A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors

Summary: Receptor clustering is the first and critical step to activate apoptosis by death receptor-5 (DR5). The recent discovery of the autoinhibitory DR5 ectodomain has challenged the long-standing view of its mechanistic activation by the natural ligand Apo2L. Because the autoinhibitory residues...

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Autores principales:	Gururaj Shivange, Tanmoy Mondal, Evan Lyerly, Sanchita Bhatnagar, Charles N. Landen, Shivani Reddy, Jonathan Kim, Britney Doan, Paula Riddle, Jogender Tushir-Singh
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	TNF superfamily receptor clustering death receptor ovarian tumors TNBC solid tumors Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/60c0e8c51e324df1a195182838329e2c
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spelling	oai:doaj.org-article:60c0e8c51e324df1a195182838329e2c2021-11-04T04:29:48ZA patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors2211-124710.1016/j.celrep.2021.109953https://doaj.org/article/60c0e8c51e324df1a195182838329e2c2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211124721014303https://doaj.org/toc/2211-1247Summary: Receptor clustering is the first and critical step to activate apoptosis by death receptor-5 (DR5). The recent discovery of the autoinhibitory DR5 ectodomain has challenged the long-standing view of its mechanistic activation by the natural ligand Apo2L. Because the autoinhibitory residues have remained unknown, here we characterize a crucial patch of positively charged residues (PPCR) in the highly variable domain of DR5. The PPCR electrostatically separates DR5 receptors to autoinhibit their clustering in the absence of ligand and antibody binding. Mutational substitution and antibody-mediated PPCR interference resulted in increased apoptotic cytotoxic function. A dually specific antibody that enables sustained tampering with PPCR function exceptionally enhanced DR5 clustering and apoptotic activation and distinctively improved the survival of animals bearing aggressive metastatic and recurrent tumors, whereas clinically tested DR5 antibodies without PPCR blockade function were largely ineffective. Our study provides mechanistic insights into DR5 activation and a therapeutic analytical design for potential clinical success.Gururaj ShivangeTanmoy MondalEvan LyerlySanchita BhatnagarCharles N. LandenShivani ReddyJonathan KimBritney DoanPaula RiddleJogender Tushir-SinghElsevierarticleTNF superfamilyreceptor clusteringdeath receptorovarian tumorsTNBCsolid tumorsBiology (General)QH301-705.5ENCell Reports, Vol 37, Iss 5, Pp 109953- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TNF superfamily receptor clustering death receptor ovarian tumors TNBC solid tumors Biology (General) QH301-705.5
spellingShingle	TNF superfamily receptor clustering death receptor ovarian tumors TNBC solid tumors Biology (General) QH301-705.5 Gururaj Shivange Tanmoy Mondal Evan Lyerly Sanchita Bhatnagar Charles N. Landen Shivani Reddy Jonathan Kim Britney Doan Paula Riddle Jogender Tushir-Singh A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors
description	Summary: Receptor clustering is the first and critical step to activate apoptosis by death receptor-5 (DR5). The recent discovery of the autoinhibitory DR5 ectodomain has challenged the long-standing view of its mechanistic activation by the natural ligand Apo2L. Because the autoinhibitory residues have remained unknown, here we characterize a crucial patch of positively charged residues (PPCR) in the highly variable domain of DR5. The PPCR electrostatically separates DR5 receptors to autoinhibit their clustering in the absence of ligand and antibody binding. Mutational substitution and antibody-mediated PPCR interference resulted in increased apoptotic cytotoxic function. A dually specific antibody that enables sustained tampering with PPCR function exceptionally enhanced DR5 clustering and apoptotic activation and distinctively improved the survival of animals bearing aggressive metastatic and recurrent tumors, whereas clinically tested DR5 antibodies without PPCR blockade function were largely ineffective. Our study provides mechanistic insights into DR5 activation and a therapeutic analytical design for potential clinical success.
format	article
author	Gururaj Shivange Tanmoy Mondal Evan Lyerly Sanchita Bhatnagar Charles N. Landen Shivani Reddy Jonathan Kim Britney Doan Paula Riddle Jogender Tushir-Singh
author_facet	Gururaj Shivange Tanmoy Mondal Evan Lyerly Sanchita Bhatnagar Charles N. Landen Shivani Reddy Jonathan Kim Britney Doan Paula Riddle Jogender Tushir-Singh
author_sort	Gururaj Shivange
title	A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors
title_short	A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors
title_full	A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors
title_fullStr	A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors
title_full_unstemmed	A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors
title_sort	patch of positively charged residues regulates the efficacy of clinical dr5 antibodies in solid tumors
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/60c0e8c51e324df1a195182838329e2c
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A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors

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