Anti-apoc3 antibodies and methods of use thereof

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 .- 39 . (canceled) 
     
     
         40 . A polynucleotide encoding a heavy chain variable region and/or a light chain variable region of an antibody, 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 SEQ ID NO: 3;   (b) CDRH2 comprises the amino acid sequence of SIX 1 TDGGGTAYRDSVKG, wherein X 1  is S or H (SEQ ID NO: 4);   (c) CDRH3 comprises the amino acid sequence of X 2 GYSD, wherein X 2  is A or H (SEQ ID NO: 5);   (d) CDRL1 comprises the amino acid sequence of SEQ ID NO: 6;   (e) CDRL2 comprises the amino acid sequence of SEQ ID NO: 7; and   (f) CDRL3 comprises the amino acid sequence of AX 3 GTYYPHT, wherein X 3  is Q or H (SEQ ID NO: 8), and   wherein at least one of X 1 , X 2 , and X 3  is H.   
     
     
         41 . An expression vector comprising the polynucleotide of  claim 40 . 
     
     
         42 . A host cell comprising the expression vector of  claim 41 . 
     
     
         43 . 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:
 (i) CDRH1 comprises the amino acid sequence of SEQ ID NO: 3;   (ii) CDRH2 comprises the amino acid sequence of SIX 1 TDGGGTAYRDSVKG, wherein X 1  is S or H (SEQ ID NO: 4);   (iii) CDRH3 comprises the amino acid sequence of X 2 GYSD, wherein X 2  is A or H (SEQ ID NO: 5);   (iv) CDRL1 comprises the amino acid sequence of SEQ ID NO: 6;   (v) CDRL2 comprises the amino acid sequence of SEQ ID NO: 7; and   (vi) CDRL3 comprises the amino acid sequence of AX 3 GTYYPHT, wherein X 3  is Q or H (SEQ ID NO: 8),   wherein at least one of X 1 , X 2 , and X 3  is H,   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 heavy chain variable region and light chain variable region are expressed, and the antibody is produced.   
     
     
         44 . A method for inhibiting the activity of ApoC3 in a subject, the method comprising administering to the subject an effective amount of 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 SEQ ID NO: 3;   (b) CDRH2 comprises the amino acid sequence of SIX 1 TDGGGTAYRDSVKG, wherein X 1  is S or H (SEQ ID NO: 4);   (c) CDRH3 comprises the amino acid sequence of X 2 GYSD, wherein X 2  is A or H (SEQ ID NO: 5);   (d) CDRL1 comprises the amino acid sequence of SEQ ID NO: 6;   (e) CDRL2 comprises the amino acid sequence of SEQ ID NO: 7; and   (f) CDRL3 comprises the amino acid sequence of AX 3 GTYYPHT, wherein X 3  is Q or H (SEQ ID NO: 8), and   wherein at least one of X 1 , X 2 , and X 3  is H.   
     
     
         45 .- 62 . (canceled) 
     
     
         63 . The polynucleotide of  claim 40 , wherein:
 (a) the CDRH2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 11;   (b) the CDRH3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 and 12; and/or   (c) the CDRL3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 13 and 14.   
     
     
         64 . The polynucleotide of  claim 40 , wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 11, 10, 6, 7, and 13; 3, 9, 12, 6, 7, and 13; 3, 9, 10, 6, 7, and 14; 3, 11, 10, 6, 7, and 14; 3, 9, 12, 6, 7, and 14; 3, 11, 12, 6, 7, and 13; or 3, 11, 12, 6, 7, and 13, respectively. 
     
     
         65 . The polynucleotide of  claim 40 , wherein the heavy chain variable region comprises an amino acid sequence that is at least 75% identical to the amino acid sequence set forth in SEQ ID NO: 15, 16, 17, or 18, and/or the light chain variable region comprises an amino acid sequence that is at least 75% identical to the amino acid sequence set forth in SEQ ID NO: 19 or 20. 
     
     
         66 . The polynucleotide of  claim 40 , wherein the heavy chain variable region and the light chain variable region, respectively, comprise amino acid sequences that are each at least 75% identical to the amino acid sequences set forth in SEQ ID NOs: 16 and 19, 17 and 19, 18 and 19, 15 and 20, 16 and 20, 17 and 20, or 18 and 20. 
     
     
         67 . The polynucleotide of  claim 40 , wherein the heavy chain variable region and the light chain variable region, respectively, comprise the amino acid sequences set forth in SEQ ID NOs: 16 and 19, 17 and 19, 18 and 19, 15 and 20, 16 and 20, 17 and 20, or 18 and 20. 
     
     
         68 . The polynucleotide of  claim 40 , wherein the antibody further comprises a human or humanized constant region. 
     
     
         69 . The polynucleotide of  claim 68 , 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. 
     
     
         70 . The polynucleotide of  claim 68 , wherein the constant region is a heavy chain constant region of a human IgG, optionally a heavy chain constant region of a human IgG 1 , IgG 2 , or IgG 4 . 
     
     
         71 . The polynucleotide of  claim 68 , 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,   optionally wherein the constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-24, 37-39, and 42-47.