Synapse - Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity (86)Y- or (177)Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity (86)Y- or (177)Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates Journal Article

Authors:	Cheal, S. M.; Xu, H.; Lee, S. G.; Guo, H. F.; Punzalan, B.; Chalasani, S.; Fung, E.; Jungbluth, A.; Zanzonico, P.; Carrasquillo, J.; O'Donoghue, J.; Smith-Jones, P.; Wittrup, K.; Cheung, N. K.; Larson, S.
Article Title:	Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity (86)Y- or (177)Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates
Abstract:	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 Lu-177-or Y-86-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 Lu-177-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm(3)) 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-mm(3) tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten Y-86-DOTA-Bn. Conclusion We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts.
Keywords:	radioimmunotherapy; pet; therapy; thyroid-cancer; colon-cancer; a33; dota; tumor uptake; pretargeting; antibody uptake; preclinical evaluation; bispecific antibodies; multistep targeting; fractionated external-beam; gpa33
Journal Title:	European Journal of Nuclear Medicine and Molecular Imaging
Volume:	43
Issue:	5
ISSN:	1619-7070
Publisher:	Springer
Date Published:	2016-05-01
Start Page:	925
End Page:	937
Language:	English
ACCESSION:	WOS:000373306800015
DOI:	10.1007/s00259-015-3254-8
PROVIDER:	wos
PMCID:	PMC4814317
PUBMED:	26596724
Notes:	Article -- Source: Wos