What question did this study set out to answer?

This research aims to evaluate the efficacy of bispecific antibodies and activated natural killer cells in targeting high-risk myeloid leukemia and myelodysplastic syndrome.

May 29, 2026

Multimodal immunotherapy for high-risk acute myeloid leukemia and myelodysplastic syndrome.

Puntos clave

This research aims to evaluate the efficacy of bispecific antibodies and activated natural killer cells in targeting high-risk myeloid leukemia and myelodysplastic syndrome.
In vitro assays tested cytotoxicity of bispecific antibodies with NK and activated NK cells on leukemia cell lines and patient samples.
NBSGW mice models were used for in vivo evaluation with human leukemia chimerism observed during treatment.
Treatment groups received a single dose of bispecific antibody combined with either NK or activated NK cells, monitored over four weeks.
CM1/3/16/16 with NK cells showed 70% cytotoxicity against Kasumi-1 and 50% against MOLM-13 cell lines at optimal conditions.
Activated NK cells demonstrated >90% cytotoxicity against Kasumi-1 cells even after 72 hours without IL21521.
In vivo, CM1/3/16/16 with activated NK cells resulted in a 70% reduction of human leukemia chimerism and 100% survival in treated mice at four weeks.

Resumen

6569 Background: CD117 is highly expressed on myeloid leukemia cells (MLC) with limited expression on normal tissues. Our group has developed an anti-CD117 monoclonal antibody and demonstrated its safety in a phase 1 clinical trial for myelodysplastic syndrome (MDS). To potentiate engagement with MLC and immune effector cells, we engineered bispecific antibodies (bsAb) to bind CD117 and CD33 or CD38 and recruit natural killer (NK) cells using an active Fc and CD16 (CM1/3/16/16) and/or NKp46 scFv (CM1/3/16/17). NK cell cytotoxicity against MLC increases several-fold when activated by IL2, IL15 or IL21. We studied the in vitro and in vivo efficacy of bsAbs with fresh NK cells or IL2, IL15 and IL21 (IL21521) activated NK cells (cNK) to deplete MLC. Methods: In vitro cytotoxicity assays were performed on Kasumi-1 (CD117 high) and MOLM-13 (CD117 negative) acute myeloid leukemia (AML) cell lines and a primary AML sample (CD117 low) with bsAb and NK or cNK cells. cNK were exposed to IL21521 for 7 days. To mimic in vivo exposure, cNK were removed from IL21521 for 24, 48 and 72 hours prior to cytotoxicity assays. Using immune deficient NBSGW mice and primary patient sample of high risk (HR)-MDS transformed to AML (MDS/AML), a patient derived xenograft (PDX) model of HR-MDS/AML was created and allowed to progress to >80% CD45+ human leukemia chimerism (HLC) before treatment. Treatment groups included CM1/3/16/16 at 1mg and/or 2e6 NK or cNK given as a single dose per animal. Weekly blood HLC and a terminal 4-week blood, marrow and spleen HLC were performed. Results: In in vitro cytotoxicity assays, among the bsAbs, CM1/3/16/16 at 100nM with NK cells at 1:1 target:effector (TE) ratio produced the highest cytotoxicity against Kasumi-1 (70%) and MOLM13 (50%). cNK cells alone produced >90% cytotoxicity of Kasumi-1 cells at 1:1 TE ratio even at 72 hours after IL21521 washout. In the HR-MDS/AML PDX advanced leukemia model, the group receiving CM1/3/16/16 with cNK demonstrated the highest depletion of MLC, with 70% reduction of HLC seen at 4 weeks post-treatment. Mice in this treatment group had 100% survival at 4 weeks at which time they were euthanized for analysis. Conclusions: Both CM1/3/16/16 and cNK cells independently killed MLC with high efficacy in vitro . A single dose of CM1/3/16/16 combined with cNK cells depleted human MLC in PDX model of HR-MDS/AML with advanced leukemia. Further clinical investigation of this bsAb with allogeneic donor cNK cells in HR-MDS/AML is warranted.

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