US20080248048A1 - Interleukin-13 Antibody Composition - Google Patents
Interleukin-13 Antibody Composition Download PDFInfo
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- US20080248048A1 US20080248048A1 US12/067,120 US6712006A US2008248048A1 US 20080248048 A1 US20080248048 A1 US 20080248048A1 US 6712006 A US6712006 A US 6712006A US 2008248048 A1 US2008248048 A1 US 2008248048A1
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K39/39516—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum from serum, plasma
- A61K39/39525—Purification
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- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A61K39/39591—Stabilisation, fragmentation
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
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- C07K1/18—Ion-exchange chromatography
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
Definitions
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an interleukin-13 antibody, more particularly a monoclonal interleukin-13 antibody, especially a human interleukin-13 monoclonal antibody, to a process for purifying said antibody and to the use of said composition in treating interleukin-13 related disorders, such as asthma.
- Interleukin (IL)-13 is a 114 amino acid cytokine with an unmodified molecular mass of approximately 12 kDa. IL-13 is most closely related to IL-4 with which it shares 30% sequence homology at the amino acid level. The human IL-13 gene is located on chromosome 5q31 adjacent to the IL-4 gene [McKenzie, A. N. et al., J Immunol, 1993. 150(12), 5436-5444; Minty, A. et al., Nature, 1993. 362(6417), 248-50].
- IL-13 is also produced by Th1 CD4+ T-cells, CD8+ T lymphocytes NK cells, and non-T-cell populations such as mast cells, basophils, eosinophils, macrophages, monocytes and airway smooth muscle cells.
- IL-13 has been linked with a number of diseases, in particular, diseases which are caused by an inflammatory response.
- diseases which are caused by an inflammatory response.
- administration of recombinant IL-13 to the airways of naive non-sensitised rodents was shown to cause many aspects of the asthma phenotype including airway inflammation, mucus production and airways hyper-responsiveness (AHR) [Wills-Karp, M. et al., Science, 1998. 282(5397), 2258-2261; Grunig, G. et al., Science, 1998. 282(5397), 2261-2263; Venkayya, R., et al., Am J Respir Cell Mol Biol, 2002. 26(2), 202-208; Morse, B.
- a number of genetic polymorphisms in the IL-13 gene have also been linked to allergic diseases.
- a variant of the IL-13 gene in which the arginine residue at amino acid 130 is substituted with glutamine has been associated with bronchial asthma, atopic dermatitis and raised serum IgE levels [Heinzmann, A. et al., Hum Mol Genet, 2000. 9(4), 549-559; Howard, T. D. et al., Am J Hum Genet, 2002. 70(1), 230-236; Kauppi, P. et al., Genomics, 2001. 77(1-2), 35-42; Graves, P. E. et al., J Allergy Clin Immunol, 2000. 105(3), 506-513].
- This particular IL-13 variant is also referred to as the Q110R variant (arginine residue at amino acid 110 is substituted with glutamine) by some groups who exclude the 20 amino acid signal sequence from the amino acid count.
- IL-13 production has also been associated with allergic asthma [van der Pouw Kraan, T. C. et al., Genes Immun, 1999. 1(1), 61-65] and raised levels of IL-13 have been measured in human subjects with atopic rhinitis (hay fever), allergic dermatitis (eczema) and chronic sinusitis.
- IL-13 has been associated with other fibrotic conditions. Increased levels of IL-13, up to a 1000 fold higher than IL-4, have been measured in the serum of patients with systemic sclerosis and in broncho-alveolar lavage (BAL) samples from patients affected with other forms of pulmonary fibrosis [Hasegawa, M. et al., J Rheumatol, 1997. 24(2), 328-332; Hancock, A. et al., Am J Respir Cell Mol Biol, 1998. 18(1), 60-65].
- BAL broncho-alveolar lavage
- IL-13 may also play a role in the pathogenesis of inflammatory bowel disease [Heller, F. et al., Immunity, 2002. 17(5), 629-38] and raised levels of IL-13 have been detected in the serum of some Hodgkin's disease patients when compared to normal controls [Fiumara, P. et al., Blood, 2001. 98(9), 2877-2878].
- IL-13 inhibitors are also believed to be therapeutically useful in the prevention of tumour recurrence or metastasis [Terabe, M. et al., Nat Immunol, 2000. 1(6), 515-520]. Inhibition of IL-13 has also been shown to enhance anti-viral vaccines in animal models and may be beneficial in the treatment of HIV and other infectious diseases [Ahlers, J. D. et al., Proc Natl Acad Sci USA, 2002. 99(20), 13020-13025].
- WO 2005/007699 Cosmetic Antibody Technology Limited
- WO 2005/007699 describes a series of human anti-IL-13 antibody molecules which are shown to neutralise IL-13 activity and which are claimed to be of potential use in the treatment of IL-13 related disorders.
- a pharmaceutical composition comprising an IL-13 antibody and one or more pharmaceutically acceptable excipients buffered to a pH of 4.5-6.0 with acetate buffer.
- antibody purification procedures typically require a number of separation techniques, such as chromatography separations (e.g. Protein A chromatography, ion exchange chromatography and the like).
- chromatography separations e.g. Protein A chromatography, ion exchange chromatography and the like.
- a consequence of this manner of separation requires the use of a number of differing buffers.
- the antibody purification procedure described in WO 2004/076485 requires the use of 50 mM glycine/glycinate pH 8.0 for Protein A chromatography, 50 mM Tris HCl pH 8.0 and 20 mM sodium phosphate pH 6.5 for Q-Sepharose chromatography, and 25 mM Tris HCl pH 8.6 for DEAE-sepharose chromatography.
- the present invention requires the use of a single acetate buffer at a fixed concentration and predetermined pH present within the composition of the invention which has the advantage of being present throughout all IL-13 antibody purification steps.
- this buffer not only at the beginning of the purification process, but throughout the entire purification process, therefore results in a reduction of processing time, cost and an increase in product yield.
- references to “antibody” include references to an immunoglobulin whether natural or partly or wholly synthetically produced.
- the term also covers any polypeptide or protein comprising an antigen binding domain.
- Antibody fragments which comprise an antigen binding domain are molecules such as Fab, scFv, Fv, dAb, Fd; and diabodies.
- novel VH or VL regions carrying CDR-derived sequences may be generated using random mutagenesis of one or more selected VH and/or VL genes to generate mutations within the entire variable domain.
- a technique is described by Gram et al., PNAS USA, 1992. 89, 3576-3580, who use error prone PCR.
- Another method which may be used is to direct mutagenesis to CDR regions of VH and VL genes.
- Such techniques are disclosed by Barbas et al., PNAS USA 1994. 91, 3809-3813 and Schier et al., J. Mol. Biol. 1996. 263, 551-567.
- antibody should be construed as covering any specific binding member or substance having an antigen-binding domain with the required specificity.
- this term covers antibody fragments and derivatives, including any polypeptide comprising an immunoglobulin binding domain, whether natural or wholly or partially synthetic. Chimeric molecules comprising an immunoglobulin binding domain, or equivalent, fused to another polypeptide are therefore included. Cloning and expression of chimeric antibodies are described in EP-A-0120694 and EP-A-0125023, and a large body of subsequent literature.
- human hybridomas can be made as described by Kontermann et al., [200]; Antibody Engineering, Springer Laboratory Manuals].
- Phage display another established technique for generating specific binding members has been described in detail in many publications such as Kontermann et al. (supra) and W092/01047.
- Transgenic mice in which the mouse antibody genes are inactivated and functionally replaced with human antibody genes while leaving intact other components of the mouse immune system, can be used for isolating human antibodies to human antigens.
- Ribosome display a cell free translation technology which introduces mutations into known gene sequences, may also be used to generate and/or optimise specific binding members [Hanes and Plückthun PNAS USA, 1994. 94, 4937-4942; He and Taussig Nucleic Acids Res. 1997. 25, 5132-5134; Schaffitzel et al., J. Immunol. Methods, 1999. 231, 119-135; He et al., J. Immunol. Methods, 1999. 231, 105-117; He et al., Methods Mol. Biol. 2004. 248, 177-189].
- Synthetic antibody molecules may be created by expression from genes generated by means of oligonucleotides synthesized and assembled within suitable expression vectors, for example as described by Knappik et al., J. Mol. Biol. 2000. 296, 57-86 or Krebs et al., Journal of Immunological Methods 2001. 254, 67-84.
- binding fragments are (i) the Fab fragment consisting of VL, VH, CL and CH1 domains; (ii) the Fd fragment consisting of the VH and CH1 domains; (iii) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment [Ward, E. S. et al., Nature, 1989. 341, 544-546; McCafferty et al., Nature, 1990. 348, 552-554; Holt et al., Trends Biotechnol. 2003.
- 21(11), 484-490] which consists of a VH or a VL domain; (v) isolated CDR regions; (vi) F(ab′) 2 fragments, a bivalent fragment comprising two linked Fab fragments (vii) single chain Fv molecules (scFv), wherein a VH domain and a VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site [Bird et al., Science, 1988. 242, 423-426; Huston et al., PNAS USA, 1988.
- Fv, scFv or diabody molecules may be stabilised by the incorporation of disulphide bridges linking the VH and VL domains [Y. Reiter et al., Nature Biotech., 1996. 14, 1239-1245].
- Minibodies comprising a scFv joined to a CH3 domain may also be made [S. Hu et al., Cancer Res., 1996. 56, 3055-3061].
- bispecific antibodies are to be used, these may be conventional bispecific antibodies, which can be manufactured in a variety of ways [Holliger and Winter Current Opinion Biotechnol. 1993. 4, 446-449], e.g. prepared chemically or from hybrid hybridomas, or may be any of the bispecific antibody fragments mentioned above.
- bispecific antibodies include those of the BiTE technology in which the binding domains of two antibodies with different specificity can be used and directly linked via short flexible peptides. This combines two antibodies on a short single polypeptide chain. Diabodies and scFv can be constructed without an Fc region using only variable domains, potentially reducing the effects of anti-idiotypic reaction.
- Bispecific diabodies as opposed to bispecific whole antibodies, may also be particularly useful because they can be readily constructed and expressed in E. coli .
- Diabodies (and many other polypeptides such as antibody fragments) of appropriate binding specificities can be readily selected using phage display (WO94/13804) from libraries. If one arm of the diabody is to be kept constant, for instance, with a specificity directed against IL-13, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected.
- Bispecific whole antibodies may be made by knobs-into-holes engineering [Ridgeway et al., Protein Eng., 1996. 9, 616-621].
- references to “an IL-13 antibody” include references to a whole antibody or antibody fragment which is capable of neutralising naturally occurring IL-13 at a concentration of less than 500 nM by following the assays as set forth in Examples 2-10 and 25 of WO 2005/007699.
- the IL-13 antibody neutralises naturally occurring IL-13 with a potency that is equal to or better than the potency of an IL-13 antigen binding site formed by BAK502G9 VH domain (SEQ ID NO:15 in WO 2005/007699) and the BAK502G9 VL domain (SEQ ID NO:16 in WO 2005/007699).
- the IL-13 antibody is a monoclonal IL-13 antibody, more preferably a human IL-13 monoclonal antibody.
- a particularly preferred IL-13 antibody is one selected from those described in WO 2003/035847, WO 2003/086451, WO 2005/007699 or WO 2005/081873.
- the IL-13 antibody is BAK278D6 HCDR1-3 and LCDR1-3 (SEQ ID NOS: 1-6 in WO 2005/007699, respectively).
- a set of CDR's with the BAK278D6 set of CDR's, BAK278D6 set of HCDR's or BAK278D6 LCDR's, or one or two substitutions therein, is said to be of the BAK278D6 lineage.
- the IL-13 antibody is BAK502G9 HCDR1-3 and LCDR1-3 (SEQ ID NOS: 7-12 in WO 2005/007699, respectively).
- the IL-13 antibody is BAK1111D10 HCDR1-3 and LCDR1-3 (SEQ ID NOS: 91-96 in WO 2005/007699, respectively).
- the IL-13 antibody is BAK1167F2 HCDR1-3 and LCDR1-3 (SEQ ID NOS: 61-66 in WO 2005/007699, respectively).
- the IL-13 antibody is BAK1183H4 HCDR1-3 and LCDR1-3 (SEQ ID NOS: 97-102 in WO 2005/007699, respectively).
- antibody framework regions or other protein scaffolds e.g. fibronectin or cytochrome B [Koide et al., J. Mol. Biol. 1998. 284, 1141-1151; Nygren et al., Current Opinion in Structural Biology, 1997. 7, 463-469].
- antibody framework regions are employed, and where they are employed they are preferably germline, more preferably the antibody framework region for the heavy chain may be DP14 from the VH1 family.
- the preferred framework region for the light chain may be ⁇ 3-3H.
- the antibody framework regions are for VH FR1-3, SEQ ID NOS: 27-29 in WO 2005/007699, respectively and for light chain FR1-3, SEQ ID NOS: 30-32 in WO 2005/007699, respectively.
- a VH domain is provided with the amino acid sequence of SEQ ID NO: 15 in WO 2005/007699, this being termed “BAK502G9 VH domain”.
- a VL domain is provided with the amino acid sequence of SEQ ID NO: 16 in WO 2005/007699, this being termed “BAK502G9 VL domain.
- the IL-13 antibody cross reacts with cynomologous IL-13 and/or the IL-13 variant, Q130R.
- the IL-13 antibody is present within the pharmaceutical composition in an amount of between 1 and 200 mg/ml, more preferably 50 and 100 mg/ml, especially 50 mg/ml.
- the pharmaceutical composition is buffered to a pH of 5.2 to 5.7, most preferably 5.5 ⁇ 0.1.
- a pH confers significant stability to the pharmaceutical composition.
- alternative buffers that control the pH in this range include succinate, gluconate, histidine, citrate, phosphate, glutaric, cacodylyte, sodium hydrogen maleate, tris-(hydroxylmethyl)aminomethane (Tris), 2-(N-morpholino)ethanesulphonic acid (MES), imidazole and other organic acid buffers.
- the buffer is acetate buffer, more preferably sodium acetate.
- the acetate buffer is present within the pharmaceutical composition in an amount of between 1 and 100 mM, more preferably 30 and 70 mM, especially 50 mM.
- references to “pharmaceutically acceptable excipient” includes references to any excipient conventionally used in pharmaceutical compositions.
- excipients may typically include one or more surfactant, inorganic or organic salt, stabilizer, diluent, solubilizer, reducing agent, antioxidant, chelating agent, preservative and the like.
- nonionic surfactants such as sorbitan fatty acid esters (e.g. sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate), glycerine fatty acid esters (e.g. glycerine monocaprylate, glycerine monomyristate, glycerine monostearate), polyglycerine fatty acid esters (e.g. decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate), polyoxyethylene sorbitan fatty acid esters (e.g.
- nonionic surfactants such as sorbitan fatty acid esters (e.g. sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate), glycerine fatty acid esters (e.g. glycerine monocaprylate, glycerine monomyristate, glycerine mono
- polyoxyethylene lauryl ether polyoxyethylene polyoxypropylene alkyl ethers (e.g. polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylene alkylphenyl ethers (e.g. polyoxyethylene nonylphenyl ether), polyoxyethylene hydrogenated castor oils (e.g. polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil), polyoxyethylene beeswax derivatives (e.g. polyoxyethylene sorbitol beeswax), polyoxyethylene lanolin derivatives (e.g. polyoxyethylene lanolin), and polyoxyethylene fatty acid amides (e.g. polyoxyethylene stearyl amide);
- polyoxyethylene polyoxypropylene alkyl ethers e.g. polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene poly
- anionic surfactants such as C 10 -C 18 alkyl sulfates salts (e.g. sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate), polyoxyethylene C 10 -C 18 alkyl ether sulfates salts with an average of 2 to 4 moles of ethylene oxide (e.g. sodium polyoxyethylene lauryl sulfate), and C 8 -C 18 alkyl sulfosuccinate ester salts (e.g. sodium lauryl sulfosuccinate ester); and natural surfactants such as lecithin, glycerophospholipid, sphingophospholipids (e.g. sphingomyelin), and sucrose esters of C 12 -C 18 fatty acids.
- C 10 -C 18 alkyl sulfates salts e.g. sodium cetyl sulfate, sodium lauryl sulfate, sodium
- the surfactant is selected from polyoxyethylene sorbitan fatty acid esters.
- the surfactant is Polysorbate 20, 21, 40, 60, 65, 80, 81 and 85, most preferably Polysorbate 20 and 80, especially Polysorbate 80.
- the surfactant is present within the pharmaceutical composition in an amount of between 0.001 and 0.1% (w/w), more preferably 0.005 and 0.05 (w/w), especially 0.01% (w/w).
- Examples of a typical inorganic salt include: sodium chloride, potassium chloride, calcium chloride, sodium phosphate, sodium sulphate, ammonium sulphate, potassium phosphate and sodium bicarbonate or any other sodium, potassium or calcium salt.
- the inorganic salt is sodium chloride.
- the inorganic salt is present within the pharmaceutical composition in an amount of between 10 and 200 mM, more preferably 60 and 130 mM, especially 85 mM.
- Examples of a reducing agent include N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and a salt thereof, sodium thiosulfate, glutathione, and a C1-C7 thioalkanoic acid.
- antioxidants examples include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, alpha-tocopherol, tocopherol acetate, L-ascorbic acid and a salt thereof, L-ascorbic acid palmitate, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, triamyl gallate and propyl gallate.
- Examples of a chelating agent include disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate and sodium metaphosphate.
- a stabiliser examples include creatinine, an amino acid selected from histidine, alanine, glutamic acid, glycine, leucine, phenylalanine, methionine, isoleucine, proline, aspartic acid, arginine, lysine and threonine, a carbohydrate selected from sucrose, trehalose, sorbitol, xylitol and mannose, surfactants selected from polyethylene glycol (PEG; e.g. PEG3350 or PEG4000) or polyoxyethylene sorbitan fatty acid esters (e.g. Polysorbate 20 or Polysorbate 80), or any combination thereof.
- PEG polyethylene glycol
- PEG polyoxyethylene sorbitan fatty acid esters
- the stabiliser comprises a single carbohydrate as hereinbefore defined (e.g. trehalose).
- the stabilizer comprises an amino acid in combination with a carbohydrate (e.g. trehalose and alanine or trehalose, alanine and glycine).
- a carbohydrate e.g. trehalose and alanine or trehalose, alanine and glycine.
- the stabiliser comprises an amino acid in combination with a carbohydrate and a surfactant (e.g. trehalose, alanine and PEG3350 or trehalose, proline and PEG3350 or trehalose, alanine and Polysorbate 80 or trehalose, proline and Polysorbate 80 or trehalose, proline and Polysorbate 80 or trehalose, alanine, glycine and PEG3350 or trehalose, alanine, glycine and Polysorbate 80).
- a surfactant e.g. trehalose, alanine and PEG3350 or trehalose, proline and PEG3350 or trehalose, alanine and Polysorbate 80.
- the stabiliser comprises an amino acid in combination with a surfactant (e.g. alanine and PEG3350 or alanine, glycine and PEG3350).
- a surfactant e.g. alanine and PEG3350 or alanine, glycine and PEG3350.
- the stabiliser comprises a carbohydrate in combination with a surfactant (e.g. trehalose and PEG3350 or trehalose and Polysorbate 80).
- a surfactant e.g. trehalose and PEG3350 or trehalose and Polysorbate 80.
- Examples of a preservative include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long-chain compounds), benzethonium chloride, aromatic alcohols such as phenol, butyl and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol.
- octadecyldimethylbenzyl ammonium chloride hexamethonium chloride
- benzalkonium chloride a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long-chain compounds
- benzethonium chloride aromatic alcohols such as phenol, butyl and benzyl
- the pharmaceutical composition comprises an IL-13 antibody, a surfactant and an inorganic salt buffered to a pH of 5.5 ⁇ 0.1 with acetate buffer.
- the pharmaceutical composition comprises an IL-13 antibody, sodium chloride and Polysorbate 80 buffered to a pH of 5.5 ⁇ 0.1 with sodium acetate buffer.
- the pharmaceutical composition comprises 50 mg/ml of an IL-13 antibody, 85 mM sodium chloride and 0.01% (w/w) Polysorbate 80 buffered to a pH of 5.5 ⁇ 0.1 with 50 mM sodium acetate buffer.
- a process for purifying an IL-13 antibody which comprises one or more chromatographic separation steps wherein each of said separation steps comprises elution with an elution buffer comprising one or more pharmaceutically acceptable excipients buffered to a pH of 3.5-7.0 with acetate buffer.
- the one or more chromatographic separation steps are selected from affinity chromatography (e.g. Protein A or Protein G affinity chromatography), ion exchange chromatography (e.g. cation and anion exchange chromatography), hydrophobic interaction chromatography (e.g. phenyl chromatography), hydroxyapatite chromatography, size exclusion chromatography, immobilised metal affinity chromatography, hydrophilic interaction chromatography, thiophilic adsorption chromatography, euglobulin adsorption chromatography, dye ligand chromatography or immobilised boronate chromatography.
- affinity chromatography e.g. Protein A or Protein G affinity chromatography
- ion exchange chromatography e.g. cation and anion exchange chromatography
- hydrophobic interaction chromatography e.g. phenyl chromatography
- hydroxyapatite chromatography size exclusion chromatography
- immobilised metal affinity chromatography hydrophilic interaction chromatography
- the one or more pharmaceutically acceptable excipients comprises an inorganic salt such as sodium chloride.
- the inorganic salt is present within the elution buffer in an amount of between 10 and 200 mM, more preferably 60 and 130 mM, especially 85 mM.
- Examples of alternative buffers that control the pH in the range of 3.5-7.0 include succinate, gluconate, histidine, citrate, phosphate and other organic acid buffers.
- the buffer is acetate buffer, more preferably sodium acetate.
- the acetate buffer is present within the elution buffer in an amount of between 1 and 100 mM, more preferably 30 and 70 mM, especially 50 mM.
- the elution buffer comprises 50 mM sodium acetate and 85 mM sodium chloride buffered to pH 5.5 ⁇ 0.1.
- a nucleic acid encoding any IL-13 antibody of the invention may be expressed by culturing under appropriate conditions recombinant host cells containing said nucleic acid. Following production by expression a VH or VL domain, or specific binding member may be isolated and/or purified using any suitable technique, then used as appropriate.
- Specific binding members, VH and/or VL domains, and encoding nucleic acid molecules and vectors may be provided isolated and/or purified, e.g. from their natural environment, in substantially pure or homogeneous form, or, in the case of nucleic acid, free or substantially free of nucleic acid or gene origin other than the sequence encoding a polypeptide with the required function.
- Nucleic acid may comprise DNA or RNA and may be wholly or partially synthetic.
- nucleotide sequence as set out herein encompasses a DNA molecule with the specified sequence, and encompasses an RNA molecule with the specified sequence in which U is substituted for T, unless context requires otherwise.
- Suitable host cells include bacteria, mammalian cells, plant cells, yeast and baculovirus systems and transgenic plants and animals.
- Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney cells, NS0 mouse melanoma cells, YB2/0 rat myeloma cells, human embryonic kidney cells, human embryonic retina cells and many others.
- said mammalian cell line is a myeloma cell culture such as e.g. NS0 cells [Galfre and Milstein Methods Enzymology, 1981. 73, 3].
- Myeloma cells are plasmacytoma cells, i.e. cells of lymphoid cell lineage.
- An exemplary NS0 cell line is e.g. cell line ECACC No. 85110503, freely available from the European Collection of Cell Cultures (ECACC), Centre for Applied Microbiology & Research, Salisbury, Wiltshire, SP4 0JG, United Kingdom.
- NS0 have been found able to give rise to extremely high product yields, in particular if used for production of recombinant antibodies.
- An alternatively preferred mammalian cell line is Chinese hamster ovary (CHO) cells. These may be dihydrofolate reductase (dhfr) deficient and so dependent on thymidine and hypoxanthine for growth [PNAS, 1990. 77, 4216-4220].
- the parental dhfr CHO cell line is transfected with the antibody gene and dhfr gene which enables selection of CHO cell transformants of dhfr positive phenotype. Selection is carried out by culturing the colonies on media devoid of thymidine and hypoxanthine, the absence of which prevents untransformed cells from growing and transformed cells from resalvaging the folate pathway and thereby bypassing the selection system.
- transformants usually express low levels of the product gene by virtue of co-integration of both transfected genes.
- the expression levels of the antibody gene may be increased by amplification using methotrexate (MTX).
- MTX methotrexate
- This drug is a direct inhibitor of the dhfr enzyme and allows isolation of resistant colonies which amplify their dhfr gene copy number sufficiently to survive under these conditions. Since the dhfr and antibody genes are more closely linked in the original transformants, there is usually concomitant amplification, and therefore increased expression of the desired antibody gene.
- GS glutamine synthetase
- MSX methionine sulphoximine
- Suitable vectors can be chosen or constructed, containing appropriate regulatory sequences, including promoter sequences, terminator sequences, polyadenylation sequences, enhancer sequences, marker genes and other sequences as appropriate.
- Vectors may be plasmids, viral e.g. ‘phage, or phagemid, as appropriate.
- phage a virus
- Many known techniques and protocols for manipulation of nucleic acid for example in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene expression, and analysis of proteins, are described in detail in Current Protocols in Molecular Biology, Second Edition, Ausubel et al.
- a nucleic acid into a host cell may employ any available technique.
- suitable techniques may include calcium phosphate transfection, DEAE-Dextran, electroporation, liposome-mediated transfection and transduction using retrovirus or other virus, e.g. vaccinia or, for insect cells, baculovirus.
- Introducing nucleic acid in the host cell, in particular a eukaryotic cell may use a viral or a plasmid based system.
- the plasmid system may be maintained episomally or may be incorporated into the host cell or into an artificial chromosome [Csonka, E. et al., Journal of Cell Science, 200. 113, 3207-3216; Vanderbyl, S.
- Incorporation may be either by random or targeted integration of one or more copies at single or multiple loci.
- suitable techniques may include calcium chloride transformation, electroporation and infection using bacteriophage.
- the introduction may be followed by causing or allowing expression from the nucleic acid, e.g. by culturing host cells under conditions for expression of the gene.
- the nucleic acid of the invention is integrated into the genome (e.g. chromosome) of the host cell.
- Integration may be promoted by inclusion of sequences which promote recombination with the genome, in accordance with standard techniques.
- a pharmaceutical antibody composition as defined herein in the manufacture of a medicament for the treatment of an IL-13 related disorder.
- the IL-13 related disorder is selected from asthma, atopic dermatitis, allergic rhinitis, fibrosis, chronic obstructive pulmonary disease, scleroderma, inflammatory bowel disease and Hodgkin's lymphoma.
- the composition of the invention may also be used in the treatment of tumours and viral infections as IL-13 antibodies will inhibit IL-13 mediated immunosuppression.
- the IL-13 related disorder is asthma.
- the invention further provides a method of treatment or prophylaxis of an IL-13 related disorder which comprises administering to the sufferer a therapeutically effective amount of a pharmaceutical antibody composition as defined herein.
- the invention further provides a pharmaceutical antibody composition as defined herein for use in the treatment of an IL-13 related disorder.
- the pharmaceutical composition of the invention may be a liquid formulation or a lyophilized formulation which is reconstituted before use.
- excipients for a lyophilized formulation for example, sugar alcohols or saccharides (e.g. mannitol or glucose) may be used.
- the pharmaceutical composition of the invention is usually provided in the form of containers with defined volume, including sealed and sterilized plastic or glass vials, ampoules and syringes, as well as in the form of large volume containers like bottles.
- the composition of the invention is a liquid formulation.
- the pharmaceutical composition of the invention may be administered orally, by injection (for example, subcutaneously, intravenously, intraperitoneal or intramuscularly), by inhalation, or topically (for example intraocular, intranasal, rectal, into wounds, on skin).
- the route of administration can be determined by the physicochemical characteristics of the treatment, by special considerations for the disease or by the requirement to optimise efficacy or to minimise side-effects.
- the composition of the invention is administered by subcutaneous injection. It is envisaged that treatment will not be restricted to use in the clinic. Therefore, subcutaneous injection using a needle free device may also be preferred.
- compositions provided may be administered to individuals. Administration is preferably in a “therapeutically effective amount”, this being sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom.
- the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors. Appropriate doses of antibody are well known in the art; [Ledermann, J. A. et al., Int. J. Cancer, 1999. 47, 659-664; Bagshawe, K. D. et al., Antibody, Immunoconjugates and Radiopharmaceuticals, 1991. 4, 915-922].
- the precise dose will depend upon a number of factors, including the size and location of the area to be treated, the precise nature of the antibody (e.g. whole antibody, fragment or diabody), and the nature of any detectable label or other molecule attached to the antibody.
- a typical antibody dose will be in the range 100 pg to 10 g for systemic applications, and 1 ⁇ g to 100 mg for topical applications.
- the antibody will be a whole antibody, preferably the IgG4 isotype.
- a dose for a single treatment of an adult patient may be proportionally adjusted for children and infants, and also adjusted for other antibody formats in proportion to molecular weight. Treatments may be repeated at daily, twice-weekly, weekly or monthly intervals, at the discretion of the physician. In preferred embodiments of the present invention, treatment is periodic, and the period between administrations is about two weeks or more, preferably about three weeks or more, more preferably about four weeks or more, or about once a month.
- FIG. 1 shows the results of SDS-PAGE analysis of samples at Day 1 of a 28 day stability assessment of the composition of the invention.
- FIG. 2 shows the results of SDS-PAGE analysis of samples at Day 21 of a 28 day stability assessment of the composition of the invention.
- FIG. 3 shows the results of GP-HPLC analysis of samples at Day 1 of a 28 day stability assessment of the composition of the invention.
- FIG. 4 shows an amalgam of results obtained from GP-HPLC analysis of samples during a 28 day stability assessment of the composition of the invention at 2-8° C.
- FIG. 5 shows an amalgam of results obtained from GP-HPLC analysis of samples during a 28 day stability assessment of the composition of the invention at 25° C.
- FIG. 6 shows an amalgam of results obtained from GP-HPLC analysis of samples during a 28 day stability assessment of the composition when neutralised with differing buffers.
- FIG. 7 shows the results of IEF analysis of samples at Day 28 of a 28 day stability assessment of the composition of the invention.
- FIG. 8 shows the results of gel filtration HPLC analysis of a 12 month stability assessment of different formulations stored at ⁇ 70° C.
- FIG. 9 shows the results of gel filtration HPLC analysis of a 12 month stability assessment of different formulations stored at +5° C.
- FIG. 10 shows the results of gel filtration HPLC analysis of a 12 month stability assessment of different formulations stored at +25° C.
- FIG. 11 shows the results of gel filtration HPLC analysis of an 8 week stability assessment of different formulations stored at +37° C.
- FIG. 12 shows the results of gel filtration HPLC analysis of a 5 day stability assessment of different formulations stored at +45° C.
- FIG. 13 shows the results of reduced SDS-PAGE analysis at 0, 6 and 12 months during a 12 month stability assessment of different formulations when stored at ⁇ 70° C.
- FIG. 14 shows the percentage abundance of BAK502G9 heavy and light chains following reduced SDS-PAGE analysis in FIG. 13 when stored at ⁇ 70° C.
- FIG. 15 shows the results of reduced SDS-PAGE analysis at 0, 6 and 12 months during a 12 month stability assessment of different formulations when stored at +5° C.
- FIG. 16 shows the percentage abundance of BAK502G9 heavy and light chains following reduced SDS-PAGE analysis in FIG. 15 when stored at +5° C.
- FIG. 17 shows the results of reduced SDS-PAGE analysis at 0, 6 and 12 months during a 12 month stability assessment of different formulations when stored at +25° C.
- FIG. 18 shows the percentage abundance of BAK502G9 heavy and light chains following reduced SDS-PAGE analysis in FIG. 17 when stored at +25° C.
- FIG. 19 shows the results of reduced SDS-PAGE analysis at 0 and 8 weeks during an 8 week stability assessment of different formulations when stored at +37° C.
- FIG. 20 shows the percentage abundance of BAK502G9 heavy and light chains following reduced SDS-PAGE analysis in FIG. 19 when stored at +37° C.
- FIG. 21 shows the results of reduced SDS-PAGE analysis at 0 and 5 days during a 5 day stability assessment of different formulations when stored at +45° C.
- FIG. 22 shows the percentage abundance of BAK502G9 heavy and light chains following reduced SDS-PAGE analysis in FIG. 21 when stored at +45° C.
- FIG. 23 shows the results of non-reduced SDS-PAGE analysis at 0, 6 and 12 months during a 12 month stability assessment of different formulations when stored at ⁇ 70° C.
- FIG. 24 shows the percentage abundance of intact BAK502G9 monomer following non-reduced SDS-PAGE analysis in FIG. 23 when stored at ⁇ 70° C.
- FIG. 25 shows the results of non-reduced SDS-PAGE analysis at 0, 6 and 12 months during a 12 month stability assessment of different formulations when stored at +5° C.
- FIG. 26 shows the percentage abundance of intact BAK502G9 monomer following non-reduced SDS-PAGE analysis in FIG. 25 when stored at +5° C.
- FIG. 27 shows the results of non-reduced SDS-PAGE analysis at 0, 6 and 12 months during a 12 month stability assessment of different formulations when stored at +25° C.
- FIG. 28 shows the percentage abundance of intact BAK502G9 monomer following non-reduced SDS-PAGE analysis in FIG. 27 when stored at +25° C.
- FIG. 29 shows the results of non-reduced SDS-PAGE analysis at 0 and 8 weeks during an 8 week stability assessment of different formulations when stored at +37° C.
- FIG. 30 shows the percentage abundance of intact BAK502G9 monomer following non-reduced SDS-PAGE analysis in FIG. 29 when stored at +37° C.
- FIG. 31 shows the results of non-reduced SDS-PAGE analysis at 0 and 5 days during a 5 day stability assessment of different formulations when stored at +45° C.
- FIG. 32 shows the percentage abundance of intact BAK502G9 monomer following non-reduced SDS-PAGE analysis in FIG. 31 when stored at +45° C.
- BAK502G9 was expressed in a GS NS0 cell line in an analogous manner to the procedures described in WO 87/04462 and WO 2004/076485 and yielded culture supernatant containing 598 mg/l BAK502G9 antibody.
- the column used for the rmp Protein A Sepharose fast flow chromatography step was 2.6 cm diameter, packed in 0.9% w / v sodium chloride, to a bed height of 14.5 cm giving a column volume of 77 ml.
- Resin was sourced from GE Healthcare/Amersham Biosciences 17-5138. Chromatography was performed using an Amersham Biosciences P-50 pump, UV1 detector and flow cell. The column was cleaned with 6M guanidine hydrochloride prior to use.
- the rmp Protein A Sepharose fast flow column was subsequently equilibrated with 350 ml phosphate buffered saline pH 7.2, following water wash and cleaning. 2.6 l culture supernatant was loaded directly onto the column at 200 cm/hour and room temperature.
- BAK502G9 antibody was eluted from the column by washing with 380 ml 50 mM sodium acetate pH 3.75. Post elution the column was washed with 50 mM acetic acid pH3.0. The elution peak was collected between 2% maximum UV deflection on the up and down slope of the peak. 1.5 g BAK502G9 antibody was recovered in 217 ml.
- the rmp Protein A Sepharose fast flow eluate was adjusted to pH 3.70 with 173 ml 100 mM acetic acid. The adjusted eluate was then held for 60 minutes for viral inactivation. After this time the adjusted eluate was neutralised with 437 ml 50 mM sodium hydroxide to pH 5.50 and 0.22 ⁇ m filtered using a Millipore stericup (product number SCGPUL11E). 1.4 g BAK502G9 antibody was recovered in 823 ml.
- the column used for the SP Sepharose fast flow chromatography step was 1.6 cm diameter, packed in phosphate buffered saline pH 7.2, to a bed height of 15.5 cm giving a column volume of 31 ml.
- Resin was sourced from GE Healthcare/Amersham Biosciences 17-0729. Chromatography was performed using an Amersham Biosciences P-50 pump, UV1 detector and flow cell. The column was cleaned with 0.5M sodium hydroxide prior to use.
- the SP Sepharose fast flow column was subsequently equilibrated with 145 ml 50 mM sodium acetate pH 5.50, following water wash and cleaning.
- BAK502G9 antibody was eluted from the column by washing with 150 ml 50 mM sodium acetate+85 mM sodium chloride pH 5.50. Post elution the column was washed with 50 mM sodium acetate+2M sodium chloride pH 5.50.
- the elution peak was collected between 2% maximum UV deflection on the up slope and 30% on the down slope of the peak. Eluate was 0.22 ⁇ m filtered using a Millipore steriflip (product number SCGPOO525). 0.67 g BAK502G9 antibody was recovered in 54 ml.
- the column used for the Q Sepharose fast flow chromatography step was 1.6 cm diameter, packed in phosphate buffered saline pH 7.2, to a bed height of 13.3 cm giving a column volume of 27 ml.
- Resin was sourced from GE Healthcare/Amersham Biosciences 17-0510. Chromatography was performed using an Amersham Biosciences P-50 pump, UV1 detector and flow cell. The column was cleaned with 0.5M sodium hydroxide prior to use.
- the Q Sepharose fast flow column was subsequently equilibrated with 138 ml 50 mM sodium acetate+85 mM sodium chloride pH 5.50, following water wash and cleaning.
- Isocratic elution of the BAK502G9 antibody was undertaken by washing the column with 124 ml 50 mM sodium acetate+85 mM sodium chloride pH 5.50. Post elution the column was washed with 50 mM sodium acetate+2M sodium chloride pH 5.50.
- the elution peak was collected between 2% maximum UV deflection on the up slope and 2% on the down slope of the peak.
- Eluate was 0.22 ⁇ m filtered using a Millipore stericup (product number SCGPU01RE). 0.52 g BAK502G9 antibody was recovered in 88 ml. This process step was repeated with the remaining 44 ml BAK502G9 antibody as SP Sepharose eluate. A further 0.54 g BAK502G9 antibody was recovered in 51 ml. The two filtered Q Sepharose eluates were then pooled.
- the product was obtained in 50 mM sodium acetate+85 mM sodium chloride pH 5.50 and did not require diafiltration.
- Guanidine hydrochloride Sigma Aldrich. G4505 Di sodium hydrogen orthophosphate. VWR. 1038349 Sodium di hydrogen orthophosphate. VWR. 102454R Sodium acetate 3-hydrate. VWR. 102354X. odium chloride. VWR. 10241AP. Acetic acid. VWR. 10001CU.
- Load capacity (mg IgG/ 16.6 mg/ml matrix ml matrix): Wash 1 buffer and CV's: Phosphate buffered saline, pH 7.2, 7.5CV's Wash 2 buffer and CV's: 50 mM sodium acetate, pH 5.50 ⁇ 0.10, 7.5CV's Elution buffer: 50 mM sodium acetate, pH 3.75 ⁇ 0.10, 1.6CV's Strip/Clean buffer and 50 mM sodium acetate, pH 3.0 ⁇ 0.10, 2 CV's: CVs.
- a 50 ml sample of virus inactivated Protein A eluate was neutralised with the original buffer (50 mM sodium hydroxide) and stored in a bioprocess container at 2 to 8° C. for twenty-eight days before analysis.
- the filtered neutralised Protein A eluate was split into ten lots; five lots being stored at each of the temperatures. A further container of unfiltered, neutralised Protein A eluate was stored at 2 to 8° C.
- each bioprocess container was filled with approximately 100 ml to mimic the ratio of product to surface contact envisaged for the final 2,000 l scale production.
- One bioprocess container was used for sampling for each temperature and each time-point and care was taken not to leave material in the tubing during storage.
- Turbidity was assessed as a measure of protein degradation over time and therefore serves as a useful stability assessment of the composition of the invention.
- Turbidity was measured by taking the average absorbance of the sample between A340 and 360 nm (Eckhardt et al. 1993). This assay was carried out without further filtration.
- rmp Protein A chromatography performed as expected generating volumes of buffers comparable to that seen at large scale.
- the neutralised eluate was visibly more turbid than is usually seen with eluate neutralised with 50 mM sodium hydroxide.
- precipitation began to be observed, this occurred within one hour of neutralisation.
- Turbidity was not assayed until after this time. Recovery was within the expected range post filtration.
- Samples were analysed using a TSK GS3000SW size exclusion column with 200 mM sodium phosphate and 0.05% sodium azide pH 7.0 as the mobile phase and detection at 280 nm.
- BAK502G9 stored for up to fifteen days at 2 to 8° C. or 25° C. is equivalent in all the assays carried out in Example 3. After twenty-one days some minor differences are observed by SDS PAGE (Example 3C) and GP HPLC (Example 3D) analysis, but the product remains comparable up to twenty-eight days.
- Samples were diluted to 1 mg/ml with the relevant buffer and 16.7 ⁇ l added to 12.5 ⁇ l of 4 ⁇ LDS sample buffer (Invitrogen), 15.8 ⁇ l of Milli-Q water and 5 ⁇ l reducing agent (Invitrogen). The samples were heated at 95° C. for one minute and then placed on ice. 15 ⁇ l of each sample was loaded onto a 4-12% BisTris gel (Invitrogen) in a tank containing 1 ⁇ MES SDS running buffer and the gel run for 35 minutes at a constant current of 500 mA.
- the gel was removed from its casing, rinsed for 3 ⁇ 10 minutes with Milli-Q water, stained with Gelcode® Blue staining reagent (Pierce) for a minimum of one hour and then destained with Milli-Q water.
- the gel was photographed and analysed using a UVP GDS8000 gel documentation system. The relative abundance of BAK502G9 heavy and light chain in each sample was determined.
- FIGS. 13 , 15 , 17 , 19 and 21 The results of reduced SDS-PAGE analysis of formulations CF, TF1A, TF1B and TF1C at each temperature are shown in FIGS. 13 , 15 , 17 , 19 and 21 . Measurements of abundance of BAK502G9 heavy and light chains at each temperature are also shown in FIGS. 14 , 16 , 18 , 20 and 22 .
- Samples were diluted to 1 mg/ml with the relevant buffer and 16.7 ⁇ l added to 25 ⁇ l of 2 ⁇ non-reducing sample buffer (0.125M Tris pH6.8, 4% (w/v) SDS, 30% (v/v) glycerol, 0.004% (w/v) bromophenol blue), 3.3 ⁇ l of Milli-Q water and 5 ⁇ l 1 M iodoacetamide.
- the samples were heated at 95° C. for one minute and then placed on ice. 15 ⁇ l of each sample was loaded onto a 4-12% BisTris gel (Invitrogen) in a tank containing 1 ⁇ MES SDS running buffer and the gel run for 35 minutes at a constant current of 500 mA.
- the electrophoresis bed Prior to sample loading, the electrophoresis bed was cooled and a pH3-10 IEF gel (Cambrex) was prefocused for 10 minutes at 1 W, 2000V, 150 mA using an Apelex PS9009TX power pack. Samples were diluted to 1 mg/ml with the relevant buffer. A sample mask was placed on the surface of the gel and 5 ⁇ l of each sample was loaded. The gel was prefocused again and the sample mask removed. The gel was then focused for 60 minutes at 25 W, 1500V, 50 mA.
- a pH3-10 IEF gel (Cambrex) was prefocused for 10 minutes at 1 W, 2000V, 150 mA using an Apelex PS9009TX power pack. Samples were diluted to 1 mg/ml with the relevant buffer. A sample mask was placed on the surface of the gel and 5 ⁇ l of each sample was loaded. The gel was prefocused again and the sample mask removed. The gel was then focused for 60 minutes at 25 W, 1500V, 50 mA.
- the gel was fixed with 50% (v/v) methanol, 6% (w/v) trichloroacetic acid, 3.6% (w/v) 5-sulphosalicyclic acid for 30 minutes, then washed with water and dried in an oven at 40-50° C. for one hour.
- the gel was stained for 30 minutes using PhastGel Blue R (Pharmacia; one tablet dissolved in 60% (v/v) methanol), washed with Milli-Q water to remove excess stain and then destained for approximately 3 minutes with 9% (v/v) glacial acetic acid, 25% (v/v) ethanol solution.
- the gel was dried in an oven at 40-50° C. for one hour.
- Both CF and TF1A were stable for 12 months at ⁇ 70° C.
- the percentage monomer for both CF and TF1A samples was 100%.
- Both CF and TF1A samples displayed 4 bands on IEF after 12 months. The results indicated that CF and TF1A are comparable at this temperature.
- Both CF and TF1A were stable for 12 months at 5° C.
- the percentage monomer for both CF and TF1A samples was 100%.
- Both CF and TF1A samples displayed 4 bands on IEF after 12 months. The results indicated that CF and TF1A are comparable at this temperature.
- Both CF and TF1A were stable for 12 months at 25° C.
- There is also a minor high molecular weight (>220 kDa) band in both formulations on the non-reduced SDS-PAGE gel that was not detected at t 0.
- the percentage monomer for both CF and TF1A samples were 98.9 and 96.42%, respectively.
- Both CF and TF1A samples displayed 4 bands on IEF after 12 months. The results indicated that CF and TF1A are comparable at this temperature.
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US12/966,377 Active 2030-01-16 US9107945B2 (en) | 2005-09-30 | 2010-12-13 | Methods of purifying anti-interleukin-13 antibodies |
US14/798,685 Active 2027-10-06 US10358488B2 (en) | 2005-09-30 | 2015-07-14 | Anti-interleukin-13 antibody compositions |
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US12/966,377 Active 2030-01-16 US9107945B2 (en) | 2005-09-30 | 2010-12-13 | Methods of purifying anti-interleukin-13 antibodies |
US14/798,685 Active 2027-10-06 US10358488B2 (en) | 2005-09-30 | 2015-07-14 | Anti-interleukin-13 antibody compositions |
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EP (1) | EP1942939B2 (fi) |
JP (2) | JP2009510046A (fi) |
KR (1) | KR101363777B1 (fi) |
AU (1) | AU2006296399B2 (fi) |
BR (1) | BRPI0616359B8 (fi) |
CA (1) | CA2623429C (fi) |
CY (1) | CY1120874T1 (fi) |
FI (1) | FIC20210042I1 (fi) |
FR (1) | FR21C1055I2 (fi) |
GB (1) | GB2430883B (fi) |
HK (1) | HK1210724A1 (fi) |
HU (1) | HUS2100053I1 (fi) |
IL (3) | IL189983A (fi) |
LT (1) | LTPA2021528I1 (fi) |
NL (1) | NL301143I2 (fi) |
NO (2) | NO344859B1 (fi) |
PL (1) | PL1942939T5 (fi) |
SI (1) | SI1942939T2 (fi) |
WO (1) | WO2007036745A2 (fi) |
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US20140369927A1 (en) * | 2002-12-13 | 2014-12-18 | Immunomedics, Inc. | Camptothecin Conjugates of Anti-CD22 Antibodies for Treatment of B Cell Diseases |
EP2631302A2 (en) | 2008-03-31 | 2013-08-28 | Genentech, Inc. | Compositions and methods for treating and diagnosing asthma |
WO2013148232A1 (en) | 2012-03-27 | 2013-10-03 | Genentech, Inc. | Methods of prognosing, diagnosing and treating idiopathic pulmonary fibrosis |
EP3725892A1 (en) | 2012-03-27 | 2020-10-21 | F. Hoffmann-La Roche AG | Methods of prognosing, diagnosing and treating idiopathic pulmonary fibrosis |
US11633476B2 (en) | 2017-05-02 | 2023-04-25 | Merck Sharp & Dohme Llc | Stable formulations of programmed death receptor 1 (PD-1) antibodies and methods of use thereof |
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