Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies

Edurne Rujas,Taylor Sicard,Hong Cui,Jean-Philippe Julien,Anthony Semesi

doi:10.1038/s41467-020-18828-4

Abstract

The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Å resolution. A central FDPPPF motif and residues within the CC’ loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors.

Highlights

The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L)
We determined the molecular basis for the co-stimulatory signal provided by ICOS (Fig. 1a) by solving the three-dimensional structure formed by the extracellular domains of ICOS and its ligand ICOS-L (Fig. 1b) at 3.3 Å resolution by x-ray crystallography (Table 1)
The main binding interface is formed by the FDPPPFK motif located in the ICOS FG loop, which interacts with residues from strands C and C’ and loops CC’ and C’D of ICOS-L

Summary

Introduction

The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L) Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Upon encounter of foreign antigens, antigen-presenting cells (APCs) display specific peptide major histocompatibility complexes (MHC) on their surface that can be recognized by the T-cell receptors (TCR) of naïve antigen-specific T cells This first signal is not sufficient for successful activation of T cells[1], and a second synergistic signal provided by interactions of co-stimulatory receptors on T cells is required with their cognate ligands in APCs2. This multiplicity of roles underpins the relevance of the ICOS/ICOS-L signaling pathway and in turn, the tremendous potential of manipulating this costimulatory signal in the development of cancer immunotherapies and in the treatment of autoimmune diseases

Methods

Results

Conclusion