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
Author(s)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; ... Show more Show less
Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Chemical Engineering
European Journal of Nuclear Medicine and Molecular Imaging
Springer Berlin Heidelberg
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.
Author's final manuscript