Complement inactivation by recombinant human C3 derivatives.
From the implications of the complement system in a large number of diseases, an urgent need for therapeutics effecting reduced complement activity in vivo has emerged. In this study we report the design of a novel class of enzymes of human origin that obliterate functional complement by a noninhibitory, catalytic mechanism. Combining the framework of human C3 and the enzymatic mechanism of cobra venom factor, a nontoxic snake venom protein, we established molecules capable of forming stable C3 convertase complexes. Although the half-life of naturally occurring C3 convertase complexes ranges between 1 and 2 min, these complexes exhibit a half-life of up to several hours. Because the overall identity to human C3 could be extended to >90%, the novel C3 derivatives can be assumed to exhibit low immunogenicity and, therefore, represent promising candidates for therapeutic reduction of complement activity in vivo.
Kölln
Johanna
J
Institut für Biochemie und Lebensmittelchemie, Abteilung für Biochemie, und Molekularbiologie, Universität Hamburg, Hamburg, Germany.
Spillner
Edzard
E
Andrä
Jörg
J
Klensang
Katrin
K
Bredehorst
Reinhard
R
D000818:Animals; D016466:CHO Cells; D002384:Catalysis; D003167:Complement Activation / Q000276:immunology; D003176:Complement C3 / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D050577:Complement C3-C5 Convertases / Q000138:chemical synthesis; D003169:Complement Inactivator Proteins / Q000302:isolation & purification / Q000502:physiology*; D003170:Complement Pathway, Alternative; D006224:Cricetinae; D004546:Elapid Venoms / Q000096:biosynthesis / Q000235:genetics; D004912:Erythrocytes / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000097:blood; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology*; D012756:Sheep; D014162:Transfection
D003176:Complement C3; D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; D007106:Immune Sera; D011994:Recombinant Proteins; C016310:cobra venom factor; D050577:Complement C3-C5 Convertases