WO2008106131A2 - Combination therapy for treatment of immune disorders - Google Patents
Combination therapy for treatment of immune disorders Download PDFInfo
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- WO2008106131A2 WO2008106131A2 PCT/US2008/002530 US2008002530W WO2008106131A2 WO 2008106131 A2 WO2008106131 A2 WO 2008106131A2 US 2008002530 W US2008002530 W US 2008002530W WO 2008106131 A2 WO2008106131 A2 WO 2008106131A2
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Definitions
- the present invention relates compositions and methods for treatment of immune disorders, such as autoimmune disorders. Specifically, the invention relates to combination therapy with agents that inhibit the development or maintenance of Th 17 cells.
- the immune system functions to protect individuals from infective agents, e.g., bacteria, multi-cellular organisms, and viruses, as well as from cancers.
- This system includes several types of lymphoid and myeloid cells such as monocytes, macrophages, dendritic cells (DCs), eosinophils, T cells, B cells, and neutrophils. These lymphoid and myeloid cells often produce signaling proteins known as cytokines.
- the immune response includes inflammation, i.e., the accumulation of immune cells systemically or in a particular location of the body. In response to an infective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate immune cell proliferation, development, differentiation, or migration.
- Immune response can produce pathological consequences, e.g., when it involves excessive inflammation, as in the autoimmune disorders. See, e.g., Abbas et al. (eds.) (2000) Cellular and Molecular Immunology, W.B. Saunders Co., Philadelphia, PA; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, CA; von Andrian and Mackay (2000) New Engl. J. Med. 343: 1020-1034; Davidson and Diamond (2001) New Engl. J. Med. 345:340-350). [0003] Many cytokines have been implicated in diseases involving aberrant inflammatory responses.
- IL- 17 which was originally named cytotoxic T-Lymphocyte-associated antigen 8 (CTLA8) is a homodimeric cytokine that binds to IL- 17RA (also known as IL 17R) and IL- 17RC.
- the functional receptor for IL- 17 is believed to be a multimeric receptor complex comprising one or both of IL- 17RA and IL- 17RC (e.g., an IL- 17RA homodimer, an IL-17RC homodimer, or an EL-17RA/IL-17RC heterodimer) and possibly a third, as yet unknown, protein (Toy et al. (2006) J. Immunol. 177(l):36-39; unpublished data).
- IL- 17 activity includes promoting accumulation of neutrophils in a localized area and the activation of neutrophils.
- IL- 17 can induce or promote the production of any of the following proinflammatory and neutrophil-mobilizing cytokines, depending on the cell type: IL-6, MCP-I, CXCL8 (IL-8), CXCLl, CXCL6, TNF ⁇ , IL- l ⁇ , G-CSF, GM-CSF, MMP-I, and MMP-13.
- Interleukin-12 (IL- 12) is a heterodimeric molecule composed of p35 and p40 subunits. Studies have indicated that IL- 12 plays a critical role in the differentiation of na ⁇ ve T cells into T-helper type 1 CD4 + lymphocytes that secrete IFN ⁇ . It has also been shown that IL- 12 is essential for T cell dependent immune and inflammatory responses in vivo. See, e.g., Cua et al. (2003) Nature 421 :744-748. IL-12 receptor is a complex of IL- 12R ⁇ l and EL-12R ⁇ 2 subunits. See Presky et al. (1996) Proc. Nat 'I Acad. Sci. USA 93:14002.
- Interleukin-23 is a heterodimeric cytokine comprised of two subunits, pl9 which is unique to IL-23, and p40, which is shared with IL-12.
- the pl9 subunit is structurally related to IL-6, granulocyte-colony stimulating factor (G-CSF), and the p35 subunit of IL-12.
- IL-23 mediates signaling by binding to a heterodimeric receptor, comprised of IL-23R, which is unique to IL-23 receptor, and IL-12R ⁇ l, which is shared by the IL-12 receptor. See Parham et al. (2000) J. Immunol. 168:5699.
- IL-23 activity includes inducing the proliferation of memory T cells, PHA blasts, CD45RO T cells; and enhance production of interferon-gamma (IFN ⁇ ) by PHA blasts or CD45RO T cells.
- IFN ⁇ interferon-gamma
- IL-23 preferentially stimulates memory as opposed to naive T cell populations in both human and mouse.
- IL-23 activates a number of intracellular cell-signaling molecules, e.g., Jak2, Tyk2, Statl, Stat2, Stat3, and Stat4.
- IL-12 activates this same group of molecules, but Stat4 response to IL-23 is relatively weak, while Stat4 response to IL-12 is strong.
- IL-23 has also been implicated in the maintenance and proliferation of EL- 17 producing cells, also known as Th 17 cells. See Cua and Kastelein (2006) Nature Immunology 7:557 - 559.
- Th 17 cells are believed to be involved in responses to catastrophic injury, such as breach of the mucosal barrier of the lung or gut, and the resulting exposure to the deadly pathogens K. pneumoniae and C. rodentium. Such catastrophic injuries would almost certainly require an immediate immune response in the form of massive neutrophil influx.
- IL- 12 receptor and IL-23 receptor make it possible to design therapy that targets only IL-23 receptor but not IL- 12 receptor.
- Compounds that bind to and inhibit the activity of IL-23pl9 or IL-23R, either in isolation of as components of their respective heterodimeric complexes, will inhibit IL-23 but not IL-12.
- Such specific binding agents will also inhibit IL-23 activity but not IL-12 activity.
- EL-23/IL-23R specific agents would be expected to be safer (i.e. have a lower side effect profile) than agents that also inhibit IL-12.
- Much of the early work on inhibition of IL-12 involved inhibition of IL-
- Th 17 cells T cell population characterized by the production of IL- 17, IL- 17F, TNF, IL-6 and other factors, referred to as "Th 17 cells" (Langrish et al. (2005) J. Exp. Med. 201 :233-240). Production of such Th 17 cells is promoted by IL-6 and TGF- ⁇ . See, e.g., Veldhoen et al. (2006) Immunity 24:179-189; Dong (2006) Nat. Rev. Immunol. 6(4):329-333. IL-22 has also been proposed as an important Thl7 cytokine. See, e.g., U.S. Patent Application Publication No. 2008/0031882Al . Based on current understanding, DL- 23 is responsible for maintenance and proliferation of this new class of helper T cells, although it is not necessary for the initial creation of ThI 7 cells.
- relapsing-remitting diseases are sometimes referred to as “relapsing-remitting” diseases.
- the prototypical relapsing-remitting disease is multiple sclerosis (MS), in which 85% of subjects suffer from the relapsing-remitting form of the disease, as opposed to a progressive form of the disease.
- MS multiple sclerosis
- Relapsing-remitting MS is characterized by clearly defined acute attacks followed by periods of full recovery, or stabilization with some deficit.
- MS Primary symptoms of MS include fatigue (also called MS lassitude to differentiate it from tiredness resulting from other causes), problems with walking, bowel and or bladder disturbances, visual problems, changes in cognitive function (including problems with memory, attention, and problem-solving), abnormal sensations (such as numbness or "pins and needles"), changes in sexual function, pain, depression and/or mood swings, and less frequently, tremor, incoordination, speech and swallowing problems and impaired hearing.
- Current pharmaceutical interventions include interferon beta Ia (IFN- ⁇ la), interferon beta Ib (IFN- ⁇ lb), and the humanized anti-integrin- ⁇ 4 antibody natalizumab.
- Relapsing-remitting autoimmune diseases also include auto-inflammatory disorders, such as various hereditary periodic fever syndromes, Crohn's disease, Blau syndrome, Bechet's disease and systemic lupus erythematosus. Church et al. (2006) Springer Semin. Immun. 27:494.
- Biologic agents for treatment of hereditary periodic fever syndromes include antagonists of tumor necrosis factor alpha (TNF - ⁇ ), such as infliximab, etanercept and adalimumab, and antagonists of interleukin-1 beta (IL- l ⁇ ), such as the IL-I receptor antagonist anakinra (Kineret ® IL-I receptor antagonist).
- compositions for treatment of immune disorders comprising an antagonist of IL-23 and an antagonist of one or more pro-inflammatory cytokines, e.g. IL- 17A, EL- 17F, IL- l ⁇ and TNF- ⁇ .
- IL- 17A, IL- 17F, IL- l ⁇ and TNF- ⁇ are referred to collectively as "acute phase cytokines," and antagonists of these cytokines are referred to collectively as "acute phase therapeutic agents”.
- the subject is experiencing a flare-up of symptoms of the immune disorder at the start of treatment with the methods and compositions of the present invention.
- the invention relates to methods of treatment of subjects having immune disorders, such as autoimmune diseases, comprising administering to said subject an effective amount of an antagonist of IL-23 and an antagonist of a proinflammatory cytokine selected from the group consisting of IL-17A, IL- 17F, IL- l ⁇ and TNF- ⁇ .
- an antagonist of IL-23 and an antagonist of a proinflammatory cytokine selected from the group consisting of IL-17A, IL- 17F, IL- l ⁇ and TNF- ⁇ .
- combination therapy is referred to herein as combination therapy.
- one or more of the antagonists binds to a cytokine itself
- one or more of the antagonists binds to a cytokine receptor.
- the immune disorder is dysregulation of the Th 17 response, giving rise to suppression of IL-12-mediated ThI tumor surveillance.
- the methods and compositions of the present invention are used to treat subject with cancer or tumors.
- one or more antagonist of the present invention is an antibody or antigen binding fragment thereof.
- the antibody is a chimeric, humanized or fully human antibody
- the antigen binding fragment is a fragment of a chimeric, humanized or fully human antibody.
- the fragment is selected from the group consisting Fab, Fab', Fab'-SH, Fv, scFv, F(ab') 2 , and a diabody.
- the antibody of antigen binding fragment thereof is
- the IL-23 antagonist is an antagonist antibody, or antigen binding fragment thereof, that binds to IL-23pl9 or IL-23R.
- the acute phase therapeutic agent is an antibody that specifically binds to a cytokine selected from the group consisting of IL-I ⁇ , TNF- ⁇ , IL- 17A, and IL- 17F.
- the acute phase therapeutic agent is an antibody that specifically binds to a receptor for a cytokine selected from the group consisting of IL-I ⁇ ,
- TNF- ⁇ TNF- ⁇ , IL- 17A, and IL- 17F.
- the antibody or antigen binding fragment thereof is a bispecific antibody or antigen binding fragment thereof.
- the bispecific antibody binds to and antagonizes IL-23 (e.g. IL-23pl9) or IL-23 receptor (e.g.
- IL-23R IL-23R
- IL-23R binds to and antagonizes an acute phase cytokine or a receptor of an acute phase cytokine.
- the invention relates to a bispecific antibody, or antigen binding fragment thereof, that binds to IL-23R and CDl 61.
- Other embodiments include bispecific reagents directed to CDl 61 and at least one of CD4, CD45RO, CCR4, CCR6, integrin- ⁇ 7, EP2, EP4, IL-IRl, or TNF- ⁇ .
- the bispecific antibody further comprises an IgGl constant domain and/or a toxic payload, such as a radionuclide or other toxin.
- the invention relates to combination therapy using a bispecific reagent comprising a first polypeptide and a second polypeptide, wherein the first polypeptide comprises IL- Ira or a soluble TNF- ⁇ receptor fragment, and the second polypeptide comprises an antigen-binding fragment of an antibody that binds to IL-23, IL- 23R, IL-17A, IL-17RA or IL-17RC.
- each of the first and second polypeptides is fused to an antibody Fc domain.
- the invention relates to use of a combination of two or more agents selected from the group consisting of IL-23, IL- l ⁇ , and PGE2, or PGE2 alone, or agonists thereof, for the in vitro generation of pathogenic mammalian Th 17 cells, e.g. mammals such as a mouse or a human.
- T cells e.g. naive CD4 + T cells
- T cells are cultured in the presence of two or more agents selected from the group consisting of IL-23, EL-l ⁇ , and PGE2, e.g. PGE2 plus either IL-23 or IL-l ⁇ , or in the presence of PGE2 alone.
- the invention relates to a method of screening for compounds for use in the treatment of disorders mediated by Thl7 cells comprising generating pathogenic Th 17 cells in vitro by culturing T cells (e.g. naive CD4 + T cells) in the presence of two or more agents selected from the group consisting of IL-23, IL- l ⁇ , and PGE2, exposing said cells to one or more potential therapeutic compounds, and evaluating the effect of such compound(s) on said Th 17 cells.
- said evaluating is by measurement of the level of expression of two or more cytokines selected from the group consisting of IL-17A, IL- 17F, IL-10, IL-22 and IFN- ⁇ .
- Compounds that inhibit the development or maintenance of Th 17 cells, e.g. by lowering the expression of IL- 17A or IL- 17F, would be considered potential therapeutic agents.
- the invention relates to use of a combination of two or more agents selected from the group consisting of antagonists of IL-23, IL-l ⁇ , and PGE2, including antagonists of any of their respective receptors or receptor subunits, for the treatment of autoimmune or proliferative disorders.
- the two or more agents are present as a single reagent, such as a bifunctional reagent (e.g. a protein) or a bispecific antibody (or antigen binding fragment thereof).
- the autoimmune or proliferative disorder is caused by pathogenic ThI 7 cells.
- the agents are administered locally at (or near) the site of inflammation, whereas in other embodiments the agents are administered systemically, such as orally or parenteral Iy.
- the invention relates to compositions comprising a combination of two or more agents selected from the group consisting of antagonists of IL- 23, IL-l ⁇ , and PGE2, including antagonists of any of their respective receptors or receptor subunits, for use in the treatment of autoimmune or proliferative disorders.
- the antagonist of PGE2 is a cyclooxygenase (COX) inhibitor.
- the antagonist of PGE2 is a specific inhibitor of a PGE2 synthase.
- the composition comprises a bifunctional reagent (e.g. a protein) or a bispecific antibody (or antigen binding fragment thereof).
- the invention relates to methods of treatment of autoimmune or proliferative disorders comprising the steps of (optionally) detecting the level of pathogenic Th 17 cells in a subject (e.g. in a bodily fluid or tissue sample), administering a composition of the present invention to said subject, and (optionally) monitoring the level of said pathogenic Th 17 cells during and/or after administration of the composition to determine whether treatment is effective.
- the composition of the present invention comprises a combination of two or more agents selected from the group consisting of antagonists of EL-23, IL-l ⁇ , and PGE2, including antagonists of any of their respective receptors or receptor subunits, wherein such antagonists optionally comprise a bifunctional reagent (e.g.
- said monitoring is by measurement of the level of expression of one, two, three or more cytokines selected from the group consisting of IL-I IA, IL- 17F, IL-10, IL-22 and IFN- ⁇ .
- treatment is considered effective if said monitoring reveals reduced expression of Th 17 cytokines, e.g. IL- 17A or IL- 17F.
- the methods of the present invention further comprise administration of an immunosuppressive or anti-inflammatory agent, such as steroids (e.g. predinisone) and non-steroidal anti-inflammatory agents.
- an immunosuppressive or anti-inflammatory agent such as steroids (e.g. predinisone) and non-steroidal anti-inflammatory agents.
- treatment with the IL-23 antagonist is continued as a series of one or more doses over a first time interval
- treatment with the acute phase therapeutic agent is continued as a series of one or more doses over a second time interval.
- the first time interval beings at substantially at the same time as the second time interval, sometime later during the second time interval, or after the end of the second time interval.
- the first time interval extends beyond the end of the second time interval, i.e. IL-23 antagonist therapy continues after the cessation of treatment with the acute phase therapeutic agent.
- the second time interval ends upon the resolution of at least one, two or more symptoms of the flare-up of the autoimmune disease.
- the first and second time intervals are selected from the group consisting of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60 or more months.
- the subject treated with the methods or compositions of the present invention has a disorder selected from the group consisting of cancer, arthritis, rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), type I diabetes.
- a disorder selected from the group consisting of cancer, arthritis, rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), type I diabetes.
- the invention relates to pharmaceutical compositions comprising an antagonist of IL-23 and an antagonist of an acute phase cytokine, e.g. IL- l ⁇ , TNF- ⁇ , IL- 17A, or EL- 17F.
- the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or diluent.
- the pharmaceutical compositions of the present invention further comprise an immunosuppressive or anti-inflammatory agent, such as steroids (e.g. prednisone) and nonsteroidal anti-inflammatory agents.
- the invention relates to use of an antagonist of IL-23 and an antagonist of an acute phase cytokine in the manufacture of a medicament for the treatment of an immune disorder, such as cancer, arthritis, RA, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, MS, SLE, type I diabetes.
- an immune disorder such as cancer, arthritis, RA, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, MS, SLE, type I diabetes.
- FIG. IA shows the number of CD161 + CD4 + CD45RO + T cells cells in lamina limbal cells (LPMC) from normal human subjects and from Crohn's disease patients.
- FIG. IB shows IL-17A expression, as measured by enzyme-linked immunosorbent assay (ELISA), in fluorescence activated cell sorting (F ACS ® ) purified CD161 + and CD161 " CD4 + CD45RO + T cells from normal human subjects and from Crohn's disease patients after three day culture with anti-CD2, anti-CD3, anti-CD28 activation beads.
- FIG. 1C shows relative mRNA expression levels for IL-23R.
- FIGS. 2A and 2B show gene expression, and cytokine production, respectively, in CD4 + CD25 " CD45RA ' memory T cells as a function of CD161 expression for peripheral blood mononuclear cells (PBMC) from healthy human donors.
- PBMC peripheral blood mononuclear cells
- Cells are sorted for CDl 61 expression by FACS ® flow cytometry. Gene expression is measured in samples from four donors by qRT-PCR. Cytokine production is measured in samples from at least three donors by ELISA after three days of culture with anti-CD2, anti-CD3, anti- CD28 activation beads.
- FIGS. 3 A and 3B show the expression of IL-17A and IFN- ⁇ , respectively, from human peripheral blood mononuclear CD4 + T lymphocytes cultured with IL-2, IL- 12,' * IL-23, PGE2, IL-I ⁇ , or (IL-I ⁇ + PGE2).
- FIGS. 4 A and 4B present results obtained in experiments in which naive human CD4 + T cells are activated with T cell activation beads and cultured in the presence or absence of PGE2 or specific EP receptors agonists.
- FIG. 4A shows the percentage of IL- 23R + cells as a function of PGE2, as measured by flow cytometric quantification of IL-23R in T cells restimulated for 48 hours, based on the results of five independent experiments (mean + s.e.m., ***P ⁇ 0.001).
- FIG. 4A shows the percentage of IL- 23R + cells as a function of PGE2, as measured by flow cytometric quantification of IL-23R in T cells restimulated for 48 hours, based on the results of five independent experiments (mean + s.e.m., ***P ⁇ 0.001).
- FIG. 4A shows the percentage of IL- 23R + cells as a function of PGE2, as measured by flow cytometric quantification of IL-23R in T cells
- FIGS. 5A, 5B and 5C present results obtained in naive human CD4 + T cells activated with T cell activation beads and cultured in the presence or absence of IL-23 and IL- l ⁇ , with or without PGE2,or the EP receptors agonists butaprost, misoprostol, and sulprostone.
- Data in FIGS. 5A - 5C reflect EL-17A, IFN- ⁇ and IL-10 production in cell-free supernatants of T cells restimulated for 48 hours, respectively. Results in each figure are representative of two independent experiments.
- FIGS. 6A, 6B and 6C present results obtained with naive human CD4 + T cells cultured as described wijth reference to FIGS. 5 A - 5C.
- FIG. 6A shows flow cytometric quantification of CCRo + in T cells restimulated for 48 h. ***P,0.001. Results represent mean + s.e.m. of nine independent experiments.
- naive T cells are cultured in the presence of IL- 1 ⁇ , IL-23, and PGE2. After reactivation, CD4 + CCR6 + and CD4 + CCR6 " T cells are sorted and cultured for seven days in the presence of IL-2.
- FIG. 6A shows flow cytometric quantification of CCRo + in T cells restimulated for 48 h. ***P,0.001. Results represent mean + s.e.m. of nine independent experiments.
- naive T cells are cultured in the presence of IL- 1 ⁇ , IL-23, and PGE2.
- FIGS. 6B and 6C show production of IL-17A, IL-17F, IL-22, and CCL20 in cell-free supernatants of T cells restimulated for 24 hours.
- FIG. 6C shows real-time RT- PCR analysis of ROR- ⁇ t, ROR- ⁇ , and IL-23R expression in T cells restimulated 24 hours. Results in each of FIGS. 6B and 6C reflect the results of four independent experiments.
- FIGS. 7A and 7B present results obtained with human memory CD4 + T cells activated and cultured for three days in the presence of IL-23, IL- l ⁇ , and/or PGE2.
- FIG. 7A and 7B present results obtained with human memory CD4 + T cells activated and cultured for three days in the presence of IL-23, IL- l ⁇ , and/or PGE2.
- FIG. 7A and 7B present results obtained with human memory CD4 + T cells activated and cultured for three days in the presence of IL-23, IL-
- FIG. 7 A shows IL- 17A, EFN- ⁇ , and IL-IO production, as indicated, in cell-free supernatants. Results from nine independent donors are shown.
- FIG. 7B shows the results of real-time RT-PCR of ROR- ⁇ t and T-bet gene expression. Results from four different donors are shown. Horizontal lines represent medians.
- Moisture proteins or “mature form” of a protein refers to the sequence after removal of the signal sequence from the amino terminus. Protein sequences provided herein
- proproteins or precursor protein sequences that include a -20 amino acid N-terminal signal sequence that is not present in the mature form of the protein.
- IL-17 refers to IL-17A.
- proteins referred to herein are the human forms of the proteins.
- Proliferative activity encompasses an activity that promotes, that is necessary for, or that is specifically associated with, e.g., normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.
- administering and “treatment,” as it applies to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
- administering and “treatment” can refer, e.g., to therapeutic, pharmacokinetic, diagnostic, research, and experimental methods.
- Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
- administering and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding composition, or by another cell.
- Treatment refers to therapeutic treatment, prophylactic or preventative measures, to research and diagnostic applications.
- Treatment as it applies to a human, veterinary, or research subject, or cell, tissue, or organ, encompasses contact of an agent with animal subject, a cell, tissue, physiological compartment, or physiological fluid.
- Treatment of a cell also encompasses situations where the agent contacts a target, such as IL-23 receptor, e.g., in the fluid phase or colloidal phase, but also situations where the agonist or antagonist does not contact the cell or the receptor.
- a target such as IL-23 receptor
- Treating” or “Treating” may also refer to administration of a therapeutic agent, such as a composition described herein, internally or externally to a patient in need of the therapeutic agent.
- a therapeutic agent such as a composition described herein
- the agent is administered in an amount effective to prevent or alleviate one or more disease symptoms, or one or more adverse effects of treatment with a different therapeutic agent, whether by preventing the development of, inducing the regression of, or inhibiting the progression of such symptom(s) or adverse effect(s) by any clinically measurable degree.
- the amount of a therapeutic agent that is effective to alleviate any particular disease symptom or adverse effect may vary according to factors such as the disease state, age, and weight of the patient, the ability of the therapeutic agent to elicit a desired response in the patient, the overall health of the patient, the method, route and dose of administration, and the severity of side affects. See, e.g., U.S. Pat. No. 5,888,530.
- a disease symptom or adverse effect has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom or adverse effect.
- a therapeutically effective amount will typically result in a reduction of the measured symptom by at least 5%, usually by at least 10%, more usually at least 20%, most usually at least 30%, preferably at least 40%, more preferably at least 50%, most preferably at least 60%, ideally at least 70%, more ideally at least 80%, and most ideally at least 90%. See, e.g., Maynard et al. (1996) A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, FL; Dent (2001) Good Laboratory and Good Clinical Practice, Urch Publ., London, UK.
- an embodiment of the present invention may not be effective in preventing or alleviating the target disease symptom(s) or adverse effect(s) in every patient, it should alleviate such symptom(s) or effect(s) in a statistically significant number of patients as determined by any statistical test known in the art such as the Student's t-test, the chi 2 -test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test.
- An "antagonist,” as used herein, is any agent that reduces the activity of a targeted molecule.
- an antagonist of a cytokine is an agent that reduces the biological activity of that cytokine, for example by blocking binding of the cytokine to its receptor or otherwise reducing its activity (e.g. as measured in a bioassay).
- an antagonist of a cytokine includes any agent that reduces signaling by the cytokine, and thus may include agents that bind to the cytokine itself, and also agents that binds to its receptor(s).
- An antagonist further includes an agent that reduces the expression of a cytokine or its receptor, including but not limited to nucleic acid-based antagonists, such as antisense nucleic acids and siRNA.
- nucleic acid-based antagonists such as antisense nucleic acids and siRNA.
- An agent that acts as an antagonist of one cytokine may optionally act as an antagonist of another cytokine, e.g. in a bispecific antibody.
- a method involving "combination therapy" and a composition for such combination therapy need not comprise more than one therapeutic agent.
- Cytokine antagonists include, but are not limited to, antagonistic antibodies, peptides, peptide-mimetics, polypeptides, and small molecules that bind to a cytokine (or any of its subunits) or its functional receptor (or any of its subunits) in a manner that interferes with cytokine signal transduction and downstream activity.
- Examples of peptide and polypeptide antagonists include truncated versions or fragments of the cytokine receptor (e.g., soluble extracellular domains) that bind to the cytokine in a manner that either reduces the amount of cytokine available to bind to its functional receptor or otherwise prevents the cytokine from binding to its functional receptor.
- the inhibitory effect of an antagonist can be measured by routine techniques.
- cytokine-induced activity human cells expressing a functional receptor for a cytokine are treated with the cytokine and the expression of genes known to be activated or inhibited by that cytokine is measured in the presence or absence of a potential antagonist.
- Antagonists useful in the present invention inhibit the targeted activity by at least 25%, preferably by at least 50%, more preferably by at least 75%, and most preferably by at least 90%, when compared to a suitable control.
- “Binding compound” refers to a molecule, small molecule, macromolecule, polypeptide, antibody or fragment or analogue thereof, or soluble receptor, capable of binding to a target.
- Binding compound also may refer to a complex of molecules, e.g., a non-covalent complex, to an ionized molecule, and to a covalently or non-covalently modified molecule, e.g., modified by phosphorylation, acylation, cross-linking, cyclization, or limited cleavage, that is capable of binding to a target.
- binding compound refers to both antibodies and antigen binding fragments thereof.
- Binding refers to an association of the binding composition with a target where the association results in reduction in the normal Brownian motion of the binding composition, in cases where the binding composition can be dissolved or suspended in solution.
- Binding composition refers to a binding compound in combination with a stabilizer, excipient, salt, buffer, solvent, or additive.
- Small molecule is defined as a molecule with a molecular weight that is less than 10 kDa, typically less than 2 kDa, and preferably less than 1 kDa.
- Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules containing an inorganic component, molecules comprising a radioactive atom, synthetic molecules, peptide mimetics, and antibody mimetics.
- a small molecule may be more permeable to cells, less susceptible to degradation, and less apt to elicit an immune response than large molecules.
- Small molecules, such as peptide mimetics of antibodies and cytokines, as well as small molecule toxins are described.
- the term "antibody” refers to any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), chimeric antibodies, humanized antibodies, fully human antibodies, etc. so long as they exhibit the desired biological activity.
- Biological activities of antagonist antibodies include inhibiting binding of a cytokine to its receptor, or inhibiting cytokine-induced signaling through a receptor.
- Antibodies used in the present invention will usually bind with at least a K j of about 10 '3 M, more usually at least 10 "6 M, typically at least 10 "7 M, more typically at least 10 "8 M, preferably at least about 10 "9 M, and more preferably at least 10 "10 M, and most preferably at least 10 '11 M. See, e.g., Presta et al. (2001) Thromb. Haemost. 85:379-389; Yang et al. (2001) CHt. Rev. Oncol. Hematol. 38: 17-23; Carnahan et al. (2003) Clin. Cancer Res. (Suppl.) 9:3982s-3990s.
- a specified ligand binds to a particular receptor and does not bind in a significant amount to other proteins present in the sample.
- an antibody is said to bind specifically to a polypeptide comprising a given sequence (e.g. IL- 23pl9) if it binds to polypeptides comprising the sequence of IL-23pl9 but does not bind to proteins lacking the sequence of IL-23pl9.
- an antibody that specifically binds to a polypeptide comprising IL-23pl9 may bind to a FLAG ® -tagged form of IL-23pl9 but will not bind to other FLAG ® -tagged proteins.
- an antagonist of IL-23 refers to an IL-23-specific antagonist. Despite their shared cytokine and receptor subunits, an IL-23-specific antagonist does not also antagonize IL- 12.
- IL-23-specific antagonists include agents that bind to IL-23 and/or IL-23 receptor, including but not limited to agents that bind to IL-23pl9 and IL-23R.
- An agent that antagonizes both IL-23 and BL- 12 is referred to herein as an "IL-12/IL-23 antagonist.”
- Such IL-12/IL-23 antagonists include, but are not limited to, agents that bind to IL-12p40 and DL-12R ⁇ l, which are shared subunits.
- the antibody, or binding composition derived from the antigen-binding site of an antibody, of the contemplated method binds to its antigen with an affinity that is at least two fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with unrelated antigens.
- the antibody will have an affinity that is greater than about 10 9 liters/mol, as determined, e.g., by Scatchard analysis. Munsen et al. (1980) Analyt. Biochem. 107:220-239.
- the term "monoclonal antibody,” as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of antibodies directed against (or specific for) different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods ⁇ see, e.g., U.S. Pat. No. 4,816,567).
- the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. MoI. Biol. 222: 581-597, for example.
- the monoclonal antibodies herein specifically include “chimeric” antibodies
- immunoglobulins in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
- humanized antibody refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin.
- the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
- the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
- the humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.
- antibody also includes “fully human” antibodies, i.e., antibodies that comprise human immunoglobulin protein sequences only.
- a fully human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
- mouse antibody or “rat antibody” refer to an antibody that comprises only mouse or rat immunoglobulin sequences, respectively.
- a fully human antibody may be generated in a human being, in a transgenic animal having human immunoglobulin germline sequences, by phage display or other molecular biological methods.
- recombinant immunoglobulins may also be made in transgenic mice. See Mendez et al. (1997) Nature Genetics 15:146-156. See also Abgenix and Medarex technologies.
- the antibodies of the present invention also include antibodies with modified
- Fc regions to provide altered effector functions. See, e.g., U.S. Pat. No. 5,624,821 ; WO 2003/086310; WO 2005/120571; WO 2006/0057702; Presta (2006) Adv. Drug Delivery Rev. 58:640-656.
- Such modification can be used to enhance or suppress various reactions of the immune system, with possible beneficial effects in diagnosis and therapy.
- Alterations of the Fc region include amino acid changes (substitutions, deletions and insertions), glycosylation or deglycosylation, and adding multiple Fc. Changes to the Fc can also alter the half-life of antibodies in therapeutic antibodies, and a longer half-life would result in less frequent dosing, with the concomitant increased convenience and decreased use of material.
- the antibodies of the present invention also include antibodies with intact Fc regions that provide full effector functions, e.g. antibodies of isotype IgGl, which induce complement-dependent cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC) in the a targeted cell.
- CDC complement-dependent cytotoxicity
- ADCC antibody dependent cellular cytotoxicity
- the antibodies may also be conjugated (e.g., covalently linked) to molecules that improve stability of the antibody during storage or increase the half-life of the antibody in vivo.
- molecules that increase the half-life are albumin (e.g., human serum albumin) and polyethylene glycol (PEG).
- Albumin-linked and PEGylated derivatives of antibodies can be prepared using techniques well known in the art. See, e.g., Chapman (2002) Adv. Drug Deliv. Rev. 54:531-545; Anderson and Tomasi (1988) J. Immunol. Methods 109:37-42; Suzuki et al. (1984) Biochim. Biophys. Acta 788:248-255; and Brekke and Sandlie (2003) Nature Rev. 2:52-62.
- binding fragment encompass a fragment or a derivative of an antibody that still substantially retains its biological activity, e.g. inhibiting cytokine signaling via the cytokine receptor.
- antibody fragment refers to a portion of a full length antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab 1 , F(ab') 2 , and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; and multispecific antibodies formed from antibody fragments. Typically, a binding fragment or derivative retains at least 10% of its inhibitory activity.
- a binding fragment or derivative retains at least 25%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 100% (or more) of its inhibitory activity, although any binding fragment with sufficient affinity to exert the desired biological effect will be useful. It is also intended that an antibody binding fragment can include variants having conservative amino acid substitutions that do not substantially alter its biologic activity.
- a "Fab fragment” is comprised of one light chain and the CHI and variable regions of one heavy chain.
- the heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.
- An "Fc" region contains two heavy chain fragments comprising the C H I and
- C H 2 domains of an antibody The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the C H 3 domains.
- a "Fab' fragment” contains one light chain and a portion of one heavy chain that contains the V H domain and the C HI domain and also the region between the C H I and
- a "F(ab') 2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the C H I and C H 2 domains, such that an interchain disulfide bond is formed between the two heavy chains.
- a F(ab') 2 fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains.
- the "Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.
- a “single-chain Fv antibody refers to antibody fragments comprising the VH and V L domains of an antibody, wherein these domains are present in a single polypeptide chain.
- the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the scFv to form the desired structure for antigen binding.
- a "diabody” is a small antibody fragment with two antigen-binding sites, which fragments comprise a heavy chain variable domain (V H ) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL or VL-V H ).
- Diabodies are described more fully in, e.g., EP 404,097; WO 93/1 1 161 ; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448. For a review of engineered antibody variants generally see Holliger and Hudson (2005) Na/. Biotechnol. 23: 1126-1136.
- a “domain antibody fragment” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In some instances, two or more VH regions are covalently joined with a peptide linker to create a bivalent domain antibody fragment. The two V H regions of a bivalent domain antibody fragment may target the same or different antigens.
- a "bivalent antibody” comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies may be bispecific (see below).
- the monoclonal antibodies herein also include camel ized single domain antibodies. See, e.g., Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231 :25; WO 94/04678; WO 94/25591; U.S. Pat. No. 6,005,079).
- the present invention provides single domain antibodies comprising two V H domains with modifications such that single domain antibodies are formed.
- bispecific antibodies are also useful in the present methods and compositions.
- the term "bispecific antibody” refers to an antibody, typically a monoclonal antibody, having binding specificities for at least two different antigenic epitopes.
- the epitopes are from the same antigen.
- the epitopes are from two different antigens.
- Methods for making bispecific antibodies are known in the art. For example, bispecific antibodies can be produced recombinantly using the co-expression of two immunoglobulin heavy chain/light chain pairs. See, e.g., Milstein et al. (1983) Nature 305: 537-39. Alternatively, bispecific antibodies can be prepared using chemical linkage.
- Bispecific antibodies include bispecific antibody fragments. See, e.g., Holliger e? al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6444-48, Gruber et al. (1994) J Immunol. 152:5368. Potentially bispecific antibody fragments include diabodies, Bis-scFv, bivalent domain antibody fragments, Fab 2 , and even Fab3 fragments (which may be trispecific) ⁇ see Holliger and Hudson (2005) Nat. Biotechnol. 23: 1 126) and Bis-scFv-Fc. Bispecific antibodies also include dual variable domain immunoglobulins, such as those disclosed at U.S. Patent Application Publication No. 2005/0071675.
- the antibodies of the present invention also include antibodies or fragments thereof conjugated to cytotoxic payloads, such as cytotoxic agents or radionuclides.
- cytotoxic payloads such as cytotoxic agents or radionuclides.
- cytotoxic agents include ricin, vinca alkaloid, methotrexate, Psuedomonas exotoxin, saporin, diphtheria toxin, cisplatin, doxorubicin, abrin toxin, gelonin and pokeweed antiviral protein.
- Exemplary radionuclides for use in immunotherapy with the antibodies of the present invention include 125 1, 131 I, 90 Y, 67 Cu, 21 1 At, 177 Lu, 143 Pr and 213 Bi. See, e.g., U.S. Patent Application Publication No. 2006/0014225.
- Immunoser condition encompasses, e.g., pathological inflammation, an inflammatory disorder, and an autoimmune disorder or disease.
- Immunune condition also refers to infections, persistent infections, and proliferative conditions, such as cancer, tumors, and angiogenesis, including infections, tumors, and cancers that resist eradication by the immune system.
- Treatment includes, e.g., cancer, cancer cells, tumors, angiogenesis, and precancerous conditions such as dysplasia.
- Intracellular disorder means a disorder or pathological condition where the pathology results, in whole or in part, from, e.g., a change in number, change in rate of migration, or change in activation, of cells of the immune system.
- Cells of the immune system include, e.g., T cells, B cells, monocytes or macrophages, antigen presenting cells (APCs), dendritic cells, microglia, NK cells, NKT cells, neutrophils, eosinophils, mast cells, or any other cell specifically associated with the immunology, for example, cytokine- producing endothelial or epithelial cells.
- An "IL-17-producing cell” means a T cell that is not a classical THl -type
- Thl7 cells T cell or classical TH2-type T cell, referred to as Thl7 cells.
- Thl7 cells are discussed in greater detail at Cua and Kastelein (2006) Na/. Immunol. 7:557-559; Tato and O'Shea (2006) Nature 441 : 166-168; Iwakura and Ishigame (2006) J. Clin. Invest. 116: 1218-1222.
- "IL-17-producing cell” also means a T cell that expresses a gene or polypeptide of Table 1OB of U.S. Patent Application Publication No.
- 2004/0219150 e.g., mitogen responsive P- protein; chemokine ligand 2; interleukin-17 (IL-17); transcription factor RAR related; and/or suppressor of cytokine signaling 3
- expression with treatment by an IL-23 agonist is greater than treatment with an IL- 12 agonist
- "greater than” is defined as follows.
- Expression with an IL-23 agonist is ordinarily at least 5-fold greater, typically at least 10-fold greater, more typically at least 15-fold greater, most typically at least 20-fold greater, preferably at least 25-fold greater, and most preferably at least 30-fold greater, than with IL- 12 treatment.
- Expression can be measured, e.g., with treatment of a population of substantially pure IL-17 producing cells.
- a Th 17 response is an immune response in which the activity and/or proliferation of ThI 7 cells are enhanced, typically coupled with a repressed ThI response.
- IL-17-producing cell includes a progenitor or precursor cell that is committed, in a pathway of cell development or cell differentiation, to differentiating into an IL-17-producing cell, as defined above.
- a progenitor or precursor cell to the IL-17 producing cell can be found in a draining lymph node (DLN).
- DNN draining lymph node
- IL- 17- producing cell encompasses an IL-17-producing cell, as defined above, that has been, e.g., activated, e.g., by a phorbol ester, ionophore, and/or carcinogen, further differentiated, stored, frozen, desiccated, inactivated, partially degraded, e.g., by apoptosis, proteolysis, or lipid oxidation, or modified, e.g., by recombinant technology.
- isolated nucleic acid molecule refers to a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the antibody nucleic acid.
- An isolated nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from the nucleic acid molecule as it exists in natural cells.
- an isolated nucleic acid molecule includes a nucleic acid molecule contained in cells that ordinarily express the antibody where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.
- immunomodulatory agent refers to natural or synthetic agents that suppress or modulate an immune response.
- the immune response can be a humoral or cellular response.
- Immunomodulatory agents encompass immunosuppressive or anti-inflammatory agents.
- immunosuppressants are therapeutics that are used in immunosuppressive therapy to inhibit or prevent activity of the immune system. Clinically they are used to prevent the rejection of transplanted organs and tissues (e.g. bone marrow, heart, kidney, liver), and/or in the treatment of autoimmune diseases or diseases that are most likely of autoimmune origin (e.g. rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, ulcerative colitis, multiple sclerosis).
- organs and tissues e.g. bone marrow, heart, kidney, liver
- autoimmune diseases or diseases that are most likely of autoimmune origin (e.g. rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, ulcerative colitis, multiple sclerosis).
- Immunosuppressive drugs can be classified into four groups: glucocorticoids cytostatics; antibodies (including Biological Response Modifiers or DMARDs); drugs acting on immunophilins; other drugs, including known chemotherpeutic agents used in the treatment of proliferative disorders.
- glucocorticoids cytostatics including Biological Response Modifiers or DMARDs
- drugs acting on immunophilins other drugs, including known chemotherpeutic agents used in the treatment of proliferative disorders.
- the antibodies of the present invention can be administered in conjunction with a new class of myelin binding protein-like therapeutics, known as copaxones.
- Anti-inflammatory agents or "anti-inflammatory drugs”, is used to represent both steroidal and non-steroidal therapeutics.
- Steroids also known as corticosteroids, are drugs that closely resemble Cortisol, a hormone produced naturally by adrenal glands. Steroids are used as the main treatment for certain inflammatory conditions, such as: Systemic vasculitis (inflammation of blood vessels); and Myositis (inflammation of muscle).
- Steroids might also be used selectively to treat inflammatory conditions such as: rheumatoid arthritis (chronic inflammatory arthritis occurring in joints on both sides of the body); systemic lupus erythematosus (a generalized disease caused by abnormal immune system function); Sjogren's syndrome (chronic disorder that causes dry eyes and a dry mouth).
- rheumatoid arthritis chronic inflammatory arthritis occurring in joints on both sides of the body
- systemic lupus erythematosus a generalized disease caused by abnormal immune system function
- Sjogren's syndrome chronic disorder that causes dry eyes and a dry mouth.
- Non-steroidal anti-inflammatory drugs are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation.
- the term "non-steroidal” is used to distinguish these drugs from steroids, which (amongst a broad range of other effects) have a similar eicosanoid-depressing, antiinflammatory action.
- NSAEDs are generally indicated for the symptomatic relief of the following conditions: rheumatoid arthritis; osteoarthritis; inflammatory arthropathies (e.g.
- NSAIDs include salicylates, arlyalknoic acids, 2-arylpropionic acids (profens), N-arylanthranilic acids (fenamic acids), oxicams, coxibs, and sulphonanilides.
- Interleukin- 17 (or “IL- 17,” or “IL- 17A”), unless otherwise indicated, means a protein consisting of one or two polypeptide chains, with each chain consisting essentially of the sequence of the mature form of human IL-17A as described in any of NCBI Protein Sequence Database Accession Numbers NP_002181, AAH67505, AAH67503, AAH67504, AAH66251, AAH66252 or naturally occurring variants thereof.
- Interleukin- 17F (or “IL- 17F”) means a protein consisting of one or two polypeptide chains, with each chain consisting essentially of the sequence of the mature form of human IL- 17F as described at NCBI Protein Sequence Database Accession Number NP 443104.1.
- IL- 17R or "IL- 17RA” means a single polypeptide chain consisting essentially of the sequence of the mature form of human IL- 17RA as described in WO 96/29408 or in any of NCBI Protein Sequence Database Accession Numbers: NP_055154, Q96F46, CAJ86450, or naturally occurring variants of these sequences.
- IL- 17RC means a single polypeptide chain consisting essentially of the sequence of the mature form of human IL- 17RC as described in WO 02/38764 or in any of NCBI Protein Sequence Database Accession Numbers NP 703191, NP 703190 and NP l 16121, or naturally occurring variants of these sequences.
- IL- 17 receptor means either IL- 17RA, IL- 17RC, or other IL- 17 receptor subunit, or a dimeric complex of two of these receptor subunits (either homodimeric or heterodimeric).
- Interleukin-23 means a protein consisting of two polypeptide subunits, pl9 and p40.
- the sequence of the pi 9 subunit (also known as EL-23pl9, IL23A) is provided at any of NCBI Protein Sequence Database Accession Numbers NP 057668, AAH6751 1, AAH66267, AAH66268, AAH66269, AAH667512, AAH67513 or naturally occurring variants of these sequences.
- Interleukin-23R or "IL-23R” means a single polypeptide chain consisting essentially of the sequence of the mature form of human IL-23R as described in NCBI
- Protein Sequence Database Accession Number NP_653302 (IL23R, Gene ID: 149233) or naturally occurring variants thereof. Additional EL-23R sequence variants are disclosed at
- Interleukin- 12R ⁇ 1 or "IL- 12R ⁇ 1” means a single polypeptide chain consisting essentially of the sequence of the mature form of human IL-12R ⁇ l as described in NCBI Protein Sequence Database Accession Numbers NP 714912, NP_005526
- TNF- ⁇ means a single polypeptide chain consisting essentially of the sequence of the mature form of human TNF- ⁇ as described in NCBI Protein Sequence
- TNF- ⁇ receptor refers to the mature form of either tumor necrosis factor receptor 1 precursor (TNFRSFlA, Gene ID: 7132) as described in NCBI Protein Sequence
- Interleukin- l ⁇ or "IL-l ⁇ ” means a single polypeptide chain consisting essentially of the sequence of the mature form of human IL-l ⁇ as described in NCBI Protein
- Interleukin- l ⁇ receptor means a single polypeptide chain consisting essentially of the sequence of the mature form of human IL-l ⁇ receptor type I precursor, as described in NCBI Protein Sequence Database Accession Number NP 000868 (ELlRl,
- CD161 refers to the NK cell surface antigen disclosed in U.S. Pat. No.
- the protein is also known as, e.g., KLRBl and NKRPlA. See GeneID 3820.
- CDl 61 The amino acid sequence for CDl 61 is available at GenBank (NCBI) accession number
- PGE2 refers to prostaglandin E2.
- PGE2 antagonist refers to any agent that inhibits the activity of PGE2 by any mechanism, such as blocking the synthesis of PGE2 or the binding of PGE2 to its receptor(s).
- a binding compound that consists essentially of a recited amino acid sequence may also include one or more amino acids, including substitutions of one or more amino acid residues, that do not materially affect the properties of the binding compound.
- the present invention provides compositions and methods for treatment of subject having immune disorders, such as autoimmune disease, involving combination therapy with an antagonist of IL-23 and an antagonist of at least one other pro-inflammatory cytokine, e.g. IL- 17A, IL- 17F, TNF- ⁇ and IL-I ⁇ .
- an antagonist of IL-23 and an antagonist of at least one other pro-inflammatory cytokine e.g. IL- 17A, IL- 17F, TNF- ⁇ and IL-I ⁇ .
- IL-6 interferon-gamma
- IFNgamma interferon-gamma
- GM-CSF granulocyte colony- stimulating factor
- IL-l ⁇ , IL-l ⁇ , and transforming growth factor-beta 1 (TGF- ⁇ l) play a role in ALS, Parkinson's disease, and Alzheimer's disease. Hoozemans et al. (2001) Exp. Gerontol.
- TNF- ⁇ , IL-l ⁇ , IL-6, IL-8, IFN- ⁇ , and DL-17 appear to modulate response to brain ischemia. See, e.g., Kostulas et al. (1999) Stroke 30:2174-2179; Li et al. (2001) J. Neuroimmunol. 1 16:5-14.
- Vascular endothelial cell growth factor (VEGF) is associated with ALS. Cleveland and Rothstein (2001) Nature 2:806-819.
- Inflammatory bowel disorders e.g., Crohn's disease, ulcerative colitis, celiac disease, and irritable bowel syndrome
- Crohn's disease is associated with increased IL- 12 and IFN ⁇
- ulcerative colitis is associated with increased IL-5, IL- 13, and TGF- ⁇
- IL- 17 expression may also increase in Crohn's disease and ulcerative colitis. See, e.g., Podolsky (2002) New Engl. J. Med. 347:417-429; Bouma and Strober (2003) Nat. Rev. Immunol. 3:521-533; Bhan et al. (1999) Immunol.
- IL-23/IL-23R blockade should prove useful in treatment of a number of immune mediated inflammatory disorders, such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, psoriasis, atopic dermatitis, multiple sclerosis, type I diabetes, and SLE.
- FL-23/IL-23R inhibitors will also find use in treatment of proliferative disorders, e.g. cancer and tumors.
- IL-23 in these various disorders can be found in the following published PCT applications: WO 04/081190; WO 04/071517; WO 00/53631 ; and WO 01/18051.
- IL-23/IL-23R inhibitors may also find use in treatment of infections, including chronic infections, such as bacterial, mycobacterial, viral and fungal infections.
- IL-23 plays an important role in the development of Th 17 cells, which have recently been implicated in the pathogenesis of a number of autoimmune diseases.
- IL-23 is "upstream" of the various pro-inflammatory effector cytokines, such as IL- 17, TNF- ⁇ , and IL-I ⁇ .
- IL-23 is said to be "upstream” in that it is primarily involved in early events in the onset of pathogenic immune response, rather than the subsequent effector (acute) phase of the response. See, e.g., Thakker et al. (2007) J. Immunol. 178:2589. These later, acute phase cytokines generate the localized inflammation that gives rise to the signs and symptoms associated with a flare-up of the disease.
- the methods and compositions of the present invention involve administration of an antagonist of an acute phase cytokine (e.g. IL- 17A, IL-17F, TNF- ⁇ , and IL-I ⁇ ) to a subject having an immune disorder, such as an autoimmune disease, early in treatment to rapidly reduce the signs and symptoms of the disease.
- an antagonist of an acute phase cytokine e.g. IL- 17A, IL-17F, TNF- ⁇ , and IL-I ⁇
- an immune disorder such as an autoimmune disease
- Antagonists of acute phase cytokines are referred to herein for convenience as "acute phase therapeutic agents.”
- more than one acute phase therapeutic agent is used.
- a subject will be experiencing a flare-up when treatment with an acute phase therapeutic agent is started.
- This initial treatment is combined with administration of an antagonist of IL-23, which is optionally started at the same time, or during, treatment with the acute phase therapeutic agent(s), and continues after administration of the acute phase therapeutic agent(s) has been discontinued.
- the acute phase therapeutic agent is intended to provide relatively rapid relief of signs and symptoms
- IL-23 antagonists are intended primarily to reduce the likelihood of recurrence of the signs and symptoms in a future flare-up.
- treatment with an IL-23 antagonist may be required even in the asymptomatic patient to prevent relapse.
- the specific combination of therapeutic agents, and the respective timing of their administration provide a comprehensive disease management protocol for autoimmune disorder, particularly those of a relapsing-remitting character.
- Antagonists useful in the present invention include a soluble receptor comprising the extracellular domain of a functional receptor for IL- 17A, IL- 17F, TNF- ⁇ , IL- l ⁇ or IL-23.
- Soluble receptors can be prepared and used according to standard methods. See, e.g., Jones et al. (2002) Biochim. Biophys. Acta 1592:251-263; Prud Subscribe et al. (2001) Expert Opinion Biol. Ther. 1 :359-373; Fernandez-Botran (1999) Crit. Rev. Clin. Lab ScL 36: 165-224.
- Preferred IL-23 antagonists are antibodies that bind to, and inhibit the activity of, any of IL-23, IL-23pl9, IL-12p40, IL-23R, IL-12R ⁇ l, and an IL-23R/IL-12R ⁇ l complex.
- Another preferred DL-23 antagonist is an IL-23 binding polypeptide which consists essentially of the extracellular domain of IL-23R, e.g., amino acids 1-353 of GenBankAAM44229, or a fragment thereof.
- IL-23 antagonists of the present invention such as inhibitory IL-23pl9 and
- IL-23R-specific antibodies can inhibit the biological activity of IL-23 in any manner, including but not limited to reducing production of IL-I ⁇ and TNF- ⁇ by peritoneal macrophages and IL- 17 by Th 17 cells. See Langrish et al. (2004) Immunol. Rev. 202:96- 105. IL-23 antagonists will also be able to inhibit the gene expression of IL-17A, IL- 17F, CCL7, CCL17, CCL20, CCL22, CCRl, and GM-CSF. See Langrish et al. (2005) J. Exp. Med. 201 :233-240.
- IL-23 antagonists will also block the ability of IL-23 to enhance proliferation or survival of Thl7 cells. Cua and Kastelein (2006) Nat. Immunol. 7:557-559.
- the inhibitory activity of IL-23 antagonists will be useful in the treatment of inflammatory, autoimmune, and proliferative disorders. Examples of such disorders are described in PCT patent application publications WO 04/081190; WO 04/071517; WO 00/53631 ; and WO 01/18051.
- Exemplary assays for the determination of IL-23 antagonist activity are provided at Examples 2 and 3, infra.
- Exemplary antibodies to IL-23pl9 are disclosed at PCT patent application publication WO 2007/024846, U.S. Patent Application Publication Nos.
- Antagonists of IL-23 also include aptamers, as disclosed at U.S. Patent Application No. 2006/0193821.
- Other nucleic acid inhibitors of IL-23 include antisense polynucleotides and siRNA molecules, e.g. as disclosed at U.S. Patent Application Publication No. 2005/0261219.
- Additional anti-IL-23 antibodies are disclosed at U.S. Patent Application Publication No. 2006/0067936.
- Compounds that reduce the production of IL-23 are disclosed at U.S. Patent Application Publication No. 2006/0135518.
- Preferred IL- 17 antagonists for use in the present invention are antibodies that specifically bind to, and inhibit the activity of, any of IL- 17, IL- 17RA, IL- 17RC, and a heteromeric complex comprising IL- 17RA and DL- 17RC. More preferably, the target of the IL-17 antagonist is IL-17 or IL-17RA. Particularly preferred IL-17 antagonists specifically bind to, and inhibit the activity of IL-17. Exemplary antibodies to IL- 17A are disclosed at WO 2006/013107 and WO 2008/021 156.
- Preferred TNF- ⁇ antagonists for use in the present invention are antibodies that specifically bind to, and inhibit the activity of, TNF- ⁇ or its receptor.
- Exemplary anti- TNF- ⁇ antibodies are available, e.g., as infliximab, etanercept and adalimumab.
- Preferred IL-l ⁇ antagonists for use in the present invention are antibodies that specifically bind to, and inhibit the activity of, IL-l ⁇ or its receptor.
- Exemplary antibodies to IL-l ⁇ include CDP 484 (a PEGylated anti-IL-l ⁇ fragment), and antibodies disclosed at U.S. Patent Application Publication No. 2003/0124617.
- IL-l ⁇ antagonists also include IL-I receptor antagonist anakinra (Kineret ® IL-I receptor antagonist). Such agents have found use in the treatment of rheumatoid arthritis. Gabay and Arend (1998) Springer Semin. Immunopathol. 20:229.
- Another preferred IL-23 antagonist for use in the present invention is a bispecific antibody, or bispecific antibody fragment, which also antagonizes the activity of a cytokine selected from the group consisting of IL-17A, IL- 17F, TNF- ⁇ , and IL-l ⁇ .
- Such bispecific antagonists specifically bind to, and inhibit the activity of, the following combinations: IL-17 and IL-23; IL-17 and IL-23pl9; IL-17 and IL-12p40; IL-17 and an IL- 23R/IL-12RB1 complex; IL-17 and IL-23R; IL-17 and IL-12RBl ; IL- 17RA and IL-23; IL- 17RA and IL-23pl9; IL-17RA and IL-12p40; IL-17RA and an IL-23R/IL-12RB1 complex; IL-17RA and IL-23R; IL-17RA and IL-12RB1; IL-17RC and IL-23; IL-17RC and IL-23pl9; IL-17RC and IL-12p40; EL-17RC and an IL-23R/IL-12RB1 complex; IL-17RC and IL-23R; IL- 17RC and IL-12RBl; an IL- 17RA/IL- 17RC complex and
- bispecific antibodies used in the present invention are: IL-17 and IL-23, e.g. IL-17 and IL- 23pl9; IL-17RA and IL-23, e.g. IL-17RA and IL-23pl9.
- a particularly preferred bispecific antibody specifically binds to, and inhibits the activity of, each of IL-17 and IL-23pl9.
- Bispecific antibodies that antagonize both IL-17 and IL-23 activity can be produced by any technique known in the art. For example, bispecific antibodies can be produced recombinantly using the co-expression of two immunoglobulin heavy chain/light chain pairs. See, e.g., Milstein et al.
- bispecific antibodies can be prepared using chemical linkage. See, e.g., Brennan et al. (1985) Science 229: 81. These bifunctional antibodies can also be prepared by disulfide exchange, production of hybrid-hybridomas (quadromas), by transcription and translation to produce a single polypeptide chain embodying a bispecific antibody, or transcription and translation to produce more than one polypeptide chain that can associate covalently to produce a bispecific antibody.
- the contemplated bispecific antibody can also be made entirely by chemical synthesis.
- the bispecific antibody may comprise two different variable regions, two different constant regions, a variable region and a constant region, or other variations.
- IL-23-antagonist bispecific antibodies relate to antagonism of IL- 17 and not to antagonism of TNF- ⁇ or IL-I ⁇
- analogous bispecific antibodies that antagonize TNF- ⁇ and IL-I ⁇ are also within the scope of the present invention.
- Such IL-23-antagonist bispecific antibodies may bind, e.g., to TNF- ⁇ or IL-I ⁇ or any of their respective receptors or receptor subunits.
- Bispecific reagents will also find use in the methods and compositions of the present invention.
- the invention relates to combination therapy using a bispecific reagent that binds to two targets selected from the group consisting of IL-23 (e.g. pi 9 and/or p40), IL-23R (e.g. IL-23R and/or IL-12R ⁇ l), IL- 17A, IL- 17F, IL- 17 receptor (e.g. IL- 17RA and/or IL-17RC), TNF- ⁇ , IL- l ⁇ , TNF- ⁇ receptor (and soluble fragments thereof), and BL-I receptor (and soluble fragments thereof).
- IL-23 e.g. pi 9 and/or p40
- IL-23R e.g. IL-23R and/or IL-12R ⁇ l
- IL- 17A IL- 17F
- IL- 17 receptor e.g. IL- 17RA and/or IL-17RC
- TNF- ⁇ IL- 17RA and/or IL-17RC
- TNF- ⁇ TNF-
- the bispecific reagent comprises a complex of a first polypeptide derived from antigen binding site of an antibody, and a second polypeptide comprising a soluble receptor fragment.
- the first and second polypeptides are fusion proteins comprising antibody Fc domains, e.g. human heavy chain IgGl or IgG2a.
- the Fc domains are modified using a "knobs into holes" approach to promote efficient heterodimeric association of the two polypeptide chains to form a bispecific reagent, rather than the monospecific (bivalent) form that might otherwise result from homodimer formation. See Zhu et al. (1997) Protein ££/.6:781.
- Antibody antagonists for use in the invention may be prepared by any method known in the art for preparing antibodies.
- the preparation of monoclonal, polyclonal, and humanized antibodies is described in Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter et al. (2000) J. Immunol. 165:6205; He et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J.
- the eliciting antigen may be a peptide containing a single epitope or multiple epitopes, or it may be the entire protein alone or in combination with one or more immunogenicity enhancing agents known in the art.
- the peptide may be conjugated to a carrier protein.
- the antigen may also be an isolated full-length protein, a cell surface protein (e.g. immunizing with cells transfected with at least a portion of the antigen), or a soluble protein (e.g. immunizing with only the extracellular domain portion of the protein).
- the antigen may be expressed by a genetically modified cell, in which the DNA encoding the antigen is genomic or non-genomic (e.g.
- a peptide consisting essentially of a region of predicted high antigenicity can be used for antibody generation.
- regions of high antigenicity of human pi 9 occur at amino acids 16-28; 57-87; 110-114; 136-154; and 182-186 of GenBank AAQ89442 (gi:37183284) and regions of high antigenicity of human IL-23R occur at amino acids 22- 33; 57-63; 68-74; 101-112; 1 17-133; 164-177; 244-264; 294-302; 315-326; 347-354; 444- 473; 510-530; and 554-558 of GenBank AAM44229 (gi: 21239252), as determined by analysis with a Parker plot using Vector NTI® Suite (Informax, Inc, Bethesda, MD).
- Any suitable method of immunization can be used. Such methods can include use of adjuvants, other immunostimulants, repeated booster immunizations, and the use of one or more immunization routes. Immunization can also be performed by DNA vector immunization. Wang et al. (1997) Virology 228:278-284. Alternatively, animals can be immunized with cells bearing the antigen of interest, which may provide superior antibody generation than immunization with purified antigen. Kaithamana et al. (1999) J. Immunol. 163:5157-5164.
- Preferred antibody antagonists are monoclonal antibodies, which may be obtained by a variety of techniques familiar to skilled artisans. Methods for generating monoclonal antibodies are generally described in Stites et al. (eds.) (1982) BASIC AND CLINICAL IMMUNOLOGY (4th ed.) Lange Medical Publications, Los Altos, CA, and references cited therein; Harlow and Lane (1988) ANTIBODIES: A LABORATORY MANUAL CSH Press; Goding (1986) MONOCLONAL ANTIBODIES: PRINCIPLES AND PRACTICE (2d ed.) Academic Press, New York, NY.
- splenocytes isolated from an immunized mammalian host are immortalized, commonly by fusion with a myeloma cell to produce a hybridoma.
- splenocytes isolated from an immunized mammalian host are immortalized, commonly by fusion with a myeloma cell to produce a hybridoma.
- Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods known in the art. See, e.g., Doyle et al. (eds.
- chimeric antibodies immunoglobulins in which the variable domain is from the parental antibody generated in an experimental mammalian animal, such as a rat or mouse, and the constant domains are obtained from a human antibody, so that the resulting chimeric antibody will be less likely to elicit an adverse immune response in a human subject than the parental mammalian antibody.
- a monoclonal antibody used in the present invention is a "humanized antibody", in which all or substantially all of the hypervariable loops (e.g., the complementarity determining regions or CDRs) in the variable domains correspond to those of a non-human immunoglobulin, and all or substantially all of the framework (FR) regions in the variable domains are those of a human immunoglobulin sequence.
- a particularly preferred monoclonal antibody for use in the present invention is a "fully human antibody", e.g., an antibody that comprises human immunoglobulin protein sequences only.
- a fully human antibody may contain carbohydrate chains from the cell species in which it is produced, e.g., if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell, a fully human antibody will typically contain murine carbohydrate chains.
- Bispecific reagents of the present invention may be particularly useful in situations where simultaneous binding of a single reagent (e.g. an antibody) to two different antigens provides added specificity and/or toxicity, such as cell surface antigens.
- bispecific reagents such as a bispecific antibodies, may also be generated with agents that bind to cell surface proteins associated with a pathogenic T cell subset, such as pathogenic Th 17 cells.
- such cell surface proteins are IL-23R and CDl 61 (also referred to as NK cell surface antigen, KLRBl (GenelD 3820), and NKRPlA). See also U.S. Pat. Nos. 5,965,401 and 5,770,387.
- the amino acid sequence for CD161 is available at GenBank (NCBI) database under accession number NP_002249.
- NCBI GenBank
- the presence of CDl 61 on the surface of memory T cells CD4 + /CD45RO + /CD45RA '
- Pathogenic Th 17 cells are also known to express IL-23R.
- Bispecific reagents that bind to both CD161 and IL-23R would be expected to be highly selective for only the most pathogenic T cells. Such specific reagents will find use in diagnosis and monitoring of subjects, including those undergoing treatment, as a tool to measure of the presence and localization of highly pathogenic Thl7 cells. These reagents will also find use in therapeutic applications, where they can specifically promote killing of the pathogenic target cells, i.e. those cells expressing both CD161 and IL-23R.
- the reagents e.g. antibodies comprising a human IgGl constant domain, may promote ADCC (antigen- dependent cellular cytotoxicity) dependent killing of pathogenic ThI 7 cells.
- the reagents may also be used to deliver a toxic payload to such pathogenic Th 17 cells, e.g. a radionuclide or other toxin.
- Additional bispecific reagents that may find use in treatment of diseases caused by pathogenic Th 17 cells include reagents directed to two or more cell surface molecules found on these cells, wherein specificity of the reagent for the combination of said two or more cell surface molecules renders the reagent more specific for the pathogenic cells. Such enhanced specificity may be helpful in reducing side effects caused by undesired effects on non-target cells expressing any one of the cell surface molecules.
- a bispecific reagent may be directed to CD161 and any other cell surface marker associated with pathogenic Th 17 cells, including but not limited to CD4, CD45RO, CCR4, CCR6, integrin- ⁇ 7, EP2, EP4, IL-IRl, or TNF- ⁇ .
- a bispecific reagent may be directed to any two of the following cell surface proteins: CD161, CD4, CD45RO, CCR4, CCR6, integrin- ⁇ 7, EP2, EP4, EL-IRl, and TNF- ⁇ .
- IL-6 / TGF- ⁇ -driven mouse ThI 7 cells secrete not only IL- 17A, but also very high levels of the immunosuppressive cytokine IL-IO. Whereas IL-23-driven Th 17 cells are able to induce experimental autoimmune encephalomyelitis (EAE) in a passive transfer model in mice (Langrish et al. (2005) J. Exp. Med. 201 :233), IL-6 / TGF- ⁇ -driven mouse Thl7 cells are non-pathogenic.
- EAE experimental autoimmune encephalomyelitis
- mice led Applicants to search for a similar pathogenic ThI 7 lineage in humans.
- culture in the presence of IL-6 and TGF- ⁇ did not promote the development of human ThI 7 cells, Applicants have found that PGE2 acts synergistically with IL-l ⁇ to promote formation of a pathogenic subset of human Th 17 cells.
- These pathogenic Th 17 cells produce high levels of IL-17A and very low levels of IFN- ⁇ , indicative of a high degree of polarization toward a Th 17 (IL-17-producing) phenotype and away from a ThI (EFN- ⁇ producing) phenotype.
- Data are presented at FIGS. 3A - 3B. See also Example 5.
- Prostaglandins and in particular prostaglandin E2 (PGE2), play an important role in the regulation of the inflammatory response.
- PGE2 a key mediator of pyrexia, hyperalgesia, and arterial dilation, increases bloodflow to inflamed tissues and, together with enhanced microvascular permeability, results in edema.
- Prostaglandin synthesis inhibitors such as cyclooxygenase inhibitors are used clinically as effective antiinflammatory agents.
- PGE2 can also exert anti-inflammatory properties, and is a key negative regulator of neutrophil, monocyte, and lymphocyte function, particularly ThI cells. Harris et al. (2002) Trends Immunol. 23: 144. This apparent paradox has puzzled many investigators for decades.
- PGE2 in the presence of IL-I ⁇ and IL-23 promotes the differentiation and pro-inflammatory function of Th 17 cells.
- PGE2 acts directly on naive human T cells and upregulates IL-23 receptor expression via prostaglandin receptor EP2 and EP4-mediated signaling.
- PGE2 synergizes with IL- l ⁇ and IL-23 to drive ROR- ⁇ t, IL- 17, and CCR6 expression, consistent with the reported Th 17 phenotype. While enhancing Th 17 cytokine expression, PGE2 inhibits IL-10 production.
- PGE2 exposure increases expression of the transcription factor FOXP3 in mice, and similar results have been reported in human CD4+ T cells. Baratelli et al. (2005) J. Immunol. 175: 1483; Mahic et al. (2006) J. Immunol. 177:246. Without intending to be limited by theory, it is possible that PGE2 plays the same role in generation of Th 17 cells in humans that TGF- ⁇ plays in mice. Regardless of the mechanism of action, PGE2 appears to be necessary for the generation of pathogenic human Th 17 cells.
- PGE2 has previously been shown to induce production of IL-23 and IL-l ⁇ from immature bone marrow-derived dendritic cells, suggesting a pro-inflammatory role for PGE2, and a potential role in autoimmune diseases such as rheumatoid arthritis. Sheibanie et al. (2004) FASEB J. 18: 1318. PGE2 has been shown to have effects in murine models of inflammatory bowel disease and rheumatoid arthritis (collagen induced arthritis) via effects on the IL-23/IL-17 pathway. Sheibanie et al. (2007) J. Immunol. 178:8138; Sheibanie et al. (2007) Arthritis Rheum. 56:2608.
- Antagonists of PGE2, IL-l ⁇ and IL-23 include agents that block the biological activities of such molecules in promoting Th 17 cell development and maintenance, and thus include antagonists that bind either to the molecules themselves or to their receptors (or subunits thereof). Antagonists also include agents that reduce the activity of any of these molecules, such as small molecule inhibitors. Antagonists also include agents that reduce the expression of IL-l ⁇ or IL-23, or the proteins (e.g.
- Antagonists may include antibodies or antigen binding fragments thereof, nucleic acid inhibitors (such as siRNA or antisense oligonucleotides), soluble receptor fragments, small molecules, etc.
- nucleic acid inhibitors such as siRNA or antisense oligonucleotides
- soluble receptor fragments small molecules, etc.
- Exemplary methods of combination therapy to prevent the formation of pathogenic Th 17 cells in humans include use of an antagonist of PGE2, in combination with an antagonist of and IL- l ⁇ or an antagonist of IL-23.
- Exemplary antagonists of PGE2 include antagonists of cyclooxygenase (COX) and other enzymes involved in PGE2 synthesis.
- COX cyclooxygenase
- COX inhibitors include aspirin, indomethacin, diclofenac, ibuprofen, naproxen, diflunisal, etodolac, fenoprofen, flurbiprofen, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin, and also include the COX-2-specific inhibitors celecoxib, valdecoxib, lumiracoxib and rofecoxib.
- COX-2 inhibitors have been suggested for the treatment of experimental autoimmune neuritis (EAN) and experimental autoimmune anterior uveitis (EAAU) in rats, and for treatment of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. See Miyamoto et al. (2002) Muscle Nerve 25:280; Bora et al. (2005) Ocul. Immunol. Inflamm. 13:183; and Ni et al. (2007) J. Neuroimmunol. 186:94, respectively. Celecoxib has been suggested for the treatment of multiple sclerosis based on data obtained in an EAE model in mice. Miyamoto et al. (2006) Brain 129: 1984.
- Antagonists of PGE2 also include antagonists of any of the enzymes involved in specifically in the synthesis of PGE2, including PGE2 synthases (PGESs) such as PGES-2 (Per-Johan Jakobsson et al. (1999) Proc. Natl. Acad. ScL (U.S.A.) 96:7220) and PGES-I (U.S. Pat. No. 7,169,580).
- PGESs PGE2 synthases
- PGES-2 Per-Johan Jakobsson et al. (1999) Proc. Natl. Acad. ScL (U.S.A.) 96:7220
- PGES-I U.S. Pat. No. 7,169,580
- Antagonists of PGE2 also include antagonists of the relevant receptors that are expressed on the surface of CD4+ T cells, i.e. EP2 and EP4. These two receptors are referred to herein, collectively, as EP2/4.
- EP2/4 have been proposed as therapeutic targets for treatment of rheumatoid arthritis. Akaogi et al. (2006) Endocr. Metab. Immune Disord. Drug Targets 6:383.
- Exemplary antagonists of EP2 and EP4 include antagonistic antibodies or antigen binding fragments thereof, and AH6809 and AH23848.
- EP2 and EP4 also include nucleic acid antagonists, such as siRNA or antisense nucleic acids.
- An exemplary EP4 antagonist is disclosed at WO 2000/016760.
- EP2 is further described at GeneID PTGER2 in the NCBI Gene database, and the protein sequence is available at GenBank Ref. NP_000947.2.
- EP4 is further described at GeneID PTGER4, and the protein sequence is available at GenBank Ref. NP_000949.1.
- Antagonists of IL-I ⁇ include antagonists of IL-I ⁇ , and also the IL-I receptor antagonist (IL-IRa, anakinra), and antagonists of the receptor subunits IL-IRl and IL- lRacp. Elimination of IL-IRl in knockout mice has been shown to abrogate induction of Thl7 cells and also to significantly lower the incidence of EAE in wild type mice, suggesting a role for IL-I functions in the formation of Th 17 cells and autoimmune disease. Sutton et al. (2006) J. Exp. Med. 203: 1685.
- Antagonists of IL-23 include antagonists of IL-23, such as antagonists of the pl9 and p40 subunits, and antagonists of the receptor subunits IL-23R and IL-12R ⁇ l .
- the antagonists are IL-23-specific in that they are directed to the IL- 23-specific subunits pi 9 and EL-23R.
- Exemplary engineered antibodies to IL-23pl9 are disclosed in commonly-assigned U.S. Provisional Patent Application Nos. 60/891,409 and 60/891,413 (both filed 23 February 2007), in U.S. Patent Application Publication Nos. 2007/0009526 and 2007/0048315, and in International Patent Publication Nos. WO 2007/076524, WO 2007/024846 and WO 2007/147019.
- Antibodies specific for IL- 23p40 are disclosed at U.S. Patent No. 7,247,711.
- Exemplary combination therapy regimens include, but are not limited to, antagonists of PGE2 and IL-l ⁇ , antagonists of EP2/4 and IL-IRl, or antagonists of EP2/4 and IL-23R. In some cases it may be preferable to target both targets at the same time in the same cells, e.g. via bispecific agents. Such combination therapy may effectively block the development and differentiation of pathogenic human ThI 7 cells, thereby inhibiting human autoimmune and proliferative disorders.
- the two or more antagonists are antagonists of different mechanistic pathways, rather than antagonists of different parts of the same pathway.
- at least one of the inhibitors binds to a cell surface receptor rather than a soluble ligand.
- the two or more antagonists comprise a bifunctional reagent, such as a bispecific antibody or antigen binding fragment thereof, that binds to at least one cell surface receptor.
- both targets of the bifunctional reagent of the present invention are cell surface receptors, e.g. EP2/4, and IL-23R or IL-IRl .
- IL- 17 antagonists and IL-23 antagonists are typically administered to a patient as a pharmaceutical composition in which the antagonist is admixed with a pharmaceutically acceptable carrier or excipient, see, e.g., Remington's Pharmaceutical Sciences and U.S.
- the pharmaceutical composition may be formulated in any manner suitable for the intended route of administration.
- examples of pharmaceutical formulations include lyophilized powders, slurries, aqueous solutions, suspensions and sustained release formulations (see, e.g., Hardman et al. (2001) Goodman and Gilman 's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al.
- the route of administration will depend on the properties of the antagonist or other therapeutic agent used in the pharmaceutical composition. Suitable routes of administration may, for example, include oral, inhalation, rectal, topical, cutaneous, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intraarterial or intravenous injection, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
- the liposomes will be targeted to and taken up selectively by the afflicted tissue.
- 2008/0019975 describes induction-maintenance treatment regimens comprising an induction regimen, involving administration of a lower dose of a therapeutic agent by a more invasive and/or localized route, followed by a maintenance regimen, involving administration of a higher dose of the therapeutic agent by a less invasive and/or localized route, e.g. systemically.
- compositions of the invention may be administered according to any treatment regimen that ameliorates or prevents one or more symptoms of the immune disorder. Selecting the treatment regimen will depend on several composition- dependent and patient-dependent factors, including but not limited to the half-life of the antagonist, the severity of the patient's symptoms, and the type or length of any adverse effects. Preferably, an administration regimen maximizes the amount of therapeutic agent delivered to the patient consistent with an acceptable level of side effects.
- Toxicity and therapeutic efficacy of the antibody compositions, administered alone or in combination with an immunosuppressive agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 5O (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio of LD50 to ED50.
- Antibodies exhibiting high therapeutic indices are preferred.
- the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
- Biological antagonists such as antibodies may be provided by continuous infusion, or by doses at intervals of, e.g., once per day, once per week, or 2 to 7 times per week, once every other week, or once per month.
- a total weekly dose is generally at least 0.05 ⁇ g/kg, 0.2 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 100 ⁇ g/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg body weight or more. See, e.g., Yang et al. (2003) New Engl. J. Med.
- a small molecule therapeutic e.g., a peptide mimetic, natural product, or organic chemical, is about the same as for an antibody or polypeptide, on a moles/kg basis.
- Determination of the appropriate dose is made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects.
- Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced.
- a biologic that will be used is substantially derived from the same species as the animal targeted for treatment (e.g. a humanized antibody for treatment of human subjects), thereby minimizing any immune response to the reagent.
- Treatment regimens using antagonists of IL-17 or other acute phase cytokines along with IL-23 antagonists will typically be determined by the treating physician and will take into account the patient's age, medical history, disease symptoms, and tolerance for different types of medications and dosing regimens.
- the treatment regimen is designed to suppress the overly aggressive immune system, allowing the body to eventually re-regulate itself, with the result often being that after the patient has been kept on systemic medications to suppress the inappropriate immune response for a finite length of time (for example, one year), medication can then be tapered and stopped without recurrence of the autoimmune attack. Sometimes resumption of the attack does occur, in which case the patient must be re-treated.
- the physician may prescribe the patient a certain number of doses of the antagonist to be taken over a prescribed time period, after which therapy with the antagonist is discontinued.
- the physician will continue the antagonist therapy for some period of time, in which the amount and/or frequency of antagonist administered is gradually reduced before treatment is stopped.
- the present invention also contemplates treatment regimens in which an IL-
- IL-17 antagonist or other acute phase cytokine antagonist is used in combination with an IL-23 antagonist.
- IL-17 antagonist relates, mutatis mutandis, to other acute phase cytokines, such as TNF- ⁇ and IL- l ⁇ .
- Such regimens may be especially useful in treating the acute phase of immune disorder, in which the IL- 17 antagonist inhibits the activity of existing Th 17 cells, while the IL-23 antagonist prevents the generation of new Th 17 cells.
- Such combination therapy may provide effective treatment of an immune disorder using a lower dose of the IL-17 antagonist and/or administering the IL-17 antagonist for a shorter period of time.
- therapy with IL-17 antagonist is preferably discontinued, while administration of the IL-23 antagonist is continued to prevent generation of new autoreactive Th 17 cells that could lead to recurrence of the disease.
- the two antagonists may be administered at the same time in a single composition, or in separate compositions. Alternately, the two antagonists may be administered at separate intervals. Different doses of the antagonists may also be used. Similarly, a bispecific antagonist may also be administered during the acute phase and gradually withdrawn, followed by treatment with an IL-23 antagonist to maintain repression of the disease.
- the treatment regimen may also include use of other therapeutic agents, to ameliorate one or more symptoms of the immune disorder or to prevent or ameliorate adverse effects from the antagonist therapy.
- a second therapeutic agent e.g., a cytokine, antibody, steroid, chemotherapeutic agent, antibiotic, or radiation, are well known in the art, see, e.g., Hardman et al.
- the pharmaceutical composition of the invention may also contain other immunosuppressive or immunomodulating agents.
- Suitable immunosuppressive agent can be employed, including but not limited to, anti-inflammatory agents, corticosteroids, dexamethasone, flurometholone, and prednisolone, cyclosporine, tacrolimus ⁇ i.e., FK-506), sirolimus, interferons, soluble cytokine receptors ⁇ e.g., sTNRF and sEL-lR), mycophenolate mofetil, 15-deoxyspergualin, thalidomide, glatiramer, azathioprine, leflunomide, cyclophosphamide, chlorambucil, non-steroidal antiinflammatories such as indomethacin, aspirin, flubiprofen and diclofenac, antimetabolites (e.g., methotrexate, azathioprine), and the like.
- the pharmaceutical composition can also be employed with other therapeutic modalities such as phototherapy and radiation.
- any of the therapies described herein in which two or more different therapeutic substances are used e.g., an IL- 17 antagonist and an IL-23 antagonist, an IL- 17 antagonist and a therapeutic agent that does not antagonize IL-17 or IL-23 activity
- the different therapeutic substances are administered in association with each other, that is, they may be administered concurrently in the same pharmaceutical composition, as separate compositions, or the substances may be administered at separate times and in different orders.
- the present invention provides methods and compositions for treatment of immune disorders, specifically autoimmune disorders that follow a relapsing-remitting pattern.
- exemplary diseases include MS, rheumatoid arthritis, psoriatic arthritis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and type I diabetes.
- Eptitope spreading may be responsible for the relapsing-remitting nature of many inflammatory autoimmune diseases, in which new epitopes drive the formation of new antigen-specific pathogenic ThI 7 cells. Interference with IL-23 signaling would stop this process by preventing the generation of new pathogenic Th 17 cells.
- Th 17 cells that cause disease in tissues other than the tissue in which the Th 17 cells originally arise.
- diseases include, but are not limited to, psoriatic arthritis, uveitis, juvenile onset arthritis, and multiple sclerosis.
- IL-23-directed therapies would also be expected to be useful in treatment of such diseases.
- Pathogenic Th 17 cells may be targeted for destruction by systemic therapy while in transit from their tissue of origin.
- Th 17 cells can be identified based on their expression of a distinctive pattern of serum biomarkers, including IL-23, IL- 17, IL-12p70, IL-12p40, TNF- ⁇ , IL-I, IL-6, IL- 22, IFN- ⁇ , IL-22, CCL20 (MIP-3 ⁇ ) and CXCLl (GRO). Measurement of any one of, or any combination of, these biomarkers may be used to assess the role of Thl7-cell mediated pathology in a disease, and thus the likely therapeutic efficacy of IL-23-neutralization as therapy. The biomarkers may also be used to monitor disease progress, e.g. during a course of treatment.
- the methods and compositions of the present invention may also be used in the treatment of cancers, e.g. tumors, in which an aberrant IL-23 -mediated Th 17 response promotes inflammation in the vicinity of a tumor, and paradoxically represses IL- 12- mediated ThI -type tumor surveillance. See WO 2004/081190. Transient suppression of the acute inflammatory response and long-term maintenance of anti-IL-23 therapy may promote recovery of IL-12-mediated ThI tumor surveillance, and promote tumor eradication.
- MS multiple sclerosis
- methods for the treatment of including relapsing-remitting MS and primary progressive MS, Alzheimer's disease, amyotrophic lateral sclerosis (a.k.a. ALS; Lou Gehrig's disease), ischemic brain injury, prion diseases, and HFV-associated dementia.
- methods for treating neuropathic pain, posttraumatic neuropathies, Guillain-Barre syndrome (GBS), peripheral polyneuropathy, and nerve regeneration are also provided.
- MRI magnetic resonance imaging
- the present invention provides methods for treating and diagnosing inflammatory bowel disorders, e.g., Crohn's disease, ulcerative colitis, celiac disease, and irritable bowel syndrome.
- inflammatory bowel disorder malabsorption of food, altered bowel motility, infection, fever, abdominal pain, diarrhea, rectal bleeding, weight loss, signs of malnutrition, perianal disease, abdominal mass, and growth failure, as well as intestinal complications such as stricture, fistulas, toxic megacolon, perforation, and cancer, and including endoscopic findings, such as, friability, aphthous and linear ulcers, cobblestone appearance, pseudopolyps, and rectal involvement and, in addition, anti-yeast antibodies. See, e.g., Podolsky, supra; Hanauer, supra; Horwitz and Fisher, supra.
- inflammatory disorders such as psoriasis, atopic dermatitis, arthritis, including rheumatoid arthritis, osteoarthritis, and psoriatic arthritis
- autoimmune disorders such as SLE and type I diabetes, autoimmune myocarditis (Sonderegger et al. (2006) Eur. J. Immunol. 36:2844), and proliferative disorders such as cancer.
- Methods for flow cytometry including fluorescence activated cell sorting detection systems (F ACS ® ), are available. See, e.g., Owens et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2 nd ed.; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ.
- Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available.
- IL-23 antagonist The ability of an IL-23 antagonist to biologically neutralize IL-23/IL-23R is assessed by the application of short-term proliferation bioassays that employ cells that express recombinant IL-23 receptors.
- the transfectant Ba/F3-2.21o cells proliferate in response to human IL-23 and the response can be inhibited by an IL-23 antagonist.
- the concentration of IL-23 chosen for the assay is selected to be within the linear region of the dose-response curve, near plateau and above EC50. Proliferation, or lack thereof, is measured by colorimetric means using Alamar Blue, a growth indicator dye based on detection of metabolic activity.
- the ability of an IL-23 antagonist to neutralize IL-23/IL- 23R is assessed by its IC50 value, or concentration of antagonist that induces half-maximal inhibition of IL-23-induced proliferation.
- the assay is performed essentially as follows. Ba/F3 transfectants are maintained in RPMI- 1640 medium, 10% fetal calf serum, 50 ⁇ M 2-mercaptoethanol, 2 mM L-Glutamine, 50 ⁇ g/mL penicillin-streptomycin, and 10 ng/mL mouse IL-3.
- Proliferation bioassays are performed in RPMI-1640 medium, 10% fetal calf serum, 50 ⁇ M 2- mercaptoethanol, 2 mM L-Glutamine, and 50 ⁇ g/mL penicillin-streptomycin. [0176] Assays are performed in 96-well flat bottom plates (Falcon 3072 or similar) in 150 ⁇ L per well. Both IL-23 and IL-23 antagonist are prepared at a series of concentrations, e.g. 1 :3 serial dilutions. Titrations of the IL-23 antagonist of interest are pre-incubated with IL-23 prior to addition of the cells.
- bioassay plates are incubated in a humidified tissue culture chamber (37°C, 5% CO 2 ) for 40-48 hr.
- Alamar Blue Biosource Cat #DAL1100
- Alamar Blue is added at 16.5 ⁇ L/well and allowed to develop for 5-12 hours.
- Absorbance is then read at 570 nm and 600 nm (VERSAmax Microplate Reader, Molecular Probes, Eugene, Oregon, USA), and an OD5 70- 6oo is obtained. Duplicates are run for each sample.
- Absorbance is plotted against cytokine or antibody concentration using GraphPad Prism ® 3.0 software (Graphpad Software Inc., San Diego, California, USA), and IC50 values are determined using nonlinear regression (curve fit) of sigmoidal dose-response.
- the biological activity of an IL-23 antagonist of the present invention may be assessed using the splenocyte assay essentially as described in Aggarwal et al. (2003) J. Biol. Chem. 278: 1910 and Stumhofer et al. (2006) Nature Immunol. 7:937.
- the splenocyte assay measures the activity of IL-23 in a sample as a level of IL- 17 production by murine splenocytes.
- the inhibitory activity of an IL-23 antagonist is then assessed by determining the concentration of antagonist necessary to reduce the IL-23/IL-23R activity in a given sample by 50% (the IC50).
- the IC50 as measured by this assay is greater than or equal to the equilibrium dissociation binding constant (Ka), i.e. the Kj may be equal to or lower than the IC50.
- Ka equilibrium dissociation binding constant
- lower IC50 and Kj values reflect higher activities and affinities.
- IL- 17 ELISA is performed as follows. Plates are coated with a capture anti-
- IL-17 antibody (100 ng/well) overnight at 4°C, washed and blocked. Samples and standards are added and incubated for two hours at room temperature with shaking. Plates are washed, and a biotinylated anti-IL-17 detection antibody (100 ng/well) is added and incubated for one hour at room temperature with shaking. The capture and detection antibodies are different antibodies that both bind to mouse IL- 17 but do not cross-block. Plates are washed, and bound detection antibody is detected using streptavidin-HRP (horseradish peroxidase) and TMB (3,3',5,5'-tetramethylbenzidine). The plate is then read at 450-650 nm and the concentration of IL-17 in samples is calculated by comparison with standards.
- streptavidin-HRP horseradish peroxidase
- TMB 3,3',5,5'-tetramethylbenzidine
- CD161 is Expressed on Pathogenic Thl7 Cells in Crohn's Disease [0180] ThI 7 cells are implicated in the pathology of numerous autoimmune inflammatory and proliferative disorders.
- IL-23R is a known cell surface receptor subunit that is expressed by Th 17 cells.
- the experiments described herein indicate that the C-type lectin CD161, which is known to be expressed on human NK and T-cells, is preferentially expressed on pathogenic ThI 7 cells.
- Such pathogenic cells may be specifically targeted by therapeutic agents that simultaneously bind to both IL-23R and CDl 61.
- the presence of both IL-23R and CDl 61 on the surface of these cells provides a convenient means of sorting cells for diagnostic and research purposes.
- Colon and peripheral blood (PB) samples are obtained from Crohn's Disease patients.
- Lamina limbal mononuclear cells (LPMC) are prepared from colon samples by dissociation of the epithelial layer of the mucosa, collagenase digestion of the lamina propria, and density gradient centrifugation.
- Peripheral blood mononuclear cells (PBMC) are isolated from PB by density gradient centrifugation and lysis of red blood cells.
- Colon samples from CD patients contain approximately 20-fold more
- CD161 + CD4 + memory T cells as determined by flow cytometry, than colon samples from normal subjects.
- FIG. IA FACS ® flow cytometry purified lamina limbal CDIoI + Th m e m cells are found to produce 4 to 6-fold more IL-17 than CD161 " Th mem cells (as measured by ELISA) in both CD and normal samples.
- FIG. IB The combination of increased IL-17 production and increased cell numbers indicate that CDl 61 + Th mem cells are a major source of IL-17 in the colon of CD patients.
- FIG. 1C Gene expression profiling demonstrates that CD161 + Th mem cells express higher levels various pro-inflammatory cytokines characteristic of the Thl7 phenotype (IL-23R, IL-17, and IL-22), but not the ThI -associated cytokine IFN- ⁇ , as compared with CD161 " cells.
- FIG. 2A shows that several genes known to be associated with Thl7 cells (IL-23RA, ROR- ⁇ T and IL-17A) are significantly upregulated in CD161 + cells as compared to CD16T cells.
- FIG. 2B shows that production of the known Thl7-associated cytokines IL- 17A, IL-22 and IL- 17F is significantly greater in CDl 61 + cells as compared to CD161 " cells.
- FACS ® flow cytometry purified CDIoI + Th mem cells from PBMC express significantly higher levels of IL-17 than CD161 " cells, but do not differ in the level of IFN- ⁇ production (both as measure by RT quantitative PCR).
- FACS ® flow cytometry demonstrates that approximately 45% of PBMC CD161 + Th mem cells from CD patients express IL-23R, as compared with -30% for PBMC CD161 + Th mem cells from normal subjects, and RT quantitative PCR indicates that IL-23R expression is somewhat higher in CDl 61 + Th mem cells compared with CDl 61 " Th mem cells in both normal and CD PBMC.
- PBMC CD161 + Th mem cells from CD patients also exhibit increased IL-17 production when cultured with IL-23.
- CCR6 is preferentially expressed on CD4 + memory T cells and facilitates trafficking to epithelial sites. Liao et al. (1999) J. Immunol. 162:186. Its sole chemokine ligand CCL20 (MIP-3 ⁇ ) is dramatically induced in Crohn's disease inflammation. Kwon et al. (2002) Gut 51 :818 and Kaser et al. (2004) J. Clin. Immunol. 24:74. These results demonstrate that the CD 161 + CD4 + memory T cells described herein exhibit the homing and chemokine receptor signature that would be expected for cells involved in gut inflammation.
- T cells are isolated and cultured as described previously (Wilson et al. (2007), supra).
- Memory CD4 + CD45RA " T cells are isolated using the memory T cell isolation kit, human (Miltenyi, Auburn, CA), according to the manufacturer's instructions. Where indicated, 50 ng/ml hIL-23, 50 ng/ml hIL-l ⁇ (R&D Systems, Minneapolis, MN), 10 ⁇ M PGE2 (Sigma, St.
- CD4 + CCR6 + and CD4 + CCR6 + cell subsets are purified by cell sorting using anti-CCR6 and anti-CD4 antibodies (BD Biosciences, San Diego, CA). Cell sorting is done with a F ACS ® Aria instrument (BD
- CD3, anti-CD45RA, anti-CCR6 (BD Biosciences), and/or anti-IL-23R (R&D Systems) antibodies are acquired on a LSR II cytometer and analyzed with FlowJo software
- ELISA and electrochemiluminescence assays are performed as described previously (Wilson et al. (2007), supra).
- IL-10 ELISA is performed using a kit from R&D
- FIG. 4A As does exposure to the EP receptor agonists butaprost and misoprostol, but not sulprostone (FIG. 4B).
- butaprost EP2 specific
- misoprostol EP4,
- EP3>EP1>EP2 mimic the effects of PGE2, whereas the EP1/EP3 agonist sulprostone does not, suggests that PGE2 signaling occurs via the EP2 and/or EP4 receptors in mediating its effects on naive human CD4 + T cells.
- IL-IRl gene expression is increased in response to PGE2 (data not shown).
- PGE2 and EP receptor agonists, together with IL-I ⁇ and IL-23 have effects on cytokine expression by naive human CD4 + T cells in culture as shown in FIGS. 5A - 5C. The results suggest that PGE2, together with IL-I ⁇ and IL-23, enhances human ThI 7 cell development via the EP2 and EP4 receptors.
- EP2 agonist butaprost induces a somewhat greater increase in IL- 17 expression than misoprostol.
- Downregulation of the antiinflammatory cytokine IL-10 (FIG. 5C) is also consistent with a role for PGE2 in induction of Thl7-mediated inflammation. See also Jankovic & Trinchieri (2007) Nature Immunol. 8:1281 and McGeachy et al. (2007) Nature Immunol. 8: 1390, suggesting that IL-10 restrains the pathogenicity of Thl7 cells in mice.
- Comparison of the results obtained with butaprost and misoprostol suggest that the increase in EL- 17A is predominantly mediated by EP2 whereas the decrease in IL-10 is predominantly mediated by EP4.
- CCR6 expression which correlates with Th 17 cytokine production (FIGS.
- FIG. 6A shows an increase in the percentage of na ⁇ ve human CD4 + T cells expressing CCR6 when PGE2 is added to IL- l ⁇ and IL-23.
- FIG. 6A shows an increase in the percentage of na ⁇ ve human CD4 + T cells expressing CCR6 when PGE2 is added to IL- l ⁇ and IL-23.
- FIGS. 3 - 6 The results presented in FIGS. 3 - 6 are consistent with a role for PGE2 in promoting the development of pathogenic effector Th 17 cells.
- results presented at FIGS. 7A (protein expression) and 7B (gene expression) demonstrate that PGE2 enhances a pathogenic Th 17 phenotype in activated memory T cells. Specifically, PGE2 generally promotes increased levels of the IL-17A and expression of ROR- ⁇ t, both of which are associated with pathogenic Th 17 cells, but it does not promote increased levels of EFN- ⁇ or EL-IO, nor does it increase expression of T-bet.
- activated/memory T cells represent a major cell population in inflamed tissue
- results presented herein suggest that the combination of inflammatory cytokines and non-cytokine immunomodulators present during both T cell differentiation in lymph nodes, and during activation in sites of tissue inflammation, will determine the ultimate phenotype of Thl7 cells.
Abstract
Description
Claims
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US13/925,525 US20130287775A1 (en) | 2007-02-28 | 2013-06-24 | Combination therapy for treatment of immune disorders |
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Citations (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0404097A2 (en) | 1989-06-22 | 1990-12-27 | BEHRINGWERKE Aktiengesellschaft | Bispecific and oligospecific, mono- and oligovalent receptors, production and applications thereof |
WO1993011161A1 (en) | 1991-11-25 | 1993-06-10 | Enzon, Inc. | Multivalent antigen-binding proteins |
WO1994004678A1 (en) | 1992-08-21 | 1994-03-03 | Casterman Cecile | Immunoglobulins devoid of light chains |
WO1994025591A1 (en) | 1993-04-29 | 1994-11-10 | Unilever N.V. | PRODUCTION OF ANTIBODIES OR (FUNCTIONALIZED) FRAGMENTS THEREOF DERIVED FROM HEAVY CHAIN IMMUNOGLOBULINS OF $i(CAMELIDAE) |
US6005079A (en) | 1992-08-21 | 1999-12-21 | Vrije Universiteit Brussels | Immunoglobulins devoid of light chains |
WO2000053631A1 (en) | 1999-03-11 | 2000-09-14 | Schering Corporation | Mammalian cytokines; related reagents and methods |
WO2001018051A2 (en) | 1999-09-09 | 2001-03-15 | Schering Corporation | Mammalian interleukin-12 p40 and interleukin b30, combinations thereof, antibodies, uses in pharmaceutical compositions |
US6329511B1 (en) | 1998-12-01 | 2001-12-11 | Protein Design Labs, Inc. | Humanized antibodies to γ-interferon |
US20030124617A1 (en) | 2000-01-21 | 2003-07-03 | Hermann Gram | Antibodies to human il 1-beta |
WO2004071517A2 (en) | 2003-02-06 | 2004-08-26 | Schering Corporation | Uses of il-23 related reagents |
WO2004081190A2 (en) | 2003-03-10 | 2004-09-23 | Schering Corporation | Uses of il-23 agonists and antagonists; related reagents |
US20050261219A1 (en) | 2001-05-18 | 2005-11-24 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (siNA) |
WO2006013107A1 (en) | 2004-08-05 | 2006-02-09 | Novartis Ag | Il-17 antagonistic antibodies |
US20060067936A1 (en) | 2004-09-24 | 2006-03-30 | Jacqueline Benson | IL-23p40 specific immunoglobulin derived proteins, compositions, epitopes, methods and uses |
US20060135518A1 (en) | 2004-11-19 | 2006-06-22 | Synta Pharmaceuticals Corp. | Pyrimidine compounds and uses thereof |
US20060193821A1 (en) | 2004-03-05 | 2006-08-31 | Diener John L | Aptamers to the human IL-12 cytokine family and their use as autoimmune disease therapeutics |
US20070009526A1 (en) | 2005-06-30 | 2007-01-11 | Jacqueline Benson | Anti-IL-23 antibodies, compositions, methods and uses |
WO2007024846A2 (en) | 2005-08-25 | 2007-03-01 | Eli Lilly And Company | Anit-il-23 antibiodies |
US20070048315A1 (en) | 2005-08-31 | 2007-03-01 | Schering Corporation | Engineered anti-IL-23 antibodies |
WO2007076524A2 (en) | 2005-12-29 | 2007-07-05 | Centocor, Inc. | Human anti-il-23 antibodies, compositions, methods and uses |
US7247711B2 (en) | 2003-05-09 | 2007-07-24 | Centocor, Inc. | IL-23p40 specific antibody |
WO2007147019A2 (en) | 2006-06-13 | 2007-12-21 | Zymogenetics, Inc. | Il-17 and il-23 antagonists and methods of using the same |
WO2008021156A2 (en) | 2006-08-11 | 2008-02-21 | Schering Corporation | Antibodies to il-17a |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE87659T1 (en) | 1986-09-02 | 1993-04-15 | Enzon Lab Inc | BINDING MOLECULES WITH SINGLE POLYPEPTIDE CHAIN. |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5260203A (en) | 1986-09-02 | 1993-11-09 | Enzon, Inc. | Single polypeptide chain binding molecules |
WO1988007089A1 (en) | 1987-03-18 | 1988-09-22 | Medical Research Council | Altered antibodies |
US6319522B1 (en) * | 1990-07-13 | 2001-11-20 | Gropep Limited | Growth-promoting agent |
WO1995002611A1 (en) * | 1993-07-16 | 1995-01-26 | Schering Corporation | Cell surface protein present on nk (natural killer cells) named dx1 |
AU1908395A (en) * | 1994-01-28 | 1995-08-15 | Board Of Trustees Of The Leland Stanford Junior University | Antibodies to mammalian natural killer antigens and uses |
US6132764A (en) | 1994-08-05 | 2000-10-17 | Targesome, Inc. | Targeted polymerized liposome diagnostic and treatment agents |
JP4373495B2 (en) | 1995-03-23 | 2009-11-25 | イミュネックス・コーポレーション | IL-17 receptor |
WO1997003715A1 (en) | 1995-07-21 | 1997-02-06 | The General Hospital Corporation | Method and apparatus of enhancing the delivery of a pharmaceutical formulation |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
US6326482B1 (en) | 1999-04-23 | 2001-12-04 | Genentech, Inc. | SH2 domain-containing peptides |
AUPP608898A0 (en) | 1998-09-23 | 1998-10-15 | Fujisawa Pharmaceutical Co., Ltd. | New use of prostaglandin E2 antagonists |
AU7445900A (en) | 1999-09-27 | 2001-04-30 | Chugai Seiyaku Kabushiki Kaisha | Novel hemopoietin receptor protein, nr12 |
WO2001057225A1 (en) * | 2000-02-03 | 2001-08-09 | Chugai Seiyaku Kabushiki Kaisha | Protein having pge2 synthase activity and use thereof |
SK287984B6 (en) * | 2000-05-10 | 2012-08-06 | Schering Corporation | Substantially pure or recombinant polypeptide, nucleic acid, host cell, method for the preparation of polypeptide, binding compound, kit, composition comprising an antibody and use thereof |
EP1326978A2 (en) | 2000-10-06 | 2003-07-16 | Immunex CorporatioN | Hematopoietin receptors hpr1 and hpr2 |
WO2002038764A2 (en) | 2000-11-10 | 2002-05-16 | The Regents Of The University Of California | Il-17 receptor-like protein, uses thereof, and modulation of catabolic activity of il-17 cytokines on bone and cartilage |
US20040018557A1 (en) * | 2002-03-01 | 2004-01-29 | Immunomedics, Inc. | Bispecific antibody point mutations for enhancing rate of clearance |
WO2003086310A2 (en) | 2002-04-12 | 2003-10-23 | Ramot At Tel Aviv University Ltd. | Prevention of brain inflammation as a result of induced autoimmune response |
US7670604B2 (en) | 2002-12-13 | 2010-03-02 | Aurelium Biopharma, Inc. | Vimentin directed diagnostics and therapeutics for multidrug resistant neoplastic disease |
US7410483B2 (en) | 2003-05-23 | 2008-08-12 | Novare Surgical Systems, Inc. | Hand-actuated device for remote manipulation of a grasping tool |
US7130995B2 (en) | 2003-09-30 | 2006-10-31 | International Business Machines Corporation | Secure switching for downloading network boots |
EP1732946B1 (en) * | 2004-03-08 | 2011-07-27 | ZymoGenetics, Inc. | Dimeric fusion proteins and materials and methods for producing them |
JP2007535930A (en) * | 2004-05-03 | 2007-12-13 | シェーリング コーポレイション | Use of IL-17 expression to predict skin inflammation; treatment methods |
WO2005120571A2 (en) | 2004-06-07 | 2005-12-22 | Ramot At Tel Aviv University Ltd. | Method of passive immunization against disease or disorder characterized by amyloid aggregation with diminished risk of neuroinflammation |
JP2009507023A (en) * | 2005-09-01 | 2009-02-19 | シェーリング コーポレイション | Use of IL-23 and IL-17 antagonists to treat autoimmune ocular inflammatory diseases |
AU2007261019A1 (en) * | 2006-06-19 | 2007-12-27 | Wyeth | Methods of modulating IL-22 and IL-17 |
US20100047235A1 (en) | 2006-07-07 | 2010-02-25 | Gorman James R | Novel regimens for treating diseases and disorders |
US7833527B2 (en) * | 2006-10-02 | 2010-11-16 | Amgen Inc. | Methods of treating psoriasis using IL-17 Receptor A antibodies |
-
2008
- 2008-02-26 NZ NZ579297A patent/NZ579297A/en not_active IP Right Cessation
- 2008-02-26 BR BRPI0807987-0A2A patent/BRPI0807987A2/en not_active IP Right Cessation
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- 2008-02-26 EP EP11173876A patent/EP2417974A1/en not_active Withdrawn
- 2008-02-26 MX MX2009009167A patent/MX2009009167A/en active IP Right Grant
- 2008-02-26 CN CN200880013960.4A patent/CN101668531B/en not_active Expired - Fee Related
- 2008-02-26 EP EP11173881A patent/EP2425838A3/en not_active Withdrawn
- 2008-02-26 AU AU2008219681A patent/AU2008219681A1/en not_active Abandoned
- 2008-02-26 WO PCT/US2008/002530 patent/WO2008106131A2/en active Application Filing
- 2008-02-26 US US12/527,459 patent/US20100135998A1/en not_active Abandoned
- 2008-02-26 JP JP2009551701A patent/JP5337055B2/en not_active Expired - Fee Related
- 2008-02-26 EP EP08714219.6A patent/EP2056838B1/en active Active
- 2008-02-26 NZ NZ597915A patent/NZ597915A/en not_active IP Right Cessation
- 2008-02-26 CA CA002679400A patent/CA2679400A1/en not_active Abandoned
-
2009
- 2009-08-27 ZA ZA200905962A patent/ZA200905962B/en unknown
-
2012
- 2012-02-24 US US13/405,024 patent/US20120156699A1/en not_active Abandoned
- 2012-09-26 JP JP2012212022A patent/JP2012251002A/en active Pending
-
2013
- 2013-06-24 US US13/925,525 patent/US20130287775A1/en not_active Abandoned
Patent Citations (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0404097A2 (en) | 1989-06-22 | 1990-12-27 | BEHRINGWERKE Aktiengesellschaft | Bispecific and oligospecific, mono- and oligovalent receptors, production and applications thereof |
WO1993011161A1 (en) | 1991-11-25 | 1993-06-10 | Enzon, Inc. | Multivalent antigen-binding proteins |
WO1994004678A1 (en) | 1992-08-21 | 1994-03-03 | Casterman Cecile | Immunoglobulins devoid of light chains |
US6005079A (en) | 1992-08-21 | 1999-12-21 | Vrije Universiteit Brussels | Immunoglobulins devoid of light chains |
WO1994025591A1 (en) | 1993-04-29 | 1994-11-10 | Unilever N.V. | PRODUCTION OF ANTIBODIES OR (FUNCTIONALIZED) FRAGMENTS THEREOF DERIVED FROM HEAVY CHAIN IMMUNOGLOBULINS OF $i(CAMELIDAE) |
US6329511B1 (en) | 1998-12-01 | 2001-12-11 | Protein Design Labs, Inc. | Humanized antibodies to γ-interferon |
WO2000053631A1 (en) | 1999-03-11 | 2000-09-14 | Schering Corporation | Mammalian cytokines; related reagents and methods |
WO2001018051A2 (en) | 1999-09-09 | 2001-03-15 | Schering Corporation | Mammalian interleukin-12 p40 and interleukin b30, combinations thereof, antibodies, uses in pharmaceutical compositions |
US20030124617A1 (en) | 2000-01-21 | 2003-07-03 | Hermann Gram | Antibodies to human il 1-beta |
US20050261219A1 (en) | 2001-05-18 | 2005-11-24 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (siNA) |
WO2004071517A2 (en) | 2003-02-06 | 2004-08-26 | Schering Corporation | Uses of il-23 related reagents |
WO2004081190A2 (en) | 2003-03-10 | 2004-09-23 | Schering Corporation | Uses of il-23 agonists and antagonists; related reagents |
US7247711B2 (en) | 2003-05-09 | 2007-07-24 | Centocor, Inc. | IL-23p40 specific antibody |
US20060193821A1 (en) | 2004-03-05 | 2006-08-31 | Diener John L | Aptamers to the human IL-12 cytokine family and their use as autoimmune disease therapeutics |
WO2006013107A1 (en) | 2004-08-05 | 2006-02-09 | Novartis Ag | Il-17 antagonistic antibodies |
US20060067936A1 (en) | 2004-09-24 | 2006-03-30 | Jacqueline Benson | IL-23p40 specific immunoglobulin derived proteins, compositions, epitopes, methods and uses |
US20060135518A1 (en) | 2004-11-19 | 2006-06-22 | Synta Pharmaceuticals Corp. | Pyrimidine compounds and uses thereof |
US20070009526A1 (en) | 2005-06-30 | 2007-01-11 | Jacqueline Benson | Anti-IL-23 antibodies, compositions, methods and uses |
WO2007024846A2 (en) | 2005-08-25 | 2007-03-01 | Eli Lilly And Company | Anit-il-23 antibiodies |
US20070048315A1 (en) | 2005-08-31 | 2007-03-01 | Schering Corporation | Engineered anti-IL-23 antibodies |
WO2007076524A2 (en) | 2005-12-29 | 2007-07-05 | Centocor, Inc. | Human anti-il-23 antibodies, compositions, methods and uses |
WO2007147019A2 (en) | 2006-06-13 | 2007-12-21 | Zymogenetics, Inc. | Il-17 and il-23 antagonists and methods of using the same |
WO2008021156A2 (en) | 2006-08-11 | 2008-02-21 | Schering Corporation | Antibodies to il-17a |
Non-Patent Citations (42)
Title |
---|
ABBAS ET AL.: "Cellular and Molecular Immunology", 2000, W.B. SAUNDERS CO. |
BACA ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 10678 - 10684 |
BRENNAN ET AL., SCIENCE, 1985 |
BRENNAN ET AL., SCIENCE, vol. 229, 1985, pages 81 |
CARPENTER ET AL., J. IMMUNOL., vol. 165, 2000, pages 6205 |
CHABNER AND LONGO: "Cancer Chemotherapy and Biotherapy", 2001, LIPPINCOTT, WILLIAMS & WILKINS |
CHOTHIA ET AL., NATURE, vol. 342, 1989, pages 877 - 883 |
CHURCH ET AL., SPRINGER SEMIN. IMMUN., vol. 27, 2006, pages 494 |
CLEVELAND; ROTHSTEIN, NATURE, vol. 2, 2001, pages 806 - 819 |
CUA; KASTELEIN, NAT. IMMUNOL., vol. 7, 2006, pages 557 - 559 |
DAVIDSON; DIAMOND, NEW ENGL. J MED., vol. 345, 2001, pages 340 - 350 |
FEMANDEZ-BOTRAN, CRIT. REV. CLIN. LAB SCI., vol. 36, 1999, pages 165 - 224 |
FOOTE; WINTER, J. MOL. BIOL., vol. 224, 1992, pages 487 - 499 |
GABAY; AREND, SPRINGER SEMIN. IMMUNOPATHOL., vol. 20, 1998, pages 229 |
GRIFFIN; MRAK, J LEUKOCYTE BIOL., vol. 72, 2002, pages 233 - 238 |
HARDMAN ET AL.: "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.", 2001, MCGRAW- HILL |
HARLOW; LANE: "Antibodies A Laboratory Manual", 1988, COLD SPRING HARBOR LABORATORY PRESS, pages: 139 - 243 |
HE ET AL., J. IMMUNOL., vol. 160, 1998, pages 1029 |
HOLLIGER ET AL., PROC. NATL. ACAD SCI. USA, vol. 90, 1993, pages 6444 - 6448 |
HOLLIGER; HUDSON, NAT. BIOTECHNOL., vol. 23, 2005, pages 1126 - 1136 |
HOOZEMANS ET AL., EXP. GERONTOL., vol. 36, 2001, pages 559 - 570 |
ILZECKA ET AL., CYTOKINE, vol. 20, 2002, pages 239 - 243 |
JONES ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1592, 2002, pages 251 - 263 |
KONTERMANN AND DUBEL: "Antibody Engineering", 2001, SPRINGER-VERLAG |
KOSTULAS ET AL., STROKE, vol. 30, 1999, pages 2174 - 2179 |
LANGRISH ET AL., IMMUNOL. REV., vol. 202, 2004, pages 96 - 105 |
LANGRISH ET AL., J EXP. MED., vol. 201, 2005, pages 233 - 240 |
LI ET AL., J. NEUROIMMUNOL., vol. 116, 2001, pages 5 - 14 |
LOCK ET AL., NATURE MED., vol. 8, 2002, pages 500 - 508 |
MATUSEVICIUS ET AL., MULTIPLE SCLEROSIS, vol. 5, 1999, pages 101 - 104 |
MILSTEIN ET AL., NATURE, vol. 305, 1983, pages 537 - 39 |
MUYLDERMANS ET AL., TRENDS BIOCHEM. SCI., vol. 26, 2001, pages 230 |
OPPENHEIM AND FELDMANN: "Cytokine Reference", 2001, ACADEMIC PRESS |
POOLE AND PETERSON: "Pharmacotherapeutics for Advanced Practice: A Practical Approach", 2001, LIPPINCOTT, WILLIAMS & WILKINS |
PRUDHOMME ET AL., EXPERT OPINION BIOL. THER., vol. 1, 2001, pages 359 - 373 |
REICHMANN ET AL., J. IMMUNOL. METHODS, vol. 231, 1999, pages 25 |
SHEPERD AND DEAN: "Monoclonal Antibodies", 2000, OXFORD UNIV. PRESS |
SUTTON ET AL., J EXP. MED., vol. 203, 2006, pages 1685 |
TANG ET AL., J. BIOL. CHEM., vol. 274, 1999, pages 27371 - 27378 |
TOY ET AL., J IMMUNOL., vol. 177, no. 1, 2006, pages 36 - 39 |
VON ANDRIAN AND MACKAY, NEW ENGL. J MED., vol. 343, 2000, pages 1020 - 1034 |
ZHU ET AL., PROTEIN SCI, vol. 6, 1997, pages 781 |
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WO2008106131A3 (en) | 2008-12-11 |
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EP2425838A3 (en) | 2012-05-02 |
BRPI0807987A2 (en) | 2014-06-24 |
EP2056838B1 (en) | 2013-09-25 |
CN103933573A (en) | 2014-07-23 |
EP2417974A1 (en) | 2012-02-15 |
EP2056838A2 (en) | 2009-05-13 |
JP2010520197A (en) | 2010-06-10 |
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