Preclinical evaluation of monoclonal antibody 14C5 for targeting pancreatic cancer.

Abstract

The use of radiolabeled antibodies that are able to target primary tumors as well as metastatic tumor sites with minimal reactivity to normal tissues is a promising approach for treating pancreatic cancer. In this study, the integrin alpha(v)beta(5) is studied as a target for the diagnosis of and potential therapy for human pancreatic cancer by using the radiolabeled murine monoclonal antibody (mAb) 14C5. Biopsy specimens from human pancreatic tumors were examined for the expression of the integrin alpha(v)beta(5). The pancreatic tumor cell line Capan-1 was used to test the in vitro targeting potency of mAb 14C5 labeled with 125/131-iodine and 111-indium. Internalization, retention, and metabolism were investigated in cellular radioimmunoassays. Biodistribution and tumor-targeting characteristics were studied in Capan-1 xenografts. All tumor sections were positive for the integrin alpha(v)beta(5), with an extensive positive staining of the stroma. Saturation binding experiments showed high affinity with comparable K(d)s. In vitro internalization experiments showed a longer intracellular retention of (111)In-p-benzyl isothiocyanate-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bz-DOTA)-14C5 in comparison to (125)I-14C5 and (111)In-p-isothiocyanatobenzyl diethylenetriaminepentaacetic acid (p-SCN-Bz-DTPA)-14C5. In vivo radioisotope tumor uptake was maximum at 48-72 hours, with the uptake of (111)In-p-SCN-Bz-DOTA-14C5 (35.84 +/- 8.64 percentage of injected dose per g [%ID/g]) being 3.9- and 2.2-folds higher than (131)I-14C5 (12.16 +/- 1.03%ID/g) and (111)In-p-SCN-Bz-DTPA-14C5 (14.30 +/- 3.76%ID/g), respectively. Planar gamma imaging with mAb 14C5 indicated clear localization of the pancreatic tumors versus minimal normal tissue uptake. mAb 14C5 is a promising new antibody for targeting the integrin alpha(v)beta(5) for the diagnosis of and potential therapy for pancreatic cancer.

• Authors: Liesbet Vervoort, Ingrid Burvenich, Steven Staelens, Caroline Dumolyn, Els Waegemans, Magali Van Steenkiste, Sarah K Baird, Andrew M Scott, Filip De Vos
• Journal: Cancer biotherapy & radiopharmaceuticals (Cancer Biother Radiopharm) Vol. 25 Issue 2 Pg. 193-205 (Apr 2010) ISSN: 1557-8852 [Electronic] United States
• PMID: 20423233 (Publication Type: Journal Article)

Chemical References

• 14C5 monoclonal antibody
• Antibodies, Monoclonal
• Iodine Radioisotopes
• Radiopharmaceuticals
• Receptors, Vitronectin
• integrin alphaVbeta5
• 1-(4-isothiocyanatobenzyl)diethylenetriaminepentaacetic acid
• Pentetic Acid

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Drug Evaluation, Preclinical
• Female
• Humans
• Iodine Radioisotopes
• Mice
• Mice, Nude
• Pancreas (immunology, metabolism, pathology)
• Pancreatic Neoplasms (immunology, metabolism, therapy)
• Pentetic Acid (analogs & derivatives, pharmacokinetics)
• Radioimmunoassay
• Radiopharmaceuticals
• Receptors, Vitronectin (immunology, metabolism)
• Tissue Distribution
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays