Induction of NK Cell Reactivity against B-Cell Acute Lymphoblastic Leukemia by an Fc-Optimized FLT3 Antibody.

Bastian J Schmied,Latifa Zekri,Gundram Jung,Hans-Jörg Bühring,Jonas S Heitmann,Martina S Lutz,Fabian Riegg,Helmut R Salih

doi:10.3390/cancers11121966

Bastian J Schmied, Latifa Zekri + Show 6 more

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https://doi.org/10.3390/cancers11121966

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Journal: Cancers	Publication Date: Dec 6, 2019
Citations: 10	License type: CC BY 4.0

Affiliation: University of Tübingen

Abstract

Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism by which antitumor antibodies mediate therapeutic efficacy. At present, we evaluate an Fc-optimized (amino acid substitutions S239D/I332E) FLT3 antibody termed 4G8-SDIEM (FLYSYN) in patients with acute myeloid leukemia (NCT02789254). Here we studied the possibility to induce NK cell ADCC against B-cell acute lymphoblastic leukemia (B-ALL) by Fc-optimized FLT3 antibody treatment. Flow cytometric analysis confirmed that FLT3 is widely expressed on B-ALL cell lines and leukemic cells of B-ALL patients. FLT3 expression did not correlate with that of CD20, which is targeted by Rituximab, a therapeutic monoclonal antibody (mAb) employed in B-ALL treatment regimens. Our FLT3 mAb with enhanced affinity to the Fc receptor CD16a termed 4G8-SDIE potently induced NK cell reactivity against FLT3-transfectants, the B-ALL cell line SEM and primary leukemic cells of adult B-ALL patients in a target-antigen dependent manner as revealed by analyses of NK cell activation and degranulation. This was mirrored by potent 4G8-SDIE mediated NK cell ADCC in experiments with FLT3-transfectants, the cell line SEM and primary cells as target cells. Taken together, the findings presented in this study provide evidence that 4G8-SDIE may be a promising agent for the treatment of B-ALL, particularly in CD20-negative cases.

Highlights

Cancer immunotherapy with its possibility to elicit a specific antitumor immune reaction has become a mainstay of treatment in many malignancies [1]
We characterized whether and to what extent the specific FMS-like tyrosine kinase 3 (FLT3) antibody clone used for generation of our Fc-optimized monoclonal antibody (mAb) recognizes FLT3 on the surface of B-cell acute lymphoblastic leukemia (B-ALL) cells
FLT3 is widely expressed on leukemic cells in acute myeloid leukemia (AML), and at present a (p-value clinical study is conducted in which we evaluate the Fc-optimized FLT3 mAb 4G8-SDIEM (FLYSYN) to

Summary

Introduction

Cancer immunotherapy with its possibility to elicit a specific antitumor immune reaction has become a mainstay of treatment in many malignancies [1]. Monoclonal antibodies (mAb) are well established and have greatly improved the treatment options for patients with malignant diseases. A promising strategy to overcome the first problem, that is limited therapeutic efficacy, is to enhance the immunostimulatory potency of a given antibody’s Fc-part [4], by increasing its capacity to induce antibody dependent cellular cytotoxicity (ADCC). The latter represents one of the most important effector mechanisms of such antitumor mAb, at least in blood cancers (e.g., [5]). Enhanced ADCC can be achieved by increasing the affinity of an antibody’s Fc part to the Fcγ receptor IIIa (FcγRIIIa/CD16a) that is expressed by immune cells like natural killer (NK)

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