Evaluation of novel highly specific antibodies to cancer testis antigen Centrin-1 for radioimmunoimaging and radioimmunotherapy of pancreatic cancer.

Abstract

BACKGROUND:

Pancreatic 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.

METHODS:

The 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 213 Bi- and 177 Lu-labeled antibodies to CETN1.

RESULTS:

Immune 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 213 Bi-labeled antibodies was effective, safe, and CETN1-specific.

CONCLUSIONS:

The 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 213 Bi is highly efficient and safe. Further evaluation of these novel reagents for diagnosis and treatment of PDAC is warranted.

• Authors: Rubin Jiao, Kevin J H Allen, Mackenzie E Malo, Muath Helal, Zewei Jiang, Karishma Smart, Susan V Buhl, David Rickles, Ruth A Bryan, Ekaterina Dadachova
• Journal: Cancer medicine (Cancer Med) Vol. 8 Issue 11 Pg. 5289-5300 (Sep 2019) ISSN: 2045-7634 [Electronic] United States
• PMID: 31309741 (Publication Type: Journal Article)
• Copyright: © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antibodies
• Antigens, Neoplasm
• CTAG1B protein, human
• Immunoglobulin G
• Immunoglobulin M
• Membrane Proteins

Topics

• Amino Acid Sequence
• Animals
• Antibodies
• Antigens, Neoplasm (chemistry, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Humans
• Immunoglobulin G (immunology)
• Immunoglobulin M (immunology)
• Male
• Membrane Proteins (antagonists & inhibitors, chemistry, metabolism)
• Mice
• Molecular Imaging (methods)
• Pancreatic Neoplasms (diagnosis, etiology, therapy)
• Radioimmunodetection (methods)
• Radioimmunotherapy (methods)
• Single Photon Emission Computed Tomography Computed Tomography
• Xenograft Model Antitumor Assays