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

Augsberger, Christian; Hanel, Gerulf; Xu, Wei; Pulko, Vesna; Hanisch, Lydia Jasmin; Augustin, Angelique; Challier, John; Hunt, Katharina; Vick, Binje; Rovatti, Pier Eduardo; Krupka, Christina; Rothe, Maurine; Schonle, Anne; Sam, Johannes; Lezan, Emmanuelle; Ducret, Axel; Ortiz-Franyuti, Daniela; Walz, Antje-Christine; Benz, Jorg; Bujotzek, Alexander; Lichtenegger, Felix S.; Gassner, Christian; Carpy, Alejandro; Lyamichev, Victor; Patel, Jigar; Konstandin, Nikola; Tunger, Antje; Schmitz, Marc; Bergwelt-Baildon, Michael von; Spiekermann, Karsten; Vago, Luca; Jeremias, Irmela; Marrer-Berger, Estelle; Umana, Pablo; Klein, Christian und Subklewe, Marion (2021): Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody. In: Blood, Bd. 138, Nr. 25: S. 2655-2669

Abstract

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 CD3(epsilon) 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).

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0006-4971
• Sprache: Englisch