Tumor pretargeting in mice using MORF conjugated CC49 antibody and radiolabeled complimentary cMORF effector.
OBJECTIVE
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.


CONCLUSIONS
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.
Liu
G
G
Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655-0243, USA. guozheng.liu@umassmed.edu
Dou
S
S
Pretorius
P H
PH
Liu
X
X
Chen
L
L
Rusckowski
M
M
Hnatowich
D J
DJ
D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000378:metabolism*; D016503:Drug Delivery Systems; D007205:Indium Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D060172:Morpholinos; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D013667:Technetium / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution
D000912:Antibodies, Neoplasm; C091202:B72.3 antibody; D007205:Indium Radioisotopes; D009025:Morpholines; D060172:Morpholinos; D019275:Radiopharmaceuticals; D013667:Technetium