PHARMACEUTICAL COMPOSITION FOR TREATING RHEUMATOID ARTHRITIS

BACKGROUND OF THE INVENTION
Field of the Invention

A portion of the contents related to the present application was published within 1 year before the effective filing date of the present application (Oct. 26, 2016) by the inventor related to the present application or a joint inventor(s) thereof, or by a third party who obtained the information of the invented object directly from the inventor related to the present application at the request of the applicant related to the present application, in a mobile app of the meeting proceedings of American College of Rheumatology (publication date: Oct. 27, 2015), the following URL (http://acrabstracts.org/abstract/safety-and-efficacy-of-e6011-an-anti-fractalkine-monoclonal-antibody-in-a-first-in-patient-phase-12-study-in-rheumatoid-arthritis/) (publication date: Oct. 27, 2015), American College of Rheumatology (publication date: Nov. 10, 2015), the conference program/conference abstract of The 60th Annual assembly and Scientific Meeting of the Japan College of Rheumatology (publication date: Mar. 18, 2016), a mobile app of the conference program/conference abstract of The 60th Annual assembly and Scientific Meeting of the Japan College of Rheumatology (publication date: Apr. 8, 2016), The 60th Annual assembly and Scientific Meeting of the Japan College of Rheumatology (publication date: Apr. 23, 2016), a mobile app of the meeting proceedings of European League Against Rheumatism (publication date: Jun. 8, 2016), and the following URL (http://www.abstracts2view.com/eular/view.php?nu=EULAR16L_FRI0236), European League Against Rheumatism (publication date: Jun. 10, 2016), respectively.

Also, a portion of the contents related to the present application was published within 1 year before the filing date of the present application by the inventor related to the present application or a joint inventor(s) thereof, or by a third party who obtained the information of the invented object directly from the inventor related to the present application at the request of the applicant related to the present application, in the conference program/conference abstract of The 61st Annual assembly and Scientific Meeting of the Japan College of Rheumatology (publication date: Mar. 18, 2017), a mobile app of the conference program/conference abstract of The 61st Annual assembly and Scientific Meeting of the Japan College of Rheumatology (publication date: Apr. 5, 2017 or later), The 61st Annual assembly and Scientific Meeting of the Japan College of Rheumatology (publication date: Apr. 20, 2017), a mobile app of the meeting proceedings of European League Against Rheumatism (publication date: May 14, 2017), the following URL (http://scientific.sparx-ip.net/archiveeular/index.cfm?searchfor=E6011&view=l&c=a&item=2017SAT0187) (publication date: May 14, 2017 or later), European League Against Rheumatism (publication date: Jun. 17, 2017), Modern Rheumatology (2017) (http://dx.doi.org/10.1080/14397595.2017.1337056, publication date: Jul. 6, 2017), a mobile app of the meeting proceedings of American College of Rheumatology (publication date: Sep. 22, 2017), and the following URL (http://acrabstracts.org/abstract/safety-pharmacokinetics-and-efficacy-of-e6011-an-anti-fractalkine-monoclonal-antibody-in-a-first-in-patient-phase-12-study-on-rheumatoid-arthritis-52-week-results/) (publication date: Sep. 18, 2017).

The present invention relates to a pharmaceutical composition for the treatment of rheumatoid arthritis, comprising an anti-fractalkine antibody, and a method for treating rheumatoid arthritis using the pharmaceutical composition.

Description of the Related Art

Fractalkine (also referred to as “FKN”) is a membrane-bound chemokine that is expressed on the surface of vascular endothelial cells by the inflammatory stimulus of LPS, TNF-α, IL-1, or the like. Cells expressing an FKN receptor CX3CR1 bind to membrane-bound FKN without any involvement of selectin or integrin and cause strong cell adhesion. Secreted FKN shed from the membrane-bound FKN exhibits cell-migrating activity against NK cells, T cells, and monocytes having CX3CR1.

The expression of FKN is induced on the surface of vascular endothelial cells by proinflammatory cytokines. The increased expression of FKN and the accumulation of CX3CR1⁺ cytotoxic effector lymphocytes and macrophages have been reported as to patients having rheumatoid arthritis (also referred to as “RA”).

Therapeutic effects by the inhibition of FKN have previously been reported as to collagen-induced arthritis (CIA) murine models, which are known as chronic rheumatoid arthritis models (J Immunol. 2004; 173: 7010-7016). The results obtained in CIA indicate significant reduction in the clinical score of arthritis, significant decrease in the incidence of arthritis, and significant decrease in inflammatory cells in synovial membranes and bony erosion, due to anti-fractalkine antibodies. Furthermore, it is suggested that an anti-fractalkine antibody inhibiting the interaction between FKN and CX3CR1 is capable of treating inflammatory diseases including rheumatoid arthritis (WO2006/046739). Thus, as for the treatment of rheumatoid arthritis, it is suggested that an antibody that can bind to FKN and inhibit this FKN is effective for the treatment of rheumatoid arthritis.

The applicant of this application has previously disclosed a plurality of mouse anti-human fractalkine (hFKN) monoclonal antibodies (clones 1F3-1, 3A5-2, 1F3, 1G1, 2B2, 3D5, 3H7, 6D1, 7F6, and 5H7-6). Particularly, the clone 3A5-2 has been humanized because of its high neutralizing activity, binding affinity, and interspecific cross reactivity against hFKN, and designated as H3-2L4 (WO2011/052799, which is incorporated herein by reference in its entirety).

An object of the present invention is to provide a pharmaceutical composition comprising an anti-fractalkine antibody (in the present specification, also referred to as an “anti-FKN antibody”), wherein the pharmaceutical composition brings about therapeutically effective amelioration in rheumatoid arthritis after administration to a human subject.

Another object of the present invention is to provide a pharmaceutical composition comprising an anti-FKN antibody, wherein the pharmaceutical composition is used in such a manner that therapeutically effective amelioration in rheumatoid arthritis is achieved.

A further alternative object of the present invention is to provide a method for treating rheumatoid arthritis which brings about therapeutically effective amelioration in rheumatoid arthritis.

A further alternative object of the present invention is to provide a method for treating rheumatoid arthritis using a pharmaceutical composition that brings about therapeutically effective amelioration in rheumatoid arthritis.

SUMMARY OF THE INVENTION

The present invention encompasses the following embodiments:

[1] A pharmaceutical composition for the treatment of rheumatoid arthritis,

the pharmaceutical composition comprising an anti-fractalkine antibody and a pharmaceutically acceptable excipient, wherein

the anti-fractalkine antibody is an antibody wherein:

a heavy chain variable region thereof comprises the amino acid sequence represented by SEQ ID NO: 13 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVKQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTADKSTNTAYMLLSSLRSEDTAVYFCATGPTDGDYFDYWGQGT TVTVSS);

a light chain variable region thereof comprises the amino acid sequence represented by SEQ ID NO: 14 (DIQMTQSPSSLSASVGDRVTITCRASGNIHNFLAWYQQKPGKAPKLLIYNEKTLAD GVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQFWSTPYTFGGGTKVEIK);

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

the pharmaceutical composition is used such that at least 100 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human.

[2] The pharmaceutical composition according to [1], wherein

the pharmaceutical composition is used such that 100 mg to 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human.

[3] The pharmaceutical composition according to [1], wherein

the pharmaceutical composition is used such that 100 mg, 200 mg, or 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human.

[4] The pharmaceutical composition according to [1], wherein

when 100 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 10 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 2.4×10³μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 3.0×10³μg·h/mL.

[5] The pharmaceutical composition according to [1], wherein

when 200 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 27 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 7.4×10³μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL.

[6] The pharmaceutical composition according to [1], wherein

when 400 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 43 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 2.7×10⁴μg·h/mL.

[7] The pharmaceutical composition according to [1], wherein

the pharmaceutical composition is subcutaneously administered by multiple administrations at dosing intervals of once a week to once every two weeks.

[8] The pharmaceutical composition according to any one of [1] to [7], wherein

the pharmaceutical composition is subcutaneously administered such that the mean trough concentration of the anti-fractalkine antibody is 10 μg/mL or higher.

[9] The pharmaceutical composition according to any one of [1] to [7], wherein

the pharmaceutical composition is subcutaneously administered such that the mean trough concentration of the anti-fractalkine antibody is 20 μg/mL or higher.

[10] A therapeutic agent for rheumatoid arthritis, comprising an anti-fractalkine antibody, wherein

the therapeutic agent for rheumatoid arthritis is used such that 100 mg to 400 mg of the anti-fractalkine antibody is subcutaneously administered at dosing intervals of once a week to once every two weeks to a human, and

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In another aspect, the present invention relates to the following inventions:

[1′] A method for treating rheumatoid arthritis,

the method comprising subcutaneously administering at least 100 mg per dose of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

[2′] The method according to [1′], wherein

the method comprises subcutaneously administering 100 mg to 400 mg per dose of the anti-fractalkine antibody to a human.

[3′] The method according to [1′], wherein

the method comprises subcutaneously administering 100 mg, 200 mg, or 400 mg per dose of the anti-fractalkine antibody to a human.

[4′] The method according to [1′], wherein

the anti-fractalkine antibody is subcutaneously administered by a pharmaceutical composition which brings about the following:

when 100 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 10 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 2.4×10³μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 3.0×10³μg·h/mL.

[5′] The method according to [1′], wherein

the anti-fractalkine antibody is subcutaneously administered by a pharmaceutical composition which brings about the following:

when 200 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 27 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 7.4×10³μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL.

[6′] The method according to [1′], wherein

the anti-fractalkine antibody is subcutaneously administered by a pharmaceutical composition which brings about the following:

when 400 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 43 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 2.7×10⁴μg·h/mL.

[7′] The method according to [1′], wherein

the method comprises subcutaneously administering the anti-fractalkine antibody by multiple administrations at dosing intervals of once a week to once every two weeks.

[8′] The method according to any one of [1′] to [7′], wherein

the anti-fractalkine antibody is subcutaneously administered such that the mean trough concentration thereof is 10 μg/mL or higher.

[9′] The method according to any one of [1′] to [7′], wherein

the anti-fractalkine antibody is subcutaneously administered such that the mean trough concentration thereof is 20 μg/mL or higher.

The present invention provides a pharmaceutical composition comprising an anti-FKN antibody, wherein the pharmaceutical composition brings about therapeutically effective amelioration in rheumatoid arthritis after administration to a human subject. The pharmaceutical composition of the present invention can be used in such a manner that a pharmacokinetic parameter useful for exerting therapeutic effects on rheumatoid arthritis is achieved.

The present invention also provides a method for treating rheumatoid arthritis, wherein the method brings about therapeutically effective amelioration in rheumatoid arthritis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows, in a time-dependent manner, the summary statistic of serum H3-2L4 concentration after a single subcutaneous administration (each dose of 50 mg, 100 mg, 200 mg, and 400 mg) of antibody H3-2L4;

FIG. 2 shows time-dependent change in the summary statistics of serum H3-2L4 concentration by multiple subcutaneous administrations (100 mg group, 200 mg group and 400 mg group) of antibody H3-2L4;

FIG. 3 shows time-dependent change in the summary statistics of serum H3-2L4 concentration and serum total FKN concentration by multiple subcutaneous administrations (100 mg group) of antibody H3-2L4;

FIG. 4 shows time-dependent change in the summary statistics of serum H3-2L4 concentration and serum total FKN concentration by multiple subcutaneous administrations (200 mg group) of antibody H3-2L4;

FIG. 5 shows time-dependent change in the summary statistics of serum H3-2L4 concentration and serum total FKN concentration by multiple subcutaneous administrations (400 mg group) of antibody H3-2L4;

FIG. 6 shows ACR20, ACR50, and ACR70 (LOCF) at week 12 of multiple subcutaneous administrations (100 mg group, 200 mg group, and 400 mg group) of antibody H3-2L4;

FIG. 7 shows ACR20, ACR50, and ACR70 (NRI) at week 12 of multiple subcutaneous administrations (100 mg group, 200 mg group, and 400 mg group) of antibody H3-2L4;

FIG. 8 shows change in ACR70 over 12 weeks of multiple subcutaneous administrations (100 mg group, 200 mg group, and 400 mg group) of antibody H3-2L4;

FIG. 9 shows change in ACR20 over 52 weeks of multiple subcutaneous administrations (100 mg group, 200 mg group, and 400 mg group) of antibody H3-2L4;

FIG. 10 shows change in DAS28-CRP over 12 weeks of multiple subcutaneous administrations (100 mg group, 200 mg group, and 400 mg group) of antibody H3-2L4;

FIG. 11 shows change in the proportions of disease activity scores of DAS28-CRP in multiple subcutaneous administrations (100 mg group, 200 mg group, and 400 mg) of antibody H3-2L4 before administration and at week 12 after the start of administration;

FIG. 12 shows the proportion of subjects who reached remission or low disease activity in disease activity scores of DAS28-ESR in multiple subcutaneous administrations (100 mg group, 200 mg group, and 400 mg group) of antibody H3-2L4 at 12 weeks after the start of administration; and

FIG. 13 shows the proportion of subjects based on EULAR response criteria of DAS28-ESR in multiple subcutaneous administrations (100 mg group, 200 mg group, and 400 mg group) of antibody H3-2L4 at 12 weeks after the start of administration.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
1. Summary of Invention and Definition

The present invention relates to a pharmaceutical composition and a method for treating rheumatoid arthritis, which bring about therapeutically effective amelioration in rheumatoid arthritis.

In one embodiment of the present invention, the “therapeutically effective amelioration in rheumatoid arthritis” can mean that the therapeutically effective amelioration is exhibited for one or more of items or parameters specified in evaluation criteria for rheumatoid arthritis established in the art. Examples of such items or parameters can include, but are not limited to, ACR (American College of Rheumatology) 20 response rates, ACR50 response rates, ACR70 response rates, erythrocyte sedimentation rates (ESR), high sensitive C-reactive protein (hs-CRP), health assessment questionnaire (HAQ), simple disease activity index (SDAI), disease activity score 28 joints (DAS28; e.g., DAS28-CRP using CRP and DAS28-ESR using ESR), clinical disease activity index (CDAI), and Boolean remission rates.

In one embodiment of the present invention, the therapeutically effective amelioration in rheumatoid arthritis can mean at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% decrease in ESR from the baseline.

In one embodiment of the present invention, the therapeutically effective amelioration in rheumatoid arthritis can mean that the DAS28 score itself or severity evaluated on the basis of DAS28 is ameliorated. For example, the therapeutically effective amelioration in rheumatoid arthritis can mean that, in severity evaluation based on DAS28-CRP or DAS28-ESR, a severe case is ameliorated to a moderate case, a moderate case is ameliorated to a mild case, or a mild case is ameliorated to remission.

In one aspect, the present invention relates to a pharmaceutical composition for the treatment of rheumatoid arthritis which brings about a therapeutically effective serum anti-FKN antibody concentration after a single administration or multiple administrations to a human subject. In another aspect, the present invention relates to a method for treating rheumatoid arthritis, comprising administering an anti-FKN antibody to a human subject in such a manner that a therapeutically effective serum anti-FKN antibody concentration is achieved.

In one embodiment of the present invention, the “therapeutically effective serum anti-FKN antibody concentration” is a serum concentration of 5 μg/mL or higher, 10 μg/mL or higher, 15 μg/mL or higher, 20 μg/mL or higher, 25 μg/mL or higher, 30 μg/mL or higher, 35 μg/mL or higher, or 40 μg/mL or higher of the anti-FKN antibody. In an alternative embodiment of the present invention, the “therapeutically effective serum anti-FKN antibody concentration” can be a mean trough concentration of 5 μg/mL or higher, 10 μg/mL or higher, 15 μg/mL or higher, 20 μg/mL or higher, 25 μg/mL or higher, 30 μg/mL or higher, 35 μg/mL or higher, or 40 μg/mL or higher of the anti-FKN antibody. In a preferred embodiment, the “therapeutically effective serum anti-FKN antibody concentration” is a mean trough concentration of 10 μg/mL or higher or 20 μg/mL or higher of the anti-FKN antibody.

In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention is formulated in such a manner that a serum concentration of 10 μg/mL or higher of the anti-FKN antibody is achieved. In an alternative preferred embodiment of the present invention, the pharmaceutical composition of the present invention is formulated in such a manner that a serum concentration of 20 μg/mL or higher of the anti-FKN antibody is achieved.

In an alternative aspect, the present invention relates to a pharmaceutical composition comprising an anti-FKN antibody, wherein the pharmaceutical composition is used in such a manner that a therapeutically effective serum anti-FKN antibody concentration is achieved after a single administration or multiple administrations to a human subject. The pharmaceutical composition of the present invention is not particularly limited and can be typically in the form of a formulation for injection prepared for subcutaneous administration. In one embodiment, the pharmaceutical composition of the present invention is used such that the mean trough concentration of the anti-FKN antibody is 5 μg/mL or higher, 10 μg/mL or higher, 15 μg/mL or higher, 20 μg/mL or higher, 25 μg/mL or higher, 30 μg/mL or higher, 35 μg/mL or higher, or 40 μg/mL or higher. In a preferred embodiment, the pharmaceutical composition of the present invention is used such that the mean trough concentration of the anti-FKN antibody is 10 μg/mL or higher or 20 μg/mL or higher.

In the present invention, the pharmacokinetic characteristics of a concentration-time curve, for example, a maximum serum concentration (C_max), a time to reach C_max(t_max), and an area under the serum concentration-time curve (AUC) are examined by statistical approaches sufficiently established in the field of pharmacokinetics. When the ratio of a population mean of an evaluation parameter as described above between a test formulation and a standard formulation is 0.80 to 1.25, these formulations are generally regarded as being biologically equivalent.

In the present invention, mean values of the pharmacokinetic parameters such as C_maxand AUC can be calculated by any of geometric mean and arithmetic mean methods. In the present specification, mean C_max, mean AUC, mean tFKN concentration, and mean trough concentration are indicated by arithmetic mean values, and t_maxis indicated by a median value. Even if a mean value of interest is calculated by a method different from that described in the present specification, the mean value is intended to belong to the scope of claims according to the present invention as long as the corresponding mean value calculated according to the method of the present specification falls within the numerical range described in the scope of claims.

In the present invention, the term “one dose” or “per dose” regarding the dose of the anti-FKN antibody refers to the absolute amount of the anti-FKN antibody per administration. Thus, for example, the term “200 mg per dose” may mean that one set of the pharmaceutical composition of the present invention comprising 200 mg of the anti-FKN antibody is administered, or may mean that two sets of the pharmaceutical composition of the present invention comprising 100 mg of the anti-FKN antibody are administered at the same time.

In the present invention, for example, the term “dosing intervals of once a week to once every two weeks” regarding the dosing interval of the anti-FKN antibody means that the dosing interval from the n^th(n represents an integer) administration to the (n+1)^thadministration is 1 week to 2 weeks, and the dosing interval between the n^thadministration and the (n+1)^thadministration may be different from the dosing interval between the (n+1)^thadministration and the (n+2)^thadministration. For example, the term “dosing intervals of once a week to once every two weeks” naturally includes the case where the dosing interval from the first administration to the second administration is 1 week and the dosing interval from the second administration to the third administration is 2 weeks.

In the present specification, the term “human” or “human subject” means a healthy adult male, and typically, any human who has rheumatoid arthritis or manifests a clinical sign and symptom of any disease or disorder that may cause rheumatoid arthritis. In the present invention, the term “human” or “human subject” is preferably a rheumatic disease patient who has not obtained adequate therapeutic effects from at least one type of antirheumatic drug or anti-TNF formulation, has not obtained sustained therapeutic effects therefrom, or has not respond thereto.

The term “rheumatoid arthritis” refers to a disease state that can be diagnosed according to the 1987 ACR Classification Criteria or the 2010 ACR/EULAR Classification Criteria. Examples of physiological indexes of rheumatoid arthritis include symmetrical joint swelling and pain on passive movement, which are characteristics, but not unchangeable, of rheumatoid arthritis. A candidate for the treatment described in the present invention can be resistant to methotrexate or an anti-TNF formulation (adalimumab, infliximab, golimumab, certolizumab pegol, or etanercept) from the viewpoint that methotrexate or the anti-TNF formulation is not effective or not completely effective for the treatment of its symptom.

2. Anti-FKN Antibody

In the present invention, the term “anti-FKN antibody” refers to humanized anti-human fractalkine antibody H3-2L4 or an antibody functionally equivalent thereto. In the present invention, the “functionally equivalent antibody” refers to an antibody that is equivalent to the antibody H3-2L4 in terms of at least any of or preferably all of binding affinity, neutralizing activity, cross reactivity, and pharmacokinetics in blood against human FKN.

In the present invention, the term “anti-FKN antibody” may include an antigen-binding fragment thereof. Such an antigen-binding fragment is not particularly limited as long as the antigen-binding fragment is a functional and structural fragment of the anti-FKN antibody, maintains the binding activity of the antibody against FKN, and does not significantly differ in pharmacokinetics in blood from the complete antibody. Examples of the antigen-binding fragment of the antibody include, but are not limited to, Fab, Fab′, F(ab′)₂, Fv, single-chain (scFv), variants thereof, fusion proteins containing the antibody moiety, other modified structures of immunoglobulin molecules containing an antigen recognition site, and the like.

In one embodiment, the anti-FKN antibody of the present invention can be any antibody comprising the following CDR sequences:

(a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 15 (NYYIH);

(b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 16 (WIYPGDGSPKFNERFKG);

(d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 18 (RASGNIHNFLA);

(e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 19 (NEKTLAD); and

(f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 20 (QQFWSTPYT).

In an alternative embodiment, the anti-FKN antibody can be an antibody comprising a heavy chain and a light chain, wherein a heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 21 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVKQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTADKSTNTAYMLLSSLRSDDTAVYFCATGPTDGDYFDYWGQGT TVTVSS), SEQ ID NO:13 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVKQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTADKSTNTAYMLLSSLRSEDTAVYFCATGPTDGDYFDYWGQGT TVTVSS), SEQ ID NO: 22 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVRQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTRDKSTNTAYMELSSLRSDDTAVYFCATGPTDGDYFDYWGQGT TVTVSS), SEQ ID NO: 23 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVRQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTMTADTSTSTAYMELSSLRSEDTAVYFCARGPTDGDYFDYWGQGT TVTVSS), or SEQ ID NO: 24 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVRQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTADKSTSTAYMELSSLRSEDTAVYFCARGPTDGDYFDYWGQGT TVTVSS), and a light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 25 (DIQMTQSPSSLSASVGDRVTITCRASGNIHNFLAWYQQKPGKAPKFLVYNEKTLAD GVPSRFSGSGSGTQYTLTISSLQPEDFATYFCQQFWSTPYTFGGGTKVEIK), SEQ ID NO: 14 (DIQMTQSPSSLSASVGDRVTITCRASGNIHNFLAWYQQKPGKAPKLLIYNEKTLAD GVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQFWSTPYTFGGGTKVEIK), or SEQ ID NO: 26 (DIQMTQSPSSLSASVGDRVTITCRASGNIHNFLAWYQQKPGKAPKLLIYNEKTLAD GVPSRFSGSGSGTQYTLTISSLQPEDFATYFCQQFWSTPYTFGGGTKVEIK).

In a preferred embodiment, the anti-FKN antibody can be an antibody comprising a heavy chain and a light chain, wherein a heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 13 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVKQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTADKSTNTAYMLLSSLRSEDTAVYFCATGPTDGDYFDYWGQGT TVTVSS) and a light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 14 (DIQMTQSPSSLSASVGDRVTITCRASGNIHNFLAWYQQKPGKAPKLLIYNEKTLAD GVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQFWSTPYTFGGGTKVEIK).

In a particular embodiment, the anti-FKN antibody is an antibody comprising a constant region of human IgG2 isotype.

In a particular embodiment, the anti-FKN antibody is an antibody wherein a Fc region of the constant region of human IgG2 isotype contains V234A and/or G237A mutations.

In a particularly preferred embodiment of the present invention, the anti-FKN antibody is antibody H3-2L4 consisting of a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVKQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTADKSTNTAYMLLSSLRSEDTAVYFCATGPTDGDYFDYWGQGT TVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPP CPAPPAAAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK) and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 12 (DIQMTQSPSSLSASVGDRVTITCRASGNIHNFLAWYQQKPGKAPKLLIYNEKTLAD GVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQFWSTPYTFGGGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC).

Needless to say, an antibody derived from any of the anti-FKN antibodies listed above by appropriate alteration (e.g., modification of the antibody or partial substitution, addition, or deletion of the amino acid sequence of the antibody) so as to maintain the functions of the antibody or in order to add or improve the functions of the antibody is also included in the antibody of the present invention. More specifically, an antibody lacking lysine (Lys) positioned at the carboxy terminus (C terminus) of the heavy chain by an artificial method such as genetic engineering in order to decrease heterogeneity among antibodies produced by antibody-producing cells is also included in the scope of the present invention. In addition, the anti-FKN antibody contained in the pharmaceutical composition of the present invention is not necessarily required to have complete homogeneity. For example, an anti-FKN antibody lacking lysine (Lys) positioned at the carboxy terminus (C terminus) of the heavy chain and an anti-FKN antibody that does not lack this lysine may coexist in the pharmaceutical composition of the present invention as long as the pharmaceutical composition of the present invention maintains the intended functions.

The anti-FKN antibody may be modified, if desired. The modification of the anti-FKN antibody may be a modification that changes (a) the three-dimensional structure of an amino acid sequence in a modification region, such as sheet or helix conformation; (b) the electric charge or hydrophobic status of the molecule at a target site; or (c) the effects of a modification on the maintenance of side chain volume, or may be a modification by which these changes are not clearly observed.

The modification of the anti-FKN antibody may be achieved by, for example, the substitution, deletion, and/or addition of a constituent amino acid residue(s).

In the present specification, the amino acid is used in the broadest sense thereof and includes not only natural amino acids, for example, serine (Ser), asparagine (Asn), valine (Val), leucine (Leu), isoleucine (Ile), alanine (Ala), tyrosine (Tyr), glycine (Gly), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), glutamine (Gln), threonine (Thr), cysteine (Cys), methionine (Met), phenylalanine (Phe), tryptophan (Trp), and proline (Pro) but non-natural amino acids such as amino acid variants and derivatives. Those skilled in the art should understand, by taking this wide definition into consideration, that examples of the amino acid in the present specification include: L-amino acids; D-amino acids; chemically modified amino acids such as amino acid variants and amino acid derivatives; amino acids, such as norleucine, β-alanine, and ornithine, which do not serve as materials constituting proteins in vivo; and chemically synthesized compounds having the characteristics of amino acids generally known to those skilled in the art. Examples of the non-natural amino acids include α-methylamino acids (α-methylalanine, etc.), D-amino acids (D-aspartic acid, D-glutamic acid, etc.), histidine-like amino acids (2-amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine, α-methyl-histidine, etc.), amino acids having extra methylene in their side chains (“homo” amino acids), and amino acids in which a carboxylic acid functional group in the side chain is replaced with a sulfonic acid group (cysteic acid, etc.).

Naturally occurring amino acid residues can be classified into, for example, the following groups based on general side chain characteristics:

(1) hydrophobic residues: Met, Ala, Val, Leu, and Ile;
(2) neutral hydrophilic residues: Cys, Ser, and Thr;
(3) acidic residues: Asp and Glu;
(4) basic residues: Asn, Gln, His, Lys, and Arg;
(5) residues influencing chain orientation: Gly and Pro; and
(6) aromatic residues: Trp, Tyr, and Phe.

The non-conservative substitution of an amino acid sequence constituting the anti-FKN antibody may be performed by replacing an amino acid belonging to one of these groups with an amino acid belonging to any of the other groups. More conservative substitution may be performed by replacing an amino acid belonging to one of these groups with another amino acid belonging to the same group thereas. Likewise, the deletion or the substitution in an amino acid sequence may be appropriately performed.

3. Pharmaceutical Composition and Formulation

The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the anti-FKN antibody. Such an amount of the anti-FKN antibody contained in the pharmaceutical composition of the present invention can vary according to the administration route and dosing interval of the pharmaceutical composition of the present invention.

In one embodiment of the present invention, the pharmaceutical composition of the present invention can comprise the anti-FKN antibody in an amount from 100 mg to 400 mg. In a particular embodiment of the present invention, the formulation of the present invention can comprise the anti-FKN antibody in an amount of at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, or at least 400 mg. In a further alternative embodiment, the formulation of the present invention can comprise the anti-FKN antibody in an amount of 100 mg, 200 mg, or 400 mg.

The dosage form of the pharmaceutical composition of the present invention is not particularly limited and is typically a formulation for injection prepared for subcutaneous administration. The pharmaceutical composition of the present invention can be prepared, for example, as a formulation for injection of the anti-FKN antibody, together with a pharmaceutically acceptable excipient, in injectable water, physiological saline, or phosphate-buffered saline without limitations. Examples of the pharmaceutically acceptable excipient used in the present invention include, but are not limited to, a stabilizer, a surfactant, and a preservative.

The stabilizer used in the present invention is, for example, a carbohydrate, a saccharide, or a sugar (e.g., sucrose) accepted by an authority as an appropriate additive or excipient for pharmaceutical formulations. The concentration of the stabilizer is 15 to 250 mM, 150 to 250 mM, or 200 mM. The formulation may contain a secondary stabilizer.

Appropriate examples of the pharmaceutically acceptable surfactant used in the present invention include, but are not limited to, polyoxyethylene sorbitan fatty acid ester (Tween), polyethylene polypropylene glycol, polyoxyethylene stearate, polyoxyethylene alkyl ether (e.g., polyoxyethylene monolauryl ether), alkylphenyl polyoxyethylene ether (Triton-X), polyoxyethylene-polyoxypropylene copolymers (Poloxamer and Pluronic), and sodium dodecyl sulfate (SDS). The most appropriate polyoxyethylene sorbitan fatty acid esters are polysorbate 20 (Tween 20) and polysorbate 80 (Tween 80). The concentration of the surfactant is 0.01 to 0.1% (w/v), 0.01 to 0.08% (w/v), or 0.025 to 0.075% (w/v), for example, 0.05% (w/v).

Examples of the preservative used in the present invention includes, but are not limited to, paraben, benzyl alcohol, sodium benzoate, phenol, benzalkonium chloride, thimerosal, chlorobutanol, benzoic acid, sodium bisulfite, sodium propionate, and arbitrary combinations or mixtures thereof.

Examples of the buffer used in the present invention include, but are not limited to, histidine, citrate, phosphate, glycine, acetate, and arbitrary combinations or mixtures thereof.

The formulation of the present invention may contain a buffer or a pH adjuster for controlling pH. In one embodiment, the formulation of the present invention has a pH in the range of 4.0 to 9.0, in the range of 5.0 to 9.0, in the range of 5.0 to 8.0, in the range of 5.0 to 7.5, in the range of 5.5 to 7.0, or in the range of 5.5 to 6.5.

Those skilled in the art should understand that the formulation of the present invention can be isotonic to human blood, i.e., the formulation of the present invention has essentially the same osmotic pressure as that of human blood. Such an isotonic formulation generally has an osmotic pressure of 250 mOSm to 350 mOSm. The isotonicity can be measured by use of, for example, a vapor pressure or ice freezing-type osmometer. Examples of the tonicity agent used in the present invention include, but are not limited to, saccharides, salts, and amino acids.

In addition to the excipients mentioned above, typical excipients and processes for the production of the formulation for injection for subcutaneous administration are known in the art. See, for example,

Introduction to Pharmaceutical Dosage Forms, 1985, Ansel, H. C., Lea and Febiger, Philadelphia, Pa.; Remington's Pharmaceutical Sciences, 1995, Mack Publ. Co., Easton, Pa. This literature is incorporated herein by reference in its entirety.

In one embodiment of the present invention, the pharmaceutical composition of the present invention can be any of

a pharmaceutical composition for subcutaneous administration formulated such that,

when 100 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 10 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 2.4×10³μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 3.0×10³μg·h/mL;

a pharmaceutical composition for subcutaneous administration formulated such that

when 200 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 27 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 7.4×10³μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL; and

a pharmaceutical composition for subcutaneous administration formulated such that

when 400 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human,

mean C_maxis a value that falls within the numerical range of 80% to 125% of 43 μg/mL,

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL, or

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 2.7×10⁴μg·h/mL.

In a preferred embodiment of the present invention, the anti-fractalkine antibody is antibody H3-2L4 consisting of a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVKQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTADKSTNTAYMLLSSLRSEDTAVYFCATGPTDGDYFDYWGQGT TVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPP CPAPPAAAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK) and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 12 (DIQMTQSPSSLSASVGDRVTITCRASGNIHNFLAWYQQKPGKAPKLLIYNEKTLAD GVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQFWSTPYTFGGGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC).

4. Dose, Dosing Interval, and the Number of Doses

The pharmaceutical composition of the present invention is administered to a human subject at a dose that brings about therapeutically effective amelioration in rheumatoid arthritis. Thus, the pharmaceutical composition of the present invention is administered such that the serum concentration or the mean trough concentration of the anti-FKN antibody is 5 μg/mL or higher, 10 μg/mL or higher, 15 μg/mL or higher, 20 μg/mL or higher, 25 μg/mL or higher, 30 μg/mL or higher, 35 μg/mL or higher, or 40 μg/mL or higher. Preferably, the pharmaceutical composition of the present invention is administered by multiple administrations such that the mean trough concentration of the anti-FKN antibody is 10 μg/mL or higher or 20 μg/mL or higher.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is used such that at least 100 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human. In one embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg, 200 mg, or 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human. In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 200 mg to 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human. In an alternative preferred embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 200 mg or 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human.

The number of doses and dosing interval of the pharmaceutical composition of the present invention can vary according to the amount of the anti-FKN antibody administered per dose and an administration route, etc.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is used such that at least 100 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two months. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that at least 100 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once a month. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that at least 100 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two weeks. In a particular embodiment of the present invention, the pharmaceutical composition of the present invention is used such that at least 100 mg per dose of the anti-FKN antibody is subcutaneously administered at dosing intervals of every other week after two once-a-week administrations.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two months. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once a month. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two weeks. In a particular embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 400 mg per dose of the anti-FKN antibody is subcutaneously administered at dosing intervals of every other week after two once-a-week administrations.

In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg, 200 mg, or 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two months. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg, 200 mg, or 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once a month. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg, 200 mg, or 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two weeks. In a particular embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg, 200 mg, or 400 mg per dose of the anti-FKN antibody is subcutaneously administered at dosing intervals of every other week after two once-a-week administrations.

In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 200 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two months. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 200 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once a month. In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 200 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two weeks. In a particular embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 100 mg to 200 mg per dose of the anti-FKN antibody is subcutaneously administered at dosing intervals of every other week after two once-a-week administrations.

In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 200 mg to 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two months. In an alternative preferred embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 200 mg to 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once a month. In an alternative preferred embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 200 mg to 400 mg per dose of the anti-FKN antibody is subcutaneously administered by multiple administrations to a human subject in need thereof at dosing intervals of once a week to once every two weeks. In an alternative preferred embodiment of the present invention, the pharmaceutical composition of the present invention is used such that 200 mg to 400 mg per dose of the anti-FKN antibody is subcutaneously administered at dosing intervals of every other week after two once-a-week administrations.

The number of doses of the pharmaceutical composition of the present invention is not particularly limited as long as the pharmaceutical composition of the present invention brings about therapeutically effective amelioration in rheumatoid arthritis. The number of doses of the pharmaceutical composition of the present invention can vary according to the amount of the anti-FKN antibody administered per dose, an administration route, and dosing intervals.

In one embodiment of the present invention, the pharmaceutical composition of the present invention can be subcutaneously administered at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, at least 26 times, at least 27 times or more at dosing intervals of once a week to once every two months.

In an alternative embodiment of the present invention, the pharmaceutical composition of the present invention can be subcutaneously administered at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, at least 26 times, at least 27 times or more at dosing intervals of once a week to once a month.

In a further alternative embodiment of the present invention, the pharmaceutical composition of the present invention can be subcutaneously administered at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, at least 26 times, at least 27 times or more at dosing intervals of once a week to once every two weeks.

In a particular embodiment of the present invention, the pharmaceutical composition of the present invention can be subcutaneously administered at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, at least 26 times, at least 27 times or more at dosing intervals of every other week after two once-a-week administrations.

In a particular embodiment of the present invention, the pharmaceutical composition of the present invention can be subcutaneously administered at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, at least 26 times, at least 27 times or more at dosing intervals of once a week to once every two months such that the mean trough concentration of the anti-FKN antibody is 5 μg/mL or higher, 10 μg/mL or higher, 15 μg/mL or higher, 20 μg/mL or higher, 25 μg/mL or higher, 30 μg/mL or higher, 35 μg/mL or higher, or 40 μg/mL or higher.

In a further alternative embodiment of the present invention, the pharmaceutical composition or the anti-FKN antibody of the present invention can be subcutaneously administered at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, at least 26 times, at least 27 times or more at dosing intervals of once a week to once every two weeks such that the mean trough concentration of the anti-FKN antibody is 5 μg/mL or higher, 10 μg/mL or higher, 15 μg/mL or higher, 20 μg/mL or higher, 25 μg/mL or higher, 30 μg/mL or higher, 35 μg/mL or higher, or 40 μg/mL or higher.

In a further alternative embodiment of the present invention, the pharmaceutical composition or the anti-FKN antibody of the present invention can be subcutaneously administered at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, at least 26 times, at least 27 times or more at dosing intervals of every other week after two once-a-week administrations such that the mean trough concentration of the anti-FKN antibody is 5 μg/mL or higher, 10 μg/mL or higher, 15 μg/mL or higher, 20 μg/mL or higher, 25 μg/mL or higher, 30 μg/mL or higher, 35 μg/mL or higher, or 40 μg/mL or higher.

Hereinafter, particular aspects of the present invention will be illustrated without limitations.

In one aspect, the present invention relates to a pharmaceutical composition for the treatment of rheumatoid arthritis,

the pharmaceutical composition comprising an anti-fractalkine antibody and a pharmaceutically acceptable excipient, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

the pharmaceutical composition is used such that at least 100 mg per dose of the anti-fractalkine antibody is subcutaneously administered to a human.

In an alternative aspect, the present invention relates to a pharmaceutical composition for the treatment of rheumatoid arthritis,

the pharmaceutical composition comprising an anti-fractalkine antibody and a pharmaceutically acceptable excipient, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

the pharmaceutical composition is used such that 100 mg to 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered by multiple administrations to a human.

In an alternative aspect, the present invention relates to a pharmaceutical composition for the treatment of rheumatoid arthritis,

the pharmaceutical composition comprising an anti-fractalkine antibody and a pharmaceutically acceptable excipient, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

the pharmaceutical composition is used such that 100 mg to 200 mg per dose of the anti-fractalkine antibody is subcutaneously administered by multiple administrations to a human.

In a further alternative aspect, the present invention relates to a pharmaceutical composition for the treatment of rheumatoid arthritis,

the pharmaceutical composition comprising an anti-fractalkine antibody and a pharmaceutically acceptable excipient, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region contains V234A and G237A mutations, and the pharmaceutical composition is used such that 200 mg to 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered by multiple administrations to a human.

In a further alternative aspect, the present invention relates to a pharmaceutical composition for the treatment of rheumatoid arthritis,

the pharmaceutical composition comprising an anti-fractalkine antibody and a pharmaceutically acceptable excipient, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

the pharmaceutical composition is used such that 100 mg, 200 mg, or 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered by multiple administrations to a human.

The pharmaceutical composition of the present invention is subcutaneously administered by multiple administrations at dosing intervals of once a week to once every two weeks to a human in such a manner that a mean trough concentration of 10 μg/mL or higher of the anti-FKN antibody is achieved. In a preferred embodiment, the pharmaceutical composition of the present invention is subcutaneously administered by multiple administrations at dosing intervals of once a week to once every two weeks to a human in such a manner that a mean trough concentration of 15 μg/mL or higher of the anti-FKN antibody is achieved. In a more preferred embodiment, the pharmaceutical composition of the present invention is subcutaneously administered by multiple administrations at dosing intervals of once a week to once every two weeks to a human in such a manner that a mean trough concentration of 20 μg/mL or higher of the anti-FKN antibody is achieved.

In a preferred embodiment, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration formulated such that when 100 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human, any one, two, or three of the following pharmacokinetic parameters are brought about:

mean C_maxis a value that falls within the numerical range of 80% to 125% of 10 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 2.4×10³μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 3.0×10³μg·h/mL.

In an alternative preferred embodiment, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration formulated such that when 200 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human, any one, two, or three of the following pharmacokinetic parameters are brought about:

mean C_maxis a value that falls within the numerical range of 80% to 125% of 27 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 7.4×10³μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL.

In a further alternative preferred embodiment, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration formulated such that when 400 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human, any one, two, or three of the following pharmacokinetic parameters are brought about:

mean C_maxis a value that falls within the numerical range of 80% to 125% of 43 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 2.7×10⁴μg·h/mL.

In an alternative aspect, the present invention relates to a pharmaceutical composition for use in a method for treating rheumatoid arthritis,

the treatment method comprising subcutaneously administering a therapeutically effective amount of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

the therapeutically effective amount is, when the pharmaceutical composition comprising the anti-fractalkine antibody is subcutaneously administered by a single administration, a dose that brings about any one, two, or three of the following pharmacokinetic parameters:

mean C_maxis a value that falls within the numerical range of 80% to 125% of 10 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 2.4×10³μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 3.0×10³μg·h/mL.

In an alternative aspect, the present invention relates to a pharmaceutical composition for use in a method for treating rheumatoid arthritis,

the treatment method comprising subcutaneously administering a therapeutically effective amount of an anti-fractalkine antibody to a human in need thereof,

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

mean C_maxis a value that falls within the numerical range of 80% to 125% of 27 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 7.4×10³μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL.

In an alternative aspect, the present invention relates to a pharmaceutical composition for use in a method for treating rheumatoid arthritis,

the treatment method comprising subcutaneously administering a therapeutically effective amount of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

mean C_maxis a value that falls within the numerical range of 80% to 125% of 43 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 2.7×10⁴μg·h/mL.

In a preferred embodiment, the anti-fractalkine antibody is antibody H3-2L4 consisting of a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 (QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVKQAPGQGLEWIGWIYPGDG SPKFNERFKGRTTLTADKSTNTAYMLLSSLRSEDTAVYFCATGPTDGDYFDYWGQGT TVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPP CPAPPAAAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK) and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 12 (DIQMTQSPSSLSASVGDRVTITCRASGNIHNFLAWYQQKPGKAPKLLIYNEKTLAD GVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQFWSTPYTFGGGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC).

In a preferred embodiment, the pharmaceutical composition is a pharmaceutical composition comprising 100 mg, 200 mg, or 400 mg of the anti-fractalkine antibody.

In a preferred embodiment, the pharmaceutical composition is a pharmaceutical composition that is used such that 100 mg, 200 mg, or 400 mg per dose of the anti-fractalkine antibody is subcutaneously administered.

In a preferred embodiment, the pharmaceutical composition is a pharmaceutical composition that is subcutaneously administered by multiple administrations at dosing intervals of once a week to once every two weeks to a human.

In a preferred embodiment, the pharmaceutical composition is a pharmaceutical composition that is subcutaneously administered such that the mean trough concentration of the anti-fractalkine antibody is 10 μg/mL or higher.

In an alternative aspect, the present invention relates to a therapeutic agent for rheumatoid arthritis, comprising an anti-fractalkine antibody, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In one embodiment, the present invention relates to a therapeutic agent for rheumatoid arthritis, comprising an anti-fractalkine antibody, wherein

the therapeutic agent for rheumatoid arthritis is used such that 100 mg to 200 mg of the anti-fractalkine antibody is subcutaneously administered at dosing intervals of once a week to once every two weeks to a human, and

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In one embodiment, the present invention relates to a therapeutic agent for rheumatoid arthritis, comprising an anti-fractalkine antibody, wherein

the therapeutic agent for rheumatoid arthritis is used such that 200 mg to 400 mg of the anti-fractalkine antibody is subcutaneously administered at dosing intervals of once a week to once every two weeks to a human, and

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In one embodiment, the present invention relates to a therapeutic agent for rheumatoid arthritis, comprising an anti-fractalkine antibody, wherein

the therapeutic agent for rheumatoid arthritis is used such that 100 mg, 200 mg, or 400 mg of the anti-fractalkine antibody is subcutaneously administered at dosing intervals of once a week to once every two weeks to a human, and

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In one embodiment, the present invention relates to the pharmaceutical composition comprising the anti-fractalkine antibody, wherein the pharmaceutical composition is subcutaneously administered such that the mean serum total FKN concentration at the steady state is 60 μg/mL or higher, 70 μg/mL or higher, 80 μg/mL or higher, 90 μg/mL or higher, 100 μg/mL or higher, 110 μg/mL or higher, 120 μg/mL or higher, 130 μg/mL or higher, 140 μg/mL or higher, 150 μg/mL or higher, or 160 μg/mL or higher.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration, wherein when 100 mg of the anti-fractalkine antibody is administered by multiple administrations to a human, the mean serum total FKN concentration at the steady state is 70 μg/mL to 100 μg/mL.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration, wherein when the pharmaceutical composition is used such that 100 mg of the anti-fractalkine antibody is subcutaneously administered at dosing intervals of once a week to once every two weeks to a human, the mean serum total FKN concentration at the steady state is 70 μg/mL to 100 μg/mL.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration, wherein when 200 mg of the anti-fractalkine antibody is administered by multiple administrations to a human, the mean serum total FKN concentration at the steady state is 160 μg/mL to 190 μg/mL.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration, wherein when the pharmaceutical composition is used such that 200 mg of the anti-fractalkine antibody is subcutaneously administered at dosing intervals of once a week to once every two weeks to a human, the mean serum total FKN concentration at the steady state is 160 μg/mL to 190 μg/mL.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration, wherein when 400 mg of the anti-fractalkine antibody is administered by multiple administrations to a human, the mean serum total FKN concentration at the steady state is 380 μg/mL to 480 μg/mL.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is a pharmaceutical composition for subcutaneous administration, wherein when the pharmaceutical composition is used such that 400 mg of the anti-fractalkine antibody is subcutaneously administered at dosing intervals of once a week to once every two weeks to a human, the mean serum total FKN concentration at the steady state is 380 μg/mL to 480 μg/mL.

In an alternative aspect, the present invention relates to a method for treating rheumatoid arthritis, the method comprising subcutaneously administering at least 100 mg per dose of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In one embodiment, the present invention relates to a method for treating rheumatoid arthritis,

the method comprising subcutaneously administering 100 to 400 mg per dose of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In one embodiment, the present invention relates to a method for treating rheumatoid arthritis,

the method comprising subcutaneously administering 100 to 200 mg per dose of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In one embodiment, the present invention relates to a method for treating rheumatoid arthritis,

the method comprising subcutaneously administering 200 to 400 mg per dose of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In one embodiment, the present invention relates to a method for treating rheumatoid arthritis,

the method comprising subcutaneously administering 100 mg, 200 mg, or 400 mg per dose of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations.

In the treatment method of the present invention, the anti-fractalkine antibody is subcutaneously administered by multiple administrations at dosing intervals of once a week to once every two weeks to a human in such a manner that a mean trough concentration of 10 μg/mL or higher of the anti-fractalkine antibody is achieved. In a preferred embodiment, the anti-fractalkine antibody in the treatment method of the present invention is subcutaneously administered by multiple administrations at dosing intervals of once a week to once every two weeks to a human in such a manner that a mean trough concentration of 15 μg/mL or higher of the anti-fractalkine antibody is achieved. In a more preferred embodiment, the anti-fractalkine antibody in the treatment method of the present invention is subcutaneously administered by multiple administrations at dosing intervals of once a week to once every two weeks to a human in such a manner that a mean trough concentration of 20 μg/mL or higher of the anti-fractalkine antibody is achieved.

In a preferred embodiment, the anti-fractalkine antibody is administered by a pharmaceutical composition for subcutaneous administration formulated such that when 100 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human, any one, two, or three of the following pharmacokinetic parameters are brought about:

mean C_maxis a value that falls within the numerical range of 80% to 125% of 10 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 2.4×10³μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 3.0×10³μg·h/mL.

In an alternative preferred embodiment, the anti-fractalkine antibody is administered by a pharmaceutical composition for subcutaneous administration formulated such that when 200 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human, any one, two, or three of the following pharmacokinetic parameters are brought about:

mean C_maxis a value that falls within the numerical range of 80% to 125% of 27 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 7.4×10³μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL.

In a further alternative preferred embodiment, the anti-fractalkine antibody is administered by a pharmaceutical composition for subcutaneous administration formulated such that when 400 mg of the anti-fractalkine antibody is subcutaneously administered by a single administration to a human, any one, two, or three of the following pharmacokinetic parameters are brought about:

mean C_maxis a value that falls within the numerical range of 80% to 125% of 43 μg/mL;

mean AUC_{(0-336 h)}is a value that falls within the numerical range of 80% to 125% of 1.2×10⁴μg·h/mL; and

mean AUC_(0-t)is a value that falls within the numerical range of 80% to 125% of 2.7×10⁴μg·h/mL.

In an alternative aspect, the present invention relates to a method for treating rheumatoid arthritis,

the treatment method comprising subcutaneously administering a therapeutically effective amount of an anti-fractalkine antibody to a human in need thereof, wherein

the anti-fractalkine antibody is an antibody wherein:

the antibody comprises a constant region of human IgG2 isotype; and

a Fc region of the constant region of human IgG2 isotype contains V234A and G237A mutations, and

when a pharmaceutical composition comprising the anti-fractalkine antibody is subcutaneously administered by a single administration,

the therapeutically effective amount is a dose that brings about any one, two, or three of the following pharmacokinetic parameters: