TR8 is a protein that behaves like annexin-A1, a protein found in many cells in the body, especially neutrophils and monocytes. Annexin-A1 is one of the body’s main defences against inflammation1–4 (Figure 1). The anti-inflammatory effect of glucocorticoids is mediated mainly through an increase in the synthesis and function of annexin-A1. Some diseases are associated with dysregulation or a deficiency of annexin-A1. Animal models of those conditions improve when given annexin-A1. We plan to study TR8 in two conditions associated with a deficiency of annexin-A1: Crohn’s disease and multiple sclerosis.
Annexin-A1 is much reduced in the blood and affected areas of the lining of the bowel in patients with Crohn’s disease5. That may allow entry of commensal (normally friendly) or harmful bacteria into the lining of the bowel and cause it to become inflamed and lead to bloody diarrhoea, abdominal pain and weight loss.
In healthy people, there’s a barrier called the blood-brain barrier (BBB) between the blood vessels around the brain and the brain cells that prevents harmful substances from crossing in to the brain. The BBB is ‘leaky’ in patients with multiple sclerosis6. That may allow harmful substances to enter the brain and cause inflammation of the nerve sheaths and multiple sclerosis. Administration of annexin-A1 reduces the leakiness of a human BBB model of multiple sclerosis in the laboratory7.
We’ve given rising doses of TR8 to healthy subjects. It was safe and well tolerated. Currently, we’re testing TR8 against an experimental model of inflammation8,9 in healthy subjects to find a dose suitable for clinical trials in patients. Also, we’re working with a leading manufacturer of proteins to improve TR8, and to make it by a novel method.
Figure 1. Annexin-A1 controls inflammation through its effect on immune cells
- Perretti M, D’Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat. Rev. Immunol 2009; 9: 62–70.
- Bruschi M, Petretto A, Vaglio A, Santucci L, Candiano G, Ghiggeri GM. Annexin A1 and autoimmunity: from basic science to clinical applications. Int J Mol Sci 2018;19: doi 10.3390/ijms19051348.
- Shao G, Zhou H, Zhang Q, Yuanting J, Caiyun F. Advancements of annexin A1 in inflammation and tumorigenesis. Onco Targets Ther 2019; 12: 3245–3254.
- Purvis G, Solito E, Thiemermann C. Annexin-A1: therapeutic potential in microvascular disease. Front Immunol 2019; 10: 938.
- Sena A, Grishina I, Thai A, Goulart L, Macal M, Fenton A, Li J, Prindiville T, Oliani SM, Dandekar S, Goulart L, Sankaran-Walters S. Dysregulation of anti-inflammatory annexin-A1 expression in progressive Crohns disease. PLoS One 2013; 8: e76969.
- Cristante E, McArthur S, Mauro C, Maggioli E, Romero IA, Wylezinska-Arridge M, Solito E. Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci 2013; 110: 832–841.
- McArthur S, Loiola RA, Maggioli E, Errede M, Virgintino D, Solito E. The restorative role of annexin A1 at the blood-brain barrier. Fluids Barriers CNS 2016; 13: 17.
- Buss NA, Gavins FN, Cover PO, Terron A, Buckingham JC. Targeting the annexin 1-formyl peptide receptor 2/ALX pathway affords protection against bacterial LPS-induced pathologic changes in the murine adrenal cortex. FASEB J 2015; 29: 2930–2942.
- Fullerton JN, Segre E, De Maeyer R P, Maini AA, Gilroy DW. Intravenous endotoxin challenge in healthy humans: an experimental platform to investigate and modulate systemic inflammation. J Vis Exp 2016; 111: doi: 10.3791/53913.