Background/Purpose: B cells and autoantibodies play a central role in the pathogenesis of various autoimmune diseases. Although CD19-targeted B cell depletion shows promising therapeutic potential, its clinical application is limited by the pharmacokinetic (PK) limitations of BLINCYTO and the high costs associated with CAR-T therapies. 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.

Methods: The 1+1+1 format trispecific antibody targeting CD19, BCMA, and CD3 was designed and optimized to meet both activity and druggability criteria. The binding affinity of each arm to its respective target was measured using FACS, while its cytotoxic activity was evaluated in pan-T cell cultures containing CD19⁺, BCMA⁺, or mixed cell populations. In vivo stability was examined in SD rats, and in vivo efficacy was assessed in PBMC-reconstituted mice bearing Raji (CD19⁺) or H929 (BCMA⁺) tumor cells.

Results: HXN-1031 exhibits sub-micromolar affinity for CD3 while maintaining nanomolar binding affinity for CD19 and BCMA. The trispecific TCE showed a maximum CD19-positive tumor cell-killing efficacy that is comparable to Blinatumomab and other clinical stage benchmarks, while inducing lower T cell activation and cytokine release. On the other end, HXN-1031 showed high potency in in vitro cytotoxicity assays across tumor cells with varying BCMA expression, exhibiting efficacy comparable to the benchmarks. Moreover, it effectively kills both CD19-positive and BCMA-positive cells simultaneously within a mixed cell population while maintaining moderate T cell activation and cytokine release. In contrast, CD19 TCE and BCMA TCE selectively target only B cells or H929 (CD19-BCMA⁺) cells, respectively. In animal models, HXN-1031 demonstrates good in vivo stability and, as a result, exhibits superior efficacy to Blinatumomab in a CD19-positive tumor model when administered twice per week. HXN-1031 significantly suppresses BCMA-positive tumor growth, showing comparable efficacy to Teclistamab analogue. Additionally, HXN-1031 showed potent efficacy in depleting B cells and plasma cells in cynomolgus monkeys.

Conclusion: HXN-1031 is an innovative T cell engager with finely tuned activity against both CD19 and BCMA, designed to reset the immune system by simultaneously depleting pathogenic B cells and plasma cells. It holds great potential to significantly enhance the clinical efficacy, with the possibility of even curing certain autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-a-noval-111-cd19-and-bcma-dual-targeted-t-cell-engager-for-autoimmune-diseases/