Pretargeting, as currently being pursued by scientists at Immunomedics and its majority-owned subsidiary, IBC Pharmaceuticals, Inc., may allow a new generation of monoclonal antibody-based diagnostic and therapeutic agents to be developed. This method requires the use of bispecific antibodies. Unlike conventional antibodies which can only attach to one receptor, bispecific antibodies have been modified to contain an additional binding site that recognizes a radioisotope-carrying peptide. This allows the separate administration of bispecific antibody before the delivery of the radioisotope.
In pretargeting, a humanized bispecific antibody is given as a first injection. When the level of bispecific antibody has reached a maximum in the tumor and non-tumor-bound bispecific antibody has substantially cleared non-target tissues, the diagnostic or therapeutic agent recognizable by the bispecific antibody is then given. The latter agent is either bound to the bispecific antibody localized at the tumor, or is rapidly cleared through urine via the kidneys, thereby reducing the systemic exposure to harmful effects of the agent.
Importantly, our pretargeting methodology relies on the second arm of the tumor-targeting bispecific antibody binding to a peptide that can be attached to almost any diagnostic or therapeutic agent. Because of this, the technology potentially comprises a universally useful system, not requiring the generation of a new second antibody for each and every individual diagnostic or therapeutic agent.
In preclinical animal work to date, the technique has been shown to be highly sensitive for detecting cancer, showing in a micrometastatic model of colorectal cancer the ability to visualize 0.3-mm lesions, while the standard oncologic imaging agent, 18F-FDG, was unable to disclose these tumors. The thorough removal of radioactivity from the normal tissues also improves tumor discrimination, and there is less uptake in inflammatory lesions, providing a higher specificity than 18F-FDG. Additionally, the technology has been shown in animal models of colorectal and pancreatic cancers, and non-Hodgkin's lymphoma, to improve therapeutic responses with less toxicity than a directly radiolabeled antibody.
One of the new bispecific antibodies is TF2, an antibody constructed using our proprietary protein engineering platform technology, called DOCK-AND-LOCKTM, or DNLTM. It specifically targets the carcinoembryonic, or CEA (specifically CEACAM5) antigen expressed in many human cancers, including colorectal cancer. TF2 is currently in three investigator-sponsored studies in the U.S. and Europe for pretargeted imaging and radioimmunotherapy of colorectal and lung cancers.
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, is conducting a Phase I study investigating the toxicity, safety and pharmacokinetics of pretargeted radioimmunotherapy with TF2 and a Lutetium-177-labeled peptide in patients with advanced colorectal cancer. The preliminary efficacy of the therapy as well as the sensitivity of pretargeted imaging with an Indium-111-labeled peptide, as compared to standard methods of tumor detection, will also be evaluated. This study is expected to enroll approximately 20 adult patients with CEA-expressing advanced colorectal tumors for which no standard treatment is available.
Sponsored by the Garden State Cancer Center at the Center for Molecular Medicine and Immunology, the second study is on preoperative detection of colorectal carcinoma with TF2 pretargeting. The goal of this Phase I study, conducted at the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, Washington, DC, is to assess the pharmacokinetics and tissue distribution of TF2 in finding tumor cells in patients with colorectal cancer.
A third study is underway at the University Hospital in Nantes, France, where patients with small-cell lung cancer are being treated by this investigational method.
- Pretargeted radioimmunotherapy of pancreatic cancer xenografts: TF10-90Y-IMP-288 alone and combined with gemcitabine. H. Karacay, R. M. Sharkey, D. V. Gold, D. R. Ragland, W. J. McBride, E. A. Rossi, C. H. Chang, D. M. Goldenberg. J Nucl Med. 50(12): 2008-16, 2009.
- Pretargeted versus directly targeted radioimmunotherapy combined with anti-CD20 antibody consolidation therapy of non-Hodgkin lymphoma. R. M. Sharkey, H. Karacay, C. R. Johnson, S. Litwin, E. A. Rossi, W. J. McBride, C. H. Chang, D. M. Goldenberg. J Nucl Med. 50(3): 444-53, 2009.
- mproved therapeutic results by pretargeted radioimmunotherapy of non-Hodgkin's lymphoma with a new recombinant, trivalent, anti-CD20, bispecific antibody. R. M. Sharkey, H. Karacay, S. Litwin, E. A. Rossi, W. J. McBride, C. H.. Chang, D. M. Goldenberg. ICancer Res. 68(13): 5282-90, 2008.
- A novel bispecific, trivalent antibody construct for targeting pancreatic carcinoma. D. V. Gold, D. M. Goldenberg, H. Karacay, E. A. Rossi, C. H. Chang, T. M. Cardillo, W. J. McBride, R. M. Sharkey. Cancer Res. 68(12): 4819-26, 2008.
- Metastatic human colonic carcinoma: molecular imaging with pretargeted SPECT and PET in a mouse model. R. M. Sharkey, H. Karacay, S. Vallabhajosula, W. J. McBride, E. A. Rossi, C. H. Chang, S. J. Goldsmith, D. M. Goldenberg. Radiology. 246(2): 497-507, 2008.