US2014161798A1PendingUtilityA1
Anti-pcsk9 and methods for treating lipid and cholesterol disorders
Est. expiryOct 26, 2027(~1.3 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 9/10A61P 3/06C07K 16/40A61K 39/3955A61K 31/397C07K 2317/34A61P 29/00C07K 2317/565A61K 2039/505C07K 2317/76A61K 45/06C07K 2317/56
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Claims
Abstract
The present invention provides compositions and methods for treating disorders of cholesterol and lipid metabolism by administration of an anti-PCSK9 antibody or a peptide inhibitor of PCSK9.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . An isolated antibody or antigen-binding fragment thereof comprising one or more members selected from the group consisting of:
(i) CDR-H1, CDR-H2 and CDR-H3 of the variable region the 11B5 heavy chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 10; (ii) CDR-H1, CDR-H2 and CDR-H3 of the variable region the 75B9 heavy chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 18; (iii) CDR-H1, CDR-H2 and CDR-H3 of the variable region the 77D10 heavy chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 26; (iv) CDR-H1, CDR-H2 and CDR-H3 of the variable region the 29C10 heavy chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 34; (v) CDR-H1, CDR-H2 and CDR-H3 of the variable region the 22D11 heavy chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 42; (vi) CDR-H1, CDR-H2 and CDR-H3 of the variable region the 1F11/1G11 heavy chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 50; (vii) CDR-L1, CDR-L2 and CDR-L3 of the variable region the 11B5 light chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 14; (viii) CDR-L1, CDR-L2 and CDR-L3 of the variable region the 75B9 light chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 22; (ix) CDR-L1, CDR-L2 and CDR-L3 of the variable region the 77D10 light chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 30; (x) CDR-L1, CDR-L2 and CDR-L3 of the variable region the 29C10 light chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 38; (xi) CDR-L1, CDR-L2 and CDR-L3 of the variable region the 22D11 light chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 46; and (xii) CDR-L1, CDR-L2 and CDR-L3 of the variable region the 1F11/1G11 light chain immunoglobulin which comprises the amino acid sequence of SEQ ID NO: 54.
2 . A composition comprising the antibody or antigen-binding fragment thereof of claim 1 in association with a further chemotherapeutic agent.
3 . The composition of claim 2 wherein the further chemotherapeutic agent is a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, an angiotensin-converting enzyme inhibitor, a coronary vasodilator, a diuretic, an adrenergic stimulant or an HMG-CoA reductase inhibitor.
4 . The composition of claim 2 wherein the further chemotherapeutic agent is ezetimibe, lovastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, rivastatin, simvastatin, an azetidinone, bunolol hydrochloride, acebutolol, alprenolol hydrochloride, atenolol, carteolol hydrochloride, celiprolol hydrochloride; cetamolol hydrochloride, labetalol hydrochloride, esmolol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, nadolol, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, bisoprolol; bisoprolol fumarate, nebivalol, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, exaprolol hydrochloride, flestolol sulfate, metalol hydrochloride, metoprolol 2-Propanol, metoprolol tartrate, pamatolol sulfate, penbutolol sulfate, practolol, tiprenolol hydrochloride or tolamolol.
5 . The composition of claim 4 wherein the further chemotherapeutic agent is ezetimibe optionally in association with simvastatin.
6 . The antibody or antigen-binding fragment thereof of claim 1 , which is a humanized antibody.
7 . The antibody or antigen-binding fragment thereof of claim 1 , which is an antibody which is a monoclonal antibody, a labeled antibody, a bivalent antibody, a polyclonal antibody, a bispecific antibody, a chimeric antibody, a recombinant antibody, an anti-idiotypic antibody, a humanized antibody or a bispecific antibody.
8 . The antibody or antigen-binding fragment thereof of claim 1 , which is an antigen-binding fragment which is a camelized single domain antibody, a diabody, an scfv, an scfv dimer, a dsfv, a (dsfv) 2 , a dsFv-dsfv′, a bispecific ds diabody, an Fv, an Fab, an Fab′, an F(ab′) 2 , or a domain antibody.
9 . The antibody or antigen-binding fragment thereof of claim 1 which is linked to an immunoglobulin constant region.
10 . The antibody or antigen-binding fragment thereof of claim 9 wherein the constant region is a K light chain, γ1 heavy chain, γ2 heavy chain, γ3 heavy chain or γ4 heavy chain.
11 . A pharmaceutical composition comprising the antibody or fragment of claim 1 in association with a pharmaceutically acceptable carrier.
12 . An isolated antibody or antigen-binding fragment thereof comprising one or more members selected from the group consisting of:
(i) HCDR1 comprising the amino acid sequence
(SEQ ID NO: 11)
G F N I K D T Y M H,
HCDR2 comprising the amino acid sequence
(SEQ ID NO: 12)
R I D P A N G H T E Y D P K F Q D
and
HCDR3 comprising the amino acid sequence
(SEQ ID NO: 13)
S Y F G S I F A Y;
(ii) HCDR1 comprising the amino acid sequence
(SEQ ID NO: 19)
G F N I K D T Y I H,
HCDR2 comprising the amino acid sequence
(SEQ ID NO: 20)
R I D P A N G H T E Y D P K F Q G
and
HCDR3 comprising the amino acid sequence
(SEQ ID NO: 21)
S Y Y G S I F A Y;
(iii) HCDR1 comprising the amino acid sequence
(SEQ ID NO: 27)
G F N I K D Y Y I H,
HCDR2 comprising the amino acid sequence
(SEQ ID NO: 28)
W I D P E N G D T E Y A P K F Q G
and
HCDR3 comprising the amino acid sequence
(SEQ ID NO: 29)
Y Y R Y D D G T W F P Y;
(iv) HCDR1 comprising the amino acid sequence
(SEQ ID NO: 35)
G F N I K D T Y I H,
HCDR2 comprising the amino acid sequence
(SEQ ID NO: 36)
W I D P A N G Y T K Y A P N F Q G
and
HCDR3 comprising the amino acid sequence
(SEQ ID NO: 37)
G Y Y R Y Y S L D Y;
(v) HCDR1 comprising the amino acid sequence
(SEQ ID NO: 43)
G F T F S N H D M A,
HCDR2 comprising the amino acid sequence
(SEQ ID NO: 44)
S I T P S G G T T Y Y R D S V E G
and
HCDR3 comprising the amino acid sequence
(SEQ ID NO: 45)
Q N Y Y D G S Y Y Y G L Y Y F D Y;
(vi) HCDR1 comprising the amino acid sequence
(SEQ ID NO: 51)
G Y T F T D Y Y M N,
HCDR2 comprising the amino acid sequence
(SEQ ID NO: 52)
D I N P N N G G A I Y N Q K F K G
and
HCDR3 comprising the amino acid sequence
(SEQ ID NO: 53)
G I I T E I A E D F;
(vii) LCDR1 comprising the amino acid sequence
(SEQ ID NO: 15)
S A S S S V S Y L Y,
LCDR2 comprising the amino acid sequence
(SEQ ID NO: 16)
R S S H R A S
and
LCDR3 comprising the amino acid sequence
(SEQ ID NO: 17)
H Q Y Q S Y P P T;
(viii) LCDR1 comprising the amino acid sequence
(SEQ ID NO: 23)
S A S S S V S Y L F,
LCDR2 comprising the amino acid sequence
(SEQ ID NO: 24)
R T S Y L A S
and
LCDR3 comprising the amino acid sequence
(SEQ ID NO: 25)
H Q Y H T Y P P T;
(ix) LCDR1 comprising the amino acid sequence
(SEQ ID NO: 31)
R A S G N I H S Y L A,
LCDR2 comprising the amino acid sequence
(SEQ ID NO: 32)
N A K T L P D
and
LCDR3 comprising the amino acid sequence
(SEQ ID NO: 33)
Q H F W N T P W T;
(x) LCDR1 comprising the amino acid sequence
(SEQ ID NO: 39)
R A S Q D I S N Y L N,
LCDR2 comprising the amino acid sequence
(SEQ ID NO: 40)
Y S S R L H S
and
LCDR3 comprising the amino acid sequence
(SEQ ID NO: 41)
Q Q G K T L P L T;
(xi) LCDR1 comprising the amino acid sequence
(SEQ ID NO: 47)
R S S Q S L V Y S D G N T Y L H,
LCDR2 comprising the amino acid sequence
(SEQ ID NO: 48)
R V S N R F S
and
LCDR3 comprising the amino acid sequence
(SEQ ID NO: 49)
L Q S T H F P P T;
and
(xii) LCDR1 comprising the amino acid sequence
(SEQ ID NO: 55)
K A S Q N V G T N V V,
LCDR2 comprising the amino acid sequence
(SEQ ID NO: 56)
S A S Y R Y S
and
LCDR3 comprising the amino acid sequence
(SEQ ID NO: 57)
Q Q Y K T Y P Y T.
13 . A composition comprising the antibody or antigen-binding fragment thereof of claim 12 in association with a further chemotherapeutic agent.
14 . The composition of claim 13 wherein the further chemotherapeutic agent is a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, an angiotensin-converting enzyme inhibitor, a coronary vasodilator, a diuretic, an adrenergic stimulant or an HMG-CoA reductase inhibitor.
15 . The composition of claim 13 wherein the further chemotherapeutic agent is ezetimibe, lovastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, rivastatin, simvastatin, an azetidinone, bunolol hydrochloride, acebutolol, alprenolol hydrochloride, atenolol, carteolol hydrochloride, celiprolol hydrochloride; cetamolol hydrochloride, labetalol hydrochloride, esmolol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, nadolol, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, bisoprolol; bisoprolol fumarate, nebivalol, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, exaprolol hydrochloride, flestolol sulfate, metalol hydrochloride, metoprolol 2-Propanol, metoprolol tartrate, pamatolol sulfate, penbutolol sulfate, practolol, tiprenolol hydrochloride, tolamolol fenspiride hydrochloride, proroxan, alfuzosin hydrochloride, labetalol hydrochloride, bretylium tosylate, dihydroergtamine mesylate, carvedilol, labetalol, bretylium tosylate, phentolamine mesylate, solypertine tartrate, zolertine hydrochloride, candesartan cilexetil, telmisartan, candesartan; losartan potassium, benazepril hydrochloride, captopril, fosinopril, moexipril hydrochloride, perindopril erbumine, quinapril, ramipril, enalapril maleate, lisinopril, delapril, spirapril, delapril hydrochloride, libenzapril, pentopril, perindopril 1H-Indole-2-carboxylic acid, quinaprilat, spirapril hydrochloride, spiraprilat, teprotide, zofenopril, amlodipine besylate, clentiazem maleate, isradipine, nimodipine, felodipine, nilvadipine; diltiazem hydrochloride, verapamil hydrochloride, teludipine hydrochloride, belfosdil, fostedil, ranolazine, butoprozine hydrochloride, tosifen, molsidomine, ranolazine hydrochloride, tosifen, diltiazem hydrochloride, isosorbide dinitrate, sosorbide mononitrate, nitroglycerin, verapamil hydrochloride, chromonar, clonitate, droprenilamine, lidoflazine, prenylamine, propatyl nitrate, mioflazine hydrochloride, mixidine, molsidomine, isosorbide mononitrate, erythrityl tetranitrate, clonitrate, dipyridamole; nicorandil, pyridinecarboxamide, nifedipine; perhexyline maleate; oxprenolol, pentrinitrol, verapamil, althiazide, benzthiazide, buthiazide, chlorothiazide, spironolactone, triamterene, guanfacine hydrochloride, methyldopa-hydrochlorothiazide combined with Hydrochlorothiazide, methyldopa-chlorothiazide, clonidine hydrochloride, chlorthalidone, clonidine hydrochloride, clonidine, althiazide, benzthiazide, captopril, carvedilol, chlorothiazide, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, delapril hydrochloride, doxazosin mesylate, fosinopril sodium, moexipril hydrochloride, monatepil maleate, metoprolol succinate, guanfacine hydrochloride, methyldopa, quinaprilat, quinapril hydrochloride, primidolol, prazosin hydrochloride, pelanserin hydrochloride, phenoxybenzamine hydrochloride, candesartan cilexetil, telmisartan, candesartan, amlodipine maleate, terazosin hydrochloride, bevantolol hydrochloride or ramipril.
16 . The composition of claim 15 wherein the further chemotherapeutic agent is ezetimibe optionally in association with simvastatin.
17 . The antibody or antigen-binding fragment thereof of claim 12 , which is a humanized antibody.
18 . The antibody or antigen-binding fragment thereof of claim 12 , which is a humanized antibody.
19 . The antibody or antigen-binding fragment thereof of claim 12 , which is an antibody which is a monoclonal antibody, a labeled antibody, a bivalent antibody, a polyclonal antibody, a bispecific antibody, a chimeric antibody, a recombinant antibody, an anti-idiotypic antibody, a humanized antibody or a bispecific antibody.
20 . The antibody or antigen-binding fragment thereof of claim 12 , which is an antigen-binding fragment which is a camelized single domain antibody, a diabody, an scfv, an scfv dimer, a dsfv, a (dsfv) 2 , a dsFv-dsfv′, a bispecific ds diabody, an Fv, an Fab, an Fab′, an F(ab′) 2 , or a domain antibody.
21 . The antibody or antigen-binding fragment thereof of claim 12 which is linked to an immunoglobulin constant region.
22 . The antibody or antigen-binding fragment thereof of claim 21 wherein the constant region is a κ light chain, γ1 heavy chain, γ2 heavy chain, γ3 heavy chain or γ4 heavy chain.
23 . A pharmaceutical composition comprising the antibody or fragment of claim 12 in association with a pharmaceutically acceptable carrier.
24 . The isolated antibody or antigen-binding fragment thereof of claim 12 comprising one or more members selected from the group consisting of:
(a) an immunoglobulin heavy chain comprising the amino acid sequence:
(SEQ ID NO: 10)
E V Q L Q Q S G A E L V K P G A S V T L S C T A S G F N I K D T Y
M H W V N Q R P E Q G L V W I G R I D P A N G H T E Y D P K F Q D
K A T I T T D T S S N T A Y L H L S S L T S G D T A V Y Y C A R S
Y E G S I F A Y W G Q G T L V T V S A;
(b) an immunoglobulin light chain comprising the amino acid sequence:
(SEQ ID NO: 14)
Q I V L T Q S P A I M S A S P G E K V T I S C S A S S S V S Y L Y
W Y Q Q K P G S S P K P W I F R S S H R A S G V P A R F S G S G S
G T S Y S L T I S S N E A E D A A T Y Y C H Q Y Q S Y P P T F G G
G T K L E I K R A;
(c) an immunoglobulin heavy chain comprising the amino acid sequence:
(SEQ ID NO: 18)
E V Q L Q Q S G A D L V K P G A S V K L S C T A S G F N I K D T Y
I H W V K Q R P E Q G L E W I G R I D P A N G H T E Y D P K F Q G
R A T L T T D T S S N T A Y L Q L F S L T S E D S A V Y F C A R S
Y Y G S I F A Y W G Q G T L V T V S A;
(d) an immunoglobulin light chain comprising the amino acid sequence:
(SEQ ID NO: 22)
Q I V L T Q S P A I M S A S P G E K V T I S C S A S S S V S Y L F
W Y Q Q K P G S S P K P W I F R T S Y L A S G V P A R F S G S G S
G T S F S L T I S S N E A E D A A T Y Y C H Q Y H T Y P P T F G G
G T K L E I K R A;
(e) an immunoglobulin heavy chain comprising the amino acid sequence:
(SEQ ID NO: 26)
E V Q L Q Q S G A E L V R S G A S V K L S C T T S G F N I K D Y Y
I H W V K Q R P E Q G L E W I G W I D P E N G D T E Y A P K F Q G
K A T M T A D T S S N T A Y L Q L S S L T S A D T A V Y Y C N A
Y Y R Y D D G T W F P Y W G Q G T L V T V S A;
(f) an immunoglobulin light chain comprising the amino acid sequence:
(SEQ ID NO: 30)
D I Q L T Q S P A S L S A S V G E T V T I T C R A S G N I H S Y L
A W Y Q Q K Q G K S P Q F L V D N A K T L P D G V P S R F S V S G
S G T Q Y S L K I N S L Q P E D F G T Y Y C Q H F W N T P W T F G
G G T K L E I K R A;
(g) an immunoglobulin heavy chain comprising the amino acid sequence:
(SEQ ID NO: 34)
E V L L Q Q S V A E L V R P G A S V R L S C T A S G F N I K D T Y
I H W V R Q R P E Q G L E W F G W I D P A N G Y T K Y A P N F Q G
K A T L T T D T S S N T A Y L H L S S L T S E D S A I Y Y C A R G
Y Y R Y Y S L D Y W G Q G T S V T V S S;
(h) an immunoglobulin light chain comprising the amino acid sequence:
(SEQ ID NO: 38)
D I Q M T Q T T S S L S A S L G D R V T I S C R A S Q D I S N Y L
N W Y Q Q K P D G T V K L L I Y Y S S R L H S G V P S R F S G R G
S G T D Y S L T I S T L E Q E D I A T Y F C Q Q G K T L P L T F G
A G T K L E L K R A;
(i) an immunoglobulin heavy chain comprising the amino acid sequence:
(SEQ ID NO: 42)
E V Q L V D S G G G L V Q P G R S L K L S C A A S G F T F S N H D
M A W V R Q A P T K G L E W V A S I T P S G G T T Y Y R D S V E G
R F T V S R D N V K S S L H L Q M D S L T S E D T A T Y Y C A R Q
N Y Y D G S Y Y Y G L Y Y F D Y W G Q G V M V T V S S;
(j) an immunoglobulin light chain comprising the amino acid sequence:
(SEQ ID NO: 46)
D V L M T Q T P V S L P V S L G G Q V S I S C R S S Q S L V Y S D
G N T Y L H W Y L Q K P G Q S P Q L L I Y R V S N R F S G V P D R
F S G S G S G T D F T L K I S R V E P E D L G L Y Y C L Q S T H F
P P T F G S G T K L E I K R A;
(k) an immunoglobulin heavy chain comprising the amino acid sequence:
(SEQ ID NO: 50)
E V Q L Q Q S G P E L V K P G A S V K I S C K V S G Y T F T D Y Y
M N W V K Q S H G K S L E W I G D I N P N N G G A I Y N Q K F K G
K A T L T V D K S S S I A Y M E L R S L T S E D S A V Y Y C T S G
I I T E I A E D F W G Q G T T L T V S S;
and
(l) an immunoglobulin light chain comprising the amino acid sequence:
(SEQ ID NO: 54)
D I V M T Q S Q K F M S T S V G D R V S V T C K A S Q N V G T N V
V W Y Q Q K P G Q S P K A L I H S A S Y R Y S G V P D R F K G S G
S G T D F T L T I T N V Q S E D L A G F F C Q Q Y K T Y P Y T F G
G G T Q L E I K R A.
25 . A composition comprising the antibody or antigen-binding fragment thereof of claim 24 in association with a further chemotherapeutic agent.
26 . The composition of claim 25 wherein the further chemotherapeutic agent is a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, an angiotensin-converting enzyme inhibitor, a coronary vasodilator, a diuretic, an adrenergic stimulant or an HMG-CoA reductase inhibitor.
27 . The composition of claim 25 wherein the further chemotherapeutic agent is ezetimibe, lovastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, rivastatin, simvastatin, an azetidinone, bunolol hydrochloride, acebutolol, alprenolol hydrochloride, atenolol, carteolol hydrochloride, celiprolol hydrochloride; cetamolol hydrochloride, labetalol hydrochloride, esmolol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, nadolol, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, bisoprolol; bisoprolol fumarate, nebivalol, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, exaprolol hydrochloride, flestolol sulfate, metalol hydrochloride, metoprolol 2-Propanol, metoprolol tartrate, pamatolol sulfate, penbutolol sulfate, practolol, tiprenolol hydrochloride, tolamolol fenspiride hydrochloride, proroxan, alfuzosin hydrochloride, labetalol hydrochloride, bretylium tosylate, dihydroergtamine mesylate, carvedilol, labetalol, bretylium tosylate, phentolamine mesylate, solypertine tartrate, zolertine hydrochloride, candesartan cilexetil, telmisartan, candesartan; losartan potassium, benazepril hydrochloride, captopril, fosinopril, moexipril hydrochloride, perindopril erbumine, quinapril, ramipril, enalapril maleate, lisinopril, delapril, spirapril, delapril hydrochloride, libenzapril, pentopril, perindopril 1H-Indole-2-carboxylic acid, quinaprilat, spirapril hydrochloride, spiraprilat, teprotide, zofenopril, amlodipine besylate, clentiazem maleate, isradipine, nimodipine, felodipine, nilvadipine; diltiazem hydrochloride, verapamil hydrochloride, teludipine hydrochloride, belfosdil, fostedil, ranolazine, butoprozine hydrochloride, tosifen, molsidomine, ranolazine hydrochloride, tosifen, diltiazem hydrochloride, isosorbide dinitrate, sosorbide mononitrate, nitroglycerin, verapamil hydrochloride, chromonar, clonitate, droprenilamine, lidoflazine, prenylamine, propatyl nitrate, mioflazine hydrochloride, mixidine, molsidomine, isosorbide mononitrate, erythrityl tetranitrate, clonitrate, dipyridamole; nicorandil, pyridinecarboxamide, nifedipine; perhexyline maleate; oxprenolol, pentrinitrol, verapamil, althiazide, benzthiazide, buthiazide, chlorothiazide, spironolactone, triamterene, guanfacine hydrochloride, methyldopa-hydrochlorothiazide combined with Hydrochlorothiazide, methyldopa-chlorothiazide, clonidine hydrochloride, chlorthalidone, clonidine hydrochloride, clonidine, althiazide, benzthiazide, captopril, carvedilol, chlorothiazide, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, delapril hydrochloride, doxazosin mesylate, fosinopril sodium, moexipril hydrochloride, monatepil maleate, metoprolol succinate, guanfacine hydrochloride, methyldopa, quinaprilat, quinapril hydrochloride, primidolol, prazosin hydrochloride, pelanserin hydrochloride, phenoxybenzamine hydrochloride, candesartan cilexetil, telmisartan, candesartan, amlodipine maleate, terazosin hydrochloride, bevantolol hydrochloride or ramipril.
28 . The composition of claim 27 wherein the further chemotherapeutic agent is ezetimibe optionally in association with simvastatin.
29 . The antibody or antigen-binding fragment thereof of claim 24 , which is a humanized antibody.
30 . The antibody or antigen-binding fragment thereof of claim 24 , which is a humanized antibody.
31 . The antibody or antigen-binding fragment thereof of claim 24 , which is an antibody which is a monoclonal antibody, a labeled antibody, a bivalent antibody, a polyclonal antibody, a bispecific antibody, a chimeric antibody, a recombinant antibody, an anti-idiotypic antibody, a humanized antibody or a bispecific antibody.
32 . The antibody or antigen-binding fragment thereof of claim 24 , which is an antigen-binding fragment which is a camelized single domain antibody, a diabody, an scfv, an scfv dimer, a dsfv, a (dsfv) 2 , a dsFv-dsfv′, a bispecific ds diabody, an Fv, an Fab, an Fab′, an F(ab′) 2 , or a domain antibody.
33 . The antibody or antigen-binding fragment thereof of claim 24 which is linked to an immunoglobulin constant region.
34 . The antibody or antigen-binding fragment thereof of claim 33 wherein the constant region is a κ light chain, γ1 heavy chain, γ2 heavy chain, γ3 heavy chain or γ4 heavy chain.
35 . A pharmaceutical composition comprising the antibody or fragment of claim 24 in association with a pharmaceutically acceptable carrier.
36 . A pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof or isolated EGF-A polypeptide which binds specifically to PCSK9, which antibody or fragment or polypeptide inhibits binding between PCSK9 and LDL receptor; and a pharmaceutically acceptable carrier.
37 . The pharmaceutical composition of claim 36 wherein the antibody binds specifically to a PCSK9 catalytic domain or to a domain of PCSK9 which interacts with an LDL receptor EGF-A domain.
38 . An isolated polypeptide comprising an amino acid sequence comprising about 90% or more amino acid sequence similarity to a fragment of the human LDL receptor which fragment consists of amino acids beginning at about amino acid position 314 and ending at about amino acid position 355 of said receptor; wherein said polypeptide optionally comprises one or more properties selected from the group consisting of:
(i) binds to PCSK9; (ii) competes with LDL receptor or an anti-PCSK9 antibody or antigen-binding fragment thereof for binding to PCSK9; (iii) reduces total cholesterol level when administered to an animal; (iv) reduces low density lipoprotein cholesterol level when administered to an animal; (v) reduces apolipoprotein B level when administered to an animal; (vi) reduces total cholesterol/high density lipoprotein ratio when administered to an animal; and (vii) reduces low density lipoprotein/high density lipoprotein ratio when administered to an animal; or a pharmaceutical composition thereof comprising a pharmaceutically acceptable carrier.
39 . The polypeptide of claim 38 which consists of the amino acid sequence of SEQ ID NO: 3; or a pharmaceutical composition thereof comprising a pharmaceutically acceptable carrier.
40 . A method for reducing:
total cholesterol level; low density lipoprotein cholesterol level; apolipoprotein B level; total cholesterol/high density lipoprotein ratio; or low density lipoprotein/high density lipoprotein ratio; in a subject, comprising administering, to said subject, a therapeutically effective amount of a PCSK9 antagonist EGF-A polypeptide; or an antibody or antigen-binding fragment thereof that binds specifically to PCSK9; which antibody or fragment or EGF-A polypeptide inhibits binding between PCSK9 and LDL receptor; optionally in association with a further chemotherapeutic agent.
41 . The method of claim 40 wherein the antibody or fragment binds specifically to a PCSK9 catalytic domain or to a domain of PCSK9 which interacts with an LDL receptor EGF-A domain.
42 . A method for treating or preventing hypercholesterolemia, hyperlipidemia, hypertriglyceridaemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, vascular inflammation or xanthoma, in an subject, comprising administering, to said subject, a therapeutically effective amount of an EGF-A polypeptide or an antibody or antigen-binding fragment thereof that binds specifically to PCSK9, which antibody or fragment or EGF-A polypeptide inhibits binding between PCSK9 and LDL receptor; optionally in association with a further chemotherapeutic agent.
43 . The method of claim 42 wherein the antibody binds specifically to a PCSK9 catalytic domain or to a domain of PCSK9 which interacts with an LDL receptor EGF-A domain.
44 . A method for reducing:
total cholesterol level; low density lipoprotein cholesterol level; apolipoprotein B level; total cholesterol/high density lipoprotein ratio; or low density lipoprotein/high density lipoprotein ratio; or for treating: hypercholesterolemia; hyperlipidemia; hypertriglyceridaemia; sitosterolemia; atherosclerosis; arteriosclerosis; coronary heart disease; vascular inflammation; or xanthoma, in a subject, comprising administering, to said subject, a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 1 .
45 . The method of claim 44 wherein the antibody or antigen-binding fragment thereof of claim 1 in administered in association with a further chemotherapeutic agent.
46 . The method of claim 45 wherein the further chemotherapeutic agent is a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, an angiotensin-converting enzyme inhibitor, a coronary vasodilator, a diuretic, an adrenergic stimulant or an HMG-CoA reductase inhibitor.
47 . The method of claim 46 wherein the further chemotherapeutic agent is ezetimibe, lovastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, rivastatin, simvastatin, an azetidinone, bunolol hydrochloride, acebutolol, alprenolol hydrochloride, atenolol, carteolol hydrochloride, celiprolol hydrochloride; cetamolol hydrochloride, labetalol hydrochloride, esmolol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, nadolol, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, bisoprolol; bisoprolol fumarate, nebivalol, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, exaprolol hydrochloride, flestolol sulfate, metalol hydrochloride, metoprolol 2-Propanol, metoprolol tartrate, pamatolol sulfate, penbutolol sulfate, practolol, tiprenolol hydrochloride, tolamolol fenspiride hydrochloride, proroxan, alfuzosin hydrochloride, labetalol hydrochloride, bretylium tosylate, dihydroergtamine mesylate, carvedilol, labetalol, bretylium tosylate, phentolamine mesylate, solypertine tartrate, zolertine hydrochloride, candesartan cilexetil, telmisartan, candesartan; losartan potassium, benazepril hydrochloride, captopril, fosinopril, moexipril hydrochloride, perindopril erbumine, quinapril, ramipril, enalapril maleate, lisinopril, delapril, spirapril, delapril hydrochloride, libenzapril, pentopril, perindopril 1H-Indole-2-carboxylic acid, quinaprilat, spirapril hydrochloride, spiraprilat, teprotide, zofenopril, amlodipine besylate, clentiazem maleate, isradipine, nimodipine, felodipine, nilvadipine; diltiazem hydrochloride, verapamil hydrochloride, teludipine hydrochloride, belfosdil, fostedil, ranolazine, butoprozine hydrochloride, tosifen, molsidomine, ranolazine hydrochloride, tosifen, diltiazem hydrochloride, isosorbide dinitrate, sosorbide mononitrate, nitroglycerin, verapamil hydrochloride, chromonar, clonitate, droprenilamine, lidoflazine, prenylamine, propatyl nitrate, mioflazine hydrochloride, mixidine, molsidomine, isosorbide mononitrate, erythrityl tetranitrate, clonitrate, dipyridamole; nicorandil, pyridinecarboxamide, nifedipine; perhexyline maleate; oxprenolol, pentrinitrol, verapamil, althiazide, benzthiazide, buthiazide, chlorothiazide, spironolactone, triamterene, guanfacine hydrochloride, methyldopa-hydrochlorothiazide combined with Hydrochlorothiazide, methyldopa-chlorothiazide, clonidine hydrochloride, chlorthalidone, clonidine hydrochloride, clonidine, althiazide, benzthiazide, captopril, carvedilol, chlorothiazide, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, delapril hydrochloride, doxazosin mesylate, fosinopril sodium, moexipril hydrochloride, monatepil maleate, metoprolol succinate, guanfacine hydrochloride, methyldopa, quinaprilat, quinapril hydrochloride, primidolol, prazosin hydrochloride, pelanserin hydrochloride, phenoxybenzamine hydrochloride, candesartan cilexetil, telmisartan, candesartan, amlodipine maleate, terazosin hydrochloride, bevantolol hydrochloride or ramipril.
48 . The method of claim 47 wherein the further chemotherapeutic agent is ezetimibe and, optionally, simvastatin.
49 . The method of claim 44 wherein the antibody or antigen-binding fragment thereof is a humanized antibody.
50 . A method for reducing:
total cholesterol level; low density lipoprotein cholesterol level; apolipoprotein B level; total cholesterol/high density lipoprotein ratio; or low density lipoprotein/high density lipoprotein ratio; or for treating: hypercholesterolemia; hyperlipidemia; hypertriglyceridaemia; sitosterolemia; atherosclerosis; arteriosclerosis; coronary heart disease; vascular inflammation; or xanthoma, in a subject, comprising administering, to said subject, a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 24 .
51 . The method of claim 50 wherein the antibody or antigen-binding fragment thereof of claim 1 in administered in association with a further chemotherapeutic agent.
52 . The method of claim 51 wherein the further chemotherapeutic agent is a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, an angiotensin-converting enzyme inhibitor, a coronary vasodilator, a diuretic, an adrenergic stimulant or an HMG-CoA reductase inhibitor.
53 . The method of claim 51 wherein the further chemotherapeutic agent is ezetimibe, lovastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, rivastatin, simvastatin, an azetidinone, bunolol hydrochloride, acebutolol, alprenolol hydrochloride, atenolol, carteolol hydrochloride, celiprolol hydrochloride; cetamolol hydrochloride, labetalol hydrochloride, esmolol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, nadolol, practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate, bisoprolol; bisoprolol fumarate, nebivalol, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, exaprolol hydrochloride, flestolol sulfate, metalol hydrochloride, metoprolol 2-Propanol, metoprolol tartrate, pamatolol sulfate, penbutolol sulfate, practolol, tiprenolol hydrochloride, tolamolol fenspiride hydrochloride, proroxan, alfuzosin hydrochloride, labetalol hydrochloride, bretylium tosylate, dihydroergtamine mesylate, carvedilol, labetalol, bretylium tosylate, phentolamine mesylate, solypertine tartrate, zolertine hydrochloride, candesartan cilexetil, telmisartan, candesartan; losartan potassium, benazepril hydrochloride, captopril, fosinopril, moexipril hydrochloride, perindopril erbumine, quinapril, ramipril, enalapril maleate, lisinopril, delapril, spirapril, delapril hydrochloride, libenzapril, pentopril, perindopril 1H-Indole-2-carboxylic acid, quinaprilat, spirapril hydrochloride, spiraprilat, teprotide, zofenopril, amlodipine besylate, clentiazem maleate, isradipine, nimodipine, felodipine, nilvadipine; diltiazem hydrochloride, verapamil hydrochloride, teludipine hydrochloride, belfosdil, fostedil, ranolazine, butoprozine hydrochloride, tosifen, molsidomine, ranolazine hydrochloride, tosifen, diltiazem hydrochloride, isosorbide dinitrate, sosorbide mononitrate, nitroglycerin, verapamil hydrochloride, chromonar, clonitate, droprenilamine, lidoflazine, prenylamine, propatyl nitrate, mioflazine hydrochloride, mixidine, molsidomine, isosorbide mononitrate, erythrityl tetranitrate, clonitrate, dipyridamole; nicorandil, pyridinecarboxamide, nifedipine; perhexyline maleate; oxprenolol, pentrinitrol, verapamil, althiazide, benzthiazide, buthiazide, chlorothiazide, spironolactone, triamterene, guanfacine hydrochloride, methyldopa-hydrochlorothiazide combined with Hydrochlorothiazide, methyldopa-chlorothiazide, clonidine hydrochloride, chlorthalidone, clonidine hydrochloride, clonidine, althiazide, benzthiazide, captopril, carvedilol, chlorothiazide, clonidine hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride, delapril hydrochloride, doxazosin mesylate, fosinopril sodium, moexipril hydrochloride, monatepil maleate, metoprolol succinate, guanfacine hydrochloride, methyldopa, quinaprilat, quinapril hydrochloride, primidolol, prazosin hydrochloride, pelanserin hydrochloride, phenoxybenzamine hydrochloride, candesartan cilexetil, telmisartan, candesartan, amlodipine maleate, terazosin hydrochloride, bevantolol hydrochloride or ramipril.
54 . The method of claim 53 wherein the further chemotherapeutic agent is ezetimibe and, optionally, simvastatin.
55 . The method of claim 50 wherein the antibody or antigen-binding fragment thereof is a humanized antibody.
56 . A method for producing an antibody or antigen-binding fragment thereof of claim 1 comprising introducing one or more polynucleotides into one or more host cells; which polynucleotides encodes and direct expression of said heavy and/or light chain immunoglobulins; and growing said host cells under conditions whereby said heavy and light chain immunoglobulins are expressed.
57 . The method of claim 56 wherein said polynucleotide encoding and directing expression of said light chain and said polynucleotide encoding and directing expression of said heavy chain are in separate host cells.Cited by (0)
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