期刊
CANCERS
卷 13, 期 23, 页码 -出版社
MDPI
DOI: 10.3390/cancers13235964
关键词
bispecific T cell engaging antibodies; mesothelin; pediatric acute myeloid leukemia; patient-derived xenograft models; immunotherapy
类别
资金
- St. Baldricks Foundation
- Leukemia Research Foundation of Delaware
- Lisa Dean Moseley Foundation
- Andrew McDonough B+ Foundation
- Delaware INBRE [P20GM103446]
- Center for Pediatric Research
- COBRE [P20GM103464]
- Delaware-CTR ACCEL [U54GM104941, U01CA232490]
- Nemours Foundation
- Nemours Cell Science Core and Histology Core
- Fred Hutchinson Center Molecular Design and Therapeutics Core
Development of immunotherapy for pediatric AML has been slow, but targeting mesothelin with bispecific antibodies has shown promising results in preclinical models, suggesting a potential new treatment option for pediatric AML patients.
Simple Summary Immunotherapy development in pediatric AML has been slow due to the paucity of validated AML-specific targets. We recently identified mesothelin (MSLN) as a therapeutic target in pediatric AML. Mice receiving T cell engaging bispecific antibodies (BsAbs) targeting MSLN and CD3 achieved complete remission and durable responses in two MSLN-positive patient-derived xenograft (PDX) models. This is a first report showing MSLN-targeting BsAbs are a viable immunotherapy for MSLN-positive pediatric AML. Advances in the treatment of pediatric AML have been modest over the past four decades. Despite maximally intensive therapy, approximately 40% of patients will relapse. Novel targeted therapies are needed to improve outcomes. We identified mesothelin (MSLN), a well-validated target overexpressed in some adult malignancies, to be highly expressed on the leukemic cell surface in a subset of pediatric AML patients. The lack of expression on normal bone marrow cells makes MSLN a viable target for immunotherapies such as T-cell engaging bispecific antibodies (BsAbs) that combine two distinct antibody-variable regions into a single molecule targeting a cancer-specific antigen and the T-cell co-receptor CD3. Using antibody single-chain variable region (scFv) sequences derived from amatuximab-recognizing MSLN, and from either blinatumomab or AMG330 targeting CD3, we engineered and expressed two MSLN/CD3-targeting BsAbs: MSLNAMA-CD3(L2K) and MSLNAMA-CD3(AMG), respectively. Both BsAbs promoted T-cell activation and reduced leukemic burden in MV4;11:MSLN xenografted mice, but not in those transplanted with MSLN-negative parental MV4;11 cells. MSLNAMA-CD3(AMG) induced complete remission in NTPL-146 and DF-5 patient-derived xenograft models. These data validate the in vivo efficacy and specificity of MSLN-targeting BsAbs. Because prior MSLN-directed therapies appeared safe in humans, MSLN-targeting BsAbs could be ideal immunotherapies for MSLN-positive pediatric AML patients.
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