# Therapeutic Approach to Clear sdLDL from Circulation

> **NIH NIH R43** · IMETABOLIC BIOPHARMA CORPORATION · 2024 · $299,504

## Abstract

Project Abstract
Cardiovascular Disease (CVD) is a significant threat in the United States and developing
countries across the globe. Widely associated with elevated low density lipoprotein cholesterol
(LDL-c), therapeutic interventions are primarily focused on reduction of LDL-c plasma levels.
Despite the ability to therapeutically reach these target levels, many patients maintain high
cardiovascular risk profiles. A causal contributor to this therapeutic paradox is the development
of triglyceride-rich lipoproteins (TRLs) and their metabolic remnants small dense LDL (sdLDL)
subclass, all of which are generated by lipolysis of very low density lipoprotein (VLDL)
remnants. Notably, increased levels of these highly atherogenic species have been attributed to
their content of Apolipoprotein C-III (ApoC-III), a protein that retards their plasma clearance due
to inhibition of lipolysis as well as interference with Apolipoprotein E (ApoE)-mediated binding
and uptake by hepatic receptors, including heparin sulfate proteoglycans (HSPGs) via syndecan
action and the LDL receptor (LDLR). Even though there is a limited understanding of sdLDL
vascular pathology, it is clear that elevation in these particles leads to significant CVD risk
despite patients achieving desired LDL-c reductions based on the current clinical guidelines. As
a potential solution, we are proposing the development of a novel therapeutic approach that
capitalizes on the excess of ApoC-III on these particles. This proof-of-concept Phase I work is
focused on sdLDL depletion, by reengineering iMBP-001, a proprietary ApoC-III antagonist, to
include bioactive ApoE memetic peptides. This dual domain therapeutic candidate can perform
highly specific particle recognition and binding through ApoC-III, but then facilitate sdLDL
particle clearance via LDL receptor (LDLR) and/or Heparin Sulfate Proteoglycan (HSPG)
syndecan uptake. This research program is to progressively narrow the candidate pipeline and
culminate in hepatic uptake feasibility testing. Uptake of purified human DiI sdLDL particles in
Hep G2 and primary hepatocyte cell lines will be evaluated. The milestone for this program is
the identification of at least one dual-domain candidate therapeutic molecule that demonstrates
a ≥ 5-fold increase in cellular uptake and a ≥ 10% reduction in Apolipoprotein B concentration in
the surrounding biological milieu versus controls. The satisfaction of this milestone would lead
to a SBIR Phase 2 application that would include further ApoE memetic peptide evaluation,
establishment of a scaled non-GMP manufacturing expression system and initiation of non-GLP
preclinical testing.

## Key facts

- **NIH application ID:** 10920333
- **Project number:** 1R43HL174270-01
- **Recipient organization:** IMETABOLIC BIOPHARMA CORPORATION
- **Principal Investigator:** Urban A Kiernan
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $299,504
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10920333

## Citation

> US National Institutes of Health, RePORTER application 10920333, Therapeutic Approach to Clear sdLDL from Circulation (1R43HL174270-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10920333. Licensed CC0.

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