Chemokines are signal proteins or peptides secreted by cells, which direct the movement of responding immune cells. The secretion of inflammatory cytokines is induced by inflammatory processes and pathogens. This causes the recruitment of leucocytes along a concentration gradient to the source of chemokine production. Dysregulation of chemokines plays a destructive role in many chronic inflammatory diseases like arthritis, multiple sclerosis and colitis. Due to the high presence of chemokines, originally providing the clearance of pathogens and damaged tissue, enhanced influx of immune cells causes attack of endogenous healthy structures in these diseases.
After cleavage of the signal peptide, some chemokines possess an N-terminal glutamine residue, which is subsequently converted to pyroglutamate under physiological conditions by glutaminyl cyclase activity. The resulting lactam ring is not protonated in the physiological pH range. This provides an elevated resistance against aminopeptidases and exoproteases, which need a protonated amino group for substrate binding.
Furthermore, enhanced receptor activation could be shown for the respective chemokines after N-terminal pyroglutamate formation. Chemokine cleavage by endoproteases, like matrix metalloproteinases, is not affected by an N-terminal pyroglutamate. However, it was described that truncation of chemokines by matrix metalloproteinases results in receptor antagonists, which are able to bind, but fail to activate the chemokine receptor.
Our approach is the development of protein drugs, which neutralize post-translationally modified chemokines. Besides the N-terminal modifications, also other structural elements might be important. In addition to antibodies, therapeutic proteins with antibody like properties will be developed in cooperation with industry partners.