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Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia

by Wang, Eric , Monetti, Mara , Li, Zhuoning , Stanley, Robert F. , Knorr, David , Ravetch, Jeffrey , Rahman, Jahan , Jones, Andrew , Kunimoto, Hiroyoshi , Knorr, Katherine , Marino, Alessandra E. , Abdel-Wahab, Omar , Greenbaum, Benjamin , Lu, Sydney X. , Jiang, Caroline , Nishimura, Koutarou , Mi, Xiaoli , Fox, Nina , Nakajima, Hideaki , Hogg, Simon J. , Ortiz-Pacheco, Juliana , Penson, Alex , Castro, Cynthia , Erickson, Caroline , Inoue, Daichi , Baez, Maria

in Antibodies / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - therapeutic use / Antigens / Antigens, Surface / Bone marrow / FDA approval / Granulocytes / Humans / Immunotherapy / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Mutation / Patients / Receptors, Fc - metabolism / Receptors, IgG - metabolism / Ribonucleoproteins, Small Nuclear / Stem cells / Tumor Microenvironment

2023

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Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia

2023

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Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia

2023

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Journal Article

Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia

Wang, Eric,

Monetti, Mara,

Li, Zhuoning,

Stanley, Robert F.,

Knorr, David,

Ravetch, Jeffrey,

Rahman, Jahan,

Jones, Andrew,

Kunimoto, Hiroyoshi,

Knorr, Katherine,

Marino, Alessandra E.,

Abdel-Wahab, Omar,

Greenbaum, Benjamin,

Lu, Sydney X.,

Jiang, Caroline,

Nishimura, Koutarou,

Mi, Xiaoli,

Fox, Nina,

Nakajima, Hideaki,

Hogg, Simon J.,

Ortiz-Pacheco, Juliana,

Penson, Alex,

Castro, Cynthia,

Erickson, Caroline,

Inoue, Daichi,

Baez, Maria

2023

Overview

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.

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Publisher

Nature Publishing Group,Nature Publishing Group US

Subject

Antibodies

/ Antibodies, Monoclonal - immunology

/ Antibodies, Monoclonal - therapeutic use