7BBG

CRYSTAL STRUCTURE OF HLA-A2-WT1-RMF AND FAB 11D06

Summary for 7BBG

• Entry DOI: 10.2210/pdb7bbg/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, Wilms tumor 1 (WT1) derived peptide, ... (7 entities in total)
• Functional Keywords: antibody, hla, mhc, rmf peptide, wt1, fab fragment 11d06, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 95365.74

Authors

Bujotzek, A.,Georges, G.,Hanisch, L.J.,Klein, C.,Benz, J. (deposition date: 2020-12-17, release date: 2021-10-27, Last modification date: 2024-10-16)

Primary citation

Augsberger, C.,Hanel, G.,Xu, W.,Pulko, V.,Hanisch, L.J.,Augustin, A.,Challier, J.,Hunt, K.,Vick, B.,Rovatti, P.E.,Krupka, C.,Rothe, M.,Schonle, 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.,Tunger, A.,Schmitz, M.,von Bergwelt-Baildon, M.,Spiekermann, K.,Vago, L.,Jeremias, I.,Marrer-Berger, E.,Umana, 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

PubMed 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 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).

PubMed: 34280257
DOI: 10.1182/blood.2020010477

Experimental method

X-RAY DIFFRACTION (2.64 Å)