title: Design of a superior cytokine antagonist for topical ophthalmic use.
abstract: IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent's size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-1 receptor ligands, IL-1β and IL-1Ra, to create an optimized receptor antagonist, EBI-005, for topical ocular administration. EBI-005 binds its target, IL-1R1, 85-fold more tightly than IL-1Ra, and this increase translates to an ∼100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-1Ra for IL-1R1 over the decoy receptor (IL-1R2), and, surprisingly, is also more thermally stable than either parental molecule. This rationally designed antagonist represents a unique approach to therapeutic design that can potentially be exploited for other β-trefoil family proteins in the IL-1 and FGF families.
authors: Eleven Biotherapeutics, Inc., Cambridge, MA 02142, USA.
authors: Jinzhao
authors: J
authors: Hou
authors: Sharon A
authors: SA
authors: Townson
authors: Joseph T
authors: JT
authors: Kovalchin
authors: Allyson
authors: A
authors: Masci
authors: Olga
authors: O
authors: Kiner
authors: Yanqun
authors: Y
authors: Shu
authors: Bracken M
authors: BM
authors: King
authors: Emily
authors: E
authors: Schirmer
authors: Kathryn
authors: K
authors: Golden
authors: Christoph
authors: C
authors: Thomas
authors: K Christopher
authors: KC
authors: Garcia
authors: Gregory
authors: G
authors: Zarbis-Papastoitsis
authors: Eric S
authors: ES
authors: Furfine
authors: Thomas M
authors: TM
authors: Barnes
mesh_terms: D000287:Administration, Topical; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004355:Drug Stability; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009883:Ophthalmic Solutions; D011487:Protein Conformation; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
chemical_list: D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008024:Ligands; D009883:Ophthalmic Solutions; D053573:Receptors, Interleukin-1 Type I; D011993:Recombinant Fusion Proteins