Diagnostic or therapeutic somatostatin or bombesin analog conjugates and uses thereof
View Patent ↗Disclosed are peptide agents and uses thereof that are analogs of biologically active peptides such as somatostatin and bombesin. The compounds of the invention have the general formula X-Y-Z-Q, where X is a cytotoxic agent, therapeutic agent, detectable label or chelating group, and Q is a biologically active peptide. In peptide agents of the invention Y is optionally a hydrophilic polymer or peptide, and Z is a linking peptide bonded to Q at the amino terminus of Q, having two, three, four, or five, amino acid residues selected to link X to Q, while retaining the biological activity of Q. Methods of using these peptide agents in the diagnosis and treatment of diseases are also disclosed.
1. A peptide agent having the formula:
X-Y-Z-Q, wherein:
X is selected from the group consisting of cytotoxic agents, therapeutic agents, detectable labels, and chelating groups;
Y is a peptide that increases the hydrophilic biodistribution of said agent, a hydrophilic polymer that includes a linker for X, or is omitted;
Q is a somatostatin peptide or analog thereof having biological activity; and
Z is D-Ser-Nle-D-Tyr-D-Ser-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH 2 , a linking peptide that, when bonded to Q at the N-terminus or at a compatible side-chain amino group of Q, preserves at least 50% of the biological activity of Q.
2. A peptide agent having the formula:
X-Y-Z-Q, wherein:
X is a cytotoxic agent or a therapeutic agent;
Y is a peptide that increases the hydrophilic biodistribution of said agent, a hydrophilic polymer that includes a linker for X, or is omitted;
Q is a somatostatin peptide having biological activity; and
Z is D-Ser-Nle-D-Tyr-D-Ser-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH 2 , a linking peptide that, when bonded to Q at the N-terminus or at a compatible side-chain amino group of Q, preserves at least 50% of the biological activity of Q.
3. The peptide agent of claim 2 , wherein Y is a peptide that increases the hydrophilic biodistribution of said agent.
4. The peptide agent of claim 3 , wherein Y is of the formula:
U(V-V) n , wherein:
U is D-Pro, L-Pro, D-4-OH-Pro, L-4-OH-Pro, Sar, or (NH 2 —(CH 2 ) m —COOH) where m=2-10, inclusive, or is deleted;
each V is independently selected from the group consisting of: D-Ser, L-Ser, D-Thr, L-Thr, D-Gln, L-Gln, D-Asn, L-Asn, D-4-OH-Pro, and L-4-OH-Pro; and
n is an integer from 1 to 50, inclusive.
5. The peptide agent of claim 4 , wherein each V is independently D-Ser or L-Ser.
6. The peptide agent of claim 2 , wherein Y is a hydrophilic polymer.
7. The peptide agent of claim 6 , wherein Y is polyethylene glycol, polyvinyl acetate, polyvinyl alcohol, HPMA (N-(2-hydroxypropyl)methacrylamide) or HPMA copolymers, α, β-poly(N-hydroxyethyl)-DL-aspartamide (PHEA), or α, β-poly(N-hydroxypropyl)-DL-aspartamide.
8. The peptide agent of claim 2 , wherein X is a cytotoxic agent.
9. The peptide agent of claim 8 , wherein X is an antimetabolic agent.
10. The peptide agent of claim 8 , wherein X is a methotrexate.
11. The peptide agent of claim 8 , wherein X is selected from the group consisting of the following compounds and their derivatives: doxorubicin, methotrexate, camptothecin, homocamptothecins, rhizoxins, dolistatins, paclitaxol, and maytansinoids.
12. The peptide agent of claim 2 , wherein Q is a somatostatin analog.
13. A peptide agent having the formula:
X-Y-Z-Q, wherein:
X is selected from the group consisting of a detectable label and a chelating group;
Y is a peptide that increases the hydrophilic biodistribution of said agent, a hydrophilic polymer that includes a linker for X, or is omitted;
Q is a somatostatin peptide or analog thereof having biological activity; and
Z is D-Ser-Nle-D-Tyr-D-Ser-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH 2 , a linking peptide that, when bonded to Q at the N-terminus or at a compatible side-chain amino group of Q, preserves at least 50% of the said biological activity of Q.
14. The peptide agent of claim 13 , wherein said peptide agent is attached to a detectable label.
15. The peptide agent of claim 14 , wherein said peptide agent is indirectly attached to a detectable label.
16. The peptide agent of claim 14 , wherein said peptide agent is directly attached to a detectable label.
17. The peptide agent of claim 14 , wherein said detectable label is radioactive.
18. The peptide agent of claim 17 , wherein said detectable label is an iodine, astatine, or bromine label that is attached to an amino acid of said peptide agent.
19. The peptide agent of claim 13 , wherein X is a chelating group.
20. The peptide agent of claim 13 , wherein X is omitted, and Y is lower acetylated, succinylated, maleinylated, or fumarylated.
21. The peptide agent of claim 13 , wherein Y is a peptide sequence that increases the hydrophilic biodistribution of said agent.
22. The peptide agent of claim 21 , wherein Y is of the formula:
U(V-V) n , wherein:
U is D-Pro, L-Pro, D-4-OH-Pro, L-4-OH-Pro, Sar, or (NH 2 —(CH 2 ) m —COOH) where m=2-10, inclusive, or is deleted;
each V is independently selected from the group consisting of: D-Ser, L-Ser, D-Thr, L-Thr, D-Gln, L-Gln, D-Asn, L-Asn, D-4-OH-Pro, and L-4-OH-Pro; and
n is an integer from 1 to 50, inclusive.
23. The peptide agent of claim 22 , wherein each V is independently D-Ser, L-Ser, or D-Gln.
24. The peptide agent of claim 13 , wherein Y is a hydrophilic polymer.
25. The peptide agent of claim 24 , wherein Y is polyethyleneglycol, PHEA, or polyvinylalcohol.
26. The peptide agent of claim 13 , wherein Q is a somatostatin analog.
27. The peptide agent of claim 4 , wherein at least one V is a D-amino acid.
28. The peptide agent of claim 22 , wherein at least one V is a D-amino acid.
29. The peptide agent of claim 19 , wherein said chelating group comprises an isotope of Lu, In, Y, or Sm.