Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA

• Published in: Structure (London) Vol. 31; no. 8; pp. 958 - 967.e3
• Main Authors: Cheung, Timothy C., Atwell, Shane, Bafetti, Lisa, Cuenca, Paulina Delgado, Froning, Karen, Hendle, Jorg, Hickey, Michael, Ho, Carolyn, Huang, Jiawen, Lieu, Ricky, Lim, Stacie, Lippner, David, Obungu, Victor, Ward-Kavanagh, Lindsay, Weichert, Kenneth, Ware, Carl F., Vendel, Andrew C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 03.08.2023; Elsevier
• Subjects: agonist antibody; Animals; Antibodies - metabolism; autoimmune disease; B and T lymphocyte attenuator; BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology; Biophysics; BTLA; Cell Biology; checkpoint inhibitory receptor; herpesvirus entry mediator; Mice; NF-κB inhibition; Receptors, Immunologic - metabolism; T cells; T-Lymphocytes - metabolism; TNFRSF14; checkpoint inhibitory receptor; agonist antibody; B and T lymphocyte attenuator; BTLA; herpesvirus entry mediator; TNFRSF14; NF-κB inhibition; T cells; autoimmune disease
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2023.05.011

B and T lymphocyte attenuator (BTLA) is an attractive target for a new class of therapeutics that attempt to rebalance the immune system by agonizing checkpoint inhibitory receptors (CIRs). Herpesvirus entry mediator (HVEM) binds BTLA in both trans- and cis-orientations. We report here the development and structural characterization of three humanized BTLA agonist antibodies, 22B3, 25F7, and 23C8. We determined the crystal structures of the antibody-BTLA complexes, showing that these antibodies bind distinct and non-overlapping epitopes of BTLA. While all three antibodies activate BTLA, 22B3 mimics HVEM binding to BTLA and shows the strongest agonistic activity in functional cell assays and in an imiquimod-induced mouse model of psoriasis. 22B3 is also capable of modulating HVEM signaling through the BTLA-HVEM cis-interaction. The data obtained from crystal structures, biochemical assays, and functional studies provide a mechanistic model of HVEM and BTLA organization on the cell surface and informed the discovery of a highly active BTLA agonist. [Display omitted] •Structural analysis of mAb complexes with BTLA, a checkpoint inhibitory receptor•Agonist antibody initiates BTLA inhibitory signaling and antagonizes HVEM activation•Cell-based assays and an in vivo model demonstrate the agonistic function of BTLA mAbs•BTLA agonistic antibodies as first-in-class drugs to treat autoimmune diseases Cheung et al. developed a new class of autoimmune disease therapeutics using antibodies that target the checkpoint inhibitory receptor, B and T lymphocyte attenuator (BTLA). The structure of the antibody-BTLA complex reveals a mechanism for the inhibitory action of BTLA that restricts immune cells from causing tissue-damaging inflammation.