Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment

Abstract

We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3 T cell/myeloma cell crosslinking, followed by CD4/CD8 T cell activation, and secretion of interferon-γ, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA cells in cynomolgus monkeys. Pharmacokinetics and pharmacodynamics indicate weekly intravenous/subcutaneous administration.

B cell maturation antigen‐specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta‐analysis

“…B cell maturation antigen (BCMA) or CD269 is a cell surface receptor expressed primarily by plasma cells and its function is to maintain long‐lived plasma cell homeostasis . BCMA is expressed consistently on MM cell lines and primary patient samples, though intensity of expression is variable . BCMA is not expressed by hematopoietic stem cells or nonhematologic cells .…”

“…13 BCMA is expressed consistently on MM cell lines and primary patient samples, though intensity of expression is variable. [14][15][16] BCMA is not expressed by hematopoietic stem cells or nonhematologic cells. 15,17 BCMA is shed from the surface of plasma cells by gamma secretase-mediated cleavage, 18 resulting in a soluble form that can be detected in peripheral blood with higher concentrations of soluble BCMA being associated with poorer clinical outcomes in patients with myeloma.…”

Preclinical development of anti-BCMA immunotoxins targeting multiple myeloma

“…B-cell maturation antigen (BCMA), a member of the tumor necrosis receptor superfamily, is a lineage-restricted differentiation antigen present on normal and malignant plasma cells [6]. Given its high expression on malignant plasma cells and lack of expression on essential organs, BCMA is an attractive target for treatment of MM [7].…”

A new perspective: Exploring future therapeutic strategies for cancer by understanding the dual role of B lymphocytes in tumor immunity

“…This proposal notion is novel and seems to be a promising approach to eliciting specific B‐cell responses against tumor antigens. Moreover, a recent study constructed a bispecific Ab (EM801) based on IgG and BCMA‐T cell to induce myeloma cell death. And it could increase CD3 + T cell/myeloma cell cross‐linking to activate CD4 + /CD8 + T cell and to promote the secretion of IFN‐γ, GrB, and perforin.…”