Abstract 4283: Evaluation of PSCA-specific minibody for in vivo imaging

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction: Molecular targeted therapy of advanced prostate cancer requires the ability to classify tumors at the molecular level without invasive tissue sampling. Noninvasive molecular imaging can yield information on tumor localization, phenotype, and response to therapy. Previously we have generated humanized antibody to prostate stem cell antigen (PSCA), a cell surface marker highly elevated in prostate cancers, and used the antibody to detect tumors by PET imaging. To improve affinity, minibody variants were obtained by yeast display, and one clone, A11, demonstrated high imaging contrast in PSCA positive xenograft tumors. However, xenograft tumors are limited as model of natural disease progression, and cannot be used to assess background uptake of antibody in normal tissues, given that the humanized antibody does not recognize the murine (m)PSCA. This study aims to evaluate the biodistribution of A11 minibody in a mouse model expressing human (h)PSCA. Such model is important for assessing minibody performance prior to further clinical development. Methods: hPSCA knock-in (KI) mouse was generated by replacing exon 1 of mPSCA with hPSCA cDNA thereby driving hPSCA expression under mPSCA promoter. hPSCA-KI line was evaluated for hPSCA expression in major organs by RT-PCR and immunohistochemistry. For imaging study, groups of 8 weeks old hPSCA-KI and wild-type mice were injected with radiolabeled (I-124) minibody A11 and imaged by microPET at 4 and 20 hrs post injection. Mice were then sacrificed and major organs collected, weighed, and counted to determine biodistribution of A11. Results: By immunohistochemistry, hPSCA is expressed in prostate, bladder and stomach of heterozygous hPSCA-KI mice as expected. Other organs showed much lower or no expression of hPSCA, as confirmed by RT-PCR. MicroPET imaging showed specific uptake of I-124 labeled A11 in the prostate, bladder and stomach of hPSCA-KI mice. A11 biodistribution (% injected dose/gram of tissue) was significantly higher in hPSCA-KI mice compared to wild-type mice: prostate (0.83 ± 0.13 vs. 0.49 ± 0.04), bladder (3.21 ± 0.42 vs. 1.66 ± 0.25) and stomach (2.00 ± 0.22 vs. 0.79 ± 0.05). There was no uptake difference between groups for other major organs including pancreas, lung, kidney, spleen and liver. Conclusions: The minibody uptake in hPSCA-KI mice was specific to normal site of expression (prostate, bladder and stomach). While the % uptake was significantly higher than wild-type controls, the actual levels were modest and should not necessarily interfere with tumor imaging. This part of the study remains to be investigated. PSCA has been shown to be elevated in the PTEN conditional knockout prostate cancer mouse model. Thus, hPSCA-KI;PTEN-knockout mice are being generated and will be used to evaluate the PSCA-specific minibody as a tumor imaging tool. PSCA minibody imaging may be useful as a surrogate to diagnose and monitor response to targeted therapy of this type of prostate cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4283. doi:10.1158/1538-7445.AM2011-4283