Synthetic oligosaccharides for moraxella vaccine
The present invention provides synthetic Moraxella catarrhalis lipooligosaccharide (LOS)-based oligosaccharides and conjugates containing various M. catarrhalis serotype-specific oligosaccharide antigens or various core M. catarrhalis oligosaccharide structures or motifs corresponding to one or more of the three major serotypes and/or members within a given serotype. The oligosaccharides may be synthesized by a chemical assembly methodology relying on a limited number of monosaccharide and disaccharide building blocks. The invention further provides M. catarrhalis LOS-based immunogenic and immunoprotective compositions and antibodies derived therefrom for diagnosing, treating, and preventing infections caused by M. catarrhalis.
1. A synthetic oligosaccharide 1b:
where R 1 and R 2 are selected from the following table
R1
R2
αGlc(1-2)
H
αGlc(1-2)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
H
αGlc(1-2)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
βGal(1-4)αGlc(1-2)
H
αGlc(1-2)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
H
αGlc(1-2)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
L is a linker, and Y is a carrier.
2. The synthetic oligosaccharide of claim 1 , wherein L is an alkylene thiol linker.
3. The synthetic oligosaccharide of claim 1 , wherein Y is a carrier selected from the group consisting of proteins, peptides, lipids, polymers, dendrimers, virosomes, and virus-like particles or combination thereof.
4. The synthetic oligosaccharide of claim 3 , wherein the carrier is a carrier protein.
5. The synthetic oligosaccharide of claim 4 , wherein the carrier protein is selected from the group consisting of bacterial toxoids, toxins, exotoxins, and nontoxic derivatives thereof.
6. The synthetic oligosaccharide of claim 5 , wherein the carrier protein is selected from the group consisting of tetanus toxoid, tetanus toxin Fragment C, diphtheria toxoid, CRM, cholera toxoid, Staphylococcus aureus exotoxins or toxoids, Escherichia coli heat labile enterotoxin, Pseudomonas aeruginosa exotoxin A, genetically detoxified variants thereof; bacterial outer membrane proteins, serotype B outer membrane protein complex (OMPC), outer membrane class 3 porin (rPorB), porins; keyhole limpet hemocyanine (KLH), hepatitis B virus core protein, thyroglobulin, albumins, and ovalbumin; pneumococcal surface protein A (PspA), pneumococcal adhesin protein (PsaA); purified protein derivative of tuberculin (PPD); transferrin binding proteins, peptidyl agonists ofTLR-5; and derivatives and/or combinations of the above carriers.
7. The synthetic oligosaccharide of claim 6 , wherein the carrier protein is selected from the group consisting of CRM 197, Neisseria meningitidis , bovine serum albumin (BSA), human serum albumin (HSA), poly(lysine:glutamic acid), flagellin of motile bacteria, and derivatives and/or combinations thereof.
8. The synthetic oligosaccharide of claim 6 , wherein the carrier protein is selected from the group consisting of tetanus toxoid, CRM 197, and OMPC.
9. A composition comprising the synthetic oligosaccharide 1b of claim 1 and a pharmaceutically acceptable vehicle.
10. The composition of claim 9 , wherein the composition further comprises a second oligosaccharide 1d
where R1 and R2 are selected from the following table
R1
R2
αGlc(1-2)
H
αGlc(1-2)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
αGlcNAc(1-2)
βGal(1-4)αGlcNAc(1-2)
αGal(1-4)βGal(1-4)αGlcNAc(1-2)
H
H
αGlc(1-2)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
αGlcNAc(1-2)
βGal(1-4)αGlcNAc(1-2)
αGal(1-4)βGal(1-4)αGlcNAc(1-2)
βGal(1-4)αGlc(1-2)
H
αGlc(1-2)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
αGlcNAc(1-2)
βGal(1-4)αGlcNAc(1-2)
αGal(1-4)βGal(1-4)αGlcNAc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
H
αGlc(1-2)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
αGlcNAc(1-2)
βGal(1-4)αGlcNAc(1-2)
αGal(1-4)βGal(1-4)αGlcNAc(1-2)
L is a linker, and Y is a carrier.
11. The composition of claim 9 , further comprising an adjuvant.
12. The composition of claim 11 , wherein the adjuvant is selected from the group consisting of aluminum salts, RIBI, toll-like receptor agonists, AS01, AS02, AS03, AS04, AS05, CpG-oligodeoxynucleotide, MF-59, Montanide ISA-51 VG, Montanide ISA-720, Quil A, QS21, synthetic saponins, immunostimulating complexes, stearyl tyrosine, virus-like particles, reconstituted influenza virosomes, cytokines, mast cell activator compound 48/80, liposomes, muramyl dipeptides, SAF-1, and combinations thereof.
13. The composition of claim 10 comprising a plurality of different synthetic oligosaccharides of formula 1b of claim 1 .