Composition of anti-endo180 antibodies and methods of use for the treatment of cancer and fibrotic diseases

Abstract

The present invention provides antibodies or antigen-binding fragments thereof that specifically bind the ENDO180 polypeptide and are internalized thereby, to conjugates comprising the molecules, to compositions comprising the antibodies and conjugates and to methods of using the same for delivery of therapeutic agents to cells that express the ENDO180 polypeptide on the surface of the cell for treating cell proliferative diseases or disorders and fibrosis, and for controlling (modulating) tumor progression.

1 . A composition comprising an anti-ENDO180 antibody or antigen-binding fragment thereof, an inhibitory oligonucleotide, and a pharmaceutically acceptable carrier, wherein the anti-ENDO180 antibody or antigen-binding fragment thereof is
 a. a monoclonal antibody produced by the hybridoma cell line E3-8D8 deposited with the BCCM under Accession Number LMBP 7203CB or an antigen-binding fragment thereof;   b. a humanized version of the antibody of (a) or an antigen-binding fragment thereof (a); or   c. a chimeric version of the antibody of (a) or an antigen-binding fragment thereof (a)   
       wherein upon contact with a cell expressing ENDO180 the antibody or antigen binding fragment thereof is internalized into the cell. 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The composition of  claim 1 , wherein the carrier comprises a particle comprising a lipid, a polysaccharide, or a combination thereof. 
     
     
         5 . The composition of  claim 4 , wherein the particle comprises a lipidated polysaccharide. 
     
     
         6 . The composition of  claim 5 , wherein the polysaccharide comprises a glycosaminoglycan. 
     
     
         7 . The composition of  claim 4 , wherein the anti-ENDO180 antibody or antigen-binding fragment thereof is immobilized on the particle. 
     
     
         8 .- 9 . (canceled) 
     
     
         10 . The composition of  claim 1 , wherein the inhibitory oligonucleotide is an antisense compound, a chemically modified siRNA compound, an unmodified siRNA compound, a chemically modified shRNA compound, an unmodified shRNA compound, a chemically modified miRNA compound, or an unmodified miRNA compound. 
     
     
         11 . The composition of  claim 10  wherein the inhibitory oligonucleotide is a chemically modified siRNA compound. 
     
     
         12 . The composition of  claim 11  wherein the chemically modified siRNA compound inhibits expression of a target gene associated with cancer, fibrosis or macrophage associated disease. 
     
     
         13 . The composition of  claim 12  wherein the chemically modified siRNA compound inhibits expression of a human target gene set forth in Table A. 
     
     
         14 . The composition of  claim 1 , wherein the inhibitory oligonucleotide is attached to the antibody or antigen-binding fragment. 
     
     
         15 . The composition of  claim 4 , wherein the inhibitory oligonucleotide is encapsulated within the particle. 
     
     
         16 . A method of delivering an inhibitory oligonucleotide to an ENDO180 expressing cell in a subject comprising administering to the subject the composition of  claim 1 , thereby delivering the inhibitory oligonucleotide to the cell. 
     
     
         17 . A method of treating a subject afflicted with cancer, fibrosis or macrophage associated disease, comprising administering an effective amount of the composition of  claim 1  to the subject. 
     
     
         18 . A method of inhibiting the growth of a cancer cell expressing ENDO180 comprising contacting the cancer cell with the composition of  claim 1 , thereby inhibiting growth of the cancer cell. 
     
     
         19 . The method of  claim 17 , wherein the composition is administered systemically or locally. 
     
     
         20 . The method of  claim 19 , wherein the composition is administered intravenously. 
     
     
         21 .- 26 . (canceled) 
     
     
         27 . The composition of  claim 1 , further comprising a linker which links the anti-ENDO189 antibody or antigen-binding fragment thereof to the inhibitory oligonucleotide. 
     
     
         28 . The composition of  claim 27 , wherein the linker attaches the 3′ terminus of the antibody or antigen-binding fragment to the inhibitory oligonucleotide. 
     
     
         29 . The composition of  claim 27 , wherein the linker is a polypeptide linker, peptide linker, lipid linker or nucleic acid linker. 
     
     
         30 . The composition of  claim 29 , wherein the linker is protamine, a fragment of protamine, (Arg)9, biotin-avidin, or antennapedia peptide. 
     
     
         31 . The composition of  claim 29 , wherein the linker is a nucleic acid linker. 
     
     
         32 .- 80 . (canceled)