The growth hormone supergene family comprises greater than 20 structurally
related cytokines and growth factors. A general method is provided for
creating site-specific, biologically active conjugates of these proteins.
The method involves adding cysteine residues to non-essential regions of
the proteins or substituting cysteine residues for non-essential amino
acids in the proteins using site-directed mutagenesis and then covalently
coupling a cysteine-reactive polymer or other type of cysteine-reactive
moiety to the proteins via the added cysteine residue. Disclosed herein
are preferred sites for adding cysteine residues or introducing cysteine
substitutions into the proteins, and the proteins and protein derivatives
produced thereby. Also disclosed are therapeutic methods for using the
cysteine variants of the invention.