T-Cell Engagers in Acute Myeloid Leukemia: Molecular Targets, Structure, and Therapeutic Challenges

The treatment of acute myeloid leukemia (AML) remains challenging, largely due to high relapse rates following standard therapies. T-cell engagers (TCEs) offer a promising immunotherapeutic approach by redirecting T cells to recognize and kill AML cells. These therapeutic proteins bind CD3 to T cells and a tumor-associated antigen to AML cells, facilitating targeted immune activation. While CD33 and CD123 are the most commonly targeted AML antigens, others such as CD135, CD38, and CLEC12A/CLL-1 are being evaluated in preclinical and clinical studies. In parallel, various TCE formats—including BiTEs, DuoBodies, DARTs, and DARPin-based constructs—have been developed to optimize pharmacokinetics, stability, and immune engagement. Despite the growing number of TCEs entering clinical evaluation, none have advanced beyond early Phase (I/II) trials, primarily due to the lack of optimal target antigens and challenges in balancing antileukemic activity with the risks of immune-related toxicities such as cytokine release syndrome (CRS). This review aims to summarize the current landscape of TCE development in AML, highlighting key targets, formats, and challenges.