KR20210021153A - Treatment for rheumatoid arthritis - Google Patents

Abstract

The present invention provides anti-GM-CSF antibodies for use in the treatment of rheumatoid arthritis. Anti-GM-CSF antibodies, especially MOR103, are administered to patients suffering from rheumatoid arthritis in dosages that are beneficial in a clinical setting.

Description

Treatment for rheumatoid arthritis {TREATMENT FOR RHEUMATOID ARTHRITIS}

The present invention provides an anti-GM-CSF antibody for use in the treatment of rheumatoid arthritis, and a method of treating rheumatoid arthritis using the antibody. Anti-GM-CSF antibodies, especially MOR103, are administered to patients suffering from rheumatoid arthritis in dosages that are beneficial 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 joints and is characterized by chronic inflammation of the synovial tissue that can eventually lead to destruction of cartilage, bone and ligaments, leading to joint deformity. RA has a maximum incidence rate between 40 and 60 years of age and primarily affects women. The cause of RA is unknown; However, certain histocompatibility antigens are associated with poor outcomes. Nonsteroidal anti-inflammatory drugs (NSAIDs) only provide symptom relief. Disease-modifying antirheumatic drugs (DMARDs), which are the cornerstone of RA treatment throughout all stages of the disease, maintain or improve bodily function and delay radiation joint damage. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNFα), interleukin-1, interleukin-6 and granulocyte macrophage colony stimulating factor (GM-CSF), which cause activation and proliferation of immune cells, have been shown to be elevated in inflammatory joints. .

More recently, biological compounds such as antibodies targeting tumor necrosis factor alpha (TNFα), B-cells, or T-cells have been used to treat RA, but still many patients have not responded to this therapy. Colony-stimulating factor (CSF) has been proposed for potential points of intervention for inflammatory diseases such as RA (see, e.g. 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 treatment regimen for RA comprising MOR103.

Summary of the invention

In one aspect, the present invention provides an anti-GM-CSF antibody for use in the treatment of a patient suffering from rheumatoid arthritis, the antibody comprising a dose of at least 1.0 mg/kg of the antibody when administered weekly for at least 4 weeks. It is administered to the patient in a manner that achieves the same or higher therapeutically effective antibody level in the patient's blood compared to intravenous administration.

In another aspect, the invention also provides a method of treating a patient suffering from rheumatoid arthritis, the method comprising the intravenous administration of the antibody at a dose of at least 1.0 mg/kg when administered weekly for at least 4 weeks. And administering an anti-GM-CSF antibody to the patient in a manner that achieves the same or higher therapeutically effective antibody level in the patient's blood.

In one embodiment, 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 one embodiment, the anti-GM-CSD antibody is administered weekly for at least 4 weeks.

In one embodiment, the anti-GM-CSF antibody is optionally administered subcutaneously at a dose of at least 2.0 mg/kg, or about 2.0 mg/kg, about 3.0 mg/kg or about 4.0 mg/kg. In one embodiment, 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 doses can be administered weekly, every other week, every 3 weeks, every 4 weeks or every 6 weeks.

In one embodiment, the dosage of anti-GM-CSF antibody administered to the patient and the frequency of administration are sufficient to provide and maintain a serum concentration of the antibody of at least 2 μg/ml in the patient for the duration of the treatment. Do.

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

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

In another embodiment, the invention provides an anti-GM-CSF antibody for use in the treatment of a patient suffering from rheumatoid arthritis, the antibody being at least 1.0 mg/kg or at least 1.5 mg when administered weekly for at least 4 weeks. The anti-GM-CSF antibody is administered to the patient in a manner that achieves the same or higher therapeutically effective antibody level in the patient's blood compared to intravenous administration of the antibody at a dose of /kg, and the anti-GM-CSF antibody is a DMARD such as methotrexate. It is administered with

In one embodiment, administration of the antibody to achieve the 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. In another embodiment, the antibody of the invention is administered intravenously at a dose of about 1.0 mg/kg or about 1.5 mg/kg. Administration can be performed monthly, every other week (every two weeks) or weekly.

In another embodiment, the invention provides an anti-GM-CSF antibody for use in the treatment of a patient suffering from rheumatoid arthritis, the antibody being at least 1.0 mg/kg or at least 1.5 mg when administered weekly for at least 4 weeks. It is administered subcutaneously to the patient in a manner that achieves the same or higher therapeutically effective antibody level in the patient's blood as compared to intravenous administration of the antibody at a dose of /kg, wherein the anti-GM-CSF antibody is used as methotrexate. It is administered with DMARD.

In one embodiment, administration of said antibody to achieve said therapeutically effective amount is subcutaneous administration of said antibody 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. Includes. In another embodiment, the antibody of the invention is administered subcutaneously at a dose of about 2.0 mg/kg, about 3.0 mg/kg, or about 4.0 mg/kg. Administration can be performed monthly, every other week (every two weeks) or weekly.

In one embodiment, administration of the antibody to achieve the therapeutically effective amount is about 40 mg of a fixed dose, 75 mg of a fixed dose, 100 mg of a fixed dose, 140 mg of a fixed dose, 150 mg of a fixed dose. , A fixed dose of 180 mg, a fixed dose of 200 mg, a fixed dose of 280 mg, a fixed dose of 300 mg, or a fixed dose of 400 mg of the antibody. Fixed doses can be administered weekly, every other week, every 3 weeks, every 4 weeks or every 6 weeks.

In another aspect, the present invention provides a method of treating a patient suffering from rheumatoid arthritis, the method comprising:

(i) a dose of at least 1.0 mg/kg, or

(ii) a fixed dose of 40 mg to 400 mg of anti-GM-CSF antibody is administered subcutaneously to the patient.

Anti-GM-CSF antibodies can be administered to the patient in a manner that achieves a serum concentration of the antibody of at least 2 μg/ml in the patient for the duration of the treatment. The antibody will be administered to the patient in a manner that achieves the same or higher therapeutically effective antibody level in the patient's blood compared to intravenous administration of the antibody at a dose of at least 1.0 mg/kg when administered weekly for at least 4 weeks. I can.

In another embodiment, the present invention provides a way to achieve the same or higher therapeutically effective antibody level in the patient's blood compared to intravenous administration of the antibody at a dose of at least 1.0 mg/kg when administered weekly for at least 4 weeks. It provides an anti-GM-CSF antibody for inhibiting the progression of structural joint damage in a patient with rheumatoid arthritis, comprising administering the antibody to the patient.

1 shows the amino acid sequence and DNA sequence of MOR04357.
2 depicts the mean change in DAS28 score comparing treatment after 4 weeks (left panel) and after 8 weeks (right panel). The change in the DAS28 score is compared to the baseline level, i.e. the disease state before treatment.
3 shows the average ACR20 score of all treatment arms after 4 weeks. An increase in the ACR20 score corresponds to an improvement in disease severity.
4 depicts the average ACR20 score of all treatment arms after 8 weeks. An increase in the ACR20 score corresponds to an improvement in disease severity.

Explanation

The terms “GM-CSF” and “GMCSF” are synonymous with the following: colony-stimulating factor 2, CSF2, GMCSF, GM-CSF, granulocyte-macrophage colony-stimulating factor, MGC131935, MGC138897, Mogramostin, Sargramostin It refers to a protein known as GM-CSF or granulocyte-macrophage colony-stimulating factor, with Sargramostim. Human GM-CSF has the following amino acid sequence (UniProt P04141):

“MOR103” is an anti-GM-CSF antibody, its amino acid sequence and DNA sequence are provided in FIG. 1. “MOR103” and “MOR04357” and “MOR4357” are used as synonyms to indicate the antibody shown in FIG. 1. MOR04357 is the HCDR1 region of the sequence GFTFSSYWMN (SEQ ID NO.: 2), the HCDR2 region of the sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), the HCDR3 region of the sequence GFGTDF (SEQ ID NO.: 4), the sequence SGDSIGKKYAY (SEQ ID NO. .: 5), the LCDR2 region of the sequence KKRPS (SEQ ID NO.: 6), and the LCDR3 region of the sequence SAWGDKGM (SEQ ID NO.: 7). MOR04357 is the sequence

Variable heavy chain and sequence of

의 가변 경쇄를 포함한다.

It includes the variable light chain of.

In certain embodiments, 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 a polypeptide encoding an amino acid sequence comprising SEQ ID NO.: 1.

As used herein, "specifically" or "specifically binds to" refers to an antibody that selectively or preferentially binds to GM-CSF. Preferably, the binding to an antigen affinity is 10 ^{- 9} mol / l or less ^{(e.g., 10 - 10 mol / l)} Kd values, preferably ^{10 -} 10 mol / l or less (e. G. 10 ^{- 12} mol/l). Binding affinity is determined with a standard binding assay, such as surface plasmon resonance technique (BIACORE ^®).

In certain embodiments, the antibody used in the present invention is MOR103. In another embodiment, the antibody used in the present invention is the HCDR1 region of the sequence GFTFSSYWMN (SEQ ID NO.: 2), the HCDR2 region of the sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), the sequence GFGTDF (SEQ ID NO.: 4) An antibody comprising the HCDR3 region of, the LCDR1 region of the sequence SGDSIGKKYAY (SEQ ID NO.: 5), the LCDR2 region of the sequence KKRPS (SEQ ID NO.: 6), and the LCDR3 region of the sequence SAWGDKGM (SEQ ID NO.: 7). to be. In another embodiment, the antibody used in the present invention is a sequence

의 가변 중쇄 및 서열

Variable heavy chain and sequence of

의 가변 경쇄를 포함하는 항체이다. 다른 구체예에서, 본 발명에서 사용되는 항체는 서열 GFTFSSYWMN (SEQ ID NO.: 2)의 HCDR1 영역, 서열 GIENKYAGGATYYAASVKG (SEQ ID NO.: 3)의 HCDR2 영역, 서열 GFGTDF (SEQ ID NO.: 4)의 HCDR3 영역, 서열 SGDSIGKKYAY (SEQ ID NO.: 5)의 LCDR1 영역, 서열 KKRPS (SEQ ID NO.: 6)의 LCDR2 영역, 및 서열 SAWGDKGM (SEQ ID NO.: 7)의 LCDR3 영역을 포함하는 항체와 교차-경쟁하는 항체이다. 다른 구체예에서, 본 발명에서 사용되는 항체는 서열 GFTFSSYWMN (SEQ ID NO.: 2)의 HCDR1 영역, 서열 GIENKYAGGATYYAASVKG (SEQ ID NO.: 3)의 HCDR2 영역, 서열 GFGTDF (SEQ ID NO.: 4)의 HCDR3 영역, 서열 SGDSIGKKYAY (SEQ ID NO.: 5)의 LCDR1 영역, 서열 KKRPS (SEQ ID NO.: 6)의 LCDR2 영역, 및 서열 SAWGDKGM (SEQ ID NO.: 7)의 LCDR3 영역을 포함하는 GM-CSF에 특이적인 항체와 같이 동일한 에피토프에 결합하는 항체이다.

It is an antibody containing the variable light chain of. In another embodiment, the antibody used in the present invention is the HCDR1 region of the sequence GFTFSSYWMN (SEQ ID NO.: 2), the HCDR2 region of the sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), the sequence GFGTDF (SEQ ID NO.: 4) An antibody comprising the HCDR3 region of, the LCDR1 region of the sequence SGDSIGKKYAY (SEQ ID NO.: 5), the LCDR2 region of the sequence KKRPS (SEQ ID NO.: 6), and the LCDR3 region of the sequence SAWGDKGM (SEQ ID NO.: 7). It is an antibody that cross-competes with. In another embodiment, the antibody used in the present invention is the HCDR1 region of the sequence GFTFSSYWMN (SEQ ID NO.: 2), the HCDR2 region of the sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), the sequence GFGTDF (SEQ ID NO.: 4) GM comprising the HCDR3 region of, the LCDR1 region of the sequence SGDSIGKKYAY (SEQ ID NO.: 5), the LCDR2 region of the sequence KKRPS (SEQ ID NO.: 6), and the LCDR3 region of the sequence SAWGDKGM (SEQ ID NO.: 7) -It is an antibody that binds to the same epitope as an antibody specific for CSF.

The term “antibody” is used in its broadest sense and specifically includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, However, they exhibit the desired biological activity.

“Antibody fragment” as used herein includes a portion of an intact antibody that retains the ability to bind to an antigen. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; Diabodies; Linear antibodies; Single chain antibody molecules; And multispecific antibodies formed from antibody fragments.

The term “monoclonal antibody” as used herein refers to an antibody that is substantially homogeneous, ie, an antibody obtained from a population of antibodies in which the individual antibodies constituting the population are the same and/or bind to the same epitope, provided that monoclonal Possible variants that may occur during the production of the antibody are excluded, such variants are usually present in small amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are not contaminated by other immunoglobulins.

Herein, a monoclonal antibody specifically refers to a portion of the heavy and/or light chain that is derived from a specific species or is identical or homologous to the corresponding sequence in an antibody belonging to a specific antibody class or subclass, while the remainder of the chain(s) is also "Chimeric" antibodies (immunoglobulins) that are identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, provided that they have the desired biological activity Represents.

The “humanized” form of a non-human (eg, murine) antibody is a chimeric antibody that contains a minimal sequence derived from a non-human immunoglobulin. In most cases, humanized antibodies are derived from hypervariable regions of non-human species (donor antibodies) such as mice, rats, rabbits, or non-human primates whose residues from the hypervariable regions of the receptor have the desired specificity, affinity, and ability. It is a human immunoglobulin (receptor antibody) replaced by a residue of. In some cases, framework region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. Moreover, humanized antibodies may contain residues not found in the acceptor antibody or donor antibody. These modifications are made to further improve antibody performance. In general, a humanized antibody will comprise substantially all of at least one, and typically two variable domains, wherein all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the FRs. All are FRs of human immunoglobulin sequences, except for the FR substitution(s) indicated above. The humanized antibody will also optionally comprise at least a portion of an immunoglobulin constant region, typically that of a human immunoglobulin.

As used herein, a "human antibody" includes an amino acid sequence structure corresponding to the amino acid sequence structure of an antibody obtainable from human B-cells, and includes antigen-binding fragments of human antibodies. Such antibodies can, upon immunization, produce transgenic animals (eg, mice) capable of producing human antibodies in the absence of endogenous immunoglobulins; Selection from human antibodies or phage display libraries that express human antibodies; Production via in vitro activation B; And isolation from human antibody-producing hybridomas by various techniques, including but not limited to.

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

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

In certain embodiments, the antibody used in the present invention is administered with an additional drug to treat RA.

The additional drug may be one or more drugs, e.g., immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), disease altering anti-rheumatic drugs (DMARD), such as methotrexate (MTX), anti-B-cell surface markers. Antibodies such as anti-CD20 antibodies (eg, rituximab), TNF-alpha-inhibitors, corticosteroids, and co-stimulatory modifiers, or any combination thereof. Optionally, the second or additional drug is selected from the group consisting of a non-biological DMARD, NSAID, and corticosteroid.

These additional drugs are generally used by the route of administration as used above and below at the same dosage. When all such additional drugs are used, preferably they are used in smaller amounts than when the first agent is not present, especially in subsequent administrations after the initial administration of the first agent, thereby eliminating or reducing the side effects arising therefrom. Let it. Combination administration of additional drugs includes co-administration (simultaneous administration) using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably both (or all) active agents (medicaments) are At the same time, there are times when they exert their biological activity.

The term “DMARD” refers to “disease-modifying anti-rheumatic drugs ( D isease- M odifying A nti- R heumatic D rugs)” and in particular hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, azathioprine, D Penicillamine, gold salt (oral), gold salt (intramuscular), minocycline, cyclosporine such as cyclosporine A and topical cyclosporine, and TNF-inhibitors, and salts, variants, and derivatives thereof. Exemplary DMARDs herein are non-biological, ie 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 antibody used in the present invention is administered in combination with a DMARD. In another embodiment, the antibody used in the present invention is administered with methotrexate.

As used herein, "TNF-inhibitor" refers to an agent that neutralizes its activity by inhibiting the biological function of TNF-alpha to some extent, generally through binding to TNF-alpha and/or its receptor. Examples of TNF inhibitors include etanercept (ENBREL ^®), an in-flight during rigs Thank (REMICADE ^®), ah otherwise mumap (HUMIRA ^®), Sertoli jumap pegol (CIMZIA ^®), and goalkeeper mumap (SIMPONI ^®).

“Treatment” of a patient or subject refers to both a therapeutic treatment and a prophylactic or preventative measure. The term “effective amount” or “therapeutically effective” refers to an amount of an antibody that is effective to treat rheumatoid arthritis. Such effective amounts may include reducing signs or symptoms of RA (e.g., achieving ACR20), reducing disease activity (e.g., disease activity score, DAS20), slowing the progression of structural joint damage or improving physical function. Any one or more can be generated. In one embodiment, such clinical response is similar to that achieved with an anti-GM-CSF antibody administered intravenously.

The antibodies of the present invention can be administered in different suitable forms. Potential dosage forms include systemic administration (subcutaneous, intravenous, intramuscular), oral administration, inhalation, transdermal administration, topical application (such as topical creams or ointments, etc.) or by other methods known in the art. Dosages (mg/kg) specified herein refer to milligrams of antibody per kilogram of body weight of a patient. In vitro cell-based assays have shown that anti-GM-CSF antibodies (MOR103) can inhibit several GM-CSF mediated responses. Responses assessed included TF-1 cell proliferation, STAT5 phosphorylation, polymorphonuclear neutrophil (PMN) migration, PMN up-regulation of CD11b, monocyte up-regulation of MHC II, and eosinophil viability. Complete inhibitory effect was generally reached at a concentration of about 0.2 μg/ml of anti-GM-CSF antibody. GM-CSF concentrations of 1 ng/ml or less were used in this study. For reference, GM-CSF levels in the synovial fluid of RA patients were reported as <500 pg/ml. It is reasonable to consider that similar GM-CSF concentrations used in these in vitro studies are present in the infected tissues of RA patients.

In order to effectively treat RA, it may be important for anti-GM-CSF antibodies to penetrate the synovial membrane. There is evidence to suggest that monoclonal antibodies can be distributed to the synovial membrane when administered subcutaneously or intravenously. A predicted permeability of 30%, based on continuous GM-CSF production, and taking into account patient heterogeneity, the minimal or suboptimal clinical effect in RA patients is expected to be at a serum concentration of about 2 μg/ml antibody (which is why Thus, about 10 times higher than the inhibitory concentration derived from in vitro studies).

A specific anti-GM-CSF antibody (MOR103) was administered to patients with active rheumatoid arthritis who received intravenous doses of 0.3, 1, and 1.5 mg/kg four times a week. The anti-GM-CSF antibody showed remarkable clinical efficacy for DAS28, EULAR, ACR20, ACR50, ACR70 and tender joint counts compared to placebo after administration of 1 and 1.5 mg/kg once a week.

In certain embodiments, the antibody of the invention is administered intravenously. In another embodiment, the antibody of the invention is administered subcutaneously.

From other therapeutic antibodies, it is known that the concentration that when administered intravenously results in a certain level of antibody in the blood is equivalent 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 found to be 52%, ie a given concentration administered subcutaneously results in a blood concentration equivalent to about 52% of the blood concentration when the same given concentration was administered intravenously. Thus, the concentration of the subcutaneous formulation should be about 2 times higher to achieve the same drug blood level compared to the intravenous formulation.

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

In an alternative embodiment, the blood concentration achieved is blood achieved by intravenous administration of an antibody of the invention in a dose of at least 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9 mg/kg when administered weekly for at least 4 weeks. Equal or higher than the concentration. In an alternative embodiment, the blood concentration achieved in the patient is equal to the blood concentration achieved by intravenous administration of an antibody of the invention at a dose of at least 1.0 mg/kg when administered weekly for at least 2 weeks or at least 3 weeks or Higher. In an alternative embodiment, the blood concentration achieved in the patient is equal to the blood concentration achieved by intravenous administration of an antibody of the invention at a dose of at least 1.0 mg/kg when administered every other week for at least 2 weeks or at least 4 weeks. Or higher.

In certain embodiments, the antibody of the invention is administered intravenously. In another embodiment, the antibody of the invention is 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 another embodiment, the antibody of the invention is administered intravenously at a dose of about 1.0 mg/kg or about 1.5 mg/kg.

In certain embodiments, the antibodies of the invention are administered subcutaneously. Various dose regimens were simulated using subcutaneous delivery of MOR103 to produce plasma concentrations similar to those obtained after 1 mg/kg iv, an effective dose in RA. Most simulations produce trough values above 2 ug/mL, a value believed to be the minimum blood concentration required to produce efficacy in the context of anti-GM-CSF antibodies. These studies indicate that subcutaneous doses of 1, 2, 3 and 4 mg/kg can produce plasma concentrations similar to 1 mg/kg, IV, depending on the frequency of dosing.

In another embodiment, the antibody of the invention 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. In another embodiment, the antibody of the invention is administered subcutaneously at a dose of about 2.0 mg/kg, about 3.0 mg/kg, or about 4.0 mg/kg. In certain embodiments, the antibodies of the invention are administered subcutaneously every other week, monthly or bimonthly.

In another embodiment, the antibody of the invention is administered subcutaneously in a fixed dose. In this “fixed dose” treatment, the antibody is administered at a specific fixed concentration, ie without taking into account the patient's body weight. In certain embodiments, the antibody of the invention comprises a fixed dose of 40 mg to 400 mg, optionally 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, It is administered as a fixed dose of 200 mg, a fixed dose of 280 mg, a fixed dose of 300 mg or a fixed dose of 400 mg. Fixed doses can be administered weekly, every other week, every 3 weeks, every 4 weeks or every 6 weeks. Typically, antibodies will be administered weekly in fixed doses.

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

In one 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 one embodiment, the antibody is administered in a dose sufficient to maintain a trough concentration of antibody at least 2 ug/mL. The trough concentration of antibody can 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 over the course of treatment.

In an alternative embodiment, 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 suffering from rheumatoid arthritis, the antibody being administered weekly for at least 4 weeks at a dose of at least 1.0 mg/kg of the antibody. Is administered to the patient in a manner that achieves the same or higher therapeutically effective antibody level in the patient's blood compared to intravenous administration of

In certain embodiments, the present invention provides a method of treating a patient suffering from rheumatoid arthritis, wherein the method is compared to intravenous administration of the antibody at a dose of at least 1.0 mg/kg when administered weekly for at least 4 weeks. And administering an anti-GM-CSF antibody to the patient in a manner that achieves the same or higher therapeutically effective antibody level in the blood of the patient.

In certain embodiments, the present invention provides a way to achieve the same or higher therapeutically effective antibody level in the patient's blood compared to intravenous administration of the antibody at a dose of at least 1.0 mg/kg when administered weekly for at least 4 weeks. It provides an anti-GM-CSF antibody for inhibiting the progression of structural joint damage in a patient with rheumatoid arthritis, comprising administering the antibody to the patient.

The terms “drug” and “drug” refer to active drugs for treating joint damage or signs or side effects associated with rheumatoid arthritis or RA. The term “pharmaceutical formulation” does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered, and that the active ingredient or ingredients, ie, such a form that allows the biological activity of the antibody of the invention to be effective. Refers to the product of. The formulation is bactericidal.

The antibody herein is preferably produced recombinantly in a host cell transformed with a nucleic acid sequence encoding the heavy and light chains of the antibody (eg, the host cell has been transformed with one or more vectors having nucleic acids therein). Preferred host cells are mammalian cells, most preferably PER.C6 cells.

Therapeutic formulations of the antibodies of the invention are prepared by mixing an antibody having the desired purity for storage with any pharmaceutically acceptable carrier, excipient or stabilizer in the form of a lyophilized formulation or aqueous solution. Acceptable carriers, excipients, or stabilizing agents are non-toxic to the receptor at the dosages and concentrations employed, and buffering agents 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, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl parabens; 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 such as glucose, mannose, or dextrins; Chelating agents such as EDTA; Sugars such as sucrose, mannitol, trehalose or sorbitol; Salt-forming counterions such as sodium; Metal complexes (eg, Zn-protein complexes); And/or nonionic surfactants such as TWEEN™ (eg Tween-80), PLURONICS™ or polyethylene glycol (PEG).

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 a specific embodiment, the formulation for an antibody of the invention consists 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 present 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 x 7H ₂ 0, 8 g / l NaCl ).

Example

Example 1: Design and Concept of Clinical Phase Ib/IIa Test

A multi-center, randomized, double-blind, placebo-controlled study was conducted to evaluate the safety, preliminary clinical activity and immunogenicity of multiple doses of MOR103 administered intravenously to patients with active rheumatoid arthritis.

The primary outcome measure was the adverse event rate and safety profile. Secondary outcome measures included DAS28 score, ACR score, and EULAR28 response criteria.

The clinical trial consisted of three treatment arms. In each treatment arm, patients received either a placebo or MOR103. The MOR103 dose was 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 in a total of 4 doses.

Overview of the treatment arm:

Eligibility to participate in the study were patients over 18 years of age of any sex (male and female). Healthy applicants were not received.

The inclusion criteria were as follows:

Rheumatoid arthritis (RA) according to the revised 1987 ACR criteria

Active RA: ≥3 swollen and 3 tender joints with at least one swollen joint in the hand, excluding the PIP joint

CRP> 5.0 mg/L (RF and anti-CCP seronegative); CRP >2 mg/l (RF and/or anti-CCP seropositive)

DAS28 ≤ 5.1

Stable regimen of concurrent RA therapy (NSAID, steroid, non-biological DMARD)

· Negative PPD tuberculin skin test

Exclusion criteria were as follows:

Previous therapy with B or T cell depletion agents other than Rituximab (eg Campath). Previous therapy with rituximab, TNF-inhibitors, other biological agents (e.g., anti-IL-1 therapy) and systemic immunosuppressants are acceptable with a washout period.

Any history of ongoing, significant or recurrent infection

· Any active inflammatory disease other than RA

Treatment with systemic test drugs within 6 months before screening

Women who are likely to become pregnant unless they receive a stable dose of methotrexate or leflunomide

Significant heart or lung disease (including methotrexate-related lung toxicity)

· Liver or kidney failure

Example 2: 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 clinical trial. 27 patients received placebo, 24 patients received the 0.3 mg/kg dose of MOR103, 22 patients received the 1.0 mg/kg dose of MOR103, and 23 patients received the 1.5 mg/kg dose of MOR103. Was accepted. Mean age and mean body mass index (BMI) were approximately the same in all treatment groups. The important features are summarized in the table below:

90% of all patients in the study were previously treated with DMARD. The most commonly used DMARD was methotrexate (75% of all patients). Previous treatment rates with DMARD were similar in all patient arms.

The disease activity of all patients prior to administration of MOR103 or placebo was calculated according to the approval guidelines for the DAS28 score, 28-joint disease activity score (see, eg, Ann Rheum Dis (2009) 68, 954-60). It was measured by. The DAS28 score is a validated tool commonly used to quantify disease status in RA patients. The average DAS28 score was similar for all treatment arms.

Example 3: Safety Profile

Based on the available observed safety data, MOR103 showed a favorable safety profile at all doses tested. Important observations are as follows:

· No death was observed during the test

No infusion-related reactions were observed

Two serious adverse events (SAEs) were observed:

-A patient in the placebo group developed perinailitis.

-One patient with 0.3 mg/kg treatment arm developed pleurisy.

More treatment-emergency side effects (TEAE) were observed in the placebo group (25.9%) than in the active group (14.5%)

· Most TEAEs were mild

No serious TEAE was observed in the active group

In summary, it can be concluded that treatment with all tested doses of MOR103 is safe. Two serious side effects were observed, both of which were not in the treatment arm showing clinical efficacy (see below). It is expected that subcutaneous administration of MOR103 at a dose that results in a patient's blood antibody drug levels equivalent to the intravenous application of this study will show a similar safety profile.

Example 4: Efficacy-DAS28

DAS28 scores for all patients were determined 4 and 8 weeks after the first administration of MOR103 (or placebo). A decrease in the DAS28 score is associated with a decrease in disease severity. Results are shown in FIG. 2 as baseline, that is, the mean change compared to the disease state before treatment.

Only the placebo group shows minor changes. Patients treated with 0.3 mg/kg MOR103 showed a slight decrease in the DAS28 score, indicating a slightly less severe disease severity. In contrast, patients treated with 1.0 mg/kg or 1.5 mg/kg of MOR103 showed a significant reduction in DAS28 score, indicating the high efficacy of this dose of MOR103.

Example 5: Efficacy-ACR20

The ACR20 criterion was used as another measure of efficacy. The ACR criterion measures improvement in tender or swollen joint number and improvement in certain other parameters. The procedure for measuring the ACR score is very standard. The clinical trials of the present invention used individual relevant regulations. The results are shown in Figures 3 and 4. A higher score corresponds to an improvement in the severity of the disease.

Consistent with the results of the DAS28 score (see Example 4), the ACR score also indicates a strong clinical improvement in patient condition upon treatment with 1.0 mg/kg of MOR103 or 1.5 mg/kg of MOR103. The improvement after 4 weeks was very remarkable for the 1.0 mg/kg group (p<0.0001). Taken together, the ACR20 score confirms the surprising results that the efficacy of MOR103 can already appear in an equally small number of patients in each treatment arm and an equally short treatment period.

Example 6: Clinical trial with additional doses of MOR103

The clinical trial set up herein above was repeated with an additional dose of MOR103. MOR103 is administered intravenously to patients at doses of 0.5 mg/kg (treatment arm 1) and 0.75 mg/kg (treatment arm 2). All other parameters are the same as in Example 1.

Both treatment arms demonstrate favorable safety profiles and demonstrate clinical efficacy as measured by the DAS28 score and ACR20 score.

Example 7: Clinical trial using the subcutaneous formulation of MOR103

The clinical trial set up herein above was repeated with the subcutaneous formulation of MOR103. To achieve a level of MOR103 in the patient's blood similar to that observed with intravenous treatment, the subcutaneous 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. Drugs are administered subcutaneously every other week, monthly or bimonthly. All other parameters are the same as in Example 1.

All treatment arms exhibit a favorable safety profile and demonstrate clinical efficacy as measured by the DAS28 score and ACR20 score.

Example 8: Clinical trial using a fixed dose of the subcutaneous formulation of MOR103

Example 7 is repeated with a fixed dose of MOR103. MOR103 is administered to patients in fixed doses of 75 mg, 100 mg, 150 mg, 200 mg, 300 mg and 400 mg in different treatment arms. The drug is administered subcutaneously every week, every other week, every 4 weeks or every 6 weeks. All other parameters are the same as the examples described herein above.

All treatment arms show a favorable safety profile and demonstrate clinical efficacy as measured by the DAS28 score and ACR20 score.

SEQUENCE LISTING <110> Morphosys AG Shebl, Amgad Haertle, Stefan Steidl, Stefan Leclair, Stephane <120> TREATMENT FOR RHEUMATOID ARTHRITIS <130> AGS/LU65485 <140> 12185235.4 <141> 2012-09-20 <150> 61/703871 <151> 2012-09-21 <160> 9 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 144 <212> PRT <213> Homo Sapiens <400> 1 Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile 1 5 10 15 Ser Ala Pro Ala Arg Ser Pro Ser Pro Ser Thr Gln Pro Trp Glu His 20 25 30 Val Asn Ala Ile Gln Glu Ala Arg Arg Leu Leu Asn Leu Ser Arg Asp 35 40 45 Thr Ala Ala Glu Met Asn Glu Thr Val Glu Val Ile Ser Glu Met Phe 50 55 60 Asp Leu Gln Glu Pro Thr Cys Leu Gln Thr Arg Leu Glu Leu Tyr Lys 65 70 75 80 Gln Gly Leu Arg Gly Ser Leu Thr Lys Leu Lys Gly Pro Leu Thr Met 85 90 95 Met Ala Ser His Tyr Lys Gln His Cys Pro Pro Thr Pro Glu Thr Ser 100 105 110 Cys Ala Thr Gln Ile Ile Thr Phe Glu Ser Phe Lys Glu Asn Leu Lys 115 120 125 Asp Phe Leu Leu Val Ile Pro Phe Asp Cys Trp Glu Pro Val Gln Glu 130 135 140 <210> 2 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> polypeptide <400> 2 Gly Phe Thr Phe Ser Ser Tyr Trp Met Asn 1 5 10 <210> 3 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> polypeptide <400> 3 Gly Ile Glu Asn Lys Tyr Ala Gly Gly Ala Thr Tyr Tyr Ala Ala Ser 1 5 10 15 Val Lys Gly <210> 4 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> polypeptide <400> 4 Gly Phe Gly Thr Asp Phe 1 5 <210> 5 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> polypeptide <400> 5 Ser Gly Asp Ser Ile Gly Lys Lys Tyr Ala Tyr 1 5 10 <210> 6 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> polypeptide <400> 6 Lys Lys Arg Pro Ser 1 5 <210> 7 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> polypeptide <400> 7 Ser Ala Trp Gly Asp Lys Gly Met 1 5 <210> 8 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> polypeptide <400> 8 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Glu Asn Lys Tyr Ala Gly Gly Ala Thr Tyr Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Gly Phe Gly Thr Asp Phe Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 9 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> polypeptide <400> 9 Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln 1 5 10 15 Thr Ala Arg Ile Ser Cys Ser Gly Asp Ser Ile Gly Lys Lys Tyr Ala 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Lys Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser 50 55 60 Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu Asp Glu 65 70 75 80 Ala Asp Tyr Tyr Cys Ser Ala Trp Gly Asp Lys Gly Met Val Phe Gly 85 90 95 Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105

Claims (20)

An anti-granulocyte macrophage colony stimulating factor (GM-CSF) antibody for use in the treatment of a patient suffering from rheumatoid arthritis, wherein the antibody is administered weekly for at least 4 weeks intravenously at a dose of at least 1.0 mg/kg An anti-GM-CSF antibody administered to the patient in a manner that achieves the same or higher therapeutically effective antibody level in the patient's blood compared to administration. 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. 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 every other week, monthly or every other month. 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. The anti-GM-CSF antibody of claim 8, wherein the antibody is administered at a dose of about 1.0 mg/kg or 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 method according to any one of claims 1 to 10, wherein the anti-GM-CSF antibody is the HCDR1 region of the sequence GFTFSSYWMN (SEQ ID NO.: 2), the HCDR2 region of the sequence GIENKYAGGATYYAASVKG (SEQ ID NO.: 3), and 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. : Anti-GM-CSF antibody which is an antibody containing the LCDR3 region of 7). 12. The anti-GM-CSF antibody of any one of claims 1 to 11, wherein the anti-GM-CSF antibody is administered in combination with a disease-altering antirheumatic drug (DMARD), such as methotrexate. A method of treating a patient suffering from rheumatoid arthritis, the method comprising:
(i) a dose of at least 1.0 mg/kg, or
(ii) A method comprising subcutaneously administering to the patient a fixed dose of 40 mg to 400 mg of the anti-GM-CSF antibody. 14. The method of claim 13, wherein the anti-GM-CSF antibody is administered to the patient in a manner that achieves a serum concentration of the antibody of at least 2 μg/ml in the patient for the duration of the treatment. The therapeutically effective antibody of claim 13 or 14, which is equal to or higher in the patient's blood compared to intravenous administration of the antibody at a dose of at least 1.0 mg/kg when the antibody is administered weekly for at least 4 weeks. A method of being administered to the patient in a manner that achieves a level. 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 said antibody is administered every other week, monthly or bimonthly. The method of any one of claims 13 to 15, wherein the antibody is 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, 180 mg. A method of being administered as a fixed dose, a fixed dose of 200 mg, a fixed dose of 280 mg, 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 other week, every 3 weeks, every 4 weeks or every 6 weeks. 19. The method of claim 18, wherein said antibody is administered weekly.

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