NASH Target Development Service for CCR2-CCR5

Non-alcoholic steatohepatitis (NASH) is a type of liver inflammation and damage caused by a buildup of fat in the liver. The expression of both chemokine receptor CCR2 and CCR5 plays an important role in the pathogenesis of many diseases, including NASH. However, clinical trials with agents against either receptor have afforded little efficacy in patients. As a top-ranking provider in the disease target development, Creative Biolabs is capable of offering the most flexible solutions to achieve the discovery, identification, and optimization of potential small molecule drugs. In particular, we can produce chemokine antagonists for NASH therapy with dual targeting of CCR2-CCR5.

Introduction of CCR2&CCR5

CCR2 (C-C motif chemokine receptor 2, CD192) is a 41.9kDa protein depicted with three extracellular and three intracellular loops and seven transmembrane domains. CCR5 (C-C motif chemokine receptor 5, CD195) is a 40.5kDa protein on the surface of white blood cells which is involved in the immune system. Both CCR2 and CCR5 are C-C chemokine receptors and expressed on monocytes, macrophages, Kupffer cells, and hepatic stellate cells. They promote recruitment of these cells to the liver, inducing inflammation and fibrogenesis. Moreover, they play an important role in the trafficking of monocytes/macrophages and in the function of other cells relevant to disease pathogenesis. CCR2 and CCR5 are a G protein-coupled receptor that can bind to multiple ligands. For CCR2, known as macrophage chemoattractant protein, it can interact with CCL2 (MCP-1), CCL8 (MCP-2), CCL7 (MCP-3), and CCL13 (MCP-4), while for CCR5, it binds to CCL4 (MIP-1β), CCL5 (RANTES), CCL3 (MIP-1α), CCL8 (MCP-2), and CCL3L1 (MIP-1α/LD78β).

Fig.1 Structures of CCR2 and CCR5.

CCR2-CCR5 Antagonist for NASH Therapy

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and now 1/4 of the adult population is suffering from NAFLD worldwide. NASH is an aggressive form of NAFLD and could progress to liver cirrhosis and hepatocellular carcinoma (HCC). It has rapidly become the primary cause of end-stage liver disease or liver transplantation. The recruitment of inflammatory monocytes and macrophages via chemokine receptor CCR2 as well as of lymphocytes and hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis.

Given evidence of targeting CCR2 or CCR5 alone showed insufficient efficacy by pharmacologically inhibiting one receptor, whereas supports on dual targeting of CCR2 and CCR5 exhibited a more efficacious strategy in recent reviews. Cenicriviroc (CVC) is an oral, dual CCR2-CCR5 antagonist, that has completed Phase IIb development in HIV and is undergoing Phase IIb evaluation in subjects with NASH and liver fibrosis. CCR2 and CCR5 promote activation and migration of Kupffer cells and hepatic stellate cells as well as increase inflammatory cells. Also, they two were identified as mediators in hepatic fibrogenesis and NASH in rat models. The antagonism of CCR2-CCR5 by CVC was evaluated in thioacetamide-induced rat models of liver fibrosis and mouse models of diet-induced NASH. Taken together, CCR2-CCR5 axis is upregulated in human liver NASH and the administration of CCR2-CCR5 antagonist produces an anti-inflammatory response in a chemotoxic or metabolic mediated inflammation model and liver injury model.

Fig.2 Mechanism of CVC in liver fibrosis.

Now, there are several innovative agents in the drug pipeline for NASH. Four drugs, obeticholic acid (OCA), elafibranor, selonsertib, and CVC, have entered Phase III trials. Cost-effective data and patient-centered benefits are required to position their medications in the practical guidelines of NASH/NAFLD.

Antagonist Developments at Creative Biolabs

From the perspective of drug discovery, targeting one chemokine receptor may not be enough to provide supports for chronic inflammatory diseases, as displayed by failed clinical studies with selective inhibitors of the CCR2-MCP-1 axis in rheumatoid arthritis (RA). Strong preclinical evidence exists for the temporally and spatially dependent modulation of expression and function of CCR2 and CCR5 and for the importance of both receptors in the pathogenesis of multiple diseases. Hence, dual targeting of CCR2-CCR5 should gain greater efficacy, and a CCR2-CCR5 dual inhibitor has broad potential for clinical use. It is an excellent opportunity that is being seized by pharmaceutical industries.

CCR2 and CCR5 play a central role in hepatic inflammation and fibrosis contributing to the pathogenesis of NASH. To prevent liver-related mortality in NASH patients, those with fibrosis should be considered for pharmacy treatment in addition to conventional dietary interventions. Notably, Creative Biolabs has rich experience in chemokine antagonist development and we can help clients to screen CCR2-CCR5 antagonists and arrange the subsequent clinical trials during all stages. And it’s reasonable to expect that such dual antagonists will be soon evaluated in NASH patients for efficacy and safety.

With dedicated devices and systematic platforms, Creative Biolabs is able to shape the best strategy and bring the valuable solutions through collaborative approaches and deep scientific understanding of specific projects. Meanwhile, our services include but not limited to: Phage Display & Antibody Library Services, Antibody Analysis Services, Antibody Engineering Services, etc. If you have any other special need, please feel free to contact us.

Reference

1. 2016 Annual Meeting of the American Association for the Study of Liver Diseases, November 23, 2016, https://www.clinicaloptions.com.