Pentraxin-2 Mechanism of Action
Promedior's drug candidates are based on Pentraxin-2. Pentraxin-2 is a normal plasma protein that, as a monocyte/macrophage differentiation factor, acts as an agonist to turn on a fibrosis resolution pathway via regulatory macrophages, simultaneously turning off the pathway mediated by pro-inflammatory and pro-fibrotic macrophages that leads to fibrosis. This switch circumvents the disease process and offers the prospect of a durable, disease-modifying effect. Other therapeutic approaches in development are predominantly not damage-specific, and focus on single downstream targets, after scarring/fibrosis has already been initiated. Blocking these downstream targets may not prevent disease progression, as there are many redundancies in the fibrosis cascade that allow for the unabated continuation of fibrosis. In contrast, Pentraxin-2 works as an upstream agonist of these resolution pathways by redirecting macrophages toward the resolution pathway, halting further progression of fibrotic disease and promoting natural healing.
The following two-part schematic depicts inflammation, proliferation, and resolution of fibrosis driven by Pentraxin-2.
In a healthy system, the body activates three immune response pathways that act in balance to address diseased or damaged tissue and promote healing: inflammation, proliferation, and resolution. The immune system responds to tissue damage by stimulating monocytes to mobilize to the site of the damage where, driven by microenvironmental cues, monocytes differentiate to the appropriate macrophage subtypes to mediate immune response pathways.
Fibrosis is the formation of excessive scarring in tissue locked in the proliferation pathway that cannot exit to the resolution pathway and return to homeostasis.
Fibrosis occurs when diseased or injured tissue triggers dysregulated activation of the proliferation pathway of the immune system, often due to excessive acute tissue damage (e.g. traumatic injury) or chronic tissue injury (e.g. chronic inflammation or cancer).
Due to specific pro-fibrotic conditions within the damaged tissue microenvironment, monocytes differentiate primarily into pro-fibrotic macrophages and fibrocytes, driving overactivation of the proliferation pathway and resulting in activation of myofibroblasts, a cell population that secretes the extracellular matrix proteins that make up scar tissue.
The ongoing tissue damage caused by fibrosis continues to recruit monocytes into the proliferation pathway, leading to further myofibroblast activation and fibrosis, perpetuating the disease process.
Resolution of Fibrosis with Pentraxin-2
Pentraxin-2 has a high affinity for the damaged tissue microenvironment and specifically binds to the cell and tissue debris that results from the pathological fibrosis process. When bound to this tissue and debris, Pentraxin-2:
- binds with high affinity to Fcγ receptors on monocytes and directs the differentiation of monocytes into pro-resolution (Mreg) macrophages, driving the activation of the resolution pathway;
- differentiation of monocytes into pro-resolution macrophages shifts the equilibrium away from the inflammation and proliferation (fibrotic) pathways;
- thus Pentraxin-2 intervenes upstream of monocyte differentiation, preventing disease progression while promoting healing and resolution of fibrosis.
Pentraxin-2 is a Natural Regulator of Monocytes in the Immune System
Recent discoveries about the biology of tissue repair and fibrosis have elucidated the important role that Pentraxin-2 plays in regulating processes related to the prevention and resolution of scar tissue. Specifically, Pentraxin-2 is an agonist that binds to and activates Fcγ receptors on monocytes and macrophages to control their differentiation and promote healing specifically at the sites of tissue damage. Monocytes are cells of the innate immune system that rapidly migrate to areas of tissue injury, where they differentiate into macrophages. Macrophages have several important roles, including killing of microorganisms, removing damaged tissue and debris, and regulating tissue repair. Pentraxin-2 promotes the differentiation of monocytes into regulatory macrophages, which function to promote epithelial healing and resolution of inflammation and the scar tissue that results from the proliferation pathway. Pentraxin-2 prevents the differentiation of monocytes into pro-fibrotic macrophages and fibrocytes, preventing the formation of scar tissue. Fibrosis is essentially a pathological condition in which severe or chronic injury locks macrophages into the pro-fibrotic proliferation pathway, creating an endless loop of aberrant scar formation. Pentraxin-2 offers the potential to reverse this pathological process and restore healthy equilibrium to tissue.