Glucagon like peptide 1 (GLP-1) fusion peptide coupled cyclic peptide tyrosine tyrosine conjugates and uses thereof

Patent metadata

Field	Value
Publication number	US-11780900-B2
Application number	US-201915733776-A
Country	US
Kind code	B2
Filing date	Apr 24, 2019
Priority date	Apr 25, 2018
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

Abstract

The present invention comprises conjugates comprising a glucagon-like peptide 1 (GLP-1) fusion peptide coupled to a cyclic PYY peptide. The invention also relates to pharmaceutical compositions and methods for use thereof. The novel conjugates are useful for preventing, treating or ameliorating diseases and disorders disclosed herein.

First claim

It is claimed:

1. A conjugate comprising a glucagon-like peptide-1 (GLP-1) fusion peptide coupled to a cyclic PYY peptide, wherein the GLP-1 fusion peptide comprises a GLP-1 peptide, an optional first linker peptide, a hinge-Fc region peptide, and a second linker peptide comprising a cysteine residue, wherein the cyclic PYY peptide is represented by Formula I:

wherein
p is 0 or 1;
m is 0, 1, 2, 3, 4, or 5;
n is 1, 2, 3, or 4;
q is 0 or 1; provided that q is 1 only when Z 30 is absent;
BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —SCH 2 C(O)NH—, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—;
Z 4 is K, A, E, S, or R;
Z 7 is A or K;
Z 9 is G or K;
Z 11 is D or K;
Z 22 is A or K;
Z 23 is S or K;
Z 26 is A or H;
Z 30 is L, W, or absent,
provided that Z 30 is absent only when q is 1;
Z 34 is

Z 35 is

wherein the cyclic PYY peptide is optionally modified by one or more processes selected from the group consisting of amidation, acylation, and pegylation.

2. The conjugate of claim 1 , wherein the cyclic PYY peptide of Formula (I) comprises an acylated K residue in at least one of Z 7 , Z 9 , Z 11 , Z 22 or Z 23 , wherein:
Z 7 is A or K, wherein the amino side chain of said K is optionally acylated substituted with:

 to provide the acylated K residue, wherein i is an integer of 0 to 24, and X=Br, I, Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 9 is G or K, wherein the amino side chain of said K is optionally acylated with:

 to provide the acylated K residue, wherein i is an integer of 0 to 24, and X=Br, I Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 11 is D or K, wherein the amino side chain of said K is optionally acylated with:

 to provide the acylated K residue, wherein i is an integer of 0 to 24, and X=Br, I Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 22 is A or K, wherein the amino side chain of said K is optionally acylated with the acylated K residue:

 wherein i is an integer of 0 to 24, and X=Br, I, Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 23 is S or K, wherein the amino side chain of said K is optionally acylated with:

 to provide the acylated K residue, wherein i is an integer of 0 to 24, and X=Br, I, Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 30 is L;
wherein the cysteine residue of the second linker peptide is reactively coupled to the K residue of the at least one of Z 7 , Z 9 , Z 11 , Z 22 or Z 23 .

3. The conjugate of claim 1 , wherein the cyclic PYY peptide of Formula (I) comprises an acylated K residue in at least one of Z 7 , Z 9 , Z 11 , Z 22 or Z 23 , wherein:
Z 7 is A or K, wherein the amino side chain of said K is optionally acylated with —C(O)CH 2 Br to provide the acylated K residue,
Z 9 is G or K, wherein the amino side chain of said K is optionally acylated with —C(O)CH 2 Br to provide the acylated K residue,
Z 11 is D or K, wherein the amino side chain of said K is optionally acylated with —C(O)CH 2 Br to provide the acylated K residue,
Z 22 is A or K, wherein the amino side chain of said K is optionally acylated with —C(O)CH 2 Br to provide the acylated K residue,
Z 23 is S or K, wherein the amino side chain of said K is optionally acylated with —C(O)CH 2 Br to provide the acylated K residue,
Z 30 is L;
wherein the cysteine residue of the second linker peptide is reactively coupled to the K residue of the at least one of Z 7 , Z 9 , Z 11 , Z 22 or Z 23 .

4. The conjugate of claim 1 , wherein the cyclic PYY peptide is selected from the group consisting of SEQ ID NOs:1-54, or a pharmaceutically acceptable salt thereof.

5. The conjugate of claim 4 , wherein the cyclic PYY peptide is selected from SEQ ID NO:24, 25, 27, 28, 29, 30, 33, or 34, or a pharmaceutically acceptable salt thereof.

6. The conjugate of claim 1 , wherein the GLP-1 fusion peptide is covalently linked to the cyclic PYY peptide at a K residue of the cyclic PYY peptide.

7. The conjugate of claim 6 , wherein only one of Z 7 , Z 9 , Z 11 , Z 22 and Z 23 in Formula I is K, and the K is covalently linked to a cysteine residue in the second linker peptide of the GLP-1 fusion peptide.

8. The conjugate of claim 7 , wherein Z 11 in Formula I is K.

9. The conjugate of claim 1 , wherein the GLP-1 peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:56-59.

10. The conjugate of claim 1 , wherein the first linker peptide is present and comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:60-83.

11. The conjugate of claim 1 , wherein the hinge-Fc region peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:84-90.

12. The conjugate of claim 1 , wherein the second linker peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:93-112.

13. The conjugate of claim 1 , wherein the second linker peptide comprises the amino acid sequence of SEQ ID NO:93, 94, 95, 106, or 111.

14. A method of producing the conjugate of claim 1 , comprising reacting an electrophile introduced onto a sidechain of the cyclic PYY peptide with the sulfhydryl group of a cysteine residue of the second linker peptide of the GLP-1 fusion peptide, thereby creating a covalent linkage between the cyclic PYY peptide and the GLP-1 fusion peptide.

15. The method of claim 14 , wherein the cysteine residue of the second linker peptide of the GLP-1 fusion peptide is reduced by contacting the GLP-1 fusion peptide with an excess of an azaphosphine reducing agent, and the reduced cysteine residue is reacted with the electrophile.

16. The method of claim 15 , wherein the azaphosphine reducing agent is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1] decane (PTA) or a derivative thereof.

17. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.

18. A method for treating a disease or disorder in a subject in need thereof, wherein said disease or disorder is obesity, type I or type II diabetes, metabolic syndrome, insulin resistance, impaired glucose tolerance, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypoglycemia due to congenital hyperinsulinism (CHI), dyslipidemia, atherosclerosis, diabetic nephropathy, and other cardiovascular risk factors such as hypertension and cardiovascular risk factors related to unmanaged cholesterol and/or lipid levels, osteoporosis, inflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal disease, and/or eczema, the method comprising administering to the subject in need thereof an effective amount of the pha

Assignees

• Janssen Sciences Ireland Unlimited Co

Inventors

• Zhang Yue-Mei
• Camacho Raul
• Case Martin A
• Chi Ellen
• Edavettal Suzanne
• Edwards Wilson
• Norquay Lisa
• Wall Mark J
• Zhang Rui
• Zheng Songmao

Classifications

• C07K14/605 Primary

  Glucagons · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K47/66

  the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title