LONG LASTING GLUCAGON-LIKE PEPTIDE 2 (GLP-2) FOR THE TREATMENT OF GASTROINTESTINAL DISEASES AND DISORDERS

1 . An gastrointestinal tissue growth promoter derivative comprising

a GLP-2 peptide or an analog or fragment thereof having gastrointestinal tissue growth promoting activity, and

a reactive entity coupled to the peptide,

the derivative being capable of covalently bonding in vivo with a functionality on a blood component.

2 . A derivative as claimed in claim 1 wherein the GLP-2 is of the sequence

R 1 -(Y 1 ) m -X 1 -X 2 -X 3 -X 4 -X 5 -Phe 6 -Ser 7 -Asp 8 -(P 1 )-X 14 -

Asp 15 -X 16 -X 17 -Ala 18 -X 19 -X 20 -X 21 -Phe 22 -(P 2 )-Trp 25 -

Leu 26 -X 27 -X 28 -Thr 29 -Lys 30 -P 3 -(Y 2 ) n -R 2

wherein

X 1 is His or Tyr;

X 2 is Ala, Gly, D-Ala, Pro, Ile, Nor-Val, α-aminobutyric acid, or an Ala-replacement amino acid conferring on said analog resistance to DPP-IV enzyme;

X 3 is Asp, Glu, Pro HPro; or X 2 -X 3 are X 2 ψ(CH(OH)CH 2 )X 3 ; X 2 ψ(CH 2 NH 2 )X 3 or X 2 ψ(CHCH)X 3 wherein X 2 and X 3 are as defined above;

X 4 is Gly or Ala;

X 5 is Ser or Ala;

P 1 is Glu-X 10 -Asn-Thr-Ile, Gly-X 10 -Asn-Thr-Val or Tyr-Ser-Lys-Tyr;

X 10 is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

X 14 is Leu or Lys;

X 16 is Asn, Lys or Ala;

X 17 is Leu or Lys;

X 19 is Ala or Thr,

X 20 is Arg, Lys, His or Ala;

X 21 is Asp or Lys;

X 27 is Ile or Leu;

X 28 is Gln or His;

P 2 is Ile-Asn, Ile-Ala or Val-Gln;

P 3 is a covalent bond, or is Ile, Ile-Thr, Ile-Thr-Asp or Ile-Thr-Asn;

R 1 is NH 2 or a N-terminal blocking group;

R 2 is COOH, CONH 2 or a C-terminal blocking group;

Y 1 is one or two of Arg, Lys, and His;

Y 2 is one or two of Arg, Lys, and His; and

m and n are independently 0 or 1.

3 . A derivative as claimed in claim 2 wherein X 1 is His; X 2 is Ala or Gly, X 3 is Asp; X 4 is Gly; X 5 is Ser; P 1 is Glu-X 10 -Asn-Thr-Ile; X 10 is Met; X 16 is Asn or Lys; X 19 is Ala; X 20 is Arg; X 27 is Ile; X 28 is Gln; P 2 is Ile-Asn; P 3 is Ile-Thr-Asp and R 2 is CONH 2 .

4 . A derivative as claimed in claim 1 wherein the reactive entity is a maleimide or a maleimido-containing group.

5 . A derivative as claimed in claim 3 wherein the GLP-2 is selected from the group consisting of:

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Lys-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys-CONH 2 ;

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Lys-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Lys-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

and

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Lys-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 .

6 . A derivative as claimed in claim 1 selected from the group consisting of:

MPA-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-

Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-

Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys-MPA-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Lys(MPA)-Leu-Ala-Ala-Arg-Asp-Phe-Ile-

Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

MPA-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-

Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-

Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Lys(MPA)-Leu-Ala-Ala-Arg-Asp-Phe-Ile-

Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(MPA)-

CONH 2 ;

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Lys(AEEA-MPA)-Leu-Ala-Ala-Arg-Asp-Phe-

Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(AEEA-MPA)-

CONH 2 ;

MPA-AEEA-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-

Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-

Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

MPA-AEEA-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-

Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-

Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-

Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(AEEA-MPA)-

CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Lys(AEEA-MPA)-Leu-Ala-Ala-Arg-Asp-Phe-

Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Lys(MPA)-Ala-Ala-Arg-Asp-Phe-Ile-

Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Lys(MPA)-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-

Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Lys(MPA)-Phe-Ile-

Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Lys(AEEA-MPA)-Ala-Ala-Arg-Asp-Phe-

Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Lys(AEEA-MPA)-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-

Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;

and

His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-

Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Lys(AEEA-MPA)-Phe-

Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 .

7 . A derivative as claimed in claim 1 wherein the blood component comprises blood proteins.

8 . A pharmaceutical composition comprising a derivative as claimed in claim 1 in combination with a pharmaceutically acceptable carrier.

9 . A composition as claimed in claim 8 for the treatment of prevention of gastrointestinal disorders or diseases.

10 . A method for the treatment of prevention of gastrointestinal disorders or diseases in a subject comprising administering to a subject an effective amount of a derivative as claimed in claim 1 , alone or in combination with a pharmaceutically acceptable carrier.

11 . A method for the promotion of gastrointestinal tissue growth in a subject comprising administering to a subject an effective amount of a derivative as claimed in claim 1 , alone or in combination with a pharmaceutical carrier.

12 . A conjugate comprising a derivative as claimed in claim 1 covalently bonded to a blood component.

13 . A conjugate as claimed in claim 12 wherein the reactive entity is a maleimide or a maleimido-containing group and the blood component is a blood protein.

14 . A conjugate as claimed in claim 13 wherein the blood protein is serum albumin.

15 . A conjugate as claimed in claim 12 wherein the derivative is as defined in claim 6 .

16 . A method for extending the in vivo half-life of a GLP-2 peptide having gastrointestinal tissue growth promoting activity, the method comprising covalently bonding the peptide to a blood component.

17 . A method as claimed in claim 16 wherein the peptide comprises GLP-2 or an analog or fragment thereof having gastrointestinal tissue growth promoting activity.

18 . A method as claimed in claim 16 wherein the GLP-2 peptide is as defined in claim 5 .

19 . A method for the treatment of prevention of gastrointestinal disorders or diseases in a subject comprising administering to a subject an effective amount of a conjugate as claimed in claim 12 , alone or in combination with a pharmaceutical carrier.