METHODS FOR DETERMINING DIFFERENCES IN ALPHA-4 INTEGRIN ACTIVITY BY CORRELATING DIFFERENCES IN sVCAM AND/OR sMadCAM LEVELS
Provided herein is a method of monitoring the change of the alpha-4 integrin activities in an individual by correlating with the soluble vascular cell adhesion molecule (sVCAM) and/or soluble mucosal addressin cell adhesion molecule (sMAd-CAM) levels. Particularly, this method can be used, for example, to evaluate the pharmacokinetics and pharmacodynamics (PK/PD) of an alpha-4 integrin inhibitor used to treat a disease associated with pathological or chronic inflammation.
1 . An in vitro method of determining a difference in alpha-4 integrin activity in an individual, comprising:
a) measuring a soluble molecule in a first biological sample obtained from the individual immediately before administration of an alpha-4 integrin inhibitor;
b) measuring the soluble molecule in a second biological sample, wherein the second biological sample has been obtained from the individual within thirty-one days after administration of the alpha-4 integrin inhibitor; and
c) determining whether there is a decrease in the levels of the soluble molecule between the first and second biological samples, wherein the decrease correlates with a decrease in alpha-4 integrin activity in the individual, and thereby determining whether there is a difference in alpha-4 integrin activity in the individual after administration of the alpha-4 integrin inhibitor compared with before administration of the alpha-4 integrin inhibitor,
and wherein the soluble molecule is sVCAM and/or sMAdCAM.
2 . The method of claim 1 , further comprising detecting a decrease in the levels of the soluble molecule in the second biological sample compared with the first biological sample, and attributing said decrease to a decrease in alpha-4 integrin activity in the individual after administration of the alpha-4 integrin inhibitor compared with before administration of the alpha-4 integrin inhibitor.
3 . The method of claim 1 or claim 2 , wherein alpha-4 integrin activity is alpha-4 beta-1 integrin activity, and wherein the soluble molecule is sVCAM.
4 . The method of claim 1 or claim 2 , wherein alpha-4 integrin activity is alpha-4 beta-7 integrin activity, and wherein the soluble molecule is sMAdCAM.
5 . The method of any of the proceeding claims, wherein the individual has a disease or disorder associated with a pathological or chronic inflammation.
6 . The method of claim 5 , wherein the disease or disorder is selected from the group consisting of multiple sclerosis (MS), meningitis, encephalitis, inflammatory bowel disease, rheumatoid arthritis (RA), asthma, acute juvenile onset diabetes, AIDS dementia, atherosclerosis, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, chronic prostatitis, complications from sickle cell anemia, lupus erythematosus, and acute leukocyte-mediated lung injury.
7 . The method of any of the preceding claims, wherein the alpha-4 integrin inhibitor is an antibody.
8 . The method of any of the preceding claims, wherein the first and/or the second biological sample is selected from the group consisting of a tissue, a cell, and a body fluid.
9 . The method of claim 8 , wherein the first and/or the second biological sample is a body fluid selected from the group consisting of blood, lymph, sera, plasma, urine, semen, synovial fluid, saliva, tears, bronchoalveolar lavage, and cerebrospinal fluid.
10 . The method of claim 8 , wherein the first and/or the second biological sample is in the form of frozen plasma or serum.
11 . The method of any of the preceding claims, wherein the second biological sample is obtained from the individual one day after administration of the alpha-4 integrin inhibitor.
12 . The method of any of the preceding claims, wherein the soluble molecule is measured by a method selected from the group consisting of enzyme-linked immunosorbent assays (ELISA), radioimmunoassay (RIA), Western blotting, and microbead-based protein detection assay.
13 . The method of any of the preceding claims, further comprising determining whether an adjustment in treatment of the individual is required, wherein no decrease or a statistically insignificant decrease (p>0.05) in the levels of the soluble molecule between the first and second biological samples indicates ineffective response to the alpha-4 integrin inhibitor requiring a treatment adjustment of the individual.
14 . The method of claim 13 , further comprising detecting no decrease, or detecting a statistically insignificant decrease (p>0.05), in the level of the soluble molecule in the second biological sample compared with the first biological sample, and concluding that a treatment adjustment of the individual is required.
15 . The method of claim 13 or claim 14 , wherein the treatment adjustment comprises changing to a different alpha-4 integrin inhibitor or increasing the dosage of the alpha-4 integrin inhibitor.
16 . In vitro use of sVCAM and/or sMAdCAM as a pharmacodynamic biomarker for the activity of (i) alpha-4 integrin or (ii) a modulator of alpha-4 integrin activity.
17 . Use according to claim 16 , comprising in vitro use of sVCAM and/or sMAdCAM as a pharmacodynamic biomarker for said activity in an individual receiving treatment with a′modulator of alpha-4 integrin activity.
18 . Use according to claim 17 , wherein the modulator is an alpha-4 integrin inhibitor.
19 . Use according to claim 17 , wherein the individual has a disease or disorder associated with a pathological or chronic inflammation, optionally selected from the group consisting of multiple sclerosis (MS), meningitis, encephalitis, inflammatory bowel disease, rheumatoid arthritis (RA), asthma, acute juvenile onset diabetes, AIDS dementia, atherosclerosis, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, chronic prostatitis, complications from sickle cell anemia, lupus erythematosus, and acute leukocyte-mediated lung injury.
20 . Use according to any of claims 16 to 19 , wherein the alpha-4 integrin activity is alpha-4 beta-1 integrin activity, and wherein the pharmacodynamic biomarker is sVCAM.
21 . Use according to any of claims 16 to 19 , wherein the alpha-4 integrin activity is alpha-4 beta-7 integrin activity, and wherein the pharmacodynamic biomarker is sMAdCAM.