 2010;116(4 suppl):1111-7.

Radioimmunotherapy of human tumours

“…Additional studies using streptavidin-biotin pretargeting are underway for patients with AML, acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS) (Pagel & Press et al ., unpublished data). Pretargeting using antibodies to carcinoembryonic antigen (CEA) 116 was tested in colorectal cancer (CRC) 117 , small-cell lung cancer (SCLC) 118 , and medullary thyroid carcinoma 116, 119 ; NR-LU-10 in CRC 115 ; CC49 in gastrointestinal cancer 114 ; and CD20 monoclonal antibodies in NHL 113, 115 —all with variable success. A three-step approach using biotinylated monoclonal antibodies, followed by avidin-streptavidin and then biotinylated radiometal-chelate, was also applied to patients with glioma with encouraging results 120, 121 .…”

Quantitative Immuno-SPECT Monitoring of Pretargeted Radioimmunotherapy with a Bispecific Antibody in an Intraperitoneal Nude Mouse Model of Human Colon Cancer

“…Former studies showed pretargeted immuno-PET and -SPECT with radionuclides, such as 68 Ga, 18 F, 124 I, and 99m Tc (7,(12)(13)(14), but these methods cannot be used for dosimetric calculations for therapy. The half-life of 68 Ga (68 min) is not matched with the therapeutic radionuclide.…”

“…The therapeutic efficacy of PRIT with TF2 and 177 Lu-IMP288 was demonstrated previously in mice with subcutaneous LS174T xenografts (5). Furthermore, several clinical studies with bsmAb and 111 Inlabeled haptens for pretargeted immuno-SPECT showed high sensitivity (18)(19)(20)(21). In patients, immuno-SPECT can be used to guide individual treatment, because this imaging modality can be repeated at multiple time points.…”

Mapping biological behaviors by application of longer-lived positron emitting radionuclides

“…For example, the tumor uptake was ~10% ID/g for 68 Ga-IMP-288 and the tumor-to-blood ratio was ~70 [112]. Moreover, in a preliminary clinical trial, an anti-CEA/anti-DTPA bispecific antibody paired with an 111 In-di-DTPA peptide was employed in patients with primary colorectal cancer [113]. Among the intervals studied, the best imaging contrast was obtained with a 4 day interval, with resulting tumor-to-background ratios of 5.1 to 14.2 at 24 hours after injection of the radiolabeled peptide.…”