Peptides and compounds that bind to the IL-5 receptor

• US 5,677,280 A
• Filed: 06/07/1995
• Issued: 10/14/1997
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Affymax Incorporated
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Barrett, Ronald W., Schatz, Peter J., Sloan, Derek, Chen, Min-Jia, England, Bruce P.
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): HARLE, JENNIFER I
• Application Number:
  US08/476,169
• Time in Patent Office: 860 Days
• Field of Search: 514/14, 530/387.3, 530/388.23, 530/866, 424/85.8
• US Class Current: 514/20.6
• CPC Class Codes: A61K 38/00 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 Class Codes: C07K 14/5409 IL-5
• CPC Class Codes: Y10S 530/866 involving immunoglobulin or antibody fragment, e.g. fab', fab, fv, fc, heavy chain or light chain

Abstract

Described are peptides and peptide mimetics that bind to and the IL-5 receptor. Such peptides and peptide mimetics are useful in methods for treating disorders that involve improper production of or response to IL-5 and or the production and accumulation of eosinophils, such as asthma, as well as in diagnostic methods employing labeled peptides and peptide mimetics.

Claims

1. A compound that binds to IL-5 receptor, said compound comprising:

(1) a core sequence of amino acids;

space="preserve" listing-type="equation">CX.sub.1 X.sub.2 W X.sub.3 R C X.sub.4 X.sub.5 C

where X₁ is G, I, V, or Y;

X₂ is D or E;

X₃ is A or V;

X₄ is Q or P; and

X₅ is A, E, K, M, N, S, or T, (SEQ ID NO;

1) and dimers and oligomers thereof, having

(a) a molecular weight of less than about 5000 daltons, and

(b) a binding affinity to IL5-R as expressed by an IC₅₀ of no more than about 100 μ

m,

wherein from zero to all of the --C(O)NH-- linkages of the peptide have been replaced by a linkage selected from the group consisting of a --CH₂ OC(O)NR-- linkage;

a phosphonate linkage;

a --CH₂ S(O)₂ NR-- linkage;

a --CH₂ NR-- linkage; and

a --C(O)NR⁶ -- linkage; and

a --NHC(O)NH-- linkage where R is hydrogen or lower alkyl and R⁶ is lower alkyl,

further wherein the N-terminus of said peptide or peptide mimetic is selected from the group consisting of a --NRR¹ group;

a --NRC(O)R group;

a --NRC(O)OR group;

a --NRS(O)₂ R group;

a --NHC(O)NHR group;

a succinimide group;

a benzyloxycarbonyl-NH-- group; and

a benzyloxycarbonyl-NH-- group having from 1 to 3 substituents on the phenyl ring selected from the group consisting of lower alkyl, lower alkoxy, chloro, and bromo, where R and R¹ are independently selected from the group consisting of hydrogen and lower alkyl,

and still further wherein the C-terminus of said peptide or peptide mimetic has the formula --C(O)R² where R² is selected from the group consisting of hydroxy, lower alkoxy, and --NR³ R⁴ where R³ and R⁴ are independently selected from the group consisting of hydrogen and lower alkyl and where the nitrogen atom of the --NR³ R⁴ group can optionally be the amine group of the N-terminus of the peptide so as to form a cyclic peptide,

or physiologically acceptable salts thereof.

2. The compound of claim 1, wherein said compound comprises a sequence of amino acids:

space="preserve" listing-type="equation">C X.sub.1 X.sub.2 W X.sub.3 R C X.sub.4 X.sub.5 C

where X₁ is V;

X₂ is E;

X₃ is A; and

X₄ is P (SEQ ID NO;

2).

3. The compound of claim 2, wherein said compound comprises either a sequence of amino acids:

space="preserve" listing-type="equation">X.sub.6 X.sub.7 X.sub.8 V C X.sub.1 X.sub.2 W X.sub.3 R C X.sub.4 X.sub.5 C

where X₆ is D, E, G, I, M, N, P, Q, S, V, or Y;

X₇ is G, V, or Y; and

X₈ is F, W, or Y (SEQ ID NO;

3);

or a sequence of amino acids;

space="preserve" listing-type="equation">C X.sub.1 X.sub.2 W X.sub.3 R C X.sub.4 X.sub.5 C X.sub.9

where X₉ is E, I, K, L, M, Q, R, T, V, or Y (SEQ ID NO;

4).

4. The compound of claim 3, wherein said compound comprises a sequence of amino acids:

space="preserve" listing-type="equation">X.sub.6 X.sub.7 X.sub.8 V C X.sub.1 X.sub.9 W X.sub.3 R C X.sub.4 X.sub.5 C X.sub.9

(SEQ ID NO;

65).

5. The compound of claim 4, wherein X₆ is D, E, G, N, P, or Q;

X₇ is G; and

X₉ is K, L, Q, R, or T (SEQ ID NO;

5).

6. The compound of claim 5, wherein X₆ is D, N, or P;

X₈ is F or Y; and

X₉ is K, R, or T(SEQ ID NO;

6).

7. The compound of claim 6, wherein said compound is selected from the group consisting of:

D G Y V C V E W A R C P T C K (SEQ ID NO;

7);

D G Y V C V E W A R C P M C T (SEQ ID NO;

8); and

D G F V C V E W A R C P N C R (SEQ ID NO;

9).

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

9. An aerosol composition for the treatment of an inflammatory disorder of the respiratory tract that is mediated by IL-5 comprising a therapeutically effective amount of a compound of claim 1 in an aerosolized pharmaceutically acceptable carrier solution or dry powder.

10. The composition of claim 9 wherein said inflammatory disorder of the respiratory tract is asthma.

11. The composition of claim 9 wherein said compound of claim 1 is present in said carrier solution in a concentration of from 0.1 to 30 mg/mL.

12. The composition of claim 9 further comprising a β

-adrenergic agonist compound.

13. The composition of claim 9 wherein said β

-adrenergic agonist compound if selected from the group consisting of albuterol, terbutaline, formoterol, fenoterol, and prenaline.

14. The composition of claim 9 further comprising an antiinflammatory corticosteroid.

15. The composition of claim 14 wherein said antiinflammatory corticosteroid is selected from the group consisting of beclomethasome, triamcinolone, flurisolide, and dexamethasone.

16. The composition of claim 9 further comprising ipratropium bromide.

17. An aerosol device comprising:

a composition of claim 9, and

means for converting said solution or dry powder into an aerosol form suitable for inhalation.