Derivatives of human complement component C3 for therapeutic complement depletion: a novel class of therapeutic agents.
To obtain proteins with the complement-depleting activity of Cobra Venom Factor (CVF), but with less immunogenicity, we have prepared human C3/CVF hybrid proteins, in which the C-terminus of the alpha-chain of human C3 is exchanged with homologous regions of the C-terminus of the beta-chain of CVF. We show that these hybrid proteins are able to deplete complement, both in vitro and in vivo. One hybrid protein, HC3-1496, is shown to be effective in reducing complement-mediated damage in two disease models in mice, collagen-induced arthritis and myocardial ischemia/reperfusion injury. Human C3/CVF hybrid proteins represent a novel class ofbiologicals as potential therapeutic agents in many diseases where complement is involved in the pathogenesis.
Fritzinger
David C
DC
Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
Hew
Brian E
BE
Lee
June Q
JQ
Newhouse
James
J
Alam
Maqsudul
M
Ciallella
John R
JR
Bowers
Mallory
M
Gorsuch
William B
WB
Guikema
Benjamin J
BJ
Stahl
Gregory L
GL
Vogel
Carl-Wilhelm
CW
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D003176:Complement C3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D003165:Complement System Proteins / Q000378:metabolism*; D004546:Elapid Venoms / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
D003176:Complement C3; D004546:Elapid Venoms; D011993:Recombinant Fusion Proteins; C016310:cobra venom factor; D003165:Complement System Proteins