WO1997005889A1 - Non-specific vaccination by d-amino-acid containing compounds - Google Patents
Non-specific vaccination by d-amino-acid containing compounds 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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- WO
- WIPO (PCT)
- Prior art keywords
- amino acid
- alanyl
- acetyl
- gmdp
- compound
- Prior art date
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- 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
Non-specific vaccination is achieved by administering muramyl or glucosaminylmuramyl peptides with D-amino acid residue in a second or third position from the proximal end. New methods for non-specific oral, vaginal, and topic vaccination is proposed. Non-specific anticancer vaccine is described as well as a combined (NMR and ultrasound) technology for its monitoring.
Description
NONSPECIFIC VACCINATION BY D-AMINO-ACID CONTAINING COMPOUNDS
BACKGROUND OF THE INVENTION
Living multicellular organisms synthesize proteins composed of only L-amino acids. D-
amino acids occur in bacterial peptides. In the early antibiotic era, Lipmann demonstrated that the
small peptides tyrocidine and gramicidin contained D-amino acids (Lipmann, F., Hotchkiss. R.D.,
Dubos, R.J. J. Biol Chem. 141 :163, 1941.) 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
form-giving component of bacterial cell wall. Peptidoglycan consists of a backbone of alternating
strings of N-acetylglucosamine and N-acetyl-muramic acid interconnected by short D-peptides.
This basic structure is found in the cell wall of nearly all bacteria, including Lactobacillus
Bulgaricus, Bifidum, and Streptococcus Thermophilous (Andronova et al, Link, Harriet. Dietary Immunostimulator European Patent 0 432 490, Sasaki, et al. Japan Patent #62265231). These
bacteria are found to be useful in preventing gastroenteritis in infants (Saavedra, J., Bauman, N.,
Oung, I., Perman, J.A., Yolken, R.H. Lancet 344: 1046-49, 1994.)
Ellouz et al. identified muramyl dipeptide (i.e., N-acetyl-D-muramyl-L-alanyl-d- isoglutamine) as the rmnimal structure capable of replacing the mycobacterial component of Freud's complete adjuvant (Ellouz, et al. Biochem. Biophys. Res. Comm. 59:1317-1325, 1974.)
Since this discovery, the synthesis of MDP has allowed study of many of the biological aspects of
adjuvants, such as immune modulation, increase of the resistance to infection and the production of fever. The many biologic properties of GMDP and MDP give promise of a wide range of
potential clinical applications such as vaccine adjuvants, non-specific anti-infection agents, anti¬
cancer agents and treatment of immunosuppressed status. However, because of its impressive
ability to induce fever (pyrogenicity), MDP itself did not prove suitable for broad clinical
development (Krueger, J.. et al, Somnogenic Compositions and Method of Use. US patent
4,698,330.) Fortunately, many structural analogs of MDP have been synthesized, several of
which appear to have vigorous immunostimulatory properties with minimal somnogenic and pyrogenic side effects (Andronova et al).
One-hundred percent prevention of the post-weaning diarrhea in the piglets by orally
administering of peptidoglycans derived from Bifidum bacteria has been demonstrated by Sasaki
et al. They have found that peptidoglycans stimulates the IgA secretion in the mucosa and decreases the number of Salmonella bacteria in the intestine. Their method was inefficient when
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
(European Patent #0 432 490).
N-acetyl-glycocyamine-muramyl dipeptide (GMDP) was isolated during analysis of the anti-tumor drug, blastolysine, which is a lysozyme cell wall hydrolysate of Lactobacillus
Bulgaricus (U.S. Patent No. 4,395,399). This compound has been extensively studied in animals, demonstrating adjuvant activity, antitumor activity, low pyrogenicity and hypnogenic effect (Andronova et al). The presence of MDP in human urine, has been reported by Krueger
(Krueger, J.M., et al. J. Biol. Chem. 257:1664-1669, 1982.) Chemical and physiological properties of this urinary factor resemble those of the sleep factor found in sterile cerebrospinal
fluid and in acid/aceton extracts of brains from sleep-deprived animals (Garcia-Arraras and Pappenheimer. J. Neurophysiol. 49:528-533, 1983.) In a accordance with this discovery, biological compositions for the induction of the sleep have been invented (U.S. Patent No. 4,698,330). It has been suggested that muramyl peptides enter the organism as a result of
adsoφtion of degradation products of normal colibacilli. Numerous reports testify to the fact that
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. Thus, muramyl peptides maintain the immune status of the organism at a normal level and
promote the normal duration of sleep by means of their specific mediators whose main function is
tightly coupled with the immune system. Similar to some vitamins, muramyl D-peptides are utilized (but not synthesized) by the host organism, and they act as regulators of various
physiological systems.
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
of stable toxin of E. coli to produce diarrhea in vivo (Newburg, D.S., et al. J. Infect. Dis.
7:1075-1080, 1990.)
In late 1994, investigators at Johns Jopkins reported a significant reduction in the
incidence of acute diarrhea and rotavirus shedding in infants aged 5 to 24 months using an infant formula supplemented with bacteria (Saavedra, J., Bauman, N., Oung, I., Perman, J.A., Yolken, R.H. Lancet 344:1046-49, 1994.) In this study, Bifidobacterin (which constitutes the
predominant intestinal flora of breast fed infants) and Streptococcus thermophilus (a lactic acid
producing bacteria that generates lactase activity) were added to infant formula in at attempt to
prevent rotavirus diarrhea. This successful reduction in the incidence of rotavirus diarrhea using such supplemented formula supports previous uncontrolled studies on the effect of bifidobacteria on the incidence of diarrhea in infants (Tasovatz, B., et al Ann. De Pediatrie. 22:291-297,
1962.) How and why the addition of "bacteria" to infant formula causes a decrease in acute
diarrhea and rotavirus shedding remains unknown.
BRIEF DESCRIPTION OF THE INVENTION
Applicants suggest that the "active ingredient" in both bifidobacteria and Streptococcus
hemophilus is a component of the bacterial cell wall, D-peptidoglycans. Furthermore, Applicants
suggest that the peptidoglycans clusters (GMDP) discovered in the human milk are also
responsible for the protective effect of the breast feeding. They are also the strong biological immunomodulating agents, which physiologically stimulate the maturation of the
immunocompetent cells in the newborns. The protocol for the identification of the bacterial
peptidoglycans in human milk and commercially available cultured yogurt is described in examples
1 and 2 of this application. Monoclonal anti-idiotypic antibodies to glucosaminyl-
muramylpeptides have been used in Applicants' technology.
Applicants have predicted the presence of bacterial D-amino acid containing compounds (GMDP) in human milk. Based on this, 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,
incorporating in its peptide fragment D-amino-acid in a first, second or third position from the end. 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,
preventing, and inhibiting precancer conditions in human beings by vaccination with D-amino-acid vaccines. The monitoring of such non-specific anti-cancer D-vaccine is provided by combined (NMR and ultrasound) in vitro tests on blood serum or peripheral lymph.
BRIEF DESCRIPTION OF THE DRAWINGS
For further details, reference is made to the discussion which follows, in light of the
accompanying drawings, wherein
Fig. 1 shows the results of an assay for GMDP in human milk. It is the adsorption of
Eg/1.2 antibody on the adsorbed GDMP-Lys-PAA (5μg/well).
Fig. 2 shows the results of another assay for GDMP in human milk. It is the adsoφtion of
E6/1.2 antibody on the adsorbed human female milk (lOOμl of 1:2 dilution of milk/well).
Figs. 3A and 3B show competitive inhibition of the adsoφtion of E6/1.2 antibody on the
adsorbed GMDP-Lys-PAA by GMDP in solution. Fig. 3 A: lμG GMDP-Lys-PAA per well; Fig.
3B: 0. lμg GMDP-Lys-PAA per well.
Fig. 4 shows competitive inhibition of the adsoφtion of E6/1.2 antibody on the adsorbed GMDP-Lys-PAA by serial dilutions of yogurt in PBS.
Fig. 5 shows the change in ΔT1 of peripheral lymph after treatment with GMDP.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, useful D-aminoacid containing compounds are muramyl peptides which conform to the general formula:
X1 and X2 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 preferred position of this D-aminoacid residue is second or third from the proximal
end, or second or third from the distal end of the linear peptide.
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
of L-amino acid and is selected from the group comprising:
L-alanyl
L-valyl
L-leucyl
L-isoleucyl
L-seryl
L-aminobutyryl
L- threonyl
L-tryptophanyl
L-lysyl
L-ornithyl
L-argynyl
L-histidil
L-ornithyl
L-cysteinyl
L-phenylalanyl
L-tyrosyl
L-arginyl
L-asparaginyl
L-prolyl
L-hydroxyprolyl
L-glutaminyl L-aspartyl L-methionyl and wherein L-alanyl is most preferred.
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.
Most preferred class of D-amino acid containing compounds for use in this invention is:
wherein:
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.
One of the most preferred compounds in this invention which corresponds to the above
formula is N-acetyl-D-glucosaminyl-(l-4)-Nacetylmuramyl-L-alanyl-D-isoglutamine (GMDP) and N-acetyl-D-glucosaminyl-(l -4)-N-acetylmuramyl-L-alanyl-D-glutamic acid (GMDP- A).
Other useful compounds which fall within the above formula II include:
N-acetyl-D-glucosaminyl-(l-4)-N-acetylmuramyl-L-alanyl-D-glutamine-n-butyl-ester (GMDP-OBu)
N-acetyl-D-glucosaminyl-(l-4)-N-acetylmutamyl-L-alanyl-D-isoglutaminyl-L-lysine
(GMDP-Lys)
N- Acetyl-D-glucosaminyl-( 1 -4)-N-acetylmuramyl- N-methyl -L-alanyl -D-isoglutamine
N- Acetyl-D-glucosaminyl-( 1 -4)-N-acetylmuramyl-L-alanyl-D-isoglutamine- 1 -adamantyl ester
L-Threonyl-N-[N-Acetyl-D-glucosaminyl]-L-lysyl-D-prolyl-L-arginine
Those compounds which are members of the most preferred class are N-acetyl-D-
glucosaminylmuramyl-L-alanyl-D-isoglutamine, N-acetyl-D-glusaminylmuramyl-L-alanyl-D-glut- amine and N-acetylmuramyl-L-alanyl-D-glutamine.
The effectiveness of these compounds in prevention of bacterial diarrhea is shown by 100% successful food vaccination of domestic animals. In particular, these D-amino acid
containing GMDP have been shown by appHcants to provide full protection against clostridia and
salmonella diarrhea in piglets by increasing secretion IgA in intestinum mucosa. 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 aspect of the present invention relating to the pharmaceutical composition varies with
the mode of administration, which may be topical, oral, vaginal, rectal, and as a food supplement.
For topical administration, these vaccine comprise an effective amount of compound of
this class in admixture with pharmaceutically acceptable nontoxic carriers. A suitable range of
composition would be 10%-30% active ingredient. The concentration of D-compound in pharmaceutical compositions suitable for topical appUcation will vary depending upon the
particular activity used in conjunction with the condition and subject to be treated. Suitable
caπies include creams, ointments, lotions, emulsions and solutions.
For oral administration, these compositions contain an effective amount of a D-compound
of this class incoφorated in a mixture with any of the usually employed excipients. such as, for example, pharmaceuticals of mannitol, lactose, starch, talcum, cellulose, glucose, or sucrose. The active ingredient comprises 65%-95% of such formulations. Such vaccine take form of solutions,
tablets, pills, capsules, sustained release formulations and the like.
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.
In the following specific examples, the results of standard bioassays are described.
Example 1. TESTING OF HUMAN MILK FOR THE PRESENCE OF GMDP.
Antibody capture assay (Antibodies: A laboratory Manual (E. Harlow and D. Lane, eds.), Cold Spring Harbor Laboratory, 1988) has been used to detect GMDP in human female milk. Highly specific mouse E6/1.2 anti-GMDP monoclonal antibody (Ka = 2x10^ M"l) and GMDP
conjugated to polyacrylamide backbone through amino group of lysine (GMDP-Lys-PAA) were
obtained from Dr. Nesmeyanov, the Shemyakin and Ovchinnikov Institute of Bioorganic
Chemistry, Russian Academy of Sciences, Moscow, Russia.
Briefly, GMDP-Lys-PAA or serial dilutions of human female milk in phosphate buffered
saline (PBS) were adsorbed onto wells of microtiter plates for several hours. After washing with
PBS, remaining binding sites were blocked by lh incubations with 200 μl PBS +3% bovine serum
albumin (BSA). After washing with PBS 100 μl of E6/1.2 antibody, diluted 1:1,000 or 1:2,000
with PBS+1%BSA, were added. The incubation was carried out for lh at room temperature. Plates were washed with PBS and incubated for lh at room temperature with 100 μl/well of
1:1000 dilution of goat anti-mouse IgG antibody conjugated to horseradish peroxidase (HRP) in
PBS+1%BSA. After washing 100 μl of OPD solution (1 mg/ml) in 20 mM sodium citrate buffer, pH 4.5, containing 0.03% H2O2 were added. The reaction was stopped 10-20 min later by
adding 50 μl well of 2.5 M H2SO4. Optical density at 492 nm was measured.
The results of the experiments are shown in Figs. 1 and 2. The specificity of the interaction was determined by comparing the adsoφtion of E6/1.2 on milk, adsorbed onto wells of microtiter plates, with the absoφtion of mouse monoclonal IgGl (k) and mouse IgG. From Fig. 2, it is evident that the difference in the absoφtion between E6/1.2 antibody and monoclonal
IgGl(k) is almost threefold and therefore it is specific.
Example 2. TESTING OF COMMERCIALLY AVAILABLE YOGHURT FOR THE PRESENCE OF GMDP.
Antibody capture assay with the antigen competition variation (Antibodies: A Laboratory Manual. (E. Harlow and D. Lane, eds.), Cold Spring Harbor Laboratory, 1988) has been used to detect GMDP in yoghurt (Mountain High Original Style plain yoghurt produced by Meadow Gold
Dairies, Inc., Inglewood, Co; ingredients: cultured milk, non-fat milk, cream, tapioca, pectin, active cultures (L. bulgaricus, S. thermophilus, L. acidophilus and B. bifidum.)).
Two different amounts of GMDP-Lys-PAA in PBS were adsorbed onto wells of microtiter plates (1 μg/well and 0.1 μg/well). Washing and blocking of remaining binding sites
were performed as described above. Before adding to wells, 50 μl of antibody (E6/1.2m, IgGl(k)
or mouse IgG) were incubated with 50 μl of an antigen (GMDP in PBS or series dilutions of
yoghurt in PBS) for 15 min. Further steps were as described above. Inhibition index (I,%) was
calculated from: I = (l-Ao/Aι)xl00, where A0 and Ai are optical densities of samples without
and with inhibitor, respectively.
Figs. 3 A and B show the inhibition of E6/1.2 antibody interaction with the adsorbed
BMDP-Lys-PAA by GMDP itself. Figure 4 shows that yogurt competitively inhibits the
interaction of E6/1.2 antibody with GMDP-Lys-PAA.
Example 3. GMDP (A) IN THE PREVENTION C.PERFRINGES DIARRHEA IN
PIGLETS.
A total of 60 mg of GMDP(A) was given to each of 3 piglets (16 weeks old).
GMDP was given orally for 3 consecutive days by administering 20 mg of active
compound diluted in the water.
After 5 days, 85 ml of water with Clostridia Perfringes (10 unit per ml) was given to all
piglets.
None of the vaccinated piglets developed diarrhea, while two control piglets developed
severe diarrhea.
All piglets were sacrificed. Histologic samples were obtained from the stomach,
duodenum, jejunum, and ileum, and stored at 80°C and then PLP fixed.
Indirect antibody fluorescence method was used to detect IgA cells. Anti pig IgA sheep
IgG serum used as the first serum, which served as antigen for anti sheep IgG rabbit IgG second
serum. To decrease the nonspecific component of this reaction, fluorochrome conjugate was diluted 400 times.
Applicants' cell counts were based on individually defined "mucosa tissue units" constituting of 6-μ-thick and 500-μ-wide blocks of tissue.
To compare mucosal specimens, Applicants took into account the localization of selected
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.
Example 4. INHIBITION HIV gpl20 BINDING TO ITS CD4 RECEPTOR.
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
removed by washing. The amount of gp 120 bound to CD4 was measured by sequential reactions with peroxidase-labeled monoclonal antibody to gpl 20 (2h, 4°C), H2θ2-o-phenylene diamine peroxidase substrate (30 min, 4°C), acidification, and measurement of the antigen-antibody
reaction at 490 nm. Inhibition percentage of this binding was calculated with the following
formula: inhibition = 1 - [(ODsam - OD bl)/(ODgpl20 - ODbl)]*100
where OD sam is 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, and ODbl is the optical
density of CD4-coated wells reacted with anti-gpl20 antibody in the absence of either gpl 20 or
inhibitor.
TABLE 2. Inhibition of gp 120 Binding to SD4 Receptor by GMDP
Buffer How Through % Inhibition GMDP
< 5 < 5 96
Example 5: COMBINED (SONIC AND NMR) DIAGNOSTIC TEST OF HUMAN PERIPHERAL LYMPH AND BLOOD SERUM.
MATERIALS AND METHODS
The NMR relaxometry of the peripheral lymph was performed in 50 patients 41-74 years
old. Clinical X-ray examinations have revealed a cancer of the lung, stomach, rectum, prostate or mammary gland in 35 of the patients. In the rest of them (15), chronic inflammation of those
organs was diagnosed. Two patients with chronic bronchitis and 3 with gastritis have been
treated by GMDP for up to 6 months, 50 mg GMDP was administered 8 times per month. In respect of the local spreading of the tumor, the patients were distributed in the following way: Tl
4 patients; T2 6 patients, T3 9 patients; T4 6 patients. The lymph was drawn from peripheral lymphatic vessels through the catheter and collected in a receptacle attached to the leg.
Relaxation time was measured using a Minispec PC-20 relaxometer (Bruker, Reinstetten) at a
resonance frequency of 19.8 mHz and a specimen temperature of 39±1°C. Spin-lattice relaxation
time was calculated using the inversion recovery pulse series. To evaluate the water phase of proteins in detail, the samples of peripheral lymph (0.1-0.3 ml) were placed for 20 minutes in a
cell for ultrasound treatment (lW/cm2).
STA TISTICAL METHODS
In vitro reproducibility was determined by calculating the means and standard deviations of differences between first and second measurement of lymph samples. A Mann-Whimey test
was used to compare the mean difference of Tl times of the lymph samples.
RESULTS
The standard deviation of the differences of the two consecutive measurements has
demonstrated a satisfactory in vitro reproducibility for Tl (2,4%). According to AppHcants' results, the average Tl value of peripheral lymph from the patients with nontumor diseases was
2.60s, as contrasted with Tl=2.85 for cancer patients. However, this difference was statistically
insignificant with P>0.05. In all patients Applicants have observed the decreasing of Tl values of the lymph after ultrasonic radiation (Tables 3 and 4).
TABLE 3. Tl AND ΔT1 OF PERIPHERAL LYMPH IN CONTROL PATIENTS
Disease Number of Tl ΔT1 Patients M±δ M±δ
Chron. Pneumonia 6 2.64 ± 0.188 0.078 ± 0.038
Ulcer of Stomach and Duodenum 4 2.45 ± 0.25 0.096 ± 0.011
Adenoma of Prostate 3 2.46 ± 0.356 0.03 ± 0.036
Benign Tumor of Lung 1 2.78 0.31
Cyst of Mammae 1 2.90 0.50
15 2.60 ± 0.253 0.11 ± 0.112
TABLE 4. Tl AND ΔTl IN CANCER PATIENTS
Location of Number of Tl ΔTl Mahgnant Tumor Patients M±δ M±δ
Lung 11 2.83 ± 0.072 0.18 ± 0.008
Stomach 7 2.84 ±0.104 0.225 ± 0.09
Rectum 6 2.88 ± 0.092 0.166 ± 0.044
Uterus 4 2.84 ± 0.084 0.135 ± 0.04
Prostate 3 2.92 ± 0.116 0.276 ± 0.098
Uterus* 4* 2.78 ± 0.05 0.10 ± 0.014
35** 2.85 ± 0.083 0.191 ± 0.067
* Patients with lymphedema after treatment
** Value of Tl and ΔTl without Tl of patients with lymphedema
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
parameter, Applicants observed statistically significant mean differences between control (n=15)
and cancer patients (n=35). Fig. 5 represents the change of ΔTl of peripheral lymph after
treatment with GMDP. ΔTl has been diminished by 30% and has dropped from 0.09 sec to 0.06
sec.
STATEMENT OF UTILITY
The method of the present invention is useful in the prevention and remediation of disease
in humans and domestic animals.
It will be understood by those skilled in the art that the present invention has been desribed
with reference to specific examples but other variations are possible without departing from the
inventive concept. Accordingly, it is desired that the scope of the invention be determined only with reference to the appended claims.
Claims
1. A method for non-specific vaccination of humans or domestically useful animals
comprising administration to the human or the animal of a biologically effective amount of
a compound based on peptides having D-amino acid at the first, second or third position from the end.
2. The method of Claim 1 wherein the D-amino acid contained in the compound is a muramyl peptide which conforms to the general formula:
X and X are Cl and C5 acyl groups such as acetyl and
R represents the residue of amino acid or linear peptides built up from 2 to 8 amino acid residues.
3.
The method of Claim 2 wherein at least one of the 2 to 8 amino acid residues is substituted with its D-isomer analogue.
4.
The method of Claim 2 wherein the D-amino acid is at the second position from the proximal end of the molecule.
5. The method of Claim 2 wherein R is a di-or or tri-peptide residue.
6. The method of Claim 5 wherein the proximal residue is an L-amino acid selected from the group of:
L-alanyl
L-valyl
L-leucyl
L-isoleucyl
L-seryl
L-aminobutyryl
L-threonyl
L-tryptophanyl
L-lysyl
L-ornithyl
L-argynyl
L-histidil
L-ornithyl
L-cysteinyl
L-phenylalanyl
L-tyrosyl
L-arginyl
L-asparaginyl
L-prolyl
L-hydroxyprolyl
L-glutaminyl
L-aspartyl
L-methionyl
7. The method of cliam 6 wherein the proximal residue is L-alanyl.
8. The method of Claim 6 wherein the proximal residue is L-lysyl.
9. The method of Claim 2 wherein the D-amino acid is D-isoglutamine.
10. The method of Claim 2 wherein the D-amino acid is D-glutamate.
11. The method of Claim 1 wherein fhe D-amino acid containing compound is of the general formula:
wherein:
R is an amino acid or linear peptide built of from 2 to 8 amino acid residues.
12. The method of Claim 9 wherein at least one R is substituted with a lipophilic group.
13. The method of Claim 11 wherein the dipeptide is L-Ala-D-isoGln.
14. The method of Claim 11 wherein the dipeptide is L-Ala-D-Glu.
15. The method of Claim 1 wherein the compound is N-acetyl-D-glucosaminyl-(l-4)-
Nacetylmuramyl-L-alanyl-D-isoglutamine (GMDP).
16. The method of Claim 1 wherein the compound is N-acetyl-D-glucosaminyl-(l-4)-N- acetylmuramyl-L-alanyl-D-glutamic acid (GMDP- A).
17. The method of Claim 1 wherein the compound is selected from the group comprising: N-acetyl-D-glucosaminyl- 1(1 -4)-Nacetylmuramyl-L-alanyl-D-glutamine n-butyl ester
(GMDP-OBu);
N-acetyl-D-glucosammyl-(l-4)-Nacetylmutamyl-L-alanyl-D-isoglutaminyl-L-lysine
(GMDP-Lys);
N-Acetyl-D-glucosaminyl-(l-4)-N-acetylmuramyl-N-methyl-L-alanyl-D-isoglutamine; N-
. Acetyl -D-glucosaminyl-( 1 -4)-N-acetylmuramyl-L-alanyl-D-isoglutamine 1 -adamantyl
ester; and L-Threonyl-N-[N-Acetyl-D-glucosaminyl]-L-lysyl-D-prolyl-L-arginine.
18. The method of Claim 1 wherein the compound is N-acetyl-D-glucosaminylmuramyl-L- alanyl-D-isoglutamine
19. The method of Claim 1 wherein the compound is N-acetyl-D-glusaminylmuramyl-L-
alanyl-D-glutamine
20. The method of Claim 1 wherein the compound is N-acetylmuramyl-L-alanyl-D-glutamine.
21. The method of Claim 1 wherein the human is an infant, and the method comprises adminstering GMDP and/or GMDP(A) as a supplement to infant formula or human milk.
22. The method of Claim 1 wherein the method results in nonspecific reduction of diaπhea in
humans and domesticaUy useful animals.
23. The method of Claim 22 wherein the reduction is due to competitive inhibition mechanisms within a human or domestically useful animal.
24. The method of Claim 1 wherein the administration of the compound is oral, vaginal, rectal
or topical.
25. The method of Claim 1 wherein the method results in nonspecific reduction of cancers.
26. The method of Claim 25 wherein the reduction is due to competitive inhibition mechanisms within a human or domestically useful animal.
27. The method of Claim 23 wherein combined NMR and ultrasonic testing are used to
monitor the efficiency of cancer prevention.
28. The method of Claim 1 wherein the method results in reduction of HIV transmission
through sexual contacts.
29. The method of Claim 28 wherein the reduction is due to competitive inhibition
mechanisms within a human or domestically useful animal.
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 (en) | 1997-02-20 |
Family
ID=24031975
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/012525 WO1997005889A1 (en) | 1995-08-03 | 1996-07-31 | Non-specific vaccination by d-amino-acid containing compounds |
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WO (1) | WO1997005889A1 (en) |
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 (en) * | 2005-04-19 | 2008-11-13 | イーライ リリー アンド カンパニー | Monovalent and polyvalent synthetic polysaccharide antigens for immunological intervention in disease |
Citations (2)
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---|---|---|---|---|
WO1993010148A1 (en) * | 1991-11-19 | 1993-05-27 | Peptech (Uk) Limited | Muramyl compounds for treatment of septic shock |
WO1995010293A1 (en) * | 1993-10-08 | 1995-04-20 | Peptech (Uk) Limited | Compounds for medicinal use |
-
1996
- 1996-07-31 WO PCT/US1996/012525 patent/WO1997005889A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993010148A1 (en) * | 1991-11-19 | 1993-05-27 | Peptech (Uk) Limited | Muramyl compounds for treatment of septic shock |
WO1995010293A1 (en) * | 1993-10-08 | 1995-04-20 | Peptech (Uk) Limited | Compounds for medicinal use |
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 (en) * | 2005-04-19 | 2008-11-13 | イーライ リリー アンド カンパニー | Monovalent and polyvalent synthetic polysaccharide antigens for immunological intervention in disease |
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