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Published in: Molecular Imaging and Biology 5/2018

Open Access 01-10-2018 | Research Article

Tumor-Specific Zr-89 Immuno-PET Imaging in a Human Bladder Cancer Model

Authors: Freddy E. Escorcia, Jeffrey M. Steckler, Dalya Abdel-Atti, Eric W. Price, Sean D. Carlin, Wolfgang W. Scholz, Jason S. Lewis, Jacob L. Houghton

Published in: Molecular Imaging and Biology | Issue 5/2018

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Abstract

Purpose

Tumor-specific molecular imaging is an important tool for assessing disease burden and treatment response. CA19.9 is an important tumor-specific marker in several malignancies, including urothelial carcinoma. [89Zr]DFO-HuMab-5B1 (MVT-2163) is a CA19.9-specific antibody-based construct that has been validated in preclinical animal models of lung, colorectal, and pancreatic malignancies for positron emission tomography (PET) imaging and is currently in a phase I trial for pancreatic cancer (NCT02687230). Here, we examine whether [89Zr]DFO-HuMab-5B1 may be useful in defining urothelial malignancies.

Procedures

Surface expression of CA19.9 was confirmed in the human bladder cancer line HT 1197. The radioimmunoconjugate [89Zr]DFO-HuMab-5B1 was injected into mice bearing HT 1197 xenografts, and followed by PET imaging, ex vivo experiments including biodistribution, histology and autoradiography, and analysis of blood samples for shed antigen levels were performed.

Results

[89Zr]DFO-HuMab-5B1 specifically accumulates in HT 1197 engrafted tumors when imaged with PET. Ex vivo biodistribution of organs and autoradiography of engrafted tumors confirm our construct’s specific tumor binding. The target antigen CA19.9 was not found to be shed in vitro or in vivo.

Conclusions

[89Zr]DFO-HuMab-5B1 can be used to delineate urothelial carcinomas by PET imaging and may provide tumor-specific information prior to, during, and after systemic therapies.
Literature
2.
go back to reference Howlader NN, A. M., Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). (2015) SEER Cancer Statistics Review, 1975–2014, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data submission, posted to the SEER web site, April 2017 Howlader NN, A. M., Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). (2015) SEER Cancer Statistics Review, 1975–2014, National Cancer Institute. Bethesda, MD, http://​seer.​cancer.​gov/​csr/​1975_​2014/​, based on November 2016 SEER data submission, posted to the SEER web site, April 2017
3.
go back to reference von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF (2000) Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068–3077CrossRefPubMed von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF (2000) Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068–3077CrossRefPubMed
4.
go back to reference Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909–1920CrossRefPubMedPubMedCentral Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909–1920CrossRefPubMedPubMedCentral
5.
go back to reference Glaser AP, Fantini D, Shilatifard A, Schaeffer EM, Meeks JJ (2017) The evolving genomic landscape of urothelial carcinoma. Nature Rev Urol 14:215–229CrossRef Glaser AP, Fantini D, Shilatifard A, Schaeffer EM, Meeks JJ (2017) The evolving genomic landscape of urothelial carcinoma. Nature Rev Urol 14:215–229CrossRef
6.
go back to reference Rose TL, Milowsky MI (2016) Improving systemic chemotherapy for bladder cancer. Current Oncol Rep 18:27CrossRef Rose TL, Milowsky MI (2016) Improving systemic chemotherapy for bladder cancer. Current Oncol Rep 18:27CrossRef
7.
go back to reference Viola-Villegas NT, Rice SL, Carlin S, Wu X, Evans MJ, Sevak KK, Drobjnak M, Ragupathi G, Sawada R, Scholz WW, Livingston PO, Lewis JS (2013) Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology. J Nucl Med 54:1876–1882CrossRefPubMed Viola-Villegas NT, Rice SL, Carlin S, Wu X, Evans MJ, Sevak KK, Drobjnak M, Ragupathi G, Sawada R, Scholz WW, Livingston PO, Lewis JS (2013) Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology. J Nucl Med 54:1876–1882CrossRefPubMed
8.
go back to reference Tizzani A, Cassetta G, Cicigoi A et al (1987) Tumor markers (CEA, TPA and CA 19-9) in urine of bladder cancer patients. Int J Biol Marker 2:121–124CrossRef Tizzani A, Cassetta G, Cicigoi A et al (1987) Tumor markers (CEA, TPA and CA 19-9) in urine of bladder cancer patients. Int J Biol Marker 2:121–124CrossRef
9.
go back to reference Wang QH, Ji ZG, Chen ZG, Li HZ, Fan H, Fan XR, Shi BB, Fang Y (2015) Serum CA 19-9 as a good prognostic biomarker in patients with bladder cancer. Int J Surg 15:113–116CrossRefPubMed Wang QH, Ji ZG, Chen ZG, Li HZ, Fan H, Fan XR, Shi BB, Fang Y (2015) Serum CA 19-9 as a good prognostic biomarker in patients with bladder cancer. Int J Surg 15:113–116CrossRefPubMed
11.
go back to reference Houghton JL, Zeglis BM, Abdel-Atti D, Sawada R, Scholz WW, Lewis JS (2016) Pretargeted Immuno-PET of pancreatic cancer: overcoming circulating antigen and internalized antibody to reduce radiation doses. J Nucl Med 57:453–459CrossRefPubMed Houghton JL, Zeglis BM, Abdel-Atti D, Sawada R, Scholz WW, Lewis JS (2016) Pretargeted Immuno-PET of pancreatic cancer: overcoming circulating antigen and internalized antibody to reduce radiation doses. J Nucl Med 57:453–459CrossRefPubMed
12.
go back to reference Houghton JL, Zeglis BM, Abdel-Atti D, Aggeler R, Sawada R, Agnew BJ, Scholz WW, Lewis JS (2015) Site-specifically labeled CA19.9-targeted immunoconjugates for the PET, NIRF, and multimodal PET/NIRF imaging of pancreatic cancer. Proc Nat Aca Sci 112:15850–15855CrossRef Houghton JL, Zeglis BM, Abdel-Atti D, Aggeler R, Sawada R, Agnew BJ, Scholz WW, Lewis JS (2015) Site-specifically labeled CA19.9-targeted immunoconjugates for the PET, NIRF, and multimodal PET/NIRF imaging of pancreatic cancer. Proc Nat Aca Sci 112:15850–15855CrossRef
14.
go back to reference Verel I, Visser GWM, Boellaard R, Stigter-van Walsum M, Snow GB, van Dongen GAMS (2003) 89Zr immuno-PET: comprehensive procedures for the production of 89Zr-labeled monoclonal antibodies. J Nucl Med 44:1271–1281PubMed Verel I, Visser GWM, Boellaard R, Stigter-van Walsum M, Snow GB, van Dongen GAMS (2003) 89Zr immuno-PET: comprehensive procedures for the production of 89Zr-labeled monoclonal antibodies. J Nucl Med 44:1271–1281PubMed
15.
go back to reference Lindmo T, Boven E, Cuttitta F, Fedorko J, Bunn PA Jr (1984) Determination of the immunoreactive function of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Method 72:77–89CrossRef Lindmo T, Boven E, Cuttitta F, Fedorko J, Bunn PA Jr (1984) Determination of the immunoreactive function of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Method 72:77–89CrossRef
16.
go back to reference Lindmo T, Bunn Jr PA (1986) Determination of the true immunoreactive fraction of monoclonal antibodies after radiolabeling. Method Enzymol 121:678–691CrossRef Lindmo T, Bunn Jr PA (1986) Determination of the true immunoreactive fraction of monoclonal antibodies after radiolabeling. Method Enzymol 121:678–691CrossRef
17.
go back to reference Houghton JL, Abdel-Atti D, Scholz WW, Lewis JS (2017) Preloading with unlabeled CA19.9 targeted human monoclonal antibody leads to improved PET imaging with 89Zr-5B1. Mol Pharm 14:908–915CrossRefPubMedPubMedCentral Houghton JL, Abdel-Atti D, Scholz WW, Lewis JS (2017) Preloading with unlabeled CA19.9 targeted human monoclonal antibody leads to improved PET imaging with 89Zr-5B1. Mol Pharm 14:908–915CrossRefPubMedPubMedCentral
18.
go back to reference Meyer JP, Houghton JL, Kozlowski P, Abdel-Atti D, Reiner T, Pillarsetty NVK, Scholz WW, Zeglis BM, Lewis JS (2016) (18)F-based pretargeted PET imaging based on bioorthogonal Diels-Alder click chemistry. Bioconjug Chem 27:298–301CrossRefPubMed Meyer JP, Houghton JL, Kozlowski P, Abdel-Atti D, Reiner T, Pillarsetty NVK, Scholz WW, Zeglis BM, Lewis JS (2016) (18)F-based pretargeted PET imaging based on bioorthogonal Diels-Alder click chemistry. Bioconjug Chem 27:298–301CrossRefPubMed
19.
go back to reference Hughes OD, Perkins AC, Frier M et al (2001) Imaging for staging bladder cancer: a clinical study of intravenous 111indium-labelled anti-MUC1 mucin monoclonal antibody C595. BJU Int 87:39–46CrossRefPubMed Hughes OD, Perkins AC, Frier M et al (2001) Imaging for staging bladder cancer: a clinical study of intravenous 111indium-labelled anti-MUC1 mucin monoclonal antibody C595. BJU Int 87:39–46CrossRefPubMed
20.
go back to reference Deri MA, Ponnala S, Kozlowski P, Burton-Pye BP, Cicek HT, Hu C, Lewis JS, Francesconi LC (2015) P-SCN-Bn-HOPO: a superior bifunctional chelator for (89)Zr ImmunoPET. Bioconjug Chem 26:2579–2591CrossRefPubMedPubMedCentral Deri MA, Ponnala S, Kozlowski P, Burton-Pye BP, Cicek HT, Hu C, Lewis JS, Francesconi LC (2015) P-SCN-Bn-HOPO: a superior bifunctional chelator for (89)Zr ImmunoPET. Bioconjug Chem 26:2579–2591CrossRefPubMedPubMedCentral
21.
go back to reference Vugts DJ, Klaver C, Sewing C, Poot AJ, Adamzek K, Huegli S, Mari C, Visser GWM, Valverde IE, Gasser G, Mindt TL, van Dongen GAMS (2017) Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET. Eur J Nucl Med Mol Imaging 44:286–295CrossRefPubMed Vugts DJ, Klaver C, Sewing C, Poot AJ, Adamzek K, Huegli S, Mari C, Visser GWM, Valverde IE, Gasser G, Mindt TL, van Dongen GAMS (2017) Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET. Eur J Nucl Med Mol Imaging 44:286–295CrossRefPubMed
22.
go back to reference Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS (2010) 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med 51:1293–1300CrossRefPubMed Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS (2010) 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med 51:1293–1300CrossRefPubMed
24.
go back to reference Magnani JL, Steplewski Z, Koprowski H, Ginsburg V (1983) Identification of the gastrointestinal and pancreatic cancer-associated antigen detected by monoclonal antibody 19-9 in the sera of patients as a mucin. Cancer Res 43:5489–5492PubMed Magnani JL, Steplewski Z, Koprowski H, Ginsburg V (1983) Identification of the gastrointestinal and pancreatic cancer-associated antigen detected by monoclonal antibody 19-9 in the sera of patients as a mucin. Cancer Res 43:5489–5492PubMed
25.
go back to reference Rosenthal EL, Warram JM, de Boer E, Basilion JP, Biel MA, Bogyo M, Bouvet M, Brigman BE, Colson YL, DeMeester SR, Gurtner GC, Ishizawa T, Jacobs PM, Keereweer S, Liao JC, Nguyen QT, Olson JM, Paulsen KD, Rieves D, Sumer BD, Tweedle MF, Vahrmeijer AL, Weichert JP, Wilson BC, Zenn MR, Zinn KR, van Dam GM (2016) Successful translation of fluorescence navigation during oncologic surgery: a consensus report. J Nucl Med 57:144–150CrossRefPubMed Rosenthal EL, Warram JM, de Boer E, Basilion JP, Biel MA, Bogyo M, Bouvet M, Brigman BE, Colson YL, DeMeester SR, Gurtner GC, Ishizawa T, Jacobs PM, Keereweer S, Liao JC, Nguyen QT, Olson JM, Paulsen KD, Rieves D, Sumer BD, Tweedle MF, Vahrmeijer AL, Weichert JP, Wilson BC, Zenn MR, Zinn KR, van Dam GM (2016) Successful translation of fluorescence navigation during oncologic surgery: a consensus report. J Nucl Med 57:144–150CrossRefPubMed
Metadata
Title
Tumor-Specific Zr-89 Immuno-PET Imaging in a Human Bladder Cancer Model
Authors
Freddy E. Escorcia
Jeffrey M. Steckler
Dalya Abdel-Atti
Eric W. Price
Sean D. Carlin
Wolfgang W. Scholz
Jason S. Lewis
Jacob L. Houghton
Publication date
01-10-2018
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 5/2018
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-018-1177-z

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