TNAX103, a humanized anti-CD300A mAb, is an innate immune checkpoint modulator that prevents DAMPs from developing into inflammation.
Phosphatidylserine (PS) is a phospholipid confined in the inner membrane leaflet of viable cells. When viable cells are subjected to stress, PS is exposed on the outer membrane. Theare are several ways in which cells die, but they all have one thing in common: PS exposure. PS sends out a signal saying “Eat me but do not cause inflammation”. If dead cells are not removed, they burst and release damage-associated molecular patterns (DAMPs), which activate immune receptors called pattern recognition receptors (PRRs).
Since living organisms cannot distinguish between “safe cell death” and “dangerous damage” based on PS alone, CD300a and CD300b integrate their antagonistic signals from these pathways — rather than competing for PS — to continuously control the inflammatory state and repair processes of tissues.
CD300a and CD300b are paired receptors.
- Expressed on myeloid cells
- Recognize the same ligand (PS)
- Elicit opposing signals
CD300a
↓Inflammation, ↓Efferocytosis, ↓ROS production, ↓Neutrophil activation
CD300b
↑Inflammation, ↑Efferocytosis, ↑ROS production, ↑Neutrophil activation
Efferocytosis
- Recognition of “Eat me” signal
- Rapid clearance of dead/dying cells
- Inhibition of inflammation (↓Activation of runaway DAMPs, ↓Progression of DAMPs to inflammation)
CD300a is an inhibitory receptor expressed on myeloid cells with immunoreceptor tyrosine-based inhibitory motif (ITIM) that suppresses inflammatory signal. CD300a bound to PS puts brakes on myeloid cells and inhibits excessive innate immunity. When bound to PS, CD300a inhibits macrophage activation, and unremoved dead cells are accumulated.
When blood flow is restored, DAMPs are released into the bloodstream from dead cells that have ruptured due to ischemia or reperfusion stress. DAMPs are contents of the ruptured cells, and they act as damage signals. DAMPs are recognized by PRRs, and the innate immunity mistakenly perceives sterile inflammation as infection. The inflammation burst occurs rapidly, and neutrophils migrate even though the body is not infected. Our drug helps the immune system recognize the difference between infection and tissue damage. TNAX103 is an anti-CD300A antibody that corrects the immune system’s error.
The suppression of runaway DAMPs is a primary therapeutic target for penumbra salvage in acute ischemic stroke, and TNAX103 inhibits CD300A activation before DAMPs surge has occurred.
Despite the achievement of timely and complete recanalization in many patients with acute ischemic stroke, the prognosis remains poor due to futile recanalization. The dominant cause of futile recanalization is no-reflow, which is an immune-mediated microcirculatory failure. Constant release of large amounts of DAMPs leads to capillary occlusion. No-reflow is not residual clots or stuck microthrombi. It is critical to stop DAMPs from running wild.
TNAX103 efficiently removes PS-exposing dead/dying cells “before” inflammation can escalate and inhibits “multiple” inflammatory pathways “at an early stage”. Selective PRR/cytokine inhibitors do not broadly inhibit inflammatory pathways, and inflammation is maintained. On the other hand, they exhibit systemic immunosuppressive effects and carry an increased risk of infection. TNAX103 may enhance local immune defense during bacterial infection.