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Augsberger, C.* ; Hänel, G.* ; Xu, W.* ; Pulko, V.* ; Hanisch, L.J.* ; Augustin, A.* ; Challier, J.* ; Hunt, K. ; Vick, B. ; Rovatti, P.E.* ; Krupka, C.* ; Rothe, M.* ; Schönle, A.* ; Sam, J.* ; Lezan, E.* ; Ducret, A.* ; Ortiz-Franyuti, D.* ; Walz, A.C.* ; Benz, J.* ; Bujotzek, A.* ; Lichtenegger, F.S.* ; Gassner, C.* ; Carpy, A.* ; Lyamichev, V.* ; Patel, J.* ; Konstandin, N.P.* ; Tunger, A.* ; Schmitz, M.* ; von Bergwelt-Baildon, M.* ; Spiekermann, K.* ; Vago, L.* ; Jeremias, I. ; Marrer-Berger, E.* ; Umaña, P.* ; Klein, C.* ; Subklewe, M.*

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

Blood 138, 2655-2669 (2021)
Licenced for HMGU: Verlagsversion online verfügbar 08/2022
Antibody-based immunotherapy is a promising strategy for targeting chemo-resistant 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 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 1 (WT1) in the context of human leukocyte antigen (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 AML cells was mediated in ex vivo long-term co-cultures utilizing allogenic (mean specific lysis: 67±6% after 13-14 days; ±SEM; n=18) or autologous, patient-derived T cells (mean specific lysis: 54±12% after 11-14 days; ±SEM; 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 specific lysis on day 3-4: 45.4±9.0% vs 70.8±8.3%; p=0.015; ±SEM; n=9-10). In vivo, WT1-TCB-treated humanized mice bearing SKM-1 tumors showed 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 I trial in patients with r/r AML (NCT04580121).
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Acute Myeloid-leukemia; Tcr-mimic Antibody; Tumor Gene Wt1; Carcinoembryonic Antigen; Progenitor Cells; Single-arm; Cancer; Lenalidomide; Expression; Blinatumomab
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Zeitschrift Blood
Quellenangaben Band: 138, Heft: 25, Seiten: 2655-2669 Artikelnummer: , Supplement: ,
Verlag American Society of Hematology
Verlagsort 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Förderungen Roche
DKMS Mechtild Harf Foundation
Associazione Italiana per la Ricerca sul Cancro
Italian Ministry of Health
European Research Council
Wilhelm-Sander Stiftung
Bavarian Elite Graduate School "i-target"
German Research Council (DFG)