US2016166634A1PendingUtilityA1
Bioconjugates of synthetic apelin polypeptides
Est. expiryJul 25, 2033(~7 yrs left)· nominal 20-yr term from priority
Inventors:Shari Lynn CaplanAndrei GolosovPhilipp GroscheCarla GuimaraesAaron KanterChanggang LouDavid Thomas ParkerEric PetersAimee Richardson UseraKayo YasoshimaJun YuanFederic ZecriHongjuan Zhao
A61P 3/10A61P 9/12A61P 9/00A61P 9/04A61P 9/10A61P 43/00A61P 9/06A61P 7/00A61P 3/04A61P 21/02A61P 25/00A61P 17/02A61P 17/16C07K 14/47A61K 45/06C07K 2319/31A61K 47/542C07K 14/765C07K 2319/30A61K 38/10A61K 47/643A61K 38/00A61K 47/68A61K 47/6811C07K 7/08C07K 16/00A61K 47/48376A61K 47/48038A61K 47/48284
40
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The invention provides a bioconjugates comprising a synthetic polypeptide of Formula I′ (SEQ ID NO: 1): or an amide, an ester or a salt thereof, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12 and X13 are defined herein and a half-life extending moiety wherein the peptide and the half-life extending moiety are covalently linked or fuse, optionally via a linker. The polypeptides are agonist of the APJ receptor. The invention also relates to a method for manufacturing the bioconjugates of the invention, and its therapeutic uses such as treatment or prevention of acute decompensated heart failure (ADHF), chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia, water retention, diabetes (including gestational diabetes), obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries (including sunburn) and preeclampsia. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A bioconjugate or a multimer thereof, comprising:
a. a peptide or polypeptide having the following formula I′ (SEQ ID NO: 1):
wherein:
X1 is the N-terminus of the polypeptide and is either absent or is selected from pE, R, Isn, Q, A, K, and 5-amino-valeric acid;
X2 is R, A, r, N-Me-R, K, H, hF, hK, F, E or Orn;
X3 is P, A, a, p, 4-PhP, K, D, pipecolic acid, or cysteine wherein the side chain of cysteine forms a disulfide bond with the side chain of the cysteine at the X7 position;
X4 is R, A, r, N-Me-R, F, E or cysteine wherein the side chain of cysteine forms a disulfide bond with the side chain of the cysteine at the X7 position;
X5 is L, Cha, A, D-L, N-Me-L, K, D, 4-PhF or F;
X6 and X12 are independently a natural or unnatural amino acid selected from C, c, hC, D-hC, K, D, Orn, Dab or E wherein the side chain of X6 and X12 are linked together via a covalent bond forming either a monosulfide (—S—), a disulfide (—S—S—) or an amide bond (—NHC(O)— or —C(O)—NH—); or alternatively X6 is K, X13 is absent and X12 is F or f wherein the C-terminus of X12 form an amide bond with the amino side chain of X6;
X7 is H, h, A, N-Me-A, a, Aib, K, Nal, F, P, Dap, N, E or cysteine wherein the side chain of the cysteine forms a disulfide bond with the side chain of the cysteine at position X3 or with the side chain of the cysteine at position X4;
X8 is K, k, F, f, A, hF, N-Me-R, E or 4-amino-Isn;
X9 is G, N-Me-G, A, D, L, R or Aib;
X10 is P, A, p, 4-PhP or pipecolic acid,
X11 is M, D-Nle, Nle, N-Me-Nle, M(O), A, F, Y, L, K, 3-PyA or Cha; and
X13 is the C-terminus and is absent or is selected from F, f, N-Me-F, Nal, D-Nal, 3-Br—F, (S)-β-3-F, I, A, a, K, Dap, H and E;
wherein:
Nle is L-norleucine;
D-hC is D-homocysteine
hC is L-homocysteine;
hF is L-homophenylalanine;
hK is L-lysine;
Nal is L-naphathaline;
Orn is ornithine;
Aib is π-aminoisobutyric acid;
Dab is (S)-diaminobutyric acid;
Dap is (S)-2,3-diaminopropionic acid;
M(O) is methionine sulfone;
Cha is (S)-π-cyclohexylalanine;
4-amino-Isn is 4-aminopiperidine-4-carboxylic acid;
Isn is isonipecotinoyl;
pE is L-pyroglutamic acid;
3-PyA is 3-(3-pyridyl)-L-alanine;
4-PhF is 4-Phenyl-L-phenylalanine;
wherein the N-terminus and the C-terminus optionally form a ring together with 1, 2, 3 or 4 glycine amino acids; and
or an amide, an ester or a salt of the polypeptide; or a polypeptide substantially equivalent thereto; and
b. a half-life extending moiety; and wherein said peptide or polypeptide and half-life extending moiety are covalently linked or fused optionally via a linker.
2 . A bioconjugate or a multimer thereof, according to claim 1 wherein the polypeptide has the following formula (SEQ ID NO: 139):
X1 is absent, pE, R, Q or Isn;
X5 is L or Cha;
X7 is H, Aib, F, K
X8 is K, F or 4-amino-Isn;
X9 is G or Aib;
X11 is Nle or Cha;
X13 is absent or is F, f, K;
X6 and X12 are independently a natural or unnatural amino acid selected from C, c, hc, D-hc, K, D, Orn, Dab or E wherein the side chain of X6 and X12 are linked together via a covalent bond forming either a disulfide or an amide bond; and wherein the N-terminus and the C-terminus optionally form a ring together with 1, 2, 3 or 4 glycine amino acids; or an amide, an ester or a salt of the polypeptide; or a polypeptide substantially equivalent thereto.
3 . The bioconjugate or a multimer thereof, according to claim 1 , wherein:
X6 and X12 are independently selected from K, Orn, Dab, E and D and wherein the side chain of X6 and X12 form together an amide bond.
4 . The bioconjugate or a multimer thereof, according to claim 1 , wherein:
X6 and X12 are independently C, c, D-hC or hC wherein the side chain of X6 and X12 form together a disulfide bond.
5 . The bioconjugate or a multimer thereof, according to claim 1 , wherein the polypeptide has Formula III (SEQ ID NO: 4):
or an amide, an ester or a salt of the polypeptide.
6 . The bioconjugate or a multimer thereof, according to claim 1 , wherein the polypeptide has Formula IV (SEQ ID NO: 5):
or an amide, an ester or a salt of the polypeptide.
7 . The bioconjugate or a multimer thereof, according to claim 1 , wherein the polypeptide has Formula V (SEQ ID NO: 6):
or an amide, an ester or a salt of the polypeptide.
8 - 18 . (canceled)
19 . The bioconjugate or a multimer thereof according to claim 1 wherein the polypeptide is selected from:
(SEQ ID NO: 23)
pE-R-P-R-L-K*-H-F-G-P-Nle-D*-Phenethylamine,
(SEQ ID NO: 24)
pE-R-P-R-L-K*-H-F-G-P-Nle-E*-Phenethylamine,
(SEQ ID NO: 25)
pE-R-P-R-L-Orn*-H-F-G-P-Nle-D*-Phenethylamine,
(SEQ ID NO: 26)
pE-R-P-R-L-Dab*-H-F-G-P-Nle-D*-Phenethylamine,
(SEQ ID NO: 27)
pE-R-P-R-L-K*-F-K-G-P-Nle-F*,
(SEQ ID NO: 28)
pE-R-P-R-L-K*-F-K-G-P-Nle-f*,
(SEQ ID NO: 29)
**Q-R-P-R-L-C*-F-K-G-P-Nle-C*-F-G-G**,
(SEQ ID NO: 30)
pE-R-P-R-L-C*-H-K-G-P-Nle-C*-F-OH,
(SEQ ID NO: 31)
pE-R-P-R-L-C*-Aib-K-G-P-Nle-C*-F-OH,
(SEQ ID NO: 32)
pE-R-P-R-L-C*-Aib-K-G-P-Nle-C*-f-OH,
(SEQ ID NO: 33)
H-Isn-R-P-R-L-C*-Aib-K-G-P-Nle-C*-f-OH,
(SEQ ID NO: 34)
pE-R-P-R-L-C*-H-K-G-P-Nle-C*-Phenethylamine,
(SEQ ID NO: 35)
pE-R-P-R-L-C*-H-K-G-P-Nle-C*-f-OH,
(SEQ ID NO: 36)
pE-R-P-R-Cha-C*-H-K-G-P-Cha-C*-F-OH,
(SEQ ID NO: 37)
pE-R-P-R-L-C*-F-K-G-P-Nle-C*-F-OH,
(SEQ ID NO: 38)
H-R-P-R-L-C*-H-K-G-P-Nle-C*-F-OH,
(SEQ ID NO: 39)
H-R-R-P-R-L-C*-H-K-G-P-Nle-C*-F-OH,
(SEQ ID NO: 40)
H-Isn-R-P-R-L-C*-H-K-G-P-Nle-C*-F-OH,
(SEQ ID NO: 41)
pE-R-P-R-L-C*-H-F-G-P-Nle-C*-Phenethylamine,
(SEQ ID NO: 42)
pE-R-P-R-L-C*-H-K-Aib-P-Nle-C*-F-OH,
(SEQ ID NO: 43)
pE-R-P-R-L-C*-H-(4-NH-Isn)-G-P-Nle-C*-F-OH,
(SEQ ID NO 44)
pE-R-P-C**-L-C*-C**-K-G-P-Nle-C*-F-OH,
(SEQ ID NO: 45)
pE-R-C**-R-L-C*-C**-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 46)
pE-r-P-R-L-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 47)
pE-F-P-R-L-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 48)
pE-E-P-R-L-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 49)
pE-R-p-R-L-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 50)
pE-R-K-R-L-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 51)
pE-R-D-R-L-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 52)
pE-R-P-F-L-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 53)
pE-R-P-R-K-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 54)
pE-R-P-R-L-C*-H-E-G-P-Nle-C*-F-OH;
(SEQ ID NO: 55)
pE-R-P-R-L-C*-H-K-D-P-Nle-C*-F-OH;
(SEQ ID NO: 56)
pE-R-P-E-L-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 57)
pE-R-P-R-(4-PhF)-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 58)
pE-R-P-R-D-C*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 59)
pE-R-P-R-L-C*-E-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 60)
pE-R-P-R-L-C*-H-K-L-P-Nle-C*-F-OH;
(SEQ ID NO: 61)
pE-R-P-R-L-C*-H-K-R-P-Nle-C*-F-OH;
(SEQ ID NO: 62)
pE-R-P-R-L-C*-H-K-G-(Pipecolic acid)-Nle-C*-F-OH;
(SEQ ID NO: 63)
pE-R-P-R-L-C*-H-K-G-P-(3-PyA)-C-F-OH;
(SEQ ID NO: 64)
pE-R-P-R-L-C*-H-K-G-P-Nle-C*-H-OH;
(SEQ ID NO: 65)
pE-R-P-R-L-C*-H-K-G-P-Nle-C*-E-OH;
(SEQ ID NO: 75)
pE-R-P-R-L-C*-H-K-G-P-Nle-C*-NH 2 ;
(SEQ ID NO: 74)
pE-R-P-R-L-C*-H-K-G-P-Nle-C*-F-NH 2 ;
(SEQ ID NO: 66)
pE-R-P-R-L-C*-H-K-G-P-Nle-C*-OH;
(SEQ ID NO: 67)
pE-R-P-R-L-C*-H-K-G-P-Nle-hC*-F-OH;
(SEQ ID NO: 68)
pE-R-P-R-L-hC*-H-K-G-P-Nle-hC*-F-OH;
(SEQ ID NO: 69)
pE-R-P-R-L-c*-H-K-G-P-Nle-C*-F-OH;
(SEQ ID NO: 70)
pE-R-P-R-L-C*-H-K-G-P-Nle-(D-hC)*-F-OH;
(SEQ ID NO: 71)
pE-R-P-R-L-(D-hC)*-H-K-G-P-Nle-(D-hC)*-F-OH;
(SEQ ID NO: 72)
pE-R-P-R-L-C*H-K-G-P-Nle-c*-F-OH;
(SEQ ID NO: 73)
pE-R-P-R-L-c*-H-K-G-P-Nle-c*-F-OH;
(SEQ ID NO: 76)
pE-R-P-R-L-C***-H-K-G-P-Nle-C***-F-OH
(SEQ ID NO: 138)
Q-R-P-R-L-C*-H-K-G-P-Nle-C*-F-OH,
and
(SEQ ID NO: 17)
Q-R-P-R-L-C*H-K-G-P-M-C*-F-OH;
wherein the two amino acids labeled with “*” represent the amino acids forming a disulfide or amide bond via their side chain or terminus, respectively and wherein the two amino acids labeled with “**” represent the amino acids forming a disulfide via their side chain or an amide bond via their termini; and wherein the 2 amino acids labeled with “***” represent the amino acids forming a monosulfide bond via their side chain; or an amide, an ester or a salt of the polypeptide.
20 . A bioconjugate according to claim 19 wherein the polypeptide is selected from:
(SEQ ID NO: 138)
Q-R-P-R-L-C*-H-K-G-P-Nle-C*-F- OH ,
(SEQ ID NO: 17)
Q-R-P-R-L-C*-H-K-G-P-M-C*-F- OH ,
(SEQ ID NO: 33)
H -Isn-R-P-R-L-C*-Aib-K-G-P-Nle-C*-f- OH ,
(SEQ ID NO: 38)
H -R-P-R-L-C*-H-K-G-P-Nle-C*-F- OH ,
(SEQ ID NO: 39)
H -R-R-P-R-L-C*-H-K-G-P-Nle-C*-F- OH ,
(SEQ ID NO: 40)
H -Isn-R-P-R-L-C*-H-K-G-P-Nle-C*-F- OH ;
wherein the side chains of the 2 cysteine amino acids C* form together a disulfide bond; or an amide, an ester or a salt of the polypeptide.
21 - 26 . (canceled)
27 . The bioconjugate or multimer thereof according to claim 1 wherein the half-life extending moiety is Human Serum Albumin.
28 . The bioconjugate according to claim 27 wherein the Human Serum Albumin is chemically linked to the N-terminus of a polypeptide of anyone of Formulae I to VII and IX via a linker of the following Formulae:
Wherein x is 1-20, R is linear or branched alkylene, cycloalkyl, aryl of heteroaryl or combination thereof, R′ is linear or branched alkylene, aryl or cycloalkyl or combination thereof.
29 . The bioconjugate according to claim 27 wherein the Human Serum Albumin is chemically linked to the C-terminus of a polypeptide of anyone of Formulae I to VII via a linker of the following Formulae:
wherein x is 1-20, R is linear or branched alkylene, cycloalkyl, aryl of heteroaryl or combination thereof, R′ is linear or branched alkylene, aryl or cycloalkyl or combination thereof.
30 . The bioconjugate according to claim 1 wherein the half-life extending moiety is a fatty acid.
31 . The bioconjugate according to claim 30 wherein the fatty acid is selected from:
wherein Ak 2 , Ak 3 , Ak 4 , Ak 5 and Ak 6 are independently a (C 8-20 )alkylene, R 6 and R 7 are independently (C 8-20 )alkyl.
32 . The bioconjugate according to claim 1 having the following formula:
wherein peptide is the N-terminus of the peptide, m is 0 or 1, n is 1, 2 or 3, A is alanine, H is histidine, L2 is a linker, Cl is a mono, di or tricyclic carbocyclic or heterocyclic ring system optionally substituted with fluorine and L 1 is a C1-C20 alkylene linker wherein the alkylene chain is optionally substituted with oxo (═O), and wherein one or more carbon is replaced with O or NH.
33 . A method of treating or preventing a disease or disorder responsive to the agonism of the APJ receptor, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polypeptide according to claim 1 or an amide, an ester or a salt thereof.
34 . The method of claim 33 wherein the disease or disorder is selected from acute decompensated heart failure (ADHF), chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia, water retention, diabetes (including gestational diabetes), obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries (including sunburn) and preeclampsia.
35 - 37 . (canceled)
38 . A Combination comprising a therapeutically effective amount of a polypeptide according to claim 1 or an amide, an ester or a salt thereof, and one or more therapeutically active co-agent.
39 . A combination according to claim 38 wherein the co-agent is selected from inotropes, beta adrenergic receptor blockers, HMG-Co-A reductase inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin inhibitors, diuretics, ApoA-I mimics, anti-diabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors (ASI), a CETP inhibitor, anti-coagulants, relaxin, BNP (nesiritide) and/or a NEP inhibitor.
40 . A pharmaceutical composition comprising a therapeutically effective amount of a polypeptide according to claim 1 or an amide, an ester or a salt thereof, and one or more pharmaceutically acceptable carriers.
41 . The bioconjugate according to claim 30 , wherein half-life extending moiety is a fatty acid defined by Formulae A1, A2 and A3:
R 2 is CO 2 H, H;
R 3 , R 4 and R 5 are independently of each other H, OH, CO 2 H, —CH═CH 2 or —C≡CH;
Ak 1 is a branched C 6 -C 30 alkylene;
q, r and p are independently of each other an integer between 6 and 30; or an amide, an ester or a pharmaceutically acceptable salt thereof.
42 . The bioconjugate according to claim 41 wherein the linker include polyethylene glycol of Formula:
wherein the linker has a molecular weight of 100 to 5000 kD, for example, 100 to 500 kD.Join the waitlist — get patent alerts
Track US2016166634A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.