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Human MAP Tau Based Targeted Cytolytic Fusion Proteins

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 c...

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Autores principales: Akinrinmade, Olusiji A., Jordaan, Sandra, Hristodorov, Dmitrij, Mladenov, Radoslav, Mungra, Neelakshi, Chetty, Shivan, Barth, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618294/
https://www.ncbi.nlm.nih.gov/pubmed/28653985
http://dx.doi.org/10.3390/biomedicines5030036
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author Akinrinmade, Olusiji A.
Jordaan, Sandra
Hristodorov, Dmitrij
Mladenov, Radoslav
Mungra, Neelakshi
Chetty, Shivan
Barth, Stefan
author_facet Akinrinmade, Olusiji A.
Jordaan, Sandra
Hristodorov, Dmitrij
Mladenov, Radoslav
Mungra, Neelakshi
Chetty, Shivan
Barth, Stefan
author_sort Akinrinmade, Olusiji A.
collection PubMed
description 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.
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spelling pubmed-56182942017-09-29 Human MAP Tau Based Targeted Cytolytic Fusion Proteins Akinrinmade, Olusiji A. Jordaan, Sandra Hristodorov, Dmitrij Mladenov, Radoslav Mungra, Neelakshi Chetty, Shivan Barth, Stefan Biomedicines Review 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. MDPI 2017-06-27 /pmc/articles/PMC5618294/ /pubmed/28653985 http://dx.doi.org/10.3390/biomedicines5030036 Text en © 2017 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
Akinrinmade, Olusiji A.
Jordaan, Sandra
Hristodorov, Dmitrij
Mladenov, Radoslav
Mungra, Neelakshi
Chetty, Shivan
Barth, Stefan
Human MAP Tau Based Targeted Cytolytic Fusion Proteins
title Human MAP Tau Based Targeted Cytolytic Fusion Proteins
title_full Human MAP Tau Based Targeted Cytolytic Fusion Proteins
title_fullStr Human MAP Tau Based Targeted Cytolytic Fusion Proteins
title_full_unstemmed Human MAP Tau Based Targeted Cytolytic Fusion Proteins
title_short Human MAP Tau Based Targeted Cytolytic Fusion Proteins
title_sort human map tau based targeted cytolytic fusion proteins
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618294/
https://www.ncbi.nlm.nih.gov/pubmed/28653985
http://dx.doi.org/10.3390/biomedicines5030036
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