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Biomedicines
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Targeted Human Cytolytic Fusion Proteins
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Targeted Human Cytolytic Fusion Proteins

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 October 2017) | Viewed by 39246

Special Issue Editor

Prof. Dr. Stefan Barth

E-Mail Website
Guest Editor
1. Medical Biotechnology and Immunotherapy Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa
2. South African Research Chair in Cancer Biotechnology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa
Interests: knowledge-driven development of disease-specific diagnostic and therapeutic solutions for unmet medical need

Special Issue Information

Dear Colleagues,

This Special Issue, “Targeted Human Cytolytic Fusion Proteins”, will focus on current advances in research using targeted approaches for disease-selective induction of apoptosis. Recombinant immunotoxins have traditionally combined an antibody targeting a specific cell of interest with a potent cell killing protein/enzyme derived from bacteria or plants. However, reduction in immunogenicity by use of T- and B-cell epitope-depleted bacterial toxins as well as their replacement by human enzymes has resulted in safer and more efficacious fusion proteins.

We cordially invite authors in the field to submit original research or review articles pertaining to this highly expanding field of recombinant immunotherapeutics. Specifically, colleagues working in the following areas are particularly encouraged to submit manuscripts: recombinant antibody technologies to select and identify promising internalizing cell surface receptors for disease-specific targeting, the use of protein engineering to combine these specific ligands with highly effective apoptosis-inducing enzymes, strategies to improve efficient delivery of the catalytic subunits into the intracellular compartments of choice, in silico methods to rationally improve function of hCFP, and lastly endeavours to break any reported resistance of hCFP function.

We look forward to receiving novel and high impact content from contributors.

Prof. Dr. Stefan Barth
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • fusion proteins
  • antibody technologies
  • cytolytic enzymes
  • immunotherapy

Published Papers (6 papers)

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Review

4868 KiB  
Review
Targeting of Tumor Neovasculature with GrB/VEGF121, a Novel Cytotoxic Fusion Protein
by Khalid A. Mohamedali and Michael G. Rosenblum
Biomedicines 2017, 5(3), 42; https://doi.org/10.3390/biomedicines5030042 - 17 Jul 2017
Cited by 1 | Viewed by 4571
Abstract
Angiogenesis is a critical process in numerous diseases, and intervention in neovascularization has therapeutic value in several disease settings, including ocular diseases, arthritis, and in tumor progression and metastatic spread. Various vascular targeting agents have been developed, including those that inhibit growth factor [...] Read more.
Angiogenesis is a critical process in numerous diseases, and intervention in neovascularization has therapeutic value in several disease settings, including ocular diseases, arthritis, and in tumor progression and metastatic spread. Various vascular targeting agents have been developed, including those that inhibit growth factor receptor tyrosine kinases, blocking antibodies that interfere with receptor signal transduction, and strategies that trap growth factor ligands. Limited anti-tumor efficacy studies have suggested that the targeted delivery of the human pro-apoptotic molecule Granzyme B to tumor cells has significant potential for cancer treatment. Here, we review biological vascular targeting agents, and describe a unique vascular targeting agent composed of Granzyme B and the VEGF receptor ligand VEGF121. The fusion protein GrB/VEGF121 demonstrates cytotoxicity at nanomolar or sub-nanomolar levels, excellent pharmacokinetic and efficacy profiles, and has significant therapeutic potential targeting tumor vasculature. Full article
(This article belongs to the Special Issue Targeted Human Cytolytic Fusion Proteins)
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2653 KiB  
Review
CSPG4: A Target for Selective Delivery of Human Cytolytic Fusion Proteins and TRAIL
by Sandra Jordaan, Shivan Chetty, Neelakshi Mungra, Iris Koopmans, Peter E. Van Bommel, Wijnand Helfrich and Stefan Barth
Biomedicines 2017, 5(3), 37; https://doi.org/10.3390/biomedicines5030037 - 28 Jun 2017
Cited by 17 | Viewed by 7536
Abstract
Chondroitin-sulfate proteoglycan 4 (CSPG4) is a transmembrane glycoprotein overexpressed on malignant cells in several cancer types with only limited expression on normal cells. CSPG4 is implicated in several signaling pathways believed to drive cancer progression, particularly proliferation, motility and metastatic spread. Expression may [...] Read more.
Chondroitin-sulfate proteoglycan 4 (CSPG4) is a transmembrane glycoprotein overexpressed on malignant cells in several cancer types with only limited expression on normal cells. CSPG4 is implicated in several signaling pathways believed to drive cancer progression, particularly proliferation, motility and metastatic spread. Expression may serve as a prognostic marker for survival and risk of relapse in treatment-resistant malignancies including melanoma, triple negative breast cancer, rhabdomyosarcoma and acute lymphoblastic leukemia. This tumor-associated overexpression of CSPG4 points towards a highly promising therapeutic target for antibody-guided cancer therapy. Monoclonal αCSPG4 antibodies have been shown to inhibit cancer progression by blocking ligand access to the CSPG4 extracellular binding sites. Moreover, CSPG4-directed antibody conjugates have been shown to be selectively internalized by CSPG4-expressing cancer cells via endocytosis. CSPG4-directed immunotherapy may be approached in several ways, including: (1) antibody-based fusion proteins for the selective delivery of a pro-apoptotic factors such as tumor necrosis factor-related apoptosis-inducing ligand to agonistic death receptors 4 and 5 on the cell surface; and (2) CSPG4-specific immunotoxins which bind selectively to diseased cells expressing CSPG4, are internalized by them and induce arrest of biosynthesis, closely followed by initiation of apoptotic signaling. Here we review various methods of exploiting tumor-associated CSPG4 expression to improve targeted cancer therapy. Full article
(This article belongs to the Special Issue Targeted Human Cytolytic Fusion Proteins)
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Figure 1

821 KiB  
Review
Human MAP Tau Based Targeted Cytolytic Fusion Proteins
by Olusiji A. Akinrinmade, Sandra Jordaan, Dmitrij Hristodorov, Radoslav Mladenov, Neelakshi Mungra, Shivan Chetty and Stefan Barth
Biomedicines 2017, 5(3), 36; https://doi.org/10.3390/biomedicines5030036 - 27 Jun 2017
Cited by 13 | Viewed by 6214
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Targeted Human Cytolytic Fusion Proteins)
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Figure 1

706 KiB  
Review
Addressing the Immunogenicity of the Cargo and of the Targeting Antibodies with a Focus on Deimmunized Bacterial Toxins and on Antibody-Targeted Human Effector Proteins
by Yehudit Grinberg and Itai Benhar
Biomedicines 2017, 5(2), 28; https://doi.org/10.3390/biomedicines5020028 - 02 Jun 2017
Cited by 9 | Viewed by 4645
Abstract
Third-generation immunotoxins are composed of a human, or humanized, targeting moiety, usually a monoclonal antibody or an antibody fragment, and a non-human effector molecule. Due to the non-human origin of the cytotoxic domain, these molecules stimulate potent anti-drug immune responses, which limit treatment [...] Read more.
Third-generation immunotoxins are composed of a human, or humanized, targeting moiety, usually a monoclonal antibody or an antibody fragment, and a non-human effector molecule. Due to the non-human origin of the cytotoxic domain, these molecules stimulate potent anti-drug immune responses, which limit treatment options. Efforts are made to deimmunize such immunotoxins or to combine treatment with immunosuppression. An alternative approach is using the so-called “human cytotoxic fusion proteins”, in which antibodies are used to target human effector proteins. Here, we present three relevant approaches for reducing the immunogenicity of antibody-targeted protein therapeutics: (1) reducing the immunogenicity of the bacterial toxin, (2) fusing human cytokines to antibodies to generate immunocytokines and (3) addressing the immunogenicity of the targeting antibodies. Full article
(This article belongs to the Special Issue Targeted Human Cytolytic Fusion Proteins)
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Figure 1

2524 KiB  
Review
Glycosylated Triterpenoids as Endosomal Escape Enhancers in Targeted Tumor Therapies
by Hendrik Fuchs, Nicole Niesler, Alexandra Trautner, Simko Sama, Gerold Jerz, Hossein Panjideh and Alexander Weng
Biomedicines 2017, 5(2), 14; https://doi.org/10.3390/biomedicines5020014 - 29 Mar 2017
Cited by 40 | Viewed by 9522
Abstract
Protein-based targeted toxins play an increasingly important role in targeted tumor therapies. In spite of their high intrinsic toxicity, their efficacy in animal models is low. A major reason for this is the limited entry of the toxin into the cytosol of the [...] Read more.
Protein-based targeted toxins play an increasingly important role in targeted tumor therapies. In spite of their high intrinsic toxicity, their efficacy in animal models is low. A major reason for this is the limited entry of the toxin into the cytosol of the target cell, which is required to mediate the fatal effect. Target receptor bound and internalized toxins are mostly either recycled back to the cell surface or lysosomally degraded. This might explain why no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date although more than 500 targeted toxins have been developed within the last decades. To overcome the problem of insufficient endosomal escape, a number of strategies that make use of diverse chemicals, cell-penetrating or fusogenic peptides, and light-induced techniques were designed to weaken the membrane integrity of endosomes. This review focuses on glycosylated triterpenoids as endosomal escape enhancers and throws light on their structure, the mechanism of action, and on their efficacy in cell culture and animal models. Obstacles, challenges, opportunities, and future prospects are discussed. Full article
(This article belongs to the Special Issue Targeted Human Cytolytic Fusion Proteins)
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Graphical abstract

2039 KiB  
Review
Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation
by Anna Bochicchio, Sandra Jordaan, Valeria Losasso, Shivan Chetty, Rodrigo Casasnovas Perera, Emiliano Ippoliti, Stefan Barth and Paolo Carloni
Biomedicines 2017, 5(1), 9; https://doi.org/10.3390/biomedicines5010009 - 17 Feb 2017
Cited by 8 | Viewed by 5941
Abstract
Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or [...] Read more.
Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such “high-resolution” detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields. Full article
(This article belongs to the Special Issue Targeted Human Cytolytic Fusion Proteins)
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