title: A preclinical 188Re tumor therapeutic investigation using MORF/cMORF pretargeting and an antiTAG-72 antibody CC49.
abstract: The utility of MORF/cMORF pretargeting for the radiotherapy of cancer requires further validation in tumored mice before clinical trials. We now report on a therapeutic study in mice pretargeted with MORF-CC49 (an anti-TAG-72 antibody CC49 conjugated with MORF, a phosphorodiamidate morpholino oligomer) and then targeted by 188Re-cMORF (a 188Re labeled complementary MORF). Before the dose-escalating therapeutic study, a pretargeting study in LS174T tumored mice was performed at tracer levels. By both necropsy and imaging, the tracer study showed that the whole body radioactivity was largely restricted to tumor in the mice pretargeted 48 h earlier with MORF-CC49 and the tumor radioactivity was retained over 90 h. After decay correction, a best-fit to the biodistribution provided the areas under the radioactivity curves (AUCs) used for the radiation dose estimates. The tumor to normal organ AUC ratios in all cases were greater than unity and ranged from 3 (kidneys) to 48 (muscle). Tumor growth was inhibited in the therapy study. At the highest 188Re dose of 1.40 mCi, a complete but temporary tumor remission was evident in 3 out of the 5 animals. Histological examination of tissues from these animals showed no evidence of cytotoxicity to normal tissues but obvious radiation damage to tumor. In conclusion, effective radiotherapy was achieved in a mouse model by MORF/cMORF pretargeting using 188Re as the therapeutic radionuclide and CC49 as the pretargeting antibody.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA. guozheng.liu@umassmed.edu
authors.forename: Guozheng
authors.initials: G
authors.lastname: Liu
authors.forename: Shuping
authors.initials: S
authors.lastname: Dou
authors.forename: Stephen
authors.initials: S
authors.lastname: Baker
authors.forename: Ali
authors.initials: A
authors.lastname: Akalin
authors.forename: Dengfeng
authors.initials: D
authors.lastname: Cheng
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Mary
authors.initials: M
authors.lastname: Rusckowski
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Hnatowich
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000737:chemistry; D019540:Area Under Curve; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics; D060172:Morpholinos; D011868:Radioisotopes / Q000008:administration & dosage* / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000737:chemistry; D011879:Radiotherapy Dosage; D012211:Rhenium / Q000008:administration & dosage; D013154:Spleen / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D023041:Xenograft Model Antitumor Assays
chemical_list: D000912:Antibodies, Neoplasm; C091202:B72.3 antibody; D009025:Morpholines; D060172:Morpholinos; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D012211:Rhenium