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  1. Artikel ; Online: AAV Immunotoxicity

    Ridhwaanah Jacobs / Makafui Dennis Dogbey / Njabulo Mnyandu / Keila Neves / Stefan Barth / Patrick Arbuthnot / Mohube Betty Maepa

    Microorganisms, Vol 11, Iss 12, p

    Implications in Anti-HBV Gene Therapy

    2023  Band 2985

    Abstract: Hepatitis B virus (HBV) has afflicted humankind for decades and there is still no treatment that can clear the infection. The development of recombinant adeno-associated virus (rAAV)-based gene therapy for HBV infection has become important in recent ... ...

    Abstract Hepatitis B virus (HBV) has afflicted humankind for decades and there is still no treatment that can clear the infection. The development of recombinant adeno-associated virus (rAAV)-based gene therapy for HBV infection has become important in recent years and research has made exciting leaps. Initial studies, mainly using mouse models, showed that rAAVs are non-toxic and induce minimal immune responses. However, several later studies demonstrated rAAV toxicity, which is inextricably associated with immunogenicity. This is a major setback for the progression of rAAV-based therapies toward clinical application. Research aimed at understanding the mechanisms behind rAAV immunity and toxicity has contributed significantly to the inception of approaches to overcoming these challenges. The target tissue, the features of the vector, and the vector dose are some of the determinants of AAV toxicity, with the latter being associated with the most severe adverse events. This review discusses our current understanding of rAAV immunogenicity, toxicity, and approaches to overcoming these hurdles. How this information and current knowledge about HBV biology and immunity can be harnessed in the efforts to design safe and effective anti-HBV rAAVs is discussed.
    Schlagwörter adeno-associated viral vectors ; gene therapy ; hepatitis B virus ; immunotolerance ; immunotoxicity ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2023-12-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: Human Granzyme B Based Targeted Cytolytic Fusion Proteins

    Precious Hlongwane / Neelakshi Mungra / Suresh Madheswaran / Olusiji A. Akinrinmade / Shivan Chetty / Stefan Barth

    Biomedicines, Vol 6, Iss 2, p

    2018  Band 72

    Abstract: Cancer immunotherapy aims to selectively target and kill tumor cells whilst limiting the damage to healthy tissues. Controlled delivery of plant, bacterial and human toxins or enzymes has been shown to promote the induction of apoptosis in cancerous ... ...

    Abstract Cancer immunotherapy aims to selectively target and kill tumor cells whilst limiting the damage to healthy tissues. Controlled delivery of plant, bacterial and human toxins or enzymes has been shown to promote the induction of apoptosis in cancerous cells. The 4th generation of targeted effectors are being designed to be as humanized as possible—a solution to the problem of immunogenicity encountered with existing generations. Granzymes are serine proteases which naturally function in humans as integral cytolytic effectors during the programmed cell death of cancerous and pathogen-infected cells. Secreted predominantly by cytotoxic T lymphocytes and natural killer cells, granzymes function mechanistically by caspase-dependent or caspase-independent pathways. These natural characteristics make granzymes one of the most promising human enzymes for use in the development of fusion protein-based targeted therapeutic strategies for various cancers. In this review, we explore research involving the use of granzymes as cytolytic effectors fused to antibody fragments as selective binding domains.
    Schlagwörter cancer immunotherapy ; granzyme B (GrB) ; human cytolytic fusion proteins (hCFPs) ; immunotoxins (ITs) ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2018-06-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: Development of a Competitive Cystatin C-Specific Bioassay Suitable for Repetitive Measurements.

    Tatjana Damm / Holger Spiegel / Stefan Barth / Rainer Fischer / Joerg Naehring

    PLoS ONE, Vol 11, Iss 1, p e

    2016  Band 0147177

    Abstract: Human cystatin C (hCC), a cysteine protease inhibitor, has been proposed as a diagnostic marker because its serum levels correlate with certain cardiovascular and kidney diseases. All current hCC assays are based on ex vivo detection. Here we describe ... ...

    Abstract Human cystatin C (hCC), a cysteine protease inhibitor, has been proposed as a diagnostic marker because its serum levels correlate with certain cardiovascular and kidney diseases. All current hCC assays are based on ex vivo detection. Here we describe the generation and evaluation of antibodies that allow the repetitive binding and release of hCC and hCC-fusion proteins, a prerequisite for long-term measurement, which is required for compatibility with implantable biochip devices and for the development of innovative antibody-based assays suitable for continuous in vivo and in vitro monitoring. Recombinant hCC and hCC-fusion proteins were produced in Escherichia coli and HEK293T cells and were used to generate antibodies by hybridoma technology. After screening by indirect and sandwich ELISAs, 12 monoclonal hybridoma cell lines producing hCC-specific monoclonal antibodies were identified. To determine their hCC association and dissociation properties, the antibodies were analysed by surface plasmon resonance spectroscopy, revealing three with the desired fast binding and moderate-to-fast release characteristics. The analysis of binding and dissociation in the presence of hCC and hCC-fusion proteins using fluorescence-based replacement assays showed that mAb CyDI-4 was the most suitable for further analysis. The results showed that repetitive replacement on mAb CyDI-4 was possible and that most of the change in signal intensity occurred after 20-30 min. Furthermore, the suitability of mAb CyDI-4 for serum hCC measurement was confirmed by a fluorescence-based replacement assay using serially-diluted reference serum from the Institute for Reference Materials and Measurements (ERM-DA471/IFCC). Our results suggest that the assay covers the physiological and pathological ranges of hCC.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 500
    Sprache Englisch
    Erscheinungsdatum 2016-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Isolation and light chain shuffling of a Plasmodium falciparum AMA1-specific human monoclonal antibody with growth inhibitory activity

    Melanie Seidel-Greven / Otchere Addai-Mensah / Holger Spiegel / Gwladys Nina Chiegoua Dipah / Stefan Schmitz / Gudrun Breuer / Margaret Frempong / Andreas Reimann / Torsten Klockenbring / Rainer Fischer / Stefan Barth / Rolf Fendel

    Malaria Journal, Vol 20, Iss 1, Pp 1-

    2021  Band 20

    Abstract: Abstract Background Plasmodium falciparum, the parasite causing malaria, affects populations in many endemic countries threatening mainly individuals with low malaria immunity, especially children. Despite the approval of the first malaria vaccine ... ...

    Abstract Abstract Background Plasmodium falciparum, the parasite causing malaria, affects populations in many endemic countries threatening mainly individuals with low malaria immunity, especially children. Despite the approval of the first malaria vaccine Mosquirix™ and very promising data using cryopreserved P. falciparum sporozoites (PfSPZ), further research is needed to elucidate the mechanisms of humoral immunity for the development of next-generation vaccines and alternative malaria therapies including antibody therapy. A high prevalence of antibodies against AMA1 in immune individuals has made this antigen one of the major blood-stage vaccine candidates. Material and methods Using antibody phage display, an AMA1-specific growth inhibitory human monoclonal antibody from a malaria-immune Fab library using a set of three AMA1 diversity covering variants (DiCo 1–3), which represents a wide range of AMA1 antigen sequences, was selected. The functionality of the selected clone was tested in vitro using a growth inhibition assay with P. falciparum strain 3D7. To potentially improve affinity and functional activity of the isolated antibody, a phage display mediated light chain shuffling was employed. The parental light chain was replaced with a light chain repertoire derived from the same population of human V genes, these selected antibodies were tested in binding tests and in functionality assays. Results The selected parental antibody achieved a 50% effective concentration (EC50) of 1.25 mg/mL. The subsequent light chain shuffling led to the generation of four derivatives of the parental clone with higher expression levels, similar or increased affinity and improved EC50 against 3D7 of 0.29 mg/mL. Pairwise epitope mapping gave evidence for binding to AMA1 domain II without competing with RON2. Conclusion We have thus shown that a compact immune human phage display library is sufficient for the isolation of potent inhibitory monoclonal antibodies and that minor sequence mutations dramatically increase expression levels ...
    Schlagwörter Malaria ; Plasmodium falciparum ; Apical membrane antigen 1 ; Human monoclonal antibodies ; Parasite growth inhibition ; Phage display ; Arctic medicine. Tropical medicine ; RC955-962 ; Infectious and parasitic diseases ; RC109-216
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2021-01-01T00:00:00Z
    Verlag BMC
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: Restoration of DAP Kinase Tumor Suppressor Function

    Mehmet Kemal Tur / Adebukola K. Daramola / Stefan Gattenlöhner / Marco Herling / Shivan Chetty / Stefan Barth

    Biomedicines, Vol 5, Iss 4, p

    A Therapeutic Strategy to Selectively Induce Apoptosis in Cancer Cells Using Immunokinase Fusion Proteins

    2017  Band 59

    Abstract: Targeted cancer immunotherapy is designed to selectively eliminate tumor cells without harming the surrounding healthy tissues. The death-associated protein kinases (DAPk) are a family of proapoptotic proteins that play a vital role in the regulation of ... ...

    Abstract Targeted cancer immunotherapy is designed to selectively eliminate tumor cells without harming the surrounding healthy tissues. The death-associated protein kinases (DAPk) are a family of proapoptotic proteins that play a vital role in the regulation of cellular process and have been identified as positive mediators of apoptosis via extrinsic and intrinsic death-regulating signaling pathways. Tumor suppressor activities have been shown for DAPk1 and DAPk2 and they are downregulated in e.g., Hodgkin’s (HL) and B cell lymphoma (CLL), respectively. Here, we review a targeted therapeutic approach which involves reconstitution of DAPks by the generation of immunokinase fusion proteins. These recombinant proteins consist of a disease-specific ligand fused to a modified version of DAPk1 or DAPk2. HL was targeted via CD30 and B-CLL via CD22 cell surface antigens.
    Schlagwörter cancer immunotherapy ; death-associated protein kinases (DAPk) ; apoptosis inducers ; humanised cytolytic fusion proteins (hCFPs) ; Biology (General) ; QH301-705.5
    Sprache Englisch
    Erscheinungsdatum 2017-10-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells

    Sandra Jordaan / Olusiji A. Akinrinmade / Thomas Nachreiner / Christian Cremer / Krupa Naran / Shivan Chetty / Stefan Barth

    Biomedicines, Vol 6, Iss 1, p

    2018  Band 28

    Abstract: Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein ...

    Abstract Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate. Ribonucleases are attractive candidates, due to their ability to induce apoptosis by abrogating protein biosynthesis via tRNA degradation. In fact, several RNases of the pancreatic RNase A superfamily have shown potential as anti-cancer agents. Coupling of a human RNase to a humanized antibody or antibody derivative putatively eliminates the immunogenicity of an IT (now known as a human cytolytic fusion protein, hCFP). However, RNases are tightly regulated in vivo by endogenous inhibitors, controlling the ribonucleolytic balance subject to the cell’s metabolic requirements. Endogenous inhibition limits the efficacy with which RNase-based hCFPs induce apoptosis. However, abrogating the natural interaction with the natural inhibitors by mutation has been shown to significantly enhance RNase activity, paving the way toward achieving cytolytic potency comparable to that of bacterial immunotoxins. Here, we review the immunoRNases that have undergone preclinical studies as anti-cancer therapeutic agents.
    Schlagwörter cancer immunotherapy ; ranpirnase ; human RNases ; apoptosis inducers ; humanized cytolytic fusion proteins (hCFPs) ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 610 ; 500
    Sprache Englisch
    Erscheinungsdatum 2018-03-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel ; Online: Using the SNAP-Tag technology to easily measure and demonstrate apoptotic changes in cancer and blood cells with different dyes.

    Mira Woitok / Elena Grieger / Olusiji A Akinrinmade / Susanne Bethke / Anh Tuan Pham / Christoph Stein / Rolf Fendel / Rainer Fischer / Stefan Barth / Judith Niesen

    PLoS ONE, Vol 15, Iss 12, p e

    2020  Band 0243286

    Abstract: In vitro and ex vivo development of novel therapeutic agents requires reliable and accurate analyses of the cell conditions they were preclinical tested for, such as apoptosis. The detection of apoptotic cells by annexin V (AV) coupled to fluorophores ... ...

    Abstract In vitro and ex vivo development of novel therapeutic agents requires reliable and accurate analyses of the cell conditions they were preclinical tested for, such as apoptosis. The detection of apoptotic cells by annexin V (AV) coupled to fluorophores has often shown limitations in the choice of the dye due to interference with other fluorescent-labeled cell markers. The SNAP-tag technology is an easy, rapid and versatile method for functionalization of proteins and was therefore used for labeling AV with various fluorophores. We generated the fusion protein AV-SNAP and analyzed its capacity for the specific display of apoptotic cells in various assays with therapeutic agents. AV-SNAP showed an efficient coupling reaction with five different fluorescent dyes. Two selected fluorophores were tested with suspension, adherent and peripheral blood cells, treated by heat-shock or apoptosis-inducing therapeutic agents. Flow cytometry analysis of apoptotic cells revealed a strong visualization using AV-SNAP coupled to these two fluorophores exemplary, which was comparable to a commercial AV-Assay-kit. The combination of the apoptosis-specific binding protein AV with the SNAP-tag provides a novel solid method to facilitate protein labeling using several, easy to change, fluorescent dyes at once. It avoids high costs and allows an ordinary exchange of dyes and easier use of other fluorescent-labeled cell markers, which is of high interest for the preclinical testing of therapeutic agents in e.g. cancer research.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2020-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  8. Artikel ; Online: Antibody-Based Immunotherapy

    Fleury Augustin Nsole Biteghe / Nyangone Ekome Toung Chalomie / Neelakshi Mungra / Guillaume Vignaux / Nan Gao / Aurelia Vergeade / Ambrose Okem / Krupa Naran / Jean De La Croix Ndong / Stefan Barth

    Biomedicines, Vol 8, Iss 327, p

    Alternative Approaches for the Treatment of Metastatic Melanoma

    2020  Band 327

    Abstract: Melanoma is the least common form of skin cancer and is associated with the highest mortality. Where melanoma is mostly unresponsive to conventional therapies (e.g., chemotherapy), BRAF inhibitor treatment has shown improved therapeutic outcomes. ... ...

    Abstract Melanoma is the least common form of skin cancer and is associated with the highest mortality. Where melanoma is mostly unresponsive to conventional therapies (e.g., chemotherapy), BRAF inhibitor treatment has shown improved therapeutic outcomes. Photodynamic therapy (PDT) relies on a light-activated compound to produce death-inducing amounts of reactive oxygen species (ROS). Their capacity to selectively accumulate in tumor cells has been confirmed in melanoma treatment with some encouraging results. However, this treatment approach has not reached clinical fruition for melanoma due to major limitations associated with the development of resistance and subsequent side effects. These adverse effects might be bypassed by immunotherapy in the form of antibody–drug conjugates (ADCs) relying on the ability of monoclonal antibodies (mAbs) to target specific tumor-associated antigens (TAAs) and to be used as carriers to specifically deliver cytotoxic warheads into corresponding tumor cells. Of late, the continued refinement of ADC therapeutic efficacy has given rise to photoimmunotherapy (PIT) (a light-sensitive compound conjugated to mAbs), which by virtue of requiring light activation only exerts its toxic effect on light-irradiated cells. As such, this review aims to highlight the potential clinical benefits of various armed antibody-based immunotherapies, including PDT, as alternative approaches for the treatment of metastatic melanoma.
    Schlagwörter antibody–drug conjugates (ADCs) ; skin cancer (melanoma) ; photodynamic therapy (PDT) ; photoimmunotherapy (PIT) ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2020-09-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  9. Artikel: Novel fusion proteins for the antigen-specific staining and elimination of B cell receptor-positive cell populations demonstrated by a tetanus toxoid fragment C (TTC) model antigen

    Klose, Diana / Annett Marita Jacobi / Rainer Fischer / Stefan Barth / Thomas Nachreiner / Ute Saunders

    BMC biotechnology. 2016 Dec., v. 16, no. 1

    2016  

    Abstract: BACKGROUND: In an earlier study we developed a unique strategy allowing us to specifically eliminate antigen-specific murine B cells via their distinct B cell receptors using a new class of fusion proteins. In the present work we elaborated our idea to ... ...

    Abstract BACKGROUND: In an earlier study we developed a unique strategy allowing us to specifically eliminate antigen-specific murine B cells via their distinct B cell receptors using a new class of fusion proteins. In the present work we elaborated our idea to demonstrate the feasibility of specifically addressing and eliminating human memory B cells. RESULTS: The present study reveals efficient adaptation of the general approach to selectively target and eradicate human memory B cells. In order to demonstrate the feasibility we engineered a fusion protein following the principle of recombinant immunotoxins by combining a model antigen (tetanus toxoid fragment C, TTC) for B cell receptor targeting and a truncated version of Pseudomonas aeruginosa exotoxin A (ETA’) to induce apoptosis after cellular uptake. The TTC-ETA’ fusion protein not only selectively bound to a TTC-reactive murine B cell hybridoma cell line in vitro but also to freshly isolated human memory B cells from immunized donors ex vivo. Specific toxicity was confirmed on an antigen-specific population of human CD27+ memory B cells. CONCLUSIONS: This protein engineering strategy can be used as a generalized platform approach for the construction of therapeutic fusion proteins with disease-relevant antigens as B cell receptor-binding domains, offering a promising approach for the specific depletion of autoreactive B-lymphocytes in B cell-driven autoimmune diseases.
    Schlagwörter antigens ; apoptosis ; autoimmune diseases ; B-lymphocytes ; exotoxins ; humans ; hybridomas ; mice ; models ; protein engineering ; Pseudomonas aeruginosa ; receptors ; staining ; tetanus ; therapeutics ; toxicity
    Sprache Englisch
    Erscheinungsverlauf 2016-12
    Umfang p. 18.
    Erscheinungsort BioMed Central
    Dokumenttyp Artikel
    ISSN 1472-6750
    DOI 10.1186/s12896-016-0249-x
    Datenquelle NAL Katalog (AGRICOLA)

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  10. Artikel ; Online: Human MAP Tau Based Targeted Cytolytic Fusion Proteins

    Olusiji A. Akinrinmade / Sandra Jordaan / Dmitrij Hristodorov / Radoslav Mladenov / Neelakshi Mungra / Shivan Chetty / Stefan Barth

    Biomedicines, Vol 5, Iss 3, p

    2017  Band 36

    Abstract: Some of the most promising small molecule toxins used to generate antibody drug conjugates (ADCs) include anti-mitotic agents (e.g., auristatin and its derivatives) which are designed to attack cancerous cells at their most vulnerable state during ... ...

    Abstract Some of the most promising small molecule toxins used to generate antibody drug conjugates (ADCs) include anti-mitotic agents (e.g., auristatin and its derivatives) which are designed to attack cancerous cells at their most vulnerable state during mitosis. We were interested in identifying a human cystostatic protein eventually showing comparable activities and allowing the generation of corresponding targeted fully human cytolytic fusion proteins. Recently, we identified the human microtubule associated protein tau (MAP tau), which binds specifically to tubulin and modulates the stability of microtubules, thereby blocking mitosis and presumably vesicular transport. By binding and stabilizing polymerized microtubule filaments, MAP tau-based fusion proteins skew microtubule dynamics towards cell cycle arrest and apoptosis. This biological activity makes rapidly proliferating cells (e.g., cancer and inflammatory cells) an excellent target for MAP tau-based targeted treatments. Their superior selectivity for proliferating cells confers additional selectivity towards upregulated tumor-associated antigens at their surface, thereby preventing off-target related toxicity against normal cells bearing tumor-associated antigens at physiologically normal to low levels. In this review, we highlight recent findings on MAP tau-based targeted cytolytic fusion proteins reported in preclinical immunotherapeutic studies.
    Schlagwörter human cytolytic fusion proteins ; immunotherapy ; microtubule associated protein tau (MAP) ; cancer ; inflammatory diseases ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2017-06-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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