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

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.

Engineering Anti-Tumor Monoclonal Antibodies and Fc Receptors to Enhance ADCC by Human NK Cells

“…An anti-FMS-related tyrosine kinase 3 (FLT-3) mAb with Ser239Asp and Ile332Glu mutations is part of a clinical phase I/II trial to treat patients with acute myeloid leukemia (AML) ( identifier: NCT02789254). Recent in vitro studies using this FLT-3 mAb suggested that it could also be suitable for the treatment of B cell acute lymphoblastic leukemia (B-ALL) [ 80 ]. A screen that aimed to elucidate increased CD16A binding/decreased off rate and also prevent increased affinity for inhibitory CD32B found that the combination of Phe243Leu, Arg292Pro, Tyr300Leu, Val305Ile, and Pro396Leu (referred to as Variant 18) achieved this [ 81 ].…”

Doxorubicin/Nucleophosmin Binding Protein-Conjugated Nanoparticle Enhances Anti-leukemia Activity in Acute Lymphoblastic Leukemia Cells in vitro and in vivo

“…In recent years, a personalized treatment approach involving the following has contributed to the progress of adult ALL therapy: response to minimal residual disease and disease genetics; adopting pediatric-inspired regimens in younger adults; advances in transplantation; incorporation of new treatments and tyrosine kinase inhibitors found in frontline regimens; as well as adoptive cellular therapy (Aldoss and Stein, 2018;Pillai et al, 2019). In particular, antibody-based therapies, such as monoclonal antibodies and antibody-drug conjugates have shown promising activity profiles for the treatment of ALL (Phelan and Advani, 2018;Schmied et al, 2019). Introduction of these strategies in the frontline setting has been ongoing and will likely unravel significant benefits for ALL.…”

Natural killer cell-based immunotherapy for acute myeloid leukemia

“…Natural killer (NK) cell-based immunotherapy represents one of the novel immunotherapeutic strategies recently, unleashing immune suppression of NK cells to attack various cancers [10][11][12]. With the progressive elucidation of NK cell immunobiology and the development of manipulative techniques, the field of NK cellbased immunotherapy in hematological malignancies has been expanding and accelerating over the past years, including adoptive NK cell transfer [13][14][15][16], chimeric antigen receptor (CAR)-modified NK cells [17][18][19][20][21][22], antibodies [23][24][25], cytokines [26,27] and drug treatment [28][29][30][31]. Despite remarkable progress has been made, the application in AML is still at the initial stage.…”