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–(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-or 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 Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 – 700 mm) 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 tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten Y-DOTA-Bn. Conclusion We have developed anti-GPA33 PRIT as a triplestep theranostic strategy for preclinical detection, dosimetry, Nai-Kong V. Cheung and Steven M. Larson are senior coauthors. Electronic supplementary material The online version of this article (doi:10.1007/s00259-015-3254-8) contains supplementary material, which is available to authorized users. * Steven M. Larson larsons@mskcc.org 1 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 415 E. 68th Street, Z-2064, New York, NY 10065, USA 3 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 6 Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY, USA 7 Department of Radiology, Stony Brook University, Stony Brook, NY, USA 8 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA 9 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA 10 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Eur J Nucl Med Mol Imaging (2016) 43:925–937 DOI 10.1007/s00259-015-3254-8