LEADERSHIP IN FIBROSIS: R&D Platform

Promedior’s initial drug products are based upon the unique structure of pentraxin-2 (PTX-2, also called SAP), which Promedior has demonstrated plays a unique role in targeting and regulating monocytes at sites of tissue damage. Promedior’s approach leverages this natural role of PTX-2 in regulating the response of important immune and inflammatory processes in the body.

Structural representation of PTX-2 (pentraxin-2) showing the unique pentameric structure of this naturally-circulating plasma protein and highlighting in orange its unique therapeutically-relevant binding sites which are present in each of the five subunits of PTX-2.

Acute and chronic injury is first recognized by the innate immune system through exposure of damage-associated molecular patterns (DAMPs). DAMPs are normally expressed molecules (such as DNA or specific lipids) that are sequestered inside the cell. When cells are damaged the DAMPs are exposed and can now be recognized by the innate immune cells such as monocytes. PTX-2 initiates its regulatory function by recognition of DAMPs on damaged cells and tissues at sites of injury and within peripheral circulation. DAMP recognition by PTX-2 is specific, Ca++-dependent and promotes subsequent binding by and removal through the Fcγ receptors (FcγRs) on monocytes. At the biochemical level, recent crystallographic data have confirmed that hPTX-2’s two unique binding sites are on opposite sides of the protein, one for Ca++-dependent ligands (structure of PTX-2, ligand binding surface) and one for FcγR (structure of PTX-2, FcγR binding surface). Furthermore, hPTX-2’s therapeutic effect is FcγR-dependent, and is blocked in vivo in FcγR knockout animals.

At the cellular level, PTX-2 suppresses the ability of monocytes to be stimulated by multiple profibrotic cytokines and growth factors by activating an FcγR-dependent regulatory signaling pathway. DAMP ligand stimulation of inflammatory and fibrotic cytokine expression is blocked by PTX-2-mediated removal. Both in vitro and in vivo, PTX-2 suppresses inflammatory and fibrotic gene and protein expression in monocyte-derived cells recruited to the injured tissue. These effects are strongly correlated with induction of a regulatory macrophage phenotype identified by an increase in the production of several key regulatory proteins, such as IL-10, which have been independently associated with inhibiting fibrosis and suppressing the innate immune response to injury. Thus, by linking recognition of injury-induced DAMP expression to FcγR-mediated stimulation of regulatory macrophages, PTX-2 inhibits fibrotic pathology specifically at the site of injury and promotes healing without scarring.

Extensive studies conducted by Promedior and its collaborators have demonstrated the ability of PTX-2 to inhibit multiple pathologic monocyte-derived cell populations and to block the development of fibrosis in several models of fibrotic disease, across all major tissue types, confirming its potential as a novel anti-fibrotic agent. Promedior and its collaborators have published many of their findings in peer-reviewed journals.

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