Pretargeting of cancer

The use of radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens for cancer imaging and therapy has been widely studied. However, MAbs slowly clear the from circulation and non-target tissue. In case of imaging, this causes high background signal in normal organs and for radionuclide therapy this results in high radiation exposure to healthy tissue, which may case for example myelotoxicity. Pretargeting has been developed to reduce the radiation dose to normal tissues. In this approach, a bispecific monoclonal antibody (bsMAb) is administered intravenously and given time to accumulate in the tumor and clear from the circulation. Then, a radiolabeled hapten peptide is administered that clears rapidly from the blood, but is trapped in the tumor by the anti–hapten-binding arm of the bsMAb (Figure 1).

Figure 1. The principle of pretargeted radioimmunotherapy with the bispecific antibody TF2 and the radiolabeled peptide IMP288











In our group, we develop novel pretargeting strategies for cancer imaging and therapy. For example, we have shown that TF2, a bsMAb with binding to CEA and the hapten HSG, and 68Ga-labeled di-HSG-DOTA peptide IMP288, can be used to image CEA-expressing tumors. Furthermore, treatment with 177Lu- or 213Bi-IMP288 delayed the growth of CEA-positive human colonic tumors in mice and a first feasibility study with 177Lu-IMP288 has been performed in colon cancer patients. Another pretargeting strategy focuses on prostate cancer imaging and treatment, using the anti-TROP-2 bsMAb TF12. Furthermore, a dual-labeled (IRDye800CW and 111In) labeled peptide has been used for pre-operative SPECT/CT imaging, intra-operative near infrared fluorescence imaging, and image guided surgery (Figure 2).

Figure 2. MicroSPECT/CT and NIRF image-guided surgery with 111In-RDC018 in a TF-12 pretargeted PC3 soft-tissue metastasis located below the scapular bone. Images were acquired at 2 hours after injection of 111In-RDC018. A, microSPECT/CT image before resection. B, NIRF image before resection illustrating the limited penetration depth of the emitted fluorescent light, since the tumor is located below a bony structure. C, NIRF image after lifting the scapular bone to the left-hand side, exposing the tumor; D, microSPECT/CT image after resection. E, corresponding NIRF image after resection. (Lutje et al. Cancer Research 2014)














People

Publications

  • C.M. van Rij, C. Frielink, D.M. Goldenberg, R.M. Sharkey, G.M. Franssen, S. Lütje, W.J. McBride, W.J.G. Oyen and O.C. Boerman. "Pretargeted ImmunoPET of Prostate Cancer with an Anti-TROP-2 x Anti-HSG Bispecific Antibody in Mice with PC3 Xenografts", Molecular Imaging and Biology 2015;17:94-101. Abstract/PDF DOI PMID

  • F.C.J. van de Watering, M. Rijpkema, M. Robillard, W.J.G. Oyen and O.C. Boerman. "Pretargeted imaging and radioimmunotherapy of cancer using antibodies and bioorthogonal chemistry", Front Med (Lausanne) 2014;1:44. Abstract DOI PMID

  • S. Lütje, M. Rijpkema, D.M. Goldenberg, C.M. van Rij, R.M. Sharkey, W.J. McBride, G.M. Franssen, C. Frielink, W. Helfrich, W.J.G. Oyen and O.C. Boerman. "Pretargeted Dual-Modality Immuno-SPECT and Near-Infrared Fluorescence Imaging for Image-Guided Surgery of Prostate Cancer", Cancer Research 2014;74:6216-6223. Abstract/PDF DOI PMID

  • R. Schoffelen, W. Woliner-van der Weg, E.P. Visser, D.M. Goldenberg, R.M. Sharkey, W.J. McBride, C.-H. Chang, E.A. Rossi, W.T.A. van der Graaf, W.J.G. Oyen and O.C. Boerman. "Predictive patient-specific dosimetry and individualized dosing of pretargeted radioimmunotherapy in patients with advanced colorectal cancer", European Journal of Nuclear Medicine and Molecular Imaging 2014;41:1593-1602. Abstract/PDF DOI PMID

  • C.M. van Rij, S. Lütje, C. Frielink, R.M. Sharkey, D.M. Goldenberg, G.M. Franssen, W.J. McBride, E.A. Rossi, W.J.G. Oyen and O.C. Boerman. "Pretargeted immuno-PET and radioimmunotherapy of prostate cancer with an anti-TROP-2 x anti-HSG bispecific antibody", European Journal of Nuclear Medicine and Molecular Imaging 2013;40:1377-1383. Abstract/PDF DOI PMID

  • R. Schoffelen, O.C. Boerman, D.M. Goldenberg, R.M. Sharkey, C.M.L. van Herpen, G.M. Franssen, W.J. McBride, C.-H. Chang, E.A. Rossi, W.T.A. van der Graaf and W.J.G. Oyen. "Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results", British Journal of Cancer 2013;109:934-942. Abstract/PDF DOI PMID

  • R. Schoffelen, R.M. Sharkey, D.M. Goldenberg, G. Franssen, W.J. McBride, E.A. Rossi, C.-H. Chang, P. Laverman, J.A. Disselhorst, A. Eek, W.T.A. van der Graaf, W.J.G. Oyen and O.C. Boerman. "Pretargeted immuno-positron emission tomography imaging of carcinoembryonic antigen-expressing tumors with a bispecific antibody and a 68Ga- and 18F-labeled hapten peptide in mice with human tumor xenografts", Molecular Cancer Therapeutics 2010;9:1019-1027. Abstract DOI PMID