An Fc-Optimized CD133 Antibody for Induction of NK Cell Reactivity against B Cell Acute Lymphoblastic Leukemia

SIMPLE SUMMARY: B cell acute lymphoblastic leukemia (B-ALL) is a common blood cancer characterized by proliferating and accumulating malignant, immature B cells within the body. Despite recent successes in B-ALL therapy, there is still a need for new therapeutic options. In the present study, we report on the characterization of 293C3-SDIE for the treatment of B-ALL. 293C3-SDIE is an improved anti-tumor antibody targeting CD133, a common protein on the surface of B-ALL cells. We demonstrated that 293C3-SDIE specifically induces activation of natural killer cells, which leads to lysis of B-ALL cells. Based on this study, we conclude that CD133 serves as a target for immune therapy, and treatment with 293C3-SDIE represents a promising therapeutic option in B-ALL therapy and warrants further preclinical and clinical evaluation. ABSTRACT: In recent decades, antibody-dependent cellular cytotoxicity (ADCC)-inducing monoclonal antibodies (mAbs) have revolutionized cancer immunotherapy, and Fc engineering strategies have been utilized to further improve efficacy. A promising option is to enhance the affinity of an antibody’s Fc-part to the Fc-receptor CD16 by altering the amino acid sequence. Herein, we characterized an S239D/I332E-modified CD133 mAb termed 293C3-SDIE for treatment of B cell acute lymphoblastic leukemia (B-ALL). Flow cytometric analysis revealed CD133 expression on B-ALL cell lines and leukemic cells of 50% (14 of 28) B-ALL patients. 293C3-SDIE potently induced NK cell reactivity against the B-ALL cell lines SEM and RS4;11, as well as leukemic cells of B-ALL patients in a target antigen-dependent manner, as revealed by analysis of NK cell activation, degranulation, and cytotoxicity. Of note, CD133 expression did not correlate with BCR-ABL, CD19, CD20, or CD22, which are presently used as therapeutic targets in B-ALL, which revealed CD133 as an independent target for B-ALL treatment. Increased CD133 expression was also observed in MLL-AF4-rearranged B-ALL, indicating that 293C3-SDIE may constitute a particularly suitable treatment option in this hard-to-treat subpopulation. Taken together, our results identify 293C3-SDIE as a promising therapeutic agent for the treatment of B-ALL.