SELECTIVE INTEGRIN INHIBITORS
This invention provides methods for selectively antagonizing the α4β1 integrin heterodimer in a subject in need thereof, and preferably in a human subject. The methods of the invention utilize conjugates comprising two or more α4β1 small molecule antagonists covalently attached to a biocompatible polymer. These methods of selectively inhibiting α4β1 may be used modulate both normal and pathological biological processes mediated at least in part through α4β1 activity.
1 . A method of treating a disease mediated by α4β1-mediated leukocyte trafficking into the CNS while substantially preserving α4β7-mediated trafficking, comprising administering a compound of Formula (I) to a subject in need of such treatment at a therapeutically effective dose and interval.
2 . The method of claim 1 , wherein the dose is from about 0.01 mg/kg to about 5 mg/kg.
3 . The method of claim 2 , wherein the dose is from about 0.2 mg/kg to about 1.0 mg/kg.
4 . The method of claim 3 , wherein the dose is about 0.2 mg/kg to about 0.5 mg/kg.
5 . The method of claim 1 , wherein the dose is from about 1.0 mg/kg to about 2.0 mg/kg.
6 . The method of claim 2 , wherein the compound of Formula (I) is administered weekly.
7 . The method of claim 2 , wherein the compound of Formula (I) is administered monthly.
8 . The method of claim 1 , wherein the dose or interval of Formula (I) administration is selected to maintain sMAdCAM levels in the subject's bloodstream at 75% or more following administration compared to sMAdCAM levels in the subject's bloodstream prior to administration of Formula (I).
9 . A method of selectively inhibiting α4β1 activity in a subject, comprising administering to the subject a therapeutically effective amount of a conjugate comprising two or more α4β1 small molecule antagonists covalently attached to a biocompatible polymer, wherein the conjugate has a 20 to 100 fold greater potency towards α4β1 than α4β7.
10 . The method of claim 9 , wherein the conjugate has a 30 to 80 fold greater potency towards α4β1 than α4β7.
11 . The method of claim 10 , wherein the conjugate comprises the compound of Formula (I).
12 . The method of claim 9 , wherein the conjugate is administered to a subject with an autoimmune disease.
13 . The method of claim 12 , wherein the conjugate is administered to a subject with multiple sclerosis.
14 . The method of claim 9 , wherein the conjugate is administered to a subject with an inflammatory disease.
15 . The method of claim 9 , wherein the conjugate is administered to a subject with a cell proliferative disorder.
16 . The method of claim 9 , wherein the conjugate is administered to a subject with to prevent transplant rejection or graft versus host disease.
17 . The method of claim 9 , wherein the conjugate is administered to a subject to promote neuroprotection following injury.
18 . The method of claims 9 , wherein the dose or interval of administration of the conjugate is selected to maintain sMAdCAM levels in the subject's bloodstream at 75% or more following administration compared to sMAdCAM levels in the subject's bloodstream prior to administration of Formula (I).
19 . A method of treating multiple sclerosis in a subject in need thereof, comprising administering to the subject a compound having a 30 to 80 fold greater potency towards α4β1 than α4β7 in a dose from about 0.01 mg/kg to about 5 mg/kg.
20 . The method of claim 19 , wherein the dose is from about 0.2 mg/kg to about 1.0 mg/kg.
21 . The method of claim 20 , wherein the dose is about 0.2 mg/kg to about 0.5 mg/kg.
22 . The method of claim 19 , wherein the dose is from about 1.0 mg/kg to about 2.0 mg/kg.
23 . The method of claim 19 , wherein the compound is administered weekly.
24 . The method of claim 19 , wherein the compound is administered monthly.
25 . A method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound having a 30 to 80 fold greater potency towards α4β1 than α4β7 in a dose from about 0.01 mg/kg to about 5 mg/kg.
26 . The method of claim 25 , wherein the dose is from about 0.2 mg/kg to about 1.0 mg/kg.
27 . The method of claim 26 , wherein the dose is about 0.2 mg/kg to about 0.5 mg/kg.
28 . The method of claim 25 , wherein the dose is from about 1.0 mg/kg to about 2.0 mg/kg.
29 . The method of claim 25 , wherein the compound is administered weekly.
30 . The method of claim 25 , wherein the compound is administered monthly.
31 . A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a compound having a 30 to 80 fold greater potency towards α4β1 than α4β7 in a dose from about 0.01 mg/kg to about 5 mg/kg.
32 . The method of claim 31 , wherein the dose is from about 0.2 mg/kg to about 1.0 mg/kg.
33 . The method of claim 32 , wherein the dose is about 0.2 mg/kg to about 0.5 mg/kg.
34 . The method of claim 31 , wherein the dose is from about 1.0 mg/kg to about 2.0 mg/kg.
35 . The method of claim 31 , wherein the compound is administered weekly.
36 . The method of claim 31 , wherein the compound is administered monthly.
37 . A method of treating a cell proliferative disorder in a subject in need thereof, comprising administering to the subject a compound having a 30 to 80 fold greater potency towards α4β1 than α4β7 in a dose from about 0.01 mg/kg to about 10 mg/kg.
38 . The method of claim 37 , wherein the dose is from about 0.2 mg/kg to about 1.0 mg/kg.
39 . The method of claim 38 , wherein the dose is about 0.2 mg/kg to about 0.5 mg/kg.
40 . The method of claim 37 , wherein the dose is from about 1.0 mg/kg to about 2.0 mg/kg.
41 . The method of claim 37 , wherein the compound is administered monthly.
42 . The method of claim 37 , wherein the compound is administered monthly.
43 . A method of treating an autoimmune disease that is mediated in part by α4β1 integrin receptors while sparing α4β7 mediated immune cell interactions in a patient comprising administering to the patient a weekly, bi-weekly or monthly dose of a compound of Formula (I) of from about 0.2 mg/kg to about 1.0 mg/kg.
44 . A method of treating an autoimmune disease that is mediated in part by α4β1 integrin receptors while sparing α4β7 mediated immune cell surveillance in a patient comprising administering to the patient a weekly, bi-weekly or monthly dose of a compound of Formula (I) of from about 0.2 mg/kg to about 1.0 mg/kg.