Abstract A77: Preclinical multimodality imaging of metastatic prostate cancer xenograft models with 89Zr-J591.
Authors: Deh Kofi , Chandrasekaran Siddarth , Fareedy Shoaib , Osborne Joseph 
Published: August 2014

Background: The goal of this study was to investigate the efficacy of a humanized antibody, J591, in targeting metastasized prostate cancer (PC). PC, the most common solid tumor affecting American males, is expected to be diagnosed in 241,740 men and to cause 28,170 deaths in 2012 [1]. Current imaging tools for the disease, such as positron emission tomography – computed tomography (PET/CT) with [18F]-fluorodeoxyglucose (FDG), are inadequate because they are non-specific to prostate cancer cells. PET imaging with prostate cancer specific monoclonal antibodies (J591) promises greater specificity by targeting the extracellular epitope of prostate specific membrane antigen (PSMA). PSMA is a 100 kDa protein over-expressed in prostate cancer cells and up-regulated in high-grade disease. Although, preclinical J591 ImmunoPET imaging has been successfully reported for primary tumors [2], there have been no similar reports for metastatic cancer. In this study, we investigate the performance of a radioimmunoconjugate, [89]Zr-J591, for PET/CT imaging of C4-2 (bone-seeking) and RM1 (lung-seeking) tumors on a small animal PET camera. The PET/CT images were compared to 7T magnetic resonance (MR) images of the tumors, to determine the added diagnostic value of [89]Zr-J591 imaging.

Methods: [89]Zr was produced in a cyclotron using 89Y(p,n)89Zr transmutation reaction and conjugated via desferrioxamine B to the J591 monoclonal antibody (mAb). PC cell lines adapted for flank tumors in xenograft mice (LNCaP cell line), lung-seeking (RM1 cell line) and orthotopic (C4-2 cell line) were kept in culture for two weeks and then implanted into male athymic nu/nu BalbC mice, by tail intravenous or subcutaneous injection. The RM1 and C4-2 cells had previously been modified to express green fluorescent protein (GFP) and after 3 weeks, bioluminescence images were acquired to verify the growth of the tumors. MR images of selected mice were also acquired. The mice were divided into two groups, and the first was administered 200 uCi of 89Zr-J591 for imaging studies. PET/CT images of these mice were acquired 3 days post-injection. The mice in the second group were injected with 50 uCi of [89]Zr-J591 for bio-distribution studies. After 3 days, the mice were sacrificed; specific tissues were extracted, weighed and measured in a gamma counter.

Results: There was excellent tumor targeting by [89]Zr-J591 with tumor-to-muscle ratios of about 10. This was confirmed by in vivo bio-distribution studies, which showed an average uptake of 22 percentage injected dose per gram (%ID/g). Standard uptake values (SUV) ranged between 3.5 and 4.7. We observed good correlation between the bioluminescence, PET/CT and MR images. We also observed that the PET/CT images provided better tumor delineation, and therefore greater diagnostic value, than MRI images

Conclusions: [89]Zr-J591 shows great promise as a prostate cancer imaging biomarker. It provides high tumor to background ratio, superior quantitative properties and specificity for PSMA. Establishing an imaging biomarker is the first step toward tailoring of therapies toward individuals or specific populations at risk.

[1] American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012.

[2] 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS. J Nucl Med. 2010 Aug;51(8):1293-300. Epub 2010 Jul 21.

Citation Format: Kofi Deh, Siddarth Chandrasekaran, Shoaib Fareedy, Joseph Osborne. Preclinical multimodality imaging of metastatic prostate cancer xenograft models with 89Zr-J591. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A77.