EP1713502A1 - Formulations liquides fortement concentrees d'anticorps anti-egfr - Google Patents

Formulations liquides fortement concentrees d'anticorps anti-egfr

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Publication number
EP1713502A1
EP1713502A1 EP05701212A EP05701212A EP1713502A1 EP 1713502 A1 EP1713502 A1 EP 1713502A1 EP 05701212 A EP05701212 A EP 05701212A EP 05701212 A EP05701212 A EP 05701212A EP 1713502 A1 EP1713502 A1 EP 1713502A1
Authority
EP
European Patent Office
Prior art keywords
highly concentrated
liquid formulation
egfr antibody
egfr
formulations
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Withdrawn
Application number
EP05701212A
Other languages
German (de)
English (en)
Inventor
Susanne Matheus
Hanns-Christian Mahler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1713502A1 publication Critical patent/EP1713502A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07K16/2863—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 growth factors, growth regulators

Definitions

  • the invention relates to processes for producing highly concentrated, liquid formulations comprising at least one anti-EGFR antibody and / or one of its variants and / or fragments, in particular monoclonal antibodies against the EGF receptor, particularly preferably Mab C225 (cetuximab) and Mab h425 (EMD 72000), by ultrafiltration.
  • EGF receptor particularly preferably Mab C225 (cetuximab) and Mab h425 (EMD 72000
  • the invention further relates to highly concentrated, liquid formulations of anti-EGFR antibodies, in particular of monoclonal antibodies against the EGF receptor, particularly preferably of Mab C225 (cetuximab) and Mab h425 (EMD 72000) and / or their variants and / or fragments, characterized in that the highly concentrated, liquid formulations have an anti-EGFR antibody content of 10-250, preferably 50-180 mg / ml, particularly preferably 100-150 mg / ml and their use.
  • Protein medicinal products such as monoclonal antibodies are used, for example, in tumor therapy, for example for specific immunotherapy or tumor vaccination.
  • Therapeutic proteins are larger and more complex than conventional organic and inorganic active substances, and they have complex three-dimensional structures and numerous functional groups that can cause the biological activity of the protein or can also have undesirable effects.
  • Protein medicinal products are exposed to numerous exogenous influences during manufacture, storage and transport, which can reduce the stability of the protein active ingredient. It is therefore necessary to study the causes and mechanisms of the special degradation reactions carefully, for example by adding certain stabilizing additives
  • No. 6,252,055 describes the production of highly concentrated antibody formulations by means of ultrafiltration, but they do so produced antibody formulations a high proportion of soluble aggregates of ⁇ 4% immediately after production.
  • the antibody formulations obtained are not characterized in terms of their native structure and stability, which is very important, for example, with regard to the immunogenicity and effectiveness of the
  • Antibody formulation is to be considered.
  • Formulations containing Mab C225 (cetuximab) or Mab h425 (EMD 72000) are known from WO03053465 and from WO03007988, but the formulations known from WO03053465 have a relatively low protein concentration and they are not stable in the long term at room temperature.
  • the formulations known from WO03007988 also have a relatively low protein concentration and the preparation (lyophilisate) still has to be reconstituted before use.
  • Protein formulations are known, for example, from WO9300807 or WO9822136, but significant disadvantages of lyophilized preparations are that the user still has to reconstitute the lyophilisate before use, which is a considerable source of error in the preparation before use. Since there is another manufacturing process compared to liquid formulations, the process is in terms of additional effort for process development (ensuring stability in lyophilization), manufacturing (manufacturing costs and duration) and e.g. Validation unfavorable.
  • ultra-concentrated pharmaceutical preparations of anti-EGFR antibodies can be obtained with the aid of ultraflitration processes, the protein concentrations in a liquid formulation of 10-250 mg / ml, particularly preferably 50-180 mg / ml, particularly preferably 100-150 mg / ml enable.
  • the formulations obtained by the ultrafiltration process are preferably stable over a longer period of time or, if necessary, they can be mixed with suitable stabilizing auxiliaries or stabilized by subsequent lyophilization.
  • the formulations according to the invention are physiologically well tolerated, easy to prepare, precisely metered and stable over the duration of storage, under mechanical stress and, for example, in the case of multiple freezing and thawing processes.
  • the highly concentrated formulations of anti-EGFR antibodies produced by the method according to the invention contain a monomer fraction of> 99%.
  • the highly concentrated, liquid formulations according to the invention obtained with a concentration of 10-250 mg / ml, particularly preferably 50-180 mg / ml, particularly preferably 100-150 mg / ml are physically and chemically stable, i.e. that there is no change in the monomer content with a concomitant increase in soluble aggregates, which would be regarded as very critical in terms of effectiveness and immunogenic side effects (Schellekens H. (2002) Bioequivalence and the immunogenicity of biopharmaceuticals .: Nat. Rev. Drug Discov ., v. 1, p.
  • the ultrafiltration processes used also do not change the primary structure of the protein.
  • the characterized aggregation products for the highly concentrated, liquid antibody formulations according to the invention are in the range of the specified specifications.
  • formulations of anti-EGFR antibodies according to the invention described below are surprisingly distinguished by one or more advantages, selected from: high protein concentration, high stability, low tendency to aggregate, low viscosity, high
  • the invention therefore relates to processes for the production of highly concentrated, liquid formulations comprising at least one anti-EGFR antibody and / or one of its variants and / or fragments by ultrafiltration.
  • Methods according to the invention are particularly characterized in that the highly concentrated, liquid formulations obtained have a content of at least one anti-EGFR antibody of 10-250 mg / ml, preferably 50-180 mg / ml, particularly preferably 100-150 mg / ml.
  • anti-EGFR antibodies are monoclonal and of murine or human origin, preferably murine origin and chimeric or humanized.
  • the anti-EGFR antibodies Mab C225 (cetuximab) or Mab h425 (EMD72000) and / or their variants and / or fragments are particularly preferred.
  • Ultrafiltration processes such as stirred ultrafiltration and tangential flow filtration (TFF).
  • the ultrafiltration of the antibodies according to the invention is preferably carried out in a suitable buffer system, ie it is not necessary to stabilize the reaction solutions, for example by means of detergents.
  • a suitable buffer system ie it is not necessary to stabilize the reaction solutions, for example by means of detergents.
  • the use of detergents in preparations for parenteral use should generally be avoided or minimized, since they have a not inconsiderable toxic and immunogenic potential (Sweetana S. & Akers MJ (1996) Solubility principles and practices for parenteral drug dosage form development. PDA J. Pharm. Sci. Technol. 50, 330-342) and they can also lead to changes in the secondary structure of proteins (Vermeer AWP & Norde W. (2000) The influence of the binding of Iow molecular weight surfactants on the thermal stability and secondary structure of IgG.
  • biologically active With regard to the anti-EGFR antibodies according to the invention and in the context of the present invention, “biologically active”, “native” and “effective” are understood to mean that anti-EGFR antibodies according to the invention can continue to exert their biological action even after conversion into formations according to the invention , in particular the binding to EGFR, inhibition of the binding of ligands, in particular EGF, to the EGFR, modulation, in particular inhibition of EGFR-mediated signal transduction and prophylaxis or therapy of EGFR-mediated diseases.
  • anti-EGFR antibodies are preferably monoclonal and of murine or human origin, particularly preferably they are of murine origin and chimeric or humanized.
  • the antibody directed against the receptor of the epidermal growth factor (EGFR) is particularly preferably Mab C225 (cetuximab) or Mab h425 (EMD 72000) and / or their variants or fragments.
  • Other antibodies directed against the EGFR are e.g. in EP0586002 and in J. Natl. Cancer Inst. 1993, 85: 27-33 (Mab 528).
  • Mab C225 (Cetuximab, Erbitux TM): Mab C225 (Cetuximab) is a clinically proven antibody that binds to the EGF receptor. Mab C225 (cetuximab) is a chimeric antibody whose variable regions are murine and whose constant regions are of human origin. It was first developed by Naramura et al., Cancer Immunol. Immunotherapy 1993, 37: 343-349 and in WO 96/40210 A1.
  • Mab h425 (EMD 72000) is a humanized monoclonal antibody (Mab), which was obtained from the murine anti-EGFR antibody 425 (Mab 425) (EP0531472).
  • the murine monoclonal antibody Mab 425 was developed in the human carcinoma cell line A431 because it binds to an extracellular epitope of the epidermal growth factor receptor (EGFR). It has been found to inhibit EGF binding (Murthy et al., 1987). Increased expression of EGFR is found in malignant tissues from different sources, making Mab 425 a possible active ingredient for the diagnosis and therapeutic treatment of human tumors.
  • EGFR epidermal growth factor receptor
  • Mab 425 mediates tumor cytotoxicity in vitro and suppresses the tumor growth of cell lines of epidermoid and colorectal carcinomas in vitro (Rodeck et al., 1987). It was also shown that Mab 425 binds to xenografts of human malignant gliomas in mice (Takahashi et al., 1987). Its humanized and chimeric forms are, for example, from EP0531472; Kettleborough et al., Protein Engineering 1991, 4: 773-783; Bier et al., Cancer Chemother Pharmacol. 2001, 47: 519-524; Bier et al., Cancer Immunol. Immunother. 1998, 46:
  • Mab h425 (EMD 72000) is one in clinical
  • Range is composed of a K and a human ⁇ -1 chain
  • Human anti-EGFR antibodies can be provided according to XenoMouse technology, as described in WO9110741, WO9402602, WO9633735.
  • An antibody produced according to this technology and in clinical trials is, for example, ABX-EGF (Abgenix, Crit. Rev. Oncol. Hematol. 2001, 38: 17-23; Cancer Research 1999, 59: 1236-43).
  • Antibody or immunoglobulin is used in the broadest scope in the context of the present invention and relates in particular to polyclonal antibodies and multispecific antibodies (for example bispecific antibodies) and particularly preferably intact monoclonal Antibodies (Mab) that are biologically active, as well as their variants and fragments. Heteroantibodies which consist of two or more antibodies or their fragments and / or have different binding specificities and are linked to one another are also included. Depending on the amino acid sequence of their constant regions, antibodies can be assigned to different “antibody (immunoglobulin) classes: IgA, IgD, IgE, IgG and IgM.
  • Antibodies usually have a molecular weight of approximately 150 kDa and consist of two identical light chains (L) and two identical heavy chains (H).
  • Monoconal antibodies are obtained from a population of homogeneous cells. They are highly specific and are directed against a single epitope, while polyclonal antibodies comprise different antibodies which are directed against different epitopes.
  • Monoclonal antibodies can also be isolated from phage antibody libraries, for example using the methods described in Clackson et al. (Nature, 352: 624-628 (1991)) and Marks et al. (J. Mol. Biol., 222: 58, 1-597 (1991)).
  • Variants (muteins) of antibodies are structurally related proteins, for example those which are modified by modifying the primary sequence (amino acid sequence)
  • Variants of the glycosylation sites or structures, also deglycosylated proteins by PEGylation, by production in modified host cells or can be obtained by other techniques.
  • Variants according to the invention are not limited to the examples above, but include all variants of antibodies according to the invention known to the person skilled in the art. Fragments (subsegments) of antibodies are
  • Antibody cleavage products that are obtained, for example, by limited enzymatic digestion using papain, pepsin and plasmin, or by genetic engineering of the subsegments.
  • Typical sub-segments are, for example, the bivalent F (ab ') 2 fragment, the monovalent Fab fragment and the Fc fragment.
  • Fragments according to the invention are not limited to the examples above, but include all fragments of antibodies according to the invention known to the person skilled in the art.
  • composition The terms pharmaceutical formulation and pharmaceutical preparation are used synonymously in the context of the present invention.
  • pharmaceutically acceptable refers to drugs, carriers, excipients, stabilizers, solvents and other agents which enable the pharmaceutical preparations obtained from them to be administered to a mammal without undesirable physiological side effects, such as nausea, dizziness, digestive problems or the like.
  • highly concentrated, liquid formulations of anti- EGFR antibodies preferably have the advantage that direct use is possible, since physiologically harmless agents are used for the production.
  • the production of highly concentrated, liquid formulations of anti-EGFR antibodies according to the invention with preferably simultaneously high yield of native and pharmaceutically acceptable protein of high purity is preferably simple, time-saving and inexpensive.
  • Ultrafiltration is a pressure-driven semi-permeable membrane process for the separation of dissolved and suspended materials.
  • the principle of separation is based on the size and extent of the molecule, i.e. Substances that are smaller than the pore size enter the filtrate (permeate), while substances that are larger than the pore size remain in the retentate (concentrate).
  • the necessary force to carry out the separation can be, for example, by
  • a gas pressure source e.g. nitrogen
  • a diaphragm pump can be applied.
  • Highly concentrated, liquid formulations of anti-EGFR antibodies according to the invention can preferably be prepared by concentrating a solution containing anti-EGFR antibodies according to the invention by means of an ultrafiltration process.
  • a solution with a defined concentration of anti-EGFR antibodies according to the invention (for example for C225: 0.01 to 150 mg / ml, preferably 2 to 100 mg / ml, particularly preferably approximately 20 mg / ml, for EMD 72000) is expediently used : 0.01 to 150 mg / ml, preferably 5 to 100 mg / ml, particularly preferably approx. 20 mg / ml), as obtained in their manufacture, are added to the ultrafiltration unit and subjected to a concentration process under defined, controlled pressure conditions. If the antibody is a solid, for example as
  • Lyophilisate before, the highly concentrated, liquid formulation according to the invention can be prepared by anti-EGFR- Antibody is first dissolved in water or in an aqueous solution containing one or more of the other ingredients and then exposed to the ultrafiltration process.
  • the product obtained by the ultrafiltration process can then be stabilized by adding the auxiliaries listed below.
  • the solution thus obtained, containing the respective antibody is adjusted to a pH of 4 to 10, preferably pH 5 to 9, sterile filtered and, if necessary, converted into a solid form by a subsequent lyophilization step for stabilization.
  • the anti-EGFR antibodies in the highly concentrated, liquid formulations according to the invention are preferably in biologically active form and the methods according to the invention preferably do not result in the antibodies being denatured. In this way, the biological effectiveness of the protein is preferably retained.
  • polyethersulfone (PES) or regenerated cellulose can be used as ultrafiltration membranes: the theoretically conceivable cutoff is in the range between 5 and 500 kDa, preferably between 10 and 100 kDa, particularly preferably between 30 and 50 kDa.
  • the centrifugal forces used for Ultrafree centrifuge tubes are in the range from 1 to 20000 * g, preferably in the range from 1000 to 12000 * g, particularly preferably at 2000 * g.
  • the gas pressure used in the Amicon stirred cell is in the range of 0.1-5 psi, preferably 4 psi.
  • the inlet pressure used in the Labscale TFF system is in the range of 0.1 - 85 psi, preferably in the range of 10-30 psi, particularly preferably at 20 psi.
  • the outlet pressure used in the Labscale TFF system is in the range from 0.1 to 85 psi, preferably in the range from 5 to 20 psi, particularly preferably at 0 psi.
  • Phosphate buffer Na (or K) phosphate
  • Citrate buffer Na citrate or citric acid, possible pH ca 2.2 - 6.5, succinate buffer pH ca 4.8 - 6.3, acetate buffer, e.g. Sodium acetate, pH ca 2.5 - 6.0
  • isotizing agents for isotonization e.g. Na- (or K-) CI or other salts.
  • the buffers mentioned above can be used, for example, in the following concentrations: 1 mM to 200 mM, preferably 2 to 20 mM, particularly preferably about 10 mM.
  • the following isotonizing agents can preferably be used (customary concentrations): sodium chloride approx. 5 mM-305 mM; Potassium chloride; Glucose; glycerol; Dextrose 4-5.5 mM; Sodium sulfate 1- 1.6 mM.
  • the following substances can preferably be used to lower the viscosity: sodium chloride, arginine hydrochloride, Sodium thiocyanate, ammonium thiocyanate, ammonium sulfate, ammonium chloride, calcium chlorides, zinc chlorides, sodium acetate.
  • the following stabilizers can preferably be used: 1) amino acids
  • sucrose (approx. 1 - 200 mg / ml, particularly preferably 30-65 mg / ml) sucrose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, raffinose, trehalose, glucosamine, N-methylglucosamine, galactosamine, neuraminic acid. 3) Antioxidants
  • BHA butylhydroxyanisole
  • BHT butylhydroxytoluen
  • NDGA nordihydroguaiaretic acid
  • monothioglycerol 0.5% sodium bisulfite 0.15%
  • sodium bisulfite 0.15% sodium bisulfite 0.15%
  • Tocopherols 0.5% glutathione 0.1%.
  • Cclodextrins e.g. Hydroxypropyl- ⁇ -cyclodextrin, sulfobutylethyl- ⁇ -cyclodextrin, y-cyclodextrin.
  • HSA Albumine Human Serum Albumin
  • BSA Bovine Serum Albumin
  • Salts Acetate salts (e.g. sodium acetate), magnesium chloride, calcium chloride,
  • Tromethamine, EDTA e.g. Na-EDTA
  • the invention also encompasses all hydrates, salts and derivatives of the above-mentioned agents known and conceivable to those skilled in the art.
  • the invention further provides highly concentrated, liquid formulations comprising at least one anti-EGFR antibody and / or one of its variants and / or fragments.
  • These highly concentrated, liquid formulations of anti-EGFR antibodies can be prepared by the ultrafiltration methods described above.
  • Other conceivable methods of concentration are chromatographic methods, such as size exclusion chromatography (for example gel filtration), affinity chromatography (for example protein A chromatography) or ion exchange chromatography, membrane separation methods such as dialysis, electrodialysis, microfiltration, reverse osmosis, electrophoretic drying or drying processes such as vacuum oven drying, such as nitrogen oven drying , Lyophilization, washing in organic solvents and subsequent air drying, fluid bed drying, fluidized bed drying, spray drying, roller drying, layer drying, air drying at room temperature and subsequent reconstitution in a smaller volume of solvent.
  • Highly concentrated, liquid formulations of anti-EG FR antibodies according to the invention are particularly characterized in that they have a content of at least one anti-EGFR antibody of 10-250 mg / ml, preferably 50-180 mg / ml, particularly preferably 100-150 mg / ml.
  • Highly concentrated, liquid formulations according to the invention are particularly characterized in that the anti-EGFR antibodies are monoclonal and of murine or human origin, preferably murine origin and chimeric or humanized.
  • the anti-EGFR antibodies Mab C225 (cetuximab) or Mab h425 (EMD72000) and / or their variants and / or fragments are particularly preferred.
  • the invention further relates to highly concentrated, liquid formulations comprising at least one anti-EGFR antibody and / or one of its variants and / or fragments obtainable by processes according to the invention, i.e. by the ultrafiltration method described above.
  • the invention also relates to highly concentrated, liquid formulations of anti-EGFR antibodies according to the invention as storage-stable pharmaceuticals.
  • Highly concentrated, liquid formulations of anti-EGFR antibodies according to the invention can optionally contain carriers and / or auxiliaries and / or further pharmaceutical active substances in addition to antibodies according to the invention.
  • the methods according to the invention preferably make it possible to prepare highly concentrated formulations without causing undesirable, undesirable aggregations of the antibodies according to the invention. Ready-to-use solutions with a high proportion of active ingredient can thus be prepared using the inventive methods. More recently, as possible, are increasing highly concentrated formulations of protein active ingredients required. Most of the antibodies used for therapy are dosed in the mg / kg range. A high dose and small volumes to be applied (for example approx. 1 to 1.5 ml with subcutaneous application) show the need for highly concentrated protein preparations with concentrations of more than 100 mg / ml.
  • highly concentrated protein formulations can be used in preclinical tests to investigate the safety and efficacy in vitro and in vivo (on animal models), in clinical tests to investigate the safety and efficacy in humans and in the clinical use of the product (especially for subcutaneous application).
  • the main advantages are that a lower volume of preparation has to be used.
  • Protein drug possible for the patient can have various reasons. For example, special targeting may be desired, which is related to a “therapeutic window”. Furthermore, subcutaneous application has the advantage that the patient can carry out the application himself without being dependent on medical personnel. The example of the insulin shows these advantages clearly, however, since the injections for subcutaneous administration can amount to a maximum of 1 - 1.5 ml, highly concentrated protein formulations with more than 100 mg / ml are often necessary.
  • highly concentrated, liquid formulations of anti-EGFR antibodies can be obtained with the method according to the invention, which formulate the protein concentrations of 10-250 mg / ml, preferably 50-180 mg / ml, particularly preferably 100-150 mg / ml Disadvantages not mentioned above.
  • the limit in known highly concentrated formulations of immunoglobulins is ready to use liquid formulations of antibodies normally at 2 - 50 mg / ml (Humira ®)
  • highly concentrated stable antibody formulations can be obtained by the method according to the invention, which has a reduced viscosity and tendency to aggregate compared to known highly concentrated, liquid antibody formulations and thereby thereby facilitates handling during parenteral administration.
  • Antibody-containing solutions with a pH of 4 to 10, preferably with a pH of 5 to 9, and an osmolality of 250 to 350 mOsmol / kg can advantageously be prepared from the formulations according to the invention.
  • Formulations according to the invention can thus be administered directly intravenously, intraarterially and also subcutaneously, largely without pain.
  • the preparation can also contain infusion solutions such as Glucose solution, isotonic saline or Ringer's solution, which can also contain other active ingredients, can be added so that even larger amounts of active ingredient can be applied.
  • the formulations according to the invention are physiologically well tolerated, easy to prepare, precisely metered and preferably stable over the duration of storage and transport and in the case of multiple freezing and thawing processes with regard to content, decomposition products and aggregates. They can preferably be stored stably at refrigerator temperature (2-8 ° C) and at room temperature (23-27 ° C) and 60% relative humidity (RH) over a longer period of time.
  • Formulations according to the invention are preferably comparatively stable even at higher temperatures and atmospheric humidity.
  • effective amount means the amount of a drug or active pharmaceutical ingredient that elicits a biological or medical response in a tissue, system, animal or human that is sought or sought by a researcher or medical professional, for example.
  • terapéuticaally effective amount means an amount which, compared to a subject who did not receive this amount, does the following: improves
  • the term "therapeutically effective amount” also includes the amounts that are effective in increasing normal physiological function.
  • Medicaments can be administered in the form of dose units which contain a predetermined amount of active ingredient per dose unit.
  • a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 800 mg, of an active ingredient according to the invention, depending on the condition of the disease being treated, the route of administration and the age, weight and condition of the patient.
  • Preferred dosage unit formulations are those which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of an active ingredient.
  • such pharmaceuticals can be produced using one of the methods generally known in the pharmaceutical field.
  • Drugs can be administered for administration by any suitable route, including oral (including buccal or sublingual), rectal, pumonal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • oral including buccal or sublingual
  • rectal including buccal or sublingual
  • pumonal nasal
  • topical including buccal, sublingual, or transdermal
  • vaginal including subcutaneous, intramuscular, intravenous, or intradermal
  • parenteral including subcutaneous, intramuscular, intravenous, or intradermal
  • Carrier (s) or auxiliary (s) is brought together.
  • Parenteral administration is preferably suitable for the administration of the medicaments according to the invention.
  • intravenous, subcutaneous or intradermal administration is particularly preferred.
  • intravenous administration the injection can take place directly or as an additive to infusion solutions.
  • Medicaments according to the invention are particularly suitable for subcutaneous or intradermal application, since with the aid of highly concentrated, liquid formulations according to the invention, the volumes to be administered which are low for subcutaneous administration can be achieved.
  • formulations of anti-EGFR antibodies according to the invention are also suitable for the production of medicaments to be administered parenterally with controlled, uniform and / or delayed active substance release (slow-release, sustained-release, controlled release), for example also for the preparation of depot formulations which are advantageous for the patient, since application is only necessary at larger time intervals.
  • Pharmaceutical preparations according to the invention can also be injected directly into the tumor and thus have their effect directly at the intended site of action.
  • Drugs adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostatics and solutes, which render the formulation isotonic with the blood of the recipient to be treated; as well as aqueous and non-aqueous sterile
  • Suspensions that may contain suspending agents and thickeners.
  • the formulations can be in single dose or multiple dose containers, e.g. sealed ampoules and vials, presented and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections is required immediately before use.
  • sterile carrier liquid e.g. Water for injections
  • Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.
  • the formulations of anti-EGFR antibodies according to the invention can also be in the form of liposome delivery systems, such as e.g. administer small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be made from various phospholipids, e.g. Cholesterol, stearylamine or phosphatidylcholines are formed.
  • Medicaments adapted for topical administration can be formulated into the formulations according to the invention as ointments, creams, suspensions, lotions, solutions, pastes, gels, sprays, aerosols or oils.
  • formulations are preferably introduced and applied in topical ointment or cream.
  • formulations according to the invention can be introduced either into a paraffinic or a water-miscible cream base.
  • a formulation according to the invention can be used in a cream an oil-in-water cream base or a water-in-oil base.
  • Drugs adapted to topical application to the eye include eye drops.
  • Drugs adapted for rectal administration can be given in the form of suppositories or enemas.
  • Medicaments adapted for administration by inhalation include fine particulate dusts or mists, which can be generated by means of various types of pressurized metering dispensers with aerosols, nebulizers or insufflators.
  • Medicines adapted for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • the pharmaceuticals according to the invention can contain, in addition to the above-mentioned components mentioned in particular, other agents customary in the art with reference to the particular type of pharmaceutical formulation.
  • the invention further relates to sets (kits) consisting of separate packs of a) a formulation according to the invention, comprising an effective amount of an anti-EGFR antibody, preferably a monoclonal anti-EGFR antibody, particularly preferably Mab C225 (cetuximab) or Mab h425 (EMD 72000) and / or their variants or fragments, and b) a formulation containing an effective amount of a further active pharmaceutical ingredient.
  • the set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules.
  • the set can contain, for example, separate ampoules, each of which contains a formulation according to the invention, containing an effective amount of an anti-EGFR antibody according to the invention and a formulation of a further active pharmaceutical ingredient in dissolved or in lyophilized form.
  • a therapeutically effective amount of an anti-EFGR antibody of the invention depends on a number of factors including, for example, the age and weight of the patient, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending doctor or veterinarian.
  • an effective amount of an anti-EFGR antibody according to the invention for the treatment of neoplastic growth, for example colon or breast carcinoma is generally in the range from 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and particularly typically in the Range from 1 to 0 mg / kg body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, which amount as a single dose per day or more usually in a series of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
  • the suitable antibody titer is determined by methods known to those skilled in the art.
  • the dosage intended for administration is generally sufficient to achieve the desired tumor-inhibiting effect. However, the dosage should also be chosen to be as low as possible so that no side effects, such as undesirable cross-reactions, anaphylactic reactions or the like occur.
  • Medicaments according to the invention can be used in particular for prophylaxis and / or for the treatment of diseases and disease states.
  • Another object of the invention is therefore the use of highly concentrated, liquid formulations of anti-EGFR antibodies according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of tumors and / or tumor metastases, the tumor being selected from the group consisting of brain tumor , Tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor,
  • Larynx tumor Larynx tumor, monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
  • EGFR is blocked by antibodies at different levels against tumors, for example by inhibiting cancer cell proliferation, reducing tumor-mediated angiogenesis, inducing cancer cell apoptosis and increasing the toxic effects of radiation therapy and conventional chemotherapy ,
  • Medicaments containing formulations according to the invention can effectively regulate, modulate or inhibit EGFR and can therefore be used for the prevention and / or treatment of diseases in connection with unregulated or impaired EGFR activity.
  • the formulations of anti-EGFR antibodies according to the invention can therefore be used in the treatment of certain forms of cancer, and in diseases such as diabetic retinopathy or inflammation caused by pathological angiogenesis.
  • Another object of the invention is therefore the use of formulations according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases caused, mediated and / or propagated by EGFR and / or by EGFR-mediated signal transduction.
  • Medicaments according to the invention are particularly suitable for the treatment and / or prophylaxis of cancer, including solid carcinomas, such as, for example, carcinomas (for example the lungs, pancreas, thyroid, bladder or colon), myeloid diseases (for example myeloid leukemia) or adenomas ( eg villous colon adenoma), pathological angiogenesis and metastatic cell migration.
  • solid carcinomas such as, for example, carcinomas (for example the lungs, pancreas, thyroid, bladder or colon), myeloid diseases (for example myeloid leukemia) or adenomas ( eg villous colon adenoma), pathological angiogenesis and metastatic cell migration.
  • the drugs are also useful in the treatment of complement activation dependent chronic inflammation (Niculescu et al. (2002) Immunol. Res., 24: 191-199) and immunodeficiency induced by HIV-1 (Human Immunodeficiency Virus Type 1) (Popik et al. (1998)
  • EGFR-related diseases refers to pathological conditions that are dependent on EGFR activity.
  • EGFR is either directly or indirectly involved in the signal transduction pathways of various cell activities, including proliferation, adhesion, and migration, as well as differentiation associated with EGFR activity include tumor cell proliferation, pathological neovascularization that promotes the growth of solid tumors, neovascularization (diabetic retinopathy, age-related macular degeneration and the like), and inflammation (psoriasis, rheumatoid arthritis and the like).
  • the diseases discussed here are divided into two groups, hyperproliferative and non-hyperproliferative diseases.
  • psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases are considered non-cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and immune deficiency diseases are usually regarded as non-hyperproliferative diseases.
  • brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma, chronic leukemia, all cancerous diseases and all types of acute leukemia belong to the group of hyperproliferative diseases.
  • cancerous cell growth and in particular cancerous cell growth mediated directly or indirectly by EGFR is a disease which is an object of the present invention.
  • the drugs according to the invention have an in vivo antiproliferative effect in a xenograft tumor model.
  • the medicaments according to the invention are administered to a patient with a hyperproliferative disease, e.g. For example, to inhibit tumor growth, to reduce the inflammation associated with a lymphoproliferative disease, to inhibit graft rejection or neurological damage due to tissue repair, etc.
  • the present drugs are useful for prophylactic or therapeutic purposes.
  • the term "treat" is used to refer to both the prevention of diseases and the treatment of pre-existing conditions.
  • the prevention of proliferation is accomplished by administering the pharmaceutical compositions of the invention prior to the development of the evident disease, e.g., to prevent tumor growth , Preventing metastatic growth, reducing cardiovascular disease Surgery associated restenosis, etc. achieved.
  • the drugs are used to treat persistent diseases by stabilizing or improving the patient's clinical symptoms.
  • the host or patient can belong to any mammalian species, e.g. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
  • mammalian species e.g. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
  • the susceptibility of a particular cell to treatment with the medicaments according to the invention can be determined by in vitro tests. Typically, a culture of the cell is incubated with a drug of the invention at various concentrations for a period of time sufficient to enable the drugs to induce cell death or to inhibit migration, usually between about an hour and a week. Cultured cells from a biopsy sample can be used for in vitro tests. The viable cells remaining after treatment are then counted.
  • a therapeutic dose is sufficient to significantly reduce the undesired cell population in the target tissue while maintaining the patient's viability. Treatment generally continues until there is a substantial reduction, e.g. B. at least about 50% reduction in the specific cell number and can be continued until essentially no unwanted cells are detected in the body.
  • Various assay systems are available for the identification of EGFR inhibitors. In the scintillation proximity assay (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) and the flash plate assay, the radioactive phosphorylation of a protein or peptide is considered
  • phospho-AK specific phospho-antibodies
  • the phospho-AK only binds the phosphorylated substrate. This binding can be detected with a second peroxidase-conjugated anti-sheep antibody by chemiluminescence (Ross et al., 2002, Biochem. J., immediately before publication, manuscript BJ20020786).
  • the diseases and disease states which can be treated, prevented or alleviated by the medicaments according to the invention include, but are not limited to, the diseases and disease states listed below.
  • the medicaments of the invention are useful in the treatment and / or prophylaxis of a number of different diseases and conditions in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells into the intimal layer of a vessel occurs, resulting in reduced blood flow to this vessel, e.g. B. in neointimal occlusive lesions.
  • Transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, vein graft stenosis, peri-anastomotic prosthesis restenosis, restenosis after angioplasty or stent placement and the like.
  • the present invention comprises the use of the medicaments according to the invention for the treatment or prevention of cancer.
  • a particularly preferred object of the invention is therefore the use of liquid formulations according to the invention of anti-EGFR antibodies for the manufacture of a medicament for the treatment and / or prophylaxis of tumors and / or tumor metastases, the tumor being particularly preferably selected from the group consisting of brain tumor , Tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor, larynx tumor, monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma, but are not limited to this.
  • Another object of the invention is the use of medicaments according to the invention for the manufacture of a medicament for the treatment of diseases, selected from the group of cancerous diseases consisting of squamous cell cancer, bladder cancer, stomach cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological Cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia.
  • diseases selected from the group of cancerous diseases consisting of squamous cell cancer, bladder cancer, stomach cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological Cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia.
  • the medicaments according to the invention can be administered to patients for the treatment of cancer.
  • the present drugs inhibit tumor angiogenesis and thus influence the growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580, 1995).
  • the angiogenesis-inhibiting properties of the invention Medicines are also useful for treating certain forms of blindness associated with retinal vascularization.
  • the invention therefore also relates to the use of formulations according to the invention for anti-EGFR antibodies for
  • Such a disease, in which angiogenesis is involved, is one
  • Eye disease such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.
  • the invention therefore also relates to the use of anti-EGFR antibody formulations according to the invention
  • a medicament for the treatment and / or prophylaxis of diseases selected from the group consisting of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or inflammatory diseases.
  • Another object of the invention is the use of formulations according to the invention of anti-EGFR antibodies for the treatment and / or prophylaxis of diseases, selected from the group consisting of psoriasis, rheumatoid arthritis, contact dermatitis, late type of hypersensitivity reaction, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases.
  • diseases selected from the group consisting of psoriasis, rheumatoid arthritis, contact dermatitis, late type of hypersensitivity reaction, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases.
  • the invention also relates to the use of formulations according to the invention of anti-EGFR antibodies for the treatment and / or prophylaxis of bone pathologies, selected from the group consisting of osteosarcoma, osteoarthritis and rickets.
  • the pharmaceutical compositions of the invention can be used to provide additive or synergistic effects in certain existing cancer chemotherapy and radiation treatments, and / or can be used to improve the efficacy of certain existing ones
  • the invention therefore also relates to the use of formulations according to the invention of anti-EGFR antibodies for the production of a medicament for the treatment and / or prophylaxis of diseases, a therapeutically effective amount of an anti-EGFR antibody according to the invention in combination with a compound from group 1 ) Estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic, 5) antiproliferative agent, 6) prenyl protein transferase inhibitors, 7) HMG-CoA reductase inhibitors, 8) HIV protease inhibitors, 9) reverse inhibitors, 9 Transcriptase inhibitors, 10) growth factor receptor inhibitors and 11) angiogenesis inhibitors is administered.
  • a compound from group 1 Estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic, 5) antiproliferative agent, 6) prenyl protein transferase inhibitors, 7) HMG-CoA reduc
  • the invention therefore also relates to the use of formulations according to the invention of anti-EGFR antibodies for the production of a medicament for the treatment and / or prophylaxis of diseases, a therapeutically effective amount of an anti-EGFR antibody according to the invention in combination with radiotherapy and a compound from the Group 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl protein transferase inhibitors, 7) HMG-CoA reductase inhibitors, 8) HIV protease inhibitors, 9) Reverse transcriptase inhibitors, 10) growth factor receptor inhibitors and 11) angiogenesis inhibitors is administered.
  • compositions according to the invention can thus also be administered together with other well-known therapeutic agents, which are selected on the basis of their particular suitability for the condition being treated.
  • therapeutic agents which are selected on the basis of their particular suitability for the condition being treated.
  • combinations which have bisphosphonates with an anti-resorptive effect such as alendronate and
  • integrin blockers such as ⁇ vß3 antagonists, conjugated estrogens used in hormone therapy such as Prempro®, Premarin® and Endometrion®; contain selective estrogen receptor modulators (SERMs) such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene, cathepsin K inhibitors and ATP proton pump inhibitors.
  • SERMs selective estrogen receptor modulators
  • the present drugs are also suitable for combination with known anti-cancer agents.
  • known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, and inhibitor inhibitors, reverse transgene inhibitors, reverse transcriptors ,
  • the present compounds are particularly suitable for joint use with radiotherapy.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this is done.
  • the estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant , 4- [7- (2,2-), raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant , 4- [7- (2,2-
  • Androgen receptor modulators refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done Androgen receptor modulators include, for example, finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole and
  • Retinoid receptor modulators refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this is done.
  • retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9- cis-retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide.
  • Cytotoxics refers to compounds that are primarily affected by direct action on cell function lead to cell death or which inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase inhibitors.
  • Cytotoxic agents include, for example tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, Dibromdulcit, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide, nimustine, Dibrospidium- chloride, Pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-amine dichloro (2-methylpyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-mu- (hexane-1, 6 -diamine) -mu-
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S ' ⁇ ' - Dideshydro ⁇ '- deoxy- ⁇ '-norvincaleukoblastin, docetaxol, Rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N - dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prolin-t-butylamide, TDX258 and BMS188797.
  • paclitaxel vindesine sulfate
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4 * -O-exo-benzylidene-chartreusin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4, 5-kl] acridin-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1 H, 12H-benzo [de] pyrano [ 3 ', 4 * : b, 7] indolizino [1, 2b] quinoline-10, 13 (9H, 15H) - dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350 , BNPI1100, BN80915, BN80942,
  • antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, Carmofur, Tegafur, pentostatin, doxifluridine, trimetrexate, flabinarababin, capud ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidencytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- 3- dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy- 4- [N
  • antiproliferative agents include monoclonal antibodies to growth factors other than those already mentioned under the “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which can be released via recombinant virus-mediated gene transfer (see, for example, US Pat. No. 6,069,134).
  • Medicaments according to the invention can also be used in combination mi t all other therapeutic antibodies known to the person skilled in the art or pharmaceutical active substances suitable in connection with the abovementioned diseases are administered.
  • formulations of anti-EGFR antibodies according to the invention can be used to isolate and to study the activity or expression of EGFR. They are also particularly suitable for use in diagnostic procedures for diseases related to unregulated or impaired EGFR activity.
  • Antibodies according to the invention can, for example, be radioactively labeled for diagnostic purposes.
  • a preferred labeling method is the iodogen method (Fraker et al., 1978).
  • the antibody is particularly preferably used as an F (ab ') 2 fragment. This gives excellent results so that no background subtraction is necessary.
  • F (ab ') 2 fragment can be produced by known methods (eg, Herlyn et al., 1983). In general, pepsin digestion is performed at acidic pH and the fragments separated from undigested IgG and heavy chain fragments by Protein A-Sepharose TM chromatography.
  • the anti-EGFR antibodies preferably show an advantageous biological activity in formulations according to the invention, which is easily detectable in enzyme assays, as described in the examples.
  • the antibodies according to the invention preferably show and bring about an inhibitory effect which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.
  • IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.
  • Glycosylation patterns of the antibodies according to the invention in formulations according to the invention include, but are not limited to, SE-HPLC, peptide mapping (digestion), N-terminal sequencing, SDS page, Tris-glycine gradient gel (non-reducing), FTIR method (Fourier transform infrared spectra), CD (circular dichroism), RAMAN spectroscopy, carbohydrate staining (PAS method), oligosaccharide profiling, determination of the monosaccharide composition or isoelectric focusing.
  • the stability of formulations according to the invention can be determined, for example, without being restricted thereto, using stability programs, for example storage at 25 ° C. and 60% relative atmospheric humidity and at 40 ° C. and 70% relative atmospheric humidity over a longer period of time and determination of the stability or structural integrity of the protein at regular intervals, for example, by the detection methods mentioned above (SE-HPLC, FT-IR; SDS-PAGE (reducing or non-reducing)).
  • Detection methods for the biological activity or effectiveness of antibodies according to the invention in formulations according to the invention include, but are not limited to, ELISA, biological cell assays, FTIR or CD.
  • Detection methods of reduced tendency towards aggregation of highly concentrated formulations include, but are not limited to, visual control, sub-visible particle analysis, nephelometry or turbidimetry, dynamic light scattering characterization.
  • Example 1 Preparation of a highly concentrated liquid anti-EGFR antibody formulation by tangential flow filtration (TFF)
  • 25 ml protein (10 mg / ml in 10 mM phosphate + 145 mM NaCl, pH 7.2) are concentrated using an Amicon stirred cell with built-in polyethersulfone ultrafiltration membrane with a cutoff of 30 kDa for 144 min at a nitrogen gas pressure of 4 bar.
  • the retentate obtained has a protein concentration of approx. 92 mg / ml.
  • the yield is 95%.
  • Example 3 Preparation of a highly concentrated liquid formulation of anti-EGFR antibodies by ultrafiltration under the action of centrifugal forces
  • the retentate obtained has a protein concentration of approximately 116 mg / ml.
  • the yield is 95%.
  • Example 4 Examination for soluble aggregates of the highly concentrated liquid formulation of anti-EGFR antibodies The retentates obtained in Examples 1 to 3 were examined by SE-HPLC for the content of soluble aggregates. The concentration of monomer after concentration was> 99%.
  • Example 5 Examination for nativity of the highly concentrated liquid formulation of anti-EGFR antibodies
  • Example 2 The retentates obtained in Example 1 were examined by FT-IR spectrometry.
  • the amides were I-2. Derivation spectra of the starting material before concentration by means of tangential flow filtration and the retentate obtained congruent.

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Abstract

L'invention concerne des procédés pour produire par ultrafiltration des formulations liquides fortement concentrées contenant au moins un anticorps anti-EGFR et/ou une de ses variantes et/ou un de ses fragments, notamment des anticorps monoclonaux contre le récepteur EGF, de préférence de Mab C225 (Cetuximab) et de Mab h425 (EMD 72000). La présente invention porte également sur des formulations liquides fortement concentrées d'anticorps anti-EGFR, notamment d'anticorps monoclonaux contre le récepteur EGF, de préférence Mab C225 (Cetuximab) et Mab h425 (EMD 72000) et/ou leurs variantes et/ou fragments, ainsi que sur leur utilisation. L'invention est caractérisée en ce que les formulations liquides fortement concentrées ont une teneur en anticorps anti-EGFR de 10 - 250 mg/ml, de préférence de 50 - 180 mg/ml, et mieux encore de 100 - 150 mg/ml.
EP05701212A 2004-02-12 2005-01-27 Formulations liquides fortement concentrees d'anticorps anti-egfr Withdrawn EP1713502A1 (fr)

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AU2005211890B2 (en) 2011-07-28
KR20060121956A (ko) 2006-11-29
CN1953768A (zh) 2007-04-25
RU2006132466A (ru) 2008-03-20
US20120076784A1 (en) 2012-03-29
AR047611A1 (es) 2006-01-25
WO2005077414A1 (fr) 2005-08-25
ZA200607600B (en) 2008-04-30
US20070172475A1 (en) 2007-07-26
JP2007522157A (ja) 2007-08-09
KR101342735B1 (ko) 2013-12-19
RU2390353C2 (ru) 2010-05-27
AU2005211890A1 (en) 2005-08-25
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