Anti-AIDS immunomodulator complex

Details Anti-AIDS immunomodulator complex Anti-AIDS immunomodulator complex

1995-01-30

2003-01-07

Housel, James (Department: 1648)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Conjugate or complex

C424S203100, C424S234100, C424S282100

Reexamination Certificate

active

06503512

ABSTRACT:

The present invention relates to an anti-AIDS therapeutic vaccinal complex, which has vaccination effectiveness connected to the presence of non-specific antigens.
It is well known in bacteriology that the antigens at the surface of walls, membranes or capsules (combined or liberated in soluble form in culture medium) are of glycoproteic, polypeptidic or polysaccharidic nature.
Recent vaccines have been widely publicized, associating with RNA (ribosomal origin) of such proteoglycanic or polysaccharidal membranal substances, extracts of pathogenic germs.
These vaccines use specific antigens corresponding to specifically predetermined microbial diseases.
However, the antigenic power is essentially connected to the RNA level (of the ribosomes in particular) of the microbial cells, among others. The ICC (immunologically competent cells) use directly the RNA as active transporters.
To build our new vaccinal complex, instead of using a serotypical bacterial antigen, we have coupled (by preferably covalent bonds) RNA (preferably of ribosomal origin) to a sequence of amino acids of glycoprotidic nature, present in collagen of type III (in humans, collagen represents approximately one-third of the proteins of the organism; type III has been selected for its amino acid sequence and because it is present essentially in the skin and the vascular walls).
Moreover, RNA is already used in the preparation of acellular vaccines (cf.
Infect. and Immunity
, 1, 574-82, 1970). This RNA is stabilized by associative factors.
In our complex, we use as stabilizer cellular membrane fractions from the same germs as those which have served for the elaboration of ribosomal RNA. These membranal fractions contain all the peptidalglycanic substances and are known moreover as immunal adjuvants.
Contrary to convention, it is not necessary to have the same membranal fractions (glucopolysaccharidal or proteoglycanic) from the same microbial germs as those which serve to supply RNA by extraction of their ribosomes.
Constituents of the Vaccinal Complex According to the Invention
A—Useful RNA of ribosomal origin can be extracted from the following strains, this list not being limiting:
Klebsiella pneumoniae
Streptococcus
(
pneumonia and pyogens
)
Staphylococcus aureus
Serratia marcescens
Escherichia coli
Salmonella typhimurium
Corynebacterium
(
granulosum, parvum, acnes
)
Mycobacterium
(
tuberculosis, smegmatis, chelonei
)
Hemophilus influenzae
Pneumocoque type II
Rothia dento cariosus
Bacterium coli
Shigella dysentariae
Enterococcus
Nocardia (asteroides, brasiliensis, rhodocrans, opaca, rubra
)
Bacillus of Calmette and Guerin
The mean molecular weights of these RNAs are between 5,104 and 108 Daltons.
Many industrial processes exist for the preparation of RNA; there will be cited as example the process for the extraction of RNA described in
Infect. and Immunity
, 1, 574-82, 1970: the bacteria are agitated and then subjected to fractional precipitation, the ribosomal proteins are solubilized, the precipitated RNA is treated with Pronase and finally, purified by ion exchange chromatography.
If RNA is obtained by enzymatic means, the final purification can be effected by molecular sieve chromatography. See particularly on this subject:
C. EHRESMAN (1972)—Biochimie, 54, 901
H. KAGAWA (1972)—J. Biochem., (1972), 827
M. SANTER (1973)—J. Bact., 116, 1304
NOMURA (1974)—Ribosomes—Ed. Cold Spring Harbor Laboratory.
B—The membranal fractions of usable bacterial cells can be extracted from the following strains, the given list not being limitative:
1 —for capsular polysaccharides
Klebsiella pneumoniae
Streptococcus pneumoniae
Hemophilus influenzae
Escherichia coli
Klebsiella pneumoniae
C. ERBING, L. KENNE, B. LINBERG, J. LONNGREN (1976)—“Structural studies of the capsular polysaccharide of Klebsiella pneumoniae type I (
Carbohydr. Res
., 50 (1976) 115-20).
W. NIMMICH (1968)—“Zur Isolierung und qualitativen Bausteianalyse der K. Angigen von. Klebsiellen” (
Med. Mikrobio. und Immunol
., 154 117, 131).
C. RICHARD (1973)—“Etude antigenique et biochimique de 500 souches de Klebsiella” (
Ann. Biol. Clin
., 1973).
Streptococcus pneumoniae
F. KAUFFMANN and E. LUND (1954) (
Int. Bull. Bact. Nomencl
. 4, 125-28).
FELTON and OTTINGER (J. of Bacteriology, 1942, 43, 94, 105)
M. COLIN, M. D. MAC LEOD and colleagues—“Prevention of
pneumococcal pneumoniae
by immunization with specific capsular polysaccharides” (
J. Exp. Med
., 1945, 82, 445-65).
A. R. DOCHEZ and O. T. AVERY—“The elaboration of specific soluble substance by Pneumococcus during growth” (1971) (
J. Exp. Med
. 16, 477-93).
WEST PHAL and LUDERITZ (1952) (Z. Naturf. 7B, 148).
C. P. J. GLAUDEMANS and H.P. TREFFERS, “An improved preparation of the capsular polysaccharide from
Diplococcus pneumoniae
(
Carbohydr. Res
. 1967, 4, 181-84).
Hemophilus Influenzae
(Capsular Polysaccharide of Poly-Ribosphorphate Type)
P. ANDERSON and colleagues (1972)—“Immunization of humans with polyribosephosphate, the capsular antigen of
Hemophilus influenzae
type B” (
J. of Clin. Invest
., Vol. 51, 1972, 39-44).
P. ANDERSON and colleagues (1977)—“Isolation of the capsular polysaccharide from supernatant of Hemophilus influenzae type B” (Infect. and Immun., 1977, 15(2), 472-77).
Escherichia coli
(Capsular Polysaccharides)
LUDERITZ and colleagues (1977)—“Somatic and capsular antigens of gram-negative bacteria” (Compr. Biochem. 26 A, 105-228).
2—for membranal lipopolysaccharides (LPS) Corynebacterium (avidum, bovis, diphteriae, enzymicum, equi, fascians, flaccum, faciens, flavidum, fusiforme, granulosum, helvolum, hypertrophicans, insidiosum, liquefaciens, parvum, paurometabolum, pyogenes, tumescens, xerosis)
and the gram negative:
Klebsiella
(
pneumoniae and rhinoscleromatis
)
Salmonella typhimurium
Serratia
(
marcescens, corralina, indica, polymuthica, kiluea
)
Neisseria meningitidis
Escherichia coli
C. ERBIN and colleagues (1977)—“Structural studies on the Klebsiella LPS” (
Carbohydr. Res
., 56, 377-81).
C. B. CASTOR and colleagues (1971)—“Characteristics of a highly purified pyrogenic LPS of
Klebsiella pneumoniae
(
J. of Pharm. Sci
., 60, (10), 1578-80).
K. FUKUSHI (1964)—“Extraction and purification of endotoxin from Enterobacteriaceae: a comparison of selected methods and sources” (
J. of Bacteriol
. 87, (2), 391-400).
G. A. LIMJUCO—“Studies on the chemical composition of LPS from
Neisseria meningitidis
group B” (
J. of Gen. Microbiol
. 1978, 104, 187-91).
G. A. ADAMS (1967)—“Extraction of LPS from gramnegative bacteria with DMSO” (
Canad. J. Biochem
., 45, 422-26).
K. G. JOHNSON (1976)—“Improved techniques for the preparation of bacterial LPS” (
Canad. J. Microbiol
. (22), 29-34).
Y. B. KIM and colleagues (1967)—“Biologically active endotoxins from Salmonella mutans (
J. of Bacteriol
., 94, (5), 1320-26).
3—For Membranal Proteins
Escherichia coli
Serratia marcescens
Streptococcus pyogenes
Salmonella typhimurium
Escherichia coli
S. F. STIRM and colleagues (1967)—“Episome, carried surface antigen K88 of
Escherichia coli
(
J. of Bacteriol
., 93, (2), 731-39).
S. J. BETZ and colleagues (1977)—“Chemical and biological properties of a protein rich fraction of bacterial LPS” (
J. of Immunol
., 119, (4), 1475-81).
Serratia marcescens
W. WOBER (1971)—“Studies on the protein moiety of endotoxin from gram-negative bacteria, characterization of the protein-moieting isolated by acetic acid hydrolysis of endotoxin of Serratia marcescens”.
Streptococcus pyogenes
M. K. WITTNER (1977)—“Homologous and heterologous protection of mice with group-A Streptococcal M protein vaccine” (
Infect. and Immun
., 1977, 15, (1), 104-8).
Salmonella thyphimurium
N. KUUSI and colleagues (1979)—“Immunization with major outer membrane protein in experimental salmonellosis of mice” (
Infect. and Immun
., 1979, 25, (3), 857-62).
C. BARBER and colleagues (1972)—“The protective role of proteins from Salmonella thyphimurium in infection of mice with their natural pathogen” (
Rev. Immunol
., 36, 77-81).
G. DELORD (1979)—“Etude d'un antigene vaccinant contenu dans le surnageant de culture de Sa

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