US2015104388A1PendingUtilityA1
Analogs of pituitary adenylate cyclase-activating polypeptide (pacap) and methods for their use
Est. expiryNov 2, 2029(~3.3 yrs left)· nominal 20-yr term from priority
A61P 5/16A61P 9/08A61P 5/14A61P 3/10A61P 9/12A61P 9/04A61P 37/06A61P 43/00A61P 9/00A61P 35/02A61P 35/00A61P 37/02A61P 9/10A61P 27/06A61P 25/16A61P 31/04A61P 31/12A61P 31/18A61P 25/14A61P 25/02A61P 3/04A61P 31/20A61P 27/02A61P 25/28A61P 27/16A61P 25/00A61P 29/00A61P 19/04A61P 21/04A61K 38/2278A61P 19/10A61K 47/64A61P 11/06A61P 17/00A61L 31/08A61L 2300/40C07K 14/57563A61K 38/00A61K 45/06A61L 2420/00A61P 1/00A61K 51/088C07K 2319/50A61P 1/04A61L 2300/252A61P 21/00A61P 13/12A61P 1/16A61P 11/00A61L 31/16A61K 47/48246A61K 33/244A61K 33/243A61K 33/242
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Claims
Abstract
This invention relates to novel analogs of pituitary adenylate cyclase-activating polypeptide (PACAP), which are agonists for the PACAP/vasoactive intestinal peptide (VIP) receptors: PAC1, VPAC1 and VPAC2 receptors. These PACAP analogs can be used as prophylactic/therapeutic agents for a wide range of medical disorders, including (but not limited to) cancer and autoimmune disease. These PACAP analogs can be coupled to suitable radionuclides and used in the localization, diagnosis and treatment of disseminated cancers and metastatic tumors, or coupled to small molecule therapeutics and used as vectors for targeted drug delivery. This invention also provides pharmaceutical compositions of one or more PACAP-like compounds of the invention either alone or in combination with one or more other prophylactic/therapeutic agents.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An isolated compound having formula (I), or a pharmaceutically acceptable salt thereof:
R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15- A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 -A 37 -A 38 -R 2 , wherein: A 1 is His, D -His, Tyr, D -Tyr, Trp, D -Trp, Pal, or D -Pal; A 2 is Ser, D -Ser, hSer, N-Me-Ser, Thr, D -Thr, Ala, D -Ala, Ile, D -Ile, Pro, D -Pro, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 3 is Pip; A 4 is Gly, Ala, D -Ala, β-Ala, Gaba, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 5 is Ile, Leu, Nle, Val, Nva, Aib, Acb, Ach, Acpe, or Acpr; A 6 is Phe, Tyr, Trp, Cha, Bip, or Nal; A 7 is Thr, Ser, hSer, or Val; A 8 is Asp, Asn, or Glu; A 9 is Ser, hSer, Thr, Asn, Asp, Ala, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 10 is Tyr, Phe, Cha, Nal, or Trp; A 11 is Ser, hSer, Thr, Ala, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 12 is Arg, Lys, Dab, Dap, or Orn; A 13 is Tyr, Phe, Cha, Nal, or Trp; A 14 is Arg, Lys, Dab, Dap, or Orn; A 15 is Lys, Ala, Dab, Dap, Orn, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 16 is Gln, Glu, Asn, Asp; Aib, Acb, Ach, Acpe, or Acpr; A 17 is Met, Nle, Leu, Ile, Ala, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 18 is Ala, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 19 is Val, Nva, Ser, Leu, Thr, Aib, Acb, Ach, Acpe, or Acpr; A 20 is Lys, Ala, Dab, Dap, Orn, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 21 is Lys, Ala, Dab, Dap, Orn, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 22 is Tyr, Phe, Cha, Nal, Trp, Ala, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 23 is Leu, Nle, Ile, Val, Nva, Aib, Acb, Ach, Acpe, or Acpr; A 24 is Ala, Asn, Abu, Aib, Acb, Ach, Acpe, or Acpr; A 25 is Ala, Val, Leu, Met, Nle, Ile, Ser, hSer, Thr, Abu, Aib, Acb, Ach, Acpe, Acpr, or is omitted; A 26 is Val, Nva, Leu, Met, Nle, Ile, Ala, Abu, Aib, Acb, Ach, Acpe, Acpr, or is omitted; A 27 is Leu, D -Leu, Met, D -Met, Nle, Ile, D -Ile, Val, D -Val, Gaba, Ala, D -Ala, Abu, Aib, Acb, Ach, Acpe, Acpr, or is omitted; A 28 is Gly, Ala, D -Ala, β-Ala, Gaba, Asn, D -Asn, Gln, D -Gln, Asp, D -Asp, Abu, Aib, Acb, Ach, Acpe, Acpr, or is omitted; A 29 is Lys, D -Lys, Arg, D -Arg, Dab, D -Dab, Dap, D -Dap, Orn, D -Orn, or is omitted; A 39 is Arg, D -Arg, Lys, D -Lys, Dab, D -Dab, Dap, D -Dap, Orn, D -Orn, or is omitted; A 31 is Tyr, D -Tyr, Phe, D -Phe, Trp, D -Trp, Cha, Nal, or is omitted; A 32 is Lys, D -Lys, Arg, D -Arg, Dab, D -Dab, Dap, D -Dap, Orn, D -Orn, or is omitted; A 33 is Gln, D -Gln, Glu, D -Glu, Asn, D -Asn, Asp; D -Asp, Abu, Aib, Acb, Ach, Acpe, Acpr, or is omitted; A 34 is Arg, D -Arg, Lys, D -Lys, Dab, D -Dab, Dap, D -Dap, Orn, D -Orn, or is omitted; A 35 is Val, D -Val, Nva, Ser, D -Ser, Thr; D -Thr, Abu, Aib, Acb, Ach, Acpe, Acpr, or is omitted; A 36 is Lys, D -Lys, Arg, D -Arg, Dab, D -Dab, Dap, D -Dap, Orn, D -Orn, or is omitted; A 37 is Asn, D -Asn, Gln, D -Gln, Asp, D -Asp, Ala, D -Ala, Aib, Acb, Ach, Acpe, Acpr, or is omitted; A 38 is Lys, D -Lys, Arg, D -Arg, Dab, D -Dab, Dap, D -Dap, Orn, D -Orn, or is omitted; R 1 is independently selected from H, (C 1 -C 18 )alkyl, and CO(C 1 -C 18 )alkyl, or is omitted; and R 2 is independently selected from OH, NH 2 , (C 1 -C 18 )alkoxyl, and NH(C 1 -C 18 )alkyl, or is omitted.
2 . The compound of claim 1 , wherein the compound is selected from the following, or pharmaceutically acceptable salts thereof:
(SEQ ID NO: 4)
His-Ser-Pip-Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ,
(SEQ ID NO: 5)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Ala Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ,
(SEQ ID NO: 6)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Ala Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ,
(SEQ ID NO: 7)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Ala Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH2,
(SEQ ID NO: 8)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Ala Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ,
(SEQ ID NO: 9)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ,
(SEQ ID NO: 10)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala
Ala Val-Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ,
(SEQ ID NO: 11)
His Ala Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ,
(SEQ ID NO: 12)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys Asn Lys-
NH 2 ,
and
(SEQ ID NO: 13)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met
Ala Val Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys
Asn Lys-NH 2 .
3 . A polypeptide having at least 90% sequence identity to a sequence selected from SEQ ID NOs: 4-13.
4 . The polypeptide of claim 3 , wherein said polypeptide has at least 95% sequence identity to a sequence selected from SEQ ID NOs: 4-13.
5 . The polypeptide of claim 3 , wherein said polypeptide has at least 99% sequence identity to a sequence selected from SEQ ID NOs: 4-13.
6 . The polypeptide of claim 3 further comprising a pharmaceutically acceptable carrier.
7 . The polypeptide of any one of claims 1 to 6 , wherein said polypeptide is conjugated one or more radionuclides or small molecules.
8 . The polypeptide of claim 7 , wherein said radionuclide is 11 C, 13 N, 15 O, 18 F, 52 Fe, 55 Co, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 62 Zn, 63 Zn, 70 As, 71 As 74 As, 76 Br, 79 Br, 82 Rb, 86 Y, 89 Zr, 110 In, 111 In, 120 I, 123 I, 124 I, 125 I, 131 I, 122 Xe, 175 Lu, 154 Gd, 155 Gd, 156 Gd, 157 Gd, 158 Gd, 94m Tc, 94 Tc, or 99m Tc.
9 . The polypeptide of claim 7 , wherein said small molecule is a therapeutic or anticancer agent.
10 . The polypeptide of claim 9 , wherein said therapeutic or anticancer agent is cisplatin, carboplatin, oxaliplatin, bleomycin, mitomycin C, calicheamicins, maytansinoids, geldanamycin, doxorubicin, idarubicin, daunorubicin, epirubicin, busulfan, carmustine (BCNU), lomustine (CCNU), semustine, thalidomide, lenalidomide, methotrexate, azathioprine, 6-mercaptopurine, fludarabine, 5-azacytidine, pentostatin (2′-deoxycoformycin), cytarabine (cytosine arabinoside), gemcitabine, 5-fluorouracil, hydroxyurea, elesclomol, etoposide, teniposide, amsacrine, camptothecin, topotecan, irinotecan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, bortezomib, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, cyclosporine A, tacrolimus (FK506), sirolimus (rapamycin), everolimus, temsirolimus, zotarolimus, or biolimus.
11 . A method for treating, managing, or preventing a disease selected from age-related neurodegenerative disease, a central nervous system disorder, Huntington's disease or other CAG codon repeat expansion disease, a retinal disease, an autoimmune disease, keratoconjunctivitis sicca caused by autoimmune diseases or LASIK surgery, type II diabetes, sepsis caused by a bacteria and/or a virus, an acute or chronic cardiovascular disease, an acute or chronic renal diseases, an acute or chronic pulmonary disease, systemic hypertension, a hematological cancer, an eating disorder, an acute or chronic liver disease, osteoporosis, pre-eclampsia, cell and solid organ transplantation, a cognitive disorder, acquired immunodeficiency syndrome (AIDS) dementia complex, aging of the central nervous system, and a disease caused in part by premature in-frame stop codons that result in the synthesis of truncated nonfunctional proteins, said method comprising administering to a subject in need thereof an effective amount of one or more PACAP-like compounds or a pharmaceutically acceptable salt thereof.
12 . The method of claim 10 , wherein:
i) said age-related neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis; ii) said central nervous system disorder is caused by stroke, heart attack or blunt force trauma, wherein preferably said blunt force trauma is a concussion or spinal cord trauma; iii) said retinal disease is diabetic retinopathy, macular degeneration or glaucoma; iv) said autoimmune disease is rheumatoid arthritis, Crohn's disease, ulcerative colitis, scleroderma, Sjögren's disease, idiopathic membranous nephropathy, Goodpasture's disease, autoimmune hepatitis, myasthenia gravis, multiple sclerosis, Guillain-Barré syndrome, type I diabetes, Hashimoto's thyroiditis, Graves' disease, pemphigus vulgaris, or lupus erythematosus; v) said septsis is caused by a bacterial or viral toxin; vi) said acute or chronic cardiovascular disease is myocardial infarction, atherosclerosis, or restenosis; vii) said acute or chronic renal disease is ischemia/reperfusion injury, nephritis, or drug-induced nephrotoxicity; viii) said acute or chronic pulmonary disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, or pulmonary arterial hypertension; ix) said hematological cancer is a lymphoid or myeloid hematopoietic cancer, wherein preferably said lymphoid or myeloid hematopoietic cancer is a leukemia, a lymphoma, a plasma cell dyscrasia, or an adenocarcinoma; x) said acute or chronic liver disease is ischemia/reperfusion injury, hepatitis, and fatty liver; or xi) said disease caused in part by premature in-frame stop codons that result in the synthesis of truncated nonfunctional proteins is selected from cystic fibrosis, Duchenne muscular dystrophy, Hurler's syndrome, nephropathic cystinosis, polycystic kidney disease, retinitis pigmentosa, and ataxia telangiectasia.
13 . The method of claim 11 or 12 , wherein said subject has an injury to one or more major organs of the body due to treatment with a prophylactic or therapeutic agent other than said PACAP-like compound, trauma, or acute or chronic disease.
14 . The method of any one of claims 11 to 13 , wherein the PACAP-like compounds, or pharmaceutically acceptable salts thereof, bind to one or more of the PACAP/VIP receptors and/or reduce one or more injuries to one or more major organs of the body of said subject due to treatment with a prophylactic or therapeutic agent other than said PACAP-like compound, trauma, or acute or chronic disease.
15 . The method of any one of claims 11 to 14 , wherein the PACAP-like compound comprises the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
16 . The method of claim 15 , wherein said PACAP-like compound is selected from one or more of the following:
(SEQ ID NO: 4)
His-Ser-Pip-Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 5)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Ala Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 6)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Ala Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 7)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Ala Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH2;
(SEQ ID NO: 8)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Ala Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 9)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 10)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala
Ala Val-Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 11)
His Ala Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 12)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys Asn Lys-
NH 2 ;
and
(SEQ ID NO: 13)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met
Ala Val Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys
Asn Lys-NH 2 .
17 . The method of claim 15 , wherein the PACAP-like compound is one or more of the compounds of claim 1 or a pharmaceutically acceptable salt thereof.
18 . The method of claim 11 , wherein said disease is a hematological cancer.
19 . The method of claim 11 , wherein said disease is an autoimmune disease.
20 . The method of claim 18 or 19 , wherein said subject is resistant to treatment with a glucocorticoid.
21 . The method of claim 20 , wherein said glucocorticoid is dexamethasone, prednisolone, methylprednisolone, or prednisone.
22 . The method of claim 18 , 20 , or 21 , wherein said hematological cancer is multiple myeloma.
23 . The method of claims 18 to 22 , wherein said PACAP-like compound has the sequence of SEQ ID NOs: 4-13.
24 . The method of any one of claims 18 and 20 - 22 , wherein said PACAP-like compound has the sequence of SEQ ID NO: 12.
25 . The method of claim 18 or 19 , wherein said administration of said PACAP-like compound in said subject replaces the corticosteroid selected from prednisone or dexamethasone using the COP (cyclophosphamide, vincristine and prednisone) or VAD (vincristine, doxorubicin and dexamethasone) regimen.
26 . The method of claim 11 , wherein the PACAP-like compound is one or more of the compounds of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, linked to a polyethylene glycol polymer with a molecular weight from about 4 kilodaltons to about 40 kilodaltons.
27 . The method of claim 11 , wherein the PACAP-like compound is the unamidated (free acid) form of one or more of the compounds of any one of claims 1 to 9 flanked by amino-acid consensus sequences for one or more proteolytic enzymes.
28 . The method of claim 11 , wherein the PACAP-like compound is one or more peptidomimetic analogs of one or more of the compounds of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
29 . The method of claim 11 , wherein the PACAP-like compound is administered at a dosage that produces a concentration of 10 −14 M to 10 −6 M in the blood of the subject.
30 . The method of claim 11 , wherein the PACAP-like compound is administered by intravenous infusion at a rate of about 1 pmol/kg body weight/hour to about 20 pmol/kg body weight/hour.
31 . The method of claim 30 , wherein the administration by intravenous infusion is for about 1-12 hours.
32 . The method of claim 13 , wherein the injuries to one or more major organs of the body are due to treatment with one or more of cisplatin, carboplatin, oxaliplatin, bleomycin, mitomycin C, calicheamicins, maytansinoids, geldanamycin, doxorubicin, idarubicin, daunorubicin, epirubicin, busulfan, carmustine (BCNU), lomustine (CCNU), semustine, thalidomide, lenalidomide, methotrexate, azathioprine, 6-mercaptopurine, fludarabine, 5-azacytidine, pentostatin (2′-deoxycoformycin), cytarabine (cytosine arabinoside), gemcitabine, 5-fluorouracil, hydroxyurea, elesclomol, etoposide, teniposide, amsacrine, camptothecin, topotecan, irinotecan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, bortezomib, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, cyclosporine A, G418, gentamicin, streptomycin, kanamycin, tobramycin, amikacin, arbekacin, neomycin, netilmicin, paromomycin, rhodostreptomycin, neomycin, framycetin, ribostamycin, bekanamycin, dibekacin, spectinomycin, hygromycin B, paraomomycin sulfate, sisomicin, isepamicin, verdmicin, astromicin, apramycin, amphotericin B, rifampicin, pentamidine, cyclosporine A, tacrolimus (FK506), sirolimus (rapamycin), everolimus, temsirolimus, zotarolimus, or biolimus.
33 . The method of claim 32 , wherein the injury is to the nervous system, heart, lung, kidneys, liver, ear, or gastrointestinal tract.
34 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is injected intraperitoneally one or more times per day.
35 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is injected subcutaneously one or more times per week.
36 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is injected intramuscularly one or more times per week.
37 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is administered intranasally one or more times per day.
38 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is administered as an aerosol one or more times per day.
39 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is administered orally in a time-dependent or pH-dependent formulation one or more times per day.
40 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is administered as a controlled release or a sustained release formulation.
41 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is administered after encapsulation in liposomes or microparticles.
42 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is administered transcutaneously after encapsulation in dendrimers.
43 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is used to coat a metallic or a biodegradable stent.
44 . The method of any one of claims 11 to 33 , wherein the PACAP-like compound is administered in combination with one or more other cytoprotective adjuvants.
45 . The method of claim 44 , wherein said cytoprotective adjuvant is amifostine, dexrazoxane, mesna, palifermin, or N-acetylcysteine.
46 . The method of claim 13 , wherein the injuries to one or more major organs of the body are due to treatment with an unconjugated therapeutic or anticancer agent, a therapeutic or anticancer agent conjugated to a monoclonal antibody or a bioactive peptide, or an unconjugated bioactive peptide.
47 . The method of claim 11 , wherein the PACAP-like compound is one or more of the compounds of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, conjugated to a therapeutic or anticancer agent.
48 . The method of claim 11 , wherein the PACAP-like compound has an additive anticancer effect with one or more other anticancer agents.
49 . The method of claim 11 , wherein the subject is being treated with one or more anticancer agents for a hematopoietic cancer.
50 . The method of claim 11 , wherein the subject is being treated with one or more therapeutic or anticancer agents for a myeloproliferative disorder.
51 . The method of claim 11 , wherein the subject is being treated with one or more therapeutic or anticancer agents for multiple myeloma.
52 . The method of claim 13 , wherein the subject is being treated with an aminoglycoside and wherein the PACAP-like compound is administered to inhibit or reduce side-effects resulting from administration of said aminoglycoside.
53 . The method of claim 52 , wherein said aminoglycoside is amikacin, arbekacin, G418, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, neomycin, framycetin, ribostamycin, bekanamycin, dibekacin, spectinomycin, hygromycin B, paraomomycin sulfate, sisomicin, isepamicin, verdmicin, tobramycin, astromicin, and apramycin.
54 . The method of claim 53 , wherein said PACAP-like compound inhibits or reduces nephotoxicity or ototoxicity caused by said aminoglycoside.
55 . The method of claim 13 or 14 , wherein said prophylactic or therapeutic agent is an anticancer agent, a steroid, an anti-inflammatory agent, or an aminoglycoside.
56 . The method of any one of claims 11 to 55 , wherein said subject is a mammal.
57 . The method of claim 56 , wherein said mammal is a human.
58 . The method of claim 49 , wherein said subject is being treated with a primary therapeutic selected from one or more of cisplatin, carboplatin, oxaliplatin, bleomycin, mitomycin C, calicheamicins, maytansinoids, geldanamycin, doxorubicin, idarubicin, daunorubicin, epirubicin, busulfan, carmustine (BCNU), lomustine (CCNU), semustine, thalidomide, lenalidomide, methotrexate, azathioprine, 6-mercaptopurine, fludarabine, 5-azacytidine, pentostatin (2′-deoxycoformycin), cytarabine (cytosine arabinoside), gemcitabine, 5-fluorouracil, hydroxyurea, elesclomol, etoposide, teniposide, amsacrine, camptothecin, topotecan, irinotecan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, bortezomib, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, cyclosporine A, G418, gentamicin, streptomycin, kanamycin, tobramycin, amikacin, arbekacin, neomycin, netilmicin, paromomycin, rhodostreptomycin, neomycin, framycetin, ribostamycin, bekanamycin, dibekacin, spectinomycin, hygromycin B, paraomomycin sulfate, sisomicin, isepamicin, verdmicin, astromicin, apramycin, amphotericin B, rifampicin, pentamidine, cyclosporine A, tacrolimus (FK506), sirolimus (rapamycin), everolimus, temsirolimus, zotarolimus, or biolimus.
59 . The method of claim 49 , wherein said subject is being treated with a primary therapy that comprises treatment with carmustine, vincristine, paclitaxel, or thalidomide.
60 . The method of claim 58 , wherein said subject has a lymphoid or myeloid cancer.
61 . A method for the localization, diagnosis, or treatment of a disseminated cancer or a metastatic tumor in a subject comprising administering an effective amount of a conjugate comprising one or more PACAP-like compounds or a pharmaceutically acceptable salt thereof coupled to one or more radionuclides.
62 . The method of claim 61 , wherein said one or more PACAP-like compounds bind to one or more of PACAP/VIP receptor on the surface of one or more cells of the disseminated cancer or metastatic tumor.
63 . The method of claim 61 or 62 , wherein said PACAP-like compound comprises the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
64 . The method of claim 63 , wherein said PACAP-like compound is selected from one or more of the following:
(SEQ ID NO: 4)
His-Ser-Pip-Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 5)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Ala Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 6)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Ala Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 7)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Ala Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH2;
(SEQ ID NO: 8)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Ala Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 9)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 10)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala
Ala Val-Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 11)
His Ala Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 12)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys Asn Lys-
NH 2 ;
and
(SEQ ID NO: 13)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met
Ala Val Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys
Asn Lys-NH 2 .
65 . The method of any one of claims 61 to 64 , wherein said disseminated cancer or metastatic tumor is a hematological cancer.
66 . The method of claim 65 , wherein said hematological cancer is leukemia, lymphoma, or myeloma.
67 . The method of any one of claims 61 to 64 , wherein said conjugate targets a cell that is a component of a granuloma caused by one or more infectious agents or an autoimmune disease.
68 . The method of claim 61 , wherein the subject is being treated with one or more of said conjugates for lymphoid or myeloid hematopoietic cancer.
69 . The method of claim 61 , wherein the subject is being treated with one or more of said conjugates for multiple myeloma.
70 . The method of any one of claims 61 to 69 , wherein said subject is a mammal.
71 . The method of claim 70 , wherein said mammal is a human.
72 . A method of producing a conjugate comprising coupling one or more radionuclides or small molecules to one or more PACAP-like compounds.
73 . The method of claim 72 , wherein said PACAP-like compound comprises the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
74 . The method of claim 73 , wherein said PACAP-like compound is selected from one or more of the following, or a pharmaceutically acceptable salt thereof:
(SEQ ID NO: 4)
His-Ser-Pip-Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 5)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Ala Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 6)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Ala Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 7)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Ala Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH2;
(SEQ ID NO: 8)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Ala Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 9)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 10)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala
Ala Val-Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 11)
His Ala Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 12)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys Asn Lys-
NH 2 ;
and
(SEQ ID NO: 13)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met
Ala Val Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys
Asn Lys-NH 2 .
75 . The method of claim 73 or 74 , wherein said radionuclide is selected from 11 C, 13 N, 15 O, 18 F, 52 Fe, 55 Co, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 62 Zn, 63 Zn, 70 As, 71 As, 74 As, 76 Br, 79 Br, 82 Rb, 86 Y, 89 Zr, 110 In, 111 In, 120 I, 123 I, 124 I, 125 I, 131 I, 122 Xe, 175 Lu, 154 Gd, 155 Gd, 156 Gd, 157 Gd, 158 Gd, 94m Tc, 94 Tc, and 99m Tc.
76 . The method of claim 73 or 74 , wherein said small molecule is a therapeutic or anticancer agent.
77 . The method of claim 76 , wherein said therapeutic or anticancer agent is cisplatin, carboplatin, oxaliplatin, bleomycin, mitomycin C, calicheamicins, maytansinoids, geldanamycin, doxorubicin, idarubicin, daunorubicin, epirubicin, busulfan, carmustine (BCNU), lomustine (CCNU), semustine, thalidomide, lenalidomide, methotrexate, azathioprine, 6-mercaptopurine, fludarabine, 5-azacytidine, pentostatin (2′-deoxycoformycin), cytarabine (cytosine arabinoside), gemcitabine, 5-fluorouracil, hydroxyurea, elesclomol, etoposide, teniposide, amsacrine, camptothecin, topotecan, irinotecan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, bortezomib, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, cyclosporine A, G418, gentamicin, streptomycin, kanamycin, tobramycin, amikacin, arbekacin, neomycin, netilmicin, paromomycin, rhodostreptomycin, neomycin, framycetin, ribostamycin, bekanamycin, dibekacin, spectinomycin, hygromycin B, paraornomycin sulfate, sisomicin, isepamicin, verdmicin, astromicin, apramycin, amphotericin B, rifampicin, pentamidine, cyclosporine A, tacrolimus (FK506), sirolimus (rapamycin), everolimus, temsirolimus, zotarolimus, or biolimus.
78 . A method for targeting delivery of a therapeutic or anticancer agent to a specific cell or tissue of a subject comprising administering to said subject an effective amount of a conjugate comprising one or more PACAP-like compounds, or a pharmaceutically acceptable salt thereof, coupled to one or more small molecules.
79 . The method of claim 78 , wherein said one or more PACAP-like compounds bind to one or more PACAP/VIP receptors on the surface of said cell or tissue and the conjugate enters the interior of the cell or tissue by receptor-mediated endocytosis.
80 . The method of claim 78 or 79 , wherein said PACAP-like compound comprises the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
81 . The method of claim 80 , wherein said PACAP-like compound is selected from one or more of the following, or a pharmaceutically acceptable salt thereof:
(SEQ ID NO: 4)
His-Ser-Pip-Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 5)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Ala Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 6)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Ala Lys Aib Ala Ala Val-
Lys Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 7)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Lys Ala Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH2;
(SEQ ID NO: 8)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val-
Ala Lys Tyr Leu Ala Ala Val Leu Aib Lys Arg Tyr Lys Gln Lys Val Lys Asn D-
Lys-NH 2 ;
(SEQ ID NO: 9)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 10)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala
Ala Val-Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 11)
His Ala Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Aib Ala Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu-NH 2 ;
(SEQ ID NO: 12)
His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met Ala Val
Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys Asn Lys-
NH 2 ;
and
(SEQ ID NO: 13)
N-acetyl-His Ser Pip Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met
Ala Val Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys
Asn Lys-NH 2 .
82 . The method of any one of claims 78 to 81 , wherein said subject has a disease.
83 . The method of claim 82 , wherein said disease is selected from age-related neurodegenerative disease, a central nervous system disorder, Huntington's disease or other CAG codon repeat expansion disease, a retinal disease, an autoimmune disease, keratoconjunctivitis sicca caused by autoimmune diseases or LASIK surgery, type II diabetes, sepsis caused by a bacteria and/or a virus, an acute or chronic cardiovascular disease, an acute or chronic renal diseases, an acute or chronic pulmonary disease, systemic hypertension, a hematological cancer, an eating disorder, an acute or chronic liver disease, osteoporosis, pre-eclampsia, cell and solid organ transplantation, a cognitive disorder, acquired immunodeficiency syndrome (AIDS) dementia complex, aging of the central nervous system, and a disease caused in part by premature in-frame stop codons that result in the synthesis of truncated nonfunctional proteins.
84 . The method of claim 83 , wherein:
i) said age-related neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis; ii) said central nervous system disorder is caused by stroke, heart attack or blunt force trauma, wherein preferably said blunt force trauma is a concussion or spinal cord trauma; iii) said retinal disease is diabetic retinopathy, macular degeneration or glaucoma, iv) said autoimmune disease is rheumatoid arthritis, Crohn's disease, ulcerative colitis, scleroderma, Sjögren's disease, idiopathic membranous nephropathy, Goodpasture's disease, autoimmune hepatitis, myasthenia gravis, multiple sclerosis, Guillain-Barré syndrome, type I diabetes, Hashimoto's thyroiditis, Graves' disease, pemphigus vulgaris, or lupus erythematosus; v) said septsis is caused by a bacterial or viral toxin; vi) said acute or chronic cardiovascular disease is myocardial infarction, atherosclerosis, or restenosis; vii) said acute or chronic renal disease is ischemia/reperfusion injury, nephritis, or drug-induced nephrotoxicity; viii) said acute or chronic pulmonary disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, or pulmonary arterial hypertension; ix) said hematological cancer is a lymphoid or myeloid hematopoietic cancer, wherein preferably said lymphoid or myeloid hematopoietic cancer is a leukemia, a lymphoma, a plasma cell dyscrasia, or an adenocarcinoma; x) said acute or chronic liver disease is ischemia/reperfusion injury, hepatitis, and fatty liver; or xi) said disease caused in part by premature in-frame stop codons that result in the synthesis of truncated nonfunctional proteins is selected from cystic fibrosis, Duchenne muscular dystrophy, Hurler's syndrome, nephropathic cystinosis, polycystic kidney disease, retinitis pigmentosa, and ataxia telangiectasia.
85 . The method of claim 83 or 84 , wherein said disease causes injury to one or more major organs of the body of said subject due to treatment with a therapeutic or anticancer agent other than said PACAP-like compound, trauma, or acute or chronic disease.
86 . The method of any one of claims 78 to 85 , wherein the conjugate, or a pharmaceutically acceptable salt thereof, binds to one or more of the PACAP/VIP receptors and/or reduce one or more injuries to one or more major organs of the body of said subject due to treatment with a prophylactic or therapeutic other than said PACAP-like compound, trauma, or acute or chronic disease.
87 . The method of claim 83 , wherein said disease is cancer or an autoimmune disease.
88 . The method of any one of claims 78 to 87 , wherein said small molecule is therapeutic agent or anticancer agent.
89 . The method of claim 88 , wherein said therapeutic or anticancer agent is cisplatin, carboplatin, oxaliplatin, bleomycin, mitomycin C, calicheamicins, maytansinoids, geldanamycin, doxorubicin, idarubicin, daunorubicin, epirubicin, busulfan, carmustine (BCNU), lomustine (CCNU), semustine, thalidomide, lenalidomide, methotrexate, azathioprine, 6-mercaptopurine, fludarabine, 5-azacytidine, pentostatin (2′-deoxycoformycin), cytarabine (cytosine arabinoside), gemcitabine, 5-fluorouracil, hydroxyurea, elesclonnol, etoposide, teniposide, amsacrine, camptothecin, topotecan, irinotecan, chlorambucil, cyclophosphamide, ifosfamide, melphalan, bortezomib, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, cyclosporine A, G418, gentamicin, streptomycin, kanamycin, tobramycin, amikacin, arbekacin, neomycin, netilmicin, paromomycin, rhodostreptomycin, neomycin, framycetin, ribostamycin, bekanamycin, dibekacin, spectinomycin, hygromycin B, paraomomycin sulfate, sisomicin, isepamicin, verdmicin, astromicin, apramycin, amphotericin B, rifampicin, pentamidine, cyclosporine A, tacrolimus (FK506), sirolimus (rapamycin), everolimus, temsirolimus, zotarolimus, or biolimus.
90 . The method of any one of claims 78 to 88 , wherein said small molecule is anti-inflammatory agent and said subject is being treated for rheumatoid arthritis.
91 . The method of any one of claims 78 to 88 , wherein said small molecule is an anticancer agent and said subject is being treated for multiple myeloma.
92 . The method of claim 86 , wherein said prophylactic or therapeutic agent is an anticancer agent, a steroid, anti-inflammatory agent, or an aminoglycoside.
93 . The method of any one of claim 82 or 92 , wherein said subject is a mammal.
94 . The method of claim 93 , wherein said mammal is a human.
95 . A method for detecting a granuloma in subject comprising administering to said subject an effective amount of the polypeptide of any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, conjugated to a radionuclide.
96 . The method of claim 95 , wherein said radionuclide is 11 C, 13 N, 15 O, 18 F, 52 Fe, 55 Co, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 62 Zn, 63 Zn, 70 As, 71 As, 74 As, 76 Br, 79 Br, 82 Rb, 86 Y, 89 Zr, 110 In, 111 In, 120 I, 123 I, 124 I, 125 I, 131 I, 122 Xe, 175 Lu, 154 Gd, 155 Gd, 156 Gd, 157 Gd, 158 Gd, 94m Tc, 94 Tc, and 99m Tc.
97 . The method of claim 95 or 96 , wherein said subject has an infectious or autoimmune disease.
98 . The method of any one of claims 95 to 97 , wherein the polypeptide is a PACAP-like compound that is capable of binding to one or more of the PACAP/VIP receptors on the surface of target cells.
99 . The method of claim 95 or 96 , wherein said subject is being treated for tuberculosis.
100 . The method of any one of claims 95 to 99 , wherein said subject is being treated with one or more of said conjugates comprising an imaging agent for tuberculosis.
101 . The method of claim 99 , wherein said subject is being treated with 99m Tc-isonicotinylhydrazine (INH).
102 . The method of claim 95 or 98 , wherein the subject is being treated for Crohn's disease.
103 . The method of claim 102 , wherein said subject is being treated with one or more of said conjugates comprising an imaging agent for Crohn's disease.
104 . The method of any one of claims 95 to 103 , wherein said subject is a mammal.
105 . The method of claim 104 , wherein said subject is a human.Join the waitlist — get patent alerts
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