Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia
Katherine Knorr, Jahan Rahman, Caroline Erickson, Eric Wang, Mara Monetti, Zhuoning Li, Juliana Ortiz-Pacheco, Andrew Jones, Sydney X. Lu, Robert Stanley, Maria Baez, Nina Fox, Cynthia Aparecida de Castro, Alessandra Marino, Caroline S. Jiang, Alex Penson, Simon J. Hogg, Xiaoli Mi, Hideaki Nakajima, Hiroyoshi Kunimoto, Koutarou Nishimura, Daichi Inoue, Benjamin D. Greenbaum, David A. Knorr, Jeffrey V. Ravetch, Omar Abdel‐Wahab
Abstract
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.