Structural surfaceomics reveals an AML-specific conformation of Integrin-β2 as a CAR-T therapy target
Mandal, K.; Wicaksono, G.; Yu, C.; Adams, J. J.; Hoopmann, M. R.; Temple, W. C.; Escobar, B. P.; Gorelik, M.; Ihling, C. H.; Nix, M. A.; Naik, A.; Ramos, E.; Kasap, C.; Steri, V.; Serrano, J. A. C.; Salangsang, F.; Phojanakong, P.; McMillan, M.; Gavallos, V.; Leavitt, A. D.; Sinz, A.; Huang, B. J.; Stieglitz, E.; Smith, C. C.; Moritz, R. L.; Sidhu, S. S.; Huang, L.; Wiita, A. P.
Show 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-{beta}2 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.
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