A CD19-specific single-chain immunotoxin mediates potent apoptosis of B-lineage leukemic cells

Schwemmlein, Michael; Stieglmaier, Julia; Kellner, Christian; Peipp, Matthias; Saul, Domenica; Oduncu, Fuat; Emmerich, Bertold; Stockmeyer, Bernhard; Lang, Peter; Beck, J. D.; Fey, Georg H.

doi:10.1038/sj.leu.2404687

Cited by 29 publications

(18 citation statements)

References 44 publications

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“…Other groups have previously reported on scFv-ETA'-fusion immunotoxins of similar format specific for CD22, CD25, CD7, CD64, CD33, CD19 and more antigens for the treatment of hematological malignancies [25,26,32,46,37,38] and others, specific for the Lewis Y antigen, IL-13, the EGF-receptor, ErbB2/HER2, EpCAM, and MUC1 for the treatment of solid tumors [33,29,34,2,13,40]. These scFv-ETA' immunotoxins have not yet been approved for routine clinical use, but in preclinical and early-stage clinical studies they have demonstrated encouraging results.…”

Section: Introductionmentioning

confidence: 99%

A single chain immunotoxin, targeting the melanoma-associated chondroitin sulfate proteoglycan, is a potent inducer of apoptosis in cultured human melanoma cells

et al. 2008

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A recombinant immunotoxin was constructed by fusing a single-chain Fv (scFv) antibody fragment, specific for the melanoma-associated chondroitin sulfate proteoglycan (MCSP), to a truncated variant of Pseudomonas Exotoxin A (ETA'), carrying a C-terminal KDEL peptide for improved intracellular transport. The resulting immunotoxin, MCSP-ETA', induced antigen-specific, potent apoptosis in the cultured human melanoma-derived cell lines A2058 and A375M, and treatment with a single dose of the agent eliminated up to 80 % of these cells within 72 h. The dose needed for half-maximum killing (EC50) was approximately 1 nM for both cell lines. MCSP-ETA' also displayed cytotoxic activity against cultured primary melanoma cells from patients with advanced disease, with net cell death reaching up to 70 % within 96 h after treatment with a single dose of 14 nM. MCSP-ETA' induced cell death synergistically with Cyclosporin A (CsA), both in established human melanoma cell lines and cultured primary melanoma cells. The distinctive antigen-restricted induction of apoptosis and the synergy with CsA justify further evaluation of this novel agent with regard to its potential applications for the treatment of melanoma and other MCSP-positive malignancies.

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Section: Introductionmentioning

confidence: 99%

A single chain immunotoxin, targeting the melanoma-associated chondroitin sulfate proteoglycan, is a potent inducer of apoptosis in cultured human melanoma cells

et al. 2008

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“…Single-chain variable fragment immunotoxins were successfully used to selectively kill cancer cells, indicating that the endosomal release function of the ETAII domain is not compromised in chimeric proteins (42). The essential role of the translocation domain in our sneaking-ligand principle is demonstrated by the inability of the DelETA to inhibit NF-κB activation.…”

Section: Discussionmentioning

confidence: 99%

NF-κB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-κB in immune-mediated diseases

Sehnert

Burkhardt

Wessels

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Activation of the nuclear transcription factor κB (NF-κB) regulates the expression of inflammatory genes crucially involved in the pathogenesis of inflammatory diseases. NF-κB governs the expression of adhesion molecules that play a pivotal role in leukocyteendothelium interactions. We uncovered the crucial role of NF-κB activation within endothelial cells in models of immune-mediated diseases using a "sneaking ligand construct" (SLC) selectively inhibiting NF-κB in the activated endothelium. The recombinant SLC1 consists of three modules: (i) an E-selectin targeting domain, (ii ) a Pseudomonas exotoxin A translocation domain, and (iii) a NF-κB Essential Modifier-binding effector domain interfering with NF-κB activation. The E-selectin-specific SLC1 inhibited NF-κB by interfering with endothelial IκB kinase 2 activity in vitro and in vivo. In murine experimental peritonitis, the application of SLC1 drastically reduced the extravasation of inflammatory cells. Furthermore, SLC1 treatment significantly ameliorated the disease course in murine models of rheumatoid arthritis. Our data establish that endothelial NF-κB activation is critically involved in the pathogenesis of arthritis and can be selectively inhibited in a cell type-and activation stage-dependent manner by the SLC approach. Moreover, our strategy is applicable to delineating other pathogenic signaling pathways in a cell type-specific manner and enables selective targeting of distinct cell populations to improve effectiveness and riskbenefit ratios of therapeutic interventions.cell targeting | intracellular signaling | autoimmune disorders | mouse models | inhibit inflammation A critical step in the effector phase of pathogenic immune responses is the extravasation of circulating leukocytes from the vasculature and their migration along gradients of chemoattractants into the target tissues (1). In inflammation, endothelial activation represents a multistep cascade of events leading to increased vascular permeability for plasma proteins; the expression of proinflammatory cytokines, chemokines, and enzymes; and an up-regulation of adhesion molecules that are regulated by the nuclear transcription factor κB (NF-κB) (2-4).Activation of NF-κB via the IκB kinase (IKK) complex is regarded as the classical NF-κB pathway. The IKK complex contains the kinases IKK1 and IKK2 and the regulatory subunit NF-κB Essential Modifier (NEMO) (5). Activation of the classical NF-κB pathway requires association of NEMO with IKK2 (5). The expression of multiple proinflammatory genes including the adhesion molecules ICAM-1, VCAM-1, E-selectin, and chemokines, like MCP-1 and IL-8, contributes to the inflammatory endothelial cell response and is initiated through activation of the classical NF-κB pathway (6).

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“…A CD19-specific ScFv fused to a 38-kDa fragment of PE prolonged the survival of nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice transplanted with Nalm-6 cells [5]. The conjugate showed synergistic toxicity along with valproic acid and cyclosporine, inducing apoptosis in 12 patients with B cell chronic lymphocytic leukemia (B-CLL).…”

Section: Cd19mentioning

confidence: 99%

Immunotoxin therapy for hematologic malignancies: where are we heading?

Madhumathi

Sithambaram

Sridevi

et al. 2016

Drug Discovery Today

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A CD19-specific single-chain immunotoxin mediates potent apoptosis of B-lineage leukemic cells

Cited by 29 publications

References 44 publications

A single chain immunotoxin, targeting the melanoma-associated chondroitin sulfate proteoglycan, is a potent inducer of apoptosis in cultured human melanoma cells

A single chain immunotoxin, targeting the melanoma-associated chondroitin sulfate proteoglycan, is a potent inducer of apoptosis in cultured human melanoma cells

NF-κB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-κB in immune-mediated diseases

Immunotoxin therapy for hematologic malignancies: where are we heading?

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