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 immuno-protective compositions and antibodies derived therefrom for diagnosing, treating, and preventing infections caused by M. catarrhalis.
1. A synthetic oligosaccharide 1a or 1b:
where R 1 and R 2 are selected from the following table
R 1
R 2
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)
βGa1(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(12)
βGal(1-4)αGlc(1-2)
αGal(1-4)βGal(1-4)αGlc(1-2)
X is H or a protecting group, L is a linker, and Y is H or a carrier.
2. The oligosaccharide of claim 1 , wherein R 1 is H and R 2 is α-Glc(1→2).
3. The oligosaccharide of claim 1 , wherein R 1 is H and R 2 is β-Gal-(1→4)-α-Glc 1→2).
4. The oligosaccharide of claim 1 , wherein R 1 is H and R 2 is α-Gal-(1→4)-β-Gal-(1→4)-α-Glc(1→2).
5. The oligosaccharide of claim 1 , wherein R 1 is α-Glc-(1→2) and R 2 is H.
6. The oligosaccharide of claim 1 , wherein R 1 is α-Glc-(1→2) and R 2 is α-Glc-(1→2).
7. The oligosaccharide of claim 1 , wherein R 1 is α-Glc-(1→2) and R 2 is β-Gal-(1→4)-α-Glc(1→2).
8. The oligosaccharide of claim 1 , wherein R 1 is α-Glc-(1→2) and R 2 is α-Gal(1→4)-β-Gal(1→4)-α-Glc(1→2).
9. The oligosaccharide of claim 1 , wherein R 1 is β-Gal-(1→4)-α-Glc(1→2) and R 2 is H.
10. The oligosaccharide of claim 1 , wherein R 1 is β-Gal-(1→4)-α-Glc(1→2) and R 2 is α-Glc(1→2).
11. The oligosaccharide of claim 1 , wherein R 1 is β-Gal-(1→4)-α-Glc(1→2) and R 2 is α-Gal-(1→4)-α-Glc(1→2).
12. The oligosaccharide of claim 1 , wherein R 1 is β-Gal-(1→4)-α-Glc(1→2) and R 2 is α-Gal-(1→4)-β-Gal-(1→4)-α-Glc(1→2).
13. The oligosaccharide of claim 1 , wherein R 1 is α-Gal-(1→4)-β-Gal-(1→4)-α-Glc(1→2) and R 2 is H.
14. The oligosaccharide of claim 1 , wherein R 1 is α-Gal-(1→4)-β-Gal-(1→4)-α-Glc(1→2) and R 2 is α-Glc(1→2).
15. The oligosaccharide of claim 1 , wherein R 1 is α-Gal-(1→4)-β-Gal-(1→4)-α-Glc(1→2) and R 2 is β-Gal-(1→4)-α-Glc(1→2).
16. The oligosaccharide of claim 1 , wherein R 1 is α-Gal-(1→4)-β-Gal-(1→4)-α-Glc(1→2) and R 2 is α-Gal-(1→4)-β-Gal-(1→4)-α-Glc(1→2).
17. The oligosaccharide of claim 1 , wherein L is an alkylene thiol linker.
18. 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.
19. The synthetic oligosaccharide of claim 18 , wherein the carrier is a carrier protein.
20. The synthetic oligosaccharide of claim 19 , wherein the carrier protein is selected from the group consisting of bacterial toxoids, toxins, exotoxins, and nontoxic derivatives thereof
21. The synthetic oligosaccharide of claim 20 , 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 of TLR-5; and derivatives and/or combinations of the above carriers.
22. The synthetic oligosaccharide of claim 21 , 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.
23. The synthetic oligosaccharide of claim 21 , wherein the carrier protein is selected from the group consisting of tetanus toxoid, CRM 197, and OMPC.
24. A composition comprising a synthetic oligosaccharide of claim 1 and a pharmaceutically acceptable vehicle.
25. The composition of claim 24 , comprising a second oligosaccharide 1c or 1d:
where R 1 and R 2 are selected from the following table
R1
R2
αGlc(1-2)
H
αGlc(1-2)
βGal(1-4)aGlc(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
aGlc(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)
X is H or a protecting group, L is a linker, and Y is H or a carrier.