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Human Growth Hormone-Releasing Factor (hGRF)_1–29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long-Lasting GRF Analog

Research Department, ConjuChem Inc., Montreal, Quebec, Canada, H2X 3Y8

Address all correspondence and requests for reprints to: Roger Léger, Ph.D., Department of Research, ConjuChem Inc., 225 President-Kennedy Avenue, Suite 3950, Montreal, Quebec, Canada, H2X 3Y8. E-mail: leger{at}conjuchem.com.

In vivo bioconjugation to the free thiol on Cys34 of serum albumin by a strategically placed reactive group on a bioactive peptide is a useful tool to extend plasma half-life. Three maleimido derivates of human GH-releasing factor (hGRF)_1–29 were synthesized and bioconjugated to human serum albumin ex vivo. All three human serum albumin conjugates showed enhanced in vitro stability against dipeptidylpeptidase-IV and were bioactive in a GH secretion assay in cultured rat anterior pituitary cells. When the maleimido derivatives were individually administered sc to normal male Sprague Dawley rats, an acute secretion of GH was measured in plasma. The best compound, CJC-1295, showed a 4-fold increase in GH area under the curve over a 2-h period compared with hGRF_1–29. CJC-1295, a tetrasubstituted form of hGRF_1–29 with an added N-3-maleimidopropionamide derivative of lysine at the C terminus, was selected for further pharmacokinetic evaluation, where it was found to be present in plasma beyond 72 h. A Western blot analysis of the plasma of a rat injected with CJC-1295 showed the presence of a CJC-1295 immunoreactive species on the band corresponding to serum albumin, appearing after 15 min and remaining in circulation beyond 24 h. These results led to the identification of CJC-1295 as a stable and active hGRF_1–29 analog with an extended plasma half-life.

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				M. Alba, D. Fintini, A. Sagazio, B. Lawrence, J.-P. Castaigne, L. A. Frohman, and R. Salvatori Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1290 - E1294. [Abstract] [Full Text] [PDF]