Enhanced in vivo Targeting of Radiolabelled Peptides with the Means of Enzyme Inhibitors

• US 20150104381A1
• Filed: 07/06/2012
• Published: 04/16/2015
• Est. Priority Date: 07/08/2011
• Status: Active Grant

• Current Assignee: Biosynthema, Inc. (Novartis Ag)
• Original Assignee: Biosynthema, Inc. (Novartis Ag)
• Inventors: Maina-Nock, Theodosia, Nock, Berthold Artur, de Jong Hendriks, Marion
• Granted Patent: US 10,449,260 B2
• Time in Patent Office: Days
• US Class Current: 424/1.45
• 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 31/265 of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
• CPC Class Codes: A61K 31/7028 Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 51/08 Peptides, e.g. proteins , carriers being peptides, polyamino acids, proteins
• CPC Class Codes: A61K 51/083 the peptide being octreotide or a somatostatin-receptor-binding peptide
• CPC Class Codes: A61K 51/085 the peptide being neurotensin
• CPC Class Codes: A61K 51/086 the peptide being alphaMSH, alpha melanocyte stimulating hormone
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention relates to a compound that inhibits the activity of a degrading enzyme for use in combination with a therapeutic or diagnostic compound, preferably a moiety conjugated peptide, in the diagnosis and/or treatment of a disease, in particular cancer, to enhance targeting of the therapeutic or diagnostic compound to the disease site.

Claims

1. Compound that inhibits the activity of a degrading enzyme for use in combination with a therapeutic or diagnostic compound, preferably a moiety conjugated peptide, in the diagnosis and/or treatment of a disease, in particular cancer, to enhance targeting of the therapeutic or diagnostic compound to the disease site.

2. Compound as claimed in claim 1, wherein the degrading enzyme is a hydrolase selected from peptidases, esterases.

3. Compound as claimed in claim 2, wherein the enzyme is a neutral endopeptidase or angiotensin converting enzyme.

4. Compound as claimed in any one of the claims 1-3, wherein the therapeutic or diagnostic compound is selected from peptide conjugates, receptor ligands, peptides, peptide receptor ligand and radioactively labeled peptides.

5. Compound according to claim 4, wherein the radioactively labeled peptide is not completely stabilized.

6. Compound as claimed in any one of the claims 1-5, wherein the peptide is an antagonist.

7. Compound as claimed in any one of the claims 1-5, wherein the peptide is an agonist.

8. Compound as claimed in any one of the claims 1-5, wherein the peptide is selected from somatostatins, in particular somatostatin-14 and its analogs, CCK2R-receptor ligands, such as CCKs, gastrins, minigastrins and their analogs, in particular minigastrin(10-17), neurotensin receptor ligands, in particular neurotensin subtype 1 receptors, such as neurotensin and its analogs, demotensins and its analogs, in particular demotensin 6, gastrin releasing peptide receptor (GRPR) ligands, in particular bombesin and its analogs, in particular ^99mTc-demobesin 4 and ^99mTc-demobesin 1, neuromedin C (NMC) and it analogs, in particular ^99mTc-SAR-NCs such as ^99mTc-SAR-NC1 and ^99mTc-SAR-NC6, or the JMV compounds, in particular compound ¹¹¹In/¹⁷⁷Lu/^67/68Ga-JMV4168, neuropeptide substance P such as SP-1, SP-2, melanocyte stimulating hormone (MSH), chemotactic peptide (CTP) or combinations thereof.

9. Compound as claimed in any one of the claims 1-8, which compound is selected from NEP inhibitors, in particular phosphoramidon, racecadotril, ACE inhibitors, in particular lisinopril, captopril, ECE inhibitors, esterase inhibitors.

10. Compound as claimed in any one of the claims 1-7, wherein the enzyme inhibitor is a competing enzyme substrate.

11. Compound as claimed in claim 10, wherein the competing enzyme substrate is a plasma expander selected from Haemaccel and Gelofusine.

12. Compound as claimed in any one of the claims 1-7, wherein the enzyme inhibitor is a bait peptide.

13. Compounds for use in combination with a diagnostic or therapeutic vector in the diagnosis or treatment of a disease, in particular cancer, that increase the uptake of said vector at the disease site(s) by inhibiting the activity of degrading enzymes.

14. A composition comprising a therapeutic or diagnostic compound that comprises a moiety conjugated peptide, preferably a peptide-ligand conjugate, and one or more compounds that inhibit the activity of a hydrolase, wherein the hydrolase is a peptidase or an esterase.

15. The composition of claim 14 wherein administration of the composition enhances in vivo targeting of the therapeutic or diagnostic peptide conjugate as compared to administration of just the therapeutic or diagnostic compound alone.

16. The composition of claim 14 or claim 15, wherein the peptide-conjugate is a native peptide-conjugate and biodegradable derivatives thereof.

17. The composition according to any of the claims 14 to 16, wherein the therapeutic or diagnostic compound is a radiolabeled peptide conjugate, or is a peptide conjugate labeled with a fluorescent molecule for optical imaging, or is coupled to a cytotoxic moiety.

18. The composition according to any of the claims 14 to 17 wherein the therapeutic or diagnostic compound is a radiolabeled biodegradable peptide-conjugate derived from the group consisting of somatostatin, gastrin, neurotensin, bombesin, neuromedin C, and a gastrin releasing peptide receptor (GRPR)-antagonist.

19. The composition according to any of the claims 14 to 18, wherein the one or more compounds that inhibit the activity of a hydrolase is selected from the group consisting of neutral endopeptidase inhibitors, angiotensin-converting enzyme inhibitors, endothelin converting enzyme inhibitors, esterase inhibitors, and combinations thereof.

20. The composition according to any of the claims 14 to 19, wherein the one or more compounds that inhibit the activity of hydrolase is a neutral endopeptidase inhibitor.

21. The composition according to claim 20, wherein the neutral endopeptidase inhibitor is phosphoramidon or racecadotril.

22. The composition according to any of the claims 14 to 21, wherein the wherein the one or more compounds that inhibit the activity of a hydrolase is an angiotensin-converting enzyme inhibitor.

23. The composition according to claim 17, wherein the radiolabeled peptide conjugate is radiometallated peptide or a peptide radiohalogenated via a prosthetic group.

24. The composition according to claim 17, wherein the radiolabeled peptide conjugate comprises a radionuclide metal selected from the group comprising ¹¹¹In, ^99mTc, ^94mTc, ⁶⁷Ga, ⁶⁶Ga, ⁶⁸Ga, ⁵²Fe, ⁶⁹Er, ⁷²As, ⁹⁷Ru, ²⁰³Pb, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ¹⁸⁶Re, ¹⁸⁸Re, ⁸⁶Y, ⁹⁰Y, ⁵¹Cr, ^52mMn, ¹⁵⁷Gd, ¹⁷⁷Lu, ¹⁶¹Tb, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁰⁵Rh, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁵³Sm, ¹⁴⁹Pm, ¹⁵¹Pm, ¹⁷²Tm, ¹²¹Sn, ^177mSn, ²¹³Bi, ¹⁴²Pr, ¹⁴³Pr, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁸F, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, and ⁸²Br.

25. The composition according to any of the claims 14 to 24, wherein the composition comprises a combination selected from the group of combinations consisting of:

[(X-DOTA)Ala1]SS-14 or [(X-DOTA)Ala1, DTrp8]SS-14 with a neutral endopeptidase inhibitor;

X-DOTA-MG11 with a neutral endopeptidase inhibitor;

X-demotensin 6 or X-demotensin 1 with a neutral endopeptidase inhibitor;

X-demotensin 1 with a neutral endopeptidase inhibitor and/or an ACE inhibitor;

X-SAR-NC1 or X-SAR-NC6 with a neutral endopeptidase inhibitor;

X-Demobesin 4 or X-Demobesin 1 with a neutral endopeptidase inhibitor; and

X-JMV4168 with a neutral endopeptidase inhibitor, wherein X is a radionuclide useful for radiotherapy or imaging.

26. The composition according to any of the claims 14 to 25, wherein the composition comprises a combination selected from the group of combinations consisting of:

[(111In-DOTA)Ala1]SS-14 or [(111In-DOTA)Ala1, DTrp8]SS-14 with a neutral endopeptidase inhibitor;

111In-DOTA-MG11 with a neutral endopeptidase inhibitor;

99mTc-demotensin 6 or 99mTc-demotensin 1 with a neutral endopeptidase inhibitor;

99mTc-demotensin 1 with a neutral endopeptidase inhibitor and/or an ACE inhibitor;

99mTc-SAR-NC1 or 99mTc-SAR-NC6 with a neutral endopeptidase inhibitor;

99mTc-Demobesin 4 or 99mTc-Demobesin 1 with a neutral endopeptidase inhibitor; and

111In-JMV4168 with a neutral endopeptidase inhibitor.

27. A method of treating and/or diagnosing a disease comprising co-administration of a therapeutic or diagnostic compound with one or more compounds that inhibit the activity of at least one hydrolase, wherein the therapeutic or diagnostic compound comprises a biodegradable peptide-ligand conjugate and the hydrolase is a peptidase or an esterase.

28. The method of claim 27, wherein in vivo targeting of the therapeutic or diagnostic compound is enhanced as compared to in vivo targeting of the therapeutic or diagnostic compound in an absence of said compound(s) that inhibit the activity of said hydrolase.

29. The method of claim 27, wherein the peptide-ligand is a native peptide-ligand or not fully stabilized analog thereof conjugated to a diagnostic or therapeutic moiety.

30. The method of claim 27, wherein the therapeutic or diagnostic compound is a peptide-ligand conjugate, radiolabeled or is labeled with a fluorescent molecule for optical imaging, or is coupled to a cytotoxic drug.

31. The method of claim 27, wherein the therapeutic or diagnostic compound is a radiolabeled biodegradable peptide-conjugate derived from the group consisting of somatostatin, gastrin, neurotensin, bombesin, neuromedin C, and a gastrin releasing peptide receptor-antagonist.

32. The method of claim 27, wherein the one or more compounds that inhibit the activity of a hydrolase is selected from the group consisting of neutral endopeptidase inhibitors, angiotensin-converting enzyme inhibitors, endothelin converting enzyme inhibitors, esterase inhibitors, and combinations thereof.

33. The method of claim 27, wherein the one or more compounds that inhibit the activity of a hydrolase is a neutral endopeptidase inhibitor.

34. The method of claim 27, wherein the neutral endopeptidase inhibitor is phosphoramidon or racecadotril.

35. The method of claim 27, wherein the one or more compounds that inhibit the activity of a hydrolase is an angiotensin-converting enzyme inhibitor.

36. The method of claim 27, wherein the peptide-radioligand is a radiometallated peptide or a peptide modified with a prosthetic group for incorporation of radiohalogens.

37. The method of claim 27, wherein the peptide-radioligand comprises a radionuclide metal selected from the group comprising ¹¹¹In, ^99mTc, ^94mTc, ⁶⁷Ga, ⁶⁶Ga, ⁶⁸Ga, ⁵²Fe, ⁶⁹Er, ⁷²As, ⁹⁷Ru, ²⁰³Pb, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ¹⁸⁶Re, ¹⁸⁸Re, ⁸⁶Y, ⁹⁰Y, ⁵¹Cr, ^52mMn, ¹⁵⁷Gd, ¹⁷⁷Lu, ¹⁶¹Tb, ¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁰⁵Rh, ¹⁶⁶Dy, ¹⁶⁶Ho, ¹⁵³Sm, ¹⁴⁹Pm, ¹⁵¹Pm, ¹⁷²Tm, ¹²¹Sn, ^177mSn, ²¹³Bi, ¹⁴²Pr, ¹⁴³Pr, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁸F, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, and ⁸²Br.

38. The method of any one of claims 27-37, wherein the co-administration comprises:

(i) administering the therapeutic or diagnostic compound at the same time as the one or more compounds that inhibit the activity of a hydrolase;

(ii) first administering the therapeutic or diagnostic compound, followed by administering the one or more compounds that inhibit the activity of a hydrolase;

or

(iii) first administering the one or more compounds that inhibit the activity of a hydrolase, followed administering the therapeutic or diagnostic compound.

39. The method of claim 27, wherein the combination of a therapeutic or diagnostic compound and one or more compounds that inhibit the activity of a hydrolase is selected from the group of combinations consisting of:

[(X-DOTA)Ala1]SS-14 or [(X-DOTA)Ala1, DTrp8]SS-14 with a neutral endopeptidase inhibitor;

X-DOTA-MG11 with a neutral endopeptidase inhibitor;

X-demotensin 6 or X-demotensin 1 with a neutral endopeptidase inhibitor;

X-demotensin 1 with a neutral endopeptidase inhibitor and/or an ACE inhibitor;

X-SAR-NC1 or X-SAR-NC6 with a neutral endopeptidase inhibitor;

X-Demobesin 4 or X-Demobesin 1 with a neutral endopeptidase inhibitor; and

X-JMV4168 with a neutral endopeptidase inhibitor, wherein X is a radionuclide useful for radiotherapy or imaging.

40. The method of claim 27, wherein the combination of a therapeutic or diagnostic compound and one or more compounds that inhibit the activity of a hydrolase is selected from the group of combinations consisting of:

[(111In-DOTA)Ala1]SS-14 or [(111In-DOTA)Ala1, DTrp8]SS-14 with a neutral endopeptidase inhibitor;

111In-DOTA-MG11 with a neutral endopeptidase inhibitor;

99mTc-demotensin 6 or 99mTc-demotensin 1 with a neutral endopeptidase inhibitor;

99mTc-demotensin 1 with a neutral endopeptidase inhibitor and/or an ACE inhibitor;

99mTc-SAR-NC1 or 99mTc-SAR-NC6 with a neutral endopeptidase inhibitor;

99mTc-Demobesin 4 or 99mTc-Demobesin 1 with a neutral endopeptidase inhibitor; and

111In-JMV4168 with a neutral endopeptidase inhibitor.