| Affiliations | Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Biotechnology Discovery Research, Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA; Immunology Discovery Research, Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA; Biotechnology Discovery Research, Eli Lilly and Company, Indianapolis, IN 46225, USA; Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: cware@sbpdiscovery.org; Immunology Discovery Research, Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA. Electronic address: vendelac@lilly.com. | |
| Abstract | 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. | |