Nonalcoholic fatty liver disease (NAFLD) incidence is rapidly rising, in link with obesity and diabetes, and has become the most common cause of liver disease in developed countries. The prevalence of NAFLD is increasing steadily from 25% in 2018 to a projected 33.5% in 2030 globally. It is estimated approximately 20% of those NAFLD patients have non-alcoholic steatohepatitis (NASH). Without medical intervention, NASH patients will develop end-stage cirrhosis and even hepatocellular carcinoma. Unfortunately, there are no pharmacological agents available for treating NASH even though they are diagnosed at early stage. Patients have to adapt healthy life style to improve the situation, and such efforts are often in vain due to complex reasons. The only treatment option left is the resection, ablation or liver transplantation if diagnosed at early stage. In a response to this urgent unmet need, we have developed a bispecific single domain antibody targeting both chemokines CCL2 and CCL5 simultaneously which are critical players in the pathogenesis of liver fibrosis. In a proof-of-concept study conducted in a STAM NASH model, we have demonstrated that our bispecific antibody OT-m225 was able to outperform a phase 3 staged NASH drug-cenicriviroc- with regard to anti-fibrotic and anti- inflammatory effects. In order to ensure the clinical success of this OT-225 bispecific antibody, we propose to generate a human version of OT-h225 under the guidance of data from the STAM mouse model. This is going to be carried out parallelly in two specific aims. In Aim 1, we will harness both the STAM and the MCD NASH mouse models to screen a lead OT-m225 candidate from a series of variants with different binding affinities toward mouse CCL2 and CCL5. The effect OT-m225 or its optimal variant in modulating Hedgehog signaling and in inhibiting HSCs activation will be assessed as a subcontract at Duke Liver Center. Meanwhile in aim 2, we will further engineer the optimal OT-m225 variant from Aim 1 by yeast surface display-based directed molecular evolution, aiming at developing a version of OT-h225 that potently neutralizes and displaces GAG- bound CCL2 and CCL5 in human NASH, paving the way for IND-enabling development. The success of this Phase I SBIR project will result in a unique human single domain antibody that will be further developed into an innovative, first-in-class therapeutic biologic for the treatment of human NAFLD and NASH. Phase II studies will focus on extensive mechanistic, anti-fibrotic efficacy, developability, and PK/PD studies for IND purpose.
Public Health Relevance Statement: Project Narrative This SBIR project aims to develop a human bispecific single domain antibody against CCL2 and CCL5, two chemokines that play a pivotal role in the liver inflammation and fibrogenesis. The success of this project will result in a unique human antibody that will be further developed into an innovative, first-in-class therapeutic biologic for the treatment of human NAFLD and NASH.
Project Terms: Acceleration; 21+ years old; Adult Human; adulthood; Adult; Animals; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; Antibodies; Antigenic Determinants; Binding Determinants; Epitopes; Biological Response Modifier Therapy; Biological Therapy; biological therapeutic; biological treatment; biologically based therapeutics; biotherapeutics; biotherapy; Bone Marrow; Bone Marrow Reticuloendothelial System; Diabetes Mellitus; diabetes; Diagnosis; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Fatty Liver; Liver Steatosis; hepatic steatosis; hepatosteatosis; Fibrosis; GAG Gene; GAG; Half-Life; Erinaceidae; Hedgehogs; Primary carcinoma of the liver cells; Hepatocarcinoma; Hepatocellular Carcinoma; Hepatocellular cancer; Hepatoma; Liver Cells Carcinoma; liver carcinoma; Human; Modern Man; In Vitro; Incidence; Inflammation; Kupffer Cells; Stellate Sinusoidal Macrophage; liver macrophage; Lead; Pb element; heavy metal Pb; heavy metal lead; Life Style; Lifestyle; Ligands; Liver; hepatic body system; hepatic organ system; Liver diseases; Hepatic Disorder; hepatic disease; hepatopathy; liver disorder; liver transplantation; Hepatic Transplantation; Liver Grafting; Liver Transplant; Macrophage; MÏ; Metabolic Clearance Rate; clearance rate; monocyte; Blood monocyte; Marrow monocyte; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Obesity; adiposity; corpulence; Patients; Play; Role; social role; Signal Pathway; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Specificity; Testing; Translating; United States; Work; Yeasts; RANTES; CCL5; Chemokine (C-C Motif) Ligand 5; D17S136E; MGC17164; SCYA5; SIS delta; SIS-delta; SISd; Small Inducible Cytokine A5; T-Cell RANTES Protein; T-Cell Specific Protein p288; TCP228; cytokine; Mediating; injuries; Injury; dosage; improved; Left; Site; Surface; Clinical; Phase; Variation; Variant; biologic; Biological; Medical; Series; Bi-specific antibodies; Bifunctional Antibodies; bsAb; Bispecific Antibodies; Link; Ensure; Endothelial Cells; Blood Serum; Serum; Failure; fibrotic liver; hepatic fibrosis; Liver Fibrosis; Recycling; C-C Chemokines; CC Chemokines; β-Chemokines; beta-Chemokines; Chemotactic Cytokines; Homologous Chemotactic Cytokines; Intercrines; SIS cytokines; chemoattractant cytokine; chemokine; directed evolution; Directed Molecular Evolution; Industrialized Countries; Industrialized Nations; developed country; developed nation; developed nations; Developed Countries; Infiltration; Inflammatory; Investigation; Complex; neutralizing antibody; chemokine receptor; Chemokine Receptor Gene; Ablation; Cell Proliferation; Cell Growth in Number; Cell Multiplication; Cellular Proliferation; receptor; Receptor Protein; success; drug clearance; Pathogenesis; drug action; Excision; Abscission; Extirpation; Removal; Surgical Removal; resection; Modeling; Property; response; Intervention; Intervention Strategies; interventional strategy; Inflammatory Response; Hedgehog (Hh) signal transduction pathway; hedgehog signaling; hedgehog signaling pathway; hh signaling pathway; smoothened signaling pathway; Molecular Interaction; Binding; small molecule; CCR5 gene; C-C CKR-5; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5; C-C Chemokine Receptor Type 5 Gene; CC Chemokine Receptor 5; CC-CKR-5; CC-CKR-5 Gene; CC-CKR5; CCCKR5; CCCKR5 Gene; CCR-5; CCR-5 Gene; CCR5; CCR5 Protein; CCR5 Receptors; CD195 Antigen; CD195 Antigen Gene; CHEMR13; CHEMR13 Gene; CKR-5; CKR-5 Gene; CKR5; CKR5 Gene; CKR5 Receptors; CMKBR5; CMKBR5 Gene; Chemokine (C-C Motif) Receptor 5; Chemokine (C-C) Receptor 5; Chemokine (C-C) Receptor 5 Gene; HIV-1 Fusion Co-Receptor; HIV-1 Fusion Co-Receptor Gene; CCL2 gene; CCL2; Chemokine, CC Motif, Ligand 2; MCAF; MCP-1; MCP1; Monocyte Chemoattractant Protein-1; Monocyte Chemotactic Protein-1; Monocyte Chemotactic and Activating Factor; Monocyte Chemotactic and Activating Protein; Monocyte Chemotactive and Activating Factor; Monocyte Secretory Protein JE; SCYA2; Small Inducible Cytokine A2; Affinity; Data; Resolution; resolutions; in vivo; Antiinflammatory Effect; anti-inflammatory effect; Ligand Binding; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Pathologic; Development; developmental; Cirrhosis; cirrhotic; Pathway interactions; pathway; Hepatic Fibrogenesis; liver fibrogenesis; Steatohepatitis; Prevalence; innovate; innovative; innovation; Therapeutic antibodies; bench bed side; bench bedside; bench to bed side; bench to clinic; bench to clinical practice; bench to bedside; murine model; mouse model; NASH; non-alcohol induced steatohepatitis; non-alcoholic steato-hepatitis; non-alcoholic steatohepatitis; nonalcoholic steato-hepatitis; nonalcoholic steatohepatitis; FDA approved; pre-clinical evaluation; preclinical evaluation; phase II study; phase 2 study; nanobody; sdAb; single domain antibodies; nanobodies; Injury to Liver; hepatic damage; hepatic injury; liver damage; liver injury; hepatic inflammation; inflamed liver; liver inflammation; biophysical characteristics; biophysical characterization; biophysical measurement; biophysical parameters; biophysical properties; phase 3 trial; phase III trial; experiment; experimental research; experiments; experimental study; NAFLD; non-alcohol fatty liver disease; non-alcoholic liver disease; nonalcoholic fatty liver disease; non-alcoholic fatty liver disease; recruit; primary end point; primary endpoint; PK/PD; pharmacokinetics and pharmacodynamics; hepatocyte injury; antagonist; antagonism; pharmacologic
