# US 9,517,263 B2 · Benzonaphthyridine-containing vaccines

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- Number: US 9,517,263 B2
- Document ID: US9517263B2
- Status: Granted
- Kind: B2
- Application number: 13/377,511
- Filed: 2010-06-10
- Published: 2012-10-18
- Granted: 2016-12-13
- Earliest claimed: 2009-06-10
- Assignees: Glaxosmithkline Biologicals SA
- Applicants: Derek O'Hagan; Manmohan Singh; Siddhartha Jain; Sushma Kommareddy
- Inventors: Derek O'Hagan; Manmohan Singh; Siddhartha Jain; Sushma Kommareddy
- Web page: https://patentgrep.com/patent/US9517263B2

## CPC

- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 37/04: Immunostimulants
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/6093: {Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine}
- 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

## Abstract

The invention provides, inter alia, immunogenic compositions that comprise (a) a first antigen, (b) polymeric particles and (c) a benzonaphthyridine compound, which compositions elicits an immune response when administered to a vertebrate subject. The invention also provides, inter alia, methods of producing immunogenic compositions and methods for using immunogenic compositions (e.g., for treatment), among other benefits.

## Claims

### Claim 1

An immunogenic composition comprising (a) a first antigen, (b) polymeric particles that comprise a polymer that is at least partially biodegradable wherein said polymer comprises a polymer block selected from a polyester block, a polyorthoester block, and a polyanhydride block, and (c) a benzonaphthyridine compound, wherein the inclusion of the polymeric particles in the composition elicits an enhanced immune response when administered to a vertebrate subject.

### Claim 2 (depends on 1)

The immunogenic composition of claim 1, wherein said biodegradable polymer comprises a polyester block that is selected from a poly(lactide) block, a poly(glycolide) block, a poly(lactide-co-glycolide) block and a poly(epsilon-caprolactone) block.

### Claim 3 (depends on 1)

The immunogenic composition of claim 1, wherein said biodegradable polymer is a block copolymer that comprises a polyhydroxyacid block and a polymer block that is not a polyhydroxyacid block.

### Claim 4 (depends on 1)

The immunogenic composition of claim 1, wherein said biodegradable polymer is a block copolymer that comprises a poly(lactide-co-glycolide) block and a polyethylene glycol block.

### Claim 5 (depends on 1)

The immunogenic composition of claim 1, wherein the polymeric particles have a negative charge or a positive charge.

### Claim 6 (depends on 1)

The immunogenic composition of claim 1, wherein the polymeric particles are formed by a solvent evaporation process or by a precipitation process.

### Claim 7 (depends on 1)

The immunogenic composition of claim 1, wherein the benzonaphthyridine compound is present in an amount that ranges from 0.05% to 25% w/w relative to the polymer content of the polymeric particles.

### Claim 8 (depends on 1)

The immunogenic composition of claim 1, wherein said benzonaphthyridine compound is established within said polymeric particles.

### Claim 9 (depends on 1)

The immunogenic composition of claim 1, wherein said benzonaphthyridine compound is admixed with said polymeric particles and then co-lyophilized with said polymeric particles.

### Claim 10 (depends on 1)

The immunogenic composition of claim 1, wherein the first antigen is present in an amount that ranges from 0.05% to 25% w/w relative to the content of polymeric particles.

### Claim 11 (depends on 1)

The immunogenic composition of claim 1, wherein said first antigen is established within said polymeric particles.

### Claim 12 (depends on 1)

The immunogenic composition of claim 1, wherein said first antigen is admixed with said polymeric particles and then co-lyophilized with said polymeric particles.

### Claim 13 (depends on 1)

The immunogenic composition of claim 1, wherein the first antigen is selected from a polypeptide-containing antigen, a polysaccharide-containing antigen, and a polynucleotide-containing antigen.

### Claim 14 (depends on 1)

The immunogenic composition of claim 1, wherein the first antigen is a tumor-cell-derived antigen.

### Claim 15 (depends on 1)

The immunogenic composition of claim 1, wherein the first antigen is a pathogenic-organism-derived antigen.

### Claim 16 (depends on 15)

The immunogenic composition of claim 15, wherein the pathogenic organism is selected from a virus, a bacterium, a fungus and a parasite.

### Claim 17 (depends on 1)

The immunogenic composition of claim 1, wherein the composition comprises a cryoprotective agent.

### Claim 18 (depends on 1)

The immunogenic composition of claim 1, wherein the benzonaphthyridine compound is a compound having the structure of Formula (VI), or a pharmaceutically acceptable salt thereof:
wherein:
R4 is selected from H, halogen, —C(O)OR7, —C(O)R7, —C(O)N(R11R12), —N(R11R12), —N(R9)2, —NHN(R9)2, —SR7, —(CH2)nOR7, —(CH2)nR7, -LR8, -LR10, —OLR8, —OLR10, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8alkene, C2-C8alkyne, C1-C6alkoxy, C1-C6haloalkoxy, aryl, heteroaryl, C3-C8cycloalkyl, and C3-C8heterocycloalkyl, wherein the C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8alkene, C2-C8alkyne, C1-C6alkoxy, C1-C6haloalkoxy, aryl, heteroaryl, C3-C8cycloalkyl, and C3-C8heterocycloalkyl groups of R4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO2, —R7, —OR8, —C(O)R8, —OC(O)R8, —C(O)OR8, —N(R9)2, —P(O)(OR8)2, —OP(O)(OR8)2, —P(O)(OR10)2, —OP(O)(OR10)2, —C(O)N(R9)2, —S(O)2R8, —S(O)R8, —S(O)2N(R9)2, and —NR9S(O)2R8;
each L is independently selected from a bond, —(O(CH2)m)t—, C1-C6alkyl, C2-C6alkenylene and C2-C6alkynylene, wherein the C1-C6alkyl, C2-C6alkenylene and C2-C6alkynylene of L are each optionally substituted with 1 to 4 substituents independently selected from halogen, —R8, —OR8, —N(R9)2, —P(O)(OR8)2, —OP(O)(OR8)2, —P(O)(OR10)2, and —OP(O)(OR10)2;
R7 is selected from H, C1-C6alkyl, aryl, heteroaryl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8 alkene, C2-C8 alkyne, C1-C6alkoxy, C1-C6haloalkoxy, and C3-C8heterocycloalkyl, wherein the C1-C6alkyl, aryl, heteroaryl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8 alkene, C2-C8 alkyne, C1-C6alkoxy, C1-C6haloalkoxy, and C3-C8heterocycloalkyl groups of R7 are each optionally substituted with 1 to 3 R13 groups;
each R8 is independently selected from H, —CH(R10)2, C1-C8alkyl, C2-C8alkene, C2-C8alkyne, C1-C6haloalkyl, C1-C6alkoxy, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C1-C6hydroxyalkyl and C1-C6haloalkoxy, wherein the C1-C8 alkyl, C2-C8 alkene, C2-C8 alkyne, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C1-C6hydroxyalkyl and C1-C6haloalkoxy groups of R8 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R11, —OR11, —SR11, —C(O)R11, —OC(O)R11, —C(O)N(R9)2, —C(O)OR11, —NR9C(O)R11, —NR9R10, —NR11R12, —N(R9)2, —OR9, —OR10, —C(O)O11R12, —C(O)NR11OH, —S(O)2R11, —S(O)R11, —S(O)2NR11R12, —NR11S(O)2R11, —P(O)(OR11)2, and —OP(O)(OR11)2;
each R9 is independently selected from H, —C(O)R8, —C(O)OR8, —C(O)R10, —C(O)OR10, —S(O)2R10, —C1-C6 alkyl, C1-C6 heteroalkyl and C3-C6 cycloalkyl, or each R9 is independently a C1-C6alkyl that together with N they are attached to form a C3-C8heterocycloalkyl, wherein the C3-C8heterocycloalkyl ring optionally contains an additional heteroatom selected from N, O and S, and wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C3-C8heterocycloalkyl groups of R9 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R11, —OR11, —SR11, —C(O)R11, —OC(O)R11, —C(O)OR11, —NR11R12, —C(O)NR11R12, —C(O)NR11OH, —S(O)2R11, —S(O)R11, —S(O)2NR11R12, —NR11S(O)2R11, —P(O)(OR11)2, and —OP(O)(OR11)2;
each R10 is independently selected from aryl, C3-C8cycloalkyl, C3-C8heterocycloalkyl and heteroaryl, wherein the aryl, C3-C8cycloalkyl, C3-C8heterocycloalkyl and heteroaryl groups are optionally substituted with 1 to 3 substituents selected from halogen, —R8, —OR8, -LR9, -LOR9, —N(R9)2, —NR9C(O)R8, —NR9CO2R8, —CO2R8, —C(O)R8 and —C(O)N(R9)2;
R11 and R12 are independently selected from H, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, aryl, heteroaryl, C3-C8cycloalkyl, and C3-C8heterocycloalkyl, wherein the C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, aryl, heteroaryl, C3-C8cycloalkyl, and C3-C8heterocycloalkyl groups of R11 and R12 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R8, —OR8, —C(O)R8, −OC(O)R8, —C(O)OR8, —N(R9)2, —NR8C(O)R8, —NR8C(O)OR8, —C(O)N(R9)2, C3-C8heterocycloalkyl, —S(O)2R8, —S(O)2N(R9)2, —NR9S(O)2R8, C1-C6haloalkyl and C1-C6haloalkoxy;
or R11 and R12 are each independently C1-C6alkyl and taken together with the N atom to which they are attached form an optionally substituted C3-C8heterocycloalkyl ring optionally containing an additional heteroatom selected from N, O and S;
each R13 is independently selected from halogen, —CN, -LR9, -LOR9, —OLR9, -LR10, -LOR10, —OLR10, -LR8, -LOR8, —OLR8, -LSR8, -LSR10, -LC(O)R8, —OLC(O)R8, -LC(O)OR8, -LC(O)R10, -LOC(O)OR8, -LC(O)NR9R11, -LC(O)NR9R8, -LN(R9)2, -LNR9R8, -LNR9R10, -LC(O)N(R9)2, -LS(O)2R8, -LS(O)R8, -LC(O)NR8OH, -LNR9C(O)R8, -LNR9C(O)OR8, -LS(O)2N(R9)2, —OLS(O)2N(R9)2, -LNR9S(O)2R8, -LC(O)NR9LN(R9)2, -LP(O)(OR8)2, -LOP(O)(OR8)2, -LP(O)(OR10)2 and—OLP(O)(OR10)2;
each RA is independently selected from —R8, —R7, —OR7, —OR8, —R10, —OR10, —SR8, —NO2, —CN, —N(R9)2, —NR9C(O)R8, —NR9C(S)R8, —NR9C(O)N(R9)2, —NR9C(S)N(R9)2, —NR9CO2R8, —NR9NR9C(O)R8, —NR9NR9C(O)N(R9)2, —NR9NR9CO2R8, —C(O)C(O)R8, —C(O)CH2C(O)R8, —CO2R8, —(CH2)—CO2R8, —C(O)R8, —C(S)R8, —C(O)N(R9)2, —C(S)N(R9)2, —OC(O)N(R9)2, —OC(O)R8, —C(O)N(OR8)R8, —C(NOR8)R8, —S(O)2R8, —S(O)3R8, —SO2N(R9)2, —S(O)R8, —NR9SO2N(R9)2, —NR9SO2R8, —P(O)(OR8)2, —OP(O)(OR8)2, —P(O)(OR10)2, —OP(O)(OR10)2, —N(OR8)R8, —CH═CHCO2R8, —C(═NH)—N(R9)2, and —(CH2)nNHC(O)R8; or two adjacent RA substituents on Ring A form a 5-6 membered ring that contains up to two heteroatoms as ring members;
n is, independently at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7 or 8;
each m is independently selected from 1, 2, 3, 4, 5 and 6, and
t is 1, 2, 3, 4, 5, 6, 7 or 8.

### Claim 19 (depends on 18)

The immunogenic composition of claim 18, wherein the compound having the structure of Formula (VI) is a compound having the structure of Formula (VII), or a pharmaceutically acceptable salt thereof:
wherein:
R4 is selected from H, halogen, —C(O)OR7, —C(O)R7, —C(O)N(R11R12), —N(R11R12), —N(R9)2, —NHN(R9)2, —SR7, —(CH2)nOR7, —(CH2)nR7, -LR8, -LR10, —OLR8, —OLR10, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8alkene, C2-C8alkyne, C1-C6alkoxy, C1-C6haloalkoxy, aryl, heteroaryl, C3-C8cycloalkyl, and C3-C8heterocycloalkyl, wherein the C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8 alkene, C2-C8 alkyne, C1-C6alkoxy, C1-C6haloalkoxy, aryl, heteroaryl, C3-C8cycloalkyl, and C3-C8heterocycloalkyl groups of R4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO2, —R7, —OR8, —C(O)R8, —OC(O)R8, —C(O)OR8, —N(R9)2, —P(O)(OR8)2, —OP(O)(OR8)2, —P(O)(OR10)2, —OP(O)(OR10)2, —C(O)N(R9)2, —S(O)2R8, —S(O)R8, —S(O)2N(R9)2, and —NR9S(O)2R8;
each L is independently selected from a bond, —(O(CH2)m)t—, C1-C6alkyl, C2-C6alkenylene and C2-C6alkynylene, wherein the C1-C6alkyl, C2-C6alkenylene and C2-C6alkynylene of L are each optionally substituted with 1 to 4 substituents independently selected from halogen, —R8, —OR8, —N(R9)2, —P(O)(OR8)2, —OP(O)(OR8)2, —P(O)(OR10)2, and —OP(O)(OR10)2;
R7 is selected from H, C1-C6alkyl, aryl, heteroaryl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8 alkene, C2-C8 alkyne, C1-C6alkoxy, C1-C6haloalkoxy, and C3-C8heterocycloalkyl, wherein the C1-C6alkyl, aryl, heteroaryl, C3-C8cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C8 alkene, C2-C8 alkyne, C1-C6alkoxy, C1-C6haloalkoxy, and C3-C8heterocycloalkyl groups of R7 are each optionally substituted with 1 to 3 R13 groups;
each R8 is independently selected from H, —CH(R10)2, C1-C8alkyl, C2-C8alkene, C2-C8alkyne, C1-C6haloalkyl, C1-C6alkoxy, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C1-C6hydroxyalkyl and C1-C6haloalkoxy, wherein the C1-C8 alkyl, C2-C8 alkene, C2-C8 alkyne, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C1-C6hydroxyalkyl and C1-C6haloalkoxy groups of R8 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R11, —OR11, —SR11, —C(O)R11, —OC(O)R11, —C(O)N(R9)2, —C(O)OR11, —NR9C(O)R11, —NR9R10, —NR11R12, —N(R9)2, —OR9, —OR10, —C(O)NR11R12, —C(O)NR11OH, —S(O)2R11, —S(O)R11, —S(O)2NR11R12, —NR11S(O)2R11, —P(O)(OR11)2, and —OP(O)(OR11)2;
each R9 is independently selected from H, —C(O)R8, —C(O)OR8, —C(O)R10, —C(O)OR10, —S(O)2R10, —C1-C6 alkyl, C1-C6 heteroalkyl and C3-C6 cycloalkyl, or each R9 is independently a C1-C6alkyl that together with N they are attached to form a C3-C8heterocycloalkyl, wherein the C3-C8heterocycloalkyl ring optionally contains an additional heteroatom selected from N, O and S, and wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or C3-C8heterocycloalkyl groups of R9 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R11, —OR11, —SR11, —C(O)R11, —OC(O)R11, —C(O)OR11, —NR11R12, —C(O)NR11R12, —C(O)NR11OH, —S(O)2R11, —S(O)R11, —S(O)2NR11R12, —NR11S(O)2R11, —P(O)(OR11)2, and —OP(O)(OR11)2;
each R10 is independently selected from aryl, C3-C8cycloalkyl, C3-C8heterocycloalkyl and heteroaryl, wherein the aryl, C3-C8cycloalkyl, C3-C8heterocycloalkyl and heteroaryl groups are optionally substituted with 1 to 3 substituents selected from halogen, —R8, —OR8, -LR9, -LOR9, —N(R9)2, —NR9C(O)R8, —NR9CO2R8, —CO2R8, —C(O)R8 and —C(O)N(R9)2;
R11 and R12 are independently selected from H, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, aryl, heteroaryl, C3-C8cycloalkyl, and C3-C8heterocycloalkyl, wherein the C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, aryl, heteroaryl, C3-C8cycloalkyl, and C3-C8heterocycloalkyl groups of R11 and R12 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R8, —OR8, —C(O)R8, −OC(O)R8, —C(O)OR8, —N(R9)2, —NR8C(O)R8, —NR8C(O)OR8, —C(O)N(R9)2, C3-C8heterocycloalkyl, —S(O)2R8, —S(O)2N(R9)2, —NR9S(O)2R8, C1-C6haloalkyl and C1-C6haloalkoxy;
or R11 and R12 are each independently C1-C6alkyl and taken together with the N atom to which they are attached form an optionally substituted C3-C8heterocycloalkyl ring optionally containing an additional heteroatom selected from N, O and S;
each R13 is independently selected from halogen, —CN, -LR9, -LOR9, —OLR9, -LR10, -LOR10, —OLR10, -LR8, -LOR8, —OLR8, -LSR8, -LSR10, -LC(O)R8, —OLC(O)R8, -LC(O)OR8, -LC(O)R10, -LOC(O)OR8, -LC(O)NR9R11, -LC(O)NR9R8, -LN(R9)2, -LNR9R8, -LNR9R10, -LC(O)N(R9)2, -LS(O)2R8, -LS(O)R8, -LC(O)NR8OH, -LNR9C(O)R8, -LNR9C(O)OR8, -LS(O)2N(R9)2, —OLS(O)2N(R9)2, -LNR9S(O)2R8, -LC(O)NR9LN(R9)2, -LP(O)(OR8)2, -LOP(O)(OR8)2, -LP(O)(OR10)2 and —OLP(O)(OR10)2;
each RA is independently selected from —R8, —R7, —OW, —OR8, —R10, —OR10, —SR8, —NO2, —CN, —N(R9)2, —NR9C(O)R8, —NR9C(S)R8, —NR9C(O)N(R9)2, —NR9C(S)N(R9)2, —NR9CO2R8, —NR9NR9C(O)R8, —NR9NR9C(O)N(R9)2, —NR9NR9CO2R8, —C(O)C(O)R8, —C(O)CH2C(O)R8, —CO2R8, —(CH2)nCO2R8, —C(O)R8, —C(S)R8, —C(O)N(R9)2, —C(S)N(R9)2, —OC(O)N(R9)2, —OC(O)R8, —C(O)N(OR8)R8, —C(NOR8)R8, —S(O)2R8, —S(O)3R8, —SO2N(R9)2, —S(O)R8, —NR9SO2N(R9)2, —NR9SO2R8, —P(O)(OR8)2, —OP(O)(OR8)2, —P(O)(OR10)2, —OP(O)(OR10)2, —N(OR8)R8, —CH═CHCO2R8, —C(═NH)—N(R9)2, and —(CH2)nNHC(O)R8;
n is, independently at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7 or 8;
each m is independently selected from 1, 2, 3, 4, 5 and 6, and
t is 1, 2, 3, 4, 5, 6, 7 or 8.

### Claim 20 (depends on 19)

The immunogenic composition of claim 19, wherein
each R13 is selected from -LR9, -LOR9, —OLR9, -LR10, -LOR10, —OLR10, -LR8, -LOR8, —OLR8, -LSR8, -LSR10, -LC(O)R8, —OLC(O)R8, -LC(O)OR8, -LC(O)R10, -LOC(O)OR8, -LC(O)NR9R11, -LC(O)NR9R8, -LN(R9)2, -LNR9R8, -LNR9R10, -LC(O)N(R9)2, -LS(O)2R8, -LS(O)R8, -LC(O)NR8OH, -LNR9C(O)R8, -LNR9C(O)OR8, -LS(O)2N(R9)2,—OLS(O)2N(R9)2, -LNR9S(O)2R8, -LC(O)NR9LN(R9)2, -LP(O)(OR8)2, -LOP(O)(OR8)2, -LP(O)(OR10)2 and—OLP(O)(OR10)2; and
each RA is independently selected from —R7, —OR7, —R8, —OR8, —R10, —OR10, —SR8, —N(R9)2, —S(O)2R8, —S(O)3R8, —SO2N(R9)2, —S(O)R8, —NR9SO2N(R9)2, —CH═CHCO2R8, (CH2)nCO2R8, —NR9SO2R8, —P(O)(OR8)2, —OP(O)(OR8)2, —P(O)(OR10)2, and —OP(O)(OR10)2.

### Claim 21 (depends on 20)

The immunogenic composition of claim 20, wherein
each L is independently selected from a —(O(CH2)m)t, and C1-C6alkyl, wherein the C1-C6alkyl of L is optionally substituted with 1 to 4 substituents independently selected from halogen, —R8, —OR8, —N(R9)2, —P(O)(OR8)2, —OP(O)(OR8)2, —P(O)(OR10)2, and —OP(O)(OR10)2.

### Claim 22 (depends on 21)

The immunogenic composition of claim 21, wherein RA is H or C1-C6alkyl.

### Claim 23 (depends on 19)

The immunogenic composition of claim 19, wherein
RA is H, —CH3 or —CH2CH3; and
each R13 is independently selected from H, —CH3, —CH2CH3, —CF3, —CH2OH, —OCH3, —COOCH3, —COOCH2CH3, F, Cl, Br, —CH2OCH3, CH2OCH2CH3, —N(CH3)2, —((O(CH2)2)2-4OH, —O(CH2)2-4—OH, —O(CH2)2-4—(PO3H2), —O(CH2)2-4—COOH, —O(CH2)2-4—CH(CH3)2 and C2-C6 alkyl substituted with 1-3 substituents selected from —OH, —CH3, —COOH, —COOCH3, cyclopropyl, —O(CH2)2-4—COOH, —O(CH2)2-4(PO3H2), and —COOCH2CH3.

### Claim 24 (depends on 19)

The immunogenic composition of claim 19, wherein R8 is H or C1-C6alkyl.

### Claim 25 (depends on 19)

The immunogenic composition of claim 19, wherein R9 is H or C1-C6alkyl.

### Claim 26 (depends on 19)

The immunogenic composition of claim 19, wherein
each R8 is independently selected from H, —CH(R10)2, C1-C8alkyl, C2-C8alkene, C2-C8alkyne, C1-C6haloalkyl, C1-C6alkoxy, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C1-C6hydroxyalkyl and C1-C6haloalkoxy, wherein the C1-C8alkyl, C2-C8alkene, C2-C8alkyne, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C1-C6hydroxyalkyl and C1-C6haloalkoxy groups of R8 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R11, —OR11, —SR11, —C(O)R11, —OC(O)R11, —C(O)N(R9)2, —C(O)OR11, —NR9C(O)R11, —NR9R10, —NR11R12, —N(R9)2, —OR9, —OR10, —C(O)NR11R12, —C(O)NR11OH, —S(O)2R11, —S(O)R11, —S(O)2NR11R12, —NR11S(O)2R11, —P(O)(OR11)2, and —OP(O)(OR11)2.

### Claim 27 (depends on 19)

The immunogenic composition of claim 19, wherein R4 is H.

### Claim 28 (depends on 18)

The immunogenic composition of claim 18, wherein the compound is selected from:
2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol;
2-(4-methoxy-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine;
2-(2,4-dimethylphenethyl)benzo[f][1,7]naphthyridin-5-amine;
ethyl 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoate;
2-(4-(dimethylamino)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine, and
2-(4-methoxyphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine.

### Claim 29 (depends on 1)

The immunogenic composition of claim 1, wherein the benzonaphthyridine compound is a compound having the structure of Formula (VIII), or a pharmaceutically acceptable salt thereof:
wherein:
R21 is H, C1-C6alkyl, —C(R25)2OH, -L21R25, -L21R26, —22R25, -L22R26, —OL22R25, or —OL22R26;
L21 is —C(O)— or —O—;
L22 is C1-C6alkylene, C2-C6alkenylene, arylene, heteroarylene or —((CR24R24)pP)q(CH2)p—, wherein the C1-C6alkylene and C2-C6alkenylene of L22 are optionally substituted with 1 to 4 fluoro groups;
each L23 is independently selected from C1-C6alkylene and —((CR24R24)pO)q(CH2)p—, wherein the C1-C6alkylene of L23 is optionally substituted with 1 to 4 fluoro groups;
L24 1, is arylene or heteroarylene;
R22 is H or C1-C6alkyl;
R23 is selected from C1-C4alkyl, -L23R25, -L21R25, -L23R27, -L23L24L23R27, -L23L24R25, - L23L24L23R25, —OL23R25, —OL23R27, —OL23L24R27, —OL23L24L23R27, —OR28, —OL23L24R25, —OL23L24L23R25 and —C(R25)2OH;
each R24 is independently selected from H and fluoro;
R25 is —P(O)(OR29)2,
R26 is —CF2P(O)(OR29)2 or —C(O)OR30;
R27 is —CF2P(O)(OR29)2 or —C(O)OR30;
R28 is H or C1-C4alkyl;
each R29 is independently selected from H and C1-C6alkyl;
R30 is H or C1-C4alkyl;
each p is independently selected from 1, 2, 3, 4, 5 and 6, and
q is 1, 2, 3 or 4;
with the proviso that when R23 is C1-C4 alkyl or —OR28, then R21 is —C(R25)2OH, -L21R25, -L21R26, -L22R25, -L22R26, —OL22R25, or —OL22R26, wherein R26 is —CF2P(O)(OR29)2 and R27 is —CF2P(O)(OR29)2.

### Claim 30 (depends on 29)

The immunogenic composition of claim 29, wherein the compound is selected from:
4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutylphosphonic acid;
3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate;
(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methylphosphonic acid;
5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid;
4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutylphosphonic acid;
3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonic acid;
2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonic acid;
2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid;
(E)-2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonic acid;
2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid;
(E)-2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonic acid;
3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenylphosphonic acid;
5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonylphosphonic acid;
3-(5-amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)(hydroxy)methylenediphosphonic acid;
3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)(hydroxy)methylenediphosphonic acid;
3-(5-amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethylphosphonic acid;
6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexylphosphonic acid;
6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexylphosphonic acid;
4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzylphosphonic acid;
3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1,1-difluoropropylphosphonic acid; and
2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethylphosphonic acid.

### Claim 31 (depends on 29)

The immunogenic composition of claim 29, further comprising a second antigen distinct from the first antigen.

### Claim 32 (depends on 29)

The immunogenic composition of claim 29, wherein the immunogenic composition is an injectable composition.

### Claim 33 (depends on 29)

The immunogenic composition of claim 29, wherein said polymer comprises an end group selected from a carboxyl end group, an alkyl ester end group, an amine end group, a hydroxyl end group, a thiol end group, a succinimidyl ester end group, and a maleimide end group.

### Claim 34 (depends on 33)

The immunogenic composition of claim 33, wherein said biodegradable polymer comprises a polymer block selected from a polyester block, a polycarbonate block, a polyorthoester block, a polyanhydride block, a polycyanoacrylate block and a polyphosphazine block.

### Claim 35 (depends on 33)

The immunogenic composition of claim 33, wherein said biodegradable polymer comprises a polyester block that is selected from a poly(lactide) block, a poly(glycolide) block and a poly(lactide-co-glycolide) block.

### Claim 36

An immunogenic composition comprising (a) a first antigen, (b) polymeric particles that comprise a polymer that comprises a biodegradable polymer block and a hydrophilic polymer block, and (c) a benzonaphthyridine compound, wherein the inclusion of the polymeric particles in the composition elicits an enhanced immune response when administered to a vertebrate subject.

### Claim 37 (depends on 36)

The immunogenic composition of claim 36, wherein said biodegradable polymer block is selected from a polyester block, a polycarbonate block, a polyorthoester block, a polyanhydride block, a polycyanoacrylate block and a polyphosphazine block.

### Claim 38 (depends on 36)

The immunogenic composition of claim 36, wherein said hydrophilic polymer block is selected from a polyethylene oxide block, a polypropylene oxide block, a polyvinyl alcohol block, a polyvinylpyrrolidone block, a poly(acrylic acid) block, a poly(methacrylic acid) block and a poly(amino acid) block.

### Claim 39 (depends on 36)

The immunogenic composition of claim 36, wherein said hydrophilic polymer block is selected from a positively charged polymer block and a negatively charged polymer block.

### Claim 40 (depends on 36)

The immunogenic composition of claim 36, wherein said hydrophilic polymer block is selected from a poly(carboxylic acid) block and a polyamine (block).

### Claim 41 (depends on 36)

The immunogenic composition of claim 36, wherein said benzonaphthyridine compound is established within said polymeric particles.