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.

1 - 73 . (canceled) 
     
     
         74 . An isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR (dual endothelin/VEGF signal peptide receptor) expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell. 
     
     
         75 . The anti-DEspR antibody or antibody fragment thereof of  claim 74 , wherein the antibody or antibody fragment thereof specifically binds to residues 1-9 of SEQ ID NO:1. 
     
     
         76 . The anti-DEspR antibody or antibody fragment thereof of  claim 74 , wherein the antibody or antibody fragment thereof comprises the complementarity determining regions (CDRs) of a variable heavy (V H ) chain amino acid sequence comprising a sequence of SEQ ID NO: 4 and the CDRs of a variable light (V L ) chain amino acid sequence comprising a sequence of SEQ ID NO: 9. 
     
     
         77 . A pharmaceutical composition comprising an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR (dual endothelin/VEGF signal peptide receptor) expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell. 
     
     
         78 . A pharmaceutical composition comprising an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR (dual endothelin/VEGF signal peptide receptor) expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell and is conjugated to a chemotherapeutic agent, a toxin, a radioactive isotope, a small molecule, an siRNA, a nanoparticle, or a microbubble. 
     
     
         79 . A pharmaceutical composition comprising an antibody that specifically binds to human VEGF signal peptide (VEGFsp). 
     
     
         80 . A method of inhibiting angiogenesis in a subject having a disease or disorder dependent or modulated by angiogenesis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR (dual endothelin/VEGF signal peptide receptor) expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell; an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell and is conjugated to a chemotherapeutic agent, a toxin, a radioactive isotope, a small molecule, an siRNA, a nanoparticle, or a microbubble; or an antibody that specifically binds to human VEGF signal peptide (VEGFsp). 
     
     
         81 . The method of  claim 80 , wherein the disease or disorder dependent or modulated by angiogenesis is 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, osteoporosis, and restenosis. 
     
     
         82 . A method of inhibiting tumor cell invasiveness in a subject having a cancer or a tumor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR (dual endothelin/VEGF signal peptide receptor) expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell; an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell and is conjugated to a chemotherapeutic agent, a toxin, a radioactive isotope, a small molecule, an siRNA, a nanoparticle, or a microbubble; or an antibody that specifically binds to human VEGF signal peptide (VEGFsp). 
     
     
         83 . A method of inhibiting tumor growth in a subject in need thereof by inhibiting DEspR expression and/or function in a tumor cell, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR (dual endothelin/VEGF signal peptide receptor) expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell; an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell and is conjugated to a chemotherapeutic agent, a toxin, a radioactive isotope, a small molecule, an siRNA, a nanoparticle, or a microbubble; or an antibody that specifically binds to human VEGF signal peptide (VEGFsp). 
     
     
         84 . 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 a DEspR (dual endothelin/VEGF signal peptide receptor) inhibitor that binds DEspR on the cell or that binds VEGFsp and inhibits VEGFsp binding to DEspR, thereby inhibiting DEspR expression and/or function in the cell. 
     
     
         85 . The method of  claim 84 , wherein the DEspR inhibitor binds to and kills a cancer stem cell. 
     
     
         86 . The method of  claim 84 , wherein the DEspR inhibitor is a pharmaceutical composition comprising an isolated anti-DEspR antibody or antibody fragment thereof that specifically binds to human DEspR expressed on a living cell, wherein the antibody, or antibody fragment thereof, is a composite fully human monoclonal antibody or antibody fragment thereof and wherein the antibody or antibody fragment thereof binds to a tumor cell. 
     
     
         87 . A method of imaging a tumor cell, a tumor initiating cell, a cancer stem-like cell, or a cancer stem cell, comprising contacting the cell with an agent that binds specifically human DEspR (dual endothelin/VEGF signal peptide receptor). 
     
     
         88 . The method of  claim 87 , wherein the agent comprises an antibody or VEGFsp. 
     
     
         89 . The method of  claim 88 , wherein the imaging is molecular imaging via targeting DEspR, wherein the agent is an antibody or VEGFsp conjugated to a targeting moiety, and further comprising determining the presence or absence of the antibody or VEGFsp conjugated to the targeting moiety using molecular imaging. 
     
     
         90 . The method of  claim 89 , wherein the molecular imaging is contrast-enhanced ultrasound imaging, MRI (magnetic resonance imaging), near infrared imaging, or photoacoustics imaging. 
     
     
         91 . A method for enhancing delivery of a therapeutic agent via DEspR (dual endothelin/VEGF signal peptide receptor)-targeted sonoporation, the method comprising delivering an effective amount of a pharmaceutical composition comprising a DEspR inhibitor and the therapeutic agent using targeted ultrasound delivery to a subject in need thereof, wherein delivery of the therapeutic agent is enhanced relative to delivering the therapeutic agent in the absence of the pharmaceutical composition comprising the DEspR inhibitor. 
     
     
         92 . The method of  claim 91 , wherein the therapeutic agent is a chemotherapeutic agent, a small molecule, a peptide, or an aptamer.