Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential

作者：Sela Passwell Nett A; Kikkeri Raghavendra; Dym Orly; Rozenberg Haim; Margalit Raanan; Arad Yellin Rina; Eisenstein Miriam; Brenner Ori; Shoham Tsipi; Danon Tamar; Shanzer Abraham; Sagi Irit^*

来源：Nature Medicine, 2012, 18(1): 143-147.

DOI：10.1038/nm.2582

Endogenous tissue inhibitors of metalloproteinases (TIMPs) have key roles in regulating physiological and pathological cellular processes(1-3). Imitating the inhibitory molecular mechanisms of TIMPs while increasing selectivity has been a challenging but desired approach for antibody-based therapy(4). TIMPs use hybrid protein-protein interactions to form an energetic bond with the catalytic metal ion, as well as with enzyme surface residues(5-7). We used an innovative immunization strategy that exploits aspects of molecular mimicry to produce inhibitory antibodies that show TIMP-like binding mechanisms toward the activated forms of gelatinases (matrix metalloproteinases 2 and 9). Specifically, we immunized mice with a synthetic molecule that mimics the conserved structure of the metalloenzyme catalytic zinc-histidine complex residing within the enzyme active site. This immunization procedure yielded selective function-blocking monoclonal antibodies directed against the catalytic zinc-protein complex and enzyme surface conformational epitopes of endogenous gelatinases. The therapeutic potential of these antibodies has been demonstrated with relevant mouse models of inflammatory bowel disease(8). Here we propose a general experimental strategy for generating inhibitory antibodies that effectively target the in vivo activity of dysregulated metalloproteinases by mimicking the mechanism employed by TIMPs.

• 出版日期2012-1