Unusual water-mediated antigenic recognition of the proinflammatory cytokine interleukin-18.
The unique cytokine interleukin-18 (IL-18) acts synergistically with IL-12 to regulate T-helper 1 and 2 lymphocytes and, as such, seems to underlie the pathogenesis of various autoimmune and allergic diseases. Several anti-IL-18 agents are in clinical development, including the recombinant human antibody ABT-325, which is entering trials for autoimmune diseases. Given competing cytokine/receptor and cytokine/receptor decoy interactions, understanding the structural basis for recognition is critical for effective development of anti-cytokine therapies. Here we report three crystal structures: the murine antibody 125-2H Fab fragment bound to human IL-18, at 1.5 A resolution; the 125-2H Fab (2.3 A); and the ABT-325 Fab (1.5 A). These structures, along with human/mouse IL-18 chimera binding data, allow us to make three key observations relevant to the biology and antigenic recognition of IL-18 and related cytokines. First, several IL-18 residues shift dramatically (> 10 A) upon binding 125-2H, compared with unbound IL-18 (Kato, Z., Jee, J., Shikano, H., Mishima, M., Ohki, I., Ohnishi, H., Li, A., Hashimoto, K., Matsukuma, E., Omoya, K., Yamamoto, Y., Yoneda, T., Hara, T., Kondo, N., and Shirakawa, M. (2003) Nat. Struct. Biol. 10, 966-971). IL-18 thus exhibits plasticity that may be common to its interactions with other receptors. Related cytokines may exhibit similar plasticity. Second, ABT-325 and 125-2H differ significantly in combining site character and architecture, thus explaining their ability to bind IL-18 simultaneously at distinct epitopes. These data allow us to define the likely ABT-325 epitope and thereby explain the distinct neutralizing mechanisms of both antibodies. Third, given the high 125-2H potency, 10 well ordered water molecules are trapped upon complex formation in a cavity between two IL-18 loops and all six 125-2H complementarity-determining regions. Thus, counterintuitively, tight and specific antibody binding may in some cases be water-mediated.
Argiriadi
Maria A
MA
Department of Biochemistry, Abbott Laboratories, Worcester, Massachusetts 01605, USA. maria.argiriadi@abbott.com
Xiang
Tao
T
Wu
Chengbin
C
Ghayur
Tariq
T
Borhani
David W
DW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011485:Protein Binding / Q000276:immunology; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry*
D000911:Antibodies, Monoclonal; D000941:Antigens; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D020382:Interleukin-18; D014867:Water