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.