“Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immunemediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, etc.”
“[0015] lnterleukin-17 (IL-17) is a T-cell derived pro-inflammatory molecule that stimulates epithelial, endothelial and fibroblastic cells to produce other inflammatory cytokines and chemokines including IL-6, IL-8, G-CSF, and MCP-1 [see, Yao, Z. et al., J. Immunol., 122(12):5483-5486 (1995); Yao, Z. et al., Immunity, 3(6):811-821 (1995); Fossiez, F., et al., 30 J. Exp. Med., 183(6): 2593-2603 (1996); Kennedy, J., et al., J. Interferon Cytokine Res., 16(8):611-7 (1996); Cai, X. Y., et al., Immunol. Lett, 62(1):51-8 (1998); Jovanovic, D.V., et al., J. Immunol. 160(7):3513-21 (1998); Laan, M., et al., J. Immunol., 162(4):2347-52 (1999); Linden, A., et al., Eur Respir J, 15(5):973-7 (2000); and Aggarwal, S. and Gurney, A.L., J Leukoc Biol, 71(1):1-8 (2002)]. IL-17 also synergizes with other cytokines including TNF-a and IL-1β to further induce chemokine expression (Chabaud, M., et al., J. Immunol. 161 (1):409-14 (1998)). Interleukin 17 (IL-17) exhibits plei[o]tropic biological activities on various types of cells. IL-17 also has the ability to induce ICAM-1 surface expression, proliferation of T cells, and growth and differentiation of CD34+ human progenitors into neutrophils. IL-17 has also been implicated in bone metabolism, and has been suggested to play an important role in pathological conditions characterized by the presence of activated T cells and TNF-α production such as rheumatoid arthritis and loosening of bone implants (Van Bezooijen et al., J. Bone Miner. Res., 14: 1513-1521 [1999]). Activated T cells of synovial tissue derived from rheumatoid arthritis patients were found to secrete higher amounts of IL-17 than those derived from normal individuals or osteoarthritis patients (Chabaud et al., Arthritis Rheum., 42: 963-970 [1999]). It was suggested that this proinflammatory cytokine actively contributes to synovial inflammation in rheumatoid arthritis. Apart from its proinflammatory role, IL-17 seems to contribute to the pathology of rheumatoid arthritis by yet another mechanism. For example, IL-17 has been shown to induce the expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts (Kotake et al., J. Clin. Invest., 161. progenitor cells into osteoclasts, the cells involved in bone resorption. Since the level of IL-17 is significantly increased in synovial fluid of rheumatoid arthritis patients, it appears that IL-17 induced osteoclast formation plays a crucial role in bone resorption in rheumatoid arthritis. IL-17 is also believed to play a key role in certain other autoimmune disorders such as multiple sclerosis (Matusevicius et al., Mult. Scler., 5: 101-104 (1999); Kurasawa, K., et al., Arthritis Rheu 43(11):2455-63 (2000)) and psoriasis (Teunissen, M.B., et al., J Invest Dermatol 111 (4):645-9 (1998); Albanesi, C., et al., J Invest Dermatol 115(1):81-7 (2000); and Homey, B., et al., J. Immunol. 164(12:6621-32 (2000)). 162. [0016] IL-17 has further been shown, by intracellular signalling, to stimulate Ca2+ influx and a reduction in [cAMP] in human macrophages (Jovanovic et al., J. Immunol., 160:3513 [1998]). Fibroblasts treated with IL-17 induce the activation of NF-κB, [Yao et al., Immunity, 3:811 (1995), Jovanovic et al., supra], while macrophages treated with it activate NF-κB and mitogen-activated protein kinases (Shalom-Barek et al., J. Biol. Chem., 273:27 467 [1998]). Additionally, IL-17 also shares sequence similarity with mammalian cytokine-like factor 7 that is involved in bone and cartilage growth. Other proteins with which IL-17 polypeptides share sequence similarity are human embryo-derived interleukin-related factor (EDIRF) and interleukin-20. 163. [0017] Consistent with IL-17's wide-range of effects, the cell surface receptor for IL-17 has been found to be widely expressed in many tissues and cell types (Yao et al., Cytokine, 9:794 [1997]). While the amino acid sequence of the human IL-17 receptor (IL-R) (866 amino acids) predicts a protein with a single transmembrane domain and a long, 525 amino acid intracellular domain, the receptor sequence is unique and is not similar to that of any of the receptors from the cytokine/growth factor receptor family. This coupled with the lack of similarity of IL-17 itself to other known proteins indicates that IL-17 and its receptor may be part of a novel family of signaling proteins and receptors. It has been demonstrated that IL-17 activity is mediated through binding to its unique cell surface receptor (designated herein as human IL-17R), wherein previous studies have shown that contacting T cells with a soluble form of the IL-17 receptor polypeptide inhibited T cell proliferation and IL-2 production induced by PHA, concanavalin A and anti-TCR monoclonal antibody (Yao et al., J. Immunol., 155:5483-5486 [1995]). As such, there is significant interest in identifying and characterizing novel polypeptides having homology to the known cytokine receptors, specifically IL-17 receptors.”
“[0018] Interleukin 17 is now recognized as the prototype member of an emerging family of cytokines. The large scale sequencing of the human and other vertebrate genomes has revealed the presence of additional genes encoding proteins clearly related to IL-17, thus defining a new family of cytokines. There are at least 6 members of the IL-17 family in humans and mice including IL-17B, IL-17C, IL-17D, IL-17E and IL-17F as well as novel receptors IL-17RH1, IL-17RH2, IL-17RH3 and IL17RH4 (see W001/46420 published June 28, 2001). One such IL-17 member (designated as IL-17F) has been demonstrated to bind to the human IL-17 receptor (IL-17R) (Yao et al., Cytokine, 9(11):794-800 (1997)). Initial characterization suggests that, like IL-17, several of these newly identified molecules have the ability to modulate immune function. The potent inflammatory actions that have been identified for several of these factors and the emerging associations with major human diseases suggest that these proteins may have significant roles in inflammatory processes and may offer opportunities for therapeutic intervention. [0019] The gene encoding human IL-17F is located adjacent to IL-17 (Hymowitz, S.G., et al., Embo J, 20(19):5332-41 (2001)). IL17 and IL-17F share 44% amino acid identity whereas the other members of the IL-17 family share a more limited 1527% amino acid identity suggesting that IL-17 and IL-17F form a distinct subgroup within the IL-17 family (Starnes, T., et al., J Immunol, 167(8):4137-40 (2001); Aggarwal, S. and Gurney, A.L., J. Leukoc Biol, 71 (1):1-8 (2002)). IL-17F appears to have similar biological actions as IL-17, and is able to promote the production of IL-6, IL-8, and GCSF from a wide variety of cells. Similar to IL-17, it is able to induce cartilage matrix release and inhibit new cartilage matrix synthesis (see US-2002-0177188-A1 published November 28, 2002). Thus, like IL-17, IL-17F may potentially contribute to the pathology of inflammatory disorders. Recently, these authors have observed that both IL-17 and IL-17F are induced in T cells by the action of interleukin 23 (IL-23) (Aggarwal, S., et al., J. Biol. Chem., 278(3):1910-4 (2003)).”
“The observation that IL-17 and IL-17F share similar chromosomal localization and significant sequence similarity [as] well as the observation that IL-17 and IL-17F appear to be induced with the same cell population in response to a specific stimuli has lead to the identification of a new human cytokine that is comprised of a covalent heterodimer of IL- 17 and IL17F (herein designated IL-17A/F). Human IL-17A/F is a distinctly new cytokine, distinguishable from human IL-17 and 1L-17F in both protein structure and in cell-based activity assays. Through the use of purified recombinant human IL-17 A/F as a standard, a human IL-17AF-specific ELISA has been developed. Through the use of this specific ELISA, the induced expression of human IL-17A/F was detected, confirming that IL-17A/F is naturally produced from activated human T cells in culture. Hence, IL-17A/F is a distinctly new cytokine, detectable as a natural product of isolated activated human T cells, whose recombinant form has been characterized, in both protein structure and cell-based assays, as to be different and distinguishable from related cytokines. Thus, these studies provide and identify a novel immune stimulant (i.e. IL-17 A/F) that can boost the immune system to respond to a particular antigen that may not have been immunologically active previously. As such, the newly identified immune stimulant has important clinical applications. This novel IL-17A/F cytokine or agonists thereof, would therefore find practical utility as an immune stimulant, whereas molecules which inhibit IL-17A/F activity (antagonists) would be expected to find practical utility when an inhibition of the immune response is desired, such as in autoimmune diseases. Specifically, antibodies to this new cytokine which either mimic (agonist antibodies) or inhibit (antagonist antibodies) the immunological activities of IL-17 A/F would possess therapeutic qualities. Small molecules which act to inhibit the activity of this novel cytokine would also have potential therapeutic uses.”
“In another embodiment, the invention relates to a method of treating an immune related disorder in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of an IL-17A/F polypeptide, an agonist thereof, or an antagonist thereto. In a preferred aspect, the immune related disorder is selected form the group consisting of: systemic lupus erythematosis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, spondyloarthropathies, systemic sclerosis, idiopathic inflammatory myopathies, Sjögren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, thyroiditis, diabetes mellitus, immune-mediated renal disease, demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or GuillainBarré syndrome, and chronic inflammatory demyelinating polyneuropathy, hepatobiliary diseases such as infectious, autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis, inflammatory bowel disease, gluten-sensitive enteropathy, and Whipple's disease, autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis, allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria, immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis, transplantation associated diseases including graft rejection and graft-versus-hostdisease.”
“[0115] A ‘species-dependent antibody,’ e.g., a mammalian antihuman lgE antibody, is an antibody which has a stronger binding affinity for an antigen from a first mammalian species than it has for a homologue of that antigen from a second mammalian species. Normally, the species-dependent antibody ‘bind[s] specifically’ to a human antigen (i.e., has a binding affinity (Kd) value of no more than about 1 x 10-7 M, preferably no more than about 1 x 10-8 and most preferably no more than about 1 x 10-9 M) but has a binding affinity for a homologue of the antigen from a second non-human mammalian species which is at least about 50 fold, or at least about 500 fold, or at least about 1000 fold, weaker than its binding affinity for the human antigen. The species-dependent antibody can be of any of the various types of antibodies as defined above, but preferably is a humanized or human antibody. [0118] [A] An antibody, oligopeptide or other organic molecule ‘which binds’ an antigen of interest, e.g. a tumor-associated polypeptide antigen target, is one that binds the antigen with sufficient affinity such that the antibody, oligopeptide or other organic molecule is useful as a diagnostic and/or therapeutic agent in targeting a cell or tissue expressing the antigen, and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antibody, oligopeptide or other organic molecule to a ‘non-target’ protein will be less than about 10% of the binding of the antibody, oligopeptide or other organic molecule to its particular target protein as determined by fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation (RIA). [B] With regard to the binding of an antibody, oligopeptide or other organic molecule to a target molecule, the term ‘specific binding’ or ‘specifically binds to’ or is ‘specific for’ a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the blinding of the labeled target to a probe is competitively inhibited by excess unlabeled target. [C] The term ‘specific binding’ or ‘specifically binds to’ or is ‘specific for’ a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a Kd for the target of at least about 10[-]4 M, alternatively at least about 10-5 M, alternatively at least about 10-6 M, alternatively at least about 10-7 M, alternatively at least about 10-8 M, alternatively at least about 10-9 M, alternatively at least about 10-10 M, alternatively at least about 10-11 M, alternatively at least about 10-12 M, or greater. [D] In one embodiment, the term ‘specific binding’ refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. [0131] ‘Active’ or ‘activity’ for the purposes herein refers to form(s) of an IL-17A/F polypeptide which retain a biological and/or an immunological activity of native or naturally-occurring IL17A/F polypeptides, wherein ‘biological’ activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally-occurring IL-17A/F polypeptide other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturallyoccurring IL-17A/F polypeptide and an ‘immunological’ activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring IL-17A/F polypeptide. One preferred biological activity includes inducing activation of NF-[κB] and stimulation of the production of the pro inflammatory chemokines IL-8 and IL-6. Another preferred biological activity includes stimulation of peripheral blood mononuclear cells or CD4+ cells. Another preferred biological activity includes stimulation of the proliferation of T-lymphocytes. Another preferred biological activity includes, for example, the release of TNF-α from THP1 cells. Another activity includes an enhancement of matrix synthesis in articular cartilage. Alternatively, another activity includes promoting breakdown of articular cartilage matrix as well as inhibiting matrix synthesis. Another preferred biological activity includes modulating the level of the interleukin-17 signalling pathway during mild to severe stages of inflammatory bowel disease or during stroke.” protein will be less than about 10% of the binding of the antibody, oligopeptide or other organic molecule to its particular target protein as determined by fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation (RIA). and stimulation of the production of the pro inflammatory chemokines IL-8 and IL-6. Another preferred biological activity includes stimulation of peripheral blood mononuclear cells or CD4+ cells. Another preferred biological activity includes stimulation of the proliferation of T-lymphocytes. Another preferred biological activity includes, for example, the release of TNF-α from THP1 cells. Another activity includes an enhancement of matrix synthesis in articular cartilage. Alternatively, another activity includes promoting breakdown of articular cartilage matrix as well as inhibiting matrix synthesis. Another preferred biological activity includes modulating the level of the interleukin-17 signalling pathway during mild to severe stages of inflammatory bowel disease or during stroke.”
“Examples of immune-related and inflammatory disease, some of which are immune or T cell mediated, which can be treated according to the invention, include systemic lupus erythematosis, rheumatoid arthritis, juvenile chronic arthritis, osteoarthritis, spondyloarthropathies, systemic sclerosis (scleroderma), idiopathic inflammatory myopathies (dermatomyositis, polymyositis), Sjögren's syndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis), diabetes mellitus, immunemediated renal disease (glomerulonephritis, tubulointerstitial nephritis), demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy, hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis, inflammatory bowel disease (ulcerative colitis: Crohn's disease), gluten-sensitive enteropathy, and Whipple's disease, autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis, allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria, immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis, transplantation associated diseases including graft rejection and graft versus-host-disease.”
“Gene expression in various tissues, alternatively, may be measured by immunological methods, such as immunohistochemical staining of tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence of an IL-17 A/F polypeptide or against a synthetic peptide based on the DNA sequences encoding the IL-17A/F polypeptide or against an exogenous sequence fused to a DNA encoding an IL-17 A/F polypeptide and encoding a specific antibody epitope. General techniques for generating antibodies, and special protocols for Northern blotting and in situ hybridization are provided below”
“Additionally, the compounds of the invention can be tested on animal models for psoriasis like diseases. Evidence suggests a T cell pathogenesis for psoriasis. The compounds of the invention can be tested in the scid/scid mouse model described by Schon, M. P. et al., Nat. Med., 3:183 (1997), in which the mice demonstrate histopathologic skin lesions resembling psoriasis. Another suitable model is the human skin/scid mouse chimera prepared as described by Nickoloff, B. J. et al., Am. J. Path., 146:580 (1995).”
“It is further important that antibodies be humanized with retention of high binding affinity for the antigen and other favourable biological properties. To achieve this goal, according to a preferred method, humanized antibodies are prepared by a process of analysis of the parental sequences and various conceptual humanized products using threedimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristic, such as increased affinity/or the target antigen(s), is achieved.”
“Western Blot analysis indicated that this novel protein species is also able to interact both with an antibody that is able to bind to IL-17 and with an antibody that is able to bind to IL-17F. Each of these observations and the distinct molecular mass of the novel isolated protein species suggest that the isolated protein IL-17A/F is a novel protein species comprised of a covalent association of IL-17 and IL-17F.”
“Interestingly, IL-17 A/F was observed to have a unique potency that differs from that of either IL-17 or IL-17F. The difference in activity differs from IL-17 and IL-17F by roughly an order of magnitude in each case. The substantially greater activity of IL-17 A/F than IL-17F in this assay suggests that IL17A/F may comprise a critical component of the cytokine activity resulting from the IL-17F gene product. This unique potency may enable the molecule to possess distinct range of actions in vivo. IL-17A/F also induced production of IL-6 from this cell line (Figure 5B). Additionally, it is likely that IL17A/F may possess additional characteristics not present in either IL-17 or IL-17F as a result of its novel heterodimeric composition that may alter the kinetics and utilization of receptor subunits in vivo, resulting in unique biological consequences.”
“[0404] … Hence, IL-17A/F is a distinctly new cytokine, detectable as a natural product of isolated activated human T cells, whose recombinant form has been characterized, in both protein structure and cell-based assays, as to be different and distinguishable from related cytokines. [0405] This new cytokine can act to modulate the activity of IL-17 in vivo, acting as a competitive inhibitor to binding sites for IL17 or other related cytokines. IL-17A/F can also modulate the activity of other related cytokines by down regulation of binding sites for itself and/or binding sites for other related cytokines. IL-17A/F can exhibit activity through intracellular adapters or signaling molecules which act to affect its own signaling activity or that of other related cytokines. IL-17A/F has the ability to affect the pairing of receptors and coreceptors found at the surface of cells or within the intracellular compartment. [0406] Thus, these studies provide and identify a novel immune stimulant (i.e. IL-17A/F) that can boost the immune system to respond to a particular antigen that may not have been immunologically active previously. As such, the newly identified immune stimulant has important clinical applications. … [0407] Thus, antibodies to this new cytokine which either mimic (agonist antibodies) or inhibit (antagonist antibodies) the immunological activities of IL-17A/F would possess therapeutic qualities. …”
“In summary, the data presented here clearly illustrate that T cell-keratinocyte interactions in psoriasis are responsible for enhanced bidirectional cellular activation. Minute quantities of cytokines released during these interactions may trigger a cascade of intercellular cytokine signals which induce or boost cutaneous inflammation, or both. Therefore, the identification of the primary signal and its cellular source in psoriasis remains extremely difficult.”
“ … increases the local production of chemokines such as IL-8, monocyte chemoattractant protein-1 (MCP-1) and Gro-α, thereby promoting the recruitment of monocytes and neutrophils, and stimulates production of G-CSF and GM-CSF. … Other actions such as the stimulation of IL-6 and PGE2 production enhance the local inflammatory environment.”
“It has been shown that TNFα is capable of increasing production of interleukin (IL)-1, IL-6, IL-8 and nuclear transcription factor κB (NFκB). These proinflammatory cytokines can be synthesized by stimulated T lymphocytes and keratinocytes, exerting specific effects in the pathogenesis of psoriasis”
“The authors’ belief of the importance of IFN-γ as a pivotal cytokine in the initiation or maintenance of psoriatic lesions has been supported with evidence throughout this article, while acknowledging that TNFα plays an important and probably synergistic role.”
“According to the pathogenic model drawn in Fig 6, IL-8 is a chemokine that amplifies T-cell–‘driven’ inflammation by recruiting neutrophils into psoriasis lesions. Although this chemokine might also affect T-cell recruitment into lesions, there is no evidence for selectivity of its receptor (CCR1) in regulating type 1 T-cell responses. ABX–IL-8 (Abgenix, Inc, Fremont, Calif), [is] a fully human anti–IL-8 antibody that neutralizes this chemokine. Moderate clinical improvements observed in most patients with psoriasis treated with anti–IL8 135 support the role of this chemokine as a part of an inflammatory cascade, but not as a sole mediator. There is also a difficult anatomic problem with respect to IL-8 neutralization in that upper spinous keratinocytes synthesize large amounts of this chemokine, whereas penetration of large proteins (anti-IL-8 antibodies) into the epidermis is likely to be quite limited. In addition, a general problem with antagonizing single chemokines is that considerable redundancy exists. For example, both IL-8 and Gro-α are neutrophil chemoattractants that bind to surface receptors CXCR1 or CXCR2. Gro-α is highly expressed in psoriatic lesions 85 and could still stimulate neutrophil trafficking even though IL-8 is fully neutralized by an antibody. The situation in T lymphocytes is similar in that multiple chemokines control T-cell migration responses. However, there is additional redundancy in that some receptors bind 2 or more chemokine ligands (Fig 5). Despite these problems, chemokines and chemokine receptors are attractive therapeutic targets because highly specific immune blockade can be obtained with[out] producing generalized immune suppression.”
“ … treatment with ABX-IL8 did not result in a significant improvement in PASI scores, the primary efficacy end point of the trial. Based on these findings, Abgenix is discontinuing clinical development of ABX-IL8 in psoriasis. In addition, the company will not proceed with a previously planned clinical study of ABX-IL8 in melanoma and will wind down its ongoing Phase 2a study in chronic obstructive pulmonary disease (COPD). Abgenix currently has no plans to conduct further clinical studies involving ABX-IL8.”
“I note that further research into anti-IL-8 therapy continued after the failed Abgenix trial. In particular, Anogen (a Canadian biopharmaceutical company) conducted studies on a topical anti-IL-8 therapy called Abcream. A phase 2/3, double blind, placebo-controlled trial involving 412 psoriasis patients demonstrated that efficacy was higher in the active treatment group than the control group (49% versus 14.9%). Subsequently, a phase 4 clinical trial of 1452 psoriasis patients showed that following Abcream treatment for 6 weeks, 62% of patients achieved PASI60, and 18% of patients achieved PASI90. Abcream has been approved in China for psoriasis treatment.10”
“Abcream (Enboke). A phase II/III, double-blind, placebocontrolled trial enrolled 412 psoriasis patients to test the efficacy of Abcream, a topical IL-8 inhibitor. After 6 weeks, the efficacy was higher in the active treatment group than in the control group (49% versus 14.9%). The adverse reactions including irritation, pain, itch and edema were 5.9% in the Abcream group and 6.6% in the control group. The therapeutic effect of IL-8 monoclonal antibody is thought to be related to the decrease of neutrophil recruitment and angiogenesis.85 Then, a phase IV clinical trial (n = 1452) showed that after Abcream treatment for 8 weeks, 62% and 18% of patients achieved PASI 60 and PASI 90, respectively.86 Abcream has been approved by China for psoriasis treatment. … Although anti-IL-8 is approved as a topical treatment for psoriasis in China, it has not been accepted as an effective treatment for psoriasis elsewhere. The use of anti-IL-8 biologics is still under development for oncologic indication, but no further development was in progress for psoriasis.”
“I have checked the clinical paper. I have seen the results in the patients being treated before and after pictures. They are there. [Reference] 86”
“Previously, the efficacy of murine IL-8 Ab in acute inflammatory diseases has been demonstrated in a number of animal models, suggesting Ab-mediated neutralization of IL-8 can potentially be used for various human inflammatory disorders (21, 23, 24, 34– 38). Few studies have been performed in chronic inflammatory diseases. The anti-IL-8 activity of another human IL-8 mAb, ABX-IL-8 (IgG2/κ), was demonstrated in vitro and in animal models in vivo (30). The result of a placebo-controlled phase IIb clinical trial for treatment of moderate-to-severe psoriasis with this Ab, however, was disappointing (39). This failure might well have resulted from the low and infrequent dosing used in these studies, leading to insufficient Ab concentrations in situ. Additionally, heterogeneity in clearance rates of the human IgG2 Ab resulting from a polymorphism for FcγRIIa that is known to affect IgG2 serum concentrations (40) may have played a role.”
“In conclusion, we show IL-8 to play a central role in PPP. Using an IL-8-neutralizing Ab, we demonstrate that targeting a single critical factor in this disease characterized by high IL-8 overexpression leads to clinically relevant reductions in disease activity. This observation bears promise for the treatment of other diseases characterized by IL-8 overexpression.”
“Elevated amounts of IL-8 have been detected in psoriatic lesional skin [30]. Many studies indicate that IL-8 may be involved in the pathomechanism of psoriasis. In fact, data currently available suggest that this cytokine exerts a critical role as a potent chemoattractant for neutrophils and T lymphocytes, as well as a factor prompting keratinocyte proliferation [10].”
“A fully human anti IL-8 antibody (ABX-IL-8) has been developed and tested in a dose-escalation study for psoriasis.[21] At the highest dose (3 mg/kg intravenously), 30% of the patients had a >50% reduction in PASI scores, but this was on the edge of clinical significance and lower doses were ineffective. Drug-specific issues cannot be excluded as the reason for the failure of the anti-IL-8 therapy; for example, whether the antibody achieved sufficient levels in the skin has not been conclusively determined. However, a consensus is emerging that IL-8 is not a suitable target for the treatment of psoriasis.”
“Although the assumption of a key role of IL-1 in the psoriatic cytokine network seemed very promising, many conflicting results have been reported by different authors on the relative amounts of IL-1alpha and IL-1beta in psoriatic skin and their roles in the pathomechanisms of the dermatosis.10-18”
“An isolated polypeptide or complex having at least 80% amino acid sequence identity to an IL-17A/F heterodimeric complex consisting of SEQ ID NO:3 …and SEQ ID NO:4 …with or without their associated signal peptides” …with or without their associated signal peptides”
“The European patent application or European patent may not be amended in such a way that it contains subject-matter which extends beyond the content of the application as filed.”
“The ‘gold standard’ … for assessing compliance with Art. 123(2) EPC is the following: any amendment to the parts of a European patent application or European patent relating to the disclosure (the description, claims and drawings) is subject to the mandatory prohibition on extension laid down by Art. 123(2) EPC and can therefore, irrespective of the context of the amendment made, only be made within the limits of what a skilled person would derive directly and unambiguously, using common general knowledge, and seen objectively and relative to the date of filing, from the whole of these documents as filed …”
“I think the test of added matter is whether a skilled [person] would, upon looking at the amended specification, learn anything about the invention which he could not learn from the unamended specification.”
“… as the line of cases leading from AC Edwards to AP Racing … explains, English patent law draws a distinction between coverage and disclosure. To amount to added matter, the intermediate generalisation must be a generalisation in terms of disclosure, not coverage. In other words, to characterise a claim as an intermediate generalisation is not sufficient to establish the presence of added matter. Proving that a claim is an intermediate generalisation in terms of coverage does not establish added matter.”
“… this is not a rigid rule. In order to see whether there is a new combination of independent features from two or more lists, the whole contents of the application as filed must be considered, including its general disclosure. It is necessary to avoid a mechanistic approach, and to compare the disclosures of the application as filed and the patent, through the eyes of the skilled person, in order to answer the overall question of whether the skilled person would learn new technical subject matter which was not disclosed in the application.”
“specific antibodies which bind selectively to the novel heterodimeric complex of IL-17A/F have been identified”
“Polynucleotides encoding human CTLA-8 and related proteins are disclosed. Human CTLA-8 proteins and methods for their production are also disclosed. Methods of treatment using human CTLA-8 proteins, rat CTLA-8 proteins and herpesvirus herpes CTLA-8 proteins are also provided.” 355. US344 states at column 4, lines 15-26: “Golstein et al. … reported a species they initially identified as ‘human CTLA-8’. However, examination of the sequence of the Golstein et al. species and the human CTLA-8 (B18) sequence of the present invention readily reveals that they are two different proteins, although they are homologous with each other and with the rat CTLA-8 and herpes CTLA-8 identified herein. The Golstein et al. species has now been renamed interleukin-17 (IL-17). Because of the homology between applicants’ human CTLA-8 (B[1]8) and IL-17, these proteins are expected to share some activities. It has also been preliminarily determined that human CTLA-8 (B18) forms homodimers when expressed. As a result, human CTLA-8 proteins may possess activity in either monomeric or dimeric forms. Human CTLA-8 proteins can also be produced as heterodimers with rat and herpes CTLA-8 proteins and with human IL-17. These heterodimers are also expected to have activities of the proteins of which they are comprised.”
“Autoimmune disorders which may be treated using a protein of the present invention include, for example, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease. Such a protein of the present invention may also to be useful in the treatment of allergic reactions and conditions, such as asthma or other respiratory problems. Other conditions, in which immune suppression is desired (including, for example, asthma and related respiratory conditions), may also be treatable using a protein of the present invention.”
“The present invention relates to a method of treating a mammal afflicted with a condition that relates to an inflammatory response, in particular, rheumatoid arthritis, by administering an IL-17 antagonist that inhibits IL-17 mediated signalling to a cell via membrane-bound IL-17 receptor. Suitable IL-17 antagonists include soluble IL-17 receptor, antagonistic antibodies that specifically bind IL-17 and antagonistic antibodies to the IL-17 receptor and combinations thereof.”
“… antibodies that specifically recognize a component of the IL-17 receptor and that prevent signalling through the receptor by IL-17 can be used to inhibit IL-17 activity. IL-17 antagonists that are antibodies include but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies… Thus, such antibodies can … be utilized as part of inflammatory disorder treatment methods.”
“… isolated genes encoding proteins of the invention, variants of the encoded protein, e.g., mutations (muteins) of the natural sequence, species and allelic variants, fusion proteins, chemical mimetics, antibodies and other structural and functional analogs. … an antibody which specifically binds to a primate CTLA-8 protein or peptide thereof; the antibody is raised against a protein sequence of SEQ ID NO: 2 [mouse IL-17A], 4 [viral IL-17A], 6 [human IL-17A fragment], 8 [human IL-17A] or 10 [mouse IL-17A fragment]; the antibody is a monoclonal antibody; the antibody blocks the CTLA-8 induced secretion of an inflammatory mediator, e.g., IL-6, IL-8 and/or PGE2; or the antibody is labelled.”
“Purified CTLA-8, when cultured with synoviocytes, is able to induce the secretion of IL-6 from these cells. This induction is reversed upon the addition of a neutralizing antibody raised against human CTLA-8-8. Endothelial, epithelial, fibroblast and carcinoma cells also exhibit responses to treatment with CTLA-8. This data suggests that CTLA-8 may be implicated in inflammatory fibrosis, e.g., psoriasis, sclerodermia, lung fibrosis, or cirrhosis. CTLA-8 may also cause proliferation of carcinomas or other cancer 25 cells inasmuch as IL-6 often acts as a growth factor for such cells.”
“Monoclonal antibodies are prepared from cells secreting the desired antibody. These antibodies can be screened for binding to normal or defective CTLA-8 proteins, or screened for agonistic or antagonistic activity, e.g., mediated through a binding partner. These monoclonal antibodies will usually bind with at least a KD of about 1mM, more usually at least 300µM, typically at least about 10µM, more typically at least about 30µM, preferably about 10µM, and more preferably at least about 3µM or better.”
“The antibodies … of this invention can have significant diagnostic or therapeutic value. They can be potent antagonists that bind to a binding partner and inhibit antigen binding or inhibit the ability of an antigen to elicit a biological response.” (column 26, lines 33-37) “The polypeptides and antibodies of the present invention may be used with or without modification, including chimeric or humanized antibodies”
“The CTLA-8 protein (naturally occurring or recombinant), fragments thereof, and antibodies thereto, along with compounds identified as having binding affinity to CTLA-8 protein, should be useful in the treatment of conditions associated with abnormal physiology or development, including abnormal proliferation, e.g. cancerous conditions or degenerative conditions. Abnormal proliferation, regeneration, degeneration, and atrophy may be modulated by appropriate therapeutic treatment using the compositions provided herein. For example, a disease or disorder associated with abnormal expression or abnormal signal[l]ing by a CTLA-8 antigen should be a likely target for an agonist or antagonist of the protein.” 401. purified and then administered to a patient.”
“[0003] Various cytokines, such as IL-1, IL-6, and TNF-a play an important role in the pathological development of RA. A particularly representative inflammatory cytokine is IL-6, and RA treatment by blocking IL-6 signal transmission has been attempted. … [0004] In recent years, interleukin-17 (hereinafter, ‘IL-17’) was discovered and its function was investigated (Clinical Immunology, 29, 678-682 (1997)). IL-17 is known not only to cause the production of inflammatory cytokines such as IL-6, IL-8, and GCSF, but also to induce the differentiation of mature neutrophils. Recently, IL-17 was surmised to possibly be involved in inflammatory diseases. However, IL-17 is a new cytokine derived from T-cells, so its role in the pathological development of RA is still unknown. … [0008] The cells that control bone metabolism are osteoblasts and osteoclasts, and these cells intimately interact with one another in a phenomenon called coupling. Osteoblast/osteoblast-like stromal cells are known to adhere to osteoclast precursor cells and mature osteoclasts, respectively inhibiting osteoclast differentiation/maturation and the bone resorption activity of mature osteoclasts. The theory has been proposed that osteoblast/osteoblast-like stromal cells produce osteoclastogenesis differentiation factors (ODFs) on the cell membrane by receiving signals via 3 different signal transmission systems for the various bone resorption factors: specifically, intranuclear D3 receptors in the case of activated vitamin D3, protein kinase in the case of interleukin-1 (IL-1), parathyroid hormone (PTH), prostaglandin fa (PGfa), etc., and gp130 in the case of the inflammatory cytokine IL-6 …”
“Although IL-17 is a new cytokine derived from T-cells, its role in osteoclast formation is almost completely unknown. The present inventors discovered that IL-17 has an important relationship with the pathology of RA….”
“The present invention relates to a chronic rheumatoid arthritis treatment drug whose active ingredient is a substance that suppresses or neutralizes IL-17 activity in the body and/or a substance that inhibits the transmission of IL-17 signals that induce osteoclastogenesis. More specifically, examples of the substance that neutralizes interleukin-17 activity may be interleukin-17 neutralizing antibodies …”
“[0012] As shown in the embodiments below, the research of the present inventors showed that IL-17 levels in synovial fluid are significantly higher in RA patients than in patients with osteoarthritis (p<;0.001). Also, it was discovered that IL-17positive cells exist among CD4+ and CD45RO+ T-cells in synovial fluid and tissue. In this way, IL-17 is suggested to be deeply involved in the pathological development of RA. … As described above, the present inventors discovered for the first time that IL-17 was markedly increased in RA patients, that increased IL-17 promoted the formation of osteoclasts and bone destruction, and that this sort of bone destruction was selectively inhibited by osteoclastogenesis inhibitory factors (OCIFs). [0013] As described above, IL-17 levels were shown to be significantly higher in RA patients compared with osteoarthritis patients (p<;0.001), and since IL-17 produced a bone resorption effect by markedly inducing osteoclastogenesis, it was discovered to be a cytokine that was deeply involved in RA lesions such as joint and bone resorption. In addition, these results revealed that suppressing or neutralizing IL-17 activity in the body and/or inhibiting osteoclastogenesis inducing signal transmission could be a treatment for RA. Therefore, a substance with properties that suppress or neutralize IL-17 activity and/or a substance that inhibits IL-17 osteoclastogenesis inducing signal transmission could be used as an active ingredient in a drug to treat RA … use of an IL-17 neutralizing antibody or OCIF is particularly preferable.”
“[0015] … Also, for a humanized antibody, a monoclonal antibody that neutralizes human IL-17 activity and that also has high affinity for human IL-17(lowest dissociation constant possible, for example, 10-10 M or below) is selected from among the mouse anti-monoclonal antibodies obtained by the abovedescribed methods. [0016] … By using a protein A column to purify the culture solution of the antibody-producing hybridoma, a complete human antihuman IL-17 monoclonal antibody can be obtained. The humanized anti-human IL-17 monoclonal antibody that is the objective of the present invention can be obtained by selecting a human monoclonal antibody that neutralizes human IL-17 activity and exhibits high affinity for human IL-17.”
“The skilled person would expect IL-17A/F to have similar effects to IL-17A and would conduct studies in relation to the function of IL-17A/F including to compare the effects and potency of IL-17A/F against IL-17A and IL-17F in inducing the production of proinflammatory cytokines by synovial fibroblasts. If, as expected, those studies were positive, IL- 17A/F would be a therapeutic target as with IL-17A for RA.”
“As there is a degree of flexibility and personal judgement, on which residues to back mutate, different labs starting from the same murine antibodies would in all likelihood produce different humanised variants. However, all of these would be designed applying well established and routine principles. And while the exact framework sequence of the final humanised antibodies produced in the different labs may vary, each successfully humanised antibody will have an antigen affinity comparable to its parental murine antibody.”
“The Court of Appeal's reference to ‘armchair inventors’ suggests that what they meant by speculative claiming was claiming by persons who had done nothing new or inventive at all but had simply sought to patent abstract possibilities. That may well be a particular risk in the case of patents for new uses of known compounds, especially when they are commercially successful in their existing use. In reality, however, speculative claiming of this kind is simply one of a number of ways in which a patentee may attempt to claim a monopoly more extensive than anything which is justified by his contribution to the art. Other ways in which this can happen include claiming a monopoly wider than the disclosure in the patent can support. An over-broad claim will not necessarily be speculative. The inventor may really have invented something corresponding to the full breadth of the claim. Research may subsequently demonstrate this. But the claim will still exceed his contribution to the art if that contribution is not sufficiently disclosed in the patent”
“The principle is that the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true. Plausibility is not a distinct condition of validity with a life of its own, but a standard against which that must be demonstrated. Its adoption is a mitigation of the principle in favour of patentability. It reflects the practical difficulty of demonstrating therapeutic efficacy to any higher standard at the stage when the patent application must in practice be made. The test is relatively undemanding. But it cannot be deprived of all meaning or reduced … to little more than a test of good faith.”
“Plausibility is not a term of art, and its content is inevitably influenced by the legal context. In the present context, the following points should be made. First, the proposition that a product is efficacious for the treatment of a given condition must be plausible. Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion. …. But, third, the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, ie not just because there was an abstract possibility that it would work but because reasonable scientific grounds were disclosed for expecting that it might well work. The disclosure of those grounds marks the difference between a speculation and a contribution to the art. This is in substance what the Technical Board of Appeal has held in the context of article 56, when addressing the sufficiency of disclosure made in support of claims extending beyond the teaching of the patent. In my opinion, there is no reason to apply a lower standard of plausibility when the sufficiency of disclosure arises in the context of EPC articles 83 and 84 and their analogues in section 14 of the Patents Act. In both contexts, the test has the same purpose. Fourth, although the disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true. Fifth, that reasonable prospect must be based on what the TBA in SALK (para 9) called ‘a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se.’ Sixth, in SALK, this point was made in the context of experimental data. But the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. For example, and it is no more than an example, the specification may point to some property of the product which would lead the skilled person to expect that it might well produce the claimed therapeutic effect; or to some unifying principle that relates the product or the proposed use to something else which would suggest as much to the skilled person. Seventh, sufficiency is a characteristic of the disclosure, and these matters must appear from the patent. The disclosure may be supplemented or explained by the common general knowledge of the skilled person. But it is not enough that the patentee can prove that the product can reasonably be expected to work in the designated use, if the skilled person would not derive this from the teaching of the patent.” 529. At [40] Lord Sumption added: “The question is not whether [the medicament] works but whether the contribution to the art consisting in the discovery that it can be expected to work has been sufficiently disclosed in the patent. The inherent difficulty of demonstrating this before clinical trials is taken into account in the modest standard (ie plausibility) which is applied to test it. … This does not mean that subsequent data is never admissible in a dispute about sufficiency, but the purpose for which it is admitted is strictly limited. Where the asserted therapeutic effect is plausible in the light of the disclosure in the patent, subsequent data may sometimes be admissible either to confirm that or else to refute a challenger's contention that it does not actually work… But it cannot be a substitute for sufficient disclosure in the specification.”
“In conclusion, the induction of secretion by stromal cells of IL-6, IL-8, and PGE 2 but not of IL-1 or TNF, and the lack of detectable activity on monocytes suggest a limited proinflammatory role of IL-17 in T cell-driven inflammatory pathological processes such as psoriasis …”
“…. I consider that the disclosure of the Patent amounts to no more than the disclosure of a mere possibility that an antibody which binds to and inhibits IL-17A/F (whether only or in addition to IL-17A/A and/or IL-17F/F) will work to treat psoriasis. The Patent discloses no reasonable scientific grounds for expecting that such an antibody might well work to treat psoriasis. There is nothing in the Patent that would cause the skilled person to think that there was a reasonable prospect that the assertion that such an antibody would treat psoriasis would prove to be true. The skilled person could not point to a direct effect of such an antibody on a metabolic mechanism specifically involved in psoriasis, this mechanism being either known from the prior art or demonstrated in the Patent itself. The Patent does not point to a property of such an antibody which would lead the skilled person to expect that it might well produce the claimed therapeutic effect of treating psoriasis nor any unifying principle that relates to such an antibody which would suggest such an effect to the skilled person. I do not consider that the skilled person can derive from the Patent that such an antibody can reasonably be expected to work to treat psoriasis.”
“Now, the IL-23/Th17 axis has been suggested as the main attributer for psoriatic disease. For instance, intradermal injection of IL-23 in mice induced erythema and induration, histopathologically resembling psoriasis [51]. IL-17A promotes the production of IL-6, IL-8, intercellular adhesion molecule (ICAM)-1 and granulocyte–macrophage colony-stimulating factor (GM-CSF) in keratinocytes, which strongly resembles the psoriatic phenotype found in humans. Finally, inhibition of IL-17A in humans consecutively resulted in reductions in hyperplasia and infiltration of the dermis and epidermis [52].”
“The current authors believe that IFN-γ is a pivotal cytokine in the development and maintenance of psoriatic lesions. Fig. 3 outlines a sequential pathway of type 1 T-cell activation, release of T-cell–derived cytokines, and production of several inflammatory mediators that the authors term the type 1 pathogenic pathway. IFN-γ is produced by effector memory CD8+ T cells, epidermal Tc1, CD4+ T cells, and NK and NK-T cells. Psoriatic CD8+ Tc1 cell lines and clones have been shown to produce heterogeneous levels of IFN-γ [15]. There is also evidence of the effects of IFN-γ at the tissue level in psoriatic lesions: keratinocytes show increased levels of HLA-DR, intercellular adhesion molecule-1 (ICAM-1) [27], and CD40 [28]; increased CXCR3 expression on lymphocytes [8]; and greater levels of keratinocyte-derived MIG and IP-10 [8]. Furthermore, this cytokine may also increase expression of costimulatory molecules on DCs [29]. IFN-γ potently activates macrophages and may also induce TNF-α release from monocytes and macrophages, which acts synergistically with IFN-γ in an inflammatory response [30]. Endothelial cells are also responsive to IFN-γ, up-regulating several adhesion molecules, such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1), which facilitates the complex process of leukocyte trafficking into tissues. The sum of cytokines and chemokines made in response to IFN-γ and TNF-α (see Fig. 3) can explain many features of the pathogenic process: angiogenesis and vascular ectasia, T-cell and neutrophil emigration into lesions, and some components of the psoriatic epidermal response.”
“Increased understanding of the immunopathogenesis of psoriasis has led to the development of multiple biologic drugs targeting specific molecules that are essential for the development of psoriatic plaques. Overproduction of interleukins 17A, 17F, and 17A/F induces the expression of proinflammatory cytokines with pathologic consequences, including the proliferation of keratinocytes and inflammation of epithelial cells in psoriasis. Therapies targeting this pathway, including interleukin-17 and interleukin-17R, are currently under investigation for the treatment of inflammatory conditions, such as psoriasis and rheumatoid arthritis.19,28-30 Brodalumab, which targets interleukin-17RA, blocks signalling of interleukins 17A and 17F and the interleukin-17A/F heterodimer, all of which play a role in the inflammation of psoriasis.”