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The B12 Anti-Tryptase Monoclonal Antibody Disrupts the Tetrameric Structure of Heparin-Stabilized -Tryptase to Form Monomers That Are Inactive at Neutral pH and Active at Acidic pH¹

Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298

The novel tetrameric structure of human -tryptase faces each active site into the central pore, thereby restricting access of most biologic protease inhibitors. The mechanism by which the anti-tryptase mAb B12 inhibits human -tryptase peptidase and proteolytic activities at neutral pH, but augments proteolytic activity at acidic pH, was examined. At neutral pH, B12--tryptase complexes are inactive. At acidic pH, B12 (intact and Fab) minimally affects peptidase activity when added to -tryptase tetramers, but does induce susceptibility to inhibition by soybean trypsin inhibitor and antithrombin III. Surprisingly, B12 Fab--tryptase complexes formed at both neutral and acidic pH exhibit the apparent molecular mass of a complex with 1 -tryptase monomer and 1 Fab by gel filtration. B12 does not compete with heparin for binding to tryptase at either neutral or acidic pH. Thus, B12 directly disrupts -tryptase tetramers to monomers that are inactive at neutral pH, whereas at acidic pH, are active and more accessible to protein inhibitors and substrates.

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				Y. Fukuoka, H.-Z. Xia, L. B. Sanchez-Munoz, A. L. Dellinger, L. Escribano, and L. B. Schwartz Generation of Anaphylatoxins by Human {beta}-Tryptase from C3, C4, and C5 J. Immunol., May 1, 2008; 180(9): 6307 - 6316. [Abstract] [Full Text] [PDF]