Selective cleavage of human IgG by the matrix metalloproteinases, matrilysin and stromelysin.
We have shown that two of the matrix metalloproteinases (MMPs), matrilysin and stromelysin-1, are capable of cleaving all of the human IgG subclasses. The cleavage occurs at a conserved site in the CH(2) domain of the heavy chain of IgG, releasing a single chain Fc-like fragment. We have not been able to demonstrate cleavage of IgA, IgD, IgM or IgE classes, which lack the cleavage site, nor could we show cleavage of IgG by collagenase, gelatinase, macrophage metalloelastase or membrane-type (MT)-MMP. This cleavage of IgG, by separating the antigen-binding (Fabprime prime or minute)(2) from the Fc portion, will remove much of the immunoglobulins' functionality, e.g. complement fixation, Fc receptor binding. In the context of a tumour producing matrilysin or stromelysin, this may represent a way in which the tumour protects itself from ADCC. In inflamed or damaged tissues where plasma protein leakage occurs, degradation by MMPs may be a mechanism for clearance of IgG.
Gearing
Andrew J H
AJ
British Biotech Pharmaceuticals Ltd., Oxford OX4 5LY, UK.
Thorpe
Susan J
SJ
Miller
Karen
K
Mangan
Matthew
M
Varley
Paul G
PG
Dudgeon
Tim
T
Ward
George
G
Turner
Christina
C
Thorpe
Robin
R
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D008969:Molecular Sequence Data; D010206:Papain / Q000378:metabolism; D010434:Pepsin A / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D007074:Immunoglobulin G; D011994:Recombinant Proteins; D010206:Papain; D010434:Pepsin A; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7