Vasoactive intestinal peptide (VIP)-ELP (PB1046) is a 634 amino acid recombinant fusion protein expressed in Escherichia coli (E. coli). The VIP moiety comprises the 28 amino acids of mature human VIP with a single methionine at the N-terminus and a repeating polymeric elastin-like peptide (ELP) at the C-terminus. The addition of the methionine confers preferential activity to the VIP receptor VPAC2, resulting in decreased activity on the VIP receptor VPAC1 compared to VIP peptide. The unique physiological properties of a VIP-ELP fusion is that it confers stability and an extended half-life to the protein resulting in a slow steady release of drug into the circulation.
PB1046 demonstrated an increase in half-life in Sprague Dawley rats from the reported 1 minute to 12 hours when dosed subcutaneously. The half-life was longer after subcutaneous than after intravenous dosing, suggesting absorption, rather than elimination, was rate limiting. This supports the gradual decrease in the local concentration of the drug at the site of injection (subcutaneous space) resulting in the reversal of phase transition and a slow steady release of drug into the circulation.
Using blood pressure as a biomarker of systemic vasodilation, PB1046 dosing in spontaneously hypertensive (SHR) rats demonstrated PB1046 reduced blood pressure in a dose dependent manner and also acted synergistically in reducing blood pressure when given concomitantly with other clinically relevant classes of anti-hypertensive agents. Although PB1046 elicited increases in heart rate in SHR rats following a single subcutaneous (SC) administration, this increase was only observable at higher doses and was transient in nature. Following repeated administration, blood pressure reduction was sustained while heart rate diminished over time back to or below baseline. In normal beagle dogs challenged with the vasoconstrictor phenylephrine, PB1046 at 6 mg/kg was associated with both a delay in onset and mild reduction of the phenylephrine induced hypertension at both 6 and 24 hours following dosing. An acute study in a rat hypoxic model of PAH showed PB1046 dosed at 3 mg/kg IV resulted in rapid reductions in pulmonary arterial pressure.
Additionally, in a 6-month toxicity study the No Observed Adverse Effect Level (NOAEL) for PB1046 when subcutaneously dosed in Sprague Dawley rats every other day for 6 months (92 administrations) was determined to be 9.0 mg/kg. The combined preclinical pharmacodynamic and safety data, support continued development of PB1046 as a potential therapeutic for the treatment of Pulmonary Arterial Hypertension (PAH).
|School:||University of the Sciences in Philadelphia|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 79/12(E), Dissertation Abstracts International|
|Subjects:||Biology, Molecular biology, Cellular biology|
|Keywords:||Acting, Arterial, Elp, Fusion, Hypertension, Intestinal, Long-acting, Peptide, Protein, Pulmonary, Treatment, Vasoactive, Vpac2|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be