BiTEs, DARTS, BiKEs and TriKEs-Are Antibody Based Therapies Changing the Future Treatment of AML?

Abstract

Nearly four decades after their conceptualization, antibody-based therapies are slowly being added to the treatment landscape of acute myeloid leukemia (AML). While the antibody-drug conjugate gemtuzumab ozogamicin is the only antibody-based therapy that has been approved for AML treatment thus far, several bispecific antibodies have been developed and shown early encouraging results. Bispecific antibodies comprise a wide variety of constructs that share the common concept of simultaneous binding of a surface target on malignant cells and most commonly CD3 on T cells leading to an endogenous, HLA-independent, immune response against malignant cells. However, the use of bispecific antibodies in AML has been limited by the absence of highly specific leukemia-associated antigens leading to on-target, off-leukemia side effects as well as reduced efficacy due to antigen escape. Herein, we discuss the history and evolution of bispecific T cell engagers as well as various adaptations such as dual affinity retargeting antibodies, bi- and tri-specific killer engager antibodies. Common side effects including cytokine release syndrome and management thereof are highlighted. Lastly, we expound on the future direction and integration of such antibody-based therapies with other immunotherapies (programmed cell death-1 inhibitors and chimeric antigen receptor T cells).

Keywords: AML; BiTE; DART; acute myeloid leukemia; bispecific antibody; safety.

Figure 1

(A) Mechanism of action and basic construct of various bispecific antibodies. Bispecific antibodies consist of a single heavy and light chain of the variable region of a tumor-associated antigen (e.g., CD33 or CD123; shown as yellow and orange squares) and CD3 (illustrated as light and dark blue squares) leading to the formation of a cytolytic synapse between T-cells and leukemic blasts. (B) In their basic construct, these bispecific T-engaging antibodies (BiTEs) are connected by a linker molecule, which defines the flexibility of the construct and antigen-binding kinetics in conjunction with the specific antigens used. (C) Dual-affinity re-targeting molecules (DARTs) have a similar basic structure but include a disulfide linker for additional stability. (D) Bispecific (BiKEs) and (E) trispecific killer cell engagers (TriKEs) consist of either two (BiKE) or three (TriKE) variable antigen regions and activate natural killer cells either by binding to IL16 or containing an IL15 linker (yellow rectangle in (D)).