Weekly BCMA BiTE Antibody for Multiple Myeloma Therapy

Multiple myeloma (MM) is a cancer of the blood characterized by the build-up of abnormal plasma cells in the bone marrow. Despite existing treatments, patients often experience relapses or develop resistance, leading to high morbidity and mortality rates. There is a need for more effective strategies to induce remission and eliminate residual disease for a chance at cure. One such strategy involves T cell-engaging agents, like BiTE antibody constructs and CAR-T cells.

Blinatumomab, a BiTE antibody construct that targets CD19, has shown promise in CD19-positive hematological malignancies. It consists of two single-chain variable fragments (scFvs), one binding CD19 on B cells and the other CD3 on T cells. However, blinatumomab's short half-life requires continuous IV infusion, prompting the development of next-generation BiTE constructs with an Fc domain to extend their duration in the body.

BCMA, a TNF receptor superfamily member that supports plasma cell survival, is widely present on MM and normal plasma cells. A half-life extended (HLE) anti-BCMA BiTE was developed and tested in vitro, in mouse xenograft models, and in non-human primates (NHP). The HLE anti-BCMA BiTE showed high binding affinity and cytotoxicity efficacy in vitro. In a mouse xenograft model with BCMA-positive NCI-H929 cells, the HLE anti-BCMA BiTE completely prevented tumor formation.

BCMA expression was confirmed on NHP bone marrow plasma cells but not on blood or bone marrow B cells. The BiTE's serum half-life in NHP was 112 hours after a single dose, and its PK/PD relationship was evaluated in a repeat-dose study. A ddPCR-based method was developed to assess the elimination of BCMA-positive plasma cells, and the treatment led to a significant reduction of BCMA mRNA, indicating effective plasma cell elimination from blood and bone marrow.

The results suggest that the HLE anti-BCMA BiTE is effective both in vitro and in vivo and could potentially be administered once a week to MM patients.

Several disclosures related to employment and equity ownership in Amgen were made by the authors Goyos, Li, Deegen, Bogner, Thomas, Matthias, Wahl, Goldstein, Coxon, Balazs, and Chapman-Arvedson.