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

Abstract

The prospects for using pretargeted immuno-SPECT to monitor the response to pretargeted radioimmunotherapy were examined. In this study, a bispecific anticarcinoembryonic antigen (CEACAM5; CD66e) · antihapten monoclonal antibody, TF2, was used in combination with a small (1.5 kD) peptide, IMP288, labeled with 111 In and 177 Lu. Methods: First, tumor uptake of 111 In-IMP288 and 177 Lu-IMP288, as determined by immuno-SPECT, was validated by ex vivo counting. Two groups of female BALB/c nude mice had LS174T tumors implanted in the peritoneal cavity. They received intravenous injections of TF2, followed by 10 MBq of 111 In-IMP288 or 90 MBq of 177 Lu-IMP288. A control group of non-tumor-bearing mice received TF2 and 111 In-IMP288. One hour after the radiolabeled IMP288 was given, small-animal SPECT/CT images were acquired, and subsequently animals were dissected. Furthermore, a survival study was performed in 3 groups of 10 mice with intraperitoneal tumors: mice received TF2 and 177 Lu-IMP288 (60 MBq), nonpretargeted 177 Lu-IMP288 (60 MBq), or phosphate-buffered saline. Immuno-SPECT scans were acquired directly after therapy and at 14 and 45 d after therapy. Tumor growth was analyzed in the successive scans in each animal. Results: 111 In-and 177 Lu-labeled IMP288 had similar in vivo distribution. The activity measured in the pretargeted immuno-SPECT images correlated well with the uptake measured in the dissected tumors (Pearson r 5 0.99, P , 0.05). In the therapy study, the SPECT images showed rapid and selective tumor targeting with high tumor-to-background contrast (30 6 12) as early as 1 h after injection. The successive images of the treated mice showed delayed tumor growth in the pretargeted radioimmunotherapy group, corresponding with their prolonged survival. Conclusion: Pretargeted immuno-SPECT with TF2 and 111 In-or 177 Lu-IMP288 can be used to predict and confirm tumor targeting and monitor the therapeutic effect of pretargeted radioimmunotherapy.

α- Versus β-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colon Cancer Xenografts

“…Pretargeting with the bsmAb TF2 and radiolabeled IMP288 allows rapid and specific targeting of CEA-expressing tumors. Therapy with 177 Lu-IMP288 has been shown to be safe and feasible (10,11,19,20). However, tumors eventually show progressive growth.…”

“…To investigate whether a lower peptide dose would improve the therapeutic efficacy, the fourth group received 0.14 nmol of 12 MBq 213 Bi-IMP288. The fifth group received 0.28 nmol of 60 MBq 177 Lu-IMP28, which is the maximum tolerable dose as determined previously (11). Mice in the control group received vehicle only (PBS, 0.5% bovine serum albumin).…”

“…We previously showed that PRIT with the anti-CEA · antihistamine-succinyl-glycine (HSG) bsmAb TF2, and 177 Lu-labeled di-HSG-DOTA peptide IMP288, inhibited the growth of carcinoembryonic antigen (CEA)-positive human colonic tumor xenografts in mice, with limited toxicity (10,11). Moreover, a phase I study in patients with metastatic colorectal cancer showed that this treatment is feasible and safe (12).…”

Inhibitory effect of gene combination in a mouse model of colon cancer with liver metastasis

“…Other routes are possible, including implantation within the portal vein, ileocolic vein and liver, however, these are rarely used due to operational difficulties (10,11). When using the cecal wall planting method, the range of tumor metastases is wide, with a relatively low incidence and slow development of liver metastasis.…”

The role of mouse models in colorectal cancer research—The need and the importance of the orthotopic models

“…The injection of tumor cells into the peritoneum and peritoneal cavity was probably one of the first ideas in order to promote tumor development in mice and its study. It is still used nowadays leading to the development of tumor nodules on the peritoneum and dissemination through the peritoneal cavity …”