期刊
EJNMMI RESEARCH
卷 4, 期 -, 页码 -出版社
SPRINGEROPEN
DOI: 10.1186/2191-219X-4-13
关键词
Prostate carcinoma (PCa); PSMA; Diabody; Single photon emission computed tomography ( SPECT); Tc-99m, Molecular imaging
资金
- Centre of Excellence in Medical Engineering - Wellcome Trust
- Engineering and Physical Sciences Research Council (EPSRC)
- Cancer Research UK/EPSRC Comprehensive Cancer Imaging Centre (CCIC)
- Experimental Cancer Medicine Centres at King's College London
- National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- Cancer Research UK [16463] Funding Source: researchfish
- Medical Research Council [MR/J006742/1] Funding Source: researchfish
Background: Sensitive and specific detection of nodal status, sites of metastases and low-volume recurrent disease could greatly improve management of patients with advanced prostate cancer. Prostate-specific membrane antigen (PSMA) is a well-established marker for prostate carcinoma with increased levels of expression in high-grade, hormone-refractory and metastatic disease. The monoclonal antibody (mAb) J591 is directed against an extracellular epitope of PSMA and has been shown to efficiently target disseminated disease including metastases in lymph nodes and bone. Its use as a diagnostic imaging agent however is limited due to its slow pharmacokinetics. In this study a diabody derived from mAb J591 was developed as a single photon emission computed tomography (SPECT) tracer with improved pharmacokinetics for the detection of PSMA expression in prostate cancer. Methods: A diabody in V-H-V-L orientation and with a C-terminal cysteine was expressed in HEK293T cells and purified by a combination of metal ion affinity and size exclusion chromatography. Specificity and affinity were determined in cell binding studies. For SPECT imaging, the diabody was site-specifically labelled with [Tc-99m(CO)(3)](+) via the C-terminal His tag and evaluated in a subcutaneous DU145/DU145-PSMA prostate carcinoma xenograft model. Results: J591C diabody binds to PSMA-expressing cells with low nanomolar affinity (3.3 +/- 0.2 nM). SPECT studies allowed imaging of tumour xenografts with high contrast from 4 h post injection (p.i.). Ex vivo biodistribution studies showed peak tumour uptake of the tracer of 12.1% +/- 1.7% injected dose (ID)/g at 8 h p.i. with a tumour to blood ratio of 8.0. Uptake in PSMA-negative tumours was significantly lower with 6.3%+/- 0.5% at 8 h p.i. (p < 0.001). Conclusion: The presented diabody has favourable properties required to warrant its further development for antibody-based imaging of PSMA expression in prostate cancer, including PSMA-specific uptake, favourable pharmacokinetics compared to the parental antibody and efficient site-specific radiolabelling with Tc-99m.
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