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

摘要

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. We here describe the utilization of the same antibody source to generate fully human antibodies against human TIMP-1 which could be potential candidates for a therapy of fibrosis in man. In order to develop a highly potent antagonist of TIMP-1 action, antibodies isolated from the library were subjected to a number of different in vitro affinity maturation strategies. By these means, affinity and potency were improved by a factor of 87 and 65 fold, respectively, resulting in a valuable human therapeutic antibody candidate with a monovalent affinity of 150 pM and a potency for in vitro inhibition of TIMP-1/MMP-1 interaction of 200 pM.