The dock and lock method: A novel platform technology for building multivalent, multifunctional structures of defined composition with retained bioactivity

The idea, approach, and proof-of-concept of the dock and lock (DNL) method, which has the potential for making a large number of bioactive molecules with multivalency and multifunctionality, are reviewed. The key to the DNL method seems to be the judicious application of a pair of distinct protein domains that are involved in the natural association between protein kinase A (PKA; cyclic AMP-dependent protein kinase) and A-kinase anchoring proteins. In essence, the dimerization and docking domain found in the regulatory subunit of PKA and the anchoring domain of an interactive A-kinase anchoring protein are each attached to a biological entity, and the resulting derivatives, when combined, readily form a stably tethered complex of a defined composition that fully retains the functions of individual constituents. Initial validation of the DNL method was provided by the successful generation of several trivalent bispecific binding proteins, each consisting of two identical Fab fragments linked site-specifically to a different Fab. The integration of genetic engineering and conjugation chemistry achieved with the DNL method may not only enable the creation of novel human therapeutics but could also provide the promise and challenge for the construction of improved recombinant products over those currently commercialized, including cytokines, vaccines, and monoclonal antibodies.