Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

Kellner, Christian; Peipp, Matthias; Gramatzki, Martin; Schrappe, Martin; Schewe, Denis

doi:10.1080/2162402x.2018.1448331

Cited by 7 publications

(8 citation statements)

References 41 publications

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“…Particularly, expanding the repertoire of antigens targeted by immunotherapy approaches appears promising, since antigen loss is a major escape mechanism during immunotherapy. Downmodulation and genetic mutation of target genes, or cell lineage change with antigen loss, constitute the involved mechanisms, which were partly reported upon treatment with Inotuzumab ozogamicin, Blinatumomab, and Tisagenlecleucel [ 13 , 31 , 32 , 33 ]. The introduction of CD133 as an additional target thus appears promising, especially since CD133 expression is not associated with the prevalence of other therapeutic targets such as BCR-ABL, CD19, CD20, and CD22.…”

Section: Discussionmentioning

confidence: 99%

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

Riegg

Lutz

Schmied

et al. 2021

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

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

Riegg

Lutz

Schmied

et al. 2021

Cancers

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“…However, while these drugs exert significant therapeutic effects, their activity is still limited, among others due to resistance mechanisms, which are for example associated with the modulation of their target antigens [23]. Downmodulation of target antigens associated with failure of therapy has been reported for approaches comprising binders of CD19 like the BiTE Blinatumomab and also anti-CD19 CAR-T cells [24,25] as well as the CD22-targeting ADC Inotuzumab ozogamicin [26][27][28]. With our FLT3 binder 4G8, we also observed downmodulation of FLT3 expression on AML and B-ALL cells [12], but even high mAb concentrations did not reduce antigen expression by more than 30%-40%.…”

Section: Discussionmentioning

confidence: 99%

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

Schmied¹,

Lutz²,

Riegg³

et al. 2019

Cancers

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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.

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“…Two Fc-optimized anti-CD19 mAbs have been developed for the treatment of paediatric B-linage acute lymphoblastic leukaemia (ALL), inebilizumab (modifying the Fc-linked Nglycan) and XmAb ® 5574 (a version of 4G7-anitbody with SDIE modification in the human Fc-domain of IgG1) (164). These antibodies have shown enhanced potency ADCC and ADCP compared to the unmodified IgG1 CD19 antibody, as demonstrated by in vitro and in vivo analyses in leukaemia and lymphoma animal models [reviewed in (165)]. XmAb ® 5574 has been demonstrated to be safe and to have some efficacy in patients with relapsed CLL (166).…”

Section: Fc-optimization Of Therapeutic Monoclonal Antibodiesmentioning

confidence: 99%

Relevance of Fc Gamma Receptor Polymorphisms in Cancer Therapy With Monoclonal Antibodies

Mata-Molanes

Rebollo-Liceaga²,

Martínez-Navarro³

et al. 2022

Front. Oncol.

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Therapeutic monoclonal antibodies (mAbs), including immune checkpoint inhibitors (ICIs), are an important breakthrough for the treatment of cancer and have dramatically changed clinical outcomes in a wide variety of tumours. However, clinical response varies among patients receiving mAb-based treatment, so it is necessary to search for predictive biomarkers of response to identify the patients who will derive the greatest therapeutic benefit. The interaction of mAbs with Fc gamma receptors (FcγR) expressed by innate immune cells is essential for antibody-dependent cellular cytotoxicity (ADCC) and this binding is often critical for their in vivo efficacy. FcγRIIa (H131R) and FcγRIIIa (V158F) polymorphisms have been reported to correlate with response to therapeutic mAbs. These polymorphisms play a major role in the affinity of mAb receptors and, therefore, can exert a profound impact on antitumor response in these therapies. Furthermore, recent reports have revealed potential mechanisms of ICIs to modulate myeloid subset composition within the tumour microenvironment through FcγR-binding, optimizing their anti-tumour activity. The purpose of this review is to highlight the clinical contribution of FcγR polymorphisms to predict response to mAbs in cancer patients.

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Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

Cited by 7 publications

References 41 publications

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

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

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

Relevance of Fc Gamma Receptor Polymorphisms in Cancer Therapy With Monoclonal Antibodies

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