A Multicenter, Randomized, Placebo-controlled, Double-blind Phase 2 Study to Evaluate the Efficacy and Safety of CJC-1295 administered for 12 weeks in HIV-Infected Patients with HIV-associated Visceral Obesity

开始日期2005-12-09

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ConjuChem, Inc.

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2000-07-01·Bioconjugate Chemistry2区 · 化学

Site Specific 1:1 Opioid:Albumin Conjugate with in Vitro Activity and Long in Vivo Duration

2区 · 化学

Article

作者: Holmes, Darren L. ; Thibaudeau, Karen ; L'Archevêque, Benoît ; Bridon, Dominique P. ; Milner, Peter G. ; Ezrin, Alan M.

A site-specific 1:1 dynorphin A-(1-13)-NH(2) derivative conjugated specifically to Cys 34 on human serum albumin (CCI-1035) was shown to be an opioid receptor agonist in vitro and to be a long lasting antinociceptive agent when administered intravenously to mice as assessed by an acetic acid writhing assay. When 10 micromol/kg of CCI-1035 was administered to mice, rapid antinociception was observed within 5 min following intravenous bolus injection and was sustained beyond 8 h. Antinociceptive activity was absent in a heat induced pain model using a mouse tail-flick assay. This finding represents the first report of a 1:1 albumin opioid conjugate retaining potent in vivo activity equal to or greater than dynorphin A, accompanied by a dramatic extension in duration of action. This novel site-specific bioconjugation technology produces an agent that may be useful for peripheral pain therapy.

Regio-selective synthesis and in vitro evaluation of insulin-albumin conjugates

作者: Boutros, A. ; Leger, R. ; Thibaudeau, K. ; Pellerin, I. ; Soucy, C. ; Huang, X. ; Robitaille, M. ; Bridon, D.

We have demonstrated that bioconjugating peptides to Cys34 of Human Serum Albumin (HSA) prolong their presence in plasma by protecting them against enzymic degradation and reducing elimination while retaining most of their desired biol. activity.Insulin has a short half-life within the circulation due to the high clearance rate and in view of this, diabetic patients need to receive multiple daily s.c. injections to maintain glycemic control.The bioconjugation of insulin to HSA should increase the plasma half-life by adopting the pharmakinetic profile of albumin.Structurally, there are three available amino groups on insulin, namely the α-amino groups Gly A1 and Phe B1 and the Nε-Lys B29.We report the regio-selective synthesis, purification and anal. of three 3-maleimidopropionic acid (MPA) derivatives via the exploitation of the different amine pKa′s.For example Gly-(A1)-MPA-Insulin was synthesized in one step with a 37% yield and the two other isomers were synthesized through selective protection with good yields.In vitro efficacy of the corresponding Insulins-MPA:Cys34 HSA bioconjugates was assessed by receptor binding assay and induction of glucose uptake.

Dramatic increase in peptide half-life through in vivo bioconjugation to serum albumin

作者: Thibaudeau, Karen ; Bridon, Dominique ; L′Archeveque, Benoit ; Jette, Lucie ; Leger, Roger ; Lawrence, Betty ; Pham, Khan ; Bousquet-Gagnon, Nathalie ; Robitaille, Martin ; van Wyk, Pieter ; Castaigne, Jean-Paul ; Huang, Xicai ; Quraishi, Omar ; Sekhon, Dalbir

Serum albumin has been recently identified as a useful carrier protein to help control distribution and protect potential peptidic drugs from metabolic degradation and clearance while retaining the desired physiol. response.The technol. described herein focuses on the formation of new drug entities derived from known peptides.The activated drug construct (also called Drug Affinity Complex, DAC-) exploits the unique reactivity of the sulfur atom on cysteine 34 of albumin (figure 1) upon intra venous administration, leading to the selective formation of a carbon sulfur bond.The half-lives increase from a few minutes for the native peptides to many hours (18-30 h) for the peptide-albumin conjugates in the rat.Representative results of DAC- derivatives of various clin. relevant peptides (GLP-1, Dynorphin A, Kringle 5) will be presented along with their reactivity toward serum albumin, identification of the conjugate species, improved stability and pharmacokinetics and selectivity of binding to albumin vs. other serum proteins.

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