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

• DOI: 10.1007/s00259-015-3254-8
• Publication Date: 2015-11-23T23:19:13Z
• Authors: Sarah M. Cheal; Hong Xu; Hong-fen Guo; Sang-gyu Lee; Blesida Punzalan; Sandhya Chalasani; Edward K. Fung; Achim Jungbluth; Pat B. Zanzonico; Jorge A. Carrasqu...; Joseph O’Donoghue; Peter M. Smith-Jones; K. Dane Wittrup; Nai-Kong V. Cheung; Steven M. Larson
• Keywords: Immunoconjugates; Membrane Glycoproteins; Antibody Affinity; Lutetium; Radioimmunotherapy; Xenograft Model Antitumor Assays; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Immunoglobulin G; Antibodies, Bispecific; Animals; Yttrium Radioisotopes; Radiopharmaceuticals; Colorectal Neoplasms; Single-Chain Antibodies

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.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.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.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.