Peptides and compounds that bind to the IL-5 receptor

• US 7,109,299 B1
• Filed: 12/16/1999
• Issued: 09/19/2006
• Est. Priority Date: 12/16/1999
• Status: Expired due to Fees

• Current Assignee: Affymax Incorporated
• Original Assignee: Affymax Incorporated
• Inventors: Balu, Palani, Yin, Qun, England, Bruce
• Primary Examiner(s): Weber, Jon
• Assistant Examiner(s): Mohamed, Abdel A.
• Application Number:
  US10/168,372
• Time in Patent Office: 2,469 Days
• Field of Search: 530/351, 530/326, 530/327, 530/324, 530/388.22, 530/402, 424/85.2, 514/13, 514/12, 514/14
• US Class Current: 530/351
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: C07K 14/5409 IL-5
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

Interleukin-5 receptor (IL-5R) ligands comprising amino sequences of formula TGGGDGYVX₃VE X₄ ARCPTCK, EGYVX₃VE X₄ ARCPTCK, EGYVX₃VE X₄ ARCPTCR, GYVX₃VE X₄ ARCPTCG, EGYVX₃VE X₄ ARCPTCG, GYVX₃VE X₄ ARCPTCR, and EGYVX₃VE X₄ AACPTCR, and methods of using the same, are described and claimed.

Claims

1. A compound comprising a sequence of amino acids selected from the groups consisting of

TGGGDGYVX₃VE X₄ ARCPTCK (residues 32–

50 of SEQ ID NO;

     1);

EGYVX₃VE X₄ ARCPTCK (residues 36–

50 of SEQ ID NO;

     2);

EGYVX₃VE X₄ ARCPTCR (residues 36–

50 of SEQ ID NO;

     3);

GYVX₃VE X₄ ARCPTCG (residues 36–

50 of SEQ ID NO;

     4);

EGYVX₃VE X₄ ARCPTCG (residues 36–

50 of SEQ ID NO;

     5);

GYVX₃VE X₄ ARCPTCR (residues 37–

50 of SEQ ID NO;

     6); and

EGYVX₃VE X₄ AACPTCR (residues 36–

50 of SEQ ID NO;

     7)

wherein X₃ is Cys, Lys, or Dpr, and X₄ is Nal, Trp, or Phe.

2. The compound of claim 1, wherein the sequence is fourteen to fifty amino acid residues in length.

3. The compound of claim 2, wherein the sequence is fourteen to twenty amino acid residues in length.

4. A compound of claim 2 or claim 3, wherein the N-terminus of said sequence is selected from the group consisting of —

NRR, —

NRC(O)R, —

NRC(O)OR, NRS (O)₂R, —

NHC(O)NHR, succinimide, benzyloxycarbonyl-NH—

, and benzyloxycarbonyl-NH—

having from 1 to 3 substituents on the phenyl ring of said benzyloxycarbonyl-NH—

, said benzyloxycarbonyl-NH—

substituents selected from the group consisting of lower alkyl, lower alkoxy, chloro, and bromo, where R and R, are independently selected from the group consisting of hydrogen and lower alkyl,

wherein the C-terminus of said sequence has the formula —

C(O)R₂ where R₂ is selected from the group consisting of hydroxy, lower alkoxy, and —

NR₃R₄ wherein R₃ and R₄ are independently selected from the group consisting of hydrogen and lower alkyl and wherein the nitrogen atom of the —

NR₃R₄ group can optionally be the amine group of the N-terminus of the peptide so as to form a cyclic peptide,

and physiologically acceptable salts thereof.

5. The compound of claim 1, wherein the compound binds to the interleukin 5 receptor (IL-5R) with an IC₅₀ of no more than about 2 mM as determined by a binding affinity assay.

6. The compound of claim 1, wherein the compound binds to the IL-5R with an IC₅₀ of no more than about 100 uM as determined by a binding affinity assay.

13. The compound of claim 1, wherein the compound further comprises an intramolecular disulfide linkage between two Cys residues.

14. The compound of claim 1, wherein the compound further comprises a dimer with intermolecular disulfide, amide, carbamate, or urea linkages.

15. The compound of claim 1, wherein the compound is coupled to a polyethylene glycol molecule.

16. The compound of claim 15, wherein the polyethylene glycol has an average molecular weight of between about 500 to about 100,000 daltons.

17. The compound of claim 15, wherein the polyethylene glycol has an average molecular weight of between about 2,000 to about 40,000 daltons.

18. A compound of claim 15, wherein the polyethylene glycol has an average molecular weight of between about 5,000 to about 20,000 daltons.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

22. A method for treating a patient having a disorder that is susceptible to treatment with an IL-5 inhibitor, comprising the steps of providing a therapeutically effective amount of a compound of claim 1, and administering said therapeutically effective amount of compound to the patient.

7. A compound comprising a sequence of amino acids selected from the groups consisting of

X₁-TGGGDGYVX₃VEX₄ARCPTCK-X₂ (residues 32–

50 of SEQ ID NO;

     1);

X₁-EGYVX₃VEX₄ARCPTCK-X₂ (residues 36–

50 of SEQ ID NO;

     2);

X₁-EGYVX₃VEX₄ARCPTCR-X₂ (residues 36–

50 of SEQ ID NO;

     3);

X₁-GYVX₃VEX₄ARCPTCG-X₂ (residues 36–

50 of SEQ ID NO;

     4);

X₁-EGYVX₃VEX₄ARCPTCG-X₂ (residues 36–

50 of SEQ ID NO;

     5);

X₁-GYVX₃VEX₄ARCPTCR-X₂ (residues 37–

50 of SEQ ID NO;

     6); and

X₁-EGYVX₃VEX₄AACPTCR-X₂ (residues 36–

50 of SEQ ID NO;

     7)

wherein X₁ is hydrogen or acyl;

X₂ is —

NH₂ or —

OH wherein —

NH₂ indicates that the carboxy terminus of the compound has been amidated and —

OH indicates that the carboxy terminus of the compounds has not been derivatized;

X₃ is Cys, Lys, or Dpr, and X₄ is Nal, Trp, or Phe.

8. The compound of claim 7, wherein the compound binds to the IL-5R with an IC₅₀ of no more than about 2 mM as determined by a binding affinity assay.

9. The compound of claim 7, wherein the compound binds to the IL-5R with an IC₅₀ of no more than about 100 uM as determined by a binding affinity assay.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 7 in combination with a pharmaceutically acceptable carrier.

23. A method for treating a patient having a disorder that is susceptible to treatment with an IL-5 inhibitor, comprising the steps of providing a therapeutically effective amount of a compound of claim 7, and administering said therapeutically effective amount of compound to the patient.

10. A compound comprising an amino acid sequence selected from the group consisting of

(H)-TGGGDGYVCVEWARCPTCK-(OH) (residues 32–

50 of SEQ ID NO;

     8);

(Ac)-EGYV(Dpr)VEWARCPTCR-(NH₂) (residues 36–

50 of SEQ ID NO;

     9);

(Ac)-EGYVCVEWAACPTCR-(NH₂) (residues 36–

50 of SEQ ID NO;

     10);

(Ac)-EGYVCVEWARCPTCK-(NH₂) (residues 36–

50 of SEQ ID NO;

     11);

(Ac)-EGYVCVEWARCPTCK-(OH) (residues 36–

50 of SEQ ID NO;

     11);

(Ac)-EGYVCVEWARCPTCR-(NH2) (residues 36–

50 of SEQ ID NO;

     12);

(Ahx)-EGYVCVEWARCPTCR-(NH2) (residues 36–

50 of SEQ ID NO;

     12);

(H)-EGYVCVEFARCPTCG-(NH2) (residues 36–

50 of SEQ ID NO;

     13);

(H)-EGYVCVEFARCPTCR-(OH) (residues 36–

50 of SEQ ID NO;

     14);

(H)-EGYVCVEWARCPTCG-(NH2) (residues 36–

50 of SEQ ID NO;

     15);

(H)-EGYVCVEWARCPTCK-(NH2) (residues 36–

50 of SEQ ID NO;

     11);

(H)-EGYVCVEWARCPTCK-(OH) (residues 36–

50 of SEQ ID NO;

     11);

(Ac)-EGYVCVEWARCPTCR-(OH) (residues 36–

50 of SEQ ID NO;

     12);

(H)-EGYVCVEWARCPTCR-(NH2) (residues 36–

50 of SEQ ID NO;

     12);

(H)-EGYVCVEWARCPTCR-(OH) (residues 36–

50 of SEQ ID NO;

     12);

(H)-EGYVKVEWARCPTCR-(OH) (residues 36–

50 of SEQ ID NO;

     16);

(H)-GYVCVEFARCPTCG-(NH2) (residues 37–

50 of SEQ ID NO;

     17); and

(H)-GYVCVEWARCPTCR-(OH) (residues 37–

50 of SEQ ID NO;

     18)

wherein —

(NH₂) indicates that the carboxy terminus of the compound has been amidated, —

(OH) indicates that the carboxy terminus of the compound has not been derivatized, (Ac) indicates that the amino terminus of the compound has been acetylated, and (Ahx)- indicates that the amino terminus of the compound has been acylated with aminohexanoic acid.

11. The compound of claim 10, wherein the compound binds to the IL-5R with an IC₅₀ of no more than about 2 mM as determined by a binding affinity assay.

12. The compound of claim 10, wherein the compound binds to the IL-5R with an IC₅₀ of no more than about 100 uM as determined by a binding affinity assay.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 10 in combination with a pharmaceutically acceptable carrier.

24. A method for treating a patient having a disorder that is susceptible to treatment with an IL-5 inhibitor, comprising the steps of providing a therapeutically effective amount of a compound of claim 10, and administering said therapeutically effective amount of compound to the patient.