CA2323071A1 - Molecules that home to various selected organs or tissues - Google Patents

Molecules that home to various selected organs or tissues Download PDF

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Publication number
CA2323071A1
CA2323071A1 CA002323071A CA2323071A CA2323071A1 CA 2323071 A1 CA2323071 A1 CA 2323071A1 CA 002323071 A CA002323071 A CA 002323071A CA 2323071 A CA2323071 A CA 2323071A CA 2323071 A1 CA2323071 A1 CA 2323071A1
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peptide
seq
mdp
identifying
group
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CA2323071C (en
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Daniel Rajotte
Renata Pasqualini
Erkki I. Ruoslahti
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Sanford Burnham Prebys Medical Discovery Institute
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Priority claimed from US09/042,107 external-priority patent/US6232287B1/en
Priority claimed from US09/258,754 external-priority patent/US6174687B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6425—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/70—Nanostructure
    • Y10S977/788—Of specified organic or carbon-based composition
    • Y10S977/802—Virus-based particle
    • Y10S977/806—Virus-based particle with exterior chemical attachment
    • Y10S977/808—Exterior attachment for targeting, e.g. drug targeting
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/908—Mechanical repair performed/surgical
    • Y10S977/911—Cancer cell destruction
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/908—Mechanical repair performed/surgical
    • Y10S977/912—Cancer cell repair

Abstract

The present invention provides molecules that selectively home to various normal organs or tissues, including to lung, pancreas, skin, retina, prostate, ovary, lymph node, adrenal gland, liver or gut; and provides molecules that selectively home to tumor bearing organs or tissues, including to pancreas bearing a pancreatic tumor or to lung bearing a lung tumor. The invention also provides conjugates, comprising an organ or tissue homing molecule linked to a moiety. Such a moiety can be, for example, a therapeutic agent or a detectable agent. The invention also provides a method of identifying a membrane dipeptidase (MDP)-binding homing molecule that selectively homes to lung endothelium. The method includes the steps of contacting MDP with one or more molecules; and determining specific binding of a molecule to the MDP, where the presence of specific binding identifies the molecule as a MDP-binding homing molecule that selectively homes to lung endothelium. Such MDP-binding homing molecules can be linked to a moiety and, when administered to a subject as a conjugate, can selectively direct the moiety to lung endothelium in the subject.

Claims (123)

1. A peptide that selectively homes to the vasculature of the prostate.
2. The peptide of claim 1, which is selected from the group consisting of SMSIARL (SEQ ID NO: 21), VSFLEYR (SEQ ID NO: 22) and RGRWLAL (SEQ ID NO: 279).
3. A conjugate, comprising the peptide of claim 1 linked to a moiety.
4. The conjugate of claim 3, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
5. A method of identifying prostate, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 1; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as prostate.
6. A method of identifying a target molecule expressed by prostate, comprising the method of claim 5, further comprising the steps of:
c) obtaining a sample of said prostate:
and d) identifying the target molecule, which is bound by said peptide.
7. A method of treating a prostate pathology in a subject, comprising administering a peptide of claim 1 to the subject, wherein said peptide selectively homes to prostate, thereby treating the prostate pathology.
8. A lung homing peptide having the amino acid sequence:
X1-G-F-E-X2 (SEQ ID NO: 17) wherein X1 and X2 each is 1 to 10 independently selected amino acids.
9. The lung homing peptide of claim 8, which is selected from the group consisting of CGFECVRQCPERC
(SEQ ID NO: 1) and CGFELETC (SEQ ID NO: 2).
10. A lung homing peptide selected from the group consisting of CTLRDRNC (SEQ ID NO: 15) and CIGEVEVC
(SEQ ID NO: 16).
11. A lung homing peptide selected from the group consisting of CLAKENVVC (SEQ ID NO: 13), CVGNLSMC
(SEQ ID NO: 37), CKGQRDFC (SEQ ID NO: 39), CNMGLTRC (SEQ
ID NO: 41), CHEGYLTC (SEQ ID NO: 42), CLRPYLNC (SEQ ID
NO: 45), CMELSKQC (SEQ ID NO: 47), CLFSDENC (SEQ ID NO:
52), CWRGDRKIC (SEQ ID NO: 56), CMSWDAVSC (SEQ ID NO:
64), CKWSRLHSC (SEQ ID NO: 65), CTVNEAYKTRMC (SEQ ID NO:
75), CRLRSYGTLSLC (SEQ ID NO: 76), CRPWHNQAHTEC (SEQ ID
NO: 82), CSEAASRMIGVC (SEQ ID NO: 84), CWEEHPSIKWWC (SEQ
ID NO: 85), CGVGCPGLCGGAC (SEQ ID NO: 104) and CGGACGGVCTGGC (SEQ ID NO: 114).
12. A conjugate, comprising the lung homing molecule of claim 8, claim 9, claim 10 or claim 11 linked to a moiety.
13. The conjugate of claim 12, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
14. A method of identifying lung, comprising the steps of:
a) contacting a tissue or organ with a lung homing peptide of claim 8, claim 9, claim 10 or claim 11; and b) detecting binding of said lung homing peptide to said organ or tissue, thereby identifying the organ or tissue as lung.
15. A method of identifying a target molecule expressed by lung, comprising the method of claim 14, further comprising the steps of:
c) obtaining a sample of said lung; and d) identifying the target molecule, which is bound by said lung homing peptide.
16. A method of treating a lung pathology in a subject, comprising administering a lung homing peptide of claim 8, claim 9, claim 10 or claim 11 to the subject, wherein said lung homing peptide selectively homes to lung, thereby treating the lung pathology.
17. A peptide that selectively homes to the vasculature of the skin.
18. The peptide of claim 17, having the amino acid sequence CVALCREACGEGC (SEQ ID NO: 3).
19. The peptide of claim 17, which is selected from the group consisting of CWNICPGGCRALC (SEQ ID
NO: 175), CKGTCVLGCSEEC (SEQ ID NO: 177), CSSGCSKNCLEMC
(SEQ ID NO: 181), CAVRCDGSCVPEC (SEQ ID NO: 184) and CGGGCQWGCAGEC (SEQ ID NO: 191).
20. A conjugate, comprising the peptide of claim 17 linked to a moiety.
21. The conjugate of claim 20, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
22. A method of identifying skin, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 17; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as skin.
23. A method of identifying a target molecule expressed by skin, comprising the method of claim 22, further comprising the steps of:
c) obtaining a sample of said skim and d) identifying the target molecule, which is bound by said peptide.
24. A method of treating a skin pathology in a subject, comprising administering a peptide of claim 17 to the subject, wherein said peptide selectively homes to skin, thereby treating the skin pathology.
25. A peptide that selectively homes to the vasculature of the retina.
26. The peptide of claim 25, having the amino acid sequence:
X1-R-D-V-X2 (SEQ ID NO: 32) wherein X1 and X2 each is 1 to 10 independently selected amino acids.
27. The peptide of claim 26, which is selected from the group consisting of CSCFRDVCC (SEQ ID NO: 5) and CRDVVSVIC (SEQ ID NO: 6).
28. The peptide of claim 25, which is selected from the group consisting of CGEFKVGC (SEQ ID NO: 14), CMDSQSSC (SEQ ID NO: 228), CNQRTNRESGNC (SEQ ID NO: 231), CLLNYTYC (SEQ ID NO: 238), CQASASDHC (SEQ ID NO: 242), CVTSNLRVC (SEQ ID NO: 250) and CRARIRAEDISC (SEQ ID NO:
263).
29. A conjugate, comprising the peptide of claim 25 linked to a moiety.
30. The conjugate of claim 29, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
31. A method of identifying retina, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 25; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as retina.
32. A method of identifying a target molecule expressed by retina, comprising the method of claim 31, further comprising the steps of:
c) obtaining a sample of said retina; and d) identifying the target molecule, which is bound by said peptide.
33. A method of treating a retina pathology in a subject, comprising administering a peptide of claim 25 to the subject, wherein said peptide selectively homes to retina, thereby treating the retina pathology.
34. A peptide that selectively homes to the vasculature of the pancreas.
35. The peptide of claim 34, having the amino acid sequence SWCEPGWCR (SEQ ID NO: 4).
36. The peptide of claim 34, having the amino acid sequence GLCNGATCM (SEQ ID NO: 123).
37. A conjugate, comprising the peptide of claim 34 linked to a moiety.
38. The conjugate of claim 37, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
39. A method of identifying pancreas, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 34; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as pancreas.
40. A method of identifying a target molecule expressed by pancreas, comprising the method of claim 39, further comprising the steps of:
c) obtaining a sample of said pancreas;
and d) identifying the target molecule, which is bound by said peptide.
41. A method of treating a pancreas pathology in a subject, comprising administering a peptide of claim 34 to the subject, wherein said peptide selectively homes to pancreas, thereby treating the pancreas pathology.
42. A peptide that selectively homes to the vasculature of the gut.
43. The peptide of claim 42, having the amino acid sequence:
Y-S-G-K-W-X1 ~(SEQ ID NO: 433) wherein X1 is 1 to 10 independently selected amino acids.
44. The peptide of claim 43, which is selected from the group consisting of YSGKWGG (SEQ.ID NO: 9) and YSGKWGW (SEQ ID NO: 156).
45. The peptide of claim 42, having the amino acid sequence:
X1-R-G-S-X2 (SEQ ID NO: 434) wherein X1 and X2 each is 1 to 10 independently selected amino acids.
46. The peptide of claim 45, which is selected from the group consisting of VRRGSPG (SEQ ID NO: 164), GGRGSWE (SEQ ID NO: 167) and FRVRGSP (SEQ ID NO: 169).
47. The peptide of claim 42, having an amino acid sequence selected from the group consisting of YAGFFLV (SEQ ID NO: 150), SRRQPLS (SEQ ID NO: 153), MSPQLAT (SEQ ID NO: 159), WIEEAER (SEQ ID NO: 161) and GISAVLS (SEQ ID NO: 166).
48. A conjugate, comprising the peptide of claim 42 linked to a moiety.
49. The conjugate of claim 48, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
50. A method of identifying gut, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 42; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as gut.
51. A method of identifying a target molecule expressed by gut, comprising the method of claim 50, further comprising the steps of:
c) obtaining a sample of said gut; and d) identifying the target molecule, which is bound by said peptide.
52. A method of treating a gut pathology in a subject, comprising administering a peptide of claim 42 to the subject, wherein said peptide selectively homes to gut, thereby treating the gut pathology.
53. A peptide that selectively homes to the vasculature of the ovary.
54. The peptide of claim 53, which is selected from the group consisting of EVRSRLS.(SEQ ID NO: 10) and RVGLVAR (SEQ ID NO: 11).
55. A conjugate, comprising the peptide of claim 53 linked to a moiety.
56. The conjugate of claim 55, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
57. A method of identifying ovary, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 53; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as ovary.
58. A method of identifying a target molecule expressed by ovary, comprising the method of claim 57, further comprising the steps of:
c) obtaining a sample of said ovary; and d) identifying the target molecule, which is bound by said peptide.
59. A method of treating an ovary pathology in a subject, comprising administering a peptide of claim 53 to the subject, wherein said peptide selectively homes to ovary, thereby treating the ovary pathology.
60. A peptide that selectively homes to the vasculature of the adrenal gland.
61. The peptide of claim 60, having the amino acid sequence:
X1-L-P-R-X2 (SEQ ID NO: 431) wherein X1 and X2 each is 1 to 10 independently selected amino acids.
62. The peptide of claim 61, which is selected from the group consisting of LMLPRAD (SEQ ID NO: 27) and LPRYLLS (SEQ ID NO: 28).
63. The peptide of claim 60, having the amino acid sequence:
X1-L-A-G-G-X2 (SEQ ID NO: 432) wherein X1 is 1 to 10 independently selected amino acids wherein X2 is 0 to 10 independently selected amino acids.
64. The peptide of claim 63, which is selected from the group consisting of R(Y/F)LLAGG (SEQ ID NO: 404) and RYPLAGG (SEQ ID NO: 389).
65. The peptide of claim 60, which is selected from the group consisting of FSDVHFW (SEQ ID NO: 381) and GYVAVMT (SEQ ID NO: 400).
66. A conjugate, comprising the peptide of claim 60 linked to a moiety.
67. The conjugate of claim 66, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
68. A method of identifying adrenal gland, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 60; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as adrenal gland.
69. A method of identifying a target molecule expressed by adrenal gland, comprising the method of claim 68, further comprising the steps of:
c) obtaining a sample of said adrenal gland; and d) identifying the target molecule, which is bound by said peptide.
70. A method of treating a adrenal gland pathology in a subject, comprising administering a peptide of claim 60 to the subject, wherein said peptide selectively homes to adrenal gland, thereby treating the adrenal gland pathology.
71. A peptide that selectively homes to the vasculature of the liver.
72. The peptide of claim 71, which is selected from the group consisting of VKSVCRT (SEQ ID NO: 12), SRRFVGG (SEQ ID NO: 406), VGSFIYS (SEQ ID NO: 411) and WRQNMPL (SEQ ID NO: 418).
73. A conjugate, comprising the peptide of claim 70 linked to a moiety.
74. The conjugate of claim 73, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
75. A method of identifying liver, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 70; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as liver.
76. A method of identifying a target molecule expressed by liver, comprising the method of claim 75, further comprising the steps of:
c) obtaining a sample of said liver; and d) identifying the target molecule, which is bound by said peptide.
77. A method of treating a liver pathology in a subject, comprising administering a peptide of claim 70 to the subject, wherein said peptide selectively homes to liver, thereby treating the liver pathology.
78. A lymph node homing peptide selected from the group consisting of AGCSVTVCG (SEQ ID NO: 315), GSCSMFPCS (SEQ ID NO: 317), SECAYRACS (SEQ ID NO: 319), WSCARPLCG (SEQ ID NO: 320), GLCQIDECR (SEQ ID NO: 329), DRCLDIWCL (SEQ ID NO: 331), PLCMATRCA (SEQ ID NO: 333), RDCSHRSCE (SEQ ID NO: 334), NPCLRAACI (SEQ ID NO: 335), PTCAYGWCA (SEQ ID NO: 336), LECVANLCT (SEQ ID NO: 337), RKCGEEVCT (SEQ ID NO: 338), EPCTWNACL (SEQ ID NO: 339) and QQCQDPYCL (SEQ ID NO: 349).
79. A conjugate, comprising the peptide of claim 78 linked to a moiety.
80. The conjugate of claim 79, wherein said moiety is selected from the group consisting of a therapeutic agent, a detectable agent and a tag.
81. A method of identifying lymph node, comprising the steps of:
a) contacting a tissue or organ with a peptide of claim 78; and b) detecting binding of said peptide to said organ or tissue, thereby identifying the organ or tissue as lymph node.
82. A method of identifying a target molecule expressed by lymph node, comprising the method of claim 81, further comprising the steps of:
c) obtaining a sample of said lymph node;
and d) identifying the target molecule, which is bound by said peptide.
83. A method of treating a lymph node pathology in a subject, comprising administering a peptide of claim 78 to the subject, wherein said peptide selectively homes to lymph node, thereby treating the lymph node pathology.
84. A method of identifying a MDP-binding homing molecule that selectively homes to lung endothelium, comprising:
(a) contacting membrane dipeptidase (MDP) with one or more molecules; and (b) determining specific binding of a molecule to said MDP, wherein the presence of specific binding identifies said molecule as a MDP-binding homing molecule that selectively homes to lung endothelium.
85. The method of claim 84, wherein said MDP
is substantially purified.
86. The method of claim 85, wherein said substantially purified MDP is immobilized to a support.
87. The method of claim 84, wherein said MDP
is human MDP having SEQ ID NO: 448.
88. A method of selectively directing a moiety to lung endothelium in a subject, comprising administering to said subject a conjugate comprising a moiety linked to a MDP-binding homing molecule identified by the method of claim 84, whereby said moiety is selectively directed to lung endothelium in said subject.
89. The method of claim 88, wherein said MDP-binding homing molecule is a peptide comprising the sequence:
X1-G-F-E-X2 (SEQ ID NO: 17) wherein X1 and X2 each is 1 to 10 independently selected amino acids.
90. The method of claim 89, wherein said MDP-binding homing peptide comprises a sequence selected from the group consisting of CGFECVRQCPERC (SEQ ID NO: 1) and CGFELETC (SEQ ID NO: 2).
91. The method of claim 88, wherein said MDP-binding homing molecule comprises the following Structure 1:
wherein R2 and R3 are hydrocarbon radicals in the range respectively of 3-10 and 1-15 carbon atoms; in either one of these R2 or R3 hydrocarbon chains 1-6 hydrogens may be replaced by halogens or a nonterminal methylene may be replaced by oxygen or sulfur, including oxidized forms of the latter; additionally, a terminal hydrogen in R3 can also be replaced by hydroxyl or thiol, which may be acylated or carbamoylated; or the hydrogen can be replaced by amino, which may be derivatized as in an acylamino, ureido, amidino, quanidino, or alkyl or substituted amino group, including quaternary nitrogen grouping; or, there may be replacement by acid groups such as carboxylic, phosphonic or sulfonic acid groups or esters or amides thereof, or cyano; or combinations thereof, such as a terminal amino acid grouping; and R1 is hydrogen or lower alkyl (C1-6) or dialkylaminoalkyl, or a pharmaceutically acceptable cation.
92. The method of claim 91, wherein said MDP-binding homing molecule is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropane carboxamido)-2-heptenoic acid.
93. The method of claim 91, wherein R2 is branched alkyl or cycloalkyl with a limitation that the carbon adjacent to the carbonyl cannot be tertiary.
94. The method of claim 93, wherein R3 is n-alkyl (1-9 carbons) or n-alkyl (1-9 carbons) having a terminal substituent which is a quaternary nitrogen, amine derivative or amino acid derived group.
95. The method of claim 94, wherein R2 is 2,2-dimethylcyclopropyl or 2,2-dichlorocyclopropyl and R2 is a hydrocarbon chain of 3 to 7 carbon atoms without a terminal substituent or having a terminal substituent which is trimethylammonium, amidino, guanidino or 2-amino-2-carboethylthio.
96. The method of claim 95, wherein said MDP-binding homing molecule is selected from the group consisting of:
Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-trimethylammonium hydroxide-2-octenoic acid inner salt;
Z-2-(2,2-dichlorocyclopropanecarboxamido)-8-trimethylammonium hydroxide-2-octenoic acid inner salt;
Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino-2-octenoic acid;
Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino-2-octenoic acid Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-ureido-2-octenoic acid Z-8-(1-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid;
Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid (racemic and dextrorotatory forms);
Z-2-(2,2-dichlorocyclopropanecarboxamido)-2-octenoic acid;
7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid; and 6-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-hexenoic acid.
97. The method of claim 88, wherein said moiety is a gene therapy vector.
98. The method of claim 88, wherein said moiety is a drug.
99. A method of reducing or preventing lung metastasis in a subject having cancer, comprising administering to said subject a membrane dipeptidase (MDP)-binding homing molecule.
100. The method of claim 99, wherein said MDP-binding homing molecule is a lung homing peptide comprising the sequence:
X1-G-F-E-X2 (SEQ ID NO: 17) wherein X1 and X2 each is 1 to 10 independently selected amino acids.
101. The method of claim 100, wherein said MDP-binding homing peptide comprises a sequence selected from the group consisting of CGFECVRQCPERC (SEQ ID NO: 1) and CGFELETC (SEQ ID NO: 2).
102. The method of claim 101, wherein said MDP-binding homing peptide is a peptide selected from the group consisting of CGFECVRQCPERC (SEQ ID NO: 1) and CGFELETC (SEQ ID NO: 2).
103. The method of claim 99, wherein said MDP-binding homing molecule comprises the following Structure 1:
wherein R2 and R3 are hydrocarbon radicals in the range respectively of 3-10 and 1-15 carbon atoms; in either one of these R2 or R3 hydrocarbon chains 1-6 hydrogens may be replaced by halogens or a nonterminal methylene may be replaced by oxygen or sulfur, including oxidized forms of the latter; additionally, a terminal hydrogen in R3 can also be replaced by hydroxyl or thiol, which may be acylated or carbamoylated; or the hydrogen can be replaced by amino, which may be derivatized as in an acylamino, ureido, amidino, quanidino, or alkyl or substituted amino group, including quaternary nitrogen grouping; or, there may be replacement by acid groups such as carboxylic, phosphonic or sulfonic acid groups or esters or amides thereof, or cyano; or combinations thereof, such as a terminal amino acid grouping; and R1 is hydrogen or lower alkyl (C1-6) or dialkylaminoalkyl, or a pharmaceutically acceptable cation.
104. The method of claim 103, wherein said MDP-binding homing molecule is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropane carboxamido)-2-heptenoic acid.
105. The method of claim 103, wherein R2 is branched alkyl or cycloalkyl with a limitation that the carbon adjacent to the carbonyl cannot be tertiary.
106. The method of claim 105, wherein R3 is n-alkyl (1-9 carbons) or n-alkyl (1-9 carbons) having a terminal substituent which is a quaternary nitrogen, amine derivative or amino acid derived group.
107. The method of claim 106, wherein R2 is 2,2-dimethylcyclopropyl or 2,2-dichlorocyclopropyl and R3 is a hydrocarbon chain of 3 to 7 carbon atoms without a terminal substituent or having a terminal substituent which is trimethylammonium, amidino, guanidino or 2-amino-2-carboethylthio.
108. The method of claim 107, wherein said MDP-binding homing molecule is selected from the group consisting of:
Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-trimethylammonium hydroxide-2-octenoic acid inner salt Z-2-(2,2-dichlorocyclopropanecarboxamido)-8-trimethylammonium hydroxide-2-octenoic acid inner salt Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino-2-octenoic acid;
Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-guanidino-2-octenoic acid;
Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-ureido-2-octenoic acid;
Z-8-(1-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid (racemic and dextrorotatory forms):
Z-2-(2,2-dichlorocyclopropanecarboxamido)-2-octenoic acid;
7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid; and 6-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-hexenoic acid.
109. The method of claim 99, wherein said MDP-binding homing molecule is an MDP inhibitor.
110. The method of claim 109, wherein said MDP
inhibitor exhibits a Ki against MDP of at most 1000 nM.
111. The method of claim 110, wherein said MDP
inhibitor exhibits a Ki against MDP of at most 100 nM.
112. The method of claim 111, wherein said MDP
inhibitor exhibits a Ki against MDP of at most 1 nM.
113. The method of claim 99, wherein said cancer is melanoma.
114. A method of reducing or preventing lung metastasis in a subject having cancer, comprising administering to said subject a membrane dipeptidase (MDP) negative regulatory factor.
115. The method of claim 114, wherein said MDP
negative regulatory factor is a soluble MDP polypeptide.
116. The method of claim 114, wherein said MDP
negative regulatory factor is an antibody that selectively reacts with MDP.
117. A method of reducing or preventing cell homing to lung endothelium in a subject, comprising administering to said subject a membrane dipeptidase (MDP) negative regulatory factor.
118. The method of claim 117, wherein said MDP
negative regulatory factor is a soluble MDP polypeptide.
119. The method of claim 117, wherein said MDP
negative regulatory factor is an antibody that selectively reacts with MDP.
120. A method of identifying a molecule that reduces or prevents lung metastasis, comprising the steps of:
(a) contacting membrane dipeptidase (MDP) with one or more molecules; and (b) determining MDP activity in the presence of said molecule as compared to a control value, wherein diminished MDP activity in the presence of said molecule identifies said molecule as a molecule that reduces or prevents lung metastasis.
121. The method of claim 120, wherein said MDP
is substantially purified.
122. The method of claim 120, wherein MDP
activity is determined by release of D-Phe from Gly-D-Phe.
123. The method of claim 120, further i comprising the steps of:
(c) administering said molecule to a subject having cancer; and (d) assaying lung metastasis in said subject as compared to a control level of metastasis.
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US09/258,754 US6174687B1 (en) 1999-02-26 1999-02-26 Methods of identifying lung homing molecules using membrane dipeptidase
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