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WO1998037100B1 - Therapeutic use of the smr1 protein and active derivatives thereof - Google Patents

Therapeutic use of the smr1 protein and active derivatives thereof

Info

Publication number
WO1998037100B1
WO1998037100B1 PCT/EP1998/000956 EP9800956W WO9837100B1 WO 1998037100 B1 WO1998037100 B1 WO 1998037100B1 EP 9800956 W EP9800956 W EP 9800956W WO 9837100 B1 WO9837100 B1 WO 9837100B1
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
xqhnpr
therapeutic
smr1
biologically active
Prior art date
Application number
PCT/EP1998/000956
Other languages
French (fr)
Other versions
WO1998037100A3 (en
WO1998037100A2 (en
Filing date
Publication date
Priority claimed from US08/801,405 external-priority patent/US6589750B2/en
Application filed filed Critical
Priority to US09/367,703 priority Critical patent/US6818405B2/en
Priority to AU67219/98A priority patent/AU6721998A/en
Priority to EP98912339A priority patent/EP1007566B1/en
Priority to DE69835680T priority patent/DE69835680T2/en
Priority to CA002281912A priority patent/CA2281912A1/en
Publication of WO1998037100A2 publication Critical patent/WO1998037100A2/en
Publication of WO1998037100A3 publication Critical patent/WO1998037100A3/en
Publication of WO1998037100B1 publication Critical patent/WO1998037100B1/en
Priority to US10/620,462 priority patent/US7429448B2/en

Links

Abstract

The present invention pertains to the use of a peptide molecule consisting in a maturation product of SMR1 (Submandibular rat protein 1) of structural formula QHNPR, as well as the biologically active derivatives of the said peptide, for preventing or treating diseases associated with a mineral ion imbalance in a human or an animal body. More particularly, the present invention relates to the therapeutic use of the above-cited molecules for preventing or treating an hydromineral imbalance in organs and tissues such as kidney, bone, dental enamel, dental ivory, gut matrix, pancreas or glandular gastric mucosa. This invention also deals with therapeutic compositions comprising a pharmaceutically active amount of the above-described therapeutic molecules as well as with therapeutic methods using the said therapeutic compositions. Finally, the present invention relates to processes for selecting ligand molecules that possess an agonist or an antagonist biological activity on the target receptor of the QHNPR pentapeptide as well as to the selected ligand molecules themselves.

Claims

88
AMENDED CLAIMS
[received by the International Bureau on 19 January 1999 (19 01 99), original claims 1-45 replaced by amended claims 1-50 (9 pages)]
1 A therapeutic method for preventing or treating diseases caused by a metabolic imbalance, such as a mineral ion imbalance in a mammal said method comprising administering to the mammal a composition comprising a pharmaceutically active amount of an SMR1 protein, or a maturation product of the SMR1 protein or of one of its biologically active derivatives 2 A therapeutic method for preventing or treating a disorder affecting the bone in a mammal, said method comprising administering to the mammal a composition comprising a pharmaceutically active amount of an SMR1 protein, or a maturation product of the SMR1 protein or of one of its biologically
active derivatives 3 A therapeutic method according to claim 2 for preventing or treating osteoporosis
4 The therapeutic method according to claim 1 or 2 nerein said mammal is a human
5 The therapeutic method according to claim 1 or 2 wherein the therapeutic composition comprises a peptide of formula XQHNPR, wherein X is a hydrogen atom, an ammo acid V, or a polypeptide VR, VRG, VRGP VRGPR or VRGPRR, or one of its biologically active derivatives
6 The therapeutic method according to claim 5 wherein the peptide
XQHNPR or one of its biologically active derivative peptides comprises one or more ammo acids in the D-form
7 The therapeutic method according to claim 1 or 2 wherein the 89
therapeutic composition is a liquid solution
8 The therapeutic method according to claim 1 or 2 wherein the
therapeutic composition is a gel
9 The therapeutic method according to claim 1 or 2 wherein the
therapeutic composition is a dry powder
10 The therapeutic method according to claim 1 or 2 wherein the
therapeutic composition is a controlled drug delivery device
11 The therapeutic method according to claim 1 or 2 wherein the
therapeutic composition is administered locally near a site to be treated 12 The therapeutic method according to claim 1 or 2 wherein the therapeutic composition is administered by the orally route
13 A method for screening ligand molecules that specifically bind to a target receptor for an XQHNPR peptide, comprising the steps of a) preparing a confluent target cell culture monolayer or preparing a target organ specimen or a tissue sample, b) adding a candidate molecule to be tested in competition with a half-saturating concentration of labeled peptide,
c) incubating the cell culture, organ specimen or tissue sample of
step a) in the presence of the labeled candidate molecule for a time sufficient for specific binding to take place, and
d) quantifying the label specifically bound to the target cell culture, organ specimen or tissue sample
14 A method for determining an affinity of ligand molecules that
specifically bind to a target receptor for a XQHNPR peptide, comprising the steps of
a) preparing a confluent target cell culture monolayer or preparing a target organ specimen or a tissue sample, b) adding a candidate molecule to be tested that has been previously
labeled with a radioactive or a nonradioactive label, c) incubating the cell culture, organ specimen or tissue sample of step a) in the presence of the labeled candidate molecule for a time sufficient for
specific binding to take place, d) quantifying the label specifically bound to the target cell culture,
organ specimen or tissue sample
15 A method for screening candidate ligand molecules that possess
an agonist or an antagonist biological activity on a target receptor of an XQHNPR peptide, comprising the steps of a) preparing a biological material comprising a confluent target cell culture monolayer, a target organ specimen or a tissue sample in cryosections or slices,
b) incubating the cell culture, organ specimen or tissue sample of step a) in the presence of (i) 10"10 - 10'5 M of a candidate molecule and (n) a
submaximal concentration of QHNPR for a time sufficient for an adeπylate cyclase activation to take place, and
c) quantifying adenylate cyclase activity present in the biological material of step a), respectively in the presence or in the absence of the candidate
ligand molecule and in the presence or in the absence of a submaximal concentration of QHNPR
16 A biologically active derivative of the XQHNPR polypeptide which has been obtained according to the method of claim 15, provided that said biologically active derivative does not have the following structure Y-HNP-Z, 91
wherein Y denotes a glutamme (Q), a pyroglutamic acid residue, or a sequence of two aminoacids arginine-glutamine (RQ) and Z represents an OH group or a basic
ammo acid, the basic ammo acid being a Lysme (K) or an Argmine (R) or said biologically active derivative does not have the sequence QHNLR or
RQHNLR
17 A method for determining the amount of XQHNPR or one of its biologically active derivatives to be administered to a patient suffering from a metabolic imbalance such as a mineral ion imbalance, comprising the steps of a) incubating a labeled XQHNPR peptide with a polyclonal or a
monoclonal antibody directed against the same peptide, b) bringing into contact immune complexes formed with a biological sample from a patient to be tested suspected to contain an endogenous non-labeled XQHNPR peptide, c) detecting monoclonal or polyclonal antibody-bound labeled peptides that have not been displaced by the endogenous non-labelled XQHNPR
peptide contained in the biological sample in order to determine a concentration of said endogenous peptide that is contained in the biological sample,
d) comparing the concentration of the XQHNPR peptide formed at step c) with the concentration of the XQHNPR peptide normally found in a healthy individual, and
e) calculating the amount of a therapeutic composition, comprising a pharmaceutically active amount of an SMR1 protein, or a maturation product of the
SMR1 protein or of one of its biologically active derivatives, necessary in order to supply the defect of the XQHNPR peptide in body fluids and tissues
18 The method according to claim 17 wherein said XQHNPR peptide is QHNPR
19 A composition comprising a pharmaceutically effective amount of
- an SMR1 protein,
- an SMR1 maturation product, or - a biologicaly active derivative of the above, in combination with a pharmaceutically effective amount of a molecule involved in regulation of metabolic balance, such as a mineral ion balance, in the
body
20 The composition according to Claim 19 wherein said SMR1
maturation product is an XQHNPR peptide
21 The composition according to Claim 20, wherein said XQHNPR
peptide is a QHNPR pentapeptide or a polymer thereof
22 The therapeutic composition according to claim 19 wherein the
molecule involved in the regulation of the mineral ion balance in the body is parathyroid hormone (PTH)
23 A composition according to claim 19 wherein the molecule involved in the regulation of the mineral ion balance in the body is calcitonm (CT)
24 A therapeutic composition according to claim 19, wherein the molecule involved in the regulation of the mineral ion balance in the body is 1 ,25-dιhydroxyvιtamιn D
25 A method for producing an SMR1 protein maturation product which comprises the steps of
a) optionally amplifying a nucleic acid coding for a desired polypeptide using a pair of primers specific for an SMR1 genomic or cDNA sequence,
b) inserting a nucleic acid coding for SMR1 protein inserted in an 93
appropriate vector, c) inserting a nucleic acid coding for furin in a suitable vector, said vector being the vector of step b) or said vector being a vector different form the
vector of step b) d) culturing, in an appropriate culture medium devoid of serum, a cell host previously transformed or transfected with the recombmant vector of step b)
and c), e) harvesting the culture medium and the cell host, f) separating or purifying, from said culture medium or from a pellet of a
resultant host cell lysate, the thus produced polypeptide of interest, g) characterizing the produced polypeptide of interest, and h) optionally assaying for specific recognition of said peptide by a polyclonal or a monoclonal antibody directed against a WQHNPR peptide
26 The method according to claim 25, wherein said SMR1 protein maturation product is an XQHNPR peptide
27 The method according to claim 25, wherein said amplifying step a) is carried out by SDA, TAS, 3SR NASBA, TMA, LCR, RCR, CPR, Q-beta replicase or PCR
28 The method according to claim 25, wherein the harvesting step e) is carried out by lysing the cell host by sonication or by an osmotic shock
29 The method according to claim 25 wherein the WQHNPR peptide is a QHNPR peptide
30 A method for screening candidate ligand molecules that possess
an agonist or an antagonist biological activity on a target receptor of an XQHNPR peptide, comprising the steps of
ARTICLE 191 a) culturing a eukaryotic cell capable of synthesizing collagen b) incubating the eukaryotic cell of step a) in beta-glycerophosphate in the presence of 1010 - 10'5 M of the candidate molecule and in the presence of a
submaximal concentration of QHNPR peptide, c) quantifying production of a specific metabolite in the presence or in
the absence of the candidate ligand molecule and in the presence or in the absence
of a submaximal concentration of QHNPR
31 The method according to claim 30, wherein said specific
metabolite is calcium, alkaline phosphatase or DNA synthesis 32 A method for screening a candidate ligand molecule that possesses an agonist or an antagonist biological activity on a target receptor of an
XQHNPR pentapeptide, comprising the steps of a) preparing a confluent target cell culture monolayer or preparing a target organ specimen or a tissue sample in cryosections or slices, b) incubating the cell culture, organ specimen or tissue sample of step a) in the presence of 10"10 - 10"5 M of the candidate molecule and in the presence of a submaximal concentration of QHNPR,
d) quantifying production of a corresponding metabolite, respectively in the presence or in the absence of the candidate ligand molecule and in the presence or in the absence of a submaximal concentration of QHNPR
33 The use of an SMR1 protein, or a maturation product of the SMR1 protein or of one of its biologically active derivatives for the preparation of a
medicament for preventing or treating diseases caused by a metabolic imbalance, such as a mineral ion imbalance in a mammal
34 The use of an SMR1 protein, or a maturation product of the SMR1 protein or of one of its biologically active derivatives for the preparation of a medicament for preventing or treating a disorder affecting the bone in a mammal
35 The use according to claim 34 for preventing or treating
osteoporosis. 36 The use according to claim 33 or 34 wherein said mammal is a
human.
37 The use according to claim 33 or 34, wherein the medicament
comprises a peptide of formula XQHNPR, wherein X is a hydrogen atom, an ammo acid V, or a polypeptide VR, VRG, VRGP, VRGPR or VRGPRR, or one of its biologically active derivatives.
38 The use according to claim 37 wherein the peptide XQHNPR or one of its biologically active derivative peptides comprises one or more ammo acids
in the D-form
39 The use according to claim 31 or 34 wherein the medicament is a
liquid solution
40 The use according to claim 33 or 34 wherein the medicament is a gel.
41. The use according to claim 33 or 34 wherein the medicament is a dry powder.
42. The use according to claim 33 or 34 wherein the medicament is a controlled drug delivery device.
43. The use according to claim 33 or 34 wherein the medicament is administered locally near a site to be treated.
44. The use according to claim 33 or 34 wherein the medicament is administered by the orally route. 45. A tissuiar receptor complex for the SMR1-pentapeptide of
sequence QHNPR.
46. A tissuiar receptor complex according to claim 45 with a pHi of 5.58/5.64 ± 0.30, mainly present in the medulla of kidney, and pancreas and in
lesser extent in the bone trabecular matrix.
47. A tissuiar receptor complex according to claim 45 with a pHi of 6.62
± 0.35 mainly present in the glandular gastric mucosa.
48. The use of the tissuiar receptor according to claims 45 to 47 for
screening ligands having an affinity for said receptor. 49. The use of the tissuiar receptor according to claim 48 comprising the steps of :
- contacting said tissuiar receptor with a potential ligand under conditions allowing the binding of said potential ligand by said tissuiar receptor; and
- detecting the complex formed thereby. 50. The use of an SMR1 protein or a maturation product of the SMR1 protein or one of its biologically active derivatives for the preparation of a medicament active on renal tubular reabsorption through the complex described in claim 45.
PCT/EP1998/000956 1997-02-20 1998-02-19 Therapeutic use of the smr1 protein and active derivatives thereof WO1998037100A2 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US09/367,703 US6818405B2 (en) 1997-02-20 1998-02-19 Therapeutic use of the SMR1 protein and active derivatives thereof
AU67219/98A AU6721998A (en) 1997-02-20 1998-02-19 Therapeutic use of the smr1 protein and active derivatives thereof
EP98912339A EP1007566B1 (en) 1997-02-20 1998-02-19 Therapeutic use of the smr1 protein and active derivatives thereof
DE69835680T DE69835680T2 (en) 1997-02-20 1998-02-19 THERAPEUTIC USE OF SMR1 PROTEIN AND ITS ACTIVE DERIVATIVES
CA002281912A CA2281912A1 (en) 1997-02-20 1998-02-19 Therapeutic use of the smr1 protein and active derivatives thereof
US10/620,462 US7429448B2 (en) 1997-02-20 2003-07-17 Therapeutic use of the SMR1 protein and active derivatives thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/801,405 US6589750B2 (en) 1997-02-20 1997-02-20 Therapeutic use of the SMR1 protein, the SMR1 maturation products, specifically the QHNPR pentapeptide as well as its biologically active derivatives
US08/801,405 1997-02-20

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US09367703 A-371-Of-International 1998-02-19
US09/367,703 A-371-Of-International US6818405B2 (en) 1997-02-20 1998-02-19 Therapeutic use of the SMR1 protein and active derivatives thereof
US10/620,462 Division US7429448B2 (en) 1997-02-20 2003-07-17 Therapeutic use of the SMR1 protein and active derivatives thereof

Publications (3)

Publication Number Publication Date
WO1998037100A2 WO1998037100A2 (en) 1998-08-27
WO1998037100A3 WO1998037100A3 (en) 1999-01-07
WO1998037100B1 true WO1998037100B1 (en) 1999-03-04

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Country Status (10)

Country Link
US (4) US6589750B2 (en)
EP (2) EP1007566B1 (en)
AT (1) ATE337339T1 (en)
AU (1) AU6721998A (en)
CA (1) CA2281912A1 (en)
DE (1) DE69835680T2 (en)
DK (1) DK1007566T3 (en)
ES (1) ES2271991T3 (en)
PT (1) PT1007566E (en)
WO (1) WO1998037100A2 (en)

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