期刊
JOURNAL OF CLINICAL MEDICINE
卷 11, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/jcm11051333
关键词
pediatric leukemia; acute myeloid leukemia; CD123; flotetuzumab; immunotherapy; patient-derived xenograft models
资金
- Leukemia Research Foundation of Delaware
- Lisa Dean Moseley Foundation
- Andrew McDonough B+ Foundation
- Cell Science Core of Delaware INBRE [P20GM103446]
- Center for Pediatric Research COBRE [P20GM103464]
- Nemours Foundation
CD123 x CD3 dual-affinity retargeting antibody MGD006 shows efficacy in killing pediatric AML cells, and combination treatment with cytarabine does not interfere with MGD006 activity.
Children with acute myeloid leukemia (AML) have a poor prognosis despite the intensification of chemotherapy. Future efforts to improve outcomes should focus on more precise targeting of leukemia cells. CD123, or IL3RA, is expressed on the surface of nearly all pediatric AML samples and is a high-priority target for immunotherapy. The efficacy of an investigational dual-affinity retargeting antibody (DART) molecule (CD123 x CD3; MGD006 or flotetuzumab) was assessed in two distinct patient-derived xenograft (PDX) models of pediatric AML. MGD006 simultaneously binds to CD123 on target cells and CD3 on effector T cells, thereby activating T cells and redirecting them to induce cytotoxicity in target cells. The concurrent treatment of cytarabine and MGD006 was performed to determine the effect of cytarabine on T-cell counts and MGD006 activity. Treatment with MGD006 along with an allogeneic human T-cell infusion to act as effector cells induced durable responses in both PDX models, with CD123 positivity. This effect was sustained in mice treated with a combination of MGD006 and cytarabine in the presence of T cells. MGD006 enhanced T-cell proliferation and decreased the burden of AML blasts in the peripheral blood with or without cytarabine treatment. These data demonstrate the efficacy of MGD006 in prolonging survival in pediatric AML PDX models in the presence of effector T cells and show that the inclusion of cytarabine in the treatment regimen does not interfere with MGD006 activity.
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