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Engineering a long-acting relaxin agonist to treat liver fibrosis

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DK131681-01
Agency Tracking Number: R41DK131681
Amount: $308,708.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 300
Solicitation Number: PA20-265
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-17
Award End Date (Contract End Date): 2022-08-31
Small Business Information
Concord, MA 01742-4736
United States
DUNS: 003090286
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (978) 318-0076
Business Contact
Phone: (978) 318-0076
Research Institution
MIAMI, FL 33199-2516
United States

 Nonprofit College or University

Project Summary/AbstractRelaxin 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, relaxinandapos;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 Biologicsandapos; 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.Narrative
Relaxin is a pleiotropic peptide hormone that acts through its GPCR receptor, RXFP1, to
elicit vasodilatory, antifibrotic, tissue remodeling, antiapoptotic, anti-inflammatory, and
angiogenic responses. Several clinical trials have been conducted with human relaxin to
treat fibrosis and heart failure; however, success has been limited due, in part, to the
short half-life of this peptide. The goal of this research proposal is to utilize Zebra
Biologicsandapos; proprietary Protein-in-Protein technology that allows insertion of the relaxin
peptide into an IgG backbone to create a long-acting relaxin agonist that can be tested
for efficacy in rodent models of liver fibrosis, thus establishing a rationale for eventual
clinical testing in human fibrotic diseases where the unmet medical need is high.

* Information listed above is at the time of submission. *

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