# Engineering a long-acting relaxin agonist to treat liver fibrosis

> **NIH NIH R41** · ZEBRA BIOLOGICS, INC. · 2021 · $308,708

## Abstract

Project Summary/Abstract
 Relaxin is a heterodimeric 53 amino acid peptide hormone that induces cardiovascular compliance and
reproductive tissue remodeling during pregnancy and parturition. In addition to reproductive organs, the relaxin
receptor, RXFP1, is also expressed in the liver, heart, lung, kidney, bone and skin. This broad tissue
localization has led to the recognition that relaxin is a pleiotropic hormone with vasodilatory, antifibrotic, tissue
remodeling, antiapoptotic, and anti-inflammatory properties in animal models. The efficacy of relaxin has been
tested in human clinical trials in diseases ranging from acute and chronic heart failure, to fibrotic diseases of
skin, lung, and liver; however, relaxin's short half-life and need for continual intravenous infusion have limited
its clinical utility. While the rationale to treat fibrosis and cardiovascular diseases with relaxin remains high,
better RXFP1 agonists must be developed that display longer serum half-lives and measurable
pharmacodynamic readouts, while maintaining a safety profile commensurate with chronic RXFP1 agonist
treatment. We have used Zebra Biologics' proprietary Protein-in-Protein (PiP) antibody technology to insert a
single-chain relaxin construct into the complementarity-determining region (CDR) of an immunoglobulin G
backbone. This technology has been used previously to engineer proteins and peptides with half-lives of days
vs. minutes for the native molecules. A relaxin-PiP, H2-PiP, has now been engineered with an intrinsic potency
comparable to recombinant relaxin in cellular assays. The objective of this proposal is to elucidate
pharmacokinetic and pharmacodynamic properties of H2-PiP. We hypothesize that this long-acting relaxin-PiP
agonist molecule will be a superior antifibrosis drug candidate compared to relaxin, allowing proof-of-concept
efficacy and safety assessment with less frequent subcutaneous injections, thus obviating the need for
continuous intravenous infusion.
 We submit a Phase 1 STTR grant application addressing the following Specific Aims (SA):
SA1: Pharmacokinetic-pharmacodynamic (PK-PD) analysis of H2-PiP. The goal of SA1 is to determine the
half-life and maximal active serum concentration of H2-PiP, and to correlate blood exposure with known
pharmacodynamic markers of RXFP1 activation in the context of acute CCl4 toxicity. This correlation will allow
us to establish estimates of dose and dose frequency for determining efficacy in models of liver fibrosis.
SA2: Efficacy of H2-PiP in mouse models of hepatic fibrosis. The goal of SA2 is to determine the efficacy
of H2-PiP in two mouse models of chronic liver fibrosis that display key molecular and histopathological
features of human liver fibrosis: 1) CCl4 exposure and 2) high fat diet (HFD) treatment.
 Successful completion of these studies will set the stage for eventual clinical studies in a range of diseases
where tissue fibrosis and hemodynamic pathologies are manifest.

## Key facts

- **NIH application ID:** 10383001
- **Project number:** 1R41DK131681-01
- **Recipient organization:** ZEBRA BIOLOGICS, INC.
- **Principal Investigator:** IRINA AGOULNIK
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $308,708
- **Award type:** 1
- **Project period:** 2021-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10383001

## Citation

> US National Institutes of Health, RePORTER application 10383001, Engineering a long-acting relaxin agonist to treat liver fibrosis (1R41DK131681-01). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10383001. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*