Relaxin-2 is a peptide hormone with important roles in
human cardiovascular
and reproductive biology. Its ability to activate cellular responses
such as vasodilation, angiogenesis, and anti-inflammatory and antifibrotic
effects has led to significant interest in using relaxin-2 as a therapeutic
for heart failure and several fibrotic conditions. However, recombinant
relaxin-2 has a very short serum half-life, limiting its clinical
applications. Here, we present protein engineering efforts targeting
the relaxin-2 hormone in order to increase its serum half-life while
maintaining its ability to activate the G protein-coupled receptor
RXFP1. To achieve this, we optimized a fusion between relaxin-2 and
an antibody Fc fragment, generating a version of the hormone with
a circulating half-life of around 3 to 5 days in mice while retaining
potent agonist activity at the RXFP1 receptor both in vitro and in
vivo.