Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies |
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Authors: | Christophe Blanchetot Natalie De Jonge Aline Desmyter Nico Ongenae Erik Hofman Alex Klarenbeek Ava Sadi Anna Hultberg Anke Kretz-Rommel Silvia Spinelli Remy Loris Christian Cambillau Hans de Haard |
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Affiliation: | From ‡argenx, 9052 Zwijnaarde, Belgium, ;§Architecture et Fonction des Macromolécules Biologiques, UMR 6098 CNRS and Universités of Marseille, 13284 Marseille, France, ;¶Bird Rock Bio, La Jolla, California 92037, ;‖Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium, and ;the **Structural Biology Research Center, Instituut voor Biotechnologie, 1050 Brussels, Belgium |
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Abstract: | Interleukin 6 plays a key role in mediating inflammatory reactions in autoimmune diseases and cancer, where it is also involved in metastasis and tissue invasion. Neutralizing antibodies against IL-6 and its receptor have been approved for therapeutic intervention or are in advanced stages of clinical development. Here we describe the crystal structures of the complexes of IL-6 with two Fabs derived from conventional camelid antibodies that antagonize the interaction between the cytokine and its receptor. The x-ray structures of these complexes provide insights into the mechanism of neutralization by the two antibodies and explain the very high potency of one of the antibodies. It effectively competes for binding to the cytokine with IL-6 receptor (IL-6R) by using side chains of two CDR residues filling the site I cavities of IL-6, thus mimicking the interactions of Phe229 and Phe279 of IL-6R. In the first antibody, a HCDR3 tryptophan binds similarly to hot spot residue Phe279. Mutation of this HCDR3 Trp residue into any other residue except Tyr or Phe significantly weakens binding of the antibody to IL-6, as was also observed for IL-6R mutants of Phe279. In the second antibody, the side chain of HCDR3 valine ties into site I like IL-6R Phe279, whereas a LCDR1 tyrosine side chain occupies a second cavity within site I and mimics the interactions of IL-6R Phe229. |
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Keywords: | antibody engineering crystal structure immunology interleukin 6 (IL-6) structure-function high affinity |
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