Inhibition of Extracellular Tissue Transglutaminase (TG2) Activity Attenuates Development of Pulmonary Fibrosis in a...

Pulmonary fibrosis is an interstitial scarring disease of the lung characterized by poor prognosis and limited treatment options. Tissue transglutaminase (TG2) is believed to promote lung fibrosis by crosslinking extracellular matrix components and activating latent TGFβ. This study evaluates the contribution of TG2 to pulmonary fibrosis in human lung tissue from donors with idiopathic pulmonary fibrosis (IPF) and in a novel rabbit model of pulmonary silicosis, using a therapeutic TG2 blocking antibody to inhibit extracellular matrix crosslinking. Human IPF tissue expressed elevated levels of TG2 antigen and Tgm2 RNA as detected by in situ hybridization. and antigen. Silica-treated rabbits developed lung fibrosis with increased collagen and increased TG2 enzymatic activity. Treatment with TG2 inhibitory antibody rbBB7, a rabbitized version of the human therapeutic antibody zampilimab, reduced TG2 activity and attenuated fibrosis by 50% when used in either a prevention or treatment strategy, which was associated, with reductions in interstitial collagen accumulation. TG2 has previously been reported to contribute to pulmonary fibrosis in the mouse bleomycin model, leading to the conclusion that TG2 contributes significantly to the pathogenesis of pulmonary fibrosis as demonstrated in human tissue specimens and two independent animal models with different fibrotic stimuli. Blockade of TG2 extracellular crosslinking activity with a therapeutic antibody significantly attenuated the development of fibrosis when given in a prevention strategy or treatment strategy. Blockade of extracellular TG2 activity has exciting therapeutic potential.