EA040016B1 - APPLICATION OF COMPOSITION CONTAINING CXCR4 CHEMOKINE RECEPTOR ANTAGONIST OR INHIBITOR FOR MANUFACTURING DRUG FOR PREVENTION AND/OR TREATMENT OF COPD AND AECOPD, METHOD FOR SUPPRESSING FIBROCYTE MIGRATION IN COPD OR AECOPD PATIENTS AND KIT - Google Patents

Description

Field of invention

The invention relates to new compositions and methods for the prevention and/or treatment of chronic obstructive pulmonary disease (COPD) and acute attacks of chronic obstructive pulmonary disease (AECOPD).

State of the art for the invention

COPD is a very common respiratory disease affecting more than 200 million people worldwide. It is currently the fourth leading cause of death, but mortality may reach the third cause of death in 2020. It is characterized by persistent airflow limitation, which is usually progressive and associated with an increased chronic inflammatory response in the airways and lungs to harmful substances or gases. The main risk factor for COPD is tobacco smoking. The disease is characterized by chronic inflammation of the bronchi and remodeling of the distal airways, and in particular by bronchial and peribronchial fibrosis, leading to persistent airflow limitation.

Exacerbations and comorbidities contribute to the overall severity of individual patients. There are several anatomical lesions contributing to the reduction in airflow found in patients with COPD. These include accumulation of mucus, peribronchial fibrosis, narrowing of the small airways, and damage to the alveolar walls, which are the defining characteristics of emphysema. The chronic course of COPD is often worsened also by acute attacks (AECOPD), most often associated with viral or bacterial infections. These AECOPDs are associated with a flare of neutrophilic and sometimes eosinophilic inflammation. AECOPD affects about 80% of patients with COPD over a 3-year period, and the frequency of exacerbations is mainly related to the presence of previous exacerbations.

AECOPD results in huge healthcare costs, especially those associated with hospitalizations. AECOPDs significantly affect quality of life and play a role in worsening the disease: lung function declines more rapidly in patients with frequent exacerbations, with an increased risk of death. In particular, a high mortality rate has been published in patients with COPD admitted to the hospital due to AECOPD, and it reaches up to 45% within 4 subsequent years. Severe AECOPD is considered as an independent predictor of mortality. However, the mechanisms for these latest findings remain completely unknown.

Current pharmacological treatments act on symptoms and quality of life, but do not improve mortality rates or the natural history of the disease, when the latter is characterized by a more rapid deterioration in lung function.

To date, fibrocyte recruitment during and after AECOPD has not been investigated, and little is known about the role of fibrocyte modulation and the resulting effect on disease progression. The authors of the present invention investigated the recruitment and migration of fibrocytes in peripheral blood in patients during an exacerbation of COPD and came to understand the need to develop new therapies based on this concept. In particular, the present inventors showed that the number of fibrocytes expressing CXCR4, CCR3, and CCR2, the chemokine receptor for CXCL12, CCL11, CCL7, CCL13, and CCL2, was significantly increased in patients during AECOPD, and that these specific fibrocytes were highly correlated with mortality. and impaired lung function. The present inventors have successfully identified a novel drug research method and novel drugs for the treatment and/or prevention of COPD and AECOPD by demonstrating that receptor/ligand pair antagonists CCR2/CCL2, CCR2/CCL7, CCR2/CCL13, CXCR4/CXCL12 and/ or CCR3/CCL11 are useful in the treatment and/or prevention of COPD and AECOPD by preventing recruitment/migration of fibrocytes in patients during AECOPD.

Brief summary of the invention

The present invention relates to the use of a composition for the manufacture of a medicament for the prevention and/or treatment of chronic obstructive pulmonary disease (COPD) and acute attacks of chronic obstructive pulmonary disease (AECOPD), wherein said composition consists essentially of a therapeutically effective amount of at least one antagonist or a CXCR4 chemokine receptor inhibitor, wherein said CXCR4 antagonist or inhibitor is a small molecule selected from bicyclams, quinolone-based CXCR4 antagonists, tetrahydroquinoline-based CXCR4 antagonists, guanidine-based CXCR4 antagonists, N-substituted indole-based CXCR4 antagonists, and/or antagonists CXCR4 based on pyrimidine, 1,4-phenylenebis(methylene) derivatives and N-containing heterocycles, and wherein said CXCR4 antagonist or inhibitor inhibits fibroblast migration and/or recruitment during an exacerbation in patients with chronic obstructive pulmonary disease (COPD).

In one aspect, the invention relates to the use of a composition wherein said CXCR4 antagonist is selected from para-xylylenediamine compounds.

In another aspect, the invention relates to the use of a composition wherein said CXCR4 antagonist is plerixaphor.

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In yet another aspect, the invention relates to the use of a composition, wherein said composition further comprises a pharmaceutically acceptable carrier.

In another aspect, the invention relates to the use of a composition, wherein said composition further comprises bronchodilators, corticoids, and/or phosphodiesterase inhibitors.

The invention relates to a method for inhibiting fibrocyte migration in patients with COPD and AECOPD or in patients at risk of developing COPD and AECOPD, comprising administering a therapeutically effective amount of at least one CXCR4 chemokine receptor antagonist or inhibitor, wherein said CXCR4 antagonist or inhibitor is a small molecule, selected from bicyclams, quinolone-based CXCR4 antagonists, tetrahydroquinoline-based CXCR4 antagonists, guanidine-based CXCR4 antagonists, N-substituted indole-based CXCR4 antagonists, and/or pyrimidine-based CXCR4 antagonists, 1,4-phenylenebis(methylene) derivatives, and N-containing heterocycles.

In one aspect, the invention provides a method wherein said CXCR4 chemokine receptor antagonist or inhibitor is administered orally, buccally or sublingually and is in the form of tablets, capsules (including soft gelatin capsules), multiparticulates, gels, films, elixirs, solutions or suspensions. , which may contain flavoring agents or colorants, for immediate, delayed, modified, sustained, dual, controlled release, or pulsatile delivery.

In another aspect, the invention relates to a method wherein said CXCR4 chemokine receptor antagonist or inhibitor is administered via inhalation and is in the form of a dry powder inhalation or aerosol spray delivered from a pressurized container, pump, nebulizer or nebulizer.

The invention also relates to a kit for the treatment and/or prevention of COPD and AECOPD, containing a therapeutically effective amount of at least one CXCR4 chemokine receptor antagonist or inhibitor in an amount sufficient to treat and/or prevent COPD and AECOPD, a pharmaceutically acceptable carrier and instructions for use and administering an CXCR4 chemokine receptor antagonist or inhibitor for the prevention and/or treatment of COPD and AECOPD, wherein said CXCR4 antagonist or inhibitor is a small molecule selected from bicyclams, quinolone-based CXCR4 antagonists, tetrahydroquinoline-based CXCR4 antagonists, guanidine-based CXCR4 antagonists , N-substituted indole based CXCR4 antagonists and/or pyrimidine based CXCR4 antagonists, 1,4-phenylenebis(methylene) derivatives and N-containing heterocycles.

In one aspect, the invention relates to a kit for suppressing fibrocyte migration in patients with COPD and AECOPD or in patients at risk of developing COPD and AECOPD, containing a therapeutically effective amount of at least one CXCR4 chemokine receptor antagonist or inhibitor in an amount sufficient to treat and/ or the warnings of COPD and AECOPD, a pharmaceutically acceptable carrier, and instructions for use and administration of a CXCR4 chemokine receptor antagonist or inhibitor to suppress fibrocyte migration in said patient, wherein said CXCR4 antagonist or inhibitor is a small molecule selected from bicyclams, quinolone-based CXCR4 antagonists, tetrahydroquinoline based CXCR4 antagonists, guanidine based CXCR4 antagonists, N-substituted indole based CXCR4 antagonists and/or pyrimidine based CXCR4 antagonists, 1,4-phenylenebis(methylene) derivatives and N-containing heterocycles.

Brief description of the drawings

In FIG. 1 shows the study design with the numbers of patients that are included and whose fibrocyte levels are quantified.

Fig. 2A-F are graphs showing the percentage of CD45+ Coll+ cells in peripheral blood mononuclear cells (PBMC) (A) and the concentration of fibrocytes in the blood (B) of control subjects (Control, n=38), COPD patients without exacerbation (Nex , n=9), COPD patients with exacerbation (V1, n=48) *: P<0.05, *** P<0.001, non-parametric Kruskal-Wallis test. Percentage of CD45+ CD34+ Coll+ cells in PBMC (C) and blood fibrocyte concentration (D) of control subjects (Control, n=25), COPD patients without exacerbation (Nex, n=8), COPD patients with exacerbation (VI , n=29) *: P<0.05, **: P<0.01, nonparametric Kruskal-Wallis test. Medians are presented as horizontal lines (A-D). Percentage of CD45+ Coll+ cells (E) and concentration of CD454+ Coll+ cells in the blood (F) in each COPD patient with exacerbation at the time of exacerbation (V1) and 2 months after (V2) ** P<0.01, test matched Wilcoxon steam.

In FIG. 3A-F are Kaplan-Meier survival analyzes of COPD subjects with exacerbations divided by threshold percentage of CD45+ Coll+ cells in PBMCs of 28 subjects, measured at time of exacerbation (V1). Of the 42 subjects with available survival data, 36 were below (gray curve) and 6 were above threshold (black curve). Percentage of CD45+ Coll+ cells in PBMCs as predictors of mortality in subjects with COPD (A). B-F, relationship between FEV1 (B), FVC (C), FEV1/CVF (D), TLCO (E), pO2 (F) and percentage

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CD45+ Coll+ cells in PBMC in COPD patients with V2 exacerbation.

FEV1: Forced expiratory volume at 1 second; FVC: forced vital capacity;

TLCO: carbon monoxide transfer coefficient; Pa _O2 : partial pressure of O ₂ in arterial blood. The correlation coefficient (r) and significance level (p-value) were obtained using Spearman's non-parametric analysis.

Fig. 4A-J are graphs showing the percentage of cells expressing CXCR4 (A), CCR2 (C), CCR3 (E), CCR5 (G), and CCR7 (I) in fibrocytes of control subjects (Contr.), COPD patients with exacerbation (VI). The concentration of CXCR4+ (B), CCR2+ (D), cCr3+ (F), CCR5+ (H) or CCR7+ (J) fibrocytes in the blood of control subjects, patients with COPD without exacerbation, patients with COPD with exacerbation. *: P<0.05, *** P<0.001, Mann-Whitney test.

In FIG. 5A-D shows A) fibrocyte migration of control subjects (n=6, gray bars) and exacerbated COPD patients (n=6, black bars) in response to plasma from exacerbated COPD patients in the presence (+) or absence of ( -) 25 µg/ml plerixaphor. * P<0.05, paired t-test. B) Plasma CXCL12 in individual subjects. Symbols represent individual subjects and horizontal lines represent medians. C) Fibrocyte migration of control subjects (n=8, gray bars) and exacerbated COPD patients (n=5, black bars) in response to CXCL12. **P<0.01, two-way ANOVA with post hoc Bonferroni analyses. D) Fibrocyte migration of control patients (n=6; gray bars) and exacerbated COPD patients (n=7; black bars) in response to CXCL12 in the presence (+) or absence (-) of 25 µg/mL plerixaphor. *: P<0.05, paired t-test.

Fig. 6 is a graph showing the percentage of CD45+ Coll+ cells in the PBMC in COPD patients with V2 exacerbation without any unscheduled visits (n=4), with one unscheduled visit (n=8), or with two or more unscheduled visits ( n=14) one year before V1. Medians are represented as gray horizontal lines. **: p<0.01, non-parametric Kruskal-Wallis test with multiple z-tests.

In FIG. 7 shows the relationship between FEV1 (L) (A), FVC (L) (B), FEF 25-75 (%) (C), FEF 25-75 (l/s) (D) and the percentage of CD45+ Coll+ cells in PBMC in patients with COPD exacerbating at V2. FEV1: forced expiratory volume at 1 second; FVC: forced vital capacity; FEF 25-75: average forced expiratory flow in the middle (25-75%) part of the FVC. Correlation coefficient (r) and significance level (p-values) were obtained using Spearman's non-parametric analysis.

Fig. 8A-D are graphs showing (A) fibrocyte migration of control subjects (n=1, gray bars) and exacerbated COPD patients (n=5, black bars) in response to plasma from exacerbated COPD patients in the presence of (+ ) or in the absence of (-) 10 μM SB 328437. (B) Plasma CCL11 in individual subjects. Symbols represent individual subjects and horizontal lines represent medians. (C) Fibrocyte migration of control subjects (n=2, gray bars) and exacerbated COPD patients (n=6, black bars) in response to CCL11. (D) Fibrocyte migration of control patients (n=2) and exacerbated COPD patients (n=5) in response to CCL11 in the presence (+) or absence (-) of 10 μM SB 328437.

Fig. 9 are graphs showing cell recovery (10 ³ /ml) after bronchoalveolar lavage (BAL), where, in particular, (A) total cells, (B) macrophage cell recovery, (C) neutrophil recovery, and (D) lymphocytes in each group of mice: mice exposed to room air and injection of PBS (□), mice exposed to room air and injected with double-stranded poly(1C) RNA (), mice exposed to cigarette smoke and injected with PBS \ mice exposed to cigarette smoke and double-stranded poly(1:C) RNA injection (®).

Fig. 10 (A) is electron microscopy images of bronchial sections obtained from a group of mice exposed to cigarette smoke and injected with poly(1:C) compared to a control group exposed to room air and injected with poly(1:C). (B) are graphs showing the ratio of fibrous areas (FA) and basement membrane perimeter (PLB) in each group of mice as described above in FIG. 9.

In FIG. 11 shows graphs showing the percentage of circulating fibrocytes (CD45+Coll+cells) in the blood and lungs for each group of mice as described above in FIG. 9.

Fig. 12 is a graph showing the percentage of lung fibrocytes (CD45+Coll+cells) for lungs in each group of mice as described above in FIG. 9.

Detailed description

The present inventors examined, in a translational clinical study, peripheral blood fibrocyte concentrations in COPD patients during an exacerbation and 2 months after an exacerbation at steady state compared to control subjects and COPD patients without exacerbations. Moreover, chemokine receptors were characterized and the migration properties of these fibrocytes were examined in patients with COPD and controls.

The authors of the present invention found a significantly increased number of circulating

- 3,040,016 fibrocytes in patients during AECOPD compared to controls, and that the number of circulating fibrocytes in the same patients decreased two months after AECOPD. The present inventors have shown that a high percentage of circulating fibrocytes during exacerbations was associated with an increased risk of death and that the percentage of fibrocytes after AECOPD was negatively correlated with several parameters of obstructive pulmonary disease, i. FEV1 (forced expiratory volume at 1 second), FVC (forced vital capacity), FEV1/FVC (Tiffno-Pinelli index), TLCO (lung carbon monoxide transfer coefficient) and Pa _O2 (partial pressure of oxygen in arterial blood) . In particular, the present inventors found that fibrocytes expressed CXCR4, CCR2 and/or CCR3, chemokine receptors for the chemokines CXCL12, CCL2, CCL7, CCL13 and/or CCL11, respectively.

CXCR4 chemokine receptor antagonists reduced fibrocyte migration in the plasma of exacerbated COPD patients and thus found to be useful in the treatment and/or prevention of COPD and AECOPD in accordance with the present invention. Preferred antagonists of the invention are CXCR4 chemokine receptor antagonists such as, but not limited to, plerixaphor.

The present invention thus relates to the use of compositions and methods of using antagonists or inhibitors of CXCR4 for use in the treatment and/or prevention of COPD or AECOPD. Preferred compounds of the invention interfere with native ligand binding to the CXCR4 receptor and inhibit receptor activation and downstream signaling pathways.

The chemokine receptor CXCR4 refers to the C-X-C type chemokine receptor 4 (CXCR4). It is also known as Fusin or Cluster of Differentiation 184 (CD 184), which is a G protein-coupled receptor (GPCR) with seven transmembrane (TM) domains belonging to class I GPCRs or the family of rhodopsin-like GPCRs. The structure of CXCR4 consists of 352 amino acid residues containing an N-terminal domain, seven TM domains, three extracellular loops (ECL), three intracellular loops (ICL), and a C-terminal domain.

CXCR4 is specific for chemokine ligand 12 (CXCL12), also called stromal factor-1 (SDF-1). As a homeostatic chemokine, SDF-1 or CXCL12 is an 8 kDa 67 amino acid residue chemokine peptide primarily localized in bone marrow stromal cells. There are two distinct isoforms CXCL12-a and CXCL12-e. The amino acid sequence of human CXCL12-a or SDF-1a has GenBank accession number NP954637. The amino acid sequence of human CXCL12-e or SDF-1e has GenBank accession number NP000600. Human CXC12 is also described in US Pat. Nos. 5,756,084 and 5,563,048.

Antagonists or inhibitors according to the present invention are intended to be drugs that inhibit, directly or indirectly, the biological activity of CCR2/CCL2, CCR2/CCL7, CCR2/CCL13, CXCR4/CXCL12 and/or CCR3/CCL11 receptor/ligand pairs. Such agents may include small molecules (organic or inorganic), natural products, synthetic compounds, antibodies (e.g. polyclonal sera, monoclonal, chimeric, humanized, human antibodies), antibody fragments such as recombinant antibody fragments, single chain antibodies (scFv ), individual antibody variable domains, proteins from a single antibody domain (dAb), antigen-binding fragments, nucleic acid-based agents such as antisense oligonucleotides, ribozymes, DNAzymes, or RNAi, siRNA or shRNA for RNA interference that act by reducing expression chemokine receptor proteins, peptides, peptide derivatives, peptidomimetics, carbohydrates, or any other compound or composition that preferentially reduces the activity of the CXCR4 chemokine receptor, either by effectively reducing the amount of CXCR4 present on the cell or by inhibiting CXCL ligand interactions 12, in particular CXCL12-a. Antagonist compounds may also include variants, isoforms, solvates, hydrates, pharmaceutically acceptable salts, tautomers, stereoisomers, and prodrugs of the antagonist compounds.

According to a preferred embodiment, the compositions and methods for use of the present invention preferably comprise CXCR4 chemokine receptor antagonists that inhibit one or more biological functions or biological activity associated with CXCR4 by inhibiting the binding of one or more ligands (e.g., CXCL12-a and/or or CXCL12-e (SDF-1-α or SDF-1-β)) with CXCR4 and/or inhibition of signaling mediated by CXCR4.

Accordingly, CXCR4-mediated cell processes and responses (eg, proliferation, migration, chemotactic responses, and fibrocyte differentiation) can be inhibited by CXCR4 antagonists.

An extensive search for CXCR4 antagonists has been carried out in the past, since CXCR4 was originally

- 4 040016 was discovered as one of the co-receptors involved in the entry of the human immunodeficiency virus into the cell. Thus, numerous compounds have been well characterized chemically and identified as significantly inhibiting CXCR4 and the CXCR4/CXCL12 axis. The first CXCR4 antagonists discovered were peptide derivatives. Subsequent CXCR4 antagonists were cationic molecules capable of binding predominantly to the anionic extracellular domain of CXCR4. To date, over 20 different classes of chemicals have been described as CXCR4 antagonists. Numerous articles have been published describing molecules that have CXCR4 antagonist activity based on their chemical backbones (Debnath B et al., Theranostics. 2013; 3(1): 47-75).

Small molecules are the first class of compounds that can be used in the compositions of CXCR4 antagonists in accordance with the present invention. They are well known in the art and have been extensively described as CXCR4 antagonists by, among others, Wilson LJ et al. Drug Development Research. 2011; 72:598-602. These include cyclam mimetics, bis-macrocycles such as, in particular, bis-tetraaza-macrocycles (bicyclams) and their derivatives, quinolone-based CXCR4 antagonists, tetrahydroquinoline-based CXCR4 antagonists, guanidine-based CXCR4 antagonists, CXCR4-based antagonists N-substituted indole base and/or pyrimidine-based CXCR4 antagonists, 1,4-phenylenebis(methylene) derivatives and N-containing heterocycles.

Bicyclams are described, inter alia, in international publication WO 00/56729. Among bicyclam molecules, the present inventors may refer to p-xylylenediamine-based compounds like plerixaphor, also designated AMD3100, marketed by Genzyme Corporation under the trade name Mozobil and described inter alia in US 5,583,131; and in Uy et al., Expert Opin Biol Ther. 2008 Nov;8(11):1797-804. doi: 10.1517/14712598.8.11.1797. Derivatives of plerixaphor or structurally modified compounds can also be used as antagonists in the composition of the present invention. Such derivatives may be polyamine aromatic macrocyclic compounds such as the tetrafluoro derivatives of plerixaphor described inter alia in WO 93/12096 and US Pat. No. 5,583,131.

Plerixaphor analogs such as AMD3465, which has a single azamacrocyclic ring, and subsequent non-macrocyclic, orally active CXCR4 antagonists retaining a p-xylylenediamine linker between two heterocyclic units of the compounds are described in Bodart et al. (Biochem Pharmacol. 2009 Oct 15;78(8):993-1000). Another bis-azamacrocyclic compound, also designated AMD3329, was identified by Bridger et al. (J. Med. Chem. 1999 Sep 23;42(19):3971-81) and is marketed by AnorMed.

Additional plerixaphor derivatives that can be used in the compositions and methods of the present invention have been developed starting with bicyclam plerixaphor and the CXCR4 peptide antagonist (TNI4003). These derivatives can be selected from N,N'-di-2-nirudinyl-1,4benzenedimethanamine, 4F-benzoyl-TN 14003, also designated BKT-140 (Peled et al, Clin. Cancer Res. 2014 Jan 15;20(2) :469-79); N,N'-(1,4-phenylenebis(methylene))dipyrimidine-2-amine, also designated MSX-122 (Liang et al, PLoS One. 2012;7(4):e34038), in clinical trial phase against refractory metastatic or locally advanced solid tumors in which Metastatix Inc is a sponsor; and N ¹ ,N ⁴ -di-2-pyridinyl-1,4-benzenedimethanamine, also designated WZ811 (Zhan W et al., J Med Chem. 2007 Nov 15;50(23):5655-64) and available from marketed by Tocris Bioscience and Selleckchem (http://www.selleckchem.com/products/wz-811.html).

Additional bicyclam mimetics include, for example, JM1657 described in De Clercq E et al. 20060264451.

As examples of quinoline-based CXCR4 antagonists, the present inventors may refer to chloroquine and hydroxychloroquine drugs such as NSC56612, described inter alia in Kim JML et al., PLoS One. 2012;7(2):e31004.

Among tetrahydroquinoline-based CXCR4 antagonists, the present inventors may refer to AMD070, a potent orally active CXCR4 antagonist. A unique structural feature of these compounds is the presence of a core structure substituted with (R), (S), or (RS) (N'(1H-benzimidazol-2-ylmethyl)-N'-5,6,7,8-tetrahydroquinolin-8- yl-1,4-alkylamine), which replaces the macrocyclic core of bicyclams. It is marketed by AnorMed under the designation AMD 11070 and is being studied in a clinical study to prevent HIV infection with Ttropism by NIAID (Crawford JB et al. Org. Process Res. Dev., 2008, 12(5), pp 823-830 ).

Guanidine-based CXCR4 antagonists are described, inter alia, in Wilkinson RA et al. (Antimicrob Agents Chemother. 2011;55:255-63) as being small molecules containing multiple guanide or biguanide groups. The present inventors may refer, for example, to NB325, for example, to the polyethylenehexamethylene biguanide described in Thakkar N et al. (Antimicrob Agents Chemother. 2009;53:631-8;) and in Krebs FC et al. (Biomed Pharmacother. 2005;59:438-45). Their derivatives are also described as including some features of NB325 polyethylenehexamethylene biguanide, as well as the T140 peptide, which has five guanide groups on the side chains of arginine residues. Other active

- 5 040016 derivatives include, for example, phenylguanides.

Indole-based CXCR4 antagonists are also described in Ueda S, et al. (Bioorg Med Chem Lett.

2008;18:4124-9) and also include, for example, 5-aminoindole-2-carboxylic acid.

Pyrimidine-based antagonists are described, inter alia, in patent publication WO

2010/147094 and US Patent Publication No. 2009/0143302.

TG-0054 is described in Hsu et al (Cell Transplant. 2014 May 12) as an injectable small molecule and a potent selective CXCR4 antagonist. It is also known under the trade name Burixaphor from TaiGen Biopharmaceuticals Holdings Ltd. and tested in multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease (ClinicalTrials.gov ID: NCT01018979).

Other compounds include the orally active, small molecular weight non-peptide compound KRH-3955 described inter alia in Nakasone T et al., (Med Microbiol Immunol. 2013 Apr; 202(2): 175-82); ghrelin receptor blocker (D-[Lys3]GHRP-6) described in Patel K et al. (Int J Biol Sci. 2012;8:108-17); diketopiperazine mimetics, thiazolylisothiourea derivatives, benzodiazepines, and dipicolylamine-zinc(II) complexes.

Compositions and methods for use in accordance with the present invention may also contain peptide-based CXCR4 antagonists. Some of these peptides are described, inter alia, in Costantini S et al. (J Pept Sci. 2014 Apr;20(4):270-8).

As examples, the present inventors may refer to cyclic pentapeptide CXCR4 antagonists such as T22 ([Tyr5,12, Lys7]-polyphemusin II), T140 and T134, which are highly potent CXCR4 antagonists described in Tamamura H et al. . (BBRC, 1998 Dec 30; 253(3):877-82; Bioorg Med Chem Lett. 2001 Feb 12; 11(3):359-62; FEBS Lett. 2004 Jul 2;569(13):99-104) . In particular, four amino acid residues are described as essential for the activity of the T140 peptide: Arg2, L-3-(2-naphthyl)alanine3 (Nal3), Tyr5 and Arg14. These key residues were found to be located through a disulfide bridge and closed in the three-dimensional structure of T140. In Tamamura H et al. (FEBS Lett. Volume 550, Issues 1-3, 28 August 2003, Pages 79-83) T140 analogs such as TC14012, TE14005 and TN14003 are also described as CXCR4 antagonists.

Another CXCR4 cyclopentapeptide antagonist that can be used in the compositions and methods of the present invention is FC131. This cyclopentapeptide has the following formula: cyclo[2-Nal-Gly-D-Tyr-Arg-Arg] (SEQ ID NO: 10) where Nal is 2naphthylalanine, Arg is arginine, Tyr is tyrosine and Gly is glycine . Yoshikawa Y et al. (Bioorg Med Chem Lett. 2012 Mar 15;22(6):2146-50), among other things, it is described as a potent and orally active CXCR4 inhibitor peptidomimetic and is marketed by Tocris Bioscience. FC122 is also described as an analogue of FC131, where the arginine residue is replaced by epimeric N-methyl-D-arginine. Additional (E)-alkene and (Z)fluoroalkene analogues of F131 and FC122 have been described as CXCR4 antagonists (Narumi T, et al., Org Biomol Chem. 2010;8:616-21).

Additional CXCR4 antagonists having cyclic tetrapeptide backbones are described in Tamamura H et al. (J Med Chem. 2005;48:3280-9).

Other modified peptides that can be used as CXCR4 antagonists include, for example, CTCE-9908, a 17 amino acid peptide that is an 8 amino acid N-terminal dimer with a P to G modification, bridging with lysine, described in Wong et al (BMC Urology, January 2014, 14:12) and marketed by Chemokine Therapeutics Corp; POL6326, described as being a recombinant protein developed by protein epitope mimetics in De Nigris F et al. (Recent Pat Anticancer Drug Discov. 2012 Sep;7(3):251-64), and marketed by Polyphor Ltd; LY2510924 described in Peng SB et al. (Mol Cancer Ther. 2015 Feb;14(2):480-90); gSt-NT21MP described in Galsky MD et al. (Clin Cancer Res. 2014 Jul 1;20(13):3581-8).

In accordance with the present invention, the CXCR4 inhibitor may further be an antibody-based moiety targeted against the CXCR4 receptor, wherein the antibody-based moiety is capable of acting as an antagonist of CXCL12. Human monoclonal antibodies are described in detail in, inter alia, Carnec X et al., J Virol. February 2005; 79(3): 1930-1933 and US Patent Publication No. 2014/0322208. One fully human monoclonal antibody is BMS-936564, (designated F7 in international publication WO 2008/060367), also previously designated MDX-1338. Numerous other monoclonal antibodies are targeted against the N-terminal, extracellular loops of ECL1, ECL2, or ECL3 of CXCR4. For example, the anti-CXCR4 monoclonal antibody A145 is described as targeting the N-terminus, while the monoclonal antibody A120 targets a conformational epitope consisting of extracellular loops of ECL1 and ECL2, and the mAb A80 targets ECL3 from CXCR4 (Adachi T et al ., Retrovirology.2011 Oct 22;8:84). Other human anti-CXCR4 antibodies are widely available on the market, such as from Thermofisher Scientific, R&D Systems, etc., and include anti-CXCR4 monoclonal antibody 12G5, monoclonal antibody 708, monoclonal antibody 716, and monoclonal antibody 717 (commercially available). by R&D Systems under catalog numbers MAB170, MAB171,

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MAB172 and MAB173), monoclonal antibodies 2B11, 44717.111, 44716.111, 44708.111 (R&D Systems, Minneapolis, Minn, see also Stalmeijer et al, J Virol. Mar 2004; 78(6):2722-2728). Also included within the scope of the invention are CXCR4 ligand antagonists, e.g. CXCL12-CX and/or CXCL12-e (SDF-1α or SDF-1-β)) antagonists, which may include small organic or synthetic molecules, natural products, peptides, proteins , peptidomimetics, antibodies, antigen binding fragments, nucleic acid agents, and the like. Truncated variants, variants, mutant proteins or muteins of SDF-1 having the ability to bind CXCR4 and having antagonistic activity can also be used to practice the method of the invention.

Inhibitors of SDF-1 activity based on nucleic acid are also described and can be used in the compositions of the present invention. These nucleic acid inhibitors can function either at the level of receptor binding or at the level of gene expression and translation. Nucleic acid-based inhibitors of CXCR4 activity include, but are not limited to, nucleic acid-based enzymes (such as ribozymes), nucleic acid aptamers, antisense nucleic acids, and RNAi, such as siRNA. Nucleic acid-based CXCR4 inhibitors are described in the following references: US Pat. No. 6,429,308B1; US Patent Publication No. 2005/0124569A1; US patent No. 6916653B2; and US Patent Publication No. 2005/0202077. Such nucleic acid inhibitors may include an antisense oligonucleotide that is complementary to certain portions of the base sequence of the chromosomal DNA and/or RNA encoding the CXCR4 protein. The antisense oligonucleotide of the present invention may be DNA or RNA.

A specific antisense oligonucleotide can be complementary to a base sequence containing an initiation codon region of +61 to +91 when the transcription initiation point of the gene for mRNA encoding the CXCR4 protein is +1, and at the same time stably hybridizes with the specified sequence specifically and blocks translation into protein , so that it has the function of inhibiting the biosynthesis of the CXCR4 protein. Alternatively, it may be a miNA, which may be unmodified or chemically modified, whereby the use of the chemically modified miNA improves various properties of native miNA molecules through increased resistance to in vivo nuclease degradation and/or through improved cellular uptake, as developed in US Patent Publication No. 2005/0202077. Also included within the scope of the invention are mRNAs encoding CXCR4 proteins that can be cleaved with hammerhead ribozymes so as to effectively block the production of these proteins, as described in US Pat. No. 6,916,653 B2. Also included within the scope of the invention are siRNAs that can be effectively used in compositions to include siRNA sequences corresponding to the target sequences set forth in SEQ ID NO: 101-823 of US Patent Publication No. 2005/0202077.

In another embodiment, compositions and methods for use of the present invention, CCR2 chemokine receptor antagonists prevent biological functions or biological activity associated with CCR2, isoforms or variants thereof, including CCR2A or CCR2B, in receptor-expressing fibrocytes, or antagonists that bind MCP. -1/CCL2 or CCR2, or which prevent CCR2 from binding to its cognate ligand(s) and thus inhibit the biological functions of CCR2. In particular, CCR2 antagonists can inhibit the binding of one or more ligands (e.g., MCP-1, MCP-2, MCP-3, MCP-4, MCP5, CCL2, CCL8, CCL16, etc.) to CCR2 and/or inhibit CCR2-mediated signaling (eg, GDP/GTP turnover via CCR2-associated G proteins, intracellular calcium flux), thus inhibiting CCR2-mediated processes and cell responses and functions.

Molecules that may antagonize one or more functions of CCR2 are well known in the art. In particular, several active, orally bioavailable small molecule CCR2 receptor antagonists have entered drug development for various indications.

As examples, the present inventors may refer to a small molecule marketed by AstraZeneca, designated AZD2423 and described inter alia in Kalliomaki et al., (Pain 2013 25 May; 154(5):761-7); a small molecule developed by UCB Research under the designation UCB102405 and described, inter alia, in Higgins PJ et al. (Progress in inflammation research, Vol. 2, 2007, pages 115-123); antagonist developed by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. under the designation JNJ-17166864 (ClinicalTrials.gov ID: NCT00604123 and also described in Anti-Inflammatory Drug Discovery edited by Jeremy I. Levin, Stefan Laufer, Page 378); RS 504393 (Mirzadegan et al, August 18, 2000 The Journal of Biological Chemistry, 275, 25562-25571), hydrochloride RS 102895 (Seok et al, Nephrol. Dial. Transplant. 2013 Jul;28(7):170010); CCR2 antagonists based on piperazine derivatives developed by Teijin and described inter alia in International Publication WO 97/44329.

Numerous small molecule CCR2 antagonists have also been developed by Incyte Corporation.

- 7 040016 under the name INCB-8696 (Matera et al., Expert Opin. Emerging Drugs (2012) 17(1):61-82); pyridinylcyclohexyl-3-pyrrolidinyl derivative INCB-3284 (Xue CB et al., ACS Med. Chem. Lett., 2011, 2(6), pp450-454); benzodioxolhydroxycyclohexyl derivative INCB3344 (Brodmerkel CMet al., J. Immunol. 2005 Oct 15;175(8):5370-8.), several series of CCR2 antagonists based on (S)-3aminopyrrolidine under the name PF-4136309 or INCB8761 (Xue CB et al., ACS Med Chem Lett. 2011 Oct 5;2(12):913-8); dimesylate INCB3284 (Mcmillin et al., J Neuroinflamination. 2014 Jul 10; 11:121).

The present inventors may also refer to the small molecule CCX14O-B developed at ChemoCentryx (De Zeeuw D et al., Lancet Diabetes Endocrinol. 2015 Sep;3(9):687-96); Derythropentitol derivative MK-0812 developed by Haihang Industry Co., Ltd. (Wisniewski T et al., J Immunol Methods. 2010 Jan 31;352(1-2):101-10).

Pfizer has developed a CCR2 antagonist under the designation PF-04634817 (ClinicalTrials.gov ID: NCT01994291), as well as hexanoic acid amide-based CCR2 inhibitors, as described, inter alia, in international publication WO 98/38167.

Bristol-Myers Squibb has developed a lactam-based compound BMS-741672 (ClinicalTrials.gov ID: NCT00699790) and another antagonist designated BMS-813160 or (S)-1[(1S,2R,4R)-4-isopropyl( methyl)amino)-2-propylcyclohexyl]-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (ClinicalTrials.gov ID: NCT01752985); BMS CCR2 22 (Kredel et al., J Biomol. Screen. 2011 Aug; 16(7):683-93).

Several tetrahydropyranylcyclopentyltetrahydropyridine compounds have been described as CCR2 antagonists and developed by Merck, and in particular [(3S,4S)-3-methoxytetrahydro2H-pyran-4-yl]amine-(1R,3S)-3-isopropyl-3-{ [3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)yl]carbonyl}cyclopentyl) described inter alia in international publication WO 2005044264. Merck also developed CCR2 antagonists based on 3-arylpiperidine as described in international publication WO 98/31364.

Several other small molecules are described and include 3-[(3S,4R)-1-((1R,3S)-3-isopropyl-2oxo-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazine -3(4H)-yl]methyl}cyclopentyl)-3-methylpiperidin-4yl]benzoic acid; (3S,4S)-N-((1R,3S)-3-isopropyl-3 - {[7-(trifluoromethyl)-3,4-dihydroisoquinolin2(1B)-yl]carbonyl}cyclopentyl)-3-methyltetrahydro- 2H-pyran-4-aminium; 3-[(3S,4R or 3R,4S)-1((1R,3S)-3-isopropyl-3- {[6-(trifluoromethyl)-2H-1,3-benzoxazine-3-(4H)- yl]carbonyl}cyclopentyl)-3-methylpiperidin-4-yl]benzoic acid, and are presented in Brodmerkel et al., (J. Immunol, 2005, 175:5370-7378) and in international publication WO 2012138880.

Numerous other derivatives have been described as CCR2 antagonists. As examples, the present inventors may refer to piperidinyl derivatives (WO 2012075115), diazepam derivatives (WO 2011048032), cyclohexane derivatives (WO 2010121046), carboxamide derivatives (WO 2010070032), cyclopentyl/cyclohexyl derivatives (WO 2013152269), bicyclic heterocycles ( WO 2011042399), indole derivatives (WO 2012125662), mercapto derivatives (WO 2005118578), dipiperidine derivatives (WO 2006036527), heteroarylsulfonamides (US 20100056509), benzenesulfonamides fused with heteroaryl and with phenyl (WO 20090).

Several CCR2 antagonist peptides have also been developed and described, inter alia, in international publication WO 2013000922. As examples, the present inventors may refer to the LGTFLKC heptapeptide called ECL1 (C) inverso, ECL1 (C), having the amino acid sequence CKLFTGL, ECL2 ( N) having the amino acid sequence LFTKC (SEQ ID NO: 2), ECL2 (N) inverso having the amino acid sequence CKTFL (SEQ ID NO: 3), ECL3 (C) having the amino acid sequence HTLMRNL (SEQ ID NO: 4) ECL3 (C) inverso having the amino acid sequence LNRMLTH (SEQ ID NO: 5), ECL3 (N) having the amino acid sequence LNTFQEF (SEQ ID NO: 6), ECL3 inverso having the amino acid sequence FEQFTNL (SEQ ID NO: 7), and /or peptides containing the sequence Thr-Phe-Leu-Lys (SEQ ID NO: 8).

Alternatively, CCR2 antagonists can be anti-CCR2 antibodies and antibody fragments. A number of anti-CCR2 antibodies are known in the art and commercially available. Several antibodies against human CD192 CCR2 have been developed by Biolegend (see http://www.biolegend.com/cd192-ccr2-antibodies-6166/). The present inventors may also refer in particular to the anti-CCR2 monoclonal antibodies 1D9 (ATCC HB-12549), 8G2 (ATCC HB12550), LS132 described in WO 01/57226, a human CCR2 blocking antibody such as MLN1202 (Millennium Pharmaceuticals, Cambridge, MA), or a human antibody that neutralizes human CCL2, such as carlumab (CNTO 888; Centocor, Inc.) described in Loberg et al., Cancer. Res. 67(19):9417 (2007).

Also included within the scope of the invention are CCR2 ligand antagonists, for example MCP-1 (CCL2), CCL7 and/or CCL13.

Such antagonists may be anti-MCP-1 antibodies well known and well described in the literature. As antibodies against MCP-1, the present inventors can

- 8 040016 refer to antibodies capable of binding a variety of beta chemokines, including MCP-1 described in (WO 03048083) and an MCP-1 binding antibody that also binds eotaxin (US 20040047860). Antibodies that selectively bind and neutralize murine homologues of human MCP-1/CCL2 or human MCP-1/CCL2, like the anti-human MCP-1/CCL2 antibody designated C775 described in US 20090297502, as well as the anti-MCP-1/CCL2 antibody human, designated CNT0888 (WO 2006125202).

The compositions of the present invention may also contain MCP-1/CCL2 truncated variants, variants, mutants or muteins having the ability to bind CCR2 and have antagonistic activity. Variants of homodimer-forming chemokines, such as CCL2, having a single amino acid substitution at the dimerization surface that changes the hydrogen bonding pattern so that it results in an obligate monomer that binds to the receptor and has in vitro agonist properties, but may antagonize natural chemokines and to have anti-inflammatory activity in vivo, as explained in international publication WO 05037305 A1, are among the options that can be used in the practice of the present invention. The peptide antagonist of MCP-1 is a truncated MCP-1 (9-76) (Jiang-Hong Gong, et al, J. Exp. Med. 1997, 186: 131).

CCL7 and CCL13 ligand antagonists include organic or synthetic small molecules, natural products, peptides, proteins, peptidomimetics, antibodies, antigen binding fragments, nucleic acid agents, and the like. Peptide antagonists of CCL7 and/or CCL13 may typically be fragments of CCL7 and/or CCL13 that compete with full-length CCL7 and/or full-length CCL13 for binding to CCR2 and thus antagonize CCL7 and/or CCL13. Using known methods and based on knowledge of the CCL7 sequence, double-stranded RNA (dsRNA) or single-stranded antisense RNA molecules can be designed to antagonize a target by targeting its RNA based on sequence homology. Such dsRNAs or ssRNAs can typically be small interfering RNAs (siRNAs), typically in a stem-loop (hairpin) configuration, or micro-RNAs (miRNAs). The sequence of such a dsRNA or ssRNA may contain a portion corresponding to the portion of the mRNA encoding the target. This moiety can typically be 100% complementary to the target moiety within the target mRNA, but lower levels of complementarity (eg, 90% or more, or 95% or more) can also be used.

As CCL7 antagonists, the present inventors may refer to anti-CCL7 antibodies having CCL7 antagonistic (blocking) properties. Preferred antagonists are monoclonal antibodies that specifically recognize an epitope within CCL7 and block CCL7 activity, in particular the interaction between CCR2 and CCL7. Specific anti-CCL7 monoclonal antibodies may include the anti-CCL7 monoclonal antibody marketed by Pierce antibodies under the name CCL7 antibody h.mcp.3; recombinant human CCL7/MCP3 protein marketed by Sino Biological Inc. (catalog # 11926-H08E); and an anti-CCL7 antibody marketed by Labome under the designation MA1-21385.

As CCL13 ligand antagonists, the present inventors may refer to anti-CCL13 antibodies such as those from Novus, Origene, Labome, Sigma Aldrich, etc. Anti-CCL13 monoclonal antibodies include H00006357-M03 (Abnova), anti-MCP-4/CCL13 8C12 (Pierce Antibodies), anti-MCP-4/CCL13 3G4 (Pierce Antibodies), anti-human CCL13/MCP4 (R&D systems) etc.

According to additional embodiments, the compositions and methods for use of the present invention comprise CCR3 chemokine receptor antagonists that prevent one or more biological functions or biological activity associated with CCR3. Such a CCR3 function antagonist can inhibit the binding of one or more ligands (eg, CCL11, CCL26, CCL7, CCL13, CCL15, CCL24, CCL5, CCL28, CCL18) to CCR3 and/or inhibit signaling mediated through CCR3. Accordingly, CCR3 mediated processes and cell responses and functions can be inhibited by CCR3 antagonists. As used herein, CCR3 refers to natural CC chemokine receptor 3 (eg, mammalian CCR3 (eg, human CCR3 (Homo sapiens)) and includes natural variants such as allelic variants and splicing variants.

Numerous molecules are described in the art as antagonists of one or more functions of the CCR3 receptor.

Compositions and methods for use in accordance with the present invention may include small molecule CCR3 antagonists. As examples, the present inventors may refer to small molecular weight CCR3 antagonists such as oral candidate GW776994 developed in GSK (Neighbour H et al., Clin Exp Allergy. 2014 Apr;44(4):508-16) substituted with benzylpiperidine aryl urea derivative DPC-168 (Pruitt JR et al., Bioorganic & Medicinal Chemistry Letters 07/2007), compound (S)-methyl-2-naphthoylamino-3-(4-nitrophenyl)propionate marketed by Calbiochem under the name SB328437 and described, among others

- 9 040016 th, in Mori A et al., (Int Immunol. 2007 Aug;19(8):913-21), as well as N-benzoyl-4nitroaniline ethyl ester SB297006, also described in Mori A. et al., (Int Immunol. 2007 Aug; 19(8):913-21), small molecules developed at AstraZeneca such as AZD1744 (Neighbour H. et al., Current Opinion in Drug Discovery & Development 2010 13(4):414- 427) and AZD 3778 (Greiff L. et al., Respir Res. 2010 Feb 9;11:17), a trans-1,2-disubstituted cyclohexane derivative developed at Bristol-Myer Squib under the name BMS639623 and described in Santella JB et al., (Bioorg Med Chem Lett. 2008 Jan 15;18(2):576-85), an oral YM-344031 antagonist described in Suzuki K et al., among others, (BBRC 2006 Jan 27;339(4 ):1217-23); A-122058 as described in Neighbor H et al., (Current Opinion in Drug Discovery & Development 2010 13(4):414-427); (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3yl)-N-(2- nitrophenyl)pyrrolidin-1,2-dicarboxamide, (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea; a morpholineacetamide-based compound such as 4[[(2S)-4-[(3,4-dichlorophenyl)methyl]-2-morpholinylmethylaminocarbonyl]aminomethylbenzamide; and the morpholine urea compound N-[[(2S)-4-[(3,4-difluorophenyl)methyl]-2-morpholinyl]-methyl]-3[(methylsulfonyl)amino]benzeneacetamide.

Other well-known CCR3 antagonists include 2-mercaptobenzothiazole derivatives, aryl or phenylsulfonamide derivatives (WO 2012051090), bridged bicyclic amine derivatives (WO 2004076448), diazepam derivatives (WO 2011048032), substituted piperidines (WO 2010115803), pyrolilidine derivatives (WO 2010115803 ) bicyclic heterocycles (WO 2011042399), piperidyl derivatives (WO 2008049874), aminoalkylamide derivatives (WO 2007034251), imidazole derivatives (WO 2007025751), azetidine derivatives (WO 03077907), pyran derivatives (WO 2010069907), pyran derivatives (WO 2010069907), substituted derivatives or morpholinyl derivatives (WO 03099798).

Antibody-based CCR3 antagonists have also been developed and include, for example, anti-human CD193 PE antibody (CCR3) available from Biolegend, anti-CCR3 antibodies ab32512, ab36827, ab36829, ab36827, ab1667, ab16231, ab157139 available from Abcam, Y31 from OriGene, eBio5E8G9-B4 from eBioscience, MAb against human CCR3 (clone 61828) from R&D systems. See also US Pat. and 20040014132 for exemplary antibodies.

Additional compounds for inhibiting the CCR3 receptor include RNA, DNA or RNA/DNA based aptamers directed against CCR3. In particular, aptamers are described in US Pat. targeting the CCR3 receptor, such as those described in US Pat. No. 6,822,087.

Peptide-based CCR3 antagonists can be obtained from a phage library, such as, for example, the CPWYFWPC peptide (SEQ ID NO: 9) as described in Houimel M et al. (Eur. J. Immunol. 2001 Dec; 31(12):3535-45) or CCR3 peptide analogs as described in WO 1999043711.

Also included within the scope of the invention are CCR3 ligand antagonists, such as, for example, CCL11 antagonists, which may include small organic or synthetic molecules, natural products, peptides, proteins, peptidomimetics, antibodies, antigen-binding fragments, nucleic acid agents, and the like. . Truncated variants, variants, mutants or muteins of CCL11 having the ability to bind CCR3 and having antagonistic activity can also be used to practice the method of the invention. A particularly preferred CCR3 antagonist is the naphthalenylcarbonyl derivative SB 328437.

Antagonists of CCR2, CCR3 and/or CXCR4 suitable for use in accordance with the present invention may be administered alone, but are generally administered for human therapy, in admixture with a suitable pharmaceutically acceptable carrier, excipient, diluent, or vehicle chosen according to attention to the intended route of administration and standard pharmaceutical practice. Such a pharmaceutically acceptable carrier or excipient may be present in an amount between 0.1% and less than 100% by weight. Optimization of drug-excipient ratios is within the skill of the art, for example, the desired drug/excipient weight ratio in the composition may be less than or equal to the drug/excipient solubilities ratio, in a suitable medium.

Thus, compositions according to the present invention are preferably pharmaceutical compositions for use in a method of treating and/or preventing COPD and AECOPD and thus contain a therapeutically effective amount of at least one antagonist or inhibitor of CCR2/CCL2 receptor/ligand pairs, CCR2/CCL7, CCR2/CCL13, CXCR4/CXCL12 and/or CCR3/CCL11 and a pharmaceutically acceptable carrier. Such pharmaceutical compositions are effective in reducing the recruitment and migration of fibrocytes associated with

- 10 040016 baths with COPD and modulated by CCR2 and/or CCR3 and/or CXCR4.

A therapeutically effective amount is a predetermined amount sufficient to achieve an effective systemic or local tissue concentration and the desired effect, i. inhibition or blocking/antagonism of one or more of the above receptor/ligand pairs. The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects can, of course, be determined by the physician depending on the condition of the patients, weight, age and sex, the compound administered, the route of administration, and the like.

Pharmaceutical compositions of the present invention may be administered orally, buccally or sublingually and may be in the form of tablets, capsules (including soft gelatin capsules), multiparticulates, gels, films, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate, delayed, modified, sustained, dual, controlled release, or pulsatile delivery methods. Such compounds can also be administered via rapidly dispersing or rapidly dissolving dosage forms, either in the form of a high energy dispersion or in the form of coated particles. Suitable pharmaceutical formulations may be in coated or uncoated form, as desired.

Such pharmaceutical compositions, for example tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch, disintegrating agents such as sodium starch glycolate, croscarmellose sodium and certain complex silicates, and binders. granulating agents such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl acetate cellulose succinate (HPMCAS), sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type can also be used as fillers in gelatin capsules or HPMC capsules. Fillers in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, CCR2, CCR3 and/or CXCR4 antagonists may be combined with various sweetening or flavoring agents, coloring or coloring agents, emulsifying and/or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin and their combinations.

Modified release and pulsatile release dosage forms may contain excipients, such as the excipients detailed for immediate release dosage forms, along with additional excipients that act as release rate modifiers, coating the device and/or incorporated into the device design. Release rate modifiers include, but are not limited to, HPMC, HPMCAS, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammoniomethacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate , hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, and mixtures thereof. Dosage forms with modifying release and pulsatile release may contain one or a combination of excipients that modify the release rate. Release rate modifying excipients may be present both within the dosage form, i. e. inside the matrix, and/or on the dosage form, i.e. on the surface or in the coating.

Rapidly dispersing or rapidly dissolving dosage forms (FDDF) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropyl methylcellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavor, polyethylene glycol, highly dispersed silicon dioxide, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersible or soluble, as used herein to describe FDDF, depend on the solubility of the drug substance used, i. in cases where the drug substance is insoluble, a rapidly dispersing dosage form can be obtained, and in cases where the drug substance is soluble, a rapidly dissolving dosage form can be obtained.

Compositions and methods for use in accordance with the present invention can be administered parenterally, for example intracavernous, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous, or they can be administered by infusion or needleless methods. For such parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, such as sufficient salt or glucose to make a solution isotonic with blood. Aqueous solutions should be suitably buffered (preferably to a pH of about 3 to 9) as needed. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical methods well known to those skilled in the art.

- 11 040016

For oral and parenteral administration to patients, the daily dosage level of CXCR4, CCR2 and/or CCR3 antagonists may be as determined by the physician and may vary depending on the age, weight and response of the individual patient. The dose may be a single dose, a divided daily dose, or multiple daily doses. Alternatively, continuous dosing, for example, such as dosing via a controlled (eg, sustained) release dosage form, can be done on a daily basis or for more than one day at a time.

The compositions of the present invention may be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhalation or aerosol spray delivered from a pressurized container, pump, nebulizer or inhaler using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane , dichlorotetrafluoroethane, hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A(TM) or 1,1,1,2,3,3,3heptafluoropropane (HFA 227EA(TM)), carbon dioxide or other suitable gas In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver the metered amount.The pressurized container, pump, nebulizer or inhaler may contain a solution or suspension of the active compound, for example using a mixture of ethanol and a propellant as solvent, which may, in addition, contain a lubricant, such as sorbitan trioleate. psules and cartridges (gelatin capsules) for use in an inhaler or insufflator may be formulated to contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

Aerosol or dry powder formulations are preferably formulated such that each metered dose or release contains a therapeutically effective amount of CXCR4, CCR2 and/or CCR3 antagonists for delivery to the patient to be treated. The total daily dose in an aerosol can range from 1 to 50 mg, which can be administered in a single dose or, more usually, in divided doses throughout the day. Antagonists of CXCR4, CCR2 and/or CCR3 suitable for use in accordance with the present invention can also be formulated for delivery by nebulizer. Nebulizer formulations may contain the following ingredients as solubilizers, emulsifiers, or suspending agents: water, ethanol, glycerin, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, and oleic acid.

Antagonists of CXCR4, CCR2 and/or CCR3 suitable for use in accordance with the present invention may also be used in combination with a cyclodextrin. It is known that cyclodextrins form inclusive and non-inclusive complexes with drug molecules. Formation of a drug-cyclodextrin complex can modify the solubility, dissolution rate, and bioavailability and/or stability properties of the drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. As an alternative to direct drug complexation, cyclodextrin can be used as an auxiliary additive, eg as a carrier, diluent or solubilizer. Alpha, beta and gamma cyclodextrins are some of the most commonly used cyclodextrins and suitable examples are described in PCT publications WO 91/11172, WO 94/02518 and WO 98/55148. In accordance with the present invention, oral administration is the preferred route.

In conditions where the recipient suffers from a swallowing disorder or from a drug absorption disorder after oral administration, the drug may be administered parenterally, sublingually or buccally. In the case where the agent is orally inactive, then parenteral administration may be used.

Other possible formulations, such as nanoparticles, liposomes, and immunological based systems, can also be used to administer a suitable dose of antagonist compositions in accordance with the present invention.

The CXCR4, CCR2 and/or CCR3 receptor antagonists may be administered alone or in any combination thereof. In addition, the CXCR4, CCR2 and/or CCR3 antagonists can be administered alone or in any combination thereof in terms of time, that is, they can be administered simultaneously, before and/or after each other. As described herein, CXCR4, CCR2 and/or CCR3 antagonists can be used to reduce and/or inhibit fibrocyte migration and differentiation and thus can be used to treat and/or prevent COPD as well as AECOPD.

The present invention also relates to kits or pharmaceutical packages comprising appropriate doses of CXCR4 antagonists or compositions as described above for use in a method for preventing and/or treating COPD and AECOPD. In addition to compositions in the form of, for example, tablets, capsules, or lyophilized powders, kits or pharmaceutical packages may include instructions for use and administration of the composition to prevent and/or treat COPD and AECOPD. Such kits or packages may be provided in a bottle or other suitable

- 12 040016 form (for example, in a blister pack). Optionally, kits or pharmaceutical packages may also include other pharmaceutically active agents and/or materials used in the administration of the drug(s), such as diluents, needles, syringes, applicators, and the like.

In particular, pharmaceutical compositions and kits in accordance with the present invention can be administered in combination with other pharmaceutically active agents, such as bronchodilators (LABA, LAMA), corticoids and/or phosphodiesterase inhibitors, either orally or by inhalation.

In addition, the present invention relates to a method for suppressing the proliferation, migration and differentiation of fibrocytes mediated and/or modulated by CXCR4, CCR2 and/or CCR3 in a subject having COPD or AECOPD or at risk of developing COPD or AECOPD, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition as described above.

Throughout this specification, various references designate and describe these publications, the entire contents of which are therefore incorporated by reference in this specification to more fully describe the state of the art in the field to which this invention pertains.

Examples

Example 1 Inclusion of Subjects in a Study.

Subjects over 40 years of age are eligible for inclusion if they have had a clinical diagnosis of exacerbation of COPD according to the GOLD guidelines (Gold 1998. Global Initiative on Chronic Obstructive Pulmonary Disease. Global Strategy for the Diagnosis, Treatment and Prevention of Chronic Obstructive Pulmonary Disease. NIH Publication - updated in 2011). Patients with exacerbated COPD were enrolled during hospitalization in the intensive care unit or as outpatients at the clinical research center CHU de Bordeaux. 48 healthy volunteers were enrolled without any history of lung disease and with normal lung function at testing. Subjects were divided into 2 subgroups according to their history of smoking (never smokers, ex-smokers or current smokers) and were matched to patients according to age and gender.

The main exclusion criteria for patients with COPD and healthy subjects were asthma, pulmonary fibrosis, idiopathic pulmonary hypertension, and chronic viral infections (hepatitis, HIV). Exacerbated COPD patients and controls were enrolled in the Firebrob study. In addition, COPD patients without exacerbation for a minimum period of one year were also enrolled as outpatients at the CHU de Bordeaux Clinical Research Center (Cobra study). They are designated as COPD patients without exacerbation in the following text. All subjects provided written informed consent. The study protocol was approved by the local research ethics committee and the French National Agency for the Safety of Medicines and Health Products.

Example 2 Firebrob study design.

The study was conducted in groups of clinical research centers for 3 years. The essence of the study is shown in Fig. 1. Study registered with ClinicalTrials.gov as NCT01196832 (i.e., the Firebrob study).

There were two visits for COPD patients with exacerbation: visit during exacerbation (inclusion, V1), visit two months ± 7 days after exacerbation (stable condition, V2). The examination for inclusion (V1) consisted of providing information and signing informed consent, taking a blood sample (50 ml) for analysis of fibrocytes. The second examination (V2) consisted of a clinical and functional assessment (plethysmography, TLCO, arterial blood gas analysis) and blood sampling for fibrocyte analysis. There was one examination for control subjects and patients with COPD without exacerbation, during which informed consent was signed, clinical and functional evaluation (plethysmography, TLCO, arterial blood gas analysis) was performed, and a blood sample was collected for fibrocyte analysis.

Example 3 Cobra study design.

There was one visit for COPD patients without exacerbation, during which an informed consent was signed, clinical and functional evaluation (plethysmography, TLCO, arterial blood gas analysis) was performed, and a blood sample was collected for fibrocyte analysis.

The study is registered under CPP 0811738 (i.e. the Cobra study).

Example 4 Fibrocyte count.

Non-adherent non-T (NANT) cells were purified. Briefly, peripheral blood mononuclear cells (PBMCs) were isolated from whole blood by Ficoll-Hypaque density gradient centrifugation. After the first centrifugation at 150 g for 15 min, the upper layer of plasma was collected and stored at -80°C for further analysis. Mononuclear cells at the interface were collected, washed once using 1X PBS. Lysis of erythrocytes was performed by adding 20 ml of hypotonic 0.2% NaCl for 30 s, followed by 20 ml of 1.6% NaCl to complete the isotonic solution. Mononuclear

- 13 040016 cells were washed again with 1X PBS, resuspended in Dulbecco's modified Eagle's medium (DMEM), 4.5 g/l glucose, L-glutamine, supplemented with 20% fetal bovine serum (FBS), penicillin/streptomycin and optional amino acids for MEM, and incubated for 1 h at 37°C. A fraction of non-adherent mononuclear cells was taken and washed with cold 1X PBS 0.5% BSA, 2 mM EDTA. T cells were further depleted using an anti-CD3 monoclonal antibody (Miltenyi Biotech). At least 0.2 x 10 ⁶ non-adherent non-T (NANT) cells were dispensed into each FACS tube and fixed overnight using Cytofix/Cytoperm (eBioscience).

Example 5 Identification and characterization of circulating fibrocytes.

Fibrocytes were identified by flow cytometry as double positive for the surface marker CD45 and intracellular marker collagen I. Fixed NANT blood cells were washed in permeabilization buffer (eBioscience) and incubated with either mouse anti-human collagen I antibodies (Millipore Cat. □ MAB3391, RRID:AB_94839 ), or with an isotype-matched IgG1 control (Santa Cruz Biotechnology Cat. □ sc-3877, RRID: AB_737222), followed by a fluorescein isothiocyanate (FITC)-conjugated anti-mouse antibody (Beckman Coulter Cat. □ IM0819). The cell pellet was then incubated with either allophycocyanin (APC)-conjugated anti-CD45 antibodies (BD Biosciences Cat. □ 555485, RRID: AB_398600) or APC-conjugated isotype control IgG1 (BD Biosciences Cat. □ 555751, RRID: AB_398613). ). The cell suspension was analyzed using a BD FACSCanto II flow cytometer (BD Biosciences, San Jose, CA). Offline analysis was performed using the FACSDiva software. The threshold for negative CD45 detection was set using APC-conjugated isotype-matched control IgG1, and all subsequent samples were limited to the CD45 positive region. CD45 restricted cells were analyzed for collagen-1 expression, where negative control thresholds were set using FITC stained cells. Collagen-1 specific staining was defined as the increase in the number of positive events above this threshold. The number of fibrocytes was expressed as a percentage of the total number of PBMC.

Example 6. Migration of fibrocytes.

Fibrocyte migration was assessed using a modified Boyden chamber assay. Transwell inserts (pore size 8 μm) and wells were coated for 1 h at room temperature with polylysine-ethylene glycol (PEG-PLL, Susos) to prevent cell adhesion. Inserts and wells were washed using PBS. 0.3 x 10 ⁶ non-adherent non-T (NANT) cells resuspended in 0.2 ml DMEM, 4.5 g/l glucose, L-glutamine, additional DMEM, 4.5 g/l glucose, L-glutamine, supplemented with ITS, penicillin /streptomycin and non-essential amino acids for MEM were added to the top of each well. Where indicated, NANT cells were pretreated for 1 h at 37°C with 25 μg/ml plerixaphor (Sigma-Aldrich) or 10 μM SB 328437 (R&D Systems) before being added to the upper compartment. Recombinant human CXCL12 (25 ng/mL to 200 ng/mL; R&D Systems), recombinant human CCL11 (25 to 200 ng/mL; R&D Systems), or plasma (50% diluted) isolated from patient blood with COPD on VI or control subject, was added to the lower compartment of each well. After approximately 12 hours, the contents of the lower compartment were removed to assess fibrocyte migration by flow cytometry using CD45-collagen I double labeling. To obtain absolute numbers of migrating cells, flow cytometry values for each condition were obtained over a constant predetermined time period (1 min). The fraction of migrating fibrocytes was determined by the ratio between the number of CD45+coll I+ cells counted in the lower chamber divided by the number of CD45+coll I+ cells added to the upper chamber. These values were normalized to the fraction of migrating fibrocytes obtained at baseline (medium only).

Example 7 Measurement of CXCL12 and CCL11 in Plasma.

Plasma CXCL12 and CCL11 were measured by ELISA according to the manufacturer's instructions (R&D Systems).

Example 8 Results of Clinical Studies.

Inclusion in the study and baseline characteristics.

exacerbated COPD patients and 48 controls were included in the study (FIG. 1). Fibrocyte levels were then quantified in 48 COPD patients with exacerbation (VI), 9 COPD patients without exacerbation, and 38 controls. Fibrocyte levels were then quantified in 27 steady state COPD patients (V2).

Circulating fibrocytes in the blood.

The percentage of fibrocytes (CD45+ Coll+ cells) in the blood was higher in patients with COPD during exacerbation (VI, median=9.6 (95% confidence interval [CI], 9.5-15.7) from PBMC, n=48 ), compared with COPD patients without exacerbation (Nex, median=2.4 (95% CI, 0.3-6.8) from PBMC, n=9, p<0.05) and controls (median =3.0 (95% CI, 3.1-5.3) from PBMC, n=38, p<0.001) (Fig. 2A).

- 14 040016

Similar results were obtained for the level of fibrocytes, expressed as an absolute number per milliliter of blood (Fig. 2B). Both the percentage (FIG. 2C) and the absolute number (FIG. 2D) of circulating CD34 positive fibrocytes were increased in exacerbated COPD patients compared to controls. However, when separating subgroups of COPD patients with exacerbations based on their treatment against COPD exacerbation (antibiotic, oral corticoids), mode of ventilation (spontaneous ventilation, non-invasive ventilation or intubation), presence or absence of hospitalization, no significant differences in fibrocyte levels were observed between the various subgroups ( data not shown).

Two months after exacerbation (V2), both percentage (FIG. 2E) and absolute count (FIG. 2F) of fibrocytes were significantly reduced compared to those assessed at V1 (p<0.01). Moreover, there was a significant increase in the percentage of fibrocytes at V2 in the subgroup of patients with 2 or more unscheduled examinations for COPD in the year prior to V1 and in patients without any unscheduled examinations (Fig. E1).

Relationship between fibrocytes, survival and functional and clinical parameters.

Survival data were obtained for patients with COPD over a median period of 1.4 years and up to 3 years after V1. A Kaplan-Meier survival analysis was performed in 2 patient subgroups based on the percentage of fibrocytes assessed at V1. Patients with more than 28% fibrocytes had a significantly reduced life expectancy compared to patients with less than 28% fibrocytes (Fig. 3A). There was no significant difference between the 2 subgroups in terms of sex ratio, age, FEV1, FVC, PaO2 (data not shown). The subgroup of patients with more than 28% fibrocytes consisted of 6 patients with an acute attack, where all required hospitalization, while the subgroup of patients with less than 28% of fibrocytes consisted of 36 patients with an acute attack (where 20 required hospitalization and 16 without hospitalization).

Correlation coefficients were also determined between the percentages of fibrocytes assessed at the second examination (ie, at V2 two months after the relapse at steady state), and various functional parameters were also determined. Fibrocyte percentage was negatively and significantly correlated with FEV1 (% predicted, Fig. 3B), FVC (% predicted, Fig. 3C), FEV1/FVC ratio (%, Fig. 3D), TLCO (% predicted, Fig. 3E), and PaO2 (mmHg, Fig. 3F). Similar negative correlations were obtained between the percentage of circulating fibrocytes at the second examination and FEV1 (L), FVC (L) or FEF25-75 (l/s and predicted %) (Fig. E2). In contrast, there was no significant correlation between percentages of circulating fibrocytes in exacerbated patients and age (data not shown).

Expression of chemokine receptors in fibrocytes.

In addition, the expression of chemokine receptors in fibrocytes was assessed by flow cytometry. CXCR4, CCR2 and CCR3 expressed a high percentage of fibrocytes (FIGS. 4A, C, E), while CCR5 and CCR7 were only found on a small percentage of CD45+ColI+ cells (FIGS. 4G and H). There was a higher level of CXCR4+ and CCR3+ fibrocytes in patients with COPD than in controls (Fig. 4B, D and F).

The role of the CXCL12/CXCR4 and CCL11/CCR3 axes in fibrocyte migration.

Because more CXCR4+ and CCR3+ fibrocytes were found in the blood of exacerbated COPD patients, the role of both CXCR4 and CCR3 in plasma-induced fibrocyte migration was investigated in an in vitro assay. Plerixaphor, a CXCR4 antagonist (De Clercq, E. 2003. The bicyclam AMD3100 story. Nat Rev Drug Discov 2(7):581-7) induced a significant decrease in plasma-induced recruitment of fibrocytes derived from exacerbated COPD patients but not a significant decrease in migration fibrocytes obtained from normal subjects (Fig. 5A). In contrast, plasma-induced fibrocyte migration from exacerbated COPD patients or controls was not affected by SB 328437, a CCR3 antagonist (White, J. R., et al. 2000. J Biol Chem 275(47):36626-31) ( Fig. E3A). Plasma concentrations of some of the CXCR4 and CCR3 ligands were also compared. Plasma concentrations of CXCL12 alpha (CXCR4 ligand), and CCL11 and CCL13 (CCR3 ligands) did not differ significantly between groups (Figure 5B, Figure E3B). Thus, the response of fibrocyte migration to increasing concentrations of CXCL12 alpha and CCL11 was examined. CXCL12 alpha (FIG. 5C), but not CCL11 (FIG. E3C), induced significant fibrocyte migration in a dose-dependent manner. Interestingly, 100 ng/mL CXCL12 alpha triggered a significantly higher migration of fibrocytes from exacerbated COPD patients compared to fibrocytes from control subjects (Fig. 5C), suggesting that fibrocytes from exacerbated COPD patients had increased sensitivity to chemical exposure to CXCL12 compared to control fibrocytes. This response was completely terminated by plerixaphor treatment, showing that this response was entirely CXCR4 mediated (FIG. 5D).

Example 9 Effects of Compositions and Methods for Use of the Invention on a Mouse Model of COPD.

The mouse model was exposed to cigarette smoke (CS) in combination with virus-induced exacerbations. These virus-induced exacerbations were provoked by injection

- 15 040016 double-stranded RNA inducing responses similar to those induced by viral infections, namely poly(1:C).

Mice were exposed to cigarette smoke (CS) or room air (RA) for 5 weeks. In the last 2 weeks of the protocol, poly(1:C) or vehicle (PBS) was injected twice a week. As shown in FIG. 9, exposure to CS and poly(1:C) caused a modest increase in total cell and macrophage shedding after bronchoalveolar lavage (BAL). However, a significant increase in the release of neutrophils and lymphocytes was observed (Fig. 9).

Also, electron microscopy image analysis of bronchial sections obtained from mice exposed to CS and poly(1:C) compared to control mice exposed to room air and PBS showed that CS and poly(1:C) induced fibrosis of small but not the large airways (Figure 10A). Thus, the combination of CS and poly(1:C) causes inflammation of the bronchial airways and structural changes characteristic of COPD disease. An increase in bronchial airway inflammation as well as an increase in peribronchial fibrosis, as observed in patients with COPD, is clearly shown in FIG. 10b.

Moreover, an increase in the percentage of circulating fibrocytes (Blood, Fig. 11) and fibrocytes in the lung (Lung, Fig. 11) was shown in mice exposed to both cigarette smoke and poly(1:C). Interestingly, the percentage of fibrocytes in the lung correlated with small airway fibrosis (Fig. 12), suggesting a role for fibrocytes in this pathophysiological process. Together, these data confirm the results obtained for patients with COPD and add significant information about the recruitment of fibrocytes to the lung, where they may play a key role in peribronchial fibrosis.

Claims (10)

CLAIM 1. Use of a composition for the manufacture of a medicament for the prevention and/or treatment of chronic obstructive pulmonary disease (COPD) and acute attacks of chronic obstructive pulmonary disease (AECOPD), wherein said composition consists essentially of a therapeutically effective amount of at least one receptor antagonist or inhibitor CXCR4 chemokines and a pharmaceutically acceptable carrier, wherein said CXCR4 antagonist or inhibitor is a small molecule selected from bicyclams, quinolone-based CXCR4 antagonists, tetrahydroquinoline-based CXCR4 antagonists, guanidine-based CXCR4 antagonists, N-substituted indole-based CXCR4 antagonists, and/ or CXCR4 antagonists based on pyrimidine, 1,4-phenylenebis(methylene) derivatives and N-containing heterocycles, and wherein said CXCR4 antagonist or inhibitor inhibits fibroblast migration and/or recruitment during an exacerbation in patients with chronic obstructive disease m lungs (COPD). 2. Use of a medicament composition according to claim 1, wherein said CXCR4 antagonist is selected from p-xylylenediamine-based compounds. 3. Use of a medicament formulation according to claim 2, wherein said CXCR4 antagonist is plerixaphor. 4. Use of a composition for the manufacture of a medicament according to any one of the preceding claims, wherein said composition further comprises a pharmaceutically acceptable carrier. 5. Use of a composition for the manufacture of a medicament according to any one of the preceding claims, wherein said composition further comprises bronchodilators, corticoids and/or phosphodiesterase inhibitors. 6. A method for inhibiting fibrocyte migration in patients with COPD or AECOPD or in patients at risk of developing COPD and AECOPD, comprising administering a therapeutically effective amount of at least one CXCR4 chemokine receptor antagonist or inhibitor, wherein said CXCR4 antagonist or inhibitor is a small molecule selected of bicyclams, quinolone-based CXCR4 antagonists, tetrahydroquinoline-based CXCR4 antagonists, guanidine-based CXCR4 antagonists, N-substituted indole-based CXCR4 antagonists, and/or pyrimidine-based CXCR4 antagonists, 1,4-phenylenebis(methylene) and N- containing heterocycles. 7. The method of claim 6 wherein said CXCR4 chemokine receptor antagonist or inhibitor is administered orally, buccally or sublingually and is in the form of tablets, capsules (including soft gelatin capsules), multiparticulates, gels, films, elixirs, solutions or suspensions , which may contain flavoring agents or colorants, for immediate, delayed, modified, sustained, dual, controlled release, or pulsatile delivery. 8. The method of claim 7 wherein said CXCR4 chemokine receptor antagonist or inhibitor is administered via inhalation and is in the form of a dry powder inhalation or aerosol spray delivered from a pressurized container, pump, nebulizer or nebulizer. 9. Use of a therapeutically effective amount of at least one CXCR4 chemokine receptor antagonist or inhibitor, wherein said CXCR4 antagonist or inhibitor is a small molecule selected from bicyclams, quinolone-based CXCR4 antagonists, antagonists - 16 040016 CXCR4 nists based on tetrahydroquinoline, CXCR4 antagonists based on guanidine, antagonists CXCR4 based on N-substituted indole and/or CXCR4 antagonists based on pyrimidine, 1,4-phenylenebis(methylene) derivatives and N-containing heterocycles for the treatment and/or prevention of COPD and AECOPD. 10. Use according to claim 9 to suppress fibrocyte migration in patients with COPD and AECOPD or in patients at risk of developing COPD and AECOPD.