Biophysical characterization of PVR family interactions and therapeutic antibody recognition to TIGIT

ABSTRACT

The clinical successes of immune checkpoint blockade have invigorated efforts to activate T cell-mediated responses against cancer. Targeting members of the PVR family, consisting of inhibitory receptors TIGIT, CD96, and CD112R, has been an active area of clinical investigation. In this study, the binding interactions and molecular assemblies of the PVR family receptors and ligands have been assessed in vitro. Furthermore, the anti-TIGIT monoclonal antibody BMS-986207 crystal structure in complex with TIGIT was determined and shows that the antibody binds an epitope that is commonly targeted by the CD155 ligand as well as other clinical anti-TIGIT antibodies. In contrast to previously proposed models, where TIGIT outcompetes costimulatory receptor CD226 for binding to CD155 due to much higher affinity (nanomolar range), our data rather suggest that PVR family members all engage in interactions with relatively weak affinity (micromolar range), including TIGIT and CD155 interactions. Thus, TIGIT and other PVR inhibitory receptors likely elicit immune suppression via increased surface expression rather than inherent differences in affinity. This work provides an improved foundational understanding of the PVR family network and mechanistic insight into therapeutic antibody intervention.

KEYWORDS:

• Antibody
• biophysics
• immunology
• oncology
• receptor–ligand interactions

Acknowledgments

The authors thank Olin Chang, Amanda Rhea, Megan Smith, Julie Zorn, and Bryant Chau for reagents, technical advice, and scientific discussions. The authors thank Steven Sheriff, Jodi Muckelbauer, and the staff at the IMCA-CAT at the Argonne National Laboratory for assistance in x-ray data collection and beamline support.

Disclosure statement

All authors are current or former employees of Bristol Myers Squibb.

Abbreviations

ADCC	=	antibody-dependent cellular cytotoxicity
Cα-RMSD	=	Cα-root-mean-square deviation
CDRs	=	complementarity-determining regions
Fab	=	fragment antigen binding
Fc	=	fragment crystallizable
IgG	=	immunoglobulin G
ITIM	=	immunoreceptor tyrosine-based inhibitory
ITT	=	immunoreceptor tyrosine tail
NK	=	natural killer cell
NRC	=	National Research Council of Canada
PVR	=	poliovirus receptor
RU	=	response unit
SEC-MALS	=	size exclusion chromatography with multi-angle light scattering
SPR	=	surface plasmon resonance
T-fh	=	follicular T helper cell
TIL	=	tumor-infiltrating lymphocyte
T-reg	=	regulatory T cell

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2023.2253788

Additional information

Funding

The author(s) reported that there is no funding associated with the work featured in this article.