Discovery of a new class of integrin antibodies for fibrosis.

Scientific reports (2021-01-24)
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

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.

Product Number
Product Description

Albumin from chicken egg white, lyophilized powder, ≥98% (agarose gel electrophoresis)
Anti-PCDH15 antibody produced in rabbit, affinity isolated antibody
Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)