Phase II year
2022
(last award dollars: 2023)
Phase II Amount
$1,999,998
Cirrhosis of the liver is among the top ten leading causes of death in the US, with more than 35,000 deaths each year. A major underlying cause of cirrhosis is liver injury associated with liver fibrosis, i.e., scar tissue that blocks the flow of blood through the liver, raising blood pressure and disturbing normal function. There are no approved drugs for fibrotic non-alcoholic steatohepatitis (NASH), which often progresses to cirrhosis, so patients are often left with "lifestyle modifications" that are difficult to sustain, and, at best, put patients in a race against disease progression. CB2 agonism is a promising mode of action for treating liver fibrosis/NASH. Small molecule agonists of the cannabinoid receptor CB2 have reduced liver fibrosis in several established animal models by inhibiting hepatic immune cells and hepatic stellate cells. However, small molecule CB2 agonists have drawbacks, including cross-reactivity with pro-inflammatory/pro-fibrotic CB1 receptors in immune cells and psychotropic CB1 receptors in the CNS, and rapid elimination from the body. Therefore, a CB2 agonist antibody (Ab) that is highly specific for CB2 over CB1, restricted from passing the blood-brain barrier into the CNS, and is long-lived would be an ideal drug for liver fibrosis. Unlike small molecules, which often show liver toxicities, Ab drugs have excellent safety track records in treating chronic diseases. Abalone Bio used its proprietary antibody discovery platform to isolate a selective CB2-activating nanobody (VHH), ABt101. In Phase I, ABt101 was successfully modified and reformatted into a VHH-Fc fusion antibody (ABt140) to increase its stability and in vivo half-life. Feasibility of the CB2 Ab agonist for liver fibrosis was demonstrated using two complementary in vivo models. In this Phase II SBIR project, Abalone Bio will improve ABt140's immunogenicity an manufacturability by rational engineering, and increase its potency by selecting stronger agonists from millions of computationally designed variants using Abalone Bio's proprietary functional Ab selection platform. Then, the selected candidate Ab will be manufactured according to Good Manufacturing Practices (GMP) standards. Progress made in parallel to this project in advancing the CB2 agonist Ab for another indication will cover remaining manufacturing development and preclinical testing (i.e., IND-enabling tox studies). The proposed GMP production run will produce clinical drug substance (DS) supply at 500L bioreactor scale, generating sufficient DS for phase I clinical studies in liver fibrosis. In parallel, the candidate Ab will be tested for efficacy in two of the most relevant disease models of NASH and fibrosis. The Ab will be applied to liver slices to understand the mechanism of action of the CB2 agonist in the context of endogenous cell-cell interactions. The FAT-NASH animal model will validate the functional anti-fibrotic activity of the CB2 agonist at a lower dose level of the optimized antibody, and the TAA model will test the activity of the CB2 agonist in a model of severe fibrosis. These studies will generate material for clinical studies and help select the most suitable patient groups for treatment with the CB2 agonist antibody.
Public Health Relevance Statement: NARRATIVE Abalone Bio is commercializing a highly specific, long-lived, peripherally restricted CB2 receptor agonist antibody as a means of attenuating and preventing fibrosis caused by chronic liver diseases. This Phase 2 project will advance this goal by (1) optimizing the stability and potency of the lead antibody drug, (2) further validating the mechanism of action in models of liver fibrosis and (3) producing a batch of the lead antibody in anticipation of clinical trials.
Project Terms: Acids; Cyclic AMP; 3'5'-cyclic ester of AMP; Adenosine Cyclic 3',5'-Monophosphate; Adenosine Cyclic Monophosphate; Adenosine, cyclic 3',5'-(hydrogen phosphate); adenosine 3'5' monophosphate; cAMP; Adoption; Antibodies; Architecture; Engineering / Architecture; Biological Assay; Assay; Bioassay; Biologic Assays; Biopsy; Blood Pressure; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Cause of Death; Cell Communication; Cell Interaction; Cell-to-Cell Interaction; Cells; Cell Body; Certification; Chronic Disease; Chronic Illness; chronic disorder; Cicatrix; Scars; Clinical Research; Clinical Study; Clinical Trials; Cessation of life; Death; Diagnosis; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Fibrosis; Freezing; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Half-Life; Human; Modern Man; In Vitro; Kupffer Cells; Stellate Sinusoidal Macrophage; liver macrophage; Lead; Pb element; heavy metal Pb; heavy metal lead; Liver; hepatic body system; hepatic organ system; Liver Cirrhosis; Hepatic Cirrhosis; Mus; Mice; Mice Mammals; Murine; Myocardial Infarction; Cardiac infarction; Myocardial Infarct; cardiac infarct; coronary attack; coronary infarct; coronary infarction; heart attack; heart infarct; heart infarction; Patients; Production; QOL; Quality of life; Racial Group; Racial Stocks; Race; Common Rat Strains; Rat; Rats Mammals; Rattus; Records; Running; Safety; Systemic Sclerosis; progressive systemic sclerosis; Systemic Scleroderma; Specificity; Technology; Testing; Tissues; Body Tissues; Liver Failure; Hepatic Failure; Apoptosis; Apoptosis Pathway; Programmed Cell Death; improved; Hepatic; Left; Peripheral; Chronic; Clinical; Phase; Variant; Variation; CB2; CB2 Receptor; CB2R; CNR2; Cannabinoid Receptor CB2; cannabinoid receptor 2; cannabinoid receptor type 2; CNR2 gene; Ito Cell; Hepatic Stellate Cell; Failure; Blood flow; Hepatotoxic effect; Liver Toxicity; Toxic effect on liver cells; hepatic toxicity; hepatoxicity; Hepatotoxicity; fibrotic liver; hepatic fibrosis; Liver Fibrosis; Summary Reports; Disease Progression; Funding; Agonist; Attenuated; Inflammatory; scaffolding; scaffold; chronic hepatic disease; chronic hepatic disorder; chronic liver disorder; chronic liver disease; microbioreactor; Bioreactors; CB1; CB1 Receptor; CB1R; Cannabinoid Receptor CB1; cannabinoid receptor 1; cannabinoid receptor type 1; CNR1 gene; Immunes; Immune; Adverse reactions; dimer; Receptor Protein; receptor; abalone; Animal Models and Related Studies; model of animal; model organism; Animal Model; disorder model; Disease model; Modeling; cross reactivity; preventing; prevent; small molecule; Address; Dose; Data; pre-clinical testing; Preclinical Testing; in vitro Assay; in vivo; in vivo Model; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Slice; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Characteristics; Development; developmental; Cirrhosis; cirrhotic; paralogous gene; paralog; painful neuropathy; neuropathic pain; immunogenicity; design; designing; Therapeutic antibodies; nonalcoholic steatohepatitis; NASH; non-alcohol induced steatohepatitis; non-alcoholic steato-hepatitis; non-alcoholic steatohepatitis; nonalcoholic steato-hepatitis; patient population; in vitro testing; clinical material; efficacy testing; GMP lots; good manufacturing practice lot; nanobodies; nanobody; sdAb; single domain antibodies; Drug Targeting; liver injury; Injury to Liver; hepatic damage; hepatic injury; liver damage; treatment group; clinical candidate; efficacy study; preclinical development; pre-clinical development; Life Style Modification; lifestyle modification; manufacturability; rational design