JP2020075927A - Treatment for rheumatoid arthritis - Google Patents

Abstract

To provide anti-GM-CSF antibodies administered to patients suffering from rheumatoid arthritis at doses effective in a clinical setting.SOLUTION: An anti-GM-CSF antibody for use in treatment of a patient suffering from rheumatoid arthritis is administered to the patient in a manner of achieving a therapeutically effective antibody level in the blood of the patient comparable to or higher than intravenous administration of the antibody at a dose of at least 1.0 mg/kg weekly for at least four weeks.SELECTED DRAWING: Figure 2

Description

  The present invention provides anti-GM-CSF antibodies for use in the treatment of rheumatoid arthritis, and methods for the treatment of rheumatoid arthritis using such antibodies. Anti-GM-CSF antibodies, particularly MOR103, are administered to patients suffering from rheumatoid arthritis at doses effective in a clinical setting.

  Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects 0.5% to 1% of the adult population worldwide. RA primarily affects the joints and is characterized by chronic inflammation of the synovial tissue, which eventually causes destruction of cartilage, bone and ligaments, which can lead to joint deformities. RA has a peak onset between the ages of 40 and 60 and primarily affects women. The cause of RA is unknown, but some histocompatibility antigens are associated with worse outcomes. Nonsteroidal anti-inflammatory drugs (NSAIDs) only provide symptomatic relief. Disease-modifying antirheumatic drugs (DMARDs), which are the basis of RA treatment across all stages of the disease, maintain or improve physical function and delay radiographic joint damage. Proinflammatory cytokines that cause the activation and proliferation of immune cells, such as tumor necrosis factor-alpha (TNFα), interleukin-1, interleukin-6 and granulocyte-macrophage colony stimulating factor (GM-CSF), Have been found to increase.

  More recently, biological compounds that target tumor necrosis factor alpha (TNFα), B cells, or T cells, such as antibodies, have been used to treat RA, but many patients still have these treatments. no response. Colony-stimulating factor (CSF) has been proposed as a potential therapeutic intervention point for inflammatory diseases such as RA (eg Nat Rev Immunol (2008) 8, 533-44 or Nat Rev Rheumatol (2009) 5 , 554-9). One such CSF is granulocyte-macrophage colony stimulating factor (GM-CSF).

  MOR103 is a fully human anti-GM-CSF antibody (Mol Immunol (2008) 46, 135-44; WO 2006/122797). MOR 103 is also in Phase Ib clinical trials for multiple sclerosis. The present invention describes the development of a clinically effective therapeutic regimen containing MOR103 for RA.

  In one aspect, the invention provides an anti-GM-CSF antibody for use in the treatment of a patient suffering from rheumatoid arthritis, said antibody being administered at a dose of at least 1.0 mg / kg weekly for at least 4 weeks. The antibody is administered to the patient in a manner that achieves a therapeutically effective blood antibody concentration in the patient that is equal to or higher than that obtained when the antibody is administered intravenously.

  In another aspect, the invention also provides a method of treating a patient suffering from rheumatoid arthritis, which method comprises intravenously administering the antibody at a dose of at least 1.0 mg / kg weekly for at least 4 weeks. Comprising administering to said patient an anti-GM-CSF antibody in a manner that achieves a therapeutically effective blood antibody concentration in said patient that is comparable or higher than that.

  In certain embodiments, the anti-GM-CSF antibody is optionally administered intravenously at a dose of at least 1.0 mg / kg, or at a dose of about 1.0 mg / kg or about 1.5 mg / kg. In certain embodiments, the anti-GM-CSF antibody is administered weekly for at least 4 weeks.

  In certain embodiments, the anti-GM-CSF antibody is optionally administered subcutaneously at a dose of at least 2.0 mg / kg, or at a dose of about 2.0 mg / kg, about 3.0 mg / kg or about 4.0 mg / kg. In certain embodiments, the anti-GM-CSF antibody is administered biweekly, monthly or bimonthly. In another embodiment, the antibody is administered at a fixed dose of about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg or about 400 mg. Fixed dose administration can be weekly, bi-weekly, tri-weekly, bi-weekly, or bi-weekly.

  In certain embodiments, the dose of anti-GM-CSF antibody administered to said patient and the frequency of said administration are such that a serum antibody concentration of at least 2 μg / ml in said patient is achieved and maintained during said treatment. It is enough.

  In another aspect, the invention provides an anti-GM-CSF antibody, wherein the anti-GM-CSF antibody is the HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO: 2) for use in treating a patient suffering from rheumatoid arthritis. , HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO: 3), HCDR3 region of sequence GFGTDF (SEQ ID NO: 4), LCDR1 region of sequence SGDSIGKKYAY (SEQ ID NO: 5), LCDR2 region of sequence KKRPS (SEQ ID NO: 6) and sequence SAWGDKGM (SEQ ID NO: 6) 7) An antibody comprising the LCDR3 region, wherein said antibody is equivalent to or higher than intravenous administration of said antibody when administered weekly at a dose of at least 1.0 mg / kg for at least 4 weeks. It is administered to the patient in a manner that achieves an effective blood antibody concentration in the patient.

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

  In another aspect, the invention provides an anti-GM-CSF antibody for use in treating a patient suffering from rheumatoid arthritis, said antibody being at least at a dose of 1.0 mg / kg or at least 1.5 mg / kg. The anti-GM-CSF is administered to the patient in a manner that achieves a therapeutically effective blood antibody concentration in the patient that is equal to or higher than that of the antibody administered weekly for 4 weeks. The antibody is co-administered with a DMARD such as methotrexate.

  In certain embodiments, administration of the antibody to achieve such a therapeutically effective amount comprises intravenous administration of the antibody at a dose of at least 0.6, at least 0.7, at least 0.8, at least 0.9 or at least 1.0 mg / kg. Including administration. In other embodiments, the antibodies of the invention are administered intravenously at a dose of about 1.0 mg / kg or a dose of about 1.5 mg / kg. Administration can be monthly, biweekly (every two weeks) or weekly.

  In another aspect, the invention provides an anti-GM-CSF antibody for use in treating a patient suffering from rheumatoid arthritis, said antibody being at least at a dose of 1.0 mg / kg or at least 1.5 mg / kg. The antibody is subcutaneously administered to the patient in a manner that achieves a therapeutically effective blood antibody concentration in the patient that is equal to or higher than that when the antibody is administered intravenously every week for 4 weeks. The CSF antibody is co-administered with a DMARD such as methotrexate.

  In certain embodiments, administration of said antibody to achieve such therapeutically effective amount is 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. Subcutaneous administration of said antibody. In other embodiments, the antibodies of the invention are 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 can be monthly, biweekly (every two weeks) or weekly.

  In certain embodiments, administration of the antibody to achieve such a therapeutically effective amount comprises administration of a fixed dose of about 40 mg, a fixed dose of about 75 mg, a fixed dose of about 100 mg, a fixed dose of about 140 mg. Subcutaneous administration of the antibody at a fixed dose of about 150 mg, a fixed dose of about 180 mg, a fixed dose of about 200 mg, a fixed dose of about 280 mg, a fixed dose of about 300 mg or a fixed dose of about 400 mg. including. Fixed dose administration can be weekly, bi-weekly, tri-weekly, bi-weekly, or bi-weekly.

In another aspect, the invention provides a method of treating a patient suffering from rheumatoid arthritis, which method comprises:
Subcutaneously administering to said patient anti-GM-CSF antibody at a dose of (i) at least 1.0 mg / kg, or (ii) a fixed dose of 40 mg to 400 mg.
The anti-GM-CSF antibody may be administered to the patient in a manner that achieves a serum antibody concentration of at least 2 μg / ml in the patient during the treatment. The antibody is administered in a manner that achieves a therapeutically effective blood antibody concentration in the patient that is equal to or higher than when the antibody is intravenously administered weekly at a dose of at least 1.0 mg / kg for at least 4 weeks. , Can be administered to the patient.

  In another aspect, the invention provides the therapeutically effective patient as above, which is equivalent or higher than intravenous administration of the antibody when administered weekly at a dose of at least 1.0 mg / kg for at least 4 weeks. The present invention provides an anti-GM-CSF antibody for suppressing the progression of structural joint damage in a patient with rheumatoid arthritis, which comprises administering the antibody to the patient in a method for achieving the blood antibody concentration of.

FIG. 1 shows the amino acid sequence and DNA sequence of MOR04357. FIG. 2 shows a comparison of mean changes in DAS28 score after 4 weeks (left panel) and 8 weeks (right panel) of treatment. Changes in DAS28 scores are compared to baseline values, ie pre-treatment disease states. Figure 3 shows the mean ACR20 score of all treatment groups after 4 weeks. An increase in ACR20 score corresponds to an improvement in disease severity. Figure 4 shows the mean ACR20 score for all treatment groups after 8 weeks. An increase in ACR20 score corresponds to an improvement in disease severity.

Description The terms "GM-CSF" and "GMCSF" are synonymous with the following synonyms: colony stimulating factor 2, CSF2, GMCSF, GM-CSF, granulocyte macrophage colony stimulating factor, MGC131935, MGC138897, Molgramostin. ), A protein known as GM-CSF or granulocyte-macrophage colony stimulating factor having Sargramostim. Human GM-CSF has the following amino acid sequence (UniProt P04141):
MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNET VEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETS CATQIITFESFKENLKDFLLVIPFDCWEPVQE (SEQ ID NO: 1).

"MOR103" is an anti-GM-CSF antibody whose amino acid and DNA sequences are shown in FIG. "MOR103" and "MOR04357" and "MOR4357" are used as synonyms to refer to the antibody shown in FIG. MOR04357 comprises HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO: 2), HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO: 3), HCDR3 region of sequence GFGTDF (SEQ ID NO: 4), LCDR1 region of sequence SGDSIGKKYAY (SEQ ID NO: 5), sequence KKRPS (sequence It includes the LCDR2 region of SEQ ID NO: 6) and the LCDR3 region of sequence SAWGDKGM (SEQ ID NO: 7). MOR04357 is an array
Variable heavy chain and sequence of QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGA TYYAASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS (SEQ ID NO: 8)
DIELTQPPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGS NSGNTATLTISGTQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ (SEQ ID NO: 9) containing a variable light chain.

  In one embodiment, the antibody used in the present invention is an antibody specific for GM-CSF. In another embodiment, the antibody used in the present invention is an antibody specific for the polypeptide encoding the amino acid sequence including SEQ ID NO: 1.

As used herein, "specifically to" or "specifically binds to" refers to an antibody that selectively or preferentially binds to GM-CSF. Preferably, the binding affinity for the antigen is a Kd value of 10 ^-9 mol / l or less (eg 10 ^-10 mol / l), preferably 10 ^-10 mol / l or less (eg 10 ^-12 mol / l) Has a Kd value of. Binding affinity is measured by standard binding assays such as surface plasmon resonance (BIACORE®).

In one embodiment, the antibody used in the present invention is MOR103. In another embodiment, the antibody used in the present invention comprises the HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO: 2), the HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO: 3), the HCDR3 region of sequence GFGTDF (SEQ ID NO: 4), the sequence SGDSIGKKYAY (sequence No. 4). An antibody comprising the LCDR1 region of SEQ ID NO: 5), the LCDR2 region of sequence KKRPS (SEQ ID NO: 6), and the LCDR3 region of sequence SAWGDKGM (SEQ ID NO: 7). In another embodiment, the antibody used in the invention has the sequence
Variable heavy chain and sequence of QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMNWVRQAPGKGLEWVSGIENKYAGGA TYYAASVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGFGTDFWGQGTLVTVSS (SEQ ID NO: 8)
DIELTQPPSVSVAPGQTARISCSGDSIGKKYAYWYQQKPGQAPVLVIYKKRPSGIPERFSGS NSGNTATLTISGTQAEDEADYYCSAWGDKGMVFGGGTKLTVLGQ (SEQ ID NO: 9) is an antibody containing the variable light chain. In another embodiment, the antibody used in the present invention comprises the HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO: 2), the HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO: 3), the HCDR3 region of sequence GFGTDF (SEQ ID NO: 4), the sequence SGDSIGKKYAY (sequence No. 4). An antibody that cross-competes with an antibody comprising the LCDR1 region of SEQ ID NO: 5), the LCDR2 region of sequence KKRPS (SEQ ID NO: 6), and the LCDR3 region of sequence SAWGDKGM (SEQ ID NO: 7). In another embodiment, the antibody used in the present invention comprises the HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO: 2), the HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO: 3), the HCDR3 region of sequence GFGTDF (SEQ ID NO: 4), the sequence SGDSIGKKYAY (sequence No. 4). An antibody that binds to the same epitope as the antibody specific for GM-CSF, including the LCDR1 region of SEQ ID NO: 5, the LCDR2 region of sequence KKRPS (SEQ ID NO: 6), and the LCDR3 region of sequence SAWGDKGM (SEQ ID NO: 7). is there.

  The term "antibody" is used in its broadest sense and specifically refers to monoclonal antibodies, polyclonal antibodies, multispecific antibodies composed of at least two intact antibodies (eg, bispecific antibodies), and Antibody fragments are included so long as they exhibit the desired biological activity.

  As used herein, "antibody fragment" includes a portion of an intact antibody that retains the ability to bind antigen. Examples of antibody fragments are Fab, Fab ', F (ab') 2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; Includes specific antibody.

  The term "monoclonal antibody", as used herein, refers to an antibody that is obtained from a population of substantially homogeneous antibodies, ie, the individual antibodies that make up that population are of the production of monoclonal antibodies. Except for possible mutations that may occur in between, they bind to the same and / or the same epitope, but such mutations are usually present in minor amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody targets a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are free of contamination by other immunoglobulins.

  The monoclonal antibody in the present specification is specifically an antibody in which a part of the heavy chain and / or the light chain therein is derived from a specific species, or a corresponding sequence of an antibody belonging to a specific antibody class or subclass. A “chimeric” antibody that is identical or homologous to, while the rest of the chain is identical to, or homologous to, the corresponding sequence of an antibody from another species, or an antibody of another antibody class or subclass. (Immunoglobulin) as well as fragments of such antibodies so long as they exhibit the desired biological activity.

  "Humanized" forms of non-human (eg, murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In most cases, the humanized antibody is a human immunoglobulin (recipient antibody) in which the residues from the recipient's hypervariable regions have the desired specificity, affinity and potency, mouse, rat, It is replaced with a residue from the hypervariable region of a rabbit or non-human species (donor antibody) such as non-human primate. In some cases, framework region (FR) residues of human immunoglobulin are replaced with corresponding non-human residues. Furthermore, humanized antibodies may contain residues that are found neither in the recipient antibody nor in the donor antibody. These modifications are made to further refine antibody performance. Generally, a humanized antibody comprises substantially all of at least one, and generally two variable domains, wherein all or substantially all of the hypervariable regions are those of non-human immunoglobulin. And all or substantially all FRs are of human immunoglobulin sequences, except for FR substitutions as described above. Humanized antibodies also optionally include immunoglobulin constant regions, usually at least part of that of human immunoglobulin.

  The "human antibody" in the present specification includes an amino acid sequence structure corresponding to the amino acid sequence structure of an antibody obtained from human B cells and includes an antigen-binding fragment of a human antibody. Such antibodies may be identified or generated by various techniques, including but not limited to: That is, when immunized, production by a transgenic animal (eg, mouse) capable of producing a human antibody in the absence of endogenous immunoglobulin; selection from a phage display library expressing a human antibody; Production by in vitro activated B cells; and isolation from human antibody producing hybridomas.

  In one embodiment, the antibody used in the present invention is a monoclonal antibody.

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

  In certain embodiments, the antibodies used in the invention are co-administered with an additional drug that treats RA.

  The additional agent may be one or more agents, eg, immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX), anti-CD20. Anti-B cell surface marker antibodies such as antibodies (eg rituximab), TNF-α inhibitors, corticosteroids, and co-stimulatory modifiers, or any combination thereof. Optionally, the second or further drug is selected from the group consisting of non-biological DMARDs, NSAIDs and corticosteroids.

  These additional drugs are usually used at the same doses and routes of administration as used above and below. When such additional drugs are used, they are preferably administered in order to eliminate or reduce the side effects caused thereby, especially in subsequent administrations beyond the initial administration by the first drug, Used in smaller amounts than if not present. Co-administration of further drugs includes co-administration (concurrent administration) with separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably , There is a time when both (or all) active agents (drugs) exert their biological activity at the same time.

The term "DMARD" refers to a "disease modifying antirheumatic drugs (D isease- M odifying A nti- R heumatic D rug) ", in particular, hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, azathioprine, D- penicillamine, gold Includes salts (oral), gold salts (intramuscular), minocycline, cyclosporine such as cyclosporin A and topical cyclosporine, and TNF-inhibitors, including salts, variants and derivatives thereof .. Typical DMARDs herein are non-biological or classical DMARDs such as azathioprine, chloroquine, hydroxychloroquine, leflunomide, methotrexate and sulfasalazine.

  Methotrexate is a particularly preferred DMARD of the present invention. Thus, in certain embodiments, the antibodies used in the present invention are co-administered with DMARD. In another embodiment, the antibody used in the invention is co-administered with methotrexate.

  As used herein, a "TNF-inhibitor" generally inhibits the biological function of TNF-α by binding to TNF-α and / or its receptor and neutralizing its activity. Refers to the drug. Examples of TNF inhibitors are etanercept (ENBREL®), infliximab (REMICADE®), adalimumab (HUMIRA®), certolizumab pegor (simdia). (CIMZIA®)), and golimumab (SIMPONI®)).

  “Treatment” of a patient or subject refers to both therapeutic treatment and prophylactic or preventative measures. The term "effective amount" or "therapeutically effective" refers to an amount of antibody effective for the treatment of rheumatoid arthritis. Such an effective amount is any one or more of the signs or symptoms of RA (eg, achievement of ACR20), decreased disease activity (eg, disease activity score, DAS20), progression of structural joint damage. Slowing down or improving physical function. In one embodiment, such clinical response is comparable to that achieved by intravenously administered anti-GM-CSF antibody.

  The antibody of the present invention can be administered in various suitable forms. Possible dosage forms include systemic (subcutaneous, intravenous, intramuscular), oral, inhalation, transdermal, topical (eg topical creams or ointments) or other known in the art. Method included. The dose (mg / kg) defined in the present invention refers to milligrams of antibody per kilogram of patient body weight. In vitro cell-based assay showed that anti-GM-CSF antibody (MOR103) was able to inhibit some GM-CSF mediated reactions. Responses assessed included TF-1 cell proliferation, STAT5 phosphorylation, polymorphonuclear neutrophil (PMN) migration, CD11b upregulation on PMNs, MHC II upregulation on monocytes, and Includes eosinophil survival. The full inhibitory effect was usually achieved at a concentration of anti-GM-CSF antibody of about 0.2 μg / ml. GM-CSF concentrations up to 1 ng / ml were applied in such studies. As a reference, the GM-CSF concentration in synovial fluid of RA patients was reported to be <500 pg / ml. It is reasonable to assume that GM-CSF concentrations similar to those used in these in vitro studies are present in the affected tissue of RA patients.

  In order to effectively treat RA, it may be important that anti-GM-CSF antibody penetrates the synovium. There is evidence to suggest that monoclonal antibodies may be distributed within the synovium when administered subcutaneously or intravenously. Based on a predicted permeability of 30%, sustained GM-CSF production, and taking into account patient heterogeneity, the minimum or suboptimal clinical effect concentration in RA patients is about 2 μg / ml antibody. It is expected to be a serum concentration (and thus approximately 10 times higher than the inhibitory concentration obtained from in vitro studies).

  A specific anti-GM-CSF antibody (MOR103) was administered to patients with active rheumatoid arthritis, who received four intravenous doses of 0.3, 1, and 1.5 mg / kg weekly. Anti-GM-CSF antibody showed significant clinical effects on DAS28, EULAR, ACR20, ACR50, ACR70 and tender joint numbers after weekly administration at 1 and 1.5 mg / kg compared to placebo.

  In certain embodiments, the antibodies of the invention are administered intravenously. In other embodiments, the antibodies of the invention are administered subcutaneously.

  Concentrations that result in specific blood antibody levels when administered intravenously from other therapeutic antibodies correspond to approximately 50-76% of the blood concentrations 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 measured to be 52%. That is, a given concentration administered subcutaneously results in a blood concentration equivalent to about 52% of the blood concentration when the same given concentration is administered intravenously. Therefore, the concentration of subcutaneous formulation should be about 2-fold higher to achieve the same blood level of drug as compared to intravenous formulation.

  In certain embodiments, the blood level to be achieved in a patient is the blood level achieved by intravenous administration of an antibody of the invention when administered weekly at a dose of at least 1.0 mg / kg for at least 4 weeks. Equal or higher than the concentration.

  In another embodiment, the blood concentration to be achieved is at least 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9 mg / kg of the antibody of the invention administered intravenously every week for at least 4 weeks. Equivalent or higher than the blood concentration achieved in. In another embodiment, the blood concentration to be achieved in the patient is a blood level achieved when the antibody of the invention is administered intravenously weekly at a dose of at least 1.0 mg / kg for at least 2 weeks or at least 3 weeks. Equivalent or higher than medium concentration. In another embodiment, the blood concentration to be achieved in the patient is achieved when the antibody of the invention is administered intravenously at a dose of at least 1.0 mg / kg at weekly intervals of at least 2 weeks or at least 4 weeks. Equivalent or higher compared to blood levels.

  In certain embodiments, the antibodies of the invention are administered intravenously. In other embodiments, the antibodies of the invention are administered intravenously at a dose of 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 antibodies of the invention are administered intravenously at a dose of about 1.0 mg / kg or a dose of about 1.5 mg / kg.

  In certain embodiments, the antibodies of the invention are administered subcutaneously. Various dosing regimens have been simulated using subcutaneous delivery of MOR103 to produce plasma concentrations similar to those obtained after an iv of 1 mg / kg, an effective dose for RA. Most of the simulations yield trough concentration values above 2 μg / mL, the value considered to be the lowest blood concentration required to produce efficacy for anti-GM-CSF antibodies. These studies show that subcutaneous doses of 1, 2, 3 and 4 mg / kg can produce plasma concentrations similar to IV at 1 mg / kg, depending on dosing frequency.

  In other embodiments, the antibodies of the invention are administered 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 embodiments, the antibodies of the invention are 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. In certain embodiments, the antibodies of the invention are administered subcutaneously biweekly, monthly or bimonthly.

  In other embodiments, the antibodies of the invention are administered subcutaneously in a fixed dose. In such "fixed dose" treatments, the antibody is administered at a particular fixed concentration, ie, without regard to the patient's weight. In certain embodiments, an antibody of the invention is a fixed dose of 40 mg to 400 mg, optionally 75 mg fixed dose, 100 mg fixed dose, 140 mg fixed dose, 150 mg fixed dose, 180 mg , Fixed dose of 200 mg, fixed dose of 280 mg, fixed dose of 300 mg or fixed dose of 400 mg. Fixed dose administration can be weekly, bi-weekly, tri-weekly, bi-weekly, or bi-weekly. Antibodies are usually given in fixed doses weekly.

  In certain embodiments, the antibody is administered at a fixed subcutaneous dose of 40, 56, 70, 75, 100, 140, 150, 180, 200, 210, or 280 mg weekly.

  In certain embodiments, the antibody is administered biweekly at a fixed subcutaneous dose of 70, 75, 100, 140, 150, 180, 200, 210, 280 or 300 mg.

  In certain embodiments, the antibody is administered at a fixed subcutaneous dose of 100, 140, 150, 180, 200, 210, 280, 300, 320, 350, 360 or 400 mg monthly.

  In certain embodiments, the antibody is administered at a dose sufficient to maintain a trough concentration of the antibody of at least 2 μg / mL. The trough concentration of antibody may be maintained at 2.0 μg / mL, 2.5 μg / mL, 3.0 μg / mL, 3.5 μg / mL, 4.0 μg / mL, 4.5 μg / mL or 5.0 μg / mL during the course of treatment.

  In another embodiment, the antibody is administered at a fixed subcutaneous dose of 28 or 35 mg weekly.

  In one embodiment, the invention provides an anti-GM-CSF antibody for use in the treatment of a patient suffering from rheumatoid arthritis, said antibody being at a dose of at least 1.0 mg / kg weekly for at least 4 weeks. The antibody is administered to the patient in a manner that achieves a therapeutically effective blood antibody concentration in the patient that is equal to or higher than that obtained when the antibody is administered intravenously.

  In one embodiment, the invention provides a method of treating a patient suffering from rheumatoid arthritis, wherein the method comprises intravenously administering the antibody at a dose of at least 1.0 mg / kg weekly for at least 4 weeks. Comprising administering to said patient an anti-GM-CSF antibody in a manner that achieves a therapeutically effective blood antibody concentration in said patient that is equal to or higher than that of said patient.

  In certain embodiments, the invention provides an anti-GM-CSF antibody for inhibiting the progression of structural joint damage in a patient with rheumatoid arthritis, wherein the antibody is administered at a dose of at least 1.0 mg / kg weekly for at least 4 weeks. Comprising administering the antibody to the patient in a manner that achieves a therapeutically effective blood antibody concentration in the patient that is equal to or higher than that when administered intravenously.

  The terms "drug" and "drug" refer to active drugs for treating joint damage or symptoms or side effects associated with rheumatoid arthritis or RA. The term "pharmaceutical formulation" is in a form such that the biological activity of the active ingredient, ie the antibody of the invention, is effective and has unacceptable toxicity to the subject to which the formulation will be administered. Refers to a preparation without additional ingredients. Such formulations are sterile.

  The antibodies herein are preferably recombinantly produced in a host cell that has been transformed with nucleic acid sequences encoding its heavy and light chains (e.g., a host cell containing one or more nucleic acids therein). It has been transformed by the above vector). Preferred host cells are mammalian cells, most preferably PER.C6 cells.

  A therapeutic formulation of an antibody of the invention may be prepared in the form of a lyophilized formulation or an aqueous solution by admixing the antibody with the desired purity for storage with an optional pharmaceutically acceptable carrier, excipient or stabilizer. Is prepared. Acceptable carriers, excipients, or stabilizers are those that are not toxic to the recipient at the doses and concentrations used and are buffering agents such as phosphates, citrates, histidine and other organic acids. Antioxidants such as ascorbic acid and methionine; Preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol Resorcinol; Cyclohexanol; 3-Pentanol; and m-cresol); Low molecular weight polypeptides (less than about 10 residues); Proteins such as serum albumin, gelatin, or immunoglobulins; Hydrophilicity such as polyvinylpyrrolidone Polymers; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; mono-, di-, and other sugars such as glucose, mannose, or dextrin; chelating agents such as EDTA; sucrose, mannitol, trehalose Or a sugar such as sorbitol; a counterion that forms a salt such as sodium; a metal complex (eg Zn-protein complex); and / or TWEEN ™ (eg Tween-80), PLURONICS ™ or polyethylene glycol ( PEG) and other nonionic surfactants.

In certain embodiments, the invention provides a pharmaceutical composition comprising an antibody of the invention and a pharmaceutically acceptable carrier and / or excipient for use in any of the methods provided herein. In certain embodiments, formulations for the antibodies of the invention consist of 30 mM histidine, pH 6.0, 200 mM sorbitol and 0.02% Tween-80. In another embodiment, the formulation for the antibody of the invention is PBS, pH 6.2 (0.2 g / l KCl, 0.96 g / l KH ₂ P0 ₄ , 0.66 g / l Na ₂ HP0 ₄ × 7H _20, 8 g / l NaCl).

Clinical Phase 1b / IIa Trial Design and Concepts A multicenter study to assess the safety, preliminary clinical activity and immunogenicity of multiple doses of MOR103 given intravenously in patients with active rheumatoid arthritis. A joint, randomized, double-blind, placebo-controlled trial was conducted.

  The primary endpoints were adverse event rate and safety profile. Secondary endpoints included DAS28 score, ACR score and EULAR28 response criteria.

  The clinical trial consisted of three treatment groups. In each treatment group, patients received either placebo or MOR103. The MOR103 dose was 0.3 mg / kg body weight in treatment group 1, 1.0 mg / kg body weight in treatment group 2, and 1.5 mg / kg body weight in treatment group 3. MOR103 and placebo were administered intravenously all four times weekly.

  Treatment group overview:

  Participants in this study were bisexual (male and female) patients age 18 and older. Healthy volunteers were not accepted.

The inclusion criteria for the study were as follows:
・ Rheumatoid arthritis (RA) according to the revised 1987 ACR standard
-Active RA: 3 or more swollen joints and 3 tender joints with at least one swollen joint of the hand, excluding PIP joints-CRP> 5.0 mg / L (RF and anti-CCP seronegative ); CRP> 2 mg / l (RF and / or anti-CCP seropositive)
・ DAS28 ≦ 5.1
-Stable treatment plan for combined RA treatment (NSAID, steroid, non-biological DMARD) -PPD tuberculin skin test negative Exclusion criteria were as follows:
History of treatment with B cell or T cell depleting agents other than rituximab (eg, campus). A history of treatment with rituximab, TNF inhibitors, other biologics (eg anti-IL-1 treatment) and systemic immunosuppressants is tolerated during the drug holidays.
・ History of ongoing, serious or recurrent infection ・ Active inflammatory disease other than RA ・ Treatment with systemic study drug within 6 months before screening ・ After continuous administration of methotrexate or leflunomide Females of childbearing potential unless they are pregnant • Severe heart or lung disease (including methotrexate-related pulmonary toxicity)
・ Liver failure or renal failure

Patient recruitment and patient population Clinical sites for patient recruitment, screening and treatment were located in Bulgaria, Germany, the Netherlands, Poland and Ukraine.

  96 patients participated in the study. Twenty-seven 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 1.5 MOR103 was administered at a dose of mg / kg. Mean age and mean body mass index (BMI) were similar in all treatment groups. The key features are summarized in the table below:

Ninety percent of all patients in the trial were previously treated with DMARD. The most commonly used DMARD was methotrexate (75% of all patients). The proportion of treatment history with DMARD was similar in all treatment groups.

  Prior to administration of MOR103 or placebo, disease activity in all patients was measured by calculating the DAS28 score, the disease activity score of 28 joints, according to accepted guidelines (eg Ann Rheum Dis (2009 ) 68, 954-60). The DAS28 score is an effective and commonly used method of quantifying the disease status of RA patients. Mean DAS28 scores were similar in all treatment groups.

Safety Profile Based on the observed safety data available, MOR103 showed a good safety profile at all doses tested. The key findings are as follows:
-No mortality was observed during the study.
-No infusion related reaction was observed.
・ Two serious adverse events (SAEs) were observed:
-One patient in the placebo group developed paronychia.

One patient in the -0.3 mg / kg treatment group developed pleurisy.
• More adverse effects (TEAEs) under treatment were observed in the placebo group (25.9%) than in the active substance group (14.5%).
-Most TEAEs were mild.
-No serious TEAE was observed in the active substance group.

  In summary, it is concluded that treatment with MOR103 at all doses tested is safe. Two serious adverse events were observed, neither of which was a clinically effective treatment group (see below). Subcutaneous administration of MOR103 at a dose that results in patient blood antibody drug concentrations corresponding to the intravenous application of this study is expected to show a similar safety profile.

Effectiveness-DAS28
DAS28 scores were measured in all patients 4 and 8 weeks after the first dose of MOR103 (or placebo). A decrease in DAS28 score correlates with a decrease in disease severity. Results are shown in FIG. 2 as the mean change compared to baseline, ie pre-treatment disease state.

  The placebo group shows only slight changes. Patients treated with 0.3 mg / kg of MOR103 showed a mild decrease in DAS28 score and a slightly lower disease severity. In contrast, patients treated with 1.0 mg / kg or 1.5 mg / kg MOR103 showed a significant decrease in DAS28 score, indicating high efficacy of MOR103 at these doses.

Effectiveness-ACR20
The ACR20 criterion was used as another measure of efficacy. The ACR20 criterion measures improvement in tender or swollen joint numbers and in other specified parameters. The method of measuring ACR scores is highly standardized. This clinical trial used each appropriate guideline. The results are shown in Figures 3 and 4. Higher scores correspond to improved disease severity.

  Consistent with the DAS28 score results (see Example 4), the ACR score also shows a significant clinical improvement in the patient's symptoms upon treatment with either 1.0 mg / kg MOR103 or 1.5 mg / kg MOR103. .. The improvement after 4 weeks is very pronounced in the 1.0 mg / kg group (p <0.0001). Taken together, the ACR20 score supports the surprising finding that the efficacy of MOR103 can already be demonstrated with a relatively small number of patients in each treatment group and a relatively short treatment period.

Clinical trials with additional doses of MOR103 The clinical trials designed above are repeated with additional doses of MOR103. MOR103 is administered to patients intravenously at doses of 0.5 mg / kg (treatment group 1) and 0.75 mg / kg (treatment group 2). All other parameters are the same as in Example 1.

  Both treatment groups show a good safety profile, demonstrating clinical efficacy as measured by the DAS28 and ACR20 scores.

Clinical trials designed clinical trials the subcutaneous formulation of MOR103 repeated with subcutaneous formulations MOR103. Subcutaneous doses of MOR103 are increased to achieve similar levels of MOR103 in blood in patients as observed with intravenous therapy.

  Patients receive MOR103 at 1.5 mg / kg, 2.0 mg / kg, 3.0 mg / kg and 4.0 mg / kg in the various treatment groups. Drugs are administered subcutaneously biweekly, monthly or bimonthly. All other parameters are the same as in Example 1.

  All treatment groups show a good safety profile, demonstrating clinical efficacy as measured by DAS28 and ACR20 scores.

Clinical trial with subcutaneous formulation of MOR103 at fixed dose Example 7 is repeated with fixed dose of MOR103. Patients receive MOR103 at fixed doses of 75 mg, 100 mg, 150 mg, 200 mg, 300 mg and 400 mg in the various treatment groups. Drugs are administered subcutaneously weekly, every 2 weeks, every 4 weeks or every 6 weeks. All other parameters are the same as in the example above.

  All treatment groups show a good safety profile, demonstrating clinical efficacy as measured by DAS28 and ACR20 scores.

Claims (20)

  An anti-GM-CSF antibody for use in the treatment of a patient suffering from rheumatoid arthritis, wherein said antibody is intravenously administered at a dose of at least 1.0 mg / kg weekly for at least 4 weeks An anti-GM-CSF antibody that is administered to the patient in a manner that achieves a therapeutically effective blood antibody concentration in the patient that is equivalent or higher.   The anti-GM-CSF antibody of claim 1, wherein the antibody is administered subcutaneously.   The anti-GM-CSF antibody of claim 2, wherein the antibody is administered at a dose of at least 2.0 mg / kg.   4. The anti-GM-CSF antibody of claim 3, wherein the antibody is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg or about 4.0 mg / kg.   The anti-GM-CSF antibody according to any one of claims 1 to 4, wherein the antibody is administered biweekly, monthly or bimonthly.   The anti-GM-CSF antibody of claim 2, wherein the antibody is administered at a fixed dose of about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg or about 400 mg.   The anti-GM-CSF antibody of claim 1, wherein the antibody is administered intravenously.   8. The anti-GM-CSF antibody of claim 7, wherein the antibody is administered at a dose of at least 1.0 mg / kg.   9. The anti-GM-CSF antibody of claim 8, wherein the antibody is administered at a dose of about 1.0 mg / kg or a dose of about 1.5 mg / kg.   10. The anti-GM-CSF antibody of any one of claims 7-9, wherein the antibody is administered weekly for at least 4 weeks.   The anti-GM-CSF antibody comprises HCDR1 region of sequence GFTFSSYWMN (SEQ ID NO: 2), HCDR2 region of sequence GIENKYAGGATYYAASVKG (SEQ ID NO: 3), HCDR3 region of sequence GFGTDF (SEQ ID NO: 4), LCDR1 of sequence SGDSIGKKYAY (SEQ ID NO: 5). The anti-GM-CSF antibody according to any one of claims 1 to 10, which is an antibody comprising a region, the LCDR2 region of the sequence KKRPS (SEQ ID NO: 6), and the LCDR3 region of the sequence SAWGDKGM (SEQ ID NO: 7).   The anti-GM-CSF antibody according to any one of claims 1 to 11, wherein the anti-GM-CSF antibody is co-administered with a DMARD such as methotrexate. A method of treating a patient suffering from rheumatoid arthritis, said method comprising:
The above method comprising subcutaneously administering to said patient an anti-GM-CSF antibody at (i) a dose of at least 1.0 mg / kg, or (ii) a fixed dose of 40 mg to 400 mg.   14. The method of claim 13, wherein the anti-GM-CSF antibody is administered to the patient in a manner that achieves a serum antibody concentration of at least 2 μg / ml in the patient during the treatment.   A method of achieving a therapeutically effective blood antibody concentration in said patient, wherein said antibody is comparable or higher than that of weekly administration of said antibody at a dose of at least 1.0 mg / kg for at least 4 weeks. 15. The method of claim 13 or 14, which is administered to the patient at.   16. The method of any one of claims 13-15, wherein the antibody is administered 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.   17. The method of claim 16, wherein the antibody is administered biweekly, monthly or bimonthly.   The antibody has a fixed dose of 40 mg, a fixed dose of 75 mg, a fixed dose of 100 mg, a fixed dose of 140 mg, a fixed dose of 150 mg, a fixed dose of 180 mg, a fixed dose of 200 mg, a fixed dose of 280 mg. 16. The method of any one of claims 13-15, which is administered at a fixed dose of 300 mg or a fixed dose of 400 mg.   19. The method of claim 18, wherein the antibody is administered weekly, every 2 weeks, every 3 weeks, every 4 weeks or every 6 weeks.   19. The method of claim 18, wherein the antibody is administered weekly.

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