Vol. 281, Issue 3, 1431-1439, 1997

In Vivo Characterization of Sustained-Release Formulations of Human Growth Hormone

Hye Jung Lee, Gary Riley, Olufumni Johnson, Jeffrey L. Cleland, Norman Kim, Margarita Charnis, Leonie Bailey, Eileen Duenas, Azin Shahzamani, Melinda Marian, Andrew J. S. Jones and Scott D. Putney

Alkermes, Inc., Cambridge, Massachusetts (H.J.L., G.R., O.J., N.K., M.C., L.B., S.D.P.) and Genentech, Inc., South San Francisco, California (J.L.C., E.D., A.S., A.J.S.J.)

Long-acting formulations of recombinant human growth hormone (rhGH) were prepared by stabilizing and encapsulating the protein into three different injectable, biodegradable microsphere formulations composed of polymers of lactic and glycolic acid. The formulations were compared in juvenile rhesus monkeys by measuring the serum levels of rhGH and two proteins induced by hGH, insulin-like growth factor-I and IGF binding protein-3 (IGFBP-3) after single s.c. administration. All three formulations, which differed principally in the composition of the polymer, provided sustained elevated levels of all three proteins for several weeks, and the rate of release of rhGH differed among the formulations consistent with the molecular weight of the polymer used. All three formulations induced a higher level of insulin-like growth factor-I and insulin-like growth factor binding protein than was induced by daily injections of the same amount of rhGH in solution. After three monthly injections of one of the formulations, both the rhGH and IGF-I levels remained elevated for nearly 90 days. Immunogenicity of the rhGH released from this formulation, as assessed by the incidence of seroconversion to hGH and the titer of anti-hGH antibody in both the rhesus monkeys and transgenic mice expressing rhGH, was no greater than that of the unencapsulated protein. In addition, the microsphere injection sites appeared normal by macroscopic evaluation between 1 to 2 mo after microsphere administration and by microscopic evaluation between 2 to 3 mo. These results show that serum levels of a therapeutic protein can be sustained for an extended period when encapsulated into different formulations of injectable, biodegradable microspheres.