Reinforced anti-myeloma therapy via dual-lymphoid activation mediated by a panel of antibodies armed with Bridging-BiTE.

Immunotherapy using bispecific antibodies including bispecific T-cell engager (BiTE) has the potential to enhance the efficacy of treatment for relapsed/refractory multiple myeloma. However, myeloma may still recur after treatment due to downregulation of a target antigen and/or myeloma cell heterogeneity. To strengthen immunotherapy for myeloma while overcoming its characteristics, we have newly developed a BiTE-based modality, referred to as Bridging-BiTE (B-BiTE). B-BiTE was able to bind to both a human IgG-Fc domain and the CD3 molecule. Clinically available monoclonal antibodies (mAbs) were bound with B-BiTE prior to administration, and the mAb/B-BiTE complex induced antitumor T-cell responses successfully while preserving and supporting NK-cell reactivity, resulting in enhanced anti-myeloma effects via dual-lymphoid activation. In contrast, any unwanted off-target immune-cell reactivity mediated by mAb/B-BiTE complexes, or B-BiTE itself, appeared not to be observed in vitro and in vivo. Importantly, sequential immunotherapy using two different mAb/B-BiTE complexes appeared to circumvent myeloma cell antigen escape, and further augmented immune responses to myeloma relative to those induced by mAb/B-BiTE monotherapy or sequential therapy with two mAbs in the absence of B-BiTE. Therefore, this modality facilitates easy and prompt generation of a broad panel of bispecific antibodies that can induce deep and durable antitumor responses in the presence of clinically available mAbs, supporting further advancement of reinforced immunotherapy for multiple myeloma and other refractory hematological malignancies.