Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia

Abstract

Purpose of review: Bispecific antibodies combine antigen recognition sites from two or more antibodies into a single construct allowing simultaneous binding to multiple targets. Bispecific antibodies exist which can redirect immune effector cells against acute myeloid leukemia (AML) targets. This review will highlight the progress to date and the challenges in developing bispecific antibodies for the treatment of AML.

Recent findings: Currently, a number of bispecific antibody formats including bispecific T cell engagers, dual affinity retargeting proteins, and tandem diabodies are in clinical development for AML. These antibodies target antigens present on AML blasts, including CD33, and the low affinity IL3 receptor, CD123. T cell redirecting bispecific antibodies in early phase clinical trials for AML include AG330, flotetuzumab, JNJ-63709178, and AMV564. Bispecific antibodies represent a promising immunotherapeutic approach for the treatment of cancer. The results of ongoing studies in AML will elucidate the potential for these agents in AML.

Keywords: Acute myeloid leukemia; Bispecific T cell engager; Bispecific antibody; Dual affinity retargeting protein.

Figure 1

(A) Bispecific antibody constructs. Single chain variable fragments (scFv) are derived from the Fab fragment of the IgG immunoglobulin and are composed of the VH and VL domains attached with a linker. Bi-specific T-cell engagers (BiTEs) consist of two scFVs, one directed against T-cell antigen and one against a chosen tumor antigen, connected via a single chain linker. Tandem diabodies (TandAbs) combine two scFVs for each target connected with a single polypeptide target. This allows them to maintain the avidity of a bivalent antibody as well as have a molecular weight that exceeds the renal clearance threshold. Dual affinity retargeting antibodies (DARTs) consist of variable domains of two antigen-binding specificities linked to two independent polypeptide chains. Each variable domain is formed by associating one VL segment on one chain with a VH segment on a second chain. The chains are covalently linked via disulfide bridge. (B) Mechanisms of action. Bi-specific antibodies have variable fragments with affinities for both a selected tumor associated antigen (TAA) as well as a selected target on an effector immune cell. Bi-specific T-cell engagers (BiTEs) bind to both TAA as well as the T-cell receptor CD3. Bi-specific killer cell engagers (BiKEs) bind a TAA with an NK cell antigen, usually CD16. Binding between effector cells and tumor cells facilitates the formation of cytolytic synapses leading to tumor cell destruction.