Anti PSMA monoclonal antibody (WuXi Biologics)

The prostate-specific membrane antigen (PSMA) represents an ideal target for imaging and targeted therapy of prostate cancer (PC) for several reasons: PSMA is a type II transmembrane protein with glutamate-carboxypeptidase activity and a known substrate, which is optimal for developing small molecule radiopharmaceuticals, typically showing fast blood clearance and excretion resulting in low background activity. Furthermore, upon ligand binding PSMA is internalised via clathrin-coated pits and subsequent endocytosis with an effective transport of the bound molecule into the cells. Since internalisation leads to enhanced tumour uptake and retention, targeting PSMA is expected to result in high image quality for diagnostic procedures and a high local intracellular deposit for therapeutic applications. In addition, PSMA is a cell surface protein that shows a significant overexpression on PC cells and especially in advanced stage PC with a low expression in normal human tissues. Therefore, several groups engaged in the development of PSMA ligands for diagnosis and therapy of PC, either based on antibodies or on small molecules [1–4]. Studies using the radiolabelled anti-PSMA monoclonal antibody J591 have shown targeting of PSMAexpressing PC. Although antibodies offer a potential for tumour imaging, their effectiveness as diagnostic radiopharmaceuticals is limited by a long biological half-life and poor tumour penetrability, particularly for bone metastases. Recent developments may overcome these limitations, such as combination with longer-lived positron emission tomography (PET) radionuclides such as Zr and Cu [1] or

Correct staging of prostate cancer is an unmet clinical need. Radionuclide targeting of prostate-specific membrane antigen (PSMA) with 111In-labeled capromab pendetide (ProstaScint) is a clinical option for prostate cancer staging. We propose the use of 124I-labeled capromab to decrease the retention of radioactivity in healthy organs (due to the non-residualizing properties of the radiolabel). The use of 124I as a label should increase imaging sensitivity due to the advantages of PET as an imaging modality. Capromab targets the intracellular domain of PSMA; accumulation of radioactivity in the tumor should not depend on internalization of the antigen/antibody complex. Capromab was iodinated, and its targeting properties were compared with indium labeled counterpart in LNCaP xenografts in dual isotope mode. PSMA-negative xenografts (PC3) were used as a negative control. Radioiodinated capromab bound to PSMA specifically. Biodistribution of 125I/111In-capromab showed a more rapid clearance of iodine radioactivity from liver, spleen, kidneys, bones, colon tissue, as well as tumors. Maximum tumor uptake (13±8% ID/g for iodine and 29±9% ID/g for indium) and tumor-to-non-tumor ratios for both agents were measured 5 days post-injection (pi). High tumor accumulation and low uptake of radioactivity in normal organs were confirmed using microPET/CT 5 days pi of 124I-capromab.