Details

Autor(en) / Beteiligte

• Augsberger, Christian
• Hänel, Gerulf
• Xu, Wei
• Pulko, Vesna
• Hanisch, Lydia Jasmin
• Augustin, Angelique
• Challier, John
• Hunt, Katharina
• Vick, Binje
• Rovatti, Pier Eduardo
• Krupka, Christina
• Rothe, Maurine
• Schönle, Anne
• Sam, Johannes
• Lezan, Emmanuelle
• Ducret, Axel
• Ortiz-Franyuti, Daniela
• Walz, Antje-Christine
• Benz, Jörg
• Bujotzek, Alexander
• Lichtenegger, Felix S.
• Gassner, Christian
• Carpy, Alejandro
• Lyamichev, Victor
• Patel, Jigar
• Konstandin, Nikola
• Tunger, Antje
• Schmitz, Marc
• von Bergwelt-Baildon, Michael
• Spiekermann, Karsten
• Vago, Luca
• Jeremias, Irmela
• Marrer-Berger, Estelle
• Umaña, Pablo
• Klein, Christian
• Subklewe, Marion

Titel

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

Ist Teil von

• Blood, 2021-12, Vol.138 (25), p.2655-2669

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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). •A T-cell bispecific antibody targeting intracellular WT1 presented on HLA-A2 for treatment of AML is characterized in vitro and in vivo.•The novel, clinical-stage WT1-TCB mediated high-level killing of primary AML cells, which was enhanced by the addition of lenalidomide. [Display omitted]