APOTEX ET AL. - EXHIBIT 1068
`Apotex Inc. et al. v. Novartis AG
`IPR2017-00854
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`PCT/US2008/007770
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`JOINT DESTRUCTION BIOMARKERS FOR ANTI-IL-17A THERAPY
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`OF INFLAMMATORY JOINT DISEASE
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`The present application claims the benefit of US. Provisional Patent Application
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`60/945239, filed 20 June 2007.
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`FIELD OF THE INVENTION
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`The present invention relates generally to the treatment of inflammatory joint diseases
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`with antagonists of interleukin-17A (IL-17A). More specifically, the invention relates to
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`biomarkers that are correlated with the efficacy of 1L-17A antagonists for inhibiting joint
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`destruction in rheumatoid arthritis and associated arthritides.
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`BACKGROUND OF THE INVENTION
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`Rheumatoid arthritis (RA) is an inflammatory disease caused by the dys-regulation of
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`the immune system resulting in joint inflammation, causing joint pain, discomfort, swelling
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`and stiffness, With progressive bone and cartilage erosion. The combination of inflammation
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`and structural joint damage results in loss of function which can lead to permanent disability.
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`1L—17A, which was originally named cytotoxic T-Lymphocyte-associated antigen 8
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`(CTLA8) is a homodimeric cytokine that binds to lL-17RA (also known as ILl7R) and IL-
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`17RC. The functional receptor for 1L-17A is believed to be a multimeric receptor complex
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`comprising one or both of 1L—17RA and IL-17RC (e.g., an 1L-17RA homodimer, an 1L-17RC
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`homodimer, or an 1L-17RA/1L-17RC heterodimer) and possibly a third, as yet unknown,
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`protein (Toy, D. et al., (2006) J. oflmmunol. 177(1):36-39; unpublished data).
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`1L-17A is produced by a subset of T cells known as Thl7 cells, whose differentiation
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`is initiated by TGF-beta signaling in the context of proinflammatory cytokines, particularly IL-
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`6,
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`IL-l-beta and TNF-alpha, and whose maintenance and survival are dependent on
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`interleukin-23 (IL-23) (Langrish, C.L. et al. (2005), J. Exp. Med 201:233-240; Harrington,
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`L.E., et al., (2005), Nat. Immunol. 6:1123—1132; Veldhoen, M. et al., (2006) Immunity 24:179-
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`189).
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`IL-23 is a heterodimeric cytokine comprised of two subunits: p19, which is unique to
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`IL-23; and p40, which is shared with 1L-12.
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`IL-23 mediates signaling by binding to a
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`heterodimeric receptor, comprised of 1L—23R and lL-lZRbetal (1Ll2RB1), which is shared by
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`the 1L-12 receptor. Studies in murine disease models suggest that IL-23-dependent Th1 7 cells
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`play a pathogenic role in autoimmune and chronic inflammatory diseases (Langrish et a1.,
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`supra, Park, H., et al. (2005), Nat. Immunol. 6:1133—1141).
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`IL-17A is present in RA synovial fluid at the earliest stages of the disease along with
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`other known inflammatory mediators such as TNF and IL-lB. Dys-regulated IL-17A
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`expression within an inflamed joint singly, and in synergy with TNF and IL-IB, stimulates
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`multiple downstream proteases, chemokines and pro-inflammatory cytokines that collectively
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`contribute to cartilage and bone erosion. A variety of IL-17A biological antagonists used in
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`multiple rodent arthritis models have demonstrated that E—17A blockade inhibits arthritis
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`progression and the resulting joint destruction that occurs with a special emphasis on bone
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`sparing (see, e.g., Koenders MI, et al., (2006) Ann. Rheum. Dis. 65 (Suppl. 3):29-33). At least
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`one anti-IL-17A antibody is being tested in clinical trials of human RA patients.
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`Currently, assessing the effect of anti-rheumatic drugs on the progression of joint
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`destruction relies mainly on radiographic evaluation. However, how to use radiographic data
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`in clinical trials is controversial (van der Heijde, D. et al, (2002) Arthritis Rheum 47;215-218).
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`In addition to being time consuming, radiography is impractical in early stages of RA in which
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`symptoms reflecting the inflammatory process often predominate over symptoms related to
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`joint destruction (Morozzi, G., et al, (2007) Clin Rheumatol.)
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`'Indeed, nonsteroidal anti-
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`inflammatory drugs (NSAIDs), which have traditionally been used as first line therapies for
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`RA, are reasonably effective at ameliorating the signs and symptoms of inflammation, but
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`have little efficacy in retarding joint destruction, leading to speculation that inflammation and
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`subsequent joint destruction can be uncoupled (van den Berg, WB (2001), Semin Arthritis
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`Rheum. 30:7-16; Geusens, RB, et al. (2006), Arthritis & Rheumatism 54 (6):1772-1777).
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`Thus, there is a well-established clinical need for better tools to predict the effect of anti-
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`rheumatic drugs on structural joint damage, with recent development efforts focused on
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`various markers of cartilage and/or bone metabolism that are elevated in the serum or urine of
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`RA patients compared to normal subjects (kaic, M. et a1., (2003) Arthritis Res. Ther.
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`5:R181-R185; Valleala, H., et a1. (2003) Eur. J. Endocrinol. 148:527-530); Ziolkowska, M.,
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`et a1. (2002) Arthritis & Rheumatism 46(7):1744-1753).
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`Articular cartilage in the joints is composed of the proteoglycan aggrecan, collagen
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`(three a-chains form a triple helix), and other non—collagenous proteins (e.g., cartilage
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`oligomer matrix protein (COMP) and human cartilage glycoprotein-39 (HC gp-39), which is
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`also known as YKL-40). Type I collagen is a major component of bone and other tissues;
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`whereas, type II collagen is specifically localized to articular cartilage of the joint. At the ends
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`of type I and H collagen helixes are short, non-helical N- and C-terminal
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`telopeptides
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`containing covalent cross-links that connect to other a-chains, both within the same trimer
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`and to adjacent trimers. Physiological and pathological cleavage of collagen by MMPs or
`Cathepsin K results in the generation of degradation products or neo-epitopes (e.g. C2C,
`C1,2C, C-terminal cross-linking telopeptide of type I collagen (CTX-I), C-terminal cross-
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`linking telopeptide of type [I collagen (CTX-II), N-terminal cross-linking telopeptide of type I
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`collagen (NTX-I)), which are released into the synovial fluid, serum, and urine. Cleavage of
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`the collagen triple helix also releases non-collagenous proteins (e.g. COMP, YKL-40,
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`aggrecan) previously incorporated in the collagen fibrils. These molecules are elevated in
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`synovial fluid and serum under conditions of normal remodeling and pathological cartilage
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`destruction.
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`Cartilage destruction also results in compensatory increased collagen synthesis by
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`chondrocytes. Type I‘and [I collagen is synthesized as a pro-molecule and once outside the
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`cell, cleavage of pro-collagen releases N-terminal and C-terminal pro-peptides. Type [I
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`collagen C—terrninal pro-peptide (CPII) levels correlate with new type [I collagen synthesis.
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`Cartilage destruction also increases aggrecan synthesis and the appearance of the “fetal form”
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`of aggrecan that has the CS846 epitope.
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`Increased CS846 levels in the serum reflect new
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`aggrecan synthesis (versus cleavage of “old” aggrecan).
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`Bone destruction occurs via the generation of excessive numbers of osteoclasts that
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`resorb the mineralized bone and degrade the organic matrix of the de-mineralized bone.
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`Receptor activator of NFKB (RANK) ligand (RANKL) is a cell-surface molecule expressed by
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`activated T—cells,
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`fibroblast-like synoviocytes (FLS), and osteoblasts that
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`is critical
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`in
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`promoting the differentiation of pre-osteoclasts into mature osteoclasts, which are cells that
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`can erode bone. RANKL can be shed by proteolytic cleavage (both cell surface and soluble
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`RANKL are active), and is elevated in mouse arthritis and human RA serum. Membrane or
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`soluble RANKL binds to RANK on pre-osteoclasts and delivers a differentiation signal.
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`Osteoprotegn'n (OPG) is a natural antagonist of this system by binding to RANKL and
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`preventing its interaction with RANK on pre-osteoclasts.
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`Tartrate-resistant acid phosphatase (TRACP) isoform 5b is released into the serum by
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`bone-resorbing osteoclasts as they transcytose degraded bone proteins fiom the resorbed bone
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`surface to outside the bone. TRACP isoform 5b serum levels are elevated in bone resorption
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`diseases.
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`The amino acid sequence for TRACPS is
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`found in Accession No.
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`for
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`NM 001102405, NM_001102404 or NM_007388.
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`‘Some of these serum markers of bone and cartilage metabolism (or destruction) are
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`elevated in RA patients and have some prognostic value in identifying patients that are at a
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`higher risk of having more aggressive bone destruction. For example, elevated levels of
`cartilage oligomeric matrix protein (COMP) have been associated with more aggressive
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`radiographic progression (den Broeder, A. A., et a1. (2002) Ann Rheum Dis 61(4): 311-318;
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`Wollheim, F. A., et a1. (1997) Br J Rheumatol 36(8): 847-8499; Skoumal, M., et al. (2003).
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`ScandJRheumatoI 32(3):156-l6l; Mansson, B., et a1. (1995), J Clin Invest 95(3):1071-1077;
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`Lindqvist, E., et a1. (2005) Ann Rheum Dis 64(2):]96-201; Forslind, K., et a1. (1992) Br J
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`Rheumatol 31(9): 593-598; Fex, E., et a1. (1997) Br JRheumatoI 36(11):]161-1165. Also, a
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`low OPG/RANKL ratio predicted increased five year radiographic progression (Geusens, P. P.
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`et a1. (2006) Arthritis Rheum 54(6):]772—1777) and elevated CTX-I and CTX-II levels were
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`associated with four year Sharp Score increase in early RA patients (Gamero, P., et al. (2002)
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`Arthritis Rheum 46(11):2847-2856).
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`However, the inventors herein are not aware of any published studies that conclude
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`that blocking IL-17A can inhibit bone erosion and modulate serum levels of any of the above
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`proteins in severely arthritic animals. Thus, a need exists to identify biomarkers that correlate
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`with inhibition ofjoint destruction by anti-IL-17A therapy.
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`SUMMARY OF THE INVENTION
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`The present invention is based on the discovery described herein that COMP, OPG and
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`RANKL serum levels in mice with collagen-induced arthritis (CIA) following treatment with
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`an anti-IL-17A monoclonal antibody (Mab) are modulated by anti-IL-17A therapy. Also, the
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`inventors have discovered that RANKL serum levels in CIA-mice decrease with increasing
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`doses of the anti-IL-17A Mab, and reach normal levels at antibody doses that are effective at
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`inhibiting joint destruction in the CIA mice as measured by traditional histological and u—CT-
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`based techniques. Based on these results with COMP, OPG and RANKL in the mouse CIA
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`arthritis model, the inventors herein believe that these markers are likely to be useful as
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`surrogate markers, i.e., biomarkers, of the effect of anti—IL-17A therapy on joint destruction in
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`inflammatory joint diseases such as RA and associated athritidies. Also, these data obtained
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`in arthritic mice support the use of other markers of cartilage and bone metabolism that are
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`elevated in human RA patients,
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`including CTX—I, CTX-II, and HC gp-39, as surrogate
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`markers for monitoring the effect of anti-IL-17A therapy on joint destruction in patients with
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`inflammatory joint disease.
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`In addition, it has been previously discovered that anti-IL-17A therapy is effective at
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`inhibiting joint destruction in the CIA arthritis model, even when that therapy produces no
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`apparent improvement in inflammation (WO 2008/021156). Thus, it is expected that anti-IL-
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`17A therapy will be usefill to inhibit ongoing bone erosion in human patients who have been
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`previously treated with a different anti-rheumatic agent, regardless of whether or not the
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`previous agent had reduced the signs and symptoms of inflammation. Thus, the present
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`discovery of non-inflammation related markers that are correlated with inhibition of bone
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`erosion by IL-17A therapy provides novel methods and products for treating patients for bone
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`erosion who are inflammatory nonresponders or inflammatory responders to previous anti-
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`rheumatic therapy.
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`Accordingly, one aspect of the present invention is a method of selecting a patient with
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`an inflammatory joint disease for treatment with an IL—17A antagonist. The patient selection
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`method comprises comparing the level(s) of at least one joint destruction biomarker in a
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`serum sample taken from the subject with the normal range of serum levels for the biomarker
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`and selecting the patient for treatment with the IL-17A antagonist if the level(s) of the joint
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`destruction biomarker in the subject’s serum sample is outside of the normal range.
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`In another aspect, the invention provides a method of predicting efficacy of an IL-17A
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`antagonist in inhibiting bone erosion in a subject with an inflammatory joint disease. This
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`efficacy prediction method comprises determining the levels of at least one joint destruction
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`biomarker in serum samples taken from the subject prior to and at the end of an initial
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`treatment period with the IL-17A antagonist, and comparing the levels of the biomarker in
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`these pre-treatment and post-treatment serum samples. A normalization in the level of the
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`biomarker during the initial treatment period predicts that the IL—17A antagonist will likely be
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`effective in inhibiting joint destruction in the subject.
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`In a preferred embodiment,
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`the
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`prediction method firrther comprises determining the level of the biomarker in a third serum
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`sample taken from the subject at the end of a subsequent treatment period with the IL-17A
`antagonist; if the level of the biomarker in the third serum sample is more normalized than the
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`level of the biomarker in the second serum sample, then the IL-17A antagonist is predicted to
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`be effective in inhibiting joint destruction in the subject. Preferred initial treatment periods
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`are at least one week, at least two weeks, at least four weeks, at least eight weeks, at least
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`twelve weeks, at least 24 weeks, or at least 48 weeks, while preferred subsequent treatment
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`periods are at least 12 weeks, at least 24 weeks or at least 48 weeks.
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`In some embodiments,
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`the subject
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`is a non—human animal with arthritis, which may be naturally present or
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`experimentally-induced.
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`Preferred non-human subjects include CIA mice or rats with
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`adjuvant-induced arthritis (AIA). In other embodiments, the subject is a human with arthritis.
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`In yet a timber aspect, the present invention provides a method of treating a subject for
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`an inflammatory joint disease with an IL-l7A antagonist. This treatment method comprises
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`determining, in a first serum sample taken from the subject, the level of at least one joint
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`destruction biomarker, administering the IL-l7A antagonist to the subject according to a first
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`dosing regimen during an initial
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`treatment period, determining the level of the selected
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`biomarker(s) in at least a second serum sample taken from the patient at the end of the initial
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`treatment period, and comparing the levels of the biomarker in the first and second serum
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`samples.
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`If the level of the biomarker in the second serum sample is within a specified range,
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`then the subject is treated with the IL-17A antagonist according to the first dosing regimen
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`during at least one subsequent treatment period. However, if the level of the biomarker in the
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`second serum sample is outside of the specified range, e.g., indicating that more aggressive
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`therapy may be necessary to achieve inhibition of joint destruction, then the subject is treated
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`with the IL-17A antagonist according to a second dosing regimen during at
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`least one
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`subsequent treatment period, wherein the second dosing regimen comprises administering a
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`total amount of the IL-17A antagonist during the subsequent treatment period that is greater
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`than the total amount administered during the initial treatment period.
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`In one preferred embodiment of this treatment method, the specified range is the
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`normal range, i.e., the range of serum levels of the biomarker found in a population of healthy,
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`, gender- and age-matched subjects.
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`In another preferred embodiment, the specified range for
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`the serum level of the biomarker is defined by a confidence interval of at least 80% of the
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`mean serum level of the biomarker in a population of subjects with the inflammatory disease
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`who were treated with the same IL-17A antagonist according to the same dosing regimen for a
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`time period equal
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`to or longer than the initial
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`treatment period, wherein the population
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`exhibited inhibition of joint destruction following treatment with the IL-17A antagonist
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`according to the first dosing regimen during a time period equal to or longer than the
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`subsequent treatment period.
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`In one preferred embodiment, when the biomarker level in the second serum sample
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`indicates that more aggressive anti—IL-17A therapy is required, the subject is treated with a
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`greater
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`total amount of the antagonist during the subsequent
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`treatment period(s) by
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`administering the IL-17A antagonist at higher doses and/or at more frequent intervals than the
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`doses and intervals employed during the initial treatment period.
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`In
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`another preferred embodiment,
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`the
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`treatment method flirther
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`comprises
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`administering an IL-23 antagonist during each of the initial
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`treatment and subsequent
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`treatment periods, or during only a subsequent treatment period. The IL-23 antagonist may
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`inhibit the expression of either subunit of the cytokine (IL-23p19 or p40), either subunit of the
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`functional receptor (IL-23R or IL-12beta1), or may inhibit IL-23 signaling by directly or
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`indirectly interacting with one or more of these polypeptides to prevent a functional ligand-
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`receptor interaction.
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`In some preferred embodiments, the IL-23 antagonist is an antibody or
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`antibody fragment that binds to and inhibits the activity of either IL-23p19 or IL—23R. In one
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`particularly preferred embodiment,
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`the IL-23 antagonist
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`is a monoclonal antibody that
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`specifically binds to IL—23p19.
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`The invention also provides a kit for treating an inflammatory joint disease. The kit
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`comprises a pharmaceutical composition of an IL-17A antagonist and reagents for measuring
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`the level of at least one joint destruction biomarker in a serum sample taken from a subject.
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`The invention also provides a manufactured drug product for treating an inflammatory
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`joint disease, which comprises a pharmaceutical formulation comprising an IL-17A antagonist
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`and instructions for determining patient serum levels of at
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`least one joint destruction
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`biomarker before and during treatment with the IL-17A antagonist.
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`Yet another aspect of the invention is the use of an IL-17A antagonist for preparing a
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`medicament for treating a patient having an inflammatory joint disease to inhibit joint
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`destruction, wherein the patient has an abnormal serum level of at least one joint destruction
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`biomarker after previous treatment with a different anti-rheumatic therapy.
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`In a preferred
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`embodiment, the medicament is for administering the IL-17A antagonist according to any of
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`the treatment regimens described herein.
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`In each of the above described aspects of the invention, the IL-17A antagonist may
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`inhibit the expression of IL-17A or IL-17RA or IL-17RC or may inhibit IL-17A signaling by
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`directly or indirectly interacting with one or more of these polypeptides to prevent a functional
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`ligand-receptor interaction.
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`In some preferred embodiments, the IL-17A antagonist is an
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`antibody or antibody fragment that binds to and inhibits the activity of either IL-17A, IL-
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`17RA or IL-17RC.
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`In one particularly preferred embodiment, the IL-17A antagonist is a
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`monoclonal antibody that specifically binds to IL-17A.
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`In other preferred embodiments, the
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`IL-17A antagonist is a bispecific antibody that binds to and inhibits the activity of IL-23p19
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`and H.-17A; H.—23p19 and H.—17RA; IL-23R and IL-17A; IL-23R and IL-17RA, IL—23p19 and
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`IL-17RC; or H.-23R and IL-17RC.
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`In another particularly preferred embodiment, the H.-17A
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`antagonist is a bispecific antibody that binds to and inhibits the activity of IL-23p19 and IL-
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`17A.
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`In each of the above—described aspects of the invention, preferred joint destruction
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`biomarkers are COMP, CTX-I, CTX-II, HC gp-39, OPG, RANKL, TRACP) isoform 5b and
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`osteocalcin. Any one of these biomarkers or any combination of two or more, or all six, of
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`these biomarkers may be employed. COMP, OPG and RANKL are more preferred
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`biomarkers, with RANKL being the most preferred biomarker.
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`Preferred inflammatory joint diseases that may be treated using any of the above
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`aspects of the invention are rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing
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`spondylitis (AS), with rheumatoid arthritis being a particularly preferred inflammatory joint
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`disease.
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`Also,
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`in each of the above-described aspects of the invention, the subject with-the
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`inflammatory joint disease may be one that is an inflammatory nonresponder, an inflammatory
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`responder, a moderate inflammatory responder, or a good inflammatory responder to the IL-
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`17A antagonist or a different anti-rheumatic drug.
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`BRIEF DESCRIPTION OF THE DRAWINGS
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`Figure 1A shows the amino acid sequence of the light chain of humanized anti-IL—17A
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`antibody 16C10 according to the present invention SEQ ID NO: 1. CDRs are indicated.
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`Figure 1B shows amino acid sequence for the heavy chain of humanized anti-IL-17A
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`antibody 16C10 according to the present invention SEQ ID NO: 2. CDRs are indicated.
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`Figures 2A-2D shows the effects of anti-IL-17A antibody treatments on pathology in
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`the CIA mouse model of rheumatoid arthritis. Treatments include administration of anti-IL-
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`17A antibody JL7.1D10 (at 28, 7, and 2 mg/kg) and administration of an isotype control (7
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`mg/kg).
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`Figure 2A presents visual disease severity score (DSS), a measure of visual paw
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`swelling and redness, as a function of antibody treatment. Scoring is: O = paw appears the
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`same as control (untreated) paw;
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`1 = inflammation of one finger on a given paw; 2 =
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`inflammation of two fingers or the palm of a given paw; 3 = inflammation of the palm and
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`finger(s) of a given paw.
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`Figure 2B presents cartilage damage (by histopathology) as a function of antibody
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`treatment. Scoring is: 0 = normal; 1 = minimal, 2 = mild; 3 = moderate; 4 = severe.
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`Figure 2C presents bone erosion (by histopathology) as a function of antibody
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`treatment. Scoring is: 0 = normal; 1 = minimal, 2 = mild; 3 = moderate; 4 = severe.
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`Figure 2D presents bone erosion (by histopathology) for paws from CIA mice that
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`scored 2 or 3 in visual DSS, i.e. highly inflamed paws. rIgGl is an isotype control antibody.
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`Scoring is: 0 = normal; 1 = minimal, 2 = mild; 3 = moderate; 4 = severe.
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`Figures 3A—3B presents data showing the effect of an anti-IL-17A antibody on serum
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`COMP levels in arthritic mice.
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`Figure 3A presents serum COMP levels in mice treated with isotype control or an anti-
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`IL-17A antibody (JL7.1D10). The solid horizontal bar denotes the average serum COMP
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`level
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`in non-diseased animals (grey circles on left side of graphs) and the two dotted
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`horizontal bars denotes +/— 2 standard deviations from the non-diseased mice average.
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`Figure 3AA presents serum COMP levels in non—diseased (normal) mice or in CIA
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`mice treated weekly for five weeks with an isotype control or an anti—IL-17A antibody
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`(JL7.1D10) at a dose of 28 mg/kg or 7 mg/kg.
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`Figure 3B presents serum COMP levels in non-diseased (un-manipulated) and severely
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`arthritic mice treated with short term isotype control (rIgGl) or an anti-IL-17A antibody
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`(JL7.1D10).
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`Figure 4 presents serum RANKL levels in arthritic mice who were untreated, treated
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`with an isotype control, or treated with one of three doses of an anti-IL-17A antibody
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`(JL7.1D10). The solid horizontal bar denotes the average serum COMP level in non-diseased
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`animals (grey circles on left side of graphs) and the two dotted horizontal bars denotes +/— 2
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`standard deviations from the non-diseased mice average.
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`Figure 5 presents serum OPG levels in normal mice (grey circles) or in arthritic mice
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`who were untreated (no dosing), treated with an isotype control (Rat IgGl), or treated with an
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`anti-IL-17A antibody.
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`Figure 6 presents serum RANKL and OPG levels in normal mice (grey circles) or in
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`severely arthritic mice following short-term exposure to an isotype control (rIgGl) or an anti-
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`IL-17A antibody (JL7.1D10).
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`Figure 7 presents micro-CT X-rays of an un-inflamed mice paw, and of severely
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`inflamed paws from arthritic mice treated with an isotype control antibody or an anti-IL-17A
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`antibody.
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`Figure 8 presents~ serum TRACP levels in non-diseased (un—manipulated) and severely
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`arthritic mice treated with long term isotype control (rIgGl) or an anti-IL-17A antibody
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`(JL7.1D10).
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`Figure 9 presents serum osteocalcin levels in normal mice and in CIA mice treated
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`with an anti-E-17A antibody (JL7.1D10) or an isotype control antibody
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`Figure 10 shows the dynamic change in serum RANKL (left panel) and OPG (right
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`panel) levels in a cohort of mice progressing through the mouse CIA mode, with horizontal
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`lines indicating mean (unbroken line) +/— SD. (broken lines) in un-manipulated healthy mice
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`and antibody dosing denoted as arrowheads.
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`Figure 11 shows the serum RANKL concentration versus total animal DSS from
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`individual normal or CIA mice at each of five weeks of treatment with a rat IgGl isotype
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`control antibody.
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`Figure 12 shows the serum OPG concentration versus total animal DSS from
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`individual normal or CIA mice at each of five weeks of treatment with a rat IgGl isotype
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`control antibody.
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`Figure 13 presents the serum RANKL levels in individual CIA mice that were not
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`treated or treated with five weekly subcutaneous doses of an isotype control antibody (rat
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`IgGl) or an anti-E-17A antibody (JL7.1D10) at 2, 7, or 28 mg/kg.
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`Figure 14 shows the serum OPG profiles for individual CIA mice that were not treated
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`or treated with five weekly subcutaneous doses of 7 mg/kg of an isotype control antibody (rat
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`IgGl) or 28 mg/kg of an anti-E-17A antibody (JL7.1D10).
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`Figure 15 shows the thickness of paws in rats with adjuvant-induced arthritis (AIA)
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`that were treated prior to adjuvant injection with an isotype antibody or with the indicated
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`doses of an anti-rat IL-17A antibody (JL8.18E10).
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`Figure 16 illustrates the effect of anti-E-l7A or anti-TNF therapy on serum RANKL
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`levels at days 14 and 25 following drug exposure in individual rats with established AIA.
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`1.
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`Definitions.
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`DETAILED DESCRIPTION
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`So that the invention may be more readily understood, certain technical and scientific
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`terms are specifically defined below. Unless specifically defined elsewhere in this document,
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`all other technical and scientific terms used herein have the meaning commonly understood by
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`one of ordinary skill in the art to which this invention belongs.
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`As used herein, including the appended claims, the singular forms of words such as
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`“a,” “an,” and “the,” include their corresponding plural references unless the context clearly
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`dictates otherwise.
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`“Abnormal” in the context of the serum level of a joint destruction biomarker means
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`that the serum level is outside of the normal range for that biomarker.
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`“Ankylosing spondylitis” or “AS” is a form of chronic inflammation of the spine and
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`the sacroiliac joints, which are located in the low back where the sacrum (the bone directly
`
`above the tailbone) meets the iliac bones (bones on either side of the upper buttocks). Chronic
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`inflammation in these areas causes pain and stiffness in and around the spine. Over time,
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`chronic spinal inflammation (spondylitis) can lead to a complete cementing together (fusion)
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`of the vertebrae, a process referred to as ankylosis. Ankylosis leads to loss of mobility of the
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`spine. Ankylosing spondylitis is also a systemic rheumatic disease, meaning it can affect
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`other tissues throughout the body. Accordingly, it can cause inflammation in or injury to
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`other joints away from the spine, as well as other organs, such as the eyes, heart, lungs, and
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`kidneys.
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`“Antagonist” means any molecule that can prevent, neutralize, inhibit or reduce a
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`targeted activity, i.e., the activity of a cytokine such as IL-17A, either in vitro or in vivo.
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`Cytokine antagonists include, but are not limited to, antagonistic antibodies, peptides, peptide-
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`mimetics, polypeptides, and small molecules that bind to a cytokine (or any of its subunits) or
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`its functional receptor (or any of its subunits) in a manner that interferes with cytokine signal
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`transduction and downstream activity. Examples of peptide and polypeptide antagonists
`
`include truncated versions or fragments of the cytokine receptor (e.g., soluble extracellular
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`domains) that bind to the cytokine in a manner that either reduces the amount of cytokine
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`available to bind to its functional receptor or otherwise prevents the cytokine from binding to
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`its functional receptor. Antagonists also include molecules that prevent expression of any
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`subunit
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`that comprises the cytokine or
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`its receptor, such as,
`
`for example, antisense
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`oligonucleotides which target mRNA, andinterfering messenger RNA, (see, e.g., Arenz and
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`Schepers (2003) Naturwz'ssenschaften 90:345-359; Sazani and K016 (2003) J. Clin. Invest.
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`112:481-486; Pirollo, et al. (2003) Pharmacol. Therapeutics 99:55-77; Wang, et al. (2003)
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`Antisense Nucl. Acid Drug Devel. 13:169-189). The inhibitory effect of an antagonist can be
`
`measured by routine techniques. For example, to assess the inhibitory effect on 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
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`measured in the presence or absence of a potential antagonist. Antagonists useful in the
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`present invention inhibit the targeted activity by at least 25%, preferably by at least 50%, more
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`preferably by at least 75%, and most preferably by at least 90%, when compared to a suitable
`
`control.
`
`"Antibody" refers to any form of antibody that exhibits the desired biological activity,
`
`such as inhibiting binding of a ligand to its receptor, or by inhibiting ligand—induced signaling
`
`of a receptor. Thus, “antibody” is used in the broadest sense and specifically covers, but is not
`
`limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal
`
`antibodies, and multispecific antibodies (e. g., bispecific antibodies).
`
`“Antibody fragment” and “antibody binding fragment” mean antigen-binding
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`fragments and analogues of an antibody, typically including at least a portion of the antigen
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`binding or variable regions (e.g. one or more CDRs) of the parental antibody. An antibody
`
`fragment retains at least some of the binding specificity of the parental antibody. Typically,
`
`an antibody fragment retains at least 10% of the parental binding activity when that activity is
`
`expressed on a molar basis. Preferably, an antibody fragment retains at least 20%, 50%, 70%,
`
`80%, 90%, 95% or 100% or more of the parental antibody’s binding affinity for the target.
`
`Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv
`
`fragments; diabodies;
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`linear antibodies; single-chain antibody molecules, e.g., sc-Fv; and
`
`multispecific antibodies formed from antibody fragments. Engineered antibody variants are
`
`reviewed in Holliger and Hudson (2005) Nat. Biotechnol. 23: 1 126-1 136.
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`A "Fab fragment" is comprised of one light chain and the CH1 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 CH1 and CH2
`
`domains of an antibody. The two heavy chain fragments are held together by two or more
`
`disulfide bonds and by hydrophobic interactions of the CH3 domains.
`
`A "Fab’ fragment" contains one light chain and a portion of one heavy chain that
`
`contains the VH domain and the C H1 domain and also the region between the CH1 and C H2
`
`domains, such that an interchain disulfide bond can be formed between the two heavy chains
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`of two Fab' fragments to form a F(ab') 2 molecule.
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`A "F(ab'); fragment" contains two light chains and two heavy chains containing a
`
`portion of the constant region between the CH1 and CH2 domains, such that an interchain
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