IL-8 as Antibody Therapeutic Target in Inflammatory Diseases: Reduction of Clinical Activity in Palmoplantar Pustulosis

Abstract

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 ≥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.

Stromal Interaction Molecule 1 (STIM1) and Orai1 Mediate Histamine-evoked Calcium Entry and Nuclear Factor of Activated T-cells (NFAT) Signaling in Human Umbilical Vein Endothelial Cells

“…It has been indicated that leukocyte recruitment can be interrupted when any of these steps is suppressed. IL-8 is a chemoattractant that directs neutrophils and other granulocytes to migrate toward the site of injury or infection, and anti-IL-8 therapy has been initiated for the treatment of inflammatory disorders (62,63,77). IL-8 production in endothelial cells has been reported to be up-regulated through the calcineurin/NFAT pathway upon histamine stimulation (12,13).…”

Lactoferrin suppresses the Epstein–Barr virus-induced inflammatory response by interfering with pattern recognition of TLR2 and TLR9

“…The chemokine IL-8, initially identified as a neutrophil-activating and chemotactic factor, has multiple roles as a proinflammatory cytokine by mediating the activation and chemotaxis of various immune cell types, and leads to chronic inflammatory conditions if aberrantly expressed. 30,31 Many types of human tumors, including breast, colon, cervical, gastric, lung, and ovarian cancers, express high levels of IL-8 relative to normal tissues. 32 IL-8 participates in tumorigenesis by promoting the proliferation, survival, and migration of tumor cells, and recruiting neutrophils to the site of the tumor.…”

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

“…While there have been reports employing this tactic with IL-8 receptor blockade both in the preclinical and clinical settings (15)(16)(17)(18), to our knowledge this study is the first to utilize an IL-8-specific antibody to target IL-8 signaling in a preclinical model of claudin-low TNBC. Here, the high-affinity, fully human, clinical-stage monoclonal anti-IL-8 antibody, termed HuMax-IL8 (19,20), was explored both in vitro and in vivo with xenografts of claudin-low breast cancer cells. These studies demonstrated the ability of an anti-IL-8 monoclonal antibody to (a) reduce mesenchymal features in cancer cells; (b) reduce the frequency of polymorphonuclear MDSCs (PMN-MDSCs) found at the tumor site, an effect that was enhanced when HuMax-IL8 was combined with docetaxel treatment in MDA-MB-231 xenografts; and (c) enhance the susceptibility of claudin-low TNBC cells to lysis mediated by immune effector NK and antigen-specific T cells in vitro.…”