Predicting the biodistribution of anti-CD74 antibody Fab fragment MD18 radiolabeled cMORF effector in MORF-pretargeted mice

Objectives: CD74 is expressed on the surface of many immune cells mediating cell adhesion, cell proliferation as well as signal transduction. Over expression of CD74 is found to be associated with gliomas. Therefore, monitoring of CD74 expression is of interest for neurosurgeons to track progression of gliomas and manage response to treatment. The goal of this study was to develop a pretargeting radiolabeled tracer to monitor CD74 expression in gliomas.

Methods: We successfully constructed ^99mTc-cMORF/MORF-MD18 pretargeting system. Pretargeting studies with phosphorodiamidate morpholino oligomers (MORFs) involves administration of a MORF-conjugated anti-CD74 antibody Fab fragment MD18 as a pretargeting agent before that of the radiolabeled complementary MORF (cMORF) with ^99mTc as the effector. The dosages of the pretargeting agent and effector, the pretargeting interval, and the detection time are verified in models of U251 malignant glioma. Whole-body images obtained with storage phosphor screen were performed to evaluate the capacity and specificity of pretargeting system to target CD74. In addition, its pharmacokinetic parameters and biological distribution in U251 malignant glioma model of nude mice was detected in vivo. RESULTS The predicted biodistribution of the radiolabeled effector and the experimental data were in agreement in normal organs, suggesting that the description of the pretargeting process was reliable. By both biological distribution and Whole-body images, the tracer study showed that the whole body radioactivity was largely restricted to tumor in the mice pretargeted 48h earlier with MORF-MD18 and the tumor radioactivity was retained over 72 h. At 48 h postinjection, Whole-body imaging of U251 malignant glioma models with^99mTc-cMORF/MORF-MD18 pretargeting system revealed tumor uptakes of 14.53 ± 2.9 %ID/g significantly higher than control (3.57± 1.06 %ID/g). CONCLUSION A description of the biodistribution of labeled cMORF was capable of predicting the biodistribution of the radiolabeled effector in the pretargeted tumored mouse model, demonstrating that the underlying pretargeting concepts are correct. In conclusion, effective monitor of CD74 expression in gliomas was achieved by ^99mTc-cMORF/MORF-MD18 pretargeting system.

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