Bispecific Antibody Pretargeting for Therapy

Summary

Principal Investigator: ROBERT SHARKEY
Abstract: The primary objective of this application is to conduct the initial clinical testing of new bispecific antibody (bsMAb) pretargeting system that uses a90Y-labeled peptide for the treatment colorectal cancer. Our hypothesis is that this pretargeting study will be able to increase the radiation dose delivered to the tumor in comparison to what has historically been achieved with directly radiolabeled antibodies. The bispecific antibody used in this clinical trial is a novel humanized recombinant bsMAb with divalent binding to carcinoembryonic antigen (CEA) for tumor targeting and monovalent binding to a unique compound, histamine-succinyl-glycine (HSG). The peptide has 2 HSG molecules that aid in the stabilization of the bsMAb when bound to the tumor cell surface and a single DOTA moiety suitable for binding '''in and 90Y. The clinical trial will seek to find the optimal conditions for pretargeting the inIn/90Y-labeled peptide using the novel bispecific triabody (-81 kDa). These initial studies will examine several doses of the bsMAb and peptide with the peptide given at differing time intervals after the bsMAb injection. 131I-bsMAb is planned to be given to aid in determining the localization properties of the bsMAb, and each patient will receive a combination of the 1HIn- and90Y-labeled peptide. In the initial testing, the 90Y-dose of peptide will be fixed so that the parameters of pretargeting can be determined. In the Phase I portion of the trial, optimum conditions to allow maximum tumor accretion of the peptide with minimal normal tissue accretion will be used, but the 90Y-radioactivity dose will be escalated to determine the dose limiting toxicity and the MTD. Quantitative imaging and pharmacokinetics will be examined in all patients over several days following the radiolabeled peptide injection to aid in the assessment of conditions that will yield the highest accretion of radiolabeled peptide in the tumor, while minimizing normal tissue accretion. Anti-antibody responses will also be measured to the humanized bsMAb. This clinical trial will be conducted at the Fox Chase Cancer Center.
Funding Period: 2006-03-01 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Recombinant bispecific monoclonal antibodies prepared by the dock-and-lock strategy for pretargeted radioimmunotherapy
    Robert M Sharkey
    Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ, USA
    Semin Nucl Med 40:190-203. 2010
  2. ncbi Multifunctional antibodies by the Dock-and-Lock method for improved cancer imaging and therapy by pretargeting
    David M Goldenberg
    Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA
    J Nucl Med 49:158-63. 2008
  3. pmc Use of antibodies and immunoconjugates for the therapy of more accessible cancers
    Robert M Sharkey
    Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA
    Adv Drug Deliv Rev 60:1407-20. 2008
  4. pmc A re-examination of radioimmunotherapy in the treatment of non-Hodgkin lymphoma: prospects for dual-targeted antibody/radioantibody therapy
    Robert M Sharkey
    Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA
    Blood 113:3891-5. 2009

Detail Information

Publications5

  1. pmc Recombinant bispecific monoclonal antibodies prepared by the dock-and-lock strategy for pretargeted radioimmunotherapy
    Robert M Sharkey
    Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ, USA
    Semin Nucl Med 40:190-203. 2010
    ....
  2. ncbi Multifunctional antibodies by the Dock-and-Lock method for improved cancer imaging and therapy by pretargeting
    David M Goldenberg
    Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA
    J Nucl Med 49:158-63. 2008
    ..Improved therapeutic efficacy is shown with pretargeting in a pancreatic cancer xenograft model given a tri-Fab to a pancreatic cancer MUC1 and the hapten peptide labeled with (90)Y...
  3. pmc Use of antibodies and immunoconjugates for the therapy of more accessible cancers
    Robert M Sharkey
    Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA
    Adv Drug Deliv Rev 60:1407-20. 2008
    ....
  4. pmc A re-examination of radioimmunotherapy in the treatment of non-Hodgkin lymphoma: prospects for dual-targeted antibody/radioantibody therapy
    Robert M Sharkey
    Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA
    Blood 113:3891-5. 2009
    ..This perspective discusses how these issues could affect current and future clinical trials...