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"METHODS OF ADMINISTERING ANTI-TNFalpha ANTIBODIES" in Patent Application Approval Process

July 26, 2014



By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A patent application by the inventors FISCHKOFF, Steven A. (Short Hills, NJ); Kempeni, Joachim (Neustadt, DE); Weiss, Roberta (Wynnewood, PA), filed on February 7, 2014, was made available online on July 10, 2014, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also AbbVie Biotechnology Ltd.).

This patent application is assigned to AbbVie Biotechnology Ltd.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Tumor necrosis factor .alpha. (TNF.alpha.) 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 cachectin, associated with cachexia, was shown to be the same molecule as TNF.alpha.. TNF.alpha. 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, TNF.alpha. 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., Vasilli, P. (1992) Annu. Rev. Immunol. 10:411-452; Tracey, K. J. and Cerami, A. (1994) Annu. Rev. Med. 45:491-503).

"Because of the harmful role of human TNF.alpha. (hTNF.alpha.) in a variety of human disorders, therapeutic strategies have been designed to inhibit or counteract hTNF.alpha. activity. In particular, antibodies that bind to, and neutralize, hTNF.alpha. have been sought as a means to inhibit hTNF.alpha. activity. Some of the earliest of such antibodies were mouse monoclonal antibodies (mAbs), secreted by hybridomas prepared from lymphocytes of mice immunized with hTNF.alpha. (see e.g., Hahn T; et al., (1985) Proc Natl Acad Sci 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; Moller, A., et al. (1990) Cytokine 2:162-169; U.S. 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-hTNF.alpha. antibodies often displayed high affinity for hTNF.alpha. (e.g., Kd.ltoreq.10.sup.-9M) and were able to neutralize hTNF.alpha. 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-hTNF.alpha. 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 antibodies, in which the hypervariable domains of the antibody variable 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) reaction, 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 344:1125-1127; Elliot, M. J., et al. (1994) Lancet 344:1105-1110).

"A preferred hTNF.alpha. inhibitory agent to murine mAbs or derivatives thereof (e.g., chimeric or humanized antibodies) would be an entirely human anti-hTNF.alpha. antibody, since such an agent should not elicit the HAMA reaction, even if used for prolonged periods. Human monoclonal autoantibodies against hTNF.alpha. 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 monoclonal autoantibodies were reported to have an affinity for hTNF.alpha. that was too low to calculate by conventional methods, were unable to bind soluble hTNF.alpha. and were unable to neutralize hTNF.alpha.-induced cytotoxicity (see Boyle, et al.; supra). Moreover, the success of the human hybridoma technique depends upon the natural presence in human peripheral blood of lymphocytes producing autoantibodies specific for hTNF.alpha.. Certain studies have detected serum autoantibodies against hTNF.alpha. 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-hTNF.alpha. antibodies would be a recombinant hTNF.alpha. antibody. Recombinant human antibodies that bind hTNF.alpha. with relatively low affinity (i.e., K.sub.d.about.10.sup.-7M) and a fast off rate (i.e., K.sub.off.about.10.sup.-2 sec.sup.-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.alpha. has been described that does not neutralize hTNF.alpha. activity, but rather enhances binding of hTNF.alpha. to the surface of cells and enhances internalization of hTNF.alpha. (Lidbury, A., et al. (1994) Biotechnol. Ther. 5:27-45; PCT Publication No. WO 92/03145 by Aston, R. et al.)

"Recombinant human antibodies that bind soluble hTNF.alpha. with high affinity and slow dissociation kinetics and that have the capacity to neutralize hTNF.alpha. activity, including hTNF.alpha.-induced cytotoxicity (in vitro and in vivo) and hTNF.alpha.-induced cell activation, have also been described (see U.S. Pat. No. 6,090,382). Typical protocols for administering antibodies are performed intravenously on a weekly basis. Weekly dosing with antibodies and/or any drug can be costly, cumbersome, and result in an increase in the number of side effects due to the frequency of administration. Intravenous administration also has limitations in that the administration is usually provided by someone with medical training."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent application: "The present invention provides methods for biweekly dosing regimens for the treatment of TNF.alpha. associated disorders, preferably via a subcutaneous route. Biweekly dosing has many advantages over weekly dosing including, but not limited to, a lower number of total injections, decreased number of injection site reactions (e.g., local pain and swelling), increased patient compliance (i.e., due to less frequent injections), and less cost to the patient as well as the health care provider. Subcutaneous dosing is advantageous because the patient may self-administer a therapeutic substance, e.g., a human TNF.alpha. antibody, which is convenient for both the patient and the health care provider.

"This invention provides methods for treating disorders in which TNF.alpha. activity is detrimental. The methods include administering biweekly, subcutaneous injections of antibodies to a subject. The antibodies preferably are recombinant human antibodies that specifically bind to human TNF.alpha.. This invention further provides methods for treating disorders in which TNF.alpha. activity is detrimental. These methods include utilizing a combination therapy wherein human antibodies are administered to a subject with another therapeutic agent, such as one or more additional antibodies that bind other targets (e.g., antibodies that bind other cytokines or that bind cell surface molecules), one or more cytokines, soluble TNF.alpha. receptor (see e.g., PCT Publication No. WO 94/06476) and/or one or more chemical agents that inhibit hTNF.alpha. production or activity (such as cyclohexane-ylidene derivatives as described in PCT Publication No. WO 93/19751), preferably methotrexate. The antibodies are preferably recombinant human antibodies that specifically bind to human TNF.alpha.. The antibodies of the invention are characterized by binding to hTNF.alpha. with high affinity and slow dissociation kinetics and by neutralizing hTNF.alpha. activity, including hTNF.alpha.-induced cytotoxicity (in vitro and in vivo) and hTNF.alpha.-induced cellular activation. The antibodies can be full-length (e.g., an IgG1 or IgG4 antibody) or can comprise only an antigen-binding portion (e.g., a Fab, F(ab').sub.2, scFv fragment or single domain). The most preferred recombinant antibody of the invention, termed D2E7, has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4 (set forth in Appendix B). Preferably, the D2E7 antibody has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. These antibodies are described in U.S. Pat. No. 6,090,382, incorporated in its entirety herein by reference.

"In one embodiment, the invention provides methods of treating disorders in which TNF.alpha. activity is detrimental. These methods include inhibiting human TNF.alpha. activity by subcutaneous, biweekly administration of an anti-TNF.alpha. antibody such that the disorder is treated. The disorder can be, for example, sepsis, an autoimmune disease (e.g., rheumatoid arthritis, allergy, multiple sclerosis, autoimmune diabetes, autoimmune uveitis and nephrotic syndrome), an infectious disease, a malignancy, transplant rejection or graft-versus-host disease, a pulmonary disorder, a bone disorder, an intestinal disorder or a cardiac disorder.

"In another embodiment, the invention provides methods of treating disorders in which TNF.alpha. activity is detrimental. These methods include inhibiting human TNF.alpha. activity by subcutaneous administration of an anti-TNF.alpha. antibody and methotrexate such that the disorder is treated. In one aspect, methotrexate is administered together with an anti-TNF.alpha. antibody. In another aspect, methotrexate is administered prior to the administration of an anti-TNF.alpha. antibody. In still another aspect, methotrexate is administered subsequent to the administration of an anti-TNF.alpha. antibody.

"In a preferred embodiment, the anti-TNF.alpha. antibody used to treat disorders in which TNF.alpha. activity is detrimental is a human anti-TNF.alpha. antibody. Even more preferably, treatment occurs by the biweekly, subcutaneous administration of an isolated human antibody, or an antigen-binding portion thereof. The antibody or antigen-binding portion thereof preferably dissociates from human TNF.alpha. with a K.sub.d of 1.times.10.sup.-8 M or less and a K.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or less, both determined by surface plasmon resonance, and neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-7 M or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off of 5.times.10.sup.-4 s.sup.-1 or less, or even more preferably, with a K.sub.off of 1.times.10.sup.-4 s.sup.-1 or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, neutralizes human TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC.sub.50 of 1.times.10.sup.-8 M or less, even more preferably with an IC.sub.50 of 1.times.10.sup.-9 M or less and still more preferably with an IC.sub.50 of 1.times.10.sup.-10 M or less.

"In another embodiment, the invention provides methods of treating disorders in which TNF.alpha. activity is detrimental by the biweekly, subcutaneous administration to the subject a human antibody, or antigen-binding portion thereof. The antibody or antigen-binding portion thereof preferably has the following characteristics:

"a) dissociates from human TNF.alpha. with a K.sub.off of 1.times.10.sup.-3 s.sup.-1 or less, as determined by surface plasmon resonance;

"b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;

"c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.

"More preferably, the antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off of 5.times.10.sup.-4 s.sup.-1 or less. Still more preferably, the antibody, or antigen-binding portion thereof, dissociates from human TNF.alpha. with a K.sub.off of 1.times.10.sup.-4 s.sup.-1 or less.

"In yet another embodiment, the invention provides methods of treating disorders in which TNF.alpha. activity is detrimental. These methods include a biweekly, subcutaneous administration to the subject a human antibody, or an antigen-binding portion thereof. The antibody or antigen-binding portion thereof preferably contains an LCVR having CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, and with an HCVR having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11. More preferably, the LCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5 and the HCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6. Still more preferably, the LCVR further has CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7 and the HCVR has a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 8.

"In still another embodiment, the invention provides methods of treating disorders in which TNF.alpha. activity is detrimental by subcutaneously administering to the subject, biweekly, an isolated human antibody, or an antigen binding portion thereof. The antibody or antigen-binding portion thereof preferably contains an LCVR comprising the amino acid sequence of SEQ ID NO: 1 and an HCVR comprising the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the antibody has an IgG1 heavy chain constant region or an IgG4 heavy chain constant region. In yet other embodiments, the antibody is a Fab fragment, an F(ab').sub.2 fragment or a single chain Fv fragment.

"In still other embodiments, the invention provides methods of treating disorders in which the administration of an anti-TNF.alpha. antibody is beneficial by subcutaneously administering to the subject, biweekly, one or more anti-TNF.alpha. antibodies, or antigen-binding portions thereof. The antibody or antigen-binding portion thereof preferably contains an LCVR having CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ED NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 or with an HCVR having a CDR3 domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 and SEQ ID NO: 35.

"Still another aspect of the invention pertains to kits containing a formulation comprising a pharmaceutical composition. The kits comprise an anti-TNF.alpha. antibody and a pharmaceutically acceptable carrier. The kits contain instructions for biweekly subcutaneous dosing of the pharmaceutical composition for the treatment of a disorder in which the administration of an anti-TNF.alpha. antibody is beneficial. In another aspect, the invention pertains to kits containing a formulation comprising a pharmaceutical composition, further comprising an anti-TNF.alpha. antibody, methotrexate, and a pharmaceutically acceptable carrier. The kits contain instructions for subcutaneous dosing of the pharmaceutical composition for the treatment of a disorder in which the administration of an anti-TNF.alpha. antibody is beneficial.

"Still another aspect of the invention provides a preloaded syringe containing a pharmaceutical composition comprising an anti-TNF.alpha. antibody and a pharmaceutically acceptable carrier. In still another aspect, the invention provides a preloaded syringe containing a pharmaceutical composition comprising an anti-TNF.alpha. antibody, methotrexate, and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

"FIG. 1 depicts the American College of Rheumatology 20 (ACR20) and ACR50 responses for patients suffering from rheumatoid arthritis (RA) after subcutaneous dosing with the antibody D2E7 every week for a total of twelve weeks (top), or subcutaneous dosing with the antibody D2E7 and methotrexate every other week (bottom) for a total of twenty-four weeks. These data indicate that every other week dosing is as effective as every week dosing.

"FIG. 2 depicts ACR20, ACR50, and ACR70 responses for patients suffering from RA after subcutaneous dosing with the antibody D2E7 and methotrexate every other week at twenty-four weeks.

"FIGS. 3A and 3B depict time courses of tender joint count (3A) and swollen joint count (3B) over twenty-four weeks for patients suffering from RA after subcutaneous dosing with D2E7 and methotrexate every other week at twenty-four weeks.

"FIG. 4 depicts results from a short form health survey (SF-36) from patients suffering from RA after subcutaneous dosing with the antibody D2E7 and methotrexate every other week at twenty-four weeks. RP, role physical; PF, physical function; BP, bodily pain; GH, general health; V, vitality; SF, social functioning; RE, role emotional; and ME, mental health.

"FIG. 5 depicts the percentage of ACR responders following a single intravenous injection of the antibody D2E7 and methotrexate in patients suffering from RA."

URL and more information on this patent application, see: FISCHKOFF, Steven A.; Kempeni, Joachim; Weiss, Roberta. METHODS OF ADMINISTERING ANTI-TNFalpha ANTIBODIES. Filed February 7, 2014 and posted July 10, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3554&p=72&f=G&l=50&d=PG01&S1=20140703.PD.&OS=PD/20140703&RS=PD/20140703

Keywords for this news article include: Patents, Peptides, rev Genes, Hybridomas, Immunology, Amino Acids, Clone Cells, Lymphocytes, Viral Genes, Hybrid Cells, Therapeutics, Autoantibodies, Blood Proteins, Joint Diseases, Immunoglobulins, Serum Globulins, Genetic Phenomena, Genome Components, Genetic Structures, Autoimmune Diseases, Autoimmune Disorders.

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Source: Obesity, Fitness & Wellness Week


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