The Dock-and-Lock (DNL) Approach to Novel Bispecific Antibodies

Abstract

Biotechnology products are being designed increasingly as multivalent, multifunctional structures based on recombinant fusion proteins. To augment the existing repertoires of such agents as produced by genetic engineering alone, we envisioned and developed the Dock-and-Lock (DNL) method, which enables site-specific conjugation of two modular components only with each other, producing a covalent construct of defined composition with retained bioactivity. The basic strategy of DNL involves the generation of two types of modules, one containing the dimerization and docking domain (DDD) of cAMP-dependent protein kinase A and the other containing the anchoring domain (AD) of an interactive A-kinase anchoring protein. Docking a DDD module with an AD module occurs spontaneously, and the resulting complex is locked with disulfide bonds to enhance in vivo stability. This new platform technology provides a versatile approach to create novel bispecific antibodies of multiple valencies, with potential applications in the detection and therapy of diverse diseases.