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).
Highlights
chimeric antigen receptor (CAR) T cell therapies are in development for myeloid malignancies, but their use has been limited by on-target off-leukemia effects
The rationale for using TIM3 as a target is its higher expression on exhausted T cells and leukemic stem cells (LSCs) compared to normal hematopoietic stem cells (HSCs), which reduced the cytotoxicity of CAR T cells in vivo [93,94]
While downregulation of target antigens has been documented in CD19-directed CAR T-cells and with blinatumomab, this has not been observed with bispecific antibodies in Acute myeloid leukemia (AML) far, but additional studies with longer follow up are needed [40,105,106]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Due to the poor prognosis of AML with a 5-year survival of only 28.7% [6], and difficulty of achieving a durable complete remission without allo-HCT, additional treatment options are warranted. Both molecularly targeted treatments and immunotherapies can be administered in parallel with chemotherapy or used alone for patients with relapsed or refractory (R/R) disease [7,8,9,10]. Bispecific T cell engagers (BiTEs) were one of the first antibody-based leukemia therapies engineered, with the anti-CD3 × CD19 antibody blinatumomab being the first agent in this class to have garnered FDA approval for the treatment of acute lymphoblastic leukemia (ALL) [11,12]. A detailed review of the immunologic background would be beyond the scope of this review and we would like to refer the reader to previously published excellent reviews on the immunology and construct design [13]
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