Next generation Fc scaffold for multispecific antibodies

Summary: Bispecific antibodies (Bispecifics) demonstrate exceptional clinical potential to address some of the most complex diseases. However, Bispecific production in a single cell often requires the correct pairing of multiple polypeptide chains for desired assembly. This is a considerable hurdle...

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Autores principales:	Bram Estes, Athena Sudom, Danyang Gong, Douglas A. Whittington, Vivian Li, Christopher Mohr, Danqing Li, Timothy P. Riley, Stone D.-H. Shi, Jun Zhang, Fernando Garces, Zhulun Wang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biochemistry Bioengineering Biomolecular engineering Structural biology Science Q
Acceso en línea:	https://doaj.org/article/daec344ee874422b8d613ca7fb390ad7
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spelling	oai:doaj.org-article:daec344ee874422b8d613ca7fb390ad72021-11-28T04:36:35ZNext generation Fc scaffold for multispecific antibodies2589-004210.1016/j.isci.2021.103447https://doaj.org/article/daec344ee874422b8d613ca7fb390ad72021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221014188https://doaj.org/toc/2589-0042Summary: Bispecific antibodies (Bispecifics) demonstrate exceptional clinical potential to address some of the most complex diseases. However, Bispecific production in a single cell often requires the correct pairing of multiple polypeptide chains for desired assembly. This is a considerable hurdle that hinders the development of many immunoglobulin G (IgG)-like bispecific formats. Our approach focuses on the rational engineering of charged residues to facilitate the chain pairing of distinct heavy chains (HC). Here, we deploy structure-guided protein design to engineer charge pair mutations (CPMs) placed in the CH3-CH3′ interface of the fragment crystallizable (Fc) region of an antibody (Ab) to correctly steer heavy chain pairing. When used in combination with our stable effector functionless 2 (SEFL2.2) technology, we observed high pairing efficiency without significant losses in expression yields. Furthermore, we investigate the relationship between CPMs and the sequence diversity in the parental antibodies, proposing a rational strategy to deploy these engineering technologies.Bram EstesAthena SudomDanyang GongDouglas A. WhittingtonVivian LiChristopher MohrDanqing LiTimothy P. RileyStone D.-H. ShiJun ZhangFernando GarcesZhulun WangElsevierarticleBiochemistryBioengineeringBiomolecular engineeringStructural biologyScienceQENiScience, Vol 24, Iss 12, Pp 103447- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biochemistry Bioengineering Biomolecular engineering Structural biology Science Q
spellingShingle	Biochemistry Bioengineering Biomolecular engineering Structural biology Science Q Bram Estes Athena Sudom Danyang Gong Douglas A. Whittington Vivian Li Christopher Mohr Danqing Li Timothy P. Riley Stone D.-H. Shi Jun Zhang Fernando Garces Zhulun Wang Next generation Fc scaffold for multispecific antibodies
description	Summary: Bispecific antibodies (Bispecifics) demonstrate exceptional clinical potential to address some of the most complex diseases. However, Bispecific production in a single cell often requires the correct pairing of multiple polypeptide chains for desired assembly. This is a considerable hurdle that hinders the development of many immunoglobulin G (IgG)-like bispecific formats. Our approach focuses on the rational engineering of charged residues to facilitate the chain pairing of distinct heavy chains (HC). Here, we deploy structure-guided protein design to engineer charge pair mutations (CPMs) placed in the CH3-CH3′ interface of the fragment crystallizable (Fc) region of an antibody (Ab) to correctly steer heavy chain pairing. When used in combination with our stable effector functionless 2 (SEFL2.2) technology, we observed high pairing efficiency without significant losses in expression yields. Furthermore, we investigate the relationship between CPMs and the sequence diversity in the parental antibodies, proposing a rational strategy to deploy these engineering technologies.
format	article
author	Bram Estes Athena Sudom Danyang Gong Douglas A. Whittington Vivian Li Christopher Mohr Danqing Li Timothy P. Riley Stone D.-H. Shi Jun Zhang Fernando Garces Zhulun Wang
author_facet	Bram Estes Athena Sudom Danyang Gong Douglas A. Whittington Vivian Li Christopher Mohr Danqing Li Timothy P. Riley Stone D.-H. Shi Jun Zhang Fernando Garces Zhulun Wang
author_sort	Bram Estes
title	Next generation Fc scaffold for multispecific antibodies
title_short	Next generation Fc scaffold for multispecific antibodies
title_full	Next generation Fc scaffold for multispecific antibodies
title_fullStr	Next generation Fc scaffold for multispecific antibodies
title_full_unstemmed	Next generation Fc scaffold for multispecific antibodies
title_sort	next generation fc scaffold for multispecific antibodies
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/daec344ee874422b8d613ca7fb390ad7
work_keys_str_mv	AT bramestes nextgenerationfcscaffoldformultispecificantibodies AT athenasudom nextgenerationfcscaffoldformultispecificantibodies AT danyanggong nextgenerationfcscaffoldformultispecificantibodies AT douglasawhittington nextgenerationfcscaffoldformultispecificantibodies AT vivianli nextgenerationfcscaffoldformultispecificantibodies AT christophermohr nextgenerationfcscaffoldformultispecificantibodies AT danqingli nextgenerationfcscaffoldformultispecificantibodies AT timothypriley nextgenerationfcscaffoldformultispecificantibodies AT stonedhshi nextgenerationfcscaffoldformultispecificantibodies AT junzhang nextgenerationfcscaffoldformultispecificantibodies AT fernandogarces nextgenerationfcscaffoldformultispecificantibodies AT zhulunwang nextgenerationfcscaffoldformultispecificantibodies
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Next generation Fc scaffold for multispecific antibodies

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