Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or ¹77Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates.
Eur J Nucl Med Mol Imaging
; 43(5): 925-937, 2016 May.
Article
em En
| MEDLINE
| ID: mdl-26596724
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 (177)Lu-or (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 (177)Lu-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 (86)Y-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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
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Neoplasias Colorretais
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Radioimunoterapia
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Anticorpos Biespecíficos
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Imunoconjugados
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Compostos Radiofarmacêuticos
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Afinidade de Anticorpos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Eur J Nucl Med Mol Imaging
Assunto da revista:
MEDICINA NUCLEAR
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos