Generation of Half-Life Extended Anti-BCMA Bite® Antibody Construct Compatible with Once-Weekly Dosing for Treatment of Multiple Myeloma (MM)

Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of abnormal plasma cells in the bone marrow. Although several treatment options are available, patients frequently develop relapsed/refractory disease leading to significant morbidity and mortality. More effective induction and elimination of residual disease are required for curative treatments. One potential strategy for improving patient outcomes is the use of T cell engaging agents such as BiTE® antibody constructs and CAR-T cells.

The bispecific T cell engager (BiTE®) antibody construct blinatumomab, which targets CD19-positive cells, has demonstrated efficacy in treating certain CD19-positive hematological malignancies. Blinatumomab comprises a single chain variable fragment (scFv) that binds CD19 on B cells and a scFv that targets the T cell CD3 protein. The short serum half-life of blinatumomab necessitates administration by continuous IV infusion to maintain therapeutic serum concentrations. To enable once-weekly dosing, next generation BiTE® antibody constructs have been modified by fusion to an Fc domain to extend half-life.

BCMA, a member of the TNF receptor super family, supports plasma cell survival, and is widely expressed on MM and normal plasma cells. A half-life extended (HLE) anti-BCMA BiTE® was generated and evaluated in vitro, in mouse xenograft models and in non-human primates (NHP). In vitro assays evaluated 1) binding to both human and NHP BCMA and CD3 proteins, and 2) cytotoxicity using human and NHP target and effector cells. The anti-BCMA BiTE® demonstrated picomolar binding affinity and efficacy in cytotoxicity assays. In a mouse xenograft model in which BCMA-positive NCI-H929 cells and human PBMC were co-administered SC, the anti-BCMA HLE BiTE® completely inhibited tumor formation in contrast to vehicle control-treated groups with or without PBMC. BCMA cell surface protein expression was assessed by flow cytometry and observed on NHP bone marrow plasma cells but not on blood or bone marrow B cells. The serum half-life in NHP was 112 hours following a single 15 µg/kg dose. The PK/PD relationship in NHP was subsequently evaluated in a repeat-dose study. To assess elimination of BCMA-positive plasma cells in blood and bone marrow, a sensitive and specific ddPCR-based method was developed. Robust depletion of BCMA mRNA was observed in NHP following anti-BCMA BiTE® treatment, indicating effective elimination of BCMA-positive plasma cells from blood and bone marrow. These results demonstrate that HLE anti-BCMA BiTE® is effective in vitro and in vivo, and may be suitable for once-weekly dosing in MM patients.