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Preclinical evaluation of monoclonal antibody 14C5 for targeting pancreatic cancer
Liesbet Vervoort1, Ingrid Burvenich, Steven Staelens
1Laboratory of Radiopharmacy, University of Ghent, Ghent, Belgium. liesbet.vervoort@ugent.be
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.
Insights
This study shows that the radiolabeled antibody 14C5 effectively targets integrin alpha(v)beta(5) in pancreatic cancer. This antibody demonstrates promising potential for both diagnosing and treating pancreatic tumors.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
Background:
- Pancreatic cancer remains a significant health challenge with limited effective treatments.
- Targeted therapies using radiolabeled antibodies offer a promising strategy for cancer treatment.
- Integrin alpha(v)beta(5) is explored as a potential therapeutic target in pancreatic cancer.
Purpose of the Study:
- To evaluate integrin alpha(v)beta(5) as a target for pancreatic cancer diagnosis and therapy.
- To assess the efficacy of the radiolabeled murine monoclonal antibody (mAb) 14C5 targeting integrin alpha(v)beta(5).
Main Methods:
- Human pancreatic tumor biopsy specimens were analyzed for integrin alpha(v)beta(5) expression.
- The pancreatic tumor cell line Capan-1 was used for in vitro and in vivo studies.
- mAb 14C5 was radiolabeled with iodine-125/131 and indium-111.
- Cellular radioimmunoassays assessed internalization, retention, and metabolism.
- Biodistribution and tumor-targeting characteristics were evaluated in Capan-1 xenografts.
Main Results:
- All examined pancreatic tumor sections showed positive integrin alpha(v)beta(5) expression, particularly in the stroma.
- Saturation binding experiments confirmed high affinity of mAb 14C5.
- (111)In-labeled p-SCN-Bz-DOTA-14C5 exhibited superior intracellular retention compared to other radiolabeling methods.
- In vivo studies showed maximum radioisotope tumor uptake at 48-72 hours, with (111)In-p-SCN-Bz-DOTA-14C5 achieving significantly higher uptake.
- Gamma imaging demonstrated clear pancreatic tumor localization with minimal uptake in normal tissues.
Conclusions:
- Integrin alpha(v)beta(5) is a viable target for pancreatic cancer.
- Radiolabeled mAb 14C5, particularly when labeled with (111)In-p-SCN-Bz-DOTA, shows significant promise for pancreatic cancer diagnosis and therapy.
- mAb 14C5 offers a potential new avenue for targeted treatment of pancreatic cancer.
