Sander M J van Duijnhoven1, Raffaella Rossin2, Sandra M van den Bosch3, Michael P Wheatcroft4, Peter J Hudson4, Marc S Robillard5. 1. Tagworks Pharmaceuticals, Eindhoven, The Netherlands. 2. Tagworks Pharmaceuticals, Eindhoven, The Netherlands Oncology Solutions, Philips Research, Eindhoven, The Netherlands. 3. Precision and Decentralized Diagnostics, Philips Research, Eindhoven, The Netherlands; and. 4. Avipep Pty. Ltd., Melbourne, Victoria, Australia. 5. Tagworks Pharmaceuticals, Eindhoven, The Netherlands marc.robillard@tagworkspharma.com.
Abstract
UNLABELLED: Radioimmunotherapy and nuclear imaging (immuno-PET/SPECT) of cancer with radiometal-labeled antibody fragments or peptides is hampered by low tumor-to-kidney ratios because of high renal radiometal retention. Therefore, we developed and evaluated a pretargeting strategy using click chemistry in vivo to reduce kidney uptake and avoid unwanted radiation toxicity. We focused on the bioorthogonal reaction between a trans-cyclooctene (TCO)-functionalized TAG72 targeting diabody, AVP04-07, and a low-molecular-weight radiolabeled tetrazine probe that was previously shown to have low kidney retention and relatively fast renal clearance. METHODS: AVP04-07 diabodies were functionalized with TCO tags, and in vitro immunoreactivity toward bovine submaxillary mucin and tetrazine reactivity were assessed. Next, pretargeting biodistribution studies were performed in LS174T tumor-bearing mice with AVP04-07-TCO(n) (where n indicates the number of TCO groups per diabody) and radiolabeled tetrazine to optimize the TCO modification grade (0, 1.8, or 4.7 TCO groups per diabody) and the (177)Lu-tetrazine dose (0.1, 1.0, or 10 Eq with respect to the diabody). Radiolabeled tetrazine was injected at 47 h after diabody injection, and mice were euthanized 3 h later. A pretargeting SPECT/CT study with (111)In-tetrazine was performed with the optimized conditions. RESULTS: Immunoreactivity for native AVP04-07 was similar to that for TCO-functionalized AVP04-07, and the latter reacted efficiently with radiolabeled tetrazine in vitro. The combination of the pretargeting component AVP04-07 functionalized with 4.7 TCO groups and 1 Eq of (177)Lu-tetrazine with respect to the diabody showed the most promising biodistribution. Specifically, high (177)Lu-tetrazine tumor uptake (6.9 percentage injected dose/g) was observed with low renal retention, yielding a tumor-to-kidney ratio of 5.7. SPECT/CT imaging confirmed the predominant accumulation of radiolabeled tetrazine in the tumor and low nontumor retention. CONCLUSION: Pretargeting provides an alternative radioimmunotherapy and nuclear imaging strategy by overcoming the high renal retention of low-molecular-weight radiometal tumor-homing agents through the separate administration of a tumor-homing agent and a radioactive probe with fast clearance.
UNLABELLED: Radioimmunotherapy and nuclear imaging (immuno-PET/SPECT) of cancer with radiometal-labeled antibody fragments or peptides is hampered by low tumor-to-kidney ratios because of high renal radiometal retention. Therefore, we developed and evaluated a pretargeting strategy using click chemistry in vivo to reduce kidney uptake and avoid unwanted radiation toxicity. We focused on the bioorthogonal reaction between a trans-cyclooctene (TCO)-functionalized TAG72 targeting diabody, AVP04-07, and a low-molecular-weight radiolabeled tetrazine probe that was previously shown to have low kidney retention and relatively fast renal clearance. METHODS: AVP04-07 diabodies were functionalized with TCO tags, and in vitro immunoreactivity toward bovine submaxillary mucin and tetrazine reactivity were assessed. Next, pretargeting biodistribution studies were performed in LS174T tumor-bearing mice with AVP04-07-TCO(n) (where n indicates the number of TCO groups per diabody) and radiolabeled tetrazine to optimize the TCO modification grade (0, 1.8, or 4.7 TCO groups per diabody) and the (177)Lu-tetrazine dose (0.1, 1.0, or 10 Eq with respect to the diabody). Radiolabeled tetrazine was injected at 47 h after diabody injection, and mice were euthanized 3 h later. A pretargeting SPECT/CT study with (111)In-tetrazine was performed with the optimized conditions. RESULTS: Immunoreactivity for native AVP04-07 was similar to that for TCO-functionalized AVP04-07, and the latter reacted efficiently with radiolabeled tetrazine in vitro. The combination of the pretargeting component AVP04-07 functionalized with 4.7 TCO groups and 1 Eq of (177)Lu-tetrazine with respect to the diabody showed the most promising biodistribution. Specifically, high (177)Lu-tetrazinetumor uptake (6.9 percentage injected dose/g) was observed with low renal retention, yielding a tumor-to-kidney ratio of 5.7. SPECT/CT imaging confirmed the predominant accumulation of radiolabeled tetrazine in the tumor and low nontumor retention. CONCLUSION: Pretargeting provides an alternative radioimmunotherapy and nuclear imaging strategy by overcoming the high renal retention of low-molecular-weight radiometal tumor-homing agents through the separate administration of a tumor-homing agent and a radioactive probe with fast clearance.
Authors: Jacob L Houghton; Rosemery Membreno; Dalya Abdel-Atti; Kristen M Cunanan; Sean Carlin; Wolfgang W Scholz; Pat B Zanzonico; Jason S Lewis; Brian M Zeglis Journal: Mol Cancer Ther Date: 2016-11-09 Impact factor: 6.261
Authors: Lei Kang; Cuicui Li; Zachary T Rosenkrans; Jonathan W Engle; Rongfu Wang; Dawei Jiang; Xiaojie Xu; Weibo Cai Journal: J Nucl Med Date: 2020-08-21 Impact factor: 10.057
Authors: Shuang Hou; Jin-Sil Choi; Mitch Andre Garcia; Yan Xing; Kuan-Ju Chen; Yi-Ming Chen; Ziyue K Jiang; Tracy Ro; Lily Wu; David B Stout; James S Tomlinson; Hao Wang; Kai Chen; Hsian-Rong Tseng; Wei-Yu Lin Journal: ACS Nano Date: 2016-01-12 Impact factor: 15.881
Authors: Mengzhe Wang; Dennis Svatunek; Katarina Rohlfing; Yu Liu; Hui Wang; Ben Giglio; Hong Yuan; Zhanghong Wu; Zibo Li; Joseph Fox Journal: Theranostics Date: 2016-04-12 Impact factor: 11.556