The literature is replete with examples of highly potent and
specific antibodies derived through the processes of phage
display, in vitro maturation, and protein engineering. While
development of high-affinity binders is becoming relatively
routine, there are practically no methods to discover and
improve antibodies that carry out relatively complex biological
functions that extend beyond direct binding of an epitope: for
example, catalytic antibodies exhibiting enzyme-like turnover
and catalytic constants have been notoriously difficult to
obtain; likewise, obtaining antibodies that act as receptor
agonists, through complex set of interactions, has been very
difficult. The primary reason for these difficulties has been
that the steps of affinity selection and maturation have often
been separated from the screening for biological function, the
latter requiring the use of biology-specific mammalian model
system. Zhang and colleagues* present an elegant solution to the
bottleneck by designing a combinatorial an