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.

An Engineered Cysteine-Modified Diabody for Imaging Activated Leukocyte Cell Adhesion Molecule (ALCAM)-Positive Tumors

“…Imaging agents that are specific to cell surface proteins on tumors cells could provide the specificity needed for improved detection and staging of pancreatic adenocarcinoma, along with evidence of a true tumor target for therapy. Recently, promising results in the preclinical setting have been obtained with a variety of such imaging agents, including an intact antibody-based anti-prostate stem cell antigen (PSCA) single photon emission computed tomography (SPECT) probe [42], anti-α v β 6 peptide [43] and intact antibody-based anti-carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6 [44] PET probes, and intact antibody-based anti-α v β 5 [45]and anti-mucin 1 (MUC1) [46] gamma imaging agents. This work adds ALCAM to the list of successfully imaged pancreatic cancer biomarkers.…”

Generation and in vivo characterization of a chimeric αvβ5-targeting antibody 14C5 and its derivatives

“…Integrin α v β 5 expression is involved in several crucial steps of cancer progression such as cell adhesion, angiogenesis, and metastasis [31,32]. Overexpression of α v β 5 has been demonstrated not only on several tumor types, but also on non-transformed tumor-promoting cells from the tumor stroma, such as cancer-associated fibroblasts [33] and cells from the neovasculature [11,14,34]. These accessory cells are less likely to lose antigen expression, making α v β 5 a very attractive target for Ab-based RID and/or RIT.…”

“…These accessory cells are less likely to lose antigen expression, making α v β 5 a very attractive target for Ab-based RID and/or RIT. The murine mAb 14C5 was shown to hold great potential for these applications, given the tenfold higher affinity for α v β 5 of the 14C5 mAb ( K D = 0.19 ± 0.07 nM) compared to the commercially available murine P1F6 mAb [13,14,17,35]. However, despite its promising characteristics, the use of mAb 14C5 in humans might provoke a HAMA response due to its murine origin.…”

“…The AUC values may be further improved by using radiometals such as 111 In and 90 Y, which have been shown to improve tumor retention times and AUC values of radiolabeled immunologicals [40]. Internalization studies with 111 In-14C5 mAb have already demonstrated extended tumor retention times compared to radioiodinated Ab 14C5 [35]. …”

Computer simulations to demonstrate new inversion methods for Compton camera data

“…Improvement in imaging is essential to maximizing the efficacy of radiotherapy when, for example, bismuth-213 is used to treat acute myeloid leukemia, 1-4 breast cancer, 5-8 gastric cancer, 9,10 glioma brain cancer, 11 non-Hodgkin lymphoma, 12 ovarian cancer, 13,14 pancreatic cancer, 15,16 peritoneal cancer, 17 prostate cancer, [18][19][20][21][22] skin cancer, [23][24][25] and HIV. Improvement in imaging is essential to maximizing the efficacy of radiotherapy when, for example, bismuth-213 is used to treat acute myeloid leukemia, 1-4 breast cancer, 5-8 gastric cancer, 9,10 glioma brain cancer, 11 non-Hodgkin lymphoma, 12 ovarian cancer, 13,14 pancreatic cancer, 15,16 peritoneal cancer, 17 prostate cancer, [18][19][20][21][22] skin cancer, [23][24][25] and HIV.…”