Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) accounts for >90% of pancreatic malignancies, and has median survival of <6 months. There is an urgent need for diagnostic and therapeutic options for PDAC. Centrin1 (CETN1) is a novel member of Cancer/Testis Antigens, with a 25‐fold increase of CETN1 gene expression in PDX from PDAC patients. The absence of selective anti‐CETN1 antibodies is hampering CETN1 use for diagnosis and therapy. Here we report the generation of highly specific for CETN1 antibodies and their evaluation for radioimmunoimaging and radioimmunotherapy (RIT) of experimental PDAC.MethodsThe antibodies to CETN1 were generated via mice immunization with immunogenic peptide distinguishing CETN1 from CETN2. Patient tumor microarrays were used to evaluate the binding of the immune serum to PDAC versus normal pancreas. The antibodies were tested for their preferential binding to CETN1 over CETN2 by ELISA. Mice bearing PDAC MiaPaCa2 xenografts were imaged with microSPECT/CT and treated with 213Bi‐ and 177Lu‐labeled antibodies to CETN1.ResultsImmune serum bind to 50% PDAC cases on patient tumor microarrays with no specific binding to normal pancreas. Antibodies demonstrated preferential binding to CETN1 versus CETN2. Antibody 69‐11 localized to PDAC xenografts in mice in vivo and ex vivo. RIT of PDAC xenografts with 213Bi‐labeled antibodies was effective, safe, and CETN1‐specific.ConclusionsThe results demonstrate the ability of these novel antibodies to detect CETN1 both in vitro and in vivo; as well, the RIT treatment of experimental PDAC when radiolabeled with 213Bi is highly efficient and safe. Further evaluation of these novel reagents for diagnosis and treatment of PDAC is warranted.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of pancreatic malignancies, is the 3rd leading cause of cancer death in the United States with a rising incidence,[1] and a median survival of less than 6 months
GeneTex tumor microarray analysis was used to evaluate the binding of the immune serum to PDAC versus normal pancreas
The discovery of CETN1 mRNA level being upregulated 25‐ fold in PDAC tumors compared to normal pancreas 2 opened new opportunities for diagnosis and therapy of PDAC by Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer including RIT and peptide receptor radionuclide therapy (PRRT) with antibodies and peptides as radiation targeting vehicles, respectively, have been performed in the last decade, and have demonstrated the safety and potential efficacy of targeted radionuclide therapy for treatment of this formidable disease
Summary
Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of pancreatic malignancies, is the 3rd leading cause of cancer death in the United States with a rising incidence,[1] and a median survival of less than 6 months. This cancer rapidly disseminates to the lymphatic system and distant organs. While CETN1 could be an ideal target for the diagnosis and treatment of PDAC and prostate cancer in patients expressing this biomarker due to its specific expression and role in cell division ; the anti‐CETN1 antibodies available on the market do not sufficiently discriminate between CETN1 and CETN2, hampering their use as effective oncology biomarker detectors and therapeutics. We report the generation of highly specific for CETN1 antibodies and their evaluation in patients’ tumor microarrays and for radioimmunoimaging and radioimmunotherapy (RIT) of experimental PDAC
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