Safety of blocking vascular adhesion protein-1 in patients with contact dermatitis.
Vascular adhesion protein-1 mediates leukocyte binding to vascular endothelia and migration to tissues. It is upregulated in inflammatory conditions. We studied the safety of vascular adhesion protein-1 blockade by a single dose of the mouse monoclonal antibody vepalimomab in patients with nickel-induced allergic contact dermatitis lesions. Vepalimomab, 0.05-0.50 mg kg(-1) was safe and well tolerated. Four of nine patients reported adverse events of mild to moderate intensity. Human antimouse antibodies were detected after infusion in all the patients and they remained above the basal level for at least one month. Vepalimomab dose-dependently labelled vascular adhesion protein-1 in the inflamed skin. Luminal upregulation of vascular adhesion protein-1 on the endothelium upon inflammation was demonstrated for the first time in patients in vivo. Vepalimomab was found on the endothelium up to 24 hr after dosing whilst it was cleared from the circulation with an apparent half-life of 25-50 min. The results provide in vivo support for the concept of blocking vascular adhesion protein-1 in human disease states and support previous proposals that vascular adhesion protein-1 is a potential target molecule for inhibition of inflammatory reactions.
Vainio
Petri J
PJ
Biotie Therapies Corp., Turku FIN-20520, Finland. petri.vainio@biotie.com
Kortekangas-Savolainen
Outi
O
Mikkola
Jari H
JH
Jaakkola
Kimmo
K
Kalimo
Kirsti
K
Jalkanen
Sirpa
S
Veromaa
Timo
T
D000328:Adult; D006631:Amine Oxidase (Copper-Containing) / Q000096:biosynthesis*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D003176:Complement C3 / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009532:Nickel; D010328:Patch Tests; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D003176:Complement C3; D003181:Complement C4; D009532:Nickel; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)