Abstract
Simple SummaryB 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.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.
Highlights
In many cancer entities, the introduction of monoclonal antibodies has significantly improved the treatment options for patients
We studied the specific binding of the CD133 antibody clone 293C3 to determine the surface expression of CD133 on the B cell acute lymphoblastic leukemia (B-ALL) cell lines REH, RS4;11, and SEM, primary leukemic cells of 28 patients diagnosed with B-ALL, as well as on Peripheral blood mononuclear cells (PBMCs) and bone marrow cells of healthy donors
Dose titration experiments of 293C3-SDIE using B-ALL cell lines and primary B-ALL cells further revealed that 1 μg/mL was sufficient for saturating antigen binding (Figure 1G)
Summary
The introduction of monoclonal antibodies (mAbs) has significantly improved the treatment options for patients. This is exemplified by the anti-CD20 mAb Rituximab and the anti-human epidermal growth factor receptor 2 (HER2)/neu mAbs Trastuzumab (Herceptin), the first clinically available antitumor antibodies, which have become a mainstay of therapy in patients with B cell non-Hodgkin’s lymphoma and HER2+ breast cancer, respectively [1,2]. The amino acid substitutions S239D/I332E (SDIE) increase the Fc-part’s affinity to FcR in general, but with a more pronounced effect achieved for activating FcRIIIa/CD16a compared to the inhibitory FcRIIb/CD32b [6,7]. Glyco-optimized mAbs, such as the CD20 mAb Obinutuzumab, are approved for treatment of certain B cell malignancies, whereas many mAbs with amino acid substitutions in their Fc-part are currently being evaluated in clinical trials [8,9]
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