Structure of IL-17A in complex with a potent, fully human neutralizing antibody

Area of Science:

• Structural Biology
• Immunology
• Biochemistry

Background:

• Interleukin-17A (IL-17A) is a key pro-inflammatory cytokine produced by Th17 cells.
• IL-17A plays a significant role in autoimmune and inflammatory diseases.
• Neutralizing IL-17A is a therapeutic strategy for these conditions.

Purpose of the Study:

• To characterize the structural basis of neutralization for the human anti-IL-17A monoclonal antibody CAT-2200.
• To define the epitope on IL-17A and the paratope of CAT-2200 at the atomic level.
• To understand the impact of affinity optimization on antibody-antigen interaction.

Main Methods:

• Crystallography was used to determine the 3D structure of the IL-17A/CAT-2200 Fab complex at 2.6 Å resolution.
• Analysis of the quaternary structure interactions between the IL-17A dimer and the antibody fragments.
• In vitro affinity optimization using random mutagenesis of CDR3 loops and cell-based neutralization assays.

Main Results:

• The crystal structure revealed the IL-17A dimer bound by two CAT-2200 Fab fragments, with significant disorder in the IL-17A dimer.
• The epitope involves 12 residues from the IL-17A quaternary structure, with each Fab interacting with both IL-17A monomers.
• Antibody optimization yielded a 30-fold increase in potency, with specific amino acid changes in CDR3 loops contributing to enhanced binding.

Conclusions:

• The determined structure provides a definitive characterization of the IL-17A-CAT-2200 interaction.
• The findings elucidate the epitope and paratope regions, crucial for understanding antibody-mediated IL-17A neutralization.
• The study validates affinity maturation strategies for developing potent therapeutic antibodies against IL-17A.