ABSTRACT
Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here, we explore the hypothesis that tumor cells express cancer-specific surface protein conformations, invisible to standard target discovery pipelines evaluating gene or protein expression, that can be identified and immunotherapeutically targeted. We term this strategy, integrating cross-linking mass spectrometry (XL-MS) with glycoprotein surface capture, “structural surfaceomics”. As a proof of principle, we apply this technology to acute myeloid leukemia, a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin-β2 as a structurally-defined, widely-expressed, AML-specific target. We develop and characterize recombinant antibodies to this protein conformation, and show that chimeric antigen receptor (CAR) T-cells eliminate AML cells and patient-derived xenografts without notable toxicity versus normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen while demonstrating a toolkit for applying these strategies more broadly.
Competing Interest Statement
K.M., J.J.A., S.S.S., and A.P.W. have filed a provisional patent related to the antibody sequences described herein. A.P.W. has received research funding from Genentech. C.S. has received research funding from Revolution Medicines, Abbvie and Erasca, Inc. and has served on advisory boards for Genentech, Abbvie and Astellas. All other authors declare no conflict of interest.
