Identification of short-term pharmacodynamic effects of interferon-beta-1a in multiple sclerosis subjects with broad- based phenotypic profiling.
We applied broad-based phenotypic profiling to identify pharmacodynamic markers for interferon-beta in multiple sclerosis subjects. A strong pharmacodynamic effect was observed 1.5 (short-term) vs. 6 days post weekly injection. Hundreds of differences were observed at a p-value <0.001. Most major cell populations, including neutrophils, B cells, CD4 T cells and CD8 T cells, decreased in absolute counts at 1.5 days. The striking exception was monocytes, which increased substantially. Changes in multiple monocyte-associated cell surface molecules and monocyte related soluble factors were also observed, including: HLA class II, CCR5, CD38, CD40, CD54, CD64, CD69, CD86, CD101, TLR2, TLR4 and MCP2. These results demonstrate that new hypotheses can be generated from broad molecular and cellular profiling in a clinical setting and provide an approach to identify candidate pharmacodynamic markers to evaluate new drug formulations, dosing and bioequivalence.
Kantor
Aaron B
AB
Biomarker Discovery Sciences, PPD, Menlo Park, CA 94025-1435, United States. aaron.kantor@menlo.ppdi.com <aaron.kantor@menlo.ppdi.com>
Deng
Jun
J
Waubant
Emmanuelle
E
Lin
Hua
H
Becker
Christopher H
CH
Lacy
Joseph R
JR
Perrone
Andrea M
AM
Bennett
Donald
D
Goelz
Susan E
SE
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects; D016000:Cluster Analysis; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007118:Immunoassay / Q000379:methods; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D013058:Mass Spectrometry / Q000379:methods; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000473:pathology*; D064547:Myxovirus Resistance Proteins; D009504:Neutrophils / Q000187:drug effects; D040901:Proteomics / Q000379:methods; D013997:Time Factors
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D064547:Myxovirus Resistance Proteins; D016899:Interferon-beta; D019204:GTP-Binding Proteins; D000068556:Interferon beta-1a