US008802101B2
`
`(12) United States Patent
`US 8,802,101 B2
`(10) Patent No.:
`Krause et al.
`(45) Date of Patent:
`*Aug. 12, 2014
`
`(54) FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-ot ASSOCIATED
`DISORDERS
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`(71) Applicant: Abbvie Biotechnology Ltd., Hamilton
`(BM)
`
`(72)
`
`Inventors: Hans-Juergen Krause, Gruenstadt
`(DE); Lisa Baust, Ludwigshafen (DE);
`Michael Dickes, Rodersheim-Gronau
`(DE)
`
`(73) Assignee: Abeie Biotechnology Ltd., Hamilton
`(BM)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl.No.: 14/091,888
`
`(22)
`
`Filed:
`
`Nov. 27, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2014/0086930 A1
`
`Mar. 27, 2014
`
`Related US. Application Data
`
`(63) Continuation of application No. 13/471,820, filed on
`May 15, 2012, which is a 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)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 39/395
`00713 16/24
`co 7K 14/525
`A61K 9/19
`A61K 47/22
`A61K 47/26
`A61K 9/00
`A61K 47/12
`A61K 47/10
`A61K 47/18
`(52) us. Cl.
`CPC .A61K47/26 (2013.01);A61K9/19 (2013.01);
`A61K 39/3955 (2013.01); C07K 231 7/21
`(2013.01); A61K39/39591 (2013.01); A61K
`47/22 (2013.01); A61K 9/0019 (2013.01);
`A61K47/12 (2013.01); A61K 47/10 (2013.01);
`A61K47/183 (2013.01); 00713 16/241
`(2013.01)
`USPC .................. 424/1581; 424/1301; 424/1411;
`424/1451; 530/351; 530/3871; 530/388.1;
`530/388.23; 530/388.24; 530/399
`(58) Field of Classification Search
`None
`
`See application file for complete search history.
`
`4,597,966 A
`4,897,465 A
`5,231,024 A
`5,237,054 A
`5,358,708 A
`5,608,038 A
`5,654,403 A
`5,792,838 A
`5,945,098 A
`6,015,557 A
`6,024,938 A
`6,090,382 A
`6,165,467 A
`6,171,586 B1
`6,177,077 B1
`6,235,281 B1
`6,258,562 B1
`6,267,958 B1
`6,379,666 B1
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`6,818,613 B2
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`
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`OTHER PUBLICATIONS
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`Adalimumab entry from National Library of Medicine website:
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`Akers et a1., “Development and Manufacture of Protein Pharmaceu-
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`
`(Continued)
`
`Primary Examiner 7 Bridget E Bunner
`(74) Attorney, Agent, or Firm 7 Ropes & Gray LLP; James
`F. Haley, Jr.; Z. Ying Li
`
`(57)
`
`ABSTRACT
`
`A liquid aqueous pharmaceutical formulation is described
`which has a high protein concentration, a pH of between
`about 4 and about 8, and enhanced stability.
`
`29 Claims, No Drawings Exhibit 1042
`
`AMGEN INC.
`
`EX. 1042 - Page 1 of 25
`
`Ex. 1042 - Page 1 of 25
`
`AMGEN INC.
`Exhibit 1042
`
`

`

`US 8,802,101 B2
`
`Page 2
`
`(56)
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`Ex. 1042 - Page 4 of 25
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`

`

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`
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`EX. 1042 - Page 5 of 25
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`Ex. 1042 - Page 5 of 25
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`US 8,802,101 B2
`
`1
`FORMULATION OF HUMAN ANTIBODIES
`FOR TREATING TNF-ot ASSOCIATED
`DISORDERS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of US. patent applica-
`tion Ser. No. 13/471,820, filed May 15, 2012 (now pending),
`which is a continuation of US. patent application Ser. No.
`10/525,292 filed Oct. 27, 2005, now US. Pat. No. 8,216,583,
`issued Jul. 10, 2012, which is a United States National Stage
`Application under 35 U.S.C. §371 of PCT/IB2003/004502,
`filed Aug. 15, 2003 (now expired), which is a continuation of
`US. patent application Ser. No. 10/222,140, filed Aug. 16,
`2002 (now abandoned). Each of these applications is herein
`incorporated by reference in its entirety.
`
`SEQUENCE LISTING
`
`The Sequence Listing associated with this application is
`provided in text format in lieu of a paper copy, and is hereby
`incorporated by reference into the specification. The name of
`the text file containing the Sequence Listing is 1 10222-0005-
`305-Sequence-Listing.txt. The text file is 1 1,273 bytes in size,
`was created on Nov. 26, 2013, and is being submitted elec-
`tronically Via EFS Web.
`
`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,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`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-
`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., etal. (1994)Lancet344:1 125-1127; 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 aut