Jimson W D'Souza1, Harvey Hensley1, Mohan Doss1,2, Charles Beigarten3, Michael Torgov3, Tove Olafsen3, Jian Q Yu1,2, Matthew K Robinson4. 1. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 2. Nuclear Medicine, Department of Diagnostic Imaging, Fox Chase Cancer Center, Philadelphia, Pennsylvania; and. 3. ImaginAb Inc., Inglewood, California. 4. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania matthew.robinson@fccc.edu.
Abstract
Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers. METHODS: The anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI. RESULTS: 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy. CONCLUSION: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.
Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers. METHODS: The anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI. RESULTS:64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy. CONCLUSION: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.
Authors: Vania Kenanova; Tove Olafsen; Desiree M Crow; Gobalakrishnan Sundaresan; Murugesan Subbarayan; Nora H Carter; David N Ikle; Paul J Yazaki; Arion F Chatziioannou; Sanjiv S Gambhir; Lawrence E Williams; John E Shively; David Colcher; Andrew A Raubitschek; Anna M Wu Journal: Cancer Res Date: 2005-01-15 Impact factor: 12.701
Authors: Neeta Pandit-Taskar; Joseph A O'Donoghue; Volkan Beylergil; Serge Lyashchenko; Shutian Ruan; Stephen B Solomon; Jeremy C Durack; Jorge A Carrasquillo; Robert A Lefkowitz; Mithat Gonen; Jason S Lewis; Jason P Holland; Sarah M Cheal; Victor E Reuter; Joseph R Osborne; Massimo F Loda; Peter M Smith-Jones; Wolfgang A Weber; Neil H Bander; Howard I Scher; Michael J Morris; Steven M Larson Journal: Eur J Nucl Med Mol Imaging Date: 2014-08-21 Impact factor: 9.236
Authors: Joanne E Mortimer; James R Bading; David M Colcher; Peter S Conti; Paul H Frankel; Mary I Carroll; Shan Tong; Erasmus Poku; Joshua K Miles; John E Shively; Andrew A Raubitschek Journal: J Nucl Med Date: 2013-12-12 Impact factor: 10.057
Authors: M J Manyak; G H Hinkle; J O Olsen; R P Chiaccherini; A W Partin; S Piantadosi; J K Burgers; J H Texter; C E Neal; J A Libertino; G L Wright; R T Maguire Journal: Urology Date: 1999-12 Impact factor: 2.649
Authors: Tove Olafsen; David Betting; Vania E Kenanova; Felix B Salazar; Pat Clarke; Jonathan Said; Andrew A Raubitschek; John M Timmerman; Anna M Wu Journal: J Nucl Med Date: 2009-08-18 Impact factor: 10.057
Authors: Chaitanya R Divgi; Robert G Uzzo; Constantine Gatsonis; Roman Bartz; Silke Treutner; Jian Qin Yu; David Chen; Jorge A Carrasquillo; Steven Larson; Paul Bevan; Paul Russo Journal: J Clin Oncol Date: 2012-12-03 Impact factor: 44.544
Authors: Toni A Pringle; Corey D Chan; Saimir Luli; Helen J Blair; Kenneth S Rankin; James C Knight Journal: Bioconjug Chem Date: 2022-07-22 Impact factor: 6.069