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Novel ex-vivo Immunoadsorption Therapy to Treat Preeclampsia

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
Program Year/Program:
2013 / SBIR
Agency Tracking Number:
R43HL117431
Solicitation Year:
2013
Solicitation Topic Code:
NHLBI
Solicitation Number:
PA12-088
Small Business Information
BIOLEAP, LLC
238 W. Delaware Ave Pennington, NJ 08534-1603
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2013
Title: Novel ex-vivo Immunoadsorption Therapy to Treat Preeclampsia
Agency: HHS
Contract: 1R43HL117431-01A1
Award Amount: $216,678.00
 

Abstract:

DESCRIPTION: Recent phase II clinical studies demonstrate that an antibody targeting proportion convertase subtilisin/kexin type 9 (PCSK9)-a target for the treatment of hypercholesterolemia and coronary heart disease-successfully and safely decreases amounts of low-density lipoprotein-cholesterol (LDL) in patients with hypercholesterolaemia undertaking statin treatment.1,2 However, to date, there are no reports of small molecules or peptides achieving the same effect. This application offers a mature fragment-based design methodology to create novel small molecule PCSK9 inhibitors that achieve a targeted activity in surface plasmon resonance direct and competition assays as well as in a functional assay, LDL uptake in hepatocyte cells. Such an alternativeapproach to this problem is compelling because high-throughput screening campaigns at large pharmaceutical companies have generally not yielded progressable hits for PCSK9. Using our recently described hot-spot mapping technique,3,6 we found sites at the low-density lipoprotein-cholesterol receptor (LDLR)/PCSK9 interface that are sites of high interaction energy and appear druggable. Our primary deliverable for the proposed research is to improve physical properties and develop SAR around our initial hits that show functional cell-based activity. The primary hits resulted from testing fewer than 50 novel compounds (one, two and three fragment builds). The small molecule ligands were specifically designed to implement a hypothesis that quantum resonance (partially covalent binding) can provide enhanced affinity to overcome the dehydration costs of the convex, solvent-exposed PCSK9/LDLR interface. Such compounds achieving success in clinical trials would show great promise as a therapeutic to lower cholesteroland treat coronary heart disease in humans. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Phase II clinical trials recently revealed that antibodies-targeting pro-protein convertase subtilisin kexin type-9 (PCSK9)-administered over an 8 to 12 week period significantly reduced bad cholesterol by 50-70% in patients with elevated cholesterol on a stable dose of statins. To date, no small molecule or peptide has been reported that is able to achieve similar results. In this application we aim toemploy our fragment-based design methodology to further develop initial hits on PCSK9 into leads with improved affinity and solubility, with a future goal of reaching the antibody performance, and licensing a clinical candidate to a major pharmaceutical company for clinical development.

Principal Investigator:

John L. Kulp
215-371-2874
jlkiii@bioleap.com

Business Contact:

Gerry Evans
267-777-7388
gerry@bioleap.com
Small Business Information at Submission:

BIOLEAP, LLC
238 W. Delaware Ave Pennington, NJ 08534-1603

EIN/Tax ID: 127139997
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No