NZ744721A - Treatment for rheumatoid arthritis - Google Patents

Abstract

The present invention provides an anti-GM-CSF antibody for use in the treatment of a patient suffering from rheumatoid arthritis, comprising administering to said patient an anti-anti‐GSM‐CSF antibody intravenously  weekly at a dose of about 1.0 mg/Kg, or at a subcutaneous dose which achieves a blood  concentration equal to that dose.

Description

TREATMENT FOR RHEUMATOID ARTHRITIS This application is a divisional ation of New Zealand application no. 705635 (which is the national phase entry of 2013/0069501, published as WO2014/044768) dated 19 September 2013, and claims the benefit of and priority to EP 12185235.4 filed 20 September 2012 and U.S. Provisional Application No. 61/703,871, filed 21 September 2012, which are hereby incorporated by reference in their entirety.

SUMMARY OF THE INVENTION The invention the subject of the t invention particularly is set out in the following clauses: 1. The use of a pharmaceutical composition comprising an M‐CSF antibody , in the manufacture of a medicament, for the treatment of a patient ing from rheumatoid arthritis, the treatment comprising administering the anti‐GM‐CSF antibody enously weekly at a dose of 1.0 mg/Kg, or at a aneous dose which achieves a blood concentration equal to that dose, wherein the anti‐GM‐CSF antibody comprises a variable heavy chain of the sequence: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGATYYAASVKGR FTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS (SEQ ID NO.: 8) and a variable light chain of the sequence: DIELTQPPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGSNSGNTATLTISG TQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ (SEQ ID NO.: 9). 2. The use of 1, wherein the pharmaceutical composition comprises pharmaceutically acceptable carriers, ents or stabilizers which are a buffer which is histidine, a sugar which is sorbitol and a non‐ionic surfactant which is polysorbate‐80. 3. The use of 2 wherein the composition ts of 30mM histidine, pH 6.0, 200mM sorbitol and 0.02% polysorbate‐80 as carriers, excipients or stabilizers. 4. The use of any one of 1 to 3, wherein the subcutaneous dose is at least about 2mg/kg, about 3.0mg/kg or about 4.0 mg/kg.

. The use of any one of 1 to 3, wherein the subcutaneous dose is a fixed dose of between about 40 mg and 400 mg. 6. The use according to 5 wherein the fixed dose is 150 mg. 7. The use of any one of 1 to 6, wherein the subcutaneous dose is administered weekly, biweekly, monthly or bimonthly. 8. The use according to any one of 1 to 7, wherein the treatment comprises administering the antibody to said patient in a manner to achieve to a serum concentration of said antibody of at least 2 µg/ml in said patient over the on of said treatment. (followed by page 2A) 9. The use according to any one of 1 to 8 wherein the treatment achieves a mean change in ACR20 score of at least 30.4 over four weeks of ent.

. The use according to 9 n the treatment es a mean change in ACR20 score of at least 68.2 over four weeks of treatment. 11. The use according to any one of 1 to 8, wherein the treatment achieves a mean change in ACR score of at least 26.1 over eight weeks of treatment. 12. The use according to 11, wherein the ent achieves a mean change in ACR 20 score of at least 31.8 over eight weeks of treatment. 13. The use ing to any one of 1 to 12, wherein the treatment comprises administering said antibody in combination with a disease‐modifying anti‐rheumatic drug (DMARD). 14. The use according to 13, wherein the DMARD is methotrexate.

. A use according to 1, substantially as herein described and exemplified.

The present invention is further described below. In certain aspects the invention is described in broader terms which are nevertheless included herein for completeness. (followed by page 2B) wed by page 3) to the enous administration of said antibody at a dose of at least 1.0 mg/kg when administered weekly over at least four weeks.

In another aspect, the present invention provides an anti-GM-CSF antibody, wherein said anti-GM-CSF antibody is an antibody comprising an HCDR1 region of ce GFTFSSYWMN (SEQ ID NO.: 2), an HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), an HCDR3 region of sequence GFGTDF (SEQ ID NO.: 4), an LCDR1 region of sequence SGDSIGKKYAY (SEQ ID NO.: 5), an LCDR2 region of sequence KKRPS (SEQ ID NO.: 6), and an LCDR3 region of sequence GM (SEQ ID NO.: 7) for use in the treatment of a patient suffering from toid arthritis, wherein said antibody is administered intravenously at a dose of about 1.0 mg/kg or at a dose of about 1.5 mg/kg and wherein said antibody in administered weekly over at least four weeks.

In another aspect, the present invention es an anti-GM-CSF antibody for use in the treatment of a patient suffering from rheumatoid arthritis, wherein said antibody is administered to said patient in a manner to achieve a therapeutically effective antibody level in the blood of said patient equal or higher compared to the enous administration of said antibody at a dose of at least 1.0 mg/kg or at least 1.5mg/kg when administered weekly over at least four weeks, and wherein said anti-GM-CSF antibody is administered in combination with a DMARD, such as rexate.

In an embodiment, the administration of said antibody to achieve such a therapeutically effective amount comprises the administration of said antibody intravenously at a dose at least 0.6, at least 0.7, at least 0.8, at least 0.9 or at least 1.0 mg/kg. In other embodiments, the antibody of the present invention is administered intravenously at a dose of about 1.0 mg/kg or a dose of about 1.5 mg/kg. Administration may be monthly, biweekly (every two weeks) or .

In another aspect, the t invention provides an anti-GM-CSF antibody for use in the treatment of a t suffering from rheumatoid arthritis, wherein said antibody is administered to said patient subcutaneously in a manner to achieve a therapeutically effective antibody level in the blood of said patient equal or higher compared to the intravenous administration of said antibody at a dose of at least 1.0 mg/kg or at least 1.5mg/kg when administered weekly over at least four weeks, and n said anti-GM- CSF antibody is administered in combination with a DMARD, such as methotrexate.

In an embodiment, the administration of said antibody to achieve such a therapeutically effective amount comprises the administration of said antibody subcutaneously at a dose of at least 1.0, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 3.5 or at least 4.0 mg/kg. In other ments, the antibody of the present ion is administered subcutaneously at a dose of about 2.0 mg/kg, a dose of about 3.0 mg/kg or a dose of about 4.0 mg/kg. Administration may be monthly, biweekly (every two weeks) or .

In an embodiment, the administration of said antibody to achieve such a therapeutically effective amount ses the administration of said antibody subcutaneously at a fixed dose of about 40 mg, at a fixed dose of 75 mg, at a fixed dose of 100 mg, at a fixed dose of 140 mg, at a fixed dose of 150 mg, at a fixed dose of 180 mg, at a fixed dose of 200 mg, at a fixed dose of 280 mg, at a fixed dose of 300 mg or at a fixed dose of 400 mg.. Administration of fixed doses may be every week, every second week, every third week, every fourth week or every sixth week.

In another aspect, the present ion provides a method of treating a patient suffering from rheumatoid arthritis, said method comprising administering to said patient an anti-GM- CSF antibody subcutaneously at (i) a dose of at least 1.0 mglkg, or (ii) a fixed dose of between 40 mg and 400 mg.

The anti-GM-CSF antibody may be administered to said patient in a manner to achieve to a serum concentration of said antibody at at least 2 pg/ml in said patient over the duration of said treatment. The antibody may be administered to said patient in a manner to achieve a therapeutically effective antibody level in the blood of said patient equal or higher compared to the intravenous administration of said antibody at a dose of at least 1.0 mg/kg when administered weekly over at least four weeks.

In another aspect, the present invention provides an anti-GM-CSF dy for ting progression of structural joint damage in a rheumatoid arthritis patient sing administering to said patient said antibody in a manner to achieve a therapeutically effective antibody level in the blood of said patient equal or higher compared to the intravenous administration of said dy at a dose of at least 1.0 mg/kg when administered weekly over at least four weeks.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the amino acid sequence and the DNA sequence of MORO4357.

Figure 2 shows the mean changes of the DA828 score after four weeks (left panel) and after eight weeks (right panel) of treatment ed. DA828 score changes are compared to ne levels, i.e. disease status prior to treatment.

Figure 3 shows the average ACR20 score of all treatment arms after four weeks. An increase of the ACR20 scores ponds to an improvement of the severity of disease.

Figure 4 shows the average ACR20 score of all ent arms after eight weeks. An increase of the ACR20 scores corresponds to an improvement of the severity of disease.

DESCRIPTION The terms “GM-CSF” and “GMCSF” refer to the protein known as GM-CSF or Granulocyte-macrophage colony-stimulating factor, having the following synonyms: Colonystimulating factor 2, CSF2, GMCSF, GM-CSF, ocyte—macrophage colony-stimulating factor, MGC131935, MGC138897, Molgramostin, Sargramostim. Human GM—CSF has the amino acid ce of (UniProt ): MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNET VEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETS CATQIITFESFKENLKDFLLVIPFDCWEPVQE (SEQ ID NO.: 1) 3” is an anti-GM-CSF dy whose amino acid sequence and DNA sequence is provided in Figure 1. “MOR103” and “MOR04357” and “MOR4357” are used as synonyms to describe the antibody shown in Figure 1. 57 comprises an HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO.: 2), an HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), an HCDR3 region of sequence GFGTDF (SEQ ID NO.: 4), an LCDR1 region of ce SGDSIGKKYAY (SEQ ID NO.: 5), an LCDR2 region of sequence KKRPS (SEQ ID NO.: 6), and an LCDR3 region of sequence SAWGDKGM (SEQ ID NO.: 7). MOR04357 comprises a variable heavy chain of the sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGA TYYAASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS (SEQ ID NO.: 8) and a variable light chain of the sequence PPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGS NSGNTATLTISGTQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ (SEQ ID NO.: 9).

In certain embodiments, the antibody used in the present invention is an antibody specific for GM-CSF. In other embodiments, the antibody used in the present invention is an antibody specific for a polypeptide encoding an amino acid sequence comprising SEQ ID NO.: 1.

As used herein, "specifically for" or "specifically binding to" refers to an antibody selectively or preferentially binding to GM—CSF. Preferably the binding affinity for antigen is of Kd value of 10'9 moI/I or lower (e.g. 10'10 mol/I), preferably with a Kd value of 10'10 moI/I or lower (e.g. 10'12 moI/I). The binding affinity is ined with a standard binding assay, such as surface plasmon resonance technique (BIACORE®).

In certain embodiments, the antibody used in the present invention is . In other embodiments, the antibody used in the present invention is an antibody comprising an HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO.: 2), an HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), an HCDR3 region of sequence GFGTDF (SEQ ID NO.: 4), an LCDR1 region of sequence SGDSIGKKYAY (SEQ ID NO.: 5), an LCDR2 region of sequence KKRPS (SEQ ID NO.: 6), and an LCDR3 region of sequence SAWGDKGM (SEQ ID NO.: 7). In other embodiments, the antibody used in the present invention is an antibody comprising a variable heavy chain of the sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGA TYYAASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS (SEQ ID NO.: 8) and a variable light chain of the sequence DIELTQPPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGS NSGNTATLTISGTQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ (SEQ ID NO.: 9). In other ments, the antibody used in the present invention is an antibody which cross- competes with an antibody comprising an HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO.: 2), an HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), an HCDR3 region of sequence GFGTDF (SEQ ID NO.: 4), an LCDR1 region of ce SGDSIGKKYAY (SEQ ID NO.: 5), an LCDR2 region of sequence KKRPS (SEQ ID NO.: 6), and an LCDR3 region of sequence SAWGDKGM (SEQ ID NO.: 7). In other embodiments, the antibody used in the present invention is an antibody which binds to the same epitope like an dy specific for GM-CSF comprising an HCDR1 region of sequence YWMN (SEQ ID NO.: 2), an HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), an HCDR3 region of sequence GFGTDF (SEQ ID NO.: 4), an LCDR1 region of sequence SGDSIGKKYAY (SEQ ID NO.: 5), an LCDR2 region of sequence KKRPS (SEQ ID NO.: 6), and an LCDR3 region of sequence SAWGDKGM (SEQ ID NO.: 7).

The term "antibody" is used in the broadest sense and specifically covers onal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact dies, and antibody fragments so long as they exhibit the desired biological activity.

"Antibody fragments" herein se a portion of an intact antibody which retains the ability to bind antigen. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear dies; single—chain antibody molecules; and multispecific antibodies formed from antibody fragments.

The term "monoclonal dy" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts. In contrast to polyclonal antibody ations that typically include different antibodies ed against different determinants pes), each monoclonal antibody is directed against a single determinant on the antigen. In on to their icity, the monoclonal antibodies are advantageous in that they are aminated by other immunoglobulins.

The monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a n of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies d from another species or belonging to another antibody class or ss, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

"Humanized" forms of non-human (e.g., murine) antibodies are ic dies that contain minimal sequence derived from non—human immunoglobulin. For the most part, zed antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman e having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human globulin are replaced by corresponding non- human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These cations are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non- human immunoglobulin and all or ntially all of the FRs are those of a human immunoglobulin sequence, except for FR substitution(s) as noted above. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region, typically that of a human globulin.

A "human antibody" herein is one comprising an amino acid sequence structure that corresponds with the amino acid sequence structure of an antibody obtainable from a human B- cell, and includes n—binding fragments of human antibodies. Such antibodies can be identified or made by a variety of techniques, including, but not limited to: production by transgenic animals (e.g., mice) that are capable, upon immunization, of producing human antibodies in the absence of endogenous immunoglobulin; selection from phage display libraries expressing human antibodies or human antibody; generation via in vitro activated B; and isolation from human antibody producing hybridomas.

In certain embodiments, the antibody used in the present invention is a monoclonal antibody.

In other embodiments, the antibody used in the present invention is a chimeric, a humanized or a human antibody. In preferred embodiments, the antibody used in the present invention is a human antibody.

In certain embodiments, the antibody used in the present invention is administered in combination with an additional drug that treats RA.

The additional drug may be one or more medicaments, and include, for e, immunosuppressive agents, non—steroidal anti—inflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs s) such as methotrexate (MTX), -cell surface marker antibodies, such as anti—CD20 antibodies (e.g. rituximab), TNF-alpha-inhibitors, osteroids, and mulatory modifiers, or any ation thereof. Optionally, the second or additional drug is selected from the group consisting of non- biological , , and corticosteroids.

These additional drugs are generally used in the same dosages and with administration routes as used hereinbefore and hereinafter. If such additional drugs are used at all, preferably, they are used in lower s than if the first medicament were not present, especially in subsequent dosings beyond the initial dosing with the first medicament, so as to eliminate or reduce side effects caused thereby. The combined administration of an additional drug includes inistration (concurrent administration), using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents (medicaments) simultaneously exert their biological ties.

The term “DMARD” refers to Disease-Modifying Anti-Rheumatic Qrugs" and includes among others hydroxycloroquine, sulfasalazine, methotrexate, leflunomide, azathioprine, D- llamine, gold salts (oral), gold salts (intramuscular), minocycline, cyclosporine including cyclosporine A and topical cyclosporine, and TNF-inhibitors, including salts, variants, and derivatives thereof. Exemplary DMARDs herein are non-biological, i.e. classic, DMARDs, including, azathioprine, quine, hydroxychloroquine, leflunomide, methotrexate and sulfasalazine.

Methotrexate is an especially preferred DMARD of the t invention. Therefore, in certain embodiments, the antibody used in the t invention is administered in combination with a DMARD. In other embodiments, the antibody used in the present invention is administered in combination with rexate.

A "TNF-inhibitor" as used herein refers to an agent that inhibits, to some extent, a biological function of TNF-alpha, generally through binding to pha and/or its receptor and lizing its activity. Examples of TNF inhibitors include cept (ENBREL®), infliximab ADE®), adalimumab (HUMIRA®), certolizumab pegol (CIMZIA®), and golimumab (SIMPON|®).

"Treatment" of a patient or a subject refers to both therapeutic treatment and prophylactic or preventative measures. The terms "effective amount" or “therapeutically effective” refer to an amount of the dy that is effective for treating rheumatoid arthritis. Such effective amount can result in any one or more of reducing the signs or symptoms of RA (e.g. achieving ACRZO), reducing disease activity (e.g. Disease Activity Score, DASZO), slowing the progression of structural joint damage or improving physical function. In one embodiment, such clinical response is comparable to that achieved with intravenously administered anti-GM-CSF antibody.

The antibody of the present ion may be administered in different suitable forms.

Potential forms of administration include systemic administration (subcutaneous, intravenous, intramuscular), oral administration, inhalation, transdermal administration, topical application (such as topical cream or ointment, etc.) or by other methods known in the art. The doses (in mg/kg) ied in the present ion refer to milligrams of antibody per kilogram of body weight of the patient. In vitro cell based assays showed that an anti-GM- CSF antibody (MOR103) is e of inhibiting several GM-CSF ed responses.

Evaluated responses include TF—1 cell proliferation, STAT5 phosphorylation, polymorphonuclear neutrophils (PMN) migration, PMN up-regulation of CD11b, monocyte up-regulation of MHC II, and eosinophil suwival. te inhibitory effects were generally reached at concentrations of about 0.2 ug/ml anti-GM-CSF antibody. GM-CSF concentrations up to 1 ng/ml were applied in such studies. As a reference, GM-CSF levels in the synovial fluid of RA patients were ed to be <500 pg/ml. It is reasonable to consider that similar GM-CSF concentrations as used in these in vitro studies are present in affected tissues of RA patients To effectively treat RA it may be important for an anti—GM-CSF antibody to penetrate the synovium. There is ce to suggest that monoclonal antibodies can distribute into the synovium when dosed subcutaneously or intravenously. Based on a predicted penetration rate of 30%, uous GM-CSF tion and considering patient heterogeneity, the minimal or sub-optimal clinical effect level in RA patients is anticipated to be at a serum tration of approximately 2 ug/ml antibody (thus, approximately d higher than the inhibitory concentration derived from in vitro studies).

A specific M-CSF antibody (MOR103) has been administered to patients with active rheumatoid arthritis who received 4 intravenous weekly doses of 0.3, 1, and 1.5 mg/kg. The anti-GM-CSF antibody showed significant clinical efficacy on DA828, EULAR, ACR20, ACR50, ACR70 and tender joint counts following once a week dosing with 1 and 1.5 mg/kg as compared to placebo.

In certain embodiments, the antibody of the present invention is administered intravenously. In other embodiments, the antibody of the present invention is administered subcutaneously.

From other therapeutic antibodies it is known that a concentration that leads to a certain level of the antibody in the blood when administered intravenously corresponds to about 50- 76% of the blood concentration achieved when the same antibody concentration is administered subcutaneously (Meibohm, B.: Pharmacokinetics and Pharmacodynamics of Biotech Drugs, Wiley-VCH, 2006). For MOR103 this ratio was determined to be 52%, Le. a given concentration administered subcutaneously leads to a blood concentration which is equivalent to about 52% of the blood concentration when the same given concentration is administered intravenously. Therefore, the concentration of a subcutaneous formulation needs to be about twice as high to achieve the same drug blood level as compared to an intravenous formulation.

In n embodiments the blood level to be achieved in a patient is equal or higher ed to the blood concentration achieved with intravenous administration of the antibody of the t invention at a dose of at least 1.0 mg/kg when administered weekly over at least four weeks.

In alternative embodiments said blood tration to be ed is equal or higher compared to the blood concentration achieved with intravenous administration of the antibody of the present invention at a doses of at least 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9 mg/kg when stered weekly over at least four weeks. In alternative embodiments the blood level to be achieved in a patient is equal or higher compared to the blood concentration ed with intravenous stration of the antibody of the present invention at a dose of at least 1.0 mg/kg when stered weekly over at least two weeks or at least three weeks.

In alternative embodiments the blood level to be achieved in a patient is equal or higher compared to the blood concentration achieved with intravenous administration of the antibody of the present invention at a dose of at least 1.0 mg/kg when administered biweekly over at least two weeks or at least four weeks.

In certain embodiments, the antibody of the t invention is administered intravenously. In other embodiments, the dy of the present invention is administered intravenously at a dose at least 0.6, at least 0.7, at least 0.8, at least 0.9 or at least 1.0 mg/kg. In other embodiments, the antibody of the present invention is administered intravenously at a dose of about 1.0 mg/kg or a dose of about 1.5 mg/kg.

In certain embodiments, the antibody of the t invention is administered subcutaneously. s dosing regimen have been simulated using the subcutaneous delivery of MOR103 in order to produce plasma concentrations that are similar those obtained after 1 mg/kg iv, a dose that was efficacious in RA. The majority of simulations produce trough concentration values greater than 2 ug/mL, a value that is believed to be the m blood concentration that is ed to produce efficacy in the context of an anti- GM-CSF antibody. These studies indicate that subcutaneous doses of 1, 2, 3 and 4 mg/kg can produce plasma concentration similar to 1 mg/kg, lV ing on the dosing frequency.

In other embodiments, the antibody of the present invention is administered subcutaneously at a dose at least 1.0, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 3.5 or at least 4.0 mg/kg. In other embodiments, the antibody of the present invention is administered aneously at a dose of about 2.0 mg/kg, a dose of about 3.0 mg/kg or a dose of about 4.0 mg/kg. In certain embodiments, the antibody of the present invention is subcutaneously administered biweekly, monthly or hly.

In other embodiments, the antibody of the present invention is administered subcutaneously at a fixed dose. In such “fixed dose” treatment the antibody is administered at a certain, fixed, concentration, i.e. without taking into t a patient’s body weight. In certain embodiments, the antibody of the present invention is administered at a fixed dose of between 40 mg and 400 mg, optionally at a fixed dose of 75 mg, at a fixed dose of 100 mg, at a fixed dose of 140 mg, at a fixed dose of 150 mg, at a fixed dose of 180 mg, at a fixed dose of 200 mg, at a fixed dose of 280 mg, at a fixed dose of 300 mg or at a fixed dose of 400 mg. stration of fixed doses may be every week, every second week, every third week, every fourth week or every sixth week. Typically, the antibody will be administered weekly at a fixed dose.

In an embodiment, the antibody will be administered weekly, at a fixed subcutaneous dose of 40, 56, 70, 75 100, 140, 150, 180, 200, 210, or 280 mg.

In an embodiment, the antibody will be administered biweekly, at a fixed subcutaneous dose of 70, 75, 100, 140, 150, 180, 200, 210, 280 or 300 mg.

In an embodiment, the antibody will be administered monthly, at a fixed subcutaneous dose of 100, 140, 150, 180, 200, 210, 280, 300, 320, 350. 360 or 400 mg.

In an embodiment, the antibody is administered in a dose sufficient to maintain trough concentration of antibody of at least 2 ug/mL. The trough concentration of dy may be maintained at 2.0 ug/mL, 2.5 ug/mL, 3.0 ug/mL, 3.5 ug/mL, 4.0 ug/mL, 4.5 ug/mL or 5.0 ug/mL, during the course of therapy.

In alternative embodiments, the antibody will be administered weekly, at a fixed subcutaneous dose of 28 or 35 mg, In certain embodiments, the present invention provides an anti-GM-CSF antibody for use in the treatment of a patient ing from rheumatoid arthritis, n said antibody is administered to said patient in a manner to achieve a therapeutically ive antibody level in the blood of said patient equal or higher compared to the intravenous administration of said antibody at a dose of at least 1.0 mgikg when administered weekly over at least four weeks.

In certain ments, the present invention provides a method to treat a patient suffering from rheumatoid arthritis, said method comprising administering to said patient an anti-GM-CSF antibody in a manner to achieve a therapeutically effective antibody level in the blood of said patient equal or higher compared to the intravenous administration of said antibody at a dose of at least 1.0 mg/kg when administered weekly over at least four weeks.

In certain ments, the t invention provides an anti-GM-CSF antibody for inhibiting progression of structural joint damage in a rheumatoid arthritis patient comprising administering to said patient said antibody in a manner to achieve a therapeutically effective antibody level in the blood of said patient equal or higher compared to the enous administration of said dy at a dose of at least 1.0 mg/kg when administered weekly over at least four weeks.

The terms “drug” and “medicament" refer to an active drug to treat rheumatoid arthritis or joint damage or symptoms or side effects associated with RA. The term "pharmaceutical formulation" refers to a preparation which is in such form as to permit the ical activity of the active ingredient or ingredients, i.e. the antibody of the present invention, to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such ations are sterile.

The antibody herein is preferably inantly produced in a host cell transformed with nucleic acid sequences encoding its heavy and light chains (e.g. where the host cell has been transformed by one or more vectors with the nucleic acid therein). The preferred host cell is a ian cell, most preferably a PER.CB cell.

Therapeutic formulations of the antibody of the present invention are prepared for storage by mixing the antibody having the desired degree of purity with al pharmaceutically acceptable carriers, excipients or stabilizers in the form of lyophilized formulations or aqueous solutions. able carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and trations employed, and include buffers such as phosphate, citrate, histidine and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, honium chloride; , butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, ol, trehalose or sorbitol; orming counter—ions such as sodium; metal complexes {e.g. Zn- protein complexes); and/or non—ionic tants such as TWEENTM (such as Tween-80), PLURONICST'V' or polyethylene glycol (PEG).

In certain embodiments, the present invention provides a ceutical composition comprising an antibody of the present invention and a pharmaceutically able carrier and/or excipient for use in any of the methods provided in the present invention. In certain embodiments, the formulation for the antibody of the present invention consists of 30 mM histidine, pH 6.0, 200 mM sorbitol and 0.02% Tween-80. In other ments, the formulation for the antibody of the present invention consists of PBS, pH 6.2 (0.2 g/l KCI, 0.96 g/l KH2PO4, 0.66 g/l Na2HPO4 x 7H20, 8 g/l NaCl).

EXAMPLES Example 1: Design and concept of a clinical Phase lb/Phase Ila trial A multi-center, randomized, —blinded, o—controlled study to evaluate the safety, preliminary clinical ty and immunogenicity of multiple doses of MOR103 administered intravenously to patients with active rheumatoid arthritis was conducted.

Primary outcome measures were the adverse event rate and the safety profile. ary outcome measures included DA828 scores, ACR scores and EULAR28 response criteria.

The clinical trial comprised three treatment arms. In each treatment arm patient received either placebo or MOR103. The MOR103 doses were 0.3 mg/kg body weight for treatment arm 1, 1.0 mg/kg body weight for treatment arm 2 and 1.5 mg/kg body weight for treatment arm 3. MOR103 and placebo were administered intravenously, weekly with 4 doses in total.

Summary of the treatment arms: Experimental: Group 1: Drug: MOR103 MOR103, experimental MOR103 0.3 mg/kg or o iv x 4 doses ical: MOR103 0.3 mg/kg or o Experimental: Group 2: Drug: MOR103 MOR103, experimental MOR103 1.0 mg/kg or placebo iv x 4 doses Biological: MOR103 1.0 mg/kg or placebo Experimental: Group 3: Drug: MOR103 MOR103, experimental MOR103 1.5 mg/kg or placebo iv x 4 doses Biological: MOR103 1.5 mg/kg or placebo Eligible for participation in the study were patients of 18 years and older and of either sex (male and female). Healthy volunteers were not accepted.

Inclusion ia were as follows: . Rheumatoid arthritis (RA) per revised 1987 ACR criteria . Active RA: 23 swollen and 3 tender joints with at least 1 swollen joint in the hand, excluding the PIP joints . CRP > 5.0 mg/L (RF and anti-CCP seronegative); CRP >2 mg/l (RF and/or anti- CCP seropositive) o DA828 S 5.1 . Stable regimen of concomitant RA therapy (NSAIDs, steroids, non- biological DMARDs). 0 Negative PPD tuberculin skin test Exclusion criteria were as follows: . Previous therapy with B or T cell depleting agents other than Rituximab (e.g. h). Prior treatment with Rituximab, TNF-inhibitors, other biologics (e.g. anti- |L-1 y) and systemic immunosuppressive agents is allowed with a washout period.

. Any history of ongoing, significant or recurring infections . Any active inflammatory diseases other than RA . Treatment with a systemic investigational drug within 6 months prior to ing . Women of childbearing potential, unless receiving stable doses of rexate or leflunomide . icant cardiac or pulmonary disease (including methotrexate- associated lung toxicity) 0 c or renal insufficiency Example 2: Patient recruitment and patient population al sites for patient recruitment, screening and treatment were located in Bulgaria, Germany, the Netherlands, Poland and the Ukraine. 96 patients were included in the trial. 27 patients received placebo, 24 patients received MOR103 at a dose of 0.3 mg/kg, 22 patients received MOR103 at a dose of 1.0 mg/kg and 23 patients received MOR103 at a dose of 1.5 mg/kg. The average age and the average Body Mass Index (BMI) was about the same for all treatment groups. Key characteristics are summarized in the following Table: MOR 103 Active Treatment Groups Characteristic Placebo 0.3 mglkg 1.0 mglkg 1.5 mglkg Total active N=27 N=24 N=22 N=23 N=69 Age £53.8 £514 £49 5£3 5£3.3 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,263263 ..................................56}....................................25.7.. ..................................256 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, White $27 $24 2$2 $23 $69 90% of all ts of the study were previously treated with . The most commonly used DMARD was methotrexate (75% of all ts). The rate of previous treatment with DMARDs was comparable in all treatment arms.

Prior to administration of MOR103 or the o the disease activity of all patients was measured according to accepted guidelines by ating the DA828 score, a 28—joint Disease Activity Score (see e.g. Ann Rheum Dis (2009) 68, 954-60). DA828 score is a validated and commonly used tool to quantify the disease status of RA patients. The average DA828 score was comparable for all treatment arms.

Example 3: Safety profile Based on the available observed safety data, MOR103 showed a favorable safety profile among all doses tested. The key observations are as follows: - No deaths were observed during the conduct of the trial . No infusion related reactions were observed . Two serious e events (SAEs) were observed: — One patient in the placebo group developed paronychia — One patient in the 0.3 mg/kg treatment arm developed pleurisy . More treatment-emergent adverse s (TEAEs) were observed in the placebo group (25.9%) than in the active groups (14.5%) - Most TEAEs were mild . No severe TEAEs were observed in the active groups In summary, it can be ded that treatment with MOR103 at all doses tested is safe.

Two serious adverse events were observed, both none in the treatment arms that showed clinical efficacy (see below). Sub-cutaneous administration of MOR103 at a dose that leads to an antibody drug level in the blood of patients equivalent to the intravenous application of the present study is expected to show a similar safety profile. e 4: Efficacy — DA828 4 weeks and 8 weeks after the first administration of MOR103 (or placebo) the DA828 scores of all patients was determined. A decrease in DA828 scores correlates to diminished disease severity. Results are shown in Figure 2 as the mean changes compared to baseline, i.e. disease status prior to treatment.

The placebo group only shows marginal changes. Patients treated with MOR103 at 0.3 mg/kg showed a slight decrease in DA828 scores, ting slightly less severity of the disease. In st, patients treated with MOR103 at 1.0 mg/kg or with 1.5 mg/kg showed a significant decrease in DA828 scores, indicating the high efficacy of MOR103 at these doses.

Example 5: Efficacy — ACR20 As another measure of efficacy the ACR20 criteria were used. ACR criteria measure improvement in tender or swollen joint counts and improvement in n other ters.

The procedure to measure ACR scores is highly standardized. The present clinical trial applied the respective able guidelines. Results are depicted in Figures 3 and 4. A higher score corresponds to an improvement in the severity of the disease.

In line with the results of the DA828 scores (see Example 4), also the ACR scores show a strong clinical ement of patients’ condition upon treatment with either 1.0 mg/kg MOR103 or 1.5 mg/kg MOR103. The improvement after 4 weeks is highly significant for the 1.0 mg/kg group (p<0.0001). Taken together, the ACR20 scores confirm the surprising finding that the efficacy of MOR103 can already be shown with a comparably low number or patients in each treatment arm and a comparably short treatment period.

Example 6: Clinical trial with additional doses of MOR103 The clinical trial set out herein above is repeated with additional doses of MOR103.

MOR103 is administered to ts intravenously at a dose of 0.5 mg/kg (treatment arm 1) and 0.75 mg/kg ment arm 2). All other parameters are identical to Example 1.

Both treatment arms show a favorable safety profile and demonstrate clinical efficacy as measured by DA828 scores and ACR20 scores.

Example 7: Clinical trial with a sub-cutaneous formulation of MOR103 The clinical trial set out herein above is repeated with a sub-cutaneous formulation of MOR103. In order to e r levels of MOR103 in the blood of patients as observed for intravenous treatment, the sub—cutaneous dose of MOR103 is increased.

In different treatment arms MOR103 is administered to patients at 1.5 mg/kg, 2.0 mg/kg, 3.0 mg/kg and 4.0 mg/kg. The drug is administered sub-cutaneously, either ly, y or bimonthly. All other parameters are identical to Example 1.

All treatment arms show a ble safety profile and trate clinical efficacy as measured by DA828 scores and ACRZO scores.

Example 8: Clinical trial with a sub-cutaneous formulation of MOR103 at a fixed dose Example 7 is repeated with a fixed dose of MOR103. In different treatment arms MOR103 is administered to patients at fixed dose of 75 mg, of 100 mg, of 150 mg, of 200 mg, of 300 mg and of 400 mg. The drug is administered sub—cutaneously every week, every second week, every fourth week or every sixth week. All other parameters are identical to the Examples described herein above.

All treatment arms show a favorable safety e and demonstrate clinical efficacy as measured by DASZ8 scores and ACRZO scores.

Claims (15)

What we claim is:

1. The use of a pharmaceutical composition sing an anti‐GM‐CSF antibody , in the manufacture of a medicament, for the treatment of a patient suffering from rheumatoid arthritis, the treatment comprising administering the anti‐GM‐CSF antibody intravenously weekly at a dose of 1.0 mg/Kg, or at a subcutaneous dose which achieves a blood concentration equal to that dose, wherein the anti‐GM‐CSF antibody comprises a variable heavy chain of the sequence: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGATYYAASVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS (SEQ ID NO.: 8) and a variable light chain of the sequence: DIELTQPPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGSNSGNTATLTIS GTQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ (SEQ ID NO.: 9).

2. The use of claim 1, n the pharmaceutical ition comprises pharmaceutically acceptable carriers, excipients or stabilizers which are a buffer which is histidine, a sugar which is sorbitol and a non‐ionic surfactant which is polysorbate‐80.

3. The use of claim 2 wherein the composition consists of 30mM ine, pH 6.0, 200mM sorbitol and 0.02% rbate‐80 as carriers, excipients or stabilizers.

4. The use of any one of claims 1 to 3, wherein the subcutaneous dose is at least about 2mg/kg, about 3.0mg/kg or about 4.0 mg/kg.

5. The use of any one of claims 1 to 3, wherein the subcutaneous dose is a fixed dose of between about 40 mg and 400 mg.

6. The use according to claim 5 wherein the fixed dose is 150 mg.

7. The use of any one of claims 1 to 6, wherein the subcutaneous dose is administered weekly, biweekly, monthly or bimonthly.

8. The use according to any one of claims 1 to 7, wherein the treatment ses administering the antibody to said patient in a manner to e to a serum concentration of said antibody of at least 2 µg/ml in said patient over the duration of said treatment.

9. The use according to any one of claims 1 to 8 n the treatment achieves a mean change in ACR20 score of at least 30.4 over four weeks of treatment.

10. The use according to claim 9 wherein the treatment achieves a mean change in ACR20 score of at least 68.2 over four weeks of treatment.

11. The use ing to any one of claims 1 to 8, wherein the treatment achieves a mean change in ACR 20 score of at least 26.1 over eight weeks of treatment.

12. The use according to claim 11, wherein the treatment achieves a mean change in ACR 20 score of at least 31.8 over eight weeks of treatment.

13. The use according to any one of claims 1 to 12, wherein the treatment comprises administering said antibody in combination with a disease‐modifying heumatic drug (DMARD).

14. The use according to claim 13, wherein the DMARD is methotrexate.

15. A use according to claim 1, substantially as herein described and exemplified.