A hybrid fibronectin motif protein as an integrin targeting selective tumor vascular thrombogen.
Targeted thrombotic eradication of solid tumors is a novel therapeutic strategy. The feasibility, efficacy, selectivity, and safety are dependent on multiple variables of protein design, molecular assembly, vascular target, and exclusive restriction of function to the tumor vasculature. To advance this strategy, we describe a design of an integrin targeting selective tumor vascular thrombogen. We adopted the fibronectin structural motif of tandem repeating modules with four type III repeat modules of fibronectin followed by two structurally homologous modules of the extracellular domain of tissue factor. This hybrid protein of six tandem modules recognizes integrins and selectively docks and initiates the thrombogenic protease cascade locally on the target cell surfaces. The protein is inactive in blood but is functionally active once assembled on integrin-positive cells. When administered i.v. to tumor-bearing mice, it selectively induces extensive local microthrombosis of the tumor microvasculature. The principles are addressed from the perspective of protein structural design for a class of selective tumor vascular thrombogen proteins that, through interaction with tumor angiogenic endothelium, elicit thrombotic occlusion rather than apoptosis or arrest of angiogenesis. This response can produce local tumor infarction followed by intratumoral ischemia-reperfusion injury, inflammation, and a local host tumor eradicative response.
Liu
Cheng
C
Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA. chengliu@scripps.edu
Dickinson
Craig
C
Shobe
Justin
J
Doñate
Fernando
F
Ruf
Wolfram
W
Edgington
Thomas
T
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D001777:Blood Coagulation / Q000187:drug effects; D016466:CHO Cells; D002196:Capillaries / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005353:Fibronectins / Q000737:chemistry / Q000494:pharmacology*; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000139:chemically induced
D000970:Antineoplastic Agents; D005353:Fibronectins; D016023:Integrins; D009842:Oligopeptides; D010446:Peptide Fragments; C496313:fibronectin-TF3-218; C047981:arginyl-glycyl-aspartic acid; D013917:Thrombin; C478632:Thrombogen