Generation and optimization of human antagonistic antibodies against TIMP-1 as potential therapeutic agents in fibrotic diseases.

Impaired matrix metalloproteinase 1 (MMP-1) function, as result of the expression of increased levels of tissue inhibitor of metalloproteinase 1 (TIMP-1), plays an important role in the pathopysiolgical mechanism of fibrosis. In a recently performed clinically relevant rat animal model of established liver fibrosis, it could be shown, that blocking the interaction between the metalloproteinase and its inhibitor has beneficial effects in vivo. The rat TIMP-1 specific antagonistic antibody used in this study was derived from a human combinatorial antibody library (HuCAL) and blocks the interaction between rat TIMP-1 and MMP-13, the rat homologue of human MMP-1.

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats.

Liver fibrosis is characterized by increased synthesis, and decreased degradation, of extracellular matrix (ECM) within the injured tissue. Decreased ECM degradation results, in part, from increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which blocks matrix metalloproteinase (MMP) activity. TIMP-1 is also involved in promoting survival of activated hepatic stellate cells (HSCs), a major source of ECM.