(12) Unlted States Patent
`(10) Patent No.:
`US 8,932,591 B2
`
`Krause et al.
`(45) Date of Patent:
`*Jan. 13, 2015
`
`US008932591B2
`
`(54) FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-ot ASSOCIATED
`DISORDERS
`
`(75)
`
`Inventors: Hans-Juergen Krause, Gruenstadt
`(DE); Lisa Baust, Ludwigshafen (DE);
`Michael Dickes, Rodersheim-Gronau
`(DE)
`~
`-
`-
`.
`~
`(73) Ass1gnee. Abele Blotechnology Ltd., Ham1lton
`(BM)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U‘S‘C‘ 154(b)by Odays‘
`This patent is subject to a terminal dis-
`claimer.
`
`( * ) Notice:
`
`<29
`(22)
`(65)
`
`Flledi
`
`May 15, 2012
`Prior Publication Data
`
`NOV. 8, 2012
`US 2012/0282270 A1
`Related US. Application Data
`(63) Continuation of application No. 10/525,292, filed as
`application No. PCT/IB03/04502 on Aug. 15, 2003,
`now Pat. No. 8,216,583, which is a continuation of
`application No. 10/222,140, filed on Aug. 16, 2002,
`now abandoned.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006 01)
`(2006.01)
`'
`(200601)
`(2006.01)
`(2006.01)
`2006.01
`(2006 013
`'
`(2006.01)
`(2006.01)
`
`Int- Cl-
`A61K 39/395
`C07K 16/00
`C07K 16/22
`C07K 14/525
`A 61K 9/00
`C07K 16/24
`A61K 9/19
`A61K 47/12
`A61K 47/26
`A61K 47/18
`A61K 47/10
`A61K 47/22
`A61K 39/00
`(52) U S Cl
`.
`I
`'
`I
`CPC """""" A61K47/26 (2013'01)’ A61K39/39591
`(2013.01); A61K 39/3955 (2013.01); A61K
`9/0019 (2013.01); C0 7K 16/241 (2013.01);
`A61K 2039/505 (2013.01); A61K 9/19
`(2013.01); A61K47/12 (2013.01); C07K
`23] 7/2] (201301); A61K47/183 (201301);
`A61K 47/10 (201301); A61K 47/22 (201301)
`USPC .................. 424/158.1; 424/130.1; 424/141.1;
`424/145.1; 530/3871; 530/3881; 530/388.23;
`530/388 24. 530/399. 530/351
`'
`’
`’
`
`(58) Field of Classification Search
`CPC ........ C07K 16/00; C07K 16/18; C07K 16/24;
`C07K 16/241; C07K 2316/96; C07K
`2317/515; C07K 2317/565; C07K 2317/94;
`C07K 2317/76; A61K 39/395; A61K 39/3955;
`A61K 203 9/505
`See application file for complete search history.
`
`56
`
`(
`
`)
`
`C't d
`R f
`l e
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`
`.
`(Commued)
`Primary Examiner 7 Bridget E Bunner
`(74) Attorney, Agent, or Firm 7 Ropes & Gray LLP; James
`P. Haley, Jr; Z. Ying Li
`
`ABSTRACT
`(57)
`.
`.
`.
`.
`.
`.
`A hqu1d aqueous pharmaceutlcal formulatlon 1s descr1bed
`vahichélhasda Eiglti Eproteiinnchonce1(11tratti§r},ta pH of between
`a ou
`an a ou
`,an e
`ance sa11y.
`
`48 Claims, No Drawings
`
`
`
`AMGEN INC'
`Exhibit 1049
`
`Ex. 1049 - Page 1 of 27
`
`Ex. 1049 - Page 1 of 27
`
`AMGEN INC.
`Exhibit 1049
`
`

`

`US 8,932,591 B2
`
`Page 2
`
`(56)
`
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`Ex. 1049 - Page 2 of 27
`
`

`

`US 8,932,591 B2
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`Page 3
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`US 8,932,591 B2
`
`1
`FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-ot ASSOCIATED
`DISORDERS
`
`RELATED APPLICATIONS
`
`This application is a continuation of US. patent applica-
`tion Ser. No. 10/525,292, filed on Oct. 27, 2005 (now issued
`as US. Pat. No. 8,216,583), which is a 35 U.S.C. §371
`national stage filing of International Application No. PCT/
`IB2003/004502, filed onAug. 15, 2003 (now expired), which
`is a continuation of US. patent application Ser. No. 10/222,
`140, filed on Aug. 16, 2002 (now abandoned). The entire
`contents of each of the foregoing applications are incorpo-
`rated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`Tumor necrosis factor (X (TNFot) is a cytokine produced by
`numerous cell types, including monocytes and macrophages,
`that was originally identified based on its capacity to induce
`the necrosis of certain mouse tumors (see e.g., Old, L. (1985)
`Science 230: 630-632). Subsequently, a factor termed cachec-
`tin, associated with cachexia, was shown to be the same
`molecule as TNFot. TNFot has been implicated in mediating
`shock (see e.g., Beutler, B. and Cerami, A. (1988)Annu. Rev.
`Biochem. 57:505-518; Beutler, B. and Cerami, A. (1989)
`Annu. Rev. Immunol. 7:625-655). Furthermore, TNFot has
`been implicated in the pathophysiology of a variety of other
`human diseases and disorders, including sepsis, infections,
`autoimmune diseases, transplant rejection and graft-versus-
`host disease (see e.g., Moeller, A., et al. (1990) Cytokine
`2:162-169; US. Pat. No. 5,231,024 to Moeller et al.; Euro-
`pean Patent Publication No. 260 610 B1 by Moeller, A., et al.
`Vasilli, P. (1992)Annu. Rev. Immunol. 10:41 1-452; Tracey, K.
`J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503).
`Because of the harmful role ofhuman TNFot (hTNFot) in a
`variety of human disorders, therapeutic strategies have been
`designed to inhibit or counteract hTNFot activity. In particu-
`lar, antibodies that bind to, and neutralize, hTNFot have been
`sought as a means to inhibit hTNFot activity. Some of the
`earliest of such antibodies were mouse monoclonal antibod-
`
`ies (mAbs), secreted by hybridomas prepared from lympho-
`cytes ofmice immunized with hTNFot (see e.g., Hahn T; et al.,
`(1985) Proc NatlAcadSci USA 82: 3814-3818; Liang, C-M.,
`et al. (1986) Biochem. Biophys. Res. Commun. 137:847-854;
`Hirai, M., et al. (1987) J. Immunol. Methods 96:57-62;
`Fendly, B. M., et al. (1987) Hybridoma 6:359-370; Moeller,
`A., et al. (1990) Cytokine 2: 162-169; US. Pat. No. 5,231,024
`to Moeller et al.; European Patent Publication No. 186 833 B1
`by Wallach, D.; European Patent Application Publication No.
`218 868 A1 by Old et al.; European Patent Publication No.
`260 610 B1 by Moeller, A., et al.). While these mouse anti-
`hTNFot antibodies often displayed high affinity for hTNFot
`(e. g., de 1 0'9M) and were able to neutralize hTNFot activity,
`their use in vivo may be limited by problems associated with
`administration of mouse antibodies to humans, such as short
`serum half life, an inability to trigger certain human effector
`functions and elicitation of an unwanted immune response
`against the mouse antibody in a human (the “human anti-
`mouse antibody” (HAMA) reaction).
`In an attempt to overcome the problems associated with use
`of fully-murine antibodies in humans, murine anti-hTNFot
`antibodies have been genetically engineered to be more
`“human-like.” For example, chimeric antibodies, in which the
`variable regions of the antibody chains are murine-derived
`and the constant regions of the antibody chains are human-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`derived, have been prepared (Knight, D. M, et al. (1993)Mol.
`Immunol. 30: 1443-1453; PCT Publication No. WO 92/16553
`by Daddona, P. E., et al.). Additionally, humanized antibod-
`ies, in which the hypervariable domains of the antibody vari-
`able regions are murine-derived but the remainder of the
`variable regions and the antibody constant regions are
`human-derived, have also been prepared (PCT Publication
`No. WO 92/11383 by Adair, J. R., et al.). However, because
`these chimeric and humanized antibodies still retain some
`
`murine sequences, they still may elicit an unwanted immune
`reaction, the human anti-chimeric antibody (HACA) reac-
`tion, especially when administered for prolonged periods,
`e.g., for chronic indications, such as rheumatoid arthritis (see
`e.g., Elliott, M. J., et al. (1994) Lancet 344:1 125-1 127; Elliot,
`M. J., et al. (1994) Lancet 344:1105-1110).
`A preferred hTNFot inhibitory agent to murine mAbs or
`derivatives thereof (e.g., chimeric or humanized antibodies)
`would be an entirely human anti-hTNFot antibody, since such
`an agent should not elicit the HAMA reaction, even ifused for
`prolonged periods. Human monoclonal
`autoantibodies
`against hTNFot have been prepared using human hybridoma
`techniques (Boyle, P., et al. (1993) Cell. Immunol. 152:556-
`568; Boyle, P., et al. (1993) Cell. Immunol. 152:569-581;
`European Patent Application Publication No. 614 984 A2 by
`Boyle, et al.). However,
`these hybridoma-derived mono-
`clonal autoantibodies were reported to have an affinity for
`hTNFot that was too low to calculate by conventional meth-
`ods, were unable to bind soluble hTNFot and were unable to
`neutralize hTNFot-induced cytotoxicity (see Boyle, et al.;
`supra). Moreover, the success of the human hybridoma tech-
`nique depends upon the natural presence in human peripheral
`blood of lymphocytes producing autoantibodies specific for
`hTNFot. Certain studies have detected serum autoantibodies
`
`against hTNFot in human subjects (Fomsgaard, A., et al.
`(1989) Scand. J. Immunol. 30:219-223; Bendtzen, K., et al.
`(1990) Prog. Leukocyte Biol. 10B:447-452), whereas others
`have not (Leusch, H-G., et al. (1991) J. Immunol. Methods
`139:145-147).
`Alternative to naturally-occurring human anti-hTNFot
`antibodies would be a recombinant hTNFot antibody. Recom-
`binant human antibodies that bind hTNFot with relatively low
`affinity (i.e., Kd~10'7M)
`and a
`fast off
`rate
`(i.e.,
`Kofv10'2 sec—1) have been described (Griffiths, A. D., et al.
`(1993) EMBO J. 12:725-734). However, because of their
`relatively fast dissociation kinetics, these antibodies may not
`be suitable for therapeutic use. Additionally, a recombinant
`human anti -hTNF(X has been described that does not neutral-
`
`ize hTNFot activity, but rather enhances binding of hTNFot to
`the surface of cells and enhances internalization of hTNFot
`
`(Lidbury, A., et al. (1994) Biotechnol. Ther. 5:27-45; PCT
`Publication No. WO 92/03145 by Aston, R. e