Interleukin-17A (IL-17A, CTLA-8, IL-17) is a cytokine secreted by activated Th17 cells, CD8+ T cells, γδ T cells and NK cells in response to cytokines such as IL-23 and TGF-β, and regulates production of mediators such as antimicrobial peptides (defensins), proinflamatory cytokines and chemokines from multiple cell types such as fibroblasts and synoviocytes that are involved in neutrophil biology, inflammation, organ destruction and host defense (reviewed in Weaver et al., Annu. Rev. Immunol. 25:821-52, 2007; Aggarwal et al., J. Biol. Chem. 278:1910-4, 2003; Mangan et al., Nature 441:231-4, 2006). IL-17A synergizes with other cytokines, such as TNF-α and IL-1β to potentiate the pro-inflammatory environment.
The IL-17A cytokine family consists of six homologs designated IL-17A, B, C, D, E and F, each with divergent and distinct biological roles (Kawaguchi et al., J. Allergy Clin. Immunol. 114:1265-73, 2004; Kolls and Linden, Immunity 21:467-76, 2004; Moseley et al., Cytokine Growth Factor Rev. 14:155-74, 2003). Of the family members, IL-17F is most homologous to IL-17A and shares many similar functional properties such as induction of neutrophilia in the lung and induction of pro-inflammatory cytokines; however, in man, IL-17F is about 10-fold less potent than IL-17A (Moseley et al., Cytokine Growth Factor Rev. 14:155-74, 2003; Kolls et al., Immunity, 21: 467-76, 2004; McAllister et al., J. Immunol. 175:404-12, 2005). IL-17A and IL-17F can also form heterodimers, which have intermediate bioactivity in vitro (Wright et al., J. Biol. Chem. 282:13447-55, 2007).
IL-17A mediates it effects by interacting with the Interleukin-17 receptor A (IL-17RA) and receptor C (IL-17RC) (Moseley et al., Cytokine Growth Factor Rev. 14:155-74, 2003; Toy et al., J. Immunol. 177:36-9, 2006). IL-17F signals through the same receptors, although IL-17F affinity to the receptors is significantly lower (Kuestner et al., J. Immunol. 179:5462-73, 2007). Crystal structures of human IL-17F and human IL-17F/IL-17RA complex identified a putative receptor-binding cavity in the IL-17F homodimer (Hymowitz et al., EMBO J. 20:5332-41, 2001; Ely et al., Nat. Immunology 10:1245-51, 2009). A similar cavity was identified in the crystal structure of human IL-17A in complex with a neutralizing Fab, although the cavity was partially occupied (Gerhardt et al., J. Mol. Biol. 394:905-21, 2009).
Inappropriate or excessive production of IL-17A is associated with the pathology of various diseases and disorders, including rheumatoid arthritis (Lubberts, Cytokine 41:84-91, 2008), airway hypersensitivity including allergic airway disease such as asthma (reviewed in Linden, Curr. Opin. Investig. Drugs. 4:1304-12, 2003; Ivanov, Trends Pharmacol. Sci. 30:95-103, 2009), psoriasis (Johansen et al., Br. J. Dermatol. 160:319-24, 2009), dermal hypersensitivity including atopic dermatitis (Toda et al., J. Allergy Clin. Immunol. 111:875-81, 2003), systemic sclerosis (Fujimoto et al., J. Dermatolog. Sci. 50:240-42, 2008), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Holtta et al., Inflamm. Bowel Dis. 14:1175-84, 2008; Zhang et al., Inflamm. Bowel Dis. 12:382-88, 2006), and pulmonary diseases including chronic obstructive pulmonary disease (Curtis et al., Proc. Am. Thorac. Soc. 4:512-21, 2007).
Antibodies to IL-17A have been proposed for use in the treatment of IL-17A mediated diseases and disorders (PCT Publ. Nos: WO08/021156, WO07/070750, WO07/149032, WO06/054059, WO06/013107, WO08/001063, WO10/034443; US Pat. Appl. Nos. US2008/095775, US2009/0175881;). As the pharmacokinetic, efficacy and safety profiles of antibody therapeutics will be dependent on specific compositions, there is a need for improved antibodies to human IL-17A that are suitable for use in the treatment of IL-17A mediated diseases and disorders.
USPTO Backgrounds
USPTO Backgrounds