Researchers at Sanford Burnham Prebys and scientists from Eli Lilly and Co., have revealed the structure and function of a drug called LY3361237, which can reduce the harmful activity of the immune system to help treat autoimmune diseases.

Their findings laid the foundation for a new treatment that’s currently in a Phase II clinical trial for lupus, and is published in Structure in an article titled, “Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA.”

“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),” wrote the researchers. “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.”

“It’s miraculous that we can change the activity of the immune system with drugs, but we’re still at an incredibly early stage in terms of figuring out how this works,” said professor Carl Ware, PhD. “The drug we describe in this study is an antibody that has shown promise in initial clinical trials, but understanding how it works on a molecular level will help scientists discover even more ways to modify the immune system to treat autoimmune diseases.”

“Immunological disorders are a major unmet medical need,” added Ware. “Some can be managed effectively, but most of these diseases have limited treatment options, so many people just have to learn to live with the symptoms.”

The newly published findings are the culmination of a collaboration between Sanford Burnham Prebys and Eli Lilly and Co. Their goal was to find a way to temper the activity of the immune system in autoimmune diseases. They were able to discover that LY3361237 can rebalance the immune system to prevent it from attacking the body.

“LY3361237 is the first antibody drug that’s known to increase the activity of BTLA to inhibit the immune system, which means it has extraordinary potential as a therapy for autoimmune diseases,” said Ware.

The drug produced by Lilly entered a Phase I clinical trial in healthy subjects in 2018, and began recruiting patients with lupus for a Phase II trial in 2021. This trial will evaluate the efficacy and safety of the new treatment and is expected to be completed in two to four years.

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