D2.463 - Development of a novel anti-CD19 x BCMA dual targeted T cell engager for the treatment of autoimmune diseases and B cell malignancies

B cells and autoantibodies play a central role in the pathogenesis of numerous autoimmune diseases. Although CD19-targeted B cell depletion has demonstrated considerable therapeutic potential, its widespread use is limited by the pharmacokinetic (PK) limitations of BLINCYTO and the substantial expenses associated with CAR-T treatments. Moreover, targeting B cells or plasma cells alone is insufficient to eliminate both pathogenic B cells and autoantibody production. To overcome these challenges, we engineered HXN-1031, an innovative trispecific T cell engager (TCE) capable of dual targeting CD19 and BCMA. This approach seeks to establish a transformative treatment strategy for autoimmune conditions.

Affinity, cell-binding and cytotoxicity were evaluated in vitro. In vivo efficacy was investigated in mice bearing CD19⁺ or BCMA⁺ tumor cells, and in non-human primates.

HXN-1031 has sub-micromolar CD3 affinity and nanomolar CD19/BCMA affinity. Against CD19⁺ target cells, it showed weaker potency (IC50) but similar maximum killing efficacy versus Blinatumomab, with significantly reduced T cell activation and cytokine release. In contrast, HXN-1031 showed high cytotoxic potency against BCMA⁺ targets in vitro. In mixed cell populations, HXN-1031 efficiently and simultaneously eliminated both CD19⁺ and BCMA⁺ cells while maintaining moderate levels of T cell activation and cytokine production. By comparison, CD19-TCE and BCMA-TCE selectively eliminated CD19⁺BCMA⁻ B cells or CD19⁻BCMA⁺ H929 cells, respectively. In vivo, HXN-1031 exhibited superior antitumor efficacy compared with blinatumomab in CD19⁺ tumor models and significantly inhibited BCMA⁺ tumor growth, achieving efficacy comparable to a teclistamab analogue. In non-human primates, HXN-1031 induced potent and sustained depletion of B cells and plasma cells in both peripheral blood and bone marrow, resulting in a prolonged and marked reduction in serum immunoglobulin levels. 

HXN-1031 is a novel trispecific T cell engager with finely tuned activity, designed to reset immune homeostasis through the concurrent depletion of pathogenic B cells and plasma cells. These results highlight its strong potential as a therapeutic modality for a broad range of B cell- and plasma cell–driven autoimmune diseases and malignancies.