Researchers at NYU Langone Health, the Chinese Academy of Sciences, and Zhejiang University have developed a novel bispecific antibody that selectively suppresses autoimmune T cells without broadly weakening the immune system. The engineered protein, published in Cell on June 30, 2025, demonstrated efficacy in three mouse models of autoimmune diseases including Type 1 diabetes, hepatitis, and multiple sclerosis.
Breakthrough in Spatial Biology
The research team discovered that the proximity between T cell receptors (TCRs) and the LAG-3 checkpoint protein is critical for immune regulation. "We discovered that, as a T cell's surface draws close to the MHC-II presenting its TCR trigger molecule, the T cell receptor gets particularly close to LAG-3," said co-first author Jasper Du, a third-year medical student in Dr. Wang's lab. "For the first time, we found that this proximity is central to the ability of LAG-3 to dial back T cell activity."
The mechanism involves LAG-3 loosely attaching to part of the T cell receptor called CD3ε, which disrupts its interaction with Lck, an enzyme crucial for T cell activation. While major histocompatibility complexes (MHC-II) can theoretically attach to both LAG-3 and TCR simultaneously, this occurs infrequently and limits LAG-3's ability to suppress T cell activity.
BiTS: A Targeted Therapeutic Approach
Based on their discovery, the research team designed a bispecific antibody called the LAG-3/TCR Bispecific T cell Silencer (BiTS). This engineered molecule holds LAG-3 and the T cell receptor together more strongly than MHC-II, enforcing proximity to achieve better LAG-3-dependent TCR inhibition.
"Our findings reveal an intricate mechanism that enables a careful treatment approach to T-cell driven autoimmune diseases, which currently lack effective immunotherapies," said co-senior study author Jun Wang, PhD, assistant professor in the Department of Pathology at NYU Grossman School of Medicine.
Preclinical Efficacy Across Multiple Disease Models
In mouse models of Type 1 diabetes, BiTS treatment potently suppressed T cell responses and reduced inflammatory damage to insulin-producing cells (insulitis). The therapy also demonstrated efficacy in autoimmune hepatitis models, where BiTS treatment reduced T cell infiltration and liver damage.
To test the approach across different T cell types, researchers used a mouse model of multiple sclerosis driven by CD4+ T cells, in contrast to the diabetes and hepatitis models primarily driven by CD8+ T cells. Mice treated with short-term, preventive BiTS prior to disease onset showed reduced disease severity by standard measures.
Advantages Over Current Approaches
Current treatments for autoimmune diseases that target T cells broadly weaken the immune system, creating risks for infections and cancer. The BiTS approach offers a more targeted solution by exploiting the spatial requirements of LAG-3 function.
LAG-3 turns off T cells less easily than another checkpoint called PD-1 due to its spatial requirements. This feature makes LAG-3 inhibitors weaker as anti-cancer treatments compared to PD-1-inhibiting antibodies, but potentially better when targeted T cell suppression is required for maximum safety in overactive immune systems.
Commercial Development and Future Directions
NYU Langone Health and its Technology Opportunities & Ventures have formed startup company Remunix Inc., with Dr. Wang as founder, to license and commercialize the patents related to this technology. Dr. Wang, Du, and You are listed as inventors of pending patents related to the study.
"Our study advances our understanding of LAG-3 biology and may foster more proximity-based, spatially-guided therapeutic designs like BiTS as immunotherapy for other human diseases," said co-first author Jia You, a research scientist in Dr. Wang's lab.
The study was supported principally by a translational advancement award from the Judith and Stewart Colton Center for Autoimmunity at NYU Langone Health, along with multiple NIH grants and National Science Foundations of China grants. The research represents a significant advance in understanding checkpoint biology and offers a promising new approach for treating autoimmune diseases through spatially-guided immunotherapy.
