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Patent Analysis of

Gamma-secretase inhibition reduce APOC3 levels and plasma triglycerides

Updated Time 12 June 2019

Patent Registration Data

Publication Number

US10149855

Application Number

US15/117155

Application Date

04 February 2015

Publication Date

11 December 2018

Current Assignee

THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

Original Assignee (Applicant)

PAJVANI, UTPAL

International Classification

C12N15/113,A61K31/55,A61K45/06,A61K31/192,A61K31/7088

Cooperative Classification

A61K31/55,A61K31/192,A61K31/4168,A61K31/5513,A61K45/06

Inventor

PAJVANI, UTPAL

Patent Images

This patent contains figures and images illustrating the invention and its embodiment.

US10149855 Gamma-secretase inhibition reduce APOC3 levels 1 US10149855 Gamma-secretase inhibition reduce APOC3 levels 2 US10149855 Gamma-secretase inhibition reduce APOC3 levels 3
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Abstract

A method of reducing a subject's plasma triglyceride level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's plasma triglyceride level.

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Claims

1. A method of treating a subject afflicted with hypertriglyceridemia, comprising administering to the subject a gamma-secretase inhibitor in an amount effective to treat the hypertriglyceridemia in the subject.

2. The method of claim 1, wherein the administration reduces the subject's serum triglyceride level.

3. The method of claim 2, wherein the administration reduces the triglyceride level in the subject's very low-density lipoprotein (VLDL) serum fraction.

4. The method of claim 2, wherein the administration reduces the subject's serum triglyceride level and serum apolipoprotein C3(ApoC3) level.

5. The method of claim 1, wherein administration of the gamma-secretase inhibitor inhibits whole-body gamma-secretase.

6. The method of claim 1, wherein administration of the gamma-secretase inhibitor inhibits liver gamma-secretase more than inhibiting gamma-secretase elsewhere in the subject.

7. The method of claim 1, wherein the administration of the gamma-secretase inhibitor targets the gamma-secretase inhibitor to the liver.

8. The method of claim 1, wherein the administration of the gamma-secretase inhibitor targets the gamma-secretase inhibitor to hepatocytes.

9. The method of claim 6, wherein the gamma-secretase inhibitor is (i) coupled to a ligand molecule targeted to a receptor on a hepatic cell, or (ii) administered by a bio-nanocapsule.

10. The method of claim 6, wherein gastrointestinal Notch activity is substantially uninhibited.

11. The method of claim 1, wherein the gamma-secretase inhibitor is a small molecule inhibitor, an oligonucleotide capable of hybridizing to an RNA encoding a subunit of gamma secretase in a cell, or an adenoviral vector capable of expressing the oligonucleotide.

12. The method of claim 11, wherein the gamma-secretase inhibitor is an oligonucleotide.

13. The method of claim 12, wherein the oligonucleotide is an antisense oligonucleotide, an RNA-interference inducing compound, or a ribozyme.

14. The method of claim 12, wherein the oligonucleotide is targeted to hepatocytes.

15. The method of claim 12, wherein the oligonucleotide comprises 1, 2, 3, 4, or 5 or more stretches of nucleotides in a sequence that is complementary to nicastrin-encoding mRNA, presenilin 1-encoding mRNA and presenilin 2-encoding mRNA, or APH1A-encoding mRNA and APH1B-encoding mRNA, wherein each stretch of complementary continguous nucleotides is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more nucleotides in length.

16. The method of claim 12, wherein the oligonucleotide is modified to increase its stability in vivo.

17. The method of claim 11, wherein the gamma-secretase inhibitor is a small molecule inhibitor.

18. The method of claim 17, wherein the small molecule inhibitor is 2,2-dimethyl-N—((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, (S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, bis(fluoroalkyl)-1,4-benzodiazepinone, (2S)-2-hydroxy-3-methyl-N-((1S)-1-methyl-2-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-2-oxoethyl)butanamide, cis-3-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl] propanoic acid, N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenyglycine t-butyl ester, bis(fluoroalkyl)-1,4-benzodiazepinone, or N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluoro-benzeneacetamide.

19. A method of reducing a subject's plasma glucose level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's glucose level.

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Claim Tree

  • 1
    1. A method of treating a subject afflicted with hypertriglyceridemia, comprising
    • administering to the subject a gamma-secretase inhibitor in an amount effective to treat the hypertriglyceridemia in the subject.
    • 2. The method of claim 1, wherein
      • the administration reduces the subject's serum triglyceride level.
    • 5. The method of claim 1, wherein
      • administration of the gamma-secretase inhibitor inhibits whole-body gamma-secretase.
    • 6. The method of claim 1, wherein
      • administration of the gamma-secretase inhibitor inhibits liver gamma-secretase more than inhibiting gamma-secretase elsewhere in the subject.
    • 7. The method of claim 1, wherein
      • the administration of the gamma-secretase inhibitor targets the gamma-secretase inhibitor to the liver.
    • 8. The method of claim 1, wherein
      • the administration of the gamma-secretase inhibitor targets the gamma-secretase inhibitor to hepatocytes.
    • 11. The method of claim 1, wherein
      • the gamma-secretase inhibitor is a small molecule inhibitor, an oligonucleotide capable of hybridizing to an RNA encoding a subunit of gamma secretase in a cell, or an adenoviral vector capable of expressing the oligonucleotide.
  • 19
    19. A method of reducing a subject's plasma glucose level, comprising
    • administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's glucose level.
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Description

REFERENCE TO A SEQUENCE LISTING

This application incorporates by reference nucleotide and/or amino acid sequences which are present in the file named “180411 86108-A-PCT-US Substitute Sequence Listing AWS.txt” which is 164 kilobytes in size, and which was created Apr. 11, 2018 in the IBM-PC machine format, having an operating system compatibility with MS-Windows, which is contained in the text file filed on Apr. 11, 2018.

All publications and other references mentioned herein are incorporated by reference in their entirety, as if each individual publication or reference were specifically and individually indicated to be incorporated by reference. Publications and references cited herein are not admitted to be prior art.

BACKGROUND OF THE INVENTION

Obesity has reached epidemic status in the United States. The Centers for Disease Control has stated that more than ⅓ of American adults are obese, and estimated the medical costs attributable to obesity at $147 billion in 2008, a number that is likely to be significantly higher today and in the future. One of the core components of obesity-induced metabolic syndrome is excess plasma triglycerides. Elevated plasma triglyceride level, or hypertriglyceridemia, is an independent risk factor for coronary heart disease, above and beyond other obesity-related complications (e.g., high LDL cholesterol, low HDL cholesterol and Type 2 Diabetes). Many patients are unable to get to plasma triglyceride targets with currently available therapies.

Thus, new therapies for reducing plasma triglycerides are needed.

SUMMARY OF THE INVENTION

The invention provides a method of reducing a subject's plasma triglyceride level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's plasma triglyceride level.

The invention also provides a method of treating a subject afflicted with hypertriglyceridemia, comprising administering to the subject a gamma-secretase inhibitor in an amount effective to treat the subject.

The invention also provides a method of reducing a subject's plasma glucose level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's glucose level.

The invention also provides a method of reducing a subject's ApoC3 level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's ApoC3 level.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Bifurcation model of hepatic insulin signaling illustrating how reduction in Notch signaling with γ-secretase inhibitor (GSI) treatment blocks mTorc1 activation, and tumorigenesis.

FIG. 2: Gamma-secretase inhibitors (GSIs) are pharmacologic inhibitors of Notch signaling.

FIG. 3: Plasma glucose levels of GSI and vehicle treated mice. *p<0.05 **p<0.01 ***p<0.001 vs. vehicle.

FIG. 4: Serum triglyceride levels in mice treated with GSI or vehicle only. *p<0.05 **p<0.01 ***p<0.001 vs. vehicle.

FIG. 5: VLDL, LDL, and HDL fraction serum triglyceride levels of mice administered GSI or vehicle only. *p<0.05 **p<0.01 ***p<0.001 vs. vehicle.

FIG. 6: Lower plasma TG levels with low dose DBZ not associated with apparent GI toxicity. *p<0.05 **p<0.01 ***p<0.001 vs. vehicle.

FIG. 7: Time course of plasma triglyceride levels of mice administered GSI or vehicle only.

FIG. 8: Time course of plasma triglyceride excursion following lipid gavage in mice administered GSI or vehicle only. *p<0.05 **p<0.01 ***p<0.001 vs. vehicle.

FIG. 9: Glucose tolerance test (GTT) and pyruvate tolerance test (PTT) plots for control and L-Ncst mice. *p<0.05 **p<0.01 ***p<0.001 vs. Cre-.

FIG. 10: Serum triglyceride levels for fasted and refed chow-fed L-Ncst mice.

FIG. 11: Serum lipid levels for control and L-Ncst mice. *p<0.05 **p<0.01 ***p<0.001 vs. Cre-.

FIG. 12: Triglyceride levels by plasma fraction for control and L-Ncst mice. *p<0.05 **p<0.01 ***p<0.001 vs. Cre-.

FIG. 13: Plasma triglyceride levels of fasted and refed control and L-Ncst mice. *p<0.05 **p<0.01 ***p<0.001 vs. Cre-.

FIG. 14: Serum triglyceride levels in HFD-fed control and L-Ncst mice.

FIG. 15: Time course of serum triglyceride levels in control and L-Ncst mice. *p<0.05 **p<0.01 ***p<0.001 vs. Cre-.

FIG. 16: Relative gene expression levels of fasted and refed control and L-Ncst mice.

FIG. 17: Western blot for ApoC3 serum levels in HFD-fed control and L-Ncst mice.

FIG. 18: Western blot for ApoC3 levels in HDL and VLDL serum fractions in HFD-fed control and L-Ncst mice.

FIG. 19: Western blot for hepatic ApoC3 levels in control and L-Ncst mice.

FIG. 20: Western blot for hepatic ApoC3 levels in L-Ncst mice.

FIG. 21: mRNA expression of Nicastrin and ApoC3 in fasted and refed control and L-Ncst mice.

FIG. 22: Correlation between ApoC3 (hepatic Apoc3 mRNA, hepatic ApoC3 protein, and serum ApoC3) with Plasma triglyceride.

FIG. 23: Serum triglyceride levels in HFD-fed control and L-Ncst mice following liver ApoC3 knockdown by adeno-delivered shRNA. *p<0.05 **p<0.01 ***p<0.001 vs. Cre-.

FIG. 24: Adenoviral transduction of L-Ncst mice with ApoC3 increases plasma TG to levels comparable to Cre-control mice. p<0.05 **p<0.01 ***p<0.001 vs. Cre-Ad-GFP mice.

FIG. 25: shRNA-mediated knockdown of Nicastrin (sequence of shRNA: CTCCTTCCACAATCGGTATTA SEQ ID NO. 59) in mouse hepatocytes reduces ApoC3 secretion.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a method of reducing a subject's plasma triglyceride level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's plasma triglyceride level.

The invention also provides a method of treating a subject afflicted with hypertriglyceridemia, comprising administering to the subject a gamma-secretase inhibitor in an amount effective to treat the subject.

In some embodiments, the administration reduces the triglyceride level in the subject's very low-density lipoprotein (VLDL) plasma fraction.

In some embodiments, the administration reduces the subject's plasma triglyceride level and apolipoprotein C3 (ApoC3) level.

In some embodiments, the administration reduces the subject's plasma triglyceride level and serum apolipoprotein C3 (ApoC3) level.

In some embodiments, the administration reduces the subject's serum triglyceride level.

In some embodiments, the administration reduces the triglyceride level in the subject's very low-density lipoprotein (VLDL) serum fraction.

In some embodiments, the administration reduces the subject's serum triglyceride level and apolipoprotein C3 (ApoC3) level.

In some embodiments, the administration reduces the subject's serum triglyceride level and serum apolipoprotein C3 (ApoC3) level.

The invention also provides a method of reducing a subject's ApoC3 level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's ApoC3 level.

In some embodiments, the administration reduces the subject's hepatic ApoC3 level.

In some embodiments, the administration reduces the subject's plasma ApoC3 level.

In some embodiments, the administration reduces the subject's serum ApoC3 level.

In some embodiments, the administration reduces the ApoC3 level in the subject's HDL or VLDL serum fraction.

In some embodiments, the administration reduces the ApoC3 level in the subject's VLDL serum fraction.

In some embodiments, the administration reduces the subject's serum ApoC3 level and serum triglyceride level.

The invention also provides a method of reducing a subject's plasma glucose level, comprising administering to a subject in need thereof a gamma-secretase inhibitor in an amount effective to reduce the subject's glucose level.

In some embodiments, the administration of the gamma-secretase inhibitor inhibits whole-body gamma-secretase.

In some embodiments, the administration of the gamma-secretase inhibitor inhibits liver gamma-secretase without significantly inhibiting gamma-secretase elsewhere in the subject.

In an embodiment, administration of the gamma-secretase inhibitor inhibits liver gamma-secretase without significantly inhibiting whole-body gamma-secretase.

In some embodiments, the administration of the gamma-secretase inhibitor targets the gamma-secretase inhibitor to the liver.

In some embodiments, the administration of the gamma-secretase inhibitor targets the gamma-secretase inhibitor to hepatocytes.

In some embodiments, the gamma-secretase inhibitor is (i) coupled to a ligand molecule targeted to a receptor on a hepatic cell, or (ii) administered by a bio-nanocapsule.

In some embodiments, the gastrointestinal Notch inhibition is substantially uninhibited.

In some embodiments, the gamma-secretase inhibitor is a small molecule inhibitor, an antisense oligonucleotide, or an adenoviral vector.

In some embodiments, the gamma-secretase inhibitor is a small molecule inhibitor, an oligonucleotide or an adenoviral vector.

In some embodiments, the gamma-secretase inhibitor is an oligonucleotide.

In some embodiments, the oligonucleotide is an antisense oligonucleotide, an RNA-interference inducing compound, or a ribozyme.

In some embodiments, the oligonucleotide is targeted to hepatocytes.

In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, or 5 or more stretches of nucleotides in a sequence that is complementary to nicastrin-encoding mRNA, presenilin 1-encoding mRNA and presenilin 2-encoding mRNA, or APH1A-encoding mRNA and APH1B-encoding mRNA, wherein each stretch of complementary continguous nucleotides is at least at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more nucleotides in length.

In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, or 5 or more stretches of nucleotides in a sequence that is complementary to nicastrin-encoding mRNA, presenilin 1-encoding mRNA, presenilin 2-encoding mRNA, APH1A-encoding mRNA, or APH1B-encoding mRNA, wherein each stretch of complementary continguous nucleotides is at least at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more nucleotides in length.

In some embodiments, the oligonucleotide is modified to increase its stability in vivo.

In some embodiments, the small molecule inhibitor is 804929097, PF-3084014, BMS-708163, LY450139, or MK-0752.

In some embodiments, the gamma-secretase inhibitor is a small molecule inhibitor.

In some embodiments, the small molecule inhibitor is 2,2-dimethyl-N—((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, (S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, bis(fluoroalkyl)-1,4-benzodiazepinone, (2S)-2-hydroxy-3-methyl-N-((1S)-1-methyl-2-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-2-oxoethyl)butanamide, cis-3-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]propanoic acid, dual anti-platelet study, bis(fluoroalkyl)-1,4-benzodiazepinone, or N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluoro-benzeneacetamide.

In some embodiments, the subject is obese.

In some embodiments, the subject has hypertriglyceridemia.

In some embodiments, the hypertriglyceridemia is obesity-induced hypertriglyceridemia.

In some embodiments, the subject has fatty liver disease.

In some embodiments, the subject has non-alcoholic fatty liver disease.

In some embodiments, the subject has atherosclerosis.

In some embodiments, the subject has coronary heart disease.

In some embodiments, the subject has diabetes.

In some embodiments, the subject has Type 2 Diabetes.

In some embodiments, the subject is a human.

In some embodiments, the subject's plasma triglyceride level is >150 mg/dL.

In some embodiments, the subject's plasma triglyceride level is >500 mg/dL, about 200 to 499 mg/dL, or about 150 to 199 mg/dL.

In some embodiments, the subject's plasma triglyceride level is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%, relative to the level prior to administration of the gamma-secretase inhibitor.

In some embodiments, the subject's serum triglyceride level is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%, relative to the level prior to administration of the gamma-secretase inhibitor.

In some embodiments, the subject's glucose level while fasting is >100 mg/dL.

In some embodiments, the subject's glucose level two hours after eating is >140 mg/dL.

In some embodiments, the subject's plasma triglyceride level is reduced by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%, relative to the level prior to administration of the gamma-secretase inhibitor.

In some embodiments, the subject's serum triglyceride level is reduced by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%, relative to the level prior to administration of the gamma-secretase inhibitor.

Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs.

TERMS

As used herein, “about” in the context of a numerical value or range means ±10% of the numerical value or range recited or claimed, unless the context requires a more limited range.

As used herein, “effective” when referring to an amount of a gamma-secretase inhibitor refers to the quantity of gamma-secretase inhibitor which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.

As used herein, “treating a subject afflicted with hypertriglyceridemia” encompasses, e.g., reducing the subject's plasma or serum triglyceride level to less than 500 mg/dL, less than 200 mg/dL or less than 150 mg/dL.

As used herein, “a subject in need thereof” encompasses, e.g., a subject with plasma or serum triglyceride level greater than 150 mg/dL, greater than 200 mg/dL, or to greater than 500 mg/dL.

As used herein, a “gamma-secretase inhibitor” is an agent which reduces in vivo activity of a gamma-secretase complex. A gamma-secretase inhibitor may be, e.g., a small molecule, an anti-sense oligonucleotide, or an adenoviral vector.

Methods of Inhibiting Gamma-Secretase

In some embodiments, each compound administered to the subject is, independently, an organic compound having a molecular weight less than 1000 Daltons, a DNA aptamer, an RNA aptamer, a polypeptide, an antibody, an oligonucleotide, an interfering RNA (RNAi) molecule, a ribozyme, or a small molecule inhibitor.

In some embodiments, a compound that is capable of inhibiting gamma-secretase is administered to the subject.

In some embodiments, the compound which is capable of inhibiting gamma-secretase is an organic compound having a molecular weight less than 1000 Daltons.

Small Molecule Inhibitor

A small molecule inhibitor may administered herein to inhibit activity of gamma-secretase.

As used herein, “RO4929097” refers to 2,2-dimethyl-N—((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide. The CAS Registry Number for 804929097 is 847925-91-1. The structure of 804929097 is:

As used herein, “PF-3084014” refers to (S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. The CAS Registry Number for PF-03084014 is 865773-15-5. The structure of PF-03084014 is:

As used herein, “BMS-708163” refers to (R)-2-(4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide. The CAS Registry Number for BMS-708163 is 1146699-66-2. The structure of BMS-708163 is:

As used herein, “LY450139” refers to (2S)-2-hydroxy-3-methyl-N-(1S)-1-methyl-2-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-2-oxoethyl)butanamide. The CAS Registry Number for LY450139 is 425386-60-3. The structure of LY450139 is:

As used herein, “MK-0752” refers to cis-3-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]propanoic acid. The CAS Registry Number for MK0752 is 471905-41-6. The structure of MK0752 is:

As used herein, dual anti-platelet study or “DAPT” refers to N—[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester. The CAS Registry Number for DAPT is 208255-80-5. The structure of DAPT is:

As used herein, “BMS-906024” refers to bis(fluoroalkyl)-1,4-benzodiazepinone. The CAS Registry Number for BMS-906024 is 1401066-79-2. The structure of BMS-906024 is:

As used herein, dibenzazepine or “YO-01027”, refers to N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluoro-benzeneacetamide. The CAS Registry Number for dibenzazepine is 209984-56-5. The structure of dibenzazepine is:

Non-limiting examples of gamma-secretase modulators which are described, for example, in the publication, Bergmans and Strooper, 2010, of which are hereby incorporated by reference in their entireties.

Non-limiting examples of gamma-secretase inhibitors which are described, for example, in the following publications: Andersson and Lendahl, 2014, Bergmans and De Strooper, 2010, Real et al., 2009, all of which are hereby incorporated by reference in their entireties.

Inhibiting Expression of Gamma-Secretase

In some embodiments, the compound which is capable of inhibiting gamma-secretase expression silences expression of a gene or silences transcription.

Oligonucleotide

Non-limiting examples of oligonucleotides capable of inhibition gamma-seretase expression include antisense oligonucleotides, ribozymes, and RNA interference molecules.

The amino acid sequence of nicastrin, NCSTN, is accessible in public databases by the GenBank accession number Q92542, and is set forth herein as SEQ ID NO: 1. The nucleotide sequence of NCSTN is also accessible in public databases by the GenBank accession number AF240468, and is set forth herein as SEQ ID NO: 2. The nucleotide sequence of NCSTN is also accessible in public databases by the GenBank accession number AK296153 and is set forth herein as SEQ ID NO: 3. The nucleotide sequence of NCSTN is also accessible in public databases by the GenBank accession number AK299142, and is set forth herein as SEQ ID NO: 4. The nucleotide sequence of NCSTN is also accessible in public databases by the GenBank accession number AK310741, and is set forth herein as SEQ ID NO: 5. The nucleotide sequence of NCSTN is also accessible in public databases by the GenBank accession number AK314764 and is set forth herein as SEQ ID NO: 6. The nucleotide sequence of NCSTN is also accessible in public databases by the accession number AY359120, and is set forth herein as SEQ ID NO: 7. The nucleotide sequence of NCSTN is also accessible in public databases by the Genbank accession number BC047621, and is set forth herein as SEQ ID NO: 8. The nucleotide sequence of NCSTN is also accessible in public databases by the GenBank accession number BC100024, and is set forth herein as SEQ ID NO: 9. The nucleotide sequence of NCSTN is also accessible in public databases by the GenBank accession number CN429672, and is set forth herein as SEQ ID NO: 10. The nucleotide sequence of nicastrin, NCSTN, is accessible in public databases by the GenBank accession number D87442, and is set forth herein as SEQ ID NO: 11.

The amino acid sequence of presenilin 1, PSEN1, is accessible in public databases by the GenBank accession number P49768, and is set forth herein as SEQ ID NO: 12. The amino acid sequence of PSEN1 is also accessible in public databases by the GenBank accession number AAL16811, and is set forth herein as SEQ ID NO: 13. The amino acid sequence which encodes NCSTN is accessible in public databases by the GenBank accession number CAA07825, and is set forth herein as SEQ ID NO: 14. The amino acid sequence of PSEN1 is also accessible in public databases by the GenBank accession number BAD96893, and is set forth herein as SEQ ID NO: 15. The amino acid sequence of PSEN1 is also accessible in public databases by the GenBank accession number BAH14071, and is set forth herein as SEQ ID NO: 16. The amino acid sequence which encodes PSEN1 is also accessible in public databases by the GenBank accession number BAG35430, and is set forth herein as SEQ ID NO: 17. The amino acid sequence which encodes PSEN1 is also accessible in public databases by the GenBank accession number AAH11729, and is set forth herein as SEQ ID NO: 18. The amino acid sequence which encodes PSEN1 is also accessible in public databases by the GenBank accession number AAB46416, and is set forth herein as SEQ ID NO 19. The amino acid sequence which encodes PSEN1 is also accessible in public databases by the GenBank accession number AAB46370, and is set forth herein as SEQ ID NO: 20. The amino acid sequence which encodes PSEN1 is also accessible in public databases by the GenBank accession number AAB05894, and is set forth herein as SEQ ID NO 21. The amino acid sequence which encodes PSEN1 is also accessible in public databases by the GenBank accession number AAB05895, and is set forth herein as SEQ ID NO: 22. The amino acid sequence which encodes PSEN1 is also accessible in public databases by the GenBank accession number CAA07825, and is set forth herein as SEQ ID NO: 23.

The amino acid sequence of presenilin 2, PSEN2, is accessible in public databases by the GenBank accession number P49810, and is set forth herein as SEQ ID NO: 24. The amino acid sequence of presenilin 2, PSEN2, is accessible in public databases by the GenBank accession number AAL16812, and is set forth herein as SEQ ID NO: 25. The amino acid sequence of PSEN2 is also accessible in public databases by the GenBank accession number BAF84988, and is set forth herein as SEQ ID NO: 26. The amino acid sequence of PSEN2 is also accessible in public databases by the GenBank accession number BAG62735, and is set forth herein as SEQ ID NO: 27. The amino acid sequence of PSEN2 is also accessible in public databases by the GenBank accession number AAH06365, and is set forth herein as SEQ ID NO: 28. The amino acid sequence of PSEN2 is also accessible in public, databases by the GenBank accession number AAP35630, and is set forth herein as SEQ ID NO: 29. The amino acid sequence of PSEN2 is also accessible in public databases by the GenBank accession number AAB59557, and is set forth herein as SEQ ID NO: 30. The amino acid sequence of PSEN2 is also accessible in public databases by the GenBank accession number AAC42012, and is set forth herein as SEQ ID NO: 31. The amino acid sequence of PSEN2 is also accessible in public databases by, the GenBank accession number AAC50290, and is set forth herein as SEQ ID NO: 32.

The amino acid sequence of APH1A gamma secretase subunit, APH1A, is accessible in public databases by the GenBank accession number Q96BI3, and is set forth herein as SEQ ID NO: 33. The amino acid sequence of APH1A is accessible in public databases by the GenBank accession number AAD34072, and is set forth herein as SEQ ID NO: 34. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number AAN63816, and is set forth herein as SEQ ID NO: 35. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number BAG51389, and is set forth herein as SEQ ID NO: 36. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number BAC11529, and is set forth herein as SEQ ID NO: 37. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number BAG52142, and is set forth herein as SEQ ID NO: 38. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number BAG60040, and is set forth herein as SEQ ID NO: 39. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number BAG60962, and is set forth herein as SEQ ID NO: 40. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number BAG60993, and is set forth herein as SEQ ID NO: 41. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number BAG62329, and is set forth herein as SEQ ID NO: 42. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number CAE11677, and is set forth herein as SEQ ID NO: 43. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number CAE11678, and is set forth herein as SEQ ID NO: 44. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number AAM61955, and is set forth herein as SEQ ID NO: 45. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number AAM61956, and is set forth herein as SEQ ID NO: 46. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number AAQ89310, and is set forth herein as SEQ ID NO: 47. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number AAH01230, and is set forth herein as SEQ ID NO: 48. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number AAH08732, and is set forth herein as SEQ ID NO: 49. The amino acid sequence of APH1A is also accessible in public databases by the GenBank accession number AAH09501, and is set forth herein as SEQ ID NO: 50.

The amino acid sequence of APH1B gamma secretase subunit, APH1B, is accessible in public databases by the accession number Q8WW43, and is set forth herein as SEQ ID NO: 51. The amino acid sequence of APH1B is also accessible in public databases by the accession number BAD95573, and is net forth herein as SEQ ID NO: 52. The amino acid sequence of APH1B is also accessible in public databases by the accession number BAE02660, and is set forth herein as SEQ ID NO: 53. The amino acid sequence of APH1B is also accessible in public databases by the accession number AAN63817, and is set forth herein as SEQ ID NO: 54. The amino acid sequence of APH1B is also accessible in public databases by the accession number BAF83893, and is set forth herein as SEQ ID NO: 55. The amino acid sequence of APH1B is also accessible in public databases by the accession number CAB66606, and is set forth herein as SEQ ID NO: 56. The amino acid sequence of APH1B is also accessible in public databases by the accession number AAQ89061, and is set forth herein as SEQ ID NO: 57. The amino acid sequence of APH1B is also accessible in public databases by the accession number AAH20905, and is set forth herein as SEQ ID NO: 58.

In some embodiments, the compound which is capable of inhibiting gamma-secretase expression is an antisense oligonucleotide, a ribozyme, or an RNA interference molecule.

Antisense Oligonucleotide

Antisense oligonucleotides are nucleotide sequences which are complementary to a specific DNA or RNA sequence. Once introduced into a cell, the complementary nucleotides combine with natural sequences produced by the cell to form complexes and block either transcription or translation. Preferably, an antisense oligonucleotide is at least 11 nucleotides in length, but can be at least 12, 15, 20, 25, 30, 35, 40, 45, or 50 or more nucleotides long. Longer sequences also can be used. Antisense oligonucleotide molecules can be provided in a DNA construct and introduced into a cell as described above to decrease the level of target gene products in the cell.

Antisense oligonucleotides can be deoxyribonucleotides, ribonucleotides, or a combination of both. Oligonucleotides can be synthesized manually or by an automated synthesizer, by covalently linking the 5′ end of one nucleotide with the 3′ end of another nucleotide with non-phosphodiester internucleotide linkages such alkylphosphonates, phosphorothioates, phosphorodithioates, alkylphosphonothioates, alkylphosphonates, phosphoramidates, phosphate esters, carbamates, acetamidate, carboxymethyl esters, carbonates, and phosphate triesters.

Modifications of gene expression can be obtained by designing antisense oligonucleotides which will form duplexes to the control, 5′, or regulatory regions of the gene. Oligonucleotides derived from the transcription initiation site, e.g., between, positions −10 and +10 from the start site, are preferred. Similarly, inhibition can be achieved using “triple helix” base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or chaperons. Therapeutic advances using triplex DNA have been described in the literature (Nicholls et al., 1993, J Immunol Meth 165:81-91). An antisense oligonucleotide also can be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.

Precise complementarity is not required for successful complex formation between an antisense oligonucleotide and the complementary sequence of a target polynucleotide. Antisense oligonucleotides which comprise, for example, 1, 2, 3, 4, or 5 or more stretches of contiguous nucleotides which are precisely complementary to a target polynucleotide, each separated by a stretch of contiguous nucleotides which are not complementary to adjacent nucleotides, can provide sufficient targeting specificity for a target mRNA. Preferably, each stretch of complementary contiguous nucleotides is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more nucleotides in length. Noncomplementary intervening sequences are preferably 1, 2, 3, or 4 nucleotides in length. One skilled in the art can easily use the calculated melting point of an antisense-sense pair to determine the degree of mismatching which will be tolerated between a particular antisense oligonucleotide and a particular target polynucleotide sequence. Antisense oligonucleotides can be modified without affecting their ability to hybridize to a target polynucleotide. These modifications can be internal or at one or both ends of the antisense molecule. For example, internucleoside phosphate linkages can be modified by adding cholesteryl or diamine moieties with varying numbers of carbon residues between the amino groups and terminal ribose. Modified bases and/or sugars, such as arabinose instead of ribose, or a 3′, 5′-substituted oligonucleotide in which the 3′ hydroxyl group or the 5′ phosphate group are substituted, also can be employed in a modified antisense oligonucleotide. These modified oligonucleotides can be prepared by methods well known in the art.

Ribozymes

Ribozymes are RNA molecules with catalytic activity (Uhlmann et al., 1987, Tetrahedron. Lett. 215, 3539-3542). Ribozymes can be used to inhibit gene function by cleaving an RNA sequence, as is known in the art. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. Examples include engineered hammerhead motif ribozyme molecules that can specifically and efficiently catalyze endonucleolytic cleavage of specific nucleotide sequences. The coding sequence of a polynucleotide can be used to generate ribozymes which will specifically bind to mRNA transcribed from the polynucleotide. Methods of designing and constructing ribozymes which can cleave other RNA molecules in trans in a highly sequence specific manner have been developed and described in the art. For example, the cleavage activity of ribozymes can be targeted to specific RNAs by engineering a discrete “hybridization” region into the ribozyme. The hybridization region contains a sequence complementary to the target RNA and thus specifically hybridizes with the target RNA.

Specific ribozyme cleavage sites within an RNA target can be identified by scanning the target molecule for ribozyme cleavage sites which include the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides corresponding to the region of the target RNA containing the cleavage site can be evaluated for secondary structural features which may render the target inoperable. Suitability of candidate RNA targets also can be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays. Longer complementary sequences can be used to increase the affinity of the hybridization sequence for the target. The hybridizing and cleavage regions of the ribozyme can be integrally related such that upon hybridizing to the target RNA through the complementary regions, the catalytic region of the ribozyme can cleave the target.

Ribozymes can be introduced into cells as part of a DNA construct. Mechanical methods, such as microinjection, liposome-mediated transfection, electroporation, or calcium phosphate precipitation, can be used to introduce a ribozyme-containing DNA construct into cells in which it is desired to decrease target gene expression. Alternatively, if it is desired that the cells stably retain the DNA construct, the construct can be supplied on a plasmid and maintained as a separate element or integrated into the genome of the cells, as is known in the art. A ribozyme-encoding DNA construct can include transcriptional regulatory elements, such as a promoter element, an enhancer or VAS element, and a transcriptional terminator signal, for controlling transcription of ribozymes in the cells (U.S. Pat. No. 5,641,673). Ribozymes also can be engineered to provide an additional level of regulation, so that destruction of mRNA occurs only when both a ribozyme and a target gene are induced in the cells.

RNA Interference

An interfering RNA (RNAi) molecule involves mRNA degradation. The use of RNAi has been described in Fire et al., 1998, Carthew et al., 2001, and Elbashir et al., 2001, the contents of which are incorporated herein by reference.

Interfering RNA or small inhibitory RNA (RNAi) molecules include short interfering RNAs (siRNAs), repeat-associated siRNAs (rasiRNAs), and micro-RNAs (miRNAs) in all stages of processing, including shRNAs, pri-miRNAs, and pre-miRNAs. These molecules have different origins: siRNAs are processed from double-stranded precursors (dsRNAs) with two distinct strands of base-paired RNA; siRNAs that are derived from repetitive sequences in the genome are called rasiRNAs; miRNAs are derived from a single transcript that forms base-paired hairpins. Base pairing of siRNAs and miRNAs can be perfect (i.e., fully complementary) or imperfect, including bulges in the duplex region.

Interfering RNA molecules encoded by recombinase-dependent transgenes of the invention can be based on existing shRNA, siRNA, piwi-interacting RNA (piRNA), micro RNA (miRNA), double-stranded RNA (dsRNA), antisense RNA, or any other RNA species that can be cleaved inside a cell to form interfering RNAs, with compatible modifications described herein.

As used herein, an “shRNA molecule” includes a conventional stem-loop shRNA, which forms a precursor miRNA (pre-miRNA). “shRNA” also includes micro-RNA embedded shRNAs (miRNA-based shRNAs), wherein the guide strand and the passenger strand of the miRNA duplex are incorporated into an existing (or natural) miRNA or into a modified or synthetic (designed) miRNA. When transcribed, a shRNA may form a primary miRNA (pri-miRNA) or a structure very similar to a natural pri-miRNA. The pri-miRNA is subsequently processed by Drosha and its cofactors into pre-miRNA. Therefore, the term “shRNA” includes pri-miRNA (shRNA-mir) molecules and pre-miRNA molecules.

A “stem-loop structure” refers to a nucleic acid having a secondary structure that includes a region of nucleotides which are known or predicted to form a double strand or duplex (stem portion) that is linked on one side by a region of predominantly single-stranded nucleotides (loop portion). The terms “hairpin” and “fold-back” structures are also used herein to refer to stem-loop structures. Such structures are well known in the art and the term is used consistently with its known meaning in the art. As is known in the art, the secondary structure does not require exact base-pairing. Thus, the stem can include one or more base mismatches or bulges. Alternatively, the base-pairing can be exact, i.e. not include any mismatches.

“RNAi-expressing construct” or “RNAi construct” is a generic term that includes nucleic acid preparations designed to achieve an RNA interference effect. An RNAi-expressing construct comprises an RNAi molecule that can be cleaved in vivo to form an siRNA or a mature shRNA. For example, an RNAi construct is an expression vector capable of giving rise to a siRNA or a mature shRNA in vivo. Non-limiting examples of vectors that may be used in accordance with the present invention are described herein and will be well known to a person having ordinary skill in the art. Exemplary methods of making and delivering long or short RNAi constructs can be found, for example, in WO01/68836 and WO01/75164.

RNAi is a powerful tool for in vitro and in vivo studies of gene function in mammalian cells and for therapy in both human and veterinary contexts. Inhibition of a target gene is sequence-specific in that gene sequences corresponding to a portion of the RNAi sequence, and the target gene itself, are specifically targeted for genetic inhibition. Multiple mechanisms of utilizing RNAi in mammalian cells have been described. The first is cytoplasmic delivery of siRNA molecules, which are either chemically synthesized or generated by DICER-digestion of dsRNA. These siRNAs are introduced into cells using standard transfection methods. The siRNAs enter the RISC to silence target mRNA expression.

Another mechanism is nuclear delivery, via viral vectors, of gene expression cassettes expressing a short hairpin RNA (shRNA). The shRNA is modeled on micro interfering RNA (miRNA), an endogenous trigger of the RNAi pathway (Lu et al., 2005, Advances in Genetics 54: 117-142, Fewell et al., 2006, Drug Discovery Today 11: 975-982). Conventional shRNAs, which mimic pre-miRNA, are transcribed by RNA Polymerase II or III as single-stranded molecules that form stem-loop structures. Once produced, they exit the nucleus, are cleaved by DICER, and enter the RISC as siRNAs.

Another mechanism is identical to the second mechanism, except that the shRNA is modeled on primary miRNA (shRNAmir), rather than pre-miRNA transcripts (Fewell et al., 2006). An example is the miR-30 miRNA construct. The use of this transcript produces a more physiological shRNA that reduces toxic effects.

The shRNAmir is first cleaved to produce shRNA, and then cleaved again by DICER to produce siRNA. The siRNA is then incorporated into the RISC for target mRNA degradation. However, aspects of the present invention relate to RNAi molecules that do not require DICER cleavage. See, e.g., U.S. Pat. No. 8,273,871, the entire contents of which are incorporated herein by reference.

For mRNA degradation, translational repression, or deadenylation, mature miRNAs or siRNAs are loaded into the RNA Induced Silencing Complex (RISC) by the RISC-loading complex (RLC). Subsequently, the guide strand leads the RISC to cognate target mRNAs in a sequence-specific manner and the Slicer component of RISC hydrolyses the phosphodiester bound coupling the target mRNA nucleotides paired to nucleotide 10 and 11 of the RNA guide strand. Slicer forms together with distinct classes of small RNAs the RNAi effector complex, which is the core of RISC. Therefore, the “guide strand” is that portion of the double-stranded RNA that associates with RISC, as opposed to the “passenger strand,” which is not associated with RISC.

It is not necessary that there be perfect correspondence of the sequences, but the correspondence must be sufficient to enable the RNA to direct RNAi inhibition by cleavage or blocking expression of the target mRNA. In preferred RNA molecules, the number of nucleotides which is complementary to a target sequence is 16 to 29, 18 to 23, or 21-23, or 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

Isolated RNA molecules can mediate RNAi. That is, the isolated RNA molecules of the present invention mediate degradation or block expression of mRNA that is the transcriptional product of the gene. For convenience, such mRNA may also be referred to herein as mRNA to be degraded. The terms RNA, RNA molecule(s), RNA segment(s) and RNA fragment(s) may be used interchangeably to refer to RNA that mediates RNA interference. These terms include double-stranded RNA, small interfering RNA (siRNA), hairpin RNA, single-stranded RNA, isolated RNA (partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA), as well as altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations can include addition of non-nucleotide material, such as to the end(s) of the RNA or internally (at one or more nucleotides of the RNA). Nucleotides in the RNA molecules of the present invention can also comprise nonstandard nucleotides, including non-naturally occurring nucleotides or deoxyribonucleotides. Collectively, all such altered RNAi molecules are referred to as analogs or analogs of naturally-occurring RNA. RNA of the present invention need only be, sufficiently similar to natural RNA that it has the ability to mediate RNAi.

As used herein the phrase “mediate RNAi” refers to and indicates the ability to distinguish which mRNA molecules are to be afflicted with the RNAi machinery or process. RNA that mediates RNAi interacts with the RNAi machinery such that it directs the machinery to degrade particular mRNAs or to otherwise reduce the expression of the target protein. In one embodiment, the present invention relates to RNA molecules that direct cleavage of specific mRNA to which their sequence corresponds. It is not necessary that there be perfect correspondence of the sequences, but the correspondence must be sufficient to enable the RNA to direct RNAi inhibition by cleavage or blocking expression of the target mRNA.

In some embodiments, an RNAi molecule of the invention is introduced into a mammalian cell in an amount sufficient to attenuate target gene expression in a sequence specific manner. The RNAi molecules of the invention can be introduced into the cell directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to the cell. In certain embodiments the RNAi molecule can be a synthetic RNAi molecule, including RNAi molecules incorporating modified nucleotides, such as those with chemical modifications to the 2′-OH group in the ribose sugar backbone, such as 2′-O-methyl (2′OMe), 2′-fluoro (2′F) substitutions, and those containing 2′OMe, or 2′F, or 2′-deoxy, or “locked nucleic acid” (LNA) modifications. In some embodiments, an RNAi molecule of the invention contains modified nucleotides that increase the stability or half-life of the RNAi molecule in vivo and/or in vitro. Alternatively, the RNAi molecule can comprise one or more aptamers, which interact(s) with a target of interest to form an aptamer:target complex. The aptamer can be at the 5′ or the 3′ end of the RNAi molecule. Aptamers can be developed through the SELEX screening process and chemically synthesized. An aptamer is generally chosen to preferentially bind to a target. Suitable targets include small organic molecules, polynucleotides, polypeptides, and proteins. Proteins can be cell surface proteins, extracellular proteins, membrane proteins, or serum proteins, such as albumin. Such target molecules may be internalized by a cell, thus effecting cellular uptake of the shRNA. Other potential targets include organelles, viruses, and cells.

As noted above, the RNA molecules of the present invention in general comprise an RNA portion and some additional portion, for example a deoxyribonucleotide portion. The total number of nucleotides in the RNA molecule is suitably less than in order to be effective mediators of RNAi. In preferred RNA molecules, the number of nucleotides is 16 to 29, more preferably 18 to 23, and most preferably 21-23.

Adenoviral Vector

An adenoviral vector encodes an oligonucleotide. The use of adenoviral vectors in gene therapy and tissue-specific targeting has been described in Beatty and Curiel, 2012, Barnett et al., 2002, and Rots et al., 2003, the contents of which are incorporated herein by reference.

Methods of Administration

“Administering” compounds in embodiments of the invention can be effected or performed using any of the various methods and delivery systems known to those skilled in the art. The administering can be, for example, intravenous, oral intramuscular, intravascular, intra-arterial, intracoronary, intramyocardial, intraperitoneal, and subcutaneous. Other non-limiting examples include topical administration, or coating of a device to be placed within the subject.

Injectable Drug Delivery

Injectable drug delivery systems may be employed in the methods described herein include solutions, suspensions, gels.

Oral Drug Delivery

Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc). Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, zanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives and antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid), anti-caking agents, coating agents, and chelating agents (e.g., EDTA).

For oral administration in liquid dosage form, a gamma-secretase inhibitor may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.

Naked Administration

The compounds used in embodiments of the present invention can be administered by naked administration.

Pharmaceutically Acceptable Carrier

The compounds used in embodiments of the present invention can be administered in a pharmaceutically acceptable carrier. As used herein, a “pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the compounds to the subject. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles are also a pharmaceutically acceptable carrier. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions. Examples of lipid carriers for antisense delivery are disclosed in U.S. Pat. Nos. 5,855,911 and 5,417,978, which are incorporated herein by reference. The compounds used in the methods of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

A compound of the invention can be administered in a mixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone but are generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. In one embodiment the carrier can be a monoclonal antibody. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297, issued Sep. 2, 1975.

Tablets

Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

Specific Administration to Liver

Embodiments of the invention relate to specific administration to the liver or hepatocytes.

In some embodiments, a compound may specifically target the liver.

In some embodiments, a compound may specifically target hepatocytes.

In some embodiments, a compound may be specifically targeted to the liver by coupling the compound to ligand molecules, targeting the compound to a receptor on a hepatic cell, or administering the compound by a bio-nanocapsule.

A compound of the invention can also be administered by coupling of ligand molecules, such as coupling or targeting moieties on preformed nanocarriers, such as (PGA-PLA nanoparticles, PLGA nanoparticles, cyclic RGD-doxorubicin-nanoparticles, and poly(ethylene glycol)-coated biodegradable nanoparticles), by the post-insertion method, by the Avidin-Biotin complex, or before nanocarriers formulation, or by targeting receptors present on various hepatic cell, such as Asialoglycoproein receptor (ASGP-R), HDL-R, LDL-R, IgA-R, Scavenger R, Transferrin R, and Insulin R, as described in: Mishra et al., (2013) Efficient Hepatic Delivery of Drugs: Novel Strategies and Their Significance, BioMed Research International 2013: 382184, dx.doi.org/10.1155/2013/382184, the entire contents of which are incorporated herein by reference.

A compound of the invention can also be administered by bio-nanocapsule, as described in Yu et al., (2005) The Specific delivery of proteins to human liver cells by engineered bio-nanocapsules, FEES Journal 272:3651-3660, dx.doi.org/10.1111/j.1742-4658.2005.04790.x, the entire contents of which are incorporated herein by reference.

In some embodiments, an oligonucleotide specifically, targets the liver.

In some embodiments, an oligonucleotide specifically targets hepatocytes.

Antisense oligonucleotides of the invention can also be targeted to hepatocytes, as described in: Prakash et al., (2014) Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice, Nucleic Acids Research 42(13): 8796-8807, dx.doi.org/10.1093/nar/gku531, the entire contents which are incorporated herein by reference.

As used herein, the term “effective amount” refers to the quantity of a component that is sufficient to treat a subject without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention, i.e. a therapeutically effective amount. The specific effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of subject being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.

Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

The dosage of a compound of the invention administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of the compound and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

A dosage unit of the compounds of the invention may comprise a compound alone, or mixtures of a compound with additional compounds used to treat cancer. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection or other methods, into the eye, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

In an embodiment, the gamma-secretase inhibitor may be administered once a day, twice a day, every other day, once weekly, or twice weekly.

In an embodiment, 0.01 to 1000 mg of a gamma-secretase inhibitor is administered per administration.

A subject's triglyceride level may be expressed herein as plasma triglyceride or serum triglyceride.

A subject's apolipoprotein C3 (ApoC3) level may be expressed herein as plasma ApoC3 or serum ApoC3.

Where a range is given in the specification it is understood that the range includes all integers and 0.1 units within that range, and any sub-range thereof. For example, a range of 1 to 5 is a disclosure of 1.0, 1.1, 1.2, etc.

This invention will be better understood by reference to the Examples which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

EXAMPLE 1

Pharmacologic Notch Inhibition Decreases Blood Glucose in Lean and Obese Mice without Affecting Weight

The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Notch signaling is well-established as critical for cell-cell communication and control of differentiation during normal development. Notch signaling is, frequently upregulated in tumors, and a variety of Notch inhibitors are in clinical development, some as advanced as Phase I/II trials, for cancer. Notch stimulates mTorc1 activity in T-cell leukemia, and reduction in Notch signaling with gamma-secretase inhibitor (GSI) treatment blocks mTorc1 activation, and tumorigenesis, as illustrated in FIG. 1. Gamma-secretase inhibitors (GSIs) are pharmacologic inhibitors of Notch signaling (FIG. 2).

There are interactions between Notch signaling and key metabolic mediators of obesity-related disease, and hepatic Notch signaling is elevated in mouse models and patients with Type 2 Diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). We hypothesized that Notch may reciprocally affect FoxO1- or mTorc1-dependent signaling, and thus carbon flux towards glucose and lipid production, and hypothesized that Notch inhibitors may be repurposed for treatment of diabetes and fatty liver disease.

Lean mice, diet induced obese (DIO) mice, and leptin-deficient obese (ob/ob) mice were administered either vehicle or GSI. GSI treatment decreased blood glucose in lean and obese mice without affecting weight as, shown in Table 1.


TABLE 1
Lean mice, diet induced obese (DIO) mice, and leptin-
deficient obese (ob/ob) mice administered gamma secretase inhibitor
(GSI), dibenzazepine (DBZ). Vehicle control for all experiments is
normal saline containing 0.5% methoxycellulose/0.1% Tween-80.
Weight
Glucose
Insulin
Cohort
Treatment
(grams)
(mg/dl)
(ng/ml)
lean
vehicle
22 ± 0.5
79 ± 4
0.45 ± 0.15
GSI
22 ± 0.6
  64 ± 2***
0.49 ± 0.04
DIO
vehicle
34 ± 0.9
135 ± 12
1.62 ± 1.18
GSI
33 ± 0.7
  72 ± 5***
1.33 ± 0.32
ob/ob
vehicle
49 ± 0.9
313 ± 33
23.2 ± 3.11
GSI
48 ± 0.9
  98 ± 6***
15.6 ± 3.25*
*p < 0.05
**p < 0.01
***p < 0.001 vs. vehicle

GSI (which will be used interchangeably with the specific drug name, dibenzazepine, DBZ) treatment reduced both fasted as well as refed (or exogenous) glucose in DIO mice as compared to vehicle (normal saline containing 0.5% methoxycellulose/0.1% Tween-80) (FIG. 3). Treatment of mice with the gamma-secretase inhibitor, dibenzazepine (DBZ) reduces fasted or refed plasma glucose (FIG. 3 Panel A), and improves glucose clearance (FIG. 3 Panel B).

EXAMPLE 2

GSI Lowers Serum Triglycerides (TG)

Mice were administered GSI or vehicle alone to determine the effect of GSI treatment on serum triglyceride levels.

Mice administered GSI had lower plasma triglycerides than mice administered vehicle alone (FIG. 4). DBZ-treated obese mice, diet-induced obese (DIO) and leptin-deficient obese (ob/ob), show lower plasma triglyceride (TG) as compared to vehicle treatment. Analysis of VLDL, LDL, and HDL fractions showed that GSI lowered triglycerides in the VLDL fraction (FIG. 5). Lower plasma TG levels with low dose DNZ was not associated with apparent gastrointestinal (GI) toxicity (FIG. 6).

DBZ-induced lower plasma TG in diet-induced obese (DIO) and leptin-deficient obese (ob/ob) mice is in the VLDL fraction. GSI treated mice showed normal triglyceride secretion (FIG. 7). Normal plasma TG levels after lipoprotein lipase inhibition with Poloxamer 407 (P407) indicates that DBZ does not affect TG secretion. GSI treated mice showed less plasma triglyceride excursion after lipid gavage compared to mice administered vehicle only (FIG. 8). Lower plasma TG levels after oral olive oil gavage indicates that DBZ increases TG clearance. The combination of these pieces of data (normal TG secretion, less fasted TG and lower TG in serum after gavage) suggests either: (1) Adipose phenotype, i.e., less lipolysis of fat stores, or (2) Liver phenotype, i.e., increased TG uptake from circulation. To differentiate these—we created a liver-specific gamma-secretase knockout mouse.

EXAMPLE 3

Hepatocyte-specific Gamma-secretase Deficiency Reduces Plasma Triglycerides

To elucidate the mechanism of the results of Example 2, a mouse that had gamma-secretase deficiency specifically in hepatocytes was created (Albumin-cre:Nicastrin fl/fl mice, henceforth L-Ncst).

L-Ncst mice showed similar glucose improvement to GSI-treated mice according to glucose tolerance test (GTT) and pyruvate tolerance test (PTT) (FIG. 9). L-Ncst (hepatocyte-specific gamma-secretase knockout) mice showed improved glucose clearance as compared to Cre-control mice, similar GSI-treatment, when challenged with either an intraperitoneal glucose (GTT) or pyruvate (PTT) load.

Chow-fed L-Ncst mice had lower plasma TG (FIG. 10). These data prove that liver γ-secretase is involved in TG clearance from circulation, or in the production of a secreted protein (hepatokine) that alters TG metabolism. Of these, the likeliest target is ApoC3, an apolipoprotein produced exclusively in liver that has been proven to affect TGs. People or mice with ApoC3 deficiency show very low plasma TG, and low risk for coronary disease (CAD). Conversely, excessive production of ApoC3 is associated with high serum TG and excess CAD.

High fat diet (HFD) fed L-Ncst mice had lower refed serum triglycerides compared to control mice (FIG. 11). L-Ncst mice showed lower serum TG compared to Cre-control mice, similar to GSI-treated mice. HFD feeding increased the difference between Cre- and L-Ncst mice in serum TG. Lower p triglycerides were observed in the VLDL fraction (FIG. 12). As with GSI treatment, reduced plasma TG seen in L-Ncst mice as compared to Cre-control mice is in the VLDL fraction. Both fasted, but more markedly refed plasma triglycerides, were lower in L-Ncst mice compared to control mice (FIG. 13). Both fasted and refed serum TG are lower in L-Ncst mice than in Cre-control mice. Triglyceride secretion was unchanged in HFD-fed L-Ncst mice compared to control mice (FIG. 14). As with GSI treatment, comparable serum TG levels after lipoprotein lipase inhibition with Poloxamer 407 (P407) indicates that L-Ncst mice show similar TG secretion as Cre-control mice. As with GSI treatment, serum TG levels after olive oil gavage in L-Ncst mice as compared to Cre-controls proves that L-Ncst mice show increased TG clearance (FIG. 15).

EXAMPLE 4

Lower Serum TG Observed in L-Ncst Mice is by Lower ApoC3

A gene expression analysis of hepatic genes that affect serum triglycerides showed that only Apoc3 expression was altered in the L-Ncst mice (FIG. 16). Serum ApoC3 levels were lower in HFD-fed L-Ncst mice compared to Cre-control mice (FIG. 17). Serum levels of the apolipoprotein ApoC3 levels were lower in both HDL and VLDL fractions in HFD-fed L-Ncst mice compared to Cre-control mice (FIG. 18). Hepatic ApoC3 levels were also decreased in L-Ncst mice compared to control mice (FIG. 19).

In fasted and refed L-Ncst mice, ApoC3 protein expression was decreased in serum and liver compared to fasted and refed control mice (FIG. 20). Serum levels of the apolipoprotein ApoC3 were lower in L-Ncst mice even though liver mRNA and protein for ApoC3 were unaffected. Also, Psen2 protein expression was decreased in liver, but no change in hepatic protein, ApoB100/48 in fasted and refed L-Ncst mice compared to control mice. Correspondingly, there was no change in Apoc3 mRNA in chow-fed L-Ncst mice (FIG. 21).

Serum ApoC3 correlated with plasma TG, but hepatic ApoC3 and Apoc3 mRNA did not correlate with plasma TG (FIG. 22). These data suggest that liver gamma-secretase is involved in either ApoC3 secretion or clearance from circulation, as only serum ApoC3 (but not hepatic Apoc3 mRNA or hepatic ApoC3 protein) are reduced in L-Ncst mice.

EXAMPLE 5

Adenoviral Transduction of Cre-control and L-Ncst Mice and shRNA Mediated Knockdown in Rat Hepatocytes

Liver ApoC3 knockdown (with adeno-delivered shRNA) eliminates difference between HFD-fed Cre- and L-Ncst mice (FIG. 23). Serum, but not hepatic, ApoC3 protein levels correlate with plasma TG. These data prove that lower serum TG observed in L-Ncst mice is by lower ApoC3. Future work will be to determine the mechanism by which this happens.

Adenoviral transduction of L-Ncst mice with ApoC3 increases serum TG to levels comparable to Cre-control mice (FIG. 24). shRNA-mediated knockdown of Nicastrin (sequence of shRNA: CTCCTTCCACAATCGGTATTA SEQ ID NO. 59) in mouse hepatocytes reduces ApoC3 secretion (FIG. 25).

Discussion

Hypertriglyceridemia is not easily treated. Currently available therapies include fibrates (fenofibrate, gemfibrozil) and other less potent triglyceride-lowering agents such as bile acid sequesterants, niacin and statins. Fibrates have been shown to reduce cardiovascular risk, but many patients are unable to reach plasma triglyceride treatment goals with these medications. As such, novel molecular targets to reduce plasma triglycerides have been long-sought.

Recent work has shown that the liver-secreted apolipoprotein, ApoC3, may impact plasma triglyceride levels. Humans with genetic variants that confer partial ApoC3 deficiency, including several Amish and Ashkenazi Jewish populations, exhibit lower plasma triglyceride levels, leading to lower risk of coronary heart disease (Pollin T I, Science, 2008). These human studies have been confirmed with mouse data—ApoC3 knockout mice demonstrate markedly lower plasma triglyceride levels (Jong et, al, J Lipid Res, 2001), whereas mouse models of ApoC3 overexpression given rise to massive hypertriglyceridemia and excess atherosclerosis (Masucci-Magoulas L, et al, Science, 1997). This data was so compelling that various pharmaceutical companies are targeting ApoC3 as a potentially novel means to reduce plasma triglycerides (Gaudet D et al., N Engl J Med, 2014), and hopefully reduce atherosclerosis and consequent coronary heart disease.

The above Examples show that inhibition of the gamma-secretase complex in liver reduces both liver, and circulating ApoC3, leading to lower plasma triglycerides. Gamma-secretase is a enzymatic complex composed of targeting (Nicastrin), catalytic (Presenlin) as well as regulatory subunits (Aph1, PEN2) (Tolia and De Strooper, Semin Cell Dev Biol, 2009). This enzyme is the prototype for intramembrane proteases, and its known targets include Notch receptors, Alzheimer's precursor protein (APP), and others (De Strooper and Annaert, Annu Rev Cel Dev Biol, 2010). Gamma-secretase inhibitors were developed, in part, to reduce APP cleavage to beta-amyloid, in a failed attempt to treat Alzheimer's disease (De Strooper B et al., Nat Rev Neurol, 2010). The present invention provides a new use for GSIs in the treatment of metabolic disease.

It was found that treatment of lean mice reduces plasma triglyceride in a dose-dependent manner. Plasma triglyceride lowering in genetic (leptin deficient ob/ob mice) or diet-induced mouse models of obesity was even more profound, with reductions approaching 75% of vehicle-treated animals. To elucidate the mechanism of this result, we created the L-Ncst mouse that had gamma-secretase deficiency specifically in hepatocytes. L-Ncst mice had similar reductions in plasma triglyceride as GSI-treated mice, proof that the mechanism of GSI-induced reduction in plasma triglyceride is through effects on liver. L-Ncst mice had approximately 40% reduced plasma triglyceride as compared to control mice when fed normal chow, but this rises to a staggering 70% reduction when mice were challenged with high-fat diet feeding. In both GSI-treated and L-Ncst mice, plasma ApoC3 levels were markedly and proportionately reduced to plasma triglyceride lowering, suggesting that this effect is ApoC3-mediated. Interestingly, plasma ApoC3 levels positively correlate with plasma triglyceride, whereas hepatic ApoC3 gene expression or protein levels do not at all. This suggests that reducing plasma ApoC3 levels, not necessarily by reducing liver ApoC3 expression, reduces plasma triglyceride. As such, gamma-secretase inhibition with GSIs or liver-specific gamma-secretase blockers would be predicted to have a greater, and perhaps synergistic, effect in reducing plasma triglyceride as compared to drugs that solely target ApoC3 expression.

It is expected that antagonism of liver or whole-body gamma-secretase in humans will reduce both hepatic and plasma ApoC3 levels, will reduce plasma glucose levels, will reduce plasma triglycerides, and will protect from obesity induced hypertriglyceridemia. As GSI-treated and L-Ncst mice show similar reductions in plasma triglyceride, this implicates gamma-secretase function in the liver as the relevant mechanism underlying this effect. GSIs have significant gut toxicity, leading to dose- and time-dependent goblet cell metaplasia (Milano J et al., Toxicol Sci; Real P J et al., Nature Medicine, 2009). This level of GI toxicity has been deemed acceptable for cancer therapy (Andersson and Lendahl, Nat Rev Drug Disc, 2014), and perhaps even for Alzheimer's Disease (Imbimbo B P et al., Expert Opin Investig Drugs, 2011), but unlikely for chronic treatment of hypertriglyceridemia. As such, liver-specific inhibitors of the gamma-secretase, by methods described above, would be advantageous to maintain efficacy while limiting or even eliminating GI toxicity.

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Gly Arg Thr Ser Arg Ile Ala Gly Leu Ala Val Ser Leu Thr Lys Pro

115 120 125

Ser Pro Ala Ser Gly Phe Ser Pro Ser Val Gln Cys Pro Asn Asp Gly

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145 150 155 160

Glu Ile Gln Trp Asn Ser Leu Gly Asn Gly Leu Ala Tyr Glu Asp Phe

165 170 175

Ser Phe Pro Ile Phe Leu Leu Glu Asp Glu Asn Glu Thr Lys Val Ile

180 185 190

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195 200 205

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Val Ser Tyr Pro Glu Trp Leu Ser Pro Glu Glu Asp Leu Asn Phe Val

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Ala Asn Asn Ser Trp Phe Gln Ser Ile Leu Arg Gln Asp Leu Arg Ser

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Tyr Leu Gly Asp Gly Pro Leu Gln His Tyr Ile Ala Val Ser Ser Pro

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gttccagtct atcctcaggc aggacctaag gtcctacttg ggtgacgggc ctcttcaaca 1800

ttacatcgct gtctccagcc ccaccaacac cacttatgtt gtacagtatg ccttggcaaa 1860

tttgactggc acagtggtca acctcacccg agagcagtgc caggatccaa gtaaagtccc 1920

aagtgaaaac aaggatctgt atgagtactc atgggtccag ggccctttgc attctaatga 1980

gacggaccga ctcccccggt gtgtgcgttc tactgcacga ttagccaggg ccttgtctcc 2040

tgcctttgaa ctgagtcagt ggagctctac tgaatactct acatggactg agagccgctg 2100

gaaagatatc cgtgcccgga tatttctcat cgccagcaaa gagcttgagt tgatcaccct 2160

gacagtgggc ttcggcatcc tcatcttctc cctcatcgtc acctactgca tcaatgccaa 2220

agctgatgtc cttttcattg ctccccggga gccaggagct gtgtcatact gagsaggacc 2280

scagcttttc ttgccagctc agcagttcac ttcctagagc atctgtccca ctgggacaca 2340

accactaatt tgtcactgga acctccctgg gcctgtctca gattgggatt aacataaaag 2400

agtggaacta tccaaaagag acagggagaa ataaataaat tgcctccctt cctccgctcc 2460

cctttcccat caccccttcc ccatttcctc ttccttctct actcatgcca gattttggga 2520

ttacaaatag aagcttcttg ctcctgttta actccctagt tacccaccct aatttgccct 2580

tcaggaccct tctacttttt ccttcctgcc ctgtacctct ctctgctcct cacccccacc 2640

cctgtaccca gccaccttcc tgactgggaa ggacataaaa ggtttaatgt cagggtcaaa 2700

ctacattgag cccctgagga caggggcatc tctgggctga gcctactgtc tccttcccac 2760

tgtcctttct ccaggccctc agatggcaca ttagggtggg cgtgctgcgg gtgggtatcc 2820

cacctccagc ccacagtgct cagttgtact ttttattaag ctgtaatatc tatttttgtt 2880

tttgtctttt tcctttattc tttttgtaaa tatatatata atgagtttca ttaaaataga 2940

ttatcccac 2949

<210> SEQ ID NO: 3

<211> LENGTH: 1912

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 3

ttactccaat tcctatgggc cagagtttgc tcactgcaga gaaatacagt ggaattcgct 60

gggcaatggt ttggcttatg aagactttag tttccccatc tttcttcttg aagatgaaaa 120

tgaaaccaaa gtcatcaagc agaaatcgtc tgtgaccccc tgtctgatta caatgtgtgg 180

agcatgctaa agcctataaa tacaactggg acattaaagc ctgacgacag ggttgtggtt 240

gctgccaccc ggctggatag tcgttccttt ttctggaatg tggccccagg ggctgaaagc 300

gcagtggctt cctttgtcac ccagctggct gctgctgaag ctttgcaaaa ggcacctgat 360

gtgaccaccc tgccccgcaa tgtcatgttt gtcttctttc aaggggaaac ttttgactac 420

attggcagct cgaggatggt ctacgatatg gagaagggca agtttcccgt gcagttagag 480

aatgttgact catttgtgga gctgggacag gtggccttaa gaacttcatt agagctttgg 540

atgcacacag atcctgtttc tcagaaaaat gagtctgtac ggaaccaggt ggaggatctc 600

ctggccacat tggagaagag tggtgctggt gtccctgctg tcatcctcag gaggccaaat 660

cagtcccagc ctctcccacc atcttccctg cagcgatttc ttcgagctcg aaacatctct 720

ggcgttgttc tggctgacca ctctggtgcc ttccataaca aatattacca gagtatttac 780

gacactgctg agaacattaa tgtgagctat cccgaatggc tgagccctga agaggacctg 840

aactttgtaa cagacactgc caaggccctg gcagatgtgg ccacggtgct gggacgtgct 900

ctgtatgagc ttgcaggagg aaccaacttc agcgacacag ttcaggctga tccccaaacg 960

gttacccgcc tgctctatgg gttcctgatt aaagccaaca actcatggtt ccagtctatc 1020

ctcaggcagg acctaaggtc ctacttgggt gacgggcctc ttcaacatta catcgctgtc 1080

tccagcccca ccaacaccac ttatgttgta cagtatgcct tggcaaattt gactggcaca 1140

gtggtcaacc tcacccgaga gcagtgccag gatccaagta aagtcccaag tgaaaacaag 1200

gatctgtatg agtactcatg ggtccagggc cctttgcatt ctaatgagac ggaccgactc 1260

ccccggtgtg tgcgttctac tgcacgatta gccagggcct tgtctcctgc ctttgaactg 1320

agtcagtgga gctctactga atactctaca tggactgaga gccgctggaa agatatccgt 1380

gcccggatat ttctcatcgc cagcaaagag cttgagttga tcaccctgac agtgggcttc 1440

ggcatcctca tcttctccct catcgtcacc tactgcatca atgccaaagc tgatgtcctt 1500

ttcattgttc cccgggagcc aggagctgtg tcatactgag gaggacccca gcttttcttg 1560

ccagctcagc agttcacttc ctagagcatc tgtcccactg ggacacaacc actaatttgt 1620

cactggaacc tccctgggcc tgtctcagat tgggattaac ataaaagagt ggaactatcc 1680

aaaagagaca gggagaaata aataaattgc ctcccttcct ccgctcccct ttcccatcac 1740

cccttcccca tttcctcttc cttctctact catgccagat tttgggatta caaatagaag 1800

cttcttgctc ctgtttaact ccctagttac ccaccctaat ttgcccttca ggacccttct 1860

actttttcct tcctgccctg tacctctctc tgctcctcac ccccacccct gt 1912

<210> SEQ ID NO: 4

<211> LENGTH: 1979

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 4

agagaggcaa gatggctacg gcagggggtg gctctggggc tgacccggga agtcggggtc 60

tccttcgcct tctgtctttc tgcgtcctac tagcaggttt gtgcagggga aactcagtgg 120

agaggaagat atatatcccc ttaaataaaa cagctccctg tgttcgcctg ctcaacgcca 180

ctcatcagat tggctgccag tcttcaatta gtggagacac aggggttatc cacgtagtag 240

agaaagagga ggacctacag tgggtattga ctgatggccc caacccccct tacatggttc 300

tgctggagag caagcatttt accagggatt taatggagaa gctgaaaggg agaaccagcc 360

gaattgctgg tcttgcagtg tccttgacca agcccagtcc tgcctcaggc ttctctccta 420

gtgtacagtg cccaaatgat gggtttggtg tttactccaa ttcctatggg ccagagtttg 480

ctcactgcag agaaatacag tggaattcgc tgggcaatgg tttggcttat gaagacttta 540

gtttccccat ctttcttctt gaagatgaaa atgaaaccaa agtcatcaag caggaaactt 600

ttgactacat tggcagctcg aggatggtct acgatatgga gaagggcaag tttcccgtgc 660

agttagagaa tgttgactca tttgtggagc tgggacaggt ggccttaaga acttcattag 720

agcttttgat gcacacagat cctgtttctc agaaaaatga gtctgtacgg aaccaggtgg 780

aggatctcct ggccacattg gagaagagtg gtgctggtgt ccctgctgtc atcctcagga 840

ggccaaatca gtcccagcct ctcccaccat cttccctgca gcgatttctt cgagctcgaa 900

acatctctgg cgttgttctg gctgaccacc ctggtgcctt ccataacaaa tattaccaga 960

gtatttacga cactgctgag aacattaatg tgagctatcc cgaatggctg agccctgaag 1020

aggacctgaa ctttgtaaca gacactgcca aggccctggc agatgtggcc acggtgctgg 1080

gacgtgctct gtatgagctt gcaggaggaa ccaacttcag cgacacagtt caggctgatc 1140

cccaaacggt tacccgcctg ctctatgggt tcctgattaa agccaacaac tcatggttcc 1200

agtctatcct caggcaggac ctaaggtcct acttgggtga cgggcctctt caacattaca 1260

tcgctgtctc cagccccacc aacaccactt atgttgtaca gtatgccttg gcaaatttga 1320

ctggcacagt ggtcaacctc acccgagagc agtgccagga tccaagtaaa gtcccaagtg 1380

aaaacaagga tctgtatgag tactcatggg tccagggccc tttgcattct aatgagacgg 1440

accgactccc ccggtgtgtg cgttctactg cacgattagc cagggccttg tctcctgcct 1500

ttgaactgag ccagtggagc tctactgaat actctacatg gactgagagc cgctggaaag 1560

atatccgtgc ccggatattt ctcatcgcca gcaaagagct tgagttgatc accctgacag 1620

tgggcttcgg catcctcatc ttctccctca tcgtcaccta ctgcatcaat gccaaagctg 1680

atgtcctttt cattgctccc cgggagccag gagctgtgtc atactgagga ggaccccagc 1740

ttttcttgcc agctcagcag ttcacttcct agagcatctg tcccactggg acacaaccac 1800

taatttgtca ctggaacctc cctgggcctg tctcagattg ggattaacat aaaagagtgg 1860

aactatccaa aagagacagg gagaaataaa taaattgcct cccttcctcc gctccccttt 1920

cccatcaccc cttccccatt tcctcttcct tctctactca tgccagattt tgggattac 1979

<210> SEQ ID NO: 5

<211> LENGTH: 580

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 5

cgctcagcag agaggcaaga tggctacggc agggggtggc tctggggctg acccgggaag 60

tcggggtctc cttcgccttc tgtctttctg cgtcctacta gcaggcctct tcctggactt 120

cgagcctgac cctctcccac tttgtccaga tgtctcgttt ttcccacaac cccagccacc 180

caccccacag tcgaaaggaa caggtgtgaa agttagcttt cttcctcgcg tttagacttt 240

ttgagacgaa agcaatcttg ttctgtgggt gctgtgcggc gcttaaaagg tttgtgcagg 300

ggaaactcag tggagaggaa gatatatatc cccttaaata aaacagctcc ctgtgttcgc 360

ctgctcaacg ccactcatca gattggctgc cagtcttcaa ttagtggaga cacaggggtt 420

atccacgtag tagagaaaga ggaggaccta cagtgggtat tgactgatgg ccccaacccc 480

ccttacatgg ttctgctgga gagcaagcat tttaccaggg atttaatgga gaagctgaaa 540

gggagaacca gccgaattgc tggtcttgca gtgtccttga 580

<210> SEQ ID NO: 6

<211> LENGTH: 2161

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 6

aacgggggct tccgctcagc agagaggcaa gatggctacg gcagggggtg gctctggggc 60

tgacccggga agtcggggtc tccttcgcct tctgtctttc tgcgtcctac tagcaggttt 120

gtgcagggga aactcagtgg agaggaagat atatatcccc ttaaataaaa cagctccctg 180

tgttcgcctg ctcaacgcca ctcatcagat tggctgccag tcttcaatta gtggagacac 240

aggggttatc cacgtagtag agaaagagga ggacctacag tgggtattga ctgatggccc 300

caacccccct tacatggttc tgctggagag caagcatttt accagggatt taatggagaa 360

gctgaaaggg agaaccagcc gaattgctgg tcttgcagtg tccttgacca agcccagtcc 420

tgcctcaggc ttctctccta gtgtacagtg cccaaatgat gggtttggtg tttactccaa 480

ttcctatggg ccagagtttg ctcactgcag agaaatacag tggaattcgc tgggcaatgg 540

tttggcttat gaagacttta gtttccccat ctttcttctt gaagatgaaa atgaaaccaa 600

agtcatcaag cagtgctatc aagatcacaa cctgagtcag aatggctcag caccaacctt 660

cccactatgc gccatgcagc tcttttcaca catgcatgct gtcatcagca ctgccacctg 720

catgcggcgc agctccatcc aaagcacctt cagcatcaac ccagaaatcg tctgtgaccc 780

cctgtctgat tacaatgtgt ggagcatgct aaagcctata aatacaactg ggacattaaa 840

gcctgacgac agggttgtgg ttgctgccac ccggctggat agtcgttcct ttttctggaa 900

tgtggcccca ggggctgaaa gcgcagtggc ttcctttgtc acccagctgg ctgctgctga 960

agctttgcaa aaggcacctg atgtgaccac cctgccccgc aatgtcatgt ttgtcttctt 1020

tcaaggggaa acttttgact acattggcag ctcgaggatg gtctacgata tggagaaggg 1080

caagtttccc gtgcagttag agaatgttga ctcatttgtg gagctgggac aggtggcctt 1140

aagaacttca ttagagcttt ggatgcacac agatcctgtt tctcagaaaa atgagtctgt 1200

acggaaccag gtggaggatc tcctggccac attggagaag agtggtgctg gtgtccctgc 1260

tgtcatcctc aggaggccaa atcagtccca gcctctccca ccatcttccc tgcagcgatt 1320

tcttcgagct cgaaacatct ctggcgttgt tctggctgac cactctggtg ccttccataa 1380

caaatattac cagagtattt acgacactgc tgagaacatt aatgtgagct atcccgaatg 1440

gctgagccct gaagaggacc tgaactttgt aacagacact gccaaggccc tggcagatgt 1500

ggccacggtg ctgggacgtg ctctgtatga gcttgcagga ggaaccaact tcagcgacac 1560

agttcaggct gatccccaaa cggttacccg cctgctctat gggttcctga ttaaagccaa 1620

caactcatgg ttccagtcta tcctcaggca ggacctaagg tcctacttgg gtgacgggcc 1680

tcttcaacat tacatcgctg tctccagccc caccaacacc acttatgttg tacagtatgc 1740

cttggcgaat ttgactggca cagtggtcaa cctcacccga gagcagtgcc aggatccaag 1800

taaagtccca agtgaaaaca aggatctgta tgagtactca tgggtccagg gccctttgca 1860

ttctaatgag acggaccgac tcccccggtg tgtgcgttct actgcacgat tagccagggc 1920

cttgtctcct gcctttgaac tgagtcagtg gagctctact gaatactcta catggactga 1980

gagccgctgg aaagatatcc gtgcccggat atttctcatc gccagcaaag agcttgagtt 2040

gatcaccctg acagtgggct tcggcatcct catcttctcc ctcatcgtca cctactgcat 2100

caatgccaaa gctgatgtcc ttttcattgc tccccgggag ccaggagctg tgtcatactg 2160

a 2161

<210> SEQ ID NO: 7

<211> LENGTH: 2806

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: misc_feature

<222> LOCATION: (2157)..(2157)

<223> OTHER INFORMATION: n is a, c, g, or t

<400> SEQENCE: 7

gatggctacg gcagggggtg gctctggggc tgacccggga agtcggggtc tccttcgcct 60

tctgtctttc tgcgtcctac tagcaggttt gtgcagggga aactcagtgg agaggaagat 120

atatatcccc ttaaataaaa cagctccctg tgttcgcctg ctcaacgcca ctcatcagat 180

tggctgccag tcttcaatta gtggagacac aggggttatc cacgtagtag agaaagagga 240

ggacctacag tgggtattga ctgatggccc caacccccct tacatggttc tgctggagag 300

caagcatttt accagggatt taatggagaa gctgaaaggg agaaccagcc gaattgctgg 360

tcttgcagtg tccttgacca agcccagtcc tgcctcaggc ttctctccta gtgtacagtg 420

cccaaatgat gggtttggtg tttactccaa ttcctatggg ccagagtttg ctcactgcag 480

agaaatacag tggaattcgc tgggcaatgg tttggcttat gaagacttta gtttccccat 540

ctttcttctt gaagatgaaa atgaaaccaa agtcatcaag cagtgctatc aagatcacaa 600

cctgagtcag aatggctcag caccaacctt cccactatgt gccatgcagc tcttttcaca 660

catgcatgct gtcatcagca ctgccacctg catgcggcgc agctccatcc aaagcacctt 720

cagcatcaac ccagaaatcg tctgtgaccc cctgtctgat tacaatgtgt ggagcatgct 780

aaagcctata aatacaactg ggacattaaa gcctgacgac agggttgtgg ttgctgccac 840

ccggctggat agtcgttcct ttttctggaa tgtggcccca ggggctgaaa gcgcagtggc 900

ttcctttgtc acccagctgg ctgctgctga agctttgcaa aaggcacctg atgtgaccac 960

cctgccccgc aatgtcatgt ttgtcttctt tcaaggggaa acttttgact acattggcag 1020

ctcgaggatg gtctacgata tggagaaggg caagtttccc gtgcagttag agaatgttga 1080

ctcatttgtg gagctgggac aggtggcctt aagaacttca ttagagcttt ggatgcacac 1140

agatcctgtt tctcagaaaa atgagtctgt acggaaccag gtggaggatc tcctggccac 1200

attggagaag agtggtgctg gtgtccctgc tgtcatcctc aggaggccaa atcagtccca 1260

gcctctccca ccatcttccc tgcagcgatt tcttcgagct cgaaacatct ctggcgttgt 1320

tctggctgac cactctggtg ccttccataa caaatattac cagagtattt acgacactgc 1380

tgagaacatt aatgtgagct atcccgaatg gctgagccct gaagaggacc tgaactttgt 1440

aacagacact gccaaggccc tggcagatgt ggccacggtg ctgggacgtg ctctgtatga 1500

gcttgcagga ggaaccaact tcagcgacac agttcaggct gatccccaaa cggttacccg 1560

cctgctctat gggttcctga ttaaagccaa caactcatgg ttccagtcta tcctcaggca 1620

ggacctaagg tcctacttgg gtgacgggcc tcttcaacat tacatcgctg tctccagccc 1680

caccaacacc acttatgttg tacagtatgc cttggcaaat ttgactggca cagtggtcaa 1740

cctcacccga gagcagtgcc aggatccaag taaagtccca agtgaaaaca aggatctgta 1800

tgagtactca tgggtccagg gccctttgca ttctaatgag acggaccgac tcccccggtg 1860

tgtgcgttct actgcacgat tagccagggc cttgtctcct gcctttgaac tgagtcagtg 1920

gagctctact gaatactcta catggactga gagccgctgg aaagatatcc gtgcccggat 1980

atttctcatc gccagcaaag agcttgagtt gatcaccctg acagtgggct tcggcatcct 2040

catcttctcc ctcatcgtca cctactgcat caatgccaaa gctgatgtcc ttttcattgc 2100

tccccgggag ccaggagctg tgtcatactg aggaggaccc cagcttttct tgccagntca 2160

gcagttcact tcctagagca tctgtcccac tgggacacaa ccactaattt gtcactggaa 2220

cctccctggg cctgtctcag attgggatta acataaaaga gtggaactat ccaaaagaga 2280

cagggagaaa taaataaatt gcctcccttc ctccgctccc ctttcccatc accccttccc 2340

catttcctct tccttctcta ctcatgccag attttgggat tacaaataga agcttcttgc 2400

tcctgtttaa ctccctagtt acccacccta atttgccctt caggaccctt ctactttttc 2460

cttcctgccc tgtacctctc tctgctcctc acccccaccc ctgtacccag ccaccttcct 2520

gactgggaag gacataaaag gtttaatgtc agggtcaaac tacattgagc ccctgaggac 2580

aggggcatct ctgggctgag cctactgtct ccttcccact gtcctttctc caggccctca 2640

gatggcacat tagggtgggc gtgctgcggg tgggtatccc acctccagcc cacagtgctc 2700

agttgtactt tttattaagc tgtaatatct atttttgttt ttgtcttttt cctttattct 2760

ttttgtaaat atatatataa tgagtttcat taaaatagat tatccc 2806

<210> SEQ ID NO: 8

<211> LENGTH: 3041

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 8

agagacggtg tcagtggtag cctagagagg ccgctaacag acaggagccg aacgggggct 60

tccgctcagc agagaggcaa gatggctacg gcagggggtg gctctggggc tgacccggga 120

agtcggggtc tccttcgcct tctgtctttc tgcgtcctac tagcagtgtc actgtcaatg 180

gcgctacatg gactttgtaa taaccctttg aggcacatag ctgggtgcca tgtagaacat 240

gtatctgtta cgataagtgt gtgcccaaga aatcagaaga atggacttta atctcatttt 300

agaaagtttg tgcaggggaa actcagtgga gaggaagata tatatcccct taaataaaac 360

agctccctgt gttcgcctgc tcaacgccac tcatcagatt ggctgccagt cttcaattag 420

tggagacaca ggggttatcc acgtagtaga gaaagaggag gacctacagt gggtattgac 480

tgatggcccc aacccccctt acatggttct gctggagagc aagcatttta ccagggattt 540

aatggagaag ctgaaaggga gaaccagccg aattgctggt cttgcagtgt ccttgaccaa 600

gcccagtcct gcctcaggct tctctcctag tgtacagtgc ccaaatgatg ggtttggtgt 660

ttactccaat tcctatgggc cagagtttgc tcactgcaga gaaatacagt ggaattcgct 720

gggcaatggt ttggcttatg aagactttag tttccccatc tttcttcttg aagatgaaaa 780

tgaaaccaaa gtcatcaagc agtgctatca agatcacaac ctgagtcaga atggctcagc 840

accaaccttc ccactatgtg ccatgcagct cttttcacac atgcatgctg tcatcagcac 900

tgccacctgc atgcggcgca gctccatcca aagcaccttc agcatcaacc cagaaatcgt 960

ctgtgacccc ctgtctgatt acaatgtgtg gagcatgcta aagcctataa atacaactgg 1020

gacattaaag cctgacgaca gggttgtggt tgctgccacc cggctggata gtcgttcctt 1080

tttctggaat gtggccccag gggctgaaag cgcagtggct tcctttgtca cccagctggc 1140

tgctgctgaa gctttgcaaa aggcacctga tgtgaccacc ctgccccgca atgtcatgtt 1200

tgtcttcttt caaggggaaa cttttgacta cattggcagc tcgaggatgg tctacgatat 1260

ggagaagggc aagtttcccg tgcagttaga gaatgttgac tcatttgtgg agctgggaca 1320

ggtggcctta agaacttcat tagagctttg gatgcacaca gatcctgttt ctcagaaaaa 1380

tgagtctgta cggaaccagg tggaggatct cctggccaca ttggagaaga gtggtgctgg 1440

tgtccctgct gtcatcctca ggaggccaaa tcagtcccag cctctcccac catcttccct 1500

gcagcgattt cttcgagctc gaaacatctc tggcgttgtt ctggctgacc actctggtgc 1560

cttccataac aaatattacc agagtattta cgacactgct gagaacatta atgtgagcta 1620

tcccgaatgg ctgagccctg aagaggacct gaactttgta acagacactg ccaaggccct 1680

ggcagatgtg gccacggtgc tgggacgtgc tctgtatgag cttgcaggag gaaccaactt 1740

cagcgacaca gttcaggctg atccccaaac ggttacccgc ctgctctatg ggttcctgat 1800

taaagccaac aactcatggt tccagtctat cctcaggcag gacctaaggt cctacttggg 1860

tgacgggcct cttcaacatt acatcgctgt ctccagcccc accaacacca cttatgttgt 1920

acagtatgcc ttggcaaatt tgactggcac agtggtcaac ctcacccgag agcagtgcca 1980

ggatccaagt aaagtcccaa gtgaaaacaa ggatctgtat gagtactcat gggtccaggg 2040

ccctttgcat tctaatgaga cggaccgact cccccggtgt gtgcgttcta ctgcacgatt 2100

agccagggcc ttgtctcctg cctttgaact gagtcagtgg agctctactg aatactctac 2160

atggactgag agccgctgga aagatatcca tgcccggata tttctcatcg ccagcaaaga 2220

gcttgagttg atcaccctga cagtgggctt cggcatcctc atcttctccc tcatcgtcac 2280

ctactgcatc aatgccaaag ctgatgtcct tttcattgct ccccgggagc caggagctgt 2340

gtcatactga ggaggacccc agcttttctt gccagctcag cagttcactt cctagagcat 2400

ctgtcccact gggacacaac cactaatttg tcactggaac ctccctgggc ctgtctcaga 2460

ttgggattaa cataaaagag tggaactatc caaaagagac agggagaaat aaataaattg 2520

cctcccttcc tccgctcccc tttcccatca ccccttcccc atttcctctt ccttctctac 2580

tcatgccaga ttttgggatt acaaatagaa gcttcttgct cctgtttaac tccctagtta 2640

cccaccctaa tttgcccttc aggacccttc tactttttcc ttcctgccct gtacctctct 2700

ctgctcctca cccccacccc tgtacccagc caccttcctg actgggaagg acataaaagg 2760

tttaatgtca gggtcaaact acattgagcc cctgaggaca ggggcatctc tgggctgagc 2820

ctactgtctc cttcccactg tcctttctcc aggccctcag atggcacatt agggtgggcg 2880

tgctgcgggt gggtatccca cctccagccc acagtgctca gttgtacttt ttattaagct 2940

gtaatatcta tttttgtttt tgtctttttc ctttattctt tttgtaaata tatatataat 3000

gagtttcatt aaaatagatt atcccaaaaa aaaaaaaaaa a 3041

<210> SEQ ID NO: 9

<211> LENGTH: 2821

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 9

tggctacggc agggggtggc tctggggctg acccgggaag tcggggtctc cttcgccttc 60

tgtctttctg cgtcctacta gcaggtttgt gcaggggaaa ctcagtggag aggaagatat 120

atatcccctt aaataaaaca gctccctgtg ttcgcctgct caacgccact catcagattg 180

gctgccagtc ttcaattagt ggagacacag gggttatcca cgtagtagag aaagaggagg 240

acctacagtg ggtattgact gatggcccca acccccctta catggttctg ctggagagca 300

agcattttac cagggattta atggagaagc tgaaagggag aaccagccga attgctggtc 360

ttgcagtgtc cttgaccaag cccagtcctg cctcaggctt ctctcctagt gtacagtgcc 420

caaatgatgg gtttggtgtt tactccaatt cctatgggcc agagtttgct cactgcagag 480

aaatacagtg gaattcgctg ggcaatggtt tggcttatga agactttagt ttccccatct 540

ttcttcttga agatgaaaat gaaaccaaag tcatcaagca gtgctatcaa gatcacaacc 600

tgagtcagaa tggctcagca ccaaccttcc cactatgtgc catgcagctc ttttcacaca 660

tgcatgctgt catcagcact gccacctgca tgcggcgcag ctccatccaa agcaccttca 720

gcatcaaccc agaaatcgtc tgtgaccccc tgtctgatta caatgtgtgg agcatgctaa 780

agcctataaa tacaactggg acattaaagc ctgacgacag ggttgtggtt gctgccaccc 840

ggctggatag tcgttccttt ttctggaatg tggccccagg ggctgaaagc gcagtggctt 900

cctttgtcac ccagctggct gctgctgaag ctttgcaaaa ggcacctgat gtgaccaccc 960

tgccccgcaa tgtcatgttt gtcttctttc aaggggaaac ttttgactac attggcagct 1020

cgaggatggt ctacgatgga gaagggcaag tttcccgtgc agttagagaa tgttgactca 1080

tttgtggagc tgggacaggt ggccttaaga acttcattag agctttggat gcacacagat 1140

cctgtttctc agaaaaatga gtctgtacgg aaccaggtgg aggatctcct ggccacattg 1200

gagaagagtg gtgctggtgt ccctgctgtc atcctcagga ggccaaatca gtcccagcct 1260

ctcccaccat cttccctgca gcgatttctt cgagctcgaa acatctctgg cgttgttctg 1320

gctgaccact ctggtgcctt ccataacaaa tattaccaga gtatttacga cactgctgag 1380

aacattaatg tgagctatcc cgaatggctg agccctgaag aggacctgaa ctttgtaaca 1440

gacactgcca aggccctggc agatgtggcc acggtgctgg gacgtgctct gtatgagctt 1500

gcaggaggaa ccaacttcag cgacacagtt caggctgatc cccaaacggt tacccgcctg 1560

ctctatgggt tcctgattaa agccaacaac tcatggttcc agtctatcct caggcaggac 1620

ctaaggtcct acttgggtga cgggcctctt caacattaca tcgctgtctc cagccccacc 1680

aacaccactt atgttgtaca gtatgccttg gcaaatttga ctggcacagt ggtcaacctc 1740

acccgagagc agtgccagga tccaagtaaa gtcccaagtg aaaacaagga tctgtatgag 1800

tactcatggg tccagggccc tttgcattct aatgagacgg accgactccc ccggtgtgtg 1860

cgttctactg cacgattagc cagggccttg tctcctgcct ttgaactgag tcagtggagc 1920

tctactgaat actctacatg gactgagagc cgctggaaag atatccgtgc ccggatattt 1980

ctcatcgcca gcaaagagct tgagttgatc accctgacag tgggcttcgg catcctcatc 2040

ttctccctca tcgtcaccta ctgcatcaat gccaaagctg atgtcctttt cattgctccc 2100

cgggagccag gagctgtgtc atactgagga ggaccccagc ttttcttgcc agctcagcag 2160

ttcacttcct agagcatctg tcccactggg acacaaccac taatttgtca ctggaacctc 2220

cctgggcctg tctcagattg ggattaacat aaaagagtgg aactatccaa aagagacagg 2280

gagaaataaa taaattgcct cccttcctcc gctccccttt cccatcaccc cttccccatt 2340

tcctcttcct tctctactca tgccagattt tgggattaca aatagaagct tcttgctcct 2400

gtttaactcc ctagttaccc accctaattt gcccttcagg acccttctac tttttccttc 2460

ctgccctgta cctctctctg ctcctcaccc ccacccctgt acccagccac cttcctgact 2520

gggaaggaca taaaaggttt aatgtcaggg tcaaactaca ttgagcccct gaggacaggg 2580

gcatctctgg gctgagccta ctgtctcctt cccactgtcc tttctccagg ccctcagatg 2640

gcacattagg gtgggcgtgc tgcgggtggg tatcccacct ccagcccaca gtgctcagtt 2700

gtacttttta ttaagctgta atatctattt ttgtttttgt ctttttcctt tattcttttt 2760

gtaaatatat atataatgag tttcattaaa atagattatc ccaaaaaaaa aaaaaaaaaa 2820

a 2821

<210> SEQ ID NO: 10

<211> LENGTH: 557

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 10

aactatccaa aagagacagg gagaaataaa taaattgcct cccttcctcc gctccccttt 60

cccatcaccc cttccccatt tcctcttcct tctctactca tgccagattt tgggattaca 120

aatagaagct tcttgctcct gtttaactcc ctagttaccc accctaattt gcccttcagg 180

acccttctac tttttccttc ctgccctgta cctctctctg ctcctcaccc ccacccctgt 240

acccagccac cttcctgact gggaaggaca taaaaggttt aatgtcaggg tcaaactaca 300

ttgagcccct gaggacaggg gcatctctgg gctgagccta ctgtctcctt cccactgtcc 360

tttctccagg ccctcagatg gcacattagg gtgggcgtgc tgcgggtggg tatcccacct 420

ccagcccaca gtgctcagtt gtacttttta ttaagctgga atatctattt ttgtttttgt 480

ctttttcctt tattcttttt gtaaatatat atataatgag tttcattaaa atagattatc 540

ccacacgaaa aaaaaaa 557

<210> SEQ ID NO: 11

<211> LENGTH: 2805

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 11

ggctacggca gggggtggct ctggggctga cccgggaagt cggggtctcc ttcgccttct 60

gtctttctgc gtcctactag caggtttgtg caggggaaac tcagtggaga ggaagatata 120

tatcccctta aataaaacag ctccctgtgt tcgcctgctc aacgccactc atcagattgg 180

ctgccagtct tcaattagtg gagacacagg ggttatccac gtagtagaga aagaggagga 240

cctacagtgg gtattgactg atggccccaa ccccccttac atggttctgc tggagagcaa 300

gcattttacc agggatttaa tggagaagct gaaagggaga accagccgaa ttgctggtct 360

tgcagtgtcc ttgaccaagc ccagtcctgc ctcaggcttc tctcctagtg tacagtgccc 420

aaatgatggg tttggtgttt actccaattc ctatgggcca gagtttgctc actgcagaga 480

aatacagtgg aattcgctgg gcaatggttt ggcttatgaa gactttagtt tccccatctt 540

tcttcttgaa gatgaaaatg aaaccaaagt catcaagcag tgctatcaag atcacaacct 600

gagtcagaat ggctcagcac caaccttccc actatgtgcc atgcagctct tttcacacat 660

gcatgctgtc atcagcactg ccacctgcat gcggcgcagc tccatccaaa gcaccttcag 720

catcaaccca gaaatcgtct gtgaccccct gtctgattac aatgtgtgga gcatgctaaa 780

gcctataaat acaactggga cattaaagcc tgacgacagg gttgtggttg ctgccacccg 840

gctggatagt cgttcctttt tctggaatgt ggccccaggg gctgaaagcg cagtggcttc 900

ctttgtcacc cagctggctg ctgctgaagc tttgcaaaag gcacctgatg tgaccaccct 960

gccccgcaat gtcatgtttg tcttctttca aggggaaact tttgactaca ttggcagctc 1020

gaggatggtc tacgatatgg agaagggcaa gtttcccgtg cagttagaga atgttgactc 1080

atttgtggag ctgggacagg tggccttaag aacttcatta gagctttgga tgcacacaga 1140

tcctgtttct cagaaaaatg agtctgtacg gaaccaggtg gaggatctcc tggccacatt 1200

ggagaagagt ggtgctggtg tccctgctgt catcctcagg aggccaaatc agtcccagcc 1260

tctcccacca tcttccctgc agcgatttct tcgagctcga aacatctctg gcgttgttct 1320

ggctgaccac tctggtgcct tccataacaa atattaccag agtatttacg acactgctga 1380

gaacattaat gtgagctatc ccgaatggct gagccctgaa gaggacctga actttgtaac 1440

agacactgcc aaggccctgg cagatgtggc cacggtgctg ggacgtgctc tgtatgagct 1500

tgcaggagga accaacttca gcgacacagt tcaggctgat ccccaaacgg ttacccgcct 1560

gctctatggg ttcctgatta aagccaacaa ctcatggttc cagtctatcc tcaggcagga 1620

cctaaggtcc tacttgggtg acgggcctct tcaacattac atcgctgtct ccagccccac 1680

caacaccact tatgttgtac agtatgcctt ggcaaatttg actggcacag tggtcaacct 1740

cacccgagag cagtgccagg atccaagtaa agtcccaagt gaaaacaagg atctgtatga 1800

gtactcatgg gtccagggcc ctttgcattc taatgagacg gaccgactcc cccggtgtgt 1860

gcgttctact gcacgattag ccagggcctt gtctcctgcc tttgaactga gtcagtggag 1920

ctctactgaa tactctacat ggactgagag ccgctggaaa gatatccgtg cccggatatt 1980

tctcatcgcc agcaaagagc ttgagttgat caccctgaca gtgggcttcg gcatcctcat 2040

cttctccctc atcgtcacct actgcatcaa tgccaaagct gatgtccttt tcattgctcc 2100

ccgggagcca ggagctgtgt catactgagg aggaccccag cttttcttgc cagctcagca 2160

gttcacttcc tagagcatct gtcccactgg gacacaacca ctaatttgtc actggaacct 2220

ccctgggcct gtctcagatt gggattaaca taaaagagtg gaactatcca aaagagacag 2280

ggagaaataa ataaattgcc tcccttcctc cgctcccctt tcccatcacc ccttccccat 2340

ttcctcttcc ttctctactc atgccagatt ttgggattac aaatagaagc ttcttgctcc 2400

tgtttaactc cctagttacc caccctaatt tgcccttcag gacccttcta ctttttcctt 2460

cctgccctgt acctctctct gctcctcacc cccacccctg tacccagcca ccttcctgac 2520

tgggaaggac ataaaaggtt taatgtcagg gtcaaactac attgagcccc tgaggacagg 2580

ggcatctctg ggctgagcct actgtctcct tcccactgtc ctttctccag gccctcagat 2640

ggcacattag ggtgggcgtg ctgcgggtgg gtatcccacc tccagcccac agtgctcagt 2700

tgtacttttt attaagctgt aatatctatt tttgtttttg tctttttcct ttattctttt 2760

tgtaaatata tatataatga gtttcattaa aatagattat cccac 2805

<210> SEQ ID NO: 12

<211> LENGTH: 467

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 12

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Val Arg Ser Gln Asn Asp Asn

20 25 30

Arg Glu Arg Gln Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu

35 40 45

Pro Leu Ser Asn Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu

50 55 60

Gln Asp Glu Glu Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys

65 70 75 80

His Val Ile Met Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val

85 90 95

Val Ala Thr Ile Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln

100 105 110

Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg

115 120 125

Ala Leu His Ser Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val

130 135 140

Val Met Thr Ile Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys

145 150 155 160

Val Ile His Ala Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe

165 170 175

Phe Ser Phe Ile Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala

180 185 190

Val Asp Tyr Ile Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val

195 200 205

Gly Met Ile Ser Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala

210 215 220

Tyr Leu Ile Met Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr

225 230 235 240

Leu Pro Glu Trp Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr

245 250 255

Asp Leu Val Ala Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val

260 265 270

Glu Thr Ala Gln Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr

275 280 285

Ser Ser Thr Met Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu

290 295 300

Ala Gln Arg Arg Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Ser Thr

305 310 315 320

Glu Arg Glu Ser Gln Asp Thr Val Ala Glu Asn Asp Asp Gly Gly Phe

325 330 335

Ser Glu Glu Trp Glu Ala Gln Arg Asp Ser His Leu Gly Pro His Arg

340 345 350

Ser Thr Pro Glu Ser Arg Ala Ala Val Gln Glu Leu Ser Ser Ser Ile

355 360 365

Leu Ala Gly Glu Asp Pro Glu Glu Arg Gly Val Lys Leu Gly Leu Gly

370 375 380

Asp Phe Ile Phe Tyr Ser Val Leu Val Gly Lys Ala Ser Ala Thr Ala

385 390 395 400

Ser Gly Asp Trp Asn Thr Thr Ile Ala Cys Phe Val Ala Ile Leu Ile

405 410 415

Gly Leu Cys Leu Thr Leu Leu Leu Leu Ala Ile Phe Lys Lys Ala Leu

420 425 430

Pro Ala Leu Pro Ile Ser Ile Thr Phe Gly Leu Val Phe Tyr Phe Ala

435 440 445

Thr Asp Tyr Leu Val Gln Pro Phe Met Asp Gln Leu Ala Phe His Gln

450 455 460

Phe Tyr Ile

465

<210> SEQ ID NO: 13

<211> LENGTH: 378

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 13

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Val Arg Ser Gln Asn Asp Asn

20 25 30

Arg Glu Arg Gln Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu

35 40 45

Pro Leu Ser Asn Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu

50 55 60

Gln Asp Glu Glu Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys

65 70 75 80

His Val Ile Met Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val

85 90 95

Val Ala Thr Ile Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln

100 105 110

Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Gly

115 120 125

Ala Leu His Ser Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val

130 135 140

Val Met Thr Ile Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys

145 150 155 160

Val Ile His Ala Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe

165 170 175

Phe Ser Phe Ile Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala

180 185 190

Val Asp Tyr Ile Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val

195 200 205

Gly Met Ile Ser Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala

210 215 220

Tyr Leu Ile Met Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr

225 230 235 240

Leu Pro Glu Trp Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr

245 250 255

Asp Leu Val Ala Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val

260 265 270

Glu Thr Ala Gln Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr

275 280 285

Ser Ser Thr Met Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu

290 295 300

Ala Gln Arg Arg Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Arg Ala

305 310 315 320

Cys Leu Pro Pro Ala Ala Ile Asn Leu Leu Ser Ile Ala Pro Met Ala

325 330 335

Pro Arg Leu Phe Met Pro Lys Gly Ala Cys Arg Pro Thr Ala Gln Lys

340 345 350

Gly Ser His Lys Thr Leu Leu Gln Arg Met Met Met Ala Gly Ser Val

355 360 365

Arg Asn Gly Lys Pro Arg Gly Thr Val Ile

370 375

<210> SEQ ID NO: 14

<211> LENGTH: 184

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 14

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Val Arg Ser Gln Asn Asp Asn

20 25 30

Arg Glu Arg Gln Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu

35 40 45

Pro Leu Ser Asn Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu

50 55 60

Gln Asp Glu Glu Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys

65 70 75 80

His Val Ile Met Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val

85 90 95

Val Ala Thr Ile Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln

100 105 110

Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg

115 120 125

Ala Leu His Ser Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val

130 135 140

Val Met Thr Ile Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys

145 150 155 160

Val Ser Met Arg His Arg Ser Leu Leu Ser Thr Leu Phe Phe Leu Trp

165 170 175

Leu Gly Ile Leu Val Thr Val Thr

180

<210> SEQ ID NO: 15

<211> LENGTH: 463

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 15

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Asn Asp Asn Arg Glu Arg Gln

20 25 30

Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu Pro Leu Ser Asn

35 40 45

Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu Gln Asp Glu Glu

50 55 60

Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys His Val Ile Met

65 70 75 80

Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val Val Ala Thr Ile

85 90 95

Lys Ser Val Ser Phe Tyr Thr Pro Lys Asp Gly Gln Leu Ile Tyr Thr

100 105 110

Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg Ala Leu His Ser

115 120 125

Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val Val Met Thr Ile

130 135 140

Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys Val Ile His Ala

145 150 155 160

Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe Phe Ser Phe Ile

165 170 175

Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala Val Asp Tyr Ile

180 185 190

Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val Gly Met Ile Ser

195 200 205

Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala Tyr Leu Ile Met

210 215 220

Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp

225 230 235 240

Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr Asp Leu Val Ala

245 250 255

Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val Glu Thr Ala Gln

260 265 270

Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr Ser Ser Thr Met

275 280 285

Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Gly Ala Gln Arg Arg

290 295 300

Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Ser Thr Glu Arg Glu Ser

305 310 315 320

Gln Asp Thr Val Ala Glu Asn Asp Asp Gly Gly Phe Ser Glu Glu Trp

325 330 335

Glu Ala Gln Arg Asp Ser His Leu Gly Pro His Arg Ser Thr Pro Glu

340 345 350

Ser Arg Ala Ala Val Gln Glu Leu Ser Ser Ser Ile Leu Ala Gly Glu

355 360 365

Asp Pro Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile Phe

370 375 380

Tyr Ser Val Leu Val Gly Lys Ala Ser Ala Thr Ala Ser Gly Asp Trp

385 390 395 400

Asn Thr Thr Ile Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys Leu

405 410 415

Thr Leu Leu Leu Leu Ala Ile Phe Lys Lys Ala Leu Pro Ala Leu Pro

420 425 430

Ile Ser Ile Thr Phe Gly Leu Val Phe Tyr Phe Ala Thr Asp Tyr Leu

435 440 445

Val Gln Pro Phe Met Asp Gln Leu Ala Phe His Gln Phe Tyr Ile

450 455 460

<210> SEQ ID NO: 16

<211> LENGTH: 264

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 16

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Asn Asp Asn Arg Glu Arg Gln

20 25 30

Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu Pro Leu Ser Asn

35 40 45

Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu Gln Asp Glu Glu

50 55 60

Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys His Val Ile Met

65 70 75 80

Leu Phe Val Pro Val Thr Leu Cys Met Val Trp Leu Val Asn Met Ala

85 90 95

Glu Gly Asn Pro Glu Ala Gln Arg Arg Val Ser Lys Asn Ser Lys Tyr

100 105 110

Asn Ala Glu Ser Thr Glu Arg Glu Ser Gln Asp Thr Val Ala Glu Asn

115 120 125

Asp Asp Gly Gly Phe Ser Glu Glu Trp Glu Ala Gln Arg Asp Ser His

130 135 140

Leu Gly Pro His Arg Ser Thr Pro Glu Ser Arg Ala Ala Val Gln Glu

145 150 155 160

Leu Ser Ser Ser Ile Leu Ala Gly Glu Asp Pro Glu Glu Arg Gly Val

165 170 175

Lys Leu Gly Leu Gly Asp Phe Ile Phe Tyr Ser Val Leu Val Gly Lys

180 185 190

Ala Ser Ala Thr Ala Ser Gly Asp Trp Asn Thr Thr Ile Ala Cys Phe

195 200 205

Val Ala Ile Leu Ile Gly Leu Cys Leu Thr Leu Leu Leu Leu Ala Ile

210 215 220

Phe Lys Lys Ala Leu Pro Ala Leu Pro Ile Ser Ile Thr Phe Gly Leu

225 230 235 240

Val Phe Tyr Phe Ala Thr Asp Tyr Leu Val Gln Pro Phe Met Asp Gln

245 250 255

Leu Ala Phe His Gln Phe Tyr Ile

260

<210> SEQ ID NO: 17

<211> LENGTH: 467

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 17

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Val Arg Ser Gln Asn Asp Asn

20 25 30

Arg Glu Arg Gln Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu

35 40 45

Pro Leu Ser Asn Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu

50 55 60

Gln Asp Glu Glu Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys

65 70 75 80

His Val Ile Met Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val

85 90 95

Val Ala Thr Ile Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln

100 105 110

Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg

115 120 125

Ala Leu His Ser Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val

130 135 140

Val Met Thr Ile Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys

145 150 155 160

Val Ile His Ala Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe

165 170 175

Phe Ser Phe Ile Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala

180 185 190

Val Asp Tyr Ile Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val

195 200 205

Gly Met Ile Ser Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala

210 215 220

Tyr Leu Ile Met Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr

225 230 235 240

Leu Pro Glu Trp Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr

245 250 255

Asp Leu Val Ala Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val

260 265 270

Glu Thr Ala Gln Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr

275 280 285

Ser Ser Thr Met Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu

290 295 300

Ala Gln Arg Arg Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Ser Thr

305 310 315 320

Glu Arg Glu Ser Gln Asp Thr Val Ala Glu Asn Asp Asp Gly Gly Phe

325 330 335

Ser Glu Glu Trp Glu Ala Gln Arg Asp Ser His Leu Gly Pro His Arg

340 345 350

Ser Thr Pro Glu Ser Arg Ala Ala Val Gln Glu Leu Ser Ser Ser Ile

355 360 365

Leu Ala Gly Glu Asp Pro Glu Glu Arg Gly Val Lys Leu Gly Leu Gly

370 375 380

Asp Phe Ile Phe Tyr Ser Val Leu Val Gly Lys Ala Ser Ala Thr Ala

385 390 395 400

Ser Gly Asp Trp Asn Thr Thr Ile Ala Cys Phe Val Ala Ile Leu Ile

405 410 415

Gly Leu Cys Leu Thr Leu Leu Leu Leu Ala Ile Phe Lys Lys Ala Leu

420 425 430

Pro Ala Leu Pro Ile Ser Ile Thr Phe Gly Leu Val Phe Tyr Phe Ala

435 440 445

Thr Asp Tyr Leu Val Gln Pro Phe Met Asp Gln Leu Ala Phe His Gln

450 455 460

Phe Tyr Ile

465

<210> SEQ ID NO: 18

<211> LENGTH: 463

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 18

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Asn Asp Asn Arg Glu Arg Gln

20 25 30

Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu Pro Leu Ser Asn

35 40 45

Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu Gln Asp Glu Glu

50 55 60

Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys His Val Ile Met

65 70 75 80

Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val Val Ala Thr Ile

85 90 95

Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln Leu Ile Tyr Thr

100 105 110

Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg Ala Leu His Ser

115 120 125

Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val Val Met Thr Ile

130 135 140

Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys Val Ile His Ala

145 150 155 160

Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe Phe Ser Phe Ile

165 170 175

Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala Val Asp Tyr Ile

180 185 190

Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val Gly Met Ile Ser

195 200 205

Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala Tyr Leu Ile Met

210 215 220

Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp

225 230 235 240

Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr Asp Leu Val Ala

245 250 255

Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val Glu Thr Ala Gln

260 265 270

Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr Ser Ser Thr Met

275 280 285

Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu Ala Gln Arg Arg

290 295 300

Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Ser Thr Glu Arg Glu Ser

305 310 315 320

Gln Asp Thr Val Ala Glu Asn Asp Asp Gly Gly Phe Ser Glu Glu Trp

325 330 335

Glu Ala Gln Arg Asp Ser His Leu Gly Pro His Arg Ser Thr Pro Glu

340 345 350

Ser Arg Ala Ala Val Gln Glu Leu Ser Ser Ser Ile Leu Ala Gly Glu

355 360 365

Asp Pro Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile Phe

370 375 380

Tyr Ser Val Leu Val Gly Lys Ala Ser Ala Thr Ala Ser Gly Asp Trp

385 390 395 400

Asn Thr Thr Ile Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys Leu

405 410 415

Thr Leu Leu Leu Leu Ala Ile Phe Lys Lys Ala Leu Pro Ala Leu Pro

420 425 430

Ile Ser Ile Thr Phe Gly Leu Val Phe Tyr Phe Ala Thr Asp Tyr Leu

435 440 445

Val Gln Pro Phe Met Asp Gln Leu Ala Phe His Gln Phe Tyr Ile

450 455 460

<210> SEQ ID NO: 19

<211> LENGTH: 467

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 19

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Val Arg Ser Gln Asn Asp Asn

20 25 30

Arg Glu Arg Gln Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu

35 40 45

Pro Leu Ser Asn Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu

50 55 60

Gln Asp Glu Glu Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys

65 70 75 80

His Val Ile Met Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val

85 90 95

Val Ala Thr Ile Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln

100 105 110

Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg

115 120 125

Ala Leu His Ser Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val

130 135 140

Val Met Thr Ile Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys

145 150 155 160

Val Ile His Ala Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe

165 170 175

Phe Ser Phe Ile Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala

180 185 190

Val Asp Tyr Ile Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val

195 200 205

Gly Met Ile Ser Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala

210 215 220

Tyr Leu Ile Met Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr

225 230 235 240

Leu Pro Glu Trp Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr

245 250 255

Asp Leu Val Ala Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val

260 265 270

Glu Thr Ala Gln Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr

275 280 285

Ser Ser Thr Met Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu

290 295 300

Ala Gln Arg Arg Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Ser Thr

305 310 315 320

Glu Arg Glu Ser Gln Asp Thr Val Ala Glu Asn Asp Asp Gly Gly Phe

325 330 335

Ser Glu Glu Trp Glu Ala Gln Arg Asp Ser His Leu Gly Pro His Arg

340 345 350

Ser Thr Pro Glu Ser Arg Ala Ala Val Gln Glu Leu Ser Ser Ser Ile

355 360 365

Leu Ala Gly Glu Asp Pro Glu Glu Arg Gly Val Lys Leu Gly Leu Gly

370 375 380

Asp Phe Ile Phe Tyr Ser Val Leu Val Gly Lys Ala Ser Ala Thr Ala

385 390 395 400

Ser Gly Asp Trp Asn Thr Thr Ile Ala Cys Phe Val Ala Ile Leu Ile

405 410 415

Gly Leu Cys Leu Thr Leu Leu Leu Leu Ala Ile Phe Lys Lys Ala Leu

420 425 430

Pro Ala Leu Pro Ile Ser Ile Thr Phe Gly Leu Val Phe Tyr Phe Ala

435 440 445

Thr Asp Tyr Leu Val Gln Pro Phe Met Asp Gln Leu Ala Phe His Gln

450 455 460

Phe Tyr Ile

465

<210> SEQ ID NO: 20

<211> LENGTH: 463

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 20

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Asn Asp Asn Arg Glu Arg Gln

20 25 30

Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu Pro Leu Ser Asn

35 40 45

Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu Gln Asp Glu Glu

50 55 60

Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys His Val Ile Met

65 70 75 80

Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val Val Ala Thr Ile

85 90 95

Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln Leu Ile Tyr Thr

100 105 110

Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg Ala Leu His Ser

115 120 125

Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val Val Met Thr Ile

130 135 140

Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys Val Ile His Ala

145 150 155 160

Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe Phe Ser Phe Ile

165 170 175

Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala Val Asp Tyr Ile

180 185 190

Thr Val Ala Leu Leu Ile Trp Asn Leu Gly Val Val Gly Met Ile Ser

195 200 205

Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala Tyr Leu Ile Met

210 215 220

Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp

225 230 235 240

Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr Asp Leu Val Ala

245 250 255

Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val Glu Thr Ala Gln

260 265 270

Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr Ser Ser Thr Met

275 280 285

Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu Ala Gln Arg Arg

290 295 300

Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Ser Thr Glu Arg Glu Ser

305 310 315 320

Gln Asp Thr Val Ala Glu Asn Asp Asp Gly Gly Phe Ser Glu Glu Trp

325 330 335

Glu Ala Gln Arg Asp Ser His Leu Gly Pro His Arg Ser Thr Pro Glu

340 345 350

Ser Arg Ala Ala Val Gln Glu Leu Ser Ser Ser Ile Leu Ala Gly Glu

355 360 365

Asp Pro Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile Phe

370 375 380

Tyr Ser Val Leu Val Gly Lys Ala Ser Ala Thr Ala Ser Gly Asp Trp

385 390 395 400

Asn Thr Thr Ile Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys Leu

405 410 415

Thr Leu Leu Leu Leu Ala Ile Phe Lys Lys Ala Leu Pro Ala Leu Pro

420 425 430

Ile Ser Ile Thr Phe Gly Leu Val Phe Tyr Phe Ala Thr Asp Tyr Leu

435 440 445

Val Gln Pro Phe Met Asp Gln Leu Ala Phe His Gln Phe Tyr Ile

450 455 460

<210> SEQ ID NO: 21

<211> LENGTH: 463

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 21

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Asn Asp Asn Arg Glu Arg Gln

20 25 30

Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu Pro Leu Ser Asn

35 40 45

Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu Gln Asp Glu Glu

50 55 60

Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys His Val Ile Met

65 70 75 80

Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val Val Ala Thr Ile

85 90 95

Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln Leu Ile Tyr Thr

100 105 110

Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg Ala Leu His Ser

115 120 125

Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val Val Met Thr Ile

130 135 140

Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys Val Ile His Ala

145 150 155 160

Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe Phe Ser Phe Ile

165 170 175

Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala Val Asp Tyr Ile

180 185 190

Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val Gly Met Ile Ser

195 200 205

Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala Tyr Leu Ile Met

210 215 220

Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp

225 230 235 240

Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr Asp Leu Val Ala

245 250 255

Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val Glu Thr Ala Gln

260 265 270

Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr Ser Ser Thr Met

275 280 285

Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu Ala Gln Arg Arg

290 295 300

Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Ser Thr Glu Arg Glu Ser

305 310 315 320

Gln Asp Thr Val Ala Glu Asn Asp Asp Gly Gly Phe Ser Glu Glu Trp

325 330 335

Glu Ala Gln Arg Asp Ser His Leu Gly Pro His Arg Ser Thr Pro Glu

340 345 350

Ser Arg Ala Ala Val Gln Glu Leu Ser Ser Ser Ile Leu Ala Gly Glu

355 360 365

Asp Pro Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile Phe

370 375 380

Tyr Ser Val Leu Val Gly Lys Ala Ser Ala Thr Ala Ser Gly Asp Trp

385 390 395 400

Asn Thr Thr Ile Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys Leu

405 410 415

Thr Leu Leu Leu Leu Ala Ile Phe Lys Lys Ala Leu Pro Ala Leu Pro

420 425 430

Ile Ser Ile Thr Phe Gly Leu Val Phe Tyr Phe Ala Thr Asp Tyr Leu

435 440 445

Val Gln Pro Phe Met Asp Gln Leu Ala Phe His Gln Phe Tyr Ile

450 455 460

<210> SEQ ID NO: 22

<211> LENGTH: 374

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 22

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Asn Asp Asn Arg Glu Arg Gln

20 25 30

Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu Pro Leu Ser Asn

35 40 45

Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu Gln Asp Glu Glu

50 55 60

Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys His Val Ile Met

65 70 75 80

Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val Val Ala Thr Ile

85 90 95

Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln Leu Ile Tyr Thr

100 105 110

Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg Ala Leu His Ser

115 120 125

Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val Val Met Thr Ile

130 135 140

Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys Val Ile His Ala

145 150 155 160

Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe Phe Ser Phe Ile

165 170 175

Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala Val Asp Tyr Ile

180 185 190

Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val Gly Met Ile Ser

195 200 205

Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala Tyr Leu Ile Met

210 215 220

Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp

225 230 235 240

Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr Asp Leu Val Ala

245 250 255

Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val Glu Thr Ala Gln

260 265 270

Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr Ser Ser Thr Met

275 280 285

Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu Ala Gln Arg Arg

290 295 300

Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Arg Ala Cys Leu Pro Pro

305 310 315 320

Ala Ala Ile Asn Leu Leu Ser Ile Ala Pro Met Ala Pro Arg Leu Phe

325 330 335

Met Pro Lys Gly Ala Cys Arg Pro Thr Ala Gln Lys Gly Ser His Lys

340 345 350

Thr Leu Leu Gln Arg Met Met Met Ala Gly Ser Val Arg Asn Gly Lys

355 360 365

Pro Arg Gly Thr Val Ile

370

<210> SEQ ID NO: 23

<211> LENGTH: 463

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 23

Met Thr Glu Leu Pro Ala Pro Leu Ser Tyr Phe Gln Asn Ala Gln Met

1 5 10 15

Ser Glu Asp Asn His Leu Ser Asn Thr Asn Asp Asn Arg Glu Arg Gln

20 25 30

Glu His Asn Asp Arg Arg Ser Leu Gly His Pro Glu Pro Leu Ser Asn

35 40 45

Gly Arg Pro Gln Gly Asn Ser Arg Gln Val Val Glu Gln Asp Glu Glu

50 55 60

Glu Asp Glu Glu Leu Thr Leu Lys Tyr Gly Ala Lys His Val Ile Met

65 70 75 80

Leu Phe Val Pro Val Thr Leu Cys Met Val Val Val Val Ala Thr Ile

85 90 95

Lys Ser Val Ser Phe Tyr Thr Arg Lys Asp Gly Gln Leu Ile Tyr Thr

100 105 110

Pro Phe Thr Glu Asp Thr Glu Thr Val Gly Gln Arg Ala Leu His Ser

115 120 125

Ile Leu Asn Ala Ala Ile Met Ile Ser Val Ile Val Val Met Thr Ile

130 135 140

Leu Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys Val Ile His Ala

145 150 155 160

Trp Leu Ile Ile Ser Ser Leu Leu Leu Leu Phe Phe Phe Ser Phe Ile

165 170 175

Tyr Leu Gly Glu Val Phe Lys Thr Tyr Asn Val Ala Val Asp Tyr Ile

180 185 190

Thr Val Ala Leu Leu Ile Trp Asn Phe Gly Val Val Gly Met Ile Ser

195 200 205

Ile His Trp Lys Gly Pro Leu Arg Leu Gln Gln Ala Tyr Leu Ile Met

210 215 220

Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp

225 230 235 240

Thr Ala Trp Leu Ile Leu Ala Val Ile Ser Val Tyr Asp Leu Val Ala

245 250 255

Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val Glu Thr Ala Gln

260 265 270

Glu Arg Asn Glu Thr Leu Phe Pro Ala Leu Ile Tyr Ser Ser Thr Met

275 280 285

Val Trp Leu Val Asn Met Ala Glu Gly Asp Pro Glu Ala Gln Arg Arg

290 295 300

Val Ser Lys Asn Ser Lys Tyr Asn Ala Glu Ser Thr Glu Arg Glu Ser

305 310 315 320

Gln Asp Thr Val Ala Glu Asn Asp Asp Gly Gly Phe Ser Glu Glu Trp

325 330 335

Glu Ala Gln Arg Asp Ser His Leu Gly Pro His Arg Ser Thr Pro Glu

340 345 350

Ser Arg Ala Ala Val Gln Glu Leu Ser Ser Ser Ile Leu Ala Gly Glu

355 360 365

Asp Pro Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile Phe

370 375 380

Tyr Ser Val Leu Val Gly Lys Ala Ser Ala Thr Ala Ser Gly Asp Trp

385 390 395 400

Asn Thr Thr Ile Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys Leu

405 410 415

Thr Leu Leu Leu Leu Ala Ile Phe Lys Lys Ala Leu Pro Ala Leu Pro

420 425 430

Ile Ser Ile Thr Phe Gly Leu Val Phe Tyr Phe Ala Thr Asp Tyr Leu

435 440 445

Val Gln Pro Phe Met Asp Gln Leu Ala Phe His Gln Phe Tyr Ile

450 455 460

<210> SEQ ID NO: 24

<211> LENGTH: 448

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 24

Met Leu Thr Phe Met Ala Ser Asp Ser Glu Glu Glu Val Cys Asp Glu

1 5 10 15

Arg Thr Ser Leu Met Ser Ala Glu Ser Pro Thr Pro Arg Ser Cys Gln

20 25 30

Glu Gly Arg Gln Gly Pro Glu Asp Gly Glu Asn Thr Ala Gln Trp Arg

35 40 45

Ser Gln Glu Asn Glu Glu Asp Gly Glu Glu Asp Pro Asp Arg Tyr Val

50 55 60

Cys Ser Gly Val Pro Gly Arg Pro Pro Gly Leu Glu Glu Glu Leu Thr

65 70 75 80

Leu Lys Tyr Gly Ala Lys His Val Ile Met Leu Phe Val Pro Val Thr

85 90 95

Leu Cys Met Ile Val Val Val Ala Thr Ile Lys Ser Val Arg Phe Tyr

100 105 110

Thr Glu Lys Asn Gly Gln Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr

115 120 125

Pro Ser Val Gly Gln Arg Leu Leu Asn Ser Val Leu Asn Thr Leu Ile

130 135 140

Met Ile Ser Val Ile Val Val Met Thr Ile Phe Leu Val Val Leu Tyr

145 150 155 160

Lys Tyr Arg Cys Tyr Lys Phe Ile His Gly Trp Leu Ile Met Ser Ser

165 170 175

Leu Met Leu Leu Phe Leu Phe Thr Tyr Ile Tyr Leu Gly Glu Val Leu

180 185 190

Lys Thr Tyr Asn Val Ala Met Asp Tyr Pro Thr Leu Leu Leu Thr Val

195 200 205

Trp Asn Phe Gly Ala Val Gly Met Val Cys Ile His Trp Lys Gly Pro

210 215 220

Leu Val Leu Gln Gln Ala Tyr Leu Ile Met Ile Ser Ala Leu Met Ala

225 230 235 240

Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp Ser Ala Trp Val Ile Leu

245 250 255

Gly Ala Ile Ser Val Tyr Asp Leu Val Ala Val Leu Cys Pro Lys Gly

260 265 270

Pro Leu Arg Met Leu Val Glu Thr Ala Gln Glu Arg Asn Glu Pro Ile

275 280 285

Phe Pro Ala Leu Ile Tyr Ser Ser Ala Met Val Trp Thr Val Gly Met

290 295 300

Ala Lys Leu Asp Pro Ser Ser Gln Gly Ala Leu Gln Leu Pro Tyr Asp

305 310 315 320

Pro Glu Met Glu Glu Asp Ser Tyr Asp Ser Phe Gly Glu Pro Ser Tyr

325 330 335

Pro Glu Val Phe Glu Pro Pro Leu Thr Gly Tyr Pro Gly Glu Glu Leu

340 345 350

Glu Glu Glu Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile

355 360 365

Phe Tyr Ser Val Leu Val Gly Lys Ala Ala Ala Thr Gly Ser Gly Asp

370 375 380

Trp Asn Thr Thr Leu Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys

385 390 395 400

Leu Thr Leu Leu Leu Leu Ala Val Phe Lys Lys Ala Leu Pro Ala Leu

405 410 415

Pro Ile Ser Ile Thr Phe Gly Leu Ile Phe Tyr Phe Ser Thr Asp Asn

420 425 430

Leu Val Arg Pro Phe Met Asp Thr Leu Ala Ser His Gln Leu Tyr Ile

435 440 445

<210> SEQ ID NO: 25

<211> LENGTH: 390

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 25

Met Leu Thr Phe Met Ala Ser Asp Ser Glu Glu Glu Val Cys Asp Glu

1 5 10 15

Arg Thr Ser Leu Met Ser Ala Glu Ser Pro Thr Pro Arg Ser Cys Gln

20 25 30

Glu Gly Arg Gln Gly Pro Glu Asp Gly Glu Asn Thr Ala Gln Trp Arg

35 40 45

Ser Gln Glu Asn Glu Glu Asp Gly Glu Glu Asp Pro Asp Arg Tyr Val

50 55 60

Cys Ser Gly Val Pro Gly Arg Pro Pro Gly Leu Glu Glu Glu Leu Thr

65 70 75 80

Leu Lys Tyr Gly Ala Lys His Val Ile Met Leu Phe Val Pro Val Thr

85 90 95

Leu Cys Met Ile Val Val Val Ala Thr Ile Lys Ser Val Arg Phe Tyr

100 105 110

Thr Glu Lys Asn Gly Gln Leu Ile Tyr Thr Thr Phe Thr Glu Asp Thr

115 120 125

Pro Ser Val Gly Gln Arg Leu Leu Asn Ser Val Leu Asn Thr Leu Ile

130 135 140

Met Ile Ser Val Ile Val Val Met Thr Ile Phe Leu Val Val Leu Tyr

145 150 155 160

Lys Tyr Arg Cys Tyr Lys Phe Ile His Gly Trp Leu Ile Met Ser Ser

165 170 175

Leu Met Leu Leu Phe Leu Phe Thr Tyr Ile Tyr Leu Gly Glu Val Leu

180 185 190

Lys Thr Tyr Asn Val Ala Met Asp Tyr Pro Thr Leu Leu Leu Thr Val

195 200 205

Trp Asn Phe Gly Ala Val Gly Met Val Cys Ile His Trp Lys Gly Pro

210 215 220

Leu Val Leu Gln Gln Ala Tyr Leu Ile Met Ile Ser Ala Leu Met Ala

225 230 235 240

Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp Ser Ala Trp Val Ile Leu

245 250 255

Gly Ala Ile Ser Val Tyr Asp Leu Val Ala Val Leu Cys Pro Lys Gly

260 265 270

Pro Leu Arg Met Leu Val Glu Thr Ala Gln Glu Arg Asn Glu Pro Ile

275 280 285

Phe Pro Ala Leu Ile Tyr Leu Ser Ala Met Val Trp Thr Val Gly Met

290 295 300

Ala Lys Leu Asp Pro Ser Ser Gln Gly Ala Leu Gln Leu Pro Tyr Asp

305 310 315 320

Pro Glu Met Glu Glu Asp Ser Tyr Asp Ser Phe Gly Glu Pro Ser Tyr

325 330 335

Pro Glu Val Phe Glu Pro Pro Leu Thr Gly Tyr Pro Gly Glu Glu Leu

340 345 350

Glu Glu Glu Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile

355 360 365

Phe Tyr Ser Val Leu Val Gly Lys Ala Ala Ala Thr Gly Ser Gly Asp

370 375 380

Trp Asn Thr Thr Leu Ala

385 390

<210> SEQ ID NO: 26

<211> LENGTH: 447

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 26

Met Leu Thr Phe Met Ala Ser Asp Ser Glu Glu Glu Val Cys Asp Glu

1 5 10 15

Arg Thr Ser Leu Met Ser Ala Glu Ser Pro Thr Pro Arg Ser Cys Gln

20 25 30

Glu Gly Arg Gln Gly Pro Glu Asp Gly Glu Asn Thr Ala Gln Trp Arg

35 40 45

Ser Gln Glu Asn Glu Glu Asp Gly Glu Glu Asp Pro Asp Arg Tyr Val

50 55 60

Cys Ser Gly Val Pro Gly Arg Pro Pro Gly Leu Glu Glu Glu Leu Thr

65 70 75 80

Leu Lys Tyr Gly Ala Lys His Val Ile Met Leu Phe Val Pro Val Thr

85 90 95

Leu Cys Met Ile Val Val Val Ala Thr Ile Lys Ser Val Arg Phe Tyr

100 105 110

Thr Glu Lys Asn Gly Gln Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr

115 120 125

Pro Ser Val Gly Gln Arg Leu Leu Asn Ser Val Leu Asn Thr Leu Ile

130 135 140

Met Ile Ser Val Ile Val Val Met Thr Ile Phe Leu Val Val Leu Tyr

145 150 155 160

Lys Tyr Arg Cys Tyr Lys Phe Ile His Gly Trp Leu Ile Met Ser Ser

165 170 175

Leu Met Leu Leu Phe Leu Phe Thr Tyr Ile Tyr Leu Gly Glu Val Leu

180 185 190

Lys Thr Tyr Asn Val Ala Met Asp Tyr Pro Thr Leu Leu Leu Thr Val

195 200 205

Trp Asn Phe Gly Ala Val Gly Met Val Cys Ile His Trp Lys Gly Pro

210 215 220

Leu Val Leu Gln Gln Ala Tyr Leu Ile Met Ile Ser Ala Leu Met Ala

225 230 235 240

Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp Ser Ala Trp Val Ile Leu

245 250 255

Gly Ala Ile Ser Val Tyr Asp Leu Val Ala Val Leu Cys Pro Lys Gly

260 265 270

Pro Leu Arg Met Leu Val Glu Thr Ala Gln Glu Arg Asn Glu Pro Ile

275 280 285

Phe Pro Ala Leu Ile Tyr Ser Ser Ala Met Val Trp Thr Val Gly Met

290 295 300

Ala Lys Leu Asp Pro Ser Ser Gln Gly Ala Leu Gln Leu Pro Tyr Asp

305 310 315 320

Pro Glu Met Glu Asp Ser Tyr Asp Ser Phe Gly Glu Pro Ser Tyr Pro

325 330 335

Glu Val Phe Glu Pro Pro Leu Thr Gly Tyr Pro Gly Glu Glu Leu Glu

340 345 350

Glu Glu Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile Phe

355 360 365

Tyr Ser Val Leu Val Gly Lys Ala Ala Ala Thr Gly Ser Gly Asp Trp

370 375 380

Asn Thr Thr Leu Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys Leu

385 390 395 400

Thr Leu Leu Leu Leu Ala Val Phe Lys Lys Ala Leu Pro Ala Leu Pro

405 410 415

Ile Ser Ile Thr Phe Gly Leu Ile Phe Tyr Phe Ser Thr Asp Asn Leu

420 425 430

Val Arg Pro Phe Met Asp Thr Leu Ala Ser His Gln Leu Tyr Ile

435 440 445

<210> SEQ ID NO: 27

<211> LENGTH: 359

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 27

Met Leu Phe Val Pro Val Thr Leu Cys Met Ile Val Val Val Ala Thr

1 5 10 15

Ile Lys Ser Val Arg Phe Tyr Thr Glu Lys Asn Gly Gln Leu Ile Tyr

20 25 30

Thr Pro Phe Thr Glu Asp Thr Pro Ser Val Gly Gln Arg Leu Leu Asn

35 40 45

Ser Val Leu Asn Thr Leu Ile Met Ile Ser Val Ile Val Val Met Thr

50 55 60

Ile Phe Leu Val Val Leu Tyr Lys Tyr Arg Cys Tyr Lys Phe Ile His

65 70 75 80

Gly Trp Leu Ile Met Ser Ser Leu Met Leu Leu Phe Leu Phe Thr Tyr

85 90 95

Ile Tyr Leu Gly Glu Val Leu Lys Thr Tyr Asn Val Ala Met Asp Tyr

100 105 110

Pro Thr Leu Leu Leu Thr Val Trp Asn Phe Gly Ala Val Gly Met Val

115 120 125

Cys Ile His Trp Lys Gly Pro Leu Val Leu Gln Gln Ala Tyr Leu Ile

130 135 140

Met Ile Ser Ala Leu Met Ala Leu Val Phe Ile Lys Tyr Leu Pro Glu

145 150 155 160

Trp Ser Ala Trp Val Ile Leu Gly Ala Ile Ser Val Tyr Asp Leu Val

165 170 175

Ala Val Leu Cys Pro Lys Gly Pro Leu Arg Met Leu Val Glu Thr Ala

180 185 190

Gln Glu Arg Asn Glu Pro Ile Phe Pro Ala Leu Ile Tyr Ser Ser Ala

195 200 205

Met Val Trp Thr Val Gly Met Ala Lys Leu Asp Pro Ser Ser Gln Gly

210 215 220

Ala Leu Gln Leu Pro Tyr Asp Pro Glu Met Glu Glu Asp Ser Tyr Asp

225 230 235 240

Ser Phe Gly Glu Pro Ser Tyr Pro Glu Val Phe Glu Pro Pro Leu Thr

245 250 255

Gly Tyr Pro Gly Glu Glu Leu Glu Glu Glu Glu Glu Arg Gly Val Lys

260 265 270

Leu Gly Leu Gly Asp Phe Ile Phe Tyr Ser Val Leu Val Gly Lys Ala

275 280 285

Ala Ala Thr Gly Ser Gly Asp Trp Asn Thr Thr Leu Ala Cys Phe Val

290 295 300

Ala Ile Leu Ile Gly Leu Cys Leu Thr Leu Leu Leu Leu Ala Val Phe

305 310 315 320

Lys Lys Ala Leu Pro Ala Leu Pro Ile Ser Ile Thr Phe Gly Leu Ile

325 330 335

Phe Tyr Phe Ser Thr Asp Asn Leu Val Arg Pro Phe Met Asp Thr Leu

340 345 350

Ala Ser His Gln Leu Tyr Ile

355

<210> SEQ ID NO: 28

<211> LENGTH: 448

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 28

Met Leu Thr Phe Met Ala Ser Asp Ser Glu Glu Glu Val Cys Asp Glu

1 5 10 15

Arg Thr Ser Leu Met Ser Ala Glu Ser Pro Thr Pro Arg Ser Cys Gln

20 25 30

Glu Gly Arg Gln Gly Pro Glu Asp Gly Glu Asn Thr Ala Gln Trp Arg

35 40 45

Ser Gln Glu Asn Glu Glu Asp Gly Glu Glu Asp Pro Asp Arg Tyr Val

50 55 60

Cys Ser Gly Val Pro Gly Arg Pro Pro Gly Leu Glu Glu Glu Leu Thr

65 70 75 80

Leu Lys Tyr Gly Ala Lys His Val Ile Met Leu Phe Val Pro Val Thr

85 90 95

Leu Cys Met Ile Val Val Val Ala Thr Ile Lys Ser Val Arg Phe Tyr

100 105 110

Thr Glu Lys Asn Gly Gln Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr

115 120 125

Pro Ser Val Gly Gln Arg Leu Leu Asn Ser Val Leu Asn Thr Leu Ile

130 135 140

Met Ile Ser Val Ile Val Val Met Thr Ile Phe Leu Val Val Leu Tyr

145 150 155 160

Lys Tyr Arg Cys Tyr Lys Phe Ile His Gly Trp Leu Ile Met Ser Ser

165 170 175

Leu Met Leu Leu Phe Leu Phe Thr Tyr Ile Tyr Leu Gly Glu Val Leu

180 185 190

Lys Thr Tyr Asn Val Ala Met Asp Tyr Pro Thr Leu Leu Leu Thr Val

195 200 205

Trp Asn Phe Gly Ala Val Gly Met Val Cys Ile His Trp Lys Gly Pro

210 215 220

Leu Val Leu Gln Gln Ala Tyr Leu Ile Met Ile Ser Ala Leu Met Ala

225 230 235 240

Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp Ser Ala Trp Val Ile Leu

245 250 255

Gly Ala Ile Ser Val Tyr Asp Leu Val Ala Val Leu Cys Pro Lys Gly

260 265 270

Pro Leu Arg Met Leu Val Glu Thr Ala Gln Glu Arg Asn Glu Pro Ile

275 280 285

Phe Pro Ala Leu Ile Tyr Ser Ser Ala Met Val Trp Thr Val Gly Met

290 295 300

Ala Lys Leu Asp Pro Ser Ser Gln Gly Ala Leu Gln Leu Pro Tyr Asp

305 310 315 320

Pro Glu Met Glu Glu Asp Ser Tyr Asp Ser Phe Gly Glu Pro Ser Tyr

325 330 335

Pro Glu Val Phe Glu Pro Pro Leu Thr Gly Tyr Pro Gly Glu Glu Leu

340 345 350

Glu Glu Glu Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile

355 360 365

Phe Tyr Ser Val Leu Val Gly Lys Ala Ala Ala Thr Gly Ser Gly Asp

370 375 380

Trp Asn Thr Thr Leu Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys

385 390 395 400

Leu Thr Leu Leu Leu Leu Ala Val Phe Lys Lys Ala Leu Pro Ala Leu

405 410 415

Pro Ile Ser Ile Thr Phe Gly Leu Ile Phe Tyr Phe Ser Thr Asp Asn

420 425 430

Leu Val Arg Pro Phe Met Asp Thr Leu Ala Ser His Gln Leu Tyr Ile

435 440 445

<210> SEQ ID NO: 29

<211> LENGTH: 448

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 29

Met Leu Thr Phe Met Ala Ser Asp Ser Glu Glu Glu Val Cys Asp Glu

1 5 10 15

Arg Thr Ser Leu Met Ser Ala Glu Ser Pro Thr Pro Arg Ser Cys Gln

20 25 30

Glu Gly Arg Gln Gly Pro Glu Asp Gly Glu Asn Thr Ala Gln Trp Arg

35 40 45

Ser Gln Glu Asn Glu Glu Asp Gly Glu Glu Asp Pro Asp Arg Tyr Val

50 55 60

Cys Ser Gly Val Pro Gly Arg Pro Pro Gly Leu Glu Glu Glu Leu Thr

65 70 75 80

Leu Lys Tyr Gly Ala Lys His Val Ile Met Leu Phe Val Pro Val Thr

85 90 95

Leu Cys Met Ile Val Val Val Ala Thr Ile Lys Ser Val Arg Phe Tyr

100 105 110

Thr Glu Lys Asn Gly Gln Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr

115 120 125

Pro Ser Val Gly Gln Arg Leu Leu Asn Ser Val Leu Asn Thr Leu Ile

130 135 140

Met Ile Ser Val Ile Val Val Met Thr Ile Phe Leu Val Val Leu Tyr

145 150 155 160

Lys Tyr Arg Cys Tyr Lys Phe Ile His Gly Trp Leu Ile Met Ser Ser

165 170 175

Leu Met Leu Leu Phe Leu Phe Thr Tyr Ile Tyr Leu Gly Glu Val Leu

180 185 190

Lys Thr Tyr Asn Val Ala Met Asp Tyr Pro Thr Leu Leu Leu Thr Val

195 200 205

Trp Asn Phe Gly Ala Val Gly Met Val Cys Ile His Trp Lys Gly Pro

210 215 220

Leu Val Leu Gln Gln Ala Tyr Leu Ile Met Ile Ser Ala Leu Met Ala

225 230 235 240

Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp Ser Ala Trp Val Ile Leu

245 250 255

Gly Ala Ile Ser Val Tyr Asp Leu Val Ala Val Leu Cys Pro Lys Gly

260 265 270

Pro Leu Arg Met Leu Val Glu Thr Ala Gln Glu Arg Asn Glu Pro Ile

275 280 285

Phe Pro Ala Leu Ile Tyr Ser Ser Ala Met Val Trp Thr Val Gly Met

290 295 300

Ala Lys Leu Asp Pro Ser Ser Gln Gly Ala Leu Gln Leu Pro Tyr Asp

305 310 315 320

Pro Glu Met Glu Glu Asp Ser Tyr Asp Ser Phe Gly Glu Pro Ser Tyr

325 330 335

Pro Glu Val Phe Glu Pro Pro Leu Thr Gly Tyr Pro Gly Glu Glu Leu

340 345 350

Glu Glu Glu Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile

355 360 365

Phe Tyr Ser Val Leu Val Gly Lys Ala Ala Ala Thr Gly Ser Gly Asp

370 375 380

Trp Asn Thr Thr Leu Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys

385 390 395 400

Leu Thr Leu Leu Leu Leu Ala Val Phe Lys Lys Ala Leu Pro Ala Leu

405 410 415

Pro Ile Ser Ile Thr Phe Gly Leu Ile Phe Tyr Phe Ser Thr Asp Asn

420 425 430

Leu Val Arg Pro Phe Met Asp Thr Leu Ala Ser His Gln Leu Tyr Ile

435 440 445

<210> SEQ ID NO: 30

<211> LENGTH: 448

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 30

Met Leu Thr Phe Met Ala Ser Asp Ser Glu Glu Glu Val Cys Asp Glu

1 5 10 15

Arg Thr Ser Leu Met Ser Ala Glu Ser Pro Thr Pro Arg Ser Cys Gln

20 25 30

Glu Gly Arg Gln Gly Pro Glu Asp Gly Glu Asn Thr Ala Gln Trp Arg

35 40 45

Ser Gln Glu Asn Glu Glu Asp Gly Glu Glu Asp Pro Asp Arg Tyr Val

50 55 60

Cys Ser Gly Val Pro Gly Arg Pro Pro Gly Leu Glu Glu Glu Leu Thr

65 70 75 80

Leu Lys Tyr Gly Ala Lys His Val Ile Met Leu Phe Val Pro Val Thr

85 90 95

Leu Cys Met Ile Val Val Val Ala Thr Ile Lys Ser Val Arg Phe Tyr

100 105 110

Thr Glu Lys Asn Gly Gln Leu Ile Tyr Thr Thr Phe Thr Glu Asp Thr

115 120 125

Pro Ser Val Gly Gln Arg Leu Leu Asn Ser Val Leu Asn Thr Leu Ile

130 135 140

Met Ile Ser Val Ile Val Val Met Thr Ile Phe Leu Val Val Leu Tyr

145 150 155 160

Lys Tyr Arg Cys Tyr Lys Phe Ile His Gly Trp Leu Ile Met Ser Ser

165 170 175

Leu Met Leu Leu Phe Leu Phe Thr Tyr Ile Tyr Leu Gly Glu Val Leu

180 185 190

Lys Thr Tyr Asn Val Ala Met Asp Tyr Pro Thr Leu Leu Leu Thr Val

195 200 205

Trp Asn Phe Gly Ala Val Gly Met Val Cys Ile His Trp Lys Gly Pro

210 215 220

Leu Val Leu Gln Gln Ala Tyr Leu Ile Met Ile Ser Ala Leu Met Ala

225 230 235 240

Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp Ser Ala Trp Val Ile Leu

245 250 255

Gly Ala Ile Ser Val Tyr Asp Leu Val Ala Val Leu Cys Pro Lys Gly

260 265 270

Pro Leu Arg Met Leu Val Glu Thr Ala Gln Glu Arg Asn Glu Pro Ile

275 280 285

Phe Pro Ala Leu Ile Tyr Ser Ser Ala Met Val Trp Thr Val Gly Met

290 295 300

Ala Lys Leu Asp Pro Ser Ser Gln Gly Ala Leu Gln Leu Pro Tyr Asp

305 310 315 320

Pro Glu Met Glu Glu Asp Ser Tyr Asp Ser Phe Gly Glu Pro Ser Tyr

325 330 335

Pro Glu Val Phe Glu Pro Pro Leu Thr Gly Tyr Pro Gly Glu Glu Leu

340 345 350

Glu Glu Glu Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile

355 360 365

Phe Tyr Ser Val Leu Val Gly Lys Ala Ala Ala Thr Gly Ser Gly Asp

370 375 380

Trp Asn Thr Thr Leu Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys

385 390 395 400

Leu Thr Leu Leu Leu Leu Ala Val Phe Lys Lys Ala Leu Pro Ala Leu

405 410 415

Pro Ile Ser Ile Thr Phe Gly Leu Ile Phe Tyr Phe Ser Thr Asp Asn

420 425 430

Leu Val Arg Pro Phe Met Asp Thr Leu Ala Ser His Gln Leu Tyr Ile

435 440 445

<210> SEQ ID NO: 31

<211> LENGTH: 448

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 31

Met Leu Thr Phe Met Ala Ser Asp Ser Glu Glu Glu Val Cys Asp Glu

1 5 10 15

Arg Thr Ser Leu Met Ser Ala Glu Ser Pro Thr Pro Arg Ser Cys Gln

20 25 30

Glu Gly Arg Gln Gly Pro Glu Asp Gly Glu Asn Thr Ala Gln Trp Arg

35 40 45

Ser Gln Glu Asn Glu Glu Asp Gly Glu Glu Asp Pro Asp Arg Tyr Val

50 55 60

Cys Ser Gly Val Pro Gly Arg Pro Pro Gly Leu Glu Glu Glu Leu Thr

65 70 75 80

Leu Lys Tyr Gly Ala Lys His Val Ile Met Leu Phe Val Pro Val Thr

85 90 95

Leu Cys Met Ile Val Val Val Ala Thr Ile Lys Ser Val Arg Phe Tyr

100 105 110

Thr Glu Lys Asn Gly Gln Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr

115 120 125

Pro Ser Val Gly Gln Arg Leu Leu Asn Ser Val Leu Asn Thr Leu Ile

130 135 140

Met Ile Ser Val Ile Val Val Met Thr Ile Phe Leu Val Val Leu Tyr

145 150 155 160

Lys Tyr Arg Cys Tyr Lys Phe Ile His Gly Trp Leu Ile Met Ser Ser

165 170 175

Leu Met Leu Leu Phe Leu Phe Thr Tyr Ile Tyr Leu Gly Glu Val Leu

180 185 190

Lys Thr Tyr Asn Val Ala Met Asp Tyr Pro Thr Leu Leu Leu Thr Val

195 200 205

Trp Asn Phe Gly Ala Val Gly Met Val Cys Ile His Trp Lys Gly Pro

210 215 220

Leu Val Leu Gln Gln Ala Tyr Leu Ile Met Ile Ser Ala Leu Met Ala

225 230 235 240

Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp Ser Ala Trp Val Ile Leu

245 250 255

Gly Ala Ile Ser Val Tyr Asp Leu Val Ala Val Leu Cys Pro Lys Gly

260 265 270

Pro Leu Arg Met Leu Val Glu Thr Ala Gln Glu Arg Asn Glu Pro Ile

275 280 285

Phe Pro Ala Leu Ile Tyr Ser Ser Ala Met Val Trp Thr Val Gly Met

290 295 300

Ala Lys Leu Asp Pro Ser Ser Gln Gly Ala Leu Gln Leu Pro Tyr Asp

305 310 315 320

Pro Glu Met Glu Glu Asp Ser Tyr Asp Ser Phe Gly Glu Pro Ser Tyr

325 330 335

Pro Glu Val Phe Glu Pro Pro Leu Thr Gly Tyr Pro Gly Glu Glu Leu

340 345 350

Glu Glu Glu Glu Glu Arg Gly Val Lys Leu Gly Leu Gly Asp Phe Ile

355 360 365

Phe Tyr Ser Val Leu Val Gly Lys Ala Ala Ala Thr Gly Ser Gly Asp

370 375 380

Trp Asn Thr Thr Leu Ala Cys Phe Val Ala Ile Leu Ile Gly Leu Cys

385 390 395 400

Leu Thr Leu Leu Leu Leu Ala Val Phe Lys Lys Ala Leu Pro Ala Leu

405 410 415

Pro Ile Ser Ile Thr Phe Gly Leu Ile Phe Tyr Phe Ser Thr Asp Asn

420 425 430

Leu Val Arg Pro Phe Met Asp Thr Leu Ala Ser His Gln Leu Tyr Ile

435 440 445

<210> SEQ ID NO: 32

<211> LENGTH: 442

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 32

Met Leu Thr Phe Met Ala Ser Asp Ser Glu Glu Glu Val Cys Asp Glu

1 5 10 15

Arg Thr Ser Leu Met Ser Ala Glu Ser Pro Thr Pro Arg Ser Cys Gln

20 25 30

Glu Gly Arg Gln Gly Pro Glu Asp Gly Glu Asn Thr Ala Gln Trp Arg

35 40 45

Ser Gln Glu Asn Glu Glu Asp Gly Glu Glu Asp Pro Asp Arg Tyr Val

50 55 60

Cys Ser Gly Val Pro Gly Arg Pro Pro Gly Leu Glu Glu Glu Leu Thr

65 70 75 80

Leu Lys Tyr Gly Ala Lys His Val Ile Met Leu Phe Val Pro Val Thr

85 90 95

Leu Cys Met Ile Val Val Val Ala Thr Ile Lys Ser Val Arg Phe Tyr

100 105 110

Thr Glu Lys Asn Gly Gln Leu Ile Tyr Thr Pro Phe Thr Glu Asp Thr

115 120 125

Pro Ser Val Gly Gln Arg Leu Leu Asn Ser Val Leu Asn Thr Leu Ile

130 135 140

Met Ile Ser Val Ile Val Val Met Thr Ile Phe Leu Val Val Leu Tyr

145 150 155 160

Lys Tyr Arg Cys Tyr Lys Phe Ile His Gly Trp Leu Ile Met Ser Ser

165 170 175

Leu Met Leu Leu Phe Leu Phe Thr Tyr Ile Tyr Leu Gly Glu Val Leu

180 185 190

Lys Thr Tyr Asn Val Ala Met Asp Tyr Pro Thr Leu Leu Leu Thr Val

195 200 205

Trp Asn Phe Gly Ala Val Gly Met Val Cys Ile His Trp Lys Gly Pro

210 215 220

Leu Val Leu Gln Gln Ala Tyr Leu Ile Met Ile Ser Ala Leu Met Ala

225 230 235 240

Leu Val Phe Ile Lys Tyr Leu Pro Glu Trp Ser Ala Trp Val Ile Leu

245 250 255

Gly Ala Ile Ser Val Tyr Asp Leu Val Ala Val Leu Cys Pro Lys Gly

260 265 270

Pro Leu Arg Met Leu Val Glu Thr Ala Gln Glu Arg Asn Glu Pro Ile

275 280 285

Phe Pro Ala Leu Ile Tyr Ser Ser Ala Met Val Trp Thr Val Gly Met

290 295 300

Ala Lys Leu Asp Pro Ser Ser Gln Gly Ala Leu Gln Leu Pro Tyr Asp

305 310 315 320

Pro Glu Met Glu Asp Ser Tyr Asp Ser Phe Gly Glu Pro Ser Tyr Pro

325 330 335

Glu Val Phe Glu Pro Pro Leu Thr Gly Tyr Pro Gly Glu Glu Leu Glu

340 345 350

Glu Glu Glu Glu Ser Gln Gly Gly Val Lys Leu Gly Leu Gly Asp Phe

355 360 365

Ile Phe Tyr Ser Val Leu Val Gly Lys Ala Ala Ala Thr Gly Ser Gly

370 375 380

Asp Trp Asn Thr Thr Leu Ala Cys Phe Val Ala Ile Leu Ile Gly Leu

385 390 395 400

Cys Leu Thr Leu Leu Leu Leu Ala Val Phe Lys Lys Ala Leu Pro Ala

405 410 415

Leu Pro Ile Ser Ile Thr Phe Gly Leu Ile Phe Tyr Phe Ser Thr Asp

420 425 430

Arg Lys His Ser Arg Phe Ile Gln Met Asn

435 440

<210> SEQ ID NO: 33

<211> LENGTH: 265

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 33

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Arg Arg Gln Glu Asp Ser Arg Val Met Val Tyr

245 250 255

Ser Ala Leu Arg Ile Pro Pro Glu Asp

260 265

<210> SEQ ID NO: 34

<211> LENGTH: 251

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 34

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Ser Cys Val Arg Thr Asp Tyr Leu Asp

245 250

<210> SEQ ID NO: 35

<211> LENGTH: 251

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 35

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Ser Cys Val Arg Thr Asp Tyr Leu Asp

245 250

<210> SEQ ID NO: 36

<211> LENGTH: 247

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 36

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Lys Asp

245

<210> SEQ ID NO: 37

<211> LENGTH: 247

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 37

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Lys Asp

245

<210> SEQ ID NO: 38

<211> LENGTH: 247

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 38

Met Gly Ala Ala Val Phe Cys Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Ser Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Lys Asp

245

<210> SEQ ID NO: 39

<211> LENGTH: 131

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 39

Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile Ser Gly Val Phe

1 5 10 15

Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro Gly Val Val Gly

20 25 30

Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser Ala Phe Leu Thr

35 40 45

Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val Val Phe Phe Asp

50 55 60

Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu Val Val Gly Ser

65 70 75 80

His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro Trp Tyr Glu Ala

85 90 95

Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met Gly Leu Trp Ala

100 105 110

Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln Arg Ser Leu Leu

115 120 125

Cys Lys Asp

130

<210> SEQ ID NO: 40

<211> LENGTH: 195

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 40

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Arg Cys Ser Ala Leu Pro Thr Thr Ser Cys

35 40 45

Leu Ile Ser Gly Leu Ser Phe Gly Ile Ile Ser Gly Val Phe Ser Val

50 55 60

Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro Gly Val Val Gly Ile His

65 70 75 80

Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser Ala Phe Leu Thr Ala Ala

85 90 95

Ile Ile Leu Leu His Thr Phe Trp Gly Val Val Phe Phe Asp Ala Cys

100 105 110

Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu Val Val Gly Ser His Leu

115 120 125

Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro Trp Tyr Glu Ala Ser Leu

130 135 140

Leu Pro Ile Tyr Ala Val Thr Val Ser Met Gly Leu Trp Ala Phe Ile

145 150 155 160

Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln Arg Ser Leu Leu Cys Arg

165 170 175

Arg Gln Glu Asp Ser Arg Val Met Val Tyr Ser Ala Leu Arg Ile Pro

180 185 190

Pro Glu Asp

195

<210> SEQ ID NO: 41

<211> LENGTH: 114

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 41

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Asn Phe

85 90 95

Trp Ser Leu Leu Arg Tyr His Gln Trp Cys Leu Leu Cys Tyr Gln Tyr

100 105 110

Phe Gly

<210> SEQ ID NO: 42

<211> LENGTH: 190

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 42

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Lys Ala Asp Glu Gly Leu Ala Ser Leu Ser

35 40 45

Glu Asp Gly Arg Ser Pro Ile Ser Ile Arg Gln Met Ala Tyr Val Ser

50 55 60

Gly Leu Ser Phe Gly Ile Ile Ser Gly Val Phe Ser Val Ile Asn Ile

65 70 75 80

Leu Ala Asp Ala Leu Gly Pro Gly Val Val Gly Ile His Gly Asp Ser

85 90 95

Pro Tyr Tyr Phe Leu Thr Ser Ala Phe Leu Thr Ala Ala Ile Ile Leu

100 105 110

Leu His Thr Phe Trp Gly Val Val Phe Phe Asp Ala Cys Glu Arg Arg

115 120 125

Arg Tyr Trp Ala Leu Gly Leu Val Val Gly Ser His Leu Leu Thr Ser

130 135 140

Gly Leu Thr Phe Leu Asn Pro Trp Tyr Glu Ala Ser Leu Leu Pro Ile

145 150 155 160

Tyr Ala Val Thr Val Ser Met Gly Leu Trp Ala Phe Ile Thr Ala Gly

165 170 175

Gly Ser Leu Arg Ser Ile Gln Arg Ser Leu Leu Cys Lys Asp

180 185 190

<210> SEQ ID NO: 43

<211> LENGTH: 247

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 43

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Lys Asp

245

<210> SEQ ID NO: 44

<211> LENGTH: 265

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 44

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Arg Arg Gln Glu Asp Ser Arg Val Met Val Tyr

245 250 255

Ser Ala Leu Arg Ile Pro Pro Glu Asp

260 265

<210> SEQ ID NO: 45

<211> LENGTH: 247

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 45

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Lys Asp

245

<210> SEQ ID NO: 46

<211> LENGTH: 265

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 46

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Arg Arg Gln Glu Asp Ser Arg Val Met Val Tyr

245 250 255

Ser Ala Leu Arg Ile Pro Pro Glu Asp

260 265

<210> SEQ ID NO: 47

<211> LENGTH: 247

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 47

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Lys Asp

245

<210> SEQ ID NO: 48

<211> LENGTH: 265

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 48

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Ile Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Arg Arg Gln Glu Asp Ser Arg Val Met Val Tyr

245 250 255

Ser Ala Leu Arg Ile Pro Pro Glu Asp

260 265

<210> SEQ ID NO: 49

<211> LENGTH: 247

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 49

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Lys Asp

245

<210> SEQ ID NO: 50

<211> LENGTH: 247

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 50

Met Gly Ala Ala Val Phe Phe Gly Cys Thr Phe Val Ala Phe Gly Pro

1 5 10 15

Ala Phe Ala Leu Phe Leu Ile Thr Val Ala Gly Asp Pro Leu Arg Val

20 25 30

Ile Ile Leu Val Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Leu

35 40 45

Ala Ser Val Val Trp Phe Ile Leu Val His Val Thr Asp Arg Ser Asp

50 55 60

Ala Arg Leu Gln Tyr Gly Leu Leu Ile Phe Gly Ala Ala Val Ser Val

65 70 75 80

Leu Leu Gln Glu Val Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Asp Glu Gly Leu Ala Ser Leu Ser Glu Asp Gly Arg Ser Pro Ile

100 105 110

Ser Ile Arg Gln Met Ala Tyr Val Ser Gly Leu Ser Phe Gly Ile Ile

115 120 125

Ser Gly Val Phe Ser Val Ile Asn Ile Leu Ala Asp Ala Leu Gly Pro

130 135 140

Gly Val Val Gly Ile His Gly Asp Ser Pro Tyr Tyr Phe Leu Thr Ser

145 150 155 160

Ala Phe Leu Thr Ala Ala Ile Ile Leu Leu His Thr Phe Trp Gly Val

165 170 175

Val Phe Phe Asp Ala Cys Glu Arg Arg Arg Tyr Trp Ala Leu Gly Leu

180 185 190

Val Val Gly Ser His Leu Leu Thr Ser Gly Leu Thr Phe Leu Asn Pro

195 200 205

Trp Tyr Glu Ala Ser Leu Leu Pro Ile Tyr Ala Val Thr Val Ser Met

210 215 220

Gly Leu Trp Ala Phe Ile Thr Ala Gly Gly Ser Leu Arg Ser Ile Gln

225 230 235 240

Arg Ser Leu Leu Cys Lys Asp

245

<210> SEQ ID NO: 51

<211> LENGTH: 257

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 51

Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro

1 5 10 15

Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Thr Glu Pro Leu Arg Ile

20 25 30

Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Ile

35 40 45

Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile Asp Asn Lys Asp

50 55 60

Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly Ala Phe Val Ser Val

65 70 75 80

Tyr Ile Gln Glu Met Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Ser Glu Gly Leu Lys Ser Ile Asn Pro Gly Glu Thr Ala Pro Ser

100 105 110

Met Arg Leu Leu Ala Tyr Val Ser Gly Leu Gly Phe Gly Ile Met Ser

115 120 125

Gly Val Phe Ser Phe Val Asn Thr Leu Ser Asp Ser Leu Gly Pro Gly

130 135 140

Thr Val Gly Ile His Gly Asp Ser Pro Gln Phe Phe Leu Tyr Ser Ala

145 150 155 160

Phe Met Thr Leu Val Ile Ile Leu Leu His Val Phe Trp Gly Ile Val

165 170 175

Phe Phe Asp Gly Cys Glu Lys Lys Lys Trp Gly Ile Leu Leu Ile Val

180 185 190

Leu Leu Thr His Leu Leu Val Ser Ala Gln Thr Phe Ile Ser Ser Tyr

195 200 205

Tyr Gly Ile Asn Leu Ala Ser Ala Phe Ile Ile Leu Val Leu Met Gly

210 215 220

Thr Trp Ala Phe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu

225 230 235 240

Cys Leu Leu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg Ser

245 250 255

Arg

<210> SEQ ID NO: 52

<211> LENGTH: 216

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 52

Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro

1 5 10 15

Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Thr Glu Pro Leu Arg Ile

20 25 30

Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Ile

35 40 45

Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile Asp Asn Lys Asp

50 55 60

Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly Ala Phe Val Ser Val

65 70 75 80

Tyr Ile Gln Glu Met Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Ser Glu Gly Leu Lys Ser Ile Asn Pro Gly Glu Thr Ala Pro Ser

100 105 110

Met Arg Leu Leu Ala Tyr Ala Phe Met Thr Leu Val Ile Ile Leu Leu

115 120 125

His Val Phe Trp Gly Ile Val Phe Phe Asp Gly Cys Glu Lys Lys Lys

130 135 140

Trp Gly Ile Leu Leu Ile Val Leu Leu Thr His Leu Leu Val Ser Ala

145 150 155 160

Gln Thr Phe Ile Ser Ser Tyr Tyr Gly Ile Asn Leu Ala Ser Ala Phe

165 170 175

Ile Ile Leu Val Leu Met Gly Thr Trp Ala Phe Leu Ala Ala Gly Gly

180 185 190

Ser Cys Arg Ser Leu Lys Leu Cys Leu Leu Cys Gln Asp Lys Asn Phe

195 200 205

Leu Leu Tyr Asn Gln Arg Ser Arg

210 215

<210> SEQ ID NO: 53

<211> LENGTH: 81

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 53

Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro

1 5 10 15

Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Thr Glu Pro Leu Arg Ile

20 25 30

Ile Phe Leu Ile Ala Gly Arg Arg Val Glu Thr Cys Lys Asn Thr Glu

35 40 45

Ala Pro Asp Cys Ala Ser Pro Ser Gly Ser Leu Ser Phe Leu Leu Val

50 55 60

Gly Val Ser Thr Asp Phe Val Pro Cys Leu Val His Gly Lys Ser His

65 70 75 80

Tyr

<210> SEQ ID NO: 54

<211> LENGTH: 257

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 54

Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro

1 5 10 15

Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Thr Glu Pro Leu Arg Ile

20 25 30

Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Ile

35 40 45

Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile Asp Asn Lys Asp

50 55 60

Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly Ala Phe Val Ser Val

65 70 75 80

Tyr Ile Arg Glu Met Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Ser Glu Gly Leu Lys Ser Ile Asn Pro Gly Glu Thr Ala Pro Ser

100 105 110

Met Arg Leu Leu Ala Tyr Val Ser Gly Leu Gly Phe Gly Ile Met Ser

115 120 125

Gly Val Phe Ser Phe Val Asn Thr Leu Ser Asp Ser Leu Gly Pro Gly

130 135 140

Thr Val Gly Ile His Gly Asp Ser Pro Gln Phe Phe Leu Tyr Ser Ala

145 150 155 160

Phe Met Thr Leu Val Ile Ile Leu Leu His Val Phe Trp Gly Ile Val

165 170 175

Phe Phe Asp Gly Cys Glu Lys Lys Lys Trp Gly Ile Leu Leu Ile Val

180 185 190

Leu Leu Thr His Leu Leu Val Ser Ala Gln Thr Phe Ile Ser Ser Tyr

195 200 205

Tyr Gly Ile Asn Leu Ala Ser Ala Phe Ile Ile Leu Val Leu Met Gly

210 215 220

Thr Trp Ala Phe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu

225 230 235 240

Cys Leu Leu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg Ser

245 250 255

Arg

<210> SEQ ID NO: 55

<211> LENGTH: 257

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 55

Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro

1 5 10 15

Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Thr Glu Pro Leu Arg Ile

20 25 30

Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Ile

35 40 45

Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile Asp Asn Lys Asp

50 55 60

Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly Ala Phe Val Ser Val

65 70 75 80

Tyr Ile Gln Glu Met Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Ser Glu Gly Leu Lys Ser Ile Asn Pro Gly Glu Thr Ala Pro Ser

100 105 110

Met Arg Leu Leu Ala Tyr Val Ser Gly Leu Gly Phe Gly Ile Met Ser

115 120 125

Gly Val Phe Ser Phe Val Asn Thr Leu Ser Asp Ser Leu Gly Pro Gly

130 135 140

Thr Val Gly Ile His Gly Asp Ser Pro Gln Phe Phe Leu Tyr Ser Ala

145 150 155 160

Phe Met Thr Leu Val Ile Ile Leu Leu His Val Phe Trp Gly Ile Val

165 170 175

Phe Phe Asp Gly Cys Glu Lys Lys Lys Trp Gly Ile Leu Leu Ile Val

180 185 190

Leu Leu Thr His Leu Leu Val Ser Ala Gln Thr Phe Ile Ser Ser Tyr

195 200 205

Tyr Gly Ile Asn Leu Ala Ser Ala Phe Ile Ile Leu Val Leu Met Gly

210 215 220

Thr Trp Ala Phe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu

225 230 235 240

Cys Leu Leu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg Ser

245 250 255

Arg

<210> SEQ ID NO: 56

<211> LENGTH: 257

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 56

Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro

1 5 10 15

Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Thr Glu Pro Leu Arg Ile

20 25 30

Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Ile

35 40 45

Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile Asp Asn Lys Asp

50 55 60

Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly Ala Phe Val Ser Val

65 70 75 80

Tyr Ile Arg Glu Met Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Ser Glu Gly Leu Lys Ser Ile Asn Pro Gly Glu Thr Ala Pro Ser

100 105 110

Met Arg Leu Leu Ala Tyr Val Ser Gly Leu Gly Phe Gly Ile Met Ser

115 120 125

Gly Val Phe Ser Phe Val Asn Thr Leu Ser Asp Ser Leu Gly Pro Gly

130 135 140

Thr Val Gly Ile His Gly Asp Ser Pro Gln Phe Phe Leu Tyr Ser Ala

145 150 155 160

Phe Met Thr Leu Val Ile Ile Leu Leu His Val Phe Trp Gly Ile Val

165 170 175

Phe Phe Asp Gly Cys Glu Lys Lys Lys Trp Gly Ile Leu Leu Ile Val

180 185 190

Leu Leu Thr His Leu Leu Val Ser Ala Gln Thr Phe Ile Ser Ser Tyr

195 200 205

Tyr Gly Ile Asn Leu Ala Ser Ala Phe Ile Ile Leu Val Leu Met Gly

210 215 220

Thr Trp Ala Phe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu

225 230 235 240

Cys Leu Leu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg Ser

245 250 255

Arg

<210> SEQ ID NO: 57

<211> LENGTH: 257

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 57

Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro

1 5 10 15

Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Ile Glu Pro Leu Arg Ile

20 25 30

Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Ile

35 40 45

Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile Asp Asn Lys Asp

50 55 60

Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly Ala Phe Val Ser Val

65 70 75 80

Tyr Ile Gln Glu Met Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Ser Glu Gly Leu Lys Ser Ile Asn Pro Gly Glu Thr Ala Pro Ser

100 105 110

Met Arg Leu Leu Ala Tyr Val Ser Gly Leu Gly Phe Gly Ile Met Ser

115 120 125

Gly Val Phe Ser Phe Val Asn Thr Leu Ser Asp Ser Leu Gly Pro Gly

130 135 140

Thr Val Gly Ile His Gly Asp Ser Pro Gln Phe Phe Leu Tyr Ser Ala

145 150 155 160

Phe Met Thr Leu Val Ile Ile Leu Leu His Val Phe Trp Gly Ile Val

165 170 175

Phe Phe Asp Gly Cys Glu Lys Lys Lys Trp Gly Ile Leu Leu Ile Val

180 185 190

Leu Leu Thr His Leu Leu Val Ser Ala Gln Thr Phe Ile Ser Ser Tyr

195 200 205

Tyr Gly Ile Asn Leu Ala Ser Ala Phe Ile Ile Leu Val Leu Met Gly

210 215 220

Thr Trp Ala Phe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu

225 230 235 240

Cys Leu Leu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg Ser

245 250 255

Arg

<210> SEQ ID NO: 58

<211> LENGTH: 257

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQENCE: 58

Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly Pro

1 5 10 15

Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Thr Glu Pro Leu Arg Ile

20 25 30

Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser Leu Leu Ile

35 40 45

Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile Asp Asn Lys Asp

50 55 60

Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly Ala Phe Val Ser Val

65 70 75 80

Tyr Ile Gln Glu Met Phe Arg Phe Ala Tyr Tyr Lys Leu Leu Lys Lys

85 90 95

Ala Ser Glu Gly Leu Lys Ser Ile Asn Pro Gly Glu Thr Ala Pro Ser

100 105 110

Met Arg Leu Leu Ala Tyr Val Ser Gly Leu Gly Phe Gly Ile Met Ser

115 120 125

Gly Val Phe Ser Phe Val Asn Thr Leu Ser Asp Ser Leu Gly Pro Gly

130 135 140

Thr Val Gly Ile His Gly Asp Ser Pro Gln Phe Phe Leu Tyr Ser Ala

145 150 155 160

Phe Met Thr Leu Val Ile Ile Leu Leu His Val Phe Trp Gly Ile Val

165 170 175

Phe Phe Asp Gly Cys Glu Lys Lys Lys Trp Gly Ile Leu Leu Ile Val

180 185 190

Leu Leu Thr His Leu Leu Val Ser Ala Gln Thr Phe Ile Ser Ser Tyr

195 200 205

Tyr Gly Ile Asn Leu Ala Ser Ala Phe Ile Ile Leu Val Leu Met Gly

210 215 220

Thr Trp Ala Phe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu

225 230 235 240

Cys Leu Leu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg Ser

245 250 255

Arg

<210> SEQ ID NO: 59

<211> LENGTH: 21

<212> TYPE: DNA

<213> ORGANISM: Rattus norvegicus

<400> SEQENCE: 59

ctccttccac aatcggtatt a 21

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Citation

Patents Cited in This Cited by
Title Current Assignee Application Date Publication Date
Modification of amyloid-beta load in non-brain tissue MODGENE LLC 13 November 2009 13 May 2010
Method and reagent for the treatment of Alzheimer's disease RIBOZYME PHARMACEUTICALS, INC. 30 August 2000 15 May 2003
Glycoconjugates of RNA Interference Agents ALNYLAM PHARMACEUTICALS, INC. 23 April 2008 13 August 2009
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