Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting.

Abstract

We describe a platform technology, termed the dock and lock method, which uses a natural binding between the regulatory subunits of cAMP-dependent protein kinase and the anchoring domains of A kinase anchor proteins for general application in constructing bioactive conjugates of different protein and nonprotein molecules from modular subunits on demand. This approach could allow quantitative and site-specific coupling of many different biological substances for diverse medical applications. The dock and lock method is validated herein by producing bispecific, trivalent-binding complexes composed of three stably linked Fab fragments capable of selective delivery of radiotracers to human cancer xenografts, resulting in rapid, significantly improved cancer targeting and imaging, providing tumor/blood ratios from 66 +/- 5 at 1 h to 395 +/- 26 at 24 h.

• Authors: Edmund A Rossi, David M Goldenberg, Thomas M Cardillo, William J McBride, Robert M Sharkey, Chien-Hsing Chang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 18 Pg. 6841-6 (May 02 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16636283 (Publication Type: Journal Article)

Chemical References

• Immunoglobulin Fab Fragments
• Multiprotein Complexes
• Protein Subunits
• Cyclic AMP-Dependent Protein Kinases

Topics

• Amino Acid Sequence
• Animals
• Cyclic AMP-Dependent Protein Kinases (chemistry, genetics, metabolism)
• Diagnostic Imaging
• Humans
• Immunoglobulin Fab Fragments (chemistry, genetics, metabolism, therapeutic use)
• Mice
• Mice, Nude
• Molecular Sequence Data
• Multiprotein Complexes
• Neoplasm Transplantation
• Neoplasms (therapy)
• Protein Binding
• Protein Subunits (chemistry, genetics, metabolism)
• Reproducibility of Results
• Transplantation, Heterologous