Nomacopan is a novel, dual-action recombinant protein derived from nature. Akari Chief Scientific Officer Dr. Miles Nunn hypothesized that parasites’ interactions with their hosts could offer the key to breakthroughs in autoimmune and inflammatory disease therapies and discovered nomacopan in ticks.
Ticks secrete immunomodulatory proteins that help them control host responses (inflammation, pain, itch and blood flow). These are the same responses that may be out of control in certain human autoimmune and inflammatory conditions.
Check out the Business of Biotech podcast to hear CEO Rachelle Jacques talk about how Akari engineered nomacopan, a recombinant protein derived from ticks, and scaled manufacturing for clinical trials and beyond. Listen to the podcast here: https://lnkd.in/eU6QAHv7.
Nomacopan inhibits complement C5 activation similarly to an on-market complement inhibitor ablating effects of terminal complement activation. It also sequesters LTB4, disrupting activation and recruitment of immune modulating cells responsible for damaging inflammation.
Nomacopan inhibits two pathways that can cause damaging inflammation, while preserving important immune functions. C5a, LTB4 and MAC act jointly on neutrophils, macrophages and other cell types that can cause inflammation and damage.
Nomacopan’s bispecific mechanism prevents two separate, but related, tissue-damaging effects. Opsonization (antibody binding) and role of complement in clearance of immune complexes that are needed for healthy immune response remain intact.
LTB4 is a key mediator of inflammation that is independently activated from complement, can amplify the effects of complement activation, and has independent potent inflammatory actions.
LTB4 & C5 are separate pathways but in vivo data point to signalling interplay that leads to damaging inflammation.
An in vivo study of autoantibody-induced inflammatory arthritis1, 2 found neutrophils infiltrate joints by way of multiple chemoattractant receptors, including LTB4 (BLT1) and chemokine receptors.
In the joint, neutrophils perpetuate their own recruitment by releasing LTB4 and IL-1β. Complement C5aR activation of neutrophils is required for LTB4 release and early neutrophil recruitment into the joint.
In another in vivo study of immune complex-induced acute lung injury (IC-ALI)3 C5 and LTB4 contributed equally to damaging inflammation. C5a receptor signaling regulates Fc receptors promoting inflammation. Activated alveolar macrophages produce proteases, cytokines and LTB4. C5a and LTB4 receptor activation upregulate adhesion molecules, recruit & degranulate neutrophils releasing super-oxides, causing further inflammation and microvascular damage.
References
1. Sadik CD, et al. Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling. Proc Natl Acad Sci U S A. 2012;109(46):E3177-E3185.
2. Sadik CD et al. Lipid-cytokine-chemokine cascades orchestrate leukocyte recruitment in inflammation. J Leuk Biol. 2012; 91(2:207-215.;
3. Roversi P, et al. Bifunctional lipocalin ameliorates murine immune complex-induced acute lung injury. J Biol Chem. 2013;288(26):18789-18802
