Multifunctional Antibodies by the Dock-and-Lock Method for Improved Cancer Imaging and Therapy by Pretargeting

¹ Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey; Immunomedics, Inc., Morris Plains, New Jersey
² IBC Pharmaceuticals, Inc., Morris Plains, New Jersey
³ Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey
⁴ Immunomedics, Inc., Morris Plains, New Jersey
⁵ IBC Pharmaceuticals, Inc., Morris Plains, New Jersey; Immunomedics, Inc., Morris Plains, New Jersey

^* To whom correspondence should be addressed. E-mail: dmg.gscancer{at}att.net.

	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 ⁹⁰Y.

Key Words: bispecific antibodies, cancer, PET, pretargeting, radioimmunodetection, radioimmunotherapy

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