Abstract
AbstractSafely 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 that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture ‘structural surfaceomics’. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), 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 T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Michelson Prize and Grants
American Society of Hematology
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
U.S. Department of Health & Human Services | NIH | NIH Office of the Director
National Science Foundation
Gouvernement du Canada | Canadian Institutes of Health Research
Bristol-Myers Squibb
Publisher
Springer Science and Business Media LLC
Cited by
1 articles.
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