Granted Patent B2

US 12,540,168 · App. 18/661,201 · Granted Feb 3, 2026

Inventors: William Blackwell (Cambridge, MA); Ved P. Srivastava (Cambridge, MA); James M. Way (Cambridge, MA)

Assignee: I2O Therapeutics, Inc.

C07K14/575A61K9/0004A61K9/0019A61P3/04A61P3/10A61K38/00

Abstract

Claims (119)

1 . A method of treating obesity in a human subject, providing weight loss to the human subject, or suppressing appetite in the human subject, comprising administering to the subject a pharmaceutical composition comprising an isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 203:

(SEQ ID NO: 203)

X 1 CNTX 5 TCATX 10 RLANX 15 X 16 X 17 X 18 SSNNFGPILPPTKVGSETY-

(OH/NH 2 ),

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is S, 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;

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 CNTX 5 TC (SEQ ID NO: 308) are optionally further bound by a disulfide bridge.

2 . The method of claim 1 , wherein the isolated polypeptide comprises 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 Kor k;

X 10 is Q or S;

X 15 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 method of claim 1 , wherein the isolated polypeptide comprises 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 method of claim 1 , wherein the isolated polypeptide comprises the amino acid sequence of:

(SEQ ID NO: 64)

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

FGPILPPTKVGSETY-(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 method of claim 1 , wherein the isolated polypeptide comprises a lipophilic substituent.

6 . The method of claim 1 , wherein the isolated polypeptide comprises the amino acid sequence of:

(SEQ ID NO: 65)

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

FGPILPPTKVGSETY-(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.

7 . The method of claim 1 , wherein the isolated polypeptide comprises the amino acid sequence 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.

8 . The method of claim 1 , wherein the isolated polypeptide comprises the amino acid sequence of:

(SEQ ID NO: 109)

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

GPILPPTKVGSETY-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.

9 . The method of claim 1 , wherein the isolated polypeptide consists of 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.

10 . The method of claim 1 , wherein the isolated polypeptide consists of the amino acid sequence of:

(SEQ ID NO: 64)

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

FGPILPPTKVGSETY-(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.

11 . The method of claim 1 , wherein the isolated polypeptide consists of the amino acid sequence of:

(SEQ ID NO: 65)

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

FGPILPPTKVGSETY-(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.

12 . The method of claim 1 , wherein the isolated polypeptide consists of the amino acid sequence 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.

13 . The method of claim 1 , wherein the isolated polypeptide consists of the amino acid sequence of:

(SEQ ID NO: 109)

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

GPILPPTKVGSETY-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.

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

15 . The method of claim 1 , wherein the isolated polypeptide comprises a lipophilic substituent and a spacer of Formula VI:

Formula VI

—(Y1) n1 —(V) r —(Y2) n2 —CO—(CH 2 ) m —Z

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.

16 . The method of claim 1 , wherein the isolated polypeptide comprises a lipophilic substituent and a spacer of Formula III:

Formula III

—(γGlu) n —CO—(CH 2 ) m —Z(″(γGlu)n″ disclosed as 

SEQ ID NO: 311)

wherein

Z is —CH 3 or —CO 2 H;

m is from 4 to 24; and

n is from 1 to 10.

17 . The method of claim 15 , wherein the lipophilic substituent, —CO—(CH 2 ) m —Z, is linked to the s-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.

18 . The method of claim 16 , 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.

19 . The method of claim 5 , 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.

Assignments (3)

Continuity (3)

References Cited (295)