Table 1.
Ang/Tie2-targeted therapies in pre-clinical studies of sepsis.
| Compound(s) | Description | Pre-clinical studies/model |
|---|---|---|
| AdhAng1/rAAV.ANG1/AdAng1 | Adenovirus construct expressing rh Ang1 | Mouse—endotoxemia (106, 204) Mouse—ECM (45) |
| rh-Ang1 | Commercial rh Ang1 protein (R&D Systems) | Mouse—endotoxemia (35) Mouse—Gram-negative sepsis (205) |
| COMP-Ang1 | Adenovirus expressing rh-Ang1 variant: N-terminal is replaced with short coiled-coil domain of COMP for increased stability, solubility and Tie2 activating potency over rh-Ang1 | Mouse—endotoxemia (107) |
| MAT.Ang1 | rh-Ang1 variant: central coiled-coil N-terminal of Ang1 is replaced with short coiled-coil domain of matrilin for increased stability and solubility over rh-Ang1 | Mouse—sepsis (58) |
| BOWAng1 | rhAng1 variant: C-terminal fibrinogen-like domain of Ang1 protein fused to human IgG Fc fragment, engineered to tetramer conformation for optimal Tie2 phosphorylation | Mouse—ECM (45) |
| ANGPT1 | Human Ang1 gene plasmid transfected into syngeneic MSCs for engraftment into injured pulmonary vasculature | Mouse—endotoxemia (206, 207) |
| CDDO-EA | Synthetic oleanane triterpenoid, activator of Nrf2. Increased Ang1 and decreased Ang2 levels in plasma, and reduced cerebrovascular leak in ECM model | Mouse—ECM (208) |
| Rosiglitazone | PPAR-γ agonist increased Ang1 levels in brains of ECM models | Mouse—ECM (133) |
| LC10, LOC06, ABA | Selective anti-Ang2 antibodies inhibit Ang2 binding to Tie2 | Mouse—polymicrobial sepsis (24, 204) |
| ABTAA | Ang2 clustering converts antibody into Tie2 activating ligand | Mouse—endotoxemia, Gram-positive bacteremia, polymicrobial sepsis (24) |
| Angpt-2 siRNA | Ang2 siRNA highly specific for pulmonary endothelium, reduced Ang2 expression in murine lung tissue and resulted in increased Tie2 phosphorylation | Mouse—endotoxemia, polymicrobial sepsis (209) |
| rh-Ang2 | Commercial rh Ang2 protein (R&D Systems) | Mouse—Gram-negative sepsis (205) Rabbit—Gram-negative sepsis (210) |
| AKB-9778 | Small molecule inhibitor of VE-PTP; promotes Tie2 activation | Mouse—endotoxemia (33) Mouse—stroke/BBB permeability (211) Mouse—choroidal neovascularization and ischemic retinopathy (43, 212) |
| Vasculotide | Synthetic tetrameric polyethylene glycol-clustered Tie2 agonist | Mouse—polymicrobial sepsis (213) Mouse—influenza infection (214) |
Therapeutic agents that target Tie2 by augmenting Ang1 levels, inhibiting Ang2, or promoting Tie2.
Abbreviations: ABA, Ang2-blocking antibody; ABTAA, Ang2-binding and Tie2 agonist antibody; Angiopoietin (Ang), CDDO-EA, 2-cyano-3,12-dioxooleana- 1,9(11)-dien-28-oic acid ethyl amide; COMP, cartilage oligomeric matrix protein; ECM, experimental cerebral malaria; Fc, IgG, immunoglobulin; MAT, matrilin; nrf2, nuclear factor-like 2; siRNA, small interfering RNA; rh, recombinant human; VE-PTP, vascular endothelial protein tyrosine phosphatase.