IL-8 as antibody therapeutic target in inflammatory diseases: reduction of clinical activity in palmoplantar pustulosis.
IL-8 is a chemokine that has been implicated in a number of inflammatory diseases involving neutrophil activation. HuMab 10F8 is a novel fully human mAb against IL-8, which binds a discontinuous epitope on IL-8 overlapping the receptor binding site, and which effectively neutralizes IL-8-dependent human neutrophil activation and migration. We investigated whether interference in the cytokine network by HuMab 10F8 might benefit patients suffering from palmoplantar pustulosis, a chronic inflammatory skin disease. Treatment of patients with HuMab 10F8 was well tolerated and significantly reduced clinical disease activity at all five endpoints, which included a >or=50% reduction in the formation of fresh pustules. IL-8 neutralization was monitored at the site of inflammation by assessing exudates of palmoplantar pustulosis lesions. HuMab 10F8 sequestered IL-8 in situ, as observed by rapid dose-dependent decreases of IL-8 concentrations immediately following Ab infusion. These data demonstrate a critical role for IL-8 in the pathophysiology of palmoplantar pustulosis. HuMab 10F8 is capable of interrupting IL-8 activity in vivo and represents a candidate for treatment of inflammatory diseases and other pathological conditions associated with IL-8 overproduction.
Department of Dermatology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
Lone
L
Skov
Frank J
FJ
Beurskens
Claus O C
CO
Zachariae
Sakari
S
Reitamo
Jessica
J
Teeling
David
D
Satijn
Kim M
KM
Knudsen
Elmieke P J
EP
Boot
Debra
D
Hudson
Ole
O
Baadsgaard
Paul W H I
PW
Parren
Jan G J
JG
van de Winkel
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000276:immunology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016209:Interleukin-8 / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000939:Epitopes; D016209:Interleukin-8