Anti-angptl3 antibodies and uses thereof

Abstract

A fully human antibody or antigen-binding fragment of a human antibody that specifically binds and inhibits or interferes with at least one activity of human angiopoietin-like protein 3 (hANGPTL3) is provided. The human anti-hANGPTL3 antibodies are useful in treating diseases or disorders associated with ANGPTL3, such as hyperlipidemia, hyperlipoproteinemia and dyslipidemia, including hypertriglyceridemia, hypercholesterolemia, chylomicronemia, and so forth. Furthermore, the anti-hANGPTL3 antibodies can be administered to a subject in need thereof to prevent or treat diseases or disorders, for which abnormal lipid metabolism is a risk factor. Such diseases or disorders include cardiovascular diseases, such as atherosclerosis and coronary artery diseases; acute pancreatitis; nonalcoholic steatohepatitis (NASH); diabetes; obesity; and the like.

We claim: 
     
         1 . An isolated human antibody or antigen-binding fragment thereof that specifically binds human angiopoietin-like protein 3 (hANGPTL3) of SEQ ID NO: 161 and neutralizes, reduces or interferes with, at least one activity of hANGPTL3, wherein: (a) the antibody or antigen-binding fragment comprises a heavy chain variable region (HCVR) with at least 90% identity to SEQ ID NO: 66 and a light chain variable region (LCVR) with at least 90% identity to SEQ ID NO: 74; and/or (b) the antibody or antigen-binding fragment comprises a heavy chain variable region (HCVR) of SEQ ID NO: 66 with 10 or fewer conservative amino acid substitutions and a light chain variable region (LCVR) of SEQ ID NO: 74 with 10 or fewer conservative amino acid substitutions. 
     
     
         2 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein:
 (a) the HCVR has at least 95% identity to SEQ ID NO: 66 and/or the LCVR has at least 95% identity to SEQ ID NO: 74; or   (b) the HCVR has at least 98% identity to SEQ ID NO: 66 and/or the LCVR has at least 98% identity to SEQ ID NO: 74.   
     
     
         3 . The antibody or antigen-binding fragment thereof of  claim 1 , which comprises a HCVR of SEQ ID NO: 66 with eight or fewer, six or fewer, four or fewer or two conservative amino acid substitutions and/or a LCVR of SEQ ID NO: 74 with eight or fewer, six or fewer, four or fewer or two conservative amino acid substitutions. 
     
     
         4 . The antibody or antigen-binding fragment thereof of  claim 1 , which comprises a HCVR of SEQ ID NO: 66 with one addition, deletion or substitution and/or a LCVR of SEQ ID NO: 74 with one addition, deletion or substitution, optionally wherein the substitution(s) are conservative amino acid substitutions. 
     
     
         5 . The antibody or antigen-binding fragment thereof of  claim 1 , which comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOS: 68/70/72/76/KAS/80. 
     
     
         6 . An isolated human antibody or antigen-binding fragment thereof that specifically binds human angiopoietin-like protein 3 (hANGPTL3) of SEQ ID NO: 161 and neutralizes, reduces or interferes with, at least one activity of hANGPTL3, wherein the antibody or fragment comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOS: 68/70/72/76/KAS/80 with one or two conservative amino acid substitutions in any of the CDR sequences. 
     
     
         7 . The antibody of antigen-binding fragment of  claim 6 , which has one conservative substitution in one of the CDR sequences. 
     
     
         8 . The antibody of antigen-binding fragment of  claim 1 , which exhibits biological activity which is essentially equivalent to an antibody comprising a HCVR/LCVR sequence pair of SEQ ID NOs: 66/74. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or fragment is a single chain antibody, an Fab, or an F(ab′)2. 
     
     
         10 . The antibody of  claim 1 , which is an IgG1 or IgG4. 
     
     
         11 . An isolated nucleic acid molecule encoding the antibody or fragment thereof of  claim 1 . 
     
     
         12 . An expression vector comprising the nucleic acid molecule of  claim 11 . 
     
     
         13 . An isolated host cell comprising the expression vector of  claim 12 . 
     
     
         14 . A method of producing an anti-hANGPTL3 antibody or antigen-binding fragment thereof, comprising growing the host cell of  claim 13  under conditions permitting production of the antibody or fragment thereof, and recovering the antibody or fragment thereof so produced. 
     
     
         15 . A pharmaceutical composition comprising one or more antibodies or antigen-binding fragments thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         16 . The pharmaceutical composition of  claim 15 , further comprising one or more additional therapeutic agents selected from the group consisting of an inhibitor of HMG-CoA reductase, niacin, a fibrate, 22-hydroxycholesterol, ezetimibe plus simvastatin, a statin with a bile resin, niacin plus a statin, niacin plus an omega-3-fatty acid ethyl ester, a statin, an anti-hANGPTL4 antibody and an anti-PCSK9 antibody. 
     
     
         17 . A method for preventing or treating a disease or disorder which is prevented, ameliorated, improved, or inhibited by reduction or inhibition of ANGPTL3 activity, comprising administering to a subject the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein the disease or disorder is selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, which is optionally homozygous familial hypercholesterolemia with LDLR chylomicronemia, atherogenic dyslipidemia, mixed dyslipidemia, a cardiovascular disease or disorder, acute pancreatitis, nonalcoholic steatohepatitis (NASH), diabetes and obesity. 
     
     
         19 . The method of  claim 17 , further comprising administering to the subject one or more additional therapeutic agents selected from the group consisting of an inhibitor of HMG-CoA reductase, niacin, a fibrate, 22-hydroxycholesterol, ezetimibe plus simvastatin, a statin with a bile resin, niacin plus a statin, niacin plus an omega-3-fatty acid ethyl ester, a statin, an anti-hANGPTL4 antibody and an anti-PCSK9 antibody. 
     
     
         20 . The method of  claim 19 , wherein the antibody or fragment thereof and the one or more additional therapeutic agents are administered concurrently or sequentially to the subject.