Front Immunol. 2014 Aug 22;5:406. doi: 10.3389/fimmu.2014.00406. eCollection 2014.
Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential.
Sharp JA1, Whitley PH2, Cunnion KM3, Krishna NK4.
Abstract
The classical pathway of complement
plays multiple physiological roles including modulating immunological
effectors initiated by adaptive immune responses and an essential
homeostatic role in the clearance of damaged self-antigens. However,
dysregulated classical pathway activation is associated with
antibody-initiated, inflammatory diseases processes like cold agglutinin
disease, acute intravascular hemolytic transfusion reaction (AIHTR),
and acute/hyperacute transplantation rejection. To date, only one
putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH),
is currently commercially available and its only approved indication is
for replacement treatment in hereditary angioedema, which is
predominantly a kinin pathway disease. Given the variety of disease
conditions in which the classical pathway is implicated, development of
therapeutics that specifically inhibits complement
initiation represents a major unmet medical need. Our laboratory has
identified a peptide that specifically inhibits the classical and lectin
pathways of complement. In vitro studies have demonstrated that these peptide inhibitors of complement C1
(PIC1) bind to the collagen-like region of the initiator molecule of
the classical pathway, C1q. PIC1 binding to C1q blocks activation of the
associated serine proteases (C1s-C1r-C1r-C1s) and subsequent downstream
complement
activation. Rational design optimization of PIC1 has resulted in the
generation of a highly potent derivative of 15 amino acids. PIC1
inhibits classical pathway mediated complement
activation in ABO incompatibility in vitro and inhibiting classical
pathway activation in vivo in rats. This review will focus on the
pre-clinical development of PIC1 and discuss its potential as a
therapeutic in antibody-mediated classical pathway disease, specifically
AIHTR.
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