WO1997005889A1 - Vaccination non specifique par des composes contenant un acide amine de type d - Google Patents
Vaccination non specifique par des composes contenant un acide amine de type d Download PDFInfo
- Publication number
- WO1997005889A1 WO1997005889A1 PCT/US1996/012525 US9612525W WO9705889A1 WO 1997005889 A1 WO1997005889 A1 WO 1997005889A1 US 9612525 W US9612525 W US 9612525W WO 9705889 A1 WO9705889 A1 WO 9705889A1
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- WIPO (PCT)
- Prior art keywords
- amino acid
- alanyl
- acetyl
- gmdp
- compound
- Prior art date
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- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 108010043277 recombinant soluble CD4 Proteins 0.000 description 1
- 238000000679 relaxometry Methods 0.000 description 1
- 238000005067 remediation Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 208000026775 severe diarrhea Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
- C07K9/005—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure containing within the molecule the substructure with m, n > 0 and m+n > 0, A, B, D, E being heteroatoms; X being a bond or a chain, e.g. muramylpeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
Definitions
- Peptidoglycan (synonym: murein) is a another D- amino acid containing a net-like molecule that surrounds and confines the bacterial cell (Andronova, T., Ivanov, V. Sov. Med. Rev. Immunol. 4: 1-63, 1991.) It is the stress-bearing and
- Peptidoglycan consists of a backbone of alternating
- the active component is used during first 5 days after birth. Lately, Link and Pahud have isolated
- MDP from Lactobacillus Bulgaricus and proposed to administer it as dietary immune stimulator
- GMDP N-acetyl-glycocyamine-muramyl dipeptide
- muramyl peptides induce different mediators of the immune response, such as interleukin- 1 (IL-1) and Ia- antigen, both in immunocompetent cells and in brain astrocytes (Dinarello, C.A., and Krueger, J.M. Fed. Proc. 45:2545-2548, 1986, Vermeulen, M.V. J. Immunol. (1987), 139:7-9.
- IL-1 interleukin- 1
- Ia- antigen both in immunocompetent cells and in brain astrocytes
- muramyl D-peptides are utilized (but not synthesized) by the host organism, and they act as regulators of various
- Human milk glycoconjugates can inhibit replication of a range of pathogenic
- microorganisms examples include mucin-associated glycoprotein that inhibits rotavirus replication and prevents experimental gastroenteritis (Yolken, R.H., et al. J. Clin. Invest. 90:1984-1991, 1992.)
- a fucosylated oligosaccharide isolated from human milk inhibits the ability
- hemophilus is a component of the bacterial cell wall, D-peptidoglycans. Furthermore, Applicants
- GMDP peptidoglycans clusters
- muramylpeptides have been used in Applicants' technology.
- one aspect of the present invention comprises the
- supplementation of infant formula with synthetic GMDP and/or MDP to treat and prevent infection in infants.
- Such supplementation is believed to modulate the immune systems of infants.
- Another aspect of the present invention is to provide a nonspecifically active vaccine
- Nonspecificity of the vaccination is achieved by exploiting newly discovered phenomena, namely inhibition of binding infectious receptor to its host cell counterpart by D-amino acid containing compounds and increased production of secretory IgA in mucosa organs.
- Yet another aspect of the present invention is a nonspecific method for detecting
- Fig. 1 shows the results of an assay for GMDP in human milk. It is the adsorption of
- Fig. 2 shows the results of another assay for GDMP in human milk. It is the adso ⁇ tion of
- E6/1.2 antibody on the adsorbed human female milk (lOO ⁇ l of 1:2 dilution of milk/well).
- Figs. 3A and 3B show competitive inhibition of the adso ⁇ tion of E6/1.2 antibody on the
- GMDP-Lys-PAA adsorbed GMDP-Lys-PAA by GMDP in solution.
- Fig. 3 A l ⁇ G GMDP-Lys-PAA per well; Fig.
- 3B 0. l ⁇ g GMDP-Lys-PAA per well.
- Fig. 4 shows competitive inhibition of the adso ⁇ tion of E6/1.2 antibody on the adsorbed GMDP-Lys-PAA by serial dilutions of yogurt in PBS.
- Fig. 5 shows the change in ⁇ T1 of peripheral lymph after treatment with GMDP.
- useful D-aminoacid containing compounds are muramyl peptides which conform to the general formula:
- X 1 and X 2 are Cl and C5 acyl groups such as acetyl
- R represents the residue of aminoacid or linear peptides built up of from 2 to 8 amino acid residues, at least one of residues being optionally substituted with D-isomer analogue.
- the most preferable position is second from the proximal end.
- R preferably represents a di-or tri-peptide residue.
- the proximal residue is preferably that
- L-amino acid is selected from the group comprising:
- the next amino acid from the proximal end of the peptide is preferably of the D- configuration. Most preferable are D-isoglutamine and D-glutamate.
- L-alanyl and L-lysyl are preferred for a third amino acid position from the proximal end of the peptide.
- D-amino acid containing compounds for use in this invention is:
- R is a an amino acid or linear peptide built of from 2 to 8 amino acid residues. One of them is being optionally substituted with a lipophilic group.
- the most preferred dipeptides are L-Ala-D-isoGln and L-Ala-D-Glu.
- GMDP N-acetyl-D-glucosaminyl-(l-4)-Nacetylmuramyl-L-alanyl-D-isoglutamine
- GMDP- A N-acetyl-D-glucosaminyl-(l -4)-N-acetylmuramyl-L-alanyl-D-glutamic acid
- glucosaminylmuramyl-L-alanyl-D-isoglutamine N-acetyl-D-glusaminylmuramyl-L-alanyl-D-glut- amine and N-acetylmuramyl-L-alanyl-D-glutamine.
- the effective dosage is in the range of 0.2-0.5 mg/kg for GMDP and 0.5-5.0 mg/kg for GMDP(A).
- the vaccination effect is dependent upon the dosage regimen and it is believed that this should consist of divided dosages.
- the protective effect has been demonstrated to last for 5-6 weeks after 3 consecutive administrations.
- the mode of administration which may be topical, oral, vaginal, rectal, and as a food supplement.
- these vaccine comprise an effective amount of compound of
- composition would be 10%-30% active ingredient.
- concentration of D-compound in pharmaceutical compositions suitable for topical appUcation will vary depending upon the
- ca ⁇ ies include creams, ointments, lotions, emulsions and solutions.
- compositions For oral administration, these compositions contain an effective amount of a D-compound
- Vaginal and rectal administration includes the use of Hquids which can be sprayed on the mucosa, or solid suppositories which can be inserted one or more times per day.
- Example 1 TESTING OF HUMAN MILK FOR THE PRESENCE OF GMDP.
- PBS saline
- BSA albumin
- IgGl(k) is almost threefold and therefore it is specific.
- Antibody capture assay with the antigen competition variation has been used to detect GMDP in yoghurt (Mountain High Original Style plain yoghurt produced by Meadow Gold
- mice IgG mice IgG were incubated with 50 ⁇ l of an antigen (GMDP in PBS or series dilutions of
- Figs. 3 A and B show the inhibition of E6/1.2 antibody interaction with the adsorbed
- GMDP was given orally for 3 consecutive days by administering 20 mg of active
- duodenum, jejunum, and ileum duodenum, jejunum, and ileum, and stored at 80°C and then PLP fixed.
- IgG serum used as the first serum which served as antigen for anti sheep IgG rabbit IgG second serum.
- fluorochrome conjugate was diluted 400 times.
- Applicants' cell counts were based on individually defined "mucosa tissue units" constituting of 6- ⁇ -thick and 500- ⁇ -wide blocks of tissue.
- tissue unit base of vilh.
- the four units counted are derived from corresponding areas in the neighboring sections; when the ceU numbers are smaU, as far as possible two units in each section were included, or enumerations in two similar specimens from the same piglet were combined.
- Microtiter wells were coated with recombinant, soluble CD4 peptide corresponding the gpl 20 binding domain.
- GMDP were added to the soHd phase SD4 along with 1 ng of recombinant HIV gp-120. Following incubation overnight at 4°C, unbound reagents were
- gp 120 bound to CD4 was measured by sequential reactions with peroxidase-labeled monoclonal antibody to gpl 20 (2h, 4°C), H2 ⁇ 2-o-phenylene diamine peroxidase substrate (30 min, 4°C), acidification, and measurement of the antigen-antibody
- inhibition 1 - [(ODsam - OD bl)/(ODgpl20 - ODbl)]*100
- OD sam optical density of the sample tested
- OD gpl 20 is the mean optical density of wells in which gp 120 was tested without added inhibitor
- ODbl is the optical density
- Example 5 COMBINED (SONIC AND NMR) DIAGNOSTIC TEST OF HUMAN PERIPHERAL LYMPH AND BLOOD SERUM.
- the NMR relaxometry of the peripheral lymph was performed in 50 patients 41-74 years
- the lymph was drawn from peripheral lymphatic vessels through the catheter and collected in a receptacle attached to the leg.
- the parameter Tl (the difference between Tl values measured before and after ultrasound treatment of the peripheral lymph) was higher than 0.12 s in all cancer patients. Based on this
- Fig. 5 represents the change of ⁇ Tl of peripheral lymph after
- the method of the present invention is useful in the prevention and remediation of disease
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Crystallography & Structural Chemistry (AREA)
- Peptides Or Proteins (AREA)
Abstract
L'invention concerne une vaccination non spécifique par l'administration de muramyle peptides ou de glucosaminylmuramyle peptides, avec un groupe acide aminé de type D dans la seconde ou la troisième position à partir de l'extrémité proximale. On propose de nouvelles méthodes permettant une vaccination non spécifique par voie orale, vaginale ou topique. L'invention concerne en particulier un vaccin non spécifique anticancer et également une technologie combinant la RMN et les ultrasons, pour son suivi.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51073795A | 1995-08-03 | 1995-08-03 | |
| US08/510,737 | 1995-08-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997005889A1 true WO1997005889A1 (fr) | 1997-02-20 |
Family
ID=24031975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1996/012525 WO1997005889A1 (fr) | 1995-08-03 | 1996-07-31 | Vaccination non specifique par des composes contenant un acide amine de type d |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1997005889A1 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7153822B2 (en) | 2002-01-29 | 2006-12-26 | Wyeth | Compositions and methods for modulating connexin hemichannels |
| JP2008539169A (ja) * | 2005-04-19 | 2008-11-13 | イーライ リリー アンド カンパニー | 疾患における免疫学的介入のための一価および多価合成多糖類抗原 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993010148A1 (fr) * | 1991-11-19 | 1993-05-27 | Peptech (Uk) Limited | Composes de muramyl utilises dans le traitement de choc septique |
| WO1995010293A1 (fr) * | 1993-10-08 | 1995-04-20 | Peptech (Uk) Limited | Composes a usage medicinal |
-
1996
- 1996-07-31 WO PCT/US1996/012525 patent/WO1997005889A1/fr active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993010148A1 (fr) * | 1991-11-19 | 1993-05-27 | Peptech (Uk) Limited | Composes de muramyl utilises dans le traitement de choc septique |
| WO1995010293A1 (fr) * | 1993-10-08 | 1995-04-20 | Peptech (Uk) Limited | Composes a usage medicinal |
Non-Patent Citations (3)
| Title |
|---|
| INT. J. IMMUNOPHARMAC., Volume 14, No. 3, issued 1992, I. AZUMA, "Review: Inducer of Cytokines In Vivo: Overview of Field and Romurtide Experience", pages 487-496. * |
| SCIENCE, Volume 208, issued 25 April 1980, C.A. McLAUGHLIN et al., "Regression of Tumors in Guinea Pigs after Treatment with Synthetic Muramyl Dipeptides and Trehalose Dimycolate", pages 415-416. * |
| VACCINE, Volume 11, No. 3, issued 1993, R.K. GUPTA et al., "Adjuvants - a Balance Between Toxicity and Adjuvanticity", pages 293-306. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7153822B2 (en) | 2002-01-29 | 2006-12-26 | Wyeth | Compositions and methods for modulating connexin hemichannels |
| JP2008539169A (ja) * | 2005-04-19 | 2008-11-13 | イーライ リリー アンド カンパニー | 疾患における免疫学的介入のための一価および多価合成多糖類抗原 |
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