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 - 64 . (canceled) 
     
     
         65 . A method for inhibiting the activity of ApoC3 in the blood of a subject, the method comprising administering to the subject an effective amount an antibody that specifically binds to ApoC3, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the CDRH1, CDRH2 and CDRH3 amino acid sequences of a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160, and/or the VL comprises the CDRL1, CDRL2 and CDRL3 amino acid sequences of a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 161-183 and 151. 
     
     
         66 . The method of  claim 65 , wherein:
 (a) CDRH1, CDRH2 and CDRH3 comprise the amino acid sequences of SEQ ID NOs: 4, 5, and 6; 7, 8, and 9; 10, 11, and 12; 13, 14, and 15; 16, 17, and 18; 19, 20, and 21; 22, 23, and 24; 25, 26, and 27; 28, 29, and 30; 16, 31, and 32; 33, 34, and 35; 25, 36, and 37; 38, 39, and 40; 41, 42, and 43; 47, 48, and 49; 50, 51, and 52; 53, 54, and 55; 56, 57, and 58; 59, 60, and 61; 62, 63, and 64; 65, 66, and 67; 68, 69, and 70; or 68, 71, and 72, respectively; and/or   (b) CDRL1, CDRL2 and CDRL3 comprise the amino acid sequences of SEQ ID NOs: 73, 74, and 75; 76, 77, and 78; 79, 80, and 81; 82, 83, and 84; 85, 86, and 87; 88, 83, and 89; 90, 91, and 92; 82, 93, and 94; 95, 96, and 97; 98, 99, and 100; 101, 99, and 102; 103, 104, and 105; 82, 106, and 107; 108, 109, and 110; 111, 83, and 113; 82, 114, and 115; 116, 117, and 118; 119, 120, and 121; 122, 123, and 124; 125, 83, and 126; 127, 128, and 129; 82, 114, and 130; 131, 132, and 133; or 124, 135, and 136, respectively.   
     
     
         67 . The method of  claim 65 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 comprise the amino acid sequences of SEQ ID NOs: 4, 5, 6, 73, 74, and 75; 7, 8, 9, 76, 77, and 78; 10, 11, 12, 79, 80, and 81; 13, 14, 15, 82, 83, and 84; 16, 17, 18, 85, 86, and 87; 19, 20, 21, 88, 83, and 89; 22, 23, 24, 90, 91, and 92; 25, 26, 27, 82, 93, and 94; 28, 29, 30, 95, 96, and 97; 16, 31, 32, 98, 99, and 100; 33, 34, 35, 101, 99, and 102; 25, 36, 37, 103, 104, and 105; 38, 39, 40, 82, 106, and 107; 41, 42, 43, 108, 109, and 110; 7, 8, 9, 111, 83, and 113; 47, 48, 49, 82, 114, and 115; 50, 51, 52, 116, 117, and 118; 53, 54, 55, 119, 120, and 121; 56, 57, 58, 122, 123, and 124; 59, 60, 61, 125, 83, and 126; 62, 63, 64, 127, 128, and 129; 65, 66, 67, 82, 114, and 130; 68, 69, 70, 131, 132, and 133; or 68, 71, 72, 124, 135, and 136, respectively. 
     
     
         68 . The method of  claim 65 , wherein the VH comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160, and/or the VL comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-183 and 15. 
     
     
         69 . The method of  claim 65 , wherein the VH and VL comprise the amino acid sequences of SEQ ID NOs: 137 and 161; 138 and 162; 139 and 163; 140 and 164; 141 and 165; 142 and 166; 143 and 167; 144 and 168; 145 and 169; 146 and 170; 147 and 171; 148 and 172; 149 and 173; 150 and 174; 138 and 175; 152 and 176; 153 and 177; 154 and 178; 155 and 179; 156 and 180; 157 and 181; 158 and 182; 159 and 183; or 160 and 151, respectively. 
     
     
         70 . The method of  claim 65 , wherein:
 (a) the antibody attenuates the ability of ApoC3 to inhibit hepatocyte uptake of very low density lipoprotein (VLDL);   (b) the antibody is capable of inhibiting post-prandial lipemia in a subject;   (c) the antibody is capable of increasing the rate of clearance of ApoB from the blood in a subject;   (d) the antibody is capable of reducing the level of ApoB in the blood in a subject;   (e) the antibody attenuates the ability of ApoC3 to inhibit lipoprotein lipase-mediated lipolysis of VLDL;   (f) the antibody inhibits the binding of ApoC3 to a lipid or is capable of binding to lipid-bound ApoC3;   (g) the antibody reduces the levels of chylomicron or chylomicron remnants in the blood of the subject;   (h) the antibody is capable of reducing triglyceride levels in the blood of a subject;   (i) the antibody is capable of treating hypertriglyceridemia in a subject;   (j) the antibody is capable of treating chylomicronemia in a subject; and/or   (k) the antibody is capable of reducing the risk of cardiovascular disease, optionally wherein the cardiovascular disease is myocardial infarction, angina, stroke, and/or atherosclerosis.   
     
     
         71 . The method of  claim 65 , wherein the subject is receiving an additional lipid lowering agent, optionally wherein:
 (a) the additional lipid lowering agent is an HMG-CoA reductase inhibitor, optionally wherein the HMG-CoA reductase inhibitor is atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin;   (b) the additional lipid lowering agent is a PCSK9 inhibitor, optionally wherein the PCSK9 inhibitor is alirocumab, evolocumab, or bococizumab;   (c) the additional lipid lowering agent is ezetimibe;   (d) the additional lipid lowering agent is a combination of ezetimibe and an HMG-CoA reductase inhibitor; and/or   (e) the additional lipid lowering agent is a combination of ezetimibe, an HMG-CoA reductase inhibitor, and a PCSK9 inhibitor.   
     
     
         72 . A method for inhibiting the activity of ApoC3 in the blood of a subject, the method comprising administering to the subject an effective amount an antibody that specifically binds to ApoC3, wherein the antibody binds to an epitope comprising:
 (a) at least one of the amino acids at position 1, 4, 6, 7, 9 or 10 of SEQ ID NO: 2; or   (b) at least one of the amino acids at position 2, 5, 6, 8, or 10 of SEQ ID NO: 3.   
     
     
         73 . The method of  claim 72 , wherein the epitope comprises:
 (a) the amino acids at positions 4 and 9 of SEQ ID NO: 2;   (b) the amino acids at positions 4, 6 and 9 of SEQ ID NO: 2;   (c) the amino acids at positions 1, 4, 6 and 9 of SEQ ID NO: 2;   (d) the amino acids at positions 1, 4, 6, 7, 9 and 10 of SEQ ID NO: 2;   (e) the amino acids at positions 5 and 6 of SEQ ID NO: 3;   (f) the amino acids at positions 2, 5, 6, and 8 of SEQ ID NO: 3;   (g) the amino acids at position 10 of SEQ ID NO: 3;   (h) the amino acids at positions 6, 8, and 10 of SEQ ID NO: 3; or   (i) the amino acids at positions 6 and 8 of SEQ ID NO: 3.   
     
     
         74 . The method of  claim 72 , wherein:
 (a) the antibody attenuates the ability of ApoC3 to inhibit hepatocyte uptake of very low density lipoprotein (VLDL);   (b) the antibody is capable of inhibiting post-prandial lipemia in a subject;   (c) the antibody is capable of increasing the rate of clearance of ApoB from the blood in a subject;   (d) the antibody is capable of reducing the level of ApoB in the blood in a subject;   (e) the antibody attenuates the ability of ApoC3 to inhibit lipoprotein lipase-mediated lipolysis of VLDL;   (f) the antibody inhibits the binding of ApoC3 to a lipid or is capable of binding to lipid-bound ApoC3;   (g) the antibody reduces the levels of chylomicron or chylomicron remnants in the blood of the subject;   (h) the antibody is capable of reducing triglyceride levels in the blood of a subject;   (i) the antibody is capable of treating hypertriglyceridemia in a subject;   (j) the antibody is capable of treating chylomicronemia in a subject; and/or   (k) the antibody is capable of reducing the risk of cardiovascular disease, optionally wherein the cardiovascular disease is myocardial infarction, angina, stroke, and/or atherosclerosis.   
     
     
         75 . The method of  claim 72 , wherein the subject is receiving an additional lipid lowering agent, optionally wherein:
 (a) the additional lipid lowering agent is an HMG-CoA reductase inhibitor, optionally wherein the HMG-CoA reductase inhibitor is atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin;   (b) the additional lipid lowering agent is a PCSK9 inhibitor, optionally wherein the PCSK9 inhibitor is alirocumab, evolocumab, or bococizumab;   (c) the additional lipid lowering agent is ezetimibe;   (d) the additional lipid lowering agent is a combination of ezetimibe and an HMG-CoA reductase inhibitor; and/or   (e) the additional lipid lowering agent is a combination of ezetimibe, an HMG-CoA reductase inhibitor, and a PCSK9 inhibitor.   
     
     
         76 . The method of  claim 75 , wherein:
 (a) the antibody attenuates the ability of ApoC3 to inhibit hepatocyte uptake of very low density lipoprotein (VLDL);   (b) the antibody is capable of inhibiting post-prandial lipemia in a subject;   (c) the antibody is capable of increasing the rate of clearance of ApoB from the blood in a subject;   (d) the antibody is capable of reducing the level of ApoB in the blood in a subject;   (e) the antibody attenuates the ability of ApoC3 to inhibit lipoprotein lipase-mediated lipolysis of VLDL;   (f) the antibody inhibits the binding of ApoC3 to a lipid or is capable of binding to lipid-bound ApoC3; and/or   (g) the antibody reduces the levels of chylomicron or chylomicron remnants in the blood of the subject.   
     
     
         77 . The method of  claim 75 , wherein the subject is receiving an additional lipid lowering agent, optionally wherein:
 (a) the additional lipid lowering agent is an HMG-CoA reductase inhibitor, optionally wherein the HMG-CoA reductase inhibitor is atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin;   (b) the additional lipid lowering agent is a PCSK9 inhibitor, optionally wherein the PCSK9 inhibitor is alirocumab, evolocumab, or bococizumab;   (c) the additional lipid lowering agent is ezetimibe;   (d) the additional lipid lowering agent is a combination of ezetimibe and an HMG-CoA reductase inhibitor; and/or   (e) the additional lipid lowering agent is a combination of ezetimibe, an HMG-CoA reductase inhibitor, and a PCSK9 inhibitor.