Abstract
Purpose
TF12 is a trivalent bispecific antibody that consists of two anti-TROP-2 Fab fragments and one anti-histamine-succinyl-glycine (HSG) Fab fragment. The TROP-2 antigen is found in many epithelial cancers, including prostate cancer (PC), and therefore this bispecific antibody could be suitable for pretargeting in this cancer. In this study, the characteristics and the potential for pretargeted radioimmunoimaging and radioimmunotherapy with TF12 and the radiolabeled di-HSG peptide IMP288 in mice with human PC were investigated.
Methods
The optimal TF12 protein dose, IMP288 peptide dose, and dose interval for PC targeting were assessed in nude mice with s.c. PC3 xenografts. Immuno-positron emission tomography (PET)/CT was performed using TF12/68Ga-IMP288 at optimized conditions. The potential of pretargeted radioimmunotherapy (PRIT) using the TF12 pretargeted 177Lu-IMP288 was determined.
Results
TF12 and 111In-IMP288 showed high and fast accumulation in the tumor [20.4 ± 0.6 %ID/g at 1 h post-injection (p.i.)] at optimized conditions, despite the internalizing properties of TF12. The potential for PRIT was shown by retention of 50 % of the 111In-IMP288 in the tumor at 48 h p.i. One cycle of treatment with TF12 and 177Lu-IMP288 showed significant improvement of survival compared to treatment with 177Lu-IMP288 alone (90 vs. 67 days, p < 0.0001) with no renal or hematological toxicity.
Conclusion
TROP-2-expressing PC can be pretargeted efficiently with TF12, with very rapid uptake of the radiolabeled hapten-peptide, IMP288, sensitive immuno-PET, and effective therapy.
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Acknowledgements
We kindly thank Bianca Lemmers and Kitty Lemmens (Central Animal Facility, Radboud University Nijmegen Medical Centre, The Netherlands) for their excellent technical assistance in the animal experiments. The work was supported by the Dutch Cancer Society (KWF Kankerbestrijding, Grant KUN-2010-0480).
Conflicts of interest
David M. Goldenberg, William J. McBride, Robert M. Sharkey, and Edmund Rossi have financial interest as employment and/or stock interest in Immunomedics, Inc. or IBC Pharmaceuticals, Inc.
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van Rij, C.M., Lütje, S., Frielink, C. et al. Pretargeted immuno-PET and radioimmunotherapy of prostate cancer with an anti-TROP-2 x anti-HSG bispecific antibody. Eur J Nucl Med Mol Imaging 40, 1377–1383 (2013). https://doi.org/10.1007/s00259-013-2434-7
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DOI: https://doi.org/10.1007/s00259-013-2434-7