Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo

Abstract FDA-approved anti-PD-L1 antibody drug Atezolizumab is a human IgG1 without glycosylation by an N297A mutation. Aglycosylation of IgG1 has been used to completely remove the unwanted Fc-mediated functions such as antibody-dependent cytotoxicity (ADCC). However, aglycosylated Atezolizumab is...

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Autores principales:	Maohua Li, Rongqing Zhao, Jianxin Chen, Wenzhi Tian, Chenxi Xia, Xudong Liu, Yingzi Li, Song Li, Hunter Sun, Tong Shen, Wenlin Ren, Le Sun
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dc40c43a4c1549208b032432432a8633
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spelling	oai:doaj.org-article:dc40c43a4c1549208b032432432a86332021-12-02T11:37:26ZNext generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo10.1038/s41598-021-85329-92045-2322https://doaj.org/article/dc40c43a4c1549208b032432432a86332021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85329-9https://doaj.org/toc/2045-2322Abstract FDA-approved anti-PD-L1 antibody drug Atezolizumab is a human IgG1 without glycosylation by an N297A mutation. Aglycosylation of IgG1 has been used to completely remove the unwanted Fc-mediated functions such as antibody-dependent cytotoxicity (ADCC). However, aglycosylated Atezolizumab is very unstable and easy to form aggregation, which causes quick development of anti-drug antibody (ADA) in 41% of Atezolizumab-treated cancer patients, eventually leading to loss of efficacy. Here, we report the development of the anti-PD-L1 antibody drug Maxatezo, a glycosylated version of Atezolizumab, with no ADCC activity, better thermo-stability, and significantly improved anti-tumor activity in vivo. Using Atezolizumab as the starting template, we back-mutated A297N to re-install the glycosylation, and inserted a short, flexible amino acid sequence (GGGS) between G237 and G238 in the hinge region of the IgG1 heavy chain. Our data shows that insertion of GGGS, does not alter the anti-PD-L1′s affinity and inhibitory activity, while completely abolishing ADCC activity. Maxatezo has a similar glycosylation profile and expression level (up to 5.4 g/L) as any normal human IgG1. Most importantly, Maxatezo’s thermal stability is much better than Atezolizumab, as evidenced by dramatic increases of Tm1 from 63.55 °C to 71.01 °C and Tagg from 60.7 °C to 71.2 °C. Furthermore, the levels of ADA in mice treated with Maxatezo were significantly lower compared with animals treated with Atezolizumab. Most importantly, at the same dose (10 mg/kg), the tumor growth inhibition rate of Maxatezo was 98%, compared to 68% for Atezolizumab.Maohua LiRongqing ZhaoJianxin ChenWenzhi TianChenxi XiaXudong LiuYingzi LiSong LiHunter SunTong ShenWenlin RenLe SunNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maohua Li Rongqing Zhao Jianxin Chen Wenzhi Tian Chenxi Xia Xudong Liu Yingzi Li Song Li Hunter Sun Tong Shen Wenlin Ren Le Sun Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo
description	Abstract FDA-approved anti-PD-L1 antibody drug Atezolizumab is a human IgG1 without glycosylation by an N297A mutation. Aglycosylation of IgG1 has been used to completely remove the unwanted Fc-mediated functions such as antibody-dependent cytotoxicity (ADCC). However, aglycosylated Atezolizumab is very unstable and easy to form aggregation, which causes quick development of anti-drug antibody (ADA) in 41% of Atezolizumab-treated cancer patients, eventually leading to loss of efficacy. Here, we report the development of the anti-PD-L1 antibody drug Maxatezo, a glycosylated version of Atezolizumab, with no ADCC activity, better thermo-stability, and significantly improved anti-tumor activity in vivo. Using Atezolizumab as the starting template, we back-mutated A297N to re-install the glycosylation, and inserted a short, flexible amino acid sequence (GGGS) between G237 and G238 in the hinge region of the IgG1 heavy chain. Our data shows that insertion of GGGS, does not alter the anti-PD-L1′s affinity and inhibitory activity, while completely abolishing ADCC activity. Maxatezo has a similar glycosylation profile and expression level (up to 5.4 g/L) as any normal human IgG1. Most importantly, Maxatezo’s thermal stability is much better than Atezolizumab, as evidenced by dramatic increases of Tm1 from 63.55 °C to 71.01 °C and Tagg from 60.7 °C to 71.2 °C. Furthermore, the levels of ADA in mice treated with Maxatezo were significantly lower compared with animals treated with Atezolizumab. Most importantly, at the same dose (10 mg/kg), the tumor growth inhibition rate of Maxatezo was 98%, compared to 68% for Atezolizumab.
format	article
author	Maohua Li Rongqing Zhao Jianxin Chen Wenzhi Tian Chenxi Xia Xudong Liu Yingzi Li Song Li Hunter Sun Tong Shen Wenlin Ren Le Sun
author_facet	Maohua Li Rongqing Zhao Jianxin Chen Wenzhi Tian Chenxi Xia Xudong Liu Yingzi Li Song Li Hunter Sun Tong Shen Wenlin Ren Le Sun
author_sort	Maohua Li
title	Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo
title_short	Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo
title_full	Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo
title_fullStr	Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo
title_full_unstemmed	Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo
title_sort	next generation of anti-pd-l1 atezolizumab with enhanced anti-tumor efficacy in vivo
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/dc40c43a4c1549208b032432432a8633
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Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo

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