WO2017042318A1 - Polypeptide de chémérine pour le traitement de la cachexie provoquée par le cancer - Google Patents

Polypeptide de chémérine pour le traitement de la cachexie provoquée par le cancer Download PDF

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Publication number
WO2017042318A1
WO2017042318A1 PCT/EP2016/071275 EP2016071275W WO2017042318A1 WO 2017042318 A1 WO2017042318 A1 WO 2017042318A1 EP 2016071275 W EP2016071275 W EP 2016071275W WO 2017042318 A1 WO2017042318 A1 WO 2017042318A1
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Prior art keywords
cancer
chemerin
vegf
cells
cell
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PCT/EP2016/071275
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English (en)
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Christian Stockmann
Ralph Klose
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paris Descartes
Association Robert Debré Pour La Recherche Médicale
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Publication of WO2017042318A1 publication Critical patent/WO2017042318A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to methods and pharmaceutical compositions for the treatment of cancer-induced cachexia.
  • chemotherapeutic agents stem not only from direct effects on the tumour cell but also from influences on the tumour microenvironment, resulting in a robust immune response that can be crucial to the therapeutic outcome 1 .
  • drug delivery poses a significant problem as the vasculature of tumours is inefficient 2 .
  • Cancer-induced cachexia is the immediate cause of death in about 15% of cancer patients 4"6 . It is characterized by involuntary weight loss that is resistant to nutritional supplementation 1 . Weight loss starts with the breakdown of white adipose tissue (WAT) mediated by the lipolytic enzymes adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) 8 as well as loss of skeletal muscle 1 . WAT lipolysis is believed to be induced by tumour-derived factors, such as tumour necrosis factor alpha (TNF-a) and interleukin (IL-) 6 9 ' 10 . After an initial reduction of tumour mass, treatment with chemotherapeutic agents frequently exacerbates cachexia, hampering further treatment and increasing mortality n,u . There is an urgent need for treatment regimens that counter the development of cachexia and thus allow continued chemotherapy.
  • TNF-a tumour necrosis factor alpha
  • IL- interleukin
  • Chemerin was initially defined as an adipokine 1 but has received considerable interest as a chemoattractant for macrophages, dendritic cells and NK cells 14 ⁇ 16 .
  • NK cells and cytotoxic T cells are particularly important in the immunosurveiUance and suppression of tumours 17 ' 18 and chemerin has been shown to improve NK cell-based tumour surveillance.
  • Expression of the chemerin gene ((Rarres ( retinoic acid receptor responder) 2) is frequently downregulated in human solid tumours, including lung cancer and melanoma. Overexpression of chemerin in melanoma cells in mouse models results in increased NK cell recruitment and tumour suppression 19 .
  • the present invention relates to methods and pharmaceutical compositions for the treatment of cancer-induced cachexia.
  • the present invention is defined by the claims.
  • VEGF Vascular Endothelial Growth Factor
  • chemerin as a critical mediator of the immune response elicited by chemotherapy as well as an important inhibitor of cancer cachexia.
  • Targeting VEGF signaling should impede the lipolysis and weight loss that is frequently associated with chemotherapy, thereby dramatically improving the therapeutic outcome.
  • the present invention relates to a method of treating cancer-induced cachexia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a chemerin polypeptide or a nucleic acid molecule encoding thereof.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • the method of the present invention is particularly suitable for inhibiting the lipolysis of white adipose tissue and the loss of skeletal muscle.
  • the subject suffers from a cancer selected from the group consisting of bile duct cancer (e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, bone cancer (e.g. osteoblastoma, osteochrondroma, hemangioma, chondromyxoid fibroma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, giant cell tumor of the bone, chordoma, lymphoma, multiple myeloma), brain and central nervous system cancer (e.g.
  • bile duct cancer e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer
  • bladder cancer e.g. osteoblastoma, osteochrondroma, hemangioma, chondromyxoid fibroma, osteosarcoma, chondrosarcom
  • meningioma astocytoma, oligodendrogliomas, ependymoma, gliomas, medulloblastoma, ganglioglioma, Schwannoma, germinoma, craniopharyngioma), breast cancer (e.g. ductal carcinoma in situ, infiltrating ductal carcinoma, infiltrating, lobular carcinoma, lobular carcinoma in, situ, gynecomastia), Castleman disease (e.g. giant lymph node hyperplasia, angiofollicular lymph node hyperplasia), cervical cancer, colorectal cancer, endometrial cancer (e.g.
  • lung cancer e.g. small cell lung cancer, non-small cell lung cancer
  • mesothelioma plasmacytoma, nasal cavity and paranasal sinus cancer (e.g. esthesioneuroblastoma, midline granuloma), nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g.
  • rhabdomyosarcoma embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, skin cancer (e.g. melanoma, nonmelanoma skin cancer), stomach cancer, testicular cancer (e.g. seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer (e.g. follicular carcinoma, anaplastic carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma, thyroid lymphoma), vaginal cancer, vulvar cancer, and uterine cancer (e.g. uterine leiomyosarcoma).
  • skin cancer e.g. melanoma, nonmelanoma skin cancer
  • stomach cancer testicular cancer (e.g. seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer (e.g. follicular carcinoma, anaplastic carcinoma
  • chemerin has its general meaning in the art and refers to a 14 kDa protein, highly expressed in adipose tissue, liver and lung. It is secreted as the inactive, 143 amino acid (AA) long, prochemerin and activated by proteolytic cleavage of a 6 AA C-terminal sequence by serine proteases involved in coagulation-, inflammation or fibrinolysis cascades. It acts as a ligand for CMKLRl, Gprl and CCRL2.
  • An exemplary human amino acid sequence is represented by SEQ ID NO: 1.
  • SEQ ID NO:l Chemerin homo sapiens
  • chemerin polypeptide has its general meaning in the art and includes naturally occurring chemerin and conservative function variants and modified forms thereof.
  • Chemerin is a family of structurally related cytokines.
  • the chemerin polypeptide comprises an amino acid sequence having at least 90% of identity with SEQ ID NO:l.
  • a first amino acid sequence having at least 90% of identity with a second amino acid sequence means that the first sequence has 90; 91; 92; 93; 94; 95; 96; 97; 98; 99 or 100% of identity with the second amino acid sequence.
  • Sequence identity is frequently measured in terms of percentage identity (or similarity or homology); the higher the percentage, the more similar are the two sequences.
  • Methods of alignment of sequences for comparison are well known in the art. Various programs and alignment algorithms are described in: Smith and Waterman, Adv. Appl. Math., 2:482, 1981; Needleman and Wunsch, J. Mol.
  • the alignment tools ALIGN Myers and Miller, CABIOS 4: 11-17, 1989
  • LFASTA Pearson and the University of Virginia, fasta20u63 version 2.0u63, release date December 1996
  • ALIGN compares entire sequences against one another
  • LFASTA compares regions of local similarity.
  • these alignment tools and their respective tutorials are available on the Internet at the NCSA Website, for instance.
  • the Blast 2 sequences function can be employed using the default BLOSUM62 matrix set to default parameters, (gap existence cost of 11, and a per residue gap cost of 1).
  • the alignment should be performed using the Blast 2 sequences function, employing the PAM30 matrix set to default parameters (open gap 9, extension gap 1 penalties).
  • the BLAST sequence comparison system is available, for instance, from the NCBI web site; see also Altschul et al, J. Mol. Biol, 215:403-410, 1990; Gish. & States, Nature Genet., 3:266-272, 1993; Madden et al. Meth. EnzymoL, 266: 131-141, 1996; Altschul et al., Nucleic Acids Res., 25:3389-3402, 1997; and Zhang & Madden, Genome Res., 7:649-656, 1997.
  • the chemerin polypeptides of the invention used in the therapeutic methods of the present invention may be modified in order to improve their therapeutic efficacy.
  • modification of therapeutic compounds may be used to decrease toxicity, increase circulatory time, or modify biodistribution.
  • the toxicity of potentially important therapeutic compounds can be decreased significantly by combination with a variety of drug carrier vehicles that modify biodistribution.
  • a strategy for improving drug viability is the utilization of water-soluble polymers.
  • Various water-soluble polymers have been shown to modify biodistribution, improve the mode of cellular uptake, change the permeability through physiological barriers; and modify the rate of clearance from the body.
  • water-soluble polymers have been synthesized that contain drug moieties as terminal groups, as part of the backbone, or as pendent groups on the polymer chain.
  • Polyethylene glycol (PEG) has been widely used as a drug carrier, given its high degree of biocompatibility and ease of modification. Attachment to various drugs, proteins, and liposomes has been shown to improve residence time and decrease toxicity.
  • the chemerin polypeptide of the invention is fused a Fc domain of an immunoglobulin. Suitable immunoglobulins are IgG, IgM, IgA, IgD, and IgE.
  • IgG and IgA are preferred IgGs are most preferred, e.g. an IgGl .
  • Said Fc domain may be a complete Fc domain or a function-conservative variant thereof.
  • the chemerin polypeptide of the invention may be linked to the Fc domain by a linker.
  • the linker may consist of about 1 to 100, preferably 1 to 10 amino acid residues.
  • the polypeptide of the invention may be produced by conventional automated peptide synthesis methods or by recombinant expression. General principles for designing and making proteins are well known to those of skill in the art.
  • the polypeptides of the invention may be synthesized in solution or on a solid support in accordance with conventional techniques. Various automatic synthesizers are commercially available and can be used in accordance with known protocols as described in Stewart and Young; Tarn et al., 1983; Merrifield, 1986 and Barany and Merrifield, Gross and Meienhofer, 1979.
  • the polypeptides of the invention may also be synthesized by solid-phase technology employing an exemplary peptide synthesizer such as a Model 433 A from Applied Biosystems Inc.
  • any given protein generated through automated peptide synthesis or through recombinant methods may be determined using reverse phase HPLC analysis. Chemical authenticity of each peptide may be established by any method well known to those of skill in the art.
  • recombinant DNA technology may be employed wherein a nucleotide sequence which encodes a protein of choice is inserted into an expression vector, transformed or transfected into an appropriate host cell and cultivated under conditions suitable for expression as described herein below. Recombinant methods are especially preferred for producing longer polypeptides.
  • a variety of expression vector/host systems may be utilized to contain and express the peptide or protein coding sequence.
  • microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid or cosmid DNA expression vectors; yeast transformed with yeast expression vectors (Giga-Hama et al, 1999); insect cell systems infected with virus expression vectors (e.g., baculovirus, see Ghosh et al., 2002); plant cell systems transfected with virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with bacterial expression vectors (e.g., Ti or pBR322 plasmid; see e.g., Babe et al., 2000); or animal cell systems.
  • microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid or cosmid DNA expression vectors; yeast transformed with yeast expression vectors (Giga-Hama et al, 1999); insect cell systems infected with virus expression vectors (e.g., baculovirus, see Ghosh
  • Mammalian cells that are useful in recombinant protein productions include but are not limited to VERO cells, HeLa cells, Chinese hamster ovary (CHO) cell lines, COS cells (such as COS-7), W138, BHK, HepG2, 3T3, RIN, MDCK, A549, PC 12, K562 and 293 cells.
  • nucleic acid molecule has its general meaning in the art and refers to a DNA or RNA molecule. However, the term captures sequences that include any of the known base analogues of DNA and RNA such as, but not limited to 4-acetylcytosine, 8- hydroxy-N6-methyladenosine, aziridinylcytosine, pseudoisocytosine, 5-
  • uracil (carboxyhydroxylmethyl) uracil, 5-fiuorouracil, 5-bromouracil, 5- carboxymethylaminomethyl-2-thiouracil, 5-carboxymethyl-aminomethyluracil, dihydrouracil, inosine, N6-isopentenyladenine, 1 -methyladenine, 1 -methylpseudouracil, 1-methylguanine, 1- methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5- methylcytosine, N6-methyladenine, 7-methylguanine, 5-methylaminomethyluracil, 5- methoxyamino-methyl-2-thiouracil, beta-D-mannosylqueosine, 5'- methoxycarbonylmethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil- 5-oxyacetic acid methyl
  • the nucleic acid molecule of the present invention is included in a suitable vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector.
  • a suitable vector such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector.
  • the vector is a viral vector which is an adeno-associated virus (AAV), a retrovirus, bovine papilloma virus, an adenovirus vector, a lentiviral vector, a vaccinia virus, a polyoma virus, or an infective virus.
  • the vector is an AAV vector.
  • AAV vector means a vector derived from an adeno- associated virus serotype, including without limitation, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, and mutated forms thereof.
  • AAV vectors can have one or more of the AAV wild-type genes deleted in whole or part, preferably the rep and/or cap genes, but retain functional flanking ITR sequences.
  • Retroviruses may be chosen as gene delivery vectors due to their ability to integrate their genes into the host genome, transferring a large amount of foreign genetic material, infecting a broad spectrum of species and cell types and for being packaged in special cell- lines.
  • a nucleic acid encoding a gene of interest is inserted into the viral genome in the place of certain viral sequences to produce a virus that is replication-defective.
  • a packaging cell line is constructed containing the gag, pol, and/or env genes but without the LTR and/or packaging components.
  • Retroviral vectors are able to infect a broad variety of cell types.
  • Lentiviruses are complex retroviruses, which, in addition to the common retroviral genes gag, pol, and env, contain other genes with regulatory or structural function. The higher complexity enables the virus to modulate its life cycle, as in the course of latent infection.
  • Some examples of lentivirus include the Human Immunodeficiency Viruses (HIV 1, HIV 2) and the Simian Immunodeficiency Virus (SIV).
  • Lentiviral vectors have been generated by multiply attenuating the HIV virulence genes, for example, the genes env, vif, vpr, vpu and nef are deleted making the vector biologically safe.
  • Lentiviral vectors are known in the art, see, e.g.. U.S. Pat. Nos. 6,013,516 and 5,994,136, both of which are incorporated herein by reference.
  • the vectors are plasmid-based or virus-based, and are configured to carry the essential sequences for incorporating foreign nucleic acid, for selection and for transfer of the nucleic acid into a host cell.
  • the gag, pol and env genes of the vectors of interest also are known in the art.
  • the relevant genes are cloned into the selected vector and then used to transform the target cell of interest.
  • Recombinant lentivirus capable of infecting a non-dividing cell wherein a suitable host cell is transfected with two or more vectors carrying the packaging functions, namely gag, pol and env, as well as rev and tat is described in U.S. Pat. No. 5,994,136, incorporated herein by reference.
  • This describes a first vector that can provide a nucleic acid encoding a viral gag and a pol gene and another vector that can provide a nucleic acid encoding a viral env to produce a packaging cell.
  • control sequences' refers collectively to promoter sequences, polyadenylation signals, transcription termination sequences, upstream regulatory domains, origins of replication, internal ribosome entry sites ("IRES"), enhancers, and the like, which collectively provide for the replication, transcription and translation of a coding sequence in a recipient cell.
  • nucleic acid sequence is a "promoter" sequence, which is used herein in its ordinary sense to refer to a nucleotide region comprising a DNA regulatory sequence, wherein the regulatory sequence is derived from a gene which is capable of binding RNA polymerase and initiating transcription of a downstream (3 '-direction) coding sequence.
  • Transcription promoters can include "inducible promoters” (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), “repressible promoters” (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), and “constitutive promoters”.
  • a “therapeutically effective amount” is meant a sufficient amount of the chemerin polypeptide or the nucleic acid molecule encoding thereof to treat cancer-induces cachexia at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the chemerin polypeptide or the nucleic acid molecule (inserted or not into a vector) of the present invention is administered to the subject in the form of a pharmaceutical composition.
  • the chemerin polypeptide or the nucleic acid molecule (inserted or not into a vector) of the present invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
  • pharmaceutically acceptable excipients such as biodegradable polymers
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the active principle alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral- route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • saline solutions monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts
  • dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the chemerin polypeptide or the nucleic acid molecule (inserted or not into a vector) of the present invention can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the chemerin polypeptide or the nucleic acid molecule encoding thereof is administered to the subject in combination with a chemotherapeutic agent.
  • chemotherapeutic agent refers to chemical compounds that are effective in inhibiting tumor growth.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaorarnide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin
  • calicheamicin especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl. 33:183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including mo holino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolin
  • paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and phannaceutically acceptable salts, acids or derivatives of any of the above.
  • antihormonal agents that act to regulate or inhibit honnone action on tumors
  • anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)- imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and phannaceutically acceptable salts, acids or derivatives of any of the above.
  • the chemerin polypeptide or the nucleic acid encoding thereof is administered sequentially (i.e. before or after) or concomitantly with the chemotherapeutic agent.
  • the chemerin polypeptide or the nucleic acid molecule encoding thereof is administered to the subject in combination with an anti-VEGF agent.
  • an anti-VEGF agent refers to a molecule that inhibits VEGF -mediated angiogenesis, vasculogenesis, or undesirable vascular permeability.
  • an anti- VEGF therapeutic may be an antibody to or other antagonist of VEGF.
  • An "anti-VEGF antibody” is an antibody that binds to VEGF with sufficient affinity and specificity to be useful in a method of the invention.
  • An anti-VEGF antibody will usually not bind to other VEGF homologues such as VEGF- B or VEGF-C, or other growth factors such as P1GF, PDGF or bFGF.
  • a preferred anti- VEGF antibody is a monoclonal antibody that binds to the same epitope as the monoclonal anti-VEGF antibody A4.6.1 produced by hybridoma ATCC® HB 10709 and is a high-affinity anti-VEGF antibody.
  • a "high-affinity anti-VEGF antibody” has at least 10-fold better affinity for VEGF than the monoclonal anti-VEGF antibody A4.6.1.
  • the anti-VEGF antibody is a recombinant humanized anti-VEGF monoclonal antibody fragment generated according to WO 98/45331, including an antibody comprising the CDRs or the variable regions of Y0317. More preferably, anti-VEGF antibody is the antibody fragment known as ranibizumab (LUCENTIS ®).
  • ranibizumab is a humanized, affinity-matured anti-human VEGF Fab fragment.
  • Ranibizumab is produced by standard recombinant technology methods in E. coli expression vector and bacterial fermentation. Ranibizumab is not glycosylated and has a molecular mass of -48,000 daltons. See W098/45331 and U.S.
  • Anti-VEGF agents include but are not limited to bevacizumab (rhuMab VEGF, Avastin®, Genentech, South San Francisco Calif), ranibizumab (rhuFAb V2, Lucentis®, Genentech), pegaptanib (Macugen®, Eyetech Pharmaceuticals, New York N.Y.), sunitinib maleate (Sutent®, Pfizer, Groton Conn.).
  • the chemerin polypeptide or the nucleic acid molecule encoding thereof is administered sequentially (i.e. before or after) or concomitantly with the anti-VEGF agent.
  • the invention will be further illustrated by the following figures and examples.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 Loss of myeloid cell VEGF- A delays tumor growth and ameliorates cancer cachexia after chemotherapy.
  • FIG. 1 Schematic representation of experimental procedure to study tumour regrowth of LLC and B 16F 10 isografts in WT and mutant mice.
  • 10 7 cells of the tumour cell line were subcutanously injected into mice and 8 mg kg c i s-d i am m i n cd i ch 1 o to p 1 a t i n u m( 11 ) (cisplatin or CDDP) was administered by intraperitoneal injection (i.p.) at the indicated time-points. Tumours were allowed to grow until the maximum size was reached .
  • FIG. 1 Chemerin protects Mut mice from chemotherapy-induced WAT lipolysis and weight loss.
  • A Amount of white adipose tissue (WAT) normalized to tibia length of untreated, cisplatin-treated and cisplatin + anti-chemerin-treated WT and Mut mice on day 18 (WT: n > 4; Mut: n > 7).
  • WAT white adipose tissue
  • Proposed model for the improved outcome of chemotherapy and prevention of body weight loss by targeting VEGF in myeloid cells increased levels of circulating chemerin due enhanced release of chemerin by the tumor endothelium improve NK cell recruitment to the tumor and prevent WAT lipolysis.
  • Rat anti-CD31 (Biolegend), mouse anti-SMA-a (Chemicon), rat anti-KI-67 (Abeam), rat anti-Cdl lc (Biolegend), rat anti-CD4 (Biolegend), rat anti-CD8 (Biolegend), mouse anti-NKl .
  • RNA extraction and RT-qPCR Total RNA was isolated by phenol/chloroform extraction. cDNA was synthesized from 3 ⁇ g of DNA-free total RNA using M-MLV Reverse Transcriptase (Promega) and oligo-dT primers (Life Technologies). Gene-specific transcription levels were determined using SYBR Green Mastermix (Promega) and an IQ5 real-time PCR machine (Bio-Rad). PCR conditions: 95 °C for 10 min followed by 40 cycles of 95 °C for 15 s and 60 °C for 1 min. Data were normalized to 16S mRNA levels.
  • DAPI Invitrogen
  • cover slips were mounted with Mounting Medium (Dako).
  • the TUNEL assay was performed in accordance with the manufacturer's instructions (Promega). Chemerin immunohistochemistry and chemerin/FSP-1 double immunofluorescence were performed with the CSA kit (DA O) after heat-induced antigen retrieval.
  • Senescence associated ⁇ -galactosidase staining ⁇ frozen sections of OCT- embedded tumours were stained for the senescence marker SA-P-galactosidase according to the manufacturer's instructions (Cell Signaling).
  • Tumours were digested with 0.1 % collagenase type III (Worthington) and 1 U/ml DNAse I (Promega) and incubated at 37 °C for 1 h. 10 7 tumour cells were incubated with Fc-Block (BD Biosciences) before labeling with fluorochrome- conjugated antibodies (Biolegend). Data were acquired on a flow cytometer (LSR II, BD Biosciences) using the FACS Diva software. Samples were stained with 7-AAD before analysis to exclude non-viable cells. Isolation of endothelial cells.
  • tumours were digested in cell lysis buffer (DMEM + 2 mg/ml collagenase type III) for 1 h at 37 °C. 4xl0 7 cells were incubated with mouse CD31 microbeads (Miltenyi Biotec) and endothelial cells (EC) were separated to a purity of > 90 % by positive selection according to the manufacturer's instruction.
  • DMEM + 2 mg/ml collagenase type III 2 mg/ml collagenase type III
  • VEGF-A and chemerin Concentrations of VEGF-A and chemerin in tumours and aliquots of medium were determined using commercial kits (Quantikine ELISA Immunoassay, R&D Systems) and expressed in pg/ml per mg of whole tissue protein. Serum levels of TNF-a and IL-6 were measured using mouse TNF-a and IL-6 quantikine ELISA kit (R&D Systems) and normalized to serum protein levels. Western Blot. Protein samples were separated using a 10 % polyacrylamide gel under reducing and denaturating conditions and transferred onto a PVDF membrane followed by ECL-detection of the antibody. For quantitative analysis, the membranes were scanned with the ImageQuant LAS 4000mini (GE Healtcare Life Sciences) and the integrated density was measured using the software ImageJ (National Institutes of Health).
  • VEGF-A Targeting of VEGF-A in myeloid cells delays tumor growth and ameliorates cancer cachexia after chemotherapy
  • mice with a /oxP-flanked Vegfa allele mice with the Cre recombinase under the control of the lysozyme M promoter.
  • the VEGF-A gene is specifically deleted in the myeloid cells of the resulting mutant (Mut, LysMCre/VEGF f / f ) mice and the animals' response to chemotherapy is improved: the mice show vascular normalization and an increase in tumour cell apoptosis 3 .
  • WT, LysMCre-/VEGF+/+ mice carrying Lewis lung carcinomas (LLC) or B16 melanomas to three cycles of cisplatin treatment (CDDP, 8 mg/kg body weight, see scheme Fig.
  • cisplatin treatment reduced levels of VEGF-A, lowered vascular density and increased pericyte coverage to varying degrees. These observations are consistent with the notion that chemotherapy induces vascular regression 20 .
  • comparison of WT and Mut mice reveals that the loss of myeloid cell- derived VEGF results in lower levels of VEGF within the tumours as well as in vascular normalization, increased pericyte coverage and decreased tumour hypoxia.
  • vascular normalization and improved oxygenation is associated with accelerated tumour growth in untreated Mut tumours, it paradoxically results in delayed tumour outgrowth after chemotherapy (Fig. 1C).
  • VEGF-A Targeting VEGF-A in myeloid cells enhances chemotherapy-induced DNA damage and immune cell recruitment
  • chemotherapeutic agents drive the apoptosis of tumour cells, they may be associated with a wide range of other outcomes including so-called premature or therapy- induced senescence, which they promote by inducing DNA damage responses 21,22 .
  • Untreated tumours show hardly any senescence irrespective of the genotype (data not shown, untreated).
  • Deleting VEGF-A in myeloid cells increases tumour-cell death upon chemotherapy and promotes therapy-induced senescence, as shown by senescence-associated ⁇ -galactosidase (SA ⁇ -Gal) staining (data not shown, day 14, CDDP).
  • SA ⁇ -Gal senescence-associated ⁇ -galactosidase
  • Senescent cells remain viable and secrete a range of inflammatory cytokines 23 .
  • the senescence-associated secretory phenotype (SASP) is believed to trigger an immune response involving macrophages and natural killer (NK) cells that facilitates immune cell-mediated tumour clearance 24 ⁇ 26 .
  • SASP senescence-associated secretory phenotype
  • NK natural killer cells
  • There were markedly higher numbers of NK cells (NKl .l) (data not shown) and significantly increased numbers of intratumoural macrophages (F4/80) and dendritic cells (CD 11c).
  • cytokines and chemokines are involved in the recruitment of immune cells to malignant tumours 27 ' 28 .
  • the chemoattractant chemerin has a crucial role in immune cell trafficking 14 ⁇ 16 . Forced expression of chemerin in tumour cells gives rise to an NK cell- based antitumour response and restricts tumour growth, while low levels of chemerin are associated with tumour progression and a poor outcome 19 . Increasing the level of chemerin within the tumour may thus represent a promising therapeutic approach.
  • chemotherapy increases the level of chemerin in tumours in WT mice (data not shown). Surprisingly, the effect was significantly enhanced in Mut mice, showing that the absence of VEGF-A in myeloid cells stimulates the chemotherapy-evoked expression of chemerin (data not shown) and drastically increases the levels of circulating chemerin (data not shown).
  • tumour cells do not release chemerin as a consequence of chemotherapy: treatment of LLC cells in vitro with 3 ⁇ g/ml cisplatin, a concentration that causes a significant DNA damage response, did not trigger chemerin release while cisplatin treatment of B 16F 10 cells produced no increase in the basal level of chemerin secreted.
  • immunohistochemical analysis of tumor sections revealed only subtle chemerin reactivity in untreated tumours of WT and Mut mice as well as in tumours from cisplatin-treated WT animals (data not shown).
  • tumours from Mut mice showed strong chemerin immunoreactivity of the tumor vasculature upon chemotherapy (data not shown). The result indicates that tumour endothelial cells release chemerin in response to chemotherapy and that VEGF-A from myeloid cells suppresses the release.
  • PPAR- ⁇ and chemerin were only expressed in endothelial cells (EC) of tumours derived from Mut mice after chemotherapy (data not shown), confirming that ablation of myeloid cell-derived VEGF-A significantly increases the expression of chemerin in response to chemotherapy (data not shown).
  • the data verify the tumor endothelium as a major source of chemerin in response to chemotherapy and show that chemerin production is suppressed by myeloid cell-derived VEGF-A.
  • Chemerin protects Mut mice from chemotherapy-induced WAT lipolysis and weight loss
  • Chemerin was initially described as an adipokine with context-dependent pro- and antilipolytic effects on WAT 13 ' 30 . It seemed conceivable that changes in chemerin levels could affect lipid metabolism in our cancer models. It was initially important to assess the contribution of loss of adipose tissue to the overall weight loss associated with chemotherapy. We thus weighed gonadal adipose depots in mice subjected to chemotherapy. Consistent with the concept that cachexia involves breakdown of WAT, chemotherapy of WT mice resulted in a >60% reduction in gonadal WAT (Fig. 2A).
  • the antibody caused Mut mice to suffer the same loss of body weight and WAT as WT mice on cisplatin treatment (Fig. 2A and B). Furthermore, following chemotherapy the Atgl and Hsl genes were expressed at similar levels in WT mice and in Mut mice treated with the antibody (Fig. 2C and D). The differences in weight and WAT loss upon chemotherapy could not be accounted for by variations in food intake, which did not depend on genotype, although chemotherapy resulted in a reduced food intake in both WT and Mut mice. Likewise, serum levels of the lipid-mobilizing cytokines TNF-a and IL-6 were similar across genotypes and treatment regimens. The protection from chemotherapy-induced cachexia in Mut mice is thus associated with the loss of myeloid cell- derived VEGF-A and the resulting increase in the level of circulating chemerin.
  • Chemotherapy causes an increase in the intratumoural release of chemerin in Mut mice.
  • Chemerin might thus be involved in the enhanced immune response in the absence of myeloid cell-derived VEGF-A, which is associated with the improved control of tumour growth.
  • the interpretation was tested by means of an anti-chemerin antibody, which drastically diminished chemotherapy-induced recruitment of NK cells in WT and Mut mice (data not shown), whereas infiltration of DCs and macrophages was unaffected.
  • the antibody completely blocked the clearance of senescent tumour cells after cytotoxic treatment in the absence of myeloid cell-derived VEGF-A, resulting in equal numbers of senescent cells in tumours from WT and Mut mice at endpoint (Fig. 3B).
  • Targeting VEGF-A in myeloid cells leads to vascular normalization 3 .
  • targeting VEGF-A is also associated with an enhanced senescence response upon chemotherapy.
  • the reduced tumour hypoxia in Mut tumours may contribute to the effect, as hypoxia has been reported to prevent cellular senescence 31 .
  • T cell-mediated immune responses are impaired by a lack of oxygen 32 , it is unknown how NK cells react under hypoxic conditions. It is attractive to speculate that the reduced hypoxia in Mut mice improves NK cell-mediated cytotoxicity.
  • VEGF-A In addition to shaping the tumour vasculature, VEGF-A modulates the performance of various immune cells 33 . It may have an effect on the migration and cytotoxicity of NK cells, although findings are inconsistent 34,35 . It clearly attracts regulatory T cells to the tumour microenvironment 36 and interferes with the maturation of dendritic cells 33 . The absence of myeloid cell-derived VEGF-A from the tumour microenvironment could thus improve antitumour immune responses.
  • the chemotherapeutic agent cisplatin reduces vascular density and increases pericyte coverage, consistent with its known anti-angiogenic properties 20 .
  • the effect is independent of myeloid cell-derived VEGF-A, although the density of blood vessels before chemotherapy is higher in tumours from wild-type mice than in those from mutant mice lacking VEGF-A in their myeloid cells.
  • the reduction in tumour blood vessels upon chemotherapy may thus be enhanced by VEGF-A.
  • the effect may stem from improved drug delivery and/or be related to the presumably higher number of proliferating endothelial cells upon VEGF-A-driven angiogenesis.
  • the proliferating cells in the vasculature would be more susceptible to cytotoxic damage than quiescent cells.
  • tumouricidal effects of many chemotherapeutic agents may depend on the active contribution of immune cell effectors, especially those of the adaptive immune compartment l .
  • therapeutic success critically depends on NK cell-mediated tumour immune surveillance and tumour cell clearance. It is important to note that not all tumours are sensitive to NK cell-mediated tumour surveillance. Further work will be necessary to evaluate the outcome of drug-induced senescence and stromal chemerin release in tumor models that are controlled by T cells.
  • chemerin is a critical mediator of NK cell-mediated antitumour defenses as well as of lipolysis and cachexia (Fig. 4).
  • VEGF-A derived from myeloid cells suppresses the stimulation of endothelial chemerin release by chemotherapy.
  • targeting VEGF signaling should impede the lipolysis and weight loss that is frequently associated with chemotherapy.
  • Our study therefore offers novel therapeutic avenues to improve the outcome of chemotherapy.
  • Zinc-alpha2-glycoprotein a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia. Proceedings of the National
  • Schmitt, C.A., et al. A senescence program controlled by p53 and pl6INK4a contributes to the outcome of cancer therapy. Cell 109, 335-346 (2002).
  • NF-kappaB promotes senescence and enhances chemosensitivity. Genes & development 25, 2125-2136 (2011).

Abstract

La présente invention concerne des méthodes et des compositions pharmaceutiques de traitement de la cachexie provoquée par le cancer. La présente invention concerne en particulier une méthode de traitement de la cachexie provoquée par le cancer chez un patient en ayant besoin, qui consiste à administrer audit patient une quantité thérapeutiquement efficace d'un polypeptide de chémérine ou d'une molécule d'acide nucléique codant celui-ci.
PCT/EP2016/071275 2015-09-10 2016-09-09 Polypeptide de chémérine pour le traitement de la cachexie provoquée par le cancer WO2017042318A1 (fr)

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