A Novel Collagen Hybridizing Peptide for Activating LAIR-1 Inhibitory Pathway at Damaged Collagen Sites
ABSTRACT TITLE: A Novel Collagen Hybridizing Peptide for Activating LAIR-1 Inhibitory Pathway at Damaged Collagen Site
AUTHORS: Regan Stephenson, Bridget Glass, Kyle Dunlap, Mallory Longacre, Lucas Bennink, Mike Kirkness
AFFILIATIONS: 3Helix, Inc, Salt Lake City, Utah, USA
ABSTRACT:
Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory collagen receptor expressed on a variety of immune cells, plays a crucial role in maintaining immune homeostasis. In autoimmune diseases characterized by collagen damage, immune regulation via LAIR-1 is impaired due to loss of LAIR-1 binding sites in damaged collagen. Collagen hybridizing peptides (CHP) are peptide sequences that mimic the Gly-X-Y repeats found in collagen which enable specific binding to the damaged collagen triple helix. Building off CHP technology, we developed bioACTIVE CHPs, a innovative peptide platform to enrich areas of damaged collagen with cell binding sites tailored for desired cellular responses. Here we present FLAIR2, a novel bioACTIVE CHP with a LAIR-1 binding motif to reinstate immune regulation to the collagen triple helix at sites of collagen damage. We hypothesized that this peptide would bind to damaged collagen and inhibit immune cell activation at those sites. In vitro testing confirmed FLAIR2 binds to damaged collagen and promotes LAIR-1 binding. At the cellular level, FLAIR2 exhibited immunomodulatory effects by attenuating IL-2 secretion and expression of interferon gamma in activated T cells. In macrophages, FLAIR2 exposure reduced expression of M1 macrophage marker transcripts for CCR7 and CD86 and the secretion of inflammatory cytokines IL-6 and IL-1β. Lastly, in an ex-vivo human psoriasis model FLAIR2 treatment demonstrated broad anti-inflammatory effect and reduced key pathogenic cytokines at levels comparable to betamethasone, the current standard for psoriasis treatment. These findings establish FLAIR2 as a novel anti-inflammatory therapeutic capable of simultaneously targeting damaged collagen and activating LAIR-1-mediated immune cell inhibition, presenting a revolutionary approach for treating inflammatory autoimmune diseases.