Serum Amyloid P Component (SAP)
Promedior is conducting leading edge research to identify and develop novel drugs for the treatment and prevention of fibrotic pathology by targeting specific cell populations that are involved in propagation of fibrosis and promoting those specific cell populations that amplify resolution of disease. Our lead program involves the development of PRM-151, a recombinant form of human serum amyloid P component (rhSAP, Pentraxin-2) for the treatment and prevention of fibrotic disease pathology based upon our proprietary discoveries into SAP’s unique roles in regulating the response of the innate immune system to injury.
Structure of SAP 
Acute and chronic injury is first recognized by the innate immune system
through neo-epitope exposure of damage-associated molecular patterns (DAMPs).
PRM-151 mediates its suppressive function by recognition of DAMPs on damaged
cells and tissues at sites of injury and within peripheral circulation.
DAMP recognition by SAP is specific, Ca++-dependent and promotes
subsequent binding by and phagocytosis through the Fcg receptors (FcgRs).
Furthermore, hSAP’s therapeutic effect is FcgR-dependent, and is blocked in
vivo in FcRg knockout animals. At the biochemical level, recent
crystallographic data has confirmed that hSAP’s two unique binding sites are on
opposite sides of the protein, one for Ca++-dependent ligands
(Structure of SAP, violet residues) and one for FcgRs (Structure of SAP, red
residues). At the cellular level, SAP suppresses the ability of monocytes
to be stimulated by multiple profibrotic cytokines and growth factors by
actively stimulating an FcgR-dependent suppressive signaling pathway. DAMP
ligand stimulation of inflammatory and fibrotic cytokine expression is blocked
by hSAP-mediated phagocytosis. Both in vitro and in vivo,
hSAP suppresses inflammatory and fibrotic gene and protein expression in
monocyte-derived cells recruited to the injured tissue. These effects are
strongly correlated with an increase in the production of several key 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 FcgR-mediated monocyte
suppression, PRM-151 inhibits fibrotic pathology specifically at the site of
injury and promotes healing without scarring.
PRM-151 (rhSAP) Blocks Fibrosis Through Suppression of
Monocytes
SAP is a member of the pentraxin family of proteins and falls
into the subclass of short pentraxins made up of CRP (Pentraxin-1) and SAP
(Pentraxin-2). SAP is a highly conserved, naturally circulating plasma
protein produced in the liver. SAP circulates at a relatively constant level
and was initially characterized as a humoral member of the innate immune system,
similar to Complement proteins. However, SAP’s precise role in
human biology was previously unknown. Pioneering work conducted by
Promedior’s scientific founders Richard Gomer and Darrell Pilling recently
demonstrated that SAP is capable of inhibiting the differentiation of monocytes
into fibrocytes in vitro, and block induction of fibrosis in vivo
in rodent models of lung fibrosis. These results suggest that SAP has
anti-fibrotic properties mediated by its unique ability to regulate
differentiation of monocyte populations. Subsequent and extensive studies
conducted by Promedior and its collaborators have demonstrated the ability of
SAP 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.
Preclinical Models in which hSAP Has Demonstrated
Efficacy
