WO2017046226A2 - Association pharmaceutique pour convertir une cellule néoplasique en cellule non-néoplasique et ses utilisations - Google Patents

Association pharmaceutique pour convertir une cellule néoplasique en cellule non-néoplasique et ses utilisations Download PDF

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WO2017046226A2
WO2017046226A2 PCT/EP2016/071792 EP2016071792W WO2017046226A2 WO 2017046226 A2 WO2017046226 A2 WO 2017046226A2 EP 2016071792 W EP2016071792 W EP 2016071792W WO 2017046226 A2 WO2017046226 A2 WO 2017046226A2
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WO2017046226A3 (fr
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Omar F. ZOUANI
Veronika GOCHEVA
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Histide Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G16B15/30—Drug targeting using structural data; Docking or binding prediction

Definitions

  • the invention relates to associations, combinations, compositions, kits, methods and processes for the design, preparation, manufacture and/or formulation thereof, and methods and uses thereof for converting or recoding a neoplastic cell into a non-neoplastic cell and treating and/or preventing a neoplastic disease.
  • Neoplastic cells such as cancer cells
  • neoplastic diseases are generally characterized by abnormal and/or uncontrolled proliferation leading, in most cases, to the development of a neoplastic disease, such as cancer.
  • Conventional methods for treating neoplastic diseases include surgical treatments, radiotherapy and chemotherapy.
  • Surgery is usually practised in order to extract localised (non-circulating) neoplastic cells from a patient's body and is most generally combined with radiotherapy treatments.
  • surgery is an invasive medical procedure which remains traumatic for the treated patient, involves the permanent removal of tissues or organs (which is sometimes not possible as some organs or organ parts are not accessible or cannot be removed due to life threatening consequences), in some cases has been shown to "unblock" dormant tumors, while only offering a "visual" selectivity to distinguish between healthy and tumor cells.
  • Radiotherapy also presents some significant drawbacks for the treated patients including the high cost of the radiation therapy equipment, the high cost of the treatment itself, side effects associated with the damage or destruction of healthy cells, limited effectiveness against metastasized neoplastic diseases, skin rashes caused by external beam radiation, the potential deleterious impact on the functioning of tissues, glands or organs located near the site of treatment, and the possible development of secondary cancers as a result of exposure to the radiations.
  • Conventional chemotherapy methods generally involve the administration of small synthetic regulatory molecules which inhibit specific intracellular target proteins thought to be responsible for the neoplastic phenotype of the cell.
  • One example is the inhibition of tyrosine kinase signal transduction by small molecule inhibitors to regulate uncontrolled cell proliferation.
  • Typical chemotherapy methods also include treatments wherein DNA is covalently altered by e.g. DNA strands crosslinking, or treatments wherein the polymerisation and depolymerisation of microtubules is enhanced prevented thus provoking apoptosis of the damaged cell.
  • Another method for treating neoplastic diseases includes gene therapy wherein a missing or defective gene is replaced with a functional, healthy copy, which is delivered to the target dysfunctional cells using a "vector.”
  • Gene transfer therapy can be done outside the body (ex vivo) by extracting bone marrow or blood from the patient and growing the cells in a laboratory. The corrected copy of the gene is then introduced and allowed to penetrate the cells' DNA before being injected back into the body. Gene transfers can also be done directly inside the patient's body (in vivo).
  • Gene therapy has been applied to a few specific cases of blood cancers (chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and multiple myeloma) through a particular form thereof in which the genetically modified cells were not the neoplastic cells themselves but instead the immune T-cells. Modified T-cells could then target and destroy specific blood cells (neoplastic as well as healthy). The body of the patient is then able to produce healthy blood cells and eventually provide a treatment to certain blood cancer types.
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphocytic leukemia
  • multiple myeloma multiple myeloma
  • Gene therapy is generally best suited for the treatment of diseases caused by a single defective gene, not neoplastic diseases, which often involve multiple defective genes.
  • neoplastic diseases using, for instance, micro-ribonucleic acids (miRNAs) or small interfering ribonucleic acids (siRNA).
  • miRNAs micro-ribonucleic acids
  • siRNA small interfering ribonucleic acids
  • the neoplastic cell is generally forced to down-regulate or repress the expression of one or more specific target genes (e.g. oncogenes) thus inhibiting the expression of defective and/or defecting proteins (e.g. oncoproteins).
  • specific target genes e.g. oncogenes
  • VEGF vascular endothelial growth factor
  • KSP kinesin spindle protein
  • Neoplastic diseases may also be treated using immunotherapy such as antibody therapies wherein the antibodies bind to a target antigen typically on the surface of the neoplastic cell.
  • Cell surface receptors are common targets for antibody therapies and include the epidermal growth factor receptor, HER2, CD52, the vascular endothelial growth factor-A and CD30.
  • an antigen e.g. a cancer antigen
  • antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor interacting with its ligand or deliver a payload of chemotherapy or radiation, which may all lead to the induction of neoplastic cell death.
  • Cetuximab is a chimeric lgG 1 monoclonal antibody that targets the extracellular domain of the epidermal growth factor receptor (EGFR). Once a ligand binds to the EGFR on the surface of the cell, signalling pathways are activated inside the cell that are associated with malignant characteristics such as cancer cell proliferation and invasion. Cetuximab competitively inhibits ligand binding, thereby preventing EGFR activation and subsequent cellular signalling. It also activates programmed cell death (apoptosis).
  • EGFR epidermal growth factor receptor
  • mRNAs messenger ribonucleic acids
  • Other intracellular treatments such as messenger ribonucleic acids (mRNAs) -based therapies have also been used in the treatment of neoplastic disease wherein administration of mRNA material into a neoplastic cell causes the neoplastic cell e.g. to express specifically encoded antigens and causing the neoplastic cell to be eliminated by the host immune system.
  • Differentiation therapy is another technique which was developed on the concept that the acquisition of the malignant phenotype (such as neoplasia) in a cell is considered as a progressive de-differentiation or a defective differentiation of that cell.
  • malignant phenotype such as neoplasia
  • tumor cell populations evolve to greater degrees of malignancy, they usually lose more and more differentiation markers.
  • differentiation therapy does not in fact induce cancer cells differentiation but instead restrains their growth thus allowing the application of more conventional therapies (such as chemotherapy) to eradicate the malignant cells.
  • Examples of differentiation therapy involve the forced (re- )expression of some specific micro-RNAs and thus rely on an intracellular action generally presenting the same drawbacks as in any other intracellular therapies such the siRNA and gene therapies.
  • a shortcoming of the medical therapies relying on previously reported methods of treatment are numerous and mainly resides in the incapacity of providing a sustainable therapeutic effect i.e. the treated cells are not healed but instead are either destroyed (e.g. through induced apoptosis) or their proliferation reduced or temporarily halted using a sustained administration of therapeutic molecules until, in most case scenarios, neoplastic cells are able to adapt themselves and render the therapy ineffective. Interrupting a known therapy will usually lead to resumption of the neoplastic cell state.
  • neoplastic cells having different invasiveness levels and/or of different lineage origins they may potentially "unblock" dormant tumors; they are often expensive; they may damage or destroy healthy cells alongside neoplastic cells thereby causing adverse treatment side effects; they may cause skin rashes and skin sensitivity; they may not target cancer stem cells as these are not proliferating; they may have a mutagenic action even towards healthy cells; they may require sustained administration to maintain treatment therapeutic effects; they may display very high cytotoxicity; they may cause multi-drug resistance whereby a drug having an intracellular action is no longer imported inside the cancer cell or is systematically exported outside of the cell.
  • the present invention thus provides associations, combinations, compositions, kits, methods and processes for the design, preparation, manufacture and/or formulation thereof, and methods and uses thereof for converting a neoplastic cell into a non-neoplastic cell including converting or recoding the neoplastic cell to induce, provide and/or reintroduce self-recovery or self-healing capabilities thereto.
  • FIG. 1 is a representation of a fluorescence intensity of non-covalent pharmaceutical associations comprising GFR-binding compounds and type-l collagen or apatite ceramics bioactive carriers according to certain embodiments of the present disclosure.
  • the images represent surfaces non-covalently coated with GFR-binding compounds of the present disclosure labeled with FITC.
  • FIG. 2 is (a) a representation of a fluorescence intensity of pharmaceutical associations comprising various GFR-binding compounds and type-l collagen immediately after association or 3, 7 and 10 days after association according to certain embodiments of the present disclosure.
  • the images represent surfaces non-covalently coated with GFR-binding compounds of the present disclosure labeled with FITC, (b) a total fluorescence intensity quantification of GFR-binding compounds labeled with FITC associated with apatite ceramics according to certain embodiments of the present disclosure after incubation in cell culture medium for the given indicated times (up to 10 days).
  • FIG. 3 is a representation of Quantitative Real Time PCR analysis of the expression of Sox-9, IBSP and Collagen-IV in neoplastic cells (chondrosarcoma cells) cultured on a native bioactive carrier (control) and on a bioactive carrier covalently associated with various GFR-binding compounds according to certain embodiments of the present disclosure after 24 hours of culture, (P ⁇ 0.001 ).
  • FIG. 4 is a diagram representing a relative quantification from western blot of the extent of phosphorylation of the pRB protein present in neoplastic cells cultured on a native bioactive carrier (control) and on a bioactive carrier covalently associated with various GFR-binding compounds according to certain embodiments of the present disclosure after 24 hours of culture.
  • FIG. 5 is a representation of a Quantitative Real Time PCR analysis of the expression of Cyclin D (average gene expression of Cyclin D1 , D2 and D3) at different time intervals during 24 hours in neoplastic cells (osteosarcoma cells) cultured on a native bioactive carrier (control) and on a bioactive carrier covalently associated with various GFR-binding compounds according to certain embodiments of the present disclosure.
  • FIG. 6 is a diagram representing the grafting or association density of various radiolabeled GFR-binding compounds covalently associated with a bioactive carrier according to certain embodiments of the present disclosure using radioactivity quantification.
  • FIG. 7 is a screen shot of the Standard Protein Blast online software used in the RMSD calculation procedure.
  • Neoplastic diseases start when a cell (or neoplastic cell) is somehow altered so that it multiplies out of control.
  • Tumors and cancers are some examples of neoplastic diseases.
  • a tumor is a mass composed of a cluster of such abnormal cells. Most cancers form tumors, but not all tumors are cancerous. Benign, or non-cancerous, tumors - such as freckles and moles - stop growing, do not spread to other parts of the body, and do not create new tumors. Malignant, or cancerous, tumors crowd out healthy cells, interfere with body functions, and draw nutrients from body tissues.
  • carcinoma is a type of cancer that develops from epithelial cells.
  • a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during embryogenesis.
  • Sarcoma is a cancer that arises from transformed cells of mesenchymal origin.
  • malignant tumors made of cancerous bone, cartilage, fat, muscle, vascular or hematopoietic tissues are, by definition, considered sarcomas.
  • This is in contrast to a malignant tumor originating from epithelial cells, which are termed carcinoma.
  • Human sarcomas are quite rare. Common malignancies, such as breast, colon, and lung cancer, are almost always carcinoma.
  • Melanoma is a type of skin cancer, which forms from melanocytes (pigment-containing cells in the skin).
  • Lymphoma is a group of blood cell tumors that develop from lymphocytes. It is sometimes used to refer to just the cancerous ones rather than all tumors. There are two main types: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), with two others, multiple myeloma and immunoproliferative diseases, also included by the World Health Organization within the category. Non-Hodgkin lymphoma makes up about 90% of cases and includes a large number of sub-types. Lymphomas are part of the broader group of neoplasms called tumors of the hematopoietic and lymphoid tissues.
  • Leukemia is a group of cancers that usually begins in the bone marrow and results in high numbers of abnormal white blood cells. These white blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising problems, feeling very tired, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically by blood tests or bone marrow biopsy.
  • Cancers include, but are not limited to, Adrenal Cancer, Anal Cancer, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain/CNS Tumors In Adults, Brain/CNS Tumors In Children, Breast Cancer, Breast Cancer In Men, Cancer in Adolescents, Cancer in Children, Cancer in Young Adults, Cancer of Unknown Primary, Castleman Disease, Cervical Cancer, Colon/Rectum Cancer, Endometrial Cancer, Esophagus Cancer, Ewing Family Of Tumors, Eye Cancer, Gallbladder Cancer, Gastrointestinal Carcinoid Tumors, Gastrointestinal Stromal Tumor (GIST), Gestational Trophoblastic Disease, Hodgkin Disease, Kaposi Sarcoma, Kidney Cancer, Laryngeal and Hypopharyngeal Cancer, Leukemia, Leukemia - Acute Lymphocytic (ALL) in Adults, Leukemia - Acute Myeloid (AML), Leukemia - Chronic Lymphocytic (CLL), Leukemia
  • GFR growth factor receptors
  • anti-Met e.g. ARQ-197
  • anti-VEGF e.g. Bevacizumab
  • anti-VEGFR e.g. Sunitinib or Semaxinib
  • anti-Her2 e.g. Trastuzumab
  • anti-EGFR e.g. Cetuximab, Gefitinib or Erlotinib
  • anti-PDGFR e.g. Imatinib
  • anti-IGF-1 e.g.
  • anti-Ras e.g. Tipifarnib
  • anti-Raf e.g. Sorafenib
  • anti-src e.g. Dastinib or Saracatinib
  • anti-Mek e.g. C1040 or PD-0325901
  • anti-PI3K e.g. LY294002
  • anti-PDK e.g. UNC01
  • anti-HSP90 e.g. 17-AGG or IPI-504
  • anti-CDK e.g. Flavopiridol
  • anti-mTOR e.g. Everolimus
  • neoplasms e.g. tumors or cancers
  • vertebrate cells such as mammalian cells, especially human cells
  • the present invention also aims at providing mechanisms for solving and/or avoiding at least one of, preferably a plurality of, the problems, issues and/or shortcomings associated with previously reported neoplasm treatment therapies.
  • Providing and/or producing a physiologically functional and/or healthy cell including an osteocyte and/or a chondrocyte and/or an adipocyte and/or a myocyte and/or a keratinocyte and/or a fibrocyte and/or a podocyte and/or a neurocyte and/or a mature endothelial cell and/or a osteoblast and/or a chondroblast and/or a neuroblast and/or a Sertoli cell and/or a Leydig cell and/or a germ cell and/or an endothelial cell and/or an angioblast and/or a fibroblast from a neoplastic cell , particularly within a shorter period of time;
  • Re-establishing, restoring and/or reactivating a cell adhesion checkpoint of a neoplastic cell Inducing and/or promoting and/or enhancing neoplastic cell differentiation, particularly within a shorter period of time;
  • articles such as “a”, “an”, and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 1 5%, 14%, 1 3%, 12%, 1 1 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less in either direction (greater than or less than) of the stated reference value unless otherwise indicated, self-evident or contradictory in context (e.g. except where such number would exceed 100% of a possible value).
  • Ci-alkyl is intended to specifically and individually disclose any branched or unbranched radical , moiety or functional group having "i" carbon atom(s).
  • (Ca-Cb)alkyl indicates an alkyl moiety of the integer "a” to the integer "b” carbon atoms, inclusive.
  • substituents of compounds of the present disclosure may be disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual sub-combination of the members of such groups and ranges.
  • the term "C1 -C5 alkyl” is an abbreviation for (and thus is specifically intended to individually disclose) C1 -alkyl (i.e. methyl), C2-alkyl (i.e. ethyl), C3-alkyl (i.e. 1 -propyl and 2-propyl), C4- alkyl (i.e.
  • alkyl and (Ca- Cb)alkyl refer to monovalent hydrocarbon radicals containing the requisite number of carbon atoms as described above, having straight or branched moieties or combinations thereof.
  • alkyl groups may be optionally substituted with between one to four substitutes.
  • Non-limiting examples of alkyl groups include, e.g. methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, t-butyl, etc.
  • alkyl groups will be readily apparent to those of skilled in the art given the benefit of the present disclosure.
  • a disclosed 0-10 range would, for example, in certain embodiments, also specifically and individually disclose the following values and ranges: 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 1 .1 , 1 .2, 1 .3, 1 .4, 1 .5, 1 .6, 1 .7, 1 .8, 1 .9, 2, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims using the appropriate disclaimer(s) or proviso(s). Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein .
  • Any particular embodiment of the compositions of the invention e.g. , any peptide or peptidomimetic; any method of production ; any method of use; etc.
  • molecular weights should be understood in the present description as being number averaged molecular weights.
  • the N-terminal amino acid of a peptide sequence may be the first amino acid in the sequence or the last amino acid.
  • the C-terminal amino acid of a peptide sequence may be the first amino acid in the sequence or the last amino acid.
  • NAIS N-terminal or C-terminal
  • S N-terminal or C-terminal. Consequently, for the purpose of the present disclosure, e.g. NAIS also covers SIAN , SAIS also covers SIAS, SPIN also covers N IPS, etc.
  • a certain peptide e.g. a GFR-binding compound as provided herein
  • said one or more other peptide(s) is(are) understood to be stably (in most cases, covalently) attached/bound to at least one part of said peptide.
  • the attachment/binding may be located anywhere on the peptide unless indicated otherwise, contradictory in context or contradictory to general scientific rules. No specific attachment/binding location of said one or more other peptide(s) to said peptide shall be assumed unless specifically mentioned.
  • Peptide or polypeptide As used herein, the term “peptide” or “polypeptide” are used interchangeably and refers to a polymer of less than or equal to 100 amino acids long , e.g ., about 2, 3, 4, 5, 1 0, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 1 00 amino acids long.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers, non- naturally occurring amino acid polymers, peptide analogs, peptide variants and peptide mimetics.
  • peptide analogs refers to polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions or deletions of amino acid residues that still maintain one or more of the properties of the parent or starting peptide.
  • Peptide variants As used herein, unless indicated otherwise or contradictory in context, the term "peptide variants" refers to a peptide which has a certain identity with a native or reference compound sequence. In one example, the peptide variant refers to any post- administration, application, injection modified peptide.
  • Such post- administration, application, injection modifications include, but are not limited to, phosphorylation, acetylation, glutamylation, tyrosination, palmitoylation, glycosylation, myristoylation, palmitoylation, isoprenylation, glypiation, lipoylation, phosphopantetheinylation, acylation, alkylation, amidation, arginylation, polyglutamylation, polyglycylation, butyrylation, gamma-carboxylation, glycosylation, polysialylation, malonylation, hydroxylation, iodination, nucleotide addition, oxidation, adenylylation, propionylation, pyroglutamate formation, S-glutathionylation, S-nitrosylation, succinylation, sulfation, glycation, biotinylation, pegylation, ISGylation, SUMOylation, ubiquitination,
  • peptido-mimetic refers to a synthetic chemical compound which comprises amino acids but not only and that is able to mimic the biological action of a peptide, often because the mimetic has a basic structure that mimics the basic structure of the peptide and/or has the salient biological properties of that peptide.
  • a peptidomimetic is a hybrid molecule containing both, at least one peptide, and at least one of a polysaccharide, a polynucleotide or a linear or branched, saturated or unsaturated, hydrocarbon chain.
  • Linear peptide As used herein, unless indicated otherwise or contradictory in context, the term "linear peptide” means a peptide in which the C-terminal and the N-terminal amino acid residues do not covalently interact with each other and none of the C-terminal or the N-terminal amino acid residues covalently interacts with another amino acid residue of the peptide chain.
  • Cyclic peptide As used herein, unless indicated otherwise or contradictory in context, the term "cyclic peptide” means peptide in which the C-terminal and N-terminal amino acid residues do covalently interact with each other or the C-terminal and/or the N-terminal amino acid residues covalently interact with at least one other amino acid residue of the peptide chain so as to form a ring-like structure.
  • amino acid refers to naturally occurring and non-naturally occurring amino acids including amino acid analogs.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, [gammaj-carboxyglutamate, and O-phosphoserine.
  • Naturally encoded amino acids are the 20 common amino acids glycine (Gly, G), alanine (Ala, A), valine (Val, V), leucine (Leu, L), isoleucine (lie, I), serine (Ser, S), threonine (Thr, T), phenylalanine (Phe, F), tyrosine (Tyr, Y), tryptophane (Trp, W), cysteine (Cys, C), methionine (Met, M), proline (Pro, P), aspartic acid (Asp, D), asparagine (Asn, N), glutamine (Gin, Q), glutamic acid (Glu, E), histidine (His, H), arginine (Arg, R) et lysine (Lys, K) and pyrrolysine and selenocysteine.
  • Non-naturally occurring amino acids include, but are not limited to, the dextrogyre (D) isomers of the above-cited naturally-occurring amino acids.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid i.e., an [alpha] carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group (i.e. side chain), and which may be used in replacement thereof without substantially affecting the overall function of the peptide to which it belongs.
  • Amino acid analogs that may be suitable for implementing embodiments of the present invention include, but are not limited to, amino acids comprising a photoactivatable cross-linker, spin-labeled amino acids, fluorescent amino acids, metal binding amino acids, metal-containing amino acids, radioactive amino acids, amino acids with novel functional groups, amino acids that covalently or noncovalently interact with other molecules, photocaged and/or photoisomerizable amino acids, amino acids comprising biotin or a biotin analogue, glycosylated amino acids such as a sugar substituted serine, other carbohydrate modified amino acids, keto-containing amino acids, amino acids comprising polyethylene glycol or polyether, heavy atom substituted amino acids, chemically cleavable and/or photocleavable amino acids, amino acids with an elongated side chains as compared to natural amino acids, including but not limited to, polyethers or long chain hydrocarbons, including but not limited to, greater than about 5 or greater than about 10 carbons,
  • amino acid side chain As used herein, unless indicated otherwise or contradictory in context, the term “amino acid side chain” means the functional group of an amino acid that differentiates it from other amino acids. All amino acid structures have a carboxyl group, an amine group and a specific side chain. AA 11 (AA roman numeral two): As used herein, unless indicated otherwise or contradictory in context, the terms “polar amino acid” or “AA 11 " means amino acids having a polar, non-charged group-containing side chain. Polar amino acids are protonated at physiological pH (about 7). Examples of polar amino acids include, but are not limited to, Cys (C), Asn (N), Gin (Q), Ser (S), Thr (T), or Tyr (Y).
  • AA 1 " (AA roman numeral three): As used herein, unless indicated otherwise or contradictory in context, the terms “acidic amino acid” or “AA 1 "” means amino acids having an acidic group-containing side chain. Acidic amino acid deprotonated forms predominate at physiological pH (about 7). Examples of acidic amino acids include, but are not limited to, Asn (N) and Glu (E). AA IV (AA roman numeral four): As used herein, unless indicated otherwise or contradictory in context, the terms “aliphatic amino acid” or “AA IV " means amino acids having an aliphatic side chain. Examples of aliphatic amino acids include, but are not limited to, Ala (A), Leu (L), lie (I), Gly (G), Val (V) and any analogs and derivatives thereof.
  • apolar amino acid or “AA V” means amino acids having an apolar side chain.
  • apolar amino acids include, but are not limited to, Ala (A), Phe (F), Gly (G), lie (I), Leu (L), Met (M), Pro (P), Val (V) or Trp (W).
  • AA VI (AA roman numeral six): As used herein, unless indicated otherwise or contradictory in context, the term "aromatic amino acid” or "AA VI " means amino acids having an aromatic group-containing side chain. Examples of aromatic amino acids include, but are not limited to, Trp (W), Tyr (Y) or Phe (F).
  • AA V (AA roman numeral seven):
  • basic amino acid or "AA VM” means amino acids having a basic group-containing side chain. Basic amino acid protonated forms predominate at physiological pH (about 7). Examples of basic amino acids include, but are not limited to, Arg (R), His (H), or Lys (K).
  • AA VI (AA roman numeral eight): As used herein, unless indicated otherwise or contradictory in context, the term “AA vm” means Leu (L) or lie (I) and any analogs and derivatives thereof. AA IX (AA roman numeral nine): As used herein, unless indicated otherwise or contradictory in context, the
  • charged amino acid or AA means amino acids having either an acidic group-containing side chain or an basic group-containing side chain. Charged amino acid charged forms predominate at physiological pH (about 7). Examples of charged amino acids include, but are not limited to, Asn (N), Glu (E), His (H), Lys (K) or Arg (R).
  • AA As used herein, unless indicated otherwise or contradictory in context, the term “AA n ", in which n is a positive integer arbitrarily chosen to identify a specific position within the primary sequence of a peptide. For instance, AA 13 means the amino acid of position 13.
  • amino acid and “AA” are interchangeably used in the present description.
  • N-terminal As used herein, unless indicated otherwise or contradictory in context, the term "N-terminal” means the amine (-NH 2 ) function/group/moiety located at one (terminal) end of a protein or polypeptide. This functional group is the only amine group which is not engage in n amide peptide bond.
  • C-terminal As used herein, unless indicated otherwise or contradictory in context, the term “C-terminal” means the carboxylate (-C0 2 H) function/group/moiety located at one (terminal) end of a protein or polypeptide. This functional group is the only carboxylic acid group which is not engage in n amide peptide bond.
  • Naturally-occurring peptide As used herein, unless indicated otherwise or contradictory in context, the terms “naturally-occurring peptide” or “natural peptide” means a peptide which may be found in nature without human direct intervention (except for its extraction and/or isolation).
  • Synthetic peptide As used herein, unless indicated otherwise or contradictory in context, the terms “synthetic peptide” or “non-natural peptide” means a peptide which may not be found in nature without human direct intervention (except for its extraction and/or isolation).
  • a synthetic peptide may have the amino acid sequence of a natural peptide except for at least one amino acid deletion or substitution relative to the natural sequence.
  • an amino acid from the natural sequence is replaced by another, different, naturally-occurring or non- naturally occurring amino acid.
  • a synthetic peptide may not possess a post-translational modification of the natural peptide such as the attachment of an acetate group, a phosphate group, a lipid, a carbohydrate, or the formation of a disulfide bridge.
  • Covalent interaction As used herein, unless indicated otherwise or contradictory in context, the term “interact covalently”, “covalent interaction” or “covalent bond” are interchangeably used and means a chemical bond or interaction that involves the sharing of electron pairs between atoms. Examples of such interactions are ⁇ -bonding and ⁇ -bonding.
  • Non-covalent interaction As used herein, unless indicated otherwise or contradictory in context, the term "interact non-covalently”, “non-covalent interaction” or “non-covalent bond” are interchangeably used and means a chemical bond or interaction that does not involve the sharing of electron pairs between atoms but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. Non-covalent interactions can be generally classified into four categories, electrostatic interactions, jt-interactions, van der Waals forces, and hydrophobic interactions.
  • Electrophile As used herein, unless indicated otherwise or contradictory in context, the term “electrophile” means an organic molecule attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons. Nucleophile: As used herein, unless indicated otherwise or contradictory in context, the term “nucleophile” means an organic molecule that donates an electron pair to an electrophile to form a chemical bond in relation to a reaction. All molecules or ions with a free pair of electrons or at least one pi bond can act as nucleophiles.
  • polysaccharide As used herein, unless indicated otherwise or contradictory in context, the term “polysaccharide” means polymeric carbohydrate molecules composed of long chains of monosaccharide units bound together by glycosidic linkages and which upon hydrolysis provide monosaccharides or oligosaccharides. They range in structure from linear to highly branched polymers.
  • polynucleotide refers to the phosphate ester polymeric form of ribonucleosides ("RNA molecules”) or deoxyribonucleosides ("DNA molecules”), or any phosphoester analogs thereof, such as phosphorothioates and thioesters, in either single stranded form, or a double-stranded helix.
  • RNA molecules ribonucleosides
  • DNA molecules deoxyribonucleosides
  • nucleic acid includes double-stranded DNA round, inter alia, in linear (e.g., restriction fragments) or circular DNA molecules.
  • nucleic acids as used herein refer to nucleic acids such as RNAs encoding for agonist of growth factor receptors as defined herein.
  • Nucleoside refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or derivative thereof in combination with an organic base (e.g. , a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”).
  • Nucleotide As used herein, the term “nucleotide” refers to a nucleoside including a phosphate group.
  • Dendrimer As used herein , unless indicated otherwise or contradictory in context, the term “dendrimer” means any repetitively branched molecules. Examples of dendrimers are phosphorous dendrimers, polylysine dendrimers, polypropylenimine dendrimers and PAMAM dendrimers, such as the ones described , for instance, in Scientific World Journal. 201 3; 2013:732340; Curr Opin Chem Biol. 1998; 2(6):733-42; J Pept Sci. 1999; 5(5):203-20; and J Pept Sci. 2008; 14(1 ):2-43, which may be used for implementing embodiments of the present invention , each of which being herein incorporated by reference in its entirety.
  • Synthetic molecule As used herein, unless indicated otherwise or contradictory in context, the term “synthetic molecule” means a molecule which may not be found in nature without human direct intervention (except for its extraction and/or isolation).
  • Synthetic polymers As used herein, unless indicated otherwise or contradictory in context, the term “synthetic polymer” refers to a macromolecule or polymer which may not be found in nature without human direct intervention (except for its extraction and/or isolation).
  • Biocompatible As used herein, unless indicated otherwise or contradictory in context, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system.
  • biologically active refers to a characteristic of any substance that has activity in a biological system and/or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active.
  • a compound, substance or pharmaceutical composition of the present disclosure may be considered biologically active even if a portion of the compound , substance or pharmaceutical composition is biologically active or mimics an activity considered biologically relevant.
  • Stem cells As used herein, unless indicated otherwise or contradictory in context, the term “stem cell” refers to the term as it is generally understood in the art.
  • stem cells regardless of their source, are cells that are capable of dividing and renewing themselves for long periods, are at least to a degree unspecialized (undifferentiated), and can give rise to (differentiate into) specialized cell types (i.e., they are progenitor or precursor cells for a variety of different, specialized cell types).
  • Mesenchymal stem cells As used herein, unless indicated otherwise or contradictory in context, the term "mesenchymal stem cells” generally means multipotent adult stromal cells that can differentiate into a variety of cell types, such as osteoblasts, chondrocytes, and adipocytes.
  • Stem cell-like refers to a cell which is not a stem cell by its origin but functions as a stem cell and presents similar characteristics such as, for example, the expression of sternness markers like Stro-1 and/or is multipotent thus has the ability to differentiate into various cell types.
  • Progenitor cells As used herein, unless indicated otherwise or contradictory in context, the term “progenitor cells” generally means a biological cell that, like any stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target” cell. Stem cells can generally replicate indefinitely, whereas progenitor cells can divide only a limited number of times.
  • Adult stem cells As used herein, unless indicated otherwise or contradictory in context, the term “adult stem cells” means undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile as well as adult animals and human bodies. Differentiation: As used herein, unless indicated otherwise or contradictory in context, the term “differentiation” refers to the process by which a less specialized cell becomes a more specialized cell type and involves a switch from one gene expression pattern to another.
  • Differentiated cells As used herein, unless indicated otherwise or contradictory in context, the term “differentiated cells” generally means any cell of a specific lineage at the exception of cells containing stem cell specific markers.
  • Non-terminally differentiated As used herein, unless indicated otherwise or contradictory in context, the term "non-terminally differentiated", when used in relation to a cell, refers to a differentiated cell as defined herein which has not reached its final state of differentiation.
  • a non-terminally differentiated cell in the Osteoblast cell lineage, is any differentiated cell of the lineage at the exception of an osteocyte.
  • Terminally differentiated refers to a differentiated cell as defined herein which has reached its final state of differentiation.
  • a terminally differentiated cell in the Osteoblast cell lineage, refers to a differentiated cell as defined herein which has reached its final state of differentiation.
  • a terminally differentiated cell in the Osteoblast cell lineage, refers to a differentiated cell as defined herein which has reached its final state of differentiation.
  • a terminally differentiated cell is an osteocyte.
  • Methods for obtaining stem cells Methods for obtaining such stem cells and providing initial culture conditions, such as a liquid culture or semi-solid culture medium, are known in the art. The cells are initially expanded in vivo or in vitro, by contacting the source of the stem cells with a suitable reagent that expands or enriches such cells in the tissue source or in culture.
  • adult stem cells are isolated from a tissue source and then expanded or enriched in vitro by exposure to a suitable agent.
  • Cells are obtained from an individual by any suitable method for obtaining a cell sample from an animal, including, but not limited, to, collection of bone marrow collection of a bodily fluid (e.g ., blood), collection of umbilical cord blood, tissue punch, and tissue dissection, including particularly, but not limited to, any biopsies of skin, intestine, cornea, spinal cord , brain tissue, scalp, stomach, breast, lung (e.g. , including lavage and bronchioschopy), fine needle aspirates of the bone marrow, amniotic fluid, placenta and yolk sac.
  • a bodily fluid e.g ., blood
  • umbilical cord blood e.g ., umbilical cord blood
  • tissue punch e.g., a cell punch
  • tissue dissection including particularly, but not limited to, any biopsies of skin, intestine, cornea,
  • Cell lineage refers to the developmental history of a particular cell from its primary state in the fertilized egg or embryo through to its fully differentiated state. The different steps and phases involved in the development of a cell produces many intermediate cells which may be referred to as progenitor or precursor cells in the present application and form an integral part of the cell lineage.
  • Bone It is conventionally known that mature osteoblasts are the cells responsible for bone formation and are derived from osteoblast precursors. Differentiation of human bone marrow mesenchymal stem cells and osteoblast precursors is one of the important processes for bone regeneration. Osteoblasts differentiate from mesenchymal stem cells. Mature osteoblasts differentiate from osteoblast precursors and into osteocytes which are non-dividing cells.
  • Bone-related neoplastic diseases include, but are not limited to, bone primary tumors (benign tumors or cancers) such as osteoma, osteoid osteoma, osteochondroma, osteoblastoma, enchondroma, giant cell tumor of bone, aneurysmal bone cyst, fibrous dysplasia of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, fibrosarcoma; and secondary tumors (i.e. metastasize) such as, for example, in certain embodiments, carcinomas of the prostate, breasts, lungs, thyroid, and kidneys.
  • bone primary tumors such as osteoma, osteoid osteoma, osteochondroma, osteoblastoma, enchondroma, giant cell tumor of bone, aneurysmal bone cyst, fibrous dysplasia of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, fibrosarcoma
  • Osteoblast cell lineage refers to bone cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, osteoblasts, osteocytes or any precursors thereof.
  • Cartilage Native chondrocytes are responsible for the synthesis and turnover of the cartilage extracellular matrix (ECM), which provides an environment of nutrition diffusion for chondrocytes and provides the joint surface with biomechanical competence. Chondrogenic cells arise from pluripotential adult mesenchymal stem cells (MSCs) through a series of differentiation pathways. Chondrogenic differentiation of MSCs is induced by various intrinsic and extrinsic factors. Growth factors play an important role in this process. For instance, in the hyaline cartilage, growth factors regulate homeostasis and integrity, as well as development.
  • ECM cartilage extracellular matrix
  • Cartilage-related neoplastic diseases include, but are not limited to, Chondroma/ecchondroma/enchondroma (Enchondromatosis, Extraskeletal chondroma), Chondrosarcoma (Mesenchymal chondrosarcoma, Myxoid chondrosarcoma), Osteochondroma (Osteochondromatosis), Chondromyxoid fibroma, and Chondroblastoma,
  • Chondrocytic cell lineage refers to cartilage cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, chondroblasts, chondrocytes or any precursors thereof.
  • Muscles Skeletal muscle is a highly complex and heterogeneous tissue serving a multitude of functions in the organism. The process of generating muscle - myogenesis - can be divided into several distinct phases. During embryonic myogenesis, mesoderm-derived structures generate the first muscle fibers of the body proper, and in subsequent waves additional fibers are generated along these template fibers. In the perinatal phase, muscle resident myogenic progenitors initially proliferate extensively but, later on, decrease as the number of myonuclei reaches a steady state and myofibrillar protein synthesis peaks. Once the muscle has matured, these progenitors will enter quiescence and henceforth reside within it as satellite cells.
  • Muscle-related neoplastic diseases include, but are not limited to, Rhabdomyosarcoma, and Leiomyosarcoma.
  • Muscle cell lineage refers to muscle cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, myoblasts, myocytes or any precursors thereof.
  • Vascular The vasculature in the human body forms through two distinct processes: vasculogenesis and angiogenesis.
  • Vasculogenesis is defined as the process of de novo blood vessel formation occurring when endothelial precursor cells (angioblasts) migrate and differentiate into endothelial cells which form the new vessel. These vascular trees are then extended through angiogenesis which is defined as the new vessel formation secondary to proliferation of endothelial cells from pre-existing vessels.
  • Vasculogenesis as well as angiogenesis occur during the embryologic development of the circulatory system but also in the adult organism from circulating endothelial progenitor cells (derivatives of stem cells) able to contribute, albeit to varying degrees, to neovascularization.
  • Vascular-related neoplastic diseases include, but are not limited to, Hemangiosarcoma, Kaposi's sarcoma, Lymphangiosarcoma, and Infantile hemangio-pericytoma.
  • vascular cell lineage refers to vascular cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, angioblast, pericytes and endothelial cells or any precursors thereof.
  • neural stem cells These are self-renewing, multipotent adult stem cells that generate the main phenotype of the nervous system. They undergo asymmetric cell division into two daughter cells, one non-specialized and one specialized. NSCs primarily differentiate into neurons, astrocytes, and oligodendrocytes. NSCs are generated throughout an adult's life via the process of neurogenesis. NSCs can be differentiated to replace lost or injured neurons or in many cases even glial cells. NSCs are stimulated to begin differentiation via exogenous cues from their microenvironment, or the neural stem cell niche.
  • NSCs neural stem cells
  • This niche defines a zone in which stem cells are retained after embryonic development for the production of new cells of the nervous system. This continual supply of new neurons and glia then provides the postnatal and adult brain with an added capacity for cellular plasticity.
  • Critical to the maintenance of the stem cell niche are microenvironmental cues and cell-cell interactions that act to balance stem cell quiescence with proliferation and to direct neurogenesis versus gliogenesis lineage decisions.
  • proteins like different growth factors are involved in the mechanisms of the neural stem cell niche as well as in the maintenance and growth of the newly formed neurons. These include the BMPs, FGFs, PDGF, VEGF, TGF ⁇ , BDNF and others.
  • Neuron-related neoplastic diseases include, but are not limited to, Anaplastic astrocytoma, Astrocytoma, Central neurocytoma, Choroid plexus carcinoma, Choroid plexus papilloma, Choroid plexus tumor, Dysembryoplastic neuroepithelial tumour, Ependymal tumor, Fibrillary astrocytoma, Giant-cell glioblastoma, Glioblastoma multiforme, Gliomatosis cerebri, Gliosarcoma, Hemangiopericytoma, Medulloblastoma, Medulloepithelioma, Meningeal carcinomatosis, Neuroblastoma, Neurocytoma, Oligoastrocytoma, Oligodendroglioma, Optic nerve sheath meningioma, Pediatric ependymoma, Pilocytic astrocytoma, Pinealoblastoma, Pineocytoma, Pleomorphic
  • Neuronal cell lineage refers to brain cells at any stage of their development and thus include, but are not limited to, neural stem cells, neuroblast, neurocyte and neuroglial cells or any precursors thereof.
  • Eye retina The vertebrate retina is a light-sensitive layer of tissue, lining the inner surface of the eye. Retinal development involves a complex progression of tissue induction, proliferation of retinal progenitor cell (RPC) populations and terminal differentiation of these cells into specific functional types.
  • Bone morphogenetic protein (BMP) is a member of the transforming growth factor (TGF) ⁇ family of signaling molecules plays an important role in the retinal cell development.
  • BMP-2, -4, and -7 and their receptors (BMPRs) are expressed in the eye during embryogenesis and are essential for multiple aspects of retinal development.
  • Retina-related neoplastic diseases include, but are not limited to, Retinoblastoma.
  • eye cancers can be primary (starts within the eye) and metastatic (spread to the eye from another organ).
  • the two most common cancers that would spread to the eyes from another organ are breast cancer and lung cancer.
  • Other, less common, sites of origin include prostate, kidney, thyroid, skin, colon and blood or bone marrow.
  • Retinal cell lineage refers to eye retina cells at any stage of their development and thus include, but are not limited to, photoreceptor, bipolar cells, rod and cone cells or any precursors thereof.
  • Kidneys The kidneys are composed of complex tissues consisting of several different cell types including glomerular podocytes, endothelial cells, mesangial cells, interstitial cells, tubular epithelial cells, and connecting duct cells. These cell types interact to establish a precise cellular environment that functions as an efficient tissue.
  • Kidneys-related neoplastic diseases include, but are not limited to, Squamous cell carcinoma, Juxtaglomerular cell, tumor (reninoma), Angiomyolipoma, Renal oncocytoma, Bellini duct carcinoma, Clear-cell sarcoma of the kidney, Mesoblastic nephroma, Wilms' tumor, Mixed epithelial stromal tumor, Clear cell adenocarcinoma, Transitional cell carcinoma, Inverted papilloma, Renal lymphoma, Teratoma, Carcinosarcoma, and Carcinoid tumor.
  • Renal cell lineage refers to renal cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, podocytes, or any precursors thereof.
  • T/L Tendons and ligaments
  • T/L are dense connective tissues of mesodermal origin. They connect and transmit force from muscle to bone and bone to bone, respectively. Both tissues are able to store elastic energy and withstand hightensile forces, on which locomotion is entirely dependent.
  • T/L are predominantly composed of collagen type I fibrils organized in a highly hierarchical manner that is unique for the T/L.
  • Other collagens types lll-VI, XI, XII, XIV, and XV
  • proteoglycans decorin, cartilage oligomeric matrix protein (COMP), byglican, lumican, fibromodulin, tenascin-C, etc.
  • L/T-related neoplastic diseases include, but are not limited to, Fibrosarcoma, Malignant fibrous, Hystiocytoma, and Dermatofibrosarcoma.
  • Ligament and tendon cell lineage refers to bone or cartilage cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, fibroblasts, fibrocytes, or any precursors thereof.
  • the skin constantly renews itself throughout adult life.
  • Stem cells (SCs) residing in the epidermis ensure the maintenance of adult skin homeostasis, but they also participate in the repair of the epidermis after injuries.
  • the skin protects the body from dehydration, injury and infection.
  • the skin consists of an underlying dermis, separated by a basement membrane from the multilayered overlaying epidermis.
  • the dermis is of mesodermal embryonic origin and contains as adult stem cells fibroblastic mesenchymal stem-cell-like cells. These cells have a multi-lineage differentiation potential, being also able to form adipose tissue or bones.
  • Skin-related neoplastic diseases include, but are not limited to, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumors, sebaceous carcinomas, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, and angiosarcoma.
  • Fibroblast lineage refers to skin cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, fibroblasts, keratinocytes, Merkel cells, melanocytes, Langerhans cells, and any precursor cells thereof.
  • Reproduction is the biological process by which new offspring individual organisms are produced from their parents.
  • Sexual reproduction is a biological process by which organisms create descendants that have a combination of genetic material contributed from two (usually) different members of the species.
  • the development and physiological functions of basic structures in the mammalian reproductive system are influenced by the tissue-specific expression of members of different growth factors families like the BMP family.
  • the establishment of the germ line is a fundamental aspect of reproduction.
  • Germ cell determination is induced in epiblast cells by the extraembryonic ectoderm, and is not acquired through the inheritance of preformed germ plasma.
  • BMP-4 and -8b play a central role in determining primordial germ cell (PGC) formation in the embryo.
  • BMP-4 and -8b have overlapping expression in the extraembryonic ectoderm before gastrulation, i.e., before PGCs are seen. Thus, PGC formation requires BMP-4 expression. There is also evidence from knockout mammals that BMP-8b is required for PGC formation. Furthermore, there is increasing evidence that locally produced BMPs play a major role in the differentiation of the pituitary gonadotrope.
  • Reproduction-related neoplastic diseases include, but are not limited to, Prostate cancer, Ovary cancer (adenocarcinoma, or glandular cancer) also known as carcinoma of the prostate or prostatic intraepithelial neoplasia.
  • Reproduction system lineage As used herein, unless indicated otherwise or contradictory in context, the term “reproduction system lineage” refers to Sertoli cells, Leydig cell and Germ cell at any stage of their development, in particular, mesenchymal stem cells.
  • Blood is a bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those cells. When it reaches the lungs, gas exchange occurs wherein carbon dioxide is diffused out of the blood into the alveoli and oxygen is diffused into the blood. This oxygenated blood is pumped to the left hand side of the heart in the pulmonary vein and enters the left atrium. From here it passes through the bicuspid valve, through the ventricle and taken all around the body by the aorta. Blood contains antibodies, nutrients, oxygen and much more to help the body work. In vertebrates, it is composed of blood cells suspended in blood plasma.
  • Plasma which constitutes 55% of blood fluid, is mostly water (92% by volume), and contains dissipated proteins, glucose, mineral ions, hormones, carbon dioxide (plasma being the main medium for excretory product transportation), and blood cells themselves.
  • Albumin is the main protein in plasma, and it functions to regulate the colloidal osmotic pressure of blood.
  • Hematopoietic stem cells are the blood cells that give rise to all the other blood cells and are derived from the mesoderm. They are located in the red bone marrow, which is contained in the core of most bones.
  • the HSCs give rise to the myeloid lineage (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and to the lymphoid lineages (T-cells, B-cells, NK-cells).
  • the most abundant cells in the vertebrate blood are red blood cells (also called RBSs or erythrocytes). These contain hemoglobin, an iron-containing protein, which facilitates oxygen transport by reversibly binding to this respiratory gas and greatly increasing its solubility in blood.
  • Blood-related neoplastic diseases include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • Blood cell lineages refers to blood cells at any stage of their development from the myeloid or from the lymphoid lineage, and thus include, but are not limited to, hematopoietic stem cells (HSC), myeloid progenitors, lymphoid progenitors, mast cells, myeloblasts, monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes, thrombocytes, dendritic cells, small lymphocytes, T-lymphocytes (T-cells), B-lymphocytes (B-cells), natural killer (NK)-cells, and any precursor cells thereof.
  • HSC hematopoietic stem cells
  • myeloid progenitors myeloid progenitors
  • lymphoid progenitors mast cells
  • myeloblasts monocytes
  • macrophages neutrophils
  • basophils basophils
  • eosinophils neutrophils
  • Adipose tissue is loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells (i.e. adipose tissue macrophages (ATMs)). Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Pre-adipocytes are thought to be undifferentiated fibroblasts that can be stimulated to form adipocytes.
  • SVF stromal vascular fraction
  • the pre-adipocytes originate from mesenchymal stem cells.
  • Areolar connective tissue is composed of adipocytes.
  • the term “lipoblast” is used to describe the precursor of the adult cell.
  • the term “lipoblastoma” is used to describe a tumor of this cell type.
  • Adipose tissue-related neoplastic diseases include, but are not limited to, lipoma, Adenolipomas, Angiolipoleiomyomas, Angiolipomas, Corpus callosum lipoma, Cerebellar pontine angle and internal auditory canal lipomas, Chondroid lipomas, Hibernomas, Intradermal spindle cell lipomas, Neural fibrolipomas, Pleomorphic lipomas, Spindle-cell lipomas, Superficial subcutaneous lipomas, Lipoblastoma, Liposarcoma.
  • Adipocyte lineage refers to adipocyte cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, areolar connective cells, adipocytes, pre- adipocytes/lipoblasts, and any precursor cells thereof.
  • Digestive system The human digestive system is composed mainly of the gastrointestinal tract (including the esophagus, stomach, small intestine, large intestine, rectum and anus) and the accessory digestive glands (the liver, the gall bladder and the pancreas).
  • the gastrointestinal wall refers to the specialized series of tissue layers surrounding the lumen of the gastrointestinal tract.
  • the general structure involves the four following layers (ordered from the lumen outward): mucosa, submucosa, muscularis externa, serosa (if the tissue is intraperitoneal) / adventitia (if the tissue is retroperitoneal).
  • Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract (Gl tract) and accessory organs of digestion.
  • the symptoms relate to the organ affected and can include obstruction (leading to difficulty swallowing or defecating), abnormal bleeding or other associated problems.
  • Gastrointestinal tissue-related neoplastic diseases include, but are not limited to, Esophageal cancer, Stomach cancer, Pancreatic cancer, Liver cancer, Gallbladder cancer, MALT lymphoma, Gastrointestinal stromal tumors and Cancers of the biliary tree, including cholangiocarcinoma.
  • Gastrointestinal cell lineages refers to gastrointestinal cells and cells of the digestive accessory organs at any stage of their development and thus include, but are not limited to interstitial cells of Cajal, gastrointestinal epithelial cells, parietal cells, acinar cells, chief cells, mucus cells, goblet cells, G cells, endocrine I cells, endocrine S cells, endocrine K cells, endocrine M cells, ECL (enterochromaffin) cells, D cells, enteroendocrine cells, APUD cells, hepatocytes, sinusoidal hepatic endothelial cells, Kupffer cells, hepatic stellate cells, centroacinar cells, pancreatic stellate cells, a-cells, ⁇ -cells, ⁇ -cells, centroacinar cells, basophilic cells, ductal cells, columnar cells,
  • Lung The lung is the essential respiration organ in many air-breathing animals. In mammals the two lungs are located near the backbone on either side of the heart. Their principal function is to transport oxygen from the atmosphere into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere. A large surface area is needed for this exchange of gases, which is accomplished by the mosaic of specialized cells that form millions of tiny, exceptionally thin-walled air sacs called alveoli.
  • Lung cells include, but are not limited to, type I pneumocytes, type II pneumocytes, clara cells and goblet cells.
  • Lung tissue-related neoplastic diseases include, but are not limited to, lung cancer also known as carcinoma of the lung or pulmonary carcinoma, Epithelial cells or small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC).
  • Lung cell Lineages refers to lung cells at any stage of their development and thus include, but are not limited to, epithelial cells, erythrocytes, alveolar cells and any precursor cells thereof.
  • Head and neck cancer refers to a group of cancers that usually starts in the lip, oral cavity, nasal cavity, paranasal sinuses, pharynx, and larynx. About 90% of head and neck cancers are squamous cell carcinomas.
  • neoplastic diseases such as head and neck cancers include, but are not limited to, oral cancer, nasopharynx cancer, oropharyngeal cancer, hypopharynx cancer and laryngeal cancer.
  • the cell lineage involved in head and neck cancers includes all the cells involved in the formation of such cancers at any stage of their development and thus include, but are not limited to, cells of the oral cavity, cells of the pharynx, cells of the larynx, cells of the paranasal sinuses and nasal cavity, cells of the salivary glands and any precursor cells thereof.
  • ratio when used in relation to GFR-binding compound with respect to the bioactive carrier in the pharmaceutical association or composition disclosed herein, refers to the (molar, weight or part as specified) ratio between the quantity of GFR-binding compound and the quantity of bioactive carrier.
  • the ratio may be a molar ratio, a weight ratio or a part ratio and will be specified as needed on a case by case basis.
  • Quantity units may conventionally be mole, millimole, gram, milligram or parts.
  • Density when used in relation to GFR-binding compound with respect to the bioactive carrier in the pharmaceutical composition disclosed herein , refers to the quantity of GFR-binding compounds, expressed in e.g. mole, millimole, gram, or milligram, with respect to one standardised surface unit e.g. squared millimetre (mm 2 ), squared micrometre ( ⁇ 2 ), or squared nanometre (nm 2 )).
  • the ratio between a GFR-binding compound and a bioactive carrier in the pharmaceutical association or composition disclosed herein may be expressed in pmol per mm 2 or pmol/mm 2 .
  • cell cycle refers to the process through which a vertebrate cell self-replicate.
  • cell cycle consists of four discrete phases: G 1 , S, G2, and M . Together, the G 1 , S, and G2 phases make up the period known as interphase.
  • G 1 , S, and G2 phases make up the period known as interphase.
  • S or "synthesis” phase the cell replicates its DNA creating an exact copy of all of its chromosomes.
  • M or “mitotic” phase the cell division actually occurs and separates the chromosomes in its cell nucleus into two identical sets in two nuclei.
  • the first phase within interphase from the end of the previous M phase until the beginning of DNA synthesis, is called G1 .
  • the G2 phase or pre-mitotic phase, is the third and final sub-phase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase and ends with the onset of prophase, the first phase of mitosis. In order to move from one phase of the cell cycle to the next, a cell must "validate" numerous checkpoints.
  • specialized proteins determine whether the necessary conditions exist. If so, the cell is free to enter into the next phase. If not, progression through the cell cycle is halted. For example, in certain embodiments, during G 1 , the cell passes through a "validation" window punctuated by the restriction point R. During the "validation" phase, different checkpoints ensure that environmental conditions are favourable for replication. If conditions are not favourable, the cell may enter a resting state known as GO.
  • the GO phase or resting phase is a period in the cell cycle in which cells exist in a quiescent state. GO phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle.
  • a healthy vertebrate cell undergoes cell division when needed e.g. to regenerate damaged tissues or simply replace old tissues by new ones, by switching from a GO resting state into the G1 state of the cell cycle and resume cell division.
  • neoplastic cells such as cancer cells
  • Another “validation” window takes place later in the cell cycle, just before a cell moves from G2 to mitosis.
  • a number of proteins scrutinize the cell's DNA ensuring proper replication has taken place.
  • another cell cycle “validation” window takes place during mitosis in which different checkpoints determines whether chromosomes are correctly attached to the spindle, and to the network of microtubules that will separate them during cell division.
  • quiescence when used in relation to a cell, refers to a resting state during which the cell does not divide, duplicate or proliferate. This state is also called the GO state.
  • inducing quiescence of a neoplastic cell thus means to provoke the passage from G1 to GO of a neoplastic cell which usually has lost the ability to do so.
  • One method to detect the passage from G1 to GO is, for instance, to monitor the state of phosphorylation of the protein Rb via Western Blot.
  • the Rb protein is normally not phosphorylated during the GO phase but becomes phosphorylated or even hyper- phosphorylated during the rest of the cell cycle.
  • Cell division or cell proliferation refers to the process by which a cell self-replicate, replicate or is caused to replicate.
  • Proliferate As used herein, unless indicated otherwise or contradictory in context, the term “proliferate” means to grow, expand or increase or cause to grow, expand or increase. “Proliferative” means having the ability to proliferate. “Anti-proliferative” means having properties to counter, reduce, or inhibit proliferation.
  • Hyperproliferation As used herein, unless indicated otherwise or contradictory in context, the term “hyperproliferation” or “uncontrolled proliferation” means the abnormal growth, expansion or increase or causing the abnormal growth, expansion or increase. Abnormal growth typically originates from the abnormal regulation of the cell cycle preventing the cell to reach the GO state and stop cell division and replication. One consequence of hyper or uncontrolled proliferation is the development of neoplastic diseases such as tumours and cancers. Hyperproliferative diseases: As used herein, unless indicated otherwise or contradictory in context, the term “hyperproliferative diseases” is used interchangeably with “neoplastic diseases” and refers to diseases that are characterized by uncontrolled cellular proliferation and/or disruption in programmed cell death.
  • Anti-mitogen activity refers to biological pathways that down-regulate, partially inhibit or suppress cell mitosis i.e. cell division.
  • a substance or pharmaceutical association which promotes, induces or favours anti-mitogen activity thus means a substance or pharmaceutical association which provides at least part of its effective biologic or therapeutic action by down-regulating, partially inhibiting or suppressing mitosis of the neoplastic cell to be treated.
  • Tumor suppressor pathways refers to biological pathways that down-regulate, partially inhibit or suppress tumor activity i.e. protect the cell against cell defects which could cause tumors or cancers.
  • a substance or pharmaceutical association which promotes, induces or favours tumor suppressor pathways thus means a substance or pharmaceutical association which provides at least part of its effective biologic or therapeutic action by up-regulating, activating or promoting the tumor suppressor genes or proteins of the neoplastic cell to be treated.
  • tumor suppressor proteins which have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis include, but are not limited to, p53, pRb, pVHL, APC, CD95, ST5, YPEL3, ST7, and ST14.
  • Anti-oncogenic activity refers to any molecule having the ability to inhibit, repress or down-regulate the gene or protein expression of oncogenes.
  • An oncogene is a gene that has the potential to cause neoplastic diseases such as cancer.
  • Examples of anti-oncogene molecules include tumor suppressor proteins.
  • a neoplastic disease such as cancer
  • a neoplastic cell is treated without inducing the entry of the neoplastic cells into apoptosis as it may be assessed by the positive expression of proteins caspase 3, 6 and 7.
  • Non-mutagenic As used herein, unless indicated otherwise or contradictory in context, the term “non- mutagenic”, when used in relation to a therapy or treatment, refers to a therapy which does not involve the alteration or modification of a cell's genome.
  • Recoding As used herein, unless indicated otherwise or contradictory in context, the term “recoding” or “converting”, when used in relation to a cell (in particular a neoplastic cell such as a cancer cell), refers to the action of providing, to a neoplastic cell to be treated, a suitable extracellular micro-environment (e.g. in the form of a pharmaceutical association or composition as defined herein) providing appropriate extracellular signals so that the cell may undergo self-recovery or -healing and be converted into a partially or fully differentiated non-neoplastic cell.
  • a suitable extracellular micro-environment e.g. in the form of a pharmaceutical association or composition as defined herein
  • Recoding therapy refers to a therapy that promotes and stimulates the cell's natural abilities to redirect its own fate by integrating accurate micro-environmental recoding signals.
  • Extracellular micro-environment refers to the environment surrounding (in functional proximity with) a specific cell which is characterized by biophysical, mechanical and biochemical properties specific for each tissue and is able to regulate cell behavior. Modification of the extracellular micro-environment of a neoplastic cell using, for instance, pharmaceutical associations or compositions as defined herein allows for the conversion or recoding of said neoplastic cell into a healthy, functional , non-neoplastic cell.
  • Self-recovery or self-healing when used in relation to a neoplastic cell such as a cancer cell , means that the neoplastic cell operates its own internal biological changes once it has been recoded or treated using a pharmaceutical association or composition as defined herein, so that it becomes a functional, healthy, non-neoplastic cell.
  • the cell heal itself when in contact with the pharmaceutical composition or association as defined herein and, in contrast with previously reported methods wherein the neoplastic cell is forced to die or maintained in a temporarily reduced or non-proliferative state.
  • Physiologically functional cell refers to a cell which is able to perform normally all of the cell functions associated with a particular cell type and necessary for the normal physiology of a cell. These functions include all of the intracellular molecular mechanisms but also all of the activities necessary for a normal communication between the cell and its microenvironment.
  • One method which may be used to verify if a cell is physiologically functional is the grafting of the cell, after the introduction of fluorescent markers, in other mammalian model organisms such as mouse models. The cell is grafted in the tissue corresponding to its cell type.
  • the cell characteristics and normal functions are monitored after a period of time with various methods such as in vivo microscopy or histological staining .
  • the term "functional" when used in relation to a molecule, compound or substance refers to a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized .
  • Healthy cell As used herein, unless indicated otherwise or contradictory in context, the term “healthy cell” refers to a cell which presents a normal morphology, normal cell functions and normal cell growth which are not damaged, altered or inactivated by a neoplastic disease.
  • Shorter period of time when used in relation to conversion or recoding duration, means substantially shorter to provide a substantial benefit for the treated patient in comparison with existing treatments.
  • a shorter period of time includes at least 1 .5-fold , at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 6-fold , at least 7-fold, at least 8-fold, at least 9-fold or at least 1 0-fold reduction with respect to an existing treatment.
  • exogenous refers to a substance coming from outside a living system such as a cell, an organ , or an individual organism.
  • exogenous factors in medicine include pathogens and therapeutics.
  • DNA introduced into a cell via transfection or viral infection may be considered as an exogenous factor.
  • Carcinogens are also commonly referred to as exogenous factors.
  • Endogenous refers to substances that originate from within an organism, tissue, or cell.
  • Intracellular As used herein, unless indicated otherwise or contradictory in context, the term “intracellular” generally means “inside the cell”. In vertebrates, such as animals, the cell membrane is the barrier between the inside of the cell and the outside of the cell (the extracellular milieu). Thus, treatments and therapies in which at least one substance, compound, pharmaceutical association , combination or composition penetrates the cell wall of a cell to be treated in order to produce/deliver its (effective) biological effect are considered as intracellular treatments and therapies.
  • Extracellular As used herein, unless indicated otherwise or contradictory in context, the term “extracellular” means “outside the cell”. In vertebrates, such as animals, the cell membrane is the barrier between the inside of the cell (the intracellular milieu) and the outside of the cell. Thus, treatments and therapies in which no substance, compound, pharmaceutical association, combination or composition requires penetration of the cell membrane in order to produce/deliver its (effective) biological effect (e.g. by interacting with trans-membrane receptors) are considered as extracellular treatments and therapies.
  • Cytostatic refers to inhibiting , reducing , or suppressing the growth, division, or multiplication of a cell (e.g., a mammalian cell (e.g. , a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.
  • Cytotoxic refers to killing or causing injurious, toxic, or deadly effect on a cell (e.g., a mammalian cell (e.g. , a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.
  • in vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel , in cell culture, in a Petri dish , etc. , rather than within an organism (e.g. , animal, plant, or microbe).
  • in vivo refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).
  • Ex vivo refers to events that occur in an external environment on tissues sourced from an organism (e.g., animal, plant, or microbe) in an attempt to replicate natural living conditions outside such an organism.
  • an organism e.g., animal, plant, or microbe
  • syndecans refers to single transmembrane domain proteins that are thought to act as co-receptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1 . Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin C.
  • the syndecan protein family has four members.
  • Syndecans 1 and 3 and syndecans 2 and 4 making up separate subfamilies, arose by gene duplication and divergent evolution from a single ancestral gene.
  • the syndecan numbers reflect the order in which the cDNAs for each family member were cloned. All syndecans have an N-terminal signal peptide, an ectodomain, a single hydrophobic transmembrane domain, and a short C-terminal cytoplasmic domain . All syndecans are anchored to plasma membrane via a 24-25 amino acid long hydrophobic transmembrane domain . In mammalian cells, syndecans are expressed by unique genes located on different chromosomes. All members of the syndecan family have 5 exons.
  • the difference in size of the syndecans is credited to the variable length of exon 3, which encodes a spacer domain.
  • the amino acid length of syndecan 1 , 2, 3 and 4 is 310, 201 , 346 and 198 respectively.
  • Glycosaminoglycan chains a member of the heparan sulfate group, are an important component of syndecans and are responsible for a diverse set of syndecan functions. The addition of glycosaminoglycans to syndecan is controlled by a series of post- translational events.
  • Cyclin-dependent kinases As used herein, unless indicated otherwise or contradictory in context, the term “Cyclin-dependent kinases” or “CDKs” refers to a family of protein involved in the regulation of the cell cycle. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved . By definition, a CDK binds a regulatory protein called a cyclin. It is reported that, without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is considered to be an active kinase.
  • CDKs phosphorylate their substrates on serines and threonines, so they can be said to belong to the serine-threonine kinase family.
  • CDKs and cyclins are thus highly conserved across species and are present in all cell types including those having a neoplastic phenotype (e.g. cancer cells). Most of the known cyclin-CDK complexes regulate the progression through the cell cycle.
  • Animal cells contain at least nine CDKs, four of which, CDK 1 , 2, 3, 4 and 6, are reported to be directly involved in cell cycle regulation: CDK1 regulated by cyclin A, cyclin B; CDK2 regulated by cyclin A, cyclin E; CDK3 regulated by cyclin C; CDK4 regulated by cyclin D1 , cyclin D2, cyclin D3; CDK5 regulated by CDK5R1 , CDK5R2; CDK6 regulated by cyclin D1 , cyclin D2, cyclin D3; CDK7 regulated by cyclin H ; CDK8 regulated by cyclin C; CDK9 regulated by cyclin T1 , cyclin T2a, cyclin T2b, cyclin K.
  • CDK1 regulated by cyclin A, cyclin B CDK2 regulated by cyclin A, cyclin E
  • CDK3 regulated by cyclin C CDK4 regulated by cyclin D
  • Cyclins As used herein, unless indicated otherwise or contradictory in context, the term “cyclins” refers to a family of proteins that control the progression of cells through the cell cycle by activating cyclin- dependent kinase (CDK) enzymes. Cyclin D is one of the major cyclins produced in terms of its functional importance. It is known to interact with four CDKs: CDK2, 4, 5, and 6. In proliferating cells, cyclin D- CDK4/6 complex accumulation is of great importance for cell cycle progression. For instance, cyclin D- CDK4/6 complexes partially phosphorylates retinoblastoma tumor suppressor protein (Rb), whose inhibition can induce expression of some genes important for S phase progression.
  • Rb retinoblastoma tumor suppressor protein
  • patient/subject refers to any organism to which a composition in accordance with the invention may be administered, e.g. , for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and humans
  • patients/subjects include those individuals who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition.
  • purify means to make substantially pure or clear from unwanted components, material defilement, admixture or imperfection.
  • Targeted cells refers to any one or more cells of interest.
  • the cells may be found in vitro, in vivo, in situ or in the tissue or organ of an organism.
  • the organism may be an animal, preferably a mammal, more preferably a human and most preferably a patient.
  • Molecule length As used herein, unless indicated otherwise or contradictory in context, the term molecule or peptide "length” or “size” means the longest 2D or 3D distance which may possibly be measured within the molecule. For cyclic molecules, “length” or “size” means the longest measurable distance across the cyclic structure. Throughout the present disclosure, when a molecule size or length is given (in general using the nanometre, nm, unit), the following procedures were used to calculate them:
  • Root Mean Square Deviation As used herein, unless indicated otherwise or contradictory in context, the term "Root Mean Square Deviation” or “RMSD” is well known in the art and means the square root of the arithmetic mean of the square of the distances between certain matched atoms.
  • RMSD Root Mean Square Deviation
  • x and y each one of them must be represented as a 3N-length (assuming N atoms) vector of coordinates.
  • the RMSD is therefore the square root of the arithmetic mean of the square of the distances between corresponding atoms of x and y. It is a measure of the average atomic displacement between the conformations of the two structures:
  • the RMSD is the measure of the average distance between the atoms (usually the backbone atoms) of superimposed polypeptides or peptidomimetics.
  • the RMSD is the measure of the average distance between the atoms (usually the backbone atoms) of superimposed polypeptides or peptidomimetics.
  • the RMSD value of a given peptide or peptidomimetic with respect to a specifically selected reference structure may be calculated using various methods all well know by the skilled person. However, for the purpose of the present disclosure and for the avoidance of doubts, the RMSD of a given peptide or peptidomimetic as used in the present disclosure is obtained precisely using the following procedure:
  • STEP 1 Creating a 3-dimensional model of (i.e. obtaining 3D structure coordinates for) a peptide or peptidomimetic for which the RMSD is to be calculated, by:
  • STEP 1 .1 Obtaining a set of polypeptide 3D structure coordinates based on the alignment with the sequence of a peptide or peptidomometic for which the RMSD value is to be calculated , using the BLAST algorithm according to the following procedure:
  • blastp protein-protein BLAST
  • the set of pdf files contains the polypeptide 3D structure coordinates of the 10 structures having the highest sequence homology with the peptide or peptidomometic for which the RMSD value is to be calculated .
  • STEP 1 .2 Performing the structural alignment of the set of 3D structure coordinates obtained in STEP 1 .1 , thereby obtaining a set of aligned polypeptide 3D structure coordinates, by using STAMP (Structural Alignment of Multiple Proteins Version 4.2) according to the following procedure:
  • STEP 1 .3 Modelling the sequence of peptide or peptidomometic for which the RMSD value is to be calculated against the set of aligned polypeptide 3D structure coordinates obtained in STEP 1 .2, thereby obtaining a set of 3D structure coordinates for the peptide or peptidomometic for which the RMSD value is to be calculated, using SCWRL (reference: "SCWRL and MollDE: computer programs for side-chain conformation prediction and homology modeling", Nature Protocols VOL.3 NO.12 2008, Qiang Wang et al.; which is hereby incorporated by reference in its entirety) according to the following procedure:
  • a first PBD file is obtained containing the predicted 3D structure coordinates of the peptide or peptidomometic for which the RMSD value is to be calculated.
  • STEP 1 .4 Minimizing the free energy (AG) of the set of 3D structure coordinates for the peptide or peptidomometic for which the RMSD value is to be calculated obtained in STEP 1 .3 using GROMACS (Reference: Hess B, Kutzner C, Van Der Spoel D, Lindahl E (2008). "GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation". J Chem Theory Comput 4 (2): 435; which is hereby incorporated by reference in its entirety) according to the following procedure:
  • the structure of lowest energy is obtained from each XMG file in the form of a PDB file. 10 PDB files each containing one structure of lowest energy are thus obtained from STEP 1 .4 for use in the next step.
  • STEP 2 Calculating the RMSD of the peptide or peptidomimetic for which the RMSD value is to be calculated by comparing the 3D structure coordinates of the peptide or peptidomimetic obtained in STEP 1 .4 with the 3D structure coordinates of PEPREF to obtain the lowest possible RMSD value using FATCAT (Flexible structure AlignmenT by Chaining Aligned fragment pairs allowing Twists) according to the following procedure:
  • the peptide or peptidomimetic structure with the lowest RMSD (out of the ten RMSD values successively obtained) is the value taken into account in the present application.
  • 3D structure coordinates of PEPREF As used herein, unless indicated otherwise or contradictory in context, the 3D structure coordinates of PEPREF are as follows:
  • Structure coordinates refers to Cartesian coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of a protein, protein complex or peptide in crystal form.
  • the diffraction data are used to calculate an electron density map of the repeating unit of the crystal.
  • the electron density maps are then used to establish the positions of the individual atoms of the molecule or molecular complex.
  • STAMP Structure Alignment of Multiple Proteins
  • STAMP Structure Alignment of Multiple Proteins
  • SCWRL This program predicts and optimizes the protein side-chain conformations. It is using the backbone of a support protein and a backbone-dependent rotamer library. The possible conformations are explored by minimizing the steric hindrance between the side-chains and between the side-chains and the backbone.
  • GROMACS is a molecular dynamics package.
  • the "gmx rms" tool included in GROMACS compares two structures by computing the root mean square deviation (RMSD).
  • RMSD root mean square deviation
  • the term "pharmaceutical association” or “pharmaceutical combination” as used herein refers to a compound or substance comprising at least two components, i.e. a (modified) GFR-binding compound and a bioactive carrier, linked, connected or bound through at least one covalent or non-covalent link, connection or bond.
  • the present disclosure provides for non-mutagenic extracellular therapies having the ability to direct cell fate. It is thus possible to convert or recode a neoplastic cell by modifying its surrounding extracellular micro-environment, in-vitro, ex-vivo or in-vivo, so that the cell operates self-recovery or self- healing and a subject possessing such a neoplastic cell may be protected from a neoplastic disease.
  • a neoplastic cell may operate self-recovery or self-healing e.g. by inducing a quiescence state so that the neoplastic cell may remain inactive or dormant for seconds, minutes, hours, days, weeks, months or years, in particular, will never resume neoplasia; and/or by preventing, reducing or suppressing cell division and/or cell proliferation, preferably uncontrolled cell division and/or cell proliferation of said neoplastic cell; and/or by regulating or promoting anti-mitogen activity and/or tumour suppressor pathways and/or anti-oncogenic activity in said neoplastic cell; and/or by inducing cytostaticity and not cytotoxicity in the neoplastic cell; and/or by inducing differentiation; and/or by regulating and/or modulating the adhesion or interactions between the cell and its micro-environment (i.e. the surrounding ECM) so as activate, reactivate or restore cell adhesion checkpoints in said
  • the present disclosure provides a pharmaceutical association or combination having the ability to convert or recode, extracellularly, a neoplastic cell, in-vitro, ex-vivo or in-vivo, so that it may be used in the treatment, prevention and/or diagnostic of a neoplastic disease, said association comprising at least one growth factor receptor-binding compound which activates at least one growth factor receptor of a neoplastic cell and at least one bioactive carrier which forms at least one covalent or non-covalent association with said at least one growth factor receptor-binding compound, and wherein said association reduces or suppresses (i) the gene expression of at least one cyclin D in the neoplastic cell and/or (ii) reduces or suppresses the formation of at least one complex formed between said at least one cyclin D and at least one of cyclin dependent-kinase (CDK) 4 or 6 in the neoplastic cell.
  • CDK cyclin dependent-kinase
  • the present disclosure provides for pharmaceutical associations or combinations comprising at least one growth factor receptor-binding compound as defined herein and a bioactive carrier as defined herein, said associations or combinations having the ability to convert or recode a neoplastic cell into a non-neoplastic cell.
  • GFR-binding compound refers to an exogenous or endogenous compound, molecule or substance (a) having an (binding) affinity for a growth factor receptor as defined herein, (b) comprising the ability to associate or combine with a bioactive carrier as defined herein, and (c) comprising the ability to activate a growth factor receptor as defined herein.
  • a having an (binding) affinity for a growth factor receptor as defined herein
  • b comprising the ability to associate or combine with a bioactive carrier as defined herein
  • c comprising the ability to activate a growth factor receptor as defined herein.
  • a GFR-binding compound is fluorescently labelled using technics well established in the art. Binding of the resulting labelled compound to a growth factor receptor results in a fluctuation of fluorescence anisotropy which is used to construct an affinity binding curve from which the GFR-binding compound binding affinity value is derived. Using this technique, binding affinity values are given in the form of dissociation constants Kd. In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) picomolar (pM).
  • GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) nanomolar (nM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 10 (ten) nanomolar (nM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 100 (one hundred) nanomolar (nM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) micromolar ( ⁇ ).
  • GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 10 (ten) micromolar ( ⁇ ). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 100 (one hundred) micromolar ( ⁇ ).
  • a given GFR-binding compound activates a growth factor receptor if it induces growth factor receptor phosphorylation as measured by the western blot method.
  • growth factor receptor phosphorylation sites on growth factor receptors There are many distinct phosphorylation sites on growth factor receptors and they may widely vary according to the type of growth factor receptor as reported in the published scientific article from Mark A. Lemmon and Joseph Schlessinger, "Cell Signaling by Receptor Tyrosine Kinases", Cell. 2010; 141 (7), 1 1 17-1 134, which is hereby incorporated by reference in its entirety.
  • a GFR-binding compound is said to possess the ability to associate or combine with a bioactive carrier if it comprises a functional chemical element, function or group allowing for the covalent or non-covalent assembly of the GFR-binding compound and the bioactive carrier.
  • a functional chemical element, function or group also referred to as a bioactive carrier-affinity-contaning group or bioactive carrier-high- affinity-containing group, include, but is not limited to, a thiol-containing compound, a cysteine-containing compound, a cysteine, or a GTPGP or a WWFWG peptide fragment.
  • Growth factor receptor As used herein, unless indicated otherwise or contradictory in context, the term “growth factor receptor” or “GFR” is a receptor which binds to growth factors which are naturally occurring substances capable of stimulating, for instance, cellular growth, proliferation, healing, and cellular differentiation.
  • Suitable as growth factor receptors for implementing embodiments of the present invention include epidermal growth factor receptors (EGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptors (VEGFR), nerve growth factor receptors (NGFR), Insulin receptor family, Trk receptor family, Eph receptor family, AXL receptor family, LTK receptor family, TIE receptor family, ROR receptor family, DDR receptor family, RET receptor family, KLG receptor family, RYK receptor family, MuSK receptor family, hepatocyte growth factor receptors (HGFR), somatomedin or insulin-like growth factor receptors (SGFR), platelet-derived growth factor receptors (PDGFR), transforming growth factor beta (TGF- ⁇ ) superfamily proteins such as AMH, ARTN, BMP10, BMP15, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, GDF1 , GDF10, GDF1 1 , GDF15, GDF2, GDF3, G
  • growth factor refers to any substance(s) having the ability to bind to a growth factor receptor and produce (a) biological effect(s) or reaction(s), such as promoting the growth of tissues, by activating such a growth factor receptor.
  • Exemplary growth factors include, but are not limited to, platelet-derived growth factor (PDGF), platelet-derived angiogenesis factor (PDAF), vascular endotheial growth factor (VEGF), platelet- derived epidermal growth factor (PDEGF), transforming growth factor beta (TGF- ⁇ ), transforming growth factor A (TGF-A), epidermal growth factor (EGF), fibroblast growth factor (FGF), acidic fibroblast growth factor (FGF-A), basic fibroblast growth factor (FGF-B), insulin-like growth factors 1 and 2 (IGF-I and IGF- 2), keratinocyte growth factor (KGF), tumor necrosis factor (TNF), fibroblast growth factor (FGF) and interleukin-1 (IL-I), Keratinocyte Growth Factor-2 (KGF-2), and combinations thereof.
  • PDGF platelet-derived growth factor
  • PDAF platelet-derived angiogenesis factor
  • VEGF vascular endotheial growth factor
  • PEGF platelet- derived epidermal
  • Activation of growth factor receptors refers to the phosphorylation of the tyrosine kinase domain of such a growth factor receptor.
  • the present disclosure provides a GFR-binding compound, as part of a pharmaceutical association, combination or composition as defined herein, as an active principle for use in methods and uses described herein.
  • the growth factor receptor involved in the interaction with said GFR-binding compound is an epidermal growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a fibroblast growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a vascular endothelial growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a nerve growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a hepatocyte growth factor receptor.
  • the growth factor receptor involved in the interaction with said GFR-binding compound is a somatomedin or insulin-like growth factor receptor.
  • the growth factor receptor involved in the interaction with said GFR-binding compound is a platelet-derived growth factor receptor.
  • the growth factor receptor involved in the interaction with said GFR-binding compound is a protein from the transforming growth factor beta (TGF- ⁇ ) superfamily.
  • the growth factor receptor(s) involved in the interaction with said GFR-binding compound is (are) preferably selected from epidermal growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, nerve growth factor receptors, hepatocyte growth factor receptors, somatomedin or insulin-like growth factor receptors, platelet-derived growth factor receptors, and transforming growth factor beta (TGF- ⁇ ) superfamily proteins.
  • TGF- ⁇ transforming growth factor beta
  • the gene expression of cyclin-D, in a neoplastic cell is reduced, down- regulated, inhibited or suppressed during phase G1 of the cell cycle.
  • the gene expression of cyclin-D is reduced or suppressed for substantially at least the entire duration of phase G1 of a cell cycle. In one particular example, the gene expression of cyclin-D is reduced by at least 20%. In one particular example, the gene expression of cyclin-D is reduced by at least 30%. In one particular example, the gene expression of cyclin-D is reduced by at least 40%. In one particular example, the gene expression of cyclin-D is reduced by at least 50%. In one particular example, the gene expression of cyclin-D is reduced by at least 60%. In one particular example, the gene expression of cyclin-D is reduced by at least 70%. In one particular example, the gene expression of cyclin-D is reduced by at least 80%. At least 40% is particularly preferred.
  • Reduction of cyclin D gene expression is assessed with respect to the wild-type gene expression of cyclin-D and is measured by Quantitative Real Time Polymerase Chain Reaction (Q-PCR or RT-PCR) by (i) extracting RNA from the treated cells, (ii) converting the extracted RNA into the corresponding cDNA, (iii) subjecting the obtained cDNA to a real-time PCR amplification, (iv) analysing the data obtained from the real-time PCR amplification and comparing them with the data obtained by the AACt method, and (v) comparing the obtained values to the wild-type value.
  • Q-PCR or RT-PCR Quantitative Real Time Polymerase Chain Reaction
  • Quantitative Real Time Polymerase Chain Reaction is carried out by (i) extracting RNA from the treated cells using the RNeasy total RNA kit from Qiagen®, (ii) converting the extracted RNA into the corresponding cDNA using a reverse transcription reaction (Gibco Brl®) and random primers from Invitrogen®, (iii) subjecting the obtained cDNA to a real-time PCR amplification in the presence of SYBR green reagents from Bio-Rad® in a thermocycler (iCycler, Biorad®), (iv) analysing the data obtained from the real-time PCR amplification with the iCycler IQTM software following the iCycler iQTM Real-Time PCR Detection System's instruction manual (Catalog Number 170-8740) and using weighted mean as a digital filter, PCR Baseline Subtracted Curve Fit as the analysis mode, FAM/490 as a fluorophore, the
  • the gene expression of cyclin-D is maintained at such a reduced level (at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%) during phase G1 of a cell cycle of the treated neoplastic cell. In one example, the gene expression of cyclin-D is maintained at such a reduced level during substantially the entire duration of the G1 phase.
  • the gene expression of cyclin-D is maintained at such a reduced level during substantially the entire duration of the G1 and S phases. In one example, the gene expression of cyclin-D is maintained at such a reduced level during substantially the entire duration of the G1 , S and G2 phases. In one example, the gene expression of cyclin-D is maintained at such a reduced level during substantially the entire duration of the G1 , S, G2 and M phases i.e. during substantially the entire duration of a cell cycle of a treated neoplastic cell. Reduction of the gene expression level of cyclin D during substantially the entire duration of G1 is preferred.
  • wild-type expression refers to the expression of a protein or a gene observed in normal, standard biological conditions i.e., in the present disclosure, without the presence of, or prior to the provision or administration to a neoplastic cell of a pharmaceutical association, combination or composition as defined herein.
  • In-vitro, ex-vivo or in-vivo natural expression level of a protein or a gene in a neoplastic cell may thus be used as a comparative data (or control) to assess and quantify the effect of the presence or administration of a pharmaceutical association, combination or composition as defined herein on the expression level of such a protein or gene in that cell.
  • Suitable GFR-binding compounds for implementing certain embodiments of the invention include, without being limited to, linear (i.e. non-cyclic) GFR-binding compounds such as peptides, or variants or analogs thereof, or peptidomimetics, and cyclic GFR-binding compounds such as cyclic peptides, or variants or analogs thereof, or cyclic peptidomimetics.
  • said non-cyclic GFR-binding compound has a molecular weight of less than 4,000 Daltons. In one particular example, said non-cyclic GFR-binding compound has a molecular weight of less than 3,000 Daltons. In one particular example, said non-cyclic GFR-binding compound has a molecular weight comprised between 600 and 4,000 Daltons. In one particular example, said non-cyclic GFR-binding compound has a molecular weight comprised between 800 and 4,000 Daltons. In one particular example, said non-cyclic GFR-binding compound has a molecular weight comprised between 600 and 3,000 Daltons.
  • said non-cyclic GFR-binding compound has a molecular weight comprised between 800 and 3,000 Daltons. Between 800 and 3,000 Daltons is particularly preferred.
  • said GFR-binding compound is a (non-cyclic) peptide, a variant or analog thereof, as defined herein, with (exclusively consisting of, or constituted of) between 7-25 amino acids, in particular between 7-20 amino acids or between 7-17 amino acids, more particularly between 10-25 amino acids, 10-22 amino acids, 10-20 amino acids or 10-17 amino acids, even more particularly between 15-25 amino acids, 15-22 amino acids, 15-20 amino acids or 15-17 amino acids, having growth factor receptor-binding capability or capabilities.
  • said GFR-binding compound is a (non-cyclic) peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, comprising (consecutively or non consecutively) between 7-25 amino acids, in particular between 7-20 amino acids or between 7-17 amino acids, more particularly between 10-25 amino acids, 10-22 amino acids, 10-20 amino acids or 10-17 amino acids, even more particularly between 1 5-25 amino acids, 15-22 amino acids, 15-20 amino acids or 15-17 amino acids; wherein said GFR-binding compound has a molecular weight comprised between 600 and 4,000 Daltons (in particular, between 800-4,000 Da, 600-3,000 Da, more particularly between 800-3,000 Da).
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, having a molecular weight comprised between 600 and 4,000 Daltons (in particular, between 800-4,000 Da, 600- 3,000 Da, more particularly between 800-3,000 Da).
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 20 and 60 (in particular between 20 and 50, and more particularly, between 20 and 45) amino acids, having growth factor receptor-binding capability or capabilities, comprising a peptide with four amino acids (PEP1 ) and a peptide with five amino acids (PEP2).
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7- 17, more particularly between 10-25, 1 0-22, 10-20 or 10-17, even more particularly between 15-25, 15- 22, 1 5-20 or 15-1 7) amino acids, comprising a peptide with five amino acids (PEP2).
  • PEP2 five amino acids
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10- 17, even more particularly between 15-25, 15-22, 15-20 or 15-17) amino acids, comprising a peptide with five amino acids (PEP2); wherein said GFR-binding compound further comprises a peptide three amino acids (PEP4).
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10- 17, even more particularly between 15-25, 15-22, 15-20 or 15-17) amino acids, comprising a peptide with five amino acids (PEP2); wherein said GFR-binding compound further comprises a peptide with between five and seven amino acids (PEP6).
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10- 17, even more particularly between 15-25, 15-22, 15-20 or 15-17) amino acids, comprising a peptide with five amino acids (PEP2); wherein said GFR-binding compound further comprises a peptide with between six and eleven amino acids (PEP10).
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10- 17, even more particularly between 15-25, 15-22, 15-20 or 15-17) amino acids, comprising a peptide with five amino acids (PEP2); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP4) and an amino acid or a peptide with between two and six amino acids (PEP8).
  • PEP2 peptide with five amino acids
  • PEP8 amino acid or a peptide with between two and six amino acids
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10- 17, even more particularly between 15-25, 15-22, 15-20 or 15-17) amino acids, comprising a peptide with five amino acids (PEP2); wherein said GFR-binding compound further comprises a peptide with between five and seven amino acids (PEP6) and an amino acid or a peptide with between two and six amino acids (PEP8).
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10- 17, even more particularly between 15-25, 15-22, 15-20 or 15-1 7) amino acids, having the following general formula (I) (hereinafter may also be referred to as compound (I) or peptide (I)):
  • PEP2-PEP(D) (I) wherein PEP2 is a peptide with five amino acids as already defined herein; wherein one end of PEP(D) interacts covalently with one end of PEP2; wherein PEP(D) is a peptide with at least 5 amino acids, in particular a peptide with between 5 and 1 1 amino acids.
  • the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(D) comprises PEP4. In one aspect, the present disclosure provides a GFR-binding compound of general formula (I), wherein wherein PEP(D) comprises PEP6. In one particular example, PEP(D) is PEP6.
  • the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(D) comprises PEP1 0.
  • PEP(D) is PEP10.
  • the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(D) comprises PEP4 and PEP8. In one aspect, the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(D) comprises PEP6 and PEP8.
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10- 17, even more particularly between 15-25, 15-22, 15-20 or 15-17) amino acids, having the following general formula (II) (hereinafter may also be referred to as compound (II) or peptide (II)):
  • PEP2-PEP6-PEP8 wherein PEP2 is a peptide with five amino acids as already defined herein; wherein PEP6 is a peptide with between five and seven amino acids as already defined herein; wherein PEP8 an amino acid or a peptide with between two and six amino acids as already defined herein; wherein one end of PEP6 interacts covalently with one end of PEP2 via AA 26 ; wherein another end of PEP6 interacts covalently with one end of PEP8 via AA 32 .
  • said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10- 17, even more particularly between 15-25, 15-22, 15-20 or 15-17) amino acids, having the following general formula (III) (hereinafter may also be referred to as compound (III) or peptide (III)): AA 21 -AA 22 -AA 23 -AA 24 -AA 25 -AA 26 -AA 27 -AA 28 -AA 29 -AA 30 -AA 31 -AA 32 -AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 (III) wherein AA 2 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 3 -AA 32 is P
  • PEP2 is selected from the group consisting of LKNYQ, LKVYP, LKKYR, LRKHR, LKYHY, KFKYE, YGKIP, YKQYE, DHHKD, EQLSN, IGEMS, LGEMS, KEVQV and KKATV.
  • PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN, EHS, EEH and EDH.
  • PEP6 is a peptide of general formula AA -AA -AA -AA -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent or is E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA m and AA V amino acids; and wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent or is S.
  • PEP6 is selected from the group consisting of DMVVE, NMTVE, EMVVE, NMVVR, NMVVK, EGMSVAE, GMAVS, GMVVD, MIVEE, MIVRS, MIVKS, MVVKS, FLQHN, LEEHS, RLEEH and TLEDH.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 ; and wherein at least one of AA 33 , AA 34 , AA 35 , AA 36 , AA 37 or AA 38 is not absent.
  • PEP8 is selected from the group consisting of GXGXR, SXAXR, SXGXH, AXGXH , XGXR, EXGXR, RXGXS, AXGXR, SXGXR, XGXL, XKXS, KXEXR, QXEXR, LEXAXA and LAXKXE.
  • PEP10 is a peptide of general formula PEP6-PEP8; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent or is E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA m and AA V amino acids; and wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent or is S; wherein PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVESXAXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, MIVEEXGXL, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS, FLQHNKXEXR, LEEHSQXEXR, RLEEHLEXAXA and TLEDHLAXKXE.
  • the pair PEP2:PEP4 is selected from the group consisting of LKNYQ:VVE, LKNYQ:TVE, LKNYQ:VVR, LKNYQ:VVK, LKNYQ:VAE, LKNYQ:AVS, LKNYQ:VVD,
  • LKVYP:TVE LKVYP:VVE
  • LKVYP:VVR LKVYP:VVK
  • LKVYP:VAE LKVYP:AVS
  • LKVYP:VVD LKVYP:VVD
  • LKVYP:VEE LKVYP:VRS
  • LKVYP:VKS LKVYP:QHN
  • LKVYP:EHS LKVYP:EEH
  • LKVYP:EDH LKVYP:EDH
  • LKKYR:VVR LKKYR:VVE, LKKYR:TVE, LKKYR:VVK, LKKYR:VAE, LKKYR:AVS, LKKYR:VVD, LKKYR:VEE, LKKYR:VRS, LKKYR:VKS, LKKYR:QHN, LKKYR:EHS, LKKYR:EEH , LKKYR:EDH,
  • KFKYE:AVS KFKYE:VVE, KFKYE:TVE, KFKYE:VVR, KFKYE:VVK, KFKYE:VAE KFKYE:VVD,
  • EQLSN:VRS EQLSN:VVE, EQLSN:TVE, EQLSN:VVR, EQLSN:VVK, EQLSN:VAE EQLSN:AVS,
  • IGEMS:QHN IGEMS:VVE, IGEMS:TVE, IGEMS:VVR, IGEMS:VVK, IGEMS:VAE IGEMS:AVS,
  • IGEMS:VVD IGEMS:VEE
  • IGEMS:VRS IGEMS:VKS
  • IGEMS:EHS IGEMS:EEH
  • IGEMS:EDH LGEMS:EHS
  • LGEMS:VVE LGEMS:TVE
  • LGEMS:VVR LGEMS:VVK
  • LGEMS:VAE LGEMS:AVS
  • LGEMS:VVD LGEMS:VEE
  • LGEMS:VRS LGEMS:VKS
  • LGEMS:QHN LGEMS:EEH
  • LGEMS:EDH LGEMS:EDH
  • KEVQV:VVD KEVQV:VEE, KEVQV:VRS, KEVQV:VKS, KEVQV:QHN, KEVQV:EHS KEVQV:EDH,
  • the pair PEP2:PEP6 is selected from the group consisting of LKNYQ:NMVVE, LKNYQ:EGMSVVE, LKNYQ:GMVVE, LKNYQ:DMVVE, LKNYQ:MIVVE, LKNYQ:MVVVE, LKNYQ:NMTVE, LKNYQ:NMVVR, LKNYQ:NMVVK, LKNYQ:EGMSVAE, LKNYQ:GMAVS, LKNYQ:GMVVD, LKNYQ:MIVEE, LKNYQ:MIVRS, LKNYQ:MIVKS, LKNYQ:MVVKS, LKNYQ:FLQHN, LKNYQ:LEEHS, LKNYQ:RLEEH, LKNYQ:TLEDH, LKVYP:DMTVE, LKVYP:EMTVE, LKVYP:NMTVE, LKVYP:EGMSTVE, LKVY
  • the pair PEP2:PEP8 is selected from the group consisting of LKNYQ:SXAXR, LKNYQ:SXGXH, LKNYQ:AXGXH , LKNYQ:XGXR, LKNYQ:EXGXR, LKNYQ:RXGXS, LKNYQ:AXGXR, LKNYQ:SXGXR, LKNYQ:XGXL, LKNYQ:XKXS, LKNYQ:KXEXR, LKNYQ:QXEXR, LKNYQ:LEXAXA, LKNYQ:LAXKXE, LKVYP:GXGXR, LKVYP:SXGXH, LKVYP:AXGXH, LKVYP:XGXR, LKVYP:EXGXR, LKVYP:RXGXS, LKVYP:AXGXS, LK
  • the pair PEP2:PEP10 is selected from the group consisting of LKNYQ:NMVVESXAXR, LKNYQ:NMVVESXGXH, LKNYQ:NMVVEAXGXH, LKNYQ:EGMSVVEXGXR, LKNYQ:GMVVEEXGXR, LKNYQ:GMVVERXGXS, LKNYQ:DMVVEAXGXR, LKNYQ:DMVVESXGXR, LKNYQ:MIVVEXGXL, LKNYQ:MIVVEXKXS, LKNYQ:MVVVEXKXS, LKNYQ:NMTVESXAXR, LKNYQ:NMVVRSXGXH, LKNYQ:NMVVRAXGXH, LKNYQ:NMVVKAXGXH, LKNYQ:EGMSVAEXGXR, LKNYQ:GMAVSEXGX
  • the triplet PEP2:PEP4:PEP8 is selected from the group consisting of LKNYQ:VVE:SXAXR, LKNYQ:VVE:SXGXH, LKNYQ:VVE:AXGXH, LKNYQ:VVE:XGXR, LKNYQ:VVE:EXGXR, LKNYQ:VVE:RXGXS, LKN YQ : VVE :AXGXR, LKNYQ:VVE:SXGXR
  • LKVYP:TVE:GXGXR LKVYP:TVE:SXGXH , LKVYP:TVE:AXGXH, LKVYP:TVE:XGXR
  • LKKYR VVR: AXGXH , LKKYR: VVR:XGXR, LKKYR: VVR:EXGXR, LKKYR: VVR:RXGXS
  • LKYH Y VVK:AXGXH , LKYHY:AVS:EXGXR, LKYHY:VVD:RXGXS, LKYHY:VVE:AXGXR
  • the triplet PEP2:PEP6:PEP8 is selected from the group consisting of LKNYQ:NMVVE:SXAXR, LKNYQ:NMVVE:SXGXH, LKNYQ:NMVVE:AXGXH,
  • YKQYE :G MVVD RXGXS, YKQYE:MIVEE:XGXL, YKQYE:MIVRS:XKXS, YKQYE:MIVKS:XKXS YKQYE:MVVKS:XKXS, YKQYE:FLQHN:KXEXR, YKQYE:LEEHS:QXEXR, YKQYE:RLEEH:LEXAXA YKQYE:TLEDH:LAXKXE, DHHKD:DMVEE:GXGXR, DHHKD:NMVEE:SXAXR, DHHKD:EMVEE:GXGXR ; DHHKD:NMVEE:SXGXH, DHHKD:NMVEE:AXGXH, DHHKD:EGMSVEE:XGXR
  • DHHKD:GMVEE:EXGXR DHHKD:GMVEE:RXGXS, DHHKD:DMVEE:AXGXR, DHHKD:DMVEE:SXGXR ;
  • DHHKD:MIVEE:XKXS DHHKD:MVVEE:XKXS, DHHKD:DMVVE:GXGXR, DHHKD:NMTVE:SXAXR.
  • DHHKD:GMVVD:RXGXS DHHKD:DMVVE:AXGXR, DHHKD:DMVVE:SXGXR, DHHKD:MIVRS:XKXS ; DHHKD:MIVKS:XKXS, DHHKD:MVVKS:XKXS, DHHKD:FLQHN :KXEXR, DHHKD:LEEHS:QXEXR.
  • the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound as defined herein with respect to PEPREF is 2.45A (Angstroms) or less, in particular is 2k or less, and more particularly is 1 .79A or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein (hereinafter may be referred to as "wherein the RMSD is 2.45A or less" for the sake of conciseness).
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • said GFR-binding compound is a non-cyclic synthetic peptide.
  • a length of said GFR-binding compound, in solution , such as in a physiologically acceptable solvent such as water or PBS, is comprised between about 6 and about 20 nm, preferably between about 6 and about 1 6 nm, as determined using the standard « 3D » procedure described above.
  • said GFR-binding compounds may be any one or a plurality of of peptides of SEQ ID NO: 1 to 2684. Cyclic GFR-binding compounds
  • said cyclic GFR-binding compound has a molecular weight of less than 5,000 Daltons. In one particular example, said cyclic GFR-binding compound has a molecular weight of less than 4,000 Daltons. In one particular example, said cyclic GFR-binding compound has a molecular weight comprised between 1 ,000 and 5,000 Daltons. In one particular example, said cyclic GFR-binding compound has a molecular weight comprised between 1 ,000 and 4,000 Daltons. In one particular example, the growth factor receptor involved in the interaction with said cyclic GFR- binding compound is an epidermal growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a fibroblast growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a vascular endothelial growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a nerve growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a hepatocyte growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a somatomedin or insulin-like growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a platelet-derived growth factor receptor.
  • the growth factor receptor involved in the interaction with said cyclic GFR-binding compound is a protein from the transforming growth factor beta (TGF- ⁇ ) superfamily.
  • the growth factor receptor(s) involved in the interaction with said cyclic GFR- binding compound is (are) preferably selected from epidermal growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, nerve growth factor receptors, hepatocyte growth factor receptors, somatomedin or insulin-like growth factor receptors, platelet-derived growth factor receptors, and transforming growth factor beta (TGF- ⁇ ) superfamily proteins.
  • epidermal growth factor receptors preferably selected from epidermal growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, nerve growth factor receptors, hepatocyte growth factor receptors, somatomedin or insulin-like growth factor receptors, platelet-derived growth factor receptors, and transforming growth factor beta (TGF- ⁇ ) superfamily proteins.
  • TGF- ⁇ transforming growth factor beta
  • said cyclic GFR-binding compound is a cyclic peptide, or a variant or analog thereof, having growth factor receptor-binding capability or capabilities, with (exclusively consisting of, or constituted of) between 10-35 amino acids, in particular between 1 0-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids.
  • said cyclic GFR-binding compound is a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, comprising (consecutively or non consecutively) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids; wherein said cyclic GFR-binding compound has a molecular weight comprised between 1 ,000 and 5,000 Daltons (in particular, between 1 ,000 and 4,000 Da).
  • said cyclic GFR-binding compound is a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, comprising (consecutively or non consecutively) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids; and containing at least one peptide portion or fragment with between 5-20 amino acids (in particular containing one peptide portion or fragment with between 5-20 amino acids); wherein said cyclic GFR-binding compound has a molecular weight comprised between 1 ,000 and 5,000 Daltons (in particular, between 1 ,000 and 4,000 Da).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, having a molecular weight of less than 5,000 Da, in particular of between 1 ,000 and 5,000 Da, more particularly of between 1 ,000 and 4,000 Da.
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with three amino acids (PEP4).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between five and seven amino acids (PEP6).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between six and eleven amino acids (PEP10).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with three amino acids (PEP4), and an amino acid or a peptide with between two and six amino acids (PEP8).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 1 0-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide with five amino acids (PEP2); wherein said cyclic GFR-binding compound further comprises a peptide with between five and seven amino acids (PEP6), and an amino acid or a peptide with between two and six amino acids (PEP8).
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (IV) (hereinafter may also be referred to as compound (IV) or peptide (IV)): LINKER-PEP(B) (IV) wherein one end of LIN KER interacts covalently with one end of PEP(B); wherein PEP(B) comprises PEP2; wherein LIN KER is a linear or branched organic divalent radical , moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between
  • Mw
  • the molecular weight of LINKER refer to the calculated molecular weight prior to being connected to / reacted with any of the elements it is configured to connect to or react with e.g. PEP(B) or any other groups defined herein.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (IV), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP4. In one aspect, the present disclosure provides a cyclic GFR-binding compound comprising compound (IV), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP6.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (IV), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP10.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (IV), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP4 and PEP8.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (IV), wherein PEP(B) comprises PEP2; and wherein PEP(B) further comprises PEP6 and PEP8.
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (V) (hereinafter may also be referred to as compound (V) or peptide (V)): LINKER-PEP2-PEP(D) (V) wherein LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with five amino acids as already defined herein; wherein one end of
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (V), wherein PEP(D) comprises PEP4.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (V), wherein PEP(D) comprises PEP6.
  • PEP(D) is PEP6.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (V), wherein PEP(D) comprises PEP10. In one particular example, PEP(D) is PEP10. In one aspect, the present disclosure provides a cyclic GFR-binding compound comprising compound (V), wherein PEP(D) comprises PEP4 and PEP8.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (V), wherein PEP(D) comprises PEP6 and PEP8.
  • the present disclosure provides a cyclic GFR-binding compound comprising compound (V), wherein PEP(D) is PEP6 or PEP10.
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (VI) (hereinafter may also be referred to as compound (VI) or peptide (VI)): LINKER-PEP2-PEP6-PEP8 (VI) wherein LINKER is a linear or branched organic divalent radical , moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with five amino acids as already defined herein; wherein
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (VI I) (hereinafter may also be referred to as compound (VI I) or peptide (VI I)):
  • LINKER is a linear or branched organic divalent radical , moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein AA 2 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 3 -AA 32 is PEP4 as defined herein; wherein AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 is PEP8 as defined herein ; wherein AA 26 , AA 27 , AA 28 , and AA 29 are as defined herein; wherein one end of LINKER interacts covalently with AA 21 ; wherein AA 21 may be an N-terminal amino acid or a C-terminal amino acid ; wherein AA 38 may be an N-
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising two LINKERS.
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, having any one of the following schematic general formulae (VI II) to (XI) (hereinafter may also be referred to as compounds (VII I) to (XI) or peptides (VI II) to (XI)):
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da;
  • PEP2 is a peptide with five amino acids as already defined herein;
  • PEP6 is a peptide with between five and seven amino acids as already defined herein;
  • PEP8 an amino acid or a peptide with between two and six amino acids as already defined herein;
  • PEP10 is a peptide with between six and eleven amino acids;
  • curved lines represents covalent bonds between LINKERS and PEP2, PEP4, PEP6, PEP8 and PEP10 "boxes". Curved lines' lengths may not be representative of the actual relative distance between the LINKERS and PEP2, PEP4, PEP6, PEP8 and PEP10 "boxes". Curved lines' length
  • said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, having any one of the following schematic general formulae (XII) or (XIII) (hereinafter may also be referred to as compounds (XII) and (XIII) or peptides (XII) and (XIII)):
  • LINKER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein AA 2 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 3 -AA 32 is PEP4 as defined herein; wherein AA 26 , AA 27 , AA 28 , and AA 29 are as defined herein; wherein one end of LINKER interacts covalently with AA 21 ; wherein another end of LINKER interacts covalently with AA 25 ; and wherein curved lines represents covalent bonds between LINKERS and AAs "boxes".
  • Mw molecular weight
  • PEP2 is selected from the group consisting of LKNYQ, LKVYP, LKKYR, LRKHR, LKYHY, KFKYE, YGKIP, YKQYE, DHHKD, EQLSN , IGEMS, LGEMS, KEVQV and KKATV.
  • PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN , EHS, EEH and EDH .
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN , EHS, EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent or is E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA m and AA V amino acids; and wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent or is S.
  • PEP6 is selected from the group consisting of DM VVE, NMTVE, EMVVE, NMVVR, NMVVK, EG MS VAE, GMAVS, GMVVD, M IVEE, M IVRS, M IVKS, MVVKS, FLQHN , LEEHS, RLEEH and TLEDH .
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 ; and wherein at least one of AA 33 , AA 34 , AA 35 , AA 36 , AA 37 or AA 38 is not absent.
  • PEP8 is selected from the group consisting of GXGXR, SXAXR, SXGXH , AXGXH , XGXR, EXGXR, RXGXS, AXGXR, SXGXR, XGXL, XKXS, KXEXR, QXEXR, LEXAXA and LAXKXE.
  • PEP10 is a peptide of general formula PEP6-PEP8; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS, VKS, QHN , EHS, EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent or is E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA m and AA V amino acids; and wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent or is S; wherein PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVESXAXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, MIVEEXGXL, MIVRSXKXS, MIVKSXKXS, MVVKSXKXS, FLQHNKXEXR, LEEHSQXEXR, RLEEHLEXAXA and TLEDHLAXKXE.
  • the pair PEP2:PEP4 is selected from the group consisting of
  • LKVYP:TVE LKVYP:VVE
  • LKVYP:VVR LKVYP:VVK
  • LKVYP:VAE LKVYP:AVS LKVYP:VVD
  • LKKYR:VVR LKKYR:VVE, LKKYR:TVE, LKKYR:VVK, LKKYR:VAE LKKYR:AVS LKKYR:VVD
  • KFKYE:AVS KFKYE:VVE, KFKYE:TVE, KFKYE:VVR, KFKYE:VVK KFKYE:VAE KFKYE:VVD
  • KFKYE:VEE KFKYE:VRS
  • KFKYE:VKS KFKYE:QHN
  • KFKYE:EHS KFKYE:EEH
  • IGEMS:QHN IGEMS:VVE, IGEMS:TVE, IGEMS:VVR, IGEMS:VVK IGEMS:VAE IGEMS:AVS
  • IGEMS:VVD IGEMS:VEE
  • IGEMS:VRS IGEMS:VKS
  • IGEMS:EHS IGEMS:EEH
  • IGEMS:EDH IGEMS:EDH
  • LGEMS:EHS LGEMS:VVE
  • LGEMS:TVE LGEMS:VVR
  • LGEMS:VVK LGEMS:VAE
  • LGEMS:VVD LGEMS:VEE
  • LGEMS:VRS LGEMS:VKS
  • LGEMS:QHN LGEMS:EEH
  • KEVQV:EEH KEVQV:VVE, KEVQV:TVE, KEVQV:VVR, KEVQV:VVK KEVQV:VAE KEVQV:AVS
  • KEVQV:VVD KEVQV:VEE, KEVQV:VRS, KEVQV:VKS, KEVQV:QHN KEVQV:EHS KEVQV:EDH
  • KKATV:EDH KKATV:VVE
  • KKATV:TVE KKATV:VVR
  • KKATV:VVK KKATV:VAE KKATV:AVS
  • KKATV:VVD KKATV:VEE, KKATV:VRS, KKATV:VKS, KKATV:QHN, KKATV:EHS and KKATV:EEH.
  • the pair PEP2:PEP6 is selected from the group consisting of LKNYQ:NMVVE, LKNYQ:EGMSVVE, LKNYQ:GMVVE, LKNYQ:DMVVE, LKNYQ:MIVVE, LKNYQ:MVVVE, LKNYQ:NMTVE, LKNYQ:NMVVR, LKNYQ:NMVVK, LKNYQ:EGMSVAE, LKNYQ:GMAVS, LKNYQ:GMVVD, LKNYQ:MIVEE, LKNYQ:MIVRS, LKNYQ:MIVKS, LKNYQ:MVVKS, LKNYQ:FLQHN, LKNYQ:LEEHS, LKNYQ:RLEEH, LKNYQ:TLEDH, LKVYP:DMTVE, LKVYP:EMTVE, LKVYP:NMTVE, LKVYP:EGMSTVE, LKVY
  • LKKYR:NMTVE LKKYR:EMVVE, LKKYR:NMVVK, LKKYR:EGMSVAE, LKKYR:GMAVS
  • LRKHR:NMTVE LRKHR:EMVVE, LRKHR:NMVVR, LRKHR:EGMSVAE, LRKHR:GMAVS
  • KFKYE:MVAVS KFKYE:DMVVE, KFKYE:NMTVE, KFKYE:EMVVE, KFKYE:NMVVR, KFKYE:NMVVK.
  • YGKIP:NMTVE YGKIP:EMVVE, YGKIP:NMVVR, YGKIP:NMVVK, YGKIP:EGMSVAE, YGKIP:GMAVS ;
  • YGKIP:RLEEH YGKIP:TLEDH
  • YKQYE:DMVVE YKQYE:NMVVE
  • YKQYE:EMVVE YKQYE:EGMSVVE
  • YKQYE:GMVVE YKQYE:MIVVE
  • YKQYE:MVVVE YKQYE:NMTVE.
  • YKQYE:NMVVR YKQYE:NMVVK
  • YKQYE:EGMSVAE YKQYE:GMAVS
  • YKQYE:GMVVD YKQYE:GMVVD.
  • YKQYE:RLEEH YKQYE:TLEDH
  • DHHKD:DMVEE DHHKD:NMVEE
  • DHHKD:EMVEE DHHKD:EMVEE.
  • DHHKD:EGMSVEE DHHKD:GMVEE, DHHKD:MIVEE, DHHKD:MVVEE, DHHKD:DMVVE.
  • DHHKD:NMTVE DHHKD:EMVVE, DHHKD:NMVVR, DHHKD:NMVVK, DHHKD:EGMSVAE
  • DHHKD:GMAVS DHHKD:GMVVD
  • DHHKD:MIVRS DHHKD:MIVKS
  • DHHKD:MVVKS DHHKD:FLQHN
  • DHHKD:LEEHS DHHKD:RLEEH
  • DHHKD:TLEDH EQLSN:DMVRS, EQLSN:NMVRS, EQLSN:EMVRS ;
  • EQLSN:EGMSVRS EQLSN:GMVRS, EQLSN:MIVRS, EQLSN:MVVRS, EQLSN:DMVVE.
  • EQLSN:NMTVE EQLSN:EMVVE, EQLSN:NMVVR, EQLSN :NMVVK, EQLSN:EGMSVAE.
  • EQLSN:GMAVS EQLSN:GMVVD
  • EQLSN:MIVEE EQLSN :MIVKS
  • EQLSN:MVVKS EQLSN:FLQHN
  • IGEMS:EMVVE IGEMS:NMVVR
  • IGEMS:NMVVK IGEMS:EGMSVAE
  • IGEMS:GMAVS IGEMS:GMAVS ;
  • IGEMS:GMVVD IGEMS:MIVEE
  • IGEMS:MIVRS IGEMS:MIVKS
  • IGEMS:MVVKS IGEMS:LEEHS
  • IGEMS:TLEDH LGEMS:FLEHS
  • LGEMS:DMVVE LGEMS:NMTVE
  • LGEMS:NMVVR LGEMS:NMVVK
  • LGEMS:EGMSVAE LGEMS:GMAVS
  • LGEMS:GMVVD LGEMS:GMVVD
  • LGEMS:MIVEE LGEMS:MIVRS, LGEMS:MIVKS, LGEMS:MVVKS, LGEMS:FLQHN, LGEMS:RLEEH.
  • KKATV:RLEDH KKATV:DMVVE, KKATV:NMTVE, KKATV:EMVVE, KKATV:NMVVR, KKATV:NMVVK.
  • KKATV:EGMSVAE KKATV:GMAVS, KKATV:GMVVD, KKATV:MIVEE, KKATV:MIVRS, KKATV:MIVKS ; KKATV:MVVKS, KKATV:FLQHN , KKATV:LEEHS and KKATV:RLEEH.
  • the pair PEP2:PEP8 is selected from the group consisting of LKNYQ:SXAXR, LKNYQ:SXGXH, LKNYQ:AXGXH , LKNYQ:XGXR, LKNYQ:EXGXR, LKNYQ:RXGXS, LKNYQ:AXGXR, LKNYQ:SXGXR, LKNYQ:XGXL, LKNYQ:XKXS, LKNYQ:KXEXR, LKNYQ:QXEXR, LKNYQ:LEXAXA, LKNYQ:LAXKXE, LKVYP:GXGXR, LKVYP:SXGXH, LKVYP:AXGXH, LKVYP:XGXR, LKVYP:EXGXR, LKVYP:RXGXS, LKVYP:AXGXS, LK
  • the pair PEP2:PEP10 is selected from the group consisting of LKNYQ:NMVVESXAXR, LKNYQ:NMVVESXGXH, LKNYQ:NMVVEAXGXH, LKNYQ:EGMSVVEXGXR, LKNYQ:GMVVEEXGXR, LKNYQ:GMVVERXGXS, LKNYQ:DMVVEAXGXR, LKNYQ:DMVVESXGXR, LKNYQ:MIVVEXGXL, LKNYQ:MIVVEXKXS, LKNYQ:MVVVEXKXS, LKNYQ:NMTVESXAXR, LKNYQ:NMVVRSXGXH, LKNYQ:NMVVRAXGXH, LKNYQ:NMVVKAXGXH, LKNYQ:EGMSVAEXGXR LKNYQ:GMAVSEXGXR
  • the triplet PEP2:PEP4:PEP8 is selected from the group consisting of LKNYQ:VVE:SXAXR, LKNYQ:VVE:SXGXH, LKNYQ:VVE:AXGXH, LKNYQ:VVE:XGXR
  • LKVYP:TVE:GXGXR LKVYP:TVE:SXGXH , LKVYP:TVE:AXGXH, LKVYP:TVE:XGXR
  • LKKYR VVR: AXGXH , LKKYR: VVR:XGXR, LKKYR: VVR:EXGXR, LKKYR: VVR:RXGXS
  • LKYH Y VVK:AXGXH , LKYHY:AVS:EXGXR, LKYHY:VVD:RXGXS, LKYHY:VVE:AXGXR
  • KFKYE : E D H LAXKXE
  • YGKIP:VVD:GXGXR YGKIP:VVD:SXAXR
  • YKQ YE VVE : RXGXS , YKQYE:VVE:SXGXR, YKQYE:VVE:XGXL, YKQYE:VVE:XKXS
  • YKQ YE :T VE SXAXR, YKQYE:VVR:SXGXH, YKQYE:VVR:AXGXH, YKQ YE :VVK: AXGXH
  • YKQYE:EDH: LAXKXE DHHKD:VEE:GXGXR
  • IGEMS:AVS:EXGXR IGEMS:VVD:RXGXS
  • IGEMS:VVE:AXGXR IGEMS:VVE:SXGXR
  • IGEMS:EEH:LEXAXA IGEMS:EDH:LAXKXE
  • LGEMS:EHS:KXEXR LGEMS:VVE:GXGXR
  • KKATV VVR:AXGXH
  • KKATV VVK:AXGXH
  • KKATV VAE:XGXR
  • KKATV AVS:EXGXR
  • KKATV:VVD:RXGXS KKATV: VVE:AXGXR
  • KKATV:VRS:XKXS KKATV:VKS:XKXS, KKATV:QHN:KXEXR, KKATV:EHS:QXEXR and
  • the triplet PEP2:PEP6:PEP8 is selected from the group consisting of LKNYQ:NMVVE:SXAXR, LKNYQ:NMVVE:SXGXH, LKNYQ:NMVVE:AXGXH, LKNYQ:EGMSVVE:XGXR, LKNYQ:GMVVE:EXGXR, LKNYQ:GMVVE:RXGXS,
  • DHHKD:GMVVD:RXGXS DHHKD:DMVVE:AXGXR, DHHKD:DMVVE:SXGXR, DHHKD:MIVRS:XKXS ; DHHKD:MIVKS:XKXS, DHHKD:MVVKS:XKXS, DHHKD:FLQHN :KXEXR, DHHKD:LEEHS:QXEXR.
  • DHHKD:RLEEH LEXAXA
  • DHHKD:TLEDH:LAXKXE EQLSN:DMVRS:GXGXR, EQLSN:NMVRS:SXAXR ; EQLSN:EMVRS:GXGXR, EQLSN:NMVRS:SXGXH, EQLSN:NMVRS:AXGXH
  • said cyclic GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said cyclic GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a cyclic peptidomimetic.
  • said cyclic GFR-binding compound is a cyclic synthetic peptide.
  • a length of said cyclic GFR-binding compound, in solution, such as in a physiologically acceptable solvent such as water or PBS, is comprised between about 6 and about 20 nm, preferably between about 6 and about 16 nm, as determined using the standard « 3D » procedure described above.
  • said cyclic GFR-binding compounds may be any one of peptides of SEQ ID NO: 2685 to 10108
  • LINKER is a linear or branched organic divalent radical , moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da.
  • Mw molecular weight
  • the chemical nature of said LINKER is not meant to be particularly limited and may be any organic molecule capable of covalently connecting two ends of a peptide or a peptidomimetic such as PEP(B) or PEP2-PEP(D) so as to form a cyclic compound and so long as LIN KER provides sufficient cycle stability to provide or conserve the required tissue regeneration activity.
  • LINKER may thus be, for example, in certain embodiments, a peptide, or variant, analog or peptidomimetic thereof, a polysaccharide, a polynucleotide, a saturated or unsaturated hydrocarbon chain, or a mixture thereof.
  • LINKER is a peptide with 6 to 30 amino acids. In one particular example, LINKER is a peptide with 6 to 25 amino acids. In one particular example, LINKER is a peptide with 6 to 20 amino acids. In one most particular example, LINKER is a peptide with 7 to 20 amino acids.
  • said cyclic GFR-binding compound is a peptide, a variant or analog thereof as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12- 30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof of general formula (IV); wherein one end of LIN KER interacts covalently with one end of PEP(B); wherein PEP(B) comprises PEP2; wherein LINKER is a peptide comprising 6 to 30 amino acids (in particular 6 to 25, 6 to 20, or 7 to 20 amino acids).
  • said cyclic GFR-binding compound is a peptide, a variant or analog thereof as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12- 30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof of general formula (V); wherein LINKER is a peptide comprising 6 to 30 amino acids (in particular 6 to 25, 6 to 20, or 7 to 20 amino acids); wherein PEP2 and PEP(D) are as already defined herein ; wherein one end of LINKER interacts covalently with one end of PEP2 via AA 2 ; wherein another end of PEP2 interacts covalently with PEP(D) via AA 25 .
  • LINKER is a peptide comprising 6 to 30 amino acids (in particular 6 to 25, 6 to 20, or 7 to 20 amino acids)
  • PEP2 and PEP(D) are as already defined herein ; wherein one end of LINKER interacts covalently with one end of PEP2 via
  • said cyclic GFR-binding compound is a peptide, a variant or analog thereof as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12- 30, and even more particularly between 12-28) amino acids, having any one of the general formula (VII I) to (XI II); wherein LINKER is a peptide comprising 6 to 30 amino acids (in particular 6 to 25, 6 to 20, or 7 to 20 amino acids).
  • said cyclic GFR-binding compound is a cyclic peptidomimetic as defined herein, comprising (consecutively or non-consecutively) between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, of general formula (V); wherein LINKER is not a peptide but may comprise amino acids or peptides in covalent or non- covalent (preferably covalent) association with other groups or residues other than amino acids or peptides.
  • LINKER comprises (or is) a peptide of general formula (XIV):
  • AA occupies position AA 201
  • AA V occupies position AA 202
  • AA M occupies position AA 204
  • AA X occupies position AA 205
  • AA X occupies position AA 206
  • AA XI occupies position AA 207
  • AA XI occupies position AA and position AA is vacants.
  • LINKER may thus comprise or be any one of the following peptides:
  • LINKER comprises a peptide of formula (XIV), (XIV -2) or (XIV
  • LINKER comprises (or is) a poly-(aliphatic amino acid) peptide such as poly-alanine peptide (A) N , or a poly-glycine (G) n , n being an integer comprised between 2 and 30, in particular between 2 to 25, more particularly between 2 and 20, such as A- A- A- A- A- A- A- A- A- A- A, A-A-A-A-A-A, A-A-A-A-A, G- G-G-G-G-G-G-G-G, G-G-G-G-G-G-G or G-G-G-G-G-G-G.
  • a poly-(aliphatic amino acid) peptide such as poly-alanine peptide (A) N , or a poly-glycine (G) n , n being an integer comprised between 2 and 30, in particular between 2 to 25, more particularly between 2 and 20, such as A- A- A- A- A- A- A-
  • LINKER comprises (or is) a peptide of general formulae (XIV) to (XIV-14), more particularly (XIV), (XIV-2) or (XIV-4), and/or a poly-(aliphatic amino acid) n peptide as defined herein.
  • LINKER is a polysaccharide comprising 6 to 30 saccharides. In one particular example, LINKER is a polysaccharide comprising 6 to 25 saccharides. In one particular example, LINKER is a polysaccharide comprising 6 to 20 saccharides. In one most particular example, LINKER is a polysaccharide comprising 7 to 20 saccharides.
  • Suitable monosaccharides include, but are not limited to, glucose (dextrose), fructose (levulose) and galactose. Monosaccharides are the building blocks of disaccharides (such as sucrose) and polysaccharides (such as celluloses, chitosans, ulvanes and starches).
  • each carbon atom that supports a hydroxyl group is chiral, giving rise to a number of isomeric forms all with the same chemical formula.
  • a large number of biologically important modified monosaccharides exists e.g. amino sugars such as Galactosamine, Glucosamine, Sialic acid, N-Acetylglucosamine, and sulfosugars such as Sulfoquinovose. All of these monosaccharide and polysaccharide derivatives may be used as LINKER in the present invention.
  • LINKER is a polynucleotide comprising 6 to 30 nucleotides. In one particular example, LINKER is a polynucleotide comprising 6 to 25 nucleotides. In one particular example, LINKER is a polynucleotide comprising 6 to 20 nucleotides. In one most particular example, LINKER is a polynucleotide comprising 7 to 20 nucleotides. Suitable nucleotides include adenine (A), guanine (G), thymine (T), cytosine (C), uracil (U) and derivatives, analogues and/or mimetic thereof.
  • A adenine
  • G guanine
  • T thymine
  • C cytosine
  • U uracil
  • LINKER is a saturated or unsaturated hydrocarbon chain of at most 10 nanometres (nm) in length, preferably at most 144 nanometres (nm) in length, in particular at most 120 nm, 96nm, 84 nm or 72 nm as determined using the standard « 2D » procedure described above.
  • such saturated or unsaturated hydrocarbon chains include polyethylene glycol (PEG) or any one of its derivatives.
  • PEG polyethylene glycol
  • LINKER is a hexapeptide (6 amino acids). More particularly, LINKER is a heptapeptide (7 amino acids). More particularly, LINKER is a octapeptide (8 amino acids). More particularly, LINKER is a nonapeptide (9 amino acids). More particularly, LINKER is a decapeptide (10 amino acids). More particularly, LINKER is a hendecapeptide (1 1 amino acids). More particularly, LINKER is a dodecapeptide (12 amino acids). More particularly, LINKER is a tridecapeptideo (13 amino acids).
  • LINKER is a tetradecapeptide (14 amino acids). More particularly, LINKER is a pentadecapeptide (15 amino acids). More particularly, LINKER is a hexadecapeptide (16 amino acids). More particularly, LINKER is a heptadecapeptide (17 amino acids). More particularly, LINKER is an octadecapeptide (18 amino acids). More particularly, LINKER is an enneadecapeptide (19 amino acids). More particularly, LINKER is an icosapeptide (20 amino acids).
  • LINKER comprises one or more of a peptide selected from the group consisting of DENEKVV, DENKNVV, DEYDKVV, DDSSNVI, DSSNNVI, DDMGVPT, DKGVVTY, NDKQQII, DAANNVV, DSANNVV, DDSSNVI, DNGRVLL, VGRKPKV, IGKTPKI, VGRTPKV, RIKPHQGQH, EYVRKKPKL, EIVRKKPIF, EYVRKKP, EIVRKKP, polyalanine ( ⁇ ,. ⁇ ) (preferably A 2 - 8 ) and polyglycine (Gi_i 2 ) (preferably G 2 . 8 ).
  • a peptide selected from the group consisting of DENEKVV, DENKNVV, DEYDKVV, DDSSNVI, DSSNNVI, DDMGVPT, DKGVVTY, NDKQQII, DAANNVV, DSANNVV
  • the covalent bonds between e.g. LINKER, PEP(B), PEP(D) or PEP2, PEP4, PEP6, PEP8 and PEP10 may be created through the chemical reaction between a free amine moiety e.g. of a N-terminal amino acid (-NH 2 or -NH 3 X, X generally being a halide anion selected from the group consisting of F " , CI " and Br " ), typically acting as a nucleophile, and an electrophile moiety of e.g. a C-terminal amino acid.
  • a free amine moiety e.g. of a N-terminal amino acid (-NH 2 or -NH 3 X, X generally being a halide anion selected from the group consisting of F " , CI " and Br " ), typically acting as a nucleophile, and an electrophile moiety of e.g. a C-terminal amino acid.
  • the covalent bonds between e.g. LINKER, PEP(B), PEP(D) or PEP2, PEP4, PEP6, PEP8 and PEP10 may be created through the chemical reaction between a free carboxylic acid moiety e.g. of a C- terminal amino acid (-C0 2 H or -C0 2 X, X generally being an inorganic cation such as alkaline cations (e.g. Li + , Na + or K + ) or an organic cation such as ammonium cations), typically acting as an electrophile, and a nucleophile moiety of e.g.
  • a free carboxylic acid moiety e.g. of a C- terminal amino acid (-C0 2 H or -C0 2 X
  • X generally being an inorganic cation such as alkaline cations (e.g. Li + , Na + or K + ) or an organic cation such as ammonium cations), typically acting as an electro
  • nucleophile moiety includes, but is not limited to, alcohols (-OH), amines (-NH 2 ), phosphines (-PR 3 ), thiols (-SH). More particularly, this covalent interaction is a peptide bond formed through conventional peptide synthesis using conventional coupling reagents as already defined herein.
  • Cyclisation of a cyclic GFR-binding compound of the present disclosure may be carried out as described above using conventional peptide bond formation procedures, click chemistry, formation of disulphide bonds, etc.
  • the present disclosure provides pharmaceutical associations, combinations and compositions, methods and uses for converting or recoding any neoplastic cell into a non-neoplastic cell (in particular, a functional and healthy cell) of any type.
  • the cell type of the converted or recoded nonneoplastic cell may be selected/chosen by e.g. a person providing the treatment to a subject.
  • said pharmaceutical association, combination or composition induces the conversion of a neoplastic cell into a physiologically functional and/or healthy cell of any cell lineage including, but not limited to, bone cell, chondrocytic cell, neuron cell, fibroblast, vascular cell, ligament cell, tendon cell, epithelial cell, retina photoreceptor cell, muscle cell, glandular cell, myoepithelial cell, subepithelial interstitial cell, smooth muscle cell, blood cell, gastrointestinal cell, adipocyte, Sertoli cells, Leydig cell, Germ cell and renal cell lineages.
  • Such cells include any progenitor or precursor cells or any partially or fully differentiated cells of these lineages.
  • a neoplastic cell of a bone tissue i.e. a neoplastic cell from the bone cell lineage
  • a neoplastic cell of a bone tissue may be or will be the cause of the development of a neoplastic bone disease (e.g. bone cancer).
  • a physiologically functional and/or healthy cell any physiologically functional and/or healthy cell of the bone cell lineage
  • a physiologically functional and/or healthy cell any physiologically functional and/or healthy cell of the bone cell lineage may protect a subject/patient carrying this cell from bone cancer.
  • a neoplastic bone cell into a functional and/or healthy cell of a different cell lineage i.e. not a cell from a bone lineage, such as, for example, in certain embodiments, a cell from a chondrocytic cell lineage, a fibroblast lineage or a ligament/tendon cell lineage.
  • a neoplastic cell of a soft tissue such as a muscle, vascular, skin or kidney tissue (i.e.
  • a neoplastic cell from the muscle, vascular, skin or kidney cell lineage, respectively) has been, may be or will be the cause of the development of a neoplastic muscle, vascular, skin or kidney disease (e.g. Rhabdomyosarcoma, Hemangiosarcoma, basal cell carcinoma or Squamous cell carcinoma, respectively).
  • a physiologically functional and/or healthy cell any physiologically functional and/or healthy cell
  • a neoplastic muscle, vascular, skin or kidney cell into a functional and/or healthy cell of a different cell lineage i.e. not a cell from a muscle, vascular, skin or kidney lineage, such as, for example, in certain embodiments, a cell from a bone cell lineage so that a medical practitioner such as a surgeon, may be able to surgically remove the newly converted bone cells more conveniently.
  • the surgery may be carried out purely for aesthetic reasons and/or because of a discomfort and/or to avoid the possibility of e.g. infections, complications, etc.
  • a neoplastic cell of an adipose tissue i.e. a neoplastic cell from the adipocyte lineage
  • a neoplastic adipose tissue disease e.g. adipose tissue cancer or lipoma
  • Several treatment routes may be envisaged to induce the conversion of this neoplastic adipocyte into a physiologically functional and/or healthy cell and thus protect a subject/patient carrying this cell from a lipoma.
  • neoplastic adipocyte into a functional and/or healthy cell of a bone cell lineage.
  • a non-neoplastic bone cell e.g. an osteocyte
  • surgical removal of the newly converted bone cells may be performed for e.g. aesthetic reasons and/or because of a discomfort and/or to avoid the possibility of e.g. infections, complications, etc.
  • neoplastic adipocyte into a functional and/or healthy cell of a muscle cell lineage.
  • a non-neoplastic muscle cell e.g. a myocyte
  • the patient would generally not feel any substantial discomfort and therefore, the surgical removal of the newly converted muscle cells may be avoided, although it may still be performed if the patient were to feel even the slight discomfort.
  • the necessity of performing surgery following the presently defined recoding treatment would generally be left to the appreciation of the patient upon supervision of a medical practitioner.
  • the present disclosure thus provides methods to convert or recode a neoplastic cell of a specific tissue/cell type (e.g. bone, cartilage, neuron, prostate, ovary, muscle, skin, vascular, ligament, tendon, eye retina, kidney, head, neck, blood, gastrointestinal, lung and adipose tissues) into a non-neoplastic cell of any tissue/cell type (e.g. bone, cartilage, neuron, prostate, ovary, muscle, skin, vascular, ligament, tendon, eye retina and kidney).
  • a neoplastic cell of a specific tissue/cell type e.g. bone, cartilage, neuron, prostate, ovary, muscle, skin, vascular, ligament, tendon, eye retina and kidney.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of a bone cell lineage.
  • PEP2 is selected from the group consisting of LKNYQ, LKKYR, LRKHR and LKYHY.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, VRS, VKS and EDH .
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, VRS, VKS and EDH ; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent or E; wherein AA 27 and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA is selected from the group consisting of D, E, N , G, M and T, preferably AA 28 is selected from the group consisting of M , I , V and L; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMVVE, E
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 ; and wherein at least one of AA
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, VRS, VKS and EDH ; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N , G, M and T, preferably AA 28 is selected from the group consisting of M, I , V and L; wherein AA 29 is absent or selected from
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, M IVRSXKXS, MIVKSXKXS, MVVKSXKXS and TLEDH LAXKXE.
  • PEP is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, M IVRSXKXS, MIVKSXKXS, MVVKSXKXS and TLEDH LAXKXE.
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, most particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of a bone cell lineage are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP1 0 are particularly useful for these applications as defined in the present bone section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of a chondrocytic cell lineage.
  • PEP2 is selected from the group consisting of LKNYQ, LKKYR, YKQYE and EQLSN .
  • PEP4 is selected from the group consisting of VVE, VVR, VRS and VKS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N and M , preferably AA 28 is selected from the group consisting of M , I and V; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably absent.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMVVR, DMVVE, M IVRS, M
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, preferably absent, G, S or A; AA 34 is absent or is selected from the group consisting of AA and AA amino acids, preferably absent; wherein AA 35 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids, preferably is G or K; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 38 is absent
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N and M , preferably AA 28 is selected from the group consisting of M , I and V; wherein
  • AA is absent or selected from the group consisting of AA amino acids, preferably absent; wherein AA is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, preferably absent, G , S or A; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, preferably absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, preferably is G or K; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 .
  • PEP1 0 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH , DMVVESXGXR, M IVRSXKXS, M IVKSXKXS and MVVKSXKXS.
  • PEP polyethylene neoplastic cell
  • PEP4 PEP2:PEP6, or PEP2:PEP6:PEP8
  • PEP10 PEP10
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of a vascular cell lineage.
  • PEP2 is selected from the group consisting of IGEMS, LGEMS, KEVQV and KKATV.
  • PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH .
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of F, L, R and T, preferably AA 28 is L or E; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent.
  • PEP6 is selected from the group consisting of LEEHS, FLQHN, RLEEH and TLEDH.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is selected from the group consisting of K, Q and L; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent, E or A; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is selected from the group consisting of E, A and K; wherein AA 37 is absent or is selected from the group consisting of
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of QHN, EHS, EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of F, L, R and T, preferably AA 28 is L or E; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent; wherein AA 33 is
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP1 0 are particularly useful for these applications as defined in the present vascular tissue section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of a neuron lineage.
  • PEP2 is selected from the group consisting of LKKYR, LKYHY, YKQYE and KFKYE.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VRS and VKS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N , G and M , preferably AA 28 is selected from the group consisting of M , I and V; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMV
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A and E; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is G or K; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N , G and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent or selected from the group consisting
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, N MVVRSXGXH , NM VVR AXGXH , NMVVKAXGXH , EGMSVAEXGXR, M IVRSXKXS, MIVKSXKXS, MVVKSXKXS and TLEDHLAXKXE.
  • PEP PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, most particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of a neuron lineage, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present neurogeneration section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of an eye retina cell lineage.
  • PEP2 is YGKIP.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably absent or E; wherein AA 27 and AA 28 are independently selected from the group consisting of AA m and AA V amino acids, preferably AA is selected from the group consisting of D, E, N, G and M, preferably AA is M or I; wherein AA is absent or selected from the group consisting of AA M amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMVVR, NMVVK, EG MS
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A, E and R; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR and XGXL.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N , G and M , preferably AA is M or I ; wherein AA is absent or selected from the group consisting of AA 11 amino acids,
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and M IVEEXGXL.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present eye retina section .
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of a renal cell lineage.
  • PEP2 is YGKIP.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N , G and M , preferably AA is M or I ; wherein AA is absent or selected from the group consisting of AA 11 amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMVVR, NMVVK, EGMSV
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G , S, A, E and R; AA 34 is absent or is selected from the group consisting of AA m and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein
  • PEP8 is selected from the group consisting of GXGXR, SXGXH , AXGXH , XGXR, EXGXR, RXGXS, AXGXR, SXGXR and XGXL.
  • PEP1 0 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N , G and M , preferably AA 28 is M or I ; wherein AA 29 is absent or selected from the group consisting of AA M
  • PEP1 0 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and M IVEEXGXL.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP1 0 are particularly useful for these applications as defined in the present renal tissue section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the ligament and tendon cell lineage.
  • PEP2 is selected from the group consisting of LKKYR, YKQYE and EQLSN.
  • PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS and VVK.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS and VVK; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent; wherein AA 27 and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA is selected from the group consisting of D, E, N and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMVVR, DMVVE, MIVRS, MIV
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S and A; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is G or K; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, SXGXR, XKXS and SXKXS.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 - AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS and VVK; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, N MVVRSXGXH , NMVVRAXGXH , DMVVESXGXR, M IVRSXKXS, M IVKSXKXS and MVVKSXKXS.
  • PEP polyethylene neoplastic cell
  • PEP4 PEP2:PEP6, or PEP2:PEP6:PEP8
  • PEP1 0 PEP1 0
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • PEP2 is YKQYE.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA 1 " amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is M or I; wherein AA 29 is absent or selected from the group consisting of AA 11 amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMVVR, NMVVK, EGM
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A, E and R; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR and XGXL.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 - AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is M or I; wherein AA 29 is absent or selected from the group consisting of AA M amino
  • PEP10 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and MIVEEXGXL.
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8 are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present L/T section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of a fibroblast lineage.
  • PEP2 is selected from the group consisting of EQLSN, IGEMS, KEVQV and KKATV.
  • PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS, VVK, QHN, EEH and EDH.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS, VVK, QHN, EEH and EDH; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent; wherein AA 27 and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA is selected from the group consisting of D, N, E, M, F, T and R, preferably AA 28 is selected from the group consisting of M, I, V and L; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent.
  • PEP6 is selected from the group consisting of DMVVE,
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A, K and L; AA 34 is absent or is selected from the group consisting of AA m and AA IV amino acids, in particular is absent, A or E; wherein AA 35 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids, in particular is selected from the group consisting of G, A, K and E; wherein AA 37 is absent or
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS, VVK, QHN , EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, N , E, M , F, T and R, preferably AA 28 is selected from the group consisting of M , I , V and
  • PEP1 0 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH , MIVRSXKXS, M IVKSXKXS, MVVKSXKXS, FLQHNKXEXR, RLEEHLEXAXA and TLEDHLAXKXE.
  • PEP polyethylene neoplastic cell
  • PEP4 PEP2:PEP6, or PEP2:PEP6:PEP8
  • PEP1 0 PEP2:PEP8 and PEP1 0 are particularly useful for these applications as defined in the present skin section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the reproduction system lineage.
  • PEP2 is LKKYR.
  • PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VRS, VKS, VVK, QHN, EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent or E; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, N, E, M and G, preferably AA 28 is M or I; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably is absent or S.
  • PEP6 is selected from the group consisting of DMVVE, EMVVE, NMVVR, NMVVK
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids, in particular is absent or is selected from the group consisting of G, S, A, E and R; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is absent; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids, in particular is G; wherein AA 37 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or
  • PEP8 is selected from the group consisting of GXGXR, SXGXH, AXGXH, XGXR, EXGXR, RXGXS, AXGXR, SXGXR and XGXL.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, VVR, VVK, VAE, AVS, VVD and VEE; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, N, E, M and G, preferably AA 28 is M or I; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably
  • PEP1 0 is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH and M IVEEXGXL.
  • PEP is selected from the group consisting of DMVVEGXGXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSX
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the reproduction system lineage are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present fertility and reproduction section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the lung cell lineage.
  • PEP2 is selected from the group consisting of LKKYR, LRKHR, LKYHY, KFKYE and YGKIP.
  • PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS ; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent or
  • AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N , G and M , preferably AA 28 is selected from the group consisting of M , I and V; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMVVE, NMTVE, EMVVE, NMVVR, NMVVK, EGMSVAE, GMAVS, GMVVD, DMVVE, M IVEE, M IVRS, M IVKS and MVVKS.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA 1 " and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA 11 amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 ; and wherein at least one of AA 33
  • PEP8 is selected from the group consisting of GXGXR, SXAXR, SXGXH , AXGXH , XGXR, EXGXR, RXGXS, AXGXR, SXGXR, XGXL and XKXS.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS ; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N , G and M , preferably AA 28 is selected from the group consisting of M , I and V; where
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVESXAXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH , M IVEEXGXL, M IVRSXKXS, M IVKSXKXS and MVVKSXKXS.
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVESXAXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRAXGXH , NMVVKAXGXH , EGMSVAEXGXR, GMAVSEXGXR
  • PEP2:PEP4, PEP2:PEP6, or PEP2:PEP6:PEP8, useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP1 0 are particularly useful for these applications as defined in the present lung section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the muscle cell lineage.
  • PEP2 is KEVQV or KKATV.
  • PEP4 is selected from the group consisting of VRS, VKS, QHN , EHS, EEH and EDH .
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VRS, VKS, QHN , EHS, EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of M , F, R, T and L, preferably AA 28 is selected from the group consisting of I , V, L and E; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably absent.
  • PEP6 is selected from the group consisting of M IVRS, M IVKS, MVVKS,
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 ; and wherein at least one of AA 33
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VRS, VKS, QHN , EHS, EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA is selected from the group consisting of M , F, R, T and L, preferably AA 28 is selected from the group consisting of I, V, L and E; wherein AA 29 is absent or selected from the group consisting of AA 11
  • PEP10 is selected from the group consisting of M IVRSXKXS, M IVKSXKXS, MVVKSXKXS, FLQHNKXEXR, LEEHSQXEXR, RLEEH LEXAXA and TLEDHLAXKXE.
  • PEP polyethylene terephthalate
  • PEP4:PEP6, or PEP2:PEP6:PEP8 useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the muscle cell lineage, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present muscle section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the blood cell lineage.
  • PEP2 is IGEMS or LGEMS.
  • PEP4 is selected from the group consisting of VVD, VVE, VVR, VEE, VRS, VKS, QHN , EHS, EEH and EDH .
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVD , VVE, VVR, VEE, VRS, VKS, QHN , EHS, EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of G , D, N , M , R, F, L and T, preferably AA 28 is selected from the group consisting of M , I , V, E and L; wherein AA is absent or selected from the group consisting of AA 11 amino acids, preferably is absent.
  • PEP6 is selected from the group consisting of GMVVD , DMVVE, NMVVR, M IVEE, MIVRS, MIVKS, MVVKS, FLQH N , LEEHS, RLEEH and TLEDH .
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 ; and wherein at least one of AA 33
  • PEP8 is selected from the group consisting of RXGXS, AXGXR, SXGXR, SXGXH , XGXL, XKXS, KXEXR, QXEXR, LEXAXA and LAXKXE.
  • PEP1 0 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVD, VVE, VVR, VEE, VRS, VKS, QHN , EHS, EEH and EDH ; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of G, D , N , M , R, F, L and T, preferably AA 28 is selected from the group consisting
  • PEP10 is selected from the group consisting of GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH , M IVEEXGXL, M IVRSXKXS, M IVKSXKXS, MVVKSXKXS, FLQHNKXEXR, LEEHSQXEXR, RLEEHLEXAXA and TLEDHLAXKXE.
  • PEP polyethylene terephthalate
  • PEP4:PEP6, or PEP2:PEP6:PEP8 useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the blood cell lineage, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP1 0 are particularly useful for these applications as defined in the present blood section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • Adipocyte cell lineage Adipocyte cell lineage
  • Certain embodiments of the invention are particularly useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the adipocyte lineage.
  • PEP2 is LKNYQ or LKKYR.
  • PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS.
  • PEP6 is a peptide of general formula AA 26 -AA 27 -AA 28 -AA 29 -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA m amino acids, preferably is absent or
  • AA and AA are independently selected from the group consisting of AA and AA amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent or selected from the group consisting of AA M amino acids, preferably absent or S.
  • PEP6 is selected from the group consisting of DMVVE, NMTVE, EMVVE, NMVVR, NMVVK, EGMSVAE, GMAVS, GMVVD, DMVVE, MIVEE, MIVRS, MIVKS and MVVKS.
  • PEP8 is an amino acid or a peptide with between two and six amino acids of general formula AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein AA 33 is absent or is selected from the group consisting of AA 1 amino acids at the exception of AA VI amino acids; AA 34 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 35 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 36 is absent or is selected from the group consisting of AA m and AA IV amino acids; wherein AA 37 is absent or is selected from the group consisting of AA M amino acids, preferably is S or C; wherein AA 38 is absent or is selected from the group consisting of AA 1 ; and wherein at least one of
  • PEP8 is selected from the group consisting of GXGXR, SXAXR, SXGXH, AXGXH , XGXR, EXGXR, RXGXS, AXGXR, SXGXR, XGXL and XKXS.
  • PEP10 is a peptide of general formula PEP6-AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 ; wherein PEP6 is a peptide of formula AA -AA -AA -AA -PEP4; wherein PEP4 is selected from the group consisting of VVE, TVE, VVR, VVK, VAE, AVS, VVD, VEE, VRS and VKS; wherein AA 26 is absent or selected from the group consisting of AA amino acids, preferably is absent or E; wherein AA and AA are independently selected from the group consisting of AA m and AA V amino acids, preferably AA 27 is selected from the group consisting of D, E, N, G and M, preferably AA 28 is selected from the group consisting of M, I and V; wherein AA 29 is absent
  • PEP10 is selected from the group consisting of DMVVEGXGXR, NMTVESXAXR, EMVVEGXGXR, NMVVRSXGXH , NMVVRSXGXH, NMVVRAXGXH, NMVVKAXGXH, EGMSVAEXGXR, GMAVSEXGXR, GMVVDRXGXS, DMVVEAXGXR, DMVVESXGXR, NMVVRSXGXH, MIVEEXGXL, MIVRSXKXS, MIVKSXKXS and MVVKSXKXS.
  • PEP polyethylene glycol
  • PEP4:PEP6, or PEP2:PEP6:PEP8 useful for inducing the conversion of a neoplastic cell into a cell (any cell) of the adipocyte lineage, are as already defined herein to the extent that PEP2, PEP4, PEP6, PEP8 and PEP10 are particularly useful for these applications as defined in the present adipose tissue section.
  • said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
  • said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
  • the present invention achieves its intended therapeutic action(s) i.e. the treatment of a neoplastic disease via extracellular, non-mutagenic, recoding or conversion of neoplastic cells, by functional combination (or association) of at least two bioactive substances, namely, a GFR-binding compound (e.g. non-cyclic or cyclic) as described above and a bioactive carrier.
  • a GFR-binding compound e.g. non-cyclic or cyclic
  • said GFR-binding compound and said bioactive carrier are thus operably associated, combined, linked or connected as defined herein and thus form a pharmaceutical association or combination for uses and methods of the present invention.
  • the present disclosure provides a bioactive carrier, as part of a pharmaceutical association as defined herein, as an active principle for use in methods and uses described herein.
  • Suitable bioactive carriers for implementing embodiments of the invention include any substance (i) which can interact and/or be compatible with a biological system and (ii) participate to the intended biological activity of a treatment as described in the present application.
  • bioactive carrier As may be used herein, the term “bioactive carrier”, “biocompatible carrier”, “bioactive material”, “biocompatible material”, “bioactive substance”, “bio-substance”, “biocompatible substance”, are used interchangeably.
  • a suitable bioactive carrier is compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system.
  • Bioactive carriers suitable for implementing embodiments of the present invention include, but are not limited to, (a) a biopolymer such as (a1 ) collagen, (a2) fibrin; (b) a synthetic polymer such as (b1 ) ultra-high molecular weight polyethylene (UHMWPE), (b2) polyurethane (PE), (b3) polyurethane (PU), (b4) polytetrafuoroethylene (PTFE), (b5) polyacetal (PA), (b6) polymethylmethacrylate (PMMA), (b7) polyethylene terepthalate (PET), (b8) silicone rubber (SR), (b9) polyetheretherketone (PEEK), (b10) poly(lactic acid) (PLA), (b1 1 ) polysulfone (PS), (b12) PLLA, (b13) PLGA or (b14) PLDA; (c) metals and metal oxides such as (d ) gold and gold alloys, (c2) silver and silver alloys, (c3) platinum and platinum alloy
  • (g) gel or solid ceramics such as (g 1 ) alumina, (g2) zirconia, (g3) carbon, (g4) titania, (g5) bioglass, or (g6) hydroxyapatite (HA); (h) composites such as (hi ) silica/SR, (h2) CF/UHMWPE, (h3) CF/PTFE, (h4) HA/PE, (h5) CF/epoxy, (h6) CF/PEEK, (h7) CF/C or (h8) Al 2 0 3 /PTFE; (i) hydrogels such as (i1 ) polyisocyanopeptide hydrogels such as oligo(ethylene)glycol poly
  • polysaccharides such as alginates, chitosans, chitins, guar gums, pectins, gellan gums, heparins, carrageenans, hyaluronans, starches, agars, xanthan gums, methylcellulose, carboxymethylcellulose, hydroxypropyl methyl cellulose, (i3) polyglycols such as polyethyleneglycol or polypropyleneglycol, (i4) polyvinylpyrrolidone, (i5) poly(vinylalcohol), (i6) polyacrylic acids, (i7) glycerophosphates, (i8) 2-acrylamido-2-methylpropanesulfonic acid, (i9) polyphosphazenes; (j) other suitable materials such as demineralized bone matrix; and any combinations thereof.
  • polysaccharides such as alginates, chitosans, chitins, guar gums, pectins, gellan gums,
  • Suitable sources of bioactive carriers for implementing embodiments of the present invention include, but are not limited to, autographs, allographs, xenographs, plants, solutions, excipients, ceramics, metals, metal alloys, organic and inorganic polymers, bioglasses, carbon-containing structures, or combination thereof.
  • bioactive carriers for implementing embodiments of the present invention include bioactive carriers comprising at least one naturally occurring hydroxyl group on at least one surface thereof and bioactive carriers which do not naturally comprise at least one hydroxyl group on a surface thereof but which have been modified using conventional surface treatment techniques such that at least one hydroxyl group is present on a surface of the bioactive carrier.
  • said hydroxyl group is an available hydroxyl group i.e. it is not prevented from interacting and/or reacting with a compound of the present disclosure.
  • Suitable as bioactive carriers naturally containing hydroxyl groups on a surface thereof for implementing embodiments of the invention specifically include metal oxides such as titanium oxides and non-metal oxides such ceramics.
  • bioactive carriers for implementing embodiments of the invention include bioactive carriers comprising at least one naturally occurring carboxylate group (-COOH) or amine group (-NH 2 ) on at least one of a surface thereof and bioactive carriers which do not naturally comprise at least one carboxylate group (-COOH) or amine group (-NH 2 ) onto a surface thereof but which have been modified using conventional surface treatment techniques such that at least one carboxylate group (-COOH) or amine group (-NH 2 ) is present on a surface of the bioactive carrier.
  • said bioactive carrier includes a biomaterial.
  • Suitable biomaterials for implementing certain embodiments of the present disclosure may be derived from nature or synthesized in the laboratory using a variety of chemical approaches utilizing metallic components, polymers, ceramics or composite materials. They are often used and/or adapted for a medical application, and thus comprise whole or part of a living structure or biomedical device.
  • Suitable biomaterials for implementing certain embodiments of the present disclosure are commonly used in joint replacements, bone plates, bone cement, artificial ligaments and tendons, dental implants for tooth fixation, blood vessel prostheses, heart valves, skin repair devices (artificial tissue), cochlear replacements, contact lenses, breast implants, drug delivery mechanisms, sustainable materials, vascular grafts, stents, nerve conduits.
  • biomaterials for implementing certain embodiments of the present disclosure such as metals and alloys (pages 94-95), ceramics (pages 95-97), polymeric biomaterials (pages 97-98) and biocomposite materials (pages 98-99) are described in Nitesh ef a/., International Journal of Emerging Technology and Advanced Engineering, ISSN 2250-2459, Volume 2, Issue 4, 2012, which is herein incorporated by reference in its entirety.
  • said bioactive carrier is a biomaterial.
  • particularly suitable bioactive carriers are selected from the group consisting of bioinert biomaterials, bioactive biomaterials and bioresorbable biomaterials.
  • the nature of the biomaterial is an important parameter. Particularly good results have been obtained using bioactive carriers composed mostly with the main material component of the tissue where the cells need to be recoded . For example, it was discovered that particularly good results may be obtained when a solid ceramic component (granulated ceramic powder or ceramic scaffolds) or a gel ceramic component is used in combination of a GFR-binding peptide of the present disclosure to recode osteosarcoma cells and thus protect from bone cancers.
  • collagen in particular collagen types I , I I , I II and XI
  • a GFR-binding peptide of the present disclosure to recode chondrosarcomas and thus protect from cartilage cancers.
  • particularly good results may be obtained when collagen, in particular collagen types I and III, or a biodegradable hydrogel is used in combination with a GFR-binding peptide of the present disclosure to recode disfunctioning muscle, skin, tendon and ligament cells.
  • a collagen or a biodegradable hydrogel is used in combination with a GFR-binding peptide of the present disclosure to recode cells and/or restore functions of vascular, neuron, eye retina, renal, wound healing, hair, fertility and reproduction, lung, and adipose tissues.
  • Bioinert biomaterials As used herein, unless indicated otherwise or contradictory in context, the term “bioinert biomaterials” refers to any material that once placed in the human body has minimal interaction with its surrounding tissue. Examples of these are stainless steel, titanium, alumina, partially stabilised zirconia, and ultra-high molecular weight polyethylene. Generally a fibrous capsule might form around bioinert implants hence its biofunctionality relies on tissue integration through the implant.
  • Bioactive biomaterial As used herein, unless indicated otherwise or contradictory in context, the term “bioactive biomaterial” refers to a material which, upon being placed within the human body, interacts with the surrounding bone and in some cases, even soft tissue.
  • Bioresorbable Biomaterials As used herein, unless indicated otherwise or contradictory in context, the term “bioresorbable biomaterials” refers to a material which, upon placement within the human body, starts to dissolve (resorbed) and slowly replaced by advancing tissue (such as bone). Examples of bioresorbable materials include, but are not limited to, tricalcium phosphate [Ca 3 (P0 4 ) 2 ], polylactic- polyglycolic acid copolymers, calcium oxide, calcium carbonate and gypsum.
  • bioactive carriers for implementing embodiments of the present invention insofar as said substance, material or molecule is (a) biocompatible as defined herein and (b) combinable or associable with a GFR- binding compound as defined herein.
  • said bioactive carrier has a stiffness of at least 5 kPa, more preferably at least 35 kPa and preferably not more than 3 or 5 GPa as measured using conventional Dynamic Mechanical Analysis such as described in details in Gong JP ef a/., Double- network hydrogels with extremely high mechanical strength, Adv Mater 2003, 15(14), 1 155e8, which is incorporated herein by reference.
  • a biomaterial as defined herein for use in neuron-related applications has a stiffness comprised between about 0.01 kPa and about 3 kPa, preferably between about 0.01 kPa and about 1 kPa.
  • a biomaterial as defined herein for use in muscle, cartilage and tendon/ligament -related applications has a stiffness comprised between about 3 kPa and about 200 kPa, preferably between about 10 kPa and about 30 kPa.
  • a biomaterial as defined herein for use in bone-related applications has a stiffness comprised between about 30 kPa and about 2 GPa, preferably between about 70 kPa and about 200 kPa.
  • a biomaterial as defined herein for use in hair-related applications has a stiffness comprised between about 0.01 kPa and about 200 kPa, preferably between about 3 kPa and about 70 kPa.
  • a biomaterial as defined herein for use in endothelization-related applications has a stiffness comprised between about 0,01 kPa and about 500 kPa.
  • a biomaterial as defined herein for use in angiogenesis-related applications has a stiffness comprised between about 0.5 kPa and about 100 kPa.
  • a biomaterial as defined herein for use in wound healing and skin- related applications has a stiffness comprised between about 0.01 kPa and about 70 kPa.
  • free hydroxyl or “available hydroxyl” means an hydroxyl group, which may be -OH or a radical (- ⁇ ' ) or an anion (-0 ) fully or partially ionised, which is able to / free to act as a nucleophile in a reaction with an electrophile such as compound (A) or compound (B) defined below.
  • Available hydroxyl-containing surface As used herein, unless indicated otherwise or contradictory in context, the term "available hydroxyl-containing surface” or “free hydroxyl-containing surface” means a surface containing at least one free or available hydroxyl group as defined herein.
  • Ceramics As used herein, unless indicated otherwise or contradictory in context, the term “ceramic” refers to an inorganic material with a high melting point, above 1000°C. Most typically, materials referred to as “ceramics” are obtained by a process in which raw material solid particles are heated in order to sinter them. Materials referred to as “ceramics” may broadly be split into two groups, these being “oxide ceramics” and “non-oxide ceramics”. “Oxide ceramics” include, but are not limited to, alkaline earth oxides such as MgO and BaO, Al 2 0 3 and aluminates, Ti0 2 and titanates, Zr0 2 and zirconates, silicates such as clays and clay-derived materials.
  • Non-oxide ceramics include, but are not limited to, carbides and nitrides, and also borides and silicides, for example silicon carbide and silicon nitride, and also metal carbides and nitrides.
  • solid ceramics e.g. in granulated powder or as a scaffold, is used as a bioactive carrier in the meaning of the present disclosure in bone-related applications.
  • gel ceramics is used as a bioactive carrier in the meaning of the present disclosure in bone-related applications.
  • Metal oxides As used herein, unless indicated otherwise or contradictory in context, the term "metal oxide” means a chemical compound that contains at least one oxygen atom and one other element in its chemical formula. Metal oxides typically contain an anion of oxygen in the oxidation state of -2. They can be obtained by hydrolysis or air/oxygen oxidation. Examples of such metal oxides are titanium oxides (e.g. TiO, Ti 2 0 3 , Ti0 2 ), silicon oxide (Si0 2 ), aluminum oxide (Al 2 0 3 ), iron (II, III) oxides such as Fe 2 0 3 , and zinc oxide (ZnO).
  • TiO titanium oxides
  • Ti 2 0 3 silicon oxide
  • Si0 2 silicon oxide
  • Al 2 0 3 aluminum oxide
  • iron oxides such as Fe 2 0 3
  • ZnO zinc oxide
  • Biopolymer refers to a polymer produced by living organisms and includes, but is not limited to, polypeptides and proteins (such as collagen and fibrin), polysaccharides (such as cellulose, starch, chitin and chitosan), nucleic acids (such as DNA and RNA), and hydrides thereof.
  • polypeptides and proteins such as collagen and fibrin
  • polysaccharides such as cellulose, starch, chitin and chitosan
  • nucleic acids such as DNA and RNA
  • Hydrogel As used herein, unless indicated otherwise or contradictory in context, the term “hydrogel” refers to "Hydrogel” refers to a class of polymeric materials which are swollen in an aqueous medium, but which do not dissolve in water. Hydrogels are highly absorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content.
  • U.S. Patent No. 6,475,516, for example provides hydrogels being covalently bound to the surface of an in-dwelling medical device such as an implant, which may be functionalized with a GFR-binding compound of the present disclosure using, for instance, a process as described herein. In one particular example, biodegradable hydrogels are used as bioactive carriers in the meaning of the present disclosure.
  • Collagen As used herein, unless indicated otherwise or contradictory in context, the term “collagen” refers to the main structural protein of the various connective tissues in animals which is mostly found in fibrous tissues such as tendons, ligaments and skin, and is also abundant in corneas, cartilage, bones, blood vessels, the gut, and intervertebral discs. Collagen is typically composed of a triple helix and generally contains high hydroxyproline content. The most common motifs in its amino acid sequence glycine-proline-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline.
  • Collagen I which may be found in skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone); Collagen II which may be found in cartilage (main component of cartilage); Collagen III which may be found in reticulate (main component of reticular fibers); Collagen IV which may be found in the basal lamina, the epithelium-secreted layer of the basement membrane; Collagen V which may be found on cell surfaces, hair and placenta.
  • suitable collagens for implementing embodiments of the present invention particularly include collagen type-l and type-IV.
  • collagen in particular collagen types I, II, III and XI
  • cartilage-related applications In one particular example, collagen, in particular collagen types I and III, is used as a bioactive carrier in the meaning of the present disclosure in muscle-related applications, skin-related applications, and T/L-related applications.
  • any type of collagen is used as a bioactive carrier in the meaning of the present disclosure in vascular, neuron, eye retina, renal, wound healing, hair, fertility and reproduction, lung, adipose -related applications.
  • said association, combination, linkage or connection between said GFR-binding compound and a bioactive carrier may occur via a bioactive carrier-affinity-containing group as defined herein.
  • a bioactive carrier-affinity-containing group as defined herein.
  • said GFR-binding compound as already defined herein is modified or functionalised with at least one bioactive carrier-affinity-containing group.
  • Said at least one bioactive carrier-affinity-containing group provides said GFR-binding compound with an ability to, covalently or non- covalently, interact with, or be connected to, a bioactive carrier as defined herein (in particular, a biomaterial as defined herein).
  • said bioactive carrier- affinity-containing group may be a thiol (SH)-containing group or a cysteine-containing group, in particular, a thiol (SH)-containing peptide or a cysteine-containing peptide.
  • said bioactive carrier-affinity-containing group may particularly be a cysteine.
  • said bioactive carrier-affinity-containing group may comprise (or be) a peptide group such as any one of the peptide groups disclosed in US patent application No. 2008/0268015 A1 , which is hereby incorporated by reference in its entirety.
  • peptides containing amino acid sequences rich in large aromatic amino acid residues that include one or more of Phe, Trp, Tyr such as sequence no: 1 to 45 described in US 2008/0268015 A1 are suitable as a biomaterial-affinity-containing fragment for implementing embodiments of the present invention.
  • Said fragment may also be a peptide fragment such as any one of the peptide fragments disclosed in US patent No. 6,818,620 B2, which is hereby incorporated by reference in its entirety.
  • peptides of sequence no: 1 to 7 described in US 6,818,620 B2 are suitable as a biomaterial-affinity-containing fragment for implementing embodiments of the present invention.
  • said biomaterial affinity- containing group may be a peptide with 3 to 25 amino acids comprising one or more of Phe, Trp or Tyr.
  • said bioactive carrier-affinity-containing group is a bioactive carrier high- affinity-containing group such as a biomaterial high-affinity-containing group.
  • said bioactive carrier-affinity-containing group has some affinity (preferably high affinity) with a given bioactive carrier (in particular, a biomaterial) such as collagen, apatite, titanium or any of those listed in e.g. US patent application No. 2008/0268015 A1 , which is incorporated herein by reference.
  • a group having some affinity with a biomaterial is any group capable to non- covalently interact/bind to a biomaterial with an affinity/specificity selected from at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, or a higher percentage, with respect to an affinity where said group binds to an appropriate control such as, for example, a different material or surface, or a protein typically used for such comparisons such as bovine serum albumin.
  • an appropriate control such as, for example, a different material or surface, or a protein typically used for such comparisons such as bovine serum albumin.
  • a biomaterial-affinity-containing group has a binding specificity that is characterized by a relative binding affinity as measured by an EC50 of 10 mM or less, and in certain emdiments, less than 1 mM.
  • a relative affinity comprised between 1 pM and 100 mM, between 1 pM and 10 mM, or between 1 pM and 1 mM is particularly suitable.
  • the EC50 is determined using any number of methods known in the art. In this case, the EC50 represents the concentration of fragment producing 50% of the maximal binding observed for that fragment in the assay.
  • said bioactive carrier-affinity-containing group is selected from the group consisting of GTPGP, which may preferably non-covalently interact with a bioactive carrier such as an apatite, and WWFWG, which may preferably non-covalently interact with a bioactive carrier such as a collagen.
  • said bioactive carrier-affinity-containing group is covalently or non-covalently (in particular, covalently) attached at an end (or extremity) of said GFR-binding compound.
  • the present disclosure provides a pharmaceutical association or combination comprising a modified (non-cyclic) GFR-binding compound and a bioactive carrier, wherein said modified (non-cyclic) GFR-binding compound comprises a (non-cyclic) GFR-binding compound as defined in the present disclosure and a bioactive carrier-affinity-containing group also as defined herein.
  • said modified GFR-binding compound comprises a GFR-binding compound as defined in the present disclosure and a bioactive carrier-affinity-containing group; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine- containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic.
  • a thiol-containing group in particular, a thiol-containing peptide
  • cysteine-containing group in particular, a cysteine- containing peptide and more particularly, a cysteine
  • an aromatic amino acid-containing peptide or peptidomimetic an aromatic amino acid-containing peptide or peptidomimetic.
  • the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR- binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7-17, more particularly between 10-25, 10-22, 10-20 or 10-17, even more particularly between 15-25, 15-22, 15-20 or 15-17) amino acids, comprising a peptide with five amino acids (PEP2) selected from the group consisting of LKNYQ, LKVYP, LKKYR, LRKHR, LKYHY, KFKYE, YGKIP, YKQYE, DHHKD, EQLSN, IGEMS, LGEMS, KEVQV and KKATV; wherein said GFR- binding compound
  • the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR- binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7- 17, more particularly between 10-25, 10-22, 10-20 or 10-17, even more particularly between 15-25, 15- 22, 15-20 or 15-17) amino acids, having the following general formula (I) (hereinafter may also be referred to as compound (I) or peptide (I)):
  • PEP2-PEP(D) (I) wherein PEP2 is a peptide with five amino acids as already defined herein; wherein one end of PEP(D) interacts covalently with one end of PEP2; wherein PEP(D) is a peptide with at least 5 amino acids, in particular a peptide with between 5 and 1 1 amino acids; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic.
  • a thiol-containing group in particular, a thiol-containing peptide
  • cysteine-containing group in particular, a cysteine-containing peptide and more particularly, a cysteine
  • the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR- binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7- 17, more particularly between 10-25, 10-22, 10-20 or 10-17, even more particularly between 15-25, 15- 22, 15-20 or 15-17) amino acids, having the following general formula (II) (hereinafter may also be referred to as compound (II) or peptide (II)):
  • PEP2-PEP6-PEP8 wherein PEP2 is a peptide with five amino acids as already defined herein; wherein PEP6 is a peptide with between five and seven amino acids as already defined herein; wherein PEP8 an amino acid or a peptide with between two and six amino acids as already defined herein; wherein one end of PEP6 interacts covalently with one end of PEP2 via AA 26 ; wherein another end of PEP6 interacts covalently with one end of PEP8 via AA 32 ; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine- containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic.
  • a thiol-containing group in particular, a thiol-containing peptid
  • the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR- binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 7-25 (in particular between 7-20 or 7- 17, more particularly between 10-25, 10-22, 10-20 or 10-17, even more particularly between 15-25, 15- 22, 15-20 or 15-17) amino acids, having the following general formula (III) (hereinafter may also be referred to as compound (III) or peptide (III)): AA 21 -AA 22 -AA 23 -AA 24 -AA 25 -AA 26 -AA 27 -AA 28 -AA 29 -AA 30 -AA 31 -AA 32 -AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 (III) wherein AA 2
  • said modified (non-cyclic) GFR-binding compound comprises a (non-cyclic) GFR-binding compound and a bioactive carrier-affinity-containing group; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said (non-cyclic) GFR-binding compound with respect to PEPREF is 2.45A (Angstroms) or less, in particular is 2k or less, and more particularly is 1 .79A or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
  • the present disclosure provides a pharmaceutical association or combination comprising a modified cyclic GFR-binding compound and a bioactive carrier, wherein said modified cyclic GFR-binding compound comprises a cyclic GFR-binding compound as defined in the present disclosure and a bioactive carrier-affinity-containing group also as defined herein.
  • said modified cyclic GFR-binding compound comprises a cyclic GFR-binding compound as defined in the present disclosure and a bioactive carrier-affinity-containing group; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic.
  • a thiol-containing group in particular, a thiol-containing peptide
  • cysteine-containing group in particular, a cysteine-containing peptide and more particularly, a cysteine
  • an aromatic amino acid-containing peptide or peptidomimetic an aromatic amino acid-containing peptide or peptidomimetic.
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids; comprising a peptide with five amino acids (PEP2) selected from the group consisting of LKNYQ, LKVYP, LKKYR, LRKHR, LKYHY, KFKYE, YGKIP, YKQYE, DHHKD, EQLSN, IGEMS, LGEMS, KEVQV and KKATV; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of LKNY
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR-binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 10-35 amino acids, in particular between 10-30 amino acids, more particularly between 12-30 amino acids, and even more particularly between 12-28 amino acids, having the following general formula (IV):
  • LINKER-PEP(B) (IV) wherein one end of LIN KER interacts covalently with one end of PEP(B); wherein PEP(B) comprises PEP2; wherein LIN KER is a linear or branched organic divalent radical, moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic.
  • Mw molecular weight
  • said bioactive carrier-affinity-containing group is selected from the group consisting of a
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (V):
  • LINKER-PEP2-PEP(D) (V) wherein LINKER is a linear or branched organic divalent radical , moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP2 is a peptide with five amino acids as already defined herein; wherein one end of PEP(D) interacts covalently with one end of PEP2; wherein one end of LINKER interacts covalently with one end of PEP2; wherein PEP(D) is a peptide with at least 5 amino acids, in particular a peptide with between 5 and 1 1 amino acids; wherein said bioactive carrier-affinity- containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol- containing peptide), a cysteine-containing group (
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (VI): LINKER-PEP2-PEP6-PEP8 (VI) wherein LINKER is a linear or branched organic divalent radical , moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein PEP
  • the present disclosure provides a modified cyclic GFR-binding compound comprising a cyclic GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said cyclic GFR- binding compound is a cyclic peptide, a variant or analog thereof, or a cyclic peptidomimetic as defined herein, with between 10-35 (in particular between 10-30, more particularly between 12-30, and even more particularly between 12-28) amino acids, comprising a peptide, a variant or analog thereof, or a peptidomimetic having the following general formula (VI I):
  • LINKER is a linear or branched organic divalent radical , moiety or compound having a molecular weight (Mw) comprised between 450 and 4,500 Daltons, in particular comprised between about 600 and about 4,500 Da, more particularly between about 600 and about 4,000 Da, and even more particularly between about 600 and about 3,500 Da; wherein AA 2 -AA 22 -AA 23 -AA 24 -AA 25 is PEP2 as already defined herein; wherein AA 30 -AA 3 -AA 32 is PEP4 as defined herein; wherein AA 33 -AA 34 -AA 35 -AA 36 -AA 37 -AA 38 is PEP8 as defined herein ; wherein AA 26 , AA 27 , AA 28 , and AA 29 are as defined herein; wherein one end of LINKER interacts covalently with AA 21 ; wherein AA 21 may be an N-terminal amino acid or a C-terminal amino acid; wherein AA 38 may be an N-termin
  • said bioactive carrier-affinity-containing group is comprised within said cyclic GFR-binding compound e.g. is comprised in said LINKER, or is said LINKER.
  • said modified cyclic GFR-binding compound may have any one of the following general schematic formulae:
  • the present disclosure provides a pharmaceutical association or combination, which may be used for converting or recoding, in-vitro, ex-vivo or in-vivo, a neoplastic cell into a non-neoplastic cell, comprising at least one (modified) GFR-binding compound and a bioactive carrier, both as defined in the present disclosure.
  • said (modified) GFR-binding compound and bioactive carrier are both active principles/ingredients.
  • said GFR-binding compound and bioactive carrier are functionally associated/combined as defined herein.
  • said pharmaceutical association or combination is a modified, functionalised, coated or grafted biomaterial as defined herein.
  • the present pharmaceutical associations or combinations may thus also be used for protecting a subject carrying a neoplastic cell from a neoplastic disease.
  • the present disclosure provides a pharmaceutical association or combination for the uses disclosed herein, substantially free from any cell adhesion promoter.
  • substantially free as applied to a given component such as a cell adhesion promoter, means that the amount of such a component is less than 20%, 15%, 10%, 5%, 1 %, 0.5%, 0.1 % or less in mole with respect to the mole content of (modified) GFR-binding compound unless otherwise indicated, self-evident or contradictory in context.
  • the present disclosure provides a pharmaceutical association as defined herein further comprising (another) anti-cancer agent thus forming a pharmaceutical composition of the invention.
  • said pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.
  • said further anti-cancer agent is functionally associated with said GFR-binding compound and/or said bioactive carrier. Suitable further anti-cancer agents include but are not limited to, agents that inhibit the synthesis of DNA molecule building blocks, agents that directly damage DNA in the cell nucleus, agents that affect the synthesis or breakdown of mitotic spindles, and agents that inhibit kinase proteins by interacting with the kinase active site.
  • agents that inhibit the synthesis of DNA molecule building blocks include, but are not limited to, methotrexate (Abitrexate®), fluorouracil (Adrucil®), gemcitabine (Gemzar®), arabinosylcytosine (araC), hydroxyurea (Hydrea®), and mercaptopurine (Purinethol®).
  • agents that directly damage DNA in the cell nucleus include, but are not limited to, carboplatin (Paraplatin® and paraplatin-AQ®), cisplatin (Platinol®) and antibiotics such as daunorubicin (Cerubidine®), doxorubicin (Adriamycin®), and etoposide (VePesid®).
  • Preferred examples of agents that affect the synthesis or breakdown of mitotic spindles include, but are not limited to, miotic disrupters such as Vinblastine (Velban®), Vincristine (Oncovin®) and Pacitaxel (Taxol®).
  • agents that inhibit kinase proteins include, but are not limited to, Afatinib®, Axitinib®, Bosulif®, Bosutinib®, Cabozantinib®, Caprelsa®, Cometriq®, Crizotinib®, Dasatinib®, Erlotinib®, Gilotrif®, Gleevec®, Ibrutinib®, lclusig®, Imatinib®, Imbruvica®, Inlyta®, Lapatinib®, Nexavar®, Nilotinib®, Pazopanib®, Ponatinib®, Regorafenib®, Sorafenib®, Sprycel®, Stivarga®, Sunitinib®, Sutent®, Tarceva®, Tasigna®, Tivopath®, Tivozanib®, Tykerb®, Vandetanib®, Votrient®, Xal
  • the L-asparaginase enzyme may also be used as a further agent in combination with the pharmaceutical association or composition as defined herein.
  • L-asparaginase enzyme has been reported e.g. in L-Asparaginase: A Promising Enzyme for Treatment of Acute Lymphoblastic Leukiemia, People's Journal of Scientific Research, Vol. 5(1 ), Jan. 2012, which is incorporated herein by reference in its entirety, to act by depriving cancer cells (such as leukemia cells) of asparagine thus inducing their death.
  • anti-cancer agents may also be used such as nitrogen mustards, ethylenimes, alkylsulfonates, triazenes, piperazines, nitrosureas and antibiotics such as anthracyclines, dactinomycin, bleomycin, adriamycin, or mithramycin.
  • the present disclosure provides a pharmaceutical association as defined herein further comprising an adhesion protein inhibitor thus forming a pharmaceutical composition of the invention.
  • said pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.
  • said adhesion protein inhibitor is functionally associated with said GFR-binding compound and/or said bioactive carrier.
  • Suitable adhesion protein inhibitors include, but are not limited to, siRNA, mRNA or microRNAs which inhibits or down-regulates the gene or protein expression of at least one integrin, syndecan, selectin or dystroglycan , anti-integrin antibodies, anti- syndecan antibodies, anti-selectin antibodies, anti-dystroglycan antibodies, foldamers, or dendrimers.
  • said pharmaceutical association or combination comprises one (modified) GFR-binding compound . In one example, said pharmaceutical association or combination comprises two or more distinct (modified) GFR-binding compounds. In one example, said pharmaceutical association or combination comprises three or more distinct (modified) GFR-binding compounds. In one example, said pharmaceutical association or combination comprises four or more distinct (modified) GFR-binding compounds.
  • the present disclosure provides a process or method for manufacturing a neoplastic disease medicament, said process comprising associating or combining at least one bioactive carrier with at least one (modified) GFR-binding compound both as defined herein.
  • Said step of associating or combining a bioactive carrier with a (modified) GFR-binding compound may be carried out using a method as already described above.
  • the present disclosure provides a process or method for manufacturing a neoplastic disease medicament precursor, said process comprising providing at least one (modified) GFR-binding compound and/or at least one bioactive carrier both as defined herein, wherein providing said bioactive carrier and/or said (modified) GFR-binding compound manufactures said neoplastic disease medicament.
  • said pharmaceutical association or composition substantially down-regulates, reduces, inhibits or suppresses the gene and/or protein expression of at least one of cyclin-D 1 , cyclin-D2 or cyclin- D3.
  • cyclins D1 , D2 and D3 regulate the activity of Cyclin-dependent kinases (CDKs) 4 and 6 by forming cyclin-CDK protein complexes including Cyclin D1 -CDK4 complex, Cyclin D1 -CDK6 complex, Cyclin D2-CDK4 complex, Cyclin D2-CDK6 complex, Cyclin D3-CDK4 complex and Cyclin D3-CDK6 complex
  • said pharmaceutical association or composition was also observed to substantially reduce, inhibit, suppress or destabilise the formation of any one of such complexes.
  • the inhibition values of a given pharmaceutical association or composition as defined herein is a measure of the gene expression of cyclins D as provided by RT-PCR. It is to be understood that the values of the gene expression of cyclins D disclosed herein correspond to the total gene expression of all cyclins D present in the tested cell i.e. D1 , D2 and D3 as known at the date of the present disclosure.
  • compositions suitable for implementing embodiments of the present invention reduce the gene expression of cyclins D by at least 20% during at least one part of the G1 phase of the cell cycle as compared to the wild-type expression.
  • the absolute and relative duration of each cell cycle phase usually varies (some phases such as the Gap phases may "shrink") amongst healthy cells of different types (e.g. bone cells, skin cells, etc ..) and between healthy cells and neoplastic cells of the same type (e.g. healthy bone cells and neoplastic bone cells).
  • Typical average cell cycle duration is commonly accepted to be about 24 hours.
  • phase durations for a healthy cell are 1 1 to 14 hours for the G1 phase, 5 to 12 hours for the S phase, 3 to 12 hours for the G2 phase and about 1 hour for the M phase.
  • neoplastic cells such as in cancer cells
  • the length of the G1 and G2 phases is generally shortened in order to increase cell division.
  • Cell cycle phase's duration may thus vary significantly from one cell type to another. Consequently, conventionally and for the purpose of facilitating the comparative representation of the inhibition of the gene expression of cyclins D for different cell types, the gene expression is represented as a function of the cell cycle progression (starting from G1 and finishing with M) and not as a direct function of time.
  • (bio)active principle” or “(bio)active ingredient” generally refers to a molecule, compound or substance which is responsible for providing the desired biological effect. Without said active ingredient, the formulation or composition containing it, would not provide the desired biological effect. For example, in certain embodiments, formulation excipients are not considered as active ingredients in the pharmaceutical composition as defined herein.
  • said (modified) GFR-binding compound and bioactive carrier are both active principles/ingredients.
  • the present disclosure also provides a GFR-binding compound modified to be associated with a bioactive carrier (i.e. a modified GFR-binding compound) to form a pharmaceutical association all as defined herein, for use in the prevention or treatment of a neoplastic disease.
  • Neoplastic disease medicament means a substance, compound, pharmaceutical association, combination, composition or formulation which is suitable for treating or preventing a neoplastic disease in a subject.
  • Subject carrying a neoplastic cell In the present description and unless otherwise indicated or contradictory in context, the term “subject carrying a neoplastic cell” means that at least one cell constitutive of the subject is a neoplastic cell as defined herein.
  • the terms “functionally associated”, “functionally combined”, “functionalized”, “immobilized”, “deposited”, “coated”, or “grafted” all refer to the action of associating or functionalising at least one part of a bioactive carrier with a (modified) GFR-binding compound so that the desired biological, therapeutic and/or cosmetic effect e.g. inducing tissue formation, is obtained.
  • the association or combination may be covalent and form, between said (modified) GFR-binding compound and said bioactive carrier, a covalent interaction as already defined herein, or, the association or combination may be non-covalent and form, between said (modified) GFR-binding compound and said bioactive carrier, a non-covalent interaction as already defined herein.
  • a (modified) GFR-binding compound interacts covalently (makes at least one functional covalent interaction) with said bioactive carrier.
  • the present disclosure thus provides a pharmaceutical association or combination comprising a (modified) GFR-binding compound and a bioactive carrier for use in converting or recoding a neoplastic cell into a non-neoplastic cell, wherein said GFR-binding compound (before any modifications) and said bioactive carrier are both as defined herein.
  • said pharmaceutical association or combination comprises at least one GFR- binding compound selected from the group consisting of peptides of SEQ ID NO: 1 to 10108.
  • the present disclosure provides a pharmaceutical association or combination comprising a (modified) GFR-binding compound, wherein all of PEP2, PEP4, PEP6, PEP10, pairs and triplets thereof, disclaimers and provisos, are as already defined herein.
  • Suitable covalent association or functionalization techniques for implementing embodiments of the present invention include, but are not limited to, reductive amination coupling or photo-grafting such as described in H. Freichel et al., Macromol. Rapid Commun. 201 1 , 32, 616-621 and V. Pourcelle et al., Biomacromol. 2009, 10, 966-974, the content of which is hereby incorporated by reference in its entirety.
  • the present disclosure provides a production method or process useful for producing a pharmaceutical association or combination according to the present disclosure wherein said bioactive carrier is a biomaterial such as a ceramic or a titanium, comprising, or exclusively consisting of, the contacting of a compound of formula (C-l) and a bioactive carrier as defined herein under suitable covalent-bond formation conditions thereby forming at least one covalent bond between said compound (C-l) and said bioactive carrier thus forming a pharmaceutical association or combination according to the present disclosure:
  • said bioactive carrier is a biomaterial such as a ceramic or a titanium

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Abstract

La présente invention concerne une association pharmaceutique à utiliser dans le traitement, la prévention et/ou le diagnostic d'une maladie néoplasique, ladite association comprenant au moins un composé de liaison au récepteur du facteur de croissance, qui active au moins un récepteur du facteur de croissance d'une cellule néoplasique, et au moins un support bioactif formant au moins une interaction covalente ou non-covalente avec ledit ou lesdits composés de liaison au récepteur du facteur de croissance, ladite association réduisant ou supprimant, dans la cellule néoplasique, l'expression génique d'une ou de plusieurs cyclines D et/ou réduisant ou supprimant la formation d'un ou de plusieurs complexes formés entre ladite ou lesdites cyclines D d'une part et la kinase dépendant de la cycline 4 et/ou la kinase dépendant de la cycline 6 d'autre part.
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