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Reinforced antimyeloma therapy via dual-lymphoid activation mediated by a panel of antibodies armed with bridging-BiTE

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 CD38^low 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.

References:

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