Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1999-10-4
pubmed:abstractText
Interleukin-8 (IL-8) is a potent chemotactic cytokine implicated in the pathogenesis of a number of inflammatory disease states. Agents that block the binding of IL-8 to its receptor have been shown to block inflammation in animal models of disease. This suggests that drugs specifically targeting IL-8 may prove efficacious in treating multiple human diseases. To this end, we developed a panel of fully human anti-IL-8 monoclonal antibodies (mAbs). These human antibodies were generated from XenoMouse strains, mice created by introducing megabase-size unrearranged human immunoglobulin heavy and kappa light chain loci into a mouse genome in which the corresponding endogenous loci have been inactivated. From the panel of more than 50 mAbs, two antibodies, K4.3 and K2.2, were further characterized and evaluated for their specificity, productivity, affinity, and biological activity. Both K4.3 and K2.2 bind human IL-8 with high affinity (Kd of K4.3 = 2.1x10(10) M; Kd of K2.2 = 2.5x10(-10) M). In vitro, in addition to blocking IL-8 binding to human neutrophils, K4.3 and K2.2 blocked a number of IL-8-dependent cellular functions including neutrophil activation, up-regulation of the cell adhesion receptor CD11b/CD18, and neutrophil chemotaxis, suggesting that the fully human anti-IL-8 mAbs derived from XenoMouse strains are potent anti-inflammatory agents. This was further supported by in vivo studies in which K4.3 and K2.2 significantly inhibited IL-8-induced skin inflammation in rabbits. A pharmacokinetic study in Cynomolgus monkeys demonstrated that the alpha phase half-life is 9.4 h and the beta phase 10.9 days, typical of human mAbs in monkeys. These data support advancing a fully human anti-IL-8 mAb into clinical trials to treat inflammatory diseases.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0741-5400
pubmed:author
pubmed:issnType
Print
pubmed:volume
66
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
401-10
pubmed:dateRevised
2005-11-17
pubmed:meshHeading
pubmed-meshheading:10496309-Animals, pubmed-meshheading:10496309-Anti-Inflammatory Agents, Non-Steroidal, pubmed-meshheading:10496309-Antibodies, Monoclonal, pubmed-meshheading:10496309-Antibody Specificity, pubmed-meshheading:10496309-Drug Eruptions, pubmed-meshheading:10496309-Genes, Immunoglobulin, pubmed-meshheading:10496309-Humans, pubmed-meshheading:10496309-Immunization, Passive, pubmed-meshheading:10496309-Immunoglobulin Heavy Chains, pubmed-meshheading:10496309-Immunoglobulin kappa-Chains, pubmed-meshheading:10496309-Inflammation, pubmed-meshheading:10496309-Interleukin-8, pubmed-meshheading:10496309-Macaca fascicularis, pubmed-meshheading:10496309-Mice, pubmed-meshheading:10496309-Mice, Knockout, pubmed-meshheading:10496309-Mice, Transgenic, pubmed-meshheading:10496309-Neutrophils, pubmed-meshheading:10496309-Rabbits, pubmed-meshheading:10496309-Recombinant Proteins
pubmed:year
1999
pubmed:articleTitle
Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states.
pubmed:affiliation
Department of Research, Abgenix, Inc., Fremont, California 94555, USA. yang_xd@abgenix.com
pubmed:publicationType
Journal Article