TNAX103, a humanized anti-CD300A mAb, is an efferocytosis promotor that prevents ischemia-reperfusion injury (IRI) from developing into inflammation.
Ischemia Reperfusion Injury (IRI)
The restoration of blood flow after ischemia itself causes new tissue damage known as ischemia-reperfusion injury (IRI), which represents an unmet medical need in many organs, including the kidneys, brain and heart.
Vicious Cycle of Inflammation in Dead/Dying Cells
Cells subjected to IRI stress release debris named damage-associated molecular patterns (DAMPs), initiating an inflammatory cascade. DAMPs activate pattern recognition receptors (PRRs) and produce pro-inflammatory cytokines. Inflammation exacerbates cell death, perpetuating the vicious cycle of inflammation. Thus, DAMPs released from dead/dying cells act as the trigger switch for the inflammatory cascade.
Vicious Cycle of Inflammation: Tissue damage, Cell death → DAMPs release from dead/dying cells Inflammation → Further tissue damage and cell death
Efferocytosis and CD300A: New drug target for IRI
Normally,phosphatidylserine(PS) is confined to the inner membrane leaflet of viable cells. When viable cells are subjected to stress such as IRI, PS becomes exposed on the outer membrane of dead and dying cells. Macrophages remove dead/dying cells via efferocytosis. However, PS bound to CD300A expressed on macrophages induces resistance to efferocytosis, and thus CD300A acts as a brake on efferocytosis.
TNAX103 is an anti-CD300A antibody that releases brake on efferocytosis. Administration to patients prior to the onset of reperfusion, TNAX103 rapidly and efficiently clear away dead/dying cells, “broadly” prevents the initial wave of DAMPs release and attenuates “multiple” pro-inflammatory pathways.
IRI, Futile Recanalization and Acute Ischemic Stroke (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.
Vascular occlusion was once thought to be the core mechanism of AIS, and recanalization therapies such as thrombolysis and endovascular thrombectomy (EVT) were developed. In recent years, blood flow restoration has been achieved in a high rate of 80 – 90 %, but beneficial clinical outcomes have not been obtained. The cause of poor prognosis is futile recanalization, which occurs in 30 to 60% of cases.
The primary cause of futile recanalization is the inflammatory cascade triggered by DAMPs released from IRI-stressed cells. In many patients with AIS involving large vessel occlusion, large thrombi are successfully removed via EVT, but IRI induces necroptosis of brain microvascular endothelial cells (BMEC). Accumulated dead/dying cells initiate the vicious cycle of inflammation by releasing DAMPs. Administration of TNAX103 prior to the onset of the reperfusion rapidly and efficiently suppresses the release of DAMPs that trigger the inflammatory cascade, thereby halting runaway upstream DAMPs and preventing IRI from developing into inflammation. Currently, the primary therapeutic target for AIS is the inflammatory cascade. Most current drugs in development target improving blood flow or neutralizing inflammatory molecules downstream of the inflammatory cascade, but they have not achieved the expected clinical efficacy.
CD300A are expressed on monocytes/macrophage, neutrophils, etc., and the therapeutic target of TNAX103 presides on peripheral and intravascular immune cells. Critical inflammation caused by IRI occurs in the perivascular space.
Pharmacological Effects of Anti-CD300a mAb in Mouse MCAO Model
Our anti-CD300a mAb decreases cerebral infarct volume and ameliorates neurological scores in a mouse middle cerebral artery occlusion (MCAO) and reperfusion model.
IRI and Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI)
Coronary artery bypass graft (CABG) surgery treats severe ischemic heart disease by restoring blood flow to the ischemic myocardium. However, on-pump CABG induces IRI and puts a heavy burden on the kidneys. Necroptosis of tubular epithelium occurs, and accumulation of dead/dying cells triggers the vicious cycle of inflammation. Dead/dying cells release DAMPs, which activate PRRs and produce inflammatory cytokines. DAMPs and complement activate each other and mutually amplify inflammation in a destructive spiral. The vicious cycle of tissue damage in the renal proximal tubular epithelium is the major cause of CSA-AKI.
Most current drugs in development target the neutralization of inflammatory molecules “downstream of the inflammatory cascade”, but they have not achieved the expected clinical efficacy. TNAX103 rapidly and efficiently inhibits the release of DAMPs, the triggering switch of the inflammatory cascade, thereby halting the runaway DAMPs “upstream” and preventing IRI from progressing to inflammation.
In addition to AKI, the transition from AKI to CKD also represents an unmet medical need. Our anti-CD300a antibody ameliorated fibrosis in mice. TNAX103 is expected to restore normal renal function 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 IRI in mice.
Our anti-CD300a mAb promotes efferocytosis and attenuates AKI and kidney fibrosis in another mouse model.
Effects of anti-CD300a mAb in acute SCI model
In a mouse spinal cord injury (SCI) model, anti-CD300a mAb ameliorated locomotor ability and historical findings: decrease in areas of SCI (H&E staining) and demyelination (LFB staining).
TNAX103 holds potential for expanded indications in chronic diseases where efferocytosis plays a key role.
Disruption of efferocytosis
Cells subjected to chronic stress play an important role in inflammation. As long as tissue damage persists, the supply of DAMPs never ceases. Efferocytosis is critically important for maintaining tissue homeostasis, and the impairment of efferocytosis may lead to various chronic inflammatory diseases. Inhibiting the release of DAMPs by anti-CD300A antibodies is expected to improve these chronic diseases.
TNAX101A (IMB1001/RVW101), a humanized anti-DNAM-1 (CD226) mAb, is an anti-inflammatory/fibrotic drug for the treatment of immune-mediated inflammatory diseases.
DNAM-1 (CD226) promotes immune responses by producing pro-inflammatory cytokines from immune cells including effector T cells and NK cells and inhibiting regulatory T cell stability and suppressive function. Inhibiting DNAM-1 suppresses immune responses and inflammation. TNAX101A (IMB1001, RVW101), anti-DNAM-1 mAb, is a promising new drug for autoimmune diseases and inflammation.
