Transporters comprising spaced arginine moieties

• US 7,585,834 B2
• Filed: 02/14/2002
• Issued: 09/08/2009
• Est. Priority Date: 02/16/2001
• Status: Expired due to Fees

• Current Assignee: Kai Pharmaceuticals, Inc. (Amgen Inc.), Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.), Cellgate, Inc. (Tbg Diagnostics Limited)
• Inventors: VanDeusen, Christopher L., Wender, Paul A., Rothbard, Jonathan B., Kreider, Erik L., Wright, Lee
• Primary Examiner(s): Kosar; Andrew D
• Assistant Examiner(s): GUDIBANDE, SATYANARAYAN R
• Application Number:
  US10/078,247
• Publication Number:
  US 20030032593A1
• Time in Patent Office: 2,763 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A61K 47/64 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 Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides compositions and methods for enhancing transport of biologically active compounds across biological membranes and across and into animal epithelial or endothelial tissues. The composition includes a biologically active agent and a transport moiety. The transport moiety includes a structure selected from the group consisting of (ZYZ)_nZ, (ZY)_nZ, (ZYY)_nZ and (ZYYY)_nZ. Subunit “Z” is L-arginine or D-arginine, and subunit “Y” is an amino acid that does not comprise an amidino or guanidino moiety. Subscript “n” is an integer ranging from 2 to 10. The method for enhancing transport involves the administration of the aforementioned composition.

Claims

1. A composition comprising a conjugate of a biologically active compound, a transport moiety and a self-immolating linker moiety linking the biologically active compound and the transport moiety, wherein the transport moiety comprises a structure selected from the group consisting of (ZY)_nZ, (ZYZ)_nZ, (ZYY)_nZ, and (ZYYY)_nZ, wherein each Z is L-arginine or D-arginine, and each Y is independently an amino acid that does not comprise an amidino or guanidino moiety, and wherein n is an integer of from 2 to 10, wherein the conjugate has a structure selected from

2. The composition according to claim 1, wherein each Y is independently selected from the group consisting of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, hydroxyproline, tyrosine, γ

-amino butyric acid, β

-alanine, sarcosine and ε

-amino caproic acid.

3. The composition according to claim 1, wherein the transport moiety comprises the structure (ZYZ)_nZ, and wherein n is an integer ranging from 2 to 5.

4. The composition according to claim 1, wherein the transport moiety comprises the structure (ZY)_nZ and wherein n is an integer ranging from 4 to 10.

5. The composition according to claim 1, wherein the transport moiety comprises the structure (ZYY)_nZ, and wherein n is an integer ranging from 4 to 10.

6. The composition according to claim 1, wherein the transport moiety comprises the structure (ZYYY)_nZ, and wherein n is an integer ranging from 4 to 10.

7. The composition according to claim 1, wherein Y is a gene-encoded amino acid.

8. The composition according to claim 1, wherein Y is an amino acid other than a gene-encoded amino acid.

9. The composition according to claim 3, wherein each Y is independently selected from the group consisting of glycine, γ

-amino butyric acid, β

-alanine and ε

-amino caproic acid, and n is 3 or 4.

11. The composition according to claim 5, wherein each Y is independently selected from the group consisting of glycine, γ

-amino butyric acid, β

-alanine and ε

-amino caproic acid, and n is 6, 7 or 8.

12. The composition according to claim 6, wherein each Y is independently selected from the group consisting of glycine, γ

-amino butyric acid, β

-alanine and ε

-amino caproic acid, and n is 6, 7 or 8.

13. The composition according to claim 1, wherein the conjugate has the following structure:

14. The composition according to claim 13, wherein each of X and Q is independently selected from the group consisting of —

C(O)O—

, —

O—

C(O)—

, —

C(O)NH—

, —

NH—

C(O)—

, —

OC(O)NH—

, —

S—

S—

, —

C(S)O—

, —

C(S)NH—

, —

NHC(O)NH—

, —

SO₂NH—

, —

SONH—

, phosphate, phosphonate and phosphinate.

15. The composition according to claim 13, wherein each of X and Q is independently selected from the group consisting of —

C(O)O—

, —

O—

C(O)—

, —

C(O)NH—

, —

NH—

C(O)—

, —

OC(O)NH— and

—

NHC(O)NH—

.

16. The composition according to claim 1, wherein the conjugate has the following structure:

17. The composition according to claim 16 wherein each of X and Q is independently selected from the group consisting of —

C(O)O—

, —

O—

C(O)—

, —

C(O)NH—

, —

NH—

C(O)—

, —

OC(O)NH—

, —

S—

S—

, —

C(S)O—

, —

C(S)NH—

, —

NHC(O)NH—

, —

SO₂NH—

, —

SONH—

, phosphate, phosphonate and phosphinate.

18. The composition according to claim 16, wherein each of X and Q is independently selected from the group consisting of —

C(O)O—

, —

O—

C(O)—

, —

C(O)NH—

, —

NH—

C(O)—

, —

OC(O)NH— and

—

NHC(O)NH—

.

19. The composition according to claim 1, wherein the conjugate has the following structure:

20. The composition according to claim 19, wherein each of X and Q is independently selected from the group consisting of —

C(O)O—

, —

O—

C(O)—

, —

C(O)NH—

, —

NH—

C(O)—

, —

OC(O)NH—

, —

S—

S—

, —

C(S)O—

, —

C(S)NH—

, —

NHC(O)NH—

, —

SO₂NH—

, —

SONH—

, phosphate, phosphonate and phosphinate.

21. The composition according to claim 19, wherein each of X and Q is independently selected from the group consisting of —

C(O)O—

, —

O—

C(O)—

, —

C(O)NH—

, —

NH—

C(O)—

, —

OC(O)NH— and

—

NHC(O)NH—

.

22. The composition according to claim 1, wherein the conjugate has the following structure:

23. The composition according to claim 22, wherein each of X and Q is independently selected from the group consisting of —

C(O)O—

, —

O—

C(O)—

, —

C(O)NH—

, —

NH—

C(O)—

, —

OC(O)NH—

, —

S—

S—

, —

C(S)O—

, —

C(S)NH—

, —

NHC(O)NH—

, —

SO₂NH—

, —

SONH—

, phosphate, phosphonate and phosphinate.

24. The composition according to claim 22, wherein each of X and Q is independently selected from the group consisting of —

C(O)O—

, —

O—

C(O)—

, —

C(O)NH—

, —

NH—

C(O)—

, —

OC(O)NH— and

—

NHC(O)NH—

.

25. The composition according to claim 15, wherein A is N, R² is benzyl, k, m and n1 are 1, and X is —

OC(O)—

.

26. A method for increasing the transport of a biologically active compound across a biological membrane comprising:

administering a composition comprising a conjugate of according to claim 1.

27. The method of claim 26, wherein the conjugate has the following structure:

28. The method of claim 26, wherein the conjugate has the following structure:

29. The method of claim 26, wherein the conjugate has the following structure:

30. The method of claim 26, wherein the conjugate is of the following structure:

31. The composition of claim 1, wherein said linker moiety covalently links the biologically active compound and the transport moiety.

32. The composition of claim 1, wherein said linker moiety capable of self-immolation is configured so as to undergo intramolecular cleavage.

33. The composition of claim 1, wherein said linker moiety comprises a half-life in the range of between about 10 minutes and about 24 hours in water at 37°

C. and at a pH of approximately 7.4.

10. A composition, comprising a conjugate of:

a biologically active compound, a transport moiety and a self-immolating linker moiety linking the biologically active compound and the transport moiety,

wherein the transport moiety comprises a structure selected from the group consisting of (ZY)_nZ, (ZYZ)_nZ, (ZYY)_nZ, and (ZYYY)_nZ,

each Z is L-arginine or D-arginine, each Y is independently glycine, γ

-amino butyric acid, β

-alanine or ε

-amino caproic acid, and n is 6, 7 or 8, wherein the conjugate has a structure selected from