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.

 

C-C Chemokine Receptor type 7 – CCR7/CD197: CCL19/CCL21 axis

 

CCR7 or CD197 (cluster of differentiation 197) is 378 amino acid residues, located on 17q21 chromosome and expressed by T cells and mature dendritic cells (DC). CCR7 is recognized by CCL19/ELC/MIP-3 beta and CCL21/SLC/6Ckine.

 

In 1993, working on Epstein-Barr virus (EBV), Birkenbach et al. stumbled upon the first G protein-coupled peptide receptors expressed in lymphocytes exclusively, the CCR7 (20). First studied in the context of viral infections (HIV, DENV, RSV…), CCR7 has been then the target of oncology treatments since CCR7 can be expressed on certain tumors (21, 22).

 

MSM Protein Technologies, Catapult Therapeutics and University of Bradford have respectively developed an anti-human CCR7 therapeutic antibody (MSM-R735) currently in preclinical studies, CAP-100 humanized anti-CCR7 antibody, and ICT13069 small molecule CCR7 antagonist.

 

C-C Chemokine Receptor type 8 – CCR8/CD198

 

CCR8 or CD198 (cluster of differentiation 198) is 355 amino acid residues, located on 3p22.1 chromosome. CCR8 is involved in Th2-mediated responses and expressed by Tregs, NKT and a subset of macrophages, monocytes, and monocyte-derived dendritic cells. CCR8 known ligands are I-309 (CCL1) and CCL18.

 

Five Prime (acquired by Amgen in 2021 for $1,9billion) has developed FPA157, a CCR8 blocking antibody engineered to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) while Surface Oncology (acquired by GSK, in 2020, for 815M$) is known for SRF114, Fc-optimized anti-CCR8 antibody. In 2020, Jounce Therapeutics presented its preclinical data on anti-CCR8 antibody and then signed $85 million upfront payment and $35 million equity deal with Gilead. At the same period, VIB spin-off Oncurious shown preclinical data on IO-1 and Harbour Biomed announced the discovery of its fully human monoclonal antibody HBM1022.

 

All mentioned therapeutic monoclonals have the ability to selectively deplete immuno-suppressive tumor-infiltrating T regulatory (TITR) cells.

 

C-C Chemokine Receptor type 9 – CCR9/CDw199: the CCL25 axis

 

Initially known as GPR-9-6, CCR9 or CDw199 (cluster of differentiation w199) is 369 amino acid residues, located on 23q24 chromosome. The sole ligand of CCR9 is CC chemokine ligand 25 (CCL25)/thymus-expressed chemokine (TECK)/chemokine beta-15 (CK beta-15) (23). CCR9/CCL25 signaling mediated the migration of leukocytes, and blocking of the CCR9/CCL25 signal has been demonstrated to be potential novel cancer (24) and intestinal inflammation therapies (Carramolino et al, 2001).

 

Takeda (former Millenium) developed MLN3126 CCR9-antagonist oral small molecule activity but discontinued it after Phase I outcomes. SunRock Biopharma reported the generation of mouse anti-human CCR9 monoclonal antibodies that specifically recognize a new and exclusive human CCR9 epitope. ChemoCentryx has suspended CCX025 development, but reconnected with success with CCX507 (currently in clinical trials for Ulcerative Colitis) and CCX282 currently in Phase III for Crohn’s disease.

 

C-C Chemokine Receptor type 10 – CCR10

 

Discovered in 1994, the gene for CCR10 was first named GPR2 (G-protein coupled receptor 2). CCR10 is 362 amino acid residues, located on 3p22.1 chromosome and expressed by Th22 and B-lymphocytes. CCR10 is recognized by two ligands of high homology: SCYA27 (CCL27) and SCYA28 (CCL28). CCL27 is expressed in the skin by keratinocytes (Morales et al., 1999) while CCL28 is expressed in mucosal sites by epithelial cells (Pan et al., 2000).

 

C-C Chemokine Receptor type 11 – CCR11/ACKR4

 

CCR11, a.k.a Atypical Chemokine Receptor 4 (ACKR4), is 350 amino acid residues, located on 3q22 chromosome. It binds to CCL19/ELC, CCL21/SLC, and CCL25/TECK ligands. As an atypical chemokine receptor, upon ligation by chemokines, CCR11 fail to induce classical signaling. CCR11 is a decoy receptor for these chemokines, preventing their interactions with other chemokine receptors (25).

 

CCR11 was identified in 1999, during a search of the human homologs of the bovine orphan PPR1 (26). Homology comparisons indicated that CCR11 is most closely related to chemokine receptors. Its closest relatives are CCR7 (36% identical), CCR6 (33%) and CCR9 (33%).

 


 

(1) Gao JL, Murphy PM. Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor. J Biol Chem. 1994 Nov 18;269(46):28539-42. PMID: 7961796.

(2) Ward, S. G.; Bacon, K.; Westwick, J. Chemokines and T lymphocytes: more than an attraction. Immunity, 1998, 9(1), 1-11.

(3) Gao, J. L.; Wynn, T. A.; Chang, Y.; Lee, E. J.; Broxmeyer, H. E. Cooper, S.; Tiffany, H. L.; Westphal, H.; Kwon-Chung, J.; Murphy, P. M. Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. J. Exp. Med., 1997, 185(11), 1959-68.

(4) Colantonio, L.; Iellem, A.; Clissi, B.; Pardi, R.; Rogge, L.; Sinigaglia, F.; D'Ambrosio, D. Upregulation of integrin alpha6/beta1 and chemokine receptor CCR1 by interleukin-12 promotes the migration of human type 1 helper T cells. Blood, 1999, 94 (9), 2981-2989.

(5) van Helden MJ, Zaiss DM, Sijts AJ. CCR2 defines a distinct population of NK cells and mediates their migration during influenza virus infection in mice. PLoS One. 2012;7(12):e52027. doi: 10.1371/journal.pone.0052027. Epub 2012 Dec 13. PMID: 23272202; PMCID: PMC3521727.

(6) Alam R, York J, Boyars M, Stafford S, Grant J, Lee J, Forsythe P, Sim T, Ida N (1996) Increased MCP-1, RANTES, and MIP-1_ in bronchoalveolar lavage fluid of allergic asthmatic patients. Am J Respir Crit Care Med 153: 1398–1404

(7)  Jahnz-Rozyk K, Kuna P, Pirozynska E (1997) MCP-1 in bronchoalveolar lavage fluid from patients with atopic asthma and chronic bronchitis. J Invest Allergol Clin Immunol 7: 254–259

(8) Ellingsen T, Buus A, Stengaard-Pederson K (2001) Plasma MCP-1 is a marker for joint inflammation in rheumatoid arthritis. J Rheumatol 28: 41–46

(9) Nelken N, Coughlin S, Gordon D, Wilcox J (1991) MCP-1 in human atheromatous plaques. J Clin Invest 88: 1121–1127

(10)               Simpson J, Newcombe J, Cuzner M, Woodroofe M (1998) Expression of MCP-1 and other chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol 84: 238–249

(11)     Ponath, P.D., Qin, S., Ringler, D.J., Clark-Lewis, I., Wang, J. et al. (1996) Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding and functional properties suggest a mechanism for the selective recruitment of eosinophils. The Journal of Clinical Investigation, 97, 604–612

(12)    Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996 Mar 19;35(11):3362-7. doi: 10.1021/bi952950g. PMID: 8639485.

(13)    Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996 Jun 20;381(6584):667-73. doi: 10.1038/381667a0. PMID: 8649512.

(14)    Kakinuma, T. and Hwang, S. T. Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol, 79: 639-651, 2006

(15)    Velasco-Velazquez, M., Jiao, X., De La Fuente, M., Pestell, T. G., Ertel, A., Lisanti, M. P., & Pestell, R. G. (2012). CCR5 Antagonist Blocks Metastasis of Basal Breast Cancer Cells. Cancer Research, 72(15), 3839–3850. doi:10.1158/0008-5472.can-11-3917 

(16)    Yamazaki, T. et al. (2008) CCR6 regulates the migration of inflammatory and regulatory T cells. Journal of Immunology (Baltimore, Md: 1950), 181, 
8391–8401. 


(17)    Michael N Hedrick, Anke S Lonsdorf, Sam T Hwang & Joshua M Farber (2010) CCR6 as a possible therapeutic target in psoriasis, Expert Opinion on Therapeutic Targets, 14:9, 911-922, DOI: 10.1517/14728222.2010.504716

(18)    KUNKEL, E. J., CAMPBELL, D. J., & BUTCHER, E. C. (2010). Chemokines in Lymphocyte Trafficking and Intestinal Immunity. Microcirculation, 10(3-4), 313–323. doi:10.1038/sj.mn.7800196 

(19)    Kadomoto, S., Izumi, K., & Mizokami, A. (2020). The CCL20-CCR6 Axis in Cancer Progression. International Journal of Molecular Sciences, 21(15), 5186. doi:10.3390/ijms21155186 

(20)Birkenbach M, Josefsen K, Yalamanchili R, Lenoir G, Kieff E. Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J Virol. 1993 Apr;67(4):2209-20. doi: 10.1128/JVI.67.4.2209-2220.1993. PMID: 8383238; PMCID: PMC240341.

(21)Fusi A, Liu Z, Kummerlen V, Nonnemacher A, Jeske J, Keilholz U. Expression of chemokine receptors on circulating tumor cells in patients with solid tumors. J Transl Med. (2012) 10:52. doi: 10.1186/1479-5876-10-52

(22)Takeuchi H, Fujimoto A, Tanaka M, Yamano T, Hsueh E, Hoon DS. CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clin Cancer Res. 2004 Apr 1;10(7):2351-8. doi: 10.1158/1078-0432.ccr-03-0195. PMID: 15073111.

(23)Yu CR, Peden KW, Zaitseva MB, Golding H, Farber JM. CCR9A and CCR9B: two receptors for the chemokine CCL25/TECK/Ck beta-15 that differ in their sensitivities to ligand. J Immunol. 2000 Feb 1;164(3):1293-305. doi: 10.4049/jimmunol.164.3.1293. PMID: 10640743.

(24)Wang C, Liu Z, Xu Z, et al. The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells. Oncol Lett. 2018;16(2):2071-2077. doi:10.3892/ol.2018.8896

(25)Watts AO, Verkaar F, van der Lee MM, Timmerman CA, Kuijer M, van Offenbeek J, van Lith LH, Smit MJ, Leurs R, Zaman GJ, Vischer HF. β-Arrestin recruitment and G protein signaling by the atypical human chemokine decoy receptor CCX-CKR. J Biol Chem. 2013 Mar 8;288(10):7169-81. doi: 10.1074/jbc.M112.406108. Epub 2013 Jan 22. PMID: 23341447; PMCID: PMC3591626.

(26)Schweickart V, Epp A, Raport C.J. CCR11 is a functional receptor for the monocyte chemoattractant protein family of chemokines. MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY| VOLUME 275, ISSUE 13, P9550-9556, MARCH 31, 2000. doi.org/10.1074/jbc.275.13.9550.