The mission of Antiger Therapeutics Inc. is to develop novel immunotherapies for transplant recipients to improve long-term graft outcomes and minimize adverse effects. Antibody-mediated rejection (AMR) is a leading cause of graft loss, with over 3000 new cases per year in the United States and estimated market size of $90 million. However, this estimate is likely to underestimate the market potential as currently no FDA- approved drugs or treatments are available for AMR. Donor-specific antibodies (DSA) against class II human leukocyte antigens (HLA) are the most frequent driver of AMR, which was reported in 68-91% of AMR after kidney, heart, or lung transplants. Current therapies, such as plasma exchange and inhibition of all B cells or plasma cells, have not demonstrated benefits for patients with AMR in randomized clinical trials. These therapies also non-selectively suppress the immune system and increase the risk of severe infections. To address these unmet needs, this SBIR will explore antigen-specific depletion of DSA-producing cells as a novel approach to AMR treatment. In our preliminary work, we generated class I HLA fusion proteins that potently and selectively depleted class I HLA-specific target cells in vitro and in vivo. This work motivated us to develop targeted immunotherapies for AMR caused by class II DSA. The product of this SBIR will be a soluble class II HLA biologic, capable of depleting a unique and more precise therapeutic target-B cells producing antibodies against the specific class II HLA expressed on the graft. The technical innovation of this product is the structure-based engineering of class II HLA to stabilize a high-risk antigen in AMR for production and clinical translation. The product will be among the first-in-class biologics to enable antigen-specific immunotherapy on the AMR market, with the potential of prolonging the graft survival and preserving the rest of the humoral immunity for infection control. We hypothesize that functional class II HLA biologics can be efficiently produced through two distinct engineering approaches, and these biologics should demonstrate selective cytotoxicity against B cell hybridomas of the corresponding specificity. In Specific Aim 1, we will generate a monovalent class II HLA biologic to deplete specific antibody-producing B cell hybridomas. In Specific Aim 2, we will create a bivalent class II HLA biologic to deplete target cells. By the end of this phase I SBIR, we expect to generate one or more candidate proteins with high production yield, purity, and selective cytotoxicity against target cells to meet pre-specified acceptance criteria. We will further demonstrate the efficacy and safety of these candidates in vivo in a phase II SBIR and then pursue licensing the product to a pharmaceutical partner for development toward FDA approval. The ultimate therapy, as a result of this project, will shift the paradigm in AMR treatment to antigen-specific immunosuppression with unprecedented precision.
Public Health Relevance Statement: PROJECT NARRATIVE/PUBLIC HEALTH RELEVANCE STATEMENT Antibody-mediated rejection (AMR) has been recognized as a leading cause of graft failure among transplant recipients and is associated with high mortality rates and increased healthcare costs. Through this SBIR funding, we will develop a novel biologic therapy with antigen-specific precision to remove the root cause of most AMR cases and prolong graft function. The ultimate product of this project should improve the well-being, quality of life, and survival of transplant recipients while reducing the infection risk and need for re- transplantation and organ demand.
Project Terms: Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Biological Response Modifier Therapy; Biological Therapy; biological therapeutic; biological treatment; biologically based therapeutics; biotherapeutics; biotherapy; Cells; Cell Body; Clinical Trials; Dialysis procedure; Dialysis; dialysis therapy; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Orphan Drugs; Engineering; Goals; Graft Rejection; Transplant Rejection; Transplantation Rejection; Graft Survival; Grant; Heart Transplantation; Cardiac Transplantation; Heart Grafting; cardiac graft; heart transplant; Histocompatibility Antigens Class I; Class I Antigens; Class I Major Histocompatibility Antigens; Complex Class 1; MHC Class I Molecule; MHC Class I Protein; MHC class I antigen; Major Histocompatibility Complex Class 1; HLA Antigens; HL-A Antigens; Human Leukocyte Antigens; Leukocyte Antigens; Hybridomas; Immune system; Immunity; Humoral Immunities; antibody-based immunity; Immunoglobulins; Immune Globulins; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; immunosuppressive response; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Infection; Kidney Transplantation; Kidney Grafting; Kidney Transplants; Renal Grafting; Renal Transplantation; Renal Transplants; kidney tx; B-Cell Acute Lymphoblastic Leukemia; Acute B-Lymphocytic Leukemia; B cell progenitor acute lymphoblastic leukemia; B-ALL; B-Cell Acute Lymphocytic Leukemia; B-Cell Lymphoblastic Leukemia; B-cell ALL; B-cell precursor acute lymphoblastic leukemia; Pre-B-Cell Leukemia; Precursor B Lymphoblastic Leukemia; Lung Transplantation; Lung Grafting; Pulmonary Graft; Pulmonary Transplant; Pulmonary Transplantation; lung transplant; Marketing; Mission; mortality; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Patients; Peptides; Personal Satisfaction; well-being; wellbeing; Plasma Cells; Blood Plasma Cell; Plasmacytes; plasmocyte; Plasma Exchange; Production; Proteins; Quality of life; QOL; Rest; Risk; Safety; Specificity; Time; United States; Work; Measures; Health Costs; Healthcare Costs; Health Care Costs; Infection Control; Antibody-Secreting Cells; Immunoglobulin-Secreting Cells; Mediating; Chimera Protein; Fusion Protein; Chimeric Proteins; Organ; improved; Specified; Specific qualifier value; Phase; biologic; Biological; Biochemical; randomized, clinical trials; Link; Licensing; Funding; antibody based therapies; antibody treatment; antibody-based therapeutics; antibody-based treatment; Antibody Therapy; Therapeutic; Transplant Recipients; transplant patient; Dimerization; Protein Dimerization; Complex; cytotoxicity; Lytotoxicity; disulfide bond; retransplantation; Structure; novel; technological innovation; Reporting; Adverse effects; Molecular Interaction; Binding; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; Effectiveness; Address; Dose; Mammalian Cell; Qualifying; in vivo; Cell Culture System; Complement-Dependent Cytotoxicity; complement-mediated cytotoxicity; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Modification; Development; developmental; immunogenicity; new approaches; novel approaches; novel strategy; novel strategies; Outcome; NH2-terminal; N-terminal; innovate; innovative; innovation; C-terminal; graft failure; murine model; mouse model; therapeutic target; graft function; commercial application; prototype; high risk; public health relevance; FDA approved; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; clinically translatable; clinical translation; antibody immunotherapy; preservation; infection risk; post-transplantation; posttransplant; posttransplantation; post-transplant; donor antibodies; donor-specific antibody; antibody rejection; antibody-mediated rejection; Accounting; Antibodies; Immunoglobulin-Producing Cells; Antibody-Producing Cells; immunogen; Antigens; Automobile Driving; driving; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Biological Assay; Assay; Bioassay; Biologic Assays
