Evaluation of multi-antigen targeting ADCC strategies in pediatric BCP-ALL

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BACKGROUND: Blinatumomab, inotuzumab or autologous anti-CD19 chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, tumor escape through antigenic modulation accounts for almost 40% of subsequent relapses. Multi-antigen targeting strategies should be developed, and it is urgent to identify new targets. METHODS: We investigated the extensive immunophenotyping of 13 BCP-ALL from pediatric patients by using the BioLegend Human Cell Surface Marker Screening Kit. Then, to assess whether targeting each antigen with monoclonal antibodies could lead to leukemic cell lysis, long-term antibody-dependent cellular cytotoxicity (ADCC) assays were performed using murine monoclonal antibodies and human T cells armed with murine CD16. RESULTS: 13 highly expressed antigens were selected. With the antibodies tested here, the most significant lysis was observed by targeting CD24 and CD156c. The double targeting of CD24-CD123 appeared to be even more effective. Triple targeting was associated with a reduction in ADCC activity. CONCLUSION: CD24 therefore emerged as an effective target in BCP-ALL, and the combination of CD24 and CD123 as a potential effective double-targeting strategy. The combination of different recognition modalities (eg, a CAR and CD16) should be tested to determine whether it provides synergistic cytotoxic activity in triple targeting.

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