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CC chemokine receptors: latest news on Beta chemokine receptor therapeutics

C-C Chemokine Receptor type 1 – CCR1/CD191

 

Cloned in 1993, CCR1 or CD191 (cluster of differentiation 191) is 355 amino acid residues, located on 3p21.31 chromosome and expressed on monocytes, T cells, dendritic cells, and neutrophils. The ligands of CCR1 receptor include CCL3 (macrophage inflammatory protein 1 alpha and delta a.k.a MIP-1 alpha, MIP-1-delta), CCL5 (regulated on activation normal T expressed and secreted protein a.k.a. RANTES), CCL7 (monocyte chemoattractant protein 3 a.k.a. MCP-3), CCL8, CCL14, CCL15 (leukotactin-1) and CCL23 (myeloid progenitor inhibitory factor-1 a.k.a. MPIF-1).

 

A homology between the open reading frame in CMV, designated US28, and C-C CKR-1 was noted (1). There is nearly 50% amino acid identity in the presumed extracellular N-terminus prior to TM1. This observation suggests that CMV-infected cells expressing US28 could bind to C-C chemokines as part of a strategy to evade immune antiviral responses.

 

It has been demonstrated that CCR1 could increase T cell activation (2) and regulate Th1/Th2 macrophage polarization (3, 4). Consequently, CCR1 is a therapeutic target of interest to modulate leukocyte infiltration and so decrease inflamed tissue damages observed in rheumatoid arthritis or multiple sclerosis. And the development of CCR1 antagonists became the new priority of several pharmaceutical companies, including Merck (C-6448 and C-4462), Pfizer (quinoxaline amide derivative CP-481,715), Bayer (BX471), Bristol Myers Squibb (BMS-817399), Takeda (MLN3701, MLN3897), AstraZeneca (AZD4818), Boehringer Ingelheim (BI 655088), ChemoCentryx (CCX354, CCX9588) and Dompé (Reparixin). To the best of our knowledge, only Reparixin entered Phase III and all other drugs were suspended.

 

C-C Chemokine Receptor type 2 – CCR2/CD192

 

CCR2 or CD192 (cluster of differentiation 192) is 374 amino acid residues, located on 3p21.31 chromosome and expressed on monocytes, immature DC, neutrophils, and Th1 lymphocytes subset population and IL2-activated NK cells (5). The ligands of CCR2 receptor include CCL2 (formely known as Monocyte chemoattractant protein-1 a.k.a. MCP-1), CCL7 (monocyte chemoattractant protein 3 a.k.a. MCP-3), CCL8, CCL11, CCL12, CCL13, CCL15 (leukotactin-1) and CCL16.

 

Since MCP-1 plays a key role in the pathogenesis of numerous inflammatory diseases like asthma (6), chronic obstructive pulmonary disease (COPD) (7), rheumatoid arthritis (8), atherosclerosis (9), and multiple sclerosis (10), a large number of therapeutic companies have developed antagonist drugs to CCR2.

 

On one hand, the majority of them have stopped their development like Roche (RS-504393), Pfizer (Benzimidazoles), ChemoCentryx (CCX140, CCX872), Takeda (MLN1202), AstraZeneca (AZD-6942), Incyte (INCB-003284), GlaxoSmithKline (SB-380732) and UCB (ucb-102405). On the other hand, Centrexion (CNTX-6970), Allergan (CVC or Cenicriviroc), Creative Bio-Peptides (receptor-active peptides RAPs) and Bristol Myers Squibb (BMS-741672) are still in the race.

 

C-C Chemokine Receptor type 3 – CCR3/CD193: targeting the eotaxin pathway

 

Cloned in 1996 (11), CCR3 or CD193 (cluster of differentiation 193) is 355 amino acid residues, located on 3p21.31 chromosome and expressed on eosinophils, basophils, mast cells and Th2 lymphocytes subset population. The ligands of CCR3 receptor include CCL5 (regulated on activation normal T expressed and secreted protein a.k.a. RANTES), CCL7 (monocyte chemoattractant protein 3 a.k.a. MCP-3), CCL11 (eotaxin-1), CCL15 (leukotactin-1), CCL24 (eotaxin-2) and CCL26 (eotaxin-3).

 

Eotaxin family of chemokines (CCL11, CCL24, CCL26) is implicated in the pathogenesis of allergic inflammation and makes CCR3 a target for treatment of allergic diseases.

 

One of the first CCR3 antagonists to be revealed in the patent literature was a molecule named UCB35625, a trans-isomer of a molecule originally identified by scientists at Banyu Pharmaceutical Company (then developed by UCB). After this, many biotech players entered the field of CCR3 targeting like GSK (SB-328437), Bristol Myers Squibb (DPC-168), Yamanouchi Pharmaceutical Company (YM-344031), Abbott Laboratories (A-122058), GlaxoSmithKline (GSK766994), Axikin (AXP1275), Pharmaxis (ASM8) in order to treat asthma and rhinitis. But without success so far.

 

 

In 2014, Alkahest identified eotaxins as markers of age-related diseases, and decided to name them chronokines. Alkahest focuses on neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and age-related macular degeneration (AMD). Alkahest’s AKST4290, currently in Phase II, seems to prove them right.

 

C-C Chemokine Receptor type 4 – CCR4/CD194

 

CCR4 or CD194 (cluster of differentiation 194) is 360 amino acid residues, located on 3p24 chromosome and especially expressed by thymocytes, regulatory T cells (Treg), as well as tissue-resident T cells like skin. The ligands of CCR4 receptor are restrictive to CCL17 (also called thymus- and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine).

 

Controlling the trafficking of Tregs, CCR4 became a therapeutic immuno-oncology suppressive target to reduce the accumulation of Treg in the tumor microenvironment (TME). Kyowa Kirin’s KW-0761 Poteligeo (mogamulizumab) is the only marketed CCR4 antagonist. RAPT Therapeutics reported Phase I/II positive data of small molecule FLX-475 in November 2020. AstraZeneca’s AZD-1678 and AZD-2098, GlaxoSmithKline’s GSK2239633, ChemoCentryx’s CCX6239 and Tizona Therapeutics’ monoclonal antibody have been discontinued.

 

C-C Chemokine Receptor type 5 – CCR5/CD195

 

Cloned in 1996 (12), CCR5 or CD195 (cluster of differentiation 195) is 352 amino acid residues, located on 3p21 chromosome and especially expressed by T lymphocytes and macrophages. The ligands of CCR5 receptor are CCL5 (RANTES), CCL4 (MIP-1β) and CCL3 (MIP-1α).

Soon after its discovery, CCR5 was intensively studied in the context of HIV infection, since the majority of primary HIV-1 strains use CCR5 as co-receptor (called R5-tropic virus) - through its interaction with gp120 viral glycoprotein - to enter CD4 T cells (13).

 

GlaxoSmithKline, in partnership with Ono Pharmaceuticals, so developed Aplaviroc (APL, AK602, GW873140), Pfizer Maraviroc (MVC, UK-427,857) and Schering-Plough (now Merck) vicriviroc (VVC, SCH-D, SCH-417690). Only Pfizer drug was approved, and Cytodyn’s PRO-140 Leronlimab remains the most advanced entity to date, currently in Phase III. Although Takeda was the pioneer in the development of anti-CCR5 for HIV (TAK-779, TAK-220), its latest molecule (Cenicriviroc, TAK-652, TBR-652) has been entrusted to Tobira Therapeutics (Allergan) for clinical development, and eventually repositioned by AbbVie for the treatment of NASH. The works of Novartis and AstraZeneca have been totally stopped.

 

Based on the finding that metastasis is regulated by chemokines (14), Velasco et al. decided to work on CCR5 blockade for breast cancer designation (15), giving to Merck’s vivriviroc, Pfizer’s Maraviroc and CytoDyn’s Leronlimab a second life.

 

But in oncology this time.

 

C-C Chemokine Receptor type 6 – CCR6/CD196: the CCL20 axis

 

CCR6 or CD196 (cluster of differentiation 196) is 374 amino acid residues, located on 6q27 chromosome and expressed by immature DC, memory T cell, Th17 cell, Treg and B cells. Curiously enough, CCR6 is exclusively activated by CCL20 (macrophage inflammatory protein 3 alpha, MIP-3 alpha) and CCL20 recognizes only CCR6.

 

CCR6 is highly expressed on Th17 cells subset of CD4+ T cells, regulating the migration of Th17 and Treg cells (16). The IL-23/TH17 axis is particularly of interest for the treatment of of a large number of autoimmune diseases, including psoriasis (17), rheumatoid arthritis, asthma, and multiple sclerosis. Since intestinal epithelial cells constitutively express CCL20, CCR6 is also a target for bowel inflammation Crohn's disease (18).  Since then, the article of Kadomoto has summarized the implication of CCL20-CCR6 in cancer progression (19).

 

ChemoCentryx was the first company to identify small molecule CCR6 antagonists (CCX587) in 2013, followed by Pfizer and Sosei Heptares (PF-07054894). To our knowledge, CCR6 antagonists remain relatively rare in the pipelines of biotech and pharmaceutical companies.