A soluble chimeric complement inhibitory protein that possesses both decay-accelerating and factor I cofactor activities.
A chimeric gene was constructed from the genes coding for the human complement regulatory proteins, membrane cofactor protein (CD46) and decay-accelerating factor (CD55). The recombinant chimeric gene was transfected into Chinese hamster ovary cells. The gene product is a soluble, glycosylated, 110-kDa protein named complement activation blocker-2 (CAB-2). This protein possesses both factor I cofactor activity and decay-accelerating activity, and inactivates classical and alternative C3/C5 convertases in vitro. The specific activity of CAB-2 against cell-associated convertases is greater than that of soluble forms of either membrane cofactor protein or decay-accelerating factor or of both factors combined. CAB-2 also blocks the activation of complement in vivo, inhibiting both the Arthus reaction and Forssman shock in guinea pigs. Studies in rats demonstrate CAB-2 to exhibit favorable biphasic pharmacokinetics with a t1/2 alpha of 10 min and a t1/2 beta of 8 h; the beta phase accounts for 93% of the administered dose. CAB-2 may be an effective therapeutic treatment of acute human diseases in which excessive complement activation causes damage to normal tissues.
Higgins
P J
PJ
CytoMed, Inc., Cambridge, MA 02139, USA.
Ko
J L
JL
Lobell
R
R
Sardonini
C
C
Alessi
M K
MK
Yeh
C G
CG
D000707:Anaphylaxis / Q000517:prevention & control; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D018958:CD55 Antigens / Q000235:genetics* / Q000502:physiology; D003167:Complement Activation / Q000187:drug effects; D003169:Complement Inactivator Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification / Q000493:pharmacokinetics; D005260:Female; D006168:Guinea Pigs; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D015202:Protein Engineering; D051381:Rats; D011919:Rats, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility
D015703:Antigens, CD; D018958:CD55 Antigens; C497860:Cd46 protein, rat; D003169:Complement Inactivator Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins