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. 10.1016/j.nucmedbio.2015.07.008. Epub 2015 Jul 29.
Tumor and organ uptake of (64)Cu-labeled MORAb-009 (amatuximab), an anti-mesothelin antibody, by PET imaging and biodistribution studies.

Abstract
OBJECTIVES:
To investigate the effect of the injection dose of MORAb-009 (amatuximab, an anti-mesothelin monoclonal antibody), the tumor size and the level of shed mesothelin on the uptake of the antibody in mesothelin-positive tumor and organs by biodistribution (BD) and positron emission tomography (PET) imaging studies.

METHODS:
2-S-(4-Isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) was conjugated to amatuximab and labeled with (64)CuCl2 in 0.25M acetate buffer, pH4.2. The resulting (64)Cu-NOTA-amatuximab was purified with a PD 10 column. To investigate the dose effect or the effect of tumor size, the BD was performed in groups of nude mice (n=5) with mesothelin-expressing A431/H9 tumors (range, 80-300mm(3)) one day after iv injection of (64)Cu-NOTA-amatuximab (10μCi) containing a total amatuximab dose of 2, 30, or 60μg. The BD and PET imaging were also investigated 3, 24 and 48h after injecting a total dose of 30μg (10μCi for BD), and 2 or 60μg (300μCi for PET), respectively.

RESULTS:
Comparing the results of the BDs from three different injection doses, the major difference was shown in the uptake (%ID/g) of the radiolabel in tumor, liver and blood. The tumor uptake and blood retention from 30 and 60μg doses were greater than those from 2μg dose, whereas the liver uptake was smaller. The BD studies also demonstrated a positive correlation between tumor size (or the level of shed mesothelin in blood) and liver uptake. However, there was a negative correlation between tumor size (or the shed mesothelin level) and tumor uptake and between tumor size and blood retention. These findings were confirmed by the PET imaging study, which clearly visualized the tumor uptake with the radiolabel concentrated in the tumor core and produced a tumor to liver ratio of 1.2 at 24h post-injection with 60μg amatuximab, whereas the injection of 2μg amatuximab produced a tumor to liver ratio of 0.4 at 24h post-injection.

CONCLUSION:
Our studies using a nude mouse model of A431/H9 tumor demonstrated that the injection of a high amatuximab dose (30 to 60μg) could provide a beneficial effect in maximizing tumor uptake while maintaining minimum liver and spleen uptakes of the radiolabel, and in facilitating its penetration into the tumor core.

Author information

Lee JH1, Kim H2, Yao Z2, Lee SJ2, Szajek LP3, Grasso L4, Pastan I5, Paik CH6.​
1Nuclear Medicine, Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, 20892, USA. Electronic address: leejaeho@mail.nih.gov.
2Nuclear Medicine, Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, 20892, USA.
3Positron Emission Tomography Department, Clinical Center, NIH, Bethesda, MD, 20892, USA.
4Morphotek, Inc., Exton, PA, 19341, USA.
5Laboratory of Molecular Biology, NCI, NIH, Bethesda, MD, 20892, USA.
6Nuclear Medicine, Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, 20892, USA. Electronic address: cpaik@mail.nih.gov.
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