ANTI-DEspR INHIBITORS AS THERAPEUTICS FOR INHIBITION OF PATHOLOGICAL ANGIOGENESIS AND TUMOR CELL INVASIVENESS AND FOR MOLECULAR IMAGING AND TARGETED DELIVERY

Abstract

Provided herein are novel compositions comprising anti-DEspR antibodies and fragments thereof, including fully human, composite engineered human, humanized, monoclonal, and polyclonal anto-DEspR antibodies and fragments thereof, and methods of their use in a variety of therapeutic applications. The compositions comprising the anti-DEspR antibodies and fragments thereof described herein are useful in diagnostic and imaging methods, such as DEspR-targeted molecular imaging of angiogenesis, and for companion diagnostic and/or in vivo-non invasive imaging and/or assessments.

We claim: 
     
         1 . A method of inhibiting angiogenesis, inhibiting tumor cell invasiveness, or inhibiting tumor growth of an angiogenesis-dependent tumor in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an anti-DEspR (dual endothelin/VEGF signal peptide receptor) antibody or antigen-binding fragment thereof; wherein the anti-DEspR antibody or antigen-binding fragment thereof specifically binds to an epitope of DEspR comprising residues 1-9 of SEQ ID NO: 1. 
     
     
         2 . The method of  claim 1 , wherein the anti-DEspR antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof or is a composite antibody or antigen-binding fragment thereof. 
     
     
         3 . The method of  claim 1 , wherein the antigen-binding fragment is a Fab fragment, a Fab′ fragment, a Fd fragment, a Fd′ fragment, a Fv fragment, a dAb fragment, a F(ab′) 2  fragment, a single chain fragment, a diabody, or a linear antibody. 
     
     
         4 . The method of  claim 1 , wherein the anti-DEspR antibody or antigen-binding fragment thereof is conjugated to an agent to form an immunoconjugate specific for DEspR. 
     
     
         5 . The method of  claim 4 , wherein the agent conjugated to the antibody or antigen-binding fragment thereof is a chemotherapeutic agent, a toxin, a radioactive isotope, a small molecule, an siRNA, a nanoparticle, or a microbubble. 
     
     
         6 . The method of  claim 1 , wherein the subject in need thereof has cancer, vascularization of the vaso vasorum, age-related macular degeneration, carotid artery disease, diabetic retinopathy, rheumatoid arthritis, neurodegenerative disorder, Alzheimer's disease, obesity, endometriosis, psoriasis, atherosclerosis, ocular neovascularization, neovascular glaucoma, osteoporsosis, or restenosis. 
     
     
         7 . The method of  claim 1 , wherein the anti-DEspR antibody or antigen-binding fragment thereof reduces or inhibits the activity of DEspR. 
     
     
         8 . A method of inhibiting angiogenesis, inhibiting tumor cell invasiveness, or inhibiting tumor growth of an angiogenesis-dependent tumor in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an anti-DEspR (dual endothelin/VEGF signal peptide receptor) antibody or antigen-binding fragment thereof; wherein the anti-DEspR antibody or antigen-binding fragment thereof blocks a second anti-DEspR antibody or antigen-binding fragment comprising:
 a V H  domain comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 5; a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 6; and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:7 and a V L  domain comprising a light chain CDR1 having the amino acid sequence of SEQ ID NO: 10; a light chain CDR2 having the amino acid sequence of SEQ ID NO: 11; and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 12;   
       from binding to DEspR. 
     
     
         9 . The method of  claim 8 , wherein the anti-DEspR antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof or is a composite antibody or antigen-binding fragment thereof. 
     
     
         10 . The method of  claim 8 , wherein the antigen-binding fragment is a Fab fragment, a Fab′ fragment, a Fd fragment, a Fd′ fragment, a Fv fragment, a dAb fragment, a F(ab′) 2  fragment, a single chain fragment, a diabody, or a linear antibody. 
     
     
         11 . The method of  claim 8 , wherein the anti-DEspR antibody or antigen-binding fragment thereof is conjugated to an agent to form an immunoconjugate specific for DEspR. 
     
     
         12 . The method of  claim 11 , wherein the agent conjugated to the antibody or antigen-binding fragment thereof is a chemotherapeutic agent, a toxin, a radioactive isotope, a small molecule, an siRNA, a nanoparticle, or a microbubble. 
     
     
         13 . The method of  claim 8 , wherein the subject in need thereof has cancer, vascularization of the vaso vasorum, age-related macular degeneration, carotid artery disease, diabetic retinopathy, rheumatoid arthritis, neurodegenerative disorder, Alzheimer's disease, obesity, endometriosis, psoriasis, atherosclerosis, ocular neovascularization, neovascular glaucoma, osteoporsosis, or restenosis. 
     
     
         14 . The method of  claim 8 , wherein the anti-DEspR antibody or antigen-binding fragment thereof reduces or inhibits the activity of DEspR. 
     
     
         15 . A method of killing a tumor cell, a tumor initiating cell, a cancer stem-like cell, or a cancer stem cell, comprising contacting the cell with an isolated anti-DEspR (dual endothelin/VEGF signal peptide receptor) antibody or antigen-binding fragment thereof, wherein the anti-DEspR antibody or antigen-binding fragment thereof specifically binds to an epitope of DEspR comprising residues 1-9 of SEQ ID NO:1. 
     
     
         16 . The method of  claim 15 , wherein the isolated anti-DEspR antibody or antigen-binding fragment thereof binds to and kills a cancer stem cell. 
     
     
         17 . The method of  claim 15 , wherein the isolated anti-DEspR antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof or is a composite antibody or antigen-binding fragment thereof. 
     
     
         18 . The method of  claim 15 , wherein the isolated antigen-binding fragment is a Fab fragment, a Fab′ fragment, a Fd fragment, a Fd′ fragment, a Fv fragment, a dAb fragment, a F(ab′) 2  fragment, a single chain fragment, a diabody, or a linear antibody. 
     
     
         19 . The method of  claim 15 , wherein the isolated anti-DEspR antibody or antigen-binding fragment thereof is conjugated to an agent to form an immunoconjugate specific for DEspR. 
     
     
         20 . The method of  claim 19 , wherein the agent conjugated to the antibody or antigen-binding fragment thereof is a chemotherapeutic agent, a toxin, a radioactive isotope, a small molecule, an siRNA, a nanoparticle, or a microbubble. 
     
     
         21 . The method of  claim 15 , wherein the isolated anti-DEspR antibody or antigen-binding fragment thereof reduces or inhibits the activity of DEspR. 
     
     
         22 . A method of killing a tumor cell, a tumor initiating cell, a cancer stem-like cell, or a cancer stem cell, comprising contacting the cell with an isolated anti-DEspR (dual endothelin/VEGF signal peptide receptor) antibody or antigen-binding fragment thereof, wherein the anti-DEspR antibody or antigen-binding fragment thereof blocks a second anti-DEspR antibody or antigen-binding fragment comprising:
 a V H  domain comprising a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 5; a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 6; and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:7 and a V L  domain comprising a light chain CDR1 having the amino acid sequence of SEQ ID NO: 10; a light chain CDR2 having the amino acid sequence of SEQ ID NO: 11; and a light chain CDR3 having the amino acid sequence of SEQ ID NO: 12;   
       from binding to DEspR. 
     
     
         23 . The method of  claim 22 , wherein the isolated anti-DEspR antibody or antigen-binding fragment thereof binds to and kills a cancer stem cell. 
     
     
         24 . The method of  claim 22 , wherein the isolated anti-DEspR antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof or is a composite antibody or antigen-binding fragment thereof. 
     
     
         25 . The method of  claim 22 , wherein the isolated antigen-binding fragment is a Fab fragment, a Fab′ fragment, a Fd fragment, a Fd′ fragment, a Fv fragment, a dAb fragment, a F(ab′) 2  fragment, a single chain fragment, a diabody, or a linear antibody. 
     
     
         26 . The method of  claim 22 , wherein the isolated anti-DEspR antibody or antigen-binding fragment thereof is conjugated to an agent to form an immunoconjugate specific for DEspR. 
     
     
         27 . The method of  claim 26 , wherein the agent conjugated to the antibody or antigen-binding fragment thereof is a chemotherapeutic agent, a toxin, a radioactive isotope, a small molecule, an siRNA, a nanoparticle, or a microbubble. 
     
     
         28 . The method of  claim 22 , wherein the isolated anti-DEspR antibody or antigen-binding fragment thereof reduces or inhibits the activity of DEspR.