TARGETING MESOTHELIN IN PEDIATRIC ACUTE MYELOID LEUKEMIA WITH DUAL ANTIBODY-COATED POLY(LACTIC-CO-GLYCOLIC ACID) NANOPARTICLES
Date
2025-05
Authors
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Publisher
University of Delaware
Abstract
Acute myeloid leukemia (AML) is a rare but aggressive cancer, accounting for
approximately seven new cases per 1 million children annually. It arises from the
malignant transformation of hematopoietic stem and progenitor cells, leading to an
accumulation of immature, nonfunctional myeloblasts in the bone marrow. Standard
treatments, such as chemotherapy and stem cell transplantation, have high relapse rates
and significant toxicity, emphasizing the need for more effective therapies.
Immunotherapy has emerged as a promising treatment strategy, however, specific
targeting of AML cells and maintaining extended circulation times of administered
agents remain major challenges. Mesothelin (MSLN) has been identified as an attractive
immunotherapeutic target that is overexpressed in one-third of young adult and pediatric
AML patients with limited expression in normal bone marrow.
Here, we report the design, characterization, and validation of dual antibody coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (duNPs) that recruit T
lymphocytes to AML to induce specific cytotoxicity of AML cells. PLGA NPs were
coated with anti-MSLN (Amatuximab) and anti-CD3 antibodies (OKT3) and
characterized for size, charge, and concentration. Microscopy analysis revealed duNPs
pull T lymphocytes and MSLN-expressing NOMO-1 cells into clusters to induce
cytotoxicity. Additionally, the duNPs facilitated significantly higher T cell activation
compared to bare NPs, as confirmed by elevated CD69 levels, suggesting the duNPs
successfully engage T cells. To evaluate the efficacy of duNPs in promoting T cell
induced killing of AML cells, the T cells were incubated with AML cells and treated
with increasing amounts of bare NPs or duNPs for 16 hours before assessing cell
viability. duNP treatment selectively killed AML cells in a dose-dependent manner
compared to bare NPs. Collectively, our data suggest that dual antibody-coated NPs are
effective agents to recruit T lymphocytes to MSLN-expressing AML cells, increase T
cell activation, and induce AML cell death.