Publication

Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody

Ter Weele, E. J., Lub-De Hooge, M. N., Maslyar, D., Van Scheltinga, A. G. T. T., Kosterink, J. G. W., De Vries, E. G. E. & Williams, S. P., 15-Apr-2013, In : Cancer Research. 73, 8

Research output: Contribution to journalArticleAcademicpeer-review

APA

Ter Weele, E. J., Lub-De Hooge, M. N., Maslyar, D., Van Scheltinga, A. G. T. T., Kosterink, J. G. W., De Vries, E. G. E., & Williams, S. P. (2013). Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody. Cancer Research, 73(8). https://doi.org/10.1158/1538-7445.AM2013-2659

Author

Ter Weele, Eva J. ; Lub-De Hooge, Marjolijn N. ; Maslyar, Daniel ; Van Scheltinga, Anton G.T. Terwisscha ; Kosterink, Jos G.W. ; De Vries, Elisabeth G.E. ; Williams, Simon P. / Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody. In: Cancer Research. 2013 ; Vol. 73, No. 8.

Harvard

Ter Weele, EJ, Lub-De Hooge, MN, Maslyar, D, Van Scheltinga, AGTT, Kosterink, JGW, De Vries, EGE & Williams, SP 2013, 'Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody', Cancer Research, vol. 73, no. 8. https://doi.org/10.1158/1538-7445.AM2013-2659

Standard

Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody. / Ter Weele, Eva J.; Lub-De Hooge, Marjolijn N.; Maslyar, Daniel; Van Scheltinga, Anton G.T. Terwisscha; Kosterink, Jos G.W.; De Vries, Elisabeth G.E.; Williams, Simon P.

In: Cancer Research, Vol. 73, No. 8, 15.04.2013.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Ter Weele EJ, Lub-De Hooge MN, Maslyar D, Van Scheltinga AGTT, Kosterink JGW, De Vries EGE et al. Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody. Cancer Research. 2013 Apr 15;73(8). https://doi.org/10.1158/1538-7445.AM2013-2659


BibTeX

@article{8252cfd0cb8f49fbbe728e7dd53d0753,
title = "Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody",
abstract = "Background: Mesothelin (MSLN) is a tumor differentiation antigen that is highly expressed by cells of many epithelial tumors, with limited expression in normal human tissues. Our understanding of therapeutic antibodies targeting MSLN might benefit from immunoPET imaging of antibody uptake. We developed and preclinically validated an 89Zr labeled anti-MSLN antibody (“89Zr-AMA”) for this noninvasive imaging of tumor and normal organ uptake. Methods: 89Zr was attached to an anti-MSLN humanized IgG1 monoclonal antibody derivatized with the bifunctional chelator reagent N-succinyldesferrioxamine-B-tetrafluorphenol. The 89Zr-AMA was characterized in terms of conjugation ratio, aggregation, radiochemical purity, stability, and immunoreactivity. Two human MSLN-expressing pancreatic tumor cell lines, HPAC and CAPAN-2, were used for xenograft studies in mice. Tumor uptake and organ distribution of 89Zr-AMA were studied in the HPAC line at three protein doses (10, 25 and 100 μg) labeled with 1 MBq 89Zr and results were compared with nonspecific 111In-IgG. After dose-finding, CAPAN-2 and HPAC tumor xenograft-bearing mice were scanned with μPET at 1, 3, and 6 days after tracer injection of the optimal AMA dose labeled with 5 MBq 89Zr, followed by ex vivo biodistribution at day 6. Tracer uptake was quantified and expressed as mean standardized uptake values (SUVmean). Results: 89Zr-AMA formed with high specific activity (> 500 MBq/mg), high yield (> 90{\%} without further purification), and high purity (> 95{\%} determined by SE-HPLC analysis). In vitro validation of 89Zr-AMA showed a fully preserved immunoreactivity with a long (> 1 week) stability in 0.9{\%} NaCl. Biodistribution analyses of the dose-finding groups revealed a dose-dependent 89Zr-AMA tumor uptake, with the highest fractional tumor uptake in the 10 μg dose group, 14.2 {\%}ID/g on day 6. Tumor uptake of the non-specific control antibody, 111In-IgG, was lower than that of the 89Zr-AMA (P <0.05, paired t test). Day 6 89Zr-AMA biodistribution data from the animals that underwent μPET showed ex vivo tumor uptake of 12.0 {\%}ID/g in HPAC and 11.8 {\%}ID/g in CAPAN-2 tumors and 4.6 and 4.4 {\%}ID/g in blood. Uptake of the nonspecific control 111In-IgG was 5.7 {\%}ID/g for HPAC and 3.6 {\%}ID/g for CAPAN-2 tumors, and 10.0 and 7.5 {\%}ID/g for their respective blood pools. MicroPET imaging was consistent with the biodistribution data. 89Zr-AMA showed a progressive increase in tumor uptake over time, whereas the activity in the blood pool decreased; in liver, spleen and kidney it remained stable. Conclusion: 89Zr-AMA tumor uptake is antigen-specific in MSLN-expressing tumors. This tracer can be translated to the clinic for serial non-invasive PET imaging.",
keywords = "mesothelin, antibody, immunoglobulin G, indium 111, tracer, chelating agent, monoclonal antibody, protein, differentiation antigen, antigen, human, pancreas tumor, tumor xenograft, cancer research, imaging, neoplasm, blood, dose calculation, mouse, ex vivo study, immunoreactivity, liver, Student t test, in vitro study, purification, human tissue, injection, normal human, epithelium tumor, organ distribution, xenograft, tumor cell line, radiochemistry, conjugation, spleen, kidney, hospital, tumor differentiation, high performance liquid chromatography",
author = "{Ter Weele}, {Eva J.} and {Lub-De Hooge}, {Marjolijn N.} and Daniel Maslyar and {Van Scheltinga}, {Anton G.T. Terwisscha} and Kosterink, {Jos G.W.} and {De Vries}, {Elisabeth G.E.} and Williams, {Simon P.}",
year = "2013",
month = "4",
day = "15",
doi = "10.1158/1538-7445.AM2013-2659",
language = "English",
volume = "73",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "AMER ASSOC CANCER RESEARCH",
number = "8",

}

RIS

TY - JOUR

T1 - Imaging human pancreatic tumor xenografts with 89Zr-labeled anti-mesothelin antibody

AU - Ter Weele, Eva J.

AU - Lub-De Hooge, Marjolijn N.

AU - Maslyar, Daniel

AU - Van Scheltinga, Anton G.T. Terwisscha

AU - Kosterink, Jos G.W.

AU - De Vries, Elisabeth G.E.

AU - Williams, Simon P.

PY - 2013/4/15

Y1 - 2013/4/15

N2 - Background: Mesothelin (MSLN) is a tumor differentiation antigen that is highly expressed by cells of many epithelial tumors, with limited expression in normal human tissues. Our understanding of therapeutic antibodies targeting MSLN might benefit from immunoPET imaging of antibody uptake. We developed and preclinically validated an 89Zr labeled anti-MSLN antibody (“89Zr-AMA”) for this noninvasive imaging of tumor and normal organ uptake. Methods: 89Zr was attached to an anti-MSLN humanized IgG1 monoclonal antibody derivatized with the bifunctional chelator reagent N-succinyldesferrioxamine-B-tetrafluorphenol. The 89Zr-AMA was characterized in terms of conjugation ratio, aggregation, radiochemical purity, stability, and immunoreactivity. Two human MSLN-expressing pancreatic tumor cell lines, HPAC and CAPAN-2, were used for xenograft studies in mice. Tumor uptake and organ distribution of 89Zr-AMA were studied in the HPAC line at three protein doses (10, 25 and 100 μg) labeled with 1 MBq 89Zr and results were compared with nonspecific 111In-IgG. After dose-finding, CAPAN-2 and HPAC tumor xenograft-bearing mice were scanned with μPET at 1, 3, and 6 days after tracer injection of the optimal AMA dose labeled with 5 MBq 89Zr, followed by ex vivo biodistribution at day 6. Tracer uptake was quantified and expressed as mean standardized uptake values (SUVmean). Results: 89Zr-AMA formed with high specific activity (> 500 MBq/mg), high yield (> 90% without further purification), and high purity (> 95% determined by SE-HPLC analysis). In vitro validation of 89Zr-AMA showed a fully preserved immunoreactivity with a long (> 1 week) stability in 0.9% NaCl. Biodistribution analyses of the dose-finding groups revealed a dose-dependent 89Zr-AMA tumor uptake, with the highest fractional tumor uptake in the 10 μg dose group, 14.2 %ID/g on day 6. Tumor uptake of the non-specific control antibody, 111In-IgG, was lower than that of the 89Zr-AMA (P <0.05, paired t test). Day 6 89Zr-AMA biodistribution data from the animals that underwent μPET showed ex vivo tumor uptake of 12.0 %ID/g in HPAC and 11.8 %ID/g in CAPAN-2 tumors and 4.6 and 4.4 %ID/g in blood. Uptake of the nonspecific control 111In-IgG was 5.7 %ID/g for HPAC and 3.6 %ID/g for CAPAN-2 tumors, and 10.0 and 7.5 %ID/g for their respective blood pools. MicroPET imaging was consistent with the biodistribution data. 89Zr-AMA showed a progressive increase in tumor uptake over time, whereas the activity in the blood pool decreased; in liver, spleen and kidney it remained stable. Conclusion: 89Zr-AMA tumor uptake is antigen-specific in MSLN-expressing tumors. This tracer can be translated to the clinic for serial non-invasive PET imaging.

AB - Background: Mesothelin (MSLN) is a tumor differentiation antigen that is highly expressed by cells of many epithelial tumors, with limited expression in normal human tissues. Our understanding of therapeutic antibodies targeting MSLN might benefit from immunoPET imaging of antibody uptake. We developed and preclinically validated an 89Zr labeled anti-MSLN antibody (“89Zr-AMA”) for this noninvasive imaging of tumor and normal organ uptake. Methods: 89Zr was attached to an anti-MSLN humanized IgG1 monoclonal antibody derivatized with the bifunctional chelator reagent N-succinyldesferrioxamine-B-tetrafluorphenol. The 89Zr-AMA was characterized in terms of conjugation ratio, aggregation, radiochemical purity, stability, and immunoreactivity. Two human MSLN-expressing pancreatic tumor cell lines, HPAC and CAPAN-2, were used for xenograft studies in mice. Tumor uptake and organ distribution of 89Zr-AMA were studied in the HPAC line at three protein doses (10, 25 and 100 μg) labeled with 1 MBq 89Zr and results were compared with nonspecific 111In-IgG. After dose-finding, CAPAN-2 and HPAC tumor xenograft-bearing mice were scanned with μPET at 1, 3, and 6 days after tracer injection of the optimal AMA dose labeled with 5 MBq 89Zr, followed by ex vivo biodistribution at day 6. Tracer uptake was quantified and expressed as mean standardized uptake values (SUVmean). Results: 89Zr-AMA formed with high specific activity (> 500 MBq/mg), high yield (> 90% without further purification), and high purity (> 95% determined by SE-HPLC analysis). In vitro validation of 89Zr-AMA showed a fully preserved immunoreactivity with a long (> 1 week) stability in 0.9% NaCl. Biodistribution analyses of the dose-finding groups revealed a dose-dependent 89Zr-AMA tumor uptake, with the highest fractional tumor uptake in the 10 μg dose group, 14.2 %ID/g on day 6. Tumor uptake of the non-specific control antibody, 111In-IgG, was lower than that of the 89Zr-AMA (P <0.05, paired t test). Day 6 89Zr-AMA biodistribution data from the animals that underwent μPET showed ex vivo tumor uptake of 12.0 %ID/g in HPAC and 11.8 %ID/g in CAPAN-2 tumors and 4.6 and 4.4 %ID/g in blood. Uptake of the nonspecific control 111In-IgG was 5.7 %ID/g for HPAC and 3.6 %ID/g for CAPAN-2 tumors, and 10.0 and 7.5 %ID/g for their respective blood pools. MicroPET imaging was consistent with the biodistribution data. 89Zr-AMA showed a progressive increase in tumor uptake over time, whereas the activity in the blood pool decreased; in liver, spleen and kidney it remained stable. Conclusion: 89Zr-AMA tumor uptake is antigen-specific in MSLN-expressing tumors. This tracer can be translated to the clinic for serial non-invasive PET imaging.

KW - mesothelin

KW - antibody

KW - immunoglobulin G

KW - indium 111

KW - tracer

KW - chelating agent

KW - monoclonal antibody

KW - protein

KW - differentiation antigen

KW - antigen

KW - human

KW - pancreas tumor

KW - tumor xenograft

KW - cancer research

KW - imaging

KW - neoplasm

KW - blood

KW - dose calculation

KW - mouse

KW - ex vivo study

KW - immunoreactivity

KW - liver

KW - Student t test

KW - in vitro study

KW - purification

KW - human tissue

KW - injection

KW - normal human

KW - epithelium tumor

KW - organ distribution

KW - xenograft

KW - tumor cell line

KW - radiochemistry

KW - conjugation

KW - spleen

KW - kidney

KW - hospital

KW - tumor differentiation

KW - high performance liquid chromatography

U2 - 10.1158/1538-7445.AM2013-2659

DO - 10.1158/1538-7445.AM2013-2659

M3 - Article

VL - 73

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 8

ER -

ID: 80660126