Researchers from Ehime University in Japan have developed a new bispecific T-cell engager (BiTE), known as briding-BiTE (B-BiTE) which provide two specific binding sites for a tumor antigen of interest as opposed to one (used in traditional mAb therapy). Using in vitro and in vivo experiments, the authors demonstrate that B-BITEs have the potential to serve as a new modality for strengthening antimyeloma responses via dual-lymphoid activation. Overall, this approach is particularly significant for improving immunotherapy in conditions like multiple myeloma (MM) and other difficult-to-treat blood cancers.
In recent decades, advancements in therapeutic approaches for MM have included the use of mAbs in combination with immunomodulatory drugs. The development of next-generation immunotherapy, such as chimeric antigen receptor (CAR)-redirected T cells and bispecific antibodies targeting GPRC5D and BCMA, has shown clinical promise in drug-resistant MM. However, applicability and difficulties in targeting the heterogeneous myeloma cell population have proven challenging. Thus, the development of B-BiTEs has allowed concurrent activation of T and NK cells against myeloma cells. B-BiTEs, binding to both IgG-Fc domains and CD3 molecules, form complexes and induce dual-lymphoid activation. This study explored the efficacy and safety of B-BiTEs and demonstrated that mAb/B-BiTE complexes successfully activate T and NK cells against target cells.
The authors first characterized efficacy and safety of the mAb/B-BiTE complex in vitro by testing the proliferation capacity of activated T cells using rituximab/B-BiTE and daratumumab/B-BiTE, which are clinically available mAbs armed with B-BiTEs. Robust proliferation of both CD8+ and CD4+ T cells upon recognition of CD20+ and CD38+ target cells in the presence of rituximab/B-BiTE and daratumumab/B-BiTE was observed, respectively. Additionally, the frequency of regulatory T cells in the activated CD4+CD25+ T-cell population did not increase. The complexes also show stability in vivo, preserving NK cell reactivity even at higher concentrations of B-BiTEs. Additionally, the mAb/B-BiTE complexes exhibit enhanced antimyeloma effects, particularly against cells with varying levels of target antigens. In vivo experiments in a CD38low tumor mouse model, as a model of resistance to daratumumab, revealed that the combination of daratumumab/B-BiTE and elotuzumab/B-BiTE effectively suppresses tumor growth. Overall, these findings demonstrate the potential of this bispecific antibody strategy in treating heterogeneous myeloma cells.
Konishi T, Ochi T, Maruta M, et al. Reinforced antimyeloma therapy via dual-lymphoid activation mediated by a panel of antibodies armed with bridging-BiTE. Blood. 2023;142(21):1789-1805. https://doi.org/10.1182/blood.2022019082
Lucca LE. Multiple myeloma treatment: one bridge closer. Blood. 2023;142(21):1763-1764. https://doi.org/10.1182/blood.2023022470
Tags: bispecific t cell engagers, BiTEs, CART, Care