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Article ; Online: Click Chemistry-Generated Auristatin F-Linker-Benzylguanine for a SNAP-Tag-Based Recombinant Antibody-Drug Conjugate Demonstrating Selective Cytotoxicity toward EGFR-Overexpressing Tumor Cells.

Huysamen, Allan M / Fadeyi, Olaolu E / Mayuni, Grace / Dogbey, Dennis M / Mungra, Neelakshi / Biteghe, Fleury A N / Hardcastle, Natasha / Ramamurthy, Dharanidharan / Akinrinmade, Olusiji A / Naran, Krupa / Cooper, Susan / Lang, Dirk / Richter, Wolfgang / Hunter, Roger / Barth, Stefan

ACS omega

2023 Volume 8, Issue 4, Page(s) 4026–4037

Abstract: Antibody-drug conjugates (ADCs) are bifunctional molecules combining the targeting potential of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs. This simple yet intelligently designed system directly addresses the lack of ... ...

Abstract	Antibody-drug conjugates (ADCs) are bifunctional molecules combining the targeting potential of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs. This simple yet intelligently designed system directly addresses the lack of specificity encountered with conventional anti-cancer treatment regimes. However, despite their initial success, the generation of clinically sustainable and effective ADCs has been plagued by poor tumor penetration, undefined chemical linkages, unpredictable pharmacokinetic profiles, and heterogeneous mixtures of products. To this end, we generated a SNAP-tag-based fusion protein targeting the epidermal growth factor receptor (EGFR)-a biomarker of aggressive and drug-resistant cancers. Here, we demonstrate the use of a novel click coupling strategy to engineer a benzylguanine (BG)-linker-auristatin F (AuriF) piece that can be covalently tethered to the EGFR-targeting SNAP-tag-based fusion protein in an irreversible 1:1 stoichiometric reaction to form a homogeneous product. Furthermore, using these recombinant ADCs to target EGFR-overexpressing tumor cells, we provide a proof-of-principle for generating biologically active antimitotic therapeutic proteins capable of inducing cell death in a dose-dependent manner, thus alleviating some of the challenges of early ADC development.
Language	English
Publishing date	2023-01-17
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.2c06844
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Human Granzyme B Based Targeted Cytolytic Fusion Proteins.

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

Biomedicines

2018 Volume 6, Issue 2

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.
Language	English
Publishing date	2018-06-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines6020072
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Article ; 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 Volume 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 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.
Keywords	cancer immunotherapy ; granzyme B (GrB) ; human cytolytic fusion proteins (hCFPs) ; immunotoxins (ITs) ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2018-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: CD64: An Attractive Immunotherapeutic Target for M1-type Macrophage Mediated Chronic Inflammatory Diseases.

Akinrinmade, Olusiji A / Chetty, Shivan / Daramola, Adebukola K / Islam, Mukit-Ul / Thepen, Theo / Barth, Stefan

Biomedicines

2017 Volume 5, Issue 3

Abstract: To date, no curative therapy is available for the treatment of most chronic inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, or autoimmune disorders. Current treatments require a lifetime supply for patients to alleviate clinical ... ...

Abstract	To date, no curative therapy is available for the treatment of most chronic inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, or autoimmune disorders. Current treatments require a lifetime supply for patients to alleviate clinical symptoms and are unable to stop the course of disease. In contrast, a new series of immunotherapeutic agents targeting the Fc γ receptor I (CD64) have emerged and demonstrated significant clinical potential to actually resolving chronic inflammation driven by M1-type dysregulated macrophages. This subpopulation plays a key role in the initiation and maintenance of a series of chronic diseases. The novel recombinant M1-specific immunotherapeutics offer the prospect of highly effective treatment strategies as they have been shown to selectively eliminate the disease-causing macrophage subpopulations. In this review, we provide a detailed summary of the data generated, together with the advantages and the clinical potential of CD64-based targeted therapies for the treatment of chronic inflammatory diseases.
Language	English
Publishing date	2017-09-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines5030056
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Article: Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells.

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

Biomedicines

2018 Volume 6, Issue 1

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.
Language	English
Publishing date	2018-03-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines6010028
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Article ; Online: Using the SNAP-Tag technology to easily measure and demonstrate apoptotic changes in cancer and blood cells with different dyes.

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

PloS one

2020 Volume 15, Issue 12, Page(s) e0243286

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.
MeSH term(s)	Affinity Labels/chemistry ; Annexin A5/chemistry ; Annexin A5/metabolism ; Apoptosis/physiology ; Blood Cells/metabolism ; Cell Line, Tumor ; Flow Cytometry/methods ; Fluorescent Dyes/chemistry ; Humans ; Neoplasms/metabolism ; Proteins/chemistry ; Proteins/metabolism ; Staining and Labeling/methods ; Technology
Chemical Substances	Affinity Labels ; Annexin A5 ; Fluorescent Dyes ; Proteins
Language	English
Publishing date	2020-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0243286
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Article ; 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 Volume 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 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.
Keywords	cancer immunotherapy ; ranpirnase ; human RNases ; apoptosis inducers ; humanized cytolytic fusion proteins (hCFPs) ; Biology (General) ; QH301-705.5
Subject code	610 ; 500
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Human MAP Tau Based Targeted Cytolytic Fusion Proteins.

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

Biomedicines

2017 Volume 5, Issue 3

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.
Language	English
Publishing date	2017-06-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines5030036
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; 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 Volume 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 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.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; 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 Volume 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 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.
Keywords	human cytolytic fusion proteins ; immunotherapy ; microtubule associated protein tau (MAP) ; cancer ; inflammatory diseases ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2017-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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