Synthesis and structure-activity relationship studies of CCR8 agonists as a novel treatment option for autoimmune diseases

Chemokines (chemoattractant cytokines) are a group of small (8 –10 kDa) and predominantly basic proteins that play an important role in the human immune system by regulating the migration and activation of immune cells. These chemokines are divided into three subfamilies based on the location of the first two cysteine (C) residues: CC-chemokines, CXC -chemokines, and CX3Cchemokines (with X being a variable amino acid). C-chemokines are exceptions as they contain only one N-terminal cysteine residue. Chemokines exert their biological effects by interaction with cellsurface receptors (chemokine receptors) that belong to the class A G protein-coupled receptors (GPCRs). In humans, approximately 50 different chemokines and 20 chemokine receptors are described. Some chemokines bind to more than one chemokine receptor, and at the same time, a single chemokine receptor can interact with a variety of chemokines, albeit often with variable affinities. Experimental evidence for the involvement of chemokine-chemokine receptor signaling in various human pathologies (e.g., inflammatory and autoimmune disorders, cancer and infectious diseases) has led to the initiation of many drug discovery campaigns. So far, two small molecules targeting chemokine receptors have received marketing approval. The first molecule being Maraviroc, which is a CCR5 antagonist that is developed as an anti-HIV drug to treat infection with R5-tropic HIV strains. The second molecule is MozobilTM (Plerixafor), which is a CXCR4 antagonist. It was initially identified as a potent anti-HIV molecule active against X4-tropic HIV strains, but was later approved for hematopoietic stem cell mobilization in non-Hodgkin’s lymphoma and multiple myeloma patients. A CCR4-targeting antibody (MogamulizumabTM) received marketing approval to support the treatment of various forms of cutaneous T-cell lymphoma. In addition, a large number of small molecules and biologicals targeting various chemokine GPCRs (e.g. CXCR4, CXCR2, CCR5, CCR9) is currently undergoing clinical trials and it is expected that in the future some of them will reach the market. The human chemokine receptor CCR8 recently emerged as a promising drug target. It is reported that CCR8 can interact with multiple chemokines (CCL1, CCL8, CCL16, CCL18), but CCL1 provides the best established interaction and solely interacts with CCR8. The expression of CCR8 is upregulated on activated T helper 2 (Th2) cells, which are an important source of several pro-inflammatory cytokines, such as IL-4, IL-5 and IL-13. Hence, CCR8 was historically studied as a therapeutic target for the treatment of inflammatory disorders as for instance asthma and atopic dermatitis. CCR8 expression is also upregulated in tumor-resident regulatory T cells (Tregs) that function as potent suppressors of the anti-tumor effector T cell responses. The presence of these CCR8-positiveTregs in the tumor microenvironment (TME) correlates with reduced survival.6 Also, depletion of Tregs enhances anti-tumor immune responses and reduces tumor burden. It is thus postulated that modulating the immunosuppressive function of CCR8-positive tumor-resident Tregs and/or inhibiting their migration towards the tumor site can be an alternative therapeutic strategy to support and extent current cancer immunotherapy.An in vivo proof-of-concept study in a mouse colorectal tumor model showed significant tumor growth inhibition and a prolonged survival as a result of blocking CCR8 with a monoclonal antibody. In addition,regulatory T cells also play a pivotal role in suppressing autoimmunity. In a recent study, CCR8-positive Tregs were identified as key drivers of immunosuppression. In a mouse model of experimental autoimmune encephalomyelitis (EAE), CCL1-induced potentiation of CCR8-positiveTregs suppressed the disease, underpinning their importance in regulating the immune system.Stimulation and expansion of CCR8-positive Tregs by CCR8 agoniststhus appear as a promising path forward in the treatment of various autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and Crohn’s disease, which warrants further investigation.