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Published on: February 3, 2015
Tumor pretargeting in mice using MORF conjugated CC49 antibody and radiolabeled complimentary cMORF effector
1Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655-0243, USA. guozheng.liu@umassmed.edu
Aim:
Using the antiCEA antibody MN14, a LS174T mouse tumor model has been successfully targeted with (⁹⁹m)Tc for imaging and ¹⁸⁸Re for radiotherapy by phosphorodiamidate morpholino oligomers (MORF)/complementary MORF (cMORF) pretargeting strategy. This investigation evaluated the antiTAG-72 antibody CC49 as an alternative to MN14 for this application.
Methods:
Both CC49 and MN14 were labeled with ¹¹¹In via SCN-benzyl-DTPA and their biodistributions were compared to that of MN14 labeled via DTPA anhydride. Since the accessibility of the antibody to the effector is required for optimization of pretargeting, the internalization of both MORF-CC49 and MORF-MN14 antibodies in LS174T cells were evaluated in culture. In addition, the accessible concentration of MORF-CC49 antibody in tumor was determined in a series of pretargeting studies with escalating dosages of the [(⁹⁹m)Tc]cMORF effector. Finally, using these results and our semi-empirical model, an imaging study was performed under optimal pretargeting conditions.
Results:
The biodistribution of ¹¹¹In to trace the MN14 antibody depended significantly on the labeling method. Furthermore, both MORF-CC49 and MORF-MN14 antibodies showed rapid internalization in culture. Fortunately, the accessibility in tumor was found to be less seriously reduced in vivo. In a pretargeting study under optimal conditions, both by imaging and by necropsy, the [(⁹⁹m)Tc]cMORF effector accumulated predominantly in the tumor of pretargeted mice. Normal tissue accumulations were minimal except in kidneys, liver, and a segment of intestines.
Conclusion:
MORF pretargeting with CC49 was equally successful in the LS174T tumor model to the MORF pretargeting with MN14. The MORF-CC49 antibody may therefore be considered for future investigations toward early clinical trials.
Insights
The anti-TAG-72 antibody CC49, using a phosphorodiamidate morpholino oligomers (MORF) pretargeting strategy, successfully targeted LS174T mouse tumors for imaging. This demonstrates CC49 is a viable alternative to MN14 for pretargeted radioimmunotherapy.
Area of Science:
- Oncology
- Radiochemistry
- Immunology
Background:
- The phosphorodiamidate morpholino oligomers (MORF)/complementary MORF (cMORF) pretargeting strategy has shown success in targeting LS174T mouse tumors with the anti-CEA antibody MN14 for imaging and radiotherapy.
- Evaluating alternative antibodies is crucial for optimizing pretargeted radioimmunotherapy efficacy and expanding clinical applications.
Purpose of the Study:
- To assess the anti-TAG-72 antibody CC49 as a potential alternative to the anti-CEA antibody MN14 in the MORF/cMORF pretargeting strategy for LS174T tumor models.
- To compare the biodistribution and tumor accessibility of CC49 and MN14 antibodies labeled with Indium-111 (¹¹¹In).
- To evaluate the internalization of MORF-conjugated CC49 and MN14 antibodies in LS174T cells and determine the accessible concentration of MORF-CC49 in tumors.
Main Methods:
- Antibodies CC49 and MN14 were labeled with ¹¹¹In using SCN-benzyl-DTPA and DTPA anhydride methods for biodistribution comparison.
- Internalization of MORF-CC49 and MORF-MN14 in LS174T cells was assessed in vitro.
- Tumor accessibility of MORF-CC49 was determined in vivo using escalating doses of [(⁹⁹m)Tc]cMORF effector.
- An imaging study was conducted under optimal pretargeting conditions based on established models.
Main Results:
- The labeling method significantly impacted the biodistribution of the ¹¹¹In-labeled MN14 antibody.
- Both MORF-CC49 and MORF-MN14 antibodies exhibited rapid internalization in LS174T cells, with less reduction in tumor accessibility in vivo.
- Optimal pretargeting conditions led to predominant accumulation of the [(⁹⁹m)Tc]cMORF effector in tumors, with minimal uptake in normal tissues except kidneys, liver, and intestines.
Conclusions:
- The MORF pretargeting strategy with the anti-TAG-72 antibody CC49 proved equally effective as MN14 in the LS174T tumor model.
- CC49 is a promising candidate for future investigations and potential early clinical trials in pretargeted radioimmunotherapy.
