Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting.
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.
Rossi
Edmund A
EA
IBC Pharmaceuticals, Inc., 300 American Road, Morris Plains, NJ 07950, USA.
Goldenberg
David M
DM
Cardillo
Thomas M
TM
McBride
William J
WJ
Sharkey
Robert M
RM
Chang
Chien-Hsing
CH
D000595:Amino Acid Sequence; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003952:Diagnostic Imaging; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D014183:Transplantation, Heterologous
D007140:Immunoglobulin Fab Fragments; D046912:Multiprotein Complexes; D021122:Protein Subunits; D017868:Cyclic AMP-Dependent Protein Kinases