PuSH - Publication Server of Helmholtz Zentrum München: Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC specific T-cell bispecific antibody.

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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)

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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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