Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy
Conventional cancer treatments lack specificity and often cause severe side effects. Targeted therapeutic approaches are therefore preferred, including the use of immunotoxins (ITs) that comprise cell-binding and cell death-inducing components to allow the direct and specific delivery of pro-apoptot...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2013-01-01
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| Series: | Antibodies |
| Subjects: | |
| Online Access: | http://www.mdpi.com/2073-4468/2/1/19 |
| _version_ | 1828161767711178752 |
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| author | Georg Melmer Stefan Barth Nina Berges Grit Hehmann-Titt Sonja Schiffer |
| author_facet | Georg Melmer Stefan Barth Nina Berges Grit Hehmann-Titt Sonja Schiffer |
| author_sort | Georg Melmer |
| collection | DOAJ |
| description | Conventional cancer treatments lack specificity and often cause severe side effects. Targeted therapeutic approaches are therefore preferred, including the use of immunotoxins (ITs) that comprise cell-binding and cell death-inducing components to allow the direct and specific delivery of pro-apoptotic agents into malignant cells. The first generation of ITs consisted of toxins derived from bacteria or plants, making them immunogenic in humans. The recent development of human cytolytic fusion proteins (hCFP) consisting of human effector enzymes offers the prospect of highly-effective targeted therapies with minimal side effects. One of the most promising candidates is granzyme B (GrB) and this enzyme has already demonstrated its potential for targeted cancer therapy. However, the clinical application of GrB may be limited because it is inactivated by the overexpression in tumors of its specific inhibitor serpin B9 (PI-9). It is also highly charged, which means it can bind non-specifically to the surface of non-target cells. Furthermore, human enzymes generally lack an endogenous translocation domain, thus the endosomal release of GrB following receptor-mediated endocytosis can be inefficient. In this review we provide a detailed overview of these challenges and introduce promising solutions to increase the cytotoxic potency of GrB for clinical applications. |
| first_indexed | 2024-04-12T00:44:15Z |
| format | Article |
| id | doaj.art-d91f291eab064c248596b38da70950e6 |
| institution | Directory Open Access Journal |
| issn | 2073-4468 |
| language | English |
| last_indexed | 2024-04-12T00:44:15Z |
| publishDate | 2013-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibodies |
| spelling | doaj.art-d91f291eab064c248596b38da70950e62022-12-22T03:54:56ZengMDPI AGAntibodies2073-44682013-01-0121194910.3390/antib2010019Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer TherapyGeorg MelmerStefan BarthNina BergesGrit Hehmann-TittSonja SchifferConventional cancer treatments lack specificity and often cause severe side effects. Targeted therapeutic approaches are therefore preferred, including the use of immunotoxins (ITs) that comprise cell-binding and cell death-inducing components to allow the direct and specific delivery of pro-apoptotic agents into malignant cells. The first generation of ITs consisted of toxins derived from bacteria or plants, making them immunogenic in humans. The recent development of human cytolytic fusion proteins (hCFP) consisting of human effector enzymes offers the prospect of highly-effective targeted therapies with minimal side effects. One of the most promising candidates is granzyme B (GrB) and this enzyme has already demonstrated its potential for targeted cancer therapy. However, the clinical application of GrB may be limited because it is inactivated by the overexpression in tumors of its specific inhibitor serpin B9 (PI-9). It is also highly charged, which means it can bind non-specifically to the surface of non-target cells. Furthermore, human enzymes generally lack an endogenous translocation domain, thus the endosomal release of GrB following receptor-mediated endocytosis can be inefficient. In this review we provide a detailed overview of these challenges and introduce promising solutions to increase the cytotoxic potency of GrB for clinical applications.http://www.mdpi.com/2073-4468/2/1/19immunotherapyimmunotoxinhuman cytolytic fusion proteinbio-engineeringserpin B9surface-chargeendosomal release |
| spellingShingle | Georg Melmer Stefan Barth Nina Berges Grit Hehmann-Titt Sonja Schiffer Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy Antibodies immunotherapy immunotoxin human cytolytic fusion protein bio-engineering serpin B9 surface-charge endosomal release |
| title | Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy |
| title_full | Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy |
| title_fullStr | Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy |
| title_full_unstemmed | Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy |
| title_short | Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy |
| title_sort | improving the therapeutic potential of human granzyme b for targeted cancer therapy |
| topic | immunotherapy immunotoxin human cytolytic fusion protein bio-engineering serpin B9 surface-charge endosomal release |
| url | http://www.mdpi.com/2073-4468/2/1/19 |
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