US2013095037A1PendingUtilityA1
Peptide derivatives of exendin-4
Est. expirySep 3, 2024(expired)· nominal 20-yr term from priority
A61P 43/00A61P 35/00A61P 25/00A61P 3/10A61P 1/00G01N 33/74C07K 14/605A61K 51/08C07K 14/57563A61K 38/16C07K 14/575
40
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Claims
Abstract
In the current invention peptides, which are derived from GLP-1 (glucagon-like peptide-1) and exendin-3 and/or exendin-4, are provided which bond to the GLP-1 receptor and can be used, labeled or unlabeled, for the production of an agent for diagnostic and therapy of benign and malignant diseases, in which GLP-1 receptor expression plays a role.
Claims
exact text as granted — not AI-modified1 . Peptide derivatives of GLP-1 and exendin-3, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor.
2 . Peptide derivatives of GLP-1 and exendin-3 according to claim 1 wherein they contain completely or partly the amino acid sequences of the peptides GLP-1 (1-37):
H-His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Lys-Gly-Arg-Gly-OH
34 35 36 37
and exendin-3:
H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39.
3 . Peptide derivatives of GLP-1 and exendin-3 according to claim 1 , wherein they are based on GLP1(x-y)A 1-37 or exendin-3 (z-k)A 1-40 with x representing the amino acids 1-36 of the GLP-1 amino acid sequence, y representing the amino acids 2-37 of the GLP-1 amino acid sequence, z representing the amino acids 1-38 of the exendin-3 amino acid sequence, k representing the amino acids 2-39 of the exendin 3 amino acid sequence and A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, whereby the exponent indicates at which position the attachment group can be found within the amino acid sequence.
4 . Peptide derivatives from GLP-1 and exendin-3 according to claim 3 , wherein the attachment group A is preferably located at the C-Terminus and represents an amine.
5 . Peptide derivatives from GLP-1 and exendin-3 according to claim 3 , wherein the attachment group A is preferably lysine.
6 . Peptide derivatives from GLP-1 and exendin-3 according to claim 3 , wherein the attachment group A is an amino acid, such as ornithine, or an organic group comprising free amine.
7 . Peptide derivatives from GLP-1 and exendin-3 according to claim 3 , wherein a chelator is coupled with attachment group A for the labeling with radionuclides or a MRI contrast agent, fluorescent pigments or a chemotherapeutic agent.
8 . Peptide derivatives from GLP-1 and exendin-3 according to claim 7 , wherein the chelator is N,N-Bis(2-[bis(carboxymethyl)amino]-ethyl)glycine), DOTA (1,4,7,10-Tetraazacyclodo-decane-1,4,7,10-tetra-acetic acid), HYNIC (6-Hydrazinopyridin-3-carbonic acid), MAG3 (mercaptoacetyl-glycylglycylglycine), N4 (1,4,8,11-tetraazaundecane) and all known derivatives, preferably DTPA (Diethylenetriaminepentaacetic acid).
9 . Peptide derivatives from GLP-1 and exendin-3 according to claim 7 , wherein the labeling is a coupling of radionuclides, MRI contrast agent, fluorescent pigments and/or a chemotherapeutic agent.
10 . Peptide derivatives from GLP-1 and exendin-3 according to claim 7 , wherein the chosen fluorescent pigments are in particular from the group Fluorescein, Rhodamin, Coumarin, BODIPY, Pyrene (Cascade Blue), Lucifer Yellow, Phycobiliprotein, Cyanin, AlexaFluoro, Oregon Green, Texas Red and their derivatives.
11 . Peptide derivatives from GLP-1 and exendin-3 according to claim 7 , wherein the chosen radionuclide is in particular from the group F-18, Cu-64, Cu-67, Ga-67, Ga-68, Y-86, Y-90, Tc-99m, In-111, I-123, I-124, I-131, Lu-177, Re-186, Re-188, Pt-193m, Pt-195m, Ac-225, At-211, Bi-213, Sm-153 or Er-169.
12 . Peptide derivatives from GLP-1 and exendin-3 according to claim 7 , wherein the chosen MRI contrast agent is in particular selected from the group comprising gadolinium, manganese, iron, europium, copper, nickel, chrome, prasodymium, dysprosium or holmium or their compounds or periluorocarbone or F-19, H-1, P-31, Na-19.
13 . Peptide derivatives from GLP-1 and exendin-3 according to claim 7 , wherein the chosen chemotherapeutic agent is in particular selected from the group comprising alkylating agents, ethylimine, nitrosomonas ( N. ureae ), nitrogen mustard derivatives, folic acid analogs, purine analogs, pyrimidine analogs, podophyllin derivatives, taxane, vincaalcaloide, anthracycline, other cytostatic antibiotics, platinum compounds, campthotecin derivatives, hormones, growth factors, interferons or interleukins or cytostatic or cytotoxic substances.
14 . Peptide derivatives from GLP-1 and exendin-3 according to claim 7 , wherein the labeling via the coupling of radionuclides for in vitro applications takes place through the saturation of the bonding sites with nat InCL 3 .
15 . Chimeric peptides from GLP-1 and exendin, with exendin being exendin 3, wherein they contain completely or in part the amino acid sequences of the peptides
GLP-1 (1-37)
H-His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Lys-Gly-Arg-Gly-OH
34 35 36 37
and exendin-3:
H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39.
16 . Chimeric peptides from GLP-1 and exendin according to claim 15 , wherein they are based on:
GLP1(x-y) exendin-3(z-k), or exendin-3(z-k) GLP1(x-y) with x representing the amino acids 1-36 of the GLP-1 amino acid sequence, y representing the amino acids 2-37 of the GLP-1 amino acid sequence, z representing the amino acids 1-38 of the exendin 3 amino acid sequence, k representing the amino acids 2-39 of the exendin 3 amino acid sequence.
17 . Chimeric peptides from GLP-1 and exendin according to claim 15 , wherein they are based on:
GLP1(x-y) exendin-3(z-k)A 1-75 , or exendin-3(z-k) GLP1(x-y)A 1-75 with x representing the amino acids 1-36 of the GLP-1 amino acid sequence, y representing the amino acids 2-37 of the GLP-1 amino acid sequence, z representing the amino acids 1-38 of the exendin-3 amino acid sequence, k representing the amino acids 2-39 of the exendin-3 amino acid sequence and A being an attachment group comprising one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, with the exponent indicating at which position the attachment group can be found within the amino acid sequence.
18 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the attachment group A is preferably located at the C-Terminus and represents an amine.
19 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the attachment group A is preferably lysine.
20 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the attachment group A is preferably an amino acid with a free amine, such as ornithine, or an organic group with a free amine.
21 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein a chelator is coupled with attachment group A for labeling with radionuclides or a MRI contrast agent, fluorescent pigments or a chemotherapeutic agent.
22 . Chimeric peptides from GLP-1 and exendin according to claim 21 , wherein the chelator is N,N-Bis(2-[bis(carboxymethyl)amino]-ethyl)glycine), DOTA (1,4,7,10-Tetraazacyclodo-decane-1,4,7,10-tetra-acetic acid), HYNIC (6-Hydrazinopyridin-3-carbonic acid), MAG3 (mercaptoacetyl-glycylglycylglycine), N4 (1,4,8,11-tetraazaundecane) and their known derivatives, preferably DTPA (Diethylenetriaminepentaacetic acid).
23 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the labeling is a coupling of radionuclides, MRI contrast agent, fluorescent pigments and/or a chemotherapeutic agent.
24 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the chosen fluorescent pigments are in particular selected from the group Fluorescein, Rhodamin, Coumarin, BODIPY, Pyrene (Cascade Blue), Lucifer Yellow, Phycobiliprotein, Cyanin, AlexaFluoro, Oregon Green, Texas Red and their derivatives.
25 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the radionuclide is selected in particular from the group F-18, Cu-64, Cu-67, Ga-67, Ga-68, Y-86, Y-90, Tc-99m, In-111, I-123, I-124, I-131, Lu-177, Re-186, Re-188, Pt-193m, Pt-195m, Ac-225, At-211, Bi-213, Sm-153 or Er-169.
26 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the chosen MRI contrast agent is in particular from the group gadolinium, manganese, iron, europium, copper, nickel, chrome, prasodymium, dysprosium or holmium or their compounds or perfluorocarbone or F-19, H-1, P-31, Na-19.
27 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the chosen chemotherapeutic agent is in particular selected from the group alkylating agents, ethylimine, nitrosomonas ( N. ureae ), nitrogen mustard derivatives, folic acid analogs, purine analogs, pyrimidine analogs, podophyllin derivatives, taxane, vincaalcaloide, anthracycline, other cytostatic antibiotics, platinum compounds, campthotecin derivatives, hormones, growth factors, interferons or interleukins or cytostatic or cytotoxic substances.
28 . Chimeric peptides from GLP-1 and exendin according to claim 17 , wherein the labeling via the coupling of radionuclides for in vitro applications takes place through the saturation of the bonding sites with nat InCL 3 .
29 . Use of peptide derivatives from GLP-1 and exendin-3, as well as chimeric peptides from GLP-1 and exendin-3 according to claim 1 for the production of an agent for diagnostic and therapy of benign and malignant diseases, in which the GLP-1 receptor expression plays a role.
30 . Application of peptide derivatives from GLP-1 and exendin-3, as well as chimeric peptides from GLP-1 and exendin-3 according to claim 1 in order to determine the density of insulin producing cells in a tissue.
31 . Application of peptide derivatives from GLP-1 and exendin-3, as well as chimeric peptides from GLP-1 and exendin 3 according to claim 1 in order to determine the expression of GLP-1 receptors or their density.
32 . Agent for the diagnostic and therapy of benign and malignant diseases, in which GLP-1 receptor expression plays a role, wherein it contains labeled peptide derivatives of GLP-1 and exendin 3, or labeled chimeric peptides from GLP-1 and exendin-3 according to claim 1 .
33 . Agent for the diagnostic and therapy of benign and malignant diseases, in which GLP-1 receptor expression plays a role, wherein it contains unlabeled peptide derivatives from GLP-1 and exendin-3, or unlabeled chimeric peptides from GLP-1 and exendin-3 according to claim 1 and claim 16 .
34 . Agent according to claim 32 wherein the labeling contains a coupling of radionuclides, MRI contrast agents, fluorescent pigments and/or chemotherapeutic agent.
35 . Use of an agent according to claim 32 for diagnostic and therapy of benign and malignant diseases, in which GLP-1 receptor expression plays a role.
36 . Use of an agent according to claim 32 for diagnostic and therapy of neuroendocrine tumors (NET), particularly insulinomas and small cell bronchial carcinomas.
37 . Use of an agent according to claim 32 in scintigraphy, PET, SPECT, MRI, optical diagnostic, receptor-mediated chemotherapy, receptor-mediated, cytostatic or cytotoxic therapy and radiopeptide therapy.
38 . Use of peptide derivatives from exendin-4, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor, with a sequence identity of over 90% to the amino acid sequence of exendin-4:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39
wherein the peptide derivatives are based on exendin-4 (1-39)A,
with A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, which is located at the C-terminus and represents an amine, wherein a chelator is coupled with attachment group A for the labeling with radionuclides for the production of an agent for diagnostic and therapy of benign and malignant diseases, in which the GLP-1 receptor expression plays a role.
39 . Application of peptide derivatives from exendin-4, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor, with a sequence identity of over 90% to the amino acid sequence of exendin-4:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39
wherein the peptide derivatives are based on exendin-4 (1-39)A,
with A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, which is located at the C-terminus and represents an amine, wherein a chelator is coupled with attachment group A for the labeling with radionuclides in order to determine the density of insulin producing cells in a tissue.
40 . Application of peptide derivatives from exendin-4, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor, with a sequence identity of over 90% to the amino acid sequence of exendin-4:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39
wherein the peptide derivatives are based on exendin-4 (1-39)A,
with A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, which is located at the C-terminus and represents an amine, wherein a chelator is coupled with attachment group A for the labeling with radionuclides in order to determine the expression of GLP-1 receptors or their density.
41 . Use of an agent for diagnostic and therapy of benign and malignant diseases, in which GLP-1 receptor expression plays a role, wherein the agent contains labeled peptide derivatives of exendin-4, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor, with a sequence identity of over 90% to the amino acid sequence of exendin-4:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39
wherein the peptide derivatives are based on exendin-4 (1-39)A,
with A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, which is located at the C-terminus and represents an amine, wherein a chelator is coupled with attachment group A for the labeling with radionuclides.
42 . Use of an agent for diagnostic and therapy of neuroendocrine tumors (NET), particularly insulinomas and small cell bronchial carcinomas, wherein the agent contains labeled peptide derivatives from exendin-4, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor, with a sequence identity of over 90% to the amino acid sequence of exendin-4:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39
wherein the peptide derivatives are based on exendin-4 (1-39)A,
with A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, which is located at the C-terminus and represents an amine, wherein a chelator is coupled with attachment group A for the labeling with radionuclides.
43 . Use of an agent in scintigraphy, PET, SPECT, MRI, optical diagnostic, receptor-mediated chemotherapy, receptor-mediated, cytostatic or cytotoxic therapy and radiopeptide therapy, wherein the agent contains labeled peptide derivatives of exendin-4, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor, with a sequence identity of over 90% to the amino acid sequence of exendin-4:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39
wherein the peptide derivatives are based on exendin-4 (1-39)A,
with A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, which is located at the C-terminus and represents an amine, wherein a chelator is coupled with attachment group A for the labeling with radionuclides.
44 . Use of an agent for diagnostic and therapy of benign and malignant diseases, in which GLP-1 receptor expression plays a role, wherein the agent contains unlabeled peptide derivatives from exendin-4, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor, with a sequence identity of over 90% to the amino acid sequence of exendin-4:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39
wherein the peptide derivatives are based on exendin-4 (1-39)A,
with A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, which is located at the C-terminus and represents an amine, wherein a chelator is coupled with attachment group A for the labeling with radionuclides.
45 . Use of an agent for diagnostic and therapy of neuroendocrine tumors (NET), particularly insulinomas and small cell bronchial carcinomas, wherein the agent contains unlabeled peptide derivatives from exendin-4, wherein their C-terminus is modified by an amine and wherein their N-terminus binds to the GLP-1 receptor, with a sequence identity of over 90% to the amino acid sequence of exendin-4:
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Pro-Pro-Pro-Ser-NH 2
36 37 38 39
wherein the peptide derivatives are based on exendin-4 (1-39)A,
with A being an attachment group comprising of one or more amino acids or its derivatives as a signal molecule, or to bond signal molecules or to stabilize them, which is located at the C-terminus and represents an amine, wherein a chelator is coupled with attachment group A for the labeling with radionuclides.Cited by (0)
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