IP Library › Patent Application 13223793

Patent Application

App. No. 13/223,793

Formulation of immunopotentiators

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Patent No.: US None
App. No.: 13/223,793

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Abstract

Immunopotentiators can be adsorbed to insoluble metal salts, such as aluminium salts, to modify their pharmacokinetics, pharmacodynamics, intramuscular retention time, and/or immunostimulatory effect. Immunopotentiators are modified to introduce a moiety, such as a phosphonate group, which can mediate adsorption. These modified compounds can retain or improve their in vivo immunological activity even when delivered in an adsorbed form.

Claims (449)

1 . A composition comprising a TLR agonist adsorbed to an insoluble metal salt, provided that the TLR agonist: (a) is not a TLR4 agonist; and (b) is not a TLR9 agonist.

2 . The composition of claim 1 , wherein the TLR agonist has the formula (A1):

wherein:

R X and R Y are independently selected from H and C 1 -C 6 alkyl;

X is selected from a covalent bond, O and NH;

Y is selected from a covalent bond, O, C(O), S and NH;

L is a linker e.g. selected from, C 1 -C 6 alkylene, C 1 -C 6 alkenylene, arylene, heteroarylene, C 1 -C 6 alkyleneoxy and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ;

each p is independently selected from 1, 2, 3, 4, 5 and 6;

q is selected from 1, 2, 3 and 4;

n is selected from 1, 2 and 3; and

A is a TLR agonist moiety.

3 . A TLR agonist comprising at least one adsorptive moiety, with the proviso that the TLR agonist:

(a) is not a TLR4 agonist;

(b) is not a TLR9 agonist;

wherein:

Z is —NH 2 or —OH;

X 1 is alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, carbocyclylene, substituted carbocyclylene, heterocyclylene, or substituted heterocyclylene;

L 1 is a covalent bond, arylene, substituted arylene, heterocyclylene, substituted heterocyclylene, carbocyclylene, substituted carbocyclylene, —S—, —S(O)—, S(O) 2 , —NR 5 —, or —O—X 2 is a covalent bond, alkylene, or substituted alkylene;

L 2 is —NR 5 —, —N(R 5 )C(O)—O—, —S—, —S(O)—, S(O) 2 , or a covalent bond;

R 3 is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

Y 1 and Y 2 are each independently a covalent bond, —O— or —NR 5 —; or —Y 1 —R 1 and —Y 2 —R 2 are each independently —O—N═C(R 6 R 7 );

R 1 and R 2 are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, -alkylene-C(O)—O—R 5 , -(substituted alkylene)-C(O)—O—R 5 , -alkylene-O—C(O)—R 5 , -(substituted alkylene)-O—C(O)—R 5 , -alkylene-O—C(O)—O—R 5 , or -(substituted alkylene)-O—C(O)—O—R 5

R 4 is H, halogen, —OH, —O-alkyl, —O-alkylene-O—C(O)—O—R 5 , —O—C(O)—O—R 5 , —SH, or —NH(R 5 );

each R 5 , R 6 , and R 7 are independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

(d) is not a compound according to formula (III)

wherein:

R 2 is H, —C(O)—C 10 -C 18 alkyl; R 2 is C 10 -C 18 alkyl; R 3 is C 10 -C 18 alkyl;

L 1 is —CH 2 O—, —CH 2 OC(O)—, —CH 2 NR 7 C(O)— or —C(O)NR 2 —;

L 2 is —O—, —OC(O)— or —NR 7 C(O)—;

R 4 is -L 3 R 5 or -L 4 R 5 ;

R 5 is —N(R 7 ) 2 , —P(O)(OR 7 ) 2 , —C(O)OR 2 , —NR 7 C(O)L 3 R 8 , —OL 3 R 6 , —C(O)NR 2 L 3 R 8 , C 1 -C 6 alkyl, a C 6 aryl, a C 10 aryl, a C 14 aryl, 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from O, S and N, C 3 -C 8 cycloalkyl or a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each optionally substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 , —OR 7 , and —C(O)OR 7 ;

L 3 is a C 1 -C 10 alkylene, wherein the C 1 -C 6 alkylene of L 3 is optionally substituted with 1 to 4 R 6 groups, or the C 1 -C 6 alkylene of L 3 is substituted with 2 C 1 -C 6 alkyl groups on the same carbon atom which together, along with the carbon atom they are attached to, form a C 3 -C 8 cycloakyl;

L 4 is —((CR 7 R 7 ) p O) q (CR 10 R 10 ) p — or —(CR 11 R 11 )((CR 7 R 7 ) p O) q (CR 10 R 10 ) p —, wherein each R 11 is a C 1 -C 6 alkyl groups which together, along with the carbon atom they are attached to, form a C 3 -C 8 cycloakyl;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 14 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4.

(e) is not a compound according to Formula (I-A)

wherein:

X 3 is N;

X 4 is N or CR 3

X 5 is —CR 4 ═CR 5 —;

R 1 and R 2 are H;

R 3 is H;

R 4 and R 5 are each independently selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 ) 2 , —NHN(R 9 ) 2 , —SR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n R 7 , -LR 8 , -LR 10 , —OLR 8 , —OLR 10 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4 and R 5 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 ) 2 , and —NR 9 S(O) 2 R 8 ;

or, R 3 and R 4 , or R 4 and R 5 , or R 5 and R 6 , when present on adjacent ring atoms, can optionally be linked together to form a 5-6 membered ring, wherein the 5-6 membered ring is optionally substituted with R 7 ;

each L is independently selected from a bond, —(O(CH 2 ) m ) t —, C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenylene and C 2 -C 6 alkynylene of L are each optionally substituted with 1 to 4 substituents independently selected from halogen, —R 8 , —OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , and) —OP(O)(OR 10 ) 2 ;

R 7 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7 are each optionally substituted with 1 to 3 R 13 groups, and each R 13 is independently selected from halogen, —CN, -LR 9 , -LOR 9 , —OLR 9 , -LR th , —OLR 10 , -LR 8 , -LOR 8 , —OLR 8 , -LSR 8 , -LSR 10 , -LC(O)R 8 , —OLC(O)R 8 , -LC(O)OR 8 , -LC(O)R 10 , -LOC(O)OR 8 , -LC(O)NR 9 R 11 , -LC(O)NR 9 R 8 , -LN(R 9 ) 2 , -LNR 9 R 8 , -LNR 9 R 10 , -LC(O)N(R 9 ) 2 , -LS(O) 2 R 8 , -LS(O)R 8 , -LC(O)NR 8 OH, -LNR 9 C(O)R 8 , -LNR 9 C(O)OR 8 , -LS(O) 2 N(R 9 ) 2 , —OLS(O) 2 N(R 9 ) 2 , -LNR 9 S(O) 2 R 8 , -LC(O)NR 9 LN(R 9 ) 2 , -LP(O)(OR 8 ) 2 , -LOP(O)(OR 8 ) 2 , -LP(O)(OR 10 ) 2 and —OLP(O)(OR 10 ) 2 ;

each R 8 is independently selected from H, —CH(R 10 ) 2 , C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy, wherein the C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy groups of R 8 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)N(R 9 ) 2 , —C(O)OR 11 , —NR 9 C(O)R 11 , —NR 9 R 10 , —NR 11 R 12 , —N(R 9 ) 2 , —OR 9 , —OR 10 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 , and —OP(O)(OR 11 ) 2 ;

each R 9 is independently selected from H, —C(O)R 8 , —C(O)OR 8 , —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 , —C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 3 -C 6 cycloalkyl, or each R 9 is independently a C 1 -C 6 alkyl that together with N they are attached to form a C 3 -C 8 heterocycloalkyl, wherein the C 3 -C 8 heterocycloalkyl ring optionally contains an additional heteroatom selected from N, O and S, and wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 8 heterocycloalkyl groups of R 9 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , OC(O)R 11 , —C(O)OR 11 , —NR 11 R 12 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 and —OP(O)(OR 11 ) 2 ;

each R 10 is independently selected from aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl, wherein the aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl groups are optionally substituted with 1 to 3 substituents selected from halogen, —R 8 , —OR 8 , -LR 9 , -LOR 9 , —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 CO 2 R 8 , —CO 2 R 8 , —C(O)R 8 and —C(O)N(R 9 ) 2 ;

R 11 and R 12 are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 11 and R 12 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, R 8 , —OR 8 , C(O)R 8 , OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —NR 8 C(O)R 8 , —NR 8 C(O)OR 8 , —C(O)N(R 9 ) 2 , C 3 -C 8 heterocycloalkyl, —S(O) 2 R 8 , —S(O) 2 N(R 9 ) 2 , —NR 9 S(O) 2 R 8 , C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy;

or R 11 and R 12 are each independently C 1 -C 6 alkyl and taken together with the N atom to which they are attached form an optionally substituted C 3 -C 8 heterocycloalkyl ring optionally containing an additional heteroatom selected from N, O and S;

ring A is an aryl or a heteroaryl, wherein the aryl and heteroaryl groups of Ring A are optionally substituted with 1 to 3 R A groups, wherein each R A is independently selected from —R 8 , —R 7 , —OR 7 , —OR 8 , —R 10 , —OR 10 , —SR 8 , —NO 2 , —CN, —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 C(S)R 8 , —NR 9 C(O)N(R 9 ) 2 , —NR 9 C(S)N(R 9 ) 2 , —NR 9 CO 2 R 8 , —NR 9 NR 9 C(O)R 8 , —NR 9 NR 9 C(O)N(R 9 ) 2 , —NR 9 NR 9 CO 2 R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —CO 2 R 8 , —(CH 2 ) n CO 2 R 8 , —C(O)R 8 , —C(S)R 8 , —C(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —OC(O)R 8 , —C(O)N(OR 8 )R 8 , —C(NOR 8 )R 8 , —S(O) 2 R 8 , —S(O) 3 R 8 , —SO 2 N(R 9 ) 2 , —S(O)R 8 , —NR 9 SO 2 N(R 9 ) 2 , —NR 9 SO 2 R 8 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —N(OR 8 )R 8 , —CH═CHCO 2 R 8 , —C(═NH)—N(R 9 ) 2 , and —(CH 2 ) n NHC(O)R 8 or two adjacent R A 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.

4 . A water-soluble TLR agonist comprising at least one adsorptive moiety, with the proviso that the water-soluble TLR agonist:

(a) is not a TLR4 agonist;

(b) is not a TLR9 agonist;

wherein:

Z is —NH 2 or —OH;

L 1 is a covalent bond, arylene, substituted arylene, heterocyclylene, substituted heterocyclylene, carbocyclylene, substituted carbocyclylene, —S—, —S(O)—, S(O) 2 , —NR 5 —, or —O—

X 2 is a covalent bond, alkylene, or substituted alkylene;

L 2 is —NR 5 —, —N(R 5 )C(O)—O—, —S—, —S(O)—, S(O) 2 , or a covalent bond;

Y 1 and Y 2 are each independently a covalent bond, —O— or —NR 5 —; or —Y 1 —R 1 and —Y 2 —R 2 are each independently —O—N═C(R 6 R 7 );

R 4 is H, halogen, —OH, —O-alkyl, —O-alkylene-O—C(O)—O—R 5 , —O—C(O)—O—R 5 , —SH, or —NH(R 5 );

(d) is not a compound according to formula (III)

wherein:

R 1 is H, —C(O)—C 10 -C 18 alkyl; R 2 is C 10 -C 18 alkyl; R 3 is C 10 -C 18 alkyl;

L, is —CH 2 O—, —CH 2 OC(O)—, —CH 2 NR 7 C(O)— or —C(O)NR 7 —;

L 2 is —O—, —OC(O)— or —NR 7 C(O)—;

R 4 is -L 3 R 5 or -L 4 R 5 ;

R 5 is —N(R 7 ) 2 , —OR 7 , —P(O)(OR 7 ) 2 , —C(O)OR 7 , —NR 7 C(O)L 3 R 8 , —OL 3 R 6 , —C(O)NR 7 L 3 R 8 , C 1 -C 6 alkyl, a C 6 aryl, a C H ) aryl, a C 1-4 aryl, 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from O, S and N, C 3 -C 8 cycloalkyl or a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each optionally substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 , —OR 7 , and —C(O)OR 7 ;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —OR 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 1-4 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4.

5 . A TLR agonist comprising at least one phosphonate group, with the proviso that the TLR agonist:

(a) is not a phosphonate-containing compound according to formula (I) or (II)

wherein:

Z is —NH 2 or —OH;

L 2 is —NR 5 —, —N(R 5 )C(O)—O—, —S—, —S(O)—, S(O) 2 , or a covalent bond;

Y 1 and Y 2 are each independently a covalent bond, —O— or —NR 5 —; or —Y 1 —R 1 and —Y 2 —R 2 are each independently —O—N═C(R 6 R 7 );

R 4 is H, halogen, —OH, —O-alkyl, —O-alkylene-O—C(O)—O—R 5 , —O—C(O)—O—R 5 , —SH, or —NH(R 5 );

(b) is not a phosphonate-containing compound according to formula (III)

wherein:

R 1 is H, —C(O)—C 10 -C 18 alkyl; R 2 is C 10 -C 18 alkyl; R 3 is C 10 -C 18 alkyl;

L 1 is —CH 2 O—, —CH 2 OC(O)—, —CH 2 NR 7 C(O)— or —C(O)NR 7 —;

L 2 is —O—, —OC(O)— or —NR 7 C(O)—;

R 4 is -L 3 R 5 or -L 4 R 5 ;

R 5 is —N(R 7 ) 2 , —OR 7 , —P(O)(OR 7 ) 2 , —C(O)OR 7 , —NR 7 C(O)L 3 R 8 , —OL 3 R 6 , —C(O)NR 7 L 3 R 8 , C 1 -C 6 alkyl, a C 6 aryl, a C 10 aryl, a C 1-4 aryl, 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from O, S and N, C 3 -C 8 cycloalkyl or a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each optionally substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 , —OR 7 , and —C(O)OR 7 ;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 14 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4; and

wherein:

X 3 is N;

X 4 is N or CR 3

X 5 is —CR 4 ═CR 5 —;

R 1 and R 2 are H;

R 3 is H;

R 4 and R 5 are each independently selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 ) 2 , —NHN(R 9 ) 2 , —SR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n R 7 , -LR 8 , -LR 10 , —OLR 8 , —OLR 10 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4 and R 5 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 ) 2 , and —NR 9 S(O) 2 R 8 ;

R 7 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7 are each optionally substituted with 1 to 3 R 13 groups, and each R 13 is independently selected from halogen, —CN, -LR 9 , -LOR 9 , —OLR 9 , -LR 10 , —OLR 10 , -LR 8 , -LOR 8 , —OLR 8 , -LSR 8 , -LSR 10 , -LC(O)R 8 , —OLC(O)R 8 , -LC(O)OR 8 , -LC(O)R 10 , -LOC(O)OR 8 , -LC(O)NR 9 R 11 , -LC(O)NR 9 R 8 , -LN(R 9 ) 2 , -LNR 9 R 8 , -LNR 9 R 10 , -LC(O)N(R 9 ) 2 , -LS(O) 2 R 8 , -LS(O)R 8 , -LC(O)NR 8 OH, -LNR 9 C(O)R 8 , -LNR 9 C(O)OR 8 , -LS(O) 2 N(R 9 ) 2 , —OLS(O) 2 N(R 9 ) 2 , -LNR 9 S(O) 2 R 8 , -LC(O)NR 9 LN(R 9 ) 2 , -LP(O)(OR 8 ) 2 , -LOP(O)(OR 8 ) 2 , -LP(O)(OR 10 ) 2 and —OLP(O)(OR 10 ) 2 ;

each R 8 is independently selected from H, —CH(R 10 ) 2 , C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy, wherein the C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy groups of R 8 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)N(R 9 ) 2 , —C(O)OR 11 , —NR 9 C(O)R 11 , —NR 9 R 10 , —NR 11 R 12 , —N(R 9 ) 2 , —OR 9 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 , and —OP(O)(OR 11 ) 2 ;

each R 9 is independently selected from H, —C(O)R 8 , —C(O)OR 8 , —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 , —C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 3 -C 6 cycloalkyl, or each R 9 is independently a C 1 -C 6 alkyl that together with N they are attached to form a C 3 -C 8 heterocycloalkyl, wherein the C 3 -C 8 heterocycloalkyl ring optionally contains an additional heteroatom selected from N, O and S, and wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 8 heterocycloalkyl groups of R 9 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , OC(O)R 11 , —C(O)OR 11 , —NR 11 R 12 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 and —OP(O)(OR 11 ) 2 ;

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.

6 . A TLR agonist compound comprising at least one adsorptive moiety, wherein the compound is an agonist of TLR1, TLR3, TLR5, TLR6, TLR8 or TLR11.

7 . A TLR agonist compound comprising at least one adsorptive moiety, wherein the compound is an agonist of TLR1, TLR2, TLR3, TLR5, TLR6, TLR 7 , TLR 8 , or TLR 11 , with the proviso that the compound:

(a) is not a compound according to formula (I) or (II)

wherein:

Z is —NH 2 or —OH;

L 1 is a covalent bond, arylene, substituted arylene, heterocyclylene, substituted heterocyclylene, carbocyclylene, substituted carbocyclylene, —S—, —S(O)—, S(O) 2 , —NR 5 —, or —O—;

X 2 is a covalent bond, alkylene, or substituted alkylene;

L 2 is —NR 5 —, —N(R 5 )C(O)—O—, —S—, —S(O)—, S(O) 2 , or a covalent bond;

Y 1 and Y 2 are each independently a covalent bond, —O— or —NR 5 —; or —Y 1 —R 1 and —Y 2 —R 2 are each independently —O—N═C(R 6 R 7 );

R 4 is H, halogen, —OH, —O-alkyl, —O-alkylene-O—C(O)—O—R 5 , —O—C(O)—O—R 5 , —SH, or —NH(R 5 );

(b) is not a compound according to formula (III),

wherein:

R 1 is H, —C(O)—C 10 -C 18 alkyl; R 2 is C 10 -C 18 alkyl; R 3 is C 10 -C 18 alkyl;

L 1 is —CH 2 O—, —CH 2 OC(O)—, —CH 2 NR 7 C(O)— or —C(O)NR 7 —;

L 2 is —O—, —OC(O)— or —NR 7 C(O)—;

R 4 is -L 3 R 5 or -L 4 R 5 ;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 14 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4; and

wherein:

X 3 is N;

X 4 is N or CR 3

X 5 is —CR 4 ═CR 5 —;

R 1 and R 2 are H;

R 3 is H;

R 4 and R 5 are each independently selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 ) 2 , —NHN(R 9 ) 2 , SR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n R 7 , -LR 8 , -LR 10 , —OLR 8 , —OLR 10 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4 and R 5 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 ) 2 , and —NR 9 S(O) 2 R 8 ;

R 7 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7 are each optionally substituted with 1 to 3 R 13 groups, and each R 13 is independently selected from halogen, —CN, -LR 9 , -LOR 9 , —OLR 9 , -LR 10 , -LOR 10 , —OLR 10 , -LR 8 , -LOR 8 , —OLR 8 , -LSR 8 , -LSR 10 , -LC(O)R 8 , —OLC(O)R 8 , -LC(O)OR 8 , -LC(O)R 10 , -LOC(O)OR 8 , -LC(O)NR 9 R 11 , -LC(O)NR 9 R 8 , -LN(R 9 ) 2 , -LNR 9 R 8 , -LNR 9 R 10 , -LC(O)N(R 9 ) 2 , -LS(O) 2 R 8 , -LS(O)R 8 , -LC(O)NR 8 OH, -LNR 9 C(O)R 8 , -LNR 9 C(O)OR 8 , -LS(O) 2 N(R 9 ) 2 , —OLS(O) 2 N(R 9 ) 2 , -LNR 9 S(O) 2 R 8 , -LC(O)NR 9 LN(R 9 ) 2 , -LP(O)(OR 8 ) 2 , -LOP(O)(OR 8 ) 2 , -LP(O)(OR 10 ) 2 and —OLP(O)(OR 10 ) 2 ;

n is, independently at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7 or 8;

each in is independently selected from 1, 2, 3, 4, 5 and 6, and

t is 1,2,3,4,5,6, 7 or 8.

8 . A TLR4 agonist comprising at least one adsorptive moiety, provided that the TLR4 agonist does not include an acyl chain.

9 . A TLR9 agonist comprising at least one adsorptive moiety, provided that the TLR9 agonist does not include a cytidine nucleoside.

10 . A TLR2 agonist comprising at least one adsorptive moiety, provided that the TLR2 agonist is not a compound according to formula (III)

wherein:

R 1 is H, —C(O)—C 10 -C 18 alkyl; R 2 is C 10 -C 18 alkyl; R 3 is C 10 -C 18 alkyl;

L 1 is —CH 2 O—, —CH 2 OC(O)—, —CH 2 NR 7 C(O)— or —C(O)NR 7 —;

L 2 is —O—, —OC(O)— or —NR 7 C(O)—;

R 4 is -L 3 R 5 or -L 4 R 5 ;

R 5 is —N(R 7 ) 2 , —OR 7 , —P(O)(OR 7 ) 2 , —C(O)OR 7 , —NR 7 C(O)L 3 R 8 , LOL 3 R 6 , —C(O)NR 7 L 3 R 8 , C 1 -C 6 alkyl, a C 6 aryl, a C 10 aryl, a C 1-4 aryl, 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from O, S and N, C 3 -C 8 cycloalkyl or a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each optionally substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 , —OR 7 , and —C(O)OR 7 ;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —OR 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 1-4 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4.

11 . A TLR7 agonist comprising at least one adsorptive moiety, provided that the TLR7 agonist is not: (a) a compound according to formula (I) or (II)

wherein:

Z is —NH 2 or —OH;

L 1 is a covalent bond, arylene, substituted arylene, heterocyclylene, substituted heterocyclylene, carbocyclylene, substituted carbocyclylene, —S—, —S(O)—, S(O) 2 , —NR 5 —, or —O—

X 2 is a covalent bond, alkylene, or substituted alkylene;

L 2 is —NR 5 —, —N(R 5 )C(O)—O—, —S—, —S(O)—, S(O) 2 , or a covalent bond;

Y 1 and Y 2 are each independently a covalent bond, —O— or —NR 5 —; or —Y 1 —R 1 and —Y 2 —R 2 are each independently —O—N═C(R 6 R 7 );

R 4 is H, halogen, —OH, —O-alkyl, —O-alkylene-O—C(O)—O—R 5 , —O—C(O)—O—R 5 , —SH, or —NH(R 5 );

(b) a compound according to formula (I-A)

wherein:

X 3 is N;

X 4 is N or CR 3

X 5 is —CR 4 ═CR 5 —;

R 1 and R 2 are H;

R 3 is H;

R 4 and R 5 are each independently selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 ) 2 , —NHN(R 9 ) 2 , —SR 7 , —(CH 2 ) n R 7 , —(CH 2 ) n R 7 , -LR 8 , -LR 10 , —OLR 8 , —OLR 10 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4 and R 5 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 ) 2 , and —NR 9 S(O) 2 R 8 ;

R 7 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7 are each optionally substituted with 1 to 3 R 13 groups, and each R 13 is independently selected from halogen, —CN, -LR 9 , -LOR 9 , —OLR 9 , -LR 10 , -LOR 10 , —OLR 10 , -LR 8 , -LOR 8 , —OLR 8 , -LSR 8 , -LSR 10 , -LC(O)R 8 , —OLC(O)R 8 , -LC(O)OR 8 , -LC(O)R 10 , -LOC(O)OR 8 , -LC(O)NR 9 R 11 , -LC(O)NR 9 R 8 , -LN(R 9 ) 2 , -LNR 9 R 8 , -LNR 9 R 10 , -LC(O)N(R 9 ) 2 , -LS(O) 2 R 8 , -LS(O)R 8 , -LC(O)NR 8 OH, -LNR 9 C(O)R 8 , -LNR 9 C(O)OR 8 , -LS(O) 2 N(R 9 ) 2 , —OLS(O) 2 N(R 9 ) 2 , -LNR 9 S(O) 2 R 8 , -LC(O)NR 9 LN(R 9 ) 2 , -LP(O)(OR 8 ) 2 , -LOP(O)(OR 8 ) 2 , -LP(O)(OR 10 ) 2 and —OLP(O)(OR 10 ) 2 ;

each R 10 is independently selected from aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl, wherein the aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl and heteroaryl groups are optionally substituted with 1 to 3 substituents selected from halogen, —R 8 , —OR 8 , LR 9 , -LOR 9 , —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 CO 2 R 8 , —CO 2 R 8 , —C(O)R 8 and —C(O)N(R 9 ) 2 ;

ring A is an aryl or a heteroaryl, wherein the aryl and heteroaryl groups of Ring A are optionally substituted with 1 to 3 R A groups, wherein each R A is independently selected from —R 8 , —R 7 , —OR 7 , —OR 8 , —R 10 , —OR 10 , —SR 8 , —NO 2 , —CN, —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 C(S)R 8 , —NR 9 C(O)N(R 9 ) 2 , —NR 9 C(S)N(R 9 ) 2 , —NR 9 CO 2 R 8 , —NR 9 NR 9 C(O)R 8 , —NR 9 NR 9 C(O)N(R 9 ) 2 , —NR 9 NR 9 CO 2 R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —CO 2 R 8 , —(CH 2 ) n CO 2 R 8 , —C(O)R 8 , —C(S)R 8 , —C(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —OC(O)R 8 , —C(O)N(OR 8 )R 8 , —C(NOR 8 )R 8 , —S(O) 2 R 8 , —S(O) 3 R 8 , —SO 2 N(R 9 ) 2 , (—S(O)R 8 , —NR 9 SO 2 N(R 9 ) 2 , —NR 9 SO 2 R 8 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —N(OR 8 )R 8 , —CH═CHCO 2 R 8 , —C(═NH)—N(R 9 ) 2 , and —(CH 2 ) n NHC(O)R 8 or two adjacent R A 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.

12 . A TLR4 agonist comprising at least one adsorptive moiety, wherein the TLR agonist has a molecular weight of less than 1000 Da.

13 . A TLR9 agonist comprising at least one adsorptive moiety, wherein the TLR agonist has a molecular weight of less than 1000 Da.

14 . A TLR7 agonist selected from compounds according to any of formulae (C), (D), (E) or (H):

wherein:

(a) P 3 is selected from H, C 1 -C 6 alkyl, CF 3 , and —((CH 2 ) p O) q (CH 2 ) p O s — and —Y-L-X—P(O)(OR X )(OR Y ); and P 4 is selected from H, C 1 -C 6 alkyl, —C 1 -C 6 alkylaryl and —Y-L-X—P(O)(OR X )(OR Y ); with the proviso that at least one of P 3 and P 4 is —Y-L-X—P(O)(OR X )(OR Y ),

(b) P 5 is selected from H, C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ); P 6 is selected from H, C 1 -C 6 alkyl each optionally substituted with 1 to 3 substituents selected from C 1 -C 4 alkyl and OH, and —Y-L-X—P(O)(OR X )(OR Y ); and P 7 is selected from H, C 1 -C 6 alkyl, —((CH 2 ) p O) q (CH 2 ) p O s —, —NHC 1 -C 6 alkyl and —Y-L-X—P(O)(OR X )(OR Y ); with the proviso that at least one of P 5 , P 6 and P 7 is —Y-L-X—P(O)(OR X )(OR Y );

(c) P 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl each optionally substituted with OH, and —Y-L-X—P(O)(OR X )(OR Y ); and P 9 and P 10 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl each optionally substituted with OH and C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ); with the proviso that at least one of P 8 , P 9 or P 10 is —Y-L-X—P(O)(OR X )(OR Y );

(d) P 16 and each P 18 are each independently selected from H, C 1 -C 6 alkyl, and —Y-L-X—P(O)(OR X )(OR Y ); P 17 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 1 -C 6 alkylaryl, C 1 -C 6 alkyl heteroaryl, C 1 -C 6 alkylaryl-Y-L-X—P(O)(OR X )(OR Y ) and —Y-L-X—P(O)(OR X )(OR Y ), each optionally substituted with 1 to 2 substituents selected from C 1 -C 6 alkyl or heterocyclyl with the proviso that at least one of P 16 , P 17 or a P 18 contains a —Y-L-X—P(O)(OR X )(OR Y ) moiety;

R X and R Y are independently selected from H and C 1 -C 6 alkyl;

R C , R D and R H are each independently selected from H and C 1 -C 6 alkyl;

X C is selected from CH and N;

R E is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)C 1 -C 6 alkyl, halogen and —((CH 2 ) p O) q (CH 2 ) p —;

X E is selected from a covalent bond, CR E2 R E3 and NR E4 ;

R E2 , R E3 and R E4 are independently selected from H and C 1 -C 6 alkyl;

X H1 —X H2 is selected from —CR H2 R H3 —CR H2 R H3 —CR H2 R H3 —, —C(O)CR H2 R H3 —, —C(O)CR H2 R H3 —, —CR H2 R H3 C(O)—, —NR H4 C(O)—, C(O)NR H4 —, CR H2 R H3 S(O) 2 and —CR H2 ═CR H2 —;

R H2 , R H3 and R H4 are each independently selected from H, C 1 -C 6 alkyl and P 18 ;

X H3 is selected from N and CN;

X is selected from a covalent bond, O and NH;

Y is selected from a covalent bond, O, C(O), S and NH;

L is selected from, a covalent bond C 1 -C 6 alkylene, C 1 -C 6 alkenylene, arylene, heteroarylene, C 1 -C 6 alkyleneoxy and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 and —P(O)(OH) 2 ;

m is selected from 0 or 1;

each p is independently selected from 1, 2, 3, 4, 5 and 6;

q is selected from 1, 2, 3 and 4; and

s is selected from 0 and 1.

15 . A compound of formula (F):

wherein:

R X and R Y are independently selected from H and C 1 -C 6 alkyl;

Q and V are independently selected from a covalent bond, NH, S, C(O) and O;

X is selected from a covalent bond, O and NH;

Y is selected from a covalent bond, O, C(O), S and NH;

L is selected from, a covalent bond C 1 -C 6 alkylene, C 1 -C 6 alkenylene, arylene, heteroarylene, C 1 -C 6 alkyleneoxy and —((CH z ) p O) q (CH 2 ) p — each optionally substituted with 1 to 4 substituents independently selected from halo, OH, C 1 -C 4 alkyl, —OP(O)(OH) 2 ; and —P(O)(OH) 2 ; and

R F1 , R F2 and R F3 are independently selected from H, C 1 -C 18 alkyl, C 1 -C 18 alkenyl, C(O)C 1 -C 18 alkyl and C(O)C 1 -C 18 alkenyl;

each p is independently selected from 1, 2, 3, 4, 5 and 6; and

q is selected from 1, 2, 3 and 4.

16 . A compound of formula (G)

wherein:

P 11 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR V R W and —Y-L-X—P(O)(OR X )(OR Y );

P 12 is selected from H, C 1 -C 6 alkyl, aryl optionally substituted by —C(O)NR V R W , and —Y-L-X—P(O)(OR X )(OR Y );

P 13 , P 14 and P 15 are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and —Y-L-X—P(O)(OR X )(OR Y );

with the proviso that at least one of P 11 , P 12 , P 13 , P 14 or P 15 is —Y-L-X—P(O)(OR X )(OR Y );

R V and R W are independently selected from H, C 1 -C 6 alkyl or together with the nitrogen atom to which they are attached form a 4 to 7 remembered heterocyclic ring;

X G is selected from C, CH and N;

represents an optional double bond, wherein X G is C if is a double bond; and

R G is selected from H and C 1 -C 6 alkyl;

X is selected from a covalent bond, O and NH;

Y is selected from a covalent bond, O, C(O), S and NH;

each p is independently selected from 1, 2, 3, 4, 5 and 6 and

q is selected from 1, 2, 3 and 4.

17 . A TLR agonist including between two and fifteen adsorptive moieties.

18 . A TLR agonist according to any preceding claim, having the formula (A1):

wherein:

R X and R Y are independently selected from H and C 1 -C 6 alkyl;

X is selected from a covalent bond, O and NH;

Y is selected from a covalent bond, O, C(O), S and NH;

each p is independently selected from 1, 2, 3, 4, 5 and 6;

q is selected from 1, 2, 3 and 4;

n is selected from 1, 2 and 3; and

A is a TLR agonist moiety;

with the proviso that the TLR agonist:

a. is not a TLR4 agonist;

b. is not a TLR9 agonist;

c. is not a compound according to formula (I) or (II)

wherein:

Z is —NH 2 or —OH;

L 1 is a covalent bond, arylene, substituted arylene, heterocyclylene, substituted heterocyclylene, carbocyclylene, substituted carbocyclylene, —S—, —S(O)—, S(O) 2 , —NR 5 —, or —O—;

X 2 is a covalent bond, alkylene, or substituted alkylene;

L 2 is —NR 5 —, —N(R 5 )C(O)—O—, —S—, —S(O)—, S(O) 2 , or a covalent bond;

Y 1 and Y 2 are each independently a covalent bond, —O— or —NR 5 —; or —Y 1 —R 1 and —Y 2 —R 2 are each independently —O—N═C(R 6 R 7 );

R 4 is H, halogen, —OH, —O-alkyl, —O-alkylene-O—C(O)—O—R 5 , —O—C(O)—O—R 5 , —SH, or —NH(R 5 );

d. is not a compound according to formula (III)

wherein:

R 1 is H, —C(O)—C 10 -C 18 alkyl; R 2 is C 10 -C 18 alkyl; R 3 is C 10 -C 18 alkyl;

L 1 is —CH 2 O—, —CH 2 OC(O)—, —CH 2 NR 7 C(O)— or —C(O)NR 7 —;

L 2 is —O—, —OC(O)— or —NR 7 C(O)—;

R 4 is -L 3 R 5 or -L 4 R 5 ;

R 5 is —N(R 7 ) 2 , —P(O)(OR 7 ) 2 , —C(O)OR 7 , —NR 7 C(O)L 3 R 8 , —OL 3 R 6 , —C(O)NR 7 L 3 R 8 , C 1 -C 6 alkyl, a C 6 aryl, a C 10 aryl, a C 14 aryl, 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from O, S and N, C 3 -C 8 cycloalkyl or a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each optionally substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 , —OR 7 , and —C(O)OR 7 ;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —OR 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 14 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4;

e. is not a compounds according to formula (I-A)

wherein:

X 3 is N;

X 4 is N or CR 3 ;

X 5 is —CR 4 ═CR 5 —;

R 1 and R 2 are H;

R 3 is H;

R 4 and R 5 are each independently selected from H, halogen, —C(O)OR 7 , —C(O)R 7 , —C(O)N(R 11 R 12 ), —N(R 11 R 12 ), —N(R 9 ) 2 , —NHN(R 9 ) 2 , —SR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n R 7 , -LR 8 , -LR 10 , —OLR 8 , —OLR 10 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocycloalkyl groups of R 4 and R 5 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, —NO 2 , —R 7 , —OR 8 , —C(O)R 8 , —OC(O)R 8 , —C(O)OR 8 , —N(R 9 ) 2 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 16 ) 2 , —C(O)N(R 9 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 9 ) 2 , and —NR 9 S(O) 2 R 8 ;

R 7 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7 are each optionally substituted with 1 to 3 R 13 groups, and each R 13 is independently selected from halogen, —CN, -LR 9 , -LOR 9 , —OLR 9 , -LR 16 , -LOR 10 , -LR 8 , -LOR 8 , —OLR 8 , -LSR 8 , -LSR 10 , -LC(O)R 8 , —OLC(O)R 8 , -LC(O)OR 8 , -LC(O)R 16 , -LOC(O)OR 8 , -LC(O)NR 9 R 11 , -LC(O)NR 9 R 8 , -LN(R 9 ) 2 , -LNR 9 R 8 , -LNR 9 R 10 , -LC(O)N(R 9 ) 2 , -LS(O) 2 R 8 , -LS(O)R 8 , -LC(O)NR 8 OH, -LNR 9 C(O)R 8 , -LNR 9 C(O)OR 8 , -LS(O) 2 N(R 9 ) 2 , —OLS(O) 2 N(R 9 ) 2 , -LNR 9 S(O) 2 R 8 , -LC(O)NR 9 LN(R 9 ) 2 , -LP(O)(OR 8 ) 2 , -LOP(O)(OR 8 ) 2 , -LP(O)(OR 16 ) 2 and —OLP(O)(OR 10 ) 2 ;

each R 8 is independently selected from H, —CH(R 10 ) 2 , C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy, wherein the C 1 -C 8 alkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 6 hydroxyalkyl and C 1 -C 6 haloalkoxy groups of R 8 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , —OC(O)R 11 , —C(O)N(R 9 ) 2 , —C(O)OR 11 , —NR 9 C(O)R 11 , —NR 9 R 10 , —NR 11 R 12 , —N(R 9 ) 2 , —OR 9 , —C(O)NR H R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O)R 11 , —S(O) 2 NR 11 R 12 , —NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 , and —OP(O)(OR 11 ) 2 ;

each R 9 is independently selected from H, —C(O)R 8 , —C(O)OR 8 , —C(O)R 10 , —C(O)OR 10 , —S(O) 2 R 10 , —C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl and C 3 -C 6 cycloalkyl, or each R 9 is independently a C 1 -C 6 alkyl that together with N they are attached to form a C 3 -C 8 heterocycloalkyl, wherein the C 3 -C 8 heterocycloalkyl ring optionally contains an additional heteroatom selected from N, O and S, and wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 8 heterocycloalkyl groups of R 9 are each optionally substituted with 1 to 3 substituents independently selected from —CN, R 11 , —OR 11 , —SR 11 , —C(O)R 11 , OC(O)R 11 , —C(O)OR 11 , —NR 11 R 12 , —C(O)NR 11 R 12 , —C(O)NR 11 OH, —S(O) 2 R 11 , —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , NR 11 S(O) 2 R 11 , —P(O)(OR 11 ) 2 and —OP(O)(OR 11 ) 2 ;

ring A is an aryl or a heteroaryl, wherein the aryl and heteroaryl groups of Ring A are optionally substituted with 1 to 3 R A groups, wherein each R A is independently selected from —R 8 , -01e, —OR 8 , —R 10 , —OR 10 , —SR 8 , —NO 2 , —CN, —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 C(S)R 8 , —NR 9 C(O)N(R 9 ) 2 , —NR 9 C(S)N(R 9 ) 2 , —NR 9 CO 2 R 8 , —NR 9 NR 9 C(O)R 8 , —NR 9 NR 9 C(O)N(R 9 ) 2 , —NR 9 NR 9 CO 2 R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —CO 2 R 8 , —(CH 2 ) n CO 2 R 8 , —C(O)R 8 , —C(S)R 8 , —C(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —OC(O)R 8 , —C(O)N(OR 8 )R 8 , —C(NOR 8 )R 8 , —S(O) 2 R 8 , —S(O) 3 R 8 , —SO 2 N(R 9 ) 2 , —S(O)R 8 , —NR 9 SO 2 N(R 9 ) 2 , —NR 9 SO 2 R 8 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10 ) 2 , —OP(O)(OR 10 ) 2 , —N(OR 8 )R 8 , —CH═CHCO 2 R 8 , —C(═NH)—N(R 9 ) 2 , and —(CH 2 ) n NHC(O)R 8 or two adjacent R A 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.

19 . A TLR agonist according to claim 18 , wherein R X and R Y are H; X is O; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 2 halogen atoms; p is selected from 1, 2 and 3; q is selected from 1 and 2; and n is 1.

20 . A TLR agonist according to claim 18 , wherein R X and R Y are H; X is a covalent bond; L is selected from C 1 -C 6 alkylene and —((CH 2 ) p O) q (CH 2 ) p — each optionally substituted with 1 to 2 halogen atoms; p is selected from 1, 2 or 3; q is selected from 1 or 2; and n is 1.

21 . A composition comprising a TLR agonist of any preceding claim and an insoluble metal salt.

22 . The composition of claim 21 , wherein the TLR agonist is adsorbed onto the insoluble metal salt.

23 . A composition comprising a TLR agonist and an insoluble metal salt, with the proviso that the TLR agonist:

(a) is not a TLR4 agonist;

(b) is not a TLR9 agonist;

wherein:

R 1 is H, —C(O)—C 10 -C 18 alkyl; R 2 is C 10 -C 18 alkyl; R 3 is C 10 -C 18 alkyl;

L 1 is —CH 2 O—, —CH 2 OC(O)—, —CH 2 NR 7 C(O)— or —C(O)NR 7 —;

L 2 is —O—, —OC(O)— or —NR 7 C(O)—;

R 4 is -L 3 R 5 or -L 4 R 5 ;

R 5 is —N(R 7 ) 2 , —P(O)(OR 7 ) 2 , —C(O)OR 7 , —NR 7 C(O)L 3 R 8 , —OL 3 R 6 , —C(O)NR 7 L 3 R 8 , C 1 -C 6 alkyl, a C 6 aryl, a C 10 aryl, a C 1-4 aryl, 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from O, S and N, C 3 -C 8 cycloalkyl or a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 5 are each optionally substituted with 1 to 3 substituents independently selected from —OR 9 , —OL 3 R 6 , —OL 4 R 6 , —OR 7 , and —C(O)OR 7 ;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —OR 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 14 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4; and

(d) is not a compound according to Formula (I-A)

wherein:

X 3 is N;

X 4 is N or CR 3 ;

X 5 is —CR 4 ═CR 5 —;

R 1 and R 2 are H;

R 3 is H;

R 7 is selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 6 alkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 alkene, C 2 -C 8 alkyne, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 8 heterocycloalkyl groups of R 7 are each optionally substituted with 1 to 3 R 13 groups, and each R 13 is independently selected from halogen, —CN, -LR 9 , -LOR 9 , —OLR 9 , -LR 10 , -LOR 10 , —OLR 10 , -LR 8 , -LOR 8 , —OLR 8 , -LSR 8 , -LSR 10 , -LC(O)R 8 , —OLC(O)R 8 , -LC(O)OR 8 , -LC(O)R 10 , -LOC(O)OR 8 , -LC(O)NR 9 R 11 , -LC(O)NR 9 R 8 , -LN(R 9 ) 2 , -LNR 9 R 8 , -LNR 9 R 10 , -LC(O)N(R 9 ) 2 , -LS(O) 2 R 8 , -LS(O)R 8 , -LC(O)NR 8 OH, -LNR 9 C(O)R 8 , -LNR 9 C(O)OR 8 , -LS(O) 2 N(R 9 ) 2 , —OLS(O) 2 N(R 9 ) 2 , -LNR 9 S(O) 2 R 8 , -LC(O)NR 9 LN(R 9 ) 2 , -LP(O)(OR 8 ) 2 , -LOP(O)(OR 8 ) 2 , -LP(O)(OR 10 ) 2 and —OLP(O)(OR 10 ) 2 ;

ring A is an aryl or a heteroaryl, wherein the aryl and heteroaryl groups of Ring A are optionally substituted with 1 to 3 R A groups, wherein each R A is independently selected from —R 8 , —R 7 , —OR 7 , —OR 8 , —R 10 , —SR 8 , —NO 2 , —CN, —N(R 9 ) 2 , —NR 9 C(O)R 8 , —NR 9 C(S)R 8 , —NR 9 C(O)N(R 9 ) 2 , —NR 9 C(S)N(R 9 ) 2 , —NR 9 CO 2 R 8 , —NR 9 NR 9 C(O)R 8 , —NR 9 NR 9 C(O)N(R 9 ) 2 , —NR 9 NR 9 CO 2 R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —CO 2 R 8 , —(CH 2 ) n CO 2 R 8 , —C(O)R 8 , —C(S)R 8 , —C(O)N(R 9 ) 2 , —C(S)N(R 9 ) 2 , —OC(O)N(R 9 ) 2 , —OC(O)R 8 , —C(O)N(OR 8 )R 8 , —C(NOR 8 )R 8 , —S(O) 2 R 8 , —S(O) 3 R 8 , —SO 2 N(R 9 ) 2 , —S(O)R 8 , —NR 9 SO 2 N(R 9 ) 2 , —NR 9 SO 2 R 8 , —P(O)(OR 8 ) 2 , —OP(O)(OR 8 ) 2 , —P(O)(OR 10) 2 , —OP(O)(OR 10 ) 2 , —N(OR 8 )R 8 , —CH═CHCO 2 R 8 , —C(═NH)—N(R 9 ) 2 , and —(CH 2 ) n NHC(O)R 8 or two adjacent R A 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.

24 . A composition comprising a TLR agonist, an insoluble metal salt, and a buffer, with the proviso that:

(a) the buffer is not a phosphate buffer;

(b) the TLR agonist is:

(i) not a TLR4 agonist;

(ii) not a TLR9 agonist;

(iii) not a compound of formula (III)

wherein:

R 1 is H, —C(O)—C 10 -C 18 alkyl; R 2 is C 10 -C 18 alkyl ; R 3 is C 10 -C 18 alkyl;

L 1 is —CH 2 O—, —CH 2 OC(O)—, —CH 2 NR 7 C(O)— or —C(O)NR 7 —;

L 2 is —O—, —OC(O)— or —NR 7 C(O)—;

R 4 is -L 3 R 5 or -L 4 R 5 ;

each R 6 is independently selected from halo, C 1 -C 6 alkyl, —OR 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —P(O)(OR 7 ) 2 , a C 6 aryl, a C 10 aryl and a C 1-4 aryl;

each R 7 is independently selected from H and C 1 -C 6 alkyl;

R 8 is selected from —SR 7 , —C(O)OH and a 5 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N;

R 9 is phenyl;

each R 10 is independently selected from H and halo;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4; and/or

(iv) not a compound of formula (IV)

wherein:

R 1 is H, C 1 -C 6 alkyl, —C(R 5 ) 2 OH, -L 1 R 5 , -L 2 R 5 , -L 2 R 6 , or —OL 2 R 6 ;

L 1 is —C(O)— or —O—;

L 2 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, arylene, heteroarylene or —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene and C 2 -C 6 alkenylene of L 2 are optionally substituted with 1 to 4 fluoro groups;

each L 3 is independently selected from C 1 -C 6 alkylene and —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 3 is optionally substituted with 1 to 4 fluoro groups;

L 4 is arylene or heteroarylene;

R 2 is H or C 1 -C 6 alkyl;

R 3 is selected from C 1 -C 4 alkyl, -L 3 R 5 , -L 1 R 5 , -L 3 R 7 , -L 3 L 4 L 3 R 7 , -L 3 L 4 L 5 , -L 3 L 4 L 3 R 5 , —OL 3 R 5 , —OL 3 R 7 , —OL 3 L 4 R 7 , —OL 3 L 4 L 3 R 7 , —OR 8 , —OL 3 L 4 R 5 , —OL 3 L 4 L 3 R 5 and —C(R 5 ) 2 OH;

each R 4 is independently selected from H and fluoro;

R 5 is —P(O)(OR 9 ) 2 ,

R 6 is —CF 2 P(O)(OR 9 ) 2 or —C(O)OR 10 ;

R 7 is —CF 2 P(O)(OR 9 ) 2 or —C(O)OR 10 ;

R 8 is H or C 1 -C 4 alkyl;

each R 9 is independently selected from H and C 1 -C 6 alkyl;

R 10 is H or C 1 -C 4 alkyl;

each p is independently selected from 1, 2, 3, 4, 5 and 6, and

q is 1, 2, 3 or 4.

25 . The composition of claim 23 or claim 24 , wherein the TLR agonist is adsorbed onto the insoluble metal salt.

26 . The composition of claim 22 or claim 25 , wherein at least 80% of the total TLR agonist in the composition is adsorbed onto insoluble metal salt.

27 . The composition of any of claim 22 , 25 or 26 , wherein the adsorbed TLR agonist is, when injected intramuscularly, still present in the injected muscle at least 12 hours later.

28 . The composition of any of claim 22 , 25 or 26 , wherein the adsorbed TLR agonist, when injected intramuscularly, has a lower peak serum concentration (Cmax) than the same TLR agonist when injected intramuscularly in non-adsorbed form.

29 . A process for preparing an adjuvant complex, comprising a step of mixing a TLR agonist with an insoluble metal salt such that the TLR agonist interact to form the complex e.g. wherein the TLR agonist adsorbs to the insoluble metal salt.

30 . A process for preparing a sterile adjuvant complex, comprising steps of: (i) mixing a TLR agonist with an insoluble metal salt such that the TLR agonist and the insoluble metal salt form the complex e.g. by adsorption of the TLR agonist to the salt; and (ii) sterilising the complex.

31 . A process for preparing an immunogenic composition, wherein the process comprises mixing a TLR agonist, an insoluble metal salt, and an immunogen, thereby providing the immunogenic composition.

32 . A method for modifying the pharmacokinetic profile and/or intramuscular retention time of an immunopotentiator, the method comprising: chemically modifying the immunopotentiator to form a modified immunopotentiator by the introduction of an adsorptive group.

33 . A composition comprising: (a) an adjuvant complex comprising a TLR agonist and an insoluble metal salt; and (b) at least two different immunogens.

34 . The composition of claim 33 , wherein the adjuvant complex comprises the TLR agonist adsorbed to the insoluble metal salt.

35 . The composition of claim 33 or claim 34 , wherein the TLR agonist is not a TLR4 agonist and is not a TLR9 agonist.

36 . The composition of claim 33 or claim 34 or claim 35 , wherein the composition includes (i) a diphtheria toxoid, a tetanus toxoid, and an acellular pertussis antigen; (ii) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, and a H. influenzae type B capsular saccharide conjugate; (iii) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, and a hepatitis B virus surface antigen; (iv) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, a hepatitis B virus surface antigen and a H. influenzae type B capsular saccharide conjugate; (v) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, and an inactivated poliovirus antigen; or (vi) a diphtheria toxoid, a tetanus toxoid, a pertussis antigen, a H. influenzae type B capsular saccharide conjugate, a hepatitis B virus surface antigen, and an inactivated poliovirus antigen.

37 . The composition of claim 36 , wherein the composition also includes further antigens, such as from N. meningitidis or S. pneumoniae.

38 . The composition of any one of claims 33 to 37 , wherein the composition includes at least one bacterial antigen and at least one viral antigen.

39 . A process for preparing the immunogenic composition of claims 33 to 38 , comprising one of: (i) combining at least two different immunogens with a mixture comprising a TLR agonist and an insoluble metal salt; (ii) combining an insoluble metal salt with a mixture comprising a TLR agonist and at least two different immunogens; (iii) combining a TLR agonist with a mixture comprising an insoluble metal salt and at least two different immunogens; or (iv) combining in any order a TLR agonist, an insoluble metal salt, a first immunogen and a second immunogen.

40 . One of the following compounds:

Assignments (9)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 22, 2016

From: NOVARTIS AG

To: GLAXOSMITHKLINE BIOLOGICALS SA

Reel/Frame 038985/0844 →

MERGER Recorded Jun 17, 2016

From: IRM, LLC

To: NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD

Reel/Frame 038942/0283 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 17, 2016

From: NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD

To: NOVARTIS AG

Reel/Frame 038942/0397 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 2, 2012

From: WU, TOM YAO-HSIANG; LI, YONGKAI; CORTEZ, ALEX; ZHANG, XIAOYUE; ZOU, YEFEN; HOFFMAN, TIMOTHY Z.; PAN, JIANFENG; YUE, KATHY

To: IRM LLC

Reel/Frame 027801/0458 →

CORRECTIVE ASSIGNMENT TO CORRECT THE APPLICATION NUMBER OF IB1150231 TO US1150231 PREVIOUSLY RECORDED ON REEL 027305 FRAME 0287. ASSIGNOR(S) HEREBY CONFIRMS THE THE PCT APPLICATION NUMBER SHOULD BE US1150231. Recorded Jan 25, 2012

From: SINGH, MANMOHAN

To: NOVARTIS VACCINES AND DIAGNOSTICS, INC.

Reel/Frame 027595/0553 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 30, 2011

From: NOVARTIS VACCINES AND DIAGNOSTICS, INC.

To: NOVARTIS AG

Reel/Frame 027303/0713 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 30, 2011

From: SINGH, MANMOHAN

To: NOVARTIS VACCINES AND DIAGNOSTICS, INC.

Reel/Frame 027305/0287 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 30, 2011