There is a central role for iNKT cells in mediating inflammatory responses in sickle cell disease. NKT Therapeutics has developed a humanized monoclonal antibody (NKTT120) that can specifically mediate iNKT cell depletion by antibody and complement directed cellular cytotoxicity. We are currently engaged in a safety/PK Phase 1 study in stable sickle cell disease patients. Although the use of specific murine SCD models has helped in defining the role of iNKT cells in SCD, the fact that NKTT120 does not cross react with murine iNKT cells has limited our ability to assess the short and long term impact of iNKT cell depletion on the pathology of SCD. Our recent identification of a monoclonal antibody (NKT-14) that binds to the mouse NKT cell to mediate murine iNKT cell depletion provides us with a unique opportunity to directly explore the impact of iNKT cell depletion in mediating the pathology of SCD. The antibody is specific for the mouse iTCR and, when bound, promotes a rapid and long lasting (> 14 days) depletion of murine iNKT cells. The Objective of this study is to utilize NKT-14 to deplete iNKT cells in SCD mice in a prophylactic or therapeutic regimen to evaluate the impact of iNKT cell depletion on experimentally induced vaso-occlusive crisis (VOC) induced by hypoxia. Knockout-transgenic SCD model mice 56 days old (SJL, 129, C57BL/6J background) bred at the Jackson Laboratories and housed at the Medical College of Georgia will be used in this study to assess the effect of NKT-14 mediated iNKT cell depletion on the severity of V O C . Prophylactic response will be assessed in SCD mice with iNKT cells maximally depleted for 28, 14 or 7 days prior to induced VOC. Mice will be monitored for survival, assessment of target tissue (lung, liver, and spleen) iNKT cell numbers and activation status by FACS and histology as well as inflammatory cytokine profiles. NKT-14 treated SCD mice will be compared to SCD mice treated with a control non-specific mouse IgG2a. Therapeutic response will be assessed in SCD mice treated immediately prior to the initiation of re-oxygenation following hypoxic stress. Animals will be monitored post treatment for the same parameters assessed in the prophylactic arm. The results of these studies will guide our planning for our human Phase 2 studies. If prophylactic treatment is beneficial but not therapeutic intervention, our focus will be on a Phase 2 study that evaluates the impact of chronic NKTT120 on SCD outcomes. If the therapeutic regimen proves beneficial, we would consider including a Phase 2 acute vaso- occlusive crisis study. Overall, the specific targeting of iNKT cells via our NKTT120 in humans and NKT-14 in mice is a highly innovative approach developing treatment for sickle cell disease
Public Health Relevance Statement: Public Health Relevance: NKT Therapeutics has developed a humanized monoclonal antibody (NKTT120) that can specifically mediate iNKT cell depletion by antibody and complement directed cellular cytotoxicity and is currently engaged in a safety/PK Phase 1 study in stable sickle cell disease patients. The human antibody does not cross react with mouse cells but we now have an antibody (NKT-14) that does deplete mouse iNKT cells that can be used to study more complex response in sickle cell disease. The results of this proposed study will provide us with data to direct our dose planning for Phase 2 efficacy studies in human sickle cell disease.
Project Terms: A/J Mouse; Acute; Aftercare; Animals; Antibodies; arm; Binding (Molecular Function); Blood; Breeding; Cell Count; Cell-Mediated Cytolysis; Cells; Chronic; Complement; Complex; Control Groups; cytokine; Data; Detection; Dose; Euthanasia; Exposure to; Galactosylceramides; Harvest; Health; Histology; Histopathology; Hour; Housing; Human; humanized monoclonal antibodies; Hypoxia; Inbred BALB C Mice; Inflammation; Inflammatory; Inflammatory Response; innovation; Intraperitoneal Injections; Knock-out; Libraries; Liver; Lung; Mediating; medical schools; Modeling; Monitor; Monoclonal Antibodies; mouse model; Mouse Strains; Mus; Outcome; Oxygen; Oxygen measurement, partial pressure, arterial; Pathology; Patients; Phage Display; Phase; phase 1 study; phase 2 study; prophylactic; Prophylactic treatment; Recombinants; Regimen; response; Role; Safety; Severities; Sickle Cell; Sickle Cell Anemia; Spleen; Stress; Structure of parenchyma of lung; T-Cell Receptor; The Jackson Laboratory; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Organisms
