AlbuBNP, a recombinant B-type natriuretic peptide and human serum albumin fusion hormone, as a long-term therapy of congestive heart failure.
OBJECTIVE
B-type natriuretic peptide (BNP) has been in clinical use for the treatment of decompensated congestive heart failure. However, BNP has a very short half-life in circulation, which limits its application to acute CHF and requires continuous i.v. infusion. To provide superior pharmacological benefits of BNP to other stages of chronic congestive heart failure and to eliminate problems associated with drug delivery via continuous i.v. infusion, we have designed and evaluated AlbuBNP, a long-acting form of BNP by recombinant fusion to human serum albumin for use in chronic congestive heart failure, post-acute follow-up, and postmyocardial infarction.


METHODS
Human BNP (1-32) was seamlessly fused to mature human serum albumin at N-terminus to create AlbuBNP. The bioactivities of AlbuBNP were evaluated by natriuretic peptide receptor-A mediated cGMP activation assay, hemodynamic responses, and plasma cGMP elevation. The pharmacokinetic properties were determined after single i.v. or s.c. bolus injection in C57/BL6 mice.


RESULTS
AlbuBNP had approxiamtely the same maximal bioactivity as BNP to activate cGMP in the in vitro NPRA/cGMP assay. The EC50s were 28.4+/-1.2 and 0.46+/-1.1 nM for AlbuBNP and BNP, respectively. In spontaneously hypertensive rats, AlbuBNP lowered both systolic and diastolic blood pressure, having sustainable mean arterial pressure reduction for more than 2 days. Six nmol/kg AlbuBNP i.v. bolus in mice increased plasma cGMP level 5.6-fold over the baseline. The elimination half-life in mice was dramatically increased from 3 min for BNP to 12-19 h for AlbuBNP.


CONCLUSIONS
AlbuBNP is bioactive and has desired pharmacokinetic properties for long-term use. It has the potential to be further developed as a new therapeutic option for chronic, acute, and post-acute CHF to alleviate symptoms, improve clinical status, and slow the disease progression by sustained drug exposure via infrequent simple subcutaneous injections.
Wang
Wei
W
Human Genome Sciences, Inc, Rockville, Maryland 20850, USA.
Ou
Ying
Y
Shi
Yanggu
Y
D000595:Amino Acid Sequence; D000818:Animals; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D007120:Immunochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020097:Natriuretic Peptide, Brain / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012709:Serum Albumin / Q000737:chemistry / Q000627:therapeutic use*
C500296:AlbuBNP protein, human; C500295:AlbuBNP protein, rat; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D020097:Natriuretic Peptide, Brain; D006152:Cyclic GMP