TNAX103, a humanized anti-CD300A mAb, is an efferocytosis promotor and anti-inflammatory neuroprotectant that fundamentally inhibits ischemia-reperfusion injury (IRI) in acute kidney injury (AKI).
AKI and Transition to CKD
Acute kidney injury (AKI) occurs in up to 7% of hospitalized patients and up to 30% of ICU patients, with very high mortality rates (40-50% in hospitalized patients and >50% in ICU patients). AKI is a high-risk factor for progression of CKD over time. The most common cause of AKI in hospitalized patients is acute tubular necrosis (ATN), which often involves injury to the renal proximal tubular epithelium. Cell death of vascular endothelium and renal tubular epithelium plays an important role in the pathological progression from AKI to CKD. Inflammation after AKI causes renal dysfunction and fibrosis. Currently, there are no effective means of preventing or treating AKI.
Inflammation in Dead Cells
Ischemic cell death induces inflammation, resulting in further cell death and tissue damage. Damage-associated molecular patterns (DAMPs) are released from ischemia-induced dead cell and produce proinflammatory cytokines. A vicious cycle of tissue damage in the renal proximal tubular epithelium is the major trigger of AKI.
“Tissue damage” -> ”DAMPs release from dead cells” -> “Inflammation” -> “Further tissue damage”
Prevention of CSA-AKI by Efferocytosis
On-pump cardiopulmonary bypass surgery often takes 4 – 6 hours, and cardiac surgery-associated AKI (CSA-AKI) is primarily initiated by ischemia/IRI. The critical downstream consequences are tubular epithelial cell necrosis and inflammatory cascade. Promoting the clearance of dead tubular epithelial cells by efferocytosis reduces the release of DAMPs, suppresses acute inflammation and blocks the vicious cycle of induction of further dead cells and tissue injury. TNAX103 is expected to restore normal kidneys from AKI and prevent progression to CKD.
Effects of Anti-CD300a mAb in Mouse AKI Models
Our anti-CD300a mAb ameliorates renal function, tubular damage and fibrosis after ischemia-reperfusion injury (IRI) in mice.
Our anti-CD300a mAb promotes efferocytosis and attenuates AKI and kidney fibrosis in another mouse model.
Problems of Current Treatment of AIS
Acute ischemic stroke (AIS) is a medical emergency caused by decreased blood flow to the brain, which results in damage to brain cells within minutes. Each year, AIS affects millions of people worldwide, with a significant impact on mortality and disability rates. Prompt treatment can reduce the brain damage and other complications, and the standard treatment for AIS is intravenous thrombolysis and endovascular thrombectomy. These recanalization therapies, however, have issues. Abrupt reperfusion, in particular, often causes secondary brain damage. Ischemia-reperfusion injury (IRI) is caused by the rapid restoration of the blood supply to tissues after ischemia, but currently no effective treatment is available. A new treatment is needed to prevent IRI after AIS.
Inflammation in Dead Cells
Inflammatory pathways begin hours or later after AIS and lead to neuronal cell death. Ischemic cell death induces inflammation, which results in further cell death and tissue damage in the penumbra (i.e., a vicious cycle of tissue damage). The penumbra, the reversibly damaged and perfused brain region surrounding the ischemic core, is a critical tissue at risk of cell death and can be rescued by controlling cell death-induced inflammation. Therefore, penumbra represents a new pharmacological target for AIS.
Pharmacological Effects of Anti-CD300a mAb in Mouse MCAO Model
Our anti-CD300a mAb decreases infarct volume and ameliorates neurological scores in mouse middle cerebral artery occlusion and reperfusion model.
CD300a and PS
Normally, phosphatidylserine (PS) is confined to the inner membrane leaflet of viable cells, whereas in dead cells PS is exposed on the outer membrane. PS exposed on the outer membrane of dead cells acts as an “Eat Me” signal, and macrophages induce efferocytosis to remove the dead cells. On the other hand, CD300a expressed on macrophages is a key anti-efferocytic molecule. PS is a ligand for CD300A expressed on macrophages, and PS bound to CD300A expressed on macrophages induces resistance to dead cell removal (efferocytosis). Anti-CD300a (efferocytosis promotor) mAb blocks CD300a binding to PS and normalizes the clearance of the diseased tissues.
TNAX101A (IBM1001), a humanized anti-DNAM-1 (CD226) mAb, is an anti-inflammatory/fibrotic drug for the treatment of immune-mediated inflammatory diseases.
The clinical candidate is TNAX101A, renamed IMB1001. IMB1001 is considered to be a preferred treatment option for ulcerative colitis. Unlike other anti-inflammatory drugs, IMB1001 is not excessively immunosuppressive and carries a low risk of serious infection. TNAX101A was discovered by TNAX Biopharma, and IMB1001 is currently being developed by our partner, IMIDomics.