New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abstract

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent an unmet clinical need whose prognosis is still dismal. Alterations of immune response play a prominent role in AML/MDS pathogenesis, revealing novel options for immunotherapy. Among immune system regulators, CD47, immune checkpoints, and toll-like receptor 2 (TLR2) are major targets. Magrolimab antagonizes CD47, which is overexpressed by AML and MDS cells, thus inducing macrophage phagocytosis with clinical activity in AML/MDS. Sabatolimab, an inhibitor of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which disrupts its binding to galectin-9, has shown promising results in AML/MDS, enhancing the effector functions of lymphocytes and triggering tumor cell death. Several other surface molecules, namely CD33, CD123, CD45, and CD70, can be targeted with monoclonal antibodies (mAbs) that exert different mechanisms of action and include naked and conjugated antibodies, bispecific T-cell engagers, trispecific killer engagers, and fusion proteins linked to toxins. These novel mAbs are currently under investigation for use as monotherapy or in combination with hypomethylating agents, BCL2 inhibitors, and chemotherapy in various clinical trials at different phases of development. Here, we review the main molecular targets and modes of action of novel mAb-based immunotherapies, which can represent the future of AML and higher risk MDS treatment.

A Bioinformatics View on Acute Myeloid Leukemia Surface Molecules by Combined Bayesian and ABC Analysis

“…As the focus of our work was more closely related to potential diagnostic applications, the following discussion primarily refers to current experimentally confirmed knowledge on CD gene expression in AML. Yet, clinical implications are clearly emerging as a future perspective, given the growing spectrum of monoclonal antibodies targeting AML and related myeloid diseases [ 71 ].…”

“…Novel treatment options for AML cases with an unfavorable prognosis are highly demanded and monoclonal antibodies that target AML surface molecules are currently evaluated in clinical trials ([ 71 , 77 ]). Although we do not have detailed information on cytogenetics or survival in both of our datasets, our study reveals potential target molecules, particularly if AML1 is indeed a stem cell near a subgroup with inferior prognosis.…”

How Azanucleosides Affect Myeloid Cell Fate

“…Indeed, the efficacy of this combination is such that it has already become standard of care for elderly or unfit AML patients [ 51 ]. Both nivolumab and magrolimab follow a complementary approach by inhibiting immune escape signals that are expressed on HMA resistant cells, thus restoring their susceptibility to immune attack [ 54 ].…”

EGCG Prevents the Transcriptional Reprogramming of an Inflammatory and Immune-Suppressive Molecular Signature in Macrophage-like Differentiated Human HL60 Promyelocytic Leukemia Cells

“…Despite significant improvements in leukemia management and diagnosis, inflammatory response mediating its crosstalk with immune function reveals clinical features in AML, which still require new therapeutic options [ 10 ]. Among those, monoclonal antibodies-based immunotherapies have recently emerged and appear to represent the future of AML treatment [ 11 ]. Here, the use of a tumorigenic HL60 cell line, isolated from the peripheral blood tissue of a 36-year-old female patient [ 12 ], has proven to be a potent model for studies of human myeloid cell differentiation and differentiation in general [ 13 ].…”