US2022213181A1PendingUtilityA1

Angiopoietin-like 4 antibodies and methods of use

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Assignee: NOVARTIS AGPriority: Aug 7, 2014Filed: Mar 21, 2022Published: Jul 7, 2022
Est. expiryAug 7, 2034(~8 yrs left)· nominal 20-yr term from priority
Inventors:Regis CebeIgor SplawskiJohn TraugerAndrei I. Voznesensky
C07K 16/22C07K 2317/94C07K 2317/565C07K 2317/92C07K 2317/76C07K 2317/71C07K 2317/33C07K 2317/24C07K 16/18A61K 2039/505C07K 2317/31A61P 9/00A61P 3/06A61P 3/00A61P 3/10A61P 3/04
76
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Claims

Abstract

The present invention relates to monoclonal antibodies binding to human angiopoietin-like 4 protein (hereinafter, sometimes referred to as “ANGPTL4”), and pharmaceutical compositions and methods of treatment comprising the same.

Claims

exact text as granted — not AI-modified
1 . An isolated anti-ANGPTL4 antibody or fragment thereof. 
     
     
         2 . An isolated antibody or fragment according to any previous claim, wherein said antibody or fragment blocks LPL binding to ANGPTL4 protein. 
     
     
         3 . An isolated antibody or fragment thereof that binds to a human ANGPTL4 protein with a KD of less than or equal to 45 pM, as measured by ForteBio kinetic binding assays, or less than or equal to 24 pM, as measured by solution equilibrium titration assay (SET). 
     
     
         4 . An isolated antibody or fragment according to any previous claim, wherein said antibody or fragment comprises at least one complementarity determining region having at least 95% identity to at least one of the CDRs recited in Table 1. 
     
     
         5 . An isolated antibody or fragment according to any previous claim, wherein said antibody or fragment comprises a CDR1, CDR2, and CDR3 from Table 1. 
     
     
         6 . An isolated antibody or fragment according to any previous claim, wherein said antibody or fragment comprises a CDR1, CDR2, and CDR3 from Table 1, wherein the variant has at least one to four amino acid changes in one of CDR1, CDR2, or CDR3. 
     
     
         7 . An isolated antibody or fragment thereof that binds human ANGPTL4, wherein the antibody or fragment comprises a heavy chain CDR3 selected from the group consisting of SEQ ID NO: 9, 34, 54, 74, 94, 114, and 134. 
     
     
         8 . An isolated antibody or fragment thereof that binds human ANGPTL4, wherein the antibody or fragment comprises a VH selected from the group consisting of SEQ ID NO: 13, 38, 58, 78, 98, 118, and 138; and a VL selected from the group consisting of SEQ ID NO: 23, 48, 68, 88, 108, 128, and 148 or an amino acid sequence with 97-99% identity thereof. 
     
     
         9 . An isolated antibody or fragment thereof comprising a heavy chain variable domain sequence selected from the group consisting of SEQ ID NO: 13, 38, 58, 78, 98, 118, and 138. 
     
     
         10 . An isolated antibody or fragment thereof comprising a light chain variable domain sequence selected from the group consisting of SEQ ID NO: 23, 48, 68, 88, 108, 128, and 148. 
     
     
         11 . An isolated antibody or fragment thereof comprising a heavy chain variable domain selected from the group consisting of SEQ ID NO: 13, 38, 58, 78, 98, 118, and 138; and light chain variable domain sequence selected from the group consisting of SEQ ID NO: 23, 48, 68, 88, 108, 128, and 148. 
     
     
         12 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 selected from the group consisting of SEQ ID NO: 7, 32, 52, 72, 92, 112, and 132; CDR2 selected from the group consisting of SEQ ID NO: 8, 33, 53, 73, 93, 113, and 133; CDR3 selected from the group consisting of 9, 34, 54, 74, 94, 114, and 134; a light chain variable region CDR1 selected from the group consisting of SEQ ID NO: 17, 42, 62, 82, 102, 122, and 142; CDR2 selected from the group consisting of SEQ ID NO: 18, 43, 63, 83, 103, 123, and 143; and CDR3 selected from the group consisting of SEQ ID NO: 19, 44, 64, 84, 104, 124, and 144. 
     
     
         13 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 selected from the group consisting of SEQ ID NO: 10, 35, 55, 75, 95, 115, and 135; CDR2 selected from the group consisting of SEQ ID NO: 11, 36, 56, 76, 96, 116, and 136; CDR3 selected from the group consisting of 12, 37, 57, 77, 97, 117, and 137; a light chain variable region CDR1 selected from the group consisting of SEQ ID NO: 20, 45, 65, 85, 105, 125, and 145; CDR2 selected from the group consisting of SEQ ID NO: 21, 46, 66, 86, 106, 126, and 146; and CDR3 selected from the group consisting of SEQ ID NO: 22, 47, 67, 87, 107, 127, and 147. 
     
     
         14 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 7; CDR2 of SEQ ID NO: 8; CDR3 of SEQ ID NO: 9; a light chain variable region CDR1 of SEQ ID NO: 17; CDR2 of SEQ ID NO: 18; and CDR3 of SEQ ID NO: 19. 
     
     
         15 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 32; CDR2 of SEQ ID NO: 33; CDR3 of SEQ ID NO: 34; a light chain variable region CDR1 of SEQ ID NO: 42; CDR2 of SEQ ID NO: 43; and CDR3 of SEQ ID NO: 44. 
     
     
         16 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 52; CDR2 of SEQ ID NO: 53; CDR3 of SEQ ID NO: 54; a light chain variable region CDR1 of SEQ ID NO: 62; CDR2 of SEQ ID NO: 63; and CDR3 of SEQ ID NO: 64. 
     
     
         17 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 72; CDR2 of SEQ ID NO: 73; CDR3 of SEQ ID NO: 74; a light chain variable region CDR1 of SEQ ID NO: 82; CDR2 of SEQ ID NO: 83; and CDR3 of SEQ ID NO: 84. 
     
     
         18 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 92; CDR2 of SEQ ID NO: 93; CDR3 of SEQ ID NO: 94; a light chain variable region CDR1 of SEQ ID NO: 102; CDR2 of SEQ ID NO: 103; and CDR3 of SEQ ID NO: 104. 
     
     
         19 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 112; CDR2 of SEQ ID NO: 113; CDR3 of SEQ ID NO: 114; a light chain variable region CDR1 of SEQ ID NO: 122; CDR2 of SEQ ID NO: 123; and CDR3 of SEQ ID NO: 124. 
     
     
         20 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 132; CDR2 of SEQ ID NO: 133; CDR3 of SEQ ID NO: 134; a light chain variable region CDR1 of SEQ ID NO: 142; CDR2 of SEQ ID NO: 143; and CDR3 of SEQ ID NO: 144. 
     
     
         21 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 10; CDR2 of SEQ ID NO: 11; CDR3 of SEQ ID NO: 12; a light chain variable region CDR1 of SEQ ID NO: 20; CDR2 of SEQ ID NO: 21; and CDR3 of SEQ ID NO: 22. 
     
     
         22 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 35; CDR2 of SEQ ID NO: 36; CDR3 of SEQ ID NO: 37; a light chain variable region CDR1 of SEQ ID NO: 45; CDR2 of SEQ ID NO: 46; and CDR3 of SEQ ID NO: 47. 
     
     
         23 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 55; CDR2 of SEQ ID NO: 56; CDR3 of SEQ ID NO: 57; a light chain variable region CDR1 of SEQ ID NO: 65; CDR2 of SEQ ID NO: 66; and CDR3 of SEQ ID NO: 67. 
     
     
         24 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 75; CDR2 of SEQ ID NO: 76; CDR3 of SEQ ID NO: 77; a light chain variable region CDR1 of SEQ ID NO: 85; CDR2 of SEQ ID NO: 86; and CDR3 of SEQ ID NO: 87. 
     
     
         25 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 95; CDR2 of SEQ ID NO: 96; CDR3 of SEQ ID NO: 97; a light chain variable region CDR1 of SEQ ID NO: 105; CDR2 of SEQ ID NO: 106; and CDR3 of SEQ ID NO: 107. 
     
     
         26 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 115; CDR2 of SEQ ID NO: 116; CDR3 of SEQ ID NO: 117; a light chain variable region CDR1 of SEQ ID NO: 125; CDR2 of SEQ ID NO: 126; and CDR3 of SEQ ID NO: 127. 
     
     
         27 . An isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 135; CDR2 of SEQ ID NO: 136; CDR3 of SEQ ID NO: 137; a light chain variable region CDR1 of SEQ ID NO: 145; CDR2 of SEQ ID NO: 146; and CDR3 of SEQ ID NO: 147. 
     
     
         28 . A pharmaceutical composition comprising an antibody or fragment thereof of one of the above claims and a pharmaceutically acceptable carrier. 
     
     
         29 . A method of treating an ANGPTL4-disorder comprising administering to a patient afflicted with an ANGPTL4-disorder an effective amount of a pharmaceutical composition comprising an antibody or fragment according to any previous claim. 
     
     
         30 . The method of  claim 29 , wherein the patient is afflicted with one or more of severe hypertriglyceridemia (e.g., with plasma triglyceride concentration >500 mg/dL), hypertriglyceridemia associated with obesity, type V hypertriglyceridemia and chylomicronemia. 
     
     
         31 . The method of  claim 29 , wherein the patient is afflicted with one or more of primary dyslipidemia, metabolic syndrome, and type 2 diabetes. 
     
     
         32 . An isolated antibody or fragment thereof that binds to the same epitope as an isolated antibody or fragment according to any previous claim. 
     
     
         33 . An isolated antibody or fragment thereof that binds to a human ANGPTL4 protein and cross-competes with an isolated antibody or fragment according to any previous claim.

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