Cargando…

Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells

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 cyto...

Descripción completa

Detalles Bibliográficos
Autores principales: Jordaan, Sandra, Akinrinmade, Olusiji A., Nachreiner, Thomas, Cremer, Christian, Naran, Krupa, Chetty, Shivan, Barth, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874685/
https://www.ncbi.nlm.nih.gov/pubmed/29510557
http://dx.doi.org/10.3390/biomedicines6010028
_version_ 1783310208491061248
author Jordaan, Sandra
Akinrinmade, Olusiji A.
Nachreiner, Thomas
Cremer, Christian
Naran, Krupa
Chetty, Shivan
Barth, Stefan
author_facet Jordaan, Sandra
Akinrinmade, Olusiji A.
Nachreiner, Thomas
Cremer, Christian
Naran, Krupa
Chetty, Shivan
Barth, Stefan
author_sort Jordaan, Sandra
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5874685
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-58746852018-03-29 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 Review 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. MDPI 2018-03-05 /pmc/articles/PMC5874685/ /pubmed/29510557 http://dx.doi.org/10.3390/biomedicines6010028 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Jordaan, Sandra
Akinrinmade, Olusiji A.
Nachreiner, Thomas
Cremer, Christian
Naran, Krupa
Chetty, Shivan
Barth, Stefan
Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells
title Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells
title_full Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells
title_fullStr Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells
title_full_unstemmed Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells
title_short Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells
title_sort updates in the development of immunornases for the selective killing of tumor cells
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874685/
https://www.ncbi.nlm.nih.gov/pubmed/29510557
http://dx.doi.org/10.3390/biomedicines6010028
work_keys_str_mv AT jordaansandra updatesinthedevelopmentofimmunornasesfortheselectivekillingoftumorcells
AT akinrinmadeolusijia updatesinthedevelopmentofimmunornasesfortheselectivekillingoftumorcells
AT nachreinerthomas updatesinthedevelopmentofimmunornasesfortheselectivekillingoftumorcells
AT cremerchristian updatesinthedevelopmentofimmunornasesfortheselectivekillingoftumorcells
AT narankrupa updatesinthedevelopmentofimmunornasesfortheselectivekillingoftumorcells
AT chettyshivan updatesinthedevelopmentofimmunornasesfortheselectivekillingoftumorcells
AT barthstefan updatesinthedevelopmentofimmunornasesfortheselectivekillingoftumorcells