Peptide Inhibitor of Complement C1, a Novel Suppressor of Classical Pathway Activation: Mechanistic Studies and Clinical Potential

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.

Effects of complement activation on allograft injury

“…Other reagents are being developed and tested as well. Among them, C1-INH partially inhibited ABMR in baboons (23) and a novel peptide inhibitor of C1 (PIC1) inhibited antibody-initiated classical pathway and lectin pathway complement activation in rodents (59, 60). …”

Complement Activation and STAT4 Expression Are Associated with Early Inflammation in Diabetic Wounds

“…PIC1 (i.e., PA-dPEG24)[25], identified and characterized by our group [26], is an inhibitor of antibody-initiated classical complement pathway activation that blocks the enzymatic activity of the first component of the classical pathway C1. PIC1 was synthesized as a lyophilized powder (>90% purity) by New England Peptide (MA).…”

“…Together, these emerging concepts and knowledge suggest that complement activation may be dysregulated in diabetic wounds. Peptide Inhibitor of Complement C1 (PIC1), is a peptide that inhibits enzymatic activation of the first component of the classical complement pathway C1[25,26], providing a proof-of-concept tool to test classical complement pathway activation.…”

Novel Evasion Mechanisms of the Classical Complement Pathway

“…To this point, small peptide mimics of S. aureus SCIN-derived AP inhibitors have been reported (115), and a peptidic derivative of HAstV-1 Coat Protein (PIC1) has shown efficacy as complement inhibitor in in vivo (68, 116). The ability of SCIN-derived peptides and PIC1 to preserve the inhibitory activities present in full-length proteins is consistent with the idea that immune evasion molecules, which often appear to target relatively small functional “hot-spots” on their host targets, hold promise as templates for drug design.…”