Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody.
Animals
Antibodies, Bispecific
/ pharmacology
Antineoplastic Agents, Immunological
/ pharmacology
Cell Line, Tumor
HLA-A2 Antigen
/ immunology
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mice
Peptides
/ pharmacology
Receptors, Antigen, T-Cell
/ immunology
T-Lymphocytes, Cytotoxic
/ drug effects
Tumor Cells, Cultured
WT1 Proteins
/ immunology
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
23 12 2021
23 12 2021
Historique:
received:
22
12
2020
accepted:
01
07
2021
pubmed:
20
7
2021
medline:
14
1
2022
entrez:
19
7
2021
Statut:
ppublish
Résumé
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).
Identifiants
pubmed: 34280257
pii: S0006-4971(21)01371-9
doi: 10.1182/blood.2020010477
pmc: PMC9037755
doi:
Substances chimiques
Antibodies, Bispecific
0
Antineoplastic Agents, Immunological
0
HLA-A*02 antigen
0
HLA-A2 Antigen
0
Peptides
0
Receptors, Antigen, T-Cell
0
WT1 Proteins
0
WT1 protein, human
0
Banques de données
ClinicalTrials.gov
['NCT04580121']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2655-2669Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
© 2021 by The American Society of Hematology.
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