Multifunctional antibodies by the Dock-and-Lock method for improved cancer imaging and therapy by pretargeting.
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.
Goldenberg
David M
DM
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA. dmg.gscancer@att.net
Rossi
Edmund A
EA
Sharkey
Robert M
RM
McBride
William J
WJ
Chang
Chien-Hsing
CH
D054758:A Kinase Anchor Proteins / Q000737:chemistry; D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000276:immunology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000276:immunology; D049268:Positron-Emission Tomography; D017434:Protein Structure, Tertiary; D016499:Radioimmunotherapy; D014183:Transplantation, Heterologous
D054758:A Kinase Anchor Proteins; D018033:Antibodies, Bispecific; D007140:Immunoglobulin Fab Fragments; D017868:Cyclic AMP-Dependent Protein Kinases