Neutrophils are responsible for tissue damage in certain inflammatory disorders. The chemokines IL-8 and GROalpha are potent chemoattractants for neutrophils, play an essential role in the recruitment of neutrophils to inflammatory sites, and bind to two closely related receptors, IL-8 RA and IL-8 RB. Recent evidence indicates that inhibition of IL-8 binding to its receptor is an effective way of reducing the neutrophil mediated tissue damage in certain diseases. We will develop human mAbs against the human IL-8 RA and RB receptors, using "humanized" mice that have been engineered to produce human mAbs. A critical component of the project is the use of cell lines expressing high levels of single IL-8 receptors (RA or RB), which will facilitate the identification of mAb antagonists to both receptors. The human mAbs to human IL-8 receptors will be characterized with respect to 1) ability to block binding of IL-8 or GROalpha to the receptors, 2) ability to inhibit function, particularly chemotaxis of transfectants or neutrophils, and 3) inability to mediate receptor signaling. These mAbs will also be useful for future (Phase II) structure/function studies of the IL-8 receptors. The "human" mAbs against IL-8 receptors will be developed as therapeutics for diseases with neutrophil-mediated tissue damage, following satisfactory preclinical and clinical studies.Proposed commercial application:Commercial applications result from the development of antibodies that bind IL-8 receptors and inhibit neutrophil recruitment to tissues. Acute inflammatory conditions would benefit from such therapeutics, such as reperfusion injuries, or flare-ups associated with inflammatory bowel disease and rheumatoid arthritis.National Institute of Allergy and Infectious Diseases (NIAID)
