Engineering a long-acting relaxin agonist to treat liver fibrosis

设计长效松弛素激动剂来治疗肝纤维化

• 批准号: 10383001
• 负责人: IRINA AGOULNIK
• 金额: $ 30.87万
• 依托单位: ZEBRA BIOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383001
• 关键词: Acute; Address; Agonist; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Applications Grants; BZLF1 gene; Biological; Birth; Blood; Carbon Tetrachloride; Cardiovascular Diseases; Cardiovascular system; Cellular Assay; Centrilobular hepatic necrosis; Choline; Chronic; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Collagen; Complementarity Determining Regions; Congestive Heart Failure; Continuous Intravenous Infusion; Diet; Disease; Dose; Drug Kinetics; Engineering; Exhibits; Extracellular Matrix; Fatty acid glycerol esters; Fibrosis; Frequencies; G-Protein-Coupled Receptors; Goals; Growth Factor; Half-Life; Heart; Heart failure; Hepatic; High Fat Diet; Hormones; Human; Immunoglobulin G; Inbred BALB C Mice; Injections; Intoxication; Intravenous infusion procedures; Joints; Kidney; Liver; Liver Fibrosis; Liver diseases; Lung; Measurable; Medical; Modeling; Molecular; Mus; Organ; Outcome; Pathologic; Pathology; Peptides; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Plasma; Pregnancy; Production; Property; Protein Engineering; Proteins; Reagent; Recombinants; Relaxin; Research; Research Proposals; Rodent Model; Safety; Serum; Skin; Small Business Technology Transfer Research; Subcutaneous Injections; Technology; Testing; Therapeutic Index; Tissues; Toxic effect; Validation; Vertebral column; Work; Zebra; antibody engineering; antifibrotic treatment; base; bone; clinical investigation; drug candidate; efficacy evaluation; efficacy study; efficacy testing; experience; hemodynamics; immunogenicity; in vivo; mouse model; nonalcoholic steatohepatitis; peptide hormone; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; receptor; relaxin receptor; reproductive; reproductive organ; research clinical testing; response; safety assessment; skin disorder; subcutaneous; success

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.

项目总结/文摘