The development of the growth hormone antagonist, Pegvisomant, is a story of modern drug design. The original observation was by John Kopchick, who noted that transgenic mice with a mutation in the third alpha helix of the GH molecule had a dwarf phenotype. This is the basis for the site 2 mutation (G120K) in the GH molecule that blocks GH signaling. At the same time the Genetech group of James Wells had characterised the crystal structure of the GH/receptor complex demonstrating the 1:2 ratio of GH to receptor and the requirement for receptor dimerisation to trigger signaling. The Genentech group showed by mutational analysis that up to 15 mutations at binding site one in the GH molecule could increase affinity for GHBP. It was then proposed that by combining the site 1 mutations (increased affinity) with the site 2 mutation (blocks signaling) they could generate a super antagonist and this molecule was called B2036. B2036 has a similar short half-life to GH and to delay its clearance 4 molecules of PEG were added to B2036 to generate the antagonist, Pegvisomant, that has been demonstrated to control acromegaly in over 90% of patients. We have been comparing structure function of the various antagonist molecules. Intriguingly the site 1 mutations although increasing binding to GHBP do not alter affinity at the membrane receptor and although B2036 and Pegvisomant both block signaling they are internalised into cells suggesting that signaling and internalisation are separate functions of the receptor. Our recent data suggests that the antagonist binds to a receptor dimer but does not generate the conformational change required for signaling but generates a non-functional dimer.
03 - 04 Dec 2001
Society for Endocrinology