A novel antigen-toxin chimeric protein: myelin basic protein-pseudomonas exotoxin (MBP-PE 40) for treatment of experimental autoimmune encephalomyelitis

Brenner, Talma; Steinberger, Ida; Soffer, Dov; Béraud, Evelyne; Ben-Nun, A; Lorberboum-Galski, Haya

doi:10.1016/s0165-2478(99)00089-9

Cited by 9 publications

(4 citation statements)

References 27 publications

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“…Antibody-mediated autoimmune diseases may be ameliorated by immunosuppressive drugs, corticosteroids or plasmapheresis, which all act only transiently or may be reason of general immunodeficiency. Elimination of pathogenic B cells by different ITs such as MOG-Fc, MOG-ETA and MBP-ETA was reported previously [39], [40], [41]. However, there is still no effective therapy based on the depletion of disease-associated B cells in autoimmune patients.…”

Section: Discussionmentioning

confidence: 98%

Design of Targeted B Cell Killing Agents

et al. 2011

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B cells play an important role in the pathogenesis of both systemic and organ-specific autoimmune diseases. Autoreactive B cells not only produce autoantibodies, but also are capable to efficiently present specific autoantigens to T cells. Furthermore, B cells can secrete proinflammatory cytokines and amplify the vicious process of self-destruction. B cell-directed therapy is a potentially important approach for treatment of various autoimmune diseases. The depletion of B cells by anti-CD20/19 monoclonal antibody Retuximab® used in autoimmune diseases therapy leads to systemic side effects and should be significantly improved. In this study we designed a repertoire of genetically engineered B cell killers that specifically affected one kind of cells carrying a respective B cell receptor. We constructed immunotoxins (ITs), fused with c-myc epitope as a model targeting sequence, based on barnase, Pseudomonas toxin, Shiga-like toxin E.coli and Fc domain of human antibody IgGγ1. C-MYC hybridoma cell line producing anti-c-myc IgG was chosen as a model for targeted cell depletion. C-myc sequence fused with toxins provided addressed delivery of the toxic agent to the target cells. We demonstrated functional activity of designed ITs in vitro and showed recognition of the fusion molecules by antibodies produced by targeted hybridoma. To study specificity of the proposed B cells killing molecules, we tested a set of created ITs ex vivo, using C-MYC and irrelevant hybridoma cell lines. Pseudomonas-containing IT showed one of the highest cytotoxic effects on the model cells, however, possessed promiscuous specificity. Shiga-like toxin construct demonstrated mild both cytotoxicity and specificity. Barnase and Fc-containing ITs revealed excellent balance between their legibility and toxic properties. Moreover, barnase and Fc molecules fused with c-myc epitope were able to selectively deplete c-myc-specific B cells and decrease production of anti-c-myc antibodies in culture of native splenocytes, suggesting their highest therapeutic potential as targeted B cell killing agents.

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Section: Discussionmentioning

confidence: 98%

Design of Targeted B Cell Killing Agents

et al. 2011

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“…MBP can stimulate T cells that migrate into the CNS, initiating a cascade of events that result in perivascular infiltration and demyelination. In a previous study we used MBP-PE40, as an antigen-toxin chimeric protein for the treatment of EAE [29]. The protein was cytotoxic to various anti-MBP T cells and blocked the clinical signs of EAE.…”

Section: Discussionmentioning

confidence: 99%

IL2-caspase3 chimeric protein controls lymphocyte reactivity by targeted apoptosis, leading to amelioration of experimental autoimmune encephalomyelitis

Irony-Tur-Sinai¹,

Lichtenstein²,

Brenner³

et al. 2009

International Immunopharmacology

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“…With this in mind, the idea of selective elimination of distinct autoreactive B cells appears very impressive. Elimination of pathogenic B cells by different immunotoxins has been reported previously [77][78][79]. Basically, these molecules consist of two parts: an effector domain (toxin, antibody fragment, RNAse) and a delivery domain (part or full length autoantigen).…”

Section: Solving the ''Chicken And Egg'' Problem For Immunodiagnosticmentioning

confidence: 97%

Antibody–antigen pair probed by combinatorial approach and rational design: Bringing together structural insights, directed evolution, and novel functionality

et al. 2012

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The unique hypervariability of the immunoglobulin (Ig) superfamily provides a means to create both binding and catalytic antibodies with almost any desired specificity and activity. The diversity of antigens and concept of adaptive response suggest that it is possible to find an antigen pair to any raised Ig. In the current review we discuss combinatorial approaches, which makes it possible to obtain an antibody with predefined properties, followed by 3D structure‐based rational design to enhance or dramatically change its characteristics. A similar strategy, but applied to the second partner of the antibody–antigen pair, may result in selection of complementary substrates to the chosen Ig. Finally, 2D screening may be performed solving the “Chicken and Egg” problem when neither antibody nor antigen is known.

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A novel antigen-toxin chimeric protein: myelin basic protein-pseudomonas exotoxin (MBP-PE 40) for treatment of experimental autoimmune encephalomyelitis

Cited by 9 publications

References 27 publications

Design of Targeted B Cell Killing Agents

Design of Targeted B Cell Killing Agents

IL2-caspase3 chimeric protein controls lymphocyte reactivity by targeted apoptosis, leading to amelioration of experimental autoimmune encephalomyelitis

Antibody–antigen pair probed by combinatorial approach and rational design: Bringing together structural insights, directed evolution, and novel functionality

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