Dual-component CAR T cell therapy: targeting BCMA with convertible CAR and MicAbodies

Abstract

Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have demonstrated considerable therapeutic advantages in treating multiple myeloma (MM) patients, increasing progression-free survival and overall survival compared to standard-of-care regimens. However, many patients still experience cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS), long-term cytopenias, B cell aplasia, and hypogammaglobulinemia, with the majority ultimately facing relapse within five years of treatment. A dual-component system comprising convertibleCAR (cCAR) T cells and MicAbodies (MAs), which bridge the cancer target to cCAR T cells to elicit a cytotoxic response, was used to assess platform flexibility by formatting MAs and evaluating their binding affinity, hydrophobicity, polyreactivity, cytotoxicity against MM cell lines, and susceptibility to inhibition by soluble BCMA (sBCMA). In vivo efficacy of the lead molecule was also assessed in a disseminated multiple myeloma tumor model. The study generated a panel of 15 MAs from three clones, revealing that clones B8 and B3 exhibited superior cytotoxicity and greater retained activity in the presence of sBCMA compared to clone B4, particularly in specific formats. In vivo administration of B8 LCm with cCAR T cells reduced tumor burden relative to untreated and untransduced T-cell control groups in a BCMA+ multiple myeloma model. The modularity and flexibility of the cCAR platform, along with the optimization of MA formats and clones, has the potential to enhance functional tuning of CAR T cell therapies, which may support improved efficacy and safety.