Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity [superscript 86]Y- or [superscipt 177]Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates
Purpose: GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn–(radiolantha...
| Main Authors: | , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Berlin Heidelberg
2016
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| Online Access: | http://hdl.handle.net/1721.1/104432 |
| _version_ | 1826197257701031936 |
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| author | Xu, Hong Guo, Hong-fen Lee, Sang-gyu Punzalan, Blesida Chalasani, Sandhya Jungbluth, Achim O’Donoghue, Joseph Cheal, Sarah M. Fung, Edward K. Zanzonico, Pat B. Carrasquillo, Jorge A. Smith-Jones, Peter M. Cheung, Nai-Kong V. Larson, Steven M. Wittrup, Karl Dane |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Xu, Hong Guo, Hong-fen Lee, Sang-gyu Punzalan, Blesida Chalasani, Sandhya Jungbluth, Achim O’Donoghue, Joseph Cheal, Sarah M. Fung, Edward K. Zanzonico, Pat B. Carrasquillo, Jorge A. Smith-Jones, Peter M. Cheung, Nai-Kong V. Larson, Steven M. Wittrup, Karl Dane |
| author_sort | Xu, Hong |
| collection | MIT |
| description | Purpose: GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn–(radiolanthanide metal) complex.
Methods: PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens [superscript 177]Lu-or [superscript 86]Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model.
Results: Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6
(TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq [superscript 177]Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 – 700 mm³) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 – 3.0 based on time to 500-mm³ tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten [superscript 86]Y-DOTA-Bn.
Conclusion: We have developed anti-GPA33 PRIT as a triplestep theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. |
| first_indexed | 2024-09-23T10:44:56Z |
| format | Article |
| id | mit-1721.1/104432 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:44:56Z |
| publishDate | 2016 |
| publisher | Springer Berlin Heidelberg |
| record_format | dspace |
| spelling | mit-1721.1/1044322022-09-30T22:43:18Z Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity [superscript 86]Y- or [superscipt 177]Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates Xu, Hong Guo, Hong-fen Lee, Sang-gyu Punzalan, Blesida Chalasani, Sandhya Jungbluth, Achim O’Donoghue, Joseph Cheal, Sarah M. Fung, Edward K. Zanzonico, Pat B. Carrasquillo, Jorge A. Smith-Jones, Peter M. Cheung, Nai-Kong V. Larson, Steven M. Wittrup, Karl Dane Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Wittrup, Karl Dane Purpose: GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn–(radiolanthanide metal) complex. Methods: PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens [superscript 177]Lu-or [superscript 86]Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Results: Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq [superscript 177]Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 – 700 mm³) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 – 3.0 based on time to 500-mm³ tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten [superscript 86]Y-DOTA-Bn. Conclusion: We have developed anti-GPA33 PRIT as a triplestep theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. National Institute of Mental Health (U.S.) (Grant R01-CA-101830) 2016-09-29T17:16:20Z 2016-09-29T17:16:20Z 2015-11 2015-07 2016-08-18T15:24:41Z Article http://purl.org/eprint/type/JournalArticle 1619-7070 1619-7089 http://hdl.handle.net/1721.1/104432 Cheal, Sarah M. et al. “Theranostic Pretargeted Radioimmunotherapy of Colorectal Cancer Xenografts in Mice Using Picomolar Affinity 86Y- or 177Lu-DOTA-Bn Binding scFv C825/GPA33 IgG Bispecific Immunoconjugates.” European Journal of Nuclear Medicine and Molecular Imaging 43.5 (2016): 925–937. en http://dx.doi.org/10.1007/s00259-015-3254-8 European Journal of Nuclear Medicine and Molecular Imaging Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ Springer-Verlag Berlin Heidelberg application/pdf Springer Berlin Heidelberg Springer Berlin Heidelberg |
| spellingShingle | Xu, Hong Guo, Hong-fen Lee, Sang-gyu Punzalan, Blesida Chalasani, Sandhya Jungbluth, Achim O’Donoghue, Joseph Cheal, Sarah M. Fung, Edward K. Zanzonico, Pat B. Carrasquillo, Jorge A. Smith-Jones, Peter M. Cheung, Nai-Kong V. Larson, Steven M. Wittrup, Karl Dane Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity [superscript 86]Y- or [superscipt 177]Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates |
| title | Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity [superscript 86]Y- or [superscipt 177]Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates |
| title_full | Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity [superscript 86]Y- or [superscipt 177]Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates |
| title_fullStr | Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity [superscript 86]Y- or [superscipt 177]Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates |
| title_full_unstemmed | Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity [superscript 86]Y- or [superscipt 177]Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates |
| title_short | Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity [superscript 86]Y- or [superscipt 177]Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates |
| title_sort | theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity superscript 86 y or superscipt 177 lu dota bn binding scfv c825 gpa33 igg bispecific immunoconjugates |
| url | http://hdl.handle.net/1721.1/104432 |
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