Human amylin analog polypeptides and methods of use

Patent metadata

Field	Value
Publication number	US-12018059-B2
Application number	US-201916598915-A
Country	US
Kind code	B2
Filing date	Oct 10, 2019
Priority date	Oct 11, 2018
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

This invention relates to isolated polypeptides that are analogs of human amylin. The disclosed amylin analog polypeptides have beneficial physicochemical properties relative to endogenous amylin, such as longer elimination half-lives (t 1/2 ) and improved solubility and thermal stability. This invention also relates to methods of using presently disclosed amylin analog polypeptides in a variety of therapeutic indications, as well as methods of producing the same. The disclosed amylin analog polypeptides are particularly useful in methods of treating metabolic diseases or disorders, such as types 1 and 2 diabetes, and providing weight loss.

First claim

What is claimed is:

1. An isolated polypeptide, comprising the amino acid sequence of SEQ ID NO: 203:
X 1 CNTX 5 TCATX 10 RLANX 15 X 16 X 17 X 18 SSNNFGPILPPTKVGSETY-(OH/NH 2 ) (SEQ ID NO: 203), wherein:
X 1 is k or K;
X 5 is S;
X 10 is Q or S;
X 15 is E or F;
X 16 is L;
X 17 is H, V, and Q; and
X 18 is K, H, or R;
wherein:
each K independently represents an L-lysine optionally covalently bound to a lipophilic substituent, optionally via a spacer;
each k independently represents a D-lysine optionally covalently bound to a lipophilic substituent, optionally via a spacer; and
the two cysteine residues of X 1 CNTX 5 TC (SEQ ID NO: 308) are optionally further bound by a disulfide bridge.

2. The isolated polypeptide of claim 1 , comprising the amino acid sequence of SEQ ID NO:209:
X 1 CNTSTCATX 10 RLANX 15 X 16 X 17 KSSNNFGPILPPTKVGSETY-(OH/NH 2 ) (SEQ ID NO:209), or a pharmaceutically acceptable salt thereof, wherein:
X 1 is K or k;
X 10 is Q or S;
X 16 is E or F;
X 16 is L; and
X 17 is H, V or Q;
each K independently represents an L-lysine optionally covalently bound to a lipophilic substituent, optionally via a spacer;
each k independently represents a D-lysine optionally covalently bound to a lipophilic substituent, optionally via a spacer; and
wherein the two cysteine residues of X 1 CNTSTC (SEQ ID NO: 318) are optionally further bound by a disulfide bridge.

3. The isolated polypeptide of claim 1 , comprising the amino acid sequence of:

(SEQ ID NO: 130)

KC*NTSTC*ATQRLANELHKSSNNFGPILPPTKVGSETY-(NH 2 ),

or a pharmaceutically acceptable salt thereof,
wherein the two cysteine residues denoted C* at positions 2 and 7 are further bound by a disulfide bridge.

4. The isolated polypeptide of claim 1 , comprising the amino acid sequence of:

(SEQ ID NO: 64)

K*((γGlu) 2 (CO(CH 2 ) 18 CO 2 H))C*NTSTC*ATQRLANELHKSSNNF

GPILPPTKVGSETY-(NH 2 ),

or a pharmaceutically acceptable salt thereof,
wherein:
K* represents an L-lysine covalently bound to (γGlu) 2 (CO(CH 2 ) 18 CO 2 H); and
the two cysteine residues denoted C* at positions 2 and 7 are further bound by a disulfide bridge.

5. The isolated polypeptide of claim 1 , comprising the amino acid sequence of:

(SEQ ID NO: 65)

K*((γGlu) 2 (CO(CH 2 ) 16 CO 2 H))C*NTSTC*ATQRLANELHKSSN

NFGPILPPTKVGSETY-(NH 2 ),

or a pharmaceutically acceptable salt thereof,
wherein:
K* represents an L-lysine covalently bound to (γGlu) 2 (CO(CH 2 ) 16 CO 2 H); and
the two cysteine residues denoted C* at positions 2 and 7 are further bound by a disulfide bridge.

6. The isolated polypeptide of claim 1 , selected from the group consisting of:

(SEQ ID NO: 131)

KC*NTSTC*ATQRLANFLQKSSNNFGPILPPTKVGSETY-(NH 2 ),

or a pharmaceutically acceptable salt thereof,
wherein the two cysteine residues denoted C* at positions 2 and 7 are further bound by a disulfide bridge.

7. The isolated polypeptide of claim 1 , selected from the group consisting of:

(SEQ ID NO: 109)

K*(γGlu-CO(CH 2 ) 16 CO 2 H)C*NTSTC*ATSRLANFLQKSSNNF G

PILPPTKVGSETY-NH 2 ,

or a pharmaceutically acceptable salt thereof,
wherein:
K* represents an L-lysine covalently bound to γGlu-CO(CH 2 ) 16 CO 2 H; and
the two cysteine residues denoted C* at positions 2 and 7 are further bound by a disulfide bridge.

8. The isolated polypeptide of claim 1 , comprising an amino acid sequence selected from the group consisting of any of SEQ ID NOS: 55, 64, 65, 109, 112-120, 126, 130, 131, and 143, or a pharmaceutically acceptable salt thereof.

9. The isolated polypeptide of claim 1 , or a pharmaceutically acceptable salt thereof, further comprising a lipophilic substituent, and optionally comprising a spacer.

10. The isolated polypeptide of claim 9 , or a pharmaceutically acceptable salt thereof, further comprising a lipophilic substituent and a spacer of Formula VI:
—(Y1) n1 —(V) r —(Y2) n2 —CO—(CH 2 ) m —Z  Formula VI

wherein
Z is —CH 3 or —CO 2 H;
m is from 4 to 24;
Y1 is selected from the group consisting of γGlu, Asp, and Gly;
Y2 is selected from the group consisting of γGlu, Asp, and Gly;
V is —[COCH 2 (O(CH 2 ) 2 ) t OCH 2 NH]—, and t is from 1 to 8;
r is from 1 to 8;
n1 is from 0 to 10; and
n2 is from 0 to 10.

11. The isolated polypeptide of claim 9 , or a pharmaceutically acceptable salt thereof, further comprising a lipophilic substituent and a spacer of Formula III:
-(γGlu) n -CO—(CH 2 ) m —Z (“(γGlu) n ” disclosed as SEQ ID NO: 311)  Formula III

wherein
Z is —CH 3 or —CO 2 H;
m is from 4 to 24; and
n is from 1 to 10.

12. The isolated polypeptide of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the lipophilic substituent, —CO—(CH 2 ) m —Z, is linked to the ε-amino group of a lysine of the isolated polypeptide via the spacer, —(Y1) n1 —(V) r —(Y2) n2 —, which spacer forms a bridge between the amino group of the disclosed polypeptide and the CO— group of the lipophilic substituent.

13. The isolated polypeptide of claim 11 , or a pharmaceutically acceptable salt thereof, wherein the lipophilic substituent, —CO—(CH 2 ) m —Z, is linked to the ε-amino group of a lysine of the isolated polypeptide via the spacer, -(γGlu) n - (“(γGlu) n ” disclosed as SEQ ID NO: 311), which spacer forms a bridge between the amino group of the disclosed polypeptide and the CO— group of the lipophilic substituent.

14. The isolated polypeptide of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
the lipophilic substituent is —CO—(CH 2 ) m —CO 2 H; and
m is from 14 to 20.

15. The isolated polypeptide of claim 14 , or a pharmaceutically acceptable salt thereof, wherein the spacer is γGlu or 2(γGlu).

16. A pharmaceutical composition comprising the isolated polypeptide of claim 1 or a pharmaceutically acceptable salt

Assignees

• Intarcia Therapeutics Inc
• I2O Therapeutics Inc

Inventors

• Blackwell William
• Srivastava Ved P
• Way James M

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · 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

• A61K9/0004

  Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas · CPC title