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Methods of Treatment Using Glycopegylated G-Csf Behandlungsverfahren Mit Glycopegyliertem G-Csf Méthodes De Traitement À L’Aide D’Un Facteur G-Csf Glycopégylé

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Methods of Treatment Using Glycopegylated G-Csf Behandlungsverfahren Mit Glycopegyliertem G-Csf Méthodes De Traitement À L’Aide D’Un Facteur G-Csf Glycopégylé (19) TZZ _ ¥_T (11) EP 2 144 923 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 1/00 (2006.01) A61K 47/48 (2006.01) 13.02.2013 Bulletin 2013/07 A61P 7/00 (2006.01) A61P 35/00 (2006.01) (21) Application number: 08744881.7 (86) International application number: PCT/US2008/059045 (22) Date of filing: 01.04.2008 (87) International publication number: WO 2008/124406 (16.10.2008 Gazette 2008/42) (54) METHODS OF TREATMENT USING GLYCOPEGYLATED G-CSF BEHANDLUNGSVERFAHREN MIT GLYCOPEGYLIERTEM G-CSF MÉTHODES DE TRAITEMENT À L’AIDE D’UN FACTEUR G-CSF GLYCOPÉGYLÉ (84) Designated Contracting States: • HILL G R ET AL: "Allogeneic Stem Cell AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Transplantationwith Peripheral Blood Stem Cells HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Mobilized by Pegylated G-CSF" BIOLOGY OF RO SE SI SK TR BLOOD AND MARROW TRANSPLANTATION, Designated Extension States: KLUGE CARDEN JENNINGS PUBLISHING, AL BA MK RS CHARLOTTESVILLE, VA, US LNKD- DOI: 10.1016/J.BBMT.2006.03.001, vol. 12, no. 6, 1 (30) Priority: 03.04.2007 US 909917 P June 2006 (2006-06-01), pages 603-607, 13.04.2007 US 911788 P XP024918695 ISSN: 1083-8791 [retrieved on 07.11.2007 US 986240 P 2006-06-01] • HÜBEL K ET AL: "Clinical applications of (43) Date of publication of application: granulocytecolony- stimulating factor: an update 20.01.2010 Bulletin 2010/03 and summary." ANNALS OF HEMATOLOGY APR 2003 LNKD- PUBMED:12707722, vol. 82, no. 4, (73) Proprietor: BioGeneriX AG April 2003 (2003-04), pages 207-213, 68199 Mannheim (DE) XP002606583 ISSN: 0939-5555 • CAPOCCIA BENJAMIN J ET AL: "G-CSF and (72) Inventors: AMD3100 mobilize monocytes into the blood that • ZOPF, David, A. stimulate angiogenesis in vivo through a Wayne, PA 19087 (US) paracrine mechanism" BLOOD, vol. 108, no. 7, • LUBENAU, Heinz October 2006 (2006-10), pages 2438-2445, 67435 Neustadt (DE) XP002606573 ISSN: 0006-4971 • FLOMENBERG N ET AL: "The use of AMD3100 (74) Representative: Lasar, Andrea Gisela et al plus G-CSF for autologous hematopoietic Maiwald Patentanwalts GmbH progenitor cell mobilization is superior to G- CSF Elisenhof alone" BLOOD 20050901 US LNKD- DOI: Elisenstraße 3 10.1182/BLOOD-2005-02-0468, vol. 106, no. 5, 1 80335 München (DE) September 2005 (2005-09-01), pages 1867-1874, XP002606574 ISSN: 0006-4971 (56) References cited: WO-A2-2005/055946 WO-A2-2006/074467 US-A1- 2007 014 759 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 144 923 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 144 923 B1 • LILES W CONRAD ET AL: "Augmented • ARSLANET AL: "Mobilization of peripheral blood mobilization and collection of CD34+ stem cells" TRANSFUSION AND APHERESIS hematopoietic cells from normal human SCIENCE, ELSEVIER SCIENCE, LONDON, GB volunteers stimulated with granulocyte-colony- LNKD- DOI:10.1016/J.TRANSCI.2007.08.002, vol. stimulating factor by single-dose administration 37, no. 2, 5 November 2007 (2007-11-05), pages of AMD3100, a CXCR4 antagonist." 179-185, XP022394206 ISSN: 1473-0502 TRANSFUSION MAR 2005 LNKD- PUBMED: • DEFREES ET AL.: ’GlycoPEGylation of 15752146, vol. 45, no. 3, March 2005 (2005-03), recombinant therapeutic proteins produced in pages 295-300, XP002606575 ISSN: 0041-1132 Escherichia coli’ GLYCOBIOLOGY vol. 16, no. 9, • CASHEN A F ET AL: "Mobilizing stem cells from September 2006, pages 833 - 443, XP002403450 normal donors: is it possible to improve upon G- CSF?" BONE MARROW TRANSPLANTATION, vol. 39, no. 10, 19 March 2007 (2007-03-19), pages 577-588, XP002606576 ISSN: 0268-3369 • KROSCHINSKY F ET AL: "The role of pegfilgrastim in mobilization of hematopoietic stem cells" TRANSFUSION AND APHERESIS SCIENCE, ELSEVIER SCIENCE, LONDON, GB LNKD- DOI:10.1016/J.TRANSCI.2008.04.007, vol. 38,no. 3, 1 June 2008 (2008-06-01), pages 237-244, XP022716857 ISSN: 1473-0502 [retrieved on 2008-06-01] 2 EP 2 144 923 B1 Description BACKGROUND OF THE INVENTION 5 [0001] Granulocyte colony stimulating factor (G-CSF) is a glycoprotein which stimulates the survival, proliferation, differentiation and function of neutrophil granulocyte progenitor cells and mature neutrophils. The two forms of recom- binant human G-CSF in clinical use are potent stimulants of neutrophil granulopoiesis and have demonstrated efficacy in preventing infectious complications of some neutropenic states. They can be used to accelerate neutrophil recovery from myelosuppressive treatments. 10 [0002] G-CSF decreases the morbidity of cancer chemotherapy by reducing the incidence of febrile neutropenia, the morbidity of high-dose chemotherapy supported by marrow transplantation, and the incidence and duration of infection in patientswith severe chronic neutropenia.Further, G- CSF has been shown to have therapeutic effect when administered after the onset of myocardial infarction. [0003] Acute myelosuppression as a consequence of cytotoxic chemotherapy is well recognized as a dose-limiting 15 factor in cancer treatment. Although other normal tissues may be adversely affected, bone marrow is particularly sensitive to proliferation-specific treatments such as chemotherapy and radiation therapy. For some cancer patients, hematopoietic toxicity frequently limits the opportunity for chemotherapy dose escalation. Repeated or high dose cycles of chemotherapy can lead to stem cell depletion of hematopoietic stem cells and their progeny. [0004] Prevention of and protection from the side effects of chemotherapy and radiation therapy would be of great 20 benefit to cancer patients. G- CSF and other growth factors have been shown to alleviate such side effects by increasing the number of normal critical target cells, particularly hematopoietic progenitor cells. [0005] The human form of G-CSF was cloned by groups from Japan and the U.S.A. in 1986 (see e.g., Nagata et al. Nature 319: 415-418, 1986). The natural human glycoprotein exists in two forms, one of 175 and the other of 178 amino acids. The more abundant and more active 175 amino acid form has been used in the development of pharmaceutical 25 products by recombinant DNA technology. [0006] The recombinant human G-CSF synthesised in an E. coli expression system is called filgrastim. The structure of filgrastim differs slightly from the natural glycoprotein. The other form of recombinant human G- CSF is called lenogras- tim and is synthesised in Chinese hamster ovary (CHO) cells. [0007] hG-CSF is a monomeric protein that dimerizes the G- CSF receptor by formation of a 2:2 complex of 2 G-CSF 30 molecules and 2 receptors (Horan et al. Biochemistry, 35(15): 4886-96 (1996)). The following hG-CSF residues have been identified by X- ray crystalographic studies as being part of the receptor binding interfaces: G4, P5, A6, S7, S8, L9, P10, Q11, S12, L15, K16, E19, Q20, L108, D109, D112, T115, T116, Q119, E122, E123, and L124 (see e.g., Aritomi et al., (1999) Nature 401: 713). [0008] The commercially available forms of rhG-CSF have a short-term pharmacological effect and must often be 35 administered more than once a day for the duration of the leukopenic state. A molecule with a longer circulation half- life would decrease the number of administrations necessary to alleviate leukopenia and prevent consequent infections. Another problem with currently available rG-CSF products is the occurrence of dose-dependent bone pain. Since bone pain is experienced by patients as a significant side effect of treatment with rG- CSF, it would be desirable to provide a rG-CSF product that does not cause bone pain, either by means of a product that inherently does not have this effect 40 or that is effective in a sufficiently small dose that no bone pain is caused. Thus, there is clearly a need for improved recombinant G-CSF molecules. [0009] Protein-engineered variants of hG-CSF have been reported (U.S. Pat. No. 5,581,476, U.S. 5,214,132, U.S. 5,362,853, U.S. 4,904,584 and Riedhaar-Olson et al. Biochemistry 35: 9034-9041, 1996). Modification of hG- CSF and other polypeptides so as to introduce at least one additional carbohydrate chain as compared to the native polypeptide 45 has also been reported (U.S. Pat. No. 5,218,092). In addition, polymer modifications of native hG- CSF, including attach- ment of PEG groups, have been reported and studied (see e.g., Satake- Ishikawa et al., (1992) Cell Structure and Function 17: 157; Bowen et al. (1999) Experimental Hematology 27: 425; U.S. Pat. No. 5,824,778, U.S. 5,824,784, WO 96/11953, WO 95/21629, and WO 94/20069). [0010] The attachment of synthetic polymers to the peptide backbone in an attempt to improve the pharmacokinetic 50 properties of glycoprotein therapeutics is known in the art. An exemplary polymer that has been conjugated to peptides is poly(ethylene glycol) ("PEG"). The use of PEG to derivatize peptide therapeutics has been demonstrated to reduce the immunogenicity of the peptides. For example, U.S. Pat. No. 4,179,337 (Davis et al.) discloses non-immunogenic polypeptides such as enzymes and peptide hormones coupled to polyethylene glycol (PEG) or polypropylene glycol. In addition to reduced immunogenicity, the clearance time in circulation is prolonged due to the increased size of the PEG- 55 conjugate of the polypeptides in question.
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