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

Jetté, Lucie; Léger, Roger; Thibaudeau, Karen; Benquet, Corinne; Robitaille, Martin; Pellerin, Isabelle; Paradis, V.; Wyk, Pieter van; Pham, Khan; Bridon, Dominique

doi:10.1210/en.2004-1286

Cited by 37 publications

(45 citation statements)

References 34 publications

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“…‡P Ͻ 0.05 vs. HTZ/pbo and CJC/24 h. Values in parentheses are fold increases compared with placebo-treated GHRHKO animals. ϳ1 day (13), we injected CJC-1295 at time intervals of 24, 48, and 72 h. The rationale for selecting these time points was based on studies showing that a single injection of CJC-1295 in rats produced the highest plasma AUC of GH within the first 2 h, with a mean residence time in plasma of Ͼ30 h, and levels still detectable at 72 h (12).…”

Section: Discussionmentioning

confidence: 99%

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Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

Alba¹,

Fintini²,

Sagazio³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Although the majority of children with isolated growth hormone (GH) deficiency have a good growth response to GH-releasing hormone (GHRH), the use of this therapeutic agent is limited by its very short half-life. Indeed, we have shown that, in mice with GHRH gene ablation (GHRH knockout; GHRHKO), even twice-daily injections of a GHRH analog are unable to normalize growth. CJC-1295 is a synthetic GHRH analog that selectively and covalently binds to endogenous albumin after injection, thereby extending its half-life and duration of action. We report the effects of CJC-1295 administration in GHRHKO animals. Three groups of 1-wk-old GHRHKO mice were treated for 5 wk with 2 μg of CJC-1295 at intervals of 24, 48, and 72 h. Placebo-treated GHRHKO mice and mice heterozygous for the GHRHKO allele served as controls. GHRHKO animals receiving daily doses of CJC-1295 exhibited normal body weight and length. Mice treated every 48 and 72 h reached higher body weight and length than placebo-treated animals, without full growth normalization. Femur and tibia length remained normal in animals treated every 24 and 48 h. Relative lean mass and subcutaneous fat mass were normal in all treated groups. CJC-1295 caused an increase in total pituitary RNA and GH mRNA, suggesting that proliferation of somatotroph cells had occurred, as confirmed by immunohistochemistry images. These findings demonstrate that treatment with once-daily administration of CJC-1295 is able to maintain normal body composition and growth in GHRHKO mice. The same dose is less effective when administered every 48 or 72 h.

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Section: Discussionmentioning

confidence: 99%

“…CJC-1295 is a synthetic human GHRH analog that selectively and covalently binds to endogenous albumin after subcutaneous administration, thereby extending its half-life and duration of action (11,12). Studies in animals (rats, pigs, and dogs) have shown that several days after a single administration of CJC-1295, serum IGF-I levels are still increased (5).…”

mentioning

confidence: 99%

Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

Alba¹,

Fintini²,

Sagazio³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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“…Because of these properties, albumin has been used as a drug carrier (1,6,7). This approach has been applied to small-molecule drugs (9), peptides (10), and protein therapeutics (2). These albumin-drug conjugates demonstrated prolonged in vivo half-life, excellent safety profiles, and therapeutic efficacy.…”

mentioning

confidence: 99%

An Albumin-Conjugated Peptide Exhibits Potent Anti-HIV Activity and LongIn VivoHalf-Life

Xie¹,

Cheng

Wang

et al. 2010

Antimicrob Agents Chemother

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The clinical application of conventional peptide drugs often is limited by their short in vivo half-life and potential immunogenicity. Frequent injection presents challenges to the treatment of chronic diseases, such as HIV infection. We chemically modified a peptide HIV fusion inhibitor with 3-maleimidopropionic acid (MPA), which allows rapid and irreversible conjugation with serum albumin at a 1:1 molar ratio. FB006M, with an MPA modification at the 13th amino acid, rapidly formed conjugate with albumin upon intravenous injection, and it exhibited a remarkably extended in vivo half-life. The albumin conjugate of FB006M displayed potent inhibitory activity against a number of laboratory and clinical isolates of HIV-1 in vitro and in vivo. No immunogenicity or antibody formation was detected after repeated dosing. The clinical application of FB006M may decrease the cost of treatment and improve treatment compliance and patient quality of life.The current treatment of HIV infection and AIDS faces the challenge of the widespread emergence of drug-resistant HIV-1 variants in both newly infected and drug-experienced patients (17). This emphasizes the need for therapeutics with new mechanisms of action. Enfuvirtide, the first and only FDA-approved HIV-1 fusion inhibitor, showed potent activity against both wild-type and drug-resistant HIV-1 (11,12). Being a peptide of 36 amino acid residues, however, it suffers from a short in vivo half-life of 3.46 to 4.35 h and requires twice-daily injection (16). To reduce the cost of treatment and improve patient quality of life, we were interested in developing a peptide-based and long-acting HIV fusion inhibitor by covalently linking an anti-HIV fusion peptide to serum albumin at a 1:1 molar ratio.Albumin is the most abundant protein in plasma. It is well distributed in different tissues and exhibits a half-life of 15 to 19 days in humans. Because of these properties, albumin has been used as a drug carrier (1,6,7). This approach has been applied to small-molecule drugs (9), peptides (10), and protein therapeutics (2). These albumin-drug conjugates demonstrated prolonged in vivo half-life, excellent safety profiles, and therapeutic efficacy. To apply this approach to peptide-based HIV-1 fusion inhibitors, we recognized three important questions that had to be addressed. First, albumin is one magnitude greater in molecular weight than the anti-fusion peptides. The linkage of albumin to peptide may prevent the peptide from accessing its target by steric hindrance (8). Therefore, the linkage site in both albumin and peptide has to be selected carefully so that the final peptide-albumin conjugate retains its biological activities. Second, the molar ratio of peptide to albumin in a conjugate can affect both activity and half-life (20). A chemical modification of peptide that allows a 1:1 molar ratio was used to assure the minimum structural alteration of albumin after peptide linkage. Third, an albumin conjugate in circulation with a long half-life may be immunogenic. It could, ther...

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“…Preparation of Albumin Conjugates-The conjugation of maleimido-C34 and maleimido-T-20 derivatives to cysteine 34 of HSA and subsequent purification were performed as reported previously (13)(14)(15)(16)(17). Mass spectrometry of each purified sample confirmed the most abundant protein product corresponded to a 1:1 covalent complex of HSA with each maleimido derivative, and reverse phase HPLC analysis of each purified sample confirmed the removal of essentially all unbound (free) maleimido derivative.…”

Section: Methodsmentioning

confidence: 92%

“…The challenge in developing therapeutic peptides is complicated primarily by their rapid renal clearance, poor distribution, and susceptibility to peptidase degradation. Despite recent predictions that cross-linking C-peptide inhibitors to larger proteins will likely reduce their antiviral activity (11), we used albumin conjugation as a vehicle to achieve superior pharmacokinetic profiles of C34 peptide as has been performed with other classes of maleimido peptides (12)(13)(14)(15)(16)(17). Such conjugation reactions may be performed in vivo by administering the compound directly into the human patient followed by conjugation to endogenous serum albumin.…”

Section: Entry Of Human Immunodeficiency Virus Type 1 (Hiv-1)mentioning

confidence: 99%

Albumin-conjugated C34 Peptide HIV-1 Fusion Inhibitor

Stoddart

Nault

Galkina

et al. 2008

Journal of Biological Chemistry

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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

Cited by 37 publications

References 34 publications

Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

An Albumin-Conjugated Peptide Exhibits Potent Anti-HIV Activity and LongIn VivoHalf-Life

Albumin-conjugated C34 Peptide HIV-1 Fusion Inhibitor

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