Peptides and related compounds having thrombopoietic activity

• US 20030176352A1
• Filed: 10/10/2002
• Published: 09/18/2003
• Est. Priority Date: 10/11/2001
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Min, Hosung, Hartley, Cynthia, Sitney, Karen C.
• Granted Patent: US 7,332,474 B2
• Time in Patent Office: Days
• US Class Current: 514/14
• 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: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07K 14/524 Thrombopoietin, i.e. C-MPL ligand

Abstract

The present invention relates generally to novel peptides and related compounds that have thrombopoietic activity. The compounds of the invention may be used to increase production of platelets or platelet precursors (e.g. megakaryocytes) in a mammal.

Claims

1. A compound that binds to an mpl receptor comprising the sequence:

X1-X2-X3-X4-G-P-T-L-X9-X10-W-L-X13-X14-X15-X16-X17-X18

wherein X1-X4, X9-X10, and X13-X18 are each independently an amino acid, said compound having a binding affinity for the mpl receptor greater than that of the sequence;

X19-X20-I-E-G-P-T-L-R-Q-W-L-A-A-R-A-X21-X22,

wherein X19-X20 and X21-X22 are each independently an amino acid, and

physiologically acceptable salts thereof.

3. The compound according to claim 1 wherein:

X1 is selected from the group consisting of A, V, W, M, G, Y, C, Q, E, R and H;

X2 is selected from the group consisting of A, V, L, I, G, S, and C;

X3 is selected from the group consisting of L, I, P, W, G, S, D, K and R;

X4 is selected from the group consisting of L, G, Q, D, E and H;

X9 is selected from the group consisting of K and R;

X10 is selected from the group consisting of Q and E;

X13 is selected from the group consisting of A, V, L, S, Q, E and R

X14 is selected from the group consisting of A, W, T, Y, C and Q;

X15 is selected from the group consisting of V, L, G, Y and R;

X16 is selected from the group consisting of A, L, F, G and R;

X17 is selected from the group consisting of A, V, L, M, G, C, Q and N;

X18 is selected from the group consisting of A, V, P, M, F, G, C, Q and K.

7. The compound according to claim 1, 2 or 6 which is cyclic

8. The compound according to claim 1, 2 or 6 wherein at least one of the amino acid residues has a D configuration.

9. The compound according to claim 1, 2 or 6 wherein all of the amino acid residues have a D configuration.

10. A dimer or multimer of the compounds according to claims 1, 2 or 6.

11. A composition of matter that binds to an mpl receptor comprising the formula:

(LN1)_l—

(TMP1)_a—

(LN2)_m13 (TMP2)_b—

(LN3)_n—

(TMP3)_c—

(LN4)_o—

(TMP4)_d

wherein TMP1, TMP2, TMP3 and TMP4 are each independently selected from the group consisting of the compounds of claims 1, 2 and 6;

LN1, LN2, LN3 and LN4 are each independently a linker;

a, b, c and d are each independently an integer from zero to 20; and

l, m, n and o are each independently an integer from zero to twenty.

12. The composition according to claim 11 further comprising a vehicle and having the formula:

(V1)_v—

(LN1)_l—

(TMP1)_a—

(LN2)_m—

(TMP2)_b—

(LN3)_n—

(TMP3)_c—

(LN4)_o—

(TMP4)_d—

(V2)_w

wherein V1 and V2 are each independently a vehicle, and v and w are each independently an integer from 0 to 1.

13. The compound according to claim 12 wherein LN1, LN2, LN3 and LN4 comprise peptides.

14. The composition according to claim 12 wherein V1 and/or V2 comprise an Fc domain.

15. The composition according to claim 12 wherein V1 and/or V2 comprise an IgG1 Fc domain.

16. A polynucleotide encoding a composition of matter selected from the group consisting of the compositions of claim 12.

17. An expression vector comprising the polynucleotide of claim 12.

18. A host cell comprising the expression vector of claim 12.

19. The host cell according to claim 12 wherein the cell is an E.coli cell.

20. The host cell according to claim 12 wherein the cell is a prokaryotic cell.

21. The host cell according to claim 12 wherein the cell is a eukaryotic cell.

22. A pharmaceutical composition comprising an effective amount of a composition according to claim 12 in admixture with a pharmaceutically acceptable carrier thereof.

23. A method of treating thrombocytopenia in a mammal comprising administering a therapeutically effective amount of the composition according to claim 12.

24. A method of increasing megakaryocytes or platelets in a patient in need thereof, which comprises administering to said patient an effective amount of a compound according to claim 12.

2. A compound that binds to an mpl receptor comprising the sequence:

X1-X2-X3-X4-G-P-T-L-X9-X10-W-L-X13-X14-X15-X16-X17-X18

wherein X1-X4, X9-X10, and X13-X18 are each independently an amino acid, said compound having a bioactivity greater than that of the sequence;

X19-X20-I-E-G-P-T-L-R-Q-W-L-A-A-R-A-X21-X22,

wherein X19-X20 and X21-X22 are each independently an amino acid, and

physiologically acceptable salts thereof.

4. The compound according to claim 2 wherein:

X1 is selected from the group consisting of A, V, W, M, G, C, E, and R;

X2 is selected from the group consisting of A, V, L, M, F, G, S, C, D and R;

X3 is selected from the group consisting of A, L, I, P, W, Q, K and R;

X4 is selected from the group consisting of L G Q D and E;

X9 is selected from the group consisting of K, R, and H;

X10 is selected from the group consisting of Q and E;

X13 is selected from the group consisting of A, L P, F, G, Q, N, E and R;

X14 is selected from the group consisting of L, W, M, C, Q and H;

X15 is selected from the group consisting of V, L, P, G, Y and R;

X16 is selected from the group consisting of A, V, L, F, S, Q, K and R;

p1 X17 is selected from the group consisting of A, V, L, W, M, G, S, C and N;

X18 is selected from the group consisting of A, V, P, M, G, C, Q and K;

5. A compound that binds to an mpl receptor comprising the sequence:

X1-X2-R-E-G-P-T-L-R-Q-W-L-X13-W-R-R-X17-X18

wherein X1, X2, X13, X17 and X18 are each independently an amino acid.

6. A compound that binds to an mpl receptor comprising a sequence which is selected from the group consisting of SEQ ID NO 2 to SEQ ID NO 30, inclusive.

25. A compound that binds to an mpl receptor comprising the formula:

(V1)_v—

(TMP1)_a—

(V2)_w

wherein V1 and V2 are each an IgG1 Fc domain, provided that where v is one, w is zero and where v is zero, w is one and TMP1 is a peptide of SEQ ID NO 2 to 30;

a is an integer from one to twenty.