Anti-apoc3 antibodies

Abstract

The instant disclosure provides antibodies that specifically bind to ApoC3 (e.g., human ApoC3) and antagonize ApoC3 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

1 .- 30 . (canceled) 
     
     
         31 . A method for producing an antibody that specifically binds to ApoC3, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein:
 (a) CDRH1 comprises the amino acid sequence of TYSMR (SEQ ID NO: 3);   (b) CDRH2 comprises the amino acid sequence of SIHTX 1 X 2 GGTAYRDSVKG, wherein X 1  is G, E, or D, and X 2  is G or A (SEQ ID NO: 87);   (c) CDRH3 comprises the amino acid sequence of AGYSD (SEQ ID NO: 10);   (d) CDRL1 comprises the amino acid sequence of KTSQGLVHSXGKTYFY, wherein X is D or G (SEQ ID NO: 88);   (e) CDRL2 comprises the amino acid sequence of QVSNRAS (SEQ ID NO: 7); and   (f) CDRL3 comprises the amino acid sequence of AXGTYYPHT, wherein X is Q or H (SEQ ID NO: 8),   wherein the CDRH1, CDRH2, and CDRH3 of the antibody are not SEQ ID NOs: 3, 11, and 10, respectively;   
       the method comprising: culturing a host cell comprising a first polynucleotide encoding the heavy chain variable region and a second polynucleotide encoding the light chain variable region under suitable conditions such that the first polynucleotide and the second polynucleotide are expressed, and the antibody is produced. 
     
     
         32 . The method of  claim 31 , wherein the first polynucleotide and the second polynucleotide are comprised within a single expression vector. 
     
     
         33 . The method of  claim 31 , wherein the first polynucleotide and the second polynucleotide are comprised within separate expression vectors. 
     
     
         34 . The method of  claim 31 , wherein CDRH2 of the antibody comprises the amino acid sequence of SIHTEAGGTAYRDSVKG (SEQ ID NO: 37), SIHTDAGGTAYRDSVKG (SEQ ID NO: 38), or SIHTEGGGTAYRDSVKG (SEQ ID NO: 39). 
     
     
         35 . The method of  claim 31 , wherein CDRL1 of the antibody comprises the amino acid sequence of KTSQGLVHSDGKTYFY (SEQ ID NO: 6) or KTSQGLVHSGGKTYFY (SEQ ID NO: 40). 
     
     
         36 . The method of  claim 31 , wherein CDRL3 of the antibody comprises the amino acid sequence of AHGTYYPHT (SEQ ID NO: 14) or AQGTYYPHT (SEQ ID NO: 13). 
     
     
         37 . The method of  claim 31 , wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the antibody comprise the amino acid sequences set forth in SEQ ID NOs: 3, 36, 10, 6, 7, and 14; 3, 37, 10, 40, 7, and 14; 3, 38, 10, 40, 7, and 14; 3, 38, 10, 6, 7, and 14; 3, 39, 10, 6, 7, and 14; or 3, 37, 10, 40, 7, and 13, respectively. 
     
     
         38 . The method of  claim 31 , wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 42-53; and/or the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-65. 
     
     
         39 . The method of  claim 31 , wherein the heavy chain variable region and light chain variable region of the antibody comprise the amino acid sequences set forth in SEQ ID NOs: 42 and 54, 43 and 55, 44 and 56, 45 and 57, 46 and 58, 46 and 54, 47 and 58, 47 and 54, 48 and 58, 48 and 54, 49 and 59, 49 and 60, 50 and 59, 50 and 60, 51 and 61, 52 and 62, 53 and 62, 43 and 63, 44 and 64, or 45 and 65, respectively. 
     
     
         40 . The method of  claim 31 , wherein the antibody further comprises a human constant region. 
     
     
         41 . The method of  claim 40 , wherein the constant region is a variant of a wild type human immunoglobulin heavy chain constant region, and wherein the variant human immunoglobulin heavy chain constant region has an increased affinity for human neonatal Fc receptor (FcRn) at pH 6 relative to the affinity of the wild type human immunoglobulin heavy chain constant region for human FcRn at pH 6. 
     
     
         42 . The method of  claim 40 , wherein the constant region is a heavy chain constant region of a human IgG. 
     
     
         43 . The method of  claim 40 , wherein the constant region is a heavy chain constant region of a human IgG 1 , IgG 2 , or IgG 4 . 
     
     
         44 . The method of  claim 40 , wherein the constant region comprises:
 (a) the amino acids K, F, and Y at EU positions 433, 434, and 436, respectively;   (b) the amino acids Y, T, and E at EU positions 252, 254, and 256, respectively; or   (c) the amino acids L and S at EU positions 428 and 434, respectively.   
     
     
         45 . The method of  claim 40 , wherein the constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 22, 23, 24, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, and 86. 
     
     
         46 . The method of  claim 31 , wherein the antibody further comprises a light chain constant region. 
     
     
         47 . The method of  claim 46 , wherein the light chain constant region comprises the amino acid sequence of SEQ ID NO: 25 or 26. 
     
     
         48 . The method of  claim 31 , wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 66-73; and/or the light chain comprises the amino acid sequence of SEQ ID NO: 74. 
     
     
         49 . The method of  claim 31 , wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain and the light chain comprise the amino acid sequences set forth in SEQ ID NOs: 66 and 74, 67 and 74, 68 and 74, 69 and 74, 70 and 74, 71 and 74, 72 and 74, or 73 and 74, respectively. 
     
     
         50 . A method for: inhibiting the activity of ApoC3 in a subject, reducing triglyceride levels in the blood of a subject, inhibiting post-prandial lipemia in a subject, treating hypertriglyceridemia in a subject, treating chylomicronemia in a subject, or reducing the risk of cardiovascular disease in a subject with hypertriglyceridemia, the method comprising administering to the subject an effective amount of an isolated antibody that specifically binds to ApoC3, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein:
 (a) CDRH1 comprises the amino acid sequence of TYSMR (SEQ ID NO: 3);   (b) CDRH2 comprises the amino acid sequence of SIHTX 1 X 2 GGTAYRDSVKG, wherein X 1  is G, E, or D, and X 2  is G or A (SEQ ID NO: 87);   (c) CDRH3 comprises the amino acid sequence of AGYSD (SEQ ID NO: 10);   (d) CDRL1 comprises the amino acid sequence of KTSQGLVHSXGKTYFY, wherein X is D or G (SEQ ID NO: 88);   (e) CDRL2 comprises the amino acid sequence of QVSNRAS (SEQ ID NO: 7); and   (f) CDRL3 comprises the amino acid sequence of AXGTYYPHT, wherein X is Q or H (SEQ ID NO: 8),