Dissertation/Thesis Abstract

A Long-Acting VPAC2 Selective Vasoactive Intestinal Peptide ELP Fusion Protein for the Treatment of Pulmonary Arterial Hypertension
by Arnold, Susan, Ph.D., University of the Sciences in Philadelphia, 2018, 138; 10904828
Abstract (Summary)

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).

Indexing (document details)
Advisor:
Commitee:
School: University of the Sciences in Philadelphia
Department: Molecular Biology
School Location: United States -- Pennsylvania
Source: DAI-B 79/12(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Biology, Molecular biology, Cellular biology
Keywords: Acting, Arterial, Elp, Fusion, Hypertension, Intestinal, Long-acting, Peptide, Protein, Pulmonary, Treatment, Vasoactive, Vpac2
Publication Number: 10904828
ISBN: 9780438157323
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