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WO2011070339A1 - Procédé de traitement d'une maladie - Google Patents

Procédé de traitement d'une maladie Download PDF

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WO2011070339A1
WO2011070339A1 PCT/GB2010/002273 GB2010002273W WO2011070339A1 WO 2011070339 A1 WO2011070339 A1 WO 2011070339A1 GB 2010002273 W GB2010002273 W GB 2010002273W WO 2011070339 A1 WO2011070339 A1 WO 2011070339A1
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tnf
agent
disease
patient
cells
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Richard Owen Williams
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Ip2ipo Innovations Ltd
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Imperial Innovations Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies

Definitions

  • the present invention relates to a method of treating a disease selected from the group consisting of rheumatoid arthritis (RA), Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis.
  • RA rheumatoid arthritis
  • Crohn's disease Crohn's disease
  • ankylosing spondylitis psoriasis
  • psoriatic arthritis rheumatoid arthritis
  • Rheumatoid arthritis is a chronic autoimmune disease in which pro-inflammatory cytokines, such as TNFa, IL-6 and IL-1 play dominant pathological roles.
  • Crohn's disease is a inflammatory disease of the intestines that may affect any part of the gastrointestinal tract.
  • Ankylosing spondylitis is a form of chronic inflammatory arthritis that mainly affects joints in the spine and the sacroilium in the pelvis, causing eventual fusion of the spine.
  • Psoriasis is a chronic autoimmune inflammatory disease that affects the skin and joints.
  • Psoriatic arthritis is a form of arthritis that is frequently associated with psoriasis.
  • RA Crohn's disease
  • ankylosing spondylitis psoriasis and psoriatic arthritis are all diseases that have been shown to be treated relatively effectively by drugs that neutralise TNF.
  • WO 2004/042009 relates to the inhibition of IL17 using an antagonist of I L23.
  • US 2007/0178099 A1 relates to the treatment of TNF-mediated diseases using the combination of a TNF antagonist and an IL12 antagonist.
  • US 7,247,71 1 B2 relates to anti-IL23p40 specific human Ig derived proteins which do not bind to the p40 subunit of IL12 and thus do not neutralise IL12-related activity.
  • US 2007/0218064 A1 relates to human anti-IL23p19 antibodies.
  • US 2008/0038831 A1 relates to anti-IL23 specific human Ig derived proteins.
  • US2008/0095775 A1 relates to molecules that block the activity of anti-IL23 via its p19 subunit.
  • a first aspect of the invention provides a method of treating a disease selected from the group consisting of rheumatoid arthritis (RA), Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient, the method comprising administering to the patient an anti-TNF agent and an anti-IL23 agent.
  • RA rheumatoid arthritis
  • Crohn's disease Crohn's disease
  • ankylosing spondylitis psoriasis and psoriatic arthritis
  • TNF tumour necrosis factor a.
  • IL23 is interleukin 23.
  • the patient is typically a human, but may be an animal, particularly a mammal such as a horse, dog or cat, or other companion or farm mammal.
  • the patient may be suffering from one or more of the aforementioned diseases.
  • the anti-TNF agent is an agent that is directed to the TNF or TNF receptor of the species of the patient to be treated.
  • the agent is an anti-human TNF agent.
  • the anti-IL23 agent is an agent that is directed to the IL23 or IL23 receptor of the species of the patient to be treated.
  • the agent is an anti-human IL23 agent.
  • the anti-TNF agent is an anti-human TNF agent and that the anti-IL23 agent is an anti-human IL23 agent and that the patient to be treated is human.
  • TNF from many species is known.
  • the amino acid sequence of human TNF is disclosed in Pennica et al (1984) Nature 312, 724-729.
  • IL23 from many species is known. In humans, IL23 occurs as a heterodimer composed of two subunits termed p40 and p19, named according to their approximate molecular mass in kDa. The subunit p40 is also found in the heterodimer IL12 where it is present in combination with the subunit p35. See the Background of the Invention on paragraphs [0003] to [0007] in US 2008/0038831 A1 , incorporated herein by reference.
  • the IL23 receptor complex contains a receptor chain, termed IL23R, and the beta-1 subunit of the IL12 receptor. IL23 does not bind the IL12 receptor.
  • the amino acid sequence of the p40 subunit of human IL23 is disclosed in Wolf et al (1991 ) J. Immunol.
  • the combination treatment of the invention is believed to be particularly suited to patients with severe RA.
  • the combination treatment of the invention may be used at any stage of the disease to be treated, but is believed to be particularly applicable to patients who have shown a poor response to conventional therapies, including patients who have shown a poor response to anti- TNF alone.
  • the anti-TNF and the anti-IL23 may be administered by any suitable route.
  • administration of the anti-TNF agent or the anti-IL23 agent or both agents is intravenously or subcutaneously, for example by injection, or orally.
  • the anti-TNF agent and the anti-IL23 agent are administered simultaneously. In another particular embodiment, the anti-TNF agent and the anti-IL23 agent are administered sequentially. If sequential, they may be administered in any order.
  • the anti-TNF agent and the anti-IL23 agent are administered either together or separately in a dose which is effective for the treatment of the disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis.
  • Efficacy of the treatment of RA or psoriatic arthritis may be determined by standard methods, such as improvements in one or more of the following: number of swollen joints, number of tender joints, erythrocyte sedimentation rate and C-reactive protein levels, or by patient assessment, physician assessment, disability/functional questionnaire or pain scale.
  • assessment will include total back pain, patient assessment of disease activity, inflammation and physical function.
  • assessment will include general well-being, abdominal pain, number of liquid stools per day, abdominal mass and presence of complications.
  • Psoriasis assessment will be by the Psoriasis Area Severity Index (PASI) which combines the assessment of the severity of lesions and the total area of skin affected.
  • PASI Psoriasis Area Severity Index
  • Doses of the anti-TNF agent and the anti-IL23 agent may be determined empirically.
  • the patient is administered an amount of each agent, whether together or separately, that is effective for the treatment of the disease, particularly, the amount is effective for the amelioration of the disease.
  • a second aspect of the invention provides the combination of an anti-TNF agent and an anti- IL23 agent for use as a medicament.
  • a third aspect of the invention provides the combination of an anti-TNF agent and an anti-IL23 agent for use in treating a disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient.
  • a fourth aspect of the invention provides an anti-TNF agent for use in treating a disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient, wherein said patient is administered an anti-IL23 agent.
  • the patient may be administered the anti-IL23 agent prior to or at the same time as or after administration of the anti-TNF agent.
  • a fifth aspect of the invention provides an anti-IL23 agent for use in treating a disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient, wherein said patient is administered an anti-TNF agent.
  • the patient may be administered the anti-TNF agent prior to or at the same time as or after administration of the anti-IL23 agent.
  • a sixth aspect of the invention provides the use of the combination of an anti-TNF agent and an anti-IL23 agent in the manufacture of a medicament for the treatment of a disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient.
  • a seventh aspect of the invention provides the use of an anti-TNF agent in the manufacture of a medicament for the treatment of a disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient, wherein the patient is administered an anti-IL23 agent.
  • the patient may be administered the anti-TNF agent prior to or at the same time as or after administration of the anti-IL23 agent.
  • An eighth aspect of the invention provides the use of an anti-IL23 agent in the manufacture of a medicament for the treatment of a disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient, wherein the patient is administered an anti-TNF agent.
  • the patient may be administered the anti-TNF agent prior to or at the same time as or after administration of the anti-IL23 agent.
  • a ninth aspect of the invention provides a system for treating a disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient, the system comprising an anti-TNF agent and an anti-IL23 agent.
  • the system suitably contains means for delivering the agents to the patient, for example a hypodermic needle and a syringe.
  • a tenth aspect of the invention provides a kit of parts for treating a disease selected from the group consisting of RA, Crohn's disease, ankylosing spondylitis, psoriasis and psoriatic arthritis in a patient, the system comprising an anti-TNF agent and an anti-IL23 agent.
  • the anti-TNF agent may be any agent that neutralises TNF or blocks the TNF receptor or inhibits the production of TNF or inhibits signalling via the TNF receptor.
  • the anti-TNF agent neutralises TNF by binding to TNF.
  • the anti-TNF agent is an anti-TNF antibody or a soluble TNF receptor (TNFr) or an anti-TNF receptor antibody.
  • the anti-IL23 agent may be any agent that neutralises IL23 or blocks the IL23 receptor or inhibits the production of IL23 or inhibits signalling via the IL23 receptor.
  • the anti-IL23 agent neutralises IL23 by binding to IL23.
  • the anti-l L23 agent is selective for IL23 and has substantially no effect on IL12 or the IL12 receptor.
  • the anti-IL23 agent may be considered to be anti-ll_23 specific.
  • the anti-IL23 agent is an anti-IL23 antibody or a soluble anti-IL23 receptor (IL23r) or an anti-IL23 receptor antibody. It is preferred that the combined therapy comprises the administration of an anti-IL23 antibody and an anti-TNF antibody. In this embodiment it is preferred that the anti-IL23 antibody is one which binds to the p19 subunit of IL23 as discussed below. In this embodiment it is preferred that the anti-TNF antibody is adalimumab.
  • antibody we include any antibody-like molecule which is able to bind TNF or the TNF receptor (or, as the case may be, IL23 or the IL23 receptor) in a similar way to an intact antibody.
  • antibodies include intact antibodies, antibody fragments such as Fab, F(ab')2 and Fv fragments, genetically engineered antibodies such as humanised antibodies, chimaeric antibodies, single-chain Fv molecules (scFv), domain antibodies (dAbs) and the like. Also included are monoclonal antibodies and polyclonal antibodies.
  • Antibodies to TNF and IL23 are known and can in any event be made using well known techniques, such as monoclonal antibody production using hybridoma cells or transfected cells or by using antibody phage display, and by using the known amino acid sequences.
  • Antibodies to TNF are commercially available for use as anti-TNF agents, including HUMIRA (adalimumab; Abbott Laboratories) and REMICADE (infliximab; Centocor, Inc). Soluble TNF receptor is commercially available as an anti-TNF agent, including ENBREL (etanercept; Immunex Corporation). Anti-TNF receptor antibodies may also be used.
  • Antibodies that bind IL23 , but do not bind IL12, and antibodies that bind the IL23 receptor, but do not bind the IL12 receptor, are disclosed in, for example, US 7,247,71 1 B2, US 2007/0218064 A1 , US 2008/0038831 A1 and US 2008/0095775 A1 , all of which are incorporated herein in their entirety.
  • the anti-IL23 antibody is one which binds to the p19 subunit of IL23.
  • Such antibodies are disclosed, for example in US 2007/0218064 A1 , US 2008/0038831 A1 and US 2008/0095775 A1.
  • the antibody should not prevent or inhibit the binding of IL12 to the IL12 receptor.
  • the antibody may conveniently be an antibody that binds to the IL23 receptor chain (but not the IL12 receptor) as disclosed in US 2008/0038831 A1 , incorporated herein by reference.
  • Soluble receptors may be readily engineered from the intact membrane bound receptor using methods well known in the art.
  • the TNF (or IL23)-binding portion of the respective receptor (as the case may be) may be joined to a soluble protein molecules to create a molecule which retains the ability to bind TNF (or IL23 as the case may be) and is soluble.
  • a portion of the receptor is joined to an Fc portion of an antibody.
  • the anti-TNF agent and the antilL23 agent are prepared in a form suitable for therapeutic administration.
  • the agents are typically present in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is sterile and pyrogen free.
  • FIG. 1 Synergy between anti-TNF and anti-IL23 in collagen-induced arthritis.
  • DBA/1 mice were immunized type II collagen in complete Freund's adjuvant.
  • mice were treated with anti-TNF alone (50 pg/mouse), anti-p 9 alone (50 pg/mouse), anti-TNF (50 pg/mouse) plus anti-p19 (50 ⁇ g/mouse) or isotype controls. Treatment was on days 1 and 4 of arthritis.
  • A Clinical scores.
  • (B) Paw-swelling. Data were analysed using the Dunnett multiple comparisons test (n 5). * P ⁇ 0.05; ** P ⁇ 0.01 (compared to controls).
  • FIG. 1 DBA/1 mice were immunised with type II collagen in CFA. After the onset of arthritis mice were treated with anti-TNF alone (300 pg/mouse), anti-p19 alone (200 pg/mouse), anti- TNF (300 pg/mouse) plus anti-p19 (200 pg/mouse) or isotype controls on days 1 , 4 and 7 of arthritis. Arthritis severity was assessed using a clinical scoring system.
  • Figure 3 C57BL/6 mice were immunised with chicken type II collagen in CFA.
  • mice After the onset of arthritis mice were treated with anti-TNF alone (250 pg/mouse), anti-p19 alone (100 pg/mouse), anti-TNF (250 pg/mouse) plus anti-p19 (100 pg/mouse) or isotype controls on days 1 , 3, 5, 7 and 9 of arthritis. Arthritis severity was assessed using a clinical scoring system and paw-swelling was measured using micocalipers.
  • Th17 cells are increased in RA.
  • PB Cs were purified from peripheral blood by Ficoll gradient centrifugation and stimulated with PMA and ionomycin.
  • B Pooled data from A. Statistical analysis was performed using Student T test. * ** P ⁇ 0.001.
  • C PBMCs were stimulated with anti-CD3 mAb for 24 hours, and supernatants were analysed for the levels of IL-17 and IFN- ⁇ by ELISA. Bars represent means ⁇ SE.
  • Anti-TNFa therapy increases Th17 cells in RA. Blood was collected prior to the initiation of anti-TNFa (pre), and at 4 and 8 weeks after.
  • PBMCs from RA patients before and after anti-TNFa therapy were lysed and RNA levels of RORy were measured by RT-PCR.
  • the relative concentration of each gene is expressed as relative units using a healthy control as a calibrator after normalizing against HuPO
  • FIG. 6 Increase in Th17 cells is more potent after monoclonal antibody therapy (adalimumab). Intracellular cytokine staining of PBMCs from patients treated with adalimumab or etanercept.
  • A. Dot plots depicting numbers of Th17 or Th1 cells per ml of blood.
  • B. Dot plots depicting percentage of Th17 or Th1 cells as in Figure 4. Bar denotes the mean.
  • C ELISA of IL-17 and IFN- ⁇ levels in culture supernatants 24h after stimulation of PBMCs with anti-CD3. D.
  • FIG. 1 Plasma levels of IL-12/IL-23 p40 following LPS stimulation of whole blood from RA patients before and after anti-TNFa therapy.
  • FIG. 9 TNF regulates IL-12/IL-23 p40 expression.
  • MoDCs from healthy donors were pre- treated with anti-TNF mAb or rTNF and stimulated with LPS after 18h.
  • IL- 2/IL-23 p40 levels in the culture supernatant were measured by ELISA after a further 24h. * P ⁇ 0.05, * *P ⁇ 0.01.
  • Example 1 Synergistic effect of anti-TNF and anti-IL23 in collagen-induced arthritis
  • Type II collagen was purified from bovine cartilage, as described and solubilised by stirring overnight at 4° C in acetic acid (0.1 M) or Tris buffer (0.05 M Tris, containing 0.2 M NaCI, pH 7.4).
  • Anti-TNF mAb (clone TN3-19.12) was purchased from Dr Robert Shreiber (Washington University, St Louis, USA).
  • Anti-p19 mAb (clone G23-8) was purchased from Ebiosciences (Hatfield, UK).
  • Complete Freund's adjuvant (CFA) was purchased from BD (Oxford, UK).
  • mice Male DBA/1 mice (8-12 weeks old) were immunized intradermal ⁇ at the base of the tail with bovine type II collagen (200 ⁇ g) emulsified in complete Freund's adjuvant (CFA; Difco, West Molesley, UK). Mice were inspected on a daily basis for signs of arthritis (redness, swelling and/or limping). On the first day arthritis was observed, mice were assigned to randomly to one of four treatment controls: anti-TNF alone (50 pg/mouse), anti-p19 alone (50 pg/mouse), anti- TNF (50 pg/mouse) plus anti-p 9 (50 pg/mouse) or isotype controls. Treatment was on days 1 and 4 of arthritis.
  • CFA complete Freund's adjuvant
  • Anti-TNF alone failed to affect the clinical scores or the degree of paw-swelling compared to control mice.
  • anti-p19 alone had no effect on severity of arthritis compared to controls.
  • anti-TNF plus anti-p19 produced significant reductions in both clinical score (P ⁇ 0.05) and paw-swelling (P ⁇ 0.01 ).
  • Type II collagen was purified from chicken cartilage, as described (Inglis et al (2008) Nature Protocols 3: 612-8) and solubilised by stirring overnight at 4°C in acetic acid (0.1 M) or Tris buffer (0.05 M Tris, containing 0.2 M NaCI, pH 7.4).
  • Anti-TNF mAb (clone TN3-19.12) was purchased from Dr Robert Shreiber (Washington University, St Louis, USA).
  • Anti-p19 mAb (clone G23-8) was purchased from Ebiosciences (Hatfield, UK). Complete Freund's adjuvant (CFA) was purchased from BD (Oxford, UK).
  • mice Male C57BIJ6 mice were purchased from Harlan UK. Methods
  • mice Male mice (12-14 weeks old) were immunized at the base of the tail with chicken type II collagen (200 g) emulsified in complete Freund's adjuvant (CFA; Difco, West Molesley, UK). Mice were inspected on a daily basis for signs of arthritis (redness, swelling and/or limping). On the first day arthritis was observed, mice were assigned to randomly to one of four treatment controls: anti-TNF alone (250 pg/mouse), anti-p19 alone (100 pg/mouse), anti-TNF (250 pg/mouse) plus anti-p19 (100 pg/mouse) or isotype controls. There were 8-10 mice per treatment group. Treatment was on days 1 , 3, 5, 7 and 9 of arthritis. Arthritis was monitored clinically for 10 days using an established clinical scoring system. Paw-swelling was measured using microcalipers. This research was approved by the local ethical review process committee and by the Home Office of Great Britain.
  • CFA complete Freund's adjuvant
  • Example 3 Combined therapeutic effect of anti-TNF and anti-IL23 in collagen-induced arthritis
  • Example 1 a synergistic therapeutic effect is demonstrated between sub-optimal doses of anti-TNF antibody and a neutralising antibody against the p19 subunit of IL-23 in collagen- induced arthritis (CIA), an animal model of rheumatoid arthritis.
  • CIA collagen- induced arthritis
  • using a system of adoptive transfer we addressed the question of whether this form of combination therapy has a sustained therapeutic effect.
  • Type II collagen was purified from bovine cartilage, as described and solubilised by stirring overnight at 4°C in acetic acid (0.1 M) or Tris buffer (0.05 M Tris, containing 0.2 M NaCI, pH 7.4).
  • Anti-TNF mAb (clone TN3-19.12) was purchased from Dr Robert Shreiber (Washington University, St Louis, USA).
  • Anti-p19 mAb (clone G23-8) was purchased from Ebiosciences (Hatfield, UK).
  • Complete Freund's adjuvant (CFA) was purchased from BD (Oxford, UK).
  • mice Male DBA/1 mice and female CB-17 SCID mice were purchased from Harlan UK. Methods
  • mice Male DBA/1 mice (8-12 weeks old) were immunized intradermal ⁇ at the base of the tail with bovine type II collagen (200 pg) emulsified in complete Freund's adjuvant (CFA; Difco, West Molesley, UK). Mice were inspected on a daily basis for signs of arthritis (redness, swelling and/or limping). On the first day arthritis was observed, mice were assigned randomly to one of four treatment controls: anti-TNF alone (300 pg/mouse), anti-p 9 alone (200 pg/mouse), anti- TNF (300 pg/mouse) plus anti-p19 (200 pg/mouse) or isotype controls. There were 8-10 mice per treatment group.
  • CFA complete Freund's adjuvant
  • arthritis was induced in DBA 1 mice as above and treated with anti-TNF alone (300 pg/mouse), anti-p19 alone (200 pg/mouse), anti-TNF (300 pg/mouse) plus anti-p19 (200 pg/mouse) or isotype controls. Treatment was on days 1 , 4 and 7 of arthritis. On day 10 the mice were killed and spleen and inguinal lymph nodes removed and made into a cell suspension. The cells were then injected intraperitoneally into SCID mice together with 100 pg of type II collagen. Onset of arthritis and clinical scores were monitored as above. Results
  • Anti-TNF treatment alone caused a significant reduction in arthritis severity compared to control mice whereas anti-p19 alone did not have a significant effect on arthritis.
  • anti-TNF plus anti-p19 produced marked reduction in clinical score that exceeded the effect of anti-TNF alone (Figure 2).
  • the aim of this study is to establish whether anti-TNFa therapy reduces disease severity but increases numbers of Th17 and Th1 cells in patients with rheumatoid arthritis.
  • Th17 cells Compared to healthy controls, the percentage of Th17 cells was higher in rheumatoid arthritis patients and increased significantly at four and eight weeks after anti-TNFa therapy.
  • Adalimumab had a more pronounced effect on Th17 cells than etanercept and this difference was explained by the fact that sera from adalimumab treated patients exhibited greater TNFa neutralising capacity than etanercept.
  • anti-TNFa naive patients failed to upregulate IL-12/IL-23 p40 in response to LPS. However, this inhibition was abrogated after adalimumab treatment, providing compelling evidence that TNFa inhibits p40 expression in vivo.
  • IL-23 was elevated in rheumatoid arthritis and increased markedly after adalimumab treatment.
  • Example 4 we have shown that there is an increase in numbers of Th17 cells in RA patients treated with TNF blocking drugs. This increase is accompanied by increased expression of IL- 23, which is known to be responsible for promoting the differentiation and survival and Th17 cells.
  • IL-23 which is known to be responsible for promoting the differentiation and survival and Th17 cells.
  • anti-TNF and anti-IL-23 act synergistically in the collagen-induced arthritis model. On this basis we conclude that the combination of anti-TNF and anti-IL-23 is suitable as a treatment for RA and other related diseases in which anti-TNF is effective.
  • Th17 cellls in the pathogenesis of rheumatoid arthritis (RA) is a matter of ongoing debate.
  • RA rheumatoid arthritis
  • IL-23 which promotes survival and functional maturation of Th17 cells, confers complete resistance to collagen-induced arthritis (CIA), an animal model of RA [1].
  • CIA collagen-induced arthritis
  • IL-12 which is the chief cytokine responsible for the differentiation of Th1 cells, exacerbates disease [1].
  • TNFa Blockade of TNFa is clearly beneficial in both CIA and RA [2] yet, surprisingly, we have recently discovered that anti-TNFa treatment of CIA leads to an expansion of antigen-specific Th17 and Th1 cells in draining lymph nodes [3]. These findings were then reproduced in TNFaRI “ ' " , but not TNFaR2 "A , mice [3]. We also found, by adoptive transfer, that the expanded population of Th17/Th1 cells was highly pathogenic when the anti-TNFa "brake” was removed. On this basis we concluded that, in addition to its well-established pro-inflammatory role, TNFa was also a negative regulator of Th17/Th1 cells.
  • TNFa acting via TNFaRI , inhibits the expression of p40, the common subunit of IL-12 and IL-23 [3-5].
  • TNFa blocking drugs include IL-12/IL- 23 p40 expression and the frequency of Th17/Th1 cells are affected by therapy.
  • PBMCs Plasma-derived PBMCs
  • Plasma plasma, or serum, respectively.
  • PBMCs were purified using Ficoll gradient centrifugation (Cedarlane), followed by wash in 1X PBS twice. Cells were counted and seeded at 1.5x10 6 or 0.75x10 s per well and stimulated for intracellular FACS analysis or ELISA, respectively.
  • PBMCs were lysed in RLT lysis buffer with DTT and RNA was extracted from the cells using the RNAeasy mini kit (QIAGEN) according to the manufacturer's instructions.
  • Reverse transcription for the production of cDNA was carried out on the RNA samples using the ABI High capacity reverse transcription system with random hexamer primers according to the manufacturer's protocol.
  • Amplification of cDNA was performed on an ABI AB7900HT real-time PCR machine in a 384 well plate using TaqMan® Gene Expression Assays sets from the ABI inventoried library for all genes and Human acidic ribosomal protein (HuPO) control. Amplification was by a three-step PCR. The relative concentration of each gene of interest was calculated using the AACt method and expressed as relative units using a healthy control as a calibrator after normalizing against HuPO.
  • Jurkat cells were transfected with the Firefly luciferase (FL) reporter gene regulated by a TNFa-sensitive chimeric promoter and Renilla luciferase (RL) under the control of a constitutive promoter.
  • TNFa activity was measured after the addition of 10ng/mL TNFa to sera from patients prior to and after therapy.
  • FL and RL activity was determined sequentially for each sample in the same assay well using the Dual-Glo luciferase assay system (Promega, Madison, Wl). Results are expressed as residual TNFa activity determined from FL expression normalized with respect to RL expression.
  • PBMCs were seeded at 0.75x10 6 cells per well in a 96 well u bottom plate.
  • Cells were stimulated with either 1 ug/mL anti-human anti-CD3 (functional grade OKT3, eBioscience) or 500ng/mL LPS (Sigma) for 24 hours before supernatant collection.
  • Supernatants were assessed for levels of IL-12, IL-23, IL- 7, IFN-y, IL- ⁇ ⁇ , IL-6, IL-10, IL-8, IL-2, IL-5 using multiplex bead array (Bender Med Systems) and analysed using BMS software.
  • Th17 cells are increased in RA patients
  • TNFa blockade increases circulating Th17 cells in RA
  • RA patients 17 RA patients and 8 healthy controls were recruited into the study.
  • RA patients grouped by the type of anti-TNFa drug (adalimumab or etanercept), were assessed for the duration of disease, disease severity and response to treatment on the basis of disease activity score 28-erythrocyte sedimentation rate (DAS28- ESR), and whether patients are also on concurrent disease modifying anti-rheumatic drugs (DMARDs).
  • DMARDS are as follows: Methotrexate (MTX), sulfasalazine (SSZ), Hydroxychloroquine (HCQ).
  • MTX Methotrexate
  • SSZ sulfasalazine
  • HCQ Hydroxychloroquine
  • Anti-TNF therapy increases Th17 cells in RA
  • IL-12 levels were below the limit of detection in the blood of most patients and controls, and LPS addition did not induce IL-12 levels significantly (data not shown). Furthermore, PCR analysis IL-12p35 levels in PBMCs from patients and healthy controls show no difference between the two groups or in patients before or after treatment (data not shown).
  • TNFa blockade may affect other cytokines produced by both T cells and APCs.
  • purified PBMCs were stimulated with LPS for 24 hours and supernatants were assessed for a panel of cytokines (Table 3).
  • IL-23 was markedly upregulated after adalimumab treatment.
  • IL-1 ⁇ and IL- 10 levels appear to be elevated after both therapies, while TNFa blockade did not appreciably vary most of the other cytokines measured.
  • Cytokine levels of PBMCs from RA patients before and after anti-TNF therapy Purified PBMCs were stimulated with 1 ug/mL anti-CD3 mAb or 500ng/mL LPS for 24 hours. Supernatants were collected and cytokine levels were measure using Th1/Th2 cytokine bead multiplex array. Symbols as shown: * LPS stimulated, ** anti-CD3 stimulated, ⁇ values in pg/mL, $ values in ng/mL.
  • PBMCs Number of PBMCs and percentage of T cell and APC populations in the blood of RA patients before and after anti-TNF therapy. Numbers represent the mean number or percentage ⁇ SEM. PBMCs were counted after Ficol separation. Purified PBMCs were stained for the various surface receptors for 30 minutes at 4°C and florescence was read using FACS Canto II machine.
  • Th17 cells are increased in RA compared to healthy controls and that TNFa blockade increases numbers of Th17 cells despite reducing disease activity.
  • This may argue against an important pathological role for Th17 cells in RA but it is also possible that their pathogenicity only reaches full expression in the presence of TNFa.
  • IL-17 induces TNFa production by myeloid cells [17] and has been shown to synergise with TNFa in a number of cellular systems [18-20].
  • Our previous study sheds light on the possibility that TNFa-blockade results in the accumulation of pathogenic Th17 cells in the lymph nodes by redirecting them away from the joints, thus relieving inflammation.
  • Th17 cells are induced by anti-TNFa in mice with CIA but not patients with RA, despite the increase in IFN- ⁇ levels. Therefore, it was of interest to observe that the expression of IL-23, but not IL-12, was increased by anti-TNFa therapy in the blood of RA patients, a finding consistent with an expansion of Th17 but not Th1 cells.
  • TNFa blocking agents result in different functional outcomes. Additional differences between the two drugs include the fact that adalimumab is more effective than etanercept in the elimination of cells bearing membrane-bound TNFa [8] and, unlike etanercept, adalimumab is effective in the treatment of Crohn's disease [9]. Interestingly, we have also observed that serum from anti-TNFa naive patients also displayed TNFa-neutralising properties, albeit modestly (Fig. 6D). This is not surprising as it has been documented that RA patients develop autoantibodies to TNFa [10] . Additionally, TNFa may be neutralised by biologically active levels of soluble TNFaRs, which are upregulated in RA [1 1].
  • Example 5 Plasma levels of IL-12/IL-23 p40 following LPS stimulation of whole blood from RA patients
  • TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med, (2003) 9(10): p. 1245-50.

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Abstract

La présente invention concerne un procédé de traitement d'une maladie choisie dans le groupe comprenant l'arthrite rhumatoïde (RA), la maladie de Crohn, la spondylite ankylosante, le psoriasis et la polyarthrite psoriasique chez un patient, le procédé comprenant l'administration au patient d'un agent anti-TNF et d'un agent anti-IL23.
PCT/GB2010/002273 2009-12-10 2010-12-10 Procédé de traitement d'une maladie Ceased WO2011070339A1 (fr)

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WO2016073406A1 (fr) 2014-11-05 2016-05-12 Eli Lilly And Company Anticorps bispécifiques anti-tnf/anti-il-3
US10059763B2 (en) 2014-09-03 2018-08-28 Boehringer Ingelheim International Gmbh Compound targeting IL-23A and TNF-alpha and uses thereof
JP2019112446A (ja) * 2013-07-23 2019-07-11 バイオコン・リミテッド Ｃｄ６結合パートナーの使用およびそれに基づく方法
US10507241B2 (en) 2014-07-24 2019-12-17 Boehringer Ingelheim International Gmbh Biomarkers useful in the treatment of IL-23A related diseases
WO2020234834A1 (fr) * 2019-05-23 2020-11-26 Janssen Biotech, Inc. Méthode de traitement de maladie intestinale inflammatoire au moyen d'une polythérapie d'anticorps dirigés contre il -23 et tnf alpha
US11078265B2 (en) 2012-05-03 2021-08-03 Boehringer Ingelheim International Gmbh Anti-IL-23 antibodies
WO2021234634A1 (fr) * 2020-05-21 2021-11-25 Janssen Biotech, Inc. Méthode de traitement d'une maladie intestinale inflammatoire au moyen d'une polythérapie d'anticorps dirigés contre il -23 et tnf alpha
US12441785B2 (en) 2015-02-04 2025-10-14 Boehringer Ingelheim International Gmbh Methods of treating inflammatory diseases
JP7805788B2 (ja) 2019-05-23 2026-01-26 ヤンセン バイオテツク，インコーポレーテツド Ｉｌ－２３及びｔｎｆアルファに対する抗体の併用療法による炎症性腸疾患の治療方法

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US10202448B2 (en) 2010-11-04 2019-02-12 Boehringer Ingelheim International Gmbh Anti-IL-23 antibodies
US11078265B2 (en) 2012-05-03 2021-08-03 Boehringer Ingelheim International Gmbh Anti-IL-23 antibodies
JP2019112446A (ja) * 2013-07-23 2019-07-11 バイオコン・リミテッド Ｃｄ６結合パートナーの使用およびそれに基づく方法
US10507241B2 (en) 2014-07-24 2019-12-17 Boehringer Ingelheim International Gmbh Biomarkers useful in the treatment of IL-23A related diseases
US11680096B2 (en) 2014-09-03 2023-06-20 Boehringer Ingelheim International Gmbh Compound targeting IL-23A and TNF-alpha and uses thereof
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CN113874073A (zh) * 2019-05-23 2021-12-31 詹森生物科技公司 用针对IL-23和TNFα的抗体的联合疗法治疗炎性肠病的方法
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WO2020234834A1 (fr) * 2019-05-23 2020-11-26 Janssen Biotech, Inc. Méthode de traitement de maladie intestinale inflammatoire au moyen d'une polythérapie d'anticorps dirigés contre il -23 et tnf alpha
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JP2023528265A (ja) * 2020-05-21 2023-07-04 ヤンセン バイオテツク，インコーポレーテツド Ｉｌ－２３に対する抗体及びｔｎｆアルファに対する抗体の組み合わせ療法を用いた炎症性腸疾患の治療方法
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