Current State of the Art and Prospects of T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma

Abstract

Multiple myeloma (MM) patients eventually develop multi-drug-resistant disease with poor survival. Hence, the development of novel treatment strategies is of great importance. Recently, different classes of immunotherapeutic agents have shown great promise in heavily pre-treated MM, including T cell-redirecting bispecific antibodies (BsAbs). These BsAbs simultaneously interact with CD3 on effector T cells and a tumor-associated antigen on MM cells, resulting in redirection of T cells to MM cells. This leads to the formation of an immunologic synapse, the release of granzymes/perforins, and subsequent tumor cell lysis. Several ongoing phase 1 studies show substantial activity and a favorable toxicity profile with BCMA-, GPRC5D-, or FcRH5-targeting BsAbs in heavily pre-treated MM patients. Resistance mechanisms against BsAbs include tumor-related features, T cell characteristics, and impact of components of the immunosuppressive tumor microenvironment. Various clinical trials are currently evaluating combination therapy with a BsAb and another agent, such as a CD38-targeting antibody or an immunomodulatory drug (e.g., pomalidomide), to further improve response depth and duration. Additionally, the combination of two BsAbs, simultaneously targeting two different antigens to prevent antigen escape, is being explored in clinical studies. The evaluation of BsAbs in earlier lines of therapy, including newly diagnosed MM, is warranted, based on the efficacy of BsAbs in advanced MM.

Keywords: BCMA; CD38; FcRH5; GPRC5D; bispecific antibody; multiple myeloma.

Figure 1

A schematic overview of different formats of bispecific antibodies used to initiate redirected lysis of multiple myeloma cells by T cells. Bispecific antibodies (BsAbs) bind simultaneously with one arm to CD3 expressed on T cells and with the other arm to a tumor-associated antigen (TAA) on the MM cell surface. This includes BCMA, CD38, FcRH5, and GPRC5D. The interaction leads to activation and degranulation of T cells (release of granzymes/perforins) and subsequent lysis of MM cells. (A,B) Next to the bivalent IgG-like BsAbs, bispecific T cell engagers (BiTEs) and trivalent IgG-like trispecific antibodies (TsAbs) are also able to mediate T cell-dependent lysis of MM cells. (A) (1) An Fc domain that connects two antigen-binding domains in IgG-like BsAbs and TsAbs. (A) (2) T cell binding domain that consists of an scFv with a monovalent binding site for CD3. (A) (3) Tumor cell-binding domain that consists of an scFv with a monovalent binding site for MM-associated antigen. (B) (1) A bispecific T cell engager (BiTE) that is comprised of two different scFvs connected with a peptide linker (e.g., AMG420). (B) (2) A bivalent IgG-like BsAb comprised of an Fc domain and two monovalent binding domains. (B) (3) A trivalent IgG-like TsAb comprised of an Fc domain and three monovalent binding domains including a binding domain for a third antigen (e.g., CD28).

Figure 2

A schematic overview of different resistance mechanisms that impair BsAb-induced T cell-mediated lysis of MM cells. BMSC = Bone marrow stromal cell; MDSC = Myeloid-derived suppressor cell; MM cell = Multiple myeloma cell; Treg = regulatory T cell.