Antibody drug conjugate for anti-inflammatory applications
Antibody drug conjugates (ADCs) comprising an antibody conjugated to an anti-inflammatory therapeutic agent via a phosphate-based linker with tunable extracellular and intracellular stability are described.
1. A composition comprising a compound having formula (I)
wherein V is selected from O and S;
W is selected from O, N, and CH 2 ;
X is a tuning element selected from a covalent bond; a carbon atom; a heteroatom;
an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic; nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C 1-30 hydrocarbon chain wherein one or more methylene units of Y are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, SO 2 N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
T is an NR, CR 2 , O, or S;
D is an anti-inflammatory agent;
Antibody is an antibody that binds a CD74 protein and comprises a heavy chain (HC) comprising an amino acid sequence selected from SEQ ID NO:69, 70, 71, and 72 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:7;
Z is a linkage formed between (i) a reactive functional group selected from the group consisting of maleimide and strained cycloalkyne, and (ii) the side chain of an amino acid in the heavy chain or light chain of the antibody;
each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
n is 1, 2, 3, or 4;
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
and a pharmaceutically acceptable carrier.
2. The composition of claim 1 , wherein the anti-inflammatory agent comprises a glucocorticoid receptor agonist.
3. The composition of claim 1 , wherein the anti-inflammatory agent comprises Cortisol, cortisone acetate, beclometasone, prednisone, prednisolone, methylprednisolone, betamethasone, trimcinolone, budesonide, dexamethasone, fluticasone, or mometasone.
4. The composition of claim 1 , wherein the antibody comprises the heavy chain comprising SEQ ID NO: 69 or SEQ ID NO: 70 and the reactive functional group comprises the strained cycloalkyne.
5. A method for treating an inflammatory disease or disorder by providing to a subject having the disease or disorder a composition comprising a compound having formula (I)
wherein V is selected from O and S;
W is selected from O, N, and CH 2 ;
X is a tuning element selected from a covalent bond; a carbon atom; a heteroatom; an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic; nucleoside, protease sensitive group, cathepsin B sensitive group, or glycosidase sensitive group;
Y is selected from a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C 1-30 hydrocarbon chain wherein one or more methylene units of Y are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, C(O)O—, OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, SO 2 N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
T is an NR, CR 2 , O, or S;
D is an anti-inflammatory agent;
Antibody is an antibody that binds a CD74 protein and comprises a heavy chain (HC) comprising an amino acid sequence selected from SEQ ID NO:69, 70, 71, and 72 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:73;
Z is a linkage formed between (i) a reactive functional group selected from the group consisting of maleimide and strained cycloalkyne and (ii) the side chain of an amino acid in the heavy chain or light chain of the antibody;
each occurrence of R is independently hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
n is 1, 2, 3, or 4;
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
and a pharmaceutically acceptable carrier to treat the inflammatory disease or disorder.
6. The method of claim 5 , wherein the anti-inflammatory agent comprises a glucocorticoid receptor agonist.
7. The method of claim 5 , wherein the anti-inflammatory agent comprises Cortisol, cortisone acetate, beclometasone, prednisone, prednisolone, methylprednisolone, betamethasone, trimcinolone, budesonide, dexamethasone, fluticasone, or mometasone.
8. The method of claim 5 , wherein the antibody comprises the heavy chain comprising SEQ ID NO: 69 or SEQ ID NO:70 and the reactive functional group comprises the strained cycloalkyne.
9. The method of claim 5 , wherein the inflammatory disease or disorder comprises Alzheimer's disease, ankylosing spondylitis arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), nephritis, Parkinson's disease, or ulcerative colitis.
10. An antibody drug conjugate comprising
(a) an antibody that binds a CD74 protein, the antibody comprising a heavy chain (HC) comprising an amino acid sequence selected from SEQ ID NO:69 or 70 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO:73, wherein the antibody comprises a para-azidophenylalanine (pAzF) conjugated to a molecule selected from the group of molecules consisting of
11. The composition of claim 4 , wherein the strained cycloalkyne is cyclooctyne.
12. The method of claim 8 , wherein the strained cycloalkyne is cyclooctyne.
13. The antibody drug conjugate of claim 10 , wherein the molecule
14. The antibody drug conjugate of claim 10 , wherein the molecule is
15. The antibody drug conjugate of claim 10 , wherein the molecule is
16. The antibody drug conjugate of claim 10 , wherein the molecule is
17. The antibody drug conjugate of claim 10 , wherein the molecule is
18. The antibody drug conjugate of claim 10 , wherein the molecule is
19. The antibody drug conjugate of claim 10 , wherein the molecule is
20. The antibody drug conjugate of claim 10 , wherein the molecule is