Plexin d1 as a target for tumor diagnosis and therapy

Abstract

The present invention relates to plexin D1 for use as a targetable protein in the treatment or diagnosis of disorders that involve expression of plexin D1. Diagnosis is suitably effected by detecting the presence of plexin D1 in the body or a bodily tissue or fluid, whereas treatment is effected by targeting plexin D1 for delivery of therapeutics to the site where treatment is needed. The invention further relates to the use of molecules that bind plexin D1, a nucleic acid encoding plexine D1 or a ligand of plexin D1 for the preparation of a therapeutical composition for the treatment or diagnosis of disorders that involve expression of plexin D1. The disorders comprise disorders in which plexin D1 is expressed on tumor cells, tumor blood vessels or activated macrophages.

1 . Plexin D1 for use as a targetable protein in the treatment or diagnosis of disorders that involve expression of plexin D1. 
     
     
         2 . Plexin D1 as claimed in  claim 1 , wherein the diagnosis is effected by detecting the presence of plexin D1 in the body or a bodily tissue or fluid. 
     
     
         3 . Plexine D1 as claimed in  claim 1 , wherein the treatment is effected by targeting plexin D1 for delivery of therapeutics to the site where treatment is needed. 
     
     
         4 . Plexine D1 as claimed in  claim 1 , wherein the treatment is effected by interfering in the interaction of plexin D1 and its ligands. 
     
     
         5 . Plexine D1 as claimed in  claim 1 , wherein the treatment is effected by interfering in the function of plexin D1. 
     
     
         6 . Plexine D1 as claimed in  claim 1 , wherein the treatment is effected by interfering in the expression of the gene encoding plexin D1. 
     
     
         7 . Use of molecules that bind plexin D1, a nucleic acid encoding plexine D1 or a ligand of plexin D1 for the preparation of a therapeutical composition for the treatment or diagnosis of disorders that involve expression of plexin D1. 
     
     
         8 . Use as claimed in  claim 7 , wherein the disorders comprise disorders in which plexin D1 is expressed on tumor cells, tumor blood vessels or activated macrophages. 
     
     
         9 . Use as claimed in  claim 7  or  8 , wherein the disorders are selected from brain tumors, in particular astrocytomas, oligodendrogliomas and hemangioblastomas, colon carcinomas, in particular ductal carcinomas of the colon, prostate carcinomas, renal cell carcinomas, in particular renal clear cell carcinomas, mamma carcinomas, in particular ductal carcinomas of the breast, ovary carcinomas, squamous cell carcinomas, melanomas, lung carcinomas, in particular small-cell lung carcinomas and non-small cell lung carcinomas, soft tissue sarcomas. 
     
     
         10 . Use as claimed in  claim 7  or  8 , wherein the disorders are inflammatory diseases. 
     
     
         11 . Use as claimed in  claim 10 , wherein the inflammatory disease is an autoimmune disease. 
     
     
         12 . Use as claimed in  claim 11 , wherein the autoimmune disease is rheumatoid arthritis. 
     
     
         13 . Use as claimed in  claim 10 , wherein the inflammatory disease is atherosclerosis or multiple sclerosis. 
     
     
         14 . Use as claimed in  claim 7 , wherein molecules that bind plexin D1 are selected from antibodies, antibody fragments, protein domains, peptides, small molecules, DNA or RNA aptamers. 
     
     
         15 . Use as claimed in  claim 7 , wherein molecules that bind the nucleic acid encoding plexin D1 are selected from siRNA, antisense RNA, antisense phosphothio oligonucleotides. 
     
     
         16 . Use as claimed in  claim 7 , wherein molecules that bind a plexin D1 ligand are selected from antibodies against the ligand, the soluble ectodomain of plexin D1, peptides with affinity for the plexin D1 binding site. 
     
     
         17 . Use as claimed in any one of the  claims 7 - 16 , wherein the binding molecule is labelled with a detectable marker. 
     
     
         18 . Use as claimed in  claim 12 , wherein the detectable marker is selected from a radioactive label, a paramagnetic label, fluorescent label, a chemiluminescent label. 
     
     
         19 . Use as claimed in any one of the  claims 7 - 18 , wherein the binding molecule is provided with an effector compound or a nanodevice comprising an effector compound. 
     
     
         20 . Use as claimed in  claim 19 , wherein the effector compound is a toxin, a thrombosis-inducing compound, a chemotherapeutic agent, a radioactive moiety, an apoptosis-inducing peptide, in particular (KLAKLAK) 2 . 
     
     
         21 . Use as claimed in  claim 20 , wherein the toxin damages or kills endothelial cells to induce thrombosis, and is in particular ricin. 
     
     
         22 . Use as claimed in  claim 20 , wherein the thrombosis-inducing compound is truncated tissue factor. 
     
     
         23 . Use as claimed in  claim 20 , wherein the chemotherapeutic agent is selected from doxorubicin, cisplatin, bleomycin sulfate, carmustine, chlorambucil and cyclophosphamide hydroxyurea. 
     
     
         24 . Use as claimed in  claim 20 , wherein the radioactive entity is selected from: technetium 99m, iodine-123, iodine-131, rhenium-186 or -188, gallium-67, yttrium-90, lutetium-177. 
     
     
         25 . Use as claimed in  claim 19 , wherein the nanodevices are liposomes, polymersomes, in particular polymersomes composed of block copolymers. 
     
     
         26 . Plexin D1 binding molecules. 
     
     
         27 . Plexin D1 binding molecules as claimed in  claim 26 , comprising the plexin D1 binding part of A12 (SEQ ID NO:1), F8 (SEQ ID NO:2), 11F5H6 (SEQ ID NO:3) or 17E9C12 (SEQ ID NO:4). 
     
     
         29 . Plexin binding molecules as claimed in  claim 26  or  27 , coupled to a detectable marker as claimed in  claim 18 . 
     
     
         30 . Plexin binding molecules as claimed in  claim 26  or  27 , coupled to an effector molecule or a nanodevice comprising an effector compound, wherein the effector compound is as defined in any one of the  claims 20 - 24 . 
     
     
         31 . Plexin binding molecules as claimed in  claim 26  or  27 , wherein the nanodevice is as defined in  claim 25 . 
     
     
         32 . Diagnostic composition comprising a plexin binding molecule as claimed in  claim 29 . 
     
     
         33 . Therapeutical composition comprising a plexin binding molecule as claimed in any one of the  claims 30 - 32 . 
     
     
         34 . Single chain antibody A12 (SEQ ID NO:1). 
     
     
         35 . Single chain antibody F8 (SEQ ID NO:2). 
     
     
         36 . Single chain antibody 11F5H6 (SEQ ID NO:3). 
     
     
         37 . Single chain antibody 17E9C12 (SEQ ID NO:4). 
     
     
         38 . Method of identifying molecules that are capable of binding to plexin D1, which method comprises contacting a collection of molecules with plexin D1 and selecting the molecules from the collection that show binding to plexin D1 as plexin D1 binding molecules.