EP2136840A2 - Use of an anti-cxcr4 antibody for treating cancer - Google Patents
Use of an anti-cxcr4 antibody for treating cancerInfo
- Publication number
- EP2136840A2 EP2136840A2 EP08787975A EP08787975A EP2136840A2 EP 2136840 A2 EP2136840 A2 EP 2136840A2 EP 08787975 A EP08787975 A EP 08787975A EP 08787975 A EP08787975 A EP 08787975A EP 2136840 A2 EP2136840 A2 EP 2136840A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- antibody
- monoclonal antibody
- cancer
- tumor
- cxcr4
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Definitions
- the present invention relates to a new use of anti-CXCR4 antibodies capable of inhibiting tumor growth, said antibodies being in particular monoclonal of murine, chimeric and humanized origin.
- the subject of the invention is the use of these antibodies, or of their functional fragments, as a medicament for the prophylactic and / or therapeutic treatment of cancers.
- the invention finally comprises products and / or compositions comprising such antibodies in combination, for example, with antibodies and / or anticancer agents or conjugated with toxins and their use for the prevention and / or treatment of certain cancers. .
- the CXCR4 receptor is a G protein-coupled membrane receptor of the chemokine receptor family. There are two isoforms of the CXCR4 receptor composed respectively of 352 and
- the residue AsnI 1 is glycosylated, the residue Tyr 2 1 is modified by the addition of a sulfate group and there is a disulphide bridge between Cys 109 and 186 on the extracellular portion of the receptor.
- This receptor is expressed by a number of healthy tissues including endothelial cells, lymphocytes, macrophages, dendritic cells, "natural killers” and weakly in the heart, colon, liver, kidneys and brain.
- the CXCR4 receptor is over-expressed in a large number of cancers including colon, breast, prostate, lung (small cell and non-small cell), ovarian, pancreatic, kidney, brain and certain lymphomas.
- the expression of CXCR4 is increased on the metastatic cells versus cancer cells from the primary tumor.
- SDF-I Stromal-Derived Factor-1
- CXCL 12 The only known ligand of this receptor is "Stromal-Derived Factor-1 (SDF-I)" or CXCL 12. This is secreted in large quantities by lymph node, bone marrow, liver, lungs and in small amounts in the kidneys, brain and skin.
- the CXCR4 / SDF-1 axis plays an important role in cancer because it is directly involved in cell migration phenomena and the formation of metastases. Indeed, the cancer cells express the CXCR4 receptor, they migrate and enter the bloodstream. They stop at organs producing large amounts of SDF-I, they multiply and form metastases (Murphy PM., 2001).
- CXCR4 / SDF-1 axis plays a role in angiogenesis. More specifically, it has been clearly demonstrated in vitro that the CXCR4 receptor and its ligand SDF-I promote angiogenesis by stimulating the expression of VEGF-A which in turn increases the expression of CXCR4 / SDF-1 (Bachelder RE et al., 2002).
- tumor-associated macrophages are key components of inflammatory circuits for tumor growth.
- Chemokines including SDF-I, participate in the recruitment of macrophages in tumors.
- Monoclonal antibodies capable of recognizing the CXCR4 receptor could also reduce the recruitment of macrophages within tumors thereby limiting their effect on tumor growth.
- the present invention is directed to the use of an antibody, or a functional fragment thereof, capable of binding specifically to the CXCR4 protein for the treatment of cancer.
- the functional fragments of antibodies according to the invention consist, for example, of fragments Fv, scFv (se for simple chain), Fab, F (ab ') 2 , Fab', scFv-Fc or diabodies, or any fragment of which the half-life time would have been increased by chemical modification, such as the addition of poly (alkylene) glycol such as poly (ethylene) glycol (“PEGylation") (PEGylated fragments called Fv-PEG, scFv-PEG, Fab- PEG, F (ab ') 2 -PEG or Fab'-PEG) ("PEG” according to the English nomenclature Poly (Ethylene) Glycol), or by incorporation into a liposome, microspheres or PLGA, said fragments being capable of generally exercising even a partial activity of the antibody from which they are derived.
- poly (alkylene) glycol such as poly (ethylene) glycol (“PEGylation")
- said functional fragments will comprise or comprise a partial sequence of the heavy or light variable chain of the antibody from which they are derived, said partial sequence being sufficient to retain the same binding specificity as the antibody from which it is derived and sufficient affinity, preferably at least equal to 1/100, more preferably at least 1/10 that of the antibody from which it is derived.
- Such a functional fragment will comprise at least 5 amino acids, preferably 10, 15, 25, 50 and 100 consecutive amino acids of the sequence of the antibody from which it is derived.
- these functional fragments will be fragments of the Fv, scFv type,
- antibody fragments of the invention can be obtained from antibodies as previously described by methods such as digestion with enzymes, such as pepsin or papain and / or by cleavage of disulfide bridges. by chemical reduction.
- the antibody fragments included in the present invention may be obtained by genetic recombination techniques well known to those skilled in the art or by peptide synthesis using, for example, automatic peptide synthesizers such as than those provided by Applied.
- the antibody used is a murine monoclonal antibody.
- Antibodies according to the present invention also include chimeric or humanized antibodies.
- chimeric antibody an antibody which contains a naturally occurring variable (light chain and heavy chain) derived from an antibody of a given species in association with the light chain and heavy chain constant regions of an antibody of a heterologous species to said given species.
- the antibodies or their chimeric-like fragments used according to the invention can be prepared using genetic recombination techniques.
- the chimeric antibody can be made by cloning a recombinant DNA comprising a promoter and a sequence coding for the variable region of an antibody non-human monoclonal, particularly murine, according to the invention and a sequence coding for the constant region of human antibody.
- a chimeric antibody of the invention encoded by such a recombinant gene will for example be a mouse-human chimera, the specificity of this antibody being determined by the variable region derived from murine DNA and its isotype determined by the constant region derived from the murine DNA. Human DNA.
- Verhoeyn et al. BioEssays, 8:74, 1988.
- humanized antibody an antibody which contains CDRs regions derived from an antibody of non-human origin, the other parts of the antibody molecule being derived from one (or more) human antibodies.
- some of the skeletal segment residues (referred to as FR) can be modified to maintain binding affinity (Jones et al., Nature, 321: 522-525, 1986, Verhoeyen et al., Science, 239: 1534 1536, 1988, Riechmann et al., Nature, 332: 323-327, 1988).
- Humanized antibodies or their functional fragments can be prepared by techniques known to those skilled in the art (such as those described in Singer et al., J. Immun., 150: 2844-2857, 1992; al., Biotechnol Genet Eng.Rev., 10: 1-142, 1992 or Bebbington et al., Bio / Technology, 10: 169-175, 1992). Such humanized antibodies are preferred for use in prophylactic and / or therapeutic treatment methods in vivo. Other humanization techniques are also known to those skilled in the art, for example the "CDR Grafting" technique described by PDL which is the subject of patents EP 0 451 261, EP 0 682 040 and EP 0 939.
- the present invention is innovative in that, for the first time and contrary to the prejudices of those skilled in the art, it describes and claims the use of an anti-CXCR4 monoclonal antibody capable of acting not only at level of metastases but especially to act directly at the level of tumor growth of primary tumors.
- the present invention relates to the use of a monoclonal antibody, or a functional fragment thereof, capable of binding specifically to the CXCR4 protein to inhibit tumor growth in vitro and / or in vivo.
- a primary tumor Tumor cell transformation results in particular in a cell cycle control loss, insensitivity to apoptosis of abnormal repair I 1 DNA. Cancers are then classified according to the type of cell in which the first transformation occurred (lymphomas, carcinomas, sarcomas); this first malignant cell having then divided, forming the primary tumor. Some primary tumors may progress to a more general invasion of the body by escape of tumor cells from this primary tumor: this is called metastasis.
- primary tumor represents the first stage of cancer development whereas metastases represent a different and subsequent stage towards which primary tumors can evolve.
- the present invention therefore provides an alternative to existing treatments in that it provides early treatment of primary tumors before the latter metastasize.
- tumor growth of a primary tumor, it is necessary to understand the increase in the volume of said primary tumor, this increase in volume resulting from different mechanisms, namely vascularization, apoptosis or cell proliferation.
- vascularization it is necessary to understand the increase of the vascularization at the level of the primary tumor by angiogenesis and / or by vasculogenesis.
- Angiogenesis consists of the formation of new vessels (neovascularization) originating from a pre-existing capillary network by proliferation and migration of endothelial cells, especially during healing or the development of a cancerous tumor.
- Vasculogenesis is a process by which endothelial cells and a primitive plexus are generated by differentiation of endothelial cell precursors (angioblasts and hemangioblasts).
- apoptosis is meant the process by which cells trigger self-destruction in response to a signal. It is a genetically programmed cell death.
- cell proliferation is meant any process involved in increasing the number of cells. These processes are more about cell division as part of the cell cycle. More specifically, cell proliferation is the uncontrolled and excessive division of cells that gives rise to a tumor.
- the present invention therefore describes the use of a monoclonal antibody as described above, or one of its functional fragments, capable of inhibiting vascularization, that is to say angiogenesis and / or vasculogenesis , within the primary tumor.
- the present invention describes the use of an antibody as described above, or one of its functional fragments, capable of inhibiting the cellular proliferation of the tumor cells constituting the primary tumor.
- the present invention describes the use of an antibody as described above, or one of its functional fragments, capable of inhibiting the vascularization within the primary tumor and the cellular proliferation of tumor cells. constituting said primary tumor.
- the present invention describes the use of an antibody as described above, or one of its functional fragments, which is also capable of inducing the apoptosis of the tumor cells constituting the primary tumor. .
- the invention consists mainly in the use of at least one anti-CXCR4 antibody, or one of its functional fragments, which consists of a monoclonal antibody.
- a monoclonal antibody means an antibody derived from a substantially homogeneous antibody population. More particularly, the individual antibodies of a population are identical with the exception of a few possible mutations that can occur naturally which can be found in minute proportions.
- a monoclonal antibody consists of a homogeneous antibody resulting from the proliferation of a single cell clone (for example a hybridoma, a eukaryotic host cell transfected with a DNA molecule encoding the homogeneous antibody, a cell prokaryotic host transfected with a DNA molecule encoding the homomgene antibody, etc.) and which is generally characterized by heavy chains of one and the same class and subclass, and light chains of one type.
- the monoclonal antibodies are highly specific and are directed against a single antigen.
- each monoclonal antibody is directed against a single epitope of the antigen.
- the monoclonal antibody used is chosen from antibodies MAB 170 (from clone 12G5), MAB 171 from clone 44708), MAB 172 (from clone 44716) and MAB 173 ( from clone 44717) (http://www.rndsystems.com).
- each antibody may be named by name or by the name of the hybridoma from which it is derived.
- the MAB 173 antibody may be indifferently named, especially in the examples, 44717 or MAB 173 or Mabl73.
- Table 1 summarizes, in a non-exhaustive manner, for each clone, the antibodies available to those skilled in the art from R & D Systems.
- the monoclonal antibody according to the invention consists of the antibody MAB 173.
- the present invention therefore describes the use of an anti-CXCR4 monoclonal antibody, or a functional fragment thereof, said monoclonal antibody consisting of the MAB 173.
- the monoclonal antibody MAB173 was produced from a hybridoma resulting from fusion of murine myeloma with isolated B cells of a mouse immunized with murine 3T3 cells transfected with the hCXCR4 protein. The IgGs were then purified from the ascites fluid by protein G affinity chromatography (R & D Systems Factsheet for MAB 173). This antibody is described as specifically recognizing the human protein
- an antibody as described above for the preparation of a medicament for the treatment and / or prevention of cancer.
- anti-CXCR4 antibodies in the context of the treatment and / or prevention of cancer is particularly justified in cancers overexpressing the same CXCR4 receptor.
- Such cancers consist of cancers of the colon, breast, prostate, lung (small cell and non-small cell), ovarian, pancreas, kidney, brain and some lymphomas.
- the present invention therefore claims the use of an antibody as described above for the treatment of cancer, said cancer being selected from cancer of the colon, breast, prostate, lung (small cell and non-small cell), ovarian, pancreatic, kidney, brain and some lymphoma.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising as active principle a compound consisting of an antibody, or one of its derivative compounds or functional fragments, preferably supplemented with an excipient and / or a pharmaceutically acceptable vehicle.
- the invention relates to the use of an antibody according to the invention for the preparation of a pharmaceutical composition
- a pharmaceutical composition comprising, in addition, at least one pharmaceutically acceptable carrier
- pharmaceutically acceptable carrier is intended to mean a compound or a combination of compounds entering into a pharmaceutical composition that does not cause side reactions and that makes it possible, for example, to facilitate the administration of the active compound (s), to increase its shelf life and / or its effectiveness in the organism, the increase of its solubility in solution or the improvement of its conservation.
- pharmaceutically acceptable vehicles are well known and will be adapted by those skilled in the art depending on the nature and mode of administration of the selected active compound (s).
- these compounds will be administered systemically, in particular intravenously, intramuscularly, intradermally, intraperitoneally or subcutaneously, or orally. More preferably, the composition comprising the antibodies according to the invention will be administered several times, spread over time.
- dosages and optimal dosage forms can be determined according to the criteria generally taken into account in the establishment of a treatment adapted to a patient such as the age or the body weight of the patient, the severity of his general condition, tolerance to treatment and side effects noted.
- compositions for the treatment of cancer characterized in that it comprises as active ingredient at least one anti-CXCR4 antibody, or one of its functional fragments, capable of binding to CXCR4 protein.
- compositions comprising at least one anti-CXCR4 antibody, or one of its functional fragments, said at least one antibody being a monoclonal antibody selected from the MAB 170, MAB171 antibodies, MAB172 or MAB173, preferentially the MAB173 antibody.
- composition which comprises a combination of the above-mentioned antibodies, or functional fragments thereof.
- the invention also relates to the use of a composition comprising at least one antibody as described above for the treatment of cancer of the colon, breast, prostate, lung (small cell and not small cells), ovary, pancreas, kidney, brain and some lymphomas.
- Another complementary embodiment of the invention consists of a composition as described above, characterized in that it comprises, in addition, as a combination product for simultaneous, separate or spread use over time, at least a cytotoxic / cytostatic agent and / or a cellular toxin and / or a radioelement.
- cytotoxic / cytostatic agent and / or a cellular toxin and / or a radioelement.
- disparate use is meant the administration, at the same time, of the two compounds of the composition according to the invention, included in different pharmaceutical forms.
- use spread over time the successive administration of the two compounds of the composition according to the invention, each included in a separate pharmaceutical form.
- the composition according to the invention considerably increases the effectiveness of cancer treatment.
- the therapeutic effect of the antibody according to the invention is unexpectedly potentiated by the administration of a cytotoxic agent.
- Another major subsequent advantage produced by a composition according to the invention concerns the possibility of using lower effective doses of active ingredient, which makes it possible to avoid or reduce the risks of occurrence of side effects, in particular the effect of the cytotoxic agent.
- this composition according to the invention would make it possible to achieve the desired therapeutic effect more rapidly.
- Anti-cancer therapeutics or "cytotoxic agents” means a substance that, when administered to a patient, treats or prevents the development of cancer in the patient.
- agents alkylating agents, antimetabolites, anti-tumor antibiotics, mitotic inhibitors, chromatin function inhibitors, anti-angiogenesis agents, anti-estrogens, anti-androgens or immunois- modulators.
- agents are, for example, cited in VIDAL, on the page dedicated to the compounds attached to oncology and hematology column "Cytotoxic", these cytotoxic compounds cited with reference to this document are cited here as preferred cytotoxic agents.
- Alkylating agents refers to any substance that can covalently couple or alkylate any molecule, preferentially a nucleic acid (eg, DNA), within a cell.
- nitrogen mustards such as mechlorethamine, chlorambucil, melphalan, hydrochloride, pipobroman, prednimustine, disodium phosphate or estramustine; oxazaphosphorines such as cyclophosphamide, altretamine, trofosfamide, sulfofosfamide or ifosfamide; aziridines or ethylenimines such as thiotepa, triethyleneamine or altetramine; nitrosoureas such as carmustine, streptozocin, fotemustine or lomustine; alkyl sulfonates such as busulfan, treosulfan or improvosulfan; triazenes such as
- Antimetabolites refers to substances that block growth and / or cell metabolism by interfering with certain activities, usually DNA synthesis.
- antimetabolite mention may be made of methotrexate, 5-fluorouracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, cytarabine, fludarabine, cytosine arabinoside, 6-mercaptopurine (6-MP), 6-thioguanine (6- TG), chlorodeoxyadenosine, 5-azacytidine, gemcitabine, cladribine, deoxycoformycin and pentostatin.
- Anti-tumor antibiotics refers to compounds that can prevent or inhibit the synthesis of DNA, RNA and / or proteins.
- anti-tumor antibiotics include doxorubicin, daunorubicin, idarubicin valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, and procarbazine.
- Mitotic inhibitors prevent normal progression of the cell cycle and mitosis.
- inhibitors of microtubules or “taxoids” paclitaxel and docetaxel are able to inhibit mitosis.
- Vinca alkaloids such as vinblsatin, vincristine, vindesine and vinorelbine are also able to inhibit mitosis.
- Chroisomerase inhibitors refer to substances that inhibit the normal function of chromatin-forming proteins such as topoisomerases I and II. Examples of such inhibitors include, for topoisomerase I, camptothecin and its derivatives such as Firinotecan or topotecan and, for topoisomerase II, etoposide, etidoside phosphate and teniposide.
- Anti-angiogenesis agents refer to any drug, compound, substance or agent that inhibits the growth of blood vessels.
- anti-angiogenesis agents include, without limitation, razoxin, marimastat, batimastat, prinomastat, tanomastat, ilomastat, CGS-27023A, halofuginone, COL-3, neovastat, BMS-275291, thalidomide, CDC 501, DMXAA, L-651582, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin and vitaxine.
- Anti-estrogen or “anti-estrogenic agents” refers to any substance that decreases, antagonizes or inhibits the action of estrogen. Examples of such agents are tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfen, anastrozole, letrozole, and exemestane.
- Anti-androgens or “anti-androgenic agents” refer to any substance that reduces, antagonizes or inhibits the action of an androgen.
- antiandrogens are flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride and cimitidine.
- Immunomodulators are substances that stimulate the immune system.
- immunomodulators examples include interferons, interleukins such as aldesleukin, OCT-43, denileukin diflitox or interleukin-2, tumor necrosis factors such as tasonermin, or other types of immunomodulators such as lentinan, sizofiran, roquinimex, pidotimod, pegademase, thymopentine, poly I: C, or levamisole in combination with 5-fluorouracil.
- interferons such as aldesleukin, OCT-43, denileukin diflitox or interleukin-2
- tumor necrosis factors such as tasonermin
- immunomodulators such as lentinan, sizofiran, roquinimex, pidotimod, pegademase, thymopentine, poly I: C, or levamisole in combination with 5-fluorouracil.
- said composition as a combination product according to the invention is characterized in that said cytotoxic agent is chemically coupled to said antibody for simultaneous use.
- said composition according to the invention is characterized in that said cytotoxic / cytostatic agent is chosen from inhibitors or spindle stabilizers, preferably vinorelbine and / or vinflunine and / or vincristine.
- said cytotoxic agent is chosen from inhibitors or spindle stabilizers, preferably vinorelbine and / or vinflunine and / or vincristine.
- spacer molecules between the two compounds to be coupled such as poly (alkylenes) glycols such as polyethylene glycol, or else amino acids, or in another embodiment, using active derivatives of said cytotoxic agents in which have been introduced functions capable of reacting with said antibody according to the invention.
- the invention is, in another aspect, relating to a composition characterized in that at least one of said antibodies, or one of their derivative compound or functional fragment, is conjugated with a cellular toxin and / or a radioissement
- said toxin or said radioelement is capable of preventing growth or proliferation of the tumor cell, in particular completely inactivating said tumor cell.
- said toxin is an enterobacterial toxin, especially exotoxin A of Pseudomonas.
- the radioelements preferably conjugated to the antibody used in therapy are radioisotopes that emit gamma rays and preferably iodine 131 , yttrium 90 , gold 199 , palladium 100 , copper 67 , bismuth 217 and Fantimony 211 . Radioisotopes that emit beta and alpha rays can also be used in therapy.
- toxin or radioelement conjugated to at least one antibody, or one of their functional fragment is meant any means for binding said toxin or said radioelement to said at least one antibody, in particular by covalent coupling between the two compounds, with or without the introduction of a binding molecule.
- benzoquinone carbodiimide and more particularly EDC (1-ethyl-3- [3] may be mentioned in particular.
- bridging agents having one or more groups, having a or more phenylase groups, reactive with ultraviolet (UV) and most preferably N - [- 4- (azidosalicylamino) butyl] -3 '- (2'-pyridyldithio) propionamide (APDP), N-succinimid-yl 3- (2-pyridyldithio) propionate (SPDP) and 6-hydrazino-nicotinamide (HYNIC).
- UV ultraviolet
- APDP N- [- 4- (azidosalicylamino) butyl] -3 '- (2'-pyridyldithio) propionamide
- SPDP N-succinimid-yl 3- (2-pyridyldithio) propionate
- HYNIC 6-hydrazino-nicotinamide
- Another form of coupling may be the use of a bifunctional ion chelator.
- chelators it is possible to mention the chelates derived from EDTA
- DTPA diethylenetriaminepentaacetic acid
- metals particularly radioactive metals, and immunoglobulins.
- DTPA and its derivatives can be substituted by different groups on the carbon chain so as to increase the stability and rigidity of the ligand-metal complex (Krejcarek et al (1977), Brechbiel et al (1991), Gansow (1991) US Patent 4,831,175).
- DTPA diethylenetriaminepentaacetic acid
- its derivatives which has been widely used in medicine and biology for a long time either in its free form or in the form of a complex with a metal ion, has the remarkable characteristic of form stable chelates with metal ions and be coupled to proteins of therapeutic or diagnostic interest as antibodies for the development of radioimmunoconjugates in cancer therapy (Meases et al., (1984), Gansow et al. (1990)).
- the composition according to the invention further comprises at least one second antibody known for its antitumor activity.
- the antibodies anti Her2 / neu (Herceptin), anti-EGFR (Erbitux) or anti-IGF-1R (7C10 or h7C10) may be mentioned.
- any antitumor antibody may be included in the composition according to the invention.
- the present invention further comprises the use of the composition according to the invention for the preparation of a medicament.
- the present invention therefore relates more particularly to the use of a composition as described above for the preparation of a medicament for the treatment of cancer.
- cancers that can be prevented and / or treated, cancer of the colon, breast, prostate, lung (small cells and non-small cells), ovary, pancreas, kidney, brain and certain lymphomas.
- the subject of the invention is also the use of an antibody according to the invention for the preparation of a medicinal product intended for the specific targeting of a biologically active compound to cells expressing or overexpressing the CXCR4 receptor.
- biologically active compound is intended to mean any compound capable of modulating, in particular of inhibiting, cell activity, in particular their growth, proliferation, transcription or gene translation.
- Figure 1 illustrates the study of the inhibition by SDF1 and the 44717 antibody of [ 125 I] SDF1 binding on CHO-K1 cell membranes constitutively expressing the human CXCR4 receptor.
- Figure 2 illustrates the study of [ 35 S] GTP ⁇ S binding to CHO-K1 cell membranes constitutively expressing the human CXCR4 receptor: influence of SDF 1 and antibody 44717.
- Figure 3 illustrates the study of intracellular calcium release on intact CHO-K1 cells expressing the CXCR4 receptor: influence of SDF1 and antibody 44717.
- Figure 4 shows the in vivo antitumour activity of monoclonal antibody 44717 in the U-937 xenograft model.
- Figure 5 shows the inhibition of tumor growth in the MDA-MB-231 xenograft model by monoclonal antibody 44717.
- Example 1 Inhibition test of the binding of [ 125 IlSDF-I by antibody 44717 (otherwise known as MAB173)
- CHO-K1 cells constitutively expressing the human CXCR4 receptor are obtained by stable transfection with an expression vector containing the entire coding sequence of human CXCR4. These cells are cultured in DMEM-Ham's F 12 complete culture medium containing 5% fetal calf serum (FCS) and 500 ⁇ g / ml geneticin. The binding assays are performed on cell membranes obtained after mechanically scraping the cells in [Hepes 20mM, pH 7.4, 15mM NaCl] buffer and harvested by centrifugation at 10000g, 15 min.
- FCS fetal calf serum
- the binding of [ 125 I] SDF1 (specific activity 1500 Ci / mmol) is measured in homogeneous medium using SPA (scintillation proximity assay - GE Healthcare) beads in 96-well plates. Briefly, the membranes (30 ⁇ g / well) are incubated in the binding buffer [Hepes 20 mM, pH 7.4, 1 mM CaCl 2 , 5 mM MgCl 2, 15 mM NaCl, 1% BSA] with the test compound (SDF1 or antibody 44717). the radioligand (InM) and then the SPA-WGA-PVT beads (7.3 mg / well) and incubated at 25 ° C. After centrifugation [10 min. at 1000g] the radioactivity is read in a scintillation counter (TopCount, Perkin Elmer). The nonspecific binding of [ 125 I] SDF1 is determined in the presence of 10 ⁇ M of unlabeled SDF1.
- SPA sintillation proximity assay -
- CHO-K1 cells constitutively expressing the human CXCR4 receptor are obtained in the same manner as described in Example 1.
- the binding assays are carried out on cell membranes obtained after mechanical scraping of the cells in a buffer [Hepes 20 mM, pH 7.4, 15OmM NaCl] and collected by centrifugation 10000g, 15 min.
- the binding of [ 35 S] GTPyS (specific activity 1000 Ci / mmol) is measured in homogeneous medium using SPA (scintillation proximity assay - GE Healthcare) beads in 96-well plates.
- SDF1 stimulates in a dose-dependent manner the binding of [ 35 S] GTPyS reflecting the activation of the CXCR4 receptor.
- This test makes it possible to evaluate the signaling of the CXCR4 receptor by the Phospholipase C pathway, inducing the release of intracellular calcium. This kinetic test makes it possible to follow the evolution of the system over time.
- CHO-K1 cells constitutively expressing the human CXCR4 receptor are obtained in the same manner as described in Example 1.
- the cells are seeded in plate 96 black wells [100,000 cells in DMEM-F 12 medium-5% FCS] / well] and weaned on the night.
- the cells are loaded with a fluorescent calcium probe (Fluo-4 No Wash) in the buffer [HBSS Ix, HEPS 20 ⁇ M, Probenicid acid 25 mM] for 30 min. at 37 0 C then 30 min. at 25 ° C.
- 10 .mu.l of solution of the antibody 44717 are added to the cells.
- the measurement is carried out using the Mithras reader LB940 (Berthold) in fluorescence mode with the following parameters: excitation at 485 nm, emission at 535 nm and lamp at an energy of 10000.
- Each well is read 0.1 seconds, every second over a period of 20 seconds (basal signal) then 20 .mu.l of SDF-I are injected and the well reads again for 2 min.
- Each experimental condition is tested in duplicate.
- the results are corrected by subtracting the values of a cell free well to the cell well values.
- the values are then expressed in% of the base signal and corrected so that the first value after adding SDF-I is 100%. This makes it possible to compensate for the random jump of fluorescence induced by the injection of the ligand
- SDF1 (300 nM) induces calcium release with CHO / CXCR4 cells, whereas no response is observed on naive CHO-Kl cells.
- the signal maximum is obtained after about 30 sec and the maximum efficiency of SDF-I is 180% of the basal signal (Fig. 3).
- Antibody 44717 (133 nM) strongly inhibited the SDF1 -induced calcium release that reached a maximum of 130% basal signal after one minute after SDF1 injection (Fig. 3).
- Example 4 Anti-tumor activity of the 44717 antibody in the U937 xenograft model in NOD scid mice.
- the U-937 cells were cultured in RPMI 1640 medium with phenol red and 4.5 g / l of glucose (Sigma, ref G8769), supplemented with 10% FCS (F7524, Sigma) and 2 mM L-Glutamine ( BioWhittaker ref BE17-605E). The cells were seeded two days before the transplant, they were exponential growth phase during implantation in the animal. Ten million U-937P ((2) +4) cells were grafted to 8 week old female Nod / Scid mice by intraperitoneal injection (strain: SOPF / NOD.CB17PRKDC / J FE 6 S, NOD.CB17- Prkdc scid / J, ref NSCSSFE06S, Charles River Laboratories).
- IgG2b group IgG2b, (Sigma ref M2695, Sigma lot 046K4843, lot 22060307, 3 mg / ml), 1 mg / dose per mouse, twice a week
- the first dose was 2 mg per mouse for the control IgG2b antibodies and the 44717 antibody.
- the choice of the sc pathway for the treatment was selected so as to avoid any direct contact between the tumor cells and the antibody in the cavity. peritoneal.
- the first mouse died after 15 days in the IgG2b group. All but one mouse died within seven days (Fig. 4). The surviving mouse was euthanized 82 days after the transplant and examined, there were no tumor cells in its abdominal cavity.
- mice began to die within 4-6 days of the other two control groups. Eight mice died between days 22 and 27. Two mice survived until day 109, the day they were euthanized (Fig. 4). A statistical analysis of the survival results (Kaplan-Meier) was performed using the Log-Rank test (Fig. 4). The experiment described here shows that monoclonal antibody 44717 directed against the CXCR4 receptor is capable of increasing mouse survival in the U937 xenograft model.
- Example 5 Inhibition of tumor growth by the 44717 antibody in the MDA-MB-231 xenograft model in the athmic Nude mouse.
- MDA-MB-231 cells (ECACC) were cultured in DMEM medium (Invitrogen Corporation, Scotland, UK), in the presence of 10% FCS (Sigma). The cells were inoculated 60 hours before the transplant. They were in an exponential phase of growth during implantation. Ten million MDA-MB-231 cells (P35 + 18) were grafted in PBS to 7 week old Nude Athymic (HARLAN) mice. Five days after implantation, the tumors were measurable (37 mm 3 ⁇ V 3 ⁇ 44 mm 3 ) and the animals were randomly divided into groups of 12 mice with comparable tumor sizes.
- mice were treated ip with a dose of monoclonal antibody 44717 (lots AUZ05607A and AUZ04512A, R & D Systems) of 2mg / mouse. Then, the mice received, twice a week, a 44717 monoclonal antibody dose of 1 mg / mouse. In this experiment a group of control mice received an equivalent volume of PBS. The volume of the tumors was measured twice a week and calculated using the following formula: ⁇ / 6 X length X width X height.
- the average tumor volume after 5 weeks of treatment was reduced by 56% for the 44717 antibody relative to the PBS.
- the experiment described here shows that monoclonal antibody 44717 directed against the CXCR4 receptor is capable of inhibiting tumor growth in a MDA-MB-231 xenograft model in athymic Nude mouse.
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Abstract
The present invention relates to the use of at least one antibody, or a functional fragment thereof, capable of binding to the CXCR4 protein and thus of inhibiting tumour growth, for the preparation of a medicament for use in the treatment of cancer. The invention also relates to a composition for treating cancer, comprising, as active ingredient, at least one anti-CXCR4 antibody, or a functional fragment thereof, capable of binding to the CXCR4 protein and/or of inhibiting the angiogenic and/or proliferative activity thereof. More particularly, said antibodies consist of the MAB 173 antibody.
Description
UTILISATION D'UN ANTICORPS ANTI-CXCR4 POUR LE TRAITEMENT DU USE OF ANTI-CXCR4 ANTIBODY FOR THE TREATMENT OF
CANCERCANCER
La présente invention est relative à une nouvelle utilisation d'anticorps anti- CXCR4 capables d'inhiber la croissance tumorale, lesdits anticorps étant notamment monoclonaux d'origine murine, chimérique et humanisée. Selon un aspect particulier, l'invention a pour objet l'utilisation de ces anticorps, ou de leurs fragments fonctionnels, à titre de médicament pour le traitement prophylactique et/ou thérapeutique des cancers. L'invention comprend enfin des produits et/ou des compositions comprenant de tels anticorps en association, par exemple, avec des anticorps et/ou des agents anticancéreux ou conjugués avec des toxines et leur utilisation pour la prévention et/ou le traitement de certains cancers.The present invention relates to a new use of anti-CXCR4 antibodies capable of inhibiting tumor growth, said antibodies being in particular monoclonal of murine, chimeric and humanized origin. According to a particular aspect, the subject of the invention is the use of these antibodies, or of their functional fragments, as a medicament for the prophylactic and / or therapeutic treatment of cancers. The invention finally comprises products and / or compositions comprising such antibodies in combination, for example, with antibodies and / or anticancer agents or conjugated with toxins and their use for the prevention and / or treatment of certain cancers. .
Le récepteur CXCR4 est un récepteur membranaire couplé aux protéines G de la famille des récepteurs de chemokines. II existe deux isoformes du récepteur CXCR4 composées respectivement de 352 etThe CXCR4 receptor is a G protein-coupled membrane receptor of the chemokine receptor family. There are two isoforms of the CXCR4 receptor composed respectively of 352 and
360 acides aminés. Le résidu Asnl l est glycosylé, le résidu Tyr21 est modifié par l'addition d'un groupe sulfate et il existe un pont disulfure entre les Cys 109 et 186 sur la partie extracellulaire du récepteur.360 amino acids. The residue AsnI 1 is glycosylated, the residue Tyr 2 1 is modified by the addition of a sulfate group and there is a disulphide bridge between Cys 109 and 186 on the extracellular portion of the receptor.
Ce récepteur est exprimé par un certain nombre de tissus sains dont les cellules endothéliales, les lymphocytes, les macrophages, les cellules dendritiques, les « Natural Killer » et faiblement dans le cœur, le colon, le foie, les reins et le cerveau. Le récepteur CXCR4 est sur-exprimé dans un grand nombre de cancers dont le cancer du colon, du sein, de la prostate, du poumon (à petites cellules et non à petites cellules), de l'ovaire, du pancréas, du rein, du cerveau et certains lymphomes. L'expression de CXCR4 est augmentée sur les cellules métastatiques versus les cellules cancéreuses provenant de la tumeur primaire.This receptor is expressed by a number of healthy tissues including endothelial cells, lymphocytes, macrophages, dendritic cells, "natural killers" and weakly in the heart, colon, liver, kidneys and brain. The CXCR4 receptor is over-expressed in a large number of cancers including colon, breast, prostate, lung (small cell and non-small cell), ovarian, pancreatic, kidney, brain and certain lymphomas. The expression of CXCR4 is increased on the metastatic cells versus cancer cells from the primary tumor.
Le seul ligand connu de ce récepteur est le « Stromal-Derived Factor-1 (SDF-I) » ou CXCL 12. Celui-ci est sécrété en grande quantité par les cellules des ganglions lymphatiques, de la moelle osseuse, du foie, du poumon et en faible quantité dans les reins, le cerveau et la peau.The only known ligand of this receptor is "Stromal-Derived Factor-1 (SDF-I)" or CXCL 12. This is secreted in large quantities by lymph node, bone marrow, liver, lungs and in small amounts in the kidneys, brain and skin.
L'axe CXCR4/SDF-1 joue un rôle important dans le cancer car il est impliqué de manière directe dans les phénomènes de migration cellulaire et la formation des métastases. En effet, les cellules cancéreuses expriment le récepteur CXCR4, elle migrent
et entrent dans la circulation sanguine. Elles s'arrêtent au niveau des organes produisant de grandes quantités de SDF-I, là, elle se multiplient et forment des métastases (Murphy PM., 2001).The CXCR4 / SDF-1 axis plays an important role in cancer because it is directly involved in cell migration phenomena and the formation of metastases. Indeed, the cancer cells express the CXCR4 receptor, they migrate and enter the bloodstream. They stop at organs producing large amounts of SDF-I, they multiply and form metastases (Murphy PM., 2001).
Il a été également montré que l'axe CXCR4/SDF-1 joue un rôle dans l'angiogénèse. Plus particulièrement, il a été clairement démontré in vitro que le récepteur CXCR4 et son ligand SDF-I favorisent l'angiogénèse en stimulant l'expression de VEGF-A qui à son tour augmente l'expression de CXCR4/SDF-1 (Bachelder R.E. et al., 2002).It has also been shown that the CXCR4 / SDF-1 axis plays a role in angiogenesis. More specifically, it has been clearly demonstrated in vitro that the CXCR4 receptor and its ligand SDF-I promote angiogenesis by stimulating the expression of VEGF-A which in turn increases the expression of CXCR4 / SDF-1 (Bachelder RE et al., 2002).
L'intérêt de cibler les métastases en interférant avec le récepteur CXCR4 a notamment été démontré in vivo en utilisant un anticorps monoclonal dirigé contre CXCR4 (Muller A. et al., 2001). En effet, dans un modèle orthotopique de cancer du sein (lignée cellulaire MDA-MB231) chez la souris SCID, un anticorps monoclonal dirigé contre CXCR4 est capable de diminuer significativement le nombre des métastases au niveau des ganglions. Une étude complémentaire (Phillips RJ et al. 2003) a également montré le rôle de l'axe SDF-1/CXCR4 dans la formation des métastases dans un modèle de cancer du poumon (A549).The interest of targeting the metastases by interfering with the CXCR4 receptor has in particular been demonstrated in vivo using a monoclonal antibody directed against CXCR4 (Muller A. et al., 2001). Indeed, in an orthotopic model of breast cancer (MDA-MB231 cell line) in SCID mice, a monoclonal antibody directed against CXCR4 is able to significantly reduce the number of lymph node metastases. A complementary study (Phillips RJ et al., 2003) also showed the role of the SDF-1 / CXCR4 axis in the formation of metastases in a lung cancer model (A549).
Par ailleurs, les macrophages associés aux tumeurs sont des composants clés des circuits inflammatoires pour la croissance des tumeurs. Les chemokines, dont SDF-I, participent au recrutement des macrophages au niveau des tumeurs. Des anticorps monoclonaux capables de reconnaître le récepteur CXCR4 pourraient également réduire le recrutement des macrophages au sein des tumeurs limitant ainsi leur effet sur la croissance tumorale.In addition, tumor-associated macrophages are key components of inflammatory circuits for tumor growth. Chemokines, including SDF-I, participate in the recruitment of macrophages in tumors. Monoclonal antibodies capable of recognizing the CXCR4 receptor could also reduce the recruitment of macrophages within tumors thereby limiting their effect on tumor growth.
Selon un aspect général, la présente invention vise l'utilisation d'un anticorps, ou l'un de ses fragments fonctionnels, capable de se lier spécifiquement à la protéine CXCR4 pour le traitement du cancer.In a general aspect, the present invention is directed to the use of an antibody, or a functional fragment thereof, capable of binding specifically to the CXCR4 protein for the treatment of cancer.
Les fragments fonctionnels d'anticorps selon l'invention consistent, par exemple, en des fragments Fv, scFv (se pour simple chaîne), Fab, F(ab')2, Fab', scFv-Fc ou diabodies, ou tout fragment dont la durée de demie-vie aurait été augmentée par modification chimique, comme l'ajout de poly(alkylène) glycol tel que le poly(éthylène)glycol ("PEGylation") (fragments PEGylés appelés Fv-PEG, scFv-PEG, Fab-PEG, F(ab')2-PEG ou Fab'-PEG) (« PEG » d'après la nomenclature anglaise Poly(Ethylene) Glycol), ou par incorporation dans un liposome, microsphères ou PLGA,
lesdits fragments étant capables d'exercer de manière générale une activité même partielle de l'anticorps dont ils sont issus.The functional fragments of antibodies according to the invention consist, for example, of fragments Fv, scFv (se for simple chain), Fab, F (ab ') 2 , Fab', scFv-Fc or diabodies, or any fragment of which the half-life time would have been increased by chemical modification, such as the addition of poly (alkylene) glycol such as poly (ethylene) glycol ("PEGylation") (PEGylated fragments called Fv-PEG, scFv-PEG, Fab- PEG, F (ab ') 2 -PEG or Fab'-PEG) ("PEG" according to the English nomenclature Poly (Ethylene) Glycol), or by incorporation into a liposome, microspheres or PLGA, said fragments being capable of generally exercising even a partial activity of the antibody from which they are derived.
De préférence, lesdits fragments fonctionnels seront constitués ou comprendront une séquence partielle de la chaîne variable lourde ou légère de l'anticorps dont ils sont dérivés, ladite séquence partielle étant suffisante pour retenir la même spécificité de liaison que l'anticorps dont elle est issue et une affinité suffisante, de préférence au moins égale à 1/100, de manière plus préférée à au moins 1/10 de celle de l'anticorps dont elle est issue.Preferably, said functional fragments will comprise or comprise a partial sequence of the heavy or light variable chain of the antibody from which they are derived, said partial sequence being sufficient to retain the same binding specificity as the antibody from which it is derived and sufficient affinity, preferably at least equal to 1/100, more preferably at least 1/10 that of the antibody from which it is derived.
Un tel fragment fonctionnel comportera au minimum 5 acides aminés, de préférence 10, 15, 25, 50 et 100 acides aminés consécutifs de la séquence de l'anticorps dont il est issu.Such a functional fragment will comprise at least 5 amino acids, preferably 10, 15, 25, 50 and 100 consecutive amino acids of the sequence of the antibody from which it is derived.
De préférence, ces fragments fonctionnels seront des fragments de type Fv, scFv,Preferably, these functional fragments will be fragments of the Fv, scFv type,
Fab, F(ab')2, F(ab'), scFv-Fc ou diabodies, qui possèdent généralement la même spécificité de fixation que l'anticorps dont ils sont issus. Selon la présente invention, des fragments d'anticorps de l'invention peuvent être obtenus à partir des anticorps tels que décrits précédemment par des méthodes telles que la digestion par des enzymes, comme la pepsine ou la papaïne et/ou par clivage des ponts disulfures par réduction chimique.Fab, F (ab ') 2 , F (ab'), scFv-Fc or diabodies, which generally possess the same binding specificity as the antibody from which they are derived. According to the present invention, antibody fragments of the invention can be obtained from antibodies as previously described by methods such as digestion with enzymes, such as pepsin or papain and / or by cleavage of disulfide bridges. by chemical reduction.
D'une autre manière les fragments d'anticorps compris dans la présente invention peuvent être obtenus par des techniques de recombinaisons génétiques bien connues également de l'homme de l'art ou encore par synthèse peptidique au moyen par exemple de synthétiseurs automatiques de peptides tels que ceux fournis par la société Applied.In another way, the antibody fragments included in the present invention may be obtained by genetic recombination techniques well known to those skilled in the art or by peptide synthesis using, for example, automatic peptide synthesizers such as than those provided by Applied.
Selon un aspect de l'invention, l'anticorps utilisé consiste en un anticorps monoclonal murin.According to one aspect of the invention, the antibody used is a murine monoclonal antibody.
Sont également compris par anticorps selon la présente invention, les anticorps chimériques ou humanisés.Antibodies according to the present invention also include chimeric or humanized antibodies.
Par anticorps chimérique, on entend désigner un anticorps qui contient une région variable (chaîne légère et chaîne lourde) naturelle dérivée d'un anticorps d'une espèce donnée en association avec les régions constantes de chaîne légère et chaîne lourde d'un anticorps d'une espèce hétérologue à ladite espèce donnée. Les anticorps ou leurs fragments de type chimérique utilisés selon l'invention peuvent être préparés en utilisant les techniques de recombinaison génétique. Par exemple, l'anticorps chimérique pourra être réalisé en clonant un ADN recombinant comportant un promoteur et une séquence codant pour la région variable d'un anticorps
monoclonal non humain, notamment murin, selon l'invention et une séquence codant pour la région constante d'anticorps humain. Un anticorps chimérique de l'invention codé par un tel gène recombinant sera par exemple une chimère souris-homme, la spécificité de cet anticorps étant déterminée par la région variable dérivée de l'ADN murin et son isotype déterminé par la région constante dérivée de l'ADN humain. Pour les méthodes de préparation d'anticorps chimériques, on pourra par exemple se référer au document Verhoeyn et al. (BioEssays, 8:74, 1988).By chimeric antibody is meant an antibody which contains a naturally occurring variable (light chain and heavy chain) derived from an antibody of a given species in association with the light chain and heavy chain constant regions of an antibody of a heterologous species to said given species. The antibodies or their chimeric-like fragments used according to the invention can be prepared using genetic recombination techniques. For example, the chimeric antibody can be made by cloning a recombinant DNA comprising a promoter and a sequence coding for the variable region of an antibody non-human monoclonal, particularly murine, according to the invention and a sequence coding for the constant region of human antibody. A chimeric antibody of the invention encoded by such a recombinant gene will for example be a mouse-human chimera, the specificity of this antibody being determined by the variable region derived from murine DNA and its isotype determined by the constant region derived from the murine DNA. Human DNA. For methods for the preparation of chimeric antibodies, reference may be made for example to Verhoeyn et al. (BioEssays, 8:74, 1988).
Par anticorps humanisé, on entend désigner un anticorps qui contient des régions CDRs dérivées d'un anticorps d'origine non humaine, les autres parties de la molécule d'anticorps étant dérivées d'un (ou de plusieurs) anticorps humains. En outre, certains des résidus des segments du squelette (dénommés FR) peuvent être modifiés pour conserver l'affinité de liaison (Jones et al., Nature, 321 :522-525, 1986 ; Verhoeyen et al., Science, 239: 1534-1536, 1988 ; Riechmann et al., Nature, 332:323-327, 1988).By humanized antibody is meant an antibody which contains CDRs regions derived from an antibody of non-human origin, the other parts of the antibody molecule being derived from one (or more) human antibodies. In addition, some of the skeletal segment residues (referred to as FR) can be modified to maintain binding affinity (Jones et al., Nature, 321: 522-525, 1986, Verhoeyen et al., Science, 239: 1534 1536, 1988, Riechmann et al., Nature, 332: 323-327, 1988).
Les anticorps humanisés ou leurs fragments fonctionnels peuvent être préparés par des techniques connues de l'homme de l'art (comme par exemple celles décrites dans les documents Singer et al., J. Immun. 150:2844-2857, 1992 ; Mountain et al., Biotechnol. Genêt. Eng. Rev., 10:1-142, 1992 ; ou Bebbington et al., Bio/Technology, 10: 169-175, 1992). De tels anticorps humanisés sont préférés pour leur utilisation dans des méthodes de traitement prophylactique et/ou thérapeutique in vivo. D'autres techniques d'humanisation sont également connues de l'homme de l'art comme par exemple la technique du « CDR Grafting » décrite par PDL faisant l'objet des brevets EP 0 451 261, EP 0 682 040, EP 0 939 127, EP 0 566 647 ou encore US 5,530,101, US 6,180,370, US 5,585,089 et US 5,693,761. On peut également citer les brevets US 5,639,641 ou encore 6,054,297, 5,886,152 et 5,877,293. Plus particulièrement, la demanderesse avance, sans vouloir être liée par une quelconque théorie, que l'utilisation d'anticorps anti-CXCR4 dans le cadre du traitement du cancer présenterait un intérêt, non pas uniquement du fait d'une inhibition de l'activité promotrice de métastase de CXCR4 comme le laisse penser l'art antérieur mais également et surtout du fait d'une action directement au niveau de la tumeur primaire. En effet comme vu plus haut, il est connu de l'homme de l'art que le blocage de l'axe CXCR4/SDF-1 par un anticorps permet de diminuer significativement le nombre des métastases au niveau des ganglions (Muller et al., 2001). En outre, il est également décrit que le blocage in vivo de cet axe, s'il diminue significativement les métastases,
n'altère pas la taille de la tumeur primaire ni l'activité angiogénique au sein de la tumeur (Phillips RJ et al., 2003).Humanized antibodies or their functional fragments can be prepared by techniques known to those skilled in the art (such as those described in Singer et al., J. Immun., 150: 2844-2857, 1992; al., Biotechnol Genet Eng.Rev., 10: 1-142, 1992 or Bebbington et al., Bio / Technology, 10: 169-175, 1992). Such humanized antibodies are preferred for use in prophylactic and / or therapeutic treatment methods in vivo. Other humanization techniques are also known to those skilled in the art, for example the "CDR Grafting" technique described by PDL which is the subject of patents EP 0 451 261, EP 0 682 040 and EP 0 939. 127, EP 0 566 647 or US 5,530,101, US 6,180,370, US 5,585,089 and US 5,693,761. It is also possible to mention US Pat. Nos. 5,639,641, 6,054,297, 5,886,152 and 5,877,293. More particularly, the applicant advances, without wishing to be bound by any theory, that the use of anti-CXCR4 antibodies in the context of cancer treatment would be of interest, not only because of an inhibition of the activity. promoter of metastasis CXCR4 as suggested by the prior art but also and especially because of an action directly at the level of the primary tumor. Indeed, as seen above, it is known to those skilled in the art that blocking the CXCR4 / SDF-1 axis with an antibody makes it possible to significantly reduce the number of metastases at the level of the ganglia (Muller et al. , 2001). In addition, it is also described that the in vivo blocking of this axis, if it significantly decreases metastasis, does not alter the size of the primary tumor or the angiogenic activity within the tumor (Phillips RJ et al., 2003).
Par conséquent, il ressort clairement de l'art antérieur que l'utilisation d'un anticorps anti-CXCR4, i.e. capable d'interférer avec l'axe CXCR4/SDF-1, présente un intérêt uniquement au niveau des métastases.Therefore, it is clear from the prior art that the use of an anti-CXCR4 antibody, i.e. capable of interfering with the CXCR4 / SDF-1 axis, is of interest only at the level of metastasis.
La présente invention est innovante en ce sens que, pour la première fois et contrairement aux préjugés de l'homme de l'art, elle décrit et revendique l'utilisation d'un anticorps monoclonal anti-CXCR4 capable non pas d'agir uniquement au niveau des métastases mais surtout d'agir directement au niveau de la croissance tumorale des tumeurs primaires.The present invention is innovative in that, for the first time and contrary to the prejudices of those skilled in the art, it describes and claims the use of an anti-CXCR4 monoclonal antibody capable of acting not only at level of metastases but especially to act directly at the level of tumor growth of primary tumors.
Plus particulièrement, la présente invention a pour objet l'utilisation d'un anticorps monoclonal, ou l'un de ses fragments fonctionnels, capable de se lier spécifiquement à la protéine CXCR4 pour inhiber in vitro et/ou in vivo la croissance tumorale d'une tumeur primaire. La transformation cellulaire tumorale se traduit notamment par une perte de contrôle du cycle cellulaire, une insensibilité à l'apoptose des anomalies de la réparation de I1ADN. Les cancers sont alors classés selon le type de la cellule dans laquelle s'est produite la première transformation (lymphomes, carcinomes, sarcomes); cette première cellule maligne s'étant ensuite divisée, formant la tumeur primaire. Certaines tumeurs primaires peuvent progresser vers un envahissement plus global de l'organisme par échappement de cellules tumorales issues de cette tumeur primaire : on parle alors de métastases.More particularly, the present invention relates to the use of a monoclonal antibody, or a functional fragment thereof, capable of binding specifically to the CXCR4 protein to inhibit tumor growth in vitro and / or in vivo. a primary tumor. Tumor cell transformation results in particular in a cell cycle control loss, insensitivity to apoptosis of abnormal repair I 1 DNA. Cancers are then classified according to the type of cell in which the first transformation occurred (lymphomas, carcinomas, sarcomas); this first malignant cell having then divided, forming the primary tumor. Some primary tumors may progress to a more general invasion of the body by escape of tumor cells from this primary tumor: this is called metastasis.
Il faut donc bien comprendre que, dans la cadre de la présente invention, l'expression « tumeur primaire » est à mettre en opposition avec les « métastases ». La tumeur primaire représentant la première étape de développement d'un cancer alors que les métastases représentent une étapes différente et ultérieure vers laquelle peuvent évoluer les tumeurs primaires.It should therefore be understood that, in the context of the present invention, the expression "primary tumor" is to be contrasted with "metastases". The primary tumor represents the first stage of cancer development whereas metastases represent a different and subsequent stage towards which primary tumors can evolve.
En effet, par « métastase », il faut comprendre un foyer infectieux secondaire, formé à la suite de la dissémination de cellules cancéreuses par voie sanguine ou lymphatique à partir du premier foyer ou tumeur primaire.Indeed, by "metastasis", it is necessary to understand a secondary infectious center, formed as a result of the dissemination of cancerous cells by blood or lymphatic system from the first focus or primary tumor.
La présente invention propose donc une alternative aux traitements existants en ce sens qu'elle apporte un traitement précoce des tumeurs primaires avant que ces dernières ne métastasent.
Par « croissance tumorale » d'un tumeur primaire, il faut comprendre l'augmentation du volume de ladite tumeur primaire, cette augmentation de volume résultant de mécanismes différents, à savoir la vascularisation, l'apoptose ou encore la prolifération cellulaire. Par « vascularisation », il faut comprendre l'augmentation de la vascularisation au niveau de la tumeur primaire par angiogenèse et/ou par vasculogenèse.The present invention therefore provides an alternative to existing treatments in that it provides early treatment of primary tumors before the latter metastasize. By "tumor growth" of a primary tumor, it is necessary to understand the increase in the volume of said primary tumor, this increase in volume resulting from different mechanisms, namely vascularization, apoptosis or cell proliferation. By "vascularization", it is necessary to understand the increase of the vascularization at the level of the primary tumor by angiogenesis and / or by vasculogenesis.
L'angiogenèse consiste en la formation de nouveaux vaisseaux (néovascularisation) prenant naissance à partir d'un réseau capillaire préexistant par prolifération et migration des cellules endothéliales notamment au cours d'une cicatrisation ou du développement d'une tumeur cancéreuse.Angiogenesis consists of the formation of new vessels (neovascularization) originating from a pre-existing capillary network by proliferation and migration of endothelial cells, especially during healing or the development of a cancerous tumor.
La vasculogenèse consiste en un processus par lequel des cellules endothéliales et un plexus primitif sont générés par différenciation de précurseurs des cellules endothéliales (angioblastes et hémangioblastes).Vasculogenesis is a process by which endothelial cells and a primitive plexus are generated by differentiation of endothelial cell precursors (angioblasts and hemangioblasts).
Par « apoptose », il faut comprendre le processus par lequel des cellules déclenchent leur auto-destruction en réponse à un signal. C'est une mort cellulaire génétiquement programmée.By "apoptosis" is meant the process by which cells trigger self-destruction in response to a signal. It is a genetically programmed cell death.
Par « prolifération cellulaire », il faut comprendre tout processus impliqué dans l'augmentation du nombre des cellules. Ces processus concernent d'avantage la division cellulaire faisant partie du cycle cellulaire. Plus particulièrement, la prolifération cellulaire consiste en la division incontrôlée et excessive de cellules qui donne naissance à une tumeur.By "cell proliferation" is meant any process involved in increasing the number of cells. These processes are more about cell division as part of the cell cycle. More specifically, cell proliferation is the uncontrolled and excessive division of cells that gives rise to a tumor.
La présente invention décrit donc l'utilisation d'un anticorps monoclonal tel que décrit plus haut, ou l'un de ses fragments fonctionnels, capable d'inhiber la vascularisation, c'est-à-dire l'angiogenèse et/ou la vasculogenèse, au sein de la tumeur primaire.The present invention therefore describes the use of a monoclonal antibody as described above, or one of its functional fragments, capable of inhibiting vascularization, that is to say angiogenesis and / or vasculogenesis , within the primary tumor.
Selon un deuxième aspect, la présente invention décrit l'utilisation d'un anticorps tel que décrit plus haut, ou l'un de ses fragments fonctionnels, capable d'inhiber la prolifération cellulaire des cellules tumorales constituant la tumeur primaire.According to a second aspect, the present invention describes the use of an antibody as described above, or one of its functional fragments, capable of inhibiting the cellular proliferation of the tumor cells constituting the primary tumor.
Selon un troisième aspect, la présente invention décrit l'utilisation d'un anticorps tel que décrit plus haut, ou l'un de ses fragments fonctionnels, capable d'inhiber la vascularisation au sein de la tumeur primaire et la prolifération cellulaire des cellules tumorales constituant ladite tumeur primaire.
Enfin, selon encore un autre aspect, la présente invention décrit l'utilisation d'un anticorps tel que décrit plus haut, ou l'un de ses fragments fonctionnels, capable en outre d'induire l'apoptose des cellules tumorales constituant la tumeur primaire.According to a third aspect, the present invention describes the use of an antibody as described above, or one of its functional fragments, capable of inhibiting the vascularization within the primary tumor and the cellular proliferation of tumor cells. constituting said primary tumor. Finally, according to yet another aspect, the present invention describes the use of an antibody as described above, or one of its functional fragments, which is also capable of inducing the apoptosis of the tumor cells constituting the primary tumor. .
De manière préférée, l'invention consiste principalement en l'utilisation d'au moins un anticorps anti-CXCR4, ou l'un de ses fragments fonctionnels, qui consiste en un anticorps monoclonal.Preferably, the invention consists mainly in the use of at least one anti-CXCR4 antibody, or one of its functional fragments, which consists of a monoclonal antibody.
Il faut entendre par « anticorps monoclonal » un anticorps issu d'une population d'anticorps sensiblement homogènes. Plus particulièrement, les anticorps individuels d'une population sont identiques à l'exception de quelques mutations éventuelles pouvant se produire naturellement qui peuvent se retrouver en proportions minimes. En d'autres termes, un anticorps monoclonal consiste en un anticorps homogène résultant de la prolifération d'un seul clone cellulaire (par exemple un hybridome, une cellule hôte eucaryote transféctée avec une molécule d'ADN codant pour l'anticorps homogène, une cellule hôte procaryote transféctée avec une molécule d'ADN codant pour l'anticorps homomgène, etc.) et qui est généralement caractérisé par des chaînes lourdes d'une seule et même classe et sous-classe, et des chaînes légères d'un seul type. Les anticorps monoclonaux sont fortement spécifiques et sont dirigés contre un seul antigène. En outre, contrairement aux préparations d'anticorps polyclonaux qui comprennent classiquement différents anticorps dirigés contre différents déterminants, ou épitopes, chaque anticorps monoclonal est dirigé contre un seul épitope de l'antigène.The term "monoclonal antibody" means an antibody derived from a substantially homogeneous antibody population. More particularly, the individual antibodies of a population are identical with the exception of a few possible mutations that can occur naturally which can be found in minute proportions. In other words, a monoclonal antibody consists of a homogeneous antibody resulting from the proliferation of a single cell clone (for example a hybridoma, a eukaryotic host cell transfected with a DNA molecule encoding the homogeneous antibody, a cell prokaryotic host transfected with a DNA molecule encoding the homomgene antibody, etc.) and which is generally characterized by heavy chains of one and the same class and subclass, and light chains of one type. The monoclonal antibodies are highly specific and are directed against a single antigen. In addition, unlike polyclonal antibody preparations which typically comprise different antibodies directed against different determinants, or epitopes, each monoclonal antibody is directed against a single epitope of the antigen.
Selon un mode de réalisation particulier de l'invention, l'anticorps monoclonal utilisé est choisi parmi les anticorps MAB 170 (issu du clone 12G5), MAB 171 issu du clone 44708), MAB 172 (issu du clone 44716) et MAB 173 (issu du clone 44717) (http://www.rndsystems.com). Dans la présente description, chaque anticorps pourra être nommé par son nom ou par le nom de l'hybridome dont il est issu. Par exemple, l'anticorps MAB 173 pourra être indifféremment nommé, notamment dans les exemples, 44717 ou MAB 173 ou encore Mabl73.According to a particular embodiment of the invention, the monoclonal antibody used is chosen from antibodies MAB 170 (from clone 12G5), MAB 171 from clone 44708), MAB 172 (from clone 44716) and MAB 173 ( from clone 44717) (http://www.rndsystems.com). In the present description, each antibody may be named by name or by the name of the hybridoma from which it is derived. For example, the MAB 173 antibody may be indifferently named, especially in the examples, 44717 or MAB 173 or Mabl73.
Le tableau 1 ci-dessous résume, de manière non exhaustive, pour chaque clone, les anticorps disponibles pour l'homme de l'art auprès de R&D Systems.
Table 1 below summarizes, in a non-exhaustive manner, for each clone, the antibodies available to those skilled in the art from R & D Systems.
Tableau 1Table 1
Plus particulièrement, l'anticorps monoclonal selon l'invention consiste en l'anticorps MAB 173.More particularly, the monoclonal antibody according to the invention consists of the antibody MAB 173.
La présente invention décrit donc l'utilisation d'un anticorps monoclonal anti- CXCR4, ou l'un de ses fragments fonctionnels, ledit anticorps monoclonal consistant en l'anticorps MAB 173. L'anticorps monoclonal MAB173 a été produit à partir d'un hybridome résultant de la fusion d'un myélome murin avec des cellules B isolées d'une souris ayant été immunisée avec des cellules murines 3T3 transfectée avec la protéine hCXCR4. Les IgG ont ensuite été purifiées à partir du liquide d'ascites par chromatographie d'affinité sur protéine G (Fiche technique R&D Systems concernant l'anticorps MAB 173). Cet anticorps est décrit comme reconnaissant spécifiquement la protéine humaineThe present invention therefore describes the use of an anti-CXCR4 monoclonal antibody, or a functional fragment thereof, said monoclonal antibody consisting of the MAB 173. The monoclonal antibody MAB173 was produced from a hybridoma resulting from fusion of murine myeloma with isolated B cells of a mouse immunized with murine 3T3 cells transfected with the hCXCR4 protein. The IgGs were then purified from the ascites fluid by protein G affinity chromatography (R & D Systems Factsheet for MAB 173). This antibody is described as specifically recognizing the human protein
CXCR4 et ne reconnaissant pas la protéine équivalente de rat. Cet anticorps ne reconnaît pas, non plus, d'autres récepteurs aux chémokines (fiche technique R&D Systems).CXCR4 and not recognizing rat equivalent protein. This antibody also does not recognize other chemokine receptors (R & D Systems data sheet).
Selon une forme d'exécution de l'invention, il est envisagé l'utilisation d'un anticorps telle que décrite précédemment pour la préparation d'un médicament destiné au traitement et/ou à la prévention du cancer.According to one embodiment of the invention, it is envisaged the use of an antibody as described above for the preparation of a medicament for the treatment and / or prevention of cancer.
De manière préférée, l'utilisation des anticorps anti-CXCR4 dans le cadre du traitement et/ou de la prévention du cancer se justifie tout particulièrement dans les cancers surexprimant ce même récepteur CXCR4.Preferably, the use of anti-CXCR4 antibodies in the context of the treatment and / or prevention of cancer is particularly justified in cancers overexpressing the same CXCR4 receptor.
De tels cancers consistent en les cancers du colon, du sein, de la prostate, du poumon (à petites cellules et non à petites cellules), de l'ovaire, du pancréas, du rein, du cerveau et certains lymphomes.Such cancers consist of cancers of the colon, breast, prostate, lung (small cell and non-small cell), ovarian, pancreas, kidney, brain and some lymphomas.
La présente invention revendique donc l'utilisation d'un anticorps tel que décrit plus haut pour le traitement du cancer, ledit cancer étant sélectionné parmi le cancer du
colon, du sein, de la prostate, du poumon (à petites cellules et non à petites cellules), de l'ovaire, du pancréas, du rein, du cerveau et certains lymphomes.The present invention therefore claims the use of an antibody as described above for the treatment of cancer, said cancer being selected from cancer of the colon, breast, prostate, lung (small cell and non-small cell), ovarian, pancreatic, kidney, brain and some lymphoma.
L'invention concerne également une composition pharmaceutique comprenant à titre de principe actif un composé consistant en un anticorps, ou l'un de ses composés dérivés ou fragments fonctionnels, de préférence additionné d'un excipient et/ou d'un véhicule pharmaceutiquement acceptable.The invention also relates to a pharmaceutical composition comprising as active principle a compound consisting of an antibody, or one of its derivative compounds or functional fragments, preferably supplemented with an excipient and / or a pharmaceutically acceptable vehicle.
Plus particulièrement, l'invention vise l'utilisation d'un anticorps selon l'invention pour la préparation d'une composition pharmaceutique comprenant, en outre, au moins un véhicule pharmaceutiquement acceptable Dans la présente description, on entend désigner par véhicule pharmaceutiquement acceptable, un composé ou une combinaison de composés entrant dans une composition pharmaceutique ne provoquant pas de réactions secondaires et qui permet par exemple la facilitation de l'administration du ou des composés actifs, l'augmentation de sa durée de vie et/ou de son efficacité dans l'organisme, l'augmentation de sa solubilité en solution ou encore l'amélioration de sa conservation. Ces véhicules pharmaceutiquement acceptables sont bien connus et seront adaptés par l'homme de l'art en fonction de la nature et du mode d'administration du ou des composés actifs choisis.More particularly, the invention relates to the use of an antibody according to the invention for the preparation of a pharmaceutical composition comprising, in addition, at least one pharmaceutically acceptable carrier In the present description, the term "pharmaceutically acceptable carrier" is intended to mean a compound or a combination of compounds entering into a pharmaceutical composition that does not cause side reactions and that makes it possible, for example, to facilitate the administration of the active compound (s), to increase its shelf life and / or its effectiveness in the organism, the increase of its solubility in solution or the improvement of its conservation. These pharmaceutically acceptable vehicles are well known and will be adapted by those skilled in the art depending on the nature and mode of administration of the selected active compound (s).
De préférence, ces composés seront administrés par voie systémique, en particulier par voie intraveineuse, par voie intramusculaire, intradermique, intrapéritonéale ou sous-cutanée, ou par voie orale. De manière plus préférée, la composition comprenant les anticorps selon l'invention, sera administrée à plusieurs reprises, de manière étalée dans le temps.Preferably, these compounds will be administered systemically, in particular intravenously, intramuscularly, intradermally, intraperitoneally or subcutaneously, or orally. More preferably, the composition comprising the antibodies according to the invention will be administered several times, spread over time.
Leurs modes d'administration, posologies et formes galéniques optimaux peuvent être déterminés selon les critères généralement pris en compte dans l'établissement d'un traitement adapté à un patient comme par exemple l'âge ou le poids corporel du patient, la gravité de son état général, la tolérance au traitement et les effets secondaires constatés.Their modes of administration, dosages and optimal dosage forms can be determined according to the criteria generally taken into account in the establishment of a treatment adapted to a patient such as the age or the body weight of the patient, the severity of his general condition, tolerance to treatment and side effects noted.
Selon l'invention, il est décrit une composition pour le traitement du cancer, caractérisée en ce qu'elle comprend à titre de principe actif au moins un anticorps anti- CXCR4, ou l'un de ses fragments fonctionnels, capable de se lier à la protéine CXCR4. Selon un autre aspect de l'invention, il est décrit une composition comprenant au moins un anticorps anti-CXCR4, ou l'un de ses fragments fonctionnels, ledit au moins un anticorps étant un anticorps monoclonal sélectionné parmi les anticorps MAB 170, MAB171, MAB172 ou MAB173, préférentiellement l'anticorps MAB173.
Selon encore un aspect de l'invention, il est revendiquée une composition qui comprend une combinaison des anticorps cités ci-dessus, ou de leur fragments fonctionnels.According to the invention, there is described a composition for the treatment of cancer, characterized in that it comprises as active ingredient at least one anti-CXCR4 antibody, or one of its functional fragments, capable of binding to CXCR4 protein. According to another aspect of the invention, there is described a composition comprising at least one anti-CXCR4 antibody, or one of its functional fragments, said at least one antibody being a monoclonal antibody selected from the MAB 170, MAB171 antibodies, MAB172 or MAB173, preferentially the MAB173 antibody. According to yet another aspect of the invention, there is claimed a composition which comprises a combination of the above-mentioned antibodies, or functional fragments thereof.
Comme vu plus haut, l'invention vise également l'utilisation d'une composition comprenant au moins un anticorps tel que décrit plus haut pour le traitement du cancer du colon, du sein, de la prostate, du poumon (à petites cellules et non à petites cellules), de l'ovaire, du pancréas, du rein, du cerveau et certains lymphomes.As seen above, the invention also relates to the use of a composition comprising at least one antibody as described above for the treatment of cancer of the colon, breast, prostate, lung (small cell and not small cells), ovary, pancreas, kidney, brain and some lymphomas.
Bien évidemment, la liste ci-dessus n'est donnée qu'à titre illustratif et tout cancer doit être compris comme surexprimant la protéine CXCR4 et donc susceptible d'être traité conformément à la présente invention. Une autre forme d'exécution complémentaire de l'invention consiste en une composition telle que décrite plus haut, caractérisée en ce qu'elle comprend, en outre, comme produit de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps, au moins un agent cytotoxique/cytostatique et/ou une toxine cellulaire et/ou un radioélément. On entend par "utilisation simultanée", l'administration des deux composés de la composition selon l'invention compris dans une seule et même forme pharmaceutique.Of course, the above list is given for illustrative purposes and any cancer must be understood as overexpressing the CXCR4 protein and therefore capable of being treated in accordance with the present invention. Another complementary embodiment of the invention consists of a composition as described above, characterized in that it comprises, in addition, as a combination product for simultaneous, separate or spread use over time, at least a cytotoxic / cytostatic agent and / or a cellular toxin and / or a radioelement. By "simultaneous use" is meant the administration of the two compounds of the composition according to the invention included in one and the same pharmaceutical form.
On entend par "utilisation séparée", l'administration, en même temps, des deux composés de la composition selon l'invention, compris dans des formes pharmaceutiques distinctes. On entend par "utilisation étalée dans le temps", l'administration successive des deux composés de la composition selon l'invention, compris chacun dans une forme pharmaceutique distincte.By "separate use" is meant the administration, at the same time, of the two compounds of the composition according to the invention, included in different pharmaceutical forms. The term "use spread over time", the successive administration of the two compounds of the composition according to the invention, each included in a separate pharmaceutical form.
D'une façon générale, la composition selon l'invention augmente considérablement l'efficacité du traitement du cancer. En d'autres termes, l'effet thérapeutique de l'anticorps selon l'invention est potentialisé de manière inattendue par l'administration d'un agent cytotoxique. Un autre avantage subséquent majeur produit par une composition selon l'invention, concerne la possibilité d'utiliser des doses efficaces en principe actif plus faibles, ce qui permet d'éviter ou de réduire les risques d'apparition des effets secondaires, en particulier l'effet de l'agent cytotoxique. De plus, cette composition selon l'invention permettrait d'atteindre l'effet thérapeutique escompté plus rapidement.In general, the composition according to the invention considerably increases the effectiveness of cancer treatment. In other words, the therapeutic effect of the antibody according to the invention is unexpectedly potentiated by the administration of a cytotoxic agent. Another major subsequent advantage produced by a composition according to the invention concerns the possibility of using lower effective doses of active ingredient, which makes it possible to avoid or reduce the risks of occurrence of side effects, in particular the effect of the cytotoxic agent. In addition, this composition according to the invention would make it possible to achieve the desired therapeutic effect more rapidly.
Par « agents thérapeutiques anti-cancer » ou « agents cytotoxiques », il faut comprendre une substance qui, lorsqu'elle est administrée à un patient, traite ou prévient le développement du cancer chez le patient. A titre d'exemple non limitatif pour de tels
agents, il peut être mentionné les agents « alkylant », les antimétabolites, les antibiotiques anti-tumoraux, les inhibiteurs mitotiques, les inhibiteurs de fonction chromatine, les agents anti-angiogénèse, les anti-œstrogène, les anti-androgène ou les immuno- modulateurs. De tels agents sont, par exemple, cités dans le VIDAL, à la page consacrée aux composés attachés à la cancérologie et l'hématologie colonne « Cytotoxiques », ces composés cytotoxiques cités par référence à ce document sont cités ici comme agents cytotoxiques préférés."Anti-cancer therapeutics" or "cytotoxic agents" means a substance that, when administered to a patient, treats or prevents the development of cancer in the patient. By way of non-limiting example for such agents, alkylating agents, antimetabolites, anti-tumor antibiotics, mitotic inhibitors, chromatin function inhibitors, anti-angiogenesis agents, anti-estrogens, anti-androgens or immunois- modulators. Such agents are, for example, cited in VIDAL, on the page dedicated to the compounds attached to oncology and hematology column "Cytotoxic", these cytotoxic compounds cited with reference to this document are cited here as preferred cytotoxic agents.
Les « agents alkylants » font référence à toute substance qui peut se coupler de manière covalente ou alkyler toute molécule, préférentiellement un acide nucléique (ex. : ADN), au sein d'une cellule. Comme exemples de tels agents alkylants, il peut être cité les moutardes à l'azote comme la méchloréthamine, le chlorambucil, le melphalan, le chlorhydrate, le pipobroman, la prednimustine, le phosphate disodique ou l'estramustine ; les oxazaphosphorines comme la cyclophosphamide, l' altretamine, la trofosfamide, la sulfofosfamide ou l'ifosfamide ; les aziridines ou ethylènes-imines comme le thiotepa, la triéthylèneamine ou l'altétramine ; les nitrosourées comme la carmustine, la streptozocine, la fotémustine ou la lomustine ; les sulfonates d'alkyle comme le busulfan, le tréosulfan ou l'improsulfan ; les triazènes comme la dacarbazine ; ou encore les complexes du platine comme le cisplatine, l'oxaliplatine ou le carboplatine. Les « antimétabolites » font référence à des substances qui bloquent la croissance et/ou le métabolisme cellulaire en interférant avec certaines activités, généralement la synthèse d'ADN. A titre d'exemple d'antimétabolite, il peut être mentionné les methotrexate, 5-fluorouracile, floxuridine, 5-fluorodeoxyuridine, capecitabine, cytarabine, fludarabine, cytosine arabinoside, 6-mercaptopurine (6-MP), 6- thioguanine (6-TG), chlorodésoxyadénosine, 5-azacytidine, gemcitabine, cladribine, deoxycoformycine et la pentostatine."Alkylating agents" refers to any substance that can covalently couple or alkylate any molecule, preferentially a nucleic acid (eg, DNA), within a cell. As examples of such alkylating agents, mention may be made of nitrogen mustards such as mechlorethamine, chlorambucil, melphalan, hydrochloride, pipobroman, prednimustine, disodium phosphate or estramustine; oxazaphosphorines such as cyclophosphamide, altretamine, trofosfamide, sulfofosfamide or ifosfamide; aziridines or ethylenimines such as thiotepa, triethyleneamine or altetramine; nitrosoureas such as carmustine, streptozocin, fotemustine or lomustine; alkyl sulfonates such as busulfan, treosulfan or improvosulfan; triazenes such as dacarbazine; or platinum complexes such as cisplatin, oxaliplatin or carboplatin. "Antimetabolites" refers to substances that block growth and / or cell metabolism by interfering with certain activities, usually DNA synthesis. By way of example of antimetabolite, mention may be made of methotrexate, 5-fluorouracil, floxuridine, 5-fluorodeoxyuridine, capecitabine, cytarabine, fludarabine, cytosine arabinoside, 6-mercaptopurine (6-MP), 6-thioguanine (6- TG), chlorodeoxyadenosine, 5-azacytidine, gemcitabine, cladribine, deoxycoformycin and pentostatin.
Les « antibiotiques anti-tumoraux » font référence aux composés qui peuvent prévenir ou inhiber la synthèse d'ADN, d'ARN et/ou de protéines. Des exemples de tels antibiotiques anti-tumoraux comprennent la doxorubicine, daunorubicine, idarubicine valrubicine, mitoxantrone, dactinomycine, mithramycine, plicamycine, mitomycine C, bleomycine, et la procarbazine."Anti-tumor antibiotics" refers to compounds that can prevent or inhibit the synthesis of DNA, RNA and / or proteins. Examples of such anti-tumor antibiotics include doxorubicin, daunorubicin, idarubicin valrubicin, mitoxantrone, dactinomycin, mithramycin, plicamycin, mitomycin C, bleomycin, and procarbazine.
Les « inhibiteurs mitotiques » préviennent la progression normale du cycle cellulaire et de la mitose. En gênerai, les inhibiteurs des microtubules ou « taxoides »
comme le paclitaxel et le docétaxel sont capables d'inhiber la mitose. Les alcaloïdes de vinca, comme la vinblsatine, la vincristine, la vindésine et la vinorelbine sont également capables d'inhiber la mitose."Mitotic inhibitors" prevent normal progression of the cell cycle and mitosis. In general, inhibitors of microtubules or "taxoids" paclitaxel and docetaxel are able to inhibit mitosis. Vinca alkaloids such as vinblsatin, vincristine, vindesine and vinorelbine are also able to inhibit mitosis.
Les « inhibiteurs de fonction chromatine » ou « inhibiteurs de topo- isomérases » font référence à des substances qui inhibent la fonction normale des protéines modelant la chromatine comme les topo-isomérases I et II. Des exemples de tels inhibiteurs comprennent, pour la topo-isomérase I, la camptothécine ainsi que ses dérivés comme Firinotécan ou le topotécan et, pour la topo-isomérase II, l'étoposide, le phosphate d'étiposide et le téniposide. Les « agents anti-angiogénèse » font références à toute drogue, composé, substance ou agent qui inhibe la croissance des vaisseaux sanguins. Des exemples d'agents anti-angiogénèse comprennent, sans aucune limitation, les razoxin, marimastat, batimastat, prinomastat, tanomastat, ilomastat, CGS-27023A, halofuginone, COL-3, neovastat, BMS-275291, thalidomide, CDC 501, DMXAA, L-651582, squalamine, endostatine, SU5416, SU6668, interferon-alpha, EMD121974, interleukine-12, IM862, angiostatine et la vitaxine."Chromatin function inhibitors" or "topoisomerase inhibitors" refer to substances that inhibit the normal function of chromatin-forming proteins such as topoisomerases I and II. Examples of such inhibitors include, for topoisomerase I, camptothecin and its derivatives such as Firinotecan or topotecan and, for topoisomerase II, etoposide, etidoside phosphate and teniposide. "Anti-angiogenesis agents" refer to any drug, compound, substance or agent that inhibits the growth of blood vessels. Examples of anti-angiogenesis agents include, without limitation, razoxin, marimastat, batimastat, prinomastat, tanomastat, ilomastat, CGS-27023A, halofuginone, COL-3, neovastat, BMS-275291, thalidomide, CDC 501, DMXAA, L-651582, squalamine, endostatin, SU5416, SU6668, interferon-alpha, EMD121974, interleukin-12, IM862, angiostatin and vitaxine.
Les « anti-œstrogène » ou « agents anti-oestrogénique » font référence à toute substance qui diminue, antagonise ou inhibe l'action des oestrogènes. Des exemples de tels agents sont les tamoxifène, toremifène, raloxifène, droloxifène, iodoxyfène, anastrozole, letrozole, et l'exemestane."Anti-estrogen" or "anti-estrogenic agents" refers to any substance that decreases, antagonizes or inhibits the action of estrogen. Examples of such agents are tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfen, anastrozole, letrozole, and exemestane.
Les « anti-androgènes » ou « agents anti-androgène » font référence à toute substance qui réduit, antagonise ou inhibe l'action d'un androgène. Des exemples d'anti- androgènes sont les flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acétate, finasteride et la cimitidine. Les immunomodulateurs sont des substances qui stimulent le système immunitaire. Des exemples de tels immunomodulateurs comprennent les interférons, les interleukines comme l'aldesleukine, OCT-43, denileukin diflitox ou l'interleukine-2, les facteurs de nécrose tumorale comme la tasonermine, ou d'autres types d'immunomodulateurs comme le lentinan, le sizofiran, le roquinimex, le pidotimod, la pégadémase, la thymopentine, le poly I :C, ou le levamisole en combinaison avec le 5- fluorouracil."Anti-androgens" or "anti-androgenic agents" refer to any substance that reduces, antagonizes or inhibits the action of an androgen. Examples of antiandrogens are flutamide, nilutamide, bicalutamide, sprironolactone, cyproterone acetate, finasteride and cimitidine. Immunomodulators are substances that stimulate the immune system. Examples of such immunomodulators include interferons, interleukins such as aldesleukin, OCT-43, denileukin diflitox or interleukin-2, tumor necrosis factors such as tasonermin, or other types of immunomodulators such as lentinan, sizofiran, roquinimex, pidotimod, pegademase, thymopentine, poly I: C, or levamisole in combination with 5-fluorouracil.
Pour plus de détails, l'homme de l'art pourra se reporter au manuel édité par l'Association Française des Enseignants de Chimie Thérapeutique intitulé « traité de
chimie thérapeutique, Vol. 6, Médicaments antitumoraux et perspectives dans le traitement des cancers, édition TEC & DOC, 2003 ».For more details, those skilled in the art can refer to the manual published by the French Association of Teachers of Therapeutic Chemistry entitled "Treaty of therapeutic chemistry, Vol. 6, Antitumour Medicines and Perspectives in the Treatment of Cancers, TEC & DOC Edition, 2003 ".
Dans un mode de réalisation particulièrement préféré, ladite composition comme produit de combinaison selon l'invention est caractérisée en ce que ledit agent cytotoxique est couplé chimiquement audit anticorps pour une utilisation simultanée.In a particularly preferred embodiment, said composition as a combination product according to the invention is characterized in that said cytotoxic agent is chemically coupled to said antibody for simultaneous use.
Dans un mode de réalisation particulièrement préféré, ladite composition selon l'invention est caractérisée en ce que ledit agent cytotoxique/cytostatique est choisi parmi les agents inhibiteurs ou stabilisateurs du fuseau, de préférence la vinorelbine et/ou la vinflunine et/ou la vincristine. Afin de faciliter le couplage entre ledit agent cytotoxique et ledit anticorps selon l'invention, on pourra notamment introduire des molécules espaceurs entre les deux composés à coupler, telles que des poly(alkylènes)glycols comme le polyéthylèneglycol, ou encore des acides aminés, ou, dans un autre mode de réalisation, utiliser des dérivés actifs desdits agents cytotoxiques dans lesquels auront été introduites des fonctions capables de réagir avec ledit anticorps selon l'invention. Ces techniques de couplage sont bien connues de l'homme de l'art et ne seront pas développées dans la présente description.In a particularly preferred embodiment, said composition according to the invention is characterized in that said cytotoxic / cytostatic agent is chosen from inhibitors or spindle stabilizers, preferably vinorelbine and / or vinflunine and / or vincristine. In order to facilitate the coupling between said cytotoxic agent and said antibody according to the invention, it will be possible in particular to introduce spacer molecules between the two compounds to be coupled, such as poly (alkylenes) glycols such as polyethylene glycol, or else amino acids, or in another embodiment, using active derivatives of said cytotoxic agents in which have been introduced functions capable of reacting with said antibody according to the invention. These coupling techniques are well known to those skilled in the art and will not be developed in the present description.
L'invention est, sous un autre aspect, relative à une composition caractérisée en ce que l'un, au moins, desdits anticorps, ou l'un de leur composé dérivé ou fragment fonctionnel, est conjugué avec une toxine cellulaire et/ou un radioélémentThe invention is, in another aspect, relating to a composition characterized in that at least one of said antibodies, or one of their derivative compound or functional fragment, is conjugated with a cellular toxin and / or a radioélément
De préférence, ladite toxine ou ledit radioélément est capable d'empêcher la croissance ou la prolifération de la cellule tumorale, notamment d'inactiver totalement ladite cellule tumorale.Preferably, said toxin or said radioelement is capable of preventing growth or proliferation of the tumor cell, in particular completely inactivating said tumor cell.
De préférence encore, ladite toxine est une toxine d'entérobactéries, notamment l'exotoxine A de Pseudomonas.More preferably, said toxin is an enterobacterial toxin, especially exotoxin A of Pseudomonas.
Les radioéléments (ou radio-isotopes) préférentiellement conjugués à l'anticorps employés en thérapie sont des radio-isotopes qui émettent des rayons gamma et préférentiellement l'iodine131, l'yttrium90, l'or199, le palladium100, le cuivre67, le bismuth217 et Fantimony211. Les radio-isotopes qui émettent des rayons beta et alpha peuvent également être utilisés en thérapie.The radioelements (or radioisotopes) preferably conjugated to the antibody used in therapy are radioisotopes that emit gamma rays and preferably iodine 131 , yttrium 90 , gold 199 , palladium 100 , copper 67 , bismuth 217 and Fantimony 211 . Radioisotopes that emit beta and alpha rays can also be used in therapy.
Par toxine ou radioélément conjugué à au moins un anticorps, ou l'un de leur fragment fonctionnel, selon l'invention, on entend désigner tout moyen permettant de lier
ladite toxine ou ledit radioélément audit au moins un anticorps, notamment par couplage covalent entre les deux composés, avec ou sans introduction de molécule de liaison.By toxin or radioelement conjugated to at least one antibody, or one of their functional fragment, according to the invention, is meant any means for binding said toxin or said radioelement to said at least one antibody, in particular by covalent coupling between the two compounds, with or without the introduction of a binding molecule.
Parmi les agents permettant une liaison chimique (covalente), électrostatique ou non covalente de tout ou partie des éléments du conjugué, il peut être mentionné tout particulièrement le benzoquinone, le carbodiimide et plus particulièrement l'EDC (1- ethyl-3-[3-dimethylaminopropyl]-carbodiimide hydrochloride), le dimaleimide, l'acide dithiobis-nitrobenzoic (DTNB), le N-succinimidyl S-acetyl thio-acetate (SATA), les agents dits de « bridging » présentant un ou plusieurs groupements, ayant un ou plusieurs groupements phenylaside, réagissant avec les ultraviolets (U.V.) et tout préférentiellement le N-[-4-(azidosalicylamino)butyl]-3'-(2'-pyridyldithio)propionamide (APDP), le N-succinimid-yl 3-(2-pyridyldithio)propionate (SPDP) et le 6-hydrazino- nicotinamide (HYNIC).Among the agents allowing a chemical (covalent), electrostatic or non-covalent bonding of all or part of the conjugate elements, benzoquinone, carbodiimide and more particularly EDC (1-ethyl-3- [3] may be mentioned in particular. -dimethylaminopropyl] -carbodiimide hydrochloride), dimaleimide, dithiobis-nitrobenzoic acid (DTNB), N-succinimidyl S-acetyl thioacetate (SATA), the so-called bridging agents having one or more groups, having a or more phenylase groups, reactive with ultraviolet (UV) and most preferably N - [- 4- (azidosalicylamino) butyl] -3 '- (2'-pyridyldithio) propionamide (APDP), N-succinimid-yl 3- (2-pyridyldithio) propionate (SPDP) and 6-hydrazino-nicotinamide (HYNIC).
Une autre forme de couplage, tout spécialement pour les radioéléments, peut consister en l'utilisation d'un chélateur d'ions bifonctionnel. Parmi ces chélateurs, il est possible de mentionner les chélates dérivés de l'EDTAAnother form of coupling, especially for radioelements, may be the use of a bifunctional ion chelator. Among these chelators, it is possible to mention the chelates derived from EDTA
(ethylenediaminetetraacetic acid) ou du DTPA (diethylenetriaminepentaacetic acid) qui ont été développés pour lier des métaux, particulièrement des métaux radioactifs, et des immunoglobulines. Ainsi, le DTPA et ses dérivés peut être substitué par différents groupements sur le chaîne de carbones de manière à augmenter la stabilité et la rigidité du complexe ligand-métal (Krejcarek et al. (1977); Brechbiel et al. (1991); Gansow (1991); US patent 4 831 175).(ethylenediaminetetraacetic acid) or DTPA (diethylenetriaminepentaacetic acid) which have been developed to bind metals, particularly radioactive metals, and immunoglobulins. Thus, DTPA and its derivatives can be substituted by different groups on the carbon chain so as to increase the stability and rigidity of the ligand-metal complex (Krejcarek et al (1977), Brechbiel et al (1991), Gansow (1991) US Patent 4,831,175).
Par exemple, le DTPA (diethylenetriaminepentaacetic acid) et ses dérivés, qui a été très largement utilisé en médecine et en biologie pendant longtemps soit sous sa forme libre, soit sous la forme d'un complexe avec un ion métallique, présente la caractéristique remarquable de former des chélates stables avec des ions métalliques et d'être couplé à des protéines d'intérêt thérapeutique ou diagnostique comme des anticorps pour le développement de radio-immunoconjugués en thérapie du cancer (Meases et al., (1984); Gansow et al. (1990)).For example, DTPA (diethylenetriaminepentaacetic acid) and its derivatives, which has been widely used in medicine and biology for a long time either in its free form or in the form of a complex with a metal ion, has the remarkable characteristic of form stable chelates with metal ions and be coupled to proteins of therapeutic or diagnostic interest as antibodies for the development of radioimmunoconjugates in cancer therapy (Meases et al., (1984), Gansow et al. (1990)).
Selon encore un autre aspect, la composition selon l'invention comprend, en outre, au moins un deuxième anticorps connu pour son activité anti-tumorale. A titre d'exemple non limitatif, peuvent être cités les anticorps anti Her2/neu (Herceptin), anti-EGFR (Erbitux) ou encore anti-IGF-lR (7C10 ou h7C10). Bien évidemment, tout anticorps antitumoral pourra entre dans la composition selon l'invention.
La présente invention comprend en outre l'utilisation de la composition selon l'invention pour la préparation d'un médicament.According to yet another aspect, the composition according to the invention further comprises at least one second antibody known for its antitumor activity. By way of non-limiting example, the antibodies anti Her2 / neu (Herceptin), anti-EGFR (Erbitux) or anti-IGF-1R (7C10 or h7C10) may be mentioned. Of course, any antitumor antibody may be included in the composition according to the invention. The present invention further comprises the use of the composition according to the invention for the preparation of a medicament.
La présente invention vise donc plus particulièrement l'utilisation d'une composition telle que décrite plus haut pour la préparation d'un médicament destiné au traitement du cancer. Parmi les cancers qui peuvent être prévenus et/ou traités, on préfère le cancer du colon, du sein, de la prostate, du poumon (à petites cellules et non à petites cellules), de l'ovaire, du pancréas, du rein, du cerveau et certains lymphomes.The present invention therefore relates more particularly to the use of a composition as described above for the preparation of a medicament for the treatment of cancer. Among the cancers that can be prevented and / or treated, cancer of the colon, breast, prostate, lung (small cells and non-small cells), ovary, pancreas, kidney, brain and certain lymphomas.
L'invention a également pour objet l'utilisation d'un anticorps selon l'invention, pour la préparation d'un médicament destiné au ciblage spécifique d'un composé biologiquement actif vers des cellules exprimant ou surexprimant le récepteur CXCR4.The subject of the invention is also the use of an antibody according to the invention for the preparation of a medicinal product intended for the specific targeting of a biologically active compound to cells expressing or overexpressing the CXCR4 receptor.
On entend désigner ici par composé biologiquement actif tout composé capable de moduler, notamment d'inhiber, l'activité cellulaire, en particulier leur croissance, leur prolifération, la transcription ou la traduction de gène.Here, the term "biologically active compound" is intended to mean any compound capable of modulating, in particular of inhibiting, cell activity, in particular their growth, proliferation, transcription or gene translation.
D'autres caractéristiques et avantages de l'invention apparaissent dans la suite de la description avec les exemples et les figures dont les légendes sont représentées ci- après.Other features and advantages of the invention appear in the following description with the examples and figures whose legends are shown below.
LEGENDES DES FIGURESLEGENDS OF FIGURES
La figure 1 illustre l'étude de l'inhibition par SDFl et l'anticorps 44717 de la liaison de [125I]SDFl sur membranes de cellules CHO-Kl exprimant de manière constitutive le récepteur CXCR4 humain.Figure 1 illustrates the study of the inhibition by SDF1 and the 44717 antibody of [ 125 I] SDF1 binding on CHO-K1 cell membranes constitutively expressing the human CXCR4 receptor.
La figure 2 illustre l'étude de la liaison de [35S]GTPyS sur membranes de cellules CHO-Kl exprimant de manière constitutive le récepteur CXCR4 humain : influence de SDF 1 et de l' anticorps 44717.Figure 2 illustrates the study of [ 35 S] GTPγS binding to CHO-K1 cell membranes constitutively expressing the human CXCR4 receptor: influence of SDF 1 and antibody 44717.
La figure 3 illustre l'étude de la libération de calcium intracellulaire sur cellules intactes CHO-Kl exprimant le récepteur CXCR4 : influence de SDFl et de l'anticorps 44717.Figure 3 illustrates the study of intracellular calcium release on intact CHO-K1 cells expressing the CXCR4 receptor: influence of SDF1 and antibody 44717.
La figure 4 représente l'activité anti-tumorale in vivo de l'anticorps monoclonal 44717 dans le modèle de xénogreffe U-937.Figure 4 shows the in vivo antitumour activity of monoclonal antibody 44717 in the U-937 xenograft model.
La figure 5 représente l'inhibition de la croissance tumorale dans le modèle de xénogreffe MDA-MB-231 par l'anticorps monoclonal 44717.
EXEMPLESFigure 5 shows the inhibition of tumor growth in the MDA-MB-231 xenograft model by monoclonal antibody 44717. EXAMPLES
Exemple 1 : Test d'inhibition de Ia liaison de [125IlSDF-I par l'anticorps 44717 (autrement nommé MAB173)Example 1: Inhibition test of the binding of [ 125 IlSDF-I by antibody 44717 (otherwise known as MAB173)
Méthode :Method:
Des cellules CHO-Kl exprimant de manière constitutive le récepteur CXCR4 humain sont obtenues par transfection stable avec un vecteur d'expression contenant la totalité de la séquence codante de CXCR4 humain. Ces cellules sont cultivées dans un milieu de culture complet DMEM-Ham's F 12 contenant 5 % de sérum de veau foetal (SVF) et 500 μg/ml de généticine. Les tests de liaison sont effectués sur des membranes cellulaires obtenues après grattage mécanique des cellules dans un tampon [Hepes 2OmM, pH 7.4, NaCl 15OmM] et récoltées par centrifugation 10000g, 15 min. La liaison de [125I]SDFl (activité spécifique 1500 Ci/mmol) est mesurée en milieu homogène à l'aide de billes SPA (scintillation proximity assay - GE Healthcare) en plaques 96-puits. Brièvement, les membranes (30 μg/puits) sont incubées dans le tampon de liaison [Hepes 2OmM, pH 7.4, CaCl2 ImM, MgCl2 5mM, NaCl 15OmM, BSA 1%] avec le composé à étudier (SDFl ou anticorps 44717), le radioligand (InM) puis les billes SPA-WGA-PVT (7.3 mg/puits) et incubées IH à 25 0C. Après centrifugation [10 min. à 1000g] la radioactivité est lue dans un compteur à scintillation (TopCount, Perkin Elmer). La liaison non-spécifique de [125I]SDFl est déterminée en présence de 10 μM de SDFl non marqué.
CHO-K1 cells constitutively expressing the human CXCR4 receptor are obtained by stable transfection with an expression vector containing the entire coding sequence of human CXCR4. These cells are cultured in DMEM-Ham's F 12 complete culture medium containing 5% fetal calf serum (FCS) and 500 μg / ml geneticin. The binding assays are performed on cell membranes obtained after mechanically scraping the cells in [Hepes 20mM, pH 7.4, 15mM NaCl] buffer and harvested by centrifugation at 10000g, 15 min. The binding of [ 125 I] SDF1 (specific activity 1500 Ci / mmol) is measured in homogeneous medium using SPA (scintillation proximity assay - GE Healthcare) beads in 96-well plates. Briefly, the membranes (30 μg / well) are incubated in the binding buffer [Hepes 20 mM, pH 7.4, 1 mM CaCl 2 , 5 mM MgCl 2, 15 mM NaCl, 1% BSA] with the test compound (SDF1 or antibody 44717). the radioligand (InM) and then the SPA-WGA-PVT beads (7.3 mg / well) and incubated at 25 ° C. After centrifugation [10 min. at 1000g] the radioactivity is read in a scintillation counter (TopCount, Perkin Elmer). The nonspecific binding of [ 125 I] SDF1 is determined in the presence of 10 μM of unlabeled SDF1.
Résultats :Results:
SDFl inhibe de manière dose-dépendante la liaison de [125I]SDFl avec une valeur d'IQso (inhibition de 50 % de la liaison spécifique de [125I]SDFl) de 25.2 ± 6.4 nM (n=6) (Fig. 1). Dans ces conditions expérimentales, l'anticorps 44717 montre une inhibition maximale de la liaison de [125I]SDFl de 75 % à une dose de 1 μM et une valeur d'IC5o deSDF1 dose-dependently inhibited the binding of [ 125 I] SDF1 with a IQso value (50% inhibition of specific [ 125 I] SDF1 binding) of 25.2 ± 6.4 nM (n = 6) (Fig. 1). Under these experimental conditions, the antibody 44717 shows a maximal inhibition of the binding of [ 125 I] SDF1 of 75% at a dose of 1 μM and a value of IC 5 o of
44.8 ± 5.6 nM (n=3) (Fig. 1).44.8 ± 5.6 nM (n = 3) (Fig. 1).
Exemple 2 : Test de modulation de la liaison de [35SIGTFyS par l'anticorpsExample 2 Test for Modulation of the Binding of [ 35 SIGTFyS by the Antibody
4471744717
Ce test permet d'étudier la modulation de l'activation des protéines G hétérotrimériques médiée par CXCR4 et les ligands s'y fixant.This test makes it possible to study the modulation of CXCR4 mediated heterotrimeric G protein activation and ligands binding thereto.
Méthode :Method:
Des cellules CHO-Kl exprimant de manière constitutive le récepteur CXCR4 humain sont obtenues de la même manière que décrit dans l'exemple 1. Les tests de liaison sont effectués sur des membranes cellulaires obtenues après grattage mécanique des cellules dans un tampon [Hepes 2OmM, pH 7.4, NaCl 15OmM] et récoltées par centrifugation 10000g, 15 min. La liaison de [35S]GTPyS (activité spécifique 1000 Ci/mmol) est mesurée en milieu homogène à l'aide de billes SPA (scintillation proximity assay - GE Healthcare) en plaques 96-puits. Brièvement, les membranes (10 μg/puits) sont incubées dans le tampon de liaison [Hepes 2OmM, GDP 3μM, MgCl2 1OmM, NaCl 10OmM, EDTA ImM, pH=7.4] avec le composé à étudier (SDFl et/ou l'anticorps 44717), le [35S]GTPyS (0.2-0.4nM) puis les billes SPA-WGA-PVT (7.3 mg/puits) et incubées IH à 25 °C. Après centrifugation [10 min. à 1000g] la radioactivité est lue dans un compteur à scintillation (TopCount, Perkin Elmer).CHO-K1 cells constitutively expressing the human CXCR4 receptor are obtained in the same manner as described in Example 1. The binding assays are carried out on cell membranes obtained after mechanical scraping of the cells in a buffer [Hepes 20 mM, pH 7.4, 15OmM NaCl] and collected by centrifugation 10000g, 15 min. The binding of [ 35 S] GTPyS (specific activity 1000 Ci / mmol) is measured in homogeneous medium using SPA (scintillation proximity assay - GE Healthcare) beads in 96-well plates. Briefly, the membranes (10 μg / well) are incubated in the binding buffer [Hepes 20 mM, GDP 3 μM, 10 mM MgCl 2, 10 mM NaCl, 1 mM EDTA, pH = 7.4] with the test compound (SDF1 and / or the antibody 44717), [ 35 S] GTPyS (0.2-0.4nM) and then SPA-WGA-PVT beads (7.3 mg / well) and incubated at 25 ° C. After centrifugation [10 min. at 1000g] the radioactivity is read in a scintillation counter (TopCount, Perkin Elmer).
Résultats : SDFl stimule de manière dose-dépendante la liaison de [35S]GTPyS traduisant l'activation du récepteur CXCR4. La stimulation maximale obtenue est de 143 % par rapport à la liaison basale de [35S]GTPyS avec une puissance de 30.8 ± 9.7 nM (n=16)
(Fig. 2). Dans ces conditions expérimentales, l'anticorps 44717 montre une inhibition maximale de la stimulation de la liaison de [35S]GTPyS induite par SDFl (10 nM) de 58 % à une dose de 300 nM et une valeur d'IC50 de 20.7 ± 5.9 nM (n=4) (Fig. 2).Results: SDF1 stimulates in a dose-dependent manner the binding of [ 35 S] GTPyS reflecting the activation of the CXCR4 receptor. The maximum stimulation obtained is 143% compared to the basal binding of [ 35 S] GTPyS with a power of 30.8 ± 9.7 nM (n = 16) (Fig 2). Under these experimental conditions, antibody 44717 shows maximal inhibition of stimulation of SDF1-induced [ 35 S] GTPγS binding (10 nM) by 58% at a dose of 300 nM and an IC 50 value of 20.7. ± 5.9 nM (n = 4) (Fig. 2).
Exemple 3 : Test de mobilisation du calcium intracellulaire médié par CXCR4Example 3: Intracellular Calcium Mobilization Test Mediated by CXCR4
Ce test permet d'évaluer la signalisation du récepteur CXCR4 par la voie de la Phospholipase C, induisant la libération de calcium intracellulaire. Ce test cinétique permet de suivre l'évolution du système au cours du temps.This test makes it possible to evaluate the signaling of the CXCR4 receptor by the Phospholipase C pathway, inducing the release of intracellular calcium. This kinetic test makes it possible to follow the evolution of the system over time.
Méthode :Method:
Des cellules CHO-Kl exprimant de manière constitutive le récepteur CXCR4 humain sont obtenues de la même manière que décrit dans l'exemple 1. Les cellules sont ensemencées en plaque 96 puits noires [100 000 cellules en milieu DMEM-F 12 - SVF 5 % / puits] et sevrées sur la nuit. Les cellules sont chargées en sonde calcique fluorescente (Fluo-4 No Wash) dans le tampon [HBSS Ix, HEPS 20 raM, Probenicid acid 25 mM] durant 30 min. à 37 0C puis 30 min. à 25°C. Pour la mesure d'antagonisme, 10 μl de solution de l'anticorps 44717 sont ajoutés sur les cellules. Après une incubation de 10 min à température ambiante, la mesure est réalisée à l'aide du lecteur Mithras LB940 (Berthold) en mode fluorescence avec les paramètres suivants : Excitation à 485 nm, Emission à 535 nm et lampe à une énergie de 10000. Chaque puits est lu 0,1 seconde, toutes les secondes sur une période de 20 secondes (signal basai) puis 20 μl de SDF-I sont injectés et la lecture du puits reprend pendant 2 min. Chaque condition expérimentale est testée en duplicata. Les résultats sont corrigés en retranchant les valeurs d'un puits sans cellule aux valeurs des puits avec cellules. Les valeurs sont ensuite exprimées en % du signal de base et corrigées afin que la première valeur après ajout de SDF-I soit de 100 %. Ceci permet de compenser le saut aléatoire de fluorescence induit par l'injection du ligandCHO-K1 cells constitutively expressing the human CXCR4 receptor are obtained in the same manner as described in Example 1. The cells are seeded in plate 96 black wells [100,000 cells in DMEM-F 12 medium-5% FCS] / well] and weaned on the night. The cells are loaded with a fluorescent calcium probe (Fluo-4 No Wash) in the buffer [HBSS Ix, HEPS 20 μM, Probenicid acid 25 mM] for 30 min. at 37 0 C then 30 min. at 25 ° C. For the measure of antagonism, 10 .mu.l of solution of the antibody 44717 are added to the cells. After incubation for 10 min at room temperature, the measurement is carried out using the Mithras reader LB940 (Berthold) in fluorescence mode with the following parameters: excitation at 485 nm, emission at 535 nm and lamp at an energy of 10000. Each well is read 0.1 seconds, every second over a period of 20 seconds (basal signal) then 20 .mu.l of SDF-I are injected and the well reads again for 2 min. Each experimental condition is tested in duplicate. The results are corrected by subtracting the values of a cell free well to the cell well values. The values are then expressed in% of the base signal and corrected so that the first value after adding SDF-I is 100%. This makes it possible to compensate for the random jump of fluorescence induced by the injection of the ligand
Résultats :Results:
SDFl (300 nM) induit un relargage de calcium avec les cellules CHO/CXCR4, alors qu'aucune réponse n'est observée sur des cellules CHO-Kl naïves. Le signal
maximal est obtenu au bout d'environ 30 sec et l'efficacité maximale de SDF-I est de 180 % du signal basai (Fig. 3). L'anticorps 44717 (133 nM) inhibe fortement le relargage de calcium SDFl -induit qui atteint un maximum de 130 % du signal basai au bout d'une minute après l'injection de SDFl (Fig. 3).SDF1 (300 nM) induces calcium release with CHO / CXCR4 cells, whereas no response is observed on naive CHO-Kl cells. The signal maximum is obtained after about 30 sec and the maximum efficiency of SDF-I is 180% of the basal signal (Fig. 3). Antibody 44717 (133 nM) strongly inhibited the SDF1 -induced calcium release that reached a maximum of 130% basal signal after one minute after SDF1 injection (Fig. 3).
Exemple 4 : Activité anti-tumorale de l'anticorps 44717 dans Ie modèle de xénogreffe U937 chez Ia souris NOD scid.Example 4 Anti-tumor activity of the 44717 antibody in the U937 xenograft model in NOD scid mice.
Méthode :Method:
Les cellules U-937 ont été cultivées en milieu RPMI 1640 avec rouge de phénol et 4,5 g/1 de glucose (Sigma, ref G8769), supplémenté de SVF 10% (F7524, Sigma) et de L-Glutamine 2 mM (BioWhittaker ref BE17-605E). Les cellules ont été ensemencées deux jours avant la greffe, elles étaient en phase exponentielle de croissance lors de l'implantation chez l'animal. Dix millions de cellules U-937 P((2)+4) ont été greffées à des souris Nod/Scid femelles de 8 semaines, par injection intrapéritonéale (souche : SOPF/NOD.CB17PRKDC /J FE 6 S, NOD.CB17-Prkdc scid/J, ref NSCSSFE06S, Laboratoires Charles River).The U-937 cells were cultured in RPMI 1640 medium with phenol red and 4.5 g / l of glucose (Sigma, ref G8769), supplemented with 10% FCS (F7524, Sigma) and 2 mM L-Glutamine ( BioWhittaker ref BE17-605E). The cells were seeded two days before the transplant, they were exponential growth phase during implantation in the animal. Ten million U-937P ((2) +4) cells were grafted to 8 week old female Nod / Scid mice by intraperitoneal injection (strain: SOPF / NOD.CB17PRKDC / J FE 6 S, NOD.CB17- Prkdc scid / J, ref NSCSSFE06S, Charles River Laboratories).
Deux jours après la greffe les souris ont été traitées (injections en sous-cutané dorsale) avec les schémas suivants :Two days after the transplant, the mice were treated (subcutaneous dorsal injections) with the following diagrams:
- Groupe contrôle : PBS, deux fois par semaine- Control group: PBS, twice a week
- Groupe IgG2b : IgG2b, (Sigma ref M2695, Sigma lot 046K4843, lot 22060307, 3 mg/ml), 1 mg/dose par souris, deux fois/semaineIgG2b group: IgG2b, (Sigma ref M2695, Sigma lot 046K4843, lot 22060307, 3 mg / ml), 1 mg / dose per mouse, twice a week
- Groupe 44717 : Anticorps monoclonal Anti-hCXCR4 (R&D Systems, ref MAB173, lot AUZ04512A, 3.43 mg/ml), 1 mg/dose par souris, deux fois/semaine- Group 44717: Anti-hCXCR4 monoclonal antibody (R & D Systems, ref MAB173, lot AUZ04512A, 3.43 mg / ml), 1 mg / dose per mouse, twice weekly
La première dose était de 2 mg par souris pour les anticorps IgG2b contrôles et l'anticorps 44717. Le choix de la voie s.c. pour le traitement a été sélectionné de façon à éviter tout contact direct entre les cellules tumorales et l'anticorps dans la cavité péritonéale.The first dose was 2 mg per mouse for the control IgG2b antibodies and the 44717 antibody. The choice of the sc pathway for the treatment was selected so as to avoid any direct contact between the tumor cells and the antibody in the cavity. peritoneal.
Un suivi quotidien de la survie des souris dans chaque groupe a été effectué.
Résultats :Daily monitoring of the survival of the mice in each group was performed. Results:
La première souris est morte après 15 jours dans le groupe IgG2b. Toutes les souris exceptée une sont mortes dans les sept jours suivants (Fig. 4). La souris ayant survécu a été euthanasiée 82 jours après la greffe et examinée, il n'y avait pas de cellules tumorale dans sa cavité abdominale.The first mouse died after 15 days in the IgG2b group. All but one mouse died within seven days (Fig. 4). The surviving mouse was euthanized 82 days after the transplant and examined, there were no tumor cells in its abdominal cavity.
Dans le groupe PBS, toutes les souris exceptée une sont mortes entre les jours 17 et 21 après la greffe (Fig. 4). La dernière est morte 82 jours après la greffe.In the PBS group, all but one mouse died between days 17 and 21 after transplantation (Fig. 4). The last one died 82 days after the transplant.
En ce qui concerne le groupe 44717, les souris ont commencé à mourir avec un délai de 4 à 6 jours par rapport au deux autres groupes contrôles. Huit souris sont mortes entre les jours 22 et 27. Deux souris ont survécu jusqu'au jour 109, jour de leur euthanasie (Fig. 4). Une analyse statistique des résultats de survie (Kaplan-Meier) a été réalisée à l'aide du test Log-Rank (Fig. 4). L'expérience décrite ici montre que l'anticorps monoclonal 44717 dirigé contre le récepteur CXCR4 est capable d'augmenter la survie des souris dans le modèle de xénogreffe U937.In 44717, the mice began to die within 4-6 days of the other two control groups. Eight mice died between days 22 and 27. Two mice survived until day 109, the day they were euthanized (Fig. 4). A statistical analysis of the survival results (Kaplan-Meier) was performed using the Log-Rank test (Fig. 4). The experiment described here shows that monoclonal antibody 44717 directed against the CXCR4 receptor is capable of increasing mouse survival in the U937 xenograft model.
Exemple 5 : Inhibition de Ia croissance tumorale par l'anticorps 44717 dans le modèle de xénogreffe MDA-MB-231 chez la souris Nude athvmique.Example 5: Inhibition of tumor growth by the 44717 antibody in the MDA-MB-231 xenograft model in the athmic Nude mouse.
Méthode :Method:
Les cellules MDA-MB-231 (ECACC) ont été cultivées en milieu DMEM (Invitrogen Corporation, Scotland, UK), en présence de SVF 10% (Sigma). Les cellules ont été ensemencées 60 heures avant la greffe. Elles étaient en phase exponentielle de croissance lors de l'implantation. Dix millions de cellules MDA-MB-231 (P35+18) ont été greffées en PBS à des souris Nude Athymique de 7 semaines (HARLAN). Cinq jours après l'implantation, les tumeurs étaient mesurables (37 mm3<V3<44 mm3) et les animaux on été divisés au hasard en groupes de 12 souris avec des tailles de tumeurs comparables. Les souris ont été traitées par voie i.p. avec une dose d'appel d'anticorps monoclonal 44717 (lots AUZ05607A et AUZ04512A, R&D Systems) de 2mg/souris. Ensuite, les souris ont reçu, deux fois par semaine, une dose d'anticorps monoclonal 44717 de 1 mg/souris. Dans cette expérience un groupe de souris control a reçu un volume équivalent de PBS.
Le volume des tumeurs a été mesuré deux fois par semaine et calculé à l'aide de la formule suivante : π/6 X longueur X largeur X hauteur.MDA-MB-231 cells (ECACC) were cultured in DMEM medium (Invitrogen Corporation, Scotland, UK), in the presence of 10% FCS (Sigma). The cells were inoculated 60 hours before the transplant. They were in an exponential phase of growth during implantation. Ten million MDA-MB-231 cells (P35 + 18) were grafted in PBS to 7 week old Nude Athymic (HARLAN) mice. Five days after implantation, the tumors were measurable (37 mm 3 <V 3 <44 mm 3 ) and the animals were randomly divided into groups of 12 mice with comparable tumor sizes. The mice were treated ip with a dose of monoclonal antibody 44717 (lots AUZ05607A and AUZ04512A, R & D Systems) of 2mg / mouse. Then, the mice received, twice a week, a 44717 monoclonal antibody dose of 1 mg / mouse. In this experiment a group of control mice received an equivalent volume of PBS. The volume of the tumors was measured twice a week and calculated using the following formula: π / 6 X length X width X height.
Une analyse statistique a été réalisée pour chaque mesure à l'aide du test Mann- Whitney.A statistical analysis was performed for each measurement using the Mann-Whitney test.
Résultats :Results:
Dans le protocole 01MDAMB23101406, aucune mortalité n'a été observée durant le traitement. Comparé au groupe PBS témoin, il y a une inhibition significative de la croissance tumorale entre les jours 6 et 35 (p <0.05) pour l'anticorps monoclonal 44717 administré à lmg/dose.In the protocol 01MDAMB23101406, no mortality was observed during the treatment. Compared to the control PBS group, there is a significant inhibition of tumor growth between days 6 and 35 (p <0.05) for monoclonal antibody 44717 administered at 1 mg / dose.
Le volume tumoral moyen après 5 semaines de traitement a été réduit de 56% pour l'anticorps 44717 par rapport au PBS.The average tumor volume after 5 weeks of treatment was reduced by 56% for the 44717 antibody relative to the PBS.
L'expérience décrite ici montre que l'anticorps monoclonal 44717 dirigé contre le récepteur CXCR4 est capable d'inhiber la croissance tumorale dans un modèle de xénogreffe MDA-MB-231 chez la souris Nude athymique.
The experiment described here shows that monoclonal antibody 44717 directed against the CXCR4 receptor is capable of inhibiting tumor growth in a MDA-MB-231 xenograft model in athymic Nude mouse.
Claims
1. Utilisation d'un anticorps monoclonal, ou l'un de ses fragments fonctionnels, capable de se lier spécifiquement à la protéine CXCR4 et d'inhiber in vitro et/ou in vivo la croissance tumorale d'une tumeur primaire pour la préparation d'un médicament destiné au traitement et/ou à la prévention du cancer, caractérisée en ce que ledit anticorps monoclonal, ou l'un de ses fragments fonctionnels, est sélectionné parmi les anticorps MAB170, MAB171, MAB172 et MAB173.1. Use of a monoclonal antibody, or a functional fragment thereof, capable of binding specifically to the CXCR4 protein and of inhibiting in vitro and / or in vivo the tumor growth of a primary tumor for the preparation of a medicament for the treatment and / or prevention of cancer, characterized in that said monoclonal antibody, or a functional fragment thereof, is selected from the antibodies MAB170, MAB171, MAB172 and MAB173.
2. Utilisation selon la revendication 1, caractérisée en ce que ledit anticorps monoclonal, ou l'un de ses fragments fonctionnels, inhibe la vascularisation au sein de la tumeur primaire.2. Use according to claim 1, characterized in that said monoclonal antibody, or one of its functional fragments, inhibits the vascularization within the primary tumor.
3. Utilisation selon la revendication 1 ou 2, caractérisée en ce que ledit anticorps monoclonal, ou l'un de ses fragments fonctionnels, inhibe la prolifération des cellules tumorales constituant la tumeur primaire. 3. Use according to claim 1 or 2, characterized in that said monoclonal antibody, or one of its functional fragments, inhibits the proliferation of tumor cells constituting the primary tumor.
4. Utilisation selon la revendication 2 ou 3, caractérisée en ce que ledit anticorps monoclonal, ou l'un de ses fragments fonctionnels, induit également l'apoptose des cellules tumorales constituant la tumeur primaire.4. Use according to claim 2 or 3, characterized in that said monoclonal antibody, or one of its functional fragments, also induces the apoptosis of the tumor cells constituting the primary tumor.
5. Utilisation selon l'une des revendications 1 à 4, caractérisée en ce que ledit anticorps monoclonal consiste en l'anticorps MAB173. 5. Use according to one of claims 1 to 4, characterized in that said monoclonal antibody consists of the antibody MAB173.
6. Utilisation selon l'une des revendications 1 à 5, caractérisée en ce que ledit cancer est sélectionné parmi le cancer du colon, du sein, de la prostate, du poumon (à petites cellules et non à petites cellules), de l'ovaire, du pancréas, du rein, du cerveau et certains lymphomes.6. Use according to one of claims 1 to 5, characterized in that said cancer is selected from cancer of the colon, breast, prostate, lung (small cells and not small cells), the ovary, pancreas, kidney, brain and some lymphomas.
7. Composition comprenant au moins un principe actif capable d'inhiber in vitro et/ou in vivo la croissance tumorale d'une tumeur primaire, caractérisée en ce que ledit au moins un principe actif consiste en un anticorps monoclonal, ou l'un de ses fragments fonctionnels, capable de se lier spécifiquement à la protéine CXCR4 sélectionné parmi les anticorps MAB 170, MAB 171, MAB 172 et MAB 173.7. Composition comprising at least one active principle capable of inhibiting in vitro and / or in vivo the tumor growth of a primary tumor, characterized in that said at least one active principle consists of a monoclonal antibody, or one of its functional fragments, capable of binding specifically to the CXCR4 protein selected from the MAB 170, MAB 171, MAB 172 and MAB 173 antibodies.
8. Composition selon la revendication 7, caractérisée en ce que ledit anticorps monoclonal anti-CXCR4, ou l'un de ses fragments fonctionnels, consiste en l'anticorps8. Composition according to claim 7, characterized in that said monoclonal antibody anti-CXCR4, or one of its functional fragments, consists of the antibody
MAB173.MAB173.
9. Composition selon l'une quelconque des revendications 7 à 8, caractérisée en ce qu'elle comprend au moins un véhicule pharmaceutiquement acceptable. 9. Composition according to any one of claims 7 to 8, characterized in that it comprises at least one pharmaceutically acceptable vehicle.
10. Composition selon l'une quelconque des revendications 7 à 9, caractérisée en ce qu'elle comprend, en outre, comme produit de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps, au moins un agent cytotoxique/cytostatique et/ou une toxine cellulaire et/ou un radioélément. 10. Composition according to any one of claims 7 to 9, characterized in that it further comprises, as combination product for simultaneous use, separated or spread over time, at least one cytotoxic / cytostatic agent and / or a cellular toxin and / or a radioelement.
11. Composition selon l'une quelconque des revendications 7 à 10, caractérisée en ce qu'elle comprend, en outre, au moins un deuxième anticorps anti-tumoral.11. Composition according to any one of claims 7 to 10, characterized in that it further comprises at least one second anti-tumor antibody.
12. Utilisation d'une composition selon l'une quelconque des revendications 7 à 11 pour la préparation d'un médicament destiné au traitement du cancer.12. Use of a composition according to any one of claims 7 to 11 for the preparation of a medicament for the treatment of cancer.
13. Utilisation selon la revendication 12, caractérisée en ce que ledit cancer est sélectionné parmi le cancer du colon, du sein, de la prostate, du poumon (à petites cellules et non à petites cellules), de l'ovaire, du pancréas, du rein, du cerveau et certains lymphomes. 13. Use according to claim 12, characterized in that said cancer is selected from cancer of the colon, breast, prostate, lung (small cell and non-small cell), ovary, pancreas, kidney, brain and some lymphomas.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR0702977A FR2915102B1 (en) | 2007-04-23 | 2007-04-23 | USE OF ANTI-CXCR4 ANTIBODY FOR THE TREATMENT OF CANCER |
PCT/FR2008/000553 WO2008142303A2 (en) | 2007-04-23 | 2008-04-18 | Use of an anti-cxcr4 antibody for treating cancer |
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EP2136840A2 true EP2136840A2 (en) | 2009-12-30 |
Family
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Family Applications (1)
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EP08787975A Withdrawn EP2136840A2 (en) | 2007-04-23 | 2008-04-18 | Use of an anti-cxcr4 antibody for treating cancer |
Country Status (6)
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US (1) | US20100150935A1 (en) |
EP (1) | EP2136840A2 (en) |
JP (1) | JP2010526044A (en) |
CA (1) | CA2683452A1 (en) |
FR (1) | FR2915102B1 (en) |
WO (1) | WO2008142303A2 (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102027015A (en) * | 2008-05-14 | 2011-04-20 | 伊莱利利公司 | Anti-CXCR4 antibodies |
GB201002238D0 (en) | 2010-02-10 | 2010-03-31 | Affitech As | Antibodies |
EP2545174B1 (en) * | 2010-03-11 | 2015-11-11 | Health Research, Inc. | Methods and compositions containing fc fusion proteins for enhancing immune responses |
ES2758884T3 (en) | 2011-06-24 | 2020-05-06 | Stephen D Gillies | Immunoglobulin fusion proteins via light chain and methods of using them |
KR102024957B1 (en) | 2011-11-09 | 2019-09-24 | 브리스톨-마이어스 스큅 컴퍼니 | Treatment of hematologic malignancies with an anti-cxcr4 antibody |
EA201792522A1 (en) | 2015-06-12 | 2018-05-31 | Бристол-Майерс Сквибб Компани | TREATMENT OF MALIGNANT TUMOR WITH THE HELP OF THE COMBINED BLOCK OF SIGNAL PATH OF PD-1 AND CXCR4 |
AU2017281830B2 (en) | 2016-06-20 | 2023-04-06 | Kymab Limited | Anti-PD-L1 antibodies |
CN112513079A (en) | 2018-03-13 | 2021-03-16 | 拉巴斯大学医院生物医学研究基金会 | anti-CXCR4 antibodies for use in the combined activation and expansion of natural killer cells for cancer immunotherapy |
JP2021519298A (en) | 2018-03-27 | 2021-08-10 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Real-time monitoring of titers using UV signals |
US20220135619A1 (en) | 2019-02-24 | 2022-05-05 | Bristol-Myers Squibb Company | Methods of isolating a protein |
EP3973274A1 (en) | 2019-05-23 | 2022-03-30 | Bristol-Myers Squibb Company | Methods of monitoring cell culture media |
EP4225770A1 (en) | 2020-10-05 | 2023-08-16 | Bristol-Myers Squibb Company | Methods for concentrating proteins |
WO2023173011A1 (en) | 2022-03-09 | 2023-09-14 | Bristol-Myers Squibb Company | Transient expression of therapeutic proteins |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2008060367A2 (en) * | 2006-10-02 | 2008-05-22 | Medarex, Inc. | Human antibodies that bind cxcr4 and uses thereof |
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US20080112950A1 (en) * | 2002-11-07 | 2008-05-15 | Lobo Peter I | Naturally occurring IgM antibodies that bind lymphocytes |
AR030631A1 (en) * | 2000-09-29 | 2003-08-27 | Abbott Lab | ANTIANGIOGEN POLYPEPTIDES AND METHODS TO INHIBIT THE ANGIOGENESIS |
US20050002939A1 (en) * | 2002-12-23 | 2005-01-06 | Albert Zlotnik | Tumor killing/tumor regression using CXCR4 antagonists |
CA2597717C (en) * | 2005-02-18 | 2014-10-21 | Dana-Farber Cancer Institute | Antibodies against cxcr4 and methods of use thereof |
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2007
- 2007-04-23 FR FR0702977A patent/FR2915102B1/en not_active Expired - Fee Related
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2008
- 2008-04-18 CA CA002683452A patent/CA2683452A1/en not_active Abandoned
- 2008-04-18 WO PCT/FR2008/000553 patent/WO2008142303A2/en active Application Filing
- 2008-04-18 EP EP08787975A patent/EP2136840A2/en not_active Withdrawn
- 2008-04-18 US US12/451,025 patent/US20100150935A1/en not_active Abandoned
- 2008-04-18 JP JP2010504784A patent/JP2010526044A/en active Pending
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WO2008060367A2 (en) * | 2006-10-02 | 2008-05-22 | Medarex, Inc. | Human antibodies that bind cxcr4 and uses thereof |
Non-Patent Citations (2)
Title |
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ANONYMOUS: "MDA-MB-231 (ATCC(R) HTB-26TM) Homo sapiens mammary gland/breast", 16 December 2013 (2013-12-16), XP055093634, Retrieved from the Internet <URL:http://www.lgcstandards-atcc.org/products/all/HTB-26.aspx?geo_country=nl#characteristics> [retrieved on 20131216] * |
N.N: "The mutation data was obtained from the Sanger Institute Catalogue Of Somatic Mutations", 16 December 2013 (2013-12-16), XP055093650, Retrieved from the Internet <URL:http://www.lgcstandards-atcc.org/~/media/CE379788822442FA8EC05617FDCF9ACD.ashx> [retrieved on 20131216] * |
Also Published As
Publication number | Publication date |
---|---|
FR2915102A1 (en) | 2008-10-24 |
WO2008142303A3 (en) | 2009-01-22 |
JP2010526044A (en) | 2010-07-29 |
CA2683452A1 (en) | 2008-11-27 |
WO2008142303A2 (en) | 2008-11-27 |
US20100150935A1 (en) | 2010-06-17 |
FR2915102B1 (en) | 2014-05-16 |
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