EXTENDED IN-VIVO HALF-LIFE OF HUMAN SOLUBLE COMPLEMENT RECEPTOR-TYPE-1 FUSED TO A SERUM ALBUMIN-BINDING RECEPTOR

A new approach has been used to extend the T-1/2 of human soluble comp lement receptor type 1 (sCR1) in rats. The albumin-binding domains B2A 3 (BA) and B1A2B2A3 (BABA) from Streptococcal protein G were fused to the carboxyl terminus of sCR1, and the recombinant genes were expresse d and amplified in Chinese hamster ovary cells. Western blot analysis and surface plasmon resonance measurements demonstrated the binding of rat serum albumin to both sCR1-BA and sCR1-BABA but not to sCR1. The in vitro complement inhibitory activity of the fusion proteins was sho wn to be similar to that of sCR1, indicating that neither the albumin- binding domains nor the presence of bovine serum albumin interfere wit h sCR1 function. Pharmacokinetic analysis showed that the T-1/2 of the distribution phase (T-1/2 alpha) was 3.3, 20.0 and 6.0 min for sCR1, sCR1-BA and scR1-BABA, respectively. The T-1/2 of the elimination phas e (T1/2 beta) was 103, 297 and 170 min for sCR1, sCR1-BA and sCR1-BABA , respectively. The plasma elimination of sCR1-BA and sCR1-BABA was si gnificantly (P < .05) prolonged as compared to sCR1. The proteins show ed similar tissue distribution; at 4-hr postdosing, the highest levels of I-125-radioactivity per gram of tissue were localized in the urine , blood, liver, stomach and small intestine.