US2022153825A1PendingUtilityA1

Anti-angptl3 antibodies and uses thereof

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Assignee: REGENERON PHARMAPriority: Jun 17, 2011Filed: Jan 27, 2022Published: May 19, 2022
Est. expiryJun 17, 2031(~4.9 yrs left)· nominal 20-yr term from priority
Inventors:Mark SleemanViktoria GusarovaAndrew J. Murphy
A61K 45/06A61P 1/16A61K 31/455C07K 2317/34C07K 2317/21A61K 2039/505C07K 2317/92C07K 2317/33C07K 16/22C07K 2317/76A61P 9/00A61P 1/18A61K 39/3955A61P 3/04A61P 3/06A61P 43/00A61P 3/10A61P 3/00
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Claims

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.

Claims

exact text as granted — not AI-modified
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. 
     
     
         2 . The antibody or fragment of  claim 1 , wherein the antibody or fragment thereof binds to an epitope situated within the N-terminal coiled-coil region at residues 17 to 209 of SEQ ID NO:161. 
     
     
         3 . The antibody or fragment of  claim 2 , wherein the antibody or fragment thereof does not bind to the ANGPTL3 peptide of SEQ ID NO:170. 
     
     
         4 . The antibody or fragment of any one of  claim 2 , wherein the epitope is situated within residues 17 to 200, 17 to 100, 17 to 70, 17 to 65, 17 to 60, 17 to 57, 17 to 50, 40 to 200, 40 to 100, 40 to 70, 50 to 200, 50 to 100, 50 to 70, 58 to 200, 58 to 100, 58 to 70, 58 to 68, or 61 to 66, of SEQ ID NO:161. 
     
     
         5 . The antibody or fragment of any one of  claim 1 , wherein the antibody or fragment is a chimeric or fully human antibody or antibody fragment. 
     
     
         6 . The antibody or fragment of any one of  claim 1 , comprising a heavy chain variable region (HCVR) selected from the group consisting of SEQ ID NO:2, 18, 34, 50, 66, 82, 98, 114, 130, 146 and 180; and/or a light chain variable region (LCVR) selected from the group consisting of SEQ ID NO:10, 26, 42, 58, 74, 90, 106, 122, 138, 154 and 188. 
     
     
         7 . The antibody or fragment of  claim 6 , wherein the antibody or fragment thereof comprises a HCVR and LCVR sequence pair (HCVR/LCVR) selected from the group consisting of SEQ ID NO:2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154 and 180/188. 
     
     
         8 . The antibody or fragment of any one of  claim 1 , wherein the antibody or fragment comprises heavy chain complementarity determining region (CDR) sequences, HCDR1, HCDR2 and HCDR3, and light chain CDR sequences, LCDR1, LCDR2 and LCDR3, contained within a heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pair (HCVR/LCVR) selected from the group consisting of SEQ ID NO:2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154 and 180/188. 
     
     
         9 . The antibody or fragment of  claim 8 , wherein the HCDR1/HCDR2/HCDR3 sequence combination is selected from the group consisting of SEQ ID NO:4/6/8, 20/22/24, 36/38/40, 52/54/56, 68/70/72, 84/86/88, 100/102/104, 116/118/120, 132/134/136, 148/150/152 and 182/184/186; and/or the LCDR1/LCDR2/LCDR3 sequence combination selected from the group consisting of SEQ ID NO:12/14/16, 28/30/32, 44/46/48, 60/62/64, 76/78/80, 92/94/96, 108/110/112, 124/126/128, 140/142/144, 156/158/160 and 190/192/194. 
     
     
         10 . The antibody or fragment of  claim 9 , wherein the antibody or fragment comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination selected from the group consisting of 4/6/8/12/14/16, 20/22/24/28/30/32, 36/38/40/44/46/48, 52/54/56/60/62/64, 68/70/72/76/78/80, 84/86/88/92/94/96, 100/102/104/108/110/112, 116/118/120/124/126/128, 132/134/136/140/142/144, 148/150/152/156/158/160 and 182/184/186/190/192/194. 
     
     
         11 . An antibody or antigen-binding fragment thereof which competes for binding to hANGPTL3 with, or which binds the same epitope on hANGPTL3 as, an antibody or antigen-binding fragment comprising a heavy chain and light chain complementarity determining region (CDR) sequence combination selected from the group consisting of 4/6/8/12/14/16, 20/22/24/28/30/32, 36/38/40/44/46/48, 52/54/56/60/62/64, 68/70/72/76/78/80, 84/86/88/92/94/96, 100/102/104/108/110/112, 116/118/120/124/126/128, 132/134/136/140/142/144, 148/150/152/156/158/160 and 182/184/186/190/192/194. 
     
     
         12 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment cross-reacts with cynomolgus monkey ANGPTL3. 
     
     
         13 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment cross-reacts with mouse or rat ANGPTL3. 
     
     
         14 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or fragment cross-reacts with any of cynomolgus monkey ANGPTL3, mouse ANGPTL3, and rat ANGPTL3. 
     
     
         15 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody fragment is a single chain antibody, an Fab, or an F(ab′) 2 . 
     
     
         16 . An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment of  claim 1 . 
     
     
         17 . An expression vector comprising the nucleic acid molecule of  claim 16 . 
     
     
         18 . An isolated host cell comprising the expression vector of  claim 17 . 
     
     
         19 . A method of producing an anti-hANGPTL3 antibody or antigen-binding fragment thereof, comprising growing the host cell of  claim 18  under conditions permitting production of the antibody or fragment thereof, and recovering the antibody or fragment thereof so produced. 
     
     
         20 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the antibody or fragment thereof comprises a heavy chain and light chain complementarity determining region (CDR) sequence combination of SEQ ID NO:68/70/72/76/78/80, or a heavy chain variable region and a light chain variable region HCVR/LCVR pair comprising SEQ ID NO:66/74. 
     
     
         22 . A method for preventing or treating a disease or disorder which is prevented, ameliorated, improved or inhibited by reduction or inhibition of ANGPTL3 activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 20 . 
     
     
         23 . The method of  claim 22 , further comprising administering to the subject one or more additional therapeutic agents selected from the group consisting of an inhibitor of HMG-CoA reductase; an inhibitor of cholesterol uptake or bile acid re-absorption, or both; an agent which increases lipoprotein catabolism; an agent which reduces the number of non-fatal heart attacks; and an activator of the LXR transcription factor. 
     
     
         24 . The method of  claim 22 , further comprising administering to the subject one or more additional therapeutic agents selected from the group consisting of a statin, niacin, fibrate, anti-hANGPTL4 antibody and anti-PCSK9 antibody. 
     
     
         25 . The method of  claim 22 , wherein the disease or disorder is selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, chylomicronemia, atherogenic dyslipidemia, a cardiovascular disease or disorder, acute pancreatitis, nonalcoholic steatohepatitis (NASH), diabetes and obesity. 
     
     
         26 . A method of enhancing the clearance of hANGPTL3 from the circulation of a subject in need thereof, the method comprising administering to the subject at least two antibodies or antigen-binding fragments thereof that do not compete with one another for binding to hANGPTL3 and do not block at least one activity of hANGPTL3. 
     
     
         27 . The method of  claim 26 , wherein the at least two antibodies or antigen-binding fragments do not block lipoprotein lipase (LPL) activity of ANGPTL3. 
     
     
         28 . The method of  claim 27 , wherein the two antibodies or antigen-binding fragments thereof comprise HCVR/LCVR amino acid sequence pairs selected from the group consisting of:
 (i) SEQ ID NO:82/90 and 180/188;   (ii) SEQ ID NO:82/90 and 18/26;   (iii) SEQ ID NO:114/122 and 180/188; and   (iv) SEQ ID NO:114/122 and 18/26.

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