# US 10,864,261 B2 · Synthetic vaccines against Streptococcus pneumoniae serotype 2

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,864,261 B2
- Document ID: US10864261B2
- Status: Granted
- Kind: B2
- Application number: 16/061,478
- Filed: 2016-12-16
- Published: 2020-01-16
- Granted: 2020-12-15
- Earliest claimed: 2015-12-17
- Assignees: Max-Planck-Gesellschaft zur Forderung der Wissenschaften e.V.
- Applicants: Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.
- Inventors: Peter H. Seeberger; Claney Lebev Pereira; Chakkumkal Anish; Naeem Khan; Madhu Emmadi
- Web page: https://patentgrep.com/patent/US10864261B2

## CPC

- A61K 39/092: {Streptococcus}
- A61K 31/7028: Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K 31/715: Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 37/04: Immunostimulants
- C07H 1/00: Processes for the preparation of sugar derivatives
- C07H 15/00: Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H 15/04: attached to an oxygen atom of the saccharide radical
- C07K 16/1275: Streptococcus (G)
- A61K 2039/55505: {Inorganic adjuvants}
- A61K 2039/6037: {Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]}
- A61K 2039/627: {characterised by the linker}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to a synthetic saccharide of general formula (I) that is related to Streptococcus pneumoniae serotype 2 capsular polysaccharide, a conjugate thereof and the use of said saccharide and conjugate for raising a protective immune response in a human and/or animal host. Furthermore, the synthetic saccharide of general formula (I) is useful as marker in immunological assays for detection of antibodies against Streptococcus pneumoniae type 2 bacteria.

## Claims

### Claim 1

A saccharide of general formula (I)
V*-Ux+3-Ux+2-Ux+1-Ux-O-L-NH2 (I)
wherein
x is an integer selected from 1, 2, 3 and 4;
V*- represents H-, H-Ux-, H-Ux+1-Ux-, H-Ux+2-Ux+1-Ux- or H-Ux+3-Ux+2-Ux+1-Ux-;
L is selected from
—CH2—, —(CH2)2—, —(CH2)3—, —(CH2)4—, —(CH2)5—, —(CH2)6—, —(CH2)7—, —(CH2)8—, —(CH2)9—, —(CH2)10—, —CF2—, —(CF2)2—, —(CF2)3—, —(CF2)4—, —(CF2)5—, —(CF2)6—, —(CF2)7—, —(CF2)8—, —(CF2)9—, —(CF2)10—, —(CH2)2—O—(CH2)2—, —CH2—O—(CH2)3—, —(CH2)3O—CH2—, —CH2—O—(CH2)2—, —(CH2)2O—CH2—, —(CH2)3—O—(CH2)2—, —(CH2)2—O—(CH2)3—, —(CH2)4—O—CH2—, —CH2—O—(CH2)4—, -La-, -La-Le-, -La-Lb-Le-, -La-Lb-Ld-Lc-Le-, and -La-Ld-Le-;
wherein
-La- is selected from: —(CH2)o—, —(CF2)o—, —(CH2—CH2—O)o—C2H4—, —(CH2—CH2—O)o—CH2—, —(CR10R11)o—,
-Lb- and -Lc- are independently of each other selected from: —O—, —NH—C(O)—NH—, —NH—C(S)—NH—, —NH—C(O)—, —C(O)—NH—, —NH—C(O)—O—, —NR9—, —NR18—, —SO2—,
-Ld- represents —(CH2)q—, —(CF2)q—, —(CR12R13)q—, —(CH2—CH2—O)q—C2H4—, —CH2—CH2—O)q—CH2—,
-Le- is selected from: —(CH2)p1—, —(CF2)p1—, —C2H4—(O—CH2—CH2)p1—, —CH2—(O—CH2—CH2)p1—, —(CH2)p1—O—(CH2)p2—, —(CR14R15)p1—, —(CR14R15)p1—O—(CR21R22)q2—,
R9 and R18 are independently of each other selected from: —CH3, —C2H5, —C3H7, and —C(O)CH3;
R10, R11, R12, R13, R14, R15, R16, R17, R19, R20, R21 and R22 are independently of each other selected from: —H, —F, —Cl, —CH3, —C2H5, —C3H7, —C5H9, —C6H13, —OCH3, —OC2H5, —CH2F, —CHF2, —CF3, —C(O)—NH2, —SCH3, —SC2H5, —NHC(O)CH3, —N(CH3)2 and —N(C2H5)2;
o, q, p1 and p2 are independently of each other an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The saccharide according to claim 1, wherein x represents 1, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The saccharide according to claim 1, wherein
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The saccharide according to claim 1, wherein
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A method of synthesis of a saccharide of general formula (I) according to claim 1, wherein x represents 1, V*- represents H- and
comprising the following steps:
A) reacting a disaccharide of general formula (II)
wherein P1-P3 represent protecting groups, and LG1 represents a leaving group, with a disaccharide of general formula (III)
wherein P4-P8 represent protecting groups and L has the meaning as defined in claim 1, to obtain a tetrasaccharide of general formula (IV)
wherein P1-P8 represent protecting groups;
and
B) subjecting the tetrasaccharide of general formula (IV) to selective deprotection to obtain a tetrasaccharide of general formula (V)
wherein P1-P4, P6-P8 represent protecting groups and L has the meaning defined in claim 1; and
C) reacting the tetrasaccharide of general formula (V) with a disaccharide of general formula (VI)
wherein P9 and P10 represent protecting groups and LG2 represents a leaving group to obtain a hexasaccharide of general formula (VII)
wherein P1-P4, P6-P10 represent protecting groups and L has the meaning defined in claim 1;
and
D) performing the removal of protecting groups P1-P4, P6-P10 on the compound of general formula (VII).

### Claim 6 (depends on 1)

An intermediate of general formula (V)
wherein P1- P4, P6-P8 represent protecting groups and L has the meaning defined in claim 1.

### Claim 7 (depends on 6)

The intermediate of general formula (V) according to claim 6, wherein P1, P6 and P7 represent a benzyl group, P2, P3 and P4 are independently of each other selected from benzoyl and acetyl group, and P8 represents a benzyloxy carbonyl group.

### Claim 8 (depends on 1)

A conjugate of general formula (X)
[V*-Ux+3-Ux+2-Ux+1-Ux-O-L-NH-W]m-CRM197 (X)
wherein m is comprised between about 2 and about 18;
-W- is selected from:
a represents an integer from 1 to 10;
b represents an integer from 1 to 4; and
V*, Ux+3, Ux+2, Ux+1, Ux, x and L have the meanings as defined in claim 1.

### Claim 9 (depends on 1)

A saccharide according to claim 1 for use in raising a protective immune response in a human and/or animal host.

### Claim 10 (depends on 1)

A saccharide according to claim 1 for use in the prevention and/or treatment of a disease caused by Streptococcus pneumoniae type 2.

### Claim 11 (depends on 1)

A vaccine comprising the saccharide and/or the pharmaceutically acceptable salt thereof according to claim 1 together with at least one pharmaceutically acceptable adjuvant and/or excipient.

### Claim 12 (depends on 11)

The vaccine composition according to claim 11, further comprising at least a capsular polysaccharide of Streptococcus pneumoniae and/or a fragment of a capsular polysaccharide of Streptococcus pneumoniae and/or a conjugate of a carrier protein and a capsular polysaccharide of Streptococcus pneumoniae or a fragment of a capsular polysaccharide of Streptococcus pneumoniae, wherein Streptococcus pneumoniae is selected from the group comprising Streptococcus pneumoniae type 1, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F and 33F.

### Claim 13 (depends on 1)

A saccharide according to claim 1 for use as marker in immunological assays for detection of antibodies against Streptococcus pneumoniae type 2.

### Claim 14 (depends on 8)

A conjugate according to claim 8 for use in raising a protective immune response in a human and/or animal host.

### Claim 15 (depends on 8)

A conjugate according to claim 8 for use in the prevention and/or treatment of a disease caused by Streptococcus pneumoniae type 2.

### Claim 16 (depends on 8)

A vaccine comprising the conjugate according to claim 8 together with at least one pharmaceutically acceptable adjuvant and/or excipient.

### Claim 17 (depends on 16)

The vaccine composition according to claim 16, further comprising at least a capsular polysaccharide of Streptococcus pneumoniae and/or a fragment of a capsular polysaccharide of Streptococcus pneumoniae and/or a conjugate of a carrier protein and a capsular polysaccharide of Streptococcus pneumoniae or a fragment of a capsular polysaccharide of Streptococcus pneumoniae, wherein Streptococcus pneumoniae is selected from the group comprising Streptococcus pneumoniae type 1, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F and 33F.