Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA

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.

doi:10.1016/j.str.2023.05.011

Title: Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA

Journal Article · Sun Jun 04 20:00:00 EDT 2023 · Structure

DOI: https://doi.org/10.1016/j.str.2023.05.011 · OSTI ID:2423419

Cheung, Timothy C. ^[1]; Atwell, Shane ^[2]; Bafetti, Lisa ^[3]; Cuenca, Paulina Delgado ^[1]; Froning, Karen ^[3]; Hendle, Jorg ^[3]; Hickey, Michael ^[3]; Ho, Carolyn ^[3]; Huang, Jiawen ^[1]; Lieu, Ricky ^[3]; Lim, Stacie ^[1]; Lippner, David ^[4]; Obungu, Victor ^[4]; Ward-Kavanagh, Lindsay ^[1]; Weichert, Kenneth ^[3];

^[1]; Vendel, Andrew C. ^[3]

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (United States)
Eli Lilly and Company, San Diego, CA (United States); Discovery Biology, San Diego, CA (United States)
Eli Lilly and Company, San Diego, CA (United States)
Eli Lilly and Company, Indianapolis, IN (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357

OSTI ID:: 2423419

Journal Information:: Structure, Journal Name: Structure Journal Issue: 8 Vol. 31; ISSN 0969-2126

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
B and T lymphocyte attenuator
BTLA
Biochemistry & Molecular Biology
Biophysics
Cell Biology
NF-κB inhibition
T cells
TNFRSF14
agonist antibody
autoimmune disease
checkpoint inhibitory receptor
herpesvirus entry mediator

Title: Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA

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