开发一种新型抗CD19 x BCMA双靶向T细胞衔接器,用于治疗自身免疫性疾病和B细胞恶性肿瘤

Rationale B cells and autoantibodies drive the progression of autoimmune diseases. Targeting B cells or plasma cells alone is often insufficient to eliminate both pathogenic B cells and autoantibody. Here, we generated HXN-1031, a novel trispecific T cell engager (TCE), simultaneously targeting CD19 and BCMA. Methods 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. Results HXN-1031 has sub-micromolar CD3 affinity and nanomolar CD19/BCMA affinity. Against CD19⁺ targets, it showed weaker potency (IC50) but similar maximum killing efficacy versus Blinatumomab, with significantly reduced T cell activation and cytokine release. For BCMA, HXN-1031 shows high potency in in vitro cytotoxicity. HXN-1031 effectively kills both CD19⁺ and BCMA⁺ cells simultaneously within a mixed cell population while maintaining moderate T cell activation and cytokine release. In contrast, CD19-TCE and BCMA-TCE only selectively target B cells (CD19 + BCMA - ) or H929 (CD19 - BCMA + ) cells, respectively. In vivo, HXN-1031 demonstrated superior efficacy to Blinatumomab against CD19⁺ tumors, and significantly suppressed BCMA⁺ tumor growth, matching Teclistamab analogue efficacy. In non-human primates, HXN-1031 potently depleted, both in peripheral and bone marrow, B cells and plasma cells, leading to significantly reduced serum immunoglobulin, for a prolonged period of times. Conclusion HXN-1031 is an innovative TCE with finely tuned activity, designed to reset immune system by simultaneously depleting pathogenic B cells and plasma cells. It holds great potential in the treatment of various B cell and plasma cell related autoimmune diseases and malignancies.