Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Current immunotherapies for acute myeloid leukemia (AML) and other cancers face limitations due to the scarcity of tumor-specific targets.
• Cell surface RNA-binding proteins (csRBPs) and glycosylated RNAs (glycoRNAs) form nanodomains on cancer cells, suggesting potential as therapeutic targets.

Purpose of the Study:

• To identify novel, tumor-specific targets for cancer immunotherapy, particularly for AML.
• To characterize the expression and therapeutic potential of cell surface nucleophosmin (csNPM1) in AML and other cancers.

Main Methods:

• Characterization of cell surface protein expression in AML blasts and leukemic stem cells.
• Development of a monoclonal antibody targeting csNPM1.
• In vivo testing of the anti-tumor activity and toxicity of the anti-csNPM1 antibody in AML models.

Main Results:

• Nucleophosmin (NPM1) was identified as an abundant cell surface protein (csNPM1) on various tumor types, including AML blasts and leukemic stem cells, but not on normal hematopoietic stem cells.
• A novel monoclonal antibody targeting csNPM1 demonstrated significant anti-tumor activity in preclinical AML models (syngeneic, xenograft, and patient-derived) with no observable toxicity.
• csNPM1 expression was found to be mutation-agnostic in primary AML cells, indicating its potential as a broadly applicable target.

Conclusions:

• Cell surface NPM1 (csNPM1), often in conjunction with glycoRNA-csRBP clusters, represents a promising and broadly applicable antigen class for the detection and therapeutic targeting of AML and other solid tumors.
• Targeting csNPM1 offers a potential new strategy to overcome current limitations in cancer immunotherapy, providing a mutation-agnostic approach for AML treatment.