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Multifunctional antibodies by the Dock-and-Lock method for improved cancer imaging and therapy by pretargeting.

Abstract
The Dock-and-Lock (DNL) method, which makes bioactive molecules with multivalency and multifunctionality, is a new approach to develop targeting molecules for improved cancer imaging and therapy. It involves the use of a pair of distinct protein domains involved in the natural association between cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) and A-kinase anchoring proteins (AKAPs). The dimerization and docking domain found in the regulatory subunit of PKA and the anchoring domain (AD) of an interactive AKAP are each attached to a biologic entity, and the resulting derivatives, when combined, readily form a stably tethered complex of a defined composition that fully retains the functions of the individual constituents. The DNL method has generated several trivalent, bispecific, binding proteins, each consisting of 2 identical Fab fragments linked site-specifically to a different Fab fragment. For example, 2 identical Fabs reacting with carcinoembryonic antigen (CEA) are bound to a Fab reacting with a hapten peptide that bears a diagnostic or therapeutic radionuclide. Using a 2-step, pretargeting method that separates the bivalent anti-CEA antibody targeting of tumor from the delivery of the radioactive peptide that is captured by the second Fab of the tri-Fab construct, an improved method of cancer imaging and therapy has been developed and shows very sensitive and specific targeting of CEA-expressing tumors for either diagnostic imaging, such as with immunoSPECT and immunoPET, or radioimmunotherapy. 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.
AuthorsDavid M Goldenberg, Edmund A Rossi, Robert M Sharkey, William J McBride, Chien-Hsing Chang
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 49 Issue 1 Pg. 158-63 (Jan 2008) ISSN: 0161-5505 [Print] United States
PMID18077530 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • A Kinase Anchor Proteins
  • Antibodies, Bispecific
  • Immunoglobulin Fab Fragments
  • Cyclic AMP-Dependent Protein Kinases
Topics
  • A Kinase Anchor Proteins (chemistry)
  • Animals
  • Antibodies, Bispecific (chemistry, therapeutic use)
  • Colonic Neoplasms (diagnostic imaging, drug therapy, immunology)
  • Cyclic AMP-Dependent Protein Kinases (chemistry)
  • Immunoglobulin Fab Fragments (chemistry)
  • Lung Neoplasms (diagnostic imaging, drug therapy, immunology)
  • Mice
  • Neoplasm Transplantation
  • Pancreatic Neoplasms (diagnostic imaging, drug therapy, immunology)
  • Positron-Emission Tomography
  • Protein Structure, Tertiary
  • Radioimmunotherapy
  • Transplantation, Heterologous

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