METHODS OF TREATMENT USING AN IFN gamma INHIBITOR

Abstract

The invention encompasses methods of treatment of interferon gamma (IFN-γ)-mediated diseases using IFN-γ inhibitors, such as anti-huIFN-γ antibodies, wherein levels of expression of one or more biomarkers are determined either before administration of the IFN-γ inhibitor and/or after administration. Also contemplated are methods of treatment using particular, pharmacodynamically effective doses of an anti-huIFN-γ antibody.

Description

PRIORITY

[0001] This application claims the benefit of U.S. Provisional Application Nos. 61/563,357, 61/616,846, and 61/651,900 filed Nov. 23, 2011, Mar. 28, 2012, and May 25, 2012, respectively, each of which are incorporated herein in their entirety.

REFERENCE TO THE SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled A-1679-US-NP_Sequence_Listing_as_filed, created Nov. 20, 2012, which is 253 KB in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

FIELD

[0003] This invention is in the field of methods of patient stratification and methods treatment using an interferon gamma (IFN-γ) inhibitor, as well as uses of IFN-γ inhibitors.

BACKGROUND

[0004] IFN-γ plays an important role in regulating the immune system. It is a cytokine with pleiotropic effects and is thought to play a role in mediating various autoimmune diseases, as well as immune responses to infectious agents and cancer cells. See, e.g., Heremans et al., Develop. Biol. Standard., 71: 113-119, in Symposium on Monoclonal Antibodies for Therapy, Prevention and in vivo diagnosis of human disease, Ultrecht, The Netherlands, 1989, S. Karger, Basel, 1990. Comparatively recent analyses of RNA and protein levels have yielded detailed information concerning the identities of collections of genes that are over- and under-expressed in biological samples from patients suffering from autoimmune diseases. For example, in patients suffering from a variety of automimmune diseases, type I (i.e., IFNα, IFNβ, IFNω, IFNε, and IFNκ) and/or type II (i.e., IFN-γ) interferon-induced genes are overexpressed. Baechler et al. (2003), Proc. Natl. Acad. Sci. 100(5): 2610-2615; Mavragani et al. (2010), Arthr. & Rheum. 62(2): 392-401; Pietrzak et al. (2008), Clinica Chimica Acta 394: 7-21; van Baarsen et al. (2006), Genes and Immunity 7: 522-531; Reynier et al. (2010), Genes and Immunity 11: 269-278; Fiorentino (2008), Arch. Dermatol. 144(10): 1379-1382. In the case of systemic lupus erythematosus (SLE), overexpression of these genes correlates with clinical and laboratory measures of disease activity. See, e.g., Bauer et al. (2006), PLoS Medicine 3(12): 2274-2284; Bauer et al. (2009), Arthr. & Rheum. 60(10): 3098-3107; Baechler et al. (2003), Proc. Natl. Acad. Sci. 100(5): 2610-2615. Type I and type II interferons affect expression of a distinct, but overlapping, set of genes, and such effects may vary depending on the tissue examined. See, e.g., van Baarsen et al. (2006), Genes and Immunity 7: 522-531 and Baechler et al. (2003), Proc. Natl. Acad. Sci. 100(5): 2610-2615.

[0005] Selection of the right patient group and dosage and assessment of patient response to a particular dosage on an ongoing basis can be key factors in the successful use of an IFN-γ inhibitor as a therapeutic for the treatment of autoimmune/inflammatory diseases. Many autoimmune/inflammatory diseases are episodic in nature and have variable clinical manifestations, and possibly also variable etiologies. Some of these diseases have long asymptomatic periods between symptoms or prior to the onset of symptoms. There is a need to determine whether a patient is a candidate for a particular treatment and/or whether an ongoing treatment is having the desired effects. Because of the biological variations between patients who are clinically diagnosed as having the same disease, it is possible that IFN-γ inhibitors may be efficacious for some patients having a particular disease and not for others. Such variations have, for example, been observed in rheumatoid arthritis patients, some of which respond to TNF inhibitors while others do not. See, e.g., Potter et al. (2010), Ann. Rheum Dis. 69: 1315-1320. Thus, it is highly desirable to distinguish patients for whom inhibition of IFN-γ is likely to be helpful from those for whom it is not. Further, the optimal dosage and nature of a particular IFN-γ inhibitor are likely to be important factors in the therapeutic suitability of a treatment, given the important role of IFN-γ in resistance to infections, among other vital functions. Thus, there is a need to assess the efficacy and safety of various doses and/or frequencies of dosing in asymptomatic, as well as symptomatic, periods of a disease. Methods provided herein utilize current technologies for assessing gene expression at the RNA and protein levels to provide more refined and effective methods of treatment using inhibitors of IFN-γ, of identifying optimal doses, and of identifying individuals who are likely to respond to treatment, and/or who are or are not responding to treatment.

SUMMARY

[0006] Described herein are methods of treatment that include administration of an IFN-γ inhibitor to a patient and determination of levels of one or more biomarkers in a biological sample from the patient before and/or after administration of the IFN-γ inhibitor so as to assess the suitability as a treatment or the biological effects of the IFN-γ inhibitor. Such methods can inform decisions as to whether to initiate or continue treatment with an IFN-γ inhibitor. Also described are methods for distinguishing patients likely to benefit from treatment with an IFN-γ inhibitor from those unlikely to benefit by assessing the levels of one or more biomarkers in a biological sample from a patient as compared to the levels of the same biomarkers in biological samples from a healthy control group. Further described herein are methods of treatment that include the use of doses of an anti-IFN-γ antibody within a specified range and/or at a specified frequency of dosing.

[0007] Herein is described a method of treating a patient suffering from an IFN-γ-mediated disease comprising administering to the patient a monoclonal anti-human interferon gamma (anti-huIFN-γ) antibody at a dose, which can be from about 15 mg (mg) to about 300 mg or from about 30, 40, 50, or 60 mg to about 80, 120, 180, 200, 250, 300 or 400 mg, wherein expression at the RNA or protein level of one or more gene(s) listed in Table 1, 2, 4, 5, and/or 6 in a biological sample from the patient taken before the antibody is administered deviates from expression of that gene(s) in a control biological sample in a direction consistent with excess IFN-γ. In addition, described herein is a use of a monoclonal anti-huIFN-γ antibody as a medicament to treat a patient suffering from an IFN-γ-mediated disease, wherein the dose of the antibody administered is from about 15, 30, 40, 50, or 60 milligrams to about 80, 120, 180, 200, 250, or 300 milligrams and wherein expression at the RNA or protein level of one or more gene(s) listed in Table 1, 2, 4, 5, and/or 6 in a biological sample taken from the patient taken before the antibody is administered deviates from expression of that gene(s) in a control biological sample in a direction consistent with excess IFN-γ. In some embodiments, the expression of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, or 40 genes listed in Table 1, 2, 4, 5, and/or 6 in the biological sample from the patient deviates from the expression of those genes in the control biological sample in a direction consistent with excess IFN-γ. The biological sample from the patient can exhibit expression of one or more of the following human genes at the RNA or protein level that deviates from expression in the control biological sample in a direction consistent with excess IFN-γ: indoleamine 2,3-dioxygenase 1 (IDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), serpin peptidase inhibitor clade B (ovalbumin), member 2 (SERPINB2), matrix metallopeptidase 19 (MMP19), radical S-adenosyl methionine domain containing 2 (RSAD2), heparin sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1), indoleamine 2,3-dioxygenase 2 (IDO2), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. In some embodiments, the biological sample from the patient can exhibit elevated expression at the RNA or protein level of GBP1 as compared to expression in the control biological sample. The IFN-γ-mediated disease can be systemic lupus erythematosus (SLE), discoid lupus, lupus nephritis, psoriasis, or an inflammatory bowel disease, including Crohn's disease and ulcerative colitis. The dose of the anti-huIFN-γ antibody can be from about 40 mg or 60 mg to about 300 mg, from about 20 mg or 80 mg to about 200 or 250 mg, from about 60 or 100 mg to about 180 mg, or about 40, 50, 60, 70, 80, 90, 100, 120, 150, or 180 mg. The anti-huIFN-γ antibody can be administered subcutaneously or intravenously. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0008] In another aspect, described herein is a method for treating a patient having an IFN-γ-mediated disease, for example SLE or an inflammatory bowel disease, with an IFN-γ inhibitor comprising: (a) determining the level(s) of expression in a biological sample from the patient of one or more genes listed in Tables 1, 2, 4, 5, and/or 6 at the RNA or protein level, wherein level of expression of the same gene(s) in a control biological sample is known or determined; (b) comparing the level(s) of expression of the gene(s) in the biological sample from the patient and in the control biological sample; and (c) if the level(s) of expression of the gene(s) in the biological sample from the patient deviate from the levels of expression of the gene(s) in the control biological sample in a direction consistent with excess IFN-γ, administering to the patient a therapeutically effective dose of an IFN-γ inhibitor. In addition, described herein is a use of an IFN-γ inhibitor as a medicament to treat a patient having an IFN-γ-mediated disease, for example SLE or an inflammatory bowel disease, (a) wherein the level(s) of expression in a biological sample from the patient of one or more gene(s) listed in Tables 1, 2, 4, 5, and/or 6 at the RNA or protein level is determined, (b) wherein the level(s) of expression of the same gene(s) in a control biological sample is known or determined, (c) wherein the level(s) of expression of the same gene(s) in the biological sample from the patient and the control biological sample are compared, and (d) wherein if the level(s) of expression of the gene(s) in the biological sample from the patient deviate from the levels of expression of the gene(s) in the control biological sample in a direction consistent with excess IFN-γ, a therapeutically effective dose of the IFN-γ inhibitor is administered. The one or more genes listed in Tables 1, 2, 4, 5, and/or 6 of (a) can include at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, or 40 genes. The IFN-γ inhibitor can be a human or humanized anti-huIFN-γ antibody. The dose of the anti-huIFN-γ antibody administered can be from about 15, 30, or 60 mg to about 300 mg, from about 20, 40, or 80 mg to about 250 mg, or from about 40, 50, or 60 mg to about 120, 150, 180 or 200 mg. The patient can have discoid lupus, lupus nephritis, psoriasis, ulcerative colitis, or Crohn's disease. The biological sample from the patient can exhibit expression of one or more of the following genes at the RNA or protein level that deviates from expression in the control biological sample in a direction consistent with excess IFN-γ: indoleamine 2,3-dioxygenase 1 (IDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), serpin peptidase inhibitor clade B (ovalbumin), member 2 (SERPINB2), matrix metallopeptidase 19 (MMP19), radical S-adenosyl methionine domain containing 2 (RSAD2), heparin sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1), indoleamine 2,3-dioxygenase 2 (IDO2), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. The IFN-γ inhibitor can be an anti-huIFN-γ antibody that has a heavy chain complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:34, a heavy chain complementarity determining region 2 (CDR2) comprising the amino acid sequence of SEQ ID NO:35, a heavy chain complementarity determining region 3 (CDR3) comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0009] In another aspect, described herein is method for identifying a patient having an IFN-γ-mediated disease who can benefit from treatment with an IFN-γ inhibitor comprising: (a) determining the level(s) of expression in a biological sample from the patient of one or more of one of the genes listed in Table 1, 2, 4, 5, and/or 6 at the RNA or protein level, wherein level(s) of expression of the same gene(s) in a control biological sample is known or determined; (b) comparing the levels of expression of the gene(s) in the biological sample from the patient and in the control biological sample; and (c) if the level(s) of expression of the gene(s) in the biological sample from the patient deviate from the level(s) in the control biological sample in a direction consistent with excess IFN-γ, determining that the patient can benefit from treatment with an IFN-γ inhibitor and/or administering a therapeutically effective dose of an IFN-γ inhibitor. The one or more genes listed in Tables 1, 2, 4, 5, and/or 6 of (a) can include at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, or 40 genes. The one or more genes can be from Table 1, 2, 4, 5, or 6. In addition, described herein is a use of an IFN-γ inhibitor as a medicament for treating a patient having an IFN-γ-mediated disease, wherein the level(s) of expression in a biological sample from the patient of one or more of one of the genes listed in Table 1, 2, 4, 5, and/or 6 is determined at the RNA or protein level, wherein the level(s) of expression of the same gene(s) in a control biological sample is known or determined; wherein the level(s) of expression of the gene(s) in the biological sample from the patient and in the control biological sample are compared; and wherein if the level(s) of expression of the gene(s) in the biological sample from the patient deviate from the level(s) in the control biological sample in a direction consistent with excess IFN-γ, determining that the patient can benefit from treatment with an IFN-γ inhibitor and/or administering a therapeutically effective dose of an IFN-γ inhibitor. The IFN-γ inhibitor can be an anti-human IFN-γ antibody, for example an antibody comprising the amino acid sequences of SEQ ID NOs: 6 and 8, 10 and 12, 14, and 16, 14 and 31, or 30 and 12. The therapeutically effective dose can be from 60 mg to 500 mg, from 80 mg to 400 mg, from 100 mg to 350 mg, from 60 mg to 180 mg, or from 120 mg to 300 mg. The IFN-γ-mediated disease can be SLE including discoid lupus and lupus nephritis, an inflammatory bowel disease including Crohn's disease and ulcerative colitis, or psoriasis, among other IFN-γ-mediated diseases disclosed herein. The gene(s) can include one or more of the following genes: indoleamine 2,3-dioxygenase 1 (IDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), serpin peptidase inhibitor clade B (ovalbumin), member 2 (SERPINB2), matrix metallopeptidase 19 (MMP19), radical S-adenosyl methionine domain containing 2 (RSAD2), heparin sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1), indoleamine 2,3-dioxygenase 2 (INDO2), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0010] Further described herein is a method for treating a patient suffering from an IFN-γ-mediated disease comprising: (a) determining the level(s) of expression at the RNA or protein level in a biological sample from the patient of one or more of the genes in Table 1, 2, 4, 5, and/or 6; (b) then administering to the patient a pharmacodynamically effective dose of an IFN-γ inhibitor, for example an anti-huIFN-γ antibody; (c) then determining the level of expression of the gene(s) of step (a) in a biological sample from the patient; and (d) if the level(s) of expression of the gene(s) determined in step (c), as compared to the level(s) of expression determined in step (a), is modulated in a direction consistent with inhibition of IFN-γ, then continuing treatment of the patient with another pharmacodynamically effective dose of the IFN-γ inhibitor. The one or more genes listed in Tables 1, 2, 4, 5, and/or 6 of (a) can include at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, or 40 genes. In addition, described herein is the use of an IFN-γ inhibitor antibody, for example an anti-huIFN-γ antibody, as a medicament for treating a patient suffering from an IFN-γ-mediated disease, wherein (a) the level of expression at the RNA or protein level in a biological sample from the patient of one or more of the genes in Table 1, 2, 4, 5, and/or 6 is determined, (b) then a pharmacodynamically effective dose of the IFN-γ inhibitor is administered to the patient, (c) then the level(s) of expression of the gene(s) of step (a) in a biological sample from the patient is determined, and (d) if the level(s) of expression of the gene(s) determined in step (c), as compared to the level(s) of expression determined in step (a), is modulated in a direction consistent with inhibition of IFN-γ, then continuing treatment of the patient with another pharmacodynamically effective dose of the IFN-γ inhibitor. For an IFN-γ inhibitor that is an anti-huIFN-γ antibody, the pharmacodynamically effective dose can be from about 15, 30, or 60 mg to about 300 mg, from about 20, 40, or 80 mg to about 250 mg, or from about 60 mg to about 180 or 220 mg. The IFN-γ-mediated disease can be selected from the group consisting of SLE, lupus nephritis, discoid lupus, psoriasis, and inflammatory bowel diseases including ulcerative colitis and Crohn's disease. The human genes whose level(s) of expression are determined in (a) and (c) can be selected from the group consisting of: indoleamine 2,3-dioxygenase 1 (IDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), serpin peptidase inhibitor clade B (ovalbumin), member 2 (SERPINB2), matrix metallopeptidase 19 (MMP19), radical S-adenosyl methionine domain containing 2 (RSAD2), heparin sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1), indoleamine 2,3-dioxygenase 2 (IDO2), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274.

[0011] In another aspect, a method is described for treating a patient suffering from an IFN-γ-mediated disease, for example SLE, lupus nephritis, discoid lupus, psoriasis, or an inflammatory bowel disease, with an IFN-γ inhibitor, for example an anti-huIFN-γ antibody, comprising the following steps: (a) determining the level(s) of expression at the RNA or protein level of one or more genes listed in Tables 1, 2, 4, 5, and/or 6 in a biological sample from the patient; (b) thereafter administering a pharmacodynamically effective dose of the IFN-γ inhibitor to the patient; (c) thereafter determining the level(s) of expression of the gene(s) of (a) in a second biological sample from the patient; and (d) if the level(s) of expression of the gene(s) in second biological sample of (c) is substantially the same as that in the biological sample of (a) or if the level of expression of the gene(s) in second biological sample of (c) deviates from the level of expression in the biological sample of (a) in a direction that is consistent with an excess of IFN-γ, then treatment with the IFN-γ inhibitor can be discontinued. In another aspect, described herein is a use of an IFN-γ inhibitor, for example an anti-huIFN-γ antibody, as a medicament for treating a patient suffering from an IFN-γ-mediated disease, wherein (a) the level(s) of expression at the RNA or protein level of one or more genes listed in Tables 1, 2, 4, 5, and/or 6 in a biological sample from the patient can be determined; (b) thereafter a pharmacodynamically effective dose of the IFN-γ inhibitor can be administered to the patient; (c) thereafter the level(s) of expression of the gene(s) of (a) in a second biological sample from the patient can be determined; and (d) if the level(s) of expression of the gene(s) in second biological sample of (c) is substantially the same as that in the biological sample of (a) or if the level of expression of the gene(s) in second biological sample of (c) deviates from the level of expression in the biological sample of (a) in a direction that is consistent with an excess of IFN-γ, then the treatment with the IFN-γ inhibitor can be discontinued. The one or more genes listed in Tables 1, 2, 4, 5, and/or 6 of (a) can include at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, or 40 genes. Where the IFN-γ inhibitor is an anti-huIFN-γ antibody, the pharmacodynamically effective dose can be from about 15, 30, or 60 mg to about 80, 100, 120, 150, 200, 250, or 300 mg, from about 20, 40, or 80 mg to about 90, 100, 120, 150, 180, or 250 mg, or from about 60 mg to about 180 or 220 mg. The patient can be suffering from systemic lupus erythematosus, lupus nephritis and/or discoid lupus. The patient can be suffering from psoriasis or an inflammatory bowel disease, including Crohn's disease or ulcerative colitis. The genes whose level(s) of expression are determined in (a) and (c) can be selected from the group consisting of: indoleamine 2,3-dioxygenase 1 (IDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), serpin peptidase inhibitor clade B (ovalbumin), member 2 (SERPINB2), matrix metallopeptidase 19 (MMP19), radical S-adenosyl methionine domain containing 2 (RSAD2), heparin sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1), indoleamine 2,3-dioxygenase 2 (IDO2), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0012] Any of the methods or uses described above or below that utilize an anti-huIFN-γ antibody can utilize an anti-huIFN-γ antibody which can have a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44. In specific embodiments, the heavy chain CDR3 can comprise the amino acid sequence of SEQ ID NO:36, the light chain CDR1 can comprise the amino acid sequence of SEQ ID NO:38, the light chain CDR2 can comprise the amino acid sequence of SEQ ID NO:41, and the light chain CDR3 can comprise the amino acid sequence of SEQ ID NO:43. The heavy chain variable region of the antibody can comprise the amino acid sequence of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30, and the light chain variable region of the antibody can comprise the amino acid sequence of SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. The heavy chain variable region can comprise the amino acid sequence of SEQ ID NO:6, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:8. The heavy chain variable region can comprise the amino acid sequence of SEQ ID NO:10, and the light chain variable region can comprise the amino acid sequence of SEQ ID NO:12. The heavy chain variable region can comprise the amino acid sequence of SEQ ID NO:14, and the light chain variable region can comprise the amino acid sequence of SEQ ID NO:16. The heavy chain variable region can comprise the amino acid sequence of SEQ ID NO:30, and the light chain variable region can comprise the amino acid sequence of SEQ ID NO:12. The heavy chain variable region can comprise the amino acid sequence of SEQ ID NO:14, and the light chain variable region can comprise the amino acid sequence of SEQ ID NO:31. The anti-huIFN-γ antibody can be a human, humanized, or chimeric antibody of the IgG, IgM, IgE, IgD, or IgA isotype. The anti-huIFN-γ antibody can be an IgG1, IgG2, IgG3, or IgG4 antibody.

[0013] In another aspect, herein is described a method for treating a patient suffering from an IFN-γ-mediated disease comprising administering to the patient a dose of an anti-IFN-γ antibody such that the concentration of total IFN-γ protein in the patient's serum is maintained at a plateau concentration for at least about two weeks following administration of the antibody, wherein the antibody comprises the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8. The dose can comprise at least about 20, 40, 60, or 80 milligrams and not more than 100, 200, 300, 400, or 500 milligrams of an anti-IFN-γ antibody. The plateau concentration can be maintained for at least about 3, 4, 5, 6, or 8 weeks after the antibody is administered. The plateau concentration of IFN-γ protein in the patient's blood can be from about 100 pg/mL to about 2000 pg/mL and/or at least about 200 or 300 pg/mL. The anti-IFN-γ antibody can comprise a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44. The anti-IFN-γ antibody can comprise the amino acid sequences of SEQ ID NOs: 6 and 8, SEQ ID NOs: 10 and 12, SEQ ID NOs: 14 and 16, SEQ ID NOs: 30 and 12, or SEQ ID NOs: 14 and 31. The dose of the anti-IFN-γ antibody can be at least about 20, 40, 60, 80, 100, 150, 180, 200, 220, or 250 mg and/or not more than 180, 200, 220, 240, 260, 280, 300, 350, 400, 450, or 500 mg and can be administered subcutaneously or intravenously. The level of IFN-γ in the patient's serum can remain above about 100, 200, 250, 300, or 350 picograms per milliliter for at least about 14, 16, 18, 20, 25, 30, 35, 40, 45, or 50 days subsequent to a single dose. The IFN-γ-mediated disease can be psoriasis, SLE, lupus nephritis, discoid lupus, or an inflammatory bowel disease such as Crohn's disease or ulcerative colitis. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0014] Also herein is described a method for identifying a patient that can benefit from treatment with an IFN-γ inhibitor comprising the following steps: obtaining a biological sample from the patient; determining the levels of IFN-γ protein in the biological sample; and comparing the levels of IFN-γ protein in the biological sample from the patient with the levels determined in a control biological sample; wherein if the levels of total IFN-γ protein in the biological sample from the patient are higher than those in the control biological sample, then the patient is identified as a patient that may benefit from treatment with an IFN-γ inhibitor; and wherein if the levels of IFN-γ protein in the biological sample from the patient are lower than or the same as those in the control biological sample, then the patient is identified as a patient that may not benefit from treatment with an IFN-γ inhibitor. The levels of IFN-γ protein determined can be the levels of total IFN-γ protein, meaning the total of free and bound IFN-γ protein. The IFN-γ inhibitor can be an anti-IFN-γ antibody. The anti-IFN-γ antibody can comprise a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44. The anti-IFN-γ antibody can comprise the amino acid sequences of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30 and SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0015] In another embodiment, herein is described a method for treating an IFN-γ-mediated disease comprising administering a dose of an IFN-γ inhibitor such that the concentration of total IFN-γ protein in serum is maintained at a plateau concentration for at least about two, three, four, five, six, seven, eight, nine, or ten weeks after administration. The plateau concentration of total IFN-γ protein in serum can be from about 200 to about 2000 picograms per milliliter (pg/mL). The plateau concentration of total IFN-γ protein in serum can be at least about 250, 300, or 350 pg/mL and/or not more than 600, 800, 1000, or 1500 pg/mL. The IFN-γ inhibitor can be a protein that binds to IFN-γ, for example, an anti-IFN-γ antibody. The anti-IFN-γ antibody can comprise a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44. The anti-IFN-γ antibody can comprise the amino acid sequences of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30 and SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. Further doses of the IFN-γ inhibitor can be administered at a frequency that maintains a serum concentration of total IFN-γ that is at least half of the plateau concentration. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0016] In still another aspect, herein is described a method of determining a suitable dose of an IFN-γ inhibitor for a patient comprising: determining the total IFN-γ protein concentration in a biological sample from the patient before dosing; administering the IFN-γ inhibitor to the patient at a first dosage amount; and determining the total IFN-γ protein concentration in similar biological samples from the patient periodically after dosing; wherein the first dosage amount is not suitable because it is too low if a plateau concentration of total IFN-γ protein lasting at least two weeks is not achieved or wherein the first dosage amount is high enough if a plateau concentration of total IFN-γ protein lasting at least two weeks is achieved. If the first dosage amount is high enough, the patient can maintain a plateau concentration of IFN-γ protein for at least about two, three, four, five, six, seven, eight, nine, or 10 weeks after dosing. If this is the case, after the concentration of IFN-γ protein has fallen below the plateau level, a second, lower dosage amount of the IFN-γ inhibitor can be administered and total IFN-γ protein concentrations in similar biological samples from the patient can be determined periodically after dosing at the second, lower dosage amount. If the first dosage amount is too low, a second, higher dosage amount of the IFN-γ inhibitor can be subsequently administered and total IFN-γ protein concentration in similar biological samples from the patient can be determined periodically after dosing at the second, higher dosage amount. The biological samples can be serum samples or peripheral blood samples. The IFN-γ inhibitor can be a protein that binds to IFN-γ, for example an anti-IFN-γ antibody, which can be an anti-huIFN-γ antibody. Such an anti-IFN-γ antibody can comprise a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44. Such an anti-IFN-γ antibody can comprise the amino acid sequences of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30 and SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. The anti-IFN-γ antibody can be a human or humanized antibody. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0017] In another aspect, herein is described a method of treating a patient suffering from an IFN-γ-mediated disease, the method comprising: selecting a patient, wherein expression at the RNA or protein level of one or more gene(s) listed in Table(s) 1, 2, 4, 5, and/or 6 in a biological sample taken from the patient before treating the patient deviates from expression of that gene(s) in a control biological sample in a direction consistent with excess IFN-γ pathway activation; and administering to the patient a monoclonal human anti-human interferon gamma (anti-huIFN-γ) antibody at a dose of from about 20 milligrams to about 300 milligrams, wherein the antibody is an IgG1 antibody and comprises the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8. The IFN-γ-mediated disease can be selected from the group consisting of systemic lupus erythematosus (SLE), discoid lupus, lupus nephritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, psoriasis, alopecia greata, Sjogren's syndrome, antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, polymyositis, dermatomyositis, type I diabetes, sarcoidosis, macrophage activation syndrome (MAS), and hemophagocytic lymphohistiocytosis (HLH). The expression of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or 50 genes listed in Table(s) 1, 2, 4, 5, and/or 6 in the biological sample from the patient can deviate from the expression of those genes in the control biological sample in a direction consistent with excess IFN-γ pathway activation. The biological sample from the patient can exhibit elevated expression at the RNA or protein level as compared to expression in the control biological sample of one or more of the following genes: indoleamine 2,3-dioxygenase 1 (IDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), and/or programmed death ligand-1 (PD-L1). The dose can be from about 20 milligrams to about 300 milligrams, from about 80 milligrams to about 200, 250, or 300 milligrams, or from about 20 milligrams to about 60, 70, or 80 milligrams. The antibody can comprise the amino acid sequences of SEQ ID NO:17 and SEQ ID NO:18 and can be administered subcutaneously or intravenously. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0018] In another embodiment, herein is described a method for treating a patient having an IFN-γ-mediated disease with a human anti-huIFN-γ antibody comprising: (a) taking a biological sample from the patient before treatment, wherein level(s) of expression of one or more genes listed in Table(s) 1, 2, 4, 5, and/or 6 at the RNA or protein level in the biological sample is determined and wherein level(s) of expression of the same gene(s) in a control biological sample is known or determined; (b) comparing the levels of expression of the gene(s) in the biological sample from the patient and in the control biological sample; and (c) if the level(s) of expression of the gene(s) in the biological sample from the patient deviate from the level(s) of expression of the gene(s) in the control biological sample in a direction consistent with excess IFN-γ pathway activation, administering to the patient a therapeutically effective dose of the antibody at a dose of from about 30, 40, 50, 60, or 70 mg to about 80, 100, 120, 150, 180, 250, or 300 mg, wherein the antibody comprises the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8. The IFN-γ-mediated disease can be selected from the group consisting of systemic lupus erythematosus (SLE), discoid lupus, lupus nephritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, psoriasis, alopecia greata, Sjogren's syndrome, antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, polymyositis, dermatomyositis, type I diabetes, sarcoidosis, macrophage activation syndrome (MAS), and hemophagocytic lymphohistiocytosis (HLH). The levels of expression of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or 50 genes from Table 5 or 6 deviate from the levels of expression of the genes in the control biological sample in a direction consistent with excess IFN-γ pathway activation. The biological sample from the patient can exhibit elevated expression at the RNA or protein level as compared to expression in the control biological sample of one or more of the following genes: indoleamine 2,3-dioxygenase 1 (IDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. The dose administered can be from about 5, 10, 20, or 30 mg to about 60, 70, or 80 mg or can be from about 60, 70, 80, 90, 100, or 120 mg to about 150, 180, 200, or 250 mg. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0019] In a further aspect, herein is described a method for treating a patient suffering from an IFN-γ-mediated disease comprising: (a) taking a biological sample from the patient before administering a human anti-huIFN-γantibody in step (b), wherein the level(s) of expression at the RNA or protein level in the biological sample from the patient of one or more of the genes in Table(s) 1, 2, 4, 5, and/or 6 is determined; (b) administering to the patient a pharmacodynamically effective dose of the human anti-huIFN-γ antibody, wherein the antibody has a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44; (c) taking a second biological sample taken from the patient after administration of the antibody, wherein the level(s) of expression of the gene(s) of step (a) in the second biological sample are determined; and (d) if the level(s) of expression of the gene(s) determined in step (c), as compared to the level(s) of expression determined in step (a), is modulated in a direction consistent with inhibition of IFN-γ, then continuing treatment of the patient with another pharmacodynamically effective dose of the antibody. The IFN-γ-mediated disease can be selected from the group consisting of systemic lupus erythematosus (SLE), discoid lupus, lupus nephritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, psoriasis, alopecia greata, Sjogren's syndrome, antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, polymyositis, dermatomyositis, type I diabetes, sarcoidosis, macrophage activation syndrome (MAS), and hemophagocytic lymphohistiocytosis (HLH). The pharmacodynamically effective dose can be from about 5, 10, 20, 30, 40, 50, or 60 mg to about 60, 70, 80, 90, or 100 mg or from about 60, 70, 80, 90, or 100 mg to about 120, 150, 180, 200, or 250 mg. The heavy chain CDR3 can comprise the amino acid sequence of SEQ ID NO:36, the light chain CDR1 comprises the amino acid sequence of SEQ ID NO:38, the light chain CDR2 comprises the amino acid sequence of SEQ ID NO:41, and the light chain CDR3 comprises the amino acid sequence of SEQ ID NO:43. The heavy chain variable region of the antibody can comprise the amino acid sequence of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30, and the light chain variable region of the antibody can comprise the amino acid sequence of SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. The antibody can comprise the amino acid sequences of SEQ ID NOs:6 and 8, 10 and 12, 14 and 16, 30 and 12, or 14 and 31. The level(s) of expression of one or more of the following genes at the protein or RNA level can be determined in steps (a) and (c): indoleamine 2,3-dioxygenase 1 (IDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274. A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0020] In still a further aspect, provided is method for treating a patient suffering from an IFN-γ-mediated disease with a human anti-huIFN-γ antibody comprising the following steps: (a) taking a biological sample from the patient before administering a human anti-huIFN-γ antibody in step (b), wherein the level(s) of expression at the RNA or protein level of one or more genes listed in Table(s) 1, 2, 3, 5 and/or 6 in the biological sample are determined; (b) administering to the patient the human anti-human IFN-γ antibody, wherein the antibody has a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44; (c) taking a second biological sample taken from the patient taken after administration of the antibody, wherein the level(s) of expression of the gene(s) of (a) are determined in the second biological sample; and (d) if the level(s) of expression of the gene(s) in second biological sample of (c): (i) is modulated in a direction consistent with inhibition of IFN-γ as compared to the level(s) of expression in the biological sample determined in (a), then continuing treatment of the patient with another pharmacodynamically effective dose of the antibody; or (ii) is substantially the same as that in the biological sample of (a) or deviates from the level of expression in the biological sample of (a) in a direction that is consistent with an excess of IFN-γ, then treatment with the anti-human IFN-γ antibody is discontinued. The anti-human IFN-γ antibody can be a human or humanized IgG1 antibody. The dose of the antibody administered in (b) can be from about 20, 30, 40, 60, 80, or 100 mg to about 120, 150, 180, 200, 250, or 300 mg or from about 10, 20, or 30 mg to about 80 mg. The dose can be about 30, 40, 50, 60, 70, 80, 100, 120, 150, or 180 mg. The IFN-γ-mediated disease can be selected from the group consisting of systemic lupus erythematosus (SLE), discoid lupus, lupus nephritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, psoriasis, alopecia greata, Sjogren's syndrome, antiphospholipid syndrome, rheumatoid arthritis, multiple sclerosis, polymyositis, dermatomyositis, type I diabetes, sarcoidosis, macrophage activation syndrome (MAS), and hemophagocytic lymphohistiocytosis (HLH). A gluococorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0021] In still a further aspect, herein is described a method for treating a patient suffering from SLE, lupus nephritis, discoid lupus, psoriasis, or an inflammatory bowel disease comprising administering to the patient a dose of at least about 15, 20, 30, 40, 50, 60, or 100 milligrams and not more than about 80, 90, 100, 120, 150, 180, 200, 250, or 300 milligrams of an anti-human IFN-γ antibody, wherein the anti-human IFN-γ antibody comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44. The anti-IFN-γ antibody can comprise the heavy and light chain variable region amino acid sequences of SEQ ID NOs: 6 and 8, SEQ ID NOs: 10 and 12, SEQ ID NOs: 14 and 16, SEQ ID NOs: 30 and 12, or SEQ ID NOs: 14 and 31. Levels of expression of at least 5 genes listed in Table(s) 1, 2, 4, 5, and/or 6 in a biological sample taken from the patient after administration of the antibody can deviate from levels of these genes in a similar biological sample taken from the patient taken at baseline in a direction consistent with inhibition of IFN-γ. The dose of the anti-IFN-γ antibody can be from about 5, 10, 20, 30, or 40 milligrams to about 60, 70, 80, 90, or 100 milligrams or from about 60, 70, 80, 90, 100, or 120 milligrams to about 125, 150, 180, 200, or 250 milligrams. The dose can be administered subcutaneously or intravenously. The level of total IFN-γ protein in the patient's serum can remain above about 200 pg/mL for at least about 2 weeks subsequent to a single dose. A gluococorticoid, optionally prednisone, and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial can be administered concurrently with the antibody.

[0022] In another embodiment, herein is described a method for identifying SLE, psoriasis, or inflammatory bowel disease patients that can benefit from treatment with a human anti-human IFN-γ antibody and treating such patients comprising the following steps: (a) obtaining a biological sample from the patient before administration of the antibody, wherein the level of total IFN-γ protein in the biological sample is determined; (b) administering to the patient a dose of the antibody; (c) obtaining a second biological sample from the patient after administration of the antibody, wherein the level of total IFN-γ protein in the second biological sample is determined; and (d) if the level of total IFN-γ protein determined in (c) is higher than the level determined in (a), then continuing treatment with the antibody; wherein the antibody is an IgG1 antibody and comprises the amino acid sequences of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30 and SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31. The antibody can comprise the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8.

[0023] In another aspect, provided herein is a method for treating an IFN-γ-mediated disease comprising administering to a patient in need thereof a dose of a human anti-human IFN-γ antibody comprising the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8 such that the concentration of total IFN-γ protein in the patient's serum is maintained at a plateau concentration for at least about two, three, four, five, or six weeks following administration. The plateau concentration of total IFN-γ protein in serum can be from about 100, 200, or 300 pg/mL to about 2000 pg/mL.

BRIEF DESCRIPTION OF THE FIGURES

[0024] FIG. 1: Volcano plot of expression of an array of genes post-vs. pre-IFN-γ stimulation of whole blood from healthy volunteers. The average fold change in RNA expression for each gene is plotted with the associated p-value from an analysis of variance (ANOVA). The circled points have been designated as the top 20 IFN-γ regulated genes, which are those with the largest absolute fold change and that have a p-value less than 0.001.

[0025] FIG. 2: Analysis of serum protein levels. Top: Boxplot of interleukin-18 (IL-18), chemokine (C--X--C motif) ligand 10 (CXCL10; also known as interferon gamma inducible protein 10 (IP10)), and chemokine (C--C motif) ligand 2 (CCL2; also known as MCP-1) protein levels in healthy volunteers (HV), SLE, and lupus nephritis (LN) subjects. The γ-axis is log-scaled. The horizontal lines are the group medians and the boxes represent the 25th and 75th percentiles. The whiskers represent the most extreme data point within 1.5 times the inter-quartile range away from the boxes. The black crosses are points outside the whiskers. The numbers above each boxplot, e.g., "n=155," refer to the number of samples from individual subjects that the boxplot represents.

[0026] FIG. 3: IFN-related gene expression in SLE patients treated with AMG 811 compared to patients treated with a placebo. Left: Volcano plot of RNA expression of an array of genes in biological samples from treated subjects at day 15 (described in Example 3) versus samples from untreated/placebo treated subjects. The average fold difference in RNA expression for each gene is plotted with the associated p-value. The top 20 IFN-γ signature genes (see FIG. 1) are circled. Right: Relationship between AMG 811 serum concentration and guanylate binding protein 1 (GBP1) transcript expression in SLE patients. Samples were taken on Day -1 (pre-dosing; (◯) and Day 15 (.box-solid.) in the clinical trial described in Example 3. The x axis indicates the serum concentration of AMG 811, and the y axis indicates the fold difference in guanylate binding protein 1 (GBP1) RNA expression from that seen in a control group of healthy people.

[0027] FIG. 4: Dose dependent decrease in CXCL10 protein level in response to AMG 811 administration. Symbols are average change from baseline in CXCL10 levels for each dose group by study day of the study described in Example 3. The error bars reflect the 95% confidence interval around the mean. Time points are indicated as follows: , day 15 (Dy15) of the study; .box-solid., day 56 (Dy56) of the study; and ⋄, end of study (EOS).

[0028] FIG. 5: Mean AMG 811 serum concentration-time profiles following a single subcutaneous or intravenous dose of AMG 811 in systemic lupus erythematosus patients. The x axis indicates the time post-injection, and the y axis indicates the serum concentration of AMG 811 in nanograms per milliliter (ng/ml). The doses represented by the various symbols and the number of patients dosed (n) are indicated in the legend in the figure.

[0029] FIGS. 6A and 6B: Median (6A) and mean (6B) serum total IFN-γ protein concentration-time profiles following a single subcutaneous or intravenous dose of AMG 811 in systemic lupus erythematosus patients. The x axis indicates time post-injection, and the y axis indicates the median or mean serum concentration of IFN-γ. The doses represented by the various symbols and the number of patients dosed (n) are indicated in the legend in the figure.

[0030] FIG. 7: Average post-dose AMG 811 score in lupus nephritis patients. An "AMG 811 score" was determined as explained in Example 4 for lupus nephritis patients. Diamonds indicate the average score for each dose while vertical lines indicate the 95% confidence interval.

[0031] FIG. 8: Dose dependent decrease in CXCL10 protein level in response to multiple doses of AMG 811 in general SLE patients. Symbols (circles, squares, triangles, etc.) indicate the average fold change from baseline values in CXCL10 levels, and the vertical lines represent the 95% confidence interval. The data are from the study described in Example 4. Each group of seven vertical lines represents data from patient samples taken at, from left to right, day 8 (D8), 16 (D16), 29 (D29), 57 (D57), 86 (D86), 113 (D113), and end of study (EOS), as indicated. The dose of AMG 811 administered is indicated below. A dose of zero indicates that those patients received a placebo.

[0032] FIG. 9: Dose dependent decrease in CXCL10 (IP-10) protein level in response to multiple doses of AMG 811 in lupus nephritis patients. Symbols (circles, squares, triangles, etc.) indicate the average fold change from baseline values in CXCL10 levels, and the vertical lines represent the 95% confidence interval. Each group of seven vertical lines represents data from patient samples taken at, from left to right, day 8 (D8), 16 (D16), 29 (D29), 57 (D57), 86 (D86), 113 (D113), and end of study (EOS) of the study described in Example 4, with the dose of AMG 811 administered indicated below. A dose of zero indicates that those patients received a placebo.

[0033] FIG. 10: Relationship between AMG 811 levels and changes in IP-10 (CXCL10) expression in SLE and lupus nephritis patients. This graph shows the AMG 811 concentration (x axis) in peripheral blood of patients plotted against the fold change in IP-10 concentration from baseline for lupus and lupus nephritis patients involved in the trial described in Example 4 at a variety of time points in the trial, as indicated.

[0034] FIG. 11: Relationship between AMG 811 serum concentration and GBP1 transcript expression in lupus nephritis patients. Blood samples were taken from lupus nephritis patients at baseline and on day 15 in the multi-dose clinical trial described in Example 4. The x axis indicates the serum concentration of AMG 811, and the y axis indicates the fold difference in guanylate binding protein 1 (GBP1) RNA expression from that seen in a control group of healthy people.

[0035] FIG. 12: Blinded data showing the amount of protein detected in 24-hour urine samples from lupus nephritis patients treated with multiple doses of AMG 811 or placebo. This graph show the levels of protein in twenty four hour urine samples from lupus nephritis patients from cohorts 4 (left panel) and 5 (right panel) of the clinical trial described in Example 4. Cohort 4 contained eight patients, two of which received placebo and six of which received 3 doses of 20 mg of AMG 811. Cohort 5 contained 12 patients, three of which received placebo and nine of which received three doses of 60 mg of AMG 811.

[0036] FIG. 13: Blinded spot urine protein/creatinine ratio (UPCR) in lupus nephritis patients. Blinded data showing the UPCR of patients in cohorts 4 (left panel) and 5 (right panel) at various time points during the clinical trial described in Example 4. Cohort 4 contained eight patients, two of which received placebo and six of which received three doses of 20 mg of AMG 811. Cohort 5 contained 12 patients, three of which received placebo and nine of which received three doses of 60 mg of AMG 811.

[0037] FIG. 14: Blinded data showing PASI scores of psoriasis patients treated with AMG 811 or placebo. This graph shows the PASI scores (y axis) of individual psoriasis patients treated with AMG 811 or placebo at various time points during the trial described in Example 6, as indicated along the x axis. The baseline measurement (B) was taken one to three days prior to the single dose of AMG 811 administered on day 1 of the study.

DETAILED DESCRIPTION

[0038] Provided herein are methods of treatment using IFN-γ inhibitors, methods for identifying patients likely to benefit from such treatment, and methods for determining suitable dosages. The methods utilize techniques for determining levels of proteins and/or RNA transcripts in a biological sample. Using such techniques, overlapping sets of transcripts, the expression of which is modulated by IFN-γ ex vivo and by AMG 811 in vivo, have been defined. Similarly, it has been found that a particular set of transcripts and at least one serum protein is downregulated by an IFN-γ inhibitor in human patients in vivo, thus making it possible to determine dosages at which these effects are observable and to determine which transcripts in blood cells are regulated by IFN-γ in vivo. Dosages determined by such methods can be used to treat patients. Similarly, assay of these sets of transcripts can be used to predict which patients are likely to respond to treatment, i.e., those that overexpress genes whose expression can be downregulated by the IFN-γ inhibitor and/or those that are up- or down-regulated by activation of the IFN-γ pathway. Similarly, these techniques can be used to determine whether a particular dosage of an IFN-γ inhibitor is having a biological effect, especially in patients suffering from an episodic disease in which changes in symptoms may not be readily apparent. Further, if an IFN-γ inhibitor is not having a biological effect as measured by expression of such biomarkers, treatment with the IFN-γ inhibitor can be discontinued and, optionally, a new treatment can be initiated. Alternatively, if an IFN-γ inhibitor is having a biological effect as measured by biomarker expression, treatment with the IFN-γ inhibitor can be continued.

DEFINITIONS

[0039] An "antibody," as meant herein, can be a full length antibody containing two full length heavy chains (containing a heavy chain variable region (V_H), a first constant domain (C_H1), a second constant domain (C_H2) and a third constant domain (C_H3)) and two full length light chains (containing a light chain variable region (V_L) and a light chain constant region (C_L)). Alternatively, an antibody can contain only a single V_H region or V_L region, such as the single variable domain antibodies described in, e.g., U.S. Pat. No. 7,563,443. The portions of this reference describing such antibodies are incorporated herein by reference. An antibody can also be a fragment of a full length antibody that binds to the target antigen, which may also contain other sequences. For example, an antibody can be an a single chain antibody that comprises V_H and V_L regions joined by a peptide linker (i.e., an scFv), a Fab fragment, which may or may not include the hinge region, an scFv-Fc, among many other possible formats. The term "antibody" comprises any protein that includes at least one V_H or V_L region.

[0040] "Baseline," as meant herein, is a timepoint before dosing begins in a clinical trial that can typically be up to about a month before dosing with a test drug or placebo begins.

[0041] A "biological sample," as meant herein, is a sample of a liquid, such as blood or cerebrospinal fluid, or a solid piece of tissue, such as a skin biopsy or an excised tumor, taken from a patient. Two biological samples are said to be "similar" if they are taken from similar tissue. For example, two whole blood samples from different patients are similar, as meant herein. Further, two skin biopsies taken from lesions from different patients are also similar as meant herein.

[0042] A drug or treatment is "concurrently" administered with another drug or treatment, as meant herein, if it is administered in the same general time frame as the other drug, optionally, on an ongoing basis. For example, if a patient is taking Drug A once a week on an ongoing basis and Drug B once every six months on an ongoing basis, Drugs A and B are concurrently administered whether or not they are ever administered on the same day. Similarly, if Drug A is taken once per week on an ongoing basis and Drug B is administered only once or a few times on a daily basis, Drugs A and B are concurrently administered as meant herein. Similarly, if both Drugs A and B are administered for short periods of time either once or multiple times within a one month period, they are administered concurrently as meant herein as long as both drugs are administered within the same month.

[0043] A "control group," as meant herein, is a group of healthy people to which a patient having a particular disease is compared in some way. For example, expression of certain genes at the protein or RNA level in a biological sample from a patient can be compared to expression of those genes in one or more similar biological samples from people in a control group. In some situations, normal ranges for levels of expression for particular genes can be established by analysis of biological samples from members of a control group. In such a situation, expression levels in a given sample from a patient having a disease can be compared to these established normal ranges to determine whether expression in the sample from the patient is normal or above or below normal.

[0044] A "control biological sample," as meant herein, is (a) a group of biological samples from a "control group" that is compared to a similar biological sample from a patient or (b) a biological sample from non-diseased tissue from a patient that is compared to a biological sample from diseased tissue from the same patient. For example, a skin biopsy from non-lesional tissue from a discoid lupus patient can be a "control biological sample" for a skin biopsy from lesional tissue from the same discoid lupus patient. Alternatively, a group of skin biopsies from a healthy "control group" can be a "control biological sample" to which a skin biopsy from a discoid lupus patient can be compared. Alternatively, a group of blood samples from healthy people can be a "control biological sample" to which to compare a blood sample from an SLE patient.

[0045] "Determining the level of expression," as meant herein, refers to determining the amount of expression of a gene in a biological sample at either the protein or RNA level. Such levels can be determined in biological samples from patients suffering from an IFN-γ-mediated disease and in control biological samples from healthy people or from non-diseased tissue from the patient (for example in a skin sample not having psoriatic plaques in a psoriasis patient). The comparison between a patient's biological sample from diseased tissue (or blood in a systemic disease) and a control biological sample can provide information as to whether the biomarkers in question are expressed at normal, elevated, or lowered levels. To assay for protein levels in liquid samples, enzyme-linked immunosorbent assay (ELISA) can be used. See, e.g., Berzofsky et al., Antigen-Antibody Interactions and Monoclonal Antibodies, Chapter 12 in FUNDAMENTAL IMMUNOLOGY, THIRD EDITION, Paul, ed., Raven Press, New York, 1993, pp. 421-466, at pp. 438-440. Many such assays are commercially available. For solid biological samples, such as, for example, skin samples, immunohistochemistry or immunofluorescence can be used to determine whether and where a particular protein is expressed. Such techniques are well known in the art. See, e.g., Antigen Retrieval Techniques: Immunohistochemistry and Molecular Morphology, Shi et al., eds. Eaton Publishing, Natick, Mass., 2000. The portions of this reference that describe techniques of immunohistochemistry and immunofluorescence are incorporated herein by reference. To assay for RNA levels, real time quantitative PCR (for example using a Taqman® kit available from Invitrogen (Carlsbad, Calif.)) or microarrays (such as described, for example, in Chen et al. (1998), Genomics 51: 313-324) are generally used.

[0046] An "IFN-γ inhibitor," as meant herein, is a molecule, which can be a protein or a small molecule, that can inhibit the activity of IFN-γ as assayed by the A549 bioassay, which can be performed as follows.

[0047] One of the established properties of IFN-γ is its anti-proliferative effect on a variety of cell populations. See e.g. Aune and Pogue (1989), J. Clin. Invest. 84: 863-875. The human lung cell line A549 has been used frequently in publications describing the bioactivity of IFN-γ. See e.g. Aune and Pogue, supra; Hill et al. (1993), Immunology 79: 236-240. In general, the activity of an inhibitor is tested at a concentration of a stimulating substance, in this case IFN-γ, that falls within a part of the dose-response curve where a small change in dose will result in a change in response. One of skill in the art will realize that if an excessive dose of the stimulating substance is used, a very large dose of an inhibitor may be required to observe a change in response. Commonly used concentrations for a stimulating substance are EC₈₀ and EC₉₀ (the concentrations at which 80% or 90%, respectively, of the maximum response is achieved).

[0048] An IFN-γ dose-response curve can be generated to determine the EC₉₀ for the lung epithelial carcinoma cell line A549. In subsequent experiments, different concentrations of an IFN-γ-inhibitor can be mixed with a fixed dose of IFN-γ, and the ability of the IFN-γ-inhibitor to inhibit the biological activity of the anti-proliferative effect of IFN-γ can be determined. The assay can be performed for 5 days, and proliferation can be measured by determining fluorescence generated by the reduction of ALAMARBLUE® (AccuMed International, Inc., Chicago, Ill.), a dye used to indicate cell growth, by metabolically active, i.e., proliferating, cells. See e.g., de Fries and Mitsuhashi, 1995, J. Clin. Lab. Analysis 9(2): 89-95; Ahmed et al., 1994, J. Immunol. Methods 170(2): 211-24.

[0049] An "IFN-γ-mediated disease," as meant herein, is a disease in which evidence from an in vitro or a non-human model system or from human patients indicates IFN-γ is likely to play a role in driving the course of the disease. Diseases that are included among "IFN-γ-mediated diseases" include, for example, diseases in which patient samples display elevated levels of a type I or II IFN or a type I-related "IFN signature" pattern of gene expression. See, e.g., Baechler et al. (2003), Proc. Natl. Acad. Sci. 100(5): 2610-2615; Bennett et al. (2003), J. Exp. Med. 197(6): 711-723. The portions of these references that describe the IFN signature pattern of gene expression are incorporated herein by reference. IFN-γ-mediated diseases include, for example, SLE, discoid lupus, lupus nephritis, alopecia greata, Graves'disease, Sjogren's syndrome, antiphospholipid syndrome, rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, dermatomyositis, polimyositis, bacterial septicemia, antigen/antibody complex diseases (Arthus-like syndromes), anaphylactic shock, multiple sclerosis (MS), type I diabetes, thyroiditis, graft versus host disease, transplant rejection, atherosclerosis, immune-mediated hepatic lesions, autoimmune hepatitis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, giant cell arteritis, uveitis, macrophage activation syndrome (MAS), hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), sarcoidosis, and scleroderma.

[0050] The term "interferon signature" refers to the characteristic pattern of over- and under-expression of genes observed in response to type 1 interferons. See, e.g., Bennett et al. (2003), J. Exp. Med. 197(6): 711-723; Baechler et al. (2003), Proc. Natl. Acad. Sci. 100(5): 2610-2615, the relevant portions of which are incorporated herein by reference.

[0051] The expression of a particular gene in a biological sample from a patient is said to "deviate" from the expression of that gene in a control biological sample or in a biological sample from the patient taken at a different time "in a direction consistent with excess IFN-γ" or "in a direction consistent with excess IFN-γ pathway activation" when it is found to be up- or down-modulated at the RNA or protein level in the same direction as noted in Table 1 below for blood samples stimulated with IFN-γ. Table 1 lists the group of genes that are up- or down-regulated in human whole blood from healthy volunteers in response to stimulation with IFN-γ ex vivo. Thus, for a gene to "deviate" from the expression of that gene in a control biological sample or in a biological sample from the patient taken at a different time "in a direction consistent with excess IFN-γ", it must be listed in Table 1.

[0052] Similarly, the expression of a gene can be "modulated in a direction consistent with inhibition of IFN-γ" or "modulated in a direction consistent with IFN-γ pathway inhibition." This means that the expression of the gene is decreased if the expression of that gene is up-regulated in response to ex vivo stimulation with IFN-γ as noted in Table 1, and that the expression is increased if the expression of that gene is down-regulated in response to ex vivo stimulation with IFN-γ as noted in Table 1.

[0053] A "monoclonal antibody," as meant herein, is an antibody that specifically binds to an antigen at an epitope, wherein a preparation of the antibody contains substantially only antibodies having the same amino acid sequence, although there may be certain low levels of antibodies that include one or more alteration of certain amino acids or internal, amino-terminal, or carboxyterminal cleavages of the amino acid chain. Such minor alterations may occur during the production of the antibodies or during storage. In contrast, a preparation of a "polyclonal" antibody contains antibodies having many different amino acid sequences that bind to different epitopes on the same antigen. The term "monoclonal antibody" includes, without limitation, the following kinds of molecules: tetrameric antibodies comprising two heavy and two light chains such as an IgG, IgA, IgD, IgM, or IgE antibody; single chain antibodies (scFv's) containing a V_H and a V_L region joined by a peptide linker; variable domain antibodies as described in, for example, U.S. Pat. No. 7,563,443, the relevant portions of which are incorporated herein by reference, that comprise one or more single variable domains, each of which can, by itself, bind specifically to antigen; Fab, Fab', or Fab(ab')₂ fragments; humanized or chimeric antibodies; various kinds of monovalent antibodies, including those described in U.S. Patent Application Publication 2007/0105199, the relevant portions of which are incorporated by reference herein; and bispecific antibodies, including those with mutationally altered constant regions such as those described in, e.g., U.S. Patent Application Publication 2010/0286374 or U.S. Patent Application Publication 2007/0014794; and scFv-Fc molecules.

[0054] A "pharmacodynamically effective dose," as meant herein, is a dose of an IFN-γ inhibitor that can modulate the expression of a gene "in a direction consistent with inhibition of IFN-γ," as defined herein. Genes regulated by IFN-γ ex vivo are listed in Table I.

[0055] A "plateau concentration," as meant herein, is a concentration of total IFN-γ that is observed in a biological sample, such as peripheral blood or serum, taken from a patient after dosing with an IFN-γ inhibitor. The plateau concentration is higher than the concentration of total IFN-γ protein in a similar biological sample taken from the same patient at baseline, and once it is attained, it is "substantially maintained" for at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. A concentration is considered to be substantially maintained if it varies by no more than ±50% of its total value.

[0056] A "therapeutically effective dose," as meant herein, is a dose that is effective to decrease one or more observable symptoms of a disease or to delay onset or mitigate the symptoms of a more serious condition that often follows after the condition that a patient is currently experiencing. A therapeutically effective dose may, but need not necessarily, completely eliminate all symptoms of the disease. For example, in lupus nephritis, a lowering of the degree of proteinuria and lowering or stabilization of serum concentration of creatinine would indicate an improvement in kidney function and, thus, an improvement in a symptom of the disease. Hence, a dose of an IFN-γ inhibitor that could cause a decrease in proteinuria and lower or stabilize serum creatinine concentration would be both a therapeutically effective dose and a phamacodynamically effective dose.

Interferons, IFN-γ-Mediated Diseases, and Biomarkers

[0057] Interferons were first recognized for their ability to impede viral infections and are now known to also play important roles in mediating host defense against infection by bacteria and other pathogens, as well as in integrating early, innate immune responses and later adaptive immune responses. Decker et al. (2002), J. Clin. Invest. 109(10): 1271-1277. There are at least two types of human and murine interferons: the type I interferons, including primarily a number of IFNα subtypes and IFNβ, plus IFNω, IFNε, IFNδ, IFNτ, and IFNκ; and type II interferon, a class of one member, that is, IFN-γ. Sozzani et al. (2010), Autoimmunity 43(3): 196-203. Type I interferons are produced by most cell types under appropriate conditions and are known to play a role in resisting viral infection, whereas IFN-γ is produced by limited cell types, such as NK cells and activated Th1 cells, and is known to strengthen immune responses to unicellular microorganisms, intracellular pathogens, and viruses. In humans, type I and type II interferons bind to distinct receptors, which are, respectively, the interferon alpha/beta receptor (IFNAR, containing IFNAR1 and IFNAR2 chains) and the interferon gamma receptor (IFNGR, containing IFNGR1 and IFNGR2 chains). Both of these receptors are associated with Janus kinases which, along with other intracellular proteins, mediate the transcriptional activation of genes having interferon-stimulated response elements (IFNAR only) and genes having IFN-γ-activated site elements (both IFNAR and IFNGR). Decker et al. (2002), J. Clin. Invest. 109(10): 1271-1277; Trinchieri (2010), J. Exp. Med. 207(10): 2053-2063. Thus, although the sets of genes activated by type I and II interferons differ, there is considerable overlap in the two sets. See, e.g., Baechler et al. (2003), Proc. Natl. Acad. Sci. 100(5): 2610-2615; van Baarsen et al. (2006), Genes and Immunity 7: 522-531. Some differences may be related to different magnitudes of response of a particular gene to a given dose of type I or II interferon. Kariuki et al. (2009), J. Immunol. 182: 34-38

[0058] The relationship between the biological activities of type I and II interferons is complex and intertwined and dependent on the expression of other genes. Thus, different cell types can have differing responses to the IFNs. IFN-γ is a more potent activator of phagocytic cell and antigen-presenting cell function than type I interferons. Trinchieri (2010), J. Exp. Med. 207(10): 2053-2063. Both type I and II interferons can be produced in the course of an immune response. In some situations, type I interferons can inhibit production of IFN-γ, and in other situations, for example, in the absence of STAT1, type I interferons can increase IFN-γ production. Nguyen et al. (2000), Nature Immunol. 1(1): 70-76; Brinkman et al. (1993), J. Exp. Med. 178: 1655-1663; Trinchieri (2010), J. Exp. Med. 207(10): 2053-2063. Further, low levels of type I IFN produced during stimulation of dendritic cells are essential for production of IL-12 heterodimer, which induces production of IFN-γ. However, in the presence of high levels of type I IFN, production of IL-12 p40 is suppressed, thus limiting the production of IL-12 heterodimer. Thus, the relationship between type I and II interferons is already known to be complex and may be even more complex in vivo than is currently understood.

[0059] A number of diseases have been associated with changes in gene expression patterns that are thought to reflect elevated activity of IFNs. Some investigators refer to such a gene expression pattern as an "interferon signature," which includes somewhat different groups of genes depending on exactly how the signature is defined. See, e.g., Baehler et al. (2003), Proc. Natl. Acad. Sci. 100(5): 2610-2615; Bennett et al. (2003), J. Exp. Med. 197(6): 711-723. Since IFN-γ- and type I IFN-activated genes are overlapping sets, an elevated interferon signature score could implicate elevated activity of IFN-γ and/or a type I IFN. In a number of autoimmune and/or inflammatory diseases, many of which characterized by extremely heterogeneous and episodic symptoms, it has been found that a substantial proportion of patients or persons at increased risk of disease have a gene expression pattern reflecting elevated IFN activity and/or have elevated levels of an IFN or a protein whose expression is known to be induced by type I IFN. These diseases include, for example, SLE (Bauer et al. (2006), PLoS Med. 2(12): 2274-2284; Armananzas et al. (2009), IEEE Transactions on Inform. Tech. in Biomed. 13(3): 341-350), systemic sclerosis (Sozzani et al. (2010), Autoimmunity 43(3): 196-203), alopecia greata (Ghoreishi et al. (2010), Br. J. Dermatol. 163: 57-62), Graves' disease (Ruiz-Riol et al. (2011), J. Autoimmunity 36: 189-200), Sjogren's syndrome (Sozzani et al. (2010), Autoimmunity 43(3): 196-203; Emamian et al. (2009), Genes Immun. 10: 285-296), antiphospholipid syndrome (Armananzas et al. (2009), IEEE Transactions on Inform. Tech. in Biomed. 13(3): 341-350), inflammatory bowel diseases including Crohn's disease and ulcerative colitis (see, e.g., U.S. Pat. No. 6,558,661), rheumatoid arthritis (Dawidowicz et al. (2011), Ann. Rheum. Dis. 70: 117-121), psoriasis (Pietrzak et al. (2008), Clin. Chim. Acta 394: 7-21), multiple sclerosis (van Baarsen et al. (2006), Genes and Immunity 7: 522-531), dermatomyositis (Somani et al. (2008), Arch. Dermatol. 145(4): 1341-1349), polymyositis (Sozzani et al. (2010), Autoimmunity 43(3): 196-203), type I diabetes (Reynier et al. (2010), Genes Immun. 11: 269-278), sarcoidosis (Lee et al. 2011, Ann. Dermatol. 23(2): 239-241; Kriegova et al. (2011), Eur. Respir. J. 38: 1136-1144), and hemophagocytic lymphohistiocytosis (HLH; Schmid et al. (2009), EMBO Molec. Med. 1(2): 112-124).

[0060] Elevated expression of genes whose expression is induced by IFNs is found in about half of adult SLE patients and the majority of pediatric SLE patients. Baechler et al. (2003), Proc. Natl. Acad. Sci. U.S.A.; 100: 2610-2615; Bennett et al. (2003), J. Exp. Med. 197: 711-723; Kirou et al. (2004), Arthr. & Rheum. 50: 3958-3967. Overexpression of some of these gene products at the protein level, such as CXCL10 (IP-10), CCL2 (MCP-1), and chemokine (C--C motif) ligand 19 (CCL19; also known as (MIP-3B), correlates with disease severity and is predictive of disease flares within a year. Bauer et al. (2009), Arthr. & Rheum 60(10): 3098-3107; Bauer et al. (2006), PLoS. Med. 3: e491; Lit et al. (2006), Ann. Rheum. Dis. 65: 209-215; Narumi et al. (2000), Cytokine 12: 1561-1565; Baechler et al. (2003), Proc. Natl. Acad. Sci. 100(5): 2610-2615. Specifically, CXCL10 has been shown to be a major contributor to the overall association of disease with IFN signature and an independent predictor of future disease flare. Bauer et al. (2009), Arthritis & Rheum. 60: 3098-3107; Bauer et al. (2009), Arthritis Rheum. 60:S209.

[0061] A variety of other data suggest a pathogenic role for IFN-γ in SLE. Studies involving murine models of SLE consistently support the role of IFN-γ in the pathogenesis of disease. Balomenos et al. (1998), J. Clin. Invest. 101: 364-371; Jacob et al. (1987), J. Exp. Med. 166: 798-803; Peng et al. (1997), J. Clin. Invest 99: 1936-1946; Hron and Peng (2004), J. Immunol. 173: 2134-2142; Seery et al. (1997), J. Exp. Med. 186: 1451-1459. In addition, lupus-like syndromes have been observed in patients treated for a variety of diseases with IFN-γ and/or IFN-α. Wandl et al. (1992), Clin. Immunol. Immunopathol. 65(1): 70-74; Graninger et al. (1991), J. Rheumatol. 18: 1621-1622. A correlation between severity of disease activity and amounts of IFN-γ secreted by a patient's peripheral blood mononuclear cells in response to stimulation by lipopolysaccharide and phytohaemagglutinin has been observed. Viallard et al. (1999), Clin. Exp. Immunol. 115: 189-195. Similarly, peripheral blood T cells from SLE patients expressed significantly more IFN-γ in response to CD28 costimulation than did T cells from normal controls. Harigai et al. (2008), J. Immunol. 181: 2211-2219. Thus, many different kinds of evidence indicate that IFN-γ is likely to play a role in mediating SLE.

[0062] SLE is an autoimmune disease of unknown etiology marked by autoreactivity to nuclear self antigens. Its clinical manifestations are so diverse that it is questionable whether it is truly a single disease or a group of related conditions. Kotzin, B. L. 1996. Systemic lupus erythematosus. Cell 85:303-306; Rahman, A., and Isenberg, D. A. 2008. Systemic lupus erythematosus. N. Engl. J. Med. 358:929-939. Symptoms can include the following: constitutional symptoms such as malaise, fatigue, fevers, anorexia, and weight loss; diverse skin symptoms including acute, transient facial rashes in adults, bullous disease, and chronic and disfiguring rashes of the head and neck; arthritis; muscle pain and/or weakness; cardiovascular symptoms such as mitral valve thickening, vegetations, regurgitation, stenosis, pericarditis, and ischemic heart disease, some of which can culminate in stroke, embolic disease, heart failure, infectious endocarditis, or valve failure; nephritis, which is a major cause of morbidity in SLE; neurological symptoms including cognitive dysfunction, depression, psychosis, coma, seizure disorders, migraine, and other headache syndromes, aseptic meningitis, chorea, stroke, and cranial neuropathies; hemotologic symptoms including leucopenia, thrombocytopenia, serositis, anemia, coagulation abnormalities, splenomegaly, and lymphadenopathy; and various gastrointestinal abnormalities. Id; Vratsanos et al., "Systemic Lupus Erythematosus," Chapter 39 in Samter's Immunological Diseases, 6th Edition, Austen et al., eds., Lippincott Williams & Wilkins, Phiiladelphia, Pa., 2001.

[0063] Severity of symptoms varies widely, as does the course of the disease. SLE can be deadly. The disease activity of SLE patients can be rated using an instrument such as the Systemic Lupus Erythrmatosus Disease Activity Index (SLEDAI), which provides a score for disease activity that takes into consideration the following symptoms, which are weighted according to severity: seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, vasculitis, arthritis, myositis, urinary casts, hematuria, proteinuria, pyuria, new rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, increased DNA binding, fever, thrombocytopenia, and leucopenia. Bombardier et al. (1992), Arthr. & Rheum. 35(6): 630-640, the relevant portions of which are incorporated herein by reference. The treatments described herein can be useful in lessening or eliminating symptoms of SLE as measured by SLEDAI.

[0064] Another method for assessing disease activity in SLE is the British Isles Lupus Assessment Group (BILAG) index, which is a disease activity assessment system for SLE patients based on the principle of the physician's intention to treat. Stoll et al. (1996), Ann. Rheum Dis. 55: 756-760; Hay et al. (1993), Q. J. Med. 86: 447-458. The portions of these references describing the BILAG are incorporated herein by reference. A BILAG score is assigned by giving separate numeric or alphabetic disease activity scores in each of eight organ-based systems, general (such as fever and fatigue), mucocutaneous (such as rash and alopecia, among many other symptoms), neurological (such as seizures, migraine headaches, and psychosis, among many other symptoms), musculoskeletal (such as arthritis), cardiorespiratory (such as cardiac failure and decreased pulmonary function), vasculitis and thrombosis, renal (such as nephritis), and hematological. Id. The treatments described herein can be useful in lessening or eliminating symptoms of SLE as measured by the BILAG index.

[0065] Discoid lupus is a particular form of chronic cutaneous lupus in which the patient has circular lesions that occur most commonly in sun-exposed areas. The lesions can leave disfiguring scars. Up to about 25% of SLE patients develop discoid lupus lesions at some point in the course of their disease. These lesions may occur in patients that have no other symptoms of SLE. The symptoms that relate specifically to skin in cutaneous forms of lupus can be scored using the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), which takes into consideration both disease activity (including erythema, scaling, and hypertrophy of the skin in various areas, as well as mucus membrane lesions and alopecia) and disease-related damage (including dyspigmentation, scarring, atrophy, and panniculitis of the skin as well as scarring of the scalp). Such symptoms can be affected by a treatment for discoid lupus such as an IFN-γ inhibitor. The CLASI is described in detail by Albrecht et al. (2005), J. Invest. Dermatol. 125: 889-894. The portions of this article that describe what the CLASI is, what symptoms are included in it, and how to use it are incorporated herein by reference. The treatments described herein can be useful for lessening or eliminating symptoms of discoid lupus as measured by the CLASI.

[0066] Another cutaneous disease that can be mediated by IFN-γ is psoriasis. Symptoms of psoriasis include itchy, dry skin that can be pink/red in color, thickened and covered with flakes. It is a common condition and is episodic in nature, that is, patients can experience flares and periods of remission. There are five type of psoriasis, erythrodermic, guttate, inverse, plaque, and pustular. Plaque psoriasis is the most common type. Clinical studies with an anti-human IFN-γ antibody indicate that inhibition of IFN-γ can lessen symptoms of psoriasis as measured by a Psoriasis Area and Severity Index (PASI) score, thus demonstrating that IFN-γ plays a role in mediating psoriasis, at least in some patients. International Application Publication WO 2003/097083.

[0067] The severity of disease in psoriasis patients can be measured in a variety of ways. One way disease activity is commonly measured in clinical trials the PASI score. A PASI score can range from 0 to 72, with 72 being the most severe disease. For purposes of PASI assessment, the body is considered to consist of four sections, legs, torso (that is, stomach, chest, back, etc.), arms, and head, which are considered to have 40%, 30%, 20%, and 10% of a person's skin, respectively. For each section, the percent of the area of skin affected is estimated and transformed into a grade of from 0 to 6, with 0 being no affected skin and 6 being 90-100% of the skin of the body section in question being affected. The severity of disease is scored by separately considering three features of the affected skin, redness (erythema), scaling, and thickness, and assigning a severity score of from 0 to 4 for each feature for each body section. The sum of the severity scores for all three features for each body section is calculated, and this sum is multiplied by the weight of the respective section as determined by how much of the total skin that body section contains and by the percent of the body section affected. After this number is calculated for each body section, these numbers are added to yield the PASI score. Thus, the PASI score can be expressed as follows:

PASI=0.1(score for percent of the head affected)(sum of 3 severity scores for the head)+0.2(score for percent of the arms affected)(sum of 3 severity scores for the arms)+0.3(score for percent of the torso affected)(sum of 3 severity scores for the torso)+0.4(score for percent of the legs affected)(sum of 3 severity scores for the legs)

[0068] The descriptions of PASI scores in the following two references are incorporated by reference herein: Feldman and Krueger (2005), Ann. Rheum. Dis. 64: 65-68, Langley and Ellis (2004), J. Am. Acad. Dermatol. 51(4): 563-69.

[0069] Many clinical trials refer to changes in PASI score over the course of the study. For example, a PASI 75 at a particular time point in a clinical trial means that the PASI score of a patient has decreased by 75% as compared to that patient's PASI score at baseline. Similarly a PASI 50 or a PASI 90 denotes a 50% or 90% reduction in PASI score.

[0070] Another commonly used measure of psoriasis severity in clinical trials is the static Physicians Global Assessment (sPGA). The sPGA is typically a six category scale rating ranging from 0=none to 5=severe. ENBREL® (etanercept), Package Insert, 2008. A sPGA score of "clear" or "minimal" (sometimes alternately referred to as "almost clear") requires no or minimal elevation of plaques, no or only very faint redness, and no scaling or minimal scaling over <5% of the area of the plaques. ENBREL® (etanercept), Package Insert, 2008. The individual elements of psoriasis plaque morphology or degree of body surface area involvement are not quantified. Nonetheless, sPGA scores correlate to some extent with PASI scores. Langley and Ellis (2004), J. Am. Acad. Dermatol. 51(4): 563-69. The methods described herein lessen or eliminate psoriasis symptoms as measured by a PASI or an sPGA score.

[0071] Multiple sclerosis (MS) is an autoimmune disease characterized by damage to the myelin sheath that surrounds nerves, which leads to inhibition or total blockage of nerve impulses. The disease is very heterogeneous in clinical presentation, and there is a wide variation in response to treatment as well. van Baarsen et al. (2006), Genes and Immunity 7: 522-531. Environmental factors, possibly viral infection, as well as genetic susceptibility, are thought to play a role in causing MS. Id. Symptoms can include loss of balance, muscle spasms, tremors, weakness, loss of ability to walk, loss of coordination, various bowel and bladder problems, numbness, pain, tingling, slurred speech, difficulty chewing and swallowing, double vision, loss of vision, uncontrollable eye movements, and depression, among many other possible symptoms. In many patients episodes in which symptoms occur are interspersed with long periods of remission. A subset of MS patients exhibit a pattern of gene expression consistent with high type I IFN activity, although a correlation between this pattern of gene expression and disease severity has not been demonstrated. Id. The methods described herein can lessen or eliminate one or more symptoms of MS.

[0072] Type I diabetes is an autoimmune disease resulting in the destruction of insulin-producing β-cells in the pancreas, which leads to a lack of insulin. Antibodies against β-cell epitopes are detected in the sera of pre-diabetic patients, suggesting that there is an autoimmune process in progress during a long asymptomatic period that precedes the onset of clinical symptoms. Reynier et al. (2010), Genes and Immunity 11: 269-278. The lack of insulin leads to high glucose levels in the blood and urine causing a variety of symptoms including frequent urination, increased hunger and thirst, fatigue, and weight loss. It is generally treated with insulin, a treatment that must be continued indefinitely. The causes of type I diabetes are not completely clear, but are thought to include a genetic component. About thirty percent of non-diabetic siblings of diabetic patients are found to express high levels of RNAs encoded by a group genes activated by type I interferon, although diabetic patients do not overexpress these RNAs. Reynier et al. (2010), Genes and Immunity 11: 269-278. Such overexpression may be an indication of future disease. Since various strategies for inhibiting the progress of the disease are known and may be discovered in the future, it is useful to detect the disease before the onset of clinical symptoms. The methods described herein may be useful to detect and/or treat type I diabetes before and/or after the onset of clinical symptoms.

[0073] Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are also IFN-γ-mediated diseases as meant herein. Crohn's disease is chronic and debilitating inflammatory bowel disease that is thought to reflect a overly-active T_H1-mediated immune response to the flora of the gut. The lesions of Crohn's disease can appear anywhere in the bowel and occasionally elsewhere in the gastrointestinal tract. Ulcerative colitis lesions, on the other hand, usually appear in the colon. The nature of the lesions is also different, but the diseases are sufficiently similar that is sometimes difficult to distinguish them clinically. See, e.g., U.S. Pat. No. 6,558,661.

[0074] A variety of evidence indicates that IFN-γ plays a role in inflammatory bowel diseases. Results from a clinical study using an anti-human IFN-γ antibody in patients with Crohn's disease indicated that the antibody produced dose dependent, though somewhat marginal, improvements in Crohn's Disease Activity Index (CDAI) scores. International Application Publication WO 2003/097082. The CDAI is described in Best et al. (1976), Gastroenterology 70: 439-444. The portions of this reference that describe the CDAI and how to use it are incorporated herein by reference. In addition, data from model systems for inflammatory bowel disease indicate that IFN-γ inhibition can be effective in reducing the symptoms of inflammatory bowel diseases. See, e.g., U.S. Pat. No. 6,558,661, the relevant portions of which are incorporated herein by reference. The methods described herein may be useful for selecting IBD patients to treat, for treating IBD patients, and/or for reducing or eliminating symptoms of IBD.

[0075] Sarcoidosis is a systemic granulomatous disease that can affect essentially any tissue, but it primarily affects the lung and lymphatic systems. It is characterized by the presence of noncaseating epithelioid cell granulomas in more than one organ system. Most commonly the granulomas are found in lung, lymph nodes, skin, liver, and/or spleen, among other possible sites. It can be fatal. For example, fibrosis of the lungs can lead to fatality. Increases in IFN-γ levels have been observed in sarcoidosis. Carter and Hunninghake, "Sarcoidosis," Chapter 47 in Samter's Immunological Diseases, 6th Edition, Austen et al., eds., Lippincott Williams & Wilkins, Phiiladelphia, Pa., 2001. IFN-γ plays a crucial role in the pathogenesis of sarcoidosis. See, e.g., Kriegova et al. (2011), Eur. Respir. J. 38: 1136-1143. The methods described herein may be useful for selecting sarcoidosis patients to treat, for treating sarcoidosis patients, and/or for reducing or eliminating symptoms of sarcoidosis.

[0076] Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal disease having clinical manifestations including fever, hepatosplenomegaly, lymphadenopathy, jaundice and rash. Laboratory findings associated with HLH include lymphocytosis and histiocytosis and the pathologic finding of hemophagocytosis. Pancytopenia, elevated serum ferritin levels, and abnormal liver enzymes are also frequently present. IFN-γ has been clearly implicated in driving the disease process in a murine model for hemophagocytic anemia. Zoller et al. (2011), J. Exp. Med. 208(6): 1203-1214. The methods described herein may be useful for selecting HLH patients to treat, for treating HLH patients, and/or for reducing or eliminating symptoms of HLH.

[0077] For any IFN-γ-mediated disease, it would be valuable to have a test to identify patients likely to benefit from a particular treatment. Due to the episodic nature of symptoms in many such diseases, it would also be desirable to be able to evaluate the biological effects of a given treatment without having to wait for the recurrence of symptoms, or lack thereof. Thus, in the methods described herein, expression of one or more biomarkers listed in Table 1, 2, 4, 5, and/or 6 can be measured before treatment begins as a method for determining whether genes regulated by IFN-γ are dysregulated in the patient. If so, an IFN-γ inhibitor may be an effective treatment. Expression of biomarkers (such as those in Table 1, 2, 4, 5, and/or 6) can also be measured after treatment has begun to determine whether the dosage of the IFN-γ inhibitor is having a biological effect. Such information can inform treatment decisions and may be correlated with clinical signs and symptoms of the disease. For example, if the IFN-γ inhibitor is not having a biological effect, treatment can be discontinued or a different dosage can be administered. If the IFN-γ inhibitor is having a biological effect, then the treatment can be continued. Such information can also be used to determine what doses are having a phamacodynamic effect, i.e., are modulating the expression of a gene or genes whose expression is regulated by IFN-γ.

Interferon Gamma Inhibitors

[0078] Appropriate for use in the methods described herein are inhibitors of human IFN-γ, which can be proteins, small molecules, or proteins conjugated to non-protein moieties, such as, for example, a pegylated protein. The capacity of a particular small molecule or protein to inhibit the activity of human IFN-γ can be measured by the A549 bioassay described above.

[0079] Numerous proteins that are IFN-γ inhibitors are known. For example, anti-IFN-γ antibodies can inhibit IFN-γ. These can be human, humanized, or chimeric antibodies that bind to human IFN-γ and/or other mammalian homologs such a rhesus, cynomolgus monkey, chimpanzee, mouse, rabbit, rat, baboon, gorilla, and/or marmoset IFN-γ. They can be of the IgG, IgE, IgM, IgA, or IgD isotypes. They can be IgG1, IgG2, IgG3, or IgG4 antibodies. In some embodiments, these antibodies that contain the following pairs of heavy and light chain variable regions: SEQ ID NOs:6 and 8; SEQ ID NOs:10 and 12; SEQ ID NOs: 14 and 16; SEQ ID NOs:14 and 31; and SEQ ID NOs:30 and 12. Further, these antibodies can contain the following pairs of heavy and light chain amino acid sequences: SEQ ID NO:19 and SEQ ID NO:20; SEQ ID NO:17 and SEQ ID NO:18; SEQ ID NO:21 and SEQ ID NO:22; SEQ ID NO:32 and SEQ ID NO:20; or SEQ ID NO:21 and SEQ ID NO:33. These antibodies, which include an antibody called AMG 811 that is used in the clinical trials described in the Examples below, are described in detail in U.S. Pat. No. 7,335,743. The portions of U.S. Pat. No. 7,335,743 that describe these antibodies are incorporated herein by reference. These antibodies can contain a heavy chain CDR1 comprising SEQ ID NO:34, a heavy chain CDR2 comprising SEQ ID NO:35, a heavy chain CDR3 comprising SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising SEQ ID NO:38. SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising SEQ ID NO:43 or SEQ ID NO:44. In particular embodiments, the antibody can include the following heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3, respectively: a) SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, and SEQ ID NO:43; b) SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:41, and SEQ ID NO:43; c) SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:41, and SEQ ID NO:43; or d) SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:40, SEQ ID NO:42, and SEQ ID NO:44.

[0080] Other IFN-γ inhibitors are also contemplated. Any monoclonal anti-IFN-γ antibody capable of inhibiting the activity of human IFN-γ can be used. Among these are the humanized anti-IFN-γ antibody fontolizumab (HUZAF® PDL Biopharma, Inc.). The sequences of the heavy and light chain variable regions of this antibody are reported in U.S. Patent Application Publication 2002/0091240 as SEQ ID NOs:6 and 8, respectively. These sequences and any other description of this antibody included in U.S. Patent Application Publication 2002/0091240 are incorporated herein by reference. The IFN-γ inhibitors described in U.S. Pat. No. 5,451,658 (the relevant portions of which, including the amino acid sequences of the inhibitors, are incorporated herein by reference) are among the IFN-γ inhibitors that can be used to perform the methods described herein. Similarly, IFN-γ inhibitors comprising a portion of a naturally occurring human IFN-γ receptor, the sequence of which is reported in Aguet et al. (1988), Cell 55: 273-280 (the relevant portions of which are incorporated herein by reference), can be used to practice the methods described herein. One such IFN-γ inhibitor is a fusion protein comprising the extracellular region of the human IFN-γ receptor fused to a human IgG1 Fc region, which is described in U.S. Pat. No. 6,558,661, the relevant portions of which are incorporated herein by reference. Other such IFN-γ inhibitors are the fusion proteins containing part or all of the extracellular regions of IFN-γ receptor α and IFN-γ receptor β, as described is U.S. Patent Application Publication 2007/0020283, the relevant portions of which are incorporated herein by reference. Another IFN-γ inhibitor is the cytokine which is a specific antagonist of IFN-γ, which is described in U.S. Pat. No. 5,612,195, the relevant portions of which are incorporated herein by reference. Still other IFN-γ inhibitors are the genetically modified, inactivated protein derivatives of human IFN-γ described in U.S. Patent Application Publication 2010/0158865, the relevant portions of which are incorporated herein by reference. Further, a BCRF1 protein, which inhibits production of IFN-γ, is an IFN-γ inhibitor that can be used to practice the methods described herein. U.S. Pat. No. 5,736,390 describes such BCRF1 proteins, and the portions of U.S. Pat. No. 5,736,390 that describe these proteins and how to make them are incorporated herein by reference.

[0081] In addition, various chemical compounds (which are not proteins) are known to inhibit the synthesis of IFN-γ and are considered to be IFN-γ inhibitors, as meant herein. Among these are the bis phenol or phenoxy compounds and derivatives thereof described in U.S. Pat. No. 5,880,146. The portions of U.S. Pat. No. 5,880,146 that describes such compounds and how to make them are incorporated herein by reference. Similarly, the compounds described in U.S. Pat. No. 5,985,863 that inhibit production of IFN-γ by inhibiting production of IFN-γ inducing factor or inhibiting interleukin-1β converting enzyme are IFN-γ inhibitors that can be used to practice the methods described herein.

Methods of Making IFN-γ Inhibitors

[0082] With regard to protein inhibitors of IFN-γ, these can be made by methods well known in the art. Antibodies, for example, can be made by introducing hybridoma cells that produce the antibody into the peritoneal cavity of a live mouse, a so-called ascites preparation. Hybridoma cells producing an antibody can also be cultured in vitro. Other in vivo methods of protein production include, for example, protein production in hen eggs, tobacco leaves, and milk. Protein inhibitors of IFN-γ can also be made in prokaryotic or eukaryotic host cells, including bacteria such as Escherichia coli, various yeasts including Saccharomyces cerevisiae and Pichia pastoris, and various kinds of mammalian cells including, without limitation, human cells, baby hamster kidney (BHK) cells, Chinese hamster ovary (CHO) cells, VERO, BHK, HeLa, CV1 (including Cos), MDCK, 293, 3T3, myeloma cell lines (e.g., NSO, NS1), PC12, and WI38 cells. Such host cells, into which nucleic acids encoding the desired protein have been introduced, can be cultured in appropriate culture medium, many of which are known in the art, and the desired protein can be recovered from the cell mass or the cell culture medium.

[0083] CHO cells are widely used for the production of complex recombinant proteins, e.g. cytokines, clotting factors, and antibodies (Brasel et al. (1996), Blood 88:2004-2012; Kaufman et al. (1988), J. Biol. Chem. 263:6352-6362; McKinnon et al. (1991), J. Mol. Endocrinol. 6:231-239; Wood et al. (1990), J. Immunol. 145:3011-3016). The dihydrofolate reductase (DHFR)-deficient mutant cell lines (Urlaub et al. (1980), Proc. Natl. Acad. Sci. U.S.A. 77: 4216-4220, which is incorporated by reference), DXB11 and DG-44, are desirable CHO host cell lines because the efficient DHFR selectable and amplifiable gene expression system allows high level recombinant protein expression in these cells (Kaufman R. J. (1990), Meth. Enzymol. 185:537-566, which is incorporated by reference). In addition, these cells are easy to manipulate as adherent or suspension cultures and exhibit relatively good genetic stability. CHO cells and recombinant proteins expressed in them have been extensively characterized and have been approved for use in clinical commercial manufacturing by regulatory agencies. The methods of the invention can also be practiced using hybridoma cell lines that produce an antibody. Methods for making hybridoma lines are well known in the art. See e.g. Berzofsky et al. in Paul, ed., Fundamental Immunology, Second Edition, pp. 315-356, at 347-350, Raven Press Ltd., New York (1989). Cell lines derived from the above-mentioned lines are also suitable for making IFN-γ inhibitor proteins.

Determining Dosage Using Biomarkers

[0084] Described herein are methods for determining a pharmacodynamically effective dosage of an IFN-γ inhibitor for treating an IFN-γ mediated disease, as well as methods of treatment using such dosages. The method includes assaying for the expression of one or more genes at either the protein or RNA level both before and after administering an IFN-γ inhibitor. The gene(s) can be selected from the genes listed in Table 1 (genes whose expression is modulated in human blood by stimulation with IFN-γ ex vivo), Table 2 (twenty genes whose expression is modulated in human blood to the greatest extent by IFN-γ stimulation ex vivo), Table 3 (ten genes whose expression is modulated to the greatest extent by administration of AMG 811 in vivo), Table 5 (genes whose expression is modulated by a neutralizing human anti-human IFN-γ antibody in vivo), and/or Table 6 (genes whose expression is modulated in human blood by stimulation with IFN-γ ex vivo and whose expression is modulated by a neutralizing human anti-human IFN-γ antibody in vivo). Those doses that modulate the expression of one or more of these genes in a direction consistent with inhibition of IFN-γ can be used to treat an IFN-γ mediated disease.

[0085] Alternatively or in addition, a pharmacodynamically effective dosage and/or dosing frequency of an IFN-γ inhibitor can be determined by the effect of an IFN-γ inhibitor on the serum concentration of total IFN-γ protein. For example, some doses of an IFN-γ inhibitor, for example an IFN-γ binding protein such as AMG 811, can cause elevation of the serum levels of total IFN-γ. See FIGS. 6A and 6B below. Presumably, this effect results from protection of IFN-γ that is bound by the IFN-γ inhibitor from degradation or more rapid clearance. If patients receiving a higher dose of an IFN-γ inhibitor (for example, 180 mg SC of AMG 811 in FIG. 6A) reach about the same levels of total IFN-γ as those attained by patients receiving a somewhat lower dose (for example, 60 mg SC of AMG 811 in FIG. 6A), it may be that all available IFN-γ is protected at the lower dose. A desirable dose of an IFN-γ binding protein, for example AMG 811, would be one that causes patients to achieve a higher-than-baseline level of total IFN-γ and to maintain this "plateau" concentration for a time period of, for example, at least about 2, 3, 4, 5, 6, 7, or 8 weeks and/or at least about 1, 2, 3, or 4 months. Based on the data in FIGS. 6A and 6B for AMG 811, a desirable dose can be greater than about 20 mg SC, at least about 60 mg SC, at least about 180 mg SC, and/or at least about 60 mg IV. Further, using a dose of an IFN-γ inhibitor such that the levels of total IFN-γ reach and maintain a higher-than-baseline plateau concentration for at least about 2 weeks, dosing frequency can be adjusted such that the levels of total IFN-γ do not fall below about 25%, 50%, 60%, 70%, or 80% of this plateau value. Thus, at a lower dose of an IFN-γ inhibitor where a plateau value is maintained for a shorter period, dosing can be more frequent, whereas at a higher dose of an IFN-γ inhibitor where a plateau value is maintained for a longer period, dosing can be less frequent. For example, based on the data in FIGS. 6A and 6B, at a dose of 60 mg SC of AMG 811, doses can be administered approximately every 2, 3, 4, or 5 weeks. Similarly, at a dose of AMG 811 of 180 mg SC or 60 mg IV, doses can be administered approximately every 6, 7, 8, 9, 10, 11, or 12 weeks.

[0086] In a particular embodiment, at least the lower end of dosage ranges for treating patients having SLE and/or lupus nephritis with a human anti-human IFN-γ antibody called AMG 811 have been clarified. See Examples 3 and 4 and FIGS. 4, 6-9, and 12-14. In that data, the lowest dose at which a clear biological effect was observed was a dose of 20 milligrams, although clearer effects were observed in some cases at a dose of 60 mg.

[0087] For any IFN-γ inhibitor that contains a protein, for example an anti-huIFN-γ antibody such as AMG 811, the dose can be at least about 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 mg and/or may not exceed 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, or 2000 mg. For example, a per-treatment dose of about 15-500, 20-400, 30-300, 60-180, 80-200, or 100-200 milligrams of the antibody can be used to treat an IFN-γ-mediated disease. Alternatively, a per-treatment dose of about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 270, 290, 300, 350, or 400 milligrams can be used.

[0088] Alternatively, a dose can be gauged on the basis of a patient's body weight. For example, a dose of at least about 0.1, 0.15, 0.2. 0.25, 0.3, 0.35, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, or 5.0 milligrams per kilogram (mg/kg) and/or not more than about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 mg/kg can be administered. In some embodiments, the dose can be from about 0.2 mg/kg to about 10 mg/kg, from about 0.25 mg/kg to about 8 mg/kg, from about 0.5 mg/kg to about 5 mg/kg, from about 1 mg/kg to about 2 mg/kg, from about 1 mg/kg to about 3 mg/kg, or from about 3 mg/kg to about 5 mg/kg.

[0089] Alternatively, a dose can be administered on the basis of the calculated body surface area of a patient. For example, a dose of at least about 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 130, 140, 150, 160, 170, 180, or 190 milligrams per square millimeter (mg/mm²) and/or not more than 200, 220, 240, 260, 280, 300, 320, 340, 360, or 380 mg/mm² can be administered. In some embodiments the dose can be from about 8 mg/mm² to about 380 mg/mm², from about 10 mg/mm² to about 300 mg/mm², from about 20 mg/mm² to about 190 mg/mm², from about 40 mg/mm² to about 80 mg/mm², from about 80 mg/mm² to about 200 mg/mm².

[0090] Since many IFN-γ-mediated diseases are chronic and/or recurrent, repeated doses of the IFN-γ inhibitor, optionally an anti-huIFN-γ antibody, may be required. Repeated doses can be administered, for example, twice per week, once a week, every two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve weeks, or once every one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve months.

Patient Stratification

[0091] It is always advantageous for clinicians and patients to be able to predict whether a given treatment will be effective for a particular patient. This is particularly true where the disease commonly includes long asymptomic periods, either alternating with symptomic periods or before the onset of symptoms. Provided herein are methods for determining which patients are likely to be successfully treated with an IFN-γ inhibitor. As discussed above, there are a number of IFN-γ mediated diseases. These include various autoimmune and inflammatory diseases including SLE, including discoid lupus and lupus nephritis, rheumatoid arthritis, type I diabetes, multiple sclerosis, psoriasis, dermatomyositis, sarcoidosis, HLH, and IBDs including Crohn's disease and ulcerative colitis, among a number of others. In the Examples below, it is shown that some genes whose expression was found to be upregulated by IFN-γ ex vivo are downregulated by an anti-human IFN-γ antibody in vivo. These genes are listed in Table 6 below.

[0092] Provided are methods for identifying patients suffering from an IFN-γ mediated disease likely to benefit from treatment with an IFN-γ inhibitor comprising determining whether the expression of one or more genes listed in Tables 1, 2, 4, 5, and/or 6 in a biological sample from the patient deviates from the expression of that gene(s) in a control biological sample in a direction consistent with excess IFN-γ. If the level of expression of one or more genes mentioned above in the biological sample from the patient deviates from the levels of expression in the control biological sample in a direction consistent with excess IFN-γ, it can indicate that the patient is a candidate for treatment with an IFN-γ inhibitor. The IFN-γ inhibitor can be an anti-huIFN-γ antibody or an IFN-γ receptor.

[0093] In another aspect, patients likely to benefit from treatment with an IFN-γ inhibitor can be identified by determining the levels of total IFN-γ in a biological sample from the patient as, for example, described in Example 3. Patients with undetectable or very low levels of total IFN-γ may not benefit from therapy with an IFN-γ inhibitor, for example an IFN-γ binding protein such an antibody. On the other hand, patients whose biological samples have total IFN-γ levels that are substantially higher than those detected in a control biological sample can benefit from therapy with an IFN-γ inhibitor, for example an IFN-γ binding protein such an antibody. Thus, determination of total IFN-γ levels in a biological sample from a patient can be used to identify patients likely to benefit from therapy with an IFN-γ inhibitor, for example an IFN-γ binding protein such as an anti-IFN-γ antibody.

Methods for Determining Treatment Efficacy

[0094] The methods provided herein can be useful for patients and clinicians in deciding whether to continue a treatment with an IFN-γ inhibitor in a particular patient. In the clinical studies reported in the Examples below, it is reported that the expression of a number of genes is modulated in a statistically significant manner in response to treatment with an anti-huIFN-γ antibody. In a variable and episodic disease such as, for example, SLE or MS, it may be impossible to tell from clinical signs and symptoms whether a treatment is having an effect within a given time period, such as, for example, 1, 2, or 3 weeks or 1, 2, 3, 4, 5, or 6 months. If, however, the expression of a biomarker listed in Table 1, 2, 4, 5, and/or 6 is modulated in a direction consistent with inhibition of IFN-γ, then it can be known that the treatment is having a biological effect, even though the patient might not show immediate changes in signs and symptoms. In such a case, according to the judgment of a clinician, it can be reasonable to continue treatment. However, if the expression of a biomarker listed in Table 1, 2, 4, 5, and/or 6 is not modulated by the IFN-γ inhibitor or is modulated in a direction consistent with an excess of IFN-γ, and there is not a change in signs and symptoms, it could be reasonably concluded that the patient is not responding to treatment. In such a situation, according to a clinician's judgment, treatment with an IFN-γ inhibitor could be discontinued, and a different treatment could be initiated.

[0095] Provided are methods for determining the efficacy of an IFN-γ inhibitor such as an anti-huIFN-γ antibody. Such an anti-huIFN-γ antibody can comprise the amino acid sequence of SEQ ID NO: 6, 10, 14, or 30 and SEQ ID NO: 8, 12, 16, or 31 and/or can comprise a light chain CDR1 comprising SEQ ID NO:38, 39, or 40, a light chain CDR2 comprising SEQ ID NO:41 or 42, a light chain CDR3 comprising SEQ ID NO:43 or 44, a heavy chain CDR1 comprising SEQ ID NO:34, a heavy chain CDR2 comprising SEQ ID NO:35, and a heavy chain CDR3 comprising SEQ ID NO:36 or 37. A method for determining the efficacy of an IFN-γ inhibitor as a treatment for an IFN-γ-mediated disease can comprise the following steps: 1) determining the level of expression of one or more of the genes listed in Table 1, 2, 4, 5, and/or 6 in a biological sample from a patient at the protein or RNA level; 2) determining the level of expression of the same gene(s) in a biological sample from the patient after administration of the drug; 3) comparing the expression of the gene(s) in biological samples from the patient before and after administration of the drug; 4) determining that the drug has shown evidence of efficacy if the level of expression of the gene(s) in the biological sample taken after administration of the drug has been modulated in a direction consistent with inhibition of IFN-γ; and 5) continuing treatment with the drug if it is determined that the drug has shown evidence of efficacy and discontinuing treatment with the drug if it is determined that the drug has not shown evidence of efficacy.

Combination Therapies

[0096] Treatments exist for most IFN-γ-mediated diseases, even though many of these treatments are relatively ineffective, effective for only a subset of patients, and/or have substantial toxicities that limit patient tolerance of treatment. The IFN-γ inhibitors described herein can be combined with other existing therapies for IFN-γ-mediated diseases.

[0097] In particular, an SLE patient can be treated concurrently with another therapy for SLE plus an IFN-γ inhibitor such as an anti-IFN-γ antibody comprising SEQ ID NO:6 and SEQ ID NO:8 and/or comprising a light chain CDR1 comprising SEQ ID NO:38, a light chain CDR2 comprising SEQ ID NO:41, a light chain CDR3 comprising SEQ ID NO:43, a heavy chain CDR1 comprising SEQ ID NO:34, a heavy chain CDR2 comprising SEQ ID NO:35, and a heavy chain CDR3 comprising SEQ ID NO:36. Existing therapies for SLE include glucocorticoids such as prednisone, prednisolone, and methylprednisolone, antimalarials such as hydroxychloroquine, quinacrine, and chloroquine, retinoic acid, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), cyclophosphamide, dehydroepiandrosterone, mycophenolate mofetil, azathioprine, chlorambucil, methotrexate, tacrolimus, dapsone, thalidomide, leflunomide, cyclosporine, anti-CD20 antibodies such as rituximab, BLyS inhibitors such as belimumab, and fusion proteins such as abatacept. Methods of patient stratification and biomarker monitoring concurrently with treatment, as described herein, can be used in patients receiving such combination drug treatments.

[0098] In other embodiments a patient suffering from an inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis, can be concurrently treated with a therapy for IBD plus an IFN-γ inhibitor, such as an anti-huIFN-γ antibody comprising SEQ ID NO:6 and SEQ ID NO:8 and/or comprising a light chain CDR1 comprising SEQ ID NO:38, a light chain CDR2 comprising SEQ ID NO:41, a light chain CDR3 comprising SEQ ID NO:43, a heavy chain CDR1 comprising SEQ ID NO:34, a heavy chain CDR2 comprising SEQ ID NO:35, and a heavy chain CDR3 comprising SEQ ID NO:36. Existing therapies for IBD include sulfasalazine, 5-aminosalicylic acid and its derivatives (such as olsalazine, balsalazide, and mesalamine), anti-TNF antibodies (including infliximab, adalimumab, golimumab, and certolizumab pegol), corticosteroids for oral or parenteral administration (including prednisone, methylprednisone, budesonide, or hydrocortisone), adrenocorticotropic hormone, antibiotics (including metronidazole, ciprofloxacin, or rifaximin), azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, tacrolimus, and thalidomide. Methods of patient stratification and biomarker monitoring concurrently with treatment, as described herein, can be used in patients receiving such combination drug treatments.

[0099] In other embodiments, a patient suffering from rheumatoid arthritis can be concurrently treated with a drug used for RA therapy plus an IFN-γ inhibitor, such as an anti-huIFN-γ antibody comprising SEQ ID NO:6 and SEQ ID NO:8 and/or comprising a light chain CDR1 comprising SEQ ID NO:38, a light chain CDR2 comprising SEQ ID NO:41, a light chain CDR3 comprising SEQ ID NO:43, a heavy chain CDR1 comprising SEQ ID NO:34, a heavy chain CDR2 comprising SEQ ID NO:35, and a heavy chain CDR3 comprising SEQ ID NO:36. Therapies for rheumatoid arthritis (RA) include non-steroidal anti-inflammatory drugs (NSAIDs) (such aspirin and cyclooxygenase-2 (COX-2) inhibitors), disease modifying anti-inflammatory drugs (DMARDs) (such as methotrexate, leflunomide, and sulfasalazine), anti-malarials (such as hydroxychloroquine), cyclophosphamide, D-penicillamine, azathioprine, gold salts, tumor necrosis factor inhibitors (such as etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol), CD20 inhibitors such as rituximab, IL-1 antagonists such as anakinra, IL-6 inhibitors such as tocilizumab, inhibitors of Janus kinases (JAK) (such as tofacitinib), abatacept, and glucocorticoids, among others. Methods of patient stratification and biomarker monitoring concurrently with treatment, as described herein, can be used in patients receiving such combination drug treatments.

[0100] In another embodiment, a patient suffering from sarcoidosis can be concurrently treated with a drug used for sarcoidosis therapy plus an IFN-γ inhibitor, such as an anti-huIFN-γ antibody comprising SEQ ID NO:6 and SEQ ID NO:8 and/or comprising a light chain CDR1 comprising SEQ ID NO:38, a light chain CDR2 comprising SEQ ID NO:41, a light chain CDR3 comprising SEQ ID NO:43, a heavy chain CDR1 comprising SEQ ID NO:34, a heavy chain CDR2 comprising SEQ ID NO:35, and a heavy chain CDR3 comprising SEQ ID NO:36. Therapies for sarcoidosis include corticosteroids (may be topical or parenteral, depending on symptoms), salicylates (such as aspirin), and colchicine. Methotrexate, cyclophosphamide, azathioprine, and nonsteroidal anti-inflammatory drugs have also been used in sarcoidosis. Various other treatment strategies can be helpful for some of the many different symptoms of sarcoidosis. For example, heart arrhythmias can be treated with antiarrhythmics or a pacemaker. Hypercalcemia can be treated with hydration, reduction in calcium and vitamin D intake, avoidance of sunlight, or ketoconazole. Skin lesions can be treated with chloroquine, hydroxychloroquine, methotrexate, or thalidomide. Methods of patient stratification and biomarker monitoring concurrently with treatment, as described herein, can be used in patients receiving such a combination treatment including an IFN-γ inhibitor plus an existing treatment for sarcoidosis.

[0101] In another embodiment, a patient suffering from HLH can be concurrently treated with a drug used for HLH therapy plus an IFN-γ inhibitor such as an anti-huIFN-γ antibody comprising SEQ ID NO:6 and SEQ ID NO:8 and/or comprising a light chain CDR1 comprising SEQ ID NO:38, a light chain CDR2 comprising SEQ ID NO:41, a light chain CDR3 comprising SEQ ID NO:43, a heavy chain CDR1 comprising SEQ ID NO:34, a heavy chain CDR2 comprising SEQ ID NO:35, and a heavy chain CDR3 comprising SEQ ID NO:36. Therapies for HLH include corticosteroids, intravenous immunoglobulin, IL-1 inhibiting agents such as anakinra, VP-16, etoposide, cyclosporine A, dexamethasone, various other chemotherapeutics, bone marrow transplant or stem cell transplant, and antiviral and/or antibacterial agents. Any one or more of these therapies can be combined with an anti-huIFN-γ treatment. Further, methods of patient stratification and biomarker monitoring concurrently with treatment, as described herein, can be used in patients receiving such a combination treatment including an IFN-γ inhibitor plus an existing treatment for HLH.

Methods of Administration

[0102] The IFN-γ inhibitors and the other disease treatments described herein can be administered by any feasible method. Therapeutics that comprise a protein will ordinarily be administered by injection since oral administration, in the absence of some special formulation or circumstance, would lead to hydrolysis of the protein in the acid environment of the stomach. Subcutaneous, intramuscular, intravenous, intraarterial, intralesional, or peritoneal injection are possible routes of administration. Topical administration is also possible, especially for diseases involving the skin. Alternatively, IFN-γ inhibitors, and/or other therapeutics comprising a protein, can be administered through contact with a mucus membrane, for example by intra-nasal, sublingual, vaginal, or rectal administration or as an inhalant. Therapeutics that are small molecules can be administered orally, although the routes of administration mentioned above are also possible.

[0103] Having described the invention in general terms above, the following examples are offered by way of illustration and not limitation.

EXAMPLES

Example 1

Determining the Identity of Genes Whose Expression in Blood is Modulated by IFN-γ Ex Vivo

[0104] To define a group of genes regulated by IFN-γ, blood from healthy volunteers was collected into sodium heparin tubes, and then incubated at 37° C., 5% CO₂ with or without 294 μM recombinant human IFN-γ for 0, 24, or 48 hours. After incubation, the blood was added to PAXGENE® whole blood tubes (Becton Dickenson Catalog #762165) and processed for RNA purification.

[0105] Total RNA was isolated from the PAXGENE® whole blood tubes using the PAXGENE® RNA Kit (Qiagen Catalog #762164) on the QIACUBE® automated sample prep system. Samples were labeled using the AGILENT® Low RNA Input Linear Amplification Kit PLUS, Two-Color (Agilent Catalog #5188-5340) per manufacturer's instructions. Briefly, double-stranded cDNA was reverse transcribed from about 300 nanograms of total RNA and acted as template for T7 RNA polymerase in an in vitro transcription reaction in which the target material was simultaneously amplified and labeled with cyanine 3- or cyanine 5-CTPs. The resulting fluorescent complementary RNA was hybridized to AGILENT® human whole genome 4×44K (Cat # G4112F) oligonucleotide microarrays per manufacturer's instructions.

[0106] Extracted feature intensities for each channel on each array were processed separately by subtracting the lower 0.1^th percentile from all intensities and then taking the log base 2. The transformed intensities were mapped using a non-linear function to ensure the distribution of the intensities were comparable between arrays and channels. Arrays were hybridized using a loop-design that allowed estimation and removal of technical bias when averaging the technical repeats.

[0107] Samples were processed in batches that roughly corresponded to samples from individual cohorts but with a small number of samples repeated between batches to allow estimation and removal of batch effects. Finally, replicates of any identical sequences on the array were averaged to produce a value we called gene intensities.

[0108] In additional to the above processing, a pre-filtering step was applied. Reporters with low levels of expression were removed if 90% of the values fell below the limit of detection, defined as 1.96 standard deviations above mean background. Background was determined by a set of sequences on the array that are specifically designed to not hybridize with human sequences. Reporters with small dispersion are unlikely to be meaningfully changed, and so, to reduce noise, these were removed. They were defined as those where the fold change between the 5^th and 95^th percentile was less than 1.5.

[0109] Statistical analysis of the data to identify genes regulated ex vivo by IFN-γ was performed using a fixed-effects regression model containing factors for donor, time, treatment and all pair wise interactions terms. The treatment effect was similar at the two post-treatment times of 24 and 48 hours (data not shown), so these data were considered a single group to display the treatment effect. The significance threshold was defined at a false discovery rate of 5% and a fold change of 1.72. See Storey, J. D. 2002. A direct approach to false discovery rates. J. R. Statist. Soc. B. 64: 479-498, the relevant portions of which are incorporated herein by reference. The fold change was selected because we expected about 90% power to detect this fold change at a significance level of 0.001 assuming a standard deviation of 0.38. The results from this analysis are shown in FIG. 1.

[0110] In FIG. 1 each dot represents the average fold change in expression of an individual gene at the RNA level in blood from a healthy volunteer stimulated ex vivo with IFN-γ as compared to the same blood pre-stimulation. The x-axis reflects the fold change, and the y-axis represents the p-value of the difference in gene expression in post-stimulation blood as compared to pre-stimulation blood. Generally, a p-value of 0.05 or less would be considered to indicate statistical significance. The circled dots in FIG. 1 correspond to the twenty genes that showed the greatest fold change in expression upon stimulation with IFN-γ, where the change had a nominal significance level of 0.001 or less. These data show that a large number of genes are up- and down-regulated by IFN-γ. Table 1 below lists genes that were found to be up- or down-regulated by ex vivo stimulation with IFN-γ. The criteria applied to select these genes from among the tens of thousands of genes on the array were a false discovery rate of <0.001, powered at 90% to detect an alpha of 0.001.

TABLE-US-00001 TABLE 1 Genes whose expression is modulated by IFN-γ Sequence Listing number of NCBI Accession Direction of AGILENT ® Probe AGILENT ® Probe Symbol of Number of Gene modulation Name Sequence Gene Sequence Gene Name by IFN-γ A_23_P112026 SEQ ID NO: 350 INDO NM_002164 indoleamine-pyrrole 2,3 dioxygenase up A_23_P161428 SEQ ID NO: 72 ANKRD22 NM_144590 ankyrin repeat domain 22 up A_23_P18452 SEQ ID NO: 109 CXCL9 NM_002416 chemokine (C--X--C motif) ligand 9 up A_23_P7827 SEQ ID NO: 83 RP1- NM_001010919 hypothetical protein LOC441168 up 93H18.5 A_24_P28722 SEQ ID NO: 351 RSAD2 NM_080657 radical S-adenosyl methionine domain up containing 2 A_23_P150457 SEQ ID NO: 352 XLKD1 NM_006691 extracellular link domain containing 1 down A_24_P165864 SEQ ID NO: 300 P2RY14 NM_014879 purinergic receptor P2Y, G-protein coupled, up 14 A_23_P74290 SEQ ID NO: 79 GBP5 NM_052942 guanylate binding protein 5 up A_23_P63390 SEQ ID NO: 73 FCGR1B NM_001017986 Fc fragment of IgG, high affinity Ib, receptor up (CD64) A_24_P245379 SEQ ID NO: 353 SERPINB2 NM_002575 serpin peptidase inhibitor, clade B down (ovalbumin), member 2 A_24_P316965 SEQ ID NO: 354 RSAD2 NM_080657 radical S-adenosyl methionine domain up containing 2 A_24_P561165 SEQ ID NO: 322 A_24_P561165 A_24_P561165 Unknown up A_23_P121657 SEQ ID NO: 355 HS3ST1 NM_005114 heparan sulfate (glucosamine) 3-O- down sulfotransferase 1 A_23_P203882 SEQ ID NO: 356 MMP19 NM_002429 matrix metallopeptidase 19 down A_24_P303091 SEQ ID NO: 311 CXCL10 NM_001565 chemokine (C--X--C motif) ligand 10 (IP-10) up A_32_P107372 SEQ ID NO: 76 GBP1 NM_002053 guanylate binding protein 1, interferon- up inducible, 67 kDa A_23_P62890 SEQ ID NO: 74 GBP1 NM_002053 guanylate binding protein 1, interferon- up inducible, 67 kDa A_23_P256487 SEQ ID NO: 78 CD274 ENST00000381577 CD274 molecule up A_23_P65651 SEQ ID NO: 278 WARS NM_004184 tryptophanyl-tRNA synthetase up A_23_P18604 SEQ ID NO: 232 LAP3 NM_015907 leucine aminopeptidase 3 up A_24_P12690 SEQ ID NO: 357 INDOL1 AK128691 indoleamine-pyrrole 2,3 dioxygenase-like 1 up A_23_P48513 SEQ ID NO: 269 IFI27 NM_005532 interferon, alpha-inducible protein 27 up A_24_P478940 SEQ ID NO: 358 A_24_P478940 THC2668815 Low quality annotation - Q4TBH3_TETNG down (Q4TBH3) Chromosome 13 SCAF7124, whole genome shotgun sequence, partial (3%) [THC2668815] A_23_P103496 SEQ ID NO: 196 GBP4 NM_052941 guanylate binding protein 4 up A_23_P42353 SEQ ID NO: 77 ETV7 NM_016135 ets variant gene 7 (TEL2 oncogene) up A_23_P62115 SEQ ID NO: 359 TIMP1 NM_003254 TIMP metallopeptidase inhibitor 1 down A_24_P270460 SEQ ID NO: 309 IFI27 NM_005532 interferon, alpha-inducible protein 27 up A_23_P74609 SEQ ID NO: 360 G0S2 NM_015714 G0/G1switch 2 up A_23_P39840 SEQ ID NO: 163 VAMP5 NM_006634 vesicle-associated membrane protein 5 up (myobrevin) A_23_P27306 SEQ ID NO: 361 COLEC12 NM_030781 collectin sub-family member 12 down A_24_P45446 SEQ ID NO: 108 GBP4 NM_052941 guanylate binding protein 4 up A_23_P76386 SEQ ID NO: 362 SLC6A12 NM_003044 solute carrier family 6 (neurotransmitter up transporter, betaine/GABA), member 12 A_23_P121253 SEQ ID NO: 110 TNFSF10 NM_003810 tumor necrosis factor (ligand) superfamily, up member 10 A_23_P91390 SEQ ID NO: 363 THBD NM_000361 thrombomodulin down A_24_P167642 SEQ ID NO: 301 GCH1 NM_000161 GTP cyclohydrolase 1 (dopa-responsive up dystonia) A_23_P338479 SEQ ID NO: 75 CD274 NM_014143 CD274 molecule up A_23_P21485 SEQ ID NO: 364 FLJ20701 NM_017933 hypothetical protein FLJ20701 down A_23_P33723 SEQ ID NO: 365 CD163 NM_004244 CD163 molecule down A_23_P420196 SEQ ID NO: 366 SOCS1 NM_003745 suppressor of cytokine signaling 1 up A_23_P165624 SEQ ID NO: 226 TNFAIP6 NM_007115 tumor necrosis factor, alpha-induced protein 6 up A_24_P912985 SEQ ID NO: 326 A_24_P912985 A_24_P912985 Unknown up A_24_P15702 SEQ ID NO: 298 LOC389386 XR_017251 similar to leucine aminopeptidase 3 up A_23_P156687 SEQ ID NO: 221 CFB NM_001710 complement factor B up A_23_P137366 SEQ ID NO: 367 SEQ ID NM_000491 complement component 1, q subcomponent, up NO: 100C1QB B chain A_23_P139123 SEQ ID NO: 210 SERPING1 NM_000062 serpin peptidase inhibitor, clade G (C1 up inhibitor), member 1, (angioedema, hereditary) A_23_P384355 SEQ ID NO: 368 A_23_P384355 BG547557 Low quality annotation - BG547557 up 602575410F1 NIH_MGC_77 Homo sapiens cDNA clone IMAGE: 4703546 5', mRNA sequence [BG547557] A_23_P55356 SEQ ID NO: 369 VMO1 NM_182566 vitelline membrane outer layer 1 homolog down (chicken) A_23_P32500 SEQ ID NO: 370 STAB1 NM_015136 stabilin 1 down A_32_P171061 SEQ ID NO: 371 ASCL2 NM_005170 achaete-scute complex homolog 2 up (Drosophila) A_23_P210763 SEQ ID NO: 238 JAG1 NM_000214 jagged 1 (Alagille syndrome) up A_24_P48204 SEQ ID NO: 320 SECTM1 NM_003004 secreted and transmembrane 1 up A_23_P354387 SEQ ID NO: 257 FER1L3 NM_013451 fer-1-like 3, myoferlin (C. elegans) up A_24_P353638 SEQ ID NO: 372 SLAMF7 NM_021181 SLAM family member 7 up A_23_P53891 SEQ ID NO: 270 KLF5 NM_001730 Kruppel-like factor 5 (intestinal) up A_32_P44394 SEQ ID NO: 87 AIM2 NM_004833 absent in melanoma 2 up A_23_P153185 SEQ ID NO: 373 SERPINB2 ENST00000299502 serpin peptidase inhibitor, clade B down (ovalbumin), member 2 A_23_P200138 SEQ ID NO: 374 SLAMF8 NM_020125 SLAM family member 8 up A_23_P207456 SEQ ID NO: 375 CCL8 NM_005623 chemokine (C-C motif) ligand 8 up A_24_P380734 SEQ ID NO: 376 SDC2 NM_002998 syndecan 2 (heparan sulfate proteoglycan 1, down cell surface-associated, fibroglycan) A_23_P370682 SEQ ID NO: 80 BATF2 NM_138456 basic leucine zipper transcription factor, up ATF-like 2 A_23_P329261 SEQ ID NO: 251 KCNJ2 NM_000891 potassium inwardly-rectifying channel, up subfamily J, member 2 A_24_P383523 SEQ ID NO: 317 SAMD4A NM_015589 sterile alpha motif domain containing 4A up A_23_P167328 SEQ ID NO: 377 CD38 NM_001775 CD38 molecule up A_23_P209625 SEQ ID NO: 236 CYP1B1 NM_000104 cytochrome P450, family 1, subfamily B, down polypeptide 1 A_23_P335661 SEQ ID NO: 253 SAMD4A AB028976 sterile alpha motif domain containing 4A up A_23_P159325 SEQ ID NO: 378 ANGPTL4 NM_139314 angiopoietin-like 4 down A_23_P2831 SEQ ID NO: 379 EDNRB NM_003991 endothelin receptor type B down A_23_P35412 SEQ ID NO: 256 IFIT3 NM_001549 interferon-induced protein with up tetratricopeptide repeats 3 A_23_P29773 SEQ ID NO: 380 LAMP3 NM_014398 lysosomal-associated membrane protein 3 up A_23_P101992 SEQ ID NO: 381 MARCO NM_006770 macrophage receptor with collagenous down structure A_23_P105794 SEQ ID NO: 197 EPSTI1 NM_033255 epithelial stromal interaction 1 (breast) up A_23_P207507 SEQ ID NO: 382 ABCC3 NM_003786 ATP-binding cassette, sub-family C down (CFTR/MRP), member 3 A_23_P45871 SEQ ID NO: 383 IFI44L NM_006820 interferon-induced protein 44-like up A_23_P75430 SEQ ID NO: 285 C11ORF75 NM_020179 chromosome 11 open reading frame 75 up A_24_P350686 SEQ ID NO: 106 TIFA NM_052864 TRAF-interacting protein with a forkhead- up associated domain A_23_P57709 SEQ ID NO: 384 PCOLCE2 NM_013363 procollagen C-endopeptidase enhancer 2 down A_23_P70095 SEQ ID NO: 385 CD74 NM_001025158 CD74 molecule, major histocompatibility up complex, class II invariant chain A_32_P56001 SEQ ID NO: 386 CD93 NM_012072 CD93 molecule down A_24_P943205 SEQ ID NO: 332 EPSTI1 ENST00000313624 epithelial stromal interaction 1 (breast) up A_24_P305067 SEQ ID NO: 387 HOXB4 NM_024015 homeobox B4 up A_23_P347541 SEQ ID NO: 99 GRIN3A NM_133445 glutamate receptor, ionotropic, N-methyl-D- up aspartate 3A A_32_P162183 SEQ ID NO: 338 C2 NM_000063 complement component 2 up A_23_P30913 SEQ ID NO: 388 HLA-DPA1 NM_033554 major histocompatibility complex, class II, DP up alpha 1 A_23_P211445 SEQ ID NO: 240 LIMK2 NM_016733 LIM domain kinase 2 up A_23_P207905 SEQ ID NO: 389 SECTM1 NM_003004 secreted and transmembrane 1 up A_23_P128050 SEQ ID NO: 390 BCL2L14 NM_030766 BCL2-like 14 (apoptosis facilitator) up A_23_P41765 SEQ ID NO: 261 IRF1 NM_002198 interferon regulatory factor 1 up A_24_P245815 SEQ ID NO: 306 ASPHD2 AK097157 aspartate beta-hydroxylase domain up containing 2 A_23_P86682 SEQ ID NO: 391 FER1L3 NM_013451 fer-1-like 3, myoferlin (C. elegans) up A_23_P58390 SEQ ID NO: 392 C4ORF32 NM_152400 chromosome 4 open reading frame 32 up A_23_P56630 SEQ ID NO: 89 STAT1 NM_007315 signal transducer and activator of up transcription 1, 91 kDa A_23_P25354 SEQ ID NO: 393 P2RX7 NM_002562 purinergic receptor P2X, ligand-gated ion up channel, 7 A_23_P358709 SEQ ID NO: 394 AHRR NM_020731 aryl-hydrocarbon receptor repressor down A_23_P207003 SEQ ID NO: 395 40790 NM_004574 septin 4 up A_24_P170136 SEQ ID NO: 396 A_24_P170136 ENST00000383097 Low quality annotation - similar to HLA class up II histocompatibility antigen, DP alpha chain precursor (HLA-SB alpha chain) (MHC class II DP3-alpha) (DP(W3)) (DP(W4)) (LOC642043), mRNA [Source: RefSeq_dna; Acc: XR_018078] [ENST00000383097] A_23_P144959 SEQ ID NO: 397 CSPG2 NM_004385 chondroitin sulfate proteoglycan 2 (versican) down A_23_P163079 SEQ ID NO: 225 GCH1 NM_000161 GTP cyclohydrolase 1 (dopa-responsive up dystonia) A_23_P134176 SEQ ID NO: 398 SOD2 NM_001024465 superoxide dismutase 2, mitochondrial up A_24_P852756 SEQ ID NO: 399 HLA-DQA2 NM_020056 major histocompatibility complex, class II, up DQ alpha 2 A_24_P165423 SEQ ID NO: 400 RBP7 NM_052960 retinol binding protein 7, cellular down A_32_P9543 SEQ ID NO: 348 APOBEC3A NM_145699 apolipoprotein B mRNA editing enzyme, up catalytic polypeptide-like 3A A_32_P15169 SEQ ID NO: 336 A_32_P15169 A_32_P15169 Unknown up A_24_P7040 SEQ ID NO: 401 LOC123862 XR_017225 similar to Interferon-induced transmembrane up protein 3 (Interferon-inducible protein 1-8U) A_24_P378019 SEQ ID NO: 402 IRF7 NM_004031 interferon regulatory factor 7 up A_23_P59005 SEQ ID NO: 113 TAP1 NM_000593 transporter 1, ATP-binding cassette, sub- up family B (MDR/TAP) A_23_P331928 SEQ ID NO: 403 CD109 NM_133493 CD109 molecule down A_23_P218928 SEQ ID NO: 243 C4ORF18 NM_016613 chromosome 4 open reading frame 18 down A_23_P8513 SEQ ID NO: 290 SNX10 NM_013322 sorting nexin 10 up A_24_P54863 SEQ ID NO: 142 C4ORF32 NM_152400 chromosome 4 open reading frame 32 up A_23_P17837 SEQ ID NO: 231 APOL1 NM_145343 apolipoprotein L, 1 up A_23_P65427 SEQ ID NO: 277 PSME2 NM_002818 proteasome (prosome, macropain)

activator up subunit 2 (PA28 beta) A_32_P30004 SEQ ID NO: 342 A_32_P30004 AF086044 Low quality annotation - Homo sapiens full up length insert cDNA clone YX74D05. [AF086044] A_23_P421423 SEQ ID NO: 263 TNFAIP2 NM_006291 tumor necrosis factor, alpha-induced protein 2 up A_23_P14174 SEQ ID NO: 213 TNFSF13B NM_006573 tumor necrosis factor (ligand) superfamily, up member 13b A_23_P29237 SEQ ID NO: 404 APOL3 NM_145641 apolipoprotein L, 3 up A_23_P64721 SEQ ID NO: 276 GPR109B NM_006018 G protein-coupled receptor 109B up A_23_P166633 SEQ ID NO: 405 ITGB5 NM_002213 integrin, beta 5 down A_24_P98109 SEQ ID NO: 334 SNX10 NM_013322 sorting nexin 10 up A_24_P243528 SEQ ID NO: 406 HLA-DPA1 NM_033554 major histocompatibility complex, class II, DP up alpha 1 A_23_P83098 SEQ ID NO: 289 ALDH1A1 NM_000689 aldehyde dehydrogenase 1 family, member up A1 A_23_P166797 SEQ ID NO: 228 RTP4 NM_022147 receptor (chemosensory) transporter protein 4 up A_23_P214821 SEQ ID NO: 407 EDN1 NM_001955 endothelin 1 up A_23_P123608 SEQ ID NO: 107 JAK2 NM_004972 Janus kinase 2 (a protein tyrosine kinase) up A_23_P11543 SEQ ID NO: 408 FUCA1 NM_000147 fucosidase, alpha-L-1, tissue down A_23_P259901 SEQ ID NO: 409 TKTL1 NM_012253 transketolase-like 1 down A_23_P145874 SEQ ID NO: 215 SAMD9L NM_152703 sterile alpha motif domain containing 9-like up A_23_P217269 SEQ ID NO: 410 VSIG4 NM_007268 V-set and immunoglobulin domain containing 4 down A_23_P33384 SEQ ID NO: 411 CIITA NM_000246 class II, major histocompatibility complex, up transactivator A_23_P85783 SEQ ID NO: 412 PHGDH NM_006623 phosphoglycerate dehydrogenase up A_32_P166272 SEQ ID NO: 96 A_32_P166272 THC2650457 Low quality annotation - ALU6_HUMAN up (P39193) Alu subfamily SP sequence contamination warning entry, partial (12%) [THC2650457] A_23_P150768 SEQ ID NO: 413 SLCO2B1 NM_007256 solute carrier organic anion transporter down family, member 2B1 A_24_P319113 SEQ ID NO: 414 P2RX7 NM_002562 purinergic receptor P2X, ligand-gated ion up channel, 7 A_23_P206212 SEQ ID NO: 415 THBS1 NM_003246 thrombospondin 1 down A_24_P239731 SEQ ID NO: 416 B4GALT5 NM_004776 UDP-Gal:betaGlcNAc beta 1,4- up galactosyltransferase, polypeptide 5 A_24_P98210 SEQ ID NO: 335 TFEC NM_012252 transcription factor EC up A_32_P87697 SEQ ID NO: 417 HLA-DRA NM_019111 major histocompatibility complex, class II, up DR alpha A_23_P417383 SEQ ID NO: 418 SASP NM_152792 skin aspartic protease up A_23_P45099 SEQ ID NO: 419 HLA-DRB5 NM_002125 major histocompatibility complex, class II, up DR beta 5 A_23_P3014 SEQ ID NO: 420 RNASE6 NM_005615 ribonuclease, RNase A family, k6 down A_24_P868905 SEQ ID NO: 421 LOC391020 XR_018907 similar to Interferon-induced transmembrane up protein 3 (Interferon-inducible protein 1-8U) A_24_P557479 SEQ ID NO: 422 BIRC4BP NM_017523 XIAP associated factor-1 up A_24_P196827 SEQ ID NO: 423 HLA-DQA1 NM_002122 major histocompatibility complex, class II, up DQ alpha 1 A_24_P365469 SEQ ID NO: 424 B4GALT5 NM_004776 UDP-Gal:betaGlcNAc beta 1,4- up galactosyltransferase, polypeptide 5 A_23_P72737 SEQ ID NO: 283 IFITM1 NM_003641 interferon induced transmembrane protein 1 up (9-27) A_23_P8108 SEQ ID NO: 425 HLA-DQB1 NM_002123 major histocompatibility complex, class II, up DQ beta 1 A_24_P322353 SEQ ID NO: 91 PSTPIP2 NM_024430 proline-serine-threonine phosphatase up interacting protein 2 A_23_P209995 SEQ ID NO: 426 IL1RN NM_173842 interleukin 1 receptor antagonist up A_23_P23074 SEQ ID NO: 427 IFI44 NM_006417 interferon-induced protein 44 up A_23_P73837 SEQ ID NO: 428 TLR8 NM_016610 toll-like receptor 8 up A_23_P160720 SEQ ID NO: 224 SNFT NM_018664 Jun dimerization protein p21SNFT up A_32_P184394 SEQ ID NO: 339 TFEC NM_012252 transcription factor EC up A_23_P87545 SEQ ID NO: 429 IFITM3 NM_021034 interferon induced transmembrane protein 3 up (1-8U) A_23_P48414 SEQ ID NO: 430 CCNA1 NM_003914 cyclin A1 up A_23_P258769 SEQ ID NO: 431 HLA-DPB1 NM_002121 major histocompatibility complex, class II, DP up beta 1 A_23_P96556 SEQ ID NO: 94 GK NM_203391 glycerol kinase up A_23_P63209 SEQ ID NO: 432 HSD11B1 NM_181755 hydroxysteroid (11-beta) dehydrogenase 1 up A_23_P31006 SEQ ID NO: 433 HLA-DRB5 NM_002125 major histocompatibility complex, class II, up DR beta 5 A_23_P120316 SEQ ID NO: 434 MTHFD2 NM_001040409 methylenetetrahydrofolate dehydrogenase up (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase A_23_P63896 SEQ ID NO: 92 FAS NM_000043 Fas (TNF receptor superfamily, member 6) up A_24_P845223 SEQ ID NO: 435 A_24_P845223 M27126 Low quality annotation - Human lymphocyte up antigen (DRw8) mRNA. [M27126] A_23_P81898 SEQ ID NO: 288 UBD NM_006398 ubiquitin D up A_23_P153320 SEQ ID NO: 217 ICAM1 NM_000201 intercellular adhesion molecule 1 (CD54), up human rhinovirus receptor A_23_P213102 SEQ ID NO: 436 PALLD NM_016081 palladin, cytoskeletal associated protein down A_23_P819 SEQ ID NO: 437 ISG15 NM_005101 ISG15 ubiquitin-like modifier up A_23_P202029 SEQ ID NO: 438 SPFH1 NM_006459 SPFH domain family, member 1 up A_23_P170719 SEQ ID NO: 439 A_23_P170719 A_23_P170719 Unknown down A_24_P367576 SEQ ID NO: 440 RCBTB2 AK125170 regulator of chromosome condensation down (RCC1) and BTB (POZ) domain containing protein 2 A_23_P69109 SEQ ID NO: 281 PLSCR1 NM_021105 phospholipid scramblase 1 up A_23_P19510 SEQ ID NO: 441 HLA-DQB2 NM_182549 major histocompatibility complex, class II, up DQ beta 2 A_24_P100387 SEQ ID NO: 85 GK NM_203391 glycerol kinase up A_23_P4283 SEQ ID NO: 442 BIRC4BP NM_017523 XIAP associated factor-1 up A_24_P288836 SEQ ID NO: 443 HLA-DPB2 NR_001435 major histocompatibility complex, class II, DP up beta 2 (pseudogene) A_24_P66027 SEQ ID NO: 324 APOBEC3B NM_004900 apolipoprotein B mRNA editing enzyme, up catalytic polypeptide-like 3B A_23_P157136 SEQ ID NO: 444 SCIN NM_033128 scinderin up A_24_P274270 SEQ ID NO: 88 STAT1 NM_139266 signal transducer and activator of up transcription 1, 91 kDa A_23_P306148 SEQ ID NO: 445 PML NM_002675 promyelocytic leukemia up A_24_P370472 SEQ ID NO: 446 HLA-DRB4 NM_021983 major histocompatibility complex, class II, up DR beta 4 A_23_P218549 SEQ ID NO: 447 EMR3 NM_032571 egf-like module containing, mucin-like, down hormone receptor-like 3 A_24_P246626 SEQ ID NO: 448 A_24_P246626 ENST00000308384 Low quality annotation - similar to HLA class up II histocompatibility antigen, DP alpha chain precursor (HLA-SB alpha chain) (MHC class II DP3-alpha) (DP(W3)) (DP(W4)) (LOC642074), mRNA [Source: RefSeq_dna; Acc: XR_018081] [ENST00000308384] A_23_P358944 SEQ ID NO: 449 PML NM_033244 promyelocytic leukemia up A_23_P69383 SEQ ID NO: 101 PARP9 NM_031458 poly (ADP-ribose) polymerase family, up member 9 A_24_P343929 SEQ ID NO: 450 OAS2 NM_016817 2'-5'-oligoadenylate synthetase 2, 69/71 kDa up A_24_P354800 SEQ ID NO: 451 HLA-DOA NM_002119 major histocompatibility complex, class II, up DO alpha A_32_P209960 SEQ ID NO: 452 CIITA NM_000246 class II, major histocompatibility complex, up transactivator A_24_P118892 SEQ ID NO: 453 IRF7 NM_004029 interferon regulatory factor 7 up A_24_P222655 SEQ ID NO: 305 C1QA NM_015991 complement component 1, q subcomponent, up A chain A_24_P119745 SEQ ID NO: 454 FN1 NM_212482 fibronectin 1 down A_23_P34835 SEQ ID NO: 455 LMNA NM_005572 lamin A/C down A_24_P578437 SEQ ID NO: 456 A_24_P578437 BE926212 Low quality annotation - BE926212 RC5- up BN0193-310800-034-A04 BN0193 Homo sapiens cDNA, mRNA sequence [BE926212] A_23_P47955 SEQ ID NO: 457 OAS3 NM_006187 2'-5'-oligoadenylate synthetase 3, 100 kDa up A_24_P169013 SEQ ID NO: 458 HLA-DRB6 NR_001298 major histocompatibility complex, class II, up DR beta 6 (pseudogene) A_23_P76450 SEQ ID NO: 459 PHLDA1 NM_007350 pleckstrin homology-like domain, family A, down member 1 A_23_P328740 SEQ ID NO: 460 LINCR BC012317 likely ortholog of mouse lung-inducible up Neutralized-related C3HC4 RING domain protein A_23_P380857 SEQ ID NO: 259 APOL4 NM_030643 apolipoprotein L, 4 up A_24_P299318 SEQ ID NO: 461 FAM101B NM_182705 family with sequence similarity 101, member B down A_32_P13337 SEQ ID NO: 462 A_32_P13337 THC2645080 Unknown down A_23_P4773 SEQ ID NO: 463 LILRB5 NM_006840 leukocyte immunoglobulin-like receptor, down subfamily B (with TM and ITIM domains), member 5 A_32_P108254 SEQ ID NO: 464 FAM20A NM_017565 family with sequence similarity 20, member A up A_24_P343233 SEQ ID NO: 465 HLA-DRB1 NM_002124 major histocompatibility complex, class II, up DR beta 1 A_32_P351968 SEQ ID NO: 466 HLA-DMB NM_002118 major histocompatibility complex, class II, up DM beta A_23_P145336 SEQ ID NO: 467 HLA-DRB3 BC106057 major histocompatibility complex, class II, up DR beta 3 A_24_P325520 SEQ ID NO: 468 SORT1 NM_002959 sortilin 1 up A_32_P75264 SEQ ID NO: 469 TMEM26 NM_178505 transmembrane protein 26 down A_23_P39364 SEQ ID NO: 470 HOMER3 NM_004838 homer homolog 3 (Drosophila) down A_24_P402222 SEQ ID NO: 471 HLA-DRB3 NM_022555 major histocompatibility complex, class II, up DR beta 3 A_24_P353300 SEQ ID NO: 472 LIMK2 NM_001031801 LIM domain kinase 2 up A_32_P167592 SEQ ID NO: 473 A_32_P167592 ENST00000339867 Low quality annotation - similar to Interferon- up induced transmembrane protein 3 (Interferon-inducible protein 1-8U) (LOC650205), mRNA [Source: RefSeq_dna; Acc: XR_018421] [ENST00000339867] A_24_P100382 SEQ ID NO: 474 GK NM_203391 glycerol kinase up A_23_P255444 SEQ ID NO: 100 DAPP1 NM_014395 dual adaptor of phosphotyrosine and 3- up phosphoinositides A_23_P359245 SEQ ID NO: 475 MET NM_000245 met proto-oncogene (hepatocyte growth down factor receptor) A_32_P78121 SEQ ID NO: 476 A_32_P78121 CD743044 Low quality annotation - CD743044 UI-H- up FT1-bjx-e-03-0-UI.s1 NCI_CGAP_FT1 Homo sapiens cDNA clone UI-H-FT1-bjx-e-03-0-UI 3', mRNA sequence [CD743044] A_23_P252106 SEQ ID NO: 166 RIPK2 NM_003821 receptor-interacting serine-threonine kinase 2 up A_23_P120883 SEQ ID NO: 477 HMOX1 NM_002133 heme oxygenase (decycling) 1 down A_23_P97064 SEQ ID NO: 296 FBXO6 NM_018438 F-box protein 6 up A_24_P416997 SEQ ID NO: 478 APOL3 NM_145641 apolipoprotein L, 3 up A_23_P68155 SEQ ID NO: 279 IFIH1 NM_022168 interferon induced with helicase C domain 1 up A_23_P149476 SEQ ID NO: 216 EFCAB2 NM_032328 EF-hand calcium binding domain 2 up A_24_P172481 SEQ ID NO: 302 TRIM22 NM_006074 tripartite motif-containing 22 up

A_23_P51487 SEQ ID NO: 93 GBP3 NM_018284 guanylate binding protein 3 up A_23_P30900 SEQ ID NO: 479 HLA-DQA1 BC008585 major histocompatibility complex, class II, up DQ alpha 1 A_24_P323148 SEQ ID NO: 313 LYPD5 NM_182573 LY6/PLAUR domain containing 5 up A_24_P928052 SEQ ID NO: 327 NRP1 NM_003873 neuropilin 1 down A_24_P166443 SEQ ID NO: 480 HLA-DPB1 NM_002121 major histocompatibility complex, class II, DP up beta 1 A_24_P16124 SEQ ID NO: 481 IFITM4P NR_001590 interferon induced transmembrane protein 4 up pseudogene A_23_P136683 SEQ ID NO: 482 HLA-DQB1 M20432 major histocompatibility complex, class II, up DQ beta 1 A_24_P278126 SEQ ID NO: 310 NBN NM_001024688 nibrin up A_23_P203498 SEQ ID NO: 233 TRIM22 NM_006074 tripartite motif-containing 22 up A_23_P125278 SEQ ID NO: 202 CXCL11 NM_005409 chemokine (C--X--C motif) ligand 11 up A_23_P79518 SEQ ID NO: 287 IL1B NM_000576 interleukin 1, beta down A_24_P923271 SEQ ID NO: 483 A_24_P923271 M15073 Low quality annotation - Human MHC class II up HLA-DR-beta-1 chain mRNA (DR4, Dw14), 3' end, clone BIN40c30. [M15073] A_23_P209678 SEQ ID NO: 237 PLEK NM_002664 pleckstrin up A_23_P258493 SEQ ID NO: 247 LMNB1 NM_005573 lamin B1 up A_23_P146943 SEQ ID NO: 484 ATP1B1 NM_001677 ATPase, Na+/K+ transporting, beta 1 up polypeptide A_23_P208119 SEQ ID NO: 84 PSTPIP2 NM_024430 proline-serine-threonine phosphatase up interacting protein 2 A_24_P915692 SEQ ID NO: 485 PHLDA1 NM_007350 pleckstrin homology-like domain, family A, down member 1 A_23_P259561 SEQ ID NO: 486 A_23_P259561 THC2632039 Low quality annotation - Q8SPE4_9PRIM up (Q8SPE4) Major histocompatibility complex (Fragment), partial (85%) [THC2632039] A_24_P361896 SEQ ID NO: 487 MT2A NM_005953 metallothionein 2A up A_23_P106844 SEQ ID NO: 488 MT2A NM_005953 metallothionein 2A up A_24_P370702 SEQ ID NO: 126 GBP3 NM_018284 guanylate binding protein 3 up A_23_P132388 SEQ ID NO: 205 SCO2 NM_005138 SCO cytochrome oxidase deficient homolog up 2 (yeast) A_23_P25155 SEQ ID NO: 489 GPR84 NM_020370 G protein-coupled receptor 84 up A_23_P64343 SEQ ID NO: 275 TIMM10 NM_012456 translocase of inner mitochondrial membrane up 10 homolog (yeast) A_24_P97405 SEQ ID NO: 490 CCRL2 NM_003965 chemokine (C-C motif) receptor-like 2 up A_24_P190472 SEQ ID NO: 491 SLPI NM_003064 secretory leukocyte peptidase inhibitor up A_23_P207058 SEQ ID NO: 492 SOCS3 NM_003955 suppressor of cytokine signaling 3 up A_24_P52168 SEQ ID NO: 493 A_24_P52168 A_24_P52168 Unknown up A_23_P29953 SEQ ID NO: 248 IL15 NM_172174 interleukin 15 up A_32_P72351 SEQ ID NO: 494 A_32_P72351 AK026140 Low quality annotation - Homo sapiens down cDNA: FLJ22487 fis, clone HRC10931. [AK026140] A_23_P35912 SEQ ID NO: 129 CASP4 NM_033306 caspase 4, apoptosis-related cysteine up peptidase A_23_P252413 SEQ ID NO: 495 MT2A ENST00000245185 metallothionein 2A up A_32_P118013 SEQ ID NO: 496 A_32_P118013 THC2657593 Low quality annotation - ALU1_HUMAN up (P39188) Alu subfamily J sequence contamination warning entry, partial (7%) [THC2657593] A_23_P201587 SEQ ID NO: 497 SORT1 NM_002959 sortilin 1 up A_23_P347040 SEQ ID NO: 255 DTX3L NM_138287 deltex 3-like (Drosophila) up A_23_P47304 SEQ ID NO: 267 CASP5 NM_004347 caspase 5, apoptosis-related cysteine up peptidase A_23_P133916 SEQ ID NO: 208 C2 NM_000063 complement component 2 up A_23_P94412 SEQ ID NO: 295 PDCD1LG2 NM_025239 programmed cell death 1 ligand 2 up A_24_P662177 SEQ ID NO: 498 A_24_P662177 THC2666469 Unknown up A_23_P85693 SEQ ID NO: 90 GBP2 NM_004120 guanylate binding protein 2, interferon- up inducible A_24_P48014 SEQ ID NO: 499 SOCS1 NM_003745 suppressor of cytokine signaling 1 up A_32_P56249 SEQ ID NO: 500 A_32_P56249 THC2670291 Low quality annotation - UBP30_HUMAN up (Q70CQ3) Ubiquitin carboxyl-terminal hydrolase 30 (Ubiquitin thioesterase 30) (Ubiquitin-specific-processing protease 30) (Deubiquitinating enzyme 30), partial (5%) [THC2670291] A_32_P56759 SEQ ID NO: 344 PARP14 NM_017554 poly (ADP-ribose) polymerase family, up member 14 A_23_P154235 SEQ ID NO: 102 NMI NM_004688 N-myc (and STAT) interactor up A_24_P397817 SEQ ID NO: 501 LEP NM_000230 leptin (obesity homolog, mouse) down A_24_P62530 SEQ ID NO: 502 RHOU NM_021205 ras homolog gene family, member U up A_23_P156788 SEQ ID NO: 222 STX11 NM_003764 syntaxin 11 up A_24_P925314 SEQ ID NO: 503 GM2A AK127910 GM2 ganglioside activator up A_23_P64828 SEQ ID NO: 504 OAS1 NM_002534 2',5'-oligoadenylate synthetase 1, 40/46 kDa up A_23_P128541 SEQ ID NO: 505 TRAFD1 NM_006700 TRAF-type zinc finger domain containing 1 up A_23_P42718 SEQ ID NO: 506 NFE2L3 NM_004289 nuclear factor (erythroid-derived 2)-like 3 up A_24_P89457 SEQ ID NO: 507 CDKN1A NM_078467 cyclin-dependent kinase inhibitor 1A (p21, up Cip1) A_23_P14754 SEQ ID NO: 508 HAPLN3 NM_178232 hyaluronan and proteoglycan link protein 3 up A_23_P103398 SEQ ID NO: 509 PSEN2 NM_000447 presenilin 2 (Alzheimer disease 4) up A_23_P75741 SEQ ID NO: 286 UBE2L6 NM_198183 ubiquitin-conjugating enzyme E2L 6 up A_23_P101434 SEQ ID NO: 510 NLRP12 NM_033297 NLR family, pyrin domain containing 12 down A_23_P141362 SEQ ID NO: 511 FZD2 NM_001466 frizzled homolog 2 (Drosophila) up A_24_P287043 SEQ ID NO: 512 IFITM2 NM_006435 interferon induced transmembrane protein 2 up (1-8D) A_24_P207139 SEQ ID NO: 513 PML NM_033238 promyelocytic leukemia up A_23_P121716 SEQ ID NO: 201 ANXA3 NM_005139 annexin A3 up A_23_P120002 SEQ ID NO: 514 SP110 NM_004510 SP110 nuclear body protein up A_23_P111000 SEQ ID NO: 119 PSMB9 NM_002800 proteasome (prosome, macropain) subunit, up beta type, 9 (large multifunctional peptidase 2) A_32_P356316 SEQ ID NO: 515 HLA-DOA NM_002119 major histocompatibility complex, class II, up DO alpha A_23_P69310 SEQ ID NO: 282 CCRL2 NM_003965 chemokine (C-C motif) receptor-like 2 up A_24_P254933 SEQ ID NO: 516 A_24_P254933 ENST00000270031 Low quality annotation - interferon induced up transmembrane protein 3 (1-8U) (IFITM3), mRNA [Source: RefSeq_dna; Acc: NM_021034] [ENST00000270031] A_23_P85240 SEQ ID NO: 517 TLR7 NM_016562 toll-like receptor 7 up A_24_P36898 SEQ ID NO: 86 GBP2 ENST00000294663 guanylate binding protein 2, interferon- up inducible A_23_P210811 SEQ ID NO: 518 CD93 NM_012072 CD93 molecule down A_23_P133142 SEQ ID NO: 207 ALPK1 NM_025144 alpha-kinase 1 up A_23_P210465 SEQ ID NO: 519 PI3 NM_002638 peptidase inhibitor 3, skin-derived (SKALP) up A_23_P24004 SEQ ID NO: 244 IFIT2 NM_001547 interferon-induced protein with up tetratricopeptide repeats 2 A_24_P48898 SEQ ID NO: 321 APOL2 NM_145637 apolipoprotein L, 2 up A_23_P82449 SEQ ID NO: 520 DFNA5 NM_004403 deafness, autosomal dominant 5 down A_23_P128447 SEQ ID NO: 203 LRRK2 NM_198578 leucine-rich repeat kinase 2 up A_23_P416894 SEQ ID NO: 521 LOC54103 AK126364 hypothetical protein LOC54103 up A_23_P57036 SEQ ID NO: 522 CD40 NM_001250 CD40 molecule, TNF receptor superfamily up member 5 A_24_P403959 SEQ ID NO: 523 RNASE1 NM_198232 ribonuclease, RNase A family, 1 (pancreatic) down A_23_P110196 SEQ ID NO: 524 HERC5 NM_016323 hect domain and RLD 5 up A_23_P1962 SEQ ID NO: 525 RARRES3 NM_004585 retinoic acid receptor responder (tazarotene up induced) 3 A_23_P500614 SEQ ID NO: 526 TNFRSF8 NM_001243 tumor necrosis factor receptor superfamily, down member 8 A_23_P11201 SEQ ID NO: 527 GPR34 NM_001033513 G protein-coupled receptor 34 down A_23_P217258 SEQ ID NO: 528 CYBB NM_000397 cytochrome b-245, beta polypeptide (chronic up granulomatous disease) A_32_P71710 SEQ ID NO: 529 A_32_P71710 AI094165 Low quality annotation - AI094165 up qa29a01.s1 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE: 1688136 3' similar to gb: X64532_rna1 INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN PRECURSOR (HUMAN);, mRNA sequence [AI094165] A_24_P935652 SEQ ID NO: 530 NUB1 CR606629 negative regulator of ubiquitin-like proteins 1 up A_24_P851254 SEQ ID NO: 531 A_24_P851254 AK026267 Low quality annotation - Homo sapiens down cDNA: FLJ22614 fis, clone HSI05089. [AK026267] A_23_P116414 SEQ ID NO: 532 HRASLS3 NM_007069 HRAS-like suppressor 3 up A_23_P59210 SEQ ID NO: 533 CDKN1A NM_000389 cyclin-dependent kinase inhibitor 1A (p21, up Cip1) A_23_P42969 SEQ ID NO: 266 FGL2 NM_006682 fibrinogen-like 2 up A_24_P403417 SEQ ID NO: 534 PTGES NM_004878 prostaglandin E synthase down A_23_P17655 SEQ ID NO: 230 KCNJ15 NM_170736 potassium inwardly-rectifying channel, up subfamily J, member 15 A_23_P91230 SEQ ID NO: 535 SLPI NM_003064 secretory leukocyte peptidase inhibitor up A_23_P152234 SEQ ID NO: 536 CMTM2 NM_144673 CKLF-like MARVEL transmembrane domain down containing 2 A_23_P62932 SEQ ID NO: 537 ATP1B1 NM_001677 ATPase, Na+/K+ transporting, beta 1 up polypeptide A_24_P161018 SEQ ID NO: 299 PARP14 NM_017554 poly (ADP-ribose) polymerase family, up member 14 A_23_P42306 SEQ ID NO: 538 HLA-DMA NM_006120 major histocompatibility complex, class II, up DM alpha A_23_P144872 SEQ ID NO: 539 GM2A NM_000405 GM2 ganglioside activator up A_32_P115555 SEQ ID NO: 540 A_32_P115555 AA991488 Low quality annotation - os91h09.s1 up NCI_CGAP_GC3 Homo sapiens cDNA clone IMAGE: 1612769 3' similar to gb: J00194 HLA CLASS II HISTOCOMPATIBILITY ANTIGEN, DR ALPHA CHAIN (HUMAN);, mRNA sequence [AA991488] A_23_P91640 SEQ ID NO: 541 ASPHD2 NM_020437 aspartate beta-hydroxylase domain up containing 2 A_23_P140807 SEQ ID NO: 211 PSMB10 NM_002801 proteasome (prosome, macropain) subunit, up beta type, 10 A_23_P378588 SEQ ID NO: 542 ARL5B NM_178815 ADP-ribosylation factor-like 5B up A_23_P104493 SEQ ID NO: 543 PAPSS2 NM_001015880 3'-phosphoadenosine 5'-phosphosulfate down synthase 2 A_23_P87709 SEQ ID NO: 293 FLJ22662 NM_024829 hypothetical protein FLJ22662 up A_23_P111804 SEQ ID NO: 544 PARP12 NM_022750 poly (ADP-ribose) polymerase family, up member 12 A_23_P129486 SEQ ID NO: 545 SEPX1 NM_016332 selenoprotein X, 1 up A_23_P9232 SEQ ID NO: 294 GCNT1 NM_001490 glucosaminyl (N-acetyl) transferase 1, core 2 up (beta-1,6-N-acetylglucosaminyltransferase) A_24_P15502 SEQ ID NO: 546 A_24_P15502 A_24_P15502 Unknown up A_23_P55998 SEQ ID NO: 547 SLC1A5 NM_005628 solute carrier family 1 (neutral amino acid up transporter), member 5 A_23_P15414 SEQ ID NO: 218 SCARF1 NM_145351 scavenger receptor class F, member 1 up A_23_P100711 SEQ ID NO: 548 PMP22 NM_000304 peripheral myelin protein 22

down A_24_P11142 SEQ ID NO: 549 KIAA0040 NM_014656 KIAA0040 up A_23_P3221 SEQ ID NO: 250 SQRDL NM_021199 sulfide quinone reductase-like (yeast) up A_23_P39237 SEQ ID NO: 550 ZFP36 NM_003407 zinc finger protein 36, C3H type, homolog up (mouse) A_23_P353717 SEQ ID NO: 551 C16ORF75 NM_152308 chromosome 16 open reading frame 75 up A_24_P382319 SEQ ID NO: 316 CEACAM1 NM_001712 carcinoembryonic antigen-related cell up adhesion molecule 1 (biliary glycoprotein) A_24_P141214 SEQ ID NO: 552 STOM NM_198194 stomatin up A_23_P252062 SEQ ID NO: 553 PPARG NM_138711 peroxisome proliferator-activated receptor down gamma A_24_P53051 SEQ ID NO: 128 LACTB NM_171846 lactamase, beta up A_32_P108277 SEQ ID NO: 554 A_32_P108277 BQ130147 Low quality annotation - BQ130147 up ij85d08.x1 Human insulinoma Homo sapiens cDNA clone IMAGE: 5778111 3', mRNA sequence [BQ130147] A_32_P95082 SEQ ID NO: 347 C9ORF39 NM_017738 chromosome 9 open reading frame 39 up A_23_P211488 SEQ ID NO: 241 APOL2 NM_145637 apolipoprotein L, 2 up A_23_P56746 SEQ ID NO: 271 FAP NM_004460 fibroblast activation protein, alpha up A_24_P935819 SEQ ID NO: 328 SOD2 BC016934 superoxide dismutase 2, mitochondrial up A_23_P329870 SEQ ID NO: 252 RHBDF2 NM_024599 rhomboid 5 homolog 2 (Drosophila) up A_23_P4821 SEQ ID NO: 268 JUNB NM_002229 jun B proto-oncogene up A_23_P95172 SEQ ID NO: 555 C17ORF27 NM_020914 chromosome 17 open reading frame 27 up A_23_P93442 SEQ ID NO: 556 SASH1 NM_015278 SAM and SH3 domain containing 1 up A_23_P112260 SEQ ID NO: 200 GNG10 NM_001017998 guanine nucleotide binding protein (G up protein), gamma 10 A_24_P260101 SEQ ID NO: 557 MME NM_007289 membrane metallo-endopeptidase (neutral down endopeptidase, enkephalinase) A_23_P20814 SEQ ID NO: 235 DDX58 NM_014314 DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 up (SEQ ID NO: 697) A_24_P98047 SEQ ID NO: 558 SLC16A10 NM_018593 solute carrier family 16, member 10 down (aromatic amino acid transporter) A_23_P401106 SEQ ID NO: 260 PDE2A NM_002599 phosphodiesterase 2A, cGMP-stimulated down A_23_P142424 SEQ ID NO: 214 TMEM149 NM_024660 transmembrane protein 149 up A_23_P216225 SEQ ID NO: 559 EGR3 NM_004430 early growth response 3 up A_23_P17663 SEQ ID NO: 560 MX1 NM_002462 myxovirus (influenza virus) resistance 1, up interferon-inducible protein p78 (mouse) A_23_P26024 SEQ ID NO: 561 C15ORF48 NM_032413 chromosome 15 open reading frame 48 up A_23_P4286 SEQ ID NO: 562 BIRC4BP NM_017523 XIAP associated factor-1 up A_23_P364024 SEQ ID NO: 563 GLIPR1 NM_006851 GLI pathogenesis-related 1 (glioma) down A_23_P166408 SEQ ID NO: 227 OSM NM_020530 oncostatin M up A_23_P155049 SEQ ID NO: 219 APOL6 NM_030641 apolipoprotein L, 6 up A_23_P141021 SEQ ID NO: 564 AYTL1 NM_017839 acyltransferase like 1 up A_24_P47329 SEQ ID NO: 319 A_24_P47329 BC063641 Low quality annotation - Homo sapiens up cDNA clone IMAGE: 4745832, partial cds. [BC063641] A_23_P44836 SEQ ID NO: 565 NT5DC2 NM_022908 5'-nucleotidase domain containing 2 down A_23_P68106 SEQ ID NO: 566 TMSB10 NM_021103 thymosin, beta 10 up A_23_P2793 SEQ ID NO: 567 ALOX5AP NM_001629 arachidonate 5-lipoxygenase-activating down protein A_24_P481844 SEQ ID NO: 568 HLA-DMB BC035650 major histocompatibility complex, class II, up DM beta A_23_P133133 SEQ ID NO: 206 ALPK1 NM_025144 alpha-kinase 1 up A_24_P315405 SEQ ID NO: 569 A_24_P315405 A_24_P315405 Unknown up A_23_P251480 SEQ ID NO: 245 NBN NM_001024688 nibrin up A_23_P402892 SEQ ID NO: 164 NLRC5 NM_032206 NLR family, CARD domain containing 5 up A_23_P427703 SEQ ID NO: 570 MT1L X97261 metallothionein 1L (pseudogene) up A_23_P112251 SEQ ID NO: 199 GNG10 NM_001017998 guanine nucleotide binding protein (G up protein), gamma 10 A_23_P34142 SEQ ID NO: 571 WBP5 NM_016303 WW domain binding protein 5 down A_23_P76823 SEQ ID NO: 572 ADSSL1 NM_199165 adenylosuccinate synthase like 1 down A_23_P161338 SEQ ID NO: 573 PPA1 NM_021129 pyrophosphatase (inorganic) 1 up A_32_P156746 SEQ ID NO: 337 A_32_P156746 BE825944 Low quality annotation - BE825944 CM2- up EN0014-310500-207-g07 EN0014 Homo sapiens cDNA, mRNA sequence [BE825944] A_24_P198598 SEQ ID NO: 574 PML NM_002675 promyelocytic leukemia up A_23_P137856 SEQ ID NO: 575 MUC1 NM_002456 mucin 1, cell surface associated up A_24_P940166 SEQ ID NO: 576 PAPSS2 NM_001015880 3'-phosphoadenosine 5'-phosphosulfate down synthase 2 A_23_P103765 SEQ ID NO: 577 FCER1A NM_002001 Fc fragment of IgE, high affinity I, receptor down for; alpha polypeptide A_23_P26583 SEQ ID NO: 158 NLRC5 NM_032206 NLR family, CARD domain containing 5 up A_23_P259692 SEQ ID NO: 578 PSAT1 NM_058179 phosphoserine aminotransferase 1 up A_23_P111583 SEQ ID NO: 579 CD36 NM_001001547 CD36 molecule (thrombospondin receptor) down A_24_P943597 SEQ ID NO: 580 PHLDA1 NM_007350 pleckstrin homology-like domain, family A, down member 1 A_24_P49199 SEQ ID NO: 581 GLDN NM_181789 gliomedin up A_24_P941912 SEQ ID NO: 331 DTX3L NM_138287 deltex 3-like (Drosophila) up A_23_P142697 SEQ ID NO: 582 TTLL4 NM_014640 tubulin tyrosine ligase-like family, member 4 down A_23_P256445 SEQ ID NO: 138 VCPIP1 NM_025054 valosin containing protein (p97)/p47 complex up interacting protein 1 A_23_P129492 SEQ ID NO: 204 SEPX1 NM_016332 selenoprotein X, 1 up A_23_P78037 SEQ ID NO: 583 CCL7 NM_006273 chemokine (C-C motif) ligand 7 down A_23_P119789 SEQ ID NO: 584 FAM11B NR_000034 family with sequence similarity 11, member B up A_23_P168828 SEQ ID NO: 229 KLF10 NM_005655 Kruppel-like factor 10 up A_24_P273716 SEQ ID NO: 585 ZBTB24 NM_014797 zinc finger and BTB domain containing 24 up A_23_P137931 SEQ ID NO: 586 ADORA3 NM_000677 adenosine A3 receptor down A_23_P255263 SEQ ID NO: 587 STOM NM_198194 stomatin up A_24_P210406 SEQ ID NO: 588 KLF5 NM_001730 Kruppel-like factor 5 (intestinal) up A_32_P91773 SEQ ID NO: 345 A_32_P91773 THC2544236 Low quality annotation - ALU1_HUMAN up (P39188) Alu subfamily J sequence contamination warning entry, partial (10%) [THC2530569] A_24_P183150 SEQ ID NO: 589 CXCL3 NM_002090 chemokine (C--X--C motif) ligand 3 down A_24_P84198 SEQ ID NO: 590 LOC441849 XR_019057 similar to Methionine-R-sulfoxide reductase up (Selenoprotein X 1) A_24_P88690 SEQ ID NO: 591 SLC11A1 NM_000578 solute carrier family 11 (proton-coupled down divalent metal ion transporters), member 1 A_32_P92415 SEQ ID NO: 346 A_32_P92415 THC2526269 Low quality annotation - ALU5_HUMAN up (P39192) Alu subfamily SC sequence contamination warning entry, partial (14%) [THC2526269] A_23_P68851 SEQ ID NO: 280 KREMEN1 NM_001039570 kringle containing transmembrane protein 1 up A_24_P50245 SEQ ID NO: 592 HLA-DMA NM_006120 major histocompatibility complex, class II, up DM alpha A_24_P935986 SEQ ID NO: 329 BCAT1 NM_005504 branched chain aminotransferase 1, down cytosolic A_24_P201360 SEQ ID NO: 593 ACSL5 NM_203380 acyl-CoA synthetase long-chain family up member 5 A_24_P124624 SEQ ID NO: 594 OLR1 NM_002543 oxidized low density lipoprotein (lectin-like) down receptor 1 A_23_P253145 SEQ ID NO: 595 TAGAP NM_054114 T-cell activation GTPase activating protein up A_24_P354724 SEQ ID NO: 596 TAGAP NM_054114 T-cell activation GTPase activating protein up A_23_P160025 SEQ ID NO: 597 IFI16 NM_005531 interferon, gamma-inducible protein 16 up A_23_P161647 SEQ ID NO: 598 PC NM_001040716 pyruvate carboxylase down A_23_P8812 SEQ ID NO: 599 A_23_P8812 W60781 Low quality annotation - W60781 zd26f05.r1 down Soares_fetal_heart_NbHH19W Homo sapiens cDNA clone IMAGE: 341793 5' similar to gb: J02874 FATTY ACID-BINDING PROTEIN, ADIPOCYTE (HUMAN);, mRNA sequence [W60781] A_23_P250245 SEQ ID NO: 600 CD72 NM_001782 CD72 molecule up A_23_P502520 SEQ ID NO: 601 IL4I1 NM_172374 interleukin 4 induced 1 up A_23_P153390 SEQ ID NO: 602 CLEC4G NM_198492 C-type lectin superfamily 4, member G up A_24_P941167 SEQ ID NO: 330 APOL6 NM_030641 apolipoprotein L, 6 up A_23_P138680 SEQ ID NO: 209 IL15RA NM_172200 interleukin 15 receptor, alpha up A_32_P191417 SEQ ID NO: 340 A_32_P191417 AI439246 Low quality annotation - AI439246 ti59a08.x1 up NCI_CGAP_Lym12 Homo sapiens cDNA clone IMAGE: 2134742 3' similar to gb: M81141 HLA CLASS II HISTOCOMPATIBILITY ANTIGEN, DQ(1) BETA CHAIN (HUMAN);, mRNA sequence [AI439246] A_23_P202978 SEQ ID NO: 603 CASP1 NM_033292 caspase 1, apoptosis-related cysteine up peptidase (interleukin 1, beta, convertase) A_23_P97990 SEQ ID NO: 604 HTRA1 NM_002775 HtrA serine peptidase 1 down A_24_P334361 SEQ ID NO: 314 FLJ20035 NM_017631 hypothetical protein FLJ20035 up A_23_P114814 SEQ ID NO: 605 RHOU NM_021205 ras homolog gene family, member U up A_23_P122924 SEQ ID NO: 606 INHBA NM_002192 inhibin, beta A (activin A, activin AB alpha up polypeptide) A_23_P152782 SEQ ID NO: 607 IFI35 NM_005533 interferon-induced protein 35 up A_24_P212481 SEQ ID NO: 304 MCTP1 NM_024717 multiple C2 domains, transmembrane 1 up A_23_P145965 SEQ ID NO: 608 TPST1 NM_003596 tyrosylprotein sulfotransferase 1 down A_24_P77008 SEQ ID NO: 609 PTGS2 NM_000963 prostaglandin-endoperoxide synthase 2 up (prostaglandin G/H synthase and cyclooxygenase) A_23_P37983 SEQ ID NO: 610 MT1B NM_005947 metallothionein 1B (functional) up A_23_P253791 SEQ ID NO: 611 CAMP NM_004345 cathelicidin antimicrobial peptide down A_23_P5273 SEQ ID NO: 612 SBNO2 NM_014963 strawberry notch homolog 2 (Drosophila) up A_23_P91802 SEQ ID NO: 613 ECGF1 NM_001953 endothelial cell growth factor 1 (platelet- up derived) A_23_P152548 SEQ ID NO: 614 SCPEP1 NM_021626 serine carboxypeptidase 1 up A_23_P4662 SEQ ID NO: 615 BCL3 NM_005178 B-cell CLL/lymphoma 3 up A_32_P222250 SEQ ID NO: 341 A_32_P222250 AF119908 Low quality annotation - Homo sapiens up PRO2955 mRNA, complete cds. [AF119908] A_23_P256724 SEQ ID NO: 616 TNFRSF10C NM_003841 tumor necrosis factor receptor superfamily, down member 10c, decoy without an intracellular domain A_23_P205489 SEQ ID NO: 617 SLC7A8 NM_182728 solute carrier family 7 (cationic amino acid down transporter, y+ system), member 8 A_24_P243749 SEQ ID NO: 618 PDK4 NM_002612 pyruvate dehydrogenase kinase, isozyme 4 down A_24_P272389 SEQ ID NO: 619 LOC285216 AK092228 hypothetical protein LOC285216 up A_23_P161125 SEQ ID NO: 620 MOV10 NM_020963 Mov10, Moloney leukemia virus 10, homolog up (mouse) A_24_P659202 SEQ ID NO: 323 A_24_P659202 THC2527772 Low quality annotation - HUMC4AA2 up complement component C4A {Homo sapiens} (exp = -1; wgp = 0; cg = 0), partial (6%) [THC2527772] A_24_P914519 SEQ ID NO: 621 CYBB S67289 cytochrome b-245, beta polypeptide (chronic up

granulomatous disease) A_24_P304071 SEQ ID NO: 622 IFIT2 NM_001547 interferon-induced protein with up tetratricopeptide repeats 2 A_23_P214176 SEQ ID NO: 623 CD109 NM_133493 CD109 molecule down A_23_P127663 SEQ ID NO: 624 PRRG4 NM_024081 proline rich Gla (G-carboxyglutamic acid) 4 up (transmembrane) A_23_P215566 SEQ ID NO: 625 AHR NM_001621 aryl hydrocarbon receptor down A_24_P398130 SEQ ID NO: 626 USP6NL ENST00000277575 USP6 N-terminal like up A_24_P42264 SEQ ID NO: 627 LYZ NM_000239 lysozyme (renal amyloidosis) up A_23_P397293 SEQ ID NO: 628 LY6K NM_017527 lymphocyte antigen 6 complex, locus K down A_23_P30243 SEQ ID NO: 629 LRAP NM_022350 leukocyte-derived arginine aminopeptidase up A_24_P133542 SEQ ID NO: 630 PML NM_002675 promyelocytic leukemia up A_24_P211106 SEQ ID NO: 631 A_24_P211106 ENST00000382790 Low quality annotation - Tumor necrosis down factor receptor superfamily member 11A precursor (Receptor activator of NF-KB) (Osteoclast differentiation factor receptor) (ODFR) (CD265 antigen). [Source: Uniprot/SWISSPROT; Acc: Q9Y6Q6] [ENST00000382790] A_24_P7322 SEQ ID NO: 632 A_24_P7322 A_24_P7322 Unknown up A_23_P343837 SEQ ID NO: 254 PARP11 NM_020367 poly (ADP-ribose) polymerase family, up member 11 A_23_P90041 SEQ ID NO: 633 NLRP12 NM_033297 NLR family, pyrin domain containing 12 down A_32_P121978 SEQ ID NO: 634 A_32_P121978 A_32_P121978 Unknown up A_23_P202837 SEQ ID NO: 635 CCND1 NM_053056 cyclin D1 up A_24_P136866 SEQ ID NO: 636 SLC8A1 NM_021097 solute carrier family 8 (sodium/calcium up exchanger), member 1 A_24_P97342 SEQ ID NO: 333 PROK2 NM_021935 prokineticin 2 down A_24_P352952 SEQ ID NO: 637 FAM20A NM_017565 family with sequence similarity 20, member A up A_23_P32233 SEQ ID NO: 638 KLF4 NM_004235 Kruppel-like factor 4 (gut) up A_23_P156327 SEQ ID NO: 639 TGFBI NM_000358 transforming growth factor, beta-induced, down 68 kDa A_23_P60933 SEQ ID NO: 640 MT1G NM_005950 metallothionein 1G up A_32_P199462 SEQ ID NO: 641 LOC389073 ENST00000341287 similar to RIKEN cDNA D630023F18 up A_24_P835388 SEQ ID NO: 642 A_24_P835388 A_24_P835388 Unknown down A_23_P217428 SEQ ID NO: 643 ARHGAP6 NM_001174 Rho GTPase activating protein 6 down A_23_P571 SEQ ID NO: 272 SLC2A1 NM_006516 solute carrier family 2 (facilitated glucose down transporter), member 1 A_23_P30069 SEQ ID NO: 249 FLJ31033 AK023743 hypothetical protein FLJ31033 up A_23_P52219 SEQ ID NO: 644 SPFH1 NM_006459 SPFH domain family, member 1 up A_23_P53763 SEQ ID NO: 645 C13ORF18 NM_025113 chromosome 13 open reading frame 18 down A_23_P42302 SEQ ID NO: 265 HLA-DQA2 NM_020056 major histocompatibility complex, class II, up DQ alpha 2 A_23_P42282 SEQ ID NO: 264 C4B NM_001002029 complement component 4B (Childo blood up group) A_23_P329353 SEQ ID NO: 646 C2ORF32 NM_015463 chromosome 2 open reading frame 32 down A_23_P46936 SEQ ID NO: 647 EGR2 NM_000399 early growth response 2 (Krox-20 homolog, up Drosophila) A_23_P74001 SEQ ID NO: 284 S100A12 NM_005621 S100 calcium binding protein A12 down A_23_P206724 SEQ ID NO: 648 MT1E NM_175617 metallothionein 1E (functional) up A_32_P118010 SEQ ID NO: 649 A_32_P118010 THC2657593 Low quality annotation - ALU1_HUMAN up (P39188) Alu subfamily J sequence contamination warning entry, partial (7%) [THC2657593] A_23_P502312 SEQ ID NO: 650 CD97 NM_078481 CD97 molecule up A_24_P135322 SEQ ID NO: 651 NRP1 NM_001024629 neuropilin 1 down A_23_P368484 SEQ ID NO: 652 C17ORF76 NM_207387 chromosome 17 open reading frame 76 down A_24_P335656 SEQ ID NO: 653 SECTM1 NM_003004 secreted and transmembrane 1 up A_23_P139066 SEQ ID NO: 654 RNF141 NM_016422 ring finger protein 141 down A_23_P138426 SEQ ID NO: 655 USP6NL BC042943 USP6 N-terminal like up A_23_P116286 SEQ ID NO: 656 AMPD3 NM_001025390 adenosine monophosphate deaminase down (isoform E) A_24_P85539 SEQ ID NO: 657 FN1 NM_212482 fibronectin 1 down A_24_P304154 SEQ ID NO: 312 AMPD3 NM_001025390 adenosine monophosphate deaminase down (isoform E) A_23_P41424 SEQ ID NO: 658 SLC39A8 NM_022154 solute carrier family 39 (zinc transporter), down member 8 A_24_P125096 SEQ ID NO: 659 MT1X NM_005952 metallothionein 1X up A_23_P138541 SEQ ID NO: 660 AKR1C3 NM_003739 aldo-keto reductase family 1, member C3 (3- down alpha hydroxysteroid dehydrogenase, type II) A_24_P372625 SEQ ID NO: 315 RNF141 NM_016422 ring finger protein 141 down A_32_P2605 SEQ ID NO: 661 A_32_P2605 AV756170 Low quality annotation - AV756170 BM up Homo sapiens cDNA clone BMFBGA09 5', mRNA sequence [AV756170] A_23_P378288 SEQ ID NO: 662 IKZF4 BX647761 IKAROS family zinc finger 4 (Eos) up A_23_P434919 SEQ ID NO: 663 RAB42 NM_152304 RAB42, member RAS oncogene family down A_23_P55738 SEQ ID NO: 664 CEACAM1 NM_001024912 carcinoembryonic antigen-related cell up adhesion molecule 1 (biliary glycoprotein) A_23_P414343 SEQ ID NO: 665 MT1H NM_005951 metallothionein 1H up Low quality annotation - xq40c08.x1 A_24_P924010 SEQ ID NO: 666 A_24_P924010 AW275876 NCI_CGAP_Lu28 Homo sapiens cDNA up clone IMAGE: 2753102 3' similar to gb: X57352 INTERFERON-INDUCIBLE PROTEIN 1-8U (HUMAN);, mRNA sequence [AW275876] A_32_P117016 SEQ ID NO: 667 A_32_P117016 AK094088 Low quality annotation - Homo sapiens up cDNA FLJ36769 fis, clone ADIPS2000245. [AK094088] A_23_P303242 SEQ ID NO: 668 MT1X NM_005952 metallothionein 1X up A_24_P156490 SEQ ID NO: 133 KCNMA1 NM_002247 potassium large conductance calcium- up activated channel, subfamily M, alpha member 1 A_32_P103695 SEQ ID NO: 669 FAM92A1 CR627475 family with sequence similarity 92, member up A1 A_24_P335305 SEQ ID NO: 670 OAS3 NM_006187 2'-5'-oligoadenylate synthetase 3, 100 kDa up A_23_P52266 SEQ ID NO: 671 IFIT1 NM_001548 interferon-induced protein with up tetratricopeptide repeats 1 A_23_P24104 SEQ ID NO: 672 PLAU NM_002658 plasminogen activator, urokinase up A_23_P161837 SEQ ID NO: 673 MRVI1 NM_130385 murine retrovirus integration site 1 homolog down A_32_P133090 SEQ ID NO: 674 A_32_P133090 BG216262 Low quality annotation - RST35951 Athersys up RAGE Library Homo sapiens cDNA, mRNA sequence [BG216262] A_24_P306810 SEQ ID NO: 675 KIAA1618 ENST00000319902 KIAA1618 up A_32_P200724 SEQ ID NO: 676 A_32_P200724 AK128013 Low quality annotation - Homo sapiens up cDNA FLJ46132 fis, clone TESTI2051627. [AK128013] A_23_P87879 SEQ ID NO: 677 CD69 NM_001781 CD69 molecule up A_23_P41344 SEQ ID NO: 678 EREG NM_001432 epiregulin down A_23_P48596 SEQ ID NO: 679 RNASE1 NM_198232 ribonuclease, RNase A family, 1 (pancreatic) down A_23_P135755 SEQ ID NO: 680 IL8RB NM_001557 interleukin 8 receptor, beta down A_23_P132822 SEQ ID NO: 115 XRN1 NM_019001 5'-3' exoribonuclease 1 up A_23_P213014 SEQ ID NO: 681 SLC2A9 NM_001001290 solute carrier family 2 (facilitated glucose up transporter), member 9 A_32_P399546 SEQ ID NO: 343 ARNTL2 AF256215 aryl hydrocarbon receptor nuclear up translocator-like 2 A_24_P62521 SEQ ID NO: 682 PSEN2 NM_000447 presenilin 2 (Alzheimer disease 4) up A_24_P277367 SEQ ID NO: 683 CXCL5 NM_002994 chemokine (C--X--C motif) ligand 5 down A_23_P39925 SEQ ID NO: 684 DYSF NM_003494 dysferlin, limb girdle muscular dystrophy 2B up (autosomal recessive) A_24_P250922 SEQ ID NO: 307 PTGS2 NM_000963 prostaglandin-endoperoxide synthase 2 up (prostaglandin G/H synthase and cyclooxygenase) A_23_P163782 SEQ ID NO: 685 LOC645745 NM_001039954 metallothionein 1H-like protein up A_23_P216712 SEQ ID NO: 686 TRPM6 NM_017662 transient receptor potential cation channel, down subfamily M, member 6 A_23_P69171 SEQ ID NO: 687 SUCNR1 NM_033050 succinate receptor 1 up A_24_P7594 SEQ ID NO: 688 APOL6 NM_030641 apolipoprotein L, 6 up A_23_P373017 SEQ ID NO: 689 CCL3 NM_002983 chemokine (C-C motif) ligand 3 up A_23_P205200 SEQ ID NO: 234 DHRS12 NM_024705 dehydrogenase/reductase (SDR family) up member 12 A_23_P304356 SEQ ID NO: 690 CLEC5A NM_013252 C-type lectin domain family 5, member A down A_23_P217049 SEQ ID NO: 691 FREQ NM_014286 frequenin homolog (Drosophila) down A_23_P157527 SEQ ID NO: 692 LRRCC1 NM_033402 leucine rich repeat and coiled-coil domain up containing 1 A_23_P206707 SEQ ID NO: 693 MT1G NM_005950 metallothionein 1G up A_32_P138348 SEQ ID NO: 694 LY6K NM_017527 lymphocyte antigen 6 complex, locus K down A_23_P110204 SEQ ID NO: 695 CXCL5 NM_002994 chemokine (C--X--C motif) ligand 5 down A_23_P113212 SEQ ID NO: 696 TMEM45A NM_018004 transmembrane protein 45A up

Amino acid and nucleotide sequences included in publicly available database entries corresponding to the National Center for Biotechnology Information (NCBI) accession numbers listed in Table 1 above are incorporated herein by reference. Similarly, the sequences of the Agilent® probes are publicly available in the Gene Expression Omnibus (GEO) Database of NCBI. In particular, these sequences are among those disclosed for the Agilent-026652 Whole Human Genome Microarray 4×44K v2 and are incorporated herein by reference.

Example 2

Serum Levels of Selected Proteins in Lupus and Lupus Nephritis Patients Compared to Healthy Volunteers

[0111] Gene dysregulation in SLE was initially examined in a study of 19 healthy volunteers and 39 lupus subjects, which included patients from the clinical trial described in Example 3 as well as other lupus patients. Further, these studies were extended to include patients participating in the clinical trial described in Example 4 below, which included lupus nephritis patients as well as patients having SLE without nephritis. Peripheral blood samples from healthy volunteers and from lupus patients (before dosing) were collected in serum separator tubes (red/black marble top) and processed for serum. Serum CXCL10, CCL2, C--C motif chemokine 5 (CCL5; also known as RANTES), and IL-18 concentrations were determined with commercially available ELISAs according to the manufacturers' instructions (R&D Systems, Minneapolis, Minn. and Medical & Biological Laboratories Co, Ltd, Des Plaines, Ill.). Samples were analyzed in triplicate and levels were quantified by interpolation from a standard curve run in parallel on each micro-titer plate. Log ratio of gene expression in lupus subjects relative to healthy subjects along with 95% confidence intervals were estimated using linear regression and expressed as fold change. See Kackar, R. N., and Harville, D. A. 1984. Approximations for Standard Errors of Estimators of Fixed and Random Effects in Mixed Linear-Models. Journal of the American Statistical Association 79: 853-862, the relevant portions of which are incorporated herein by reference.

[0112] The results are shown in FIG. 2. These data indicate that median serum levels of CXCL10, IL-18, and CCL2 were elevated in SLE and lupus nephritis subjects compared to healthy volunteers. Further, median levels observed in lupus nephritis patients were at least numerically higher than levels observed in SLE patients, though differences were statistically significant only for IL-18 expression. No difference in levels of RANTES could be demonstrated (data not shown). As will be shown below, expression of CXCL10 at the RNA and protein levels is decreased in vivo in human lupus and lupus nephritis patients in response to treatment with the anti-huIFN-γ antibody AMG 811.

[0113] Similarly, gene dysregulation in SLE compared to healthy subjects at the RNA level was investigated using microarray analysis performed essentially as described in Example 1 except that the pre-filtering step was omitted. These results are reported in part in Table 2 below. Like the results displayed in FIG. 2, data in Table 2 indicate that levels of expression of some genes at the RNA level differ in SLE patients as compared to healthy volunteers.

Example 3

Single Dose Escalation Study of a Neutralizing Anti-huIFN-γ Antibody

[0114] Described below is a phase 1, randomized, double-blind, placebo-controlled, single dose escalation study of an anti-huIFN-γ antibody (AMG 811) in subjects with mild, stable SLE. Anti-huIFN-γ antibodies, including AMG 811, are described herein (above under the heading "Interferon Gamma Inhibitors") and in U.S. Pat. No. 7,335,743, the relevant portions of which are incorporated herein by reference. Adults aged 18 to 65 with a diagnosis of SLE (as defined by the American College of Rheumatology classification criteria) of at least 6 months duration were enrolled. Anti-malarials, leflunomide, or methotrexate, and up to 20 mg/day of prednisone (or equivalent) were permitted as concomitant therapies. The subjects had stable disease, that is, symptoms that were constant with no change in therapy for at least 30 days prior to randomization.

[0115] Twenty-six subjects with mild, stable SLE were enrolled in this Phase 1, single dose, double blind, randomized, placebo controlled, clinical trial. There were three subjects treated with active drug in each cohort (total of eighteen subjects) and eight subjects in the combined placebo group. The mean age was 43.3 years in the active group and 44.1 in the placebo group. The subjects were predominantly female (92%) and Caucasian (62%). The mean Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; see Bombardier et al. (1992), Arthritis & Rheum. 35(6): 630-640, the relevant portions of which are incorporated herein by reference) score was low (2.3 and 3.8 for placebo and AMG 811 groups, respectively). Fifty percent of placebo subjects and 28% of the subjects receiving AMG 811 were on corticosteroids, receiving mean doses of 10 mg/day and 13.5 mg/day, respectively. Seventy five percent of placebo subjects and 100% of the subjects receiving AMG 811 were on anti-malarials, while a single subject in the AMG 811 group was on an immunosuppressant (methotrexate).

[0116] Each subject was treated with a single dose of AMG 811 (2 milligrams (mg) subcutaneous (SC), 6 mg SC, 20 mg SC, 60 mg SC, 180 mg SC, or 60 mg intravenous (IV)) or placebo (vehicle control) on day 1 of the study. The end of study (EOS) ranged from day 84 to day 196 depending on the dose level. Serum tube and PAXgene® blood RNA tube samples were collected from all cohorts at baseline, that is, on day 1 prior to dosing and at days 15, 56, and EOS after treatment. All samples were collected and included for analysis with the exception of one placebo EOS sample, one EOS sample from the 6 mg treated cohort, and two day 15 samples from the 20 mg cohort. One sample at the day 15 time point (60 mg IV) was subsequently determined to be from an unscheduled day 8 visit. As an actual day 15 sample was not available from this patient, and the expected drug exposure was not anticipated to be very different between day 8 and day 15, this sample was included with the day 15 results.

[0117] Total RNA was isolated from each sample and processed and analyzed by hybridization to a microarray as described in Example 1 above, except that the pre-filtering step to remove genes having low levels of expression was not performed.

[0118] These results are shown in the left panel of FIG. 3, which shows the fold difference in expression of individual genes at the RNA level in day 15 blood samples from patients treated with AMG 811 and baseline or placebo-treated subjects. As in FIG. 1, dots represent data from a particular gene sequence. The x-axis shows the fold difference in RNA expression in samples from patients treated with AMG 811 versus in samples from patients treated with placebo. Dots representing the same twenty genes that were circled in FIG. 1 are also circled here.

[0119] More detailed data on these twenty genes from this experiment, as well as from the ex vivo stimulation experiment described in Example 1 and the comparison of healthy vs. SLE subjects described in Example 2, is shown in Table 2 below.

TABLE-US-00002 TABLE 2 Data from the top 20 IFN-γ regulated genes P-value for D 15 treatment Lupus v. treatment effect Sequence Listing Symbol, Product(NCBI Sequene Listing IFN-γ-Stim healthy effect (treated at Agilent ® Probe Number of the accession number of Number of Fold change Fold change Fold change day 15 vs. Designation probe sequence cDNA sequence) cDNA sequence (95% CI) (95% CI) (95% CI) baseline) A_23_P112026 SEQ ID NO: 350 INDO1, indoleamine 2,3- SEQ ID NO: 50 11.3 1.1 -1.4 0.076 dioxygenase 1 (10.0, 12.8) (-1.2, 1.4) (-2.0, 1.0) (NM_002164) A_23_P161428 SEQ ID NO: 72 ANKRD22, ankyrin repeat SEQ ID NO: 51 10.8 1.3 -2.2 <0.001 domain 22 (NM_144590) (8.8, 13.2) (-1.0, 1.7) (-3.0, -1.6) A_23_P18452 SEQ ID NO: 109 CXCL9, chemokine SEQ ID NO: 52 9.8 1.3 -1.3 <0.001 (C-X-C motif) ligand 9 (8.4, 11.4) (1.1, 1.5) (-1.6, -1.2) (NM_002416) A_24_P28722 SEQ ID NO: 351 RSAD2, radical S- SEQ ID NO: 53 7.7 5.2 -1.3 0.184 adenosyl methionine (5.9, 10.1) (2.3, 11.5) (-1.8, 1.1) domain containing 2 (NM_080657) A_23_P7827 SEQ ID NO: 83 FAM26F, family with SEQ ID NO: 54 7.4 1.2 -1.6 <0.001 sequence similarity 26, (6.9, 8.0) (-1.0, 1.5) (-1.9, -1.3) member F (NM_001010919) A_24_P165864 SEQ ID NO: 300 P2RY14, purinergic SEQ ID NO: 55 7.3 -1.1 -1.7 0.001 receptor P2Y, G-protein (5.0, 10.7) (-1.5, 1.2) (-2.4, -1.3) coupled, 14 (NM_001081455) A_23_P74290 SEQ ID NO: 79 GBP5, guanylate binding SEQ ID NO: 56 7.0 1.3 -1.8 <0.001 protein 5 (NM_052942) (5.0, 9.8) (1.0, 1.7) (-2.3, -1.5) A_24_P561165 SEQ ID NO: 322 SERPING1, serpin SEQ ID NO: 57 6.4 2.5 -1.7 0.001 peptidase inhibitor, clade (4.5, 8.9) (1.7, 3.8) (-2.4, -1.3) G, member 1 (NM_000062) A_23_P63390 SEQ ID NO: 73 FCGR1B or CD64Fc SEQ ID NO: 58 6.3 1.2 -2.1 <0.001 fragment of IgG, high (4.8, 8.2) (-1.1, 1.6) (-2.6, -1.6) affinity Ib, receptor (NM_001017986)) A_23_P150457 SEQ ID NO: 352 LYVE1, lymphatic vessel SEQ ID NO: 59 -6.0 -1.0 -1.1 0.367 endothelial hyaluronan (-7.1, 5.1) (-1.2, 1.1) (-1.2, 1.1) receptor 1 (NM_006691) A_24_P245379 SEQ ID NO: 353 SERPINB2, serpin SEQ ID NO: 60 -5.9 1.0 -1.1 0.536 peptidase inhibitor, clade (-7.6, 4.6) (-1.2, 1.2) (-1.3, 1.1) B (ovalbumin), member 2 (NM_001143818) A_23_P203882 SEQ ID NO: 356 MMP19, matrix SEQ ID NO: 61 -5.8 1.2 -1.0 0.699 metallopeptidase 19 (-7.6, -4.4) (1.0, 1.4) (-1.2, 1.1) (NM_002429) A_23_P62890 SEQ ID NO: 74 GBP1, guanylate binding SEQ ID NO: 62 5.6 1.6 -2.0 <0.001 protein 1, interferon- (4.0, 7.7) (1.1, 2.2) (-2.4, -1.6) inducible, 67 kDa (NM_002053) A_32_P107372 SEQ ID NO: 76 GBP1, guanylate binding SEQ ID NO: 62 5.6 1.6 -1.9 <0.001 protein 1, interferon- (4.1, 7.6) (1.2, 2.1) (-2.4.-1.5) inducible, 67 kDa (NM_002053) A_24_P303091 SEQ ID NO: 311 CXCL10, chemokine SEQ ID NO: 63 5.4 1.3 -1.6 0.008 (C-X-C motif) ligand 10 (4.1, 7.1) (-1.0, 1.8) (-2.2, -1.1) (NM_001565) A_24_P316965 SEQ ID NO: 354 RSAD2, radical S- SEQ ID NO: 53 5.4 3.6 -1.2 0.235 adenosyl methionine (4.6, 6.3) (2.1, 6.2) (-1.7, 1.1) domain containing 2 (NM_080657) A_23_P42353 SEQ ID NO: 77 ETV7, ets variant 7 SEQ ID NO: 64 5.2 1.8 -1.8 <0.001 (NM_016135) (3.6, 7.5) (1.3, 2.6) (-2.4, -1.4) A_23_P256487 SEQ ID NO: 78 PD-L1, Programmed SEQ ID NO: 65 5.0 1.2 -1.8 <0.001 Death Ligand-1 (3.9, 6.4) (1.1, 1.4) (-2.3, -1.4) (AY254342) A_23_P121657 SEQ ID NO: 355 HS3ST1, heparan sulfate SEQ ID NO: 66 -4.9 1.0 -1.0 0.892 (glucosamine) 3-O- (-5.4, 4.4) (-1.3, 1.3) (-1.2, 1.1) sulfotransferase 1 (NM_005114) A_24_P12690 SEQ ID NO: 357 INDO2, indoleamine 2,3- SEQ ID NO: 67 4.8 1.0 -1.1 0.126 dioxygenase 2 (3.7, 6.2) (-1.1, 1.2) (-1.3, 1.0) (BC113498)

[0120] Many of the transcripts that were most impacted by treatment with IFN-γ ex vivo, which are circled in FIG. 1 and the left panel of FIG. 3, are downregulated by treatment with AMG 811 in vivo. These data provide strong evidence that AMG 811 can inhibit IFN-γ-regulated gene expression in vivo in SLE patients. These data are also reported in more detail Table 5 (described in more detail below) which names a broader set of genes whose expression is modulated by AMG 811 in vivo.

[0121] An example of the in vivo effect of AMG 811 on gene expression at the RNA level is provided by guanylate binding protein 1 (GBP1). Levels of GBP1 RNA observed in individual patients before dosing with AMG 811 on Day -1 and on Day 15 of the study (after dosing) are shown in the right panel of FIG. 3. The gene expression levels for the GBP1 transcript were standardized against levels seen in healthy volunteers (y-axis of the figure) and plotted against the serum levels of AMG 811 observed at days -1 and 15, which, of course, varied according to dosage. GBP1 RNA expression decreased at day 15 as compared to day -1 in each patient treated with AMG 811. In samples from patients treated with placebo, considerable change in GBP1 expression was also observed, but the direction of change was not consistent, and the expression was, on average, not different between study days (p=0.54, data not shown). Since GBP-1 is one of the genes whose expression is upregulated by IFN-γ stimulation of blood of healthy volunteers ex vivo, these results suggest that inhibition of IFN-γ is occurring in every patient treated with AMG 811 in this study.

[0122] To determine the effects of various doses of AMG 811 on CXCL10 protein expression, peripheral blood samples were taken and processed for serum, and CXCL10 protein concentrations were determined by ELISA assay. Differences between levels of protein expression at baseline and after a single dose of AMG 811 were estimated by a fixed-effects regression model containing factors for visit and dose, a random factor for subject, and an interaction term for visit and dose. FIG. 4 shows the fold change in CXCL10 protein levels at Days 15 and 56 and at the end of study (EOS) as compared to baseline CXCL10 protein levels, with error bars showing the 95% confidence intervals using small sample size correction. Kackar, R. N., and Harville, D. A. 1984. Approximations for Standard Errors of Estimators of Fixed and Random Effects in Mixed Linear-Models. Journal of the American Statistical Association 79:853-862. These data indicate that a single dose of AMG 811 greater than 20 mg, that is, 60 mg or 180 mg, decreased levels of serum CXCL10 protein in vivo in SLE patients.

[0123] Levels of AMG 811 in serum were determined using a validated sandwich immunoassay at Amgen Inc., Thousand Oaks, Calif. Study samples were added to a plate coated with a mouse anti-AMG 811 monoclonal antibody. After capture of AMG 811 with the immobilized antibody, unbound materials were removed by a wash step. Biotin conjugated rabbit anti-AMG 811 polyclonal antibody (Amgen Inc., CA) was added to detect the captured AMG 811. After another incubation step with streptavidin-HRP, a tetramethylbenzidine (TMB) peroxide substrate solution (KPL Inc., MD) was added to produce a colorimetric signal, which was proportional to the amount of AMG 811 bound by the capture reagent. The color development was stopped by addition of H₂SO₄, and the optical density (OD) signal was measured at 450 nm with reference to 650 nm. The absorbance versus concentration relationship was regressed according to a four-parameter logistic (auto-estimate) regression model with a weighting factor of 1/Y. The lower limit of quantification (LLOQ) was 15.2 ng/mL. Results from the single-dose escalation study are shown in FIG. 5. AMG 811 exhibited linear pharmacokinetics (PK, with a mean terminal half-life (t₁/2,z) ranging from 12 to 21 days. Following a single 60 mg IV dose, the mean area under the curve (AUC) value was approximately 3-fold higher than for the 60 mg SC dose, indicating an approximate 30% bioavailability. Mean AMG 811 PK parameters are presented in Table 3.

TABLE-US-00003 TABLE 3 Serum PK Parameters for AMG 811 AMG 811 PK Parameters Route Dose (mg) t_max^b (day) C_max^c (μg/mL) AUC_last^d (μg day/mL) t₁/2,z^e (day) SC .sup. 2^a 7.1 (7.1-13) 0.143 (0.161) 6.25 (NA) 21.0 (NA) 6 14 (14-14) 0.323 (0.275) 11.6 (7.61) 17.0 (2.97) 20 4.0 (4.0-7.0) 1.81 (0.541) 45.0 (9.72) 15.2 (3.01) 60 4.0 (1.2-7.2) 4.93 (0.705) 117 (38.6) 12.3 (4.75) 180 4.0 (4.0-14) 17.6 (9.14) 595 (121) 19.3 (0.667) IV 60 0.04 (0.02, 0.04) 25.6 (10.0) 369 (188) 18.6 (4.61) ^aOne subject in cohort 1 (receiving a dose of 2 mg) had only 2 measurable AMG 811 concentrations (data included where applicable) ^bTime to maximum observed concentration (t_max) are presented as median (range of values observed) ^cMean (standard deviation) maximum serum concentration achieved. ^dMean (standard deviation) area under the curve value to last measured time point. ^eMean (standard deviation) serum terminal half life.

[0124] Levels of total IFN-γ protein in patients dosed with AMG 811 were also determined. The total IFN-γ concentration in human serum was measured using a validated sandwich immunoassay at Amgen Inc., Thousand Oaks, Calif. Specifically, study samples were incubated with 25 μg/mL of AMG 811 at 37° C. to form IFN-γ-AMG 811 complexes prior to being added to a plate coated with a mouse anti-IFN-γ monoclonal antibody (Hycult Biotechnology, Uden, Netherlands). After capture of IFN-γ-AMG 811 complex with the immobilized anti-IFN-γ monoclonal antibody, unbound materials were removed by a wash step. Biotin conjugated rabbit anti-AMG 811 polyclonal antibody (Amgen Inc., CA) was added for detection of the captured IFNγ-AMG 811 complex. After another incubation step with streptavidin-HRP, a tetramethylbenzidine (TMB) peroxide substrate solution (KPL Inc., MD) was added to produce a colorimetric signal, which was proportional to the amount of IFNγ bound by the capture reagent. The color development was stopped by addition of H₂SO₄, and the optical density (OD) signal was measured at 450 nm with reference to 650 nm. The absorbance versus concentration relationship was regressed according to a four-parameter logistic (auto-estimate) regression model with a weighting factor of 1/Y. The LLOQ of the method was 50 pg/mL.

[0125] The total IFN-γ concentration represents both bound and free endogenous levels. Free IFN-γ levels were not assessed separately. An amount of AMG 811 sufficient to saturate all IFN-γ was added to the serum samples, and the resulting AMG 811:IFN-γ complexes were detected by means of the sandwich immunoassay, as described above. These results are shown in FIGS. 6A (median levels) and 6B (mean levels). Total IFN-γ median levels increased in a dose-dependent manner, then returned to baseline by approximately 6 to 7 months postdose. FIG. 6A. The plateau in C_max values at doses of 60 and 180 mg SC and 60 mg IV may indirectly reflect the saturation of circulating, IFN-γ levels by AMG 811. These data suggest that 60 mg SC was the lowest dose tested that saturated the available IFN-γ in patients. At doses of 180 mg SC or 60 mg IV, the data suggest that this saturation of available IFN-γ was maintained for a longer period of time.

[0126] In addition, these data suggest that dosing frequency can be adjusted so as to maintain levels of total IFN-γ at or near the plateau concentrations observed at the higher doses. For example, at a dose of 60 mg SC, a level of total IFN-γ of almost 400 pg/ml is achieved at early timepoints, which starts to drop off at about three or four weeks post-dosing. Dosing repeated about every 3, 4, 5, or 6 weeks could be beneficial at a dose of 60 mg SC. Similarly, at doses of 60 mg IV or 180 SC, levels of total IFN-γ of around 400 pg/ml are achieved, but start to drop off at about 8, 9, 10, 11, or 12 weeks post dosing. Dosing repeated about every 4, 6, 8, 9, 10, 11, 12, 13, or 14 weeks could be beneficial at doses of 180 mg SC or 60 mg IV.

[0127] These data also have surprising implications about the production and turnover of IFN-γ. Generally, IFN-γ is undetectable or detectable at only low levels in peripheral blood. The comparatively high levels of total IFN-γ detected upon dosing with AMG 811 indicate that IFN-γ is likely produced at much higher levels than are generally appreciated and rapidly clearly from circulation. The relatively high levels of IFN-γ detected in the presence of AMG 811 may be due to protection of the IFN-γ from degradation and/or reduced clearance by binding to AMG 811. This assay allows for a better determination of the total production of IFN-γ in an individual and can be useful for determination of dose, dosing frequency, and stratification purposes.

[0128] Additionally, although mean total IFN-γ levels observed in the 60 mg IV dose group were significantly higher than in other groups (FIG. 6B), this may be attributed to one subject with very high baseline levels of total IFN-γ. Median profiles (FIG. 6A) indicate that the 60 mg IV dose group had similar to IFN-γ levels to those observed in the 180 mg SC dose group.

Example 4

Multi-Dose Clinical Trial in SLE Patients with and without Lupus Nephritis

[0129] In addition to the single dose clinical trial described in Example 3, a multi-dose trial was initiated to determine the safety and tolerability of multiple subcutaneous doses of AMG 811 in SLE patients with or without lupus nephritis. Part A of the study included three cohorts, 1, 2, and 3, each containing eight SLE patients without lupus nephritis. To be eligible for cohorts 1-3, a patient must have been diagnosed with SLE at least 6 months before the start of the study. Prednisone at a dose of 20 mg/day was permitted during the study, as were concurrently administered medications used for treating SLE including mycophenolate mofetil, azathioprine, leflunomide, methotrexate, and anti-malarials. Two of the eight patients in each of cohorts 1-3 received three doses of placebo administered every four weeks, and the other six received three doses AMG 811 (6, 20, or 60 mg for cohorts 1, 2, and 3, respectively) administered every four weeks, that is on days 1, 29, and 57. Part B of the study will include cohorts, 4, 5, and 6. Patients in cohorts 4-6 are required to have been diagnosed with SLE at least 6 months before the start of the study and with proliferative glomerulonephritis, as evidenced by a renal biopsy and urine protein/creatinine ratio of >1 or a 24 hour urine protein level of >1 g/day. These patients were also permitted to take prednisone at a dose of ≦20 mg/day and to take SLE medications including mycophenolate mofetil, azathioprine, leflunomide, methotrexate, and anti-malarials. Cohorts 4 and 5, for which dosing is now complete, contained eight and twelve SLE patients that had lupus nephritis, respectively. Cohort 6 is to contain eight lupus nephritis patients. Two of the patients in each of cohorts 4 and 6 and three of the twelve patients in cohort 5 will receive (and, in some cases, have received) three doses of placebo administered every four weeks, and the other patients will receive three doses AMG 811 (20, 60, or 120 mg for cohorts 4, 5, and 6, respectively) administered every four weeks, that is, on days 1, 29, and 57. Blood samples will be taken at baseline, i.e., one to three days before dosing, and on days, 1 (after dosing), 3, 8, 15, 29, 57, 85, 113, and 197 (which was the end of the study (EOS)) to determine levels of expression of various biomarker genes. Samples will be analyzed for RNA expression by DNA array as described above in Example 3 or for expression of selected proteins by ELISA assay. Blood samples taken at baseline and on days 1 (after dosing), 3, 5, 8, 15, 22, 29 (pre-dosing), 43, 57 (pre- and post-dosing), 59, 61, 64, 71, 78, 85, 113,141, 169, and 197 will be analyzed to assess a number of laboratory parameters. Twenty four hour urine samples were taken at baseline and on days 15, 29 (pre-dosing), 57 (pre-dosing), 85, 113, 141, 169, and 197 (EOS). Spot urine samples were taken at baseline and on days 3, 8, 15, 22, 29 (pre-dosing), 43, 57 (pre-dosing), 71, 85, 113, 141, 169, and 197 (EOS). Urine samples were analyzed for levels of urine protein using the a dye-binding assay (pyrocatechol violet-ammonium molybdate dye), which was analyzed in a "dry-slide" format using an automated laboratory analyzer such as the Ortho-Clinical VITROS® 5,1 FS Chemistry Analyzer from Ortho Clinical Diagnostics. Creatinine levels in urine samples were assessed by a multi-step coupled enzymatic two-point rate colorimetric assay (creatinine amidohydrolase/creatine amidinohydrolase/sarcosine oxidase/peroxidase) analyzed using a dry-slide format and automated laboratory analyzer. Such an assay is described in, e.g., Guder et al. (1986), J. Clin. Chem. Clin Biochem. 24(11): 889-902.

[0130] In Table 4 below are listed the ten genes whose expression, as detected at the RNA level, was most significantly correlated with the concentration of AMG 811 in serum as assessed in the single dose clinical trial described in Example 3. Data from the multiple dose clinical trial described in Example 4 showed that the average of the expression levels of these ten genes was responsive to the dosage level of AMG 811.

TABLE-US-00004 TABLE 4 Ten genes whose expression is most affected by AMG 811 concentration in serum Sequence Listing Sequence Listing AGILENT ® Number of Agilent Probe NCBI Accession No. of Number of cDNA probe designation Sequence Gene symbol cDNA Sequence Sequence A_33_P3407880 SEQ ID NO: 349 ANKRD22 NM_144590 SEQ ID NO: 51 A_23_P62890 SEQ ID NO: 74 GBP1 NM_002053 SEQ ID NO: 62 A_23_P370682 SEQ ID NO: 80 BATF2 NM_138456 SEQ ID NO: 68 A_23_P42353 SEQ ID NO: 77 ETV7 NM_016135 SEQ ID NO: 64 A_23_P63390 SEQ ID NO: 73 FCGR1B NM_001017986 SEQ ID NO: 58 A_23_P34915 SEQ ID NO: 81 ATF3 NM_001040619 SEQ ID NO: 69 A_23_P139123 SEQ ID NO: 210 SERPING1 NM_000062 SEQ ID NO: 57 A_23_P74290 SEQ ID NO: 79 GBP5 NM_052942 SEQ ID NO: 56 A_24_P243749 SEQ ID NO: 82 PDK4 NM_002612 SEQ ID NO: 70 A_23_P338479 SEQ ID NO: 75 CD274 NM_014143 SEQ ID NO: 71

[0131] Based on average RNA expression of the ten genes listed in Table 4, an "AMG 811 Score" could be assigned to each patient. FIG. 7 shows the average AMG 811 Score for the lupus nephritis patients receiving placebo or 20 or 60 mg of AMG 811. The average AMG 811 Score for patients receiving 20 mg or 60 mg was significantly less than the average score for patients receiving placebo. The amount of reduction in the AMG 811 Score was smaller than what was seen in the general SLE population (data not shown), suggesting that the 60 mg doses may not be high enough to achieve the maximal pharmacodynamic effect of AMG 811 in lupus nephritis patients.

[0132] Data from cohorts 1-3 was combined to create FIG. 8, which shows the fold change from baseline in the expression of CXCL10 at the protein level as measured by ELISA. FIG. 9 shows similar data from the lupus nephritis patients in cohorts 4 and 5, who received multiple doses of 20 mg and 60 mg, respectively. These data indicate that the 20 mg and 60 mg multiple dose regimes used were effective to reduce in vivo expression of CXCL10 among SLE patients, indicating that these dosage regimes are having a biological effect. These data indicate that the 60 mg multiple dose regime did reduce in vivo expression of CXCL10 in lupus nephritis patients at some early time points, although effects were not as clear as those observed in SLE patients without nephritis. Further, lupus nephritis patients dosed with 20 mg of AMG 811 did not exhibit a clear decrease in serum levels of CXCL10. This difference in apparent dosing requirements between SLE and lupus nephritis patients could reflect a generally more highly activated IFN-γ pathway in lupus nephritis patients as compared to SLE patients. More highly expressed IL-18, IP-10, and CCL2 proteins (FIG. 2) are consistent with this interpretation. Further, these data suggest that expression of biomarkers, for example, CXCL10, IL-18, CCL2, etc., could guide dose selection.

[0133] The data in FIG. 10 shows serum CXCL10 levels as fold change from baseline plotted against serum concentration of AMG 811 in combined patients with general SLE and with lupus nephritis. Higher levels of AMG 811 correlate with further reduction in CXCL10 levels. This suggests that AMG 811 is reducing CXCL10 levels in these patients.

[0134] Data from the single dose clinical trial described above was used to compile a list of genes whose expression is significantly (with a p value<0.001) modulated (either up- or down-regulated) in vivo in SLE patients dosed with AMG 811 as compared to SLE patients dosed with placebo. This list of genes is shown in Table 5 below.

TABLE-US-00005 TABLE 5 Genes whose expression is modulated in vivo by AMG 811 Sequence Listing NCBI Accession Direction of AGILENT ® Probe Number of Agilent Number of cDNA Modulation by Designation Probe Sequence Gene Symbol Sequence AMG 811 A_23_P161428 SEQ ID NO: 72 ANKRD22 NM_144590 down A_23_P63390 SEQ ID NO: 73 FCGR1B NM_001017986 down A_23_P62890 SEQ ID NO: 74 GBP1 NM_002053 down A_23_P338479 SEQ ID NO: 75 CD274 NM_014143 down A_32_P107372 SEQ ID NO: 76 GBP1 NM_002053 down A_23_P42353 SEQ ID NO: 77 ETV7 NM_016135 down A_23_P256487 SEQ ID NO: 78 A_23_P256487 THC2651085 down A_23_P74290 SEQ ID NO: 79 GBP5 NM_052942 down A_23_P370682 SEQ ID NO: 80 BATF2 NM_138456 down A_23_P34915 SEQ ID NO: 81 ATF3 NM_001040619 down A_24_P243749 SEQ ID NO: 82 PDK4 NM_002612 down A_23_P7827 SEQ ID NO: 83 FAM26F NM_001010919 down A_23_P208119 SEQ ID NO: 84 PSTPIP2 NM_024430 down A_24_P100387 SEQ ID NO: 85 GK NM_203391 down A_24_P36898 SEQ ID NO: 86 A_24_P36898 AL832451 down A_32_P44394 SEQ ID NO: 87 AIM2 NM_004833 down A_24_P274270 SEQ ID NO: 88 STAT1 NM_139266 down A_23_P56630 SEQ ID NO: 89 STAT1 NM_007315 down A_23_P85693 SEQ ID NO: 90 GBP2 NM_004120 down A_24_P322353 SEQ ID NO: 91 PSTPIP2 NM_024430 down A_23_P63896 SEQ ID NO: 92 FAS NM_000043 down A_23_P51487 SEQ ID NO: 93 GBP3 NM_018284 down A_23_P96556 SEQ ID NO: 94 GK NM_203391 down A_23_P319792 SEQ ID NO: 95 XRN1 NM_019001 down A_32_P166272 SEQ ID NO: 96 STX11 NM_003764 down A_24_P196382 SEQ ID NO: 97 ATG3 BC002830 down A_24_P33895 SEQ ID NO: 98 ATF3 NM_001040619 down A_23_P347541 SEQ ID NO: 99 GRIN3A NM_133445 down A_23_P255444 SEQ ID NO: 100 DAPP1 NM_014395 down A_23_P69383 SEQ ID NO: 101 PARP9 NM_031458 down A_23_P154235 SEQ ID NO: 102 NMI NM_004688 down A_24_P7594 SEQ ID NO: 103 APOL6 NM_030641 down A_32_P11058 SEQ ID NO: 104 A_32_P11058 THC2646969 down A_23_P202978 SEQ ID NO: 105 CASP1 NM_033292 down A_24_P350686 SEQ ID NO: 106 TIFA NM_052864 down A_23_P123608 SEQ ID NO: 107 JAK2 NM_004972 down A_24_P45446 SEQ ID NO: 108 GBP4 NM_052941 down A_23_P18452 SEQ ID NO: 109 CXCL9 NM_002416 down A_23_P121253 SEQ ID NO: 110 TNFSF10 NM_003810 down A_24_P192805 SEQ ID NO: 111 CARD17 NM_001007232 down A_24_P687326 SEQ ID NO: 112 C9ORF109 NR_024366 down A_23_P59005 SEQ ID NO: 113 TAP1 NM_000593 down A_32_P159254 SEQ ID NO: 114 A_32_P159254 AK123584 down A_23_P132822 SEQ ID NO: 115 XRN1 NM_019001 down A_23_P64173 SEQ ID NO: 116 CARD16 NM_001017534 down A_23_P502797 SEQ ID NO: 117 WDFY1 NM_020830 down A_32_P131401 SEQ ID NO: 118 A_32_P131401 AI276257 down A_23_P111000 SEQ ID NO: 119 PSMB9 NM_002800 down A_32_P34552 SEQ ID NO: 120 POLB NM_002690 down A_23_P102060 SEQ ID NO: 121 SSFA2 NM_006751 down A_24_P71938 SEQ ID NO: 122 SMAD1 NM_005900 down A_32_P74366 SEQ ID NO: 123 VCPIP1 ENST00000310421 down A_23_P213247 SEQ ID NO: 124 FBXL5 NM_033535 down A_23_P202199 SEQ ID NO: 125 SLK NM_014720 down A_24_P370702 SEQ ID NO: 126 GBP3 NM_018284 down A_24_P937817 SEQ ID NO: 127 A_24_P937817 AK026195 down A_24_P53051 SEQ ID NO: 128 LACTB NM_171846 down A_23_P35912 SEQ ID NO: 129 CASP4 NM_033306 down A_23_P212706 SEQ ID NO: 130 ATG3 NM_022488 down A_23_P119992 SEQ ID NO: 131 VRK2 NM_006296 down A_24_P707156 SEQ ID NO: 132 A_24_P707156 BG623116 down A_24_P156490 SEQ ID NO: 133 KCNMA1 NM_002247 down A_23_P113263 SEQ ID NO: 134 A_23_P113263 A_23_P113263 down A_23_P35906 SEQ ID NO: 135 CASP4 NM_033306 down A_24_P393740 SEQ ID NO: 136 FYB NM_001465 down A_24_P239606 SEQ ID NO: 137 GADD45B NM_015675 down A_23_P256445 SEQ ID NO: 138 VCPIP1 NM_025054 down A_23_P251962 SEQ ID NO: 139 ZNF273 BC019234 down A_23_P83073 SEQ ID NO: 140 HIATL1 NM_032558 down A_32_P65804 SEQ ID NO: 141 A_32_P65804 THC2661836 down A_24_P54863 SEQ ID NO: 142 C4ORF32 NM_152400 down A_23_P356163 SEQ ID NO: 143 WDR49 NM_178824 down A_32_P35256 SEQ ID NO: 144 A_32_P35256 BF436068 down A_24_P211689 SEQ ID NO: 145 A_24_P211689 AK021629 down A_23_P417261 SEQ ID NO: 146 EFHB NM_144715 down A_23_P407090 SEQ ID NO: 147 NFXL1 NM_152995 down A_32_P164061 SEQ ID NO: 148 A_32_P164061 A_32_P164061 down A_23_P102582 SEQ ID NO: 149 C20ORF24 NM_018840 down A_24_P393353 SEQ ID NO: 150 XRN1 NM_001042604 down A_24_P50543 SEQ ID NO: 151 TRIM69 BC031266 down A_24_P920333 SEQ ID NO: 152 A_24_P920333 AA748674 down A_24_P101921 SEQ ID NO: 153 A_24_P101921 ENST00000391612 down A_23_P382148 SEQ ID NO: 154 RAB1A NM_004161 down A_24_P43391 SEQ ID NO: 155 TMEM165 NM_018475 down A_24_P167473 SEQ ID NO: 156 ARPC3 NM_005719 down A_23_P380901 SEQ ID NO: 157 PTH2R NM_005048 down A_23_P26583 SEQ ID NO: 158 NLRC5 NM_032206 down A_24_P263623 SEQ ID NO: 159 PTGES3 NM_006601 down A_23_P367610 SEQ ID NO: 160 SESTD1 NM_178123 down A_24_P372223 SEQ ID NO: 161 MSR1 NM_138715 down A_24_P367326 SEQ ID NO: 162 A_24_P367326 A_24_P367326 down A_23_P39840 SEQ ID NO: 163 VAMP5 NM_006634 down A_23_P402892 SEQ ID NO: 164 NLRC5 NM_032206 down A_23_P211080 SEQ ID NO: 165 IFNAR2 NM_207585 down A_23_P252106 SEQ ID NO: 166 RIPK2 NM_003821 down A_23_P12603 SEQ ID NO: 167 40607 NM_017824 down A_23_P259272 SEQ ID NO: 168 WSB2 NM_018639 down A_23_P209805 SEQ ID NO: 169 NAB1 NM_005966 down A_23_P79942 SEQ ID NO: 170 PANK2 NM_153638 down A_23_P383053 SEQ ID NO: 171 APPBP2 NM_006380 down A_23_P147238 SEQ ID NO: 172 WSB2 NM_018639 down A_23_P90589 SEQ ID NO: 173 MRPL44 NM_022915 down A_23_P250629 SEQ ID NO: 174 PSMB8 NM_004159 down A_23_P200560 SEQ ID NO: 175 CDC42 NM_001039802 down A_24_P390403 SEQ ID NO: 176 RTF1 NM_015138 down A_24_P269619 SEQ ID NO: 177 DECR1 NM_001359 down A_23_P71464 SEQ ID NO: 178 DECR1 NM_001359 down A_23_P164536 SEQ ID NO: 179 PIK3C3 NM_002647 down A_23_P11915 SEQ ID NO: 180 GDAP2 NM_017686 down A_23_P74928 SEQ ID NO: 181 MR1 NM_001531 down A_24_P206736 SEQ ID NO: 182 ZNF143 NM_003442 down A_23_P12920 SEQ ID NO: 183 RAD9A NM_004584 up A_23_P56188 SEQ ID NO: 184 UBA52 NM_001033930 up A_24_P914134 SEQ ID NO: 185 PRNP NM_001080122 up A_32_P108870 SEQ ID NO: 186 PMP2 NM_002677 up A_24_P921683 SEQ ID NO: 187 FOXP2 NM_014491 up A_23_P342612 SEQ ID NO: 188 HCN2 NM_001194 up A_24_P227326 SEQ ID NO: 189 RCOR2 NM_173587 up A_23_P111571 SEQ ID NO: 190 HOXA3 NM_153631 up A_23_P55716 SEQ ID NO: 191 BCAM NM_005581 up A_23_P397208 SEQ ID NO: 192 GSTM2 NM_000848 up A_23_P150162 SEQ ID NO: 193 DRD4 NM_000797 up A_32_P151317 SEQ ID NO: 194 A_32_P151317 BI818647 up A_24_P142305 SEQ ID NO: 195 HBA2 NM_000517 up

[0135] The amino acid and protein sequences included in the database entries having the accession numbers listed in Table 5 are incorporated herein by reference. In addition, the sequences of the AGILENT® probes are publicly available in GEO database of NCBI website as mentioned above.

[0136] These data indicate that administration of AMG 811 affects expression of many genes in viva Among these are a number of genes whose expression is also modulated by IFN-γ ex vivo as described in Example 1 and Table 1 above. A group of genes whose expression is modulated by IFN-γ ex vivo and by AMG 811 in vivo (in opposite directions), is listed in Table 6 below. The thresholds for being included in this list included (a) being included in Table 1 and (b) being significantly (p<0.05) modulated in vivo in patients receiving AMG 811 as compared to patients receiving placebo. This different cutoff value (as compared to p<0.001) for in vivo modulation by AMG 811 is appropriate and was used in view of the fact that this list was selected only from among the genes included in Table 1, rather than from the tens of thousands of genes represented in the array.

TABLE-US-00006 TABLE 6 Genes modulated by IFN-γ ex vivo and by AMG 811 in vivo Sequence Listing Direction of Number of Probe Accession No. of modulation Probe Identifier Sequence Symbol Sequence of cDNA by AMG 811 A_23_P103496 SEQ ID NO: 196 GBP4 NM_052941 down A_23_P105794 SEQ ID NO: 197 EPSTI1 NM_033255 down A_23_P111000 SEQ ID NO: 198 PSMB9 NM_002800 down A_23_P112251 SEQ ID NO: 199 GNG10 NM_001017998 down A_23_P112260 SEQ ID NO: 200 GNG10 NM_001017998 down A_23_P121253 SEQ ID NO: 110 TNFSF10 NM_003810 down A_23_P121716 SEQ ID NO: 201 ANXA3 NM_005139 down A_23_P123608 SEQ ID NO: 107 JAK2 NM_004972 down A_23_P125278 SEQ ID NO: 202 CXCL11 NM_005409 down A_23_P128447 SEQ ID NO: 203 LRRK2 NM_198578 down A_23_P129492 SEQ ID NO: 204 SEPX1 NM_016332 down A_23_P132388 SEQ ID NO: 205 SCO2 NM_005138 down A_23_P132822 SEQ ID NO: 115 XRN1 NM_019001 down A_23_P133133 SEQ ID NO: 206 ALPK1 NM_025144 down A_23_P133142 SEQ ID NO: 207 ALPK1 NM_025144 down A_23_P133916 SEQ ID NO: 208 C2 NM_000063 down A_23_P138680 SEQ ID NO: 209 IL15RA NM_172200 down A_23_P139123 SEQ ID NO: 210 SERPING1 NM_000062 down A_23_P140807 SEQ ID NO: 211 PSMB10 NM_002801 down A_23_P14105 SEQ ID NO: 212 RCBTB2 NM_001268 down A_23_P14174 SEQ ID NO: 213 TNFSF13B NM_006573 down A_23_P142424 SEQ ID NO: 214 TMEM149 NM_024660 down A_23_P145874 SEQ ID NO: 215 SAMD9L NM_152703 down A_23_P149476 SEQ ID NO: 216 EFCAB2 NM_032328 down A_23_P153320 SEQ ID NO: 217 ICAM1 NM_000201 down A_23_P15414 SEQ ID NO: 218 SCARF1 NM_145351 down A_23_P154235 SEQ ID NO: 102 NMI NM_004688 down A_23_P155049 SEQ ID NO: 219 APOL6 NM_030641 down A_23_P155052 SEQ ID NO: 220 APOL6 NM_030641 down A_23_P156687 SEQ ID NO: 221 CFB NM_001710 down A_23_P156788 SEQ ID NO: 222 STX11 NM_003764 down A_23_P160025 SEQ ID NO: 223 IFI16 NM_005531 down A_23_P160720 SEQ ID NO: 224 BATF3 NM_018664 down A_23_P161428 SEQ ID NO: 72 ANKRD22 NM_144590 down A_23_P163079 SEQ ID NO: 225 GCH1 NM_000161 down A_23_P165624 SEQ ID NO: 226 TNFAIP6 NM_007115 down A_23_P166408 SEQ ID NO: 227 OSM NM_020530 down A_23_P166797 SEQ ID NO: 228 RTP4 NM_022147 down A_23_P168828 SEQ ID NO: 229 KLF10 NM_005655 down A_23_P17655 SEQ ID NO: 230 KCNJ15 NM_170736 down A_23_P17837 SEQ ID NO: 231 APOL1 NM_145343 down A_23_P18452 SEQ ID NO: 109 CXCL9 NM_002416 down A_23_P18604 SEQ ID NO: 232 LAP3 NM_015907 down A_23_P202978 SEQ ID NO: 105 CASP1 NM_033292 down A_23_P203498 SEQ ID NO: 233 TRIM22 NM_006074 down A_23_P205200 SEQ ID NO: 234 DHRS12 NM_024705 down A_23_P208119 SEQ ID NO: 84 PSTPIP2 NM_024430 down A_23_P20814 SEQ ID NO: 235 DDX58 NM_014314 down A_23_P209625 SEQ ID NO: 236 CYP1B1 NM_000104 down A_23_P209678 SEQ ID NO: 237 PLEK NM_002664 down A_23_P210763 SEQ ID NO: 238 JAG1 NM_000214 down A_23_P211401 SEQ ID NO: 239 KREMEN1 NM_001039570 down A_23_P211445 SEQ ID NO: 240 LIMK2 NM_016733 down A_23_P211488 SEQ ID NO: 241 APOL2 NM_145637 down A_23_P215154 SEQ ID NO: 242 NUB1 NM_016118 down A_23_P218928 SEQ ID NO: 243 C4ORF18 NM_016613 down A_23_P24004 SEQ ID NO: 244 IFIT2 NM_001547 down A_23_P251480 SEQ ID NO: 245 NBN NM_002485 down A_23_P252106 SEQ ID NO: 166 RIPK2 NM_003821 down A_23_P255444 SEQ ID NO: 100 DAPP1 NM_014395 down A_23_P256445 SEQ ID NO: 138 VCPIP1 NM_025054 down A_23_P256487 SEQ ID NO: 78 A_23_P256487 THC2651085 down A_23_P257087 SEQ ID NO: 246 PDK4 NM_002612 down A_23_P258493 SEQ ID NO: 247 LMNB1 NM_005573 down A_23_P26583 SEQ ID NO: 158 NLRC5 NM_032206 down A_23_P29953 SEQ ID NO: 248 IL15 NM_172174 down A_23_P30069 SEQ ID NO: 249 DDX60L NM_001012967 down A_23_P3221 SEQ ID NO: 250 SQRDL NM_021199 down A_23_P329261 SEQ ID NO: 251 KCNJ2 NM_000891 down A_23_P329870 SEQ ID NO: 252 RHBDF2 NM_024599 down A_23_P335661 SEQ ID NO: 253 SAMD4A AB028976 down A_23_P338479 SEQ ID NO: 75 CD274 NM_014143 down A_23_P343837 SEQ ID NO: 254 PARP11 NM_020367 down A_23_P347040 SEQ ID NO: 255 DTX3L NM_138287 down A_23_P347541 SEQ ID NO: 99 GRIN3A NM_133445 down A_23_P35412 SEQ ID NO: 256 IFIT3 NM_001549 down A_23_P354387 SEQ ID NO: 257 MYOF NM_013451 down A_23_P358904 SEQ ID NO: 258 IKZF4 NM_022465 up A_23_P35906 SEQ ID NO: 135 CASP4 NM_033306 down A_23_P35912 SEQ ID NO: 129 CASP4 NM_033306 down A_23_P370682 SEQ ID NO: 80 BATF2 NM_138456 down A_23_P380857 SEQ ID NO: 259 APOL4 NM_030643 down A_23_P39840 SEQ ID NO: 163 VAMP5 NM_006634 down A_23_P401106 SEQ ID NO: 260 PDE2A NM_002599 up A_23_P402892 SEQ ID NO: 164 NLRC5 NM_032206 down A_23_P41765 SEQ ID NO: 261 IRF1 NM_002198 down A_23_P420942 SEQ ID NO: 262 MT1E AF495759 up A_23_P421423 SEQ ID NO: 263 TNFAIP2 NM_006291 down A_23_P42282 SEQ ID NO: 264 C4B NM_001002029 up A_23_P42302 SEQ ID NO: 265 HLA-DQA2 NM_020056 up A_23_P42353 SEQ ID NO: 77 ETV7 NM_016135 down A_23_P42969 SEQ ID NO: 266 FGL2 NM_006682 down A_23_P47304 SEQ ID NO: 267 CASP5 NM_004347 down A_23_P4821 SEQ ID NO: 268 JUNB NM_002229 down A_23_P48513 SEQ ID NO: 269 IFI27 NM_005532 up A_23_P51487 SEQ ID NO: 93 GBP3 NM_018284 down A_23_P53891 SEQ ID NO: 270 KLF5 NM_001730 down A_23_P56630 SEQ ID NO: 89 STAT1 NM_007315 down A_23_P56746 SEQ ID NO: 271 FAP NM_004460 down A_23_P571 SEQ ID NO: 272 SLC2A1 NM_006516 up A_23_P57983 SEQ ID NO: 273 PARP14 AB033094 down A_23_P58390 SEQ ID NO: 274 C4ORF32 NM_152400 down A_23_P59005 SEQ ID NO: 113 TAP1 NM_000593 down A_23_P62890 SEQ ID NO: 74 GBP1 NM_002053 down A_23_P63390 SEQ ID NO: 73 FCGR1B NM_001017986 down A_23_P63896 SEQ ID NO: 92 FAS NM_000043 down A_23_P64343 SEQ ID NO: 275 TIMM10 NM_012456 down A_23_P64721 SEQ ID NO: 276 GPR109B NM_006018 down A_23_P65427 SEQ ID NO: 277 PSME2 NM_002818 down A_23_P65651 SEQ ID NO: 278 WARS NM_004184 down A_23_P68155 SEQ ID NO: 279 IFIH1 NM_022168 down A_23_P68851 SEQ ID NO: 280 KREMEN1 NM_001039570 down A_23_P69109 SEQ ID NO: 281 PLSCR1 NM_021105 down A_23_P69310 SEQ ID NO: 282 CCRL2 NM_003965 down A_23_P69383 SEQ ID NO: 101 PARP9 NM_031458 down A_23_P72737 SEQ ID NO: 283 IFITM1 NM_003641 down A_23_P74001 SEQ ID NO: 284 S100A12 NM_005621 down A_23_P74290 SEQ ID NO: 79 GBP5 NM_052942 down A_23_P75430 SEQ ID NO: 285 C11ORF75 NM_020179 down A_23_P75741 SEQ ID NO: 286 UBE2L6 NM_198183 down A_23_P7827 SEQ ID NO: 83 FAM26F NM_001010919 down A_23_P79518 SEQ ID NO: 287 IL1B NM_000576 down A_23_P81898 SEQ ID NO: 288 UBD NM_006398 down A_23_P83098 SEQ ID NO: 289 ALDH1A1 NM_000689 down A_23_P8513 SEQ ID NO: 290 SNX10 NM_013322 down A_23_P85693 SEQ ID NO: 90 GBP2 NM_004120 down A_23_P85783 SEQ ID NO: 291 PHGDH NM_006623 up A_23_P86390 SEQ ID NO: 292 NRP1 NM_003873 up A_23_P87709 SEQ ID NO: 293 FLJ22662 NM_024829 down A_23_P9232 SEQ ID NO: 294 GCNT1 NM_001490 down A_23_P94412 SEQ ID NO: 295 PDCD1LG2 NM_025239 down A_23_P96556 SEQ ID NO: 94 GK NM_203391 down A_23_P97064 SEQ ID NO: 296 FBXO6 NM_018438 down A_24_P100387 SEQ ID NO: 85 GK NM_203391 down A_24_P124032 SEQ ID NO: 297 RIPK2 NM_003821 down A_24_P156490 SEQ ID NO: 133 KCNMA1 NM_002247 down A_24_P15702 SEQ ID NO: 298 LOC389386 XR_017251 down A_24_P161018 SEQ ID NO: 299 PARP14 NM_017554 down A_24_P165864 SEQ ID NO: 300 P2RY14 NM_014879 down A_24_P167642 SEQ ID NO: 301 GCH1 NM_000161 down A_24_P172481 SEQ ID NO: 302 TRIM22 NM_006074 down A_24_P184445 SEQ ID NO: 303 MMP19 NM_002429 up A_24_P212481 SEQ ID NO: 304 MCTP1 NM_024717 down A_24_P222655 SEQ ID NO: 305 C1QA NM_015991 down A_24_P243749 SEQ ID NO: 82 PDK4 NM_002612 down A_24_P245815 SEQ ID NO: 306 ASPHD2 NM_020437 down A_24_P250922 SEQ ID NO: 307 PTGS2 NM_000963 down A_24_P251764 SEQ ID NO: 308 CXCL3 NM_002090 up A_24_P270460 SEQ ID NO: 309 IF127 NM_005532 up A_24_P274270 SEQ ID NO: 88 STAT1 NM_139266 down A_24_P278126 SEQ ID NO: 310 NBN NM_002485 down A_24_P303091 SEQ ID NO: 311 CXCL10 NM_001565 down A_24_P304154 SEQ ID NO: 312 AMPD3 NM_001025390 down A_24_P322353 SEQ ID NO: 91 PSTPIP2 NM_024430 down A_24_P323148 SEQ ID NO: 313 LYPD5 NM_182573 down A_24_P334361 SEQ ID NO: 314 DDX60 NM_017631 down A_24_P350686 SEQ ID NO: 106 TIFA NM_052864 down A_24_P36898 SEQ ID NO: 86 A_24_P36898 AL832451 down A_24_P370702 SEQ ID NO: 126 GBP3 NM_018284 down A_24_P372625 SEQ ID NO: 315 RNF141 NM_016422 down A_24_P382319 SEQ ID NO: 316 CEACAM1 NM_001712 down A_24_P383523 SEQ ID NO: 317 SAMD4A NM_015589 down A_24_P393353 SEQ ID NO: 318 XRN1 NM_001042604 down A_24_P45446 SEQ ID NO: 108 GBP4 NM_052941 down A_24_P47329 SEQ ID NO: 319 A_24_P47329 BC063641 down A_24_P48204 SEQ ID NO: 320 SECTM1 NM_003004 down A_24_P48898 SEQ ID NO: 321 APOL2 NM_145637 down A_24_P53051 SEQ ID NO: 128 LACTB NM_171846 down A_24_P54863 SEQ ID NO: 142 C4ORF32 NM_152400 down A_24_P561165 SEQ ID NO: 322 A_24_P561165 A_24_P561165 down A_24_P659202 SEQ ID NO: 323 A_24_P659202 THC2527772 up A_24_P66027 SEQ ID NO: 324 APOBEC3B NM_004900 down A_24_P7594 SEQ ID NO: 103 APOL6 NM_030641 down A_24_P87931 SEQ ID NO: 325 APOL1 NM_145343 down A_24_P912985 SEQ ID NO: 326 A_24_P912985 A_24_P912985 down A_24_P928052 SEQ ID NO: 327 NRP1 NM_003873 down A_24_P935819 SEQ ID NO: 328 SOD2 BC016934 down A_24_P935986 SEQ ID NO: 329 BCAT1 NM_005504 down A_24_P941167 SEQ ID NO: 330 APOL6 NM_030641 down A_24_P941912 SEQ ID NO: 331 DTX3L NM_138287 down A_24_P943205 SEQ ID NO: 332 EPSTI1 AL831953 down A_24_P97342 SEQ ID NO: 333 PROK2 NM_021935 down A_24_P98109 SEQ ID NO: 334 SNX10 NM_013322 down A_24_P98210 SEQ ID NO: 335 TFEC NM_012252 down A_32_P107372 SEQ ID NO: 76 GBP1 NM_002053 down A_32_P15169 SEQ ID NO: 336 A_32_P15169 A_32_P15169 down A_32_P156746 SEQ ID NO: 337 A_32_P156746 BE825944 down A_32_P162183 SEQ ID NO: 338 C2 NM_000063 down A_32_P166272 SEQ ID NO: 96 STX11 NM_003764 down A_32_P184394 SEQ ID NO: 339 TFEC NM_012252 down A_32_P191417 SEQ ID NO: 340 A_32_P191417 AW276186 down A_32_P222250 SEQ ID NO: 341 A_32_P222250 AF119908 down A_32_P30004 SEQ ID NO: 342 A_32_P30004 AF086044 down A_32_P399546 SEQ ID NO: 343 ARNTL2 AF256215 down A_32_P44394 SEQ ID NO: 87 AIM2 NM_004833 down A_32_P56759 SEQ ID NO: 344 PARP14 NM_017554 down A_32_P91773 SEQ ID NO: 345 A_32_P91773 THC2544236 down A_32_P92415 SEQ ID NO: 346 A_32_P92415 AA455656 down A_32_P95082 SEQ ID NO: 347 CNTLN NM_017738 down A_32_P9543 SEQ ID NO: 348 APOBEC3A NM_145699 down

[0137] Assaying for levels of expression of one or more of the genes in Tables 1, 2, 4, 5, and/or 6 in a biological sample from a diseased patient, optionally an SLE patient, before treatment with an IFN-γ inhibitor, such as AMG 811, and comparison to levels of expression in a control biological sample can indicate which patients might benefit from treatment with an IFN-γ inhibitor. Patients expressing elevated levels of an RNA or protein that is downregulated in vivo by AMG 811 or decreased levels of an RNA or protein that is upregulated by AMG 811 in vivo might benefit from treatment with an IFN-γ inhibitor. Similarly, patients expressing elevated or lowered levels of an RNA or protein that is up- or down-regulated by IFN-γ could also benefit from treatment with an IFN-γ inhibitor. Further, comparison of expression levels of one or more of the genes listed in Tables 1, 2, 4, 5, and/or 6 before and after treatment with an IFN-γ inhibitor can indicate whether the IFN-γ inhibitor is having a biological effect in a particular patient in vivo. If so, continuing treatment can be advantageous for that patient. If not, treatment can be discontinued, or the IFN-γ inhibitor can be administered at a higher dose or at a greater frequency.

[0138] In FIG. 11, levels of GBP1 transcript versus AMG 811 concentration in serum on days 1 and 15 of the study in lupus nephritis patients are plotted. Comparing FIG. 11 to the right panel of FIG. 3, which contains similar data from SLE patients, a number of conclusions can be made. First, lupus nephritis patients as a group have higher levels of GBP1 expression at baseline than SLE patients as a group. Further, whereas all SLE patients exhibited a decrease in GBP1 expression upon administration of AMG 811, this was not true for lupus nephritis patients. Also, the magnitude of the decreases observed among general SLE patients was apparently greater than the decreases observed among lupus nephritis patients. Hence, these data indicate that SLE and lupus nephritis patients, as groups, have different responses to AMG 811. These differences may be related to differences in the nature and severity of disease activity in these two groups and may indicate that dosing requirements can differ between these two categories of patients. These data also suggest that expression of biomarkers such as GBP1 could inform dose selection. For example, patients having, for example, higher GBP1 expression could require higher doses of AMG 811, whereas patients with lower GBP1 expression could require lower doses of AMG 811.

[0139] Clinical parameters related to kidney function were assessed for patients in cohorts 4 and 5 in this trial. Spot urine protein, spot urine creatinine, 24 hour urine protein, 24 hour urine creatinine, serum creatinine, serum albumin, antibodies against double stranded DNA, and complement factors C3 and C4 were assessed.

[0140] Urine protein amounts were determined by a dye-binding assay (pyrocatechol violet-ammounium molybdate dye) analyzed in a "dry slide" format using an automated laboratory analyzer. Samples used were either a collection of all the patient's urine over a 24 hour period (24 hour urine protein) or a single urine sample (spot urine protein). Urine creatinine was assessed by a multi-step coupled enzymatic two-point rate colorimetric assay (creatininie amidohydrolase/creatine amidinohydrolase/sarcosine oxidase/peroxidase) analyzed using a "dry slide" format in an automated laboratory analyzer.

[0141] Cohorts 4 and 5 comprised lupus nephritis patients receiving doses of 20 mg or 60 mg AMG 811, respectively, or placebo. Although some results from these cohorts are now available, the results are still blinded. Since only two of eight (cohort 4) and three of twelve (cohort 5) patients received placebo, differences in clinical parameters between cohorts 4 and 5 might indicate dose-dependent responses to AMG 811. Among the various measurements made, the following tests indicated no clear difference between cohorts 4 and 5: spot urine creatinine, 24 hour urine creatinine, serum creatinine, serum albumin, complement factors C3 and C4, and anti-double stranded DNA antibodies. On the other hand, urine protein in a 24 hour urine collection and the ratio of urine protein to urine creatinine (UPCR) clearly differed between cohorts 4 and 5, as shown in FIGS. 12 and 13. High amounts of urine protein and/or high UPCR indicate impairment of kidney function. Since all but two of the patients in cohort 4 and two or three in cohort 5 received AMG 811, these data suggest that AMG 811 may have a dose-dependent effect on kidney function in lupus nephritis patients. More specifically, these results suggest that a dose of more than 20 mg of AMG 811 is necessary to have a positive effect on kidney function in lupus nephritis patients.

Example 5

Single Dose Trial in Discoid Lupus

[0142] A phase 1b single dose crossover study in discoid lupus has been enrolled. Sixteen subjects (of twenty planned subjects) with discoid lupus were dosed with a single dose of 180 milligrams of AMG 811 and a single dose of placebo, each administered subcutaneously, in one of two sequences. Per study protocol, twelve patients were to receive 180 mg SC of AMG 811 on day 1 and a dose of placebo on day 85, and eight patients were to receive a dose of placebo on day 1 and 180 mg SC of AMG 811 on day 85. However, enrollment of the study was stopped after sixteen patients had been enrolled. As primary endpoints of the study, treatment-emergent adverse events, vital signs, clinical laboratory tests, ECGs, and the incidence of binding and neutralizing antibodies to AMG 811 were monitored. Physical examinations were also to be performed.

[0143] In secondary endpoints of the study, the pharmacokinetic profile of AMG 811 is determined, and CLASI scores are determined. Expression of biomarkers in peripheral blood at the RNA level are assessed by hybridization to a DNA array as described above in samples taken at baseline (in the time period from three days prior to dosing to one day prior to dosing) and on days 15, 29, 57, 85, 99, 113, 141, 169, and 197 (which is the end of study). Analysis of selected biomarkers at the protein level by ELISA may also be performed. In addition, skin samples were taken at baseline and on days 15 and 57 for analysis of biomarker expression at the RNA level by hybridization to a DNA array. Selected biomarkers may also be assayed at the protein level in the skin samples using immunohistochemistry, immunofluorescence, or ELISA. Information available to date indicates that clinical parameters, such as improvements in the CLASI score, did not correlate clearly with dosing of AMG 811. The results of this trial are still blinded.

Example 6

Single Dose Trial in Psoriasis

[0144] A phase 1b single dose, double-blind, placebo-controlled study in psoriasis is in progress. Nine subjects with moderate to severe plaque psoriasis (having a PASI score 10 and an affected body surface area 10) were enrolled in the study. The study is still blinded. Proceeding with a study plan that originally included ten, not nine, patients, seven or eight patients will receive drug, and one or two patients will receive placebo. Those that receive drug will receive (or have received) a single dose of 180 milligrams of AMG 811 on study day 1. As primary endpoints of the study, treatment-emergent adverse events, vital signs, clinical laboratory tests, ECGs, and the incidence of binding and neutralizing antibodies to AMG 811 were monitored. Physical examinations were also performed.

[0145] As secondary endpoints, clinicians assessed PASI scores, PGA scores, and target lesions. Photos were taken to document skin lesions. The pharmacokinetic profile of AMG 811 will also be determined. All of these primary and secondary endpoints were assessed at baseline (from three days to one day before dosing) and on days 15, 29, 43, 57, 85, and 113 (which is the end of study). Skin biopsies were taken at baseline and at baseline and on days 15 and 57 for analysis of biomarker expression at the RNA level as described above. In addition selected biomarkers may be assessed for expression at the protein level by ELISA for serum samples or by immunohistochemistry or immunofluorescence for skin biopsies.

[0146] In FIG. 14, blinded data showing PASI scores for the nine patients in this trial are displayed. Given the design of the trial, one or two of these patients received placebo, and seven or eight received AMG 811. All but one of these eight patients experienced a decrease, i.e., an improvement, in PASI score at some or all post-dose time points, a result indicating that most patients receiving AMG 811 experienced at least a temporary clinical benefit. However, since the data is blinded and one or two of these patients received placebo, the effects of AMG 811 on PASI scores will be more clear when the data is unblinded.

Sequence CWU 1

1

6971990DNAHomo sapiens 1gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa 9902330PRTHomo sapiens 2Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 3321DNAHomo sapiens 3cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300agcttcaaca ggggagagtg t 3214107PRTHomo sapiens 4Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 5351DNAHomo sapiens 5gaggtgcagc tggtacagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60tcctgtaagg gttctggata caactttacc agctactgga tcggctgggt gcgccagatg 120cccgggaaag gcctggagtt gatggggatc atctatcctg gtgactctga taccagatac 180agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgg ttcggggagc 300tacttttact tcgatctctg gggccgtggc accctggtca ccgtctctag t 3516117PRTHomo sapiens 6Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Leu Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ser Gly Ser Tyr Phe Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 7324DNAHomo sapiens 7gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatatat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cggtctggtg gctcatcatt cactttcggc 300cctgggacca aagtggatat caaa 3248108PRTHomo sapiens 8Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser Gly Gly Ser Ser 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 9351DNAHomo sapiens 9gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgg ttcggggagc 300tactggtact tcgatctctg gggccgtggc accctggtca ccgtctctag t 35110117PRTHomo sapiens 10Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ser Gly Ser Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 11324DNAHomo sapiens 11gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctcct tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatatat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cggtctggtg gctcatcatt cactttcggc 300cctgggacca aagtggatat caaa 32412108PRTHomo sapiens 12Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser Gly Gly Ser Ser 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 13351DNAHomo sapiens 13gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60tcctgtaagg gttctggata caactttacc agctactgga tcggctgggt gcgccagatg 120cccgggaaag gcctggagtt gatggggatc atctatcctg gtgactctga taccagatac 180agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgg ttcggggagc 300tactggtact tcgatctctg gggccgtggc accctggtca ccgtctctag t 35114117PRTHomo sapiens 14Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Leu Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ser Gly Ser Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 15324DNAHomo sapiens 15gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatatat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cggtctggtg gctcatcatt cactttcggc 300cctgggacca aagtggatat caaa 32416108PRTHomo sapiens 16Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser Gly Gly Ser Ser 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 17447PRTHomo sapiens 17Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Leu Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ser Gly Ser Tyr Phe Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 18215PRTHomo sapiens 18Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser Gly Gly Ser Ser 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln

Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 19447PRTHomo sapiens 19Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ser Gly Ser Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 20215PRTHomo sapiens 20Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser Gly Gly Ser Ser 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 21447PRTHomo sapiens 21Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ser Gly Ser Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 22215PRTHomo sapiens 22Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Ser Gly Gly Ser Ser 85 90 95 Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 2324DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 23ggccggatag gcctccannn nnnt 242421DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 24ggggtcaggc tggaactgag g 212519DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 25tgaggacgct gaccacacg 192648DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 26acaacaaagc ttctagacca ccatggaaac cccagctcag cttctctt 482733DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 27cttgtcgact caacactctc ccctgttgaa gct 332844DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 28cagcagaagc ttctagacca ccatggggtc aaccgccatc ctcg 442942DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 29cttggtggag gcactagaga cggtgaccag ggtgccacgg cc 4230117PRTHomo sapiens 30Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ser Gly Ser Tyr Trp Tyr Phe Asp Leu Arg Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 31109PRTHomo sapiens 31Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ile Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Thr Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Val Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Phe 85 90 95 Met Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 32447PRTHomo sapiens 32Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ser Gly Ser Tyr Trp Tyr Phe Asp Leu Arg Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 33216PRTHomo sapiens 33Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ile Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Thr Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Val Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu 65

70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Phe 85 90 95 Met Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val 100 105 110 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 115 120 125 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 145 150 155 160 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205 Lys Ser Phe Asn Arg Gly Glu Cys 210 215 345PRTHomo sapiens 34Ser Tyr Trp Ile Gly 1 5 3517PRTHomo sapiens 35Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln 1 5 10 15 Gly 368PRTHomo sapiens 36Gly Ser Tyr Phe Tyr Phe Asp Leu 1 5 378PRTHomo sapiens 37Gly Ser Tyr Trp Tyr Phe Asp Leu 1 5 3812PRTHomo sapiens 38Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 3912PRTHomo sapiens 39Arg Ala Ser Gln Ser Val Ser Ser Ser Ser Leu Ala 1 5 10 4012PRTHomo sapiens 40Arg Ala Ser Gln Ser Ile Ile Ser Ser Tyr Leu Ala 1 5 10 417PRTHomo sapiens 41Gly Ala Ser Ser Arg Ala Thr 1 5 427PRTHomo sapiens 42Gly Val Ser Ser Arg Ala Thr 1 5 439PRTHomo sapiens 43Gln Arg Ser Gly Gly Ser Ser Phe Thr 1 5 4410PRTHomo sapiens 44Gln Gln Tyr Gly Asn Ser Phe Met Tyr Thr 1 5 10 4524DNAHomo sapiens 45gggagctact tttacttcga tctc 244624DNAHomo sapiens 46gggagctact ggtacttcga tctc 244727DNAHomo sapiens 47cagcggtctg gtggctcatc attcact 2748351DNAHomo sapiens 48gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60tcctgtaagg gttctggata cagctttacc agctactgga tcggctgggt gcgccagatg 120cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgg ttcggggagc 300tactggtact tcgatctccg gggccgtggc accctggtca ccgtctctag t 35149327DNAHomo sapiens 49gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtattatc agcagctact tagcctggta ccagcagaaa 120cctggccaga ctcccaggct cctcatctat ggtgtatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcac cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta actcatttat gtacactttt 300ggccagggga ccaagctgga gatcaaa 327501944DNAHomo sapiens 50aatttctcac tgcccctgtg ataaactgtg gtcactggct gtggcagcaa ctattataag 60atgctctgaa aactcttcag acactgaggg gcaccagagg agcagactac aagaatggca 120cacgctatgg aaaactcctg gacaatcagt aaagagtacc atattgatga agaagtgggc 180tttgctctgc caaatccaca ggaaaatcta cctgattttt ataatgactg gatgttcatt 240gctaaacatc tgcctgatct catagagtct ggccagcttc gagaaagagt tgagaagtta 300aacatgctca gcattgatca tctcacagac cacaagtcac agcgccttgc acgtctagtt 360ctgggatgca tcaccatggc atatgtgtgg ggcaaaggtc atggagatgt ccgtaaggtc 420ttgccaagaa atattgctgt tccttactgc caactctcca agaaactgga actgcctcct 480attttggttt atgcagactg tgtcttggca aactggaaga aaaaggatcc taataagccc 540ctgacttatg agaacatgga cgttttgttc tcatttcgtg atggagactg cagtaaagga 600ttcttcctgg tctctctatt ggtggaaata gcagctgctt ctgcaatcaa agtaattcct 660actgtattca aggcaatgca aatgcaagaa cgggacactt tgctaaaggc gctgttggaa 720atagcttctt gcttggagaa agcccttcaa gtgtttcacc aaatccacga tcatgtgaac 780ccaaaagcat ttttcagtgt tcttcgcata tatttgtctg gctggaaagg caacccccag 840ctatcagacg gtctggtgta tgaagggttc tgggaagacc caaaggagtt tgcagggggc 900agtgcaggcc aaagcagcgt ctttcagtgc tttgacgtcc tgctgggcat ccagcagact 960gctggtggag gacatgctgc tcagttcctc caggacatga gaagatatat gccaccagct 1020cacaggaact tcctgtgctc attagagtca aatccctcag tccgtgagtt tgtcctttca 1080aaaggtgatg ctggcctgcg ggaagcttat gacgcctgtg tgaaagctct ggtctccctg 1140aggagctacc atctgcaaat cgtgactaag tacatcctga ttcctgcaag ccagcagcca 1200aaggagaata agacctctga agacccttca aaactggaag ccaaaggaac tggaggcact 1260gatttaatga atttcctgaa gactgtaaga agtacaactg agaaatccct tttgaaggaa 1320ggttaatgta acccaacaag agcacatttt atcatagcag agacatctgt atgcattcct 1380gtcattaccc attgtaacag agccacaaac taatactatg caatgtttta ccaataatgc 1440aatacaaaag acctcaaaat acctgtgcat ttcttgtagg aaaacaacaa aaggtaatta 1500tgtgtaatta tactagaagt tttgtaatct gtatcttatc attggaataa aatgacattc 1560aataaataaa aatgcataag atatattctg tcggctgggc gcggtggctc acgcctgtaa 1620tcccagcact ttgggaggcc gaggcgggcg gatcacaagg tcaggagatc gagaccatct 1680tggctaacac ggtgaaaccc cgtctctact aaaaatacaa aaaattagcc gggcgcggtg 1740gcgggcacct gtagtcccag ctactcggga ggctgaggca ggagaatggc gtgaacctgg 1800gaggcggagc ttgcagtgag ccaagattgt gccactgcaa tccggcctgg gctaaagagc 1860gggactccgt ctcaaaaaaa aaaaaaaaaa gatatattct gtcataataa ataaaaatgc 1920ataagatata aaaaaaaaaa aaaa 1944513993DNAHomo sapiens 51aatgtaagaa cttttcttcc tcccttaact ttgcttcctt ctttcctgca tgttaccact 60ggcagagcaa atatgactca gaaaccggct cctcagggtt gtaacattag atgatacagg 120cttgggtcgt tacacatgac accagtgcct ttgtttcatt gggctgggct ctctggaagg 180tgtgctgctg cctgagctgc tggaaaagca ctgacaggtg tttgctagaa aagcactcct 240ggagcttgcc accagcttgg acttctaggg actttcctct cagccaggaa ggattttgat 300attcatcaga aatacctcca gaagattcaa ggagctgtag aggtgaagta agcctgtgaa 360ggaccagcat gggaatccta tactctgagc ccatctgcca agcagcctat cagaatgact 420ttggacaagt gtggcggtgg gtgaaagaag acagcagcta tgccaacgtt caagatggct 480ttaatggaga cacgcccctg atctgtgctt gcaggcgagg gcatgtgaga atcgtttcct 540tccttttaag aagaaatgct aatgtcaacc tcaaaaacca gaaagagaga acctgcttgc 600attatgctgt gaagaaaaaa tttaccttca ttgattatct actaattatc ctcttaatgc 660ctgttctgct tattgggtat ttcctcatgg tatcaaagac aaagcagaat gaggctcttg 720tacgaatgct acttgatgct ggcgtcgaag ttaatgctac agattgttat ggctgtaccg 780cattacatta tgcctgtgaa atgaaaaacc agtctcttat ccctctgctc ttggaagccc 840gtgcagaccc cacaataaag aataagcatg gtgagagctc actggatatt gcacggagat 900taaaattttc ccagattgaa ttaatgctaa ggaaagcatt gtaatccttg tgaccacacc 960gatggagata cagaaaaagt taacgactgg attctatctt cattttagac ttttggtctg 1020tgggccattt aacctggatg ccaccatttt atggggataa tgatgcttac catggttaat 1080gttttggaag agctttttat ttatagcatt gtttactcag tcaagttcac catggccgta 1140atccttctaa gggaaacact aaagttgttg tagtctccac ttcagtcaga aactgatgtt 1200tcagctaggc acagtggtac atgcctgtaa tcccagctac ttgggaggct gaggtgggag 1260gatcacttga actcaggagt ttgagagcag ccagggcaac acagcgagac cctgtctcaa 1320aaaaaaaaaa aaaaaaaaaa gccctggtgt tccaaactca gtctttcctg aagaagagga 1380tctgagttat cttctgaaac agcgttctcc cttcccagtt gtatcactct tataaaaaga 1440ctgtccagtc tatgtcatgc cctaggagac aaactgttcc tcccagcccc ctttgagtat 1500tgagcagaag aatcaaatta ttaaatacgt atgtttgtac agaatggtat ttgtgtatgt 1560gtgtgggctt agagattcac aagtaaatat tcctttggtg aaggaatttc aataaaaaca 1620tctatcaagt gtcagcggtg agtgtgttta caccacagaa attggcaaat tgacaaatca 1680gagtttgttt ttgttttttt gttttttact ttccataaag ttcgtttacc agcataccac 1740tagagatttc ggtttacaaa taaaagccat cttggtttga gcaagactat gcaactatga 1800aaatgttcgt ttaaaaaaat cttcatgatc cttttgtaaa tacaaggtgg ttgccaagct 1860tgttagtttt gtttatttta ttgatagatg taaaatatta ttgtaactta tttggataaa 1920gttcttcaaa agaaacagag ctatacaatg aggtaggatc tggattattt gtctaagtga 1980gagattgcga atatcaaaat atctgtctca cttcttctgt gaatgacaca gagtagaaat 2040aaattcactt taaaaatatg actgaatttt gaaaatcaag actgaatctc acatagctgc 2100agacaggaac taagccagcc tctttgtatg tggtaacaag tacagtataa gaatgaaaga 2160tttaccatcc ttgaaagctc taatgaaaat caaatccagc aatatatatt caactgtgta 2220caggatttaa gaaacttatt ttatgaagga agtaatagtg tgtagatata gattctgaag 2280tctttaaacg tgtcttaata aattaagatt cactggcatt gagctgagct accaggtgac 2340ccttggggac aaaaaaccca cacaagtgaa tttcacacac cagtatacct tcaacaatat 2400acttttgaca cacacaaacc tttgatttgg tttcagagat tttgcaaaat agtaccaatg 2460taatttacaa ctgtcatctt tgaaattgtg taaaagtgga ataattttct gaagaaataa 2520atcatggttt gtcaatgagt tgcagagact gtctgacatt aactttgtca agattaaagg 2580ataaagtata tgacaatttg tttcatcatg ctcatgacat tatgcaattt tctccctagc 2640ttttaatttt tggaggcaga aaattgagcc agaaattttt agtcattagg tctcctagca 2700acaagctgta aaccttccaa caagcttgga ctagaatcta gacactgaaa tgcacataca 2760tgctttatgt aatgcagaat gcatttattg gagaactcat aaacatccta taaaattttc 2820ttccctgaga tgcaactata aaacttggcc ttattctgag aatgcttaac atagatttca 2880tccatactgt aacactgatt ttgttgttgt tgtccttaaa gcagctcagc ttcctgaggt 2940agtgttatgt ctctgtggca acaaggtgaa aatgtctagc ttattttgtc aaagtcaaca 3000ataatccaca gactccagac ctcaatatct gtcccaattt gccattttac tttagtgctc 3060caaaaatatg gcttatagaa aaaacaatag gtgttttaaa gagatttacc tgaatgatat 3120agagaatgtc tagatatttt ctggctatca ggtaaaacct acccttcaag atggtagaat 3180atataatagc atacaaaacc tctatttacc taataagtac tttaatttac agaaaaaaaa 3240tgtaaatgta agtgtcggat ttagtgccaa gtgcagggaa tctgaaaaat gtatactagg 3300tctctgctct ccgtaattct gccttcatgg gtcctagccc catccctcag gaggttgtcc 3360taagatcgtc agtgtcagat gcttcacaat acggcctcac accgtccctg ggaaaggttg 3420gtctcctcct gctgcatcag atggatgatt tcattgtaca tacggtgagg agcatccaaa 3480ccccagatga aatccacgtg agcccattca ggaatattct tatggtagat gaggttggtc 3540acctcagaga gcagcatttt cacgtcttct ggatttgaaa gccagtcctg acctcctgtc 3600cacattgctg tagggaccgt catatctctg actctgtacc ttacaggagt tggctagaga 3660aaaggaatag ttcttaactc taggtaacat ttggactttc aggctcataa tttatgtttc 3720aaatagacat aataaacatg ccatctgttg tggtgaaggg tacatgggtg ttagagccac 3780acaactctgt taagaatttc tgttcccgcc cttactttaa ggtaaaatta cttaacatta 3840ttgaacctca gtttcttctt ctgtgactgg ggataatatc tgtaataact tgctagatca 3900aatgacaaaa cacataaaaa catgtaatgc cttgtatttc ttttttcttc ctattaaata 3960ttttgtaaat aaattgtttt taaaaaaaaa aaa 3993522545DNAHomo sapiens 52atccaataca ggagtgactt ggaactccat tctatcacta tgaagaaaag tggtgttctt 60ttcctcttgg gcatcatctt gctggttctg attggagtgc aaggaacccc agtagtgaga 120aagggtcgct gttcctgcat cagcaccaac caagggacta tccacctaca atccttgaaa 180gaccttaaac aatttgcccc aagcccttcc tgcgagaaaa ttgaaatcat tgctacactg 240aagaatggag ttcaaacatg tctaaaccca gattcagcag atgtgaagga actgattaaa 300aagtgggaga aacaggtcag ccaaaagaaa aagcaaaaga atgggaaaaa acatcaaaaa 360aagaaagttc tgaaagttcg aaaatctcaa cgttctcgtc aaaagaagac tacataagag 420accacttcac caataagtat tctgtgttaa aaatgttcta ttttaattat accgctatca 480ttccaaagga ggatggcata taatacaaag gcttattaat ttgactagaa aatttaaaac 540attactctga aattgtaact aaagttagaa agttgatttt aagaatccaa acgttaagaa 600ttgttaaagg ctatgattgt ctttgttctt ctaccaccca ccagttgaat ttcatcatgc 660ttaaggccat gattttagca atacccatgt ctacacagat gttcacccaa ccacatccca 720ctcacaacag ctgcctggaa gagcagccct aggcttccac gtactgcagc ctccagagag 780tatctgaggc acatgtcagc aagtcctaag cctgttagca tgctggtgag ccaagcagtt 840tgaaattgag ctggacctca ccaagctgct gtggccatca acctctgtat ttgaatcagc 900ctacaggcct cacacacaat gtgtctgaga gattcatgct gattgttatt gggtatcacc 960actggagatc accagtgtgt ggctttcaga gcctcctttc tggctttgga agccatgtga 1020ttccatcttg cccgctcagg ctgaccactt tatttctttt tgttcccctt tgcttcattc 1080aagtcagctc ttctccatcc taccacaatg cagtgccttt cttctctcca gtgcacctgt 1140catatgctct gatttatctg agtcaactcc tttctcatct tgtccccaac accccacaga 1200agtgctttct tctcccaatt catcctcact cagtccagct tagttcaagt cctgcctctt 1260aaataaacct ttttggacac acaaattatc ttaaaactcc tgtttcactt ggttcagtac 1320cacatgggtg aacactcaat ggttaactaa ttcttgggtg tttatcctat ctctccaacc 1380agattgtcag ctccttgagg gcaagagcca cagtatattt ccctgtttct tccacagtgc 1440ctaataatac tgtggaacta ggttttaata attttttaat tgatgttgtt atgggcagga 1500tggcaaccag accattgtct cagagcaggt gctggctctt tcctggctac tccatgttgg 1560ctagcctctg gtaacctctt acttattatc ttcaggacac tcactacagg gaccagggat 1620gatgcaacat ccttgtcttt ttatgacagg atgtttgctc agcttctcca acaataagaa 1680gcacgtggta aaacacttgc ggatattctg gactgttttt aaaaaatata cagtttaccg 1740aaaatcatat aatcttacaa tgaaaaggac tttatagatc agccagtgac caaccttttc 1800ccaaccatac aaaaattcct tttcccgaag gaaaagggct ttctcaataa gcctcagctt 1860tctaagatct aacaagatag ccaccgagat ccttatcgaa actcatttta ggcaaatatg 1920agttttattg tccgtttact tgtttcagag tttgtattgt gattatcaat taccacacca 1980tctcccatga agaaagggaa cggtgaagta ctaagcgcta gaggaagcag ccaagtcggt 2040tagtggaagc atgattggtg cccagttagc ctctgcagga tgtggaaacc tccttccagg 2100ggaggttcag tgaattgtgt aggagaggtt gtctgtggcc agaatttaaa cctatactca 2160ctttcccaaa ttgaatcact gctcacactg ctgatgattt agagtgctgt ccggtggaga 2220tcccacccga acgtcttatc taatcatgaa actccctagt tccttcatgt aacttccctg 2280aaaaatctaa gtgtttcata aatttgagag tctgtgaccc acttaccttg catctcacag 2340gtagacagta tataactaac aaccaaagac tacatattgt cactgacaca cacgttataa 2400tcatttatca tatatataca tacatgcata cactctcaaa gcaaataatt tttcacttca 2460aaacagtatt gacttgtata ccttgtaatt tgaaatattt tctttgttaa aatagaatgg 2520tatcaataaa tagaccatta atcag 2545533512DNAHomo sapiens 53aactcagctg agtgttagtc aaagaaggtg tgtcctgctc cccaatgaca ggttgctcag 60agactgctga tttccatccc tatataaaga gagtccctgg catacagaga ctgctctgct 120ccaggcatct gccacaatgt gggtgcttac acctgctgct tttgctggga agctcttgag 180tgtgttcagg caacctctga gctctctgtg gaggagcctg gtcccgctgt tctgctggct 240gagggcaacc ttctggctgc tagctaccaa gaggagaaag cagcagctgg tcctgagagg 300gccagatgag accaaagagg aggaagagga ccctcctctg cccaccaccc caaccagcgt 360caactatcac ttcactcgcc agtgcaacta caaatgcggc ttctgtttcc acacagccaa 420aacatccttt gtgctgcccc ttgaggaagc aaagagagga ttgcttttgc ttaaggaagc 480tggtatggag aagatcaact tttcaggtgg agagccattt cttcaagacc ggggagaata 540cctgggcaag ttggtgaggt tctgcaaagt agagttgcgg ctgcccagcg tgagcatcgt 600gagcaatgga agcctgatcc gggagaggtg gttccagaat tatggtgagt atttggacat 660tctcgctatc tcctgtgaca gctttgacga ggaagtcaat gtccttattg gccgtggcca 720aggaaagaag aaccatgtgg aaaaccttca aaagctgagg aggtggtgta gggattatag 780agtcgctttc aagataaatt ctgtcattaa tcgtttcaac gtggaagagg acatgacgga 840acagatcaaa gcactaaacc ctgtccgctg gaaagtgttc cagtgcctct taattgaggg 900tgagaattgt ggagaagatg ctctaagaga agcagaaaga tttgttattg gtgatgaaga 960atttgaaaga ttcttggagc gccacaaaga agtgtcctgc ttggtgcctg aatctaacca 1020gaagatgaaa gactcctacc ttattctgga tgaatatatg cgctttctga actgtagaaa 1080gggacggaag gacccttcca agtccatcct ggatgttggt gtagaagaag ctataaaatt 1140cagtggattt gatgaaaaga tgtttctgaa gcgaggagga aaatacatat ggagtaaggc 1200tgatctgaag ctggattggt agagcggaaa gtggaacgag acttcaacac accagtggga 1260aaactcctag agtaactgcc attgtctgca atactatccc gttggtattt cccagtggct 1320gaaaacctga ttttctgctg cacgtggcat ctgattacct gtggtcactg aacacacgaa 1380taacttggat agcaaatcct gagacaatgg aaaaccatta actttacttc attggcttat 1440aaccttgttg ttattgaaac agcacttctg tttttgagtt tgttttagct aaaaagaagg 1500aatacacaca ggaataatga ccccaaaaat gcttagataa ggcccctata cacaggacct 1560gacatttagc tcaatgatgc gtttgtaaga aataagctct agtgatatct gtgggggcaa 1620aatttaattt ggatttgatt ttttaaaaca atgtttactg cgatttctat atttccattt 1680tgaaactatt tcttgttcca ggtttgttca tttgacagag tcagtatttt ttgccaaata 1740tccagataac cagttttcac atctgagaca ttacaaagta tctgcctcaa ttatttctgc 1800tggttataat gctttttttt ttttgccttt atgccattgc agtcttgtac tttttactgt 1860gatgtacaga aatagtcaac agatgtttcc aagaacatat gatatgataa tcctaccaat 1920tttcaagaag tctctagaaa gagataacac atggaaagac ggtgtggtgc agcccagccc 1980acggtggctg ttccatgaat gctggctacc tatgtgtgtg gtacctgttg tgtccctttc 2040tcttcaaaga tcctgagcaa aacaaagata cgctttccat ttgatgatgg agttgacatg 2100gaggcagtgc ttgcattgct ttgttcgcct atcatctggc cacatgaggc tgtcaagcaa 2160aagaatagga gtgtagttga gtagctggtt ggccctacat ctctgagaag tgacggcaca 2220ctgggttggc ataagatatc ctaaaatcac gctggaacct tgggcaagga agaatgtgag 2280caagagtaga gagagtgcct ggatttcatg tcagtgaagc caagtcacca tatcatattt 2340ttgaatgaac tctgagtcag ttgaaatagg gtaccatcta ggtcagttta agaagagtca 2400gctcagagaa agcaagcata agggaaaatg tcacgtaaac tagatcaggg aacaaaatcc 2460tctccttgtg gaaatatccc atgcagtttg ttgatacaac ttagtatctt attgcctaaa 2520aaaaaatttc ttatcattgt ttcaaaaaag caaaatcatg gaaaattttt gttgtccagg 2580caaataaaag gtcattttaa tttagctgca atttcagtgt tcctcactag gtggcattta 2640aatgtcgcct gatgtcatta agcaccatcc aaaaagtctg cttcataatc tattttcaag 2700acttggtgat tctgaaagtt ttggtttttg tgactttgtt tctcaggaaa aaaaatattc 2760ctacttaaat tttaagtcta taattcaatt taaatatgtg tgtgtctcat ccaggatagg 2820ataggttgtc ttctattttc cattttacct atttactttt tttgtaagaa aagagaaaaa 2880tgaattctaa agatgttccc catgggtttt gattgtgtct aagctatgat gaccttcata 2940taatcagcat aaacataaaa caaatttttt acttaacatg agtgcacttt actaatcctc 3000atggcacagt ggctcacgcc tgtaatccca gcacttggga ggacaatgtg ggtggatcac 3060gaggtcagga gttcgagaac agcctggcca acatggtgaa accccgtctc cactaaaaat 3120acaaaaatta gccaggcatg gtggcgtaca cttgtaattc cagctactca agaggctgag 3180gcaggaggat tgcttgaacc ctgaaggcag aggttacaga gccaagatag cgccactgca 3240ctccagcctg gatgacagag caagactccg tctcaaaaaa aaaaaaaaaa aaaagcaaga 3300gagttcaact aagaaaggtc acatatgtga aagcccaagg acactgtttg atatacagca 3360ggtattcaat cagtgttatt tgaaaccaaa tctgaatttg aagtttgaat cttctgagtt 3420ggaatgaatt tttttctagc tgagggaaac tgtatttttc tttccccaaa gaggaatgta 3480atgtaaagtg aaataaaact ataagctatg tt 3512541109DNAHomo sapiens 54agaggaacca gaaatttgtc

cttgaataat gtttcccgac aacgaagagg cagaaggatc 60tgggcctgtg cgcgacgccc cgggggacga ggctcatgga gaagtttcgg gcggtgctgg 120acctgcacgt caagcaccac agcgccttgg gctacggcct ggtgaccctg ctgacggcgg 180gcggggagcg catcttctcc gccgtggcat tccagtgccc gtgcagcgcc gcctggaacc 240tgccctacgg cctggtcttc ttgctggtgc cggcgctcgc gctcttcctc ctgggctacg 300tgctgagcgc acgcacgtgg cgcctgctca ccggatgctg ctccagcgcc cgcgcgagtt 360gcggatcggc gctgcgcggc tccctggtgt gcacgcaaat cagcgcggcc gccgcgctcg 420cgcccctcac ctgggtggcc gtggcgctgc tcgggggcgc cttttacgag tgcgcggcca 480ccgggagcgc ggccttcgcg cagcgcctgt gcctcggccg caaccgcagc tgcgccgcgg 540agctgccgct ggtgccgtgc aaccaggcca aggcgtcgga cgtgcaggac ctcctgaagg 600atctgaaggc tcagtcgcag gtgttgggct ggatcttgat agcagttgtt atcatcattc 660ttctgatttt tacatctgtc acccgatgcc tatctccagt tagttttctg cagctgaaat 720tctggaaaat ctatttggaa caggagcagc agatccttaa aagtaaagcc acagagcatg 780caactgaatt ggcaaaagag aatattaaat gtttctttga gggctcgcat ccaaaagaat 840ataacactcc aagcatgaaa gagtggcagc aaatttcatc actgtatact ttcaatccga 900agggccagta ctacagcatg ttgcacaaat atgtcaacag aaaagagaag actcacagta 960tcaggtctac tgaaggagat acggtgattc ctgttcttgg ctttgtagat tcatctggta 1020taaacagcac tcctgagtta tgaccttttg aatgagtaga aaaaaaaatt gttttgaatt 1080attgctttat taaaaaataa acattggta 1109552694DNAHomo sapiens 55tctccctttt cacagctggt ttcatactat ttactatttg gtcaagccgt gctaatctgt 60aaccctaagc aaatccaaat caggtccaac ttatgcaagc atatattaga gctgggctcc 120aaagaatact ggacatctgt agtacctgac attcaagcat ttggcgagat gtcaatattt 180cagagagcac tttaaatgtt ttgatttgaa agctaatgca gtgtttccca ctggtcaaca 240cgagcagtcc agcagagagc aaaatctatt tccctcaaca tcaaatgcta cactcagttg 300ctgatcctat cttgcctaca gagaacctaa aagactggaa aaattggatc tttaatgaaa 360aaacacttgg gccacttcaa gacgacaaac gctcactggg caaaacacct tcactgaaaa 420gagacctcat attatgcaaa aaaaatctta aaaggcctct gccttcagaa gttacaagat 480gatcaattca acctccacac agcctccaga tgaatcctgc tctcagaacc tcctgatcac 540tcagcagatc attcctgtgc tgtactgtat ggtcttcatt gcaggaatcc tactcaatgg 600agtgtcagga tggatattct tttacgtgcc cagctctaag agtttcatca tctatctcaa 660gaacattgtt attgctgact ttgtgatgag cctgactttt cctttcaaga tccttggtga 720ctcaggcctt ggtccctggc agctgaacgt gtttgtgtgc agggtctctg ccgtgctctt 780ctacgtcaac atgtacgtca gcattgtgtt ctttgggctc atcagctttg acagatatta 840taaaattgta aagcctcttt ggacttcttt catccagtca gtgagttaca gcaaacttct 900gtcagtgata gtatggatgc tcatgctcct ccttgctgtt ccaaatatta ttctcaccaa 960ccagagtgtt agggaggtta cacaaataaa atgtatagaa ctgaaaagtg aactgggacg 1020gaagtggcac aaagcatcaa actacatctt cgtggccatc ttctggattg tgtttctttt 1080gttaatcgtt ttctatactg ctatcacaaa gaaaatcttt aagtcccacc ttaagtcaag 1140tcggaattcc acttcggtca aaaagaaatc tagccgcaac atattcagca tcgtgtttgt 1200gttttttgtc tgttttgtac cttaccatat tgccagaatc ccctacacaa agagtcagac 1260cgaagctcat tacagctgcc agtcaaaaga aatcttgcgg tatatgaaag aattcactct 1320gctactatct gctgcaaatg tatgcttgga ccctattatt tatttctttc tatgccagcc 1380gtttagggaa atcttatgta agaaattgca cattccatta aaagctcaga atgacctaga 1440catttccaga atcaaaagag gaaatacaac acttgaaagc acagatactt tgtgagttcc 1500taccctcttc caaagaaaga ccacgtgtgc atgttgtcat cttcaattac ataacagaaa 1560tcaataagat atgtgccctc atcataaata tcatctctag cactgccatc caatttagtt 1620caataaaatt caaatataag tttccatgct tttttgtaac atcaaagaaa acatacccat 1680cagtaatttc tctaatactg acctttctat tctctattaa taaaaaatta atacatacaa 1740ttattcaatt ctattatatt aaaataagtt aaagtttata accactagtc tggtcagtta 1800atgtagaaat ttaaatagta aataaaacac aacataatca aagacaactc actcaggcat 1860cttctttctc taaataccag aatctagtat gtaattgttt tcaacactgt ccttaaagac 1920taacttgaaa gcaggcacag tttgatgaag ggctagagag ctgtttgcaa taaaaagtca 1980ggtttttttc ctgatttgaa gaagcaggaa aagctgacac ccagacaatc acttaagaaa 2040ccccttattg atgtatttca tggcactgca aaggaagagg aatattaatt gtatacttag 2100caagaaaatt ttttttttct gatagcactt tgaggatatt agatacatgc taaatatgtt 2160ttctacaaag acttacgtca tttaatgagc ctggggttct ggtgttagaa tatttttaag 2220taggctttac tgagagaaac taaatattgg catacgttat cagcaacttc ccctgttcaa 2280tagtatggga aaaataagat gactgggaaa aagacacacc cacaccgtag aacatatatt 2340aatctactgg cgaatgggaa aggagaccat tttcttagaa agcaaataaa cttgattttt 2400ttaaatctaa aatttacatt aatgagtgca aaataacaca taaaatgaaa attcacacat 2460cacatttttc tggaaaacag acggatttta cttctggaga catggcatac ggttactgac 2520ttatgagcta ccaaaactaa attctttctc tgctattaac tggctagaag acattcatct 2580atttttcaaa tgttctttca aaacattttt ataagtaatg tttgtatcta tttcatgctt 2640tactgtctat atactaataa agaaatgttt taatactgaa aaaaaaaaaa aaaa 2694564065DNAHomo sapiens 56cactgaggtc accctccagg ctgtggaacc tttgttcttt cactctttgc aataaatctt 60gctgctgctc actctttggg tccacactgc ctttatgagc tgtaacactc actgggaatg 120tctgcagctt cactcctgaa gccagcgaga ccacgaaccc accaggagga acaaacaact 180ccagacgcgc agccttaaga gctgtaacac tcaccgcgaa ggtctgcagc ttcactcctg 240agccagccag accacgaacc caccagaagg aagaaactcc aaacacatcc gaacatcaga 300aggagcaaac tcctgacacg ccacctttaa gaaccgtgac actcaacgct agggtccgcg 360gcttcattct tgaagtcagt gagaccaaga acccaccaat tccggacacg ctaattgttg 420tagatcatca cttcaaggtg cccatatctt tctagtggaa aaattattct ggcctccgct 480gcatacaaat caggcaacca gaattctaca tatataaggc aaagtaacat cctagacatg 540gctttagaga tccacatgtc agaccccatg tgcctcatcg agaactttaa tgagcagctg 600aaggttaatc aggaagcttt ggagatcctg tctgccatta cgcaacctgt agttgtggta 660gcgattgtgg gcctctatcg cactggcaaa tcctacctga tgaacaagct ggctgggaag 720aacaagggct tctctgttgc atctacggtg cagtctcaca ccaagggaat ttggatatgg 780tgtgtgcctc atcccaactg gccaaatcac acattagttc tgcttgacac cgagggcctg 840ggagatgtag agaaggctga caacaagaat gatatccaga tctttgcact ggcactctta 900ctgagcagca cctttgtgta caatactgtg aacaaaattg atcagggtgc tatcgaccta 960ctgcacaatg tgacagaact gacagatctg ctcaaggcaa gaaactcacc cgaccttgac 1020agggttgaag atcctgctga ctctgcgagc ttcttcccag acttagtgtg gactctgaga 1080gatttctgct taggcctgga aatagatggg caacttgtca caccagatga atacctggag 1140aattccctaa ggccaaagca aggtagtgat caaagagttc aaaatttcaa tttgccccgt 1200ctgtgtatac agaagttctt tccaaaaaag aaatgcttta tctttgactt acctgctcac 1260caaaaaaagc ttgcccaact tgaaacactg cctgatgatg agctagagcc tgaatttgtg 1320caacaagtga cagaattctg ttcctacatc tttagccatt ctatgaccaa gactcttcca 1380ggtggcatca tggtcaatgg atctcgtcta aagaacctgg tgctgaccta tgtcaatgcc 1440atcagcagtg gggatctgcc ttgcatagag aatgcagtcc tggccttggc tcagagagag 1500aactcagctg cagtgcaaaa ggccattgcc cactatgacc agcaaatggg ccagaaagtg 1560cagctgccca tggaaaccct ccaggagctg ctggacctgc acaggaccag tgagagggag 1620gccattgaag tcttcatgaa aaactctttc aaggatgtag accaaagttt ccagaaagaa 1680ttggagactc tactagatgc aaaacagaat gacatttgta aacggaacct ggaagcatcc 1740tcggattatt gctcggcttt acttaaggat atttttggtc ctctagaaga agcagtgaag 1800cagggaattt attctaagcc aggaggccat aatctcttca ttcagaaaac agaagaactg 1860aaggcaaagt actatcggga gcctcggaaa ggaatacagg ctgaagaagt tctgcagaaa 1920tatttaaagt ccaaggagtc tgtgagtcat gcaatattac agactgacca ggctctcaca 1980gagacggaaa aaaagaagaa agaggcacaa gtgaaagcag aagctgaaaa ggctgaagcg 2040caaaggttgg cggcgattca aaggcagaac gagcaaatga tgcaggagag ggagagactc 2100catcaggaac aagtgagaca aatggagata gccaaacaaa attggctggc agagcaacag 2160aaaatgcagg aacaacagat gcaggaacag gctgcacagc tcagcacaac attccaagct 2220caaaatagaa gccttctcag tgagctccag cacgcccaga ggactgttaa taacgatgat 2280ccatgtgttt tactctaaag tgctaaatat gggagtttcc tttttttact ctttgtcact 2340gatgacacaa cagaaaagaa actgtagacc ttgggacaat caacatttaa ataaacttta 2400taattatttt ttcaaacttt catatagagt tataagatta tgatgctggt atctggtaaa 2460atgtacatcc cagtagtcca atagtttaaa tgtttattgc ttcctttaag agattataaa 2520ttgtataagg gacattgtat cactgccttc atttatgcgt gatattggga tggtttcatc 2580aggagatgct ttccttgcat ctcaatgtca tctgtctaat ttctcataag gggattatgt 2640tacctagagc agggcttccc aaccctcagg ccatagacta gctctgatct gtggcctctt 2700aggaacccgg ccacacagca ggaggtgagc agcaggtaag tgagcattac agcctgagct 2760ccacctcctg tcagatcagc agtgacatta gattctcaca ggagtgggaa ccctattgtg 2820aactgtgcat gcaaaagatc taggttgtgt gatccttgtg gaacaatata aaccagaaac 2880caataacgcc accccacctc caacccccgc caaccctctg tggaaaaatt accttccacg 2940aaactggtcc ctgatgccaa ataggttggg ggaccgctga cctagaggga gttatgcaca 3000tgggcttata aggttagcca agagaaagga caagaagacc caaagtcggc aagcaaattt 3060attaacctgc tgggctgctc tacagaaatc tgaggaggca gacaccgggc ttacaggcta 3120aggggtataa gtaggtctgc aggggttttg tgtgtgtgtg cgggggtgtc gggggggcaa 3180ggccatttgt ggagactttt cctcccagta tggccacatc ctgcagtttg tcagtttttg 3240cccccgcctg gctcagggta ccaggatgtg gtttagctta ggggtggtta tagtggcacc 3300taagttctgg gaacttgcgg tgggggcgac cttttggacg aaaaataagc tgcagggcag 3360ctaggggagg gggcttgtta tattcctctg ggggcagggt gtccctaact gggctcagtc 3420ggaaggaact tgaccaaagt ctgggctcag ttgggcatca ctcaggctaa tggtcgtgtg 3480ctggatgcca tcagagggaa gtaccaatgg taaagtggaa acaatgtgca gctttcaact 3540gggtggaggc tgctattctg tggacagtga gatgtttcct tggcactgtc aatagacaat 3600ctgcgtagag aaattccaag ctgaaagcca ataatgttat aataaaatag agattcttca 3660gaagatgaaa ggaattacca gcatggaaat tgtgtcatag gcttaagggc taaagaagaa 3720gccttttctt ttctgttcac cctcaccaag agcacaactt aaatagggca ttttataacc 3780tgaacacaat ttatattgga cttaattatt atgtgtaata tgtttataat cctttagatc 3840ttataaatat gtggtataag gaatgccata taatgtgcca aaaatctgag tgcatttaat 3900ttaatgcttg cttatagtgc taaagttaaa tgatcttaat tctttgcaat tatatatgaa 3960aaatgactga tttttcttaa aatatgtaac ttatataaat atatctgttt gtacagattt 4020taaccataaa aacatttttg gaaaaccata aaaaaaaaaa aaaaa 4065571984DNAHomo sapiens 57ctgatttaca ggaactcaca ccagcgatca atcttcctta atttgtaact gggcagtgtc 60ccgggccagc caatagctaa gactgccccc cccgcacccc accctccctg accctggggg 120actctctact cagtctgcac tggagctgcc tggtgaccag aagtttggag tccgctgacg 180tcgccgccca gatggcctcc aggctgaccc tgctgaccct cctgctgctg ctgctggctg 240gggatagagc ctcctcaaat ccaaatgcta ccagctccag ctcccaggat ccagagagtt 300tgcaagacag aggcgaaggg aaggtcgcaa caacagttat ctccaagatg ctattcgttg 360aacccatcct ggaggtttcc agcttgccga caaccaactc aacaaccaat tcagccacca 420aaataacagc taataccact gatgaaccca ccacacaacc caccacagag cccaccaccc 480aacccaccat ccaacccacc caaccaacta cccagctccc aacagattct cctacccagc 540ccactactgg gtccttctgc ccaggacctg ttactctctg ctctgacttg gagagtcatt 600caacagaggc cgtgttgggg gatgctttgg tagatttctc cctgaagctc taccacgcct 660tctcagcaat gaagaaggtg gagaccaaca tggccttttc cccattcagc atcgccagcc 720tccttaccca ggtcctgctc ggggctgggg agaacaccaa aacaaacctg gagagcatcc 780tctcttaccc caaggacttc acctgtgtcc accaggccct gaagggcttc acgaccaaag 840gtgtcacctc agtctctcag atcttccaca gcccagacct ggccataagg gacacctttg 900tgaatgcctc tcggaccctg tacagcagca gccccagagt cctaagcaac aacagtgacg 960ccaacttgga gctcatcaac acctgggtgg ccaagaacac caacaacaag atcagccggc 1020tgctagacag tctgccctcc gatacccgcc ttgtcctcct caatgctatc tacctgagtg 1080ccaagtggaa gacaacattt gatcccaaga aaaccagaat ggaacccttt cacttcaaaa 1140actcagttat aaaagtgccc atgatgaata gcaagaagta ccctgtggcc catttcattg 1200accaaacttt gaaagccaag gtggggcagc tgcagctctc ccacaatctg agtttggtga 1260tcctggtacc ccagaacctg aaacatcgtc ttgaagacat ggaacaggct ctcagccctt 1320ctgttttcaa ggccatcatg gagaaactgg agatgtccaa gttccagccc actctcctaa 1380cactaccccg catcaaagtg acgaccagcc aggatatgct ctcaatcatg gagaaattgg 1440aattcttcga tttttcttat gaccttaacc tgtgtgggct gacagaggac ccagatcttc 1500aggtttctgc gatgcagcac cagacagtgc tggaactgac agagactggg gtggaggcgg 1560ctgcagcctc cgccatctct gtggcccgca ccctgctggt ctttgaagtg cagcagccct 1620tcctcttcgt gctctgggac cagcagcaca agttccctgt cttcatgggg cgagtatatg 1680accccagggc ctgagacctg caggatcagg ttagggcgag cgctacctct ccagcctcag 1740ctctcagttg cagccctgct gctgcctgcc tggacttggc ccctgccacc tcctgcctca 1800ggtgtccgct atccaccaaa agggctccct gagggtctgg gcaagggacc tgcttctatt 1860agcccttctc catggccctg ccatgctctc caaaccactt tttgcagctt tctctagttc 1920aagttcacca gactctataa ataaaacctg acagaccatg actttcaaaa aaaaaaaaaa 1980aaaa 1984581917DNAHomo sapiens 58aatatcttgc atgttacaga tttcactact cccaccagct tggagacaac atgtggttct 60tgacaactct gctcctttgg gttccagttg atgggcaagt ggacaccaca aaggcagtga 120tcactttgca gcctccatgg gtcagcgtgt tccaagagga aaccgtaacc ttgcactgtg 180aggtgctcca tctgcctggg agcagctcca cacagtggtt tctcaatggc acagccactc 240agacctcgac ccccagctac agaatcacct ctgccagtgt caatgacagt ggtgaataca 300ggtgccagag aggtctctca gggcgaagtg accccataca gctggaaatc cacagaggct 360ggctactact gcaggtctcc agcagagtct tcatggaagg agaacctctg gccttgaggt 420gtcatgcgtg gaaggataag ctggtgtaca atgtgcttta ctatcgaaat ggcaaagcct 480ttaagttttt ccactggaat tctaacctca ccattctgaa aaccaacata agtcacaatg 540gcacctacca ttgctcaggc atgggaaagc atcgctacac atcagcagga atatcacaat 600acactgtgaa aggcctccag ttaccaactc ctgtctggtt tcatgtcctt ttctatctgg 660cagtgggaat aatgttttta gtgaacactg ttctctgggt gacaatacgt aaagaactga 720aaagaaagaa aaagtggaat ttagaaatct ctttggattc tggtcatgag aagaaggtaa 780tttccagcct tcaagaagac agacatttag aagaagagct gaaatgtcag gaacaaaaag 840aagaacagct gcaggaaggg gtgcaccgga aggagcccca gggggccacg tagcagcggc 900tcagttggtg gccatcgatc tggaccgtcc cctgcccact tgctccccgt gagcactgcg 960tacaaacatc caaaagttca acaacaccag aactgtgtgt ctcatggtat ataactctta 1020aagcaaataa atgaactgac ttcaactggg atacatttgg aaatgtggtc atcaaagatg 1080acttgaaatg aggcctactc taaagaattc ttgaaaaact tacaagtcaa gcctagcctg 1140ataatcctat tacatagttt gaaaaatagt attttatttc tcagaacaag gtaaaaaggt 1200gagtgggtgc atatgtacag aagattaaga cagagaaaca gacagaaaga gacacacaca 1260cagccaggag tgggtagatt tcagggagac aagagggaat agtatagaca ataaggaagg 1320aaatagtact tacaaatgac tcctaaggga ctgtgagact gagagggctc acgcctctgt 1380gttcaggata cttagttcat ggcttttctc tttgacttta ctaaaagaga atgtctccat 1440acgcgttcta ggcatacaag ggggtaactc atgatgagaa atggatgtgt tattcttgcc 1500ctctcttttg aggctctctc ataacccctc tatttctaga gacaacaaaa atgttgccag 1560tcctaggccc ctgccctgta ggaaggcaga atgtaactgt tctttttgtt taacgattaa 1620gtccaaatct ccaagtgcgg cactgcaaag agacgcttca agtggggaga agcggcgata 1680tcatagagtc cagatcttgc ctccagagat ttgctttacc ttcctgattt tctggttact 1740aattagcttc aggatacgct gctctcatac ttgggctgta gtttggagac aaaatatttt 1800cctgccactg tgtaacatag ctgaggtaaa aactgaacta tgtaaatgac tctactaaaa 1860gtttagggaa aaaaaacagg aggagtatga cacacacagc aaaaaaaaaa aaaaaaa 1917592518DNAHomo sapiens 59ctcatttgtg tgttttctga gtcagcatta gctaaatttt ccagaaggcc atccacaaag 60tacagcctgg gcgttcaagg gacgtcattc atttccccca gtgaccttga caagtcagaa 120gcttgaaagc agggaaatcc ggatgtctcg gttatgaagt ggagcagtga gtgtgagcct 180caacatagtt ccagaactct ccatccggac tagttattga gcatctgcct ctcatatcac 240cagtggccat ctgaggtgtt tccctggctc tgaaggggta ggcacgatgg ccaggtgctt 300cagcctggtg ttgcttctca cttccatctg gaccacgagg ctcctggtcc aaggctcttt 360gcgtgcagaa gagctttcca tccaggtgtc atgcagaatt atggggatca cccttgtgag 420caaaaaggcg aaccagcagc tgaatttcac agaagctaag gaggcctgta ggctgctggg 480actaagtttg gccggcaagg accaagttga aacagccttg aaagctagct ttgaaacttg 540cagctatggc tgggttggag atggattcgt ggtcatctct aggattagcc caaaccccaa 600gtgtgggaaa aatggggtgg gtgtcctgat ttggaaggtt ccagtgagcc gacagtttgc 660agcctattgt tacaactcat ctgatacttg gactaactcg tgcattccag aaattatcac 720caccaaagat cccatattca acactcaaac tgcaacacaa acaacagaat ttattgtcag 780tgacagtacc tactcggtgg catcccctta ctctacaata cctgccccta ctactactcc 840tcctgctcca gcttccactt ctattccacg gagaaaaaaa ttgatttgtg tcacagaagt 900ttttatggaa actagcacca tgtctacaga aactgaacca tttgttgaaa ataaagcagc 960attcaagaat gaagctgctg ggtttggagg tgtccccacg gctctgctag tgcttgctct 1020cctcttcttt ggtgctgcag ctggtcttgg attttgctat gtcaaaaggt atgtgaaggc 1080cttccctttt acaaacaaga atcagcagaa ggaaatgatc gaaaccaaag tagtaaagga 1140ggagaaggcc aatgatagca accctaatga ggaatcaaag aaaactgata aaaacccaga 1200agagtccaag agtccaagca aaactaccgt gcgatgcctg gaagctgaag tttagatgag 1260acagaaatga ggagacacac ctgaggctgg tttctttcat gctccttacc ctgccccagc 1320tggggaaatc aaaagggcca aagaaccaaa gaagaaagtc cacccttggt tcctaactgg 1380aatcagctca ggactgccat tggactatgg agtgcaccaa agagaatgcc cttctcctta 1440ttgtaaccct gtctggatcc tatcctccta cctccaaagc ttcccacggc ctttctagcc 1500tggctatgtc ctaataatat cccactggga gaaaggagtt ttgcaaagtg caaggaccta 1560aaacatctca tcagtatcca gtggtaaaaa ggcctcctgg ctgtctgagg ctaggtgggt 1620tgaaagccaa ggagtcactg agaccaaggc tttctctact gattccgcag ctcagaccct 1680ttcttcagct ctgaaagaga aacacgtatc ccacctgaca tgtccttctg agcccggtaa 1740gagcaaaaga atggcagaaa agtttagccc ctgaaagcca tggagattct cataacttga 1800gacctaatct ctgtaaagct aaaataaaga aatagaacaa ggctgaggat acgacagtac 1860actgtcagca gggactgtaa acacagacag ggtcaaagtg ttttctctga acacattgag 1920ttggaatcac tgtttagaac acacacactt actttttctg gtctctacca ctgctgatat 1980tttctctagg aaatatactt ttacaagtaa caaaaataaa aactcttata aatttctatt 2040tttatctgag ttacagaaat gattactaag gaagattact cagtaatttg tttaaaaagt 2100aataaaattc aacaaacatt tgctgaatag ctactatatg tcaagtgctg tgcaaggtat 2160tacactctgt aattgaatat tattcctcaa aaaattgcac atagtagaac gctatctggg 2220aagctatttt tttcagtttt gatatttcta gcttatctac ttccaaacta atttttattt 2280ttgctgagac taatcttatt cattttctct aatatggcaa ccattataac cttaatttat 2340tattaacata cctaagaagt acattgttac ctctatatac caaagcacat tttaaaagtg 2400ccattaacaa atgtatcact agccctcctt tttccaacaa gaagggactg agagatgcag 2460aaatatttgt gacaaaaaat taaagcattt agaaaacttc aaaaaaaaaa aaaaaaaa 2518602180DNAHomo sapiens 60gtaacaactc tcagaggagc attgcccgtc agacagcaac tcagagaata accagagaac 60aaccagcatt tcttgcacta caacttgctt aagctcttac acttcatagt gaagctatgc 120accaccgagt gaagcgatgt ggaacattgg aaagagtggg cttccttaga cagacctggg 180cttgaatccc tgctccacta cctaccagct gtgtgacctt atacaagtta cttaatgttt 240ctgagcatca ggatataatc tataaaatag ggagaatcac ctctacctca tacagattct 300gcaaagatta aacgaggaga ggagattgaa acaatggagg atctttgtgt ggcaaacaca 360ctctttgccc tcaatttatt caagcatctg gcaaaagcaa gccccaccca gaacctcttc 420ctctccccat ggagcatctc gtccaccatg gccatggtct acatgggctc caggggcagc 480accgaagacc agatggccaa ggtgcttcag tttaatgaag tgggagccaa tgcagttacc 540cccatgactc cagagaactt

taccagctgt gggttcatgc agcagatcca gaagggtagt 600tatcctgatg cgattttgca ggcacaagct gcagataaaa tccattcatc cttccgctct 660ctcagctctg caatcaatgc atccacaggg aattatttac tggaaagtgt caataagctg 720tttggtgaga agtctgcgag cttccgggaa gaatatattc gactctgtca gaaatattac 780tcctcagaac cccaggcagt agacttccta gaatgtgcag aagaagctag aaaaaagatt 840aattcctggg tcaagactca aaccaaaggc aaaatcccaa acttgttacc tgaaggttct 900gtagatgggg ataccaggat ggtcctggtg aatgctgtct acttcaaagg aaagtggaaa 960actccatttg agaagaaact aaatgggctt tatcctttcc gtgtaaactc ggctcagcgc 1020acacctgtac agatgatgta cttgcgtgaa aagctaaaca ttggatacat agaagaccta 1080aaggctcaga ttctagaact cccatatgct ggagatgtta gcatgttctt gttgcttcca 1140gatgaaattg ccgatgtgtc cactggcttg gagctgctgg aaagtgaaat aacctatgac 1200aaactcaaca agtggaccag caaagacaaa atggctgaag atgaagttga ggtatacata 1260ccccagttca aattagaaga gcattatgaa ctcagatcca ttctgagaag catgggcatg 1320gaggacgcct tcaacaaggg acgggccaat ttctcaggga tgtcggagag gaatgacctg 1380tttctttctg aagtgttcca ccaagccatg gtggatgtga atgaggaggg cactgaagca 1440gccgctggca caggaggtgt tatgacaggg agaactggac atggaggccc acagtttgtg 1500gcagatcatc cttttctttt tcttattatg cataagataa ccaactgcat tttatttttc 1560ggcagatttt cctcacccta aaactaagcg tgctgcttct gcaaaagatt tttgtagatg 1620agctgtgtgc ctcagaattg ctatttcaaa ttgccaaaaa tttagagatg ttttctacat 1680atttctgctc ttctgaacaa cttctgctac ccactaaata aaaacacaga aataattaga 1740caattgtcta ttataacatg acaaccctat taatcatttg gtcttctaaa atgggatcat 1800gcccatttag attttcctta ctatcagttt atttttataa cattaacttt tactttgtta 1860tttattattt tatataatgg tgagttttta aattattgct cactgcctat ttaatgtagc 1920taataaagtt atagaagcag atgatctgtt aatttcctat ctaataaatg cctttaattg 1980ttctcataat gaagaataag taggtatccc tccatgccct tctgtaataa atatctggaa 2040aaaacattaa acaataggca aatatatgtt atgtgcattt ctagaaatac ataacacata 2100tatatgtctg tatcttatat tcaattgcaa gtatataata aataaacctg cttccaaaca 2160acaataaaaa aaaaaaaaaa 2180613262DNAHomo sapiens 61ggctggagag taaaaagaac tgggggtaag agcccctctg cctagcactg ctcccccaag 60gctcccagaa atctcaggtc agaggcacgg acagcctctg gagctctcgt ctggtgggac 120catgaactgc cagcagctgt ggctgggctt cctactcccc atgacagtct caggccgggt 180cctggggctt gcagaggtgg cgcccgtgga ctacctgtca caatatgggt acctacagaa 240gcctctagaa ggatctaata acttcaagcc agaagatatc accgaggctc tgagagcttt 300tcaggaagca tctgaacttc cagtctcagg tcagctggat gatgccacaa gggcccgcat 360gaggcagcct cgttgtggcc tagaggatcc cttcaaccag aagaccctta aatacctgtt 420gctgggccgc tggagaaaga agcacctgac tttccgcatc ttgaacctgc cctccaccct 480tccaccccac acagcccggg cagccctgcg tcaagccttc caggactgga gcaatgtggc 540tcccttgacc ttccaagagg tgcaggctgg tgcggctgac atccgcctct ccttccatgg 600ccgccaaagc tcgtactgtt ccaatacttt tgatgggcct gggagagtcc tggcccatgc 660cgacatccca gagctgggca gtgtgcactt cgacgaagac gagttctgga ctgaggggac 720ctaccgtggg gtgaacctgc gcatcattgc agcccatgaa gtgggccatg ctctggggct 780tgggcactcc cgatattccc aggccctcat ggccccagtc tacgagggct accggcccca 840ctttaagctg cacccagatg atgtggcagg gatccaggct ctctatggca agaagagtcc 900agtgataagg gatgaggaag aagaagagac agagctgccc actgtgcccc cagtgcccac 960agaacccagt cccatgccag acccttgcag tagtgaactg gatgccatga tgctggggcc 1020ccgtgggaag acctatgctt tcaaggggga ctatgtgtgg actgtatcag attcaggacc 1080gggccccttg ttccgagtgt ctgccctttg ggaggggctc cccggaaacc tggatgctgc 1140tgtctactcg cctcgaacac aatggattca cttctttaag ggagacaagg tgtggcgcta 1200cattaatttc aagatgtctc ctggcttccc caagaagctg aatagggtag aacctaacct 1260ggatgcagct ctctattggc ctctcaacca aaaggtgttc ctctttaagg gctccgggta 1320ctggcagtgg gacgagctag cccgaactga cttcagcagc taccccaaac caatcaaggg 1380tttgtttacg ggagtgccaa accagccctc ggctgctatg agttggcaag atggccgagt 1440ctacttcttc aagggcaaag tctactggcg cctcaaccag cagcttcgag tagagaaagg 1500ctatcccaga aatatttccc acaactggat gcactgtcgt ccccggacta tagacactac 1560cccatcaggt gggaatacca ctccctcagg tacgggcata accttggata ccactctctc 1620agccacagaa accacgtttg aatactgact gctcacccac agacacaatc ttggacatta 1680acccctgagg ctccaccacc caccctttca tttccccccc agaagcctaa ggcctaatag 1740ctgaatgaaa tacctgtctg ctcagtagaa ccttgcaggt gctgtagcag gcgcaagacc 1800gtagatctca ggcctctaac acttccaact ccagccacca ctttcctgtg cattttcact 1860cctgagaagt gctcccctaa ctcagatccc ctaacttaga tttggccccc aactccattt 1920cctgtctgtc ttagacagcc cttccaactg tgtcatctct tctctggagg tcaatggtgg 1980agggagatgc ctgggtcctg ttcttcctac ataaaatgca agaaaacagc atggccagta 2040aactgagcaa gggccttgga atccttgaga atcacattta tgtgcttatg attacgggca 2100agctaattaa ccttgttgaa tctcagattc cccatttgca acattaggtt aagaccagta 2160ctgcaggatt gttgcactaa atgaaatact gtatgtgaag tgcctggcac agtgtctggt 2220acatttgtgt ttaataaaag ctaactccat gttcataaga gaggactgaa cagctcttcc 2280tctagctgtc tggctgtata actcttacag tagtctgtat aataagggca tctctattag 2340atctttaggg gacagaggat ttgtcaagat ggttagctct ttgttttggg gtgcagagaa 2400agaaaagagc agcaacagca gaggctggac tccctggttc agtatttaat gccattttat 2460tcacatgctc ccatgttctc cctccctccc attgtagcct tgctgcccag gggagggata 2520tgtcttcctt tatgcatctg ggaaaccagg aacagaccct gcgcaggaga gtcagagggg 2580gaagagttag aatgggtcag tggctggaac aaagttctgg ttaaggagga aattagtgcc 2640acccacggtg agaagcagag aaggcacttg catcctatgc agccctgaag accaggctcc 2700tttgggcaaa aggcaagact ctggcaggtg ggtcaatgct ctctccttgg agcaagaagc 2760cagcttttgg ggaaggcagg tcctgaggca ggcactgccc tgtggtcttc cccaggttga 2820ggagagaagt ggaagcccca tggaagacag tgctcccagc tgaggtagga ggcggaggtg 2880ggggtggggg tagtttaagc ctatggggcc cagggggaaa ggccaaacag aaacccaact 2940accccctaat gaagggcctg gaggttgggg tatcttggag ctcctcagag cccttcttcc 3000catcaaaaag gtatcaaatg ccttggaagc tccctgatcc tacaaaacaa aaaaatgctt 3060atttttacca ctgtgaggca agctgaggtg aacatttaaa aggctatttc aagacgaggt 3120gcggtggcta taatcctagc actttgggag gctgaagcag gaggatcact tgagcccagg 3180agttcaagac cagcttgggc aacataggga gaccctgtct ctgcaaaaaa ataaaaacga 3240atacataaaa attaaaaaaa aa 3262623050DNAHomo sapiens 62ggagtcagtg atttgaacga agtactttca gtttcatatt actctaaatc cattacaaat 60ctgcttagct tctaaatatt tcatcaatga ggaaatccca gccctacaac ttcggaacag 120tgaaatatta gtccagggat ccagtgagag acacagaagt gctagaagcc agtgctcgtg 180aactaaggag aaaaagaaca gacaagggaa cagcctggac atggcatcag agatccacat 240gacaggccca atgtgcctca ttgagaacac taatgggcga ctgatggcga atccagaagc 300tctgaagatc ctttctgcca ttacacagcc tatggtggtg gtggcaattg tgggcctcta 360ccgcacaggc aaatcctacc tgatgaacaa gctggctgga aagaaaaagg gcttctctct 420gggctccacg gtgcagtctc acactaaagg aatctggatg tggtgtgtgc cccaccccaa 480gaagccaggc cacatcctag ttctgctgga caccgagggt ctgggagatg tagagaaggg 540tgacaaccag aatgactcct ggatcttcgc cctggccgtc ctcctgagca gcaccttcgt 600gtacaatagc ataggaacca tcaaccagca ggctatggac caactgtact atgtgacaga 660gctgacacat agaatccgat caaaatcctc acctgatgag aatgagaatg aggttgagga 720ttcagctgac tttgtgagct tcttcccaga ctttgtgtgg acactgagag atttctccct 780ggacttggaa gcagatggac aacccctcac accagatgag tacctgacat actccctgaa 840gctgaagaaa ggtaccagtc aaaaagatga aacttttaac ctgcccagac tctgtatccg 900gaaattcttc ccaaagaaaa aatgctttgt ctttgatcgg cccgttcacc gcaggaagct 960tgcccagctc gagaaactac aagatgaaga gctggacccc gaatttgtgc aacaagtagc 1020agacttctgt tcctacatct ttagtaattc caaaactaaa actctttcag gaggcatcca 1080ggtcaacggg cctcgtctag agagcctggt gctgacctac gtcaatgcca tcagcagtgg 1140ggatctgccg tgcatggaga acgcagtcct ggccttggcc cagatagaga actcagctgc 1200agtgcaaaag gctattgccc actatgaaca gcagatgggc cagaaggtgc agctgcccac 1260agaaaccctc caggagctgc tggacctgca cagggacagt gagagagagg ccattgaagt 1320cttcatcagg agttccttca aagatgtgga ccatctattt caaaaggagt tagcggccca 1380gctagaaaaa aagcgggatg acttttgtaa acagaatcag gaagcatcat cagatcgttg 1440ctcagcttta cttcaggtca ttttcagtcc tctagaagaa gaagtgaagg cgggaattta 1500ttcgaaacca gggggctatc gtctctttgt tcagaagcta caagacctga agaaaaagta 1560ctatgaggaa ccgaggaagg ggatacaggc tgaagagatt ctgcagacat acttgaaatc 1620caaggagtct atgactgatg caattctcca gacagaccag actctcacag aaaaagaaaa 1680ggagattgaa gtggaacgtg tgaaagctga gtctgcacag gcttcagcaa aaatgttgca 1740ggaaatgcaa agaaagaatg agcagatgat ggaacagaag gagaggagtt atcaggaaca 1800cttgaaacaa ctgactgaga agatggagaa cgacagggtc cagttgctga aagagcaaga 1860gaggaccctc gctcttaaac ttcaggaaca ggagcaacta ctaaaagagg gatttcaaaa 1920agaaagcaga ataatgaaaa atgagataca ggatctccag acgaaaatga gacgacgaaa 1980ggcatgtacc ataagctaaa gaccagagcc ttcctgtcac ccctaaccaa ggcataattg 2040aaacaatttt agaatttgga acaagcgtca ctacatttga taataattag atcttgcatc 2100ataacaccaa aagtttataa aggcatgtgg tacaatgatc aaaatcatgt tttttcttaa 2160aaaaaaaaaa agactgtaaa ttgtgcaaca aagatgcatt tacctctgta tcaactcagg 2220aaatctcata agctggtacc actcaggaga agtttattct tccagatgac cagcagtaga 2280caaatggata ctgagcagag tcttaggtaa aagtcttggg aaatatttgg gcattggtct 2340ggccaagtct acaatgtccc aatatcaagg acaaccaccc tagcttctta gtgaagacaa 2400tgtacagtta tccgttagat caagactaca cggtctatga gcaataatgt gatttctgga 2460cattgcccat gtataatcct cactgatgat ttcaagctaa agcaaaccac cttatacaga 2520gatctagaat ctctttatgt tctccagagg aaggtggaag aaaccatggg caggagtagg 2580aattgagtga taaacaattg ggctaatgaa gaaaacttct cttattgttc agttcatcca 2640gattataact tcaatgggac actttagacc attagacaat tgacactgga ttaaacaaat 2700tcacataatg ccaaatacac aatgtattta tagcaacgta taatttgcaa agatggactt 2760taaaagatgc tgtgtaacta aactgaaata attcaattac ttattattta gaatgttaaa 2820gcttatgata gtcttttcta actcttaaca ctcatacttg aaaactttct gagtttcccc 2880agaagagaat atgggatttt ttttgacatt tttgactcat ttaataatgc tcttgtgttt 2940acctagtata tgtagacttt gtcttatgtg tgaaaagtcc taggaaagtg gttgatgttt 3000cttatagcaa ttaaaaatta tttttgaact gaaaatacaa tgtatttcac 3050631227DNAHomo sapiens 63ctttgcagat aaatatggca cactagcccc acgttttctg agacattcct caattgctta 60gacatattct gagcctacag cagaggaacc tccagtctca gcaccatgaa tcaaactgcc 120attctgattt gctgccttat ctttctgact ctaagtggca ttcaaggagt acctctctct 180agaactgtac gctgtacctg catcagcatt agtaatcaac ctgttaatcc aaggtcttta 240gaaaaacttg aaattattcc tgcaagccaa ttttgtccac gtgttgagat cattgctaca 300atgaaaaaga agggtgagaa gagatgtctg aatccagaat cgaaggccat caagaattta 360ctgaaagcag ttagcaagga aaggtctaaa agatctcctt aaaaccagag gggagcaaaa 420tcgatgcagt gcttccaagg atggaccaca cagaggctgc ctctcccatc acttccctac 480atggagtata tgtcaagcca taattgttct tagtttgcag ttacactaaa aggtgaccaa 540tgatggtcac caaatcagct gctactactc ctgtaggaag gttaatgttc atcatcctaa 600gctattcagt aataactcta ccctggcact ataatgtaag ctctactgag gtgctatgtt 660cttagtggat gttctgaccc tgcttcaaat atttccctca cctttcccat cttccaaggg 720tactaaggaa tctttctgct ttggggttta tcagaattct cagaatctca aataactaaa 780aggtatgcaa tcaaatctgc tttttaaaga atgctcttta cttcatggac ttccactgcc 840atcctcccaa ggggcccaaa ttctttcagt ggctacctac atacaattcc aaacacatac 900aggaaggtag aaatatctga aaatgtatgt gtaagtattc ttatttaatg aaagactgta 960caaagtagaa gtcttagatg tatatatttc ctatattgtt ttcagtgtac atggaataac 1020atgtaattaa gtactatgta tcaatgagta acaggaaaat tttaaaaata cagatagata 1080tatgctctgc atgttacata agataaatgt gctgaatggt tttcaaaata aaaatgaggt 1140actctcctgg aaatattaag aaagactatc taaatgttga aagatcaaaa ggttaataaa 1200gtaattataa ctaagaaaaa aaaaaaa 1227641761DNAHomo sapiens 64cccgctcttt cgttttcgtt tcccggaagg atagcgatta ccggagcgcc tcgcgcgcct 60gcccgcctgc ggaggacccg ggcgcacacg ccttggcgct tctcgaaaga gatttcctcc 120cacgcgacct tccagttctc ggagccaggt taggggtttg gcggaggagg actgcggggc 180gcgggcctag ggccccagca gccacagcca ggggagcgct caagacagaa agccggtggc 240ttcctcacct ccacctgtaa tgcaggaggg agaattggct atttctccta taagccctgt 300ggcagccatg cctcccctag gcacccacgt gcaagccaga tgtgaagctc aaattaacct 360gctgggtgaa ggggggatct gcaagctgcc aggaagactc cgcatccagc ccgcactgtg 420gagcagggag gacgtgctgc actggctgcg ctgggcagag caggagtact ctctgccatg 480caccgcggag cacgggttcg agatgaacgg acgcgccctc tgcatcctca ccaaggacga 540cttccggcac cgtgcgccca gctcaggtga cgtcctgtat gagctgctcc agtacatcaa 600gacccagcgg cgagccctgg tgtgtgggcc cttttttgga gggatcttca ggctgaagac 660gcccacccag cactctccag tccccccgga agaggtgact ggcccctctc agatggacac 720ccgaaggggc cacctgctgc agccaccaga cccagggctt accagcaact tcggccacct 780ggatgaccct ggcctggcaa ggtggacccc tggcaaggag gagtccctca acttatgtca 840ctgtgcagag ctcggctgca ggacccaggg ggtctgttcc ttccccgcga tgccgcaggc 900ccccattgac ggcaggatcg ctgactgccg cctgctgtgg gattacgtgt atcagctgct 960ccttgatacc cgatatgagc cctacatcaa gtgggaagac aaggacgcca agatcttccg 1020agttgtggat ccaaatgggc tcgccagact ctggggaaat cacaagaacc gggtgaacat 1080gacctacgag aagatgtctc gtgccctgcg ccactattat aagcttaata tcattaagaa 1140ggaaccgggg cagaaactcc tgttcagatt tctaaagact ccgggaaaga tggtccagga 1200caagcacagc cacctggagc cgctggagag ccaggagcag gacagaatag agttcaagga 1260caagaggcca gaaatctctc cgtgaggggc aggtggactc caggcacccg gtaccgatgg 1320ggcagggacc gagtctccca tgaaggcaga ctcctcctcc cagcagagca gcaggatccc 1380cagccagact ctgtacccac aggattacag ccattgcttg ggaaggctgg gaggcctccc 1440atccaggaca ctgggggcag gagtgtcatc ttttgggcag ggcaatcctg gggctaaatg 1500aggtacaggg gaatggactc tcccctactg cacccctggg agaggaagcc aggcaccgat 1560agagcaccca gccccacccc tgtaaatgga atttaccaga tgaagggaat gaagtccctc 1620actgagcctc agatttcctc acctgtgaaa tgggctgagg caggaaatgg gaaaaagtgt 1680tagtgcttcc aggcggcact gacagcctca gtaacaataa aaacaatggt agctgaaaaa 1740aaaaaaaaaa aaaaaaaaaa a 176165873DNAHomo sapiens 65atgaggatat ttgctgtctt tatattcatg acctactggc atttgctgaa cgcatttact 60gtcacggttc ccaaggacct atatgtggta gagtatggta gcaatatgac aattgaatgc 120aaattcccag tagaaaaaca attagacctg gctgcactaa ttgtctattg ggaaatggag 180gataagaaca ttattcaatt tgtgcatgga gaggaagacc tgaaggttca gcatagtagc 240tacagacaga gggcccggct gttgaaggac cagctctccc tgggaaatgc tgcacttcag 300atcacagatg tgaaattgca ggatgcaggg gtgtaccgct gcatgatcag ctatggtggt 360gccgactaca agcgaattac tgtgaaagtc aatgccccat acaacaaaat caaccaaaga 420attttggttg tggatccagt cacctctgaa catgaactga catgtcaggc tgagggctac 480cccaaggccg aagtcatctg gacaagcagt gaccatcaag tcctgagtgg taagaccacc 540accaccaatt ccaagagaga ggagaagctt ttcaatgtga ccagcacact gagaatcaac 600acaacaacta atgagatttt ctactgcact tttaggagat tagatcctga ggaaaaccat 660acagctgaat tggtcatccc agaactacct ctggcacatc ctccaaatga aaggactcac 720ttggtaattc tgggagccat cttattatgc cttggtgtag cactgacatt catcttccgt 780ttaagaaaag ggagaatgat ggatgtgaaa aaatgtggca tccaagatac aaactcaaag 840aagcaaagtg atacacattt ggaggagacg taa 873661965DNAHomo sapiens 66aacgcccgcc tgcaaggtcc tctgcgccct ggcagccagg agtcgccgcc acgaccgccg 60ggtctcagtg ggtgcctgcg ccttctcccc gcccgcctgc cccgggccat ccagaaactt 120gctctacccg ccgcgggtgc tcggcagtgc tgcccatggc ccagcccagg agcctattta 180gggcgccgga cgggctggac agaggcgcgg ctcagtaatt gaaggcctga aacgcccatg 240tgccactgac taggaggctt ccctgctgcg gcacttcatg acccagcggc gcgcggccca 300gtgaagccac cgtggtgtcc agcatggccg cgctgctcct gggcgcggtg ctgctggtgg 360cccagcccca gctagtgcct tcccgccccg ccgagctagg ccagcaggag cttctgcgga 420aagcggggac cctccaggat gacgtccgcg atggcgtggc cccaaacggc tctgcccagc 480agttgccgca gaccatcatc atcggcgtgc gcaagggcgg cacgcgcgca ctgctggaga 540tgctcagcct gcaccccgac gtggcggccg cggagaacga ggtccacttc ttcgactggg 600aggagcatta cagccacggc ttgggctggt acctcagcca gatgcccttc tcctggccac 660accagctcac agtggagaag acccccgcgt atttcacgtc gcccaaagtg cctgagcgag 720tctacagcat gaacccgtcc atccggctgc tgctcatcct gcgagacccg tcggagcgcg 780tgctatctga ctacacccaa gtgttctaca accacatgca gaagcacaag ccctacccgt 840ccatcgagga gttcctggtg cgcgatggca ggctcaatgt ggactacaag gccctcaacc 900gcagcctcta ccacgtgcac atgcagaact ggctgcgctt tttcccgctg cgccacatcc 960acattgtgga cggcgaccgc ctcatcaggg accccttccc tgagatccaa aaggtcgaga 1020ggttcctaaa gctgtcgccg cagatcaatg cttcgaactt ctactttaac aaaaccaagg 1080gcttttactg cctgcgggac agcggccggg accgctgctt acatgagtcc aaaggccggg 1140cgcaccccca agtcgatccc aaactactca ataaactgca cgaatatttt catgagccaa 1200ataagaagtt cttcgagctt gttggcagaa catttgactg gcactgattt gcaataagct 1260aagctcagaa actttcctac tgtaagttct ggtgtacatc tgaggggaaa aagaatttta 1320aaaaagcatt taaggtataa tttatttgta aaatccataa agtacttctg tacagtatta 1380gattcacaat tgccatatat actagttata tttttctact tgttaaatgg agggcatttt 1440gtattgtttt tcatggttgt taacattgtg taatatgtct ctatatgaag gaactaaact 1500atttcactga aaaaaaaaaa aagatttttt ctggagacgc tatgtttttt tgaatataat 1560taacttgccc ccaactcaaa atagctgtct gtgttgcaat cattgcaaaa tctaaattct 1620tttgttactt aaaaaaacat gtttttcatg gctattacaa tcctctctct cccctctcct 1680ttctgcattg ctctttttaa tttttaatgt ctcattgtga tcatcagatt tatttttact 1740tggattgtaa gatttatctc ctcggcgatt ccttgtcatt tttggaggtc acagttttac 1800tcattcccat gtgtaaactt caagtaaaca aagcaatatt caggatggag aagcagttag 1860tgactggcta gaggtctctt gggatccatc ttgacctcaa agaatatttg cacatgcttc 1920tgatctcagc agttataata aagaggatta aacccttggc cttca 196567581DNAHomo sapiens 67acccaccagg ccaccacaag aatgttgcat tttcattatt atgatacttc aaacaaaata 60atggagcccc acagaccgaa tgtgaagaca gcagtgccat tgtctttgga aagctatcac 120atatctgaag agtatggctt tcttcttcca gattctctga aagaacttcc agatcattat 180aggccttgga tggaaattgc caacaaactt cctcaattga ttgatgctca ccagcttcaa 240gctcatgtgg acaagatgcc cctgctgagc tgccagttcc tgaagggtca ccgggagcag 300cgcctggccc acctggtcct gagcttcctc accatgggtt atgtctggca ggaaggagag 360gcgcagcctg cagaggtcct gccaaggaat cttgcccttc catttgtcga agtctccagg 420aacttggggc tccctcctat cctggtccac tcagacttgg tgctgacgaa ctggaccaaa 480aaagatccag acggagacgg agtctccctc tgtctcccag gctggagtgc agtggcatga 540tctcggctca ctgcaacctc tgcctcctgg gtttgagcgg t 581682142DNAHomo sapiens 68gaaactgaaa cttggccctc tgggggcgga gtggccactg gggatttaaa gagctgccac 60ttccttaggc ctccagaggg cactgggaag tcacagctgc tgagggacca ctctgctccc 120ccgcctaagc catgcacctc tgtgggggca atgggctgct gacccagaca gaccccaagg 180agcaacaaag gcagctgaag aagcagaaga accgggcagc cgcccagcga agccggcaga 240agcacacaga caaggcagac gccctgcacc agcagcacga gtctctggaa aaagacaacc 300tcgccctgcg gaaggagatc cagtccctgc aggccgagct

ggcgtggtgg agccggaccc 360tgcacgtgca tgagcgcctg tgccccatgg attgtgcctc ctgctcagct ccagggctcc 420tgggctgctg ggaccaggct gaggggctcc tgggccctgg cccacaggga caacatggct 480gccgggagca gctggagctg ttccagaccc cgggttcctg ttacccagct cagccgctct 540ctccaggtcc acagcctcat gattctccca gcctcctcca gtgccccctg ccctcactgt 600cccttggccc cgctgtggtt gctgaacctc ctgtccagct gtcccccagc cctctcctgt 660ttgcctcgca cactggttcc agcctgcagg ggtcttcctc taagctcagt gccctccagc 720ccagcctcac ggcccaaact gcccctccac agcccctcga gctggagcat cccaccagag 780ggaagctggg gtcctctccc gacaaccctt cctctgccct ggggcttgca cgtctgcaga 840gcagggagca caaacctgct ctctcagcag ccacttggca agggctggtt gtggatccca 900gccctcaccc tctcctggcc tttcctctgc tctcctctgc tcaagtccac ttctaacctg 960gtcttcggag ctgggttggc cccttctttg ggctcaggaa gcagccttag cacacgggcc 1020tctcctccct cactactggg tgctgccctg cgtggctgac cagctggccc aggatttcac 1080agtcgaaaag gaagccacca ctgatgcctc ccactgtgac aggccctgtc accaccaata 1140tcttatttca acctcacagt tgacctgaga aatcgagatt atcactccac tttttcagac 1200aaggaaactg aggctcaggg aagccaagtg acaagtccaa ggtcacgaag actttcttgg 1260agcccgaaac accaccctct gctcctcctt ctcctgtcct ggcccaggca tcctaggggc 1320tgaaatcctg gaaaccgtgg gctggtgtga gaaggtttgc atgctcagag cagagaaggg 1380ctctccccac tgcttcgtga ttccagggcc agagccatgc agtcccagaa accccaacct 1440agctggggca ggtccagagt ccaagccctg gtgggtagag gccaagcaga agccctgaag 1500tggactcttg cttcccctag tagtgttttc agtgccaaga agctgaaact gtgagctgga 1560gttggggaga ggtctggaag aggaccatct gggatttcta cagcctgggt acccatagcc 1620acaccaaggc ttctgggaga ttctgcaggg tcagctttcc aggctgttcc caaatagctc 1680cctgcctccc cactgcccct aaagccacag cagaagagcc attcatctca taaacaaaaa 1740ggaagaggaa agaatgagga aggaccctgt gcaaggttat ttgcaggcag ggatgggctt 1800gtacctgaca gcacccaccc ctgtgtggcc cccaggccct catcaccctc agacccctcc 1860taagcagttc cctcattgct ctttggacta ggctgacagc aggaagagca gggcccatga 1920ccgggtggaa gttcagtttt ggtgtctgct tcaagagggg gttttacact ctgattccag 1980gacaagcact ctgaggcggg tgggggagag aaaccctggc tcttcaccca ggtttcacac 2040acatgtaaat gaaacactat gttagtatct aacacactcc tggatacaga acacaagtct 2100tggcacatat gtgatggaaa taaagtgttt tgcaatcttt aa 2142692400DNAHomo sapiens 69tccgctccgt tcggccggtt ctcccgggaa gctattaata gcattacgtc agcctgggac 60tggcaacacg gagtaaacga ccgcgccgcc agcctgaggg ctataaaagg ggtgatgcaa 120cgctctccaa gccacagtcg cacgcagcca ggcgcgcact gcacagctct cttctctcgc 180cgccgcccga gcgcaccctt cagcccgcgc gccggccgtg agtcctcggt gctcgcccgc 240cggccagaca aacagcccgc ccgaccccgt cccgaccctg gccgccccga gcggagcctg 300gagcaaaatg atgcttcaac acccaggcca ggtctctgcc tcggaagtga gtgcttctgc 360catcgtcccc tgcctgtccc ctcctgggtc actggtgttt gaggattttg ctaacctgac 420gccctttgtc aaggaagagc tgaggtttgc catccagaac aagcacctct gccaccggat 480gtcctctgcg ctggaatcag tcactgtcag cgacagaccc ctcggggtgt ccatcacaaa 540agccgaggta gcccctgaag aagatgaaag gaaaaagagg cgacgagaaa gaaataagat 600tgcagctgca aagtgccgaa acaagaagaa ggagaagacg gagtgcctgc agaaactccc 660aaggcccttt tgggtccaga agacctgcat atgggctgtt gactcatgca aatgaggtat 720ctgaactgca gcttcagtat tagcagagcc acaggccgcc tctgtggcat caccagggtt 780tctctgaaga agagggtctg cattttccta aacccagtgc tgctctccca tctcccatct 840tcctctcgca gcttgatgag ccccggtgtg tcccaggtac acccctgcat ccaggcagca 900gcccaggcca ccccctcctc actggccctt ggctcctttc ttgatgcctc tgttgcttgt 960cccccaggag tcggagaagc tggaaagtgt gaatgctgaa ctgaaggctc agattgagga 1020gctcaagaac gagaagcagc atttgatata catgctcaac cttcatcggc ccacgtgtat 1080tgtccgggct cagaatggga ggactccaga agatgagaga aacctcttta tccaacagat 1140aaaagaagga acattgcaga gctaagcagt cgtggtatgg gggcgactgg ggagtcctca 1200ttgaatcctc attttatacc caaaaccctg aagccattgg agagctgtct tcctgtgtac 1260ctctagaatc ccagcagcag agaaccatca aggcgggagg gcctgcagtg attcagcagg 1320cccttcccat tctgccccag agtgggtctt ggaccagggc aagtgcatct ttgcctcaac 1380tccaggattt aggccttaac acactggcca ttcttatgtt ccagatggcc cccagctggt 1440gtcctgcccg cctttcatct ggattctaca aaaaaccagg atgcccaccg ttaggattca 1500ggcagcagtg tctgtacctc gggtgggagg gatggggcca tctccttcac cgtggctacc 1560attgtcactc gtaggggatg tggagtgaga acagcattta gtgaagttgt gcaacggcca 1620gggttgtgct ttctagcaaa tatgctgtta tgtccagaaa ttgtgtgtgc aagaaaacta 1680ggcaatgtac tcttccgatg tttgtgtcac acaacactga tgtgactttt atatgctttt 1740tctcagatct ggtttctaag agttttgggg ggcggggctg tcaccacgtg cagtatctca 1800agatattcag gtggccagaa gagcttgtca gcaagaggag gacagaattc tcccagcgtt 1860aacacaaaat ccatgggcag tatgatggca ggtcctctgt tgcaaactca gttccaaagt 1920cacaggaaga aagcagaaag ttcaacttcc aaagggttag gactctccac tcaatgtctt 1980aggtcaggag ttgtgtctag gctggaagag ccaaagaata ttccattttc ctttccttgt 2040ggttgaaaac cacagtcagt ggagagatgt ttggaaacca cagtcagtgg agcctgggtg 2100gtacccaggc tttagcatta ttggatgtca atagcattgt ttttgtcatg tagctgtttt 2160aagaaatctg gcccagggtg tttgcagctg tgagaagtca ctcacactgg ccacaaggac 2220gctggctact gtctattaaa attctgatgt ttctgtgaaa ttctcagagt gtttaattgt 2280actcaatggt atcattacaa ttttctgtaa gagaaaatat tacttattta tcctagtatt 2340cctaacctgt cagaataata aatattggaa ccaagacatg gtaaacaaaa aaaaaaaaaa 2400703710DNAHomo sapiens 70aggacgcgtt tccaagttcc agtgactcct cctgtttggg actcgggggg agagtgcggg 60gagacaaata aaacctcggg cggcggcggc tggtgggaag acttgaactt gaatctcgaa 120ccactgcatc tccgactctg cccagactct tcactccgcg gcaccctcaa accccagccc 180aggccggggc gcacaagcca gccagcgcac ctgcagtcct cgcccggacg cgccgcgccc 240cctcggaacc aggctctgct ccgagcagcc ttcgcccctc aagccagcca cagtccccgc 300caggccgggt gggcgtcaag atgaaggcgg cccgcttcgt gctgcgcagc gctggctcgc 360tcaacggcgc cggcctggtg ccccgagagg tggagcattt ctcgcgctac agcccgtccc 420cgctgtccat gaagcagcta ctggactttg gttcagaaaa tgcatgtgaa agaacttctt 480ttgcattttt gcgacaagaa ttgcctgtga gactcgccaa cattctgaag gaaattgata 540tcctcccgac ccaattagta aatacctctt cagtgcaatt ggttaaaagc tggtatatac 600agagcctgat ggatttggtg gaattccatg agaaaagccc agatgaccag aaagcattat 660cagactttgt agatacactc atcaaagttc gaaatagaca ccataatgta gtccctacaa 720tggcacaagg aatcatagag tataaagatg cctgtacagt tgacccagtc accaatcaaa 780atcttcaata tttcttggat cgattttaca tgaaccgtat ttctactcgg atgctgatga 840accagcacat tcttatattt agtgactcac agacaggaaa cccaagccac attggaagca 900ttgatcctaa ctgtgatgtg gtagcagtgg tccaagatgc ctttgagtgt tcaaggatgc 960tctgtgatca gtattattta tcatctccag aattaaagct tacacaagtg aatggaaaat 1020ttccagacca accaattcac atcgtgtatg ttccttctca cctccatcat atgctctttg 1080aactatttaa gaatgcaatg cgggcaacag ttgaacacca ggaaaatcag ccttccctta 1140caccaataga ggttattgtt gtcttgggaa aagaagacct taccattaag atttcagaca 1200gaggaggtgg tgttcccctg agaattattg accgcctctt tagttataca tactccactg 1260caccaacgcc tgtgatggat aattcccgga atgctccttt ggctggtttt ggttacggct 1320tgccaatttc tcgtctgtat gcaaagtact ttcaaggaga tctgaatctc tactctttat 1380caggatatgg aacagatgct atcatctact taaaggcttt gtcttctgag tctatagaaa 1440aacttccagt ttttaacaag tcagccttca aacattatca gatgagctct gaggctgatg 1500actggtgtat cccaagcagg gaaccaaaga acctggcaaa agaagtggcc atgtgaagag 1560ggacactcag gacactttac gggatcaaag tgggtctaca ccagtgctgc ttcctgaatg 1620tttgtgtgtg aacccttgtt tcctccaaaa caaacgacag caacgaaaac tccttaatca 1680gaacactgat ccaatgagga atggagcttg tttctgtgac ccaggagaac ttagtgcaag 1740actacaggag ttaacagatg gccagctcct tattttttaa tgtagaataa ctcctgagtt 1800tatatcaaat cctgaagaaa taagcctcag ttttccatct gtttttgata agaataagaa 1860agggagtgag tgtgaagatg gtggttagca gtttcactaa gactgatatt ttaggcctct 1920tgttcacatc aaaagatatt ggtgtcagaa taccagcatt ttcctgccat gcaaaggatt 1980aaaacttagt ttacactatg tggttacaaa tatatgtcaa tgtacatttt gaacatattt 2040atgtgctatg gaaggaaatg ctggtgacta aaataaggtt tactctgaaa gaggaggaat 2100tttattcaaa gcattcaaac attttattca agtgtttcaa aattcaaagc attgtattca 2160aagttgcagt gaaggcatca acttatgtaa aaactcagaa ggaaggctcc tctgataaaa 2220acacagctcc tttattatgc tgcttttctt gttcacttta cacactaagt aaacacttat 2280tgtcaggtgc ctagtcttga gtgaattgtt agatgtgcac tgaactcggg atgttgggga 2340ttggagagag agaattgcca aagtaacagc aaaaatatct cttactttgc tttgtttata 2400aataaattag tagattggaa aaactagtgt tagggaaaga aatcacatgt tcagagccta 2460attcagtagg aagggctttt ctctaccctg aaatgaaggt aatccaaagg catccatttt 2520ctaggcttaa aagatatatt tttgatatat ttaattatat tctctacact ccagcattaa 2580tatgtctgtt taaaaattac taattctcaa atggctcaag aacattagaa tttaagtacc 2640ttttagagta attattttaa gcaaatagcc tggacgtaag agattctcat gccagcatgc 2700tttcatttgt cagttgttgt gactgagaga taatgaatga cacctgaaat gcatatggta 2760tttttgggag agttaaggta taatttgaag gttggcagac cagttgcgct gattactctt 2820agagaagaag aaatggaaaa atgaaagaag gcaggaagga aagaaaggat ataggaagag 2880agggaagcag aaggcaggca tttttctatt ttccccacaa attatttcaa aaaaaatctg 2940tattttctgg gatatgtcat tggcaagagg aagaactggt gttttgaaag cagtatggat 3000tctttaaatg cctctcactc ttacaagata gtaggctttg agataataaa cttacccgtg 3060tcaattaaca tttaaactgg catatagaaa aaaaggagga tttttctgca ttgtaaaata 3120atcagtatgg tttatatgtt gaatttgaca tttgtgtgta atttcatggt ggcctagtgt 3180tgtggtgctt ctggtaatgg taatagaagc tcaactattt ttttgtggat ttcagttttt 3240atcatcagaa gtcctagaca gtgacatttc ttaatggtgg gagtccagct catgcatttc 3300tgattataca aaacagtttg cagtaggtta tttgtcattt cagtttttta ctgaaatttg 3360agctaaacat ttttacatgt aaatacttgt atttaccaaa gatttaaatc agttgattaa 3420ttaattaact caaatactgt gaactatctc taaaacacta gaaaaaagaa atgttagtat 3480ctcaattaca ccaactgtgc aaatgaactt tgataaaata gaaataatct acattggcct 3540ttgtgaaatc tggggaagag ctttaggatt ctagtagatg gatactgaat actcaggccc 3600acttaaatta ttaatgtata cattgtgttt ttgtctttat gctatgtaca gagaaatgtg 3660ataatttttt ataataaata ttttttatga tgataaaaga aaaaaaaaaa 3710713691DNAHomo sapiens 71ggcgcaacgc tgagcagctg gcgcgtcccg cgcggcccca gttctgcgca gcttcccgag 60gctccgcacc agccgcgctt ctgtccgcct gcagggcatt ccagaaagat gaggatattt 120gctgtcttta tattcatgac ctactggcat ttgctgaacg catttactgt cacggttccc 180aaggacctat atgtggtaga gtatggtagc aatatgacaa ttgaatgcaa attcccagta 240gaaaaacaat tagacctggc tgcactaatt gtctattggg aaatggagga taagaacatt 300attcaatttg tgcatggaga ggaagacctg aaggttcagc atagtagcta cagacagagg 360gcccggctgt tgaaggacca gctctccctg ggaaatgctg cacttcagat cacagatgtg 420aaattgcagg atgcaggggt gtaccgctgc atgatcagct atggtggtgc cgactacaag 480cgaattactg tgaaagtcaa tgccccatac aacaaaatca accaaagaat tttggttgtg 540gatccagtca cctctgaaca tgaactgaca tgtcaggctg agggctaccc caaggccgaa 600gtcatctgga caagcagtga ccatcaagtc ctgagtggta agaccaccac caccaattcc 660aagagagagg agaagctttt caatgtgacc agcacactga gaatcaacac aacaactaat 720gagattttct actgcacttt taggagatta gatcctgagg aaaaccatac agctgaattg 780gtcatcccag aactacctct ggcacatcct ccaaatgaaa ggactcactt ggtaattctg 840ggagccatct tattatgcct tggtgtagca ctgacattca tcttccgttt aagaaaaggg 900agaatgatgg atgtgaaaaa atgtggcatc caagatacaa actcaaagaa gcaaagtgat 960acacatttgg aggagacgta atccagcatt ggaacttctg atcttcaagc agggattctc 1020aacctgtggt ttaggggttc atcggggctg agcgtgacaa gaggaaggaa tgggcccgtg 1080ggatgcaggc aatgtgggac ttaaaaggcc caagcactga aaatggaacc tggcgaaagc 1140agaggaggag aatgaagaaa gatggagtca aacagggagc ctggagggag accttgatac 1200tttcaaatgc ctgaggggct catcgacgcc tgtgacaggg agaaaggata cttctgaaca 1260aggagcctcc aagcaaatca tccattgctc atcctaggaa gacgggttga gaatccctaa 1320tttgagggtc agttcctgca gaagtgccct ttgcctccac tcaatgcctc aatttgtttt 1380ctgcatgact gagagtctca gtgttggaac gggacagtat ttatgtatga gtttttccta 1440tttattttga gtctgtgagg tcttcttgtc atgtgagtgt ggttgtgaat gatttctttt 1500gaagatatat tgtagtagat gttacaattt tgtcgccaaa ctaaacttgc tgcttaatga 1560tttgctcaca tctagtaaaa catggagtat ttgtaaggtg cttggtctcc tctataacta 1620caagtataca ttggaagcat aaagatcaaa ccgttggttg cataggatgt cacctttatt 1680taacccatta atactctggt tgacctaatc ttattctcag acctcaagtg tctgtgcagt 1740atctgttcca tttaaatatc agctttacaa ttatgtggta gcctacacac ataatctcat 1800ttcatcgctg taaccaccct gttgtgataa ccactattat tttacccatc gtacagctga 1860ggaagcaaac agattaagta acttgcccaa accagtaaat agcagacctc agactgccac 1920ccactgtcct tttataatac aatttacagc tatattttac tttaagcaat tcttttattc 1980aaaaaccatt tattaagtgc ccttgcaata tcaatcgctg tgccaggcat tgaatctaca 2040gatgtgagca agacaaagta cctgtcctca aggagctcat agtataatga ggagattaac 2100aagaaaatgt attattacaa tttagtccag tgtcatagca taaggatgat gcgaggggaa 2160aacccgagca gtgttgccaa gaggaggaaa taggccaatg tggtctggga cggttggata 2220tacttaaaca tcttaataat cagagtaatt ttcatttaca aagagaggtc ggtacttaaa 2280ataaccctga aaaataacac tggaattcct tttctagcat tatatttatt cctgatttgc 2340ctttgccata taatctaatg cttgtttata tagtgtctgg tattgtttaa cagttctgtc 2400ttttctattt aaatgccact aaattttaaa ttcatacctt tccatgattc aaaattcaaa 2460agatcccatg ggagatggtt ggaaaatctc cacttcatcc tccaagccat tcaagtttcc 2520tttccagaag caactgctac tgcctttcat tcatatgttc ttctaaagat agtctacatt 2580tggaaatgta tgttaaaagc acgtattttt aaaatttttt tcctaaatag taacacattg 2640tatgtctgct gtgtactttg ctatttttat ttattttagt gtttcttata tagcagatgg 2700aatgaatttg aagttcccag ggctgaggat ccatgccttc tttgtttcta agttatcttt 2760cccatagctt ttcattatct ttcatatgat ccagtatatg ttaaatatgt cctacatata 2820catttagaca accaccattt gttaagtatt tgctctagga cagagtttgg atttgtttat 2880gtttgctcaa aaggagaccc atgggctctc cagggtgcac tgagtcaatc tagtcctaaa 2940aagcaatctt attattaact ctgtatgaca gaatcatgtc tggaactttt gttttctgct 3000ttctgtcaag tataaacttc actttgatgc tgtacttgca aaatcacatt ttctttctgg 3060aaattccggc agtgtacctt gactgctagc taccctgtgc cagaaaagcc tcattcgttg 3120tgcttgaacc cttgaatgcc accagctgtc atcactacac agccctccta agaggcttcc 3180tggaggtttc gagattcaga tgccctggga gatcccagag tttcctttcc ctcttggcca 3240tattctggtg tcaatgacaa ggagtacctt ggctttgcca catgtcaagg ctgaagaaac 3300agtgtctcca acagagctcc ttgtgttatc tgtttgtaca tgtgcatttg tacagtaatt 3360ggtgtgacag tgttctttgt gtgaattaca ggcaagaatt gtggctgagc aaggcacata 3420gtctactcag tctattccta agtcctaact cctccttgtg gtgttggatt tgtaaggcac 3480tttatccctt ttgtctcatg tttcatcgta aatggcatag gcagagatga tacctaattc 3540tgcatttgat tgtcactttt tgtacctgca ttaatttaat aaaatattct tatttatttt 3600gttacttggt acaccagcat gtccattttc ttgtttattt tgtgtttaat aaaatgttca 3660gtttaacatc ccagtggaga aagttaaaaa a 36917260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 72aatccttgtg accacaccga tggagataca gaaaaagtta acgactggat tctatcttca 607360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 73tttagtgaac actgttctct gggtgacaat acgtaaagaa ctgaaaagaa agaaaaagtg 607460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 74caaagatgca tttacctctg tatcaactca ggaaatctca taagctggta ccactcagga 607560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 75gagtttttcc tatttatttt gagtctgtga ggtcttcttg tcatgtgagt gtggttgtga 607660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 76ggtactgagc agagtcttag gtaaaagtct tgggaaatat ttgggcattg gtctggccaa 607760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 77tgagccctac atcaagtggg aagacaagga cgccaagatc ttccgagttg tggatccaaa 607860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 78agagtttcct ttccctcttg gccatattct ggtgtcaatg acaaggagta ccttggcttt 607960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 79agtgagctcc agcacgccca gaggactgtt aataacgatg atccatgtgt tttactctaa 608060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 80tggaagttca gttttggtgt ctgcttcaag agggggtttt acactctgat tccaggacaa 608160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 81gatgtcaata gcattgtttt tgtcatgtag ctgttttaag aaatctggcc cagggtgttt 608260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 82atttgacatt tgtgtgtaat ttcatggtgg cctagtgttg tggtgcttct ggtaatggta 608360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 83caaatttcat cactgtatac tttcaatccg aagggccagt actacagcat gttgcacaaa 608460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 84aattaggttt tcaacatggg aagcatgaaa tccacttctg gatttggagc atccacttga 608560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 85taaaaggttc tgttttgttt ggaatcaatg gtagctttat tgactgttct gattgtgctg 608660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 86agctaagcct cacaaaagtc aatctgcagg gaagaatcta aatcatatgc ctacccatgg 608760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 87gaaggagata aggttcgact tacattcttc acactgtcaa aaaatggaga aaaactacag 608860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 88ttgaacccta cacgaagaaa gaactttctg ctgttacttt ccctgacatc attcgcaatt 608960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 89taaagtcagt gcccaactgt tataggttgt tggataaatc agtggttatt tagggaactg 609060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 90atacaggcca aagaggtgct gaaaaaatat ttggagtcca aggaggatgt ggctgatgca 609160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 91agaatctttc ccttgctaga ccccagaatt ttaaatgcat ccgtcttaca ctttcacaaa 609260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 92atgtctatcc acaggctaac cccactctat gaatcaatag aagaagctat gaccttttgc 609360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 93aatcctaaag cataagttag tcttttcctg attcttaaag gtcatacttg aaatcctgcc 609460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 94cataatgaaa gaacccagca attctgtctc ttaatgcaat gacactattc atagactttg 609560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 95atctttacat tgtctgccaa ttaaagtgtt ttaaacttgc attggaatgg

actccgaatg 609660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 96atacatttta attcctcacg ttttatattg gagagttcgg tacagactgt ccattactgc 609760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 97gtgtgtccct aagaagaact ttgaactgat ttgatattga aacaaaccaa aaacttccag 609860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 98tccagaagat gagagaaacc tctttatcca acagataaaa gaaggaacat tgcagagcta 609960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 99tttgcattgt gtcttcattt taatgtgttt gcaatcgctc cgctccagga agaacggaaa 6010060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 100agaagaatga gatactgatg tccacagttc attggcagaa tctaacccct tctgttatct 6010160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 101tttttagtgg catgcaggct atacctcagt atttgtggac atgcacccag gaatatgtac 6010260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 102ccatgtttct gaatcttctt tgtttcaaat ggtgctgcat gttttcaact acaataagtg 6010360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 103tgcttttaac ttccccacca tgttgcacct aaagctttgg agttttcctg tgattagtgt 6010460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 104tcttataaat aagtatgaag aagctgtttg tcatctggca tcatcccatc agttagttac 6010560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 105ctgttcctgt gatgtggagg aaattttccg caaggttcga ttttcatttg agcagccaga 6010660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 106tacagagtta tagtgtgttt actcctaaga tgacagttct ctttgtctat attcagcatc 6010760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 107ggataacatg gctggatgaa agaaatgacc ttcattctga gaccaaagta gatttacaga 6010860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 108aggggacaca ggcttcttaa aacaacccgg cttcctcacc ctatgtcctt tatttacaaa 6010960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 109tgtgacccac ttaccttgca tctcacaggt agacagtata taactaacaa ccaaagacta 6011060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 110gcaacaatcc atctctcaag tagtgtatca cagtagtagc ctccaggttt ccttaaggga 6011160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 111gctgggactc tcagcaggtc caacatctgg aaatcacctt actacacaag attctcaaat 6011260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 112ggaaaacgag ctaattccgt gccgatggag gtgttgatgg atgtccacca ctctccactt 6011360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 113tccaggatga gttacttgaa atttgccttg agtgtgttac ctcctttcca agctcctcgt 6011460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 114ttaaagggtt gctttaagtg ggatagaaaa accttaagga aagttcatag taggtcctca 6011560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 115aaagggttgc aaacaaaaag aactttgaga ataaggaagc ccagagttct caagccactc 6011660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 116accaggaaga gatggagaaa gtaaaacgtg aaaatgctac agttatggat aagacccgag 6011760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 117gtaacagttt actggttgtt ccattcctga atatgcaggc taatttgtac agatagggat 6011860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 118tcagaaaaaa cagagtaagg caccactctt gggaaattaa ggtagcttgc agtaacaagt 6011960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 119accatcatgg cagtggagtt tgacgggggc gttgtgatgg gttctgattc ccgagtgtct 6012060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 120aaacactaga agatctcaga aaaaatgaag ataaattgaa ccatcatcag cgaattgggc 6012160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 121gtatcatcca aataatgggg cctatgactt gaatgaatag aaatgaataa gctggtgttt 6012260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 122tgtattcact tatgctctcg tacattgagt acttttattc caaaactagt gggttttctc 6012360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 123attacctttc ctttaggtgt tggctacagt tatcccaaac ttggacttga ggtcttgtat 6012460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 124atggaggtga ttggttctct ttacacatta acactgtacc aagctttgca gatcttttcc 6012560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 125agcaaagatg aagggaaaac gaactaagac agacgctagg ccatgttggc aaagtagcat 6012660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 126gagatgccaa ggtgaaagta cccaacttca aaatgagata caaaagctac agaagaccct 6012760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 127aaaggctatt tgcagaagga gctcacagat cacattgaaa gcattgcata ttcaaacatc 6012860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 128gagcttcagg atgtaaatat ttggactata tgcagaaaat attccatgac ttggatatgc 6012960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 129gccaaagctc aaatgcccac catagaacga ctgtccatga caagatattt ctacctcttt 6013060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 130aagacatcag tcaggatcat gtgaagaaaa cagtgaccat tgaaaatcac cctcatctgc 6013160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 131tttaagtttc cagctcttca ccgaaatgtt gtattcttat ttcagtgttt ccttccagac 6013260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 132tatgcaagta cttttagact aaatgcctta tgcatctgag gagatacacc gtaggatcgt 6013360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 133gacagtttaa aagcattgta aaactcacat agcttacttc tctctctaaa gtgcaacaag 6013460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 134atgtgttcta tgaagatgac atttggcctg gagaaaatga gaatgggtaa gcaagattta 6013560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 135agcccagccc tccttaatca acttcaagga gcaccttcat tagtacagct tgcatattta 6013660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 136gatcaagaga atatttcaga gttttggttt acacatcaag aaacagacac acatacctag 6013760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 137tgagagcgag atgggaagca tagatatcta tatttttatt tctactatga gggccttgta 6013860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 138ctggtttgcc tgaatctttt cctttaactg gtggtactga aaatttgaat acagaaacaa 6013960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 139gttgttgagt tttgtatacc tatgttagga atatttgttt tatactgcct tcaggtcctc 6014060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 140aaacaactca agcattctgg tggcaacata gagattgtag gctgcttcta agaaagttat 6014160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 141tctgaagctc tttatgatgc accggtgcat ttttatttaa aaaatagatt gtgactcctc 6014260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 142ggcttcacaa ggatgtattt tggagaacga atagtggaac cagtaatagt cattttcttt 6014360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 143tggatggttg aaaatctgga atatagagga gtactgtctt aactccagta agaacaaaat 6014460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 144cttcaaatgg ctctcaatca tatgcttcaa atcaagacag tgctaagttc cagcagcata 6014560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 145ctagatgtga ggtacaaaac ttgggatcaa atggaatctt gattcactaa ccaatttaag 6014660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 146tagagttcac agtggtaaga ctcatatgcc tgtatgtgtt gctaataaat tagattttgg 6014760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 147aagtacgtga aaatcaggtt tcaatagaat gtgacacaac gtgcaaggaa atgaagcgga 6014860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 148atgaaagact gttctacatt cgttgcattc ttagcactgg tttccaaaaa cggaattcca 6014960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 149taaactatca atggcatttc aagtcttctg aaacagcatg gctgtatgtg cgtggtccat 6015060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 150tgaaggcgaa atgataactt ctaaggataa tttagaagat gagactgaag atgatgacct 6015160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 151aaatcagcct ccatcagtat cactgcagtt atatatgatg tatgccttat tgctcaagac 6015260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 152ttttttcaca tttgagattg gatgatcatg atattgaggg ggtaatggta aagcagaccc 6015360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 153aggacacttc atctactctg gttgactgtc attttcaaca tcataattta cataaggtag 6015460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 154agatcgttat gccagtgaaa atgtcaacaa attgttggta gggaacaaat gtgatctgac 6015560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 155gcattttatt tcacccattt ttgttcaagc tcttacatta acattcttag cagaatgggg 6015660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 156ggagaaaaga aagtgggtta tcaagggtga tttgaaattt tctgcagcat taaagctggc 6015760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 157taacgacatg aaaatgcaag tgtcaatgga gtagtttatt accttctatt ggcatcaagt 6015860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 158aggatacatg attgtgggcc tatatatgac acatgacaaa tgtccctgtc acaggactca 6015960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 159gtggtacgat caaaggcact atgtcttcat tgaattttgt gttgaagaca gtaaggatgt 6016060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 160caatagcatc tgaagagaga gtacatagat tggaaatggc tattgcattt cactcaaatg 6016160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 161cctttttgta tttgagagaa tctactaagt tcagtccagt caagaaaaga acctaatagc 6016260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 162gctcagtttc tcttaaatga ggatgatgat gaccaaccta gaggactcac taaagaacag 6016360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 163ctgcagcagc gttcagacca actcctggat atgagctcaa ccttcaacaa gactacacag 6016460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 164tgctgccgaa gatgggccgg ctgaagagag tggacctgga gaagaatcag atcacagctt 6016560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 165tatggggacc atagtatcat tcagtgcatt gtttacatat tcaaagtggt gcactttgaa 6016660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 166agcaaaaggg aagacattgt gaaccaaatg acagaagcct gccttaacca gtcgctagat 6016760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 167gcacatgctg ttttattcaa atgcctcttt tgtacatgtt catgtttagt gttttctcag 6016860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 168aacgttacat gactcgttga gaaagttgag gaatttcctc taccaccttt gttgcttgaa 6016960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 169ctcattcagc tcaaacagat ttcatagcca aagcaaaagg actggtacgg tagtctgtgg 6017060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 170gattattggt ccaaggggca gttgaaagca cttttttcgg aacacgaggg ttattttgga 6017160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 171agaatcagat gctgcagtaa aggaaaaagc cattcaggtt ggctttgttt taggtggctt 6017260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 172attttcagtc cagttatgaa cagcaagtgt tgaactcttt ctgcttgttt tgattcaaag 6017360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 173gccatggatg cagcagcctg aaacttgaga gcgaaagtga gataaatgtc aaaggtgttt 6017460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 174agactgtcag tactgggagc gcctgctggc caaggaatgc aggctgtact atctgcgaaa 6017560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 175gcttattttg gttgcagttt ccaattttta aaaatgttga ggtaatcttt cccaccttcc 6017660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 176acttgaatag tccattgacc gaaactcttt atagactatt gtgtaaatgt ggaatcacag 6017760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 177ctcaaactgg aaataaggtt catgcaattc agtgtgatgt gagggatcct gatatggttc 6017860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 178gcctggggac tgtagaagaa ctcgcaaatc ttgctgcttt cctttgtagt gattatgctt 6017960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 179cctgagttct gcttccttgg atgtcattgc ttaaatatag tcttgaaggg cttgttttga 6018060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 180ggagctgata attggcaaaa gaccactttt accactcagg ctctatttgt gccttagctt 6018160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 181gaattggctg gaagaagaat gtattgcctg gctaaagaga ttcctggagt atgggaaaga 6018260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 182gggcaataca gtaaattttc atgttactct tttatcagat cacaaactcc tagagtctac 6018360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 183tcctgtctgt cttccgctca ctggcgatgc tggagaagac ggtggaaaaa tgctgcatct 6018460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 184ctcgtgctgt caactgccgc aagaagaagt gtggtcacac caacaacctg cgtcccaaga 6018560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 185cttccccgcc ccgcgtccct ccccctcggc cccgcgcgtc gcctgtcctc cgagccagtc 6018660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 186tacgagttta aaaactgcgt tgttattttt agagatttgt gataatacaa cttgttataa 6018760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 187gcaacagttc aatgaatcaa aatggaatga gcactctaag cagccaatta gatgctggca 6018860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 188tcccccctca tcgccccgcg cccaccccca tcgcccctgc ccccggcggc ggcctcgcgt 6018960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 189ggcccccaac cagcccccac cgcctctcat ccgccccgct ctggctgccc cccgccacag 6019060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 190gccccaggcc gcgccccctg ccccacagcc gcctcagccc gcacctcagc cccctgcacc 6019160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 191ctcaccccgc ccctggtccc actcctgccc ccgccctacc tccgccccac cccatcatct 6019260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 192gaagcagcca tggtttcttg gggacaagat cacctttgtg gatttcatcg cttatgatgt 6019360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 193cccccgcgcc cggcctcccc ccggacccct gcggctccaa ctgtgctccc cccgacgccg 6019460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 194cccctcctcc ccgccgcttg gagtaagaac ccaaaacccc gaagccgggc ccgcgtgcaa 6019560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 195cacagactca gagagaaccc accatggtgc tgtctcctgc cgacaagacc aacgtcaagg 6019660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 196gaggaaaggg aaaaccttct cagagagcat gaaaggctgc taaaacacaa gctgaaggta 6019760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 197agaagagaag catttagaga gcatcagcaa tacaaaaccg ctgagttctt gagcaaactg 6019860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 198accatcatgg cagtggagtt tgacgggggc gttgtgatgg gttctgattc ccgagtgtct 6019960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 199agaattctta acttcacaag tgttttactt cgacgatgtg cctttgattt aatttgggac 6020060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 200ctagatcctg tgctttactc tgaagactct aggagagaag tttgctgagg aatgccttca 6020160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 201tggacattcg aacagagttc aagaagcatt atggctattc cctatattca gcaattaaat 6020260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 202taagaaaggc tggttaccat cggagtttac aaagtgcttt cacgttctta cttgttgtat 6020360DNAArtificial SequenceDescription of Artificial Sequence Synthetic

probe 203gcagaaagag atacaatctt gcttgaccgt ttgggacatc aatcttccac atgaagtgca 6020460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 204gtggccaagc gtccggagca caatagatct gaagccttga aggtgtcctg tggcaagtgt 6020560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 205agtcacagtt accgcgtgta ctacaatgcc ggccccaagg atgaggacca ggactacatc 6020660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 206atgtgagcct ttgtgatacg aattcaattt gttttcctgt cttttgacat ttgactttgc 6020760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 207tgttgtggtc gatttacaag gttgggtaac cggtaatgga aaaggactca tctacctcac 6020860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 208gaatgaactg ctgaacaaac agagtgttcc tgctcatttt gtcgccttga atgggagcaa 6020960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 209gaatcttccg tccctcatcc taacttgcag ttcacagaga aaagtgacat acccaaagct 6021060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 210gacaacattt gatcccaaga aaaccagaat ggaacccttt cacttcaaaa actcagttat 6021160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 211acactgagct cacccacaga gcccgtgaag aggtctggcc gctaccactt tgtgcctgga 6021260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 212tgactttcat gtcactcact ataaaatagg tctcttaacc tggcaccagt ataactataa 6021360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 213tgaaccacca gctccaggag aaggcaactc cagtcagaac agcagaaata agcgtgccgt 6021460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 214atgcattgcg ggtgctgtcc aagcttggct catctggggt ttgctgggct taacacccaa 6021560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 215cattgatatc cactggtcac atcataactg tctatagggc aataaaatct gtgttaaact 6021660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 216tcgagctttt gaggttttag attcagctaa acgtgggttt cttactaagg acgagctgat 6021760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 217gaaatactga aacttgctgc ctattgggta tgctgaggcc cacagactta cagaagaagt 6021860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 218ctgtcctgga ccctgtgtgc ctcataaggg ctattctttc tttcacgtgc aaaacatttt 6021960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 219tatgtacagt ttacatgaat gttcctcagg acatggcata caatggcctt ggaggtccaa 6022060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 220atcttagaaa caccttgaag tatgccaaga aaaacgtccg tgcattttgg aaactcagag 6022160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 221aaggaggtct acatcaagaa tggggataag aaaggcagct gtgagagaga tgctcaatat 6022260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 222ggagctctgc cctgcaggga gttgccccaa ccctttccgg aactcagtct ttagaaaaga 6022360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 223gaccaggaaa aacaagaaag acatactcaa tcctgattca agtatggaaa cttcaccaga 6022460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 224atacctggga ggaaggcttt tccttcacaa ttgtatacag ggggcacctg tggccaggcc 6022560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 225agtggtgtag tgccgaaagt gctaaaatat ttagtgcggt attgctctgt gaattcaagt 6022660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 226aaatgagtac gaagataacc aaatctgcta ctggcacatt agactcaagt atggtcagcg 6022760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 227tggtggtgga tcctggaatt ttctcacgca ggagccattg ctctcctaga gggggtctca 6022860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 228caagcaggat caagtttgta gaataaacac tggtttccta gccatcctct gaaaacagta 6022960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 229gtgtgcttta ttgaattaga aaattagtga ccattattca caggtggaca aatgttgtcc 6023060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 230gctgtttcca catcagaact cccttcaaac acaaagattg ctgtgaaaac gaaaatgtgt 6023160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 231acgacctggt catcaaaagc cttgacaaat tgaaggaggt gaaggagttt ttgggtgaga 6023260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 232ttcgtttcag tcaagacaat gcttagttca gatactcaaa aatgtcttca ctctgtctta 6023360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 233gtacataaga atctatcact aagtaatgta tccttcagaa tgtgttggtt taccagtgac 6023460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 234gtaccagaat tgcttagaag ataccagaag gtgcggtcta gggaccagtg aataagaaga 6023560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 235tgagtggaga agaaacaaac atagtgggta taatcatgga tcgcttgtac ccctgtgaaa 6023660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 236ctgtgtttat atggaagaaa gtaaggtgct tggagtttac ctggcttatt taatatgctt 6023760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 237tgagaaagac agcacccatt gaaacagata tgtgtgtgaa agtatatttt tcaattccag 6023860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 238agtaagggaa caagttgagc tatgacttaa catagccaaa atgtgagtgg ttgaatatga 6023960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 239gagcattttt tacaagcctt ccacttcaat ttccatcttt aagaagaaac tcaagggtca 6024060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 240tgcctcttct aagtgtctat gagcttgcac catatttaat aaattgggaa tgggtttggg 6024160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 241tgggtgcagc cactggaggc atcttgcttc tgctggatgt ggtcagcctt gcatatgagt 6024260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 242cgcccccgaa attcaagatt gagtgtcagg ctttatatat attcagcatt cctcattaca 6024360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 243cagatgagtt catttgcttc tgtagatgtg ttttcagagc taggtacaga ggaatgtttg 6024460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 244agctgaccca gcatcagcca cactctgggt tggaaaatgt ttgcctgttg gaattaattt 6024560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 245ttgggaagaa acgtgaactc aaggaagact cactatggtc agctaaagaa atatctaaca 6024660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 246ctttcaagga gatctgaatc tctactcttt atcaggatat ggaacagatg ctatcatcta 6024760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 247aatattaacc taatcaccat gtaagcactc tggatgatgg attccacaaa acttggtttt 6024860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 248ctgtgtggaa ccactgacta ctggctctca ttgacttcct tactaagcat agcaaacaga 6024960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 249agatttgttt aagtccccta cactttctta tttctaaatg atcaagagta cacttcctgg 6025060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 250tcccttttca gtacctttga acagcaacca tgtgggctac tcatgatggg cttgattctt 6025160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 251aagttgaaca atcctagcca ttgacaatcg tgatagttat tattttccca tttgctgtct 6025260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 252aaagtaacgc taactttgta gggacgatgt ctcatggatt aaataatatt ctttatggca 6025360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 253cctcatgtat ttatgcctaa tgtaagctga cttttaaaaa gctttctttt gttgcatgcc 6025460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 254tggaagcaat ctgcattcat aactttgatt ggagaataaa tggtatacat ggtgctgtct 6025560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 255agctgatttt tacagtgggg tactctcgcg tattaggagt ctcagatgtc atcacttgga 6025660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 256attcgaataa agctcttgag aagggactga atcctctgaa tgcatactcc gatctcgctg 6025760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 257tcaaaaatct ctgcatcctg aggtgatata cttcatattt gtaatcaact gaaagagctg 6025860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 258gctgcactca tcctctgagc gggcaacttt catcgatcgt ctggccaata gccttaccaa 6025960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 259taaagtttat ggaactcagt gttaggaact ttggcatctg tagctgagca cagcagggga 6026060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 260acctgcctta cctttctgag ttgcctttag agagatgcgt ttttctagga ctctgtgcaa 6026160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 261cttgggtcat tgacctctca gggcctggca ggccagtgtc tgggtttttc ttgtggtgta 6026260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 262tttttctcgt gggacacaaa ccccaactgt accccctatg gtttcagaac agagctgtgc 6026360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 263gccggtataa aggatgccca aggtctttgt acgtgtgtag gagttagcgt gtttgatatt 6026460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 264gctttccgcc tctttgagac caagatcacc caagtcctgc acttcaccaa ggatgtcaag 6026560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 265tagcaaattt ataagttttg acccgcagag tgcactgaga aatatggctg tgggaaaaca 6026660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 266ttcaggctgg tggtttgatg catgtctttc tgcaaactta aatggcaaat attatcacca 6026760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 267accgcacaag gggctccatc ttcattacgg aactcatcac atgcttccag aaatattctt 6026860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 268attttaagac gtgtttgtgt ttgtgtgtgt ttgttctttt tattgaatct atttaagtaa 6026960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 269acccagcgag gagccaacta tcccaaatat acctggggtg aaatatacca aattctgcat 6027060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 270cgttgaattg atgatgcagt tttcatatat cgagatgttc gctcgtgcag tactgttggt 6027160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 271tttctggtac tctgtgaaag aagagaaaag ggagtcatgc attttgcttt ggacacagtg 6027260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 272taaatacaga cactaagtta tagtatatct ggacaagcca acttgtaaat acaccacctc 6027360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 273taatgtccgt aaatcaaaaa gcaaaccatt tgataaggag gctcacagct cctcacaata 6027460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 274taatactaac tatttagtat actgtcagta ctgtacatct gcacactggt gttaataggg 6027560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 275atgagcggat gggcaaaaag ttgacagagt tgtctatgca ggatgaagag ctgatgaaga 6027660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 276ggaagagact cacatgcttt ggttagtatc tgtgtttccg gtgggtgtaa taggggatta 6027760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 277aaagccatct atgtactgaa cccgggacta gaaggaaaat aaatgatcta tatgttgtgt 6027860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 278ggcctggcct ctgtaagcct gtgtatgtta tcaatactgt ttcttcctgt gagttccatt 6027960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 279ctacgtcctg gttgctcaca gtggttcagg agttatcgaa cgtgagacag ttaatgattt 6028060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 280catcgtgggt ctcatgcacg tcaagacctt cccacatcca aactcagctt ccagcaggga 6028160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 281gtttagctct tacactctat ccttcctaga aaatggtaat tgagattact cagatattaa 6028260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 282gtgagctaac atttgctaag cactgaattt gtctcaggca ccgtgcaagg ctctttacaa 6028360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 283atacagcagt ttatacccac acacctgtct acagtgtcat tcaataaagt gcacgtgctt 6028460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 284tgaaggcttt ttacccagca atgtcctcaa tgagggtctt ttctttccct caccaaaacc 6028560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 285acctcattcc cattgtttgg atcatgcttc tttccaacac gtgttcacaa tctccaaagg 6028660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 286aatagaccga atatcaggga gcccctgcgg atggacctcg ctgacctgct gacacagaat 6028760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 287ggaatcaatt caatttggac tggtgtgctc tctttaaatc aagtccttta attaagactg 6028860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 288atttgggtgg gatgggtagg atgaagtata ttgcccaact ctatgtttct ttgattctaa 6028960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 289ggagagtacg gtttccatga atatacagag gtcaaaacag tcacagtgaa aatctctcag 6029060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 290tttaagagcg atcctcatcc cttcagcaat atgtatttga gttcacacta tttctgtttt 6029160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 291ttggtccaag gcactacacc tgtactgcag gggctcaatg gagctgtctt caggccagaa 6029260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 292tgtctgccct ggagaactat aactttgaac ttgtggatgg tgtgaagttg aaaaaagaca 6029360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 293gactagaaga ctgtaaataa gataccaaag gcactatttt agctatgttt ttcccatcag 6029460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 294gaaaggtgat agcattaaat gttcatctag agttaatagt gggaggagta aaggtagcct 6029560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 295tggaatactc acgtgaggga acttactttg gccagcattg accttcaaag tcagatggaa 6029660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 296caacagtgga acaatgccac atggacagag gtctcctaca ccttctcaga ctacccccgg 6029760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 297tccctgccct aaaatcccag gcttaattgc cctacaaagg gttattaatt taaaactcca 6029860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 298ccaatgcaga caaaccaccc ctttttgttg ggaaaggaat tacctttgac agtggtggta 6029960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 299aaatattaac atttccctgg accataagag acctttgatt aaggttttgg gaattagcag 6030060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 300tttttctgga aaacagacgg attttacttc tggagacatg gcatacggtt actgacttat 6030160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 301tattccatga agtttagtat ttggttgaca tagtgctctt caaattcatc ccattaccct 6030260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 302tgccccttaa aagattgaag aaagagaaac ttgtcaactc atatccacgt tatctagcaa 6030360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 303agagcccttc ttcccatcaa aaaggtatca aatgccttgg aagctccctg atcctacaaa 6030460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 304tgtgtggtag aactgaacaa cgatagactg ctaacacata ctgtctacaa aaatctcaat 6030560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 305gggtgaccag gtctgggttg aaaaagaccc caaaaagggt cacatttacc agggctctga 6030660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 306agaccagttt gaggcactca ctctagaaat agcctgtgtt agctgatgtg tgaaagcgta 6030760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 307tgagatattt aaggttgaat gtttgtcctt aggataggcc tatgtgctag cccacaaaga 6030860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 308tgtctcaacc ccgcatcccc catggttcag aaaatcatcg aaaagatact gaacaagggg 6030960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 309tgaaatatac caaattctgc atctccagag gaaaataaga aataaagatg aattgttgca 6031060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 310tgatgaaatg gagtcatttg agtctcttaa tagccatgta tcataattac caagtgaagc

6031160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 311gtcaagccat aattgttctt agtttgcagt tacactaaaa ggtgaccaat gatggtcacc 6031260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 312aaagcatttt taaagattaa tctgaattaa gctttatcag tgtactcttt atctgtgtta 6031360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 313tcataactgc atgaacttca tagagatggg atcctttagc atgttctctg tgcacatgct 6031460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 314gtgaaaatga agacgacaac gttgtcttag cctttgaaca actgagtaca actttttggg 6031560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 315ctatgtactg aatttagagg ttgagaataa taggatctgt gttattctta gtacccactg 6031660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 316ccatgctgtg ctgtgttatt taatttttcc tggctaagat catgtctgaa ttatgtatga 6031760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 317ccatcttcag ggttgcacag aatcctccaa gatactttgc agcctttttt ccccctggtc 6031860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 318tgaaggcgaa atgataactt ctaaggataa tttagaagat gagactgaag atgatgacct 6031960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 319atgtgtgtgt actcttccta gacgtacaag agacttttta atgctaaata tttgtcagtg 6032060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 320agttctttga aaaagttcca tgactcgaat atctgaaatg aagaaaacaa accgactcac 6032160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 321aggtttgatg tccttccaag aataaagtct ttccctggtg atggtctctc gctctgtctt 6032260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 322cgatttttct tcatgacctt aacctgtgtg ggctaacaga ggacccagat cttacaggtt 6032360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 323ttaaggttct ccgaagaaaa gacagcaaga gctgctttcc gcctctttga agaccaagat 6032460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 324gctgcccgca tctatgatta cgacccccta tataaggagg cgctgcaaat gctgcgggat 6032560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 325acagcggctc cactacagac ccagccccag gttcaatgtc ctccgaagaa tgaagtcttt 6032660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 326gttcagacca actcctggat atgagctcag ccttcagcaa gacaacaaag accctggccc 6032760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 327gttgatataa tcctaccaga aggaaagcac taagaaacac tcgtttgttg tttttaaagg 6032860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 328gaagataatc gatagtcatg ttttttagac tctctgtatt gcttggtaag ctacgtagta 6032960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 329atgctctgaa ggttttgtag aagcacaatt aaacatctaa aatggctttg ttacaccaga 6033060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 330gtctgtggtg agcaaagttt gccttattac actgataaag tgtaattaca ctaataaagc 6033160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 331tttataataa ccgtagccca cattgtagta gtttttcagc tctttactaa gtcccaccaa 6033260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 332aaccaaatat ctatgtaggc agaggtaacc aggagagaag caagacttgc tgcctaaagg 6033360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 333gttgtaattt aaaccttgtt tgtaactgaa aggtcgattg taatggattg ccgtttgtac 6033460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 334aagagtggca gaggctacta caaaaagcaa ccttttcatt ttcactaaga gtttaaaagc 6033560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 335acatggggct tacaagtgct tcttgtccaa gtagtctacc aatgaaaaga gaaattacag 6033660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 336gagaagccat ctatgtactg aacccaggac tagaaggaaa ataaatgatc tacatgttgt 6033760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 337gagattgtcc agagtcctat gacagacctt caaggtttta agttccacag acttggactt 6033860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 338ggttgacttg actcatgctt gtttcacttt cacatggaat ttcccagtta tgaaattaat 6033960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 339agttgcttat ggcatacaag gctaaaatta attcagctat ttaatcttaa taattattat 6034060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 340tggttttcat gtgcttctct tgagcagtct gaggagagaa tagaaacaga aaccccttgg 6034160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 341tgcaagtttc ctgtcatgac aagaagctgt catgttcagt agcaccttac acgaaaggtg 6034260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 342atttctcttt ctaaagggga gtaacttttt aaacccttcc tgattttagc ctggcaatgt 6034360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 343ggaacatgct ttctgaactc acttgagagt gtatggtgta tgtcacttct catatattct 6034460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 344gaaaacttcc aattcaagaa ggatggacac tgcttgaaag aaatctacct tgtggatgta 6034560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 345aggcgctcaa tagaaattca aatctcactt taagaccatg aatttcaagt tgcaatgaag 6034660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 346gaagggtttc acaatgaaga tgtgtagcag gcgttatccc attgttatca ctgggcagaa 6034760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 347tgacctgcta aatgacctgg agaaattgag gaagcaggaa gcacatttga gaaaagaaaa 6034860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 348ttggcttcat atctagacta acacaaaatt aagaatcttc cataattgct tttgctcagt 6034960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 349cttcttctgt gactggggat aatatctgta ataacttgct agatcaaatg acaaaacaca 6035060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 350atctgcaaat cgtgactaag tacatcctga ttcctgcaag ccagcagcca aaggagaata 6035160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 351actctgagtc agttgaaata gggtaccatc taggtcagtt taagaagagt cagctcagag 6035260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 352ctctgtaaag ctaaaataaa gaaatagaac aaggctgagg atacgacagt acactgtcag 6035360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 353aagttgaggt atacataccc cagttcaaat tagaagagca ttatgaactc agatccattc 6035460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 354attctggatg aatatatgcg ctttctgaac tgtagaaagg gacggaagga cccttccaag 6035560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 355ggcagaacat ttgactggca ctgatttgca ataagctaag ctcagaaact ttcctactgt 6035660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 356accagtactg caggattgtt gcactaaatg aaatactgta tgtgaagtgc ctggcacagt 6035760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 357gttaatgata tgggaacgga tgagactttc cacgtggtac ctagatttgc aaattctatt 6035860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 358tttttcctag acccgtgacc tgagatgtgt gatttttagt cattaaatgg aagtgtttgc 6035960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 359catggagagt gtctgcggat acttccacag gtcccacaac cgcagcgagg agtttctcat 6036060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 360ccaacactgt gtgaattatc taaatgcgtc taccattttg cactagggag gaaggataaa 6036160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 361gtatggaaca ctccaatcag aaaaaggtta tcattggtcg ttgagttatg ggaagaactt 6036260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 362ggaagtgaca actgaacaca ctgtgttgga tcggaggttc cgttagggga tccttcctta 6036360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 363acagggtctg caaggtcttt ggttcagcta agctaggaat gaaatcctgc ttcagtgtat 6036460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 364tgctccttcc taaaagtctg ttttcaatcc tggtaatatt aggggcactg cggcacctaa 6036560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 365attcacctct ctcactgact attacagttg catttttatg gagttcttct tctcctagga 6036660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 366acctgaactc gcacctccta cctcttcatg tttacatata cccagtatct ttgcacaaac 6036760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 367caccgacaag aactcactac tgggcatgga gggtgccaac agcatctttt ccgggttcct 6036860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 368acagtggatc ttggagtggg atttcttggg taaattatct ttgccctttg aaatgtctcc 6036960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 369caagatccag ggacctagag gcctcggcga tgacactgcg ctgaacgacg cgcgcttatt 6037060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 370gtggttagcc gtatcattgt gtgggacatc atggccttca atggcatcat ccatgctctg 6037160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 371ctgctggagg gacactgctg gcaaacggag acctattttt gtacaaagaa cccttgacct 6037260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 372ggagacctcc ctaccaagtg atgaaagtgt tgaaaaactt aataacaaat gcttgttggg 6037360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 373gtaggtatcc ctccatgccc ttctgtaata aatatctgga aaaaacatta aacaataggc 6037460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 374tgcaccaggg ccttgttgaa cagatccaca ctgctctaat aaagttccca tccttaatga 6037560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 375gttttaactc tatctgtcat acatcctagt gaatgtaaaa tgcaaaatcc tggtgatgtg 6037660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 376tacagaacaa gatacctgct cagacaaagt cacctgaaga aactgataaa gagaaagttc 6037760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 377tgaaaaatcc tgaggattca tcttgcacat ctgagatctg agccagtcgc tgtggttgtt 6037860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 378tgtaggtccc ctggggacac aagcaggcgc caatggtatc tgggcggagc tcacagagtt 6037960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 379gcttcactga attcctgcat taacccaatt gctctgtatt tggtgagcaa aagattcaaa 6038060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 380accatgttga ctttcctcat gtgtttcctt atgactcagt aagttggcaa ggtcctgact 6038160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 381tggctggata atgttcagtg tcggggcacg gagagtaccc tgtggagctg caccaagaat 6038260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 382gtaactgtgc tgaatgcttt agatgaggaa atgatcccca agtggtgaat gacacgccta 6038360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 383ttgttcgttt tgccttctgt ccttggaaca gtcatatctc aagttcaaag gccaaaacct 6038460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 384tatctgattg gaaacctgcc gacttagtgc ggtgatagga agctaaaagt gtcaagcgtt 6038560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 385aagatcagaa gccagtcatg gatgaccagc gcgaccttat ctccaacaat gagcaactgc 6038660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 386ttcactaatc aaagacacta ttttcatact agattcctga gacaaatact cactgaaggg 6038760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 387gatcaactca aactatgtcg accccaagtt ccctccatgc gaggaatatt cacagagcga 6038860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 388ctaatatgga gattatcctt tcattgagcc ttttatcctc tgttctcctt tgaagaaccc 6038960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 389gaagaagttc ttcctcctag aaccccagat gaaggtcgca gccctcagag cgggagccca 6039060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 390aagtggtgat gttgtttcaa acgttcagaa cagataccat catcctgcct ttgttagctg 6039160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 391agagggtctt agtcctggaa agtcaggcca acaagcaacg tttgcatcat gttatctctt 6039260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 392taatactaac tatttagtat actgtcagta ctgtacatct gcacactggt gttaataggg 6039360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 393aagagtttcc gaagagtgaa gggcagtaca gtggcttcaa gagtccttac tgaagccagg 6039460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 394agaaagtgtg gatgtatcac ttctctctaa aatgtcattg ttagcactaa ttacaggttc 6039560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 395cgaagtggac cacaagaaac gcaaaatccg ggaggagatt gagcattttg gaatcaagat 6039660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 396gtgcaatggg gagccagtca ttgagggtat tgcagagacc atcttcctgc ccagcaagaa 6039760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 397acttcctgtg cctttcctat cacctcgaga agtaattatc agttggtttg gatttttgga 6039860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 398ttgatgtgtg ggagcacgct tactaccttc agtataaaaa tgtcaggcct gattatctaa 6039960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 399gccactcagc tacctaattc ctcaatgacc tttatctaaa atctccatgg aagcaataaa 6040060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 400aaggagacaa actccacctg gaaatgttct gtgaaggtca agtgtgcaaa cagacattcc 6040160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 401cgccaagcat gtgaacatct gggccctgac tgtgggcatc ctcatgacca ttctgctcat 6040260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 402caacagcctc tatgacgaca tcgagtgctt ccttatggag ctggagcagc ccgcctagaa 6040360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 403atttcattca cgaatctctt attttgggaa gctgttttgc atatgagaag aacactgttg 6040460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 404ccaaacatcc tggagagtat gcgagaacct accaagaaaa acagtctcat tactcatata 6040560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 405tacagaaagc ctatctccac gcacactgtg gacttcacct tcaacaagtt caacaaatcc 6040660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 406gggctggcta acattgctat attgaacaac aacttgaata ccttgatcca gcgttccaac 6040760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 407aggcgcctgg cacatttcag ggagaaactc caaagtccac acaaagattt tctaaggaat 6040860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 408ttctctgata acctacttgc ttactcaatg cctttaagcc aagtcaccct gttgcctatg 6040960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 409gatgtcctgt gctgcttgtg atgagagcct ccacactgta ctgttcaagt caatgttaat 6041060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 410ctcagaggac cagctatatc caggatcatt tctctttctt cagggccaga cagcttttaa 6041160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 411ccagctgtgc tctggacagg catgttctct gaggacacta accacgctgg accttgaact 6041260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 412ttggtccaag gcactacacc tgtactgcag gggctcaatg gagctgtctt caggccagaa 6041360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 413tgctggttgg tatctgtaaa tgtttaataa atatctgagc atgtatctat caacgccaag 6041460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 414tgttgagaaa cggactctga taaaagtctt cgggatccgt ttcgacatcc tggtttttgg 6041560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 415tgagcagtgg actcaaaagc attttcaggc atgtcagaga agggaggact cactagaatt 6041660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 416ttgtcaggcg atcttgtttg aagctctatg ttgccataat taccatcaag tacacactgt 6041760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 417agaagatcac tgaagaaact tctgctttaa tggctttaca aagctggcaa tattacaatc 6041860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe

418tctgtcattt gctttgaagc ccattgtgcc ttatgccaat aattcaattg ctgcaaacac 6041960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 419atgaaaagct ttcctgcttg gctcttattc ttccacaaga gaggactttc tcaggccctg 6042060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 420caattgcatc cacgttttct tttcttttgt tgattttctt gttcccgtag aagaaagaag 6042160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 421atcctcatga gcattctgct catcttcatc ccagtgttga tctttcaagt ctatcaatag 6042260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 422caaataaacc aacgggaaaa aagaaaggtt ccagttttgt ctgaaaattc tgattaagcc 6042360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 423accttttctc tgggacttaa gctgctatat cccctcagag ctcacaaatg cctttacatt 6042460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 424ggggggtatt tgcaagaata ctcattttga cataataggt cctcttgtca gagatcctct 6042560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 425tcaatctgaa tctgcccaga gcaagatgct gagtggcatt ggaggcttcg tgctggggct 6042660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 426tattcctgca tttgtgaaat gatggtgaaa gtaagtggta gcttttccct tctttttctt 6042760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 427aaggatgttc taattctttc tgctctgaga cgaatgctat gggctgcaga tgacttctta 6042860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 428gtcgattcca ttaagcaata ctaactgacg ttaagtcatg atttcgcgcc ataataaaga 6042960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 429gggccctgat tctgggcatc ctcatgacca ttctgctcat cgtcatccca gtgctgatct 6043060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 430ttgtctatat caccgatgat acatacacaa aacgacaact gttaaaaatg gaacacttgc 6043160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 431catttgctgt gtttcgttag catctggctc caggacagac cttcaacttc caaattggat 6043260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 432tgggactgtt ctgtctcatg tttatctgag ctcttatcta tgaagacatc ttcccagagt 6043360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 433aagcctgacg agccctctca cagtggaatg gagagcacgg tctgaatctg cacagagcaa 6043460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 434aggattattc cttgctatta gtactcattt tatgtatgtt acccttcagt aagttctccc 6043560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 435aagcgtgaca agccctctca cagtggaatg gatgaagtgc agatgacaat ttaaggaaga 6043660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 436ggtgctggat tccaaggttt gtaaaggcat ctcggtaaag actgcttttt gaatgcatat 6043760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 437cacggtcctg ctggtggtgg acaaatgcga cgaacctctg agcatcctgg tgaggaataa 6043860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 438tgaggaacag ggaaatgccg ctgtgaagtc ttaaagcact tctgcttaaa ctccatgtgt 6043960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 439agactctaga ggcgtggacc aaggggcatg gagcttcact ccttgctggc caggggagtt 6044060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 440ctgattgaga agccaaatat tgttaaccat tttccccgtc tggcacggtt cttttgcaca 6044160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 441ggaatgacca ggaggagaca gccggtgttg tgtccacctc cctcattagg aatggtgact 6044260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 442tcaacttgac ttcatgttaa aaaccctcaa caaaccaggc gtcgaaggaa catacctcaa 6044360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 443gattctgtgc agagcaagat gctgacagga gctaggggct tcatgctggg gctcatcatc 6044460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 444tggtatttgt aaaaagcaaa caaacattac aaggcagtta tctcattgct gttttgggag 6044560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 445aggcagagga acgcgttgtg gtgatcagca gctcggaaga ctcagatgcc gaaaactcgt 6044660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 446gcatccaagc atgatgagcc ctctcacggt gcaatggagt gcacggtctg aatctgcaca 6044760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 447ggtcctgact caaaacccag tgagggggat gtttttccag gacaagtgaa gagaaaatat 6044860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 448ttgacaagtt cttcccacca gtgctgaaca tcacgtggct gcgcaatggg gagccagtca 6044960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 449ggactggcta tcccaagacc tggcagatgt ggctgctcaa taaacacttg ttgaaccatc 6045060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 450ggaaggtcaa ttacaacttt gaagatgaga ccgtgaggaa gtttctactg agccagttgc 6045160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 451atttgttccg caagttccac tacctgccct tcgtgccctc agccgaggac gtctatgact 6045260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 452gcttcatttc ctgtgtcttt tttcactaca ttataaatgt ctctttaatg tcacaggcag 6045360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 453tcagccggga gctgtgctgg cgagaaggcc caggcacgga ccagactgag gcagaggccc 6045460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 454tacaaccagt attctcagag ataccatcag agaacaaaca ctaatgttaa ttgcccaatt 6045560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 455ctcagtgact gtggttgagg acgacgagga tgaggatgga gatgacctgc tccatcacca 6045660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 456gtccaccaac atgattcata atgagactag accttccaga tcccagtgat gctggaaatg 6045760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 457agaaggcaga gaaagtgaag accaagtcca gaactgaatc ctaagaaatg caggactgca 6045860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 458ttcaatggga tgaagcgggt gcagtacctg aacagataca tccataaacg ggaggagaac 6045960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 459aaagggcggt ggaggggaaa acattaagaa tttattcatt atttctcgag tactttcaga 6046060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 460ctgaagatga tttaaaacat gaaagtgtat tgttgtcact gtggtaattt ccttgccagt 6046160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 461acttaatttg agcgagtacc ttttcatttg acacttttcc tgtttctaac cttaggaaac 6046260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 462atcctccatg gtatctgaat cccagaatcc tacaatcctg catggtatct gaaacatact 6046360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 463ctagattctg cagtcaaaga tgactaatat ccttgcattt ttgaaatgaa gccacagact 6046460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 464tcgtgcgttg ccttgctccg tttttcccaa aaagcactgg cttcatcaag gccaccgacg 6046560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 465ttcgtgctgg gcctgctctt ccttggggcc gggctgttca tctacttcag gaatcagaaa 6046660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 466ggactatgct gtaaccaaat tattgtccaa ggctatattt ctgggatgaa tataatctga 6046760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 467ctgcttaagt ctgagtgtca tttcttcaat gggacggagc gggtgcggtt cctggagaga 6046860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 468cacgaaagtg taaagcagta ttaagatcat tactgcatgt gccctaaaaa cccaagtttt 6046960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 469ttctaatttc agacttggct ttttacttag aggacattct gatttgctct cagaaacatc 6047060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 470tggcagcttt ggggctgttt ttgagcttct cattgtgtag aatttctaga tcccccgatt 6047160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 471agcagaagcg gggccgggtg gacaattact gcagacacaa ctacggggtt ggtgagagct 6047260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 472gatcgttctc tgtgagatca ttgggcaggt gtatgcagat cctgactgcc ttccccgaac 6047360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 473atcttcatga ccattctgct catcatcatc ccagtgttga tcttccaagc ctatcaatag 6047460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 474agattacatt aatttttcta taaattggaa gatttataaa tgtttgaaat tgtacacatt 6047560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 475gtgtctggac agattgtggg agtaagtgat tcttctaaga attagatact tgtcactgcc 6047660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 476agtggaataa ggcctgttgt tccttgcagt ggatcctgat ttggacaagc agcaatttgt 6047760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 477tggggaggga ggtgtttaac ggcactgtgg ccttggtcta acttttgtgt gaaataataa 6047860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 478aagaaatttc ctttagacta acgaatatat tggggggagg aatagagggg aggtgtgcag 6047960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 479acttaaattg ctatatctgc tcagagctca caaatgcctt tgaattattt ccctgacttc 6048060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 480ctggatagtc ctgtcaccgt ggagtggaag gcacagtctg attctgcccg gagtaagaca 6048160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 481gggattcata gcattcacct actccctgaa gtctagggac aggaagatgg ttggagacct 6048260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 482cctgagacta ttttaactag gattggttat cactcttctg tgatgcctgc ttatgcctgc 6048360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 483actctggact tcagccaaca ggtaatacct tttcatcctc tttaagaaac agatttggag 6048460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 484aactgtcata cgtatgggac ctacacttaa tctctatgct ttacactagc ttctgcattt 6048560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 485tacaggatct aaaagggttt tcttagaaag ggcaatattg tccaatgaag taagcagaag 6048660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 486actggagtta cactcctctt cctgggtcca attattcaga aggatggcac atttcctaga 6048760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 487cgctcccaga tgtaaagaac gcgacttcca caaacctgga ttttttatgt acaaccctga 6048860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 488caaccctgac cgtgaccgtt tgctatattc ctttttctat gaaataatgt gaatgataat 6048960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 489aattcaggac tgtctcctcc aggaccaaag tggccaggta ataggagaat aggtgaaata 6049060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 490tccccctatt tatttttaca tttctctatg tgcaaatgag aaaaacacta aggttcaggg 6049160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 491aagagatgtt gtcctgacac ttgtggcatc aaatgcctgg atcctgttga caccccaaac 6049260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 492gcaactaaac aaacacaaag tattctgtgt caggtattgg gctggacagg gcagttgtgt 6049360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 493caactgcctg tgtcaggctt gtcccccctg agatcaaagt cttacaagtg gctgtcaagg 6049460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 494tttccttctg atgcagacat ggtccccact ggggcaaggc tgcagttttc ttttaaaaaa 6049560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 495ctgaccgtga ccgtttgcta tattcctttt tctatgaaat aatgtgaata ataattaaac 6049660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 496tgttcattgt gttgtcagcc agaaagctag tctaaatcaa ctcctagatc aaagcaaggg 6049760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 497ttttgagtcc ggaaaaacag aattccaagt caaattctgt tccaattatc ctggccatcg 6049860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 498gggcaggtag gatttcaatg gcatgttaca taaccatcct ctaaagggac agaatgtaca 6049960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 499tttttcgccc ttagcgtgaa gatggcctcg ggacccacga gcatccgcgt gcactttcag 6050060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 500tggggctgct tggttttcag atttgcttag gctccattca taaatacaga tggcacactt 6050160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 501gctgaaggga ccttgaaggg taaagaagtt tgatattaaa ggagttaaga gtagcaagtt 6050260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 502ggctgaacta caagtgtagg ccaccattat aatttataaa tacagcatac ttcaaaactg 6050360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 503ttcttagggg tgggggatga ggagttaaag gtggcatctt caatcgcagg tcaaagcaga 6050460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 504ctctgcatct actggacaaa gtattatgac tttaaaaacc ccattattga aaagtacctg 6050560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 505tgcaaccaac catgtgacag aggggattcc tagactggat tcccagcctc aagagacctc 6050660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 506cagccatcct ttttaagagt aagttggtta cttcaaaaag agcaaacact ggggatcaaa 6050760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 507tctgctgcag gggacagcag aggaagacca tgtggacctg tcactgtctt gtacccttgt 6050860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 508tactgccctc aaggggcggg tgtactacct ggagcaccct gagaagctga cgctgacaga 6050960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 509ggagtgttcc caatgctttg tccatgatgt ccttgttatt ttattgcctt tagaaactga 6051060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 510aaatgaccca cagtaggttg gcagcgcttc gagtaacaaa accttatttg gacattggct 6051160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 511cacggtctac atgatcaaat acctcatgac gctcatcgtg ggcatcacgt cgggcttctg 6051260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 512ttcatgacca ttctgctcgt catcatccca gtgttggtcg tccaggccca gcgatagatc 6051360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 513acagtgaatt ttgatgcatt taaaataaga ttctgatgcc agactgttaa aacaggcgct 6051460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 514aaggaacgca aagaactgga aacggaatat acgttgtgaa ggaatgaccc taggagagct 6051560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 515tggaaaggtg tttctctcat ctctgtccta aggcttgata aagtcattaa aattgtgttc 6051660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 516ccgaccatgt cctggtccct gttcaacacc cacttcatga atgctgcctg ggcttcatag 6051760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 517aaaggtgttt gtgccatttg gaaaacagcg tgcatgtgtt caagccttag attggcgatg 6051860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 518tctgctcact tccgccatct aagaggaata ggtgagttgc tcatgctgat taggattgaa 6051960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 519tcctgcccca ttatcttgat ccggtgcgcc atgttgaatc cccctaaccg ctgcttgaaa 6052060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 520agtacgtgtt actggccaag gctatttttc agaactgtta aaggtcatat gcacgttaaa 6052160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 521aagaaggcat acagtggcat aaacgatgct cttcctagta gcttaatagg ccacaagcta 6052260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 522aacactgctg ctccagtgca ggagacttta catggatgcc aaccggtcac ccaggaggat 6052360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 523aaatgatgag gcgccggaat atgacacagg ggcggtgcaa accagtgaac acctttgtgc 6052460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 524tgtcctgaaa gttggaatga aagagaccct ataagagcac tgacatgttt cagtgtcctc 6052560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 525aggcgttctc tagatccttt cctctgtttc cctctctcgc tggcaaaagt atgatctaat 6052660DNAArtificial

SequenceDescription of Artificial Sequence Synthetic probe 526gagggattga catgtttcaa caaaataatg cacttcctta cctagtggcc cttcacacaa 6052760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 527agtaggagtg aaagcacttc agaatttaaa ccaggatact ccctgcatga tacatctgtg 6052860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 528acaattgcaa gtcaacaccc taataccaga ataggagttt tcctctgtgg acctgaagcc 6052960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 529aagattttat tgtaaaacag agctgaagtc acaggaagta gggaactttg cacccaacat 6053060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 530tttttgcata tcagttattt tatatgtgga ggtacaattt gtataggaaa gttagaataa 6053160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 531cggcactatg aaaaatcata ggccaacaaa ctggataacc tagcagaaac caaagacaag 6053260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 532catcaagggg gtcttgtttt gctagagagt ttggggtttg gtttgtggat ttcattgtga 6053360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 533catccctccc cagttcattg cactttgatt agcagcggaa caaggagtca gacattttaa 6053460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 534ctaacagtga aaagagagaa gggagactct atttaagatt cccaaaccta atgatcatct 6053560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 535aggtcctttc caccctgaga cttggctcca ccactgatat cctcctttgg ggaaaggctt 6053660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 536tggagttttt gcttttatcg atgtgtgtct tcaaagaaac cacttcagag gcaagaaggc 6053760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 537aataattgcc aggagtacag tgctcttgtt gatcttgtat tcagtcaggt taaaacaacg 6053860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 538gtttgatgcc agcagcttcg gccatccaaa cagaggatgc tcagatttct cacatcctgc 6053960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 539cattctctct aaagagcctc gttcatttcc aaagcagtta aggaatggga accagagtgt 6054060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 540tgctgaagat gactgctttc actgaggtca aggattgtaa tattgccagc tttgtaaagc 6054160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 541tgctgggcag aagggcgctg ccttctcttt gatgactctt tcctgcatgc tgcgttccat 6054260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 542tcaaatacag agttcatcat tcttgttgtt gatagcattg acagggaacg actagctatt 6054360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 543aaagccatgg acttctatga tccagcaagg cacaatgagt ttgacttcat ctcaggaact 6054460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 544tgattcggtt tctcagagtc tcatggcatc atagtttttc cagaatgaca cagtagccac 6054560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 545ttggcctctc gtccacgagg ggagaaacct aaaccctgtt tcacaatctg tgcggaagta 6054660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 546ctgttcaaca ccctcttcat gaactctggc tgcctgtgct tcacagcatt tgtgtactct 6054760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 547gcaggactcc tccaaaatta tgtggaccgt acggagtcga gaagcacaga gcctgagttg 6054860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 548tgtgcctcca aggactgtct ggcaatgact tgtattggcc accaactgta gatgtatata 6054960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 549ggctatgtac tttgtgcagg gaagtacatt atctacagtc acaaaaatgt ctcatgggaa 6055060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 550ggtgctcaaa ttaccctcca aaagcaagta gccaaagccg ttgccaaacc ccacccataa 6055160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 551ttcataactt tcggcgagac gtggtgagcc tcctggtgta gagttctttt gtctttgtat 6055260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 552gggtgacatt tgtaacattt cctctttgag actctgagtt cacctagaga agtctaagca 6055360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 553ccaaggcttc atgacaaggg agtttctaaa gagcctgcga aagccttttg gtgactttat 6055460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 554agacagtttg gtggatctga taattgacca gttagttatt cagatcaact agacagcatt 6055560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 555gacactctcg taagttacat gcaaactaaa gaaagtgaaa ttcttcctga aatggcatct 6055660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 556taggccaaag taacagactc aagagttatt gtacattact gaccacgctc atttgttcaa 6055760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 557gacatatctc taattccatc cataaatcca gttctactat ggctgagttc tggtcaaaga 6055860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 558catgtctgaa agtcacatat tgtgaaaatt tgaagctatc tcagtaaaaa gcagctttgg 6055960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 559ggttgtgaat ttccaggtac ttggactttt tgtagaagta gagagaagaa gatgaagttt 6056060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 560cagcttattt cctcattttt ataatgtccc ttcacaaacc cagtgtttta ggagcatgag 6056160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 561agtgtgcgga aatgcttctg ctacattttt agggtttgtc tacatttttt gggctctgga 6056260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 562tttaacactg gcattcctgc ctacttgctg tggtggtctt gtgaaaggtg atgggtttta 6056360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 563cagctcaagt accctaattt agttcttttg gactaataca attcaggaaa gaaaaaaccc 6056460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 564gaagaattcg ccaagtattt aaagttgcct gtttcagatg tcttgagaca actttttgca 6056560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 565gtgggaccgg atcacccgct tggaaaaggg caagatctat cggcagggaa acctgtttga 6056660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 566gcgagtggga gcaccaggat ctcgggctcg gaacgagact gcacggattg ttttaagaaa 6056760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 567gccccttgaa catgaccgtg gccccaaatt tgctattccc atgcattttg tttgtttctt 6056860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 568gatggatcca ctggaggtta agacatgtgg taagacagtg taataggaag ctgctcagtt 6056960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 569ggactgggtt agaaggtata aggttcctga tggaaaaaga aatgagtttg cttttaatgc 6057060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 570ctgctgtgcc tgatgtgggg acagacctgc tcccagatgt aaacagagca acctgcacaa 6057160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 571gatgagataa ggagagtcag aaacaaactt atagtgatgc gttggaaggt taatcgaaac 6057260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 572gggttggtgt tggcaagtca agagagtcga tgatccagct gttttagtcg cagactgagc 6057360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 573ttccatcacc agaaaaacta atgagatttc tctggaatac aagctgatat tgctacatcg 6057460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 574ctgaccccca agcagaagac agacctctgg ttttctttga cctcaagatt gacaatgaaa 6057560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 575gtaccgatcg tagcccctat gagaaggttt ctgcaggtaa tggtggcagc agcctctctt 6057660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 576gctattccaa agatttcaag ctgttctgag acatcttctg atggctttac ttcctgagag 6057760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 577agctccgcgt gagaagtact ggctacaatt ttttatccca ttgttggtgg tgattctgtt 6057860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 578taccattctt tccataggta gaagagaaag ttgattggtt ggttgttttt caattatgcc 6057960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 579ctttggctta atgagactgg gaccattggt gatgagaagg caaacatgtt cagaagtcaa 6058060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 580agtggctcta ttctacctgt aagaaaatga tacaaaacca cctaagatat tttgaagcct 6058160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 581aggtgaaaag tcaaatgaaa cagtacaatt cttgatgagt gaggtgtcat cttccaacca 6058260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 582ctatctcaaa ggatgacgtg atactcaatg ccttcagcaa atcagagact agcaagctgg 6058360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 583aacccaaact ccaaagcttt gaacattcat gactgaactg aaaacaagcc atgacttgag 6058460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 584atgctgaaga aacatcagtt ccagaagctc cgaaaattgc tccaatattt ggaaagaagg 6058560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 585caagccagag tcgatacagc aagcggagga tttggagatc cgtcaaactt aaagattaca 6058660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 586ctatcatcaa ctgcatcatc tactttaatg gtgaggtacc acagcttgtg ctgtacatgg 6058760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 587tggctaaatg ctttgcagaa agtgatgacc ttacaccaca accagcttct ccaggtcata 6058860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 588gcgattaccc tggttgcaca aaagtttata ccaagtcttc tcatttaaaa gctcacctga 6058960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 589gatgtgagtg tgtttcatca aacatagctc agtcctgatt atttaattgg aatatgatgg 6059060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 590cagagcacaa tcatcctgaa gtcttgaagg tgtcttgcaa gtgtggcaac acgttgagcc 6059160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 591gttcaccagc atgcccaccc tcatgcagga gtttgccaat ggcctgctga acaaggtcgt 6059260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 592cttacttaaa cttcacacca gaaccttctg acattttctc ctgcattgtg actcacgaaa 6059360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 593tacattgcac cagagaagat agaaaatatc tacaacagga gtcaaccagt gttacaaatt 6059460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 594ttgtagatga actcttctca actctgtttt gctatgctat aattccgaaa catacaagac 6059560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 595atgtggcctc aaatgtcatg ccaattttca catcttccac aaactccatt tagggagaaa 6059660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 596ggccatacgc catgccatag cttgtgctat ctgtaaatat gagacttgta aagaactgcc 6059760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 597gaccaggaaa aacaagaaag acatactcaa tcctgattca agtatggaaa cttcaccaga 6059860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 598tttaggggtc ctatctcctg ggggaagggg agatctaaga tgtcccaggt cctgggaagt 6059960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 599aagggacgtt gacctggact gaagttcgca ttgaactcta caacattctg tggggatata 6060060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 600tgctcaaagc tcaaaatgta acaaggtaca taaaacttgg tcatggtgga cactggagtc 6060160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 601ccagttatct ctccaaaaca cgacccacac gaggacctcg cattaaagta ttttcggaaa 6060260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 602taaccaaggt taggtgactg aggactggag ctgtttggtt ttctcgcatt ttccaccaaa 6060360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 603ctgttcctgt gatgtggagg aaattttccg caaggttcga ttttcatttg agcagccaga 6060460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 604ccgaagttgc ctcttttagg aatctctttg gaattgggag cacgatgact ctgagtttga 6060560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 605actccagata aaatgaaaaa cctctccaag tcctggtgga agaagtactg ctgtttcgta 6060660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 606aaacatcatc aaaaaggaca ttcagaacat gatcgtggag gagtgtgggt gctcatagag 6060760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 607cggaagtgcc taagtcttta gtttccaatt tgcggatcca ctgccctctg cttgcgggct 6060860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 608acgtttgttt tcaaggagag ggtttaaaaa tgggatcctg taagcagact tgggcagtct 6060960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 609gtcacaagat ggcaaaatgc tgaaagtttt tacactgtcg atgtttccaa tgcatcttcc 6061060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 610tcatcagaga agtgccgctg ctgtgcctga tgttgggaga gccctgctcc cagacataaa 6061160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 611gaattgtcca gagaatcaag gattttttgc ggaatcttgt acccaggaca gagtcctagt 6061260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 612cccaagacac agggaccgtt tctcccctag gagcagcggt ggggagcagg gccaaggtcc 6061360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 613ccgcctgggg gtgggcgcag agctgctggt cgacgtgggt cagaggctgc gccgtgggac 6061460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 614ctgtatctaa ctggggctgt gatcaagaag gttctgacca gcttctgcag aggataaaat 6061560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 615taccagataa ctgaggaggg gagaggtggg ccgtaacggg cacggatcac gatgtaaatt 6061660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 616acctctcatg caccatcgta gggatcatag ttctaattgt gcttctgatt gtgtttgttt 6061760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 617ttttttgtaa agttgatgcc ttactttttg gataaatatt tttgaagctg gtatttctat 6061860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 618atttgacatt tgtgtgtaat ttcatggtgg cctagtgttg tggtgcttct ggtaatggta 6061960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 619gtgcatgaac gtcccagaga tgatgccacc gttagaatat ctcatggata tactcccaaa 6062060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 620tccccgtacc ggaaacaggt ggagaaaatc cgttactgca tcaccaaact tgacagggag 6062160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 621acatttttca cccagacgaa ttgtacgtgg gcagaccgca gagagtttgc ctgtgcataa 6062260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 622tctaagagag aatggaatgt atgggaaaag aaagttactg gaactaatag gacacgctgt 6062360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 623ctgtttcaag cttctgtact ttatggaact ttggctgtga tttattttta aaggactctg 6062460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 624tgggcacaca aaaggattta gggtatttaa aaaatctatg tctctcccat ctcactgact 6062560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 625aatggcttcg gacaaaatat ctctgagttc tgtgtatttt cagtcaaaac tttaaacctg 6062660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 626ctgtgacttg taataaacca agctgtacaa tttagtttat aatagcagta tctgagctgc 6062760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 627gattatggga tatttcagat caatagccgc tactggtgta atgatggcaa aaccccagga 6062860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 628gagcatggac tcgctccaga ccgttgtcac ctgttgcatt aaacttgttt tctgttgatt 6062960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 629ggctggagaa gaatcttccg actctgagga cttggctaat ggttaatact taaatggtca 6063060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 630ccaggaaggt catcaagatg gagtctgagg aggggaagga ggcaaggttg gctcggagct 6063160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 631tggcttacta aaaccgagct cactgtaaaa tcatgatcca acttattgct aatctttatg 6063260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 632taatgtggga ataaatagag ttcaagatcc cgtaactaaa cccaagttag ttggagatgt 6063360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 633acaggaaatg cactggagga tttgggcctg

aggttactat gccagggact gaggcaccca 6063460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 634cagattagac cacctcataa tgagttcttg attgcacttc agattgtctt gatggggcac 6063560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 635gctctattcc aaaaaggttg ctgtttcaca atacctcatg cttcacttag ccatggtgga 6063660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 636ccaccttttc aatgggattt catctgttag ttactgtgag tctcttattt tcccatgtgg 6063760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 637gtgggaggtc aatccccttt actgtgacac agtgaaacag atctacccgt acaacaacag 6063860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 638cgttccagtg ccaaaaatgc gaccgagcat tttccaggtc ggaccacctc gccttacaca 6063960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 639agctatgagt tgaaatgttc tgtcaaatgt gtctcacatc tacacgtggc ttggaggctt 6064060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 640agctgctgtg cctgatgtcg ggacagccct gctcccaagt acaaatagag tgacccgtaa 6064160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 641gcaagctggc tttgtagcac attttacaaa tgtgtggcat tgaatattgc acagtgatgg 6064260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 642gcctggtaaa atcatacacc aataccagcc acatcatgca gtacggaaac gaaacgatct 6064360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 643tgttctaccg tactttagta gtttgaagtt ttcaagtgca taactatttt tgaccagcag 6064460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 644acacaaatat gccacctcaa acaagcacaa gttgaccccg gaatatctgg agctcaaaaa 6064560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 645tgtgtcaagg aaagggcttt atttgtgaat tttgccagaa tacgactgtc atcttcccat 6064660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 646ataacgtatt aaaactcttt taagtagctt aaggtattgt gcaatggcct agcctagtag 6064760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 647aagaatgtac ataatgttac cggagctgat ttgtttggtc attagctctt aatagttgtg 6064860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 648ggcatcggag aagtgcagct gctgtgcctg atgtgggaac agctcttctc ccagatgtaa 6064960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 649tctaaatcaa ctcctagatc aaagcaaggg ctcctttttg gcaatagact gctagattga 6065060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 650tcctggactt ttcctctcat gtctttgctg cagaactgaa gagactaggc gctggggctc 6065160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 651gaagatgatc atggatgaca gcaaacgcaa ggcgaagtct tttgagggca acaacaacta 6065260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 652cagggaagtt tacaagctag agcgaatatc tggactgcta atatctgaca acagtaggcg 6065360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 653caccgtcatg tcctgcaaca tctccaacgc cttctcccat gtcaacatca agctgcgtgc 6065460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 654ccccacaggc catgaccttg aagtgaaagt cttctgttgc tattgtgggc tcaaatattt 6065560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 655agggatgcac gcacagtggt aatttattac tcagttccgg ttatgttttt ctccaaaacc 6065660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 656aatctgaatt aagctttatc agtgtactct ttatctgtgt tactagtgcc tggtatgtag 6065760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 657cctgttggca ctgatgaaga acccttacag ttcagggttc ctggaacttc taccagtgcc 6065860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 658ggaaaatgat tgacaaagcc caacaatgat ctcaggaatt acattttcca acagaccaaa 6065960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 659ccagggctgc atctgcaaag ggacgtcaga caagtgcagc tgctgtgcct gatgccagga 6066060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 660ttttgagttc cagttgactg cagaggacat gaaagccata gatggcctag acagaaatct 6066160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 661aagataggaa ggttatttgg agatatctgt gcctgctaaa cacaaatgca tcggcccaca 6066260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 662aatatttgtg taacggagat atactactgt aagttttgta ctgtactggc tgaaagtctg 6066360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 663atgacagaag ggttcatata aacagtatcc tgacacagtc atgcttcctg gattttggag 6066460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 664atgctgaacg taaactataa tgctctacca caagaaaatg gcctctcacc tggggccatt 6066560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 665tgtgccaagt gtgcccacgg ctgcatctgc aaagggacgt cggagaagtg cagctgctgt 6066660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 666cacgtgcact ttattgaatg ccattgtaga aaagcgtgtg aggataaagg gctgatacag 6066760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 667tcaaggaaaa tctgggctaa gagtaggata tgagggatga tggataaggc atgagacatg 6066860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 668tgccaagtgt gcccagggct gcatctgcaa agggacgtca gacaagtgca gctgctgtgc 6066960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 669ctctgtatgc accagattat tcatctcgtt tagatattgt aagagcaaat tcaaagtcac 6067060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 670tctttggcaa tggccaccct ggtgttggca tattggcccc actgtaactt ttgggggctt 6067160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 671actttgagaa ctctgtgaga caaggtcctt aggcacccag atatcagcca ctttcacatt 6067260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 672ctgtgaccag cactgtctca gtttcacttt cacatagatg tccctttctt ggccagttat 6067360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 673ctaagcatca gacctggaat ttggagttgc aaagtgacta tcttcccatt tcccatctca 6067460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 674tctgcaatga atcccaaaag tatgtagttg agctgactgc aaggtgcttg agatgcaaga 6067560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 675actgaacggt gacttcagtg ttctcaacac tttactaaat tttactgata acttcgacga 6067660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 676agaacaaagt aattttctga agggaagctg cagaatatgg aaaacatata ttggagctac 6067760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 677tgtgcaatat gtgatgtggc aaatctctat taggaaatat tctgtaatct tcagacctag 6067860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 678tgttcatatg ggagaagggg gagtaatgac ttgtacaaac agtatttctg gtgtatattt 6067960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 679gttagggctc ctattcaaca cacacatgct tccctttcct gagtcccatc cctgcgtgat 6068060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 680tcacaggaag tagaggaggc cacgttctta ctagtttccc ttgcatggtt tagaaagctt 6068160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 681ctgtattttg tgctgcctga gaccaaaaac agaacctatg cagaaatcag ccaggcattt 6068260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 682cacggacagg aagcacagca ggtttatcca gatgaactga gaaggtcaga ttagggcggg 6068360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 683agatgcggta atgaaaccgg ttagtcagtg ttgtcttaat atccttgata atgctgtaaa 6068460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 684cagacagaca gatggaccgg cccacactcc cagagttgct aacatggagc tctgagatca 6068560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 685aagtgcaaat gcacctcctg caagaagagc tgctgctcct gttgccccct gggctgtgcc 6068660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 686tgcccaattg ccaaactaaa gacatcagtt cattggtcaa atatttgtta cctggaatgg 6068760DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 687aatcagagag tgtcacagat ttaaccttga tctaaagaca agttgtaccc agagtatgtg 6068860DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 688tgcttttaac ttccccacca tgttgcacct aaagctttgg agttttcctg tgattagtgt 6068960DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 689tgggaaacat gcgtgtgacc tccacagcta cctcttctat ggactggttg ttgccaaaca 6069060DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 690aagatcagga aatgtagaca tctagtgatt tctttagtag acagtttaat ttcccccaag 6069160DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 691cttttggcag caaaaccacc tgcgtggcta ggatgattaa ttatgaggat gatgattttt 6069260DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 692aattcagcaa gatatgtgat ggttctgaga atgaatttaa ttgaaataga ccagcagacc 6069360DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 693ttgggaactc tagtctcgcc tcgggttgca atggacccca actgctcctg tgccgctggt 6069460DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 694acctcaagtg ttgtaaaatt cgctactgca atttagaggg gccacctatc aactcatcag 6069560DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 695tttgctgtta ttttatctgc tatgctattg aagttttggc aattgactat agtgtgagcc 6069660DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 696tcctgcatgg gatctgatgg atcatgaaaa tattttgttt ctcaccatat gcttttgttg 606974PRTHomo sapiens 697Asp Glu Ala Asp 1

Claims

1. A method for treating a patient suffering from an IFN-.gamma.-mediated disease comprising administering to the patient a monoclonal anti-human interferon gamma (anti-huIFN-.gamma.) antibody at a dose of from about 15 milligrams to about 200 milligrams, wherein the anti-huIFN-.gamma. antibody has a heavy chain complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:34, a heavy chain complementarity determining region 2 (CDR2) comprising the amino acid sequence of SEQ ID NO:35, a heavy chain complementarity determining region 3 (CDR3) comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44.

2. The method of claim 1, wherein the heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:36, the light chain CDR1 comprises the amino acid sequence of SEQ ID NO:38, the light chain CDR2 comprises the amino acid sequence of SEQ ID NO:41, and the light chain CDR3 comprises the amino acid sequence of SEQ ID NO:43.

3. The method of claim 1, wherein the heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30.

4. The method of claim 3, wherein the light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31.

5. The method of claim 4, wherein the heavy chain variable region and the light chain variable region comprise, respectively, SEQ ID NO:6 and SEQ ID NO:8, SEQ ID NO:10 and SEQ ID NO:12, SEQ ID NO:14 and SEQ ID NO:16, SEQ ID NO:30 and SEQ ID NO:12, or SEQ ID NO:14 and SEQ ID NO:31.

6. The method of claim 1, wherein the dose is from about 40 milligrams to about 200 milligrams.

7. The method of claim 6, wherein the dose is from about 60 milligrams to about 150 milligrams.

8. The method of claim 6, wherein the dose is from about 100 milligrams to about 180 milligrams.

9. The method of claim 1, wherein a glucocorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial is concurrently administered to the patient.

10. The method of claim 1, wherein expression at the RNA or protein level of one or more gene(s) listed in Table 1, 2, 4, 5, and/or 6 in a biological sample from the patient taken before the antibody is administered deviates from expression of that gene(s) in a control biological sample in a direction consistent with excess IFN-.gamma..15.

11. The method of claim 10, wherein the expression of at least five genes listed in Table 5 and/or 6 in the biological sample from the patient deviates from the expression of those genes in the control biological sample in a direction consistent with excess IFN-.gamma..

12. The method of claim 10, wherein the biological sample from the patient exhibits elevated expression at the RNA or protein level as compared to expression in the control biological sample of one or more of the following genes: indoleamine 2,3-dioxygenase 1 (INDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274.

13. The method of claim 12, wherein the biological sample from the patient exhibits elevated expression at the RNA or protein level of GBP1 as compared to expression in the control biological sample.

14. The method of claim 1, wherein the IFN-.gamma.-mediated disease is selected from the group consisting of systemic lupus erythematosus (SLE), including discoid lupus and lupus nephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis.

15. The method of claim 14, wherein the IFN-.gamma.-mediated disease is SLE.

16. The method of claim 15, wherein the IFN-.gamma.-mediated disease is lupus nephritis.

17. The method of claim 1, wherein the antibody is a human IgG1 antibody.

18. A method for treating a patient having an IFN-.gamma.-mediated disease comprising administering to the patient a therapeutically effective dose an anti-huIFN-.gamma. antibody, wherein the anti-huIFN-.gamma. antibody has a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:34, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:35, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44, and wherein the level(s) of expression in a biological sample taken from the patient before administration of the antibody of one or more genes listed in Table 1, 2, 4, 5, and/or 6 at the RNA or protein level deviate from the level(s) of expression of the gene(s) in a control biological sample in a direction consistent with excess IFN-.gamma..

19. The method of claim 18, wherein the levels expression in the biological sample of at least 5 genes from Table 5 and/or 6 deviate from the levels of expression of the genes in the control biological sample in a direction consistent with excess IFN-.gamma..

20. The method of claim 18, wherein the antibody comprises the amino acid sequences of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30 and SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31.

21. The method of claim 18, wherein the dose administered is from 40 mg to 300 mg.

22. The method of claim 21, wherein the dose administered is from 60 mg to 200 mg.

23. The method of claim 18, wherein the IFN-.gamma.-mediated disease is SLE, an inflammatory bowel disease, or psoriasis patient.

24. The method of claim 23, wherein the IFN-.gamma.-mediated disease is SLE.

25. The method of claim 24, wherein IFN-.gamma.-mediated disease is lupus nephritis.

26. The method of claim 18, wherein a glucocorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial is concurrently administered to the patient.

27. A method for treating an IFN-.gamma. mediated disease comprising administering to a patient in need thereof a dose of a human IgG anti-huIFN-.gamma. antibody such that the concentration of total IFN-.gamma. protein in the patient's serum is maintained at a plateau concentration for at least about two weeks following administration, wherein the antibody comprises the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8.

28. The method of claim 27, wherein the plateau concentration of total IFN-.gamma. protein in serum is maintained for at least about three weeks after administration.

29. The method of claim 28, wherein the plateau concentration of total IFN-.gamma. protein in serum is maintained for at least about six weeks after administration.

30. The method of claim 27, wherein the plateau concentration of total IFN-.gamma. protein in serum is from about 100 pg/mL to about 2000 pg/mL.

31. The method of claim 30, wherein the plateau concentration of total IFN-.gamma. protein in serum is at least about 200 pg/mL.

32. The method of claim 27, wherein the antibody is a human IgG1 antibody.

33. The method of claim 27, wherein the IFN-.gamma.-mediated disease is psoriasis or SLE including lupus nephritis.

34. A method of treating a patient suffering from a disease selected from the group consisting of SLE, discoid lupus, lupus nephritis, inflammatory bowel disease, and psoriasis, the method comprising selecting a patient, wherein expression at the RNA or protein level of one or more gene(s) listed in Table(s) 2, 4, 5, and/or 6 in a biological sample taken from the patient before treating the patient deviates from expression of that gene(s) in a control biological sample in a direction consistent with excess IFN-.gamma. pathway activation, and administering to the patient a monoclonal human anti-human interferon gamma (anti-huIFN-.gamma.) antibody at a dose of from about 20 milligrams to about 300 milligrams, wherein the antibody is an IgG1 antibody and comprises the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:8.

35. The method of claim 34, wherein the expression of at least five genes listed in Table(s) 5 and/or 6 in the biological sample from the patient deviates from the expression of those genes in the control biological sample in a direction consistent with excess IFN-.gamma. pathway activation.

36. The method of claim 34, wherein the biological sample from the patient exhibits elevated expression at the RNA or protein level as compared to expression in the control biological sample of one or more of the following genes: indoleamine 2,3-dioxygenase 1 (INDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274.

37. The method of claim 34, wherein the disease is SLE and/or lupus nephritis.

38. A method for treating a patient suffering from SLE, an inflammatory bowel disease, or psoriasis comprising: (a) taking a biological sample from the patient before administering a human anti-huIFN-.gamma. antibody in step (b), wherein the level(s) of expression at the RNA or protein level in the biological sample from the patient of one or more of the genes in Table(s) 2, 4, 5, and/or 6 is determined; (b) administering to the patient a pharmacodynamically effective dose of the human anti-huIFN-.gamma. antibody, wherein the antibody has a heavy chain complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:34, a heavy chain complementarity determining region 2 (CDR2) comprising the amino acid sequence of SEQ ID NO:35, a heavy chain complementarity determining region 3 (CDR3) comprising the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:37, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:41 or SEQ ID NO:42, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:44; (c) taking a second biological sample taken from the patient after administration of the antibody, wherein the level(s) of expression of the gene(s) of step (a) in the second biological sample are determined; and (d) if the level(s) of expression of the gene(s) in the second biological sample determined in step (c), as compared to the level(s) of expression in the biological sample determined in step (a) (i) is modulated in a direction consistent with inhibition of IFN-.gamma., then continuing treatment of the patient with another pharmacodynamically effective dose of the antibody or (ii) is substantially the same as that in the biological sample of (a) or if the level of expression of the gene(s) in second biological sample of (c) deviates from the level of expression in the biological sample of (a) in a direction that is consistent with an excess of IFN-.gamma., then discontinuing treatment with the anti-human IFN-.gamma. antibody.

39. The method of claim 38, wherein the pharmacodynamically effective dose is from about 20 mg to about 80 mg.

40. The method of claim 38, wherein the pharmacodynamically effective dose is from about 80 mg to about 250 mg.

41. The method of claim 38, wherein the heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO:36, the light chain CDR1 comprises the amino acid sequence of SEQ ID NO:38, the light chain CDR2 comprises the amino acid sequence of SEQ ID NO:41, and the light chain CDR3 comprises the amino acid sequence of SEQ ID NO:43.

42. The method of claim 38, wherein the heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:14, or SEQ ID NO:30 and the light chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:12, SEQ ID NO:16, or SEQ ID NO:31.

43. The method of claim 42, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:6, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:8.

44. The method of claim 38, wherein the patient has SLE.

45. The method of claim 44, wherein the patient has lupus nephritis.

46. The method of claim 38, wherein a glucocorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial is concurrently administered to the patient.

47. The method of claim 38, wherein the patient has psoriasis, Crohn's disease, or ulcerative colitis.

48. The method of claim 38, wherein the level(s) of expression of one or more of the following genes at the protein or RNA level is determined in steps (a) and (c): indoleamine 2,3-dioxygenase 1 (INDO1), ankyrin repeat domain 22 (ANKRD22), chemokine (C--X--C motif) ligand 9 (CXCL9), family with sequence similarity 26, member F (FAM26F), purinergic receptor P2Y, G-protein coupled, 14 (P2RY14), guanylate binding binding protein 5 (GBP5), serpin peptidase inhibitor, clade G, member 1 (SERPING1), Fc fragment of IgG, high affinity Ib, receptor (CD64), guanylate binding protein 1, interferon-inducible, 67 kDa (GBP1), chemokine (C--X--C motif) ligand 10 (CXCL10), ets variant 7 (ETV7), programmed death ligand-1 (PD-L1), basic leucine zipper transcription factor, ATF-like 2 (BATF2), Fc fragment of IgG, high affinity Ib, receptor (FCGR1B or CD64), activating transcription factor 3 (ATF3), pyruvate dehydrogenase kinase, isozyme 4 (nuclear gene encoding mitochondrial protein; PDK4), and/or CD274.

49. The method of claim 48, wherein the level of expression of CXCL10 is determined in steps (a) and (c).

50. A method for treating a patient suffering from SLE comprising administering to the patient a dose of at least about 60 milligrams, and not more than about 180 milligrams, of an anti-human IFN-.gamma. antibody, wherein the anti-human IFN-.gamma. antibody comprises SEQ ID NOs: 6 and 8.

51. The method of claim 50, wherein the level of total IFN-.gamma. in the patient's serum remains above about 200 pg/mL for at least about 2 weeks subsequent to a single dose.

52. The method of claim 50, wherein a glucocorticoid and/or mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or an anti-malarial is concurrently administered to the patient.

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