Immune conjugates for prophylaxis and treatment of organ damage - caused by inflammation, esp. sepsis, contain monoclonal antibody, crosslinker and enzyme inhibitor of protein kinase C or calcium antagonist

摘要

Immunocomplexes for the prophylaxis and therapy of organ damage in inflammatory processes have the formula Mab-(F1-(crosslinker R)m-F2-inhibitor)n (I) Where m = 0-1; n = 1-10. The MAb (monoclonal antibody) is an immunoglobulin which binds specifically to an antigen (A). The MAb may be of any immunoglobulin class (IgG, IgM, IgA or IgE) or a fragment, or a chemically modified immunoglobulin (e.g. Fab, F(ab')2, Fab', Fv) that binds specifically with (A). (A) is a leucocyte- or blood vessel endothelial-associated antigen. Crosslinker R binds the antibody and inhibitor by two, pref. different, covalent linkages. It is e.g. succinimidyl-4-(N-maleiminodmethyl) cyclohexane-1-carboxylate (SMCC), m-maleimidobenzoyl-N- hydrosulpho succinimide ester (MBS), succinimidyl-4- (p-maleimido phenyl)butyrate (SMPR), N,N'-(1,2-phenylene) dimaleimide, N,N'-(1,4-phenylene) dimaleimide, 4,4'-bis(maleoylamino) azobenene, bis(N-maleimidomethyl)ester, N,N'-alkylene bis(bromoacetamide) or N,N'-alkylene-bis (iodoacetamide). F1 and F2 are atoms or groups. F1 is e.g. S linked to a disulphide bridge of the MAb and F2 is e.g. N. The inhibitor is an enzyme inhibitor or antagonist. It inhibits intracellular protein kinase C, calcium increase or the calcium-calmodulin system. It is e.g. staurosporine or its derivatives, polymixin beta, H-7, chlorpromazine, calmidazolium, W-7, verpamil, trifluoroperazine or TMB-8. USE/ADVANTAGE - (I) have a high selectivity for leucocytes and endothelial cells and influence their function and metabolism. (I) are useful inpreventing damage to the reticuloendothelial system in inflammation, especially sepsis.