Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody.

Autor:	Augsberger C; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany., Hänel G; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany., Xu W; Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland., Pulko V; Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland., Hanisch LJ; Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland., Augustin A; Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland., Challier J; Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland., Hunt K; Research Unit Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany., Vick B; Research Unit Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany., Rovatti PE; Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Krupka C; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany., Rothe M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany., Schönle A; Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland., Sam J; Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland., Lezan E; Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland., Ducret A; Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland., Ortiz-Franyuti D; Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland., Walz AC; Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland., Benz J; Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland., Bujotzek A; Roche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, Germany., Lichtenegger FS; Roche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, Germany., Gassner C; Roche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, Germany., Carpy A; Roche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, Germany., Lyamichev V; Nimble Therapeutics, Madison, WI., Patel J; Nimble Therapeutics, Madison, WI., Konstandin N; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Tunger A; Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.; National Center for Tumor Diseases, Partner Site Dresden, Dresden, Germany., Schmitz M; Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.; National Center for Tumor Diseases, Partner Site Dresden, Dresden, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., von Bergwelt-Baildon M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Spiekermann K; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Vago L; Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Jeremias I; Research Unit Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany; and.; Department of Pediatrics, Dr von Hauner Children's Hospital, Ludwig Maximilian University (LMU), Munich, Germany., Marrer-Berger E; Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland., Umaña P; Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland., Klein C; Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland., Subklewe M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Dec 23; Vol. 138 (25), pp. 2655-2669.
DOI:	10.1182/blood.2020010477
Abstrakt:	Antibody-based immunotherapy is a promising strategy for targeting chemoresistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated by using CrossMAb and knob-into-holes technology, containing a bivalent T-cell receptor-like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms tumor protein (WT1) in the context of HLA-A*02. Binding to CD3ε recruits T cells irrespective of their T-cell receptor specificity. WT1-TCB elicited antibody-mediated T-cell cytotoxicity against AML cell lines in a WT1- and HLA-restricted manner. Specific lysis of primary acute myeloid leukemia (AML) cells was mediated in ex vivo long-term cocultures by using allogeneic (mean ± standard error of the mean [SEM] specific lysis, 67 ± 6% after 13-14 days; n = 18) or autologous, patient-derived T cells (mean ± SEM specific lysis, 54 ± 12% after 11-14 days; n = 8). WT1-TCB-treated T cells exhibited higher cytotoxicity against primary AML cells than an HLA-A*02 RMF-specific T-cell clone. Combining WT1-TCB with the immunomodulatory drug lenalidomide further enhanced antibody-mediated T-cell cytotoxicity against primary AML cells (mean ± SEM specific lysis on days 3-4, 45.4 ± 9.0% vs 70.8 ± 8.3%; P = .015; n = 9-10). In vivo, WT1-TCB-treated humanized mice bearing SKM-1 tumors exhibited a significant and dose-dependent reduction in tumor growth. In summary, we show that WT1-TCB facilitates potent in vitro, ex vivo, and in vivo killing of AML cell lines and primary AML cells; these results led to the initiation of a phase 1 trial in patients with relapsed/refractory AML (#NCT04580121). (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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