Discovery of a new class of integrin antibodies for fibrosis
Abstract Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of αv integrins that reduces prot...
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Nature Portfolio
2021
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oai:doaj.org-article:3c77d995775e4a3aa500d4b475ea85912021-12-02T10:49:34ZDiscovery of a new class of integrin antibodies for fibrosis10.1038/s41598-021-81253-02045-2322https://doaj.org/article/3c77d995775e4a3aa500d4b475ea85912021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81253-0https://doaj.org/toc/2045-2322Abstract Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab’s yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFβ activation. In IPF patient lung fibroblasts, TGFβ treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated potent in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFβ action though mechanisms beyond the inhibition of latent TGFβ activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases.Ji ZhangTao WangAshmita SaigalJosephine JohnsonJennifer MorrissonSahba TabrizifardScott A. HollingsworthMichael J. EddinsWenxian MaoKim O’NeillMargarita Garcia-CalvoEster Carballo-JaneDingGang LiuTaewon HamQiong ZhouWeifeng DongHsien-Wei MengJacqueline HicksTian-Quan CaiTaro AkiyamaShirly PintoAlan C. ChengThomas GreshockJohn C. MarquisZhao RenSaswata TalukdarHussam Hisham ShaheenMasahisa HandaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
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Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Ji Zhang Tao Wang Ashmita Saigal Josephine Johnson Jennifer Morrisson Sahba Tabrizifard Scott A. Hollingsworth Michael J. Eddins Wenxian Mao Kim O’Neill Margarita Garcia-Calvo Ester Carballo-Jane DingGang Liu Taewon Ham Qiong Zhou Weifeng Dong Hsien-Wei Meng Jacqueline Hicks Tian-Quan Cai Taro Akiyama Shirly Pinto Alan C. Cheng Thomas Greshock John C. Marquis Zhao Ren Saswata Talukdar Hussam Hisham Shaheen Masahisa Handa Discovery of a new class of integrin antibodies for fibrosis |
| description |
Abstract Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab’s yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFβ activation. In IPF patient lung fibroblasts, TGFβ treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated potent in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFβ action though mechanisms beyond the inhibition of latent TGFβ activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases. |
| format |
article |
| author |
Ji Zhang Tao Wang Ashmita Saigal Josephine Johnson Jennifer Morrisson Sahba Tabrizifard Scott A. Hollingsworth Michael J. Eddins Wenxian Mao Kim O’Neill Margarita Garcia-Calvo Ester Carballo-Jane DingGang Liu Taewon Ham Qiong Zhou Weifeng Dong Hsien-Wei Meng Jacqueline Hicks Tian-Quan Cai Taro Akiyama Shirly Pinto Alan C. Cheng Thomas Greshock John C. Marquis Zhao Ren Saswata Talukdar Hussam Hisham Shaheen Masahisa Handa |
| author_facet |
Ji Zhang Tao Wang Ashmita Saigal Josephine Johnson Jennifer Morrisson Sahba Tabrizifard Scott A. Hollingsworth Michael J. Eddins Wenxian Mao Kim O’Neill Margarita Garcia-Calvo Ester Carballo-Jane DingGang Liu Taewon Ham Qiong Zhou Weifeng Dong Hsien-Wei Meng Jacqueline Hicks Tian-Quan Cai Taro Akiyama Shirly Pinto Alan C. Cheng Thomas Greshock John C. Marquis Zhao Ren Saswata Talukdar Hussam Hisham Shaheen Masahisa Handa |
| author_sort |
Ji Zhang |
| title |
Discovery of a new class of integrin antibodies for fibrosis |
| title_short |
Discovery of a new class of integrin antibodies for fibrosis |
| title_full |
Discovery of a new class of integrin antibodies for fibrosis |
| title_fullStr |
Discovery of a new class of integrin antibodies for fibrosis |
| title_full_unstemmed |
Discovery of a new class of integrin antibodies for fibrosis |
| title_sort |
discovery of a new class of integrin antibodies for fibrosis |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/3c77d995775e4a3aa500d4b475ea8591 |
| work_keys_str_mv |
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| _version_ |
1718396583964311552 |