Academic Journal
Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo
| Title: | Next generation of anti-PD-L1 Atezolizumab with enhanced anti-tumor efficacy in vivo |
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| Authors: | Maohua Li, Rongqing Zhao, Jianxin Chen, Wenzhi Tian, Chenxi Xia, Xudong Liu, Yingzi Li, Song Li, Hunter Sun, Tong Shen, Wenlin Ren, Le Sun |
| Source: | Scientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) |
| Publisher Information: | Nature Portfolio, 2021. |
| Publication Year: | 2021 |
| Collection: | LCC:Medicine LCC:Science |
| Subject Terms: | Medicine, Science |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2045-2322 |
| Relation: | https://doaj.org/toc/2045-2322 |
| DOI: | 10.1038/s41598-021-85329-9 |
| Access URL: | https://doaj.org/article/dc40c43a4c1549208b032432432a8633 |
| Accession Number: | edsdoj.40c43a4c1549208b032432432a8633 |
| Database: | Directory of Open Access Journals |
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| ISSN: | 20452322 |
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| DOI: | 10.1038/s41598-021-85329-9 |
| Published in: | Scientific Reports |
| Language: | English |