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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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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 177Lu-or 86Y-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 177Lu-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 86Y-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.

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Acknowledgments

The authors thank Donald Axworthy, Dr. Kelly Orcutt, and Dr. James Russell for helpful discussions. The authors gratefully acknowledge Teja Muralidhar Kalidindi, Valerie Longo, and the Memorial Sloan Kettering Small Animal Imaging Core Facility for support with experiments. The authors also thank Leah Bassity for her editorial work on the manuscript.

Author information

Authors and Affiliations

  1. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sarah M. Cheal, Sang-gyu Lee, Blesida Punzalan, Sandhya Chalasani, Jorge A. Carrasquillo & Steven M. Larson

  2. Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 415 E. 68th Street, Z-2064, New York, NY, 10065, USA

    Sarah M. Cheal, Sang-gyu Lee, Blesida Punzalan, Edward K. Fung, Nai-Kong V. Cheung & Steven M. Larson

  3. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Hong Xu, Hong-fen Guo & Nai-Kong V. Cheung

  4. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Achim Jungbluth

  5. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Edward K. Fung, Pat B. Zanzonico & Joseph O’Donoghue

  6. Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY, USA

    Peter M. Smith-Jones

  7. Department of Radiology, Stony Brook University, Stony Brook, NY, USA

    Peter M. Smith-Jones

  8. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    K. Dane Wittrup

  9. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    K. Dane Wittrup

  10. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    K. Dane Wittrup

Authors
  1. Sarah M. Cheal
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  2. Hong Xu
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  3. Hong-fen Guo
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  9. Pat B. Zanzonico
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  15. Steven M. Larson
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Corresponding author

Correspondence to Steven M. Larson.

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Funding

This study was supported in part by the following: Donna & Benjamin M. Rosen Chair (to S.M. Larson), Enid A. Haupt Chair (to N.K. Cheung), The Center for Targeted Radioimmunotherapy and Theranostics, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center (to S.M. Larson), a training grant from the National Institutes of Health (R25-CA096945; principal investigator H. Hricak, fellow S.M. Cheal), and a National Institutes of Health grant (R01-CA-101830; to K.D. Wittrup). S.M. Larson was also supported in part by P50-CA86438. Technical services provided by the Memorial Sloan Kettering Small-Animal Imaging Core Facility were supported by National Institutes of Health grants R24-CA83084 (to H. Hricak), P30-CA08748 (to C. Thompson), and P50-CA92629 (to H. Scher). National Institutes of Health Shared Instrumentation grant No. 1 S10 RR028889-01 (to P.B. Zanzonico), and a Shared Resources Grant from the Memorial Sloan Kettering Cancer Center Metastasis Research Center (to P. B. Zanzonico), which provided funding support for the purchase of the Focus 120 microPET and the NanoSPECT/CT Plus, respectively, are gratefully acknowledged.

Conflicts of interest

None.

Ethical approval

All animal experiments were approved by the Institutional Animal Care and Use Committee of Memorial Sloan Kettering Cancer Center, and institutional guidelines for the proper and humane use of animals in research were followed.

Additional information

Nai-Kong V. Cheung and Steven M. Larson are senior coauthors.

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Cheal, S.M., Xu, H., Guo, Hf. 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. Eur J Nucl Med Mol Imaging 43, 925–937 (2016). https://doi.org/10.1007/s00259-015-3254-8

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