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Numéro de publicationUS20080161243 A1
Type de publicationDemande
Numéro de demandeUS 11/929,714
Date de publication3 juil. 2008
Date de dépôt30 oct. 2007
Date de priorité21 déc. 2001
Autre référence de publicationCA2471363A1, CA2471363C, CA2841097A1, EP1463751A2, EP1463751A4, EP1463751B1, EP1997829A1, EP2261250A1, EP2261250B1, EP2277888A2, EP2277888A3, EP2277889A2, EP2277889A3, EP2277889B1, EP2277910A1, EP2990417A1, US7141547, US7238667, US7592010, US7799759, US7847079, US8012464, US8071539, US8211439, US8252739, US8513189, US8993517, US9221896, US9296809, US20050186664, US20060194735, US20060276396, US20070244047, US20070259815, US20080146503, US20080153751, US20080167239, US20080167240, US20080213886, US20090093402, US20090099073, US20110009312, US20120046221, US20130150296, US20140179596, US20140303077, US20150203568, US20150329619, US20160152687, US20170096472, WO2003060071A2, WO2003060071A3
Numéro de publication11929714, 929714, US 2008/0161243 A1, US 2008/161243 A1, US 20080161243 A1, US 20080161243A1, US 2008161243 A1, US 2008161243A1, US-A1-20080161243, US-A1-2008161243, US2008/0161243A1, US2008/161243A1, US20080161243 A1, US20080161243A1, US2008161243 A1, US2008161243A1
InventeursCraig A. Rosen, William A. Haseltine, David J. Ballance, Andrew J. Turner, Steven M. Ruben
Cessionnaire d'origineHuman Genome Sciences, Inc., Delta Biotechnology Limited
Exporter la citationBiBTeX, EndNote, RefMan
Liens externes: USPTO, Cession USPTO, Espacenet
Albumin Fusion Proteins
US 20080161243 A1
Résumé
The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.
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Revendications(19)
1-21. (canceled)
22. An albumin fusion protein comprising a B-type natriuretic peptide (BNP) polypeptide fused to albumin, wherein the fusion protein has BNP activity, and wherein:
(a) the BNP polypeptide is selected from a wild-type BNP, a BNP fragment, and a BNP variant, and
(b) the albumin is selected from a wild-type albumin, an albumin fragment, and an albumin variant, wherein the albumin fragment increases the serum plasma half-life of the BNP polypeptide.
23. The albumin fusion protein of claim 22, wherein the BNP polypeptide comprises the amino acid sequence of SEQ ID NO:1802 or SEQ ID NO:442.
24. The albumin fusion protein of claim 22, wherein the albumin is selected from:
a) human albumin;
b) Bos taurus albumin;
c) Sus scrofa albumin;
d) Equus caballus albumin;
e) Ovis aries albumin;
f) Salmo salar albumin;
g) Gallus gallus albumin;
h) Felis catus albumin;
i) Canis Familiaris albumin;
j) an albumin fragment;
k) an albumin variant;
l) SEQ ID NO:1038;
m) a fragment of albumin consisting of amino acids 1-194 of SEQ ID NO:1038;
n) a fragment of albumin consisting of amino acids 195-387 of SEQ ID NO:1038;
o) a fragment of albumin consisting of amino acids 388-585 of SEQ ID NO:1038;
p) a fragment of albumin consisting of amino acids 1-387 of SEQ ID NO: 1038;
q) a fragment of albumin consisting of amino acids 195-585 of SEQ ID NO:1038;
r) a fragment of albumin consisting of amino acids 1-105 of SEQ ID NO:1038;
s) a fragment of albumin consisting of amino acids 120-194 of SEQ ID NO:1038;
t) a fragment of albumin consisting of amino acids 195-291 of SEQ ID NO:1038;
u) a fragment of albumin consisting of amino acids 316-387 of SEQ ID NO:1038;
v) a fragment of albumin consisting of amino acids 388-491 of SEQ ID NO:1038;
w) a fragment of albumin consisting of amino acids 512-585 of SEQ ID NO:1038;
x) a fragment of albumin that is 10, 15, 20, 25, 30, 50, 100, or 150 amino acids in length;
y) a fragment of albumin consisting of one or more domains of albumin; and
z) a variant of SEQ ID NO: 1038 selected from
i) L407A;
ii) L408V;
iii) V409A;
iv) R410A;
v) K413Q; and
vi) K414Q.
25. The albumin fusion protein of claim 22, wherein the albumin fusion protein further comprises a leader sequence.
26. The albumin fusion protein of claim 25, wherein the leader sequence is selected from:
a) HSA;
b) kex2;
c) native BNP; and
d) a fusion of at least one of the leader sequences selected from HSA, kex2 and native BNP.
27. The albumin fusion protein of claim 22, further comprising one or more additional therapeutic polypeptides.
28. The albumin fusion protein of claim 22 comprising the amino acid sequence of SEQ ID NO:1634 or SEQ ID NO: 1275.
29. A nucleotide sequence encoding the albumin fusion protein of claim 22.
30. The nucleotide sequence of claim 29, wherein the nucleotide sequence comprises SEQ ID NO: 1466 or SEQ ID NO: 1276.
31. A construct expressing the albumin fusion protein of claim 22.
32. A host cell expressing the albumin fusion protein of claim 22.
33. The host cell of claim 32, wherein the host cell is a mammalian cell, a yeast cell or a prokaryotic cell.
34. A method for expressing an albumin fusion protein comprising culturing the host cell of claim 32 under conditions suitable for the expression of the albumin fusion protein and recovering the albumin fusion protein.
35. An albumin fusion protein expressed by the host cell of claim 32, wherein the albumin fusion protein is glycosylated, non-glycosylated or a glycosylation isomer.
36. A composition comprising the albumin fusion protein of claim 22 and a pharmaceutically acceptable carrier.
37. A kit comprising the composition of claim 36 and instructions for the use thereof.
38. A method of treating, preventing, diagnosing or ameliorating a disease, disorder or condition in a subject in need thereof comprising administering an effective amount of an albumin fusion protein comprising a B-type natriuretic peptide (BNP) polypeptide fused to albumin, wherein the fusion protein has BNP activity, and wherein:
(a) the BNP polypeptide is selected from a wild-type BNP, a BNP fragment, and a BNP variant, and
(b) the albumin is selected from a wild-type albumin, an albumin fragment, and an albumin variant, wherein the albumin fragment increases the serum plasma half-life of the BNP polypeptide.
39. The method of claim 38, wherein the disease, disorder or condition is selected from congestive heart failure, cardiac volume overload, cardiac decompensation, cardiac failure, left ventricular dysfunction and dyspnea.
Description
    CROSS REFERENCE TO RELATED APPLICATION
  • [0001]
    This is a divisional of U.S. application Ser. No. 11/429,276, filed May 8, 2006, which is a continuation of U.S. application Ser. No. 10/775,204, filed Feb. 11, 2004, which is a continuation of International Application No. PCT/US02/40891, filed Dec. 23, 2002, which claims benefit under 35 USC 119(e) of U.S. Provisional Application Nos. 60/341,811, filed Dec. 21, 2001; 60/350,358, filed Jan. 24, 2002; 60/351,360, filed Jan. 28, 2002; 60/359,370, filed Feb. 26, 2002; 60/360,000, filed Feb. 28, 2002; 60/367,500, filed Mar. 27, 2002; 60/370,227, filed Apr. 8, 2002; 60/378,950, filed May 10, 2002; 60/382,617, filed May 24, 2002; 60/383,123, filed May 28, 2002; 60/385,708, filed Jun. 5, 2002; 60/394,625, filed Jul. 10, 2002; 60/398,008, filed Jul. 24, 2002; 60/402,131, filed Aug. 9, 2002; 60/402,708, filed Aug. 13, 2002; 60/411,426, filed Sep. 18, 2002; 60/411,355, filed Sep. 18, 2002; 60/414,984, filed Oct. 2, 2002; 60/417,611, filed Oct. 11, 2002; 60/420,246, filed Oct. 23, 2002; and 60/423,623, filed Nov. 5, 2002. All of the above listed applications are incorporated by reference herein.
  • REFERENCE TO SEQUENCE LISTING ON COMPACT DISC
  • [0002]
    This application refers to a “Sequence Listing” listed below, which is provided as an electronic document on three identical compact disc (CD-R), labeled “Copy 1,” “Copy 2,” and “CRF.” These compact discs each contain the file “PF564D1 SEQLIST FINAL.txt” (3,568,877 bytes, created on Apr. 19, 2006), which is incorporated by reference in its entirety. The Sequence Listing may be viewed on an IBM-PC machine running the MS-Windows operating system.
  • BACKGROUND OF THE INVENTION
  • [0003]
    The invention relates generally to Therapeutic proteins (including, but not limited to, at least one polypeptide, antibody, peptide, or fragment and variant thereof) fused to albumin or fragments or variants of albumin. The invention encompasses polynucleotides encoding therapeutic albumin fusion proteins, therapeutic albumin fusion proteins, compositions, pharmaceutical compositions, formulations and kits. Host cells transformed with the polynucleotides encoding therapeutic albumin fusion proteins are also encompassed by the invention, as are methods of making the albumin fusion proteins of the invention using these polynucleotides, and/or host cells.
  • [0004]
    Human serum albumin (HSA, or HA), a protein of 585 amino acids in its mature form (as shown in FIG. 1 (SEQ ID NO:1038)), is responsible for a significant proportion of the osmotic pressure of serum and also functions as a carrier of endogenous and exogenous ligands. At present, HA for clinical use is produced by extraction from human blood. The production of recombinant HA (rHA) in microorganisms has been disclosed in EP 330 451 and EP 361 991.
  • [0005]
    Therapeutic proteins in their native state or when recombinantly produced, such as interferons and growth hormones, are typically labile molecules exhibiting short shelf-lives, particularly when formulated in aqueous solutions. The instability in these molecules when formulated for administration dictates that many of the molecules must be lyophilized and refrigerated at all times during storage, thereby rendering the molecules difficult to transport and/or store. Storage problems are particularly acute when pharmaceutical formulations must be stored and dispensed outside of the hospital environment.
  • [0006]
    Few practical solutions to the storage problems of labile protein molecules have been proposed. Accordingly, there is a need for stabilized, long lasting formulations of proteinaceous therapeutic molecules that are easily dispensed, preferably with a simple formulation requiring minimal post-storage manipulation.
  • SUMMARY OF THE INVENTION
  • [0007]
    The present invention encompasses albumin fusion proteins comprising a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragment or variant thereof) fused to albumin or a fragment (portion) or variant of albumin. The present invention also encompasses polynucleotides comprising, or alternatively consisting of, nucleic acid molecules encoding a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragment or variant thereof) fused to albumin or a fragment (portion) or variant of albumin. The present invention also encompasses polynucleotides, comprising, or alternatively consisting of, nucleic acid molecules encoding proteins comprising a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragment or variant thereof) fused to albumin or a fragment (portion) or variant of albumin, that is sufficient to prolong the shelf life of the Therapeutic protein, and/or stabilize the Therapeutic protein and/or its activity in solution (or in a pharmaceutical composition) in vitro and/or in vivo. Albumin fusion proteins encoded by a polynucleotide of the invention are also encompassed by the invention, as are host cells transformed with polynucleotides of the invention, and methods of making the albumin fusion proteins of the invention and using these polynucleotides of the invention, and/or host cells.
  • [0008]
    In a preferred aspect of the invention, albumin fusion proteins include, but are not limited to, those encoded by the polynucleotides described in Table 2.
  • [0009]
    The invention also encompasses pharmaceutical formulations comprising an albumin fusion protein of the invention and a pharmaceutically acceptable diluent or carrier. Such formulations may be in a kit or container. Such kit or container may be packaged with instructions pertaining to the extended shelf life of the Therapeutic protein. Such formulations may be used in methods of treating, preventing, ameliorating or diagnosing a disease or disease symptom in a patient, preferably a mammal, most preferably a human, comprising the step of administering the pharmaceutical formulation to the patient.
  • [0010]
    In other embodiments, the present invention encompasses methods of preventing, treating, or ameliorating a disease or disorder. In preferred embodiments, the present invention encompasses a method of treating a disease or disorder listed in the “Preferred Indication: Y” column of Table 1 comprising administering to a patient in which such treatment, prevention or amelioration is desired an albumin fusion protein of the invention that comprises a Therapeutic protein or portion corresponding to a Therapeutic protein (or fragment or variant thereof) disclosed in the “Therapeutic Protein: X” column of Table 1 (in the same row as the disease or disorder to be treated is listed in the “Preferred Indication: Y” column of Table 1) in an amount effective to treat, prevent or ameliorate the disease or disorder.
  • [0011]
    In one embodiment, an albumin fusion protein described in Table 1 or 2 has extended shelf life.
  • [0012]
    In a second embodiment, an albumin fusion protein described in Table 1 or 2 is more stable than the corresponding unfused Therapeutic molecule described in Table 1.
  • [0013]
    The present invention further includes transgenic organisms modified to contain the nucleic acid molecules of the invention (including, but not limited to, the polynucleotides described in Tables 1 and 2), preferably modified to express an albumin fusion protein of the invention.
  • BRIEF DESCRIPTION OF THE FIGURES
  • [0014]
    FIG. 1A-D shows the amino acid sequence of the mature form of human albumin (SEQ ID NO:1038) and a polynucleotide encoding it (SEQ ID NO:1037).
  • [0015]
    FIG. 2 shows the restriction map of the pPPC0005 cloning vector ATCC deposit PTA-3278.
  • [0016]
    FIG. 3 shows the restriction map of the pSAC35 yeast S. cerevisiae expression vector (Sleep et al., BioTechnology 8:42 (1990)).
  • [0017]
    FIG. 4 shows the effect of various dilutions of EPO albumin fusion proteins encoded by DNA comprised in Construct ID NOS. (hereinafter CID) 1966 and 1981 and recombinant human EPO on the proliferation of TF-1 cells (see Examples 8 and 9). Cells were washed 3× to remove GM-CSF and plated at 10,000 cells/well for 72 hours in the presence of 3-fold dilutions of CID 1966 protein or CID 1981 protein. Concentrations used were calculated based on the weight of Epo alone, not HSA plus Epo. Recombinant human Epo (rhEpo) was used as the positive control and serially diluted 3 fold from 100 ng/ml to 0.01 ng/ml. Cells were exposed to 0.5 mCi/well of 3H-thymidine for an additional 18 hours. (□) rhEpo; (▾) HSA-Epo 1981; () Epo-HSA 1966.
  • [0018]
    FIG. 5 is a dose response analysis and shows the effect of various doses of recombinant human EPO and EPO albumin fusion proteins encoded by DNA comprised in CID 1966 and 1981 on the percent change in hematocrit from day 0 to day 7 (see Examples 8 and 9). 48 eight-week old female DBA/2NHsd mice were divided into 12 groups of 4 animals each. Recombinant human Epo (rhEpo) was administered subcutaneously at 0.5, 1.5, 4.5 and 12 μg/kg on days 0, 2, 4, and 6. Epo albumin fusion proteins made from constructs CID 1966 and CID 1981 were administered subcutaneously at 2, 6, 18, and 54 μg/kg on days 0, 2, 4, and 6. The higher doses of the Epo albumin fusion proteins allows a rough equimolar comparison with recombinant human Epo (note that the weight of the fusions is about 4.35 times the weight of non-glycosylated Epo). On days 0 and 7 of the experiment, the animals were bled via a tail vein and the hematocrit was determined by centrifugation. (▪) rhEpo; (◯) CID 1981; (▴) CID 1966.
  • [0019]
    FIG. 6A shows the effect of various subcutaneous administrations of Epo albumin fusion proteins encoded by DNA comprised in CID 1966 and 1997, respectively, on the percent change in hematocrit from day 0 to day 8 (see Examples 8 and 10). *, p<0.005 compared to rhEpo as determined by Mann-Whitney nonparametric analysis (n=6).
  • [0020]
    FIG. 6B shows the effect of subcutaneous administrations of Epo albumin fusion proteins encoded by DNA comprised in CID 1997 and 1966 on the percent change in hematocrit from day 0 to day 14 (see Examples 8 and 10). *, p<0.005 compared to rhEpo as determined by Mann-Whitney nonparametric analysis (n=6); **, p<0.05 compared to rhEpo as determined by Mann-Whitney nonparametric analysis (n=6).
  • [0021]
    FIG. 7 shows the effect of various dilutions albumin fusion proteins encoded by DNA comprised in CID 1981 and 1997, respectively, on the proliferation of TF-1 cells (see Examples 9 and 10). Cells were washed 3× to remove GM-CSF and plated at 10,000 cells/well for 72 hours in the presence of 3-fold dilutions of Epo albumin fusion proteins encoded by CID 1981 or 1997. Equimolar amounts of rhEpo were used as a positive control (4.35 times less protein added since weight of non-glycosylated Epo is 20 kd, while Epo albumin fusion proteins are 87 kd). Cells were exposed to 0.5 μCi/well of 3H-thymidine for an additional 24 hours. (▪) rhEpo Standard; (▴) CID 1981 (CHO); (∘) CID 1997 (NSO).
  • [0022]
    FIG. 8 shows the effect of various doses of recombinant human EPO (rhEpo) and EPO albumin fusion protein encoded by DNA comprised in construct 1997 (CID 1997) on the percent change in hematocrit from day 0 to day 8 (see Example 10). (▴)=rhEpo, ( )=CID 1997.
  • [0023]
    FIG. 9 shows the effect of various dilutions of IL2 albumin fusion proteins encoded by DNA comprised in CID 1812 (see Example 15) on CTLL-2 proliferation. 1×104 cells/well were seeded in a 96-well plate in a final volume of 200 ul of complete medium containing the indicated amount of IL2 albumin fusion protein (CID 1812). All samples were run in triplicate. The cells were incubated for 40 hours at 37° C., then 20 ul of Alamar Blue was added and cells incubated for 8 hours. Absorbance at 530/590 was used as a measure of proliferation. EC50=0.386±0.021. (Δ)=CID 1812.
  • [0024]
    FIG. 10 shows the effect of IL2 albumin fusion protein encoded by DNA comprised in CID 1812 on RENCA tumor growth at day 21 (see Example 15). BALB/c mice (n=10) were injected SC (midflank) with 105 RENCA cells. 10 days later mice received 2 cycles (Day 10 to Day 14 and Days 17-21) of daily (QD) injections of rIL2 (0.9 mg/kg), IL2 albumin fusion protein (CID 1812 protein; 0.6 mg/kg), or PBS (Placebo) or injections every other day (QOD) of CID 1812 protein (0.6 mg/kg). The tumor volume was determined on Day 21 after RENCA inoculation. The data are presented in scatter analysis (each dot representing single animal). Mean value of each group is depicted by horizontal line. *, p=0.0035 between placebo control and CID 1812 protein. The number in parentheses indicates number of mice alive over the total number of mice per group. (◯)=Placebo; ()=IL2; (Δ)=CID 1812 protein (QD); (□)=CID 1812 protein (QOD).
  • [0025]
    FIG. 11 shows the effect of various dilutions of GCSF albumin fusion proteins encoded by DNA comprised in CID 1642 and 1643 on NFS-60 cell proliferation (see Examples 19 and 20). (▪)=CID 1642; (▴)=CID 1643; (◯)=HSA.
  • [0026]
    FIG. 12 shows the effect of recombinant human GCSF (Neupogen) and GCSF albumin fusion protein on total white blood cell count (see Example 19). Total WBC (103 cells/ul) on each day are presented as the group mean ±SEM. GCSF albumin fusion protein was administered sc at either 25 or 100 ug/kg every 4 days×4 (Q4D), or at 100 ug/kg every 7 days×2 (Q7D). Data from Days 8 and 9 for GCSF albumin fusion protein 100 ug/kg Q7 are presented as Days 9 and 10, respectively, to facilitate comparison with other groups. Controls were saline vehicle administered SC every 4 days×4 (Vehicle Q4D), or Neupogen administered SC daily×14 (Neupogen 5 ug/kg QD). The treatment period is considered Days 1-14, and the recovery period, Days 15-28.
  • [0027]
    FIG. 13 shows the effect of various dilutions of IFNb albumin fusion proteins encoded by DNA comprised in CID 2011 and 2053 on SEAP activity in the ISRE-SEAP/293F reporter cells (see Example 25). Proteins were serially diluted from 5e-7 to 1e-14 g/ml in DMEM/10% FBS and used to treat ISRE-SEAP/293F reporter cells. After 24 hours supernatants were removed from reporter cells and assayed for SEAP activity. IFNb albumin fusion protein was purified from three stable clones: 293F/#2011, CHO/#2011 and NSO/#2053. Mammalian derived IFNb, Avonex, came from Biogen and was reported to have a specific activity of 2.0e5 IU/ug.
  • [0028]
    FIG. 14 illustrates the steady-state levels of insulin mRNA in INS-1 (832/13) cells after treatment with GLP-1 or GLP-1 albumin fusion protein encoded by construct ID 3070 (CID 3070 protein). Both GLP-1 and the CID 3070 protein stimulate transcription of the insulin gene in INS-1 cells. The first bar (black) represents the untreated cells. Bars 2-4 (white) represent cells treated with the indicated concentrations of GLP-1. Bars 5-7 (gray) represent cells treated with the indicated concentrations of CID 3070 protein.
  • [0029]
    FIG. 15 compares the anti-proliferative activity of IFN albumin fusion protein encoded by CID 3165 (CID 3165 protein) and recombinant IFNa (rIFNa) on Hs294T melanoma cells. The cells were cultured with varying concentrations of either CID 3165 protein or rIFNa and proliferation was measured by BrdU incorporation after 3 days of culture. CID 3165 protein caused measurable inhibition of cell proliferation at concentrations above 10 ng/ml with 50% inhibition achieved at approximately 200 ng/ml. (▪)=CID 3165 protein, (♦)=rIFNa.
  • [0030]
    FIG. 16 shows the effect of various dilutions of IFNa albumin fusion proteins on SEAP activity in the ISRE-SEAP/293F reporter cells. One preparation of IFNa fused upstream of albumin (♦) was tested, as well as two different preparations of IFNa fused downstream of albumin (▴) and (▪).
  • [0031]
    FIG. 17 shows the effect of time and dose of IFNa albumin fusion protein encoded by DNA comprised in construct 2249 (CID 2249 protein) on the mRNA level of OAS (p41) in treated monkeys (see Example 31). Per time point: first bar=Vehicle control, 2nd bar=30 ug/kg CID 2249 protein day 1 iv, third bar=30 ug/kg CID 2249 protein day 1 sc, 4th bar=300 ug/kg CID 2249 protein day 1 sc, 5th bar=40 ug/kg recombinant IFNa day 1, 3 and 5 sc.
  • [0032]
    FIG. 18 shows the effect of various dilutions of insulin albumin fusion proteins encoded by DNA comprised in constructs 2250 and 2276 on glucose uptake in 3T3-L1 adipocytes (see Examples 33 and 35).
  • [0033]
    FIG. 19 shows the effect of various GCSF albumin fusion proteins, including those encoded by CID #1643 and #2702 (L-171, see Example 114), on NFS cell proliferation. The horizontal dashed line indicates the minimum level of detection.
  • DETAILED DESCRIPTION
  • [0034]
    Definitions
  • [0035]
    The following definitions are provided to facilitate understanding of certain terms used throughout this specification.
  • [0036]
    As used herein, “polynucleotide” refers to a nucleic acid molecule having a nucleotide sequence encoding a fusion protein comprising, or alternatively consisting of, at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one Therapeutic protein X (or fragment or variant thereof); a nucleic acid molecule having a nucleotide sequence encoding a fusion protein comprising, or alternatively consisting of, the amino acid sequence of SEQ ID NO:Y (as described in column 6 of Table 2) or a fragment or variant thereof; a nucleic acid molecule having a nucleotide sequence comprising or alternatively consisting of the sequence shown in SEQ ID NO:X; a nucleic acid molecule having a nucleotide sequence encoding a fusion protein comprising, or alternatively consisting of, the amino acid sequence of SEQ ID NO:Z; a nucleic acid molecule having a nucleotide sequence encoding an albumin fusion protein of the invention generated as described in Table 2 or in the Examples; a nucleic acid molecule having a nucleotide sequence encoding a Therapeutic albumin fusion protein of the invention, a nucleic acid molecule having a nucleotide sequence contained in an albumin fusion construct described in Table 2, or a nucleic acid molecule having a nucleotide sequence contained in an albumin fusion construct deposited with the ATCC (as described in Table 3).
  • [0037]
    As used herein, “albumin fusion construct” refers to a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one polynucleotide encoding at least one molecule of a Therapeutic protein (or fragment or variant thereof); a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one polynucleotide encoding at least one molecule of a Therapeutic protein (or fragment or variant thereof) generated as described in Table 2 or in the Examples; or a nucleic acid molecule comprising, or alternatively consisting of, a polynucleotide encoding at least one molecule of albumin (or a fragment or variant thereof) joined in frame to at least one polynucleotide encoding at least one molecule of a Therapeutic protein (or fragment or variant thereof), further comprising, for example, one or more of the following elements: (1) a functional self-replicating vector (including but not limited to, a shuttle vector, an expression vector, an integration vector, and/or a replication system), (2) a region for initiation of transcription (e.g., a promoter region, such as for example, a regulatable or inducible promoter, a constitutive promoter), (3) a region for termination of transcription, (4) a leader sequence, and (5) a selectable marker. The polynucleotide encoding the Therapeutic protein and albumin protein, once part of the albumin fusion construct, may each be referred to as a “portion,” “region” or “moiety” of the albumin fusion construct.
  • [0038]
    The present invention relates generally to polynucleotides encoding albumin fusion proteins; albumin fusion proteins; and methods of treating, preventing, or ameliorating diseases or disorders using albumin fusion proteins or polynucleotides encoding albumin fusion proteins. As used herein, “albumin fusion protein” refers to a protein formed by the fusion of at least one molecule of albumin (or a fragment or variant thereof) to at least one molecule of a Therapeutic protein (or fragment or variant thereof). An albumin fusion protein of the invention comprises at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another by genetic fusion (i.e., the albumin fusion protein is generated by translation of a nucleic acid in which a polynucleotide encoding all or a portion of a Therapeutic protein is joined in-frame with a polynucleotide encoding all or a portion of albumin). The Therapeutic protein and albumin protein, once part of the albumin fusion protein, may each be referred to as a “portion”, “region” or “moiety” of the albumin fusion protein (e.g., a “Therapeutic protein portion” or an “albumin protein portion”). In a highly preferred embodiment, an albumin fusion protein of the invention comprises at least one molecule of a Therapeutic protein X or fragment or variant of thereof (including, but not limited to a mature form of the Therapeutic protein X) and at least one molecule of albumin or fragment or variant thereof (including but not limited to a mature form of albumin).
  • [0039]
    In a further preferred embodiment, an albumin fusion protein of the invention is processed by a host cell and secreted into the surrounding culture medium. Processing of the nascent albumin fusion protein that occurs in the secretory pathways of the host used for expression may include, but is not limited to signal peptide cleavage; formation of disulfide bonds; proper folding; addition and processing of carbohydrates (such as for example, N- and O-linked glycosylation); specific proteolytic cleavages; and assembly into multimeric proteins. An albumin fusion protein of the invention is preferably in the processed form. In a most preferred embodiment, the “processed form of an albumin fusion protein” refers to an albumin fusion protein product which has undergone N-terminal signal peptide cleavage, herein also referred to as a “mature albumin fusion protein”.
  • [0040]
    In several instances, a representative clone containing an albumin fusion construct of the invention was deposited with the American Type Culture Collection (herein referred to as “ATCC®”). Furthermore, it is possible to retrieve a given albumin fusion construct from the deposit by techniques known in the art and described elsewhere herein. The ATCC® is located at 10801 University Boulevard, Manassas, Va. 20110-2209, USA. The ATCC® deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.
  • [0041]
    In one embodiment, the invention provides a polynucleotide encoding an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a serum albumin protein. In a further embodiment, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a serum albumin protein. In a preferred embodiment, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a serum albumin protein encoded by a polynucleotide described in Table 2. In a further preferred embodiment, the invention provides a polynucleotide encoding an albumin fusion protein whose sequence is shown as SEQ ID NO:Y in Table 2. In other embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment of a Therapeutic protein and a serum albumin protein. In other embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active variant of a Therapeutic protein and a serum albumin protein. In preferred embodiments, the serum albumin protein component of the albumin fusion protein is the mature portion of serum albumin. The invention further encompasses polynucleotides encoding these albumin fusion proteins.
  • [0042]
    In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein, and a biologically active and/or therapeutically active fragment of serum albumin. In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a biologically active and/or therapeutically active variant of serum albumin. In preferred embodiments, the Therapeutic protein portion of the albumin fusion protein is the mature portion of the Therapeutic protein. In a further preferred embodiment, the Therapeutic protein portion of the albumin fusion protein is the extracellular soluble domain of the Therapeutic protein. In an alternative embodiment, the Therapeutic protein portion of the albumin fusion protein is the active form of the Therapeutic protein. The invention further encompasses polynucleotides encoding these albumin fusion proteins.
  • [0043]
    In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment or variant of a Therapeutic protein and a biologically active and/or therapeutically active fragment or variant of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of a Therapeutic protein and the mature portion of serum albumin. The invention further encompasses polynucleotides encoding these albumin fusion proteins.
  • [0044]
    Therapeutic Proteins
  • [0045]
    As stated above, a polynucleotide of the invention encodes a protein comprising or alternatively consisting of, at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another, preferably by genetic fusion.
  • [0046]
    An additional embodiment includes a polynucleotide encoding a protein comprising or alternatively consisting of at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are linked with one another by chemical conjugation.
  • [0047]
    As used herein, “Therapeutic protein” refers to proteins, polypeptides, antibodies, peptides or fragments or variants thereof, having one or more therapeutic and/or biological activities. Therapeutic proteins encompassed by the invention include but are not limited to, proteins, polypeptides, peptides, antibodies, and biologics. (The terms peptides, proteins, and polypeptides are used interchangeably herein.) It is specifically contemplated that the term “Therapeutic protein” encompasses antibodies and fragments and variants thereof. Thus a protein of the invention may contain at least a fragment or variant of a Therapeutic protein, and/or at least a fragment or variant of an antibody. Additionally, the term “Therapeutic protein” may refer to the endogenous or naturally occurring correlate of a Therapeutic protein.
  • [0048]
    By a polypeptide displaying a “therapeutic activity” or a protein that is “therapeutically active” is meant a polypeptide that possesses one or more known biological and/or therapeutic activities associated with a therapeutic protein such as one or more of the Therapeutic proteins described herein or otherwise known in the art. As a non-limiting example, a “Therapeutic protein” is a protein that is useful to treat, prevent or ameliorate a disease, condition or disorder. As a non-limiting example, a “Therapeutic protein” may be one that binds specifically to a particular cell type (normal (e.g., lymphocytes) or abnormal e.g., (cancer cells)) and therefore may be used to target a compound (drug, or cytotoxic agent) to that cell type specifically.
  • [0049]
    For example, a non-exhaustive list of “Therapeutic protein” portions which may be comprised by an albumin fusion protein of the invention includes, but is not limited to, erythropoietin (EPO), IL-2, G-CSF, Insulin, Calcitonin, Growth Hormone, IFN-alpha, IFN-beta, PTH, TR6 (International Publication No. WO 98/30694), BLyS, BLyS single chain antibody, Resistin, Growth hormone releasing factor, VEGF-2, KGF-2, D-SLAM, KDI, and TR2, GLP-1, Extendin 4, and GM-CSF.
  • [0050]
    Interferon hybrids may also be fused to the amino or carboxy terminus of albumin to form an interferon hybrid albumin fusion protein. Interferon hybrid albumin fusion protein may have enhanced, or alternatively, suppressed interferon activity, such as antiviral responses, regulation of cell growth, and modulation of immune response (Lebleu et al., PNAS USA, 73:3107-3111 (1976); Gresser et al., Nature, 251:543-545 (1974); and Johnson, Texas Reports Biol Med, 35:357-369 (1977)). Each interferon hybrid albumin fusion protein can be used to treat, prevent, or ameliorate viral infections (e.g., hepatitis (e.g., HCV); or HIV), multiple sclerosis, or cancer.
  • [0051]
    In one embodiment, the interferon hybrid portion of the interferon hybrid albumin fusion protein comprises an interferon alpha-interferon alpha hybrid (herein referred to as an alpha-alpha hybrid). For example, the alpha-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon alpha A fused to interferon alpha D. In a further embodiment, the A/D hybrid is fused at the common BgIII restriction site to interferon alpha D, wherein the N-terminal portion of the A/D hybrid corresponds to amino acids 1-62 of interferon alpha A and the C-terminal portion corresponds to amino acids 64-166 of interferon alpha D. For example, this A/D hybrid would comprise the amino acid sequence: CDLPQTHSLGSRRTLMLLAQMRX1ISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHE MIQQIFNLFTTKDSSAAWDEDLLDKFCTELYQQLNDLEACVMQEERVGETPLMNX2D SILAVKKYFRRITLYLTEKKYSPCAWEVVRAEIMRSLSLSTNLQERLRRKE (SEQ ID NO:1326), wherein the X1 is R or K and the X2 is A or V (see, for example, Construct ID #2875). In an additional embodiment, the A/D hybrid is fused at the common PvuIII restriction site, wherein the N-terminal portion of the A/D hybrid corresponds to amino acids 1-91 of interferon alpha A and the C-terminal portion corresponds to amino acids 93-166 of interferon alpha D. For example, this A/D hybrid would comprise the amino acid sequence: CDLPQTHSLGSRRTLMLLAQMRX1ISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHE MIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVMQEERVGETPLMNX2D SILAVKKYFRRITLYLTEKKYSPCAWEVVRAEIMRSLSLSTNLQERLRRKE (SEQ ID NO:1311), wherein the X1 is R or K and the second X2 is A or V (see, for example, Construct ID #2872). These hybrids are further described in U.S. Pat. No. 4,414,510, which is hereby incorporated by reference in its entirety.
  • [0052]
    In an additional embodiment, the alpha-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon alpha A fused to interferon alpha F. In a further embodiment, the A/F hybrid is fused at the common PvuIII restriction site, wherein the N-terminal portion of the A/F hybrid corresponds to amino acids 1-91 of interferon alpha A and the C-terminal portion corresponds to amino acids 93-166 of interferon alpha F. For example, this A/F hybrid would comprise the amino acid sequence: CDLPQTHSLGSRRTLMLLAQMRXISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHE MIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDMEACVIQEVGVEETPLMNVDSI LAVKKYFQRITLYLTEKKYSPCAWEVVRAEIMRSFSLSKIFQERLRRKE (SEQ ID NO:1321), wherein X is either R or K (see, for example, Construct ID #2874). These hybrids are further described in U.S. Pat. No. 4,414,510, which is hereby incorporated by reference in its entirety. In a further embodiment, the alpha-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon alpha A fused to interferon alpha B. In an additional embodiment, the A/B hybrid is fused at the common PvuIII restriction site, wherein the N-terminal portion of the A/B hybrid corresponds to amino acids 1-91 of interferon alpha A and the C-terminal portion corresponds to amino acids 93-166 of interferon alpha B. For example, this A/B hybrid would comprise an amino acid sequence: CDLPQTHSLGSRRTLMLLAQMRX1ISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHE MIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEX2X3X4X5QEVGVIESPLMYE DSILAVRKYFQRITLYLTEKKYSSCAWEVVRAEIMRSFSLSINLQKRLKSKE (SEQ ID NO:1316), wherein the X1 is R or K and X2 through X5 is SCVM or VLCD (see, for example, Construct ID #2873). These hybrids are further described in U.S. Pat. No. 4,414,510, which is hereby incorporated by reference in its entirety.
  • [0053]
    In another embodiment, the interferon hybrid portion of the interferon hybrid albumin fusion protein comprises an interferon beta-interferon alpha hybrid (herein referred to as a beta-alpha hybrid). For example, the beta-alpha hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon beta-1 fused to interferon alpha D (also referred to as interferon alpha-1). In a further embodiment, the beta-1/alpha D hybrid is fused wherein the N-terminal portion corresponds to amino acids 1-73 of interferon beta-1 and the C-terminal portion corresponds to amino acids 74-167 of interferon alpha D. For example, this beta-1/alpha D hybrid would comprise an amino acid sequence: MSYNLLGFLQRSSNFQCQKLLWQLNGRLEYCLKDRMNFDIPEEIKQLQQFQKEDAAL TIYEMLQNIFAIFRQDSSAAWDEDLLDKFCTELYQQLNDLEACVMQEERVGETPLMN XDSILAVKKYFRRITLYLTEKKYSPCAWEVVRAEIMRSLSLSTNLQERLRRKE (SEQ ID NO:2130), wherein X is A or V. These hybrids are further described in U.S. Pat. No. 4,758,428, which is hereby incorporated by reference in its entirety.
  • [0054]
    In another embodiment, the interferon hybrid portion of the interferon hybrid albumin fusion protein comprises an interferon alpha-interferon beta hybrid (herein referred to as a alpha-beta hybrid). For example, the alpha-beta hybrid portion of the interferon hybrid albumin fusion protein consists, or alternatively comprises, of interferon alpha D (also referred to as interferon alpha-1) fused to interferon beta-1. In a further embodiment, the alpha D/beta-1 hybrid is fused wherein the N-terminal portion corresponds to amino acids 1-73 of interferon alpha D and the C-terminal portion corresponds to amino acids 74-166 of interferon beta-1. For example, this alpha D/beta-1 hybrid would have an amino acid sequence: MCDLPETHSLDNRRTLMLLAQMSRISPSSCLMDRHDFGFPQEEFDGNQFQKAPAISVL HELIQQIFNLFTTKDSSSTGWNETIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKL MSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINRLTGYLRN (SEQ ID NO:2131). These hybrids are further described in U.S. Pat. No. 4,758,428, which is hereby incorporated by reference in its entirety.
  • [0055]
    In further embodiments, the interferon hybrid portion of the interferon hybrid albumin fusion proteins may comprise additional combinations of alpha-alpha interferon hybrids, alpha-beta interferon hybrids, and beta-alpha interferon hybrids. In additional embodiments, the interferon hybrid portion of the interferon hybrid albumin fusion protein may be modified to include mutations, substitutions, deletions, or additions to the amino acid sequence of the interferon hybrid. Such modifications to the interferon hybrid albumin fusion proteins may be made, for example, to improve levels of production, increase stability, increase or decrease activity, or confer new biological properties.
  • [0056]
    The above-described interferon hybrid albumin fusion proteins are encompassed by the invention, as are host cells and vectors containing polynucleotides encoding the polypeptides. In one embodiment, a interferon hybrid albumin fusion protein encoded by a polynucleotide as described above has extended shelf life. In an additional embodiment, a interferon hybrid albumin fusion protein encoded by a polynucleotide described above has a longer serum half-life and/or more stabilized activity in solution (or in a pharmaceutical composition) in vitro and/or in vivo than the corresponding unfused interferon hybrid molecule.
  • [0057]
    In another non-limiting example, a “Therapeutic protein” is a protein that has a biological activity, and in particular, a biological activity that is useful for treating, preventing or ameliorating a disease. A non-inclusive list of biological activities that may be possessed by a Therapeutic protein includes, enhancing the immune response, promoting angiogenesis, inhibiting angiogenesis, regulating endocrine function, regulating hematopoietic functions, stimulating nerve growth, enhancing an immune response, inhibiting an immune response, or any one or more of the biological activities described in the “Biological Activities” section below and/or as disclosed for a given Therapeutic protein in Table 1 (column 2).
  • [0058]
    As used herein, “therapeutic activity” or “activity” may refer to an activity whose effect is consistent with a desirable therapeutic outcome in humans, or to desired effects in non-human mammals or in other species or organisms. Therapeutic activity may be measured in vivo or in vitro. For example, a desirable effect may be assayed in cell culture. As an example, when EPO is the Therapeutic protein, the effects of EPO on cell proliferation as described in Example 8 may be used as the endpoint for which therapeutic activity is measured. Such in vitro or cell culture assays are commonly available for many Therapeutic proteins as described in the art. Examples of assays include, but are not limited to those described herein in the Examples section or in the “Exemplary Activity Assay” column (column 3) of Table 1.
  • [0059]
    Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention, such as cell surface and secretory proteins, are often modified by the attachment of one or more oligosaccharide groups. The modification, referred to as glycosylation, can dramatically affect the physical properties of proteins and can be important in protein stability, secretion, and localization. Glycosylation occurs at specific locations along the polypeptide backbone. There are usually two major types of glycosylation: glycosylation characterized by O-linked oligosaccharides, which are attached to serine or threonine residues; and glycosylation characterized by N-linked oligosaccharides, which are attached to asparagine residues in an Asn-X-Ser or Asn-X-Thr sequence, where X can be any amino acid except proline. N-acetylneuramic acid (also known as sialic acid) is usually the terminal residue of both N-linked and 0-linked oligosaccharides. Variables such as protein structure and cell type influence the number and nature of the carbohydrate units within the chains at different glycosylation sites. Glycosylation isomers are also common at the same site within a given cell type.
  • [0060]
    For example, several types of human interferon are glycosylated. Natural human interferon-α2 is O-glycosylated at threonine 106, and N-glycosylation occurs at asparagine 72 in interferon-α14 (Adolf et al., J. Biochem 276:511 (1991); Nyman T A et al., J. Biochem 329:295 (1998)). The oligosaccharides at asparagine 80 in natural interferon-β1α may play an important factor in the solubility and stability of the protein, but may not be essential for its biological activity. This permits the production of an unglycosylated analog (interferon-β1b) engineered with sequence modifications to enhance stability (Hosoi et al., J. Interferon Res. 8:375 (1988; Karpusas et al., Cell Mol Life Sci 54:1203 (1998); Knight, J. Interferon Res. 2:421 (1982); Runkel et al., Pharm Res 15:641 (1998); Lin, Dev. Biol. Stand. 96:97 (1998)). Interferon-γ contains two N-linked oligosaccharide chains at positions 25 and 97, both important for the efficient formation of the bioactive recombinant protein, and having an influence on the pharmacokinetic properties of the protein (Sareneva et al., Eur. J. Biochem 242:191 (1996); Sareneva et al., Biochem J. 303:831 (1994); Sareneva et al., J. Interferon Res. 13:267 (1993)). Mixed O-linked and N-linked glycosylation also occurs, for example in human erythropoietin, N-linked glycosylation occurs at asparagine residues located at positions 24, 38 and 83 while O-linked glycosylation occurs at a serine residue located at position 126 (Lai et al., J. Biol. Chem. 261:3116 (1986); Broudy et al., Arch. Biochem. Biophys. 265:329 (1988)).
  • [0061]
    Glycosylation of EPO albumin fusion proteins may influence the activity and/or stability of the EPO albumin fusion proteins. The EPO portion of the albumin fusion protein may contain 3 N-linked sites for glycosylation, each of which can carry one tetra-antennary structure. When the EPO albumin fusion protein is glycosylated, the half-life of the molecule may be increased. In one embodiment, the EPO albumin fusion protein is glycosylated. In another embodiment, the EPO albumin fusion protein is hyperglycosylated.
  • [0062]
    One type of sugar commonly found in oligosaccharides is sialic acid. Each tetra-antennary structure of the N-linked glycosylation sites of EPO may carry four sialic acid residues. Accordingly, in a preferred embodiment, the EPO albumin fusion protein is glycosylated with a carbohydrate group containing sialic acid. In an additional embodiment, the EPO albumin fusion protein comprises a fully sialylated EPO protein containing four sialic acid residues per tetra-antennerary structure per site with a molar ratio of sialic acid to protein 12:1 or greater. In alternative embodiments, the EPO albumin fusion protein comprises a hypersialylated EPO protein wherein one, two, or three sialic acid residues are attached at each tetra-antennerary structure per site with a molar ratio of sialic acid to protein less than 12:1.
  • [0063]
    Two types of sialic acid that may be used in the sialylation of the EPO albumin fusion protein are N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). In a preferred embodiment, hypersialylated EPO albumin fusion proteins contain Neu5Ac. More preferably, the total sialic acid content of hypersialylated EPO albumin fusion proteins is at least 97% Neu5Ac. Most preferred are EPO albumin fusion protein structures with little or no Neu5Gc.
  • [0064]
    Preferably, the albumin EPO fusion protein has at least 4 moles of sialylation, and more preferably, at least 8-9 moles of sialylation. An additional embodiment comprises an albumin EPO fusion protein with 4 moles of sialylation, 5 moles of sialylation, 6 moles of sialylation, 7 moles of sialylation, 8-9 moles of sialylation, 8 moles of sialylation, 9 moles of sialylation, 10 moles of sialylation, 11 moles of sialylation, or 12 moles of sialylation.
  • [0065]
    The degree of sialylation of a protein changes the charge of the protein and its retention time on a chromatography column. Therefore, certain chromatography steps used in the purification process may be used to monitor or enrich for hypersialylated EPO albumin fusion proteins. In a preferred embodiment, the amount of sialylation may be monitored by HPLC chromatography. In an additional embodiment, steps in the purification process of EPO albumin fusions may be used to enrich for hypersialylated EPO albumin fusion proteins. In a preferred embodiment the purification steps that may be used to enrich for hypersialylated EPO albumin fusion proteins comprise the butyl-sepharose FF purification step to remove virus particles by high ammonium salt and the hydroxyapatite chromatography at pH 6.8 for the final purification step.
  • [0066]
    Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention, as well as analogs and variants thereof, may be modified so that glycosylation at one or more sites is altered as a result of manipulation(s) of their nucleic acid sequence, by the host cell in which they are expressed, or due to other conditions of their expression. For example, glycosylation isomers may be produced by abolishing or introducing glycosylation sites, e.g., by substitution or deletion of amino acid residues, such as substitution of glutamine for asparagine, or unglycosylated recombinant proteins may be produced by expressing the proteins in host cells that will not glycosylate them, e.g. in E. coli or glycosylation-deficient yeast. These approaches are described in more detail below and are known in the art.
  • [0067]
    Therapeutic proteins, particularly those disclosed in Table 1, and their nucleic acid and amino acid sequences are well known in the art and available in public databases such as Chemical Abstracts Services Databases (e.g., the CAS Registry), GenBank, and subscription provided databases such as GenSeq (e.g., Derwent). Exemplary nucleotide sequences of Therapeutic proteins which may be used to derive a polynucleotide of the invention are shown in column 7, “SEQ ID NO:X,” of Table 2. Sequences shown as SEQ ID NO:X may be a wild type polynucleotide sequence encoding a given Therapeutic protein (e.g., either full length or mature), or in some instances the sequence may be a variant of said wild type polynucleotide sequence (e.g., a polynucleotide which encodes the wild type Therapeutic protein, wherein the DNA sequence of said polynucleotide has been optimized, for example, for expression in a particular species; or a polynucleotide encoding a variant of the wild type Therapeutic protein (i.e., a site directed mutant; an allelic variant)). It is well within the ability of the skilled artisan to use the sequence shown as SEQ ID NO:X to derive the construct described in the same row. For example, if SEQ ID NO:X corresponds to a full length protein, but only a portion of that protein is used to generate the specific CID, it is within the skill of the art to rely on molecular biology techniques, such as PCR, to amplify the specific fragment and clone it into the appropriate vector.
  • [0068]
    Additional Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention include, but are not limited to, one or more of the Therapeutic proteins or peptides disclosed in the “Therapeutic Protein X” column of Table 1 (column 1), or fragment or variable thereof.
  • [0069]
    Table 1 provides a non-exhaustive list of Therapeutic proteins that correspond to a Therapeutic protein portion of an albumin fusion protein of the invention, or an albumin fusion protein encoded by a polynucleotide of the invention. The first column, “Therapeutic Protein X,” discloses Therapeutic protein molecules that may be followed by parentheses containing scientific and brand names of proteins that comprise, or alternatively consist of, that Therapeutic protein molecule or a fragment or variant thereof. “Therapeutic protein X” as used herein may refer either to an individual Therapeutic protein molecule, or to the entire group of Therapeutic proteins associated with a given Therapeutic protein molecule disclosed in this column. The “Biological activity” column (column 2) describes Biological activities associated with the Therapeutic protein molecule. Column 3, “Exemplary Activity Assay,” provides references that describe assays which may be used to test the therapeutic and/or biological activity of a Therapeutic protein:X or an albumin fusion protein comprising a Therapeutic protein X (or fragment thereof) portion. Each of the references cited in the “Exemplary Activity Assay” column are herein incorporated by reference in their entireties, particularly with respect to the description of the respective activity assay described in the reference (see Methods section therein, for example) for assaying the corresponding biological activity set forth in the “Biological Activity” column of Table 1. The fourth column, “Preferred Indication: Y,” describes disease, disorders, and/or conditions that may be treated, prevented, diagnosed, and/or ameliorated by Therapeutic protein X or an albumin fusion protein comprising a Therapeutic protein X (or fragment thereof) portion. The “Construct ID” column (column 5) provides a link to an exemplary albumin fusion construct disclosed in Table 2 which encodes an albumin fusion protein comprising, or alternatively consisting of the referenced Therapeutic Protein X (or fragment thereof) portion.
  • [0000]
    TABLE 1
    Therapeutic Exemplary Activity
    Protein: X Biological Activity Assay Preferred Indication: Y
    EPO Stimulates cellular Cell proliferation assay Anemia; Anemia in Renal Disease;
    (Erythropoietin; differentiation of using a Anemia in Oncology Patients; Bleeding
    Epoetin bone-marrow stem erythroleukemic cell Disorders; Chronic Renal Failure;
    alfa; Epoetin cells at an early stage line TF-1. (Kitamura et Chronic Renal Failure in Pre-Dialysis
    beta; Gene- of erythropoiesis; al. 1989 J. Cell. Physiol. Patients; Renal Disease; End-Stage
    activated accelerates the 140: 323) Renal Disease; End-Stage Renal Disease
    erythropoietin; proliferation and in Dialysis Patients; Chemotherapy;
    Darbepoetin- maturation of Chemotherapy in Cancer Patients;
    alpha; NESP; terminally Anemia in zidovudine-treated HIV
    Epogen; differentiating cells patients; Anemia in zidovudine-treated
    Procrit; Eprex; into erythrocytes; patients; Anemia in HIV patients;
    Erypo; Espo; and modulates the Anemia in premature infants; Surgical
    Epoimmun; level of circulating patients (pre and/or post surgery);
    EPOGIN; erythrocytes. Surgical patients (pre and/or post
    NEORECORMON; surgery) who are anemic; Surgical
    HEMOLINK; patients (pre and/or post surgery) who
    Dynepo; are undergoing elective surgery; Surgical
    ARANESP) patients (pre and/or post surgery) who
    are undergoing elective, non-cardiac
    surgery; Surgical patients (pre and/or
    post surgery) who are undergoing
    elective, non-cardiac, non-vascular
    surgery; Surgical patients (pre and/or
    post surgery) who are undergoing
    elective, non-vascular surgery; Surgical
    patients (pre and/or post surgery) who
    are undergoing cardiac and/or vascular
    surgery; Aplastic anemia; Refractory
    anemia; Anemia in Inflammatory Bowel
    Disease; Refractory anemia in
    Inflammatory Bowel Disease;
    Transfusion avoidance; Transfusion
    avoidance for surgical patients;
    Transfusion avoidance for elective
    surgical patients; Transfusion avoidance
    for elective orthopedic surgical patients;
    Patients who want to Increase Red Blood
    Cells.
    G-CSF Stimulates the Proliferation of murine Chemoprotection; Adjunct to
    (Granulocyte proliferation and NFS-60 cells Chemotherapy; Inflammatory disorders;
    colony- differentiation of the (Weinstein et al, Proc Cancer; Leukemia; Myelocytic leukemia;
    stimulating progenitor cells for Natl Acad Sci USA Neutropenia, Primary neutropenias (e.g.;
    factor; granulocytes and 1986; 83, pp5010-4) Kostmann syndrome); Secondary
    Granulokine; monocytes- neutropenia; Prevention of neutropenia;
    KRN 8601; macrophages. Prevention and treatment of neutropenia
    Filgrastim; in HIV-infected patients; Prevention and
    Lenograstim; treatment of neutropenia associated with
    Meograstim; chemotherapy; Infections associated with
    Nartograstim; neutropenias; Myelopysplasia;
    Neupogen; Autoimmune disorders; Psoriasis;
    NOPIA; Gran; Mobilization of hematopoietic
    GRANOCYTE; progenitor cells; Wound Healing;
    Granulokine; Autoimmune Disease; Transplants; Bone
    Neutrogin; marrow transplants; Acute
    Neu-up; myelogeneous leukemia; Lymphoma,
    Neutromax) Non-Hodgkin's lymphoma; Acute
    lymphoblastic leukemia; Hodgkin's
    disease; Accelerated myeloid recovery;
    Glycogen storage disease.
    GM-CSF Regulates Colony Stimulating Bone Marrow Disorders; Bone marrow
    (Granulocyte- hematopoietic cell Assay: Testa, N. G., et transplant; Chemoprotection; Hepatitis
    macrophage differentiation, gene al., “Assays for C; HIV Infections; Cancer; Lung Cancer;
    colony- expression, growth, hematopoietic growth Melanoma; Malignant melanoma;
    stimulating and function. factors.” Balkwill FR Mycobacterium avium complex;
    factor; rhuGM- (edt) Cytokines, A Mycoses; Leukemia; Myeloid Leukemia;
    CSF; BI practical Approach, pp Infections; Neonatal infections;
    61012; 229-44; IRL Press Neutropenia; Mucositis; Oral Mucositis;
    Prokine; Oxford 1991. Prostate Cancer; Stem Cell Mobilization;
    Molgramostim; Vaccine Adjuvant; Ulcers (such as
    Sargramostim; Diabetic, Venous Stasis, or Pressure
    GM-CSF/IL 3 Ulcers); Prevention of neutropenia;
    fusion; Acute myelogenous leukemia;
    Milodistim; Hematopoietic progenitor cell
    Leucotropin; mobilization; Lymphoma; Non-
    PROKINE; Hodgkin's lymphoma; Acute
    LEUKOMAX; Lymphoblastic Leukemia; Hodgkin's
    Interberin; disease; Accelerated myeloid recovery;
    Leukine; Transplant Rejection; Xenotransplant
    Leukine Rejection.
    Liquid;
    Pixykine)
    Human growth Binds to two GHR Ba/F3-hGHR Acromegaly; Growth failure; Growth
    hormone molecules and proliferation assay, a hormone replacement; Growth hormone
    (Pegvisamont; Induces signal novel specific bioassay deficiency; Pediatric Growth Hormone
    Somatrem; transduction through for serum human Deficiency; Adult Growth Hormone
    Somatropin; receptor dimerization growth hormone. J Clin Deficiency; Idiopathic Growth Hormone
    TROVERT; Endocrinol Metab 2000 Deficiency; Growth retardation; Prader-
    PROTROPIN; Nov; 85(11): 4274-9 Willi Syndrome; Prader-Willi Syndrome
    BIO-TROPIN; Plasma growth in children 2 years or older; Growth
    HUMATROPE; hormone (GH) deficiencies; Growth failure associated
    NUTROPIN; immunoassay and with chronic renal insufficiency;
    NUTROPINAQ; tibial bioassay, Appl Osteoporosis; Postmenopausal
    NUTROPHIN; Physiol 2000 osteoporosis; Osteopenia,
    NORDITROPIN; Dec; 89(6): 2174-8 Osteoclastogenesis; burns; Cachexia;
    GENOTROPIN; Growth hormone Cancer Cachexia; Dwarfism; Metabolic
    SAIZEN; (hGH) receptor Disorders; Obesity; Renal failure;
    SEROSTIM) mediated cell mediated Turner's Syndrome; Fibromyalgia;
    proliferation, Growth Fracture treatment; Frailty, AIDS
    Horm IGF Res 2000 wasting; Muscle Wasting; Short Stature;
    Oct; 10(5): 248-55 Diagnostic Agents; Female Infertility;
    International standard lipodystrophy.
    for growth hormone,
    Horm Res 1999; 51
    Suppl 1: 7-12
    Insulin Stimulates glucose Insulin activity may be Hyperglycemia; Diabetes; Diabetes
    (Human uptake and promotes assayed in vitro using a Insipidus; Diabetes mellitus; Type 1
    insulin; Insulin glycogenesis and [3-H]-glucose uptake diabetes; Type 2 diabetes; Insulin
    aspart; Insulin lipogenesis. assay. (J Biol Chem resistance; Insulin deficiency;
    Glargine; 1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    Insulin lispro; 274(43): 30864-30873). insulin dependent Diabetes Mellitus
    Lys-B28 Pro- (NIDDM); Insulin-dependent Diabetes
    B29; lyspro; Mellitus (IDDM); A Condition
    LY 275585; Associated With Diabetes Including, But
    diarginylinsulin; Not Limited To Obesity, Heart Disease,
    Des-B26- Hyperglycemia, Infections, Retinopathy,
    B30-insulin- And/Or Ulcers; Metabolic Disorders;
    B25-amide; Immune Disorders; Obesity; Vascular
    Insulin Disorders; Suppression of Body Weight;
    detemir; Suppression of Appetite; Syndrome X.
    LABI;
    NOVOLIN;
    NOVORAPID;
    HUMULIN;
    NOVOMIX
    30;
    VELOSULIN;
    NOVOLOG;
    LANTUS;
    ILETIN;
    HUMALOG;
    MACRULIN;
    EXUBRA;
    INSUMAN;
    ORALIN;
    ORALGEN;
    HUMAHALE;
    HUMAHALIN)
    Interferon alfa Confers a range of Anti-viral assay: Viral infections; HIV Infections;
    (Interferon cellular responses Rubinstein S, Familletti PC, Hepatitis; Chronic Hepatitis; Hepatitis B;
    alfa-2b; including antiviral, Pestka S. (1981) Chronic Hepatitis B; Hepatitis C;
    recombinant; antiproliferative, Convenient assay for Chronic Hepatitis C; Hepatitis D;
    Interferon alfa- antitumor and interferons. J. Virol. Chronic Hepatitis D; Human
    n1; Interferon immunomodulatory 37(2): 755-8; Anti- Papillomavirus; Herpes Simplex Virus
    alfa-n3; activities; stimulate proliferation assay: Infection; External Condylomata
    Peginterferon production of two Gao Y, et al (1999) Acuminata; HIV; HIV Infection;
    alpha-2b; enzymes: a protein Sensitivity of an Oncology; Cancer; Solid Tumors;
    Ribavirin and kinase and an epstein-barr virus- Melanoma; Malignant Melanoma; Renal
    interferon alfa- oligoadenylate positive tumor line, Cancer (e.g., Renal Cell Carcinoma);
    2b; Interferon synthetase. Daudi, to alpha Lung Cancer (e.g,. Non-Small Cell Lung
    alfacon-1; interferon correlates Cancer or Small Cell Lung Cancer)
    interferon with expression of a Colon Cancer; Breast Cancer; Liver
    consensus; GC-rich viral Cancer; Prostate Cancer; Bladder
    YM 643; transcript. Mol Cell Cancer; Gastric Cancer; Sarcoma; AIDS-
    CIFN; Biol. 19(11): 7305-13. Related Kaposi's Sarcoma; Lymphoma;
    interferon - T Cell Lymphoma; Cutaneous
    alpha T-Cell Lymphoma; Non-Hodgkin's Lymphoma;
    consensus; Brain Cancer; Glioma; Glioblastoma
    recombinant Multiforme; Cervical Dysplasia;
    methionyl Leukemia; Preleukemia; Bone Marrow
    consensus Disorders; Bone Disorders; Hairy Cell
    interferon; Leukemia; Chronic Myelogeonus
    recombinant Leukemia; Hematological Malignancies;
    consensus Hematological Disorders; Multiple
    interferon; Myeloma; Bacterial Infections;
    CGP 35269; Chemoprotection; Thrombocytopenia;
    RO 253036; Multiple Sclerosis; Pulmonary Fibrosis;
    RO 258310; Age-Related Macular Degeneration;
    INTRON A; Macular Degeneration; Crohn's Disease;
    PEG- Neurological Disorders; Arthritis;
    INTRON; Rheumatoid Arthritis; Ulcerative Colitis;
    OIF; Osteoporosis, Osteopenia,
    OMNIFERON; Osteoclastogenesis; Fibromyalgia;
    PEG- Sjogren's Syndrome; Chronic Fatigue
    OMNIFERON; Syndrome; Fever; Hemmorhagic Fever;
    VELDONA; Viral Hemmorhagic Fevers;
    PEG- Hyperglycemia; Diabetes; Diabetes
    REBETRON; Insipidus; Diabetes mellitus; Type 1
    ROFERON A; diabetes; Type 2 diabetes; Insulin
    WELLFERON; resistance; Insulin deficiency;
    ALFERON Hyperlipidemia; Hyperketonemia; Non-
    N/LDO; insulin dependent Diabetes Mellitus
    REBETRON; (NIDDM); Insulin-dependent Diabetes
    ALTEMOL; Mellitus (IDDM); A Condition
    VIRAFERON Associated With Diabetes Including, But
    PEG; Not Limited To Obesity, Heart Disease,
    PEGASYS; Hyperglycemia, Infections, Retinopathy,
    VIRAFERON; And/Or Ulcers; Metabolic Disorders;
    VIRAFON; Immune Disorders; Obesity; Vascular
    AMPLIGEN; Disorders; Suppression of Body Weight;
    INFERGEN; Suppression of Appetite; Syndrome X.
    INFAREX;
    ORAGEN)
    Calcitonin Regulates levels of Hypocalcemic Rat Bone Disorders; Fracture prevention;
    (Salmon calcium and Bioassay, bone Hypercalcemia; Malignant
    Calcitonin phosphate in serum; resorbing assay and the hypercalcemia; Osteoporosis; Paget's
    (Salcatonin); causes a reduction in pit assay, CT receptor disease; Osteopenia, Osteoclastogenesis;
    Calcitonin serum calcium--an binding assay, CAMP osteolysis; osteomyelitis; osteonecrosis;
    human-salmon effect opposite to that stimulation assay: J periodontal bone loss; osteoarthritis;
    hybrid; of human parathyroid Bone Miner Res 1999 rheumatoid arthritis; osteopetrosis;
    Forcaltonin; hormone. Aug; 14(8): 1425-31 periodontal, lytic, or metastatic bone
    Fortical; disease; osteoclast differentiation
    Calcitonin; Calcitonina inhibition; bone disorders; bone healing
    Almirall; and regeneration.
    Calcitonina
    Hubber;
    Calcimar; Calsynar;
    Calogen;
    Miacalcic;
    Miacalcin;
    SB205614;
    Macritonin;
    Cibacalcin;
    Cibacalcina;
    Cibacalcine;
    Salmocalcin;
    PowderJect
    Calcitonin)
    (CAS-21215-
    62-3)
    Interferon beta Modulates MHC Anti-viral assay: Multiple Sclerosis; Oncology; Cancer;
    (Interferon antigen expression, Rubinstein S, Familletti PC, Solid Tumors; Melanoma; Malignant
    beta-1a; NK cell activity and Pestka S. (1981) Melanoma; Renal Cancer (e.g., Renal
    Interferon beta IFNg production and Convenient assay for Cell Carcinoma); Lung Cancer (e.g,.
    1b; Interferon- IL12 production in interferons. J. Virol. Non-Small Cell Lung Cancer or Small
    beta-serine; monocytes. 37(2): 755-8; Anti- Cell Lung Cancer) Colon Cancer; Breast
    SH 579; ZK proliferation assay: Cancer; Liver Cancer; Prostate Cancer;
    157046; Gao Y, et al (1999) Bladder Cancer; Gastric Cancer;
    BCDF; beta-2 Sensitivity of an Sarcoma; AIDS-Related Kaposi's
    IF; Interferon- epstein-barr virus- Sarcoma; Lymphoma; T Cell
    beta-2; rhIL-6; positive tumor line, Lymphoma; Cutaneous T-Cell
    SJ0031; DL Daudi, to alpha Lymphoma; Non-Hodgkin's Lymphoma;
    8234; FERON; interferon correlates Brain Cancer; Glioma; Glioblastoma
    IFNbeta; with expression of a Multiforme; Cervical Dysplasia;
    BETASERON; GC-rich viral Leukemia; Preleukemia; Bone Marrow
    AVONEX; transcript. Mol Cell Disorders; Bone Disorders; Hairy Cell
    REBIF; Biol. 19(11): 7305-13. Leukemia; Chronic Myelogeonus
    BETAFERON; Leukemia; Hematological Malignancies;
    SIGOSIX) Hematological Disorders; Multiple
    Myeloma; Bacterial Infections;
    Chemoprotection; Thrombocytopenia;
    Viral infections; HIV Infections;
    Hepatitis; Chronic Hepatitis; Hepatitis B;
    Chronic Hepatitis B; Hepatitis C;
    Chronic Hepatitis C; Hepatitis D;
    Chronic Hepatitis D; Human
    Papillomavirus; Herpes Simplex Virus
    Infection; External Condylomata
    Acuminata; HIV; HIV Infection;
    Pulmonary Fibrosis; Age-Related
    Macular Degeneration; Macular
    Degeneration; Crohn's Disease;
    Neurological Disorders; Arthritis;
    Rheumatoid Arthritis; Ulcerative Colitis;
    Osteoporosis, Osteopenia,
    Osteoclastogenesis; Fibromyalgia;
    Sjogren's Syndrome; Chronic Fatigue
    Syndrome; Fever; Hemmorhagic Fever;
    Viral Hemmorhagic Fevers;
    Hyperglycemia; Diabetes; Diabetes
    Insipidus; Diabetes mellitus; Type 1
    diabetes; Type 2 diabetes; Insulin
    resistance; Insulin deficiency;
    Hyperlipidemia; Hyperketonemia; Non-
    insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    Growth Acts on the anterior Growth hormone- Acromegaly; Growth failure; Growth
    hormone pituitary to stimulate releasing peptides hormone replacement; Growth hormone
    releasing the production and (GHRPs) are known to deficiency; Pediatric Growth Hormone
    factor; Growth secretion of growth release growth Deficiency; Adult Growth Hormone
    hormone hormone and exert a hormone (GH) in vivo Deficiency; Idiopathic Growth Hormone
    releasing trophic effect on the and in vitro by a direct Deficiency; Growth retardation; Prader-
    hormone gland. action on receptors in Willi Syndrome; Prader-Willi Syndrome
    (Sermorelin anterior pituitary cells. in children 2 years or older; Growth
    acetate; Biological activity can deficiencies; Growth failure associated
    Pralmorelin; be measured in cell with chronic renal insufficiency;
    Somatorelin; lines expressing growth Osteoporosis; Osteopenia,
    Somatoliberin; hormone releasing Osteoclastogenesis; Postmenopausal
    Geref; Gerel; factor receptor (Mol osteoporosis; burns; Cachexia; Cancer
    Groliberin) Endocrinol 1992 Cachexia; Dwarfism; Metabolic
    Oct; 6(10): 1734-44, Disorders; Obesity; Renal failure;
    Molecular Turner's Syndrome; Fibromyalgia;
    Endocrinology, Vol 7, Fracture treatment; Frailty, AIDS
    77-84). wasting; Muscle Wasting; Short Stature;
    Diagnostic Agents; Female Infertility;
    lipodystrophy.
    IL-2 Promotes the growth T cell proliferation Cancer; Solid Tumors; Metastatic Renal
    (Aldesleukin; of B and T cells and assay “Biological Cell Carcinoma; Metastatic Melanoma;
    interleukin-2 augments NK cell activity of recombinant Malignant Melanoma; Melanoma; Renal
    fusion toxin; T and CTL cell killing human interleukin-2 Cell Carcinoma; Renal Cancer; Lung
    cell growth activity. produced in Cancer (e.g,. Non-Small Cell Lung
    factor; Escherichia coli.” Cancer or Small Cell Lung Cancer);
    PROLEUKIN; Science 223: 1412-1415, Colon Cancer; Breast Cancer; Liver
    IMMUNACE; 1984. natural Cancer; Leukemia; Preleukemia;
    CELEUK; killer (NK) cell and Hematological Malignancies;
    ONCOLIPIN CTL cytotoxicity assay Hematological Disorders; Acute Myeloid
    2; “Control of Leukemia; Melanoma; Malignant
    MACROLIN) homeostasis of CD8+ Melanoma; Non-Hodgkin's Lymphoma;
    memory T cells by Ovarian Cancer; Prostate Cancer; Brain
    opposing cytokines. Cancer; Glioma; Glioblastoma
    Science 288: 675-678, Multiforme; Hepatitis; Hepatitis C;
    2000; CTLL-2 Lymphoma; HIV Infection (AIDS);
    Proliferation: Gillis et Inflammatory Bowel Disorders; Kaposi's
    al (1978) J. Immunol. Sarcoma; Multiple Sclerosis; Arthritis;
    120, 2027 Rheumatoid Arthritis; Transplant
    Rejection; Diabetes; Type 1 Diabetes
    Mellitus; Type 2 Diabetes.
    Parathyroid Acts in conjuction Adenylyl cyclase Bone Disorders; Fracture prevention;
    hormone; with calcitonin to stimulation in rat Hypercalcemia; Malignant
    parathyrin control calcium and osteosarcoma cells, hypercalcemia; Osteoporosis; Paget's
    (PTH; phosphate ovariectomized rat disease; Osteopenia, Osteoclastogenesis;
    Ostabolin; metabolism; elevates model of osteoporosis: osteolysis; osteomyelitis; osteonecrosis;
    ALX1-11; blood calcium level; IUBMB Life 2000 periodontal bone loss; osteoarthritis;
    hPTH 1-34; stimulates the activity Feb; 49(2): 131-5 rheumatoid arthritis; osteopetrosis;
    LY 333334; of osteocytes; periodontal, lytic, or metastatic bone
    MN 10T; enhances absorption disease; osteoclast differentiation
    parathyroid of Ca+/Pi from small inhibition; bone disorders; bone healing
    hormone (1-31); intestine into blood; and regeneration.
    FORTEO; promotes
    PARATHAR) reabsorption of Ca+
    and inhibits Pi by
    kidney tubules.
    Resistin Mediates insulin Ability of resistin to Hyperglycemia; Diabetes; Diabetes
    resistance in Type II influence type II Insipidus; Diabetes mellitus; Type 1
    diabetes; inhibits diabetes can be diabetes; Type 2 diabetes; Insulin
    insulin-stimulated determined using resistance; Insulin deficiency;
    glucose uptake assays known in the Hyperlipidemia; Hyperketonemia; Non-
    art: Pontoglio et al., J insulin dependent Diabetes Mellitus
    Clin Invest 1998 May (NIDDM); Insulin-dependent Diabetes
    15; 101(10): 2215-22. Mellitus (IDDM); A Condition
    Associated With Diabetes Including,
    But Not Limited To Obesity, Heart
    Disease, Hyperglycemia, Infections,
    Retinopathy, And/Or Ulcers; Metabolic
    Disorders; Immune Disorders; Obesity;
    Vascular Disorders; Suppression of
    Body Weight; Suppression of Appetite;
    Syndrome X.
    TR6 (DcR3; Inhibits Fas Ligand Cellular apoptosis can Fas Ligand or LIGHT induced
    Decoy and AIM-2 (TL5, be measured by apoptotic disorders: hepatitis; liver
    Receptor 3; LIGHT) mediated annexin staining, failure (including fulminant liver
    FASTR) apoptosis. TUNEL staining, failure); graft versus host disease; graft
    measurement of rejection; myelodysplastic syndrome;
    caspase levels. renal failure; insulin dependent
    Inhibition of cell diabetes mellitus; rheumatoid arthritis;
    growth can also be inflammatory bowel disease;
    directly measured, for autoimmune disease; toxic epidermal
    example by ALOMAR necrolysis; multiple sclerosis.
    Blue staining. Assay
    refs: cytotoxicity assay
    on human
    fibrosarcoma (Epsevik
    and Nissen-Meyer,
    1986, J. Immunol.
    methods).
    DeCAF (D- Inhibits DeCAF activity can be B cell and/or T cell mediated immune
    SLAM; proliferation and determined using disorders; Immunodeficiency (e.g.,
    BCM-like differentiation of B assays known in the Common Variable Immunodeficiency,
    membrane cells; Antagonize art, such as for Selective IgA Deficiency)
    protein; BLyS activity example, those
    BLAME (B described in Examples
    lymphocyte 32-33 of International
    activator Publication No.
    macrophage WO0111046.
    expressed))
    BLyS (B Promotes BLyS activity can be B cell and/or T cell mediated immune
    Lymphocyte proliferation, determined using disorders, particularly immune system
    Stimulator; differentiation and assays known in the disorders associated with low B cell
    Neutrokine survival of B cells; art, such as, for numbers or low serum
    alpha; TL7; Promotes example, the immunoglobulin; Immunodeficiency
    BAFF; immunoglobulin costimulatory (e.g., Common Variable
    TALL-1; production by B proliferation assay and Immunodeficiency, Selective IgA
    THANK; cells. other assays disclosed Deficiency). Radiolabeled forms:
    radiolabeled by Moore et al., 1999, lymphoma, non-Hodgkins lymphoma,
    BLyS) Science, chronic lymphocytic leukemia,
    285(5425): 260-3. multiple myeloma.
    Anti-BLyS Agonize or BLyS agonist or B cell and/or T cell mediated immune
    single chain antagonize BlyS antagonist activity can disorders; Autoimmune disorders,
    antibody (scFvI116A01, activity. be determined using particularly autoimmune diseases
    scFvI050B11, assays known in the associated with the production of
    scFvI006D08) art, such as, for autoantibodies; Rheumatoid Arthritis,
    and others. example, a modified Systemic Lupus Erythmatosus;
    version the Sjogren's Syndrome, cancers
    costimulatory expressing Blys as an autocrine growth
    proliferation assay factor, e.g. certain chronic lymphocytic
    disclosed by Moore et leukemias.
    al., 1999, Science,
    285(5425): 260-3, in
    which BlyS is mixed
    or preincubated with
    the anti-BlyS antibody
    prior to being applied
    to the responder B
    lymphocytes.
    MPIF-1 Inhibits myeloid MPIF-1 activity can be Chemoprotection; Adjunct to
    (Myeloid progenitor cells; measured using the Chemotherapy; Inflammatory
    Progenitor and activates myeloprotection assay disorders; Cancer; Leukemia;
    Inhibitory monocytes and chemotaxis assay Myelocytic leukemia; Neutropenia,
    Factor; CK described in U.S. Pat. No. Primary neutropenias (e.g.; Kostmann
    beta-8; 6,001,606. syndrome); Secondary neutropenia;
    Mirostipen) Prevention of neutropenia; Prevention
    and treatment of neutropenia in HIV-
    infected patients; Prevention and
    treatment of neutropenia associated
    with chemotherapy; Infections
    associated with neutropenias;
    Myelopysplasia; Autoimmune
    disorders; Psoriasis; Mobilization of
    hematopoietic progenitor cells; Wound
    Healing; Autoimmune Disease;
    Transplants; Bone marrow transplants;
    Acute myelogeneous leukemia;
    Lymphoma, Non-Hodgkin's
    lymphoma; Acute lymphoblastic
    leukemia; Hodgkin's disease;
    Accelerated myeloid recovery;
    Glycogen storage disease.
    KDI Inhibits bone KDI activity can be Multiple sclerosis; Hepatitis; Cancer;
    (Keratinocyte marrow measured using the Viral infections, HIV infections,
    Derived proliferation; and antiviral and cell Leukemia.
    Interferon; shows antiviral proliferation assays
    Interferon activity. described in Examples
    Kappa 57-63 of International
    Precursor) Publication No.
    WO0107608.
    TNFR2 (p75) Binds both TNFa T-cell proliferation can Autoimmune disease; Rheumatoid
    (ENBREL) and TNFb; be measured using Arthritis; Psoriatic arthritis; Still's
    mediates T-cell assays known in the Disease; Ankylosing Spondylitis;
    proliferation by art. For example, Cardiovascular Diseases; Vasulitis;
    TNF; reduces signs “Lymphocytes: a Wegener's granulomatosis;
    and structural practical approach” Amyloidosis; Systemic Lupus
    damage in patients edited by: SL Rowland, Erythematosus, Insulin-Dependent
    with moderately to AJ McMichael - Diabetes Mellitus; Immunodeficiency
    severly active chapter Disorders; Infection; Inflammation;
    rheumatoid arthritis 6, pages 138-160 Inflammatory Bowel Disease; Chrohn's
    (RA). Oxford University Disease; Psoriasis; AIDS; Graft
    Press (2000); and Rejection; Graft Versus Host Disease.
    “Current Protocols on
    CD-ROM” section
    3.12 Proliferation
    Assays for T-cell
    Function John Wiley
    & Soncs, Inc. (1999).
    Keratinocyte Stimulates KGF-2 activity can be Stimulate Epithelial Cell Proliferation;
    growth factor 2 epithelial cell measured using the Stimulate Basal Keratinocytes; Wound
    (Repifermin; growth. wound healing assays Healing; Stimulate Hair Follicle
    KGF-2; and epithelial cell Production; Healing Of Dermal
    Fibroblast proliferation assays Wounds. Wound Healing; Eye Tissue
    Growth described in U.S. Pat. No. Wounds, Dental Tissue Wounds, Oral
    Factor-10; 6,077,692. Cavity Wounds, Diabetic Ulcers,
    FGF-10) Dermal Ulcers, Cubitus Ulcers,
    Arterial Ulcers, Venous Stasis Ulcers,
    Burns Resulting From Heat Exposure
    Or Chemicals, or Other Abnormal
    Wound Healing Conditions such as
    Uremia, Malnutrition, Vitamin
    Deficiencies or Complications
    Associated With Systemic Treatment
    With Steroids, Radiation Therapy or
    Antineoplastic Drugs or
    Antimetabolites; Promote Dermal
    Reestablishment Subsequent To
    Dermal Loss; Increase the Adherence
    Of Skin Grafts To A Wound Bed;
    Stimulate Re-Epithelialization from
    The Wound Bed; To Promote Skin
    Strength; Improve The Appearance Of
    Aged Skin; Proliferate Hepatocytes,
    Lung, Breast, Pancreas, Stomach,
    Bladder, Small Intestine, Large
    Intestine; Sebocytes, Hair Follicles,
    Type II Pneumocytes, Mucin-
    Producing Goblet Cells, or Other
    Epithelial Cells, Endothelial Cells,
    Keratinocytes, or Basal Keratinocytes
    (and Their Progenitors) Contained
    Within The Skin, Lung, Liver, Bladder,
    Eye, Salivary Glands, or
    Gastrointestinal Tract; Reduce The
    Side Effects Of Gut Toxicity That
    Result From Radiation, Chemotherapy
    Treatments Or Viral Infections;
    Cytoprotector, especially of the Small
    Intestine Mucosa or Bladder; Mucositis
    (Mouth Ulcers); Regeneration Of Skin;
    Full and/or Partial Thickness Skin
    Defects, including Burns, (e.g.,
    Repopulation Of Hair Follicles, Sweat
    Glands, And Sebaceous Glands);
    Psoriasis; Epidermolysis Bullosa;
    Blisters; Gastric and/or Doudenal
    Ulcers; Reduce Scarring;
    Inflamamatory Bowel Diseases;
    Crohn's Disease; Ulcerative Colitis;
    Gut Toxicity; Lung Damage; Repair Of
    Alveoli And/or Brochiolar Epithelium;
    Acute Or Chronic Lung Damage;
    Emphysema, ARDS; Inhalation
    Injuries; Hyaline Membrane Diseases;
    Infant Respiratory Distress Syndrome;
    Bronchopulmonary Displasia In
    Premature Infants; Fulminant Liver
    Failure; Cirrhosis, Liver Damage
    caused by Viral Hepatitis and/or Toxic
    Substances; Diabetes Mellitus;
    Inflammation.
    TR2 (and Inhibits B cell Co-stimulation B-cell Herpes; immune disorders;
    TR2sv1, proliferation, and proliferation assay and autoimmune disease; graft versus host
    TR2SV2; mediates and Ig production assay disease; graft rejection; variable
    TNFRSF14; inhibits Herpes (Moore et al., 1999, immunodeficiency; immunodeficiency
    HVEM; Simplex Virus Science, syndromes; cancer.
    Herpes Virus (HSV) infection. 285(5425): 260-3.).
    Entry HSV-1 and HSV-2
    Mediator; Infectivity Assay:
    ATAR) International
    Publication No. WO
    97/04658
    Macrophage Chemotactic for Chemokine activities Inflammatory diseases; wound healing;
    derived monocyte-derived can be determined angiogenesis; AIDS infection.
    chemokine, dendritic cells and using assays known in
    MDC IL-2-activated the art: Methods in
    (Ckbeta-13) natural killer cells. Molecular Biology,
    2000, vol. 138:
    Chemokine Protocols.
    Edited by: A. E. I. Proudfoot,
    T. N. C. Wells,
    and C. A. Power.
    © Humana
    Press Inc., Totowa, NJ
    HAGDG59 Activates MIP1a Dendritic cell assays Immune disorders; cancer; viral
    (Retinal release in Dendritic are well known in the infection; inflammation; sepsis;
    short-chain Cells. art. For example, J. arthritis; asthma.
    dehydrogenase) Immunol. 158: 2919-2925
    (1997); J.
    Leukoc. Biol. 65: 822-828
    (1999).
    GnRH Promotes release of GnRH is known to Infertility; Kallmann's syndrome or
    (Gonadotropin follicle-stimulating cause the release of other forms of hypergonadotropic
    Releasing hormone and follicle stimulating hypergonadism (failure to go through
    Hormone) luteinizing hormone hormone (FSH) and/or puberty naturally).
    from anterior luteinizing hormone
    pituitary. (LH) in vivo by a
    direct action on
    receptors in anterior
    pituitary gonadotropes.
    GnRH activity can be
    determined by
    measuring FSH levels
    in the medium of
    cultured gonadotropes
    before and after GnRH
    supplementation. For
    example, Baker et al.
    Biol Reprod 2000
    Sep; 63(3): 865-71.
    Teprotide Inhibits angiotensin Inhibition of ACE can Hypertension; congestive heart failure.
    converting enzyme be determined using
    (ACE). assays known in the
    art. For example,
    Anzenbacherova et al.,
    J. Pharma Biomed Anal
    2001 Mar; 24(5-6):
    1151-6.
    Human Involved in Chemokine activities Autoimmune disorders; Immunity;
    chemokine inflammation, can be determined Vascular and Inflammatory disorders;
    HCC-1 allergy, tissue using assays known in HIV; AIDS; infectious diseases.
    (ckBeta-1; rejection, viral the art: Methods in
    HWFBD) infection, and Molecular Biology,
    tumor biology; 2000, vol. 138:
    enhances Chemokine Protocols.
    proliferation of Edited by: A. E. I. Proudfoot,
    CD34+ myeloid T. N. C. Wells,
    progenitor cells. and C. A. Power.
    © Humana
    Press Inc., Totowa, NJ
    ACE2 Inhibits production Inhibition of Treatment for elevated angiotensin II
    inhibitor of angiotensin II angiotensin can be and/or aldosterone levels, which can
    (DX512) which induces determined using lead to vasoconstriction, impaired
    aldosterone assays known in the cardiac output and/or hypertension;
    production, art. For example, in Cardiovascular Disease; Cardiac
    arteriolar smooth vitro using a Failure; Diabetes; Type II Diabetes;
    muscle proliferation assay with Proteinuria; Renal disorders,
    vasoconstriction, rat cardiac fibroblasts congestive heart failure.
    and proliferation of as described in Naunyn
    cardiac fibroblasts, Schmiedebergs Arch
    Induces Pharmacol 1999
    angiogenesis; an May; 359(5): 394-9.
    enzyme that
    converts
    angiotensin I to
    angiotensin1-9; also
    cleaves des-Arg,
    bradykinin and
    neurotensin.
    TR1 (OCIF; Inhibits Coculture Assay for Osteoporosis; Paget's disease;
    Osteoclastogenesis osteoclastogenesis Osteoclastogenesis, osteopenia; osteolysis; osteomyelitis;
    inhibitory and bone Bone resorption assay osteonecrosis; periodontal bone loss;
    factor; resorption, and using fetal long-bone osteoarthritis; rheumatoid arthritis;
    osteoprotegerin, induces fibroblast organ culture system, osteopetrosis; periodontal, lytic, or
    OPG; proliferation. dentine resorption metastatic bone disease; osteoclast
    tumor assay, and fibroblast differentiation inhibition; bone
    necrosis proliferation assays are disorders; bone healing and
    factor each described in regeneration; organ calcification;
    receptor Kwon et al., FASEB J. vascular calcification.
    superfamily 12: 845-854 (1998).
    member 11B
    precursor;)
    Human Chemotactic for Chemokine activities Cancer; Wound healing; Inflammatory
    chemokine both activated can be determined disorders; Immmunoregulatory
    Ckbeta-7 (CD3+) T cells and using assays known in disorders; Atherosclerosis;
    nonactivated the art: Methods in Parasitic Infection; Rheumatoid
    (CD14−) Molecular Biology, Arthritis; Asthma; Autoimmune
    lymphocytes and 2000, vol. 138: disorders.
    (CD4+) and Chemokine Protocols.
    (CD8+) T Edited by: A. E. I. Proudfoot,
    lymphocytes and T. N. C. Wells,
    (CD45RA+) T cells and C. A. Power.
    © Humana
    Press Inc., Totowa, NJ
    CKbeta4 Attracts and Chemokine activities Cancer; Solid Tumors; Chronic
    (HGBAN46; activates can be determined Infection; Autoimmune Disorders;
    HE9DR66) microbicidal using assays known in Psoriasis; Asthma; Allergy;
    leukocytes; Attracts the art: Methods in Hematopoiesis; Wound Healing; Bone
    CCR6-expressing Molecular Biology, Marrow Failure; Silicosis; Sarcoidosis;
    immature dendritic 2000, vol. 138: Hyper-Eosinophilic Syndrome; Lung
    cells and Chemokine Protocols. Inflammation; Fibrotic Disorders;
    memory/effector T Edited by: A. E. I. Proudfoot, Atherosclerosis; Periodontal diseases;
    cells; B-cell T. N. C. Wells, Viral diseases; Hepatitis.
    chemotaxis; inhibits and C. A. Power.
    proliferation of © Humana
    myeloid Press Inc., Totowa, NJ
    progenitors;
    chemotaxis of
    PBMC's.
    Leptin Controls obesity in vivo modulation of Hyperglycemia; Diabetes; Diabetes
    through regulation food intake, reduction Insipidus; Diabetes mellitus; Type 1
    of appetite, in body weight, and diabetes; Type 2 diabetes; Insulin
    reduction of body lowering of insulin and resistance; Insulin deficiency;
    weight, and glucose levels in ob/ob Hyperlipidemia; Hyperketonemia;
    lowering of insulin mice, Non-insulin dependent Diabetes
    and glucose level. radioimmunoassay Mellitus (NIDDM); Insulin-dependent
    (RIA) and activation of Diabetes Mellitus (IDDM); a Condition
    the leptin receptor in a Associated With Diabetes Including,
    cell-based assay. But Not Limited To Obesity, Heart
    Protein Expr Purif Disease, Hyperglycemia, Infections,
    1998 Dec; 14(3): 335-42 Retinopathy, And/Or Ulcers; Metabolic
    Disorders; Immune Disorders; Obesity;
    Vascular Disorders; Suppression of
    Body Weight; Suppression of Appetite;
    Syndrome X; Immunological
    Disorders; Immunosuppression.
    IL-1 receptor Binds IL1 receptor 1) Competition for Autoimmune Disease; Arthritis;
    antagonist without activating IL-1 binding to IL-1 Rheumatoid Arthritis; Asthma;
    (Anakinra; the target cells; receptors in YT-NCI or Diabetes; Diabetes Mellitus; GVHD;
    soluble inhibits the binding C3H/HeJ cells (Carter Inflammatory Bowel Disorders;
    interleukin-1 of IL1-alpha and et al., Nature 344: 633-638, Chron's Disease; Ocular Inflammation;
    receptor; IL1-beta; and 1990); Psoriasis; Septic Shock; Transplant
    IRAP; neutralizes the 2) Inhibition of IL-1- Rejection; Inflammatory Disorders;
    KINERET; biologic activity of induced endothelial Rheumatic Disorders; Osteoporosis;
    ANTRIL) IL1-alpha and IL1- cell-leukocyte adhesion Postmenopausal Osteoporosis; Stroke.
    beta. (Carter et al., Nature
    344: 633-638, 1990);
    3) Proliferation assays
    on A375-C6 cells, a
    human melanoma cell
    line highly susceptible
    to the antiproliferative
    action of IL-1 (Murai T
    et al., J. Biol. Chem.
    276: 6797-6806, 2001).
    TREM-1 Mediates activation Secretion of cytokines, Inflammation; Sepsis; bacterial
    (Triggering of neutrophil and chemokines, infection; autoimmune diseases;
    Receptor monocytes; degranulation, and cell GVHD.
    Expressed on Stimulates surface activation
    Monocytes neutrophil and markers can be
    1) monocyte-mediated determined using
    inflammatory assays described in
    response; Promotes Bouchon et al, J
    secretion of TNF, Immunol 2000 May
    IL-8, and MCP-1; 15; 164(10): 4991-5.
    Induces neutrophil
    degranulation,
    Ca2+ mobilization
    and tyrosine
    phosphorylation of
    extracellular signal-
    related kinase 1
    (ERK1), ERK2 and
    phospholipase C-
    gamma.
    HCNCA73 Induces T-cell FMAT can be used to Autoimmune disorders; Inflammation
    activation- measure T-cell surface of the gastrointestinal tract; Cancer;
    expression of markers (CD69, Colon Cancer; Allergy; Crohn's
    CD152 marker; CD152, CD71, HLA- disease.
    Stimulates release DR) and T-cell
    of TNF-a and MIP- cytokine production
    1a from immature, (e.g., IFNg
    monocyte-derived production). J. of
    dendritic cells; Biomol. Screen. 4: 193-204
    Promotes (1999). Other T-
    maturation of cell proliferation
    dendritic cells. assays: “Lymphocytes:
    a practical approach”
    edited by: SL Rowland,
    AJ McMichael -
    Chapter 6,
    pages 138-160 Oxford
    University Press
    (2000); WO 01/21658
    Examples 11-14, 16-17
    and 33.
    VEGF-2 Promotes VEGF activity can be Coronary artery disease; Critical limb
    (Vascular endothelial cell determined using ischemia; Vascular disease;
    Endothelial proliferation. assays known in the proliferation of endothelial cells, both
    Growth art, such as those vascular and lymphatic. Antagonists
    Factor-2; disclosed in may be useful as anti-angiogenic
    VEGF-C) International agents; Cancer.
    Publication No.
    WO0045835, for
    example.
    HCHNF25 Activates MIP1a Dendritic cell assays Immune disorders; cancer.
    (jumping Release in are well known in the
    translocation Dendritic Cells. art. For example, J.
    breakpoint) Immunol. 158: 2919-2925
    (1997); J.
    Leukoc. Biol. 65: 822-828
    (1999).
    HLDOU18 Activates L6/GSK3 Assays for activation Hyperglycemia; Diabetes; Diabetes
    (Bone kinase assay. of GSK3 kinase Insipidus; Diabetes mellitus; Type 1
    Morphogenic activity are well diabetes; Type 2 diabetes; Insulin
    Protein 9 known in the art. For resistance; Insulin deficiency;
    (BMP9); example, Biol. Chem. Hyperlipidemia; Hyperketonemia; Non-
    Growth 379(8-9): (1998) insulin dependent Diabetes Mellitus
    differentiation 1101-1110.; Biochem (NIDDM); Insulin-dependent Diabetes
    factor-2 J. 1993 Nov 15; 296 Mellitus (IDDM); A Condition
    precursor (Pt 1): 15-9. Associated With Diabetes Including,
    (GDF-2 But Not Limited To Obesity, Heart
    precursor)) Disease, Hyperglycemia, Infections,
    Retinopathy, And/Or Ulcers; Metabolic
    Disorders; Immune Disorders; Obesity;
    Vascular Disorders; Suppression of
    Body Weight; Suppression of Appetite;
    Syndrome X.
    Glucagon- Stimulates the GLP1 activity may be Hyperglycemia; Diabetes; Diabetes
    Like-Peptide 1 synthesis and release assayed in vitro using a Insipidus; Diabetes mellitus; Type 1
    (GLP1; of insulin; enhances [3-H]-glucose uptake diabetes; Type 2 diabetes; Insulin
    Insulinotropin) the sensitivity of assay. (J Biol Chem resistance; Insulin deficiency;
    adipose, muscle, and 1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    liver tissues towards 274(43): 30864-30873). insulin dependent Diabetes Mellitus
    insulin; stimulates (NIDDM); Insulin-dependent Diabetes
    glucose uptake; slows Mellitus (IDDM); A Condition
    the digestive process; Associated With Diabetes Including, But
    suppresses appetite; Not Limited To Obesity, Heart Disease,
    blocks the secretion Hyperglycemia, Infections, Retinopathy,
    of glucagon. And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    Exendin-4 Stimulates the Exendin-4 activity may Hyperglycemia; Diabetes; Diabetes
    (AC-2993) synthesis and release be assayed in vitro Insipidus; Diabetes mellitus; Type 1
    of insulin; enhances using a [3-H]-glucose diabetes; Type 2 diabetes; Insulin
    the sensitivity of uptake assay. (J Biol resistance; Insulin deficiency;
    adipose, muscle, and Chem 1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    liver tissues towards 274(43): 30864-30873). insulin dependent Diabetes Mellitus
    insulin; stimulates (NIDDM); Insulin-dependent Diabetes
    glucose uptake; slows Mellitus (IDDM); A Condition
    the digestive process; Associated With Diabetes Including, But
    suppresses appetite; Not Limited To Obesity, Heart Disease,
    blocks the secretion Hyperglycemia, Infections, Retinopathy,
    of glucagon. And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    T20 (T20 HIV a peptide from Virus inhibition assays HIV; AIDS; SIV (simian
    inhibitory residues 643-678 of as described in Zhang immunodeficiency virus) infection.
    peptide, the HIV gp41 et al., Sep. 26 2002,
    DP178; DP178 transmembrane Sciencexpress
    HIV inhibitory protein ectodomain (www.sciencexpress.org).
    peptide) which binds to gp41
    in its resting state and
    prevents
    transformation to the
    fusogenic state
    T1249 (T1249 a second generation Virus inhibition assays HIV; AIDS; SIV (simian
    HIV inhibitory HIV fusion inbitor as described in Zhang immunodeficiency virus) infection
    peptide; T1249 et al., Sep. 26 2002,
    anti-HIV Sciencexpress
    peptide) (www.sciencexpress.org).
    Interferon Confers a range of Anti-viral assay: Viral infections; HIV Infections;
    Hybrids, cellular responses Rubinstein S, Familletti PC, Hepatitis; Chronic Hepatitis; Hepatitis B;
    specifically including antiviral, Pestka S. (1981) Chronic Hepatitis B; Hepatitis C;
    preferred: antiproliferative, Convenient assay for Chronic Hepatitis C; Hepatitis D;
    IFNalpha A/D antitumor and interferons. J. Virol. Chronic Hepatitis D; Human
    hybrid (BgIII immunomodulatory 37(2): 755-8; Anti- Papillomavirus; Herpes Simplex Virus
    version) activities; stimulate proliferation assay: Infection; External Condylomata
    IFNalpha A/D production of two Gao Y, et al (1999) Acuminata; HIV; HIV Infection;
    hybrid (PvuII enzymes: a protein Sensitivity of an Oncology; Cancer; Solid Tumors;
    version) kinase and an epstein-barr virus- Melanoma; Malignant Melanoma; Renal
    IFNalpha A/F oligoadenylate positive tumor line, Cancer (e.g., Renal Cell Carcinoma);
    hybrid synthetase. Also, Daudi, to alpha Lung Cancer (e.g., Non-Small Cell Lung
    IFNalpha A/B modulates MHC interferon correlates Cancer or Small Cell Lung Cancer)
    hybrid antigen expression, with expression of a Colon Cancer; Breast Cancer; Liver
    IFNbeta NK cell activity and GC-rich viral Cancer; Prostate Cancer; Bladder
    1/alpha D IFNg production and transcript. Mol Cell Cancer; Gastric Cancer; Sarcoma; AIDS-
    hybrid IL12 production in Biol. 19(11): 7305-13. Related Kaposi's Sarcoma; Lymphoma;
    (IFNbeta- monocytes. T Cell Lymphoma; Cutaneous T-Cell
    1/alpha-1 Lymphoma; Non-Hodgkin's Lymphoma;
    hybrid) Brain Cancer; Glioma; Glioblastoma
    IFNalpha/beta Multiforme; Cervical Dysplasia;
    hybrid Leukemia; Preleukemia; Bone Marrow
    Disorders; Bone Disorders; Hairy Cell
    Leukemia; Chronic Myelogeonus
    Leukemia; Hematological Malignancies;
    Hematological Disorders; Multiple
    Myeloma; Bacterial Infections;
    Chemoprotection; Thrombocytopenia;
    Multiple Sclerosis; Pulmonary Fibrosis;
    Age-Related Macular Degeneration;
    Macular Degeneration; Crohn's Disease;
    Neurological Disorders; Arthritis;
    Rheumatoid Arthritis; Ulcerative Colitis;
    Osteoporosis, Osteopenia,
    Osteoclastogenesis; Fibromyalgia;
    Sjogren's Syndrome; Chronic Fatigue
    Syndrome; Fever; Hemmorhagic Fever;
    Viral Hemmorhagic Fevers;
    Hyperglycemia; Diabetes; Diabetes
    Insipidus; Diabetes mellitus; Type 1
    diabetes; Type 2 diabetes; Insulin
    resistance; Insulin deficiency;
    Hyperlipidemia; Hyperketonemia; Non-
    insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    B-type stimulates smooth Inhibition of Congestive heart failure; cardiac volume
    natriuretic muscle relaxation angiotensin can be overload; cardiac decompensation;
    peptide (BNP, and vasodilation, determined using Cardiac Failure; Left Ventricular
    brain natriuresis, and assays known in the art, Dysfunction; Dyspnea
    natriuretic suppression of renin- for example using an in
    peptide) angiotensin and vitro proliferation assay
    endothelin. with rat cardiac
    fibroblasts as described
    in Naunyn
    Schmiedebergs Arch
    Pharmacol 1999
    May; 359(5): 394-9.
    Vasodilation can be
    measured in animals by
    measuring the
    myogenic responses of
    small renal arteries in
    an isobaric arteriograph
    system (see Am J
    Physiol Regul Integr
    Comp Physiol 2002
    Aug; 283(2): R349-R355).
    Natriuesis is
    determined by
    measuring the amount
    of sodium in the urine.
    α-defensin, Suppression of HIV Virus inhibition assays HIV, AIDS; ARC.
    including replication; active as described in Zhang
    alpha 1 against bacteria, et al., Sep. 26 2002,
    defensin, alpha fungi, and enveloped Sciencexpress
    2 defensin, viruses. (www.sciencexpress.org).
    alpha 3
    defensin
    (myeloid-
    related
    defensin;
    DEFA1;
    neutrophil-
    specific
    defensin;
    CAF)
    Phosphatonin Regulation of Blood phosphate levels Hyperphosphatemia; Hyperphosphatemia
    (matrix phosphate can be measured using in chronic renal failure;
    extracellular metabolism. methods known in the hypophosphatemia; Osteomalacia;
    phosphoglycoprotein; art such as the Rickets; X-linked dominant
    MEPE) Hypophosphatemic Rat hypophosphatemic rickets/osteomalacia
    Bioassay. Zoolog Sci (XLH); autosomal dominant
    1995 Oct; 12(5): 607-10. hypophosphatemic rickets/osteomalacia
    (ADHR); tumor-induced
    rickets/osteomalacia (TIO).
    P1pal-12 Regulation of Platelet aggregation can Protection against systemic platelet
    (pepducin, protease-activated be measured using activation, thrombus, heart attack, stroke,
    PAR1-based receptor (PAR) signal methods known in the and/or coagulation disorders.
    pepducin) transduction and art such as described in
    thrombin-mediated Nature Medicine 2002
    aggregation of human Oct; 8(10): 1161-1165.
    platelets.
    P4pal-10 Regulation of Platelet aggregation can Protection against systemic platelet
    (pepducin, protease-activated be measured using activation, thrombus, heart attack, stroke,
    PAR4-based receptor (PAR) signal methods known in the and/or coagulation disorders.
    pepducin) transduction and art such as described in
    thrombin-mediated Nature Medicine 2002
    aggregation of human Oct; 8(10): 1161-1165.
    platelets.
    HRDFD27 Involved in the T-cell proliferation can Chemoprotection; Adjunct to
    proliferation of T be measured using Chemotherapy; Inflammatory disorders;
    cells; Production of assays known in the art. Cancer; Leukemia; Myelocytic leukemia;
    TNFgamma. For example, Neutropenia, Primary neutropenias (e.g.;
    “Lymphocytes: a Kostmann syndrome); Secondary
    practical approach” neutropenia; Prevention of neutropenia;
    edited by: SL Rowland, Prevention and treatment of neutropenia
    AJ McMichael - in HIV-infected patients; Prevention and
    chapter 6, pages 138-160 treatment of neutropenia associated with
    Oxford University chemotherapy; Infections associated with
    Press (2000); and neutropenias; Myelopysplasia;
    “Current Protocols on Autoimmune disorders; Psoriasis;
    CD-ROM” section 3.12 Mobilization of hematopoietic
    Proliferation Assays for progenitor cells; Wound Healing;
    T-cell Function John Autoimmune Disease; Transplants; Bone
    Wiley & Soncs, Inc. marrow transplants; Acute
    (1999). myelogeneous leukemia; Lymphoma,
    Non-Hodgkin's lymphoma; Acute
    lymphoblastic leukemia; Hodgkin's
    disease; Accelerated myeloid recovery;
    Glycogen storage disease
    HWHGZ51 Stimulates an The ability to affect Skeletal diseases and disorders;
    (CD59; immune response and chondrocyte Musculoskeletal diseases and disorders;
    Metastasis- induces inflammation differentiation can be Bone fractures and/or breaks;
    associated by inducing measured using Osteoporosis (postmenopausal, senile, or
    GPI-adhered mononuclear cell, methods known in the idiopathic juvenile); Gout and/or
    protein eosinophil and PMN art, such as described in pseudogout; Paget's disease;
    homolog) infiltration; Inhibits Bone (1995) Sep; Osteoarthritis; Tumors and/or cancers of
    growth of breast 17(3): 279-86. the bone (osteochondromas, benign
    cancer, ovarian chondromas, chondroblastomas,
    cancer, leukemia, and chondromyxoid fibromas, osteoid
    melanoma; osteomas, giant cell tumors, multiple
    Overexpressed in myelomas, osteosarcomas,
    colon, lung, breast fibrosarcomas, malignant fibrous
    and rectal tumors; histiocytomas, chondrosarcomas,
    Regulates glucose Ewing's tumors, and/or malignant
    and/or FFA update by lymphomas); Bone and joint infections
    adipocytes and (osteomyelitits and/or infectious
    skeletal muscle; arthritis); Charcot's joints; Heel spurs;
    Induces Sever's disease; Sport's injuries; Cancer;
    redifferentiation of Solid Tumors; Melanoma; Malignant
    chondrocytes Melanoma; Renal Cancer (e.g., Renal
    Cell Carcinoma); Lung Cancer (e.g,.
    Non-Small Cell Lung Cancer or Small
    Cell Lung Cancer) Colon Cancer; Breast
    Cancer; Liver Cancer; Prostate Cancer;
    Bladder Cancer; Gastric Cancer;
    Sarcoma; AIDS-Related Kaposi's
    Sarcoma; Lymphoma; T Cell
    Lymphoma; Cutaneous T-Cell
    Lymphoma; Non-Hodgkin's Lymphoma;
    Brain Cancer; Glioma; Glioblastoma
    Multiforme; Cervical Dysplasia;
    Leukemia; Preleukemia; Bone Marrow
    Disorders; Bone Disorders; Hairy Cell
    Leukemia; Chronic Myelogeonus
    Leukemia; Hematological Malignancies;
    Hematological Disorders; Multiple
    Myeloma; Kidney diseases and
    disorders; Shonlein-Henoch purpura,
    Berger disease, celiac disease, dermatitis
    herpetiformis, Chron disease; Diabetes;
    Diabetes Insipidus; Diabetes mellitus;
    Type 1 diabetes; Type 2 diabetes; Insulin
    resistance; Insulin deficiency;
    Hyperlipidemia; Hyperketonemia; Non-
    insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X;
    Kidney disorders; Hyperinsulinemia;
    Hypoinsulinemia; Immunological
    disorders (e.g. arthritis, asthma,
    immunodeficiency diseases, AIDS,
    rheumatoid arthritis, granulomatous
    disease, inflammatory bowl disease,
    sepsis, acne, neutropenia, neutrophilia,
    psoriasis, hypersensitivities, T-cell
    mediated cytotoxicity, host-versus-graft
    disease, autoimmunity disorders,
    demyelination, systemic lupus
    erythematosis, drug induced hemolytic
    anemia, rheumatoid arthritis, Sjorgren's
    disease, scleroderma)
    C17 (cytokine- Inhibits glucose Proliferation of kidney Kidney diseases and disorders; Shonlein-
    like protein and/or FFA uptake by mesangial cells can be Henoch purpura, Berger disease, celiac
    C17) adipocytes; Induces assayed using disease, dermatitis herpetiformis, Chron
    proliferation of techniques described in disease; Diabetes; Diabetes Insipidus;
    kidney mesangial J. Investig. Med. (1998) Diabetes mellitus; Type 1 diabetes; Type
    cells; Regulation of Aug; 46(6): 297-302. 2 diabetes; Insulin resistance; Insulin
    cytokine production deficiency; Hyperlipidemia;
    and antigen Hyperketonemia; Non-insulin dependent
    presentation Diabetes Mellitus (NIDDM); Insulin-
    dependent Diabetes Mellitus (IDDM); A
    Condition Associated With Diabetes
    Including, But Not Limited To Obesity,
    Heart Disease, Hyperglycemia,
    Infections, Retinopathy, And/Or Ulcers;
    Metabolic Disorders; Immune Disorders;
    Obesity; Vascular Disorders;
    Suppression of Body Weight;
    Suppression of Appetite; Syndrome X;
    Kidney disorders; Hyperinsulinemia;
    Hypoinsulinemia; Hematopoietic
    disorders; Immunological diseases and
    disorders; Developmental diseases and
    disorders; Hepatic diseases and
    disorders; Cancer (particularly
    leukemia); Immunological disorders (e.g.
    arthritis, asthma, immunodeficiency
    diseases, AIDS, rheumatoid arthritis,
    granulomatous disease, inflammatory
    bowl disease, sepsis, acne, neutropenia,
    neutrophilia, psoriasis, hypersensitivities,
    T-cell mediated cytotoxicity, host-
    versus-graft disease, autoimmunity
    disorders, demyelination, systemic lupus
    erythematosis, drug induced hemolytic
    anemia, rheumatoid arthritis, Sjorgren's
    disease, scleroderma)
    HDPBQ71 Regulates production Such assays that may Blood disorders and infection (e.g., viral
    and secretion of be used or routinely infections, tuberculosis, infections
    IFNgamma; modified to test associated with chronic granulomatosus
    Activation of immunomodulatory disease and malignant osteoporosis);
    myeloid cells and/or activity of polypeptides Autoimmune disease (e.g., rheumatoid
    hematopoietic cells of the invention arthritis, systemic lupus erythematosis,
    (including antibodies multiple sclerosis); Immunodeficiency,
    and agonists or boosting a T cell-mediated immune
    antagonists of the response, and suppressing a T cell-
    invention) include the mediated immune response;
    assays disclosed in Inflammation and inflammatory
    Miraglia et al., J disorders; Idiopathic pulmonary fibrosis;
    Biomolecular Neoplastic diseases (e.g., leukemia,
    Screening 4: 193-204 lymphoma, melanoma); Neoplasms and
    (1999); Rowland et al., cancers, such as, for example, leukemia,
    ““Lymphocytes: a lymphoma, melanoma, and prostate,
    practical approach”” breast, lung, colon, pancreatic,
    Chapter 6: 138-160 esophageal, stomach, brain, liver and
    (2000); Gonzalez et al., urinary cancer;. Benign dysproliferative
    J Clin Lab Anal disorders and pre-neoplastic conditions,
    8(5): 225-233 (1995); such as, for example, hyperplasia,
    Billiau et al., Ann NY metaplasia, and/or dysplasia; Anemia;
    Acad Sci 856: 22-32 Pancytopenia; Leukopenia;
    (1998); Boehm et al., Thrombocytopenia; Hodgkin's disease;
    Annu Rev Immunol Acute lymphocytic anemia (ALL);
    15: 749-795 (1997), and Plasmacytomas; Multiple myeloma;
    Rheumatology Burkitt's lymphoma; Arthritis; AIDS;
    (Oxford) 38(3): 214-20 Granulomatous disease; Inflammatory
    (1999) bowel disease; Sepsis; Neutropenia;
    Neutrophilia; Psoriasis; Suppression of
    immune reactions to transplanted organs
    and tissues; Hemophilia;
    Hypercoagulation; Diabetes mellitus;
    Endocarditis; Meningitis; Lyme Disease;
    Asthma; Allergy
    Oscar Regulator of Assay to detect Skeletal diseases and disorders;
    (osteoclast- osteoclast osteoclast Musculoskeletal diseases and disorders;
    associated differentiation; differentiation is Bone fractures and/or breaks;
    receptor regulator of innate described in J. Exp. Osteoporosis (postmenopausal, senile, or
    isoform-3) and adaptive immune Med. (2002) Jan 21; idiopathic juvenile); Gout and/or
    responses 195(2): 201-9. pseudogout; Paget's disease;
    Osteoarthritis; Tumors and/or cancers of
    the bone (osteochondromas, benign
    chondromas, chondroblastomas,
    chondromyxoid fibromas, osteoid
    osteomas, giant cell tumors, multiple
    myelomas, osteosarcomas,
    fibrosarcomas, malignant fibrous
    histiocytomas, chondrosarcomas,
    Ewing's tumors, and/or malignant
    lymphomas); Bone and joint infections
    (osteomyelitits and/or infectious
    arthritis); Charcot's joints; Heel spurs;
    Sever's disease; Sport's injuries
    Tumstatin (T5, Inhibits angiogenesis; A tumor cell Cancer; Solid Tumors; Melanoma;
    T7 or T8 Inhibits tumor proliferation assay is Malignant Melanoma; Renal Cancer
    peptide; growth; Inhibits described in J. Biol. (e.g., Renal Cell Carcinoma); Lung
    α3(IV)NC1) protein synthesis Chem. (1997) Cancer (e.g,. Non-Small Cell Lung
    272: 20395-20401. Cancer or Small Cell Lung Cancer)
    Protein synthesis can be Colon Cancer; Breast Cancer; Liver
    measured as described Cancer; Prostate Cancer; Bladder
    in Science (2002) Jan Cancer; Gastric Cancer; Sarcoma; AIDS-
    4; 295(5552): 140-3. Related Kaposi's Sarcoma; Lymphoma;
    T Cell Lymphoma; Cutaneous T-Cell
    Lymphoma; Non-Hodgkin's Lymphoma;
    Brain Cancer; Glioma; Glioblastoma
    Multiforme; Cervical Dysplasia;
    Leukemia; Preleukemia; Bone Marrow
    Disorders; Bone Disorders; Hairy Cell
    Leukemia; Chronic Myelogeonus
    Leukemia; Hematological Malignancies;
    Hematological Disorders; Multiple
    Myeloma; Angiogenesis
    CNTF (Ciliary Enhances myelin Regulation of myelin Neurological and neural diseases and
    neurotrophic formation; Reduces formation can be disorders, particularly diseases and
    factor) photoreceptor assayed as described in disorders associated with myelin and
    degredation; J. Neurosci. (2002) demyelination, such as, for example,
    Regulates calcium Nov. 1; 22(21): 9221-7. ALS, multiple sclerosis, Huntington's
    currents disease; Neuronal and spinal cord
    injuries; Disorders of the eye, such as,
    for example, retinitis pigmentosa,
    blindness, color-blindness, macular
    degeneration.
    Somatostatin Inhibits growth Inhibition of growth Cancer; Metastatic carcinoid tumors;
    (Octreotide; hormone, glucagons hormone release in Vasoactive Intestinal Peptide secreting
    octreotide and insulin; humans by adenomas; Diarrhea and Flushing;
    acetate; Suppresses LF somatostatin can be Prostatic disorders and cancers; Breast
    Sandostating response to GnRH; measured as described cancer; Gastrointestinal disorders and
    LAR ®) Decreases splanchnic in J. Clin. Endocrinol. cancers; Cancers of the endocrine
    blood flow; Inhibits Metab. (1973) Oct; system; Head and neck paragangliomas;
    release of serotonin, 37(4): 632-4. Liver disorders and cancers;
    gastrin, vasoactive Inhibition of insulin Nasopharyngeal cancers; Thyroid
    intestinal peptide, secretion by disorders and cancers; Acromegaly;
    secretin, motilin, and somatostatin can be Carcinoid Syndrome; Gallbladder
    pancreatic measured as described disorders, such as gallbladder
    polypeptide. in the Lancet (1973) contractility diseases and abnormal bile
    Dec. 8; 2(7841): 1299-1301. secretion; Psoriasis; Diabetes; Diabetes
    Insipidus; Diabetes mellitus; Type 1
    diabetes; Type 2 diabetes; Insulin
    resistance; Insulin deficiency;
    Hyperlipidemia; Hyperketonemia; Non-
    insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X;
    Kidney disorders; Neurological disorders
    and diseases, including Alzheimers
    Disease, Parkinson's disease and
    dementia; Neuropsychotic disorders,
    including Bipolar affective disorder;
    Rheumatoid arthritis; Hypertension;
    Intracranial hypertension; Esophageal
    varices; Graves' disease; Seizures;
    Epilepsy; Gastritis; Angiogenesis;
    IL-22 (IL22, Stimulates glucose IL-22 activity may be Hyperglycemia; Diabetes; Diabetes
    interleukin-22; uptake in skeletal assayed in vitro using a Insipidus; Diabetes mellitus; Type 1
    IL17D, IL27) muscle cells; [3-H]-glucose uptake diabetes; Type 2 diabetes; Insulin
    increases skeletal assay. (J Biol Chem resistance; Insulin deficiency;
    muscle insulin 1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    sensitivity. 274(43): 30864-30873). insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    HCE1P80 Stimulates glucose HCE1P80 activity may Hyperglycemia; Diabetes; Diabetes
    uptake in; increases be assayed in vitro Insipidus; Diabetes mellitus; Type 1
    insulin sensitivity, using a [3-H]-glucose diabetes; Type 2 diabetes; Insulin
    uptake assay. (J Biol resistance; Insulin deficiency;
    Chem 1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    274(43): 30864-30873). insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    HDRMI82 Stimulates glucose HDRMI82 activity may Hyperglycemia; Diabetes; Diabetes
    uptake; increases be assayed in vitro Insipidus; Diabetes mellitus; Type 1
    insulin sensitivity. using a [3-H]-glucose diabetes; Type 2 diabetes; Insulin
    uptake assay. (J Biol resistance; Insulin deficiency;
    Chem 1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    274(43): 30864-30873). insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    HDALV07 Modulates insulin Insulin activity may be Diabetes; Diabetes Insipidus; Diabetes
    (adiponectin; action assayed in vitro using a mellitus; Type 1 diabetes; Type 2
    gelatin-binding [3-H]-glucose uptake diabetes; Insulin resistance; Insulin
    28k protein assay. (J Biol Chem deficiency; Hyperlipidemia;
    precurson; 1999 Oct 22; Hyperketonemia; Non-insulin dependent
    adipose most 274(43): 30864-30873). Diabetes Mellitus (NIDDM); Insulin-
    abundant gene dependent Diabetes Mellitus (IDDM); A
    transcript; Condition Associated With Diabetes
    APM-1; Including, But Not Limited To Obesity,
    GBP28; Heart Disease, Hyperglycemia,
    ACRP30; Infections, Retinopathy, And/Or Ulcers;
    ADIPOQ) Metabolic Disorders; Immune Disorders;
    Obesity; Vascular Disorders;
    Suppression of Body Weight;
    Suppression of Appetite; Syndrome X;
    Hyperglycemia; Familial combined
    hyperlipidemia; Metabolic syndrome;
    Inflammatory disorders; Atherogenic
    disorders
    C Peptide An insulin precursor C-peptide Diabetes; Diabetes Insipidus; Diabetes
    involved in insulin concentrations can be mellitus; Type 1 diabetes; Type 2
    regulation measured using assays diabetes; Insulin resistance; Insulin
    well known in the art, deficiency; Hyperlipidemia;
    such as the one Hyperketonemia; Non-insulin dependent
    described in PNAS Diabetes Mellitus (NIDDM); Insulin-
    (1970) Sep; 67(1): 148-55 dependent Diabetes Mellitus (IDDM); A
    Condition Associated With Diabetes
    Including, But Not Limited To Obesity,
    Heart Disease, Hyperglycemia,
    Infections, Retinopathy, And/Or Ulcers;
    Metabolic Disorders; Immune Disorders;
    Obesity; Vascular Disorders;
    Suppression of Body Weight;
    Suppression of Appetite; Syndrome X;
    Hyperglycemia; Familial combined
    hyperlipidemia; Metabolic syndrome
    HCBOG68 Controls Activation of cAMP- Treatment of Obesity; treatment of
    (enteric proliferation/ mediated transcription Diabetes; suppression of body weight
    adipokine; Fat differentiation or in adipocytes can be gain; suppression of appetite.
    SID; proline metabolism/ assayed using methods Hyperglycemia; Diabetes; Diabetes
    rich acidic physiology/pathology/ known in the art Insipidus; Diabetes mellitus; Type 1
    protein) of adipocytes and (Berger et al., Gene diabetes; Type 2 diabetes; Insulin
    adipose tissue in 66: 1-10 (1998); Cullen resistance; Insulin deficiency;
    response to dietary and Malm, Methods in Hyperlipidemia; Hyperketonemia; Non-
    conditions. Enzymol 216: 362-368 insulin dependent Diabetes Mellitus
    (1992); Henthorn et al., (NIDDM); Insulin-dependent Diabetes
    Proc Natl Acad Sci Mellitus (IDDM); A Condition
    USA 85: 6342-6346 Associated With Diabetes Including, But
    (1988); Reusch et al., Not Limited To Obesity, Heart Disease,
    Mol Cell Biol Hyperglycemia, Infections, Retinopathy,
    20(3): 1008-1020 And/Or Ulcers; Metabolic Disorders;
    (2000); and Klemm et Immune Disorders; Obesity; Vascular
    al., J Biol Chem Disorders; Suppression of Body Weight;
    273: 917-923 (1998)). Suppression of Appetite; Syndrome X.
    Other indications for antibodies and/or
    antagonists, include treatment of weight
    loss; treatment of AIDS wasting; appetite
    stimulant; treatment of cachexia.
    PYY (Peptide Decreases appetite; Appetite and food Most preferred: Treatment of Obesity;
    YY), including increases satiety; intake can be can be treatment of Diabetes; suppression of
    PYY3-36 decreases food measured by methods body weight gain; suppression of
    (amino acid intake. known in the art appetite.
    residues 31-64 (Batterham et al. Hyperglycemia; Diabetes; Diabetes
    of full length Nature 2002; Insipidus; Diabetes mellitus; Type 1
    PYY, amino 418: 650654) diabetes; Type 2 diabetes; Insulin
    acid residues resistance; Insulin deficiency;
    3-36 of mature Hyperlipidemia; Hyperketonemia; Non-
    PYY) insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    Other indications for antibodies,
    antagonists: treatment of weight loss;
    treatment of AIDS wasting; appetite
    stimulant; treatment of cachexia.
    WNT10b Inhibits adipogenesis. WNT10b activity can Most preferred: Treatment of Obesity;
    be measured using suppression of body weight gain;
    adipogenesis inhibition suppression of appetite.
    assays (Ross et al., Other indications: Hyperglycemia;
    Science 2000; Diabetes; Diabetes Insipidus; Diabetes
    289(5481): 950-953 mellitus; Type 1 diabetes; Type 2
    diabetes; Insulin resistance; Insulin
    deficiency; Hyperlipidemia;
    Hyperketonemia; Non-insulin dependent
    Diabetes Mellitus (NIDDM); Insulin-
    dependent Diabetes Mellitus (IDDM).
    WNT11 Promotes WNT11 activity can be Treatment of Cardiovascular disorders;
    cardiogenesis. measured using assays Congestive Heart Failure; Myocardial
    known in the art, Infarction.
    including cardiogenesis
    assays (Eisenberg et al.,
    Dev Dyn 1999
    Sep; 216(1): 45-58).
    Herstatin Inhibits cancer Herstatin activity can Oncology; Cancer; Solid Tumors;
    proliferation. be measured using cell Melanoma; Malignant Melanoma; Renal
    proliferation assays Cancer (e.g., Renal Cell Carcinoma);
    known in the art Lung Cancer (e.g,. Non-Small Cell Lung
    (Doherty et al., PNAS Cancer or Small Cell Lung Cancer);
    1999; 96(19): 10869-10874. Colon Cancer; Breast Cancer; Liver
    Cancer; Prostate Cancer; Bladder
    Cancer; Gastric Cancer; Sarcoma; AIDS-
    Related Kaposi's Sarcoma; Lymphoma;
    T Cell Lymphoma; Cutaneous T-Cell
    Lymphoma; Non-Hodgkin's Lymphoma;
    Brain Cancer; Glioma; Glioblastoma
    Multiforme; Cervical Dysplasia;
    Leukemia; Preleukemia; Hairy Cell
    Leukemia; Chronic Myelogeonus
    Leukemia; Hematological Malignancies;
    Hematological Disorders; Multiple
    Myeloma.
    Adrenomedullin stimulates Vasodilation can be Treatment of Congestive Heart Failure;
    vasodilation; measured using assays Hypertension; Myocardial Infarction;
    promotes bone known in the art Septic Shock; Osteoporosis;
    growth. (Ashton et al. Postmenopausal osteoporosis;
    Pharmacology 2000; Osteopenia.
    61(2): 101-105. The
    promotion of bone
    growth can be
    measured using assays
    known in the art, such
    as the osteoblast
    proliferation assay
    (Cornish et al. Am J
    Physiol 1997
    Dec; 273(6 Pt 1): E1113-
    20).
    Nogo Receptor Receptor for the axon The promotion of axon Treatment of Central Nervous System
    growth inhibitor, regeneration and Damage; Spinal Cord Injury; Peripheral
    Nogo. growth can be Nerve Damage; Neurodegenerative
    measured using assays Diseases; Parkinson's Disease;
    known in the art Alzheimer's Disease; Huntington's
    (Fournier et al. Nature Disease; Amyotrophic Lateral Sclerosis;
    2001; 409(6818): 341-346). Progressive Supranuclear Palsy;
    Creutzfeld-Jacob Disease; Motor Neuron
    Disease.
    CART Inhibits food intact Appetite and food Most preferred: Treatment of Obesity;
    (Cocaine- and and fat storage; intake can be can be suppression of body weight gain;
    Amphetamine- promotes lipid measured by methods suppression of appetite.
    Regulated oxidation. known in the art Other indications: Hyperglycemia;
    Transcript) (Batterham et al. Diabetes; Diabetes Insipidus; Diabetes
    Nature 2002; mellitus; Type 1 diabetes; Type 2
    418: 650654) diabetes; Insulin resistance; Insulin
    deficiency; Hyperlipidemia;
    Hyperketonemia; Non-insulin dependent
    Diabetes Mellitus (NIDDM); Insulin-
    dependent Diabetes Mellitus (IDDM).
    RegIV (Colon Stimulates glucose RegIV activity may be Hyperglycemia; Diabetes; Diabetes
    Specific Gene; uptake; increases assayed in vitro using a Insipidus; Diabetes mellitus; Type 1
    Colon Specific insulin sensitivity. [3-H]-glucose uptake diabetes; Type 2 diabetes; Insulin
    Protein) assay. (J Biol Chem resistance; Insulin deficiency;
    1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    274(43): 30864-30873). insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    Cosyntropin Synthetic The activity of Endocrine; Addison's disease; Cushing's
    (Cortrosyn) corticotropin; cosyntropin can be syndrome; pituitary dysfunction; acute
    (CAS-16960- stimulates the release assessed in vivo by adrenal crisis
    16-0) of cortisol. measuring serum
    cortisol levels. (Frank
    et al. J. Am. Vet. Med.
    Assoc. 1998
    212(10): 1569-71).
    Pexiganan Disrupts bacterial Pexiganan acetate Treatment of Infectious Diseases;
    Acetate membranes. activity can be assessed Treatment of Bacterial Infections.
    (CAS-172820- using in vitro
    23-4) antibacterial assays
    known in the art.
    (Zasloff et al.,
    Antimicrobial Agents
    and Chemotherapy
    1999, 43: 782-788).
    Pramlintide Slows gastric Appetite and food Treatment of Obesity; treatment of
    (Amylin) emptying; decreases intake can be can be Diabetes; suppression of body weight
    (CAS-151126- food intake. measured by methods gain; suppression of appetite; treatment
    32-8) known in the art of endocrine disorders;
    (Batterham et al. Hyperglycemia; Diabetes; Diabetes
    Nature 2002; Insipidus; Diabetes mellitus; Type 1
    418: 650654) diabetes; Type 2 diabetes; Insulin
    resistance; Insulin deficiency;
    Hyperlipidemia; Hyperketonemia; Non-
    insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    Other indications for antibodies,
    antagonists: treatment of weight loss;
    treatment of AIDS wasting; appetite
    stimulant; treatment of cachexia.
    Teriparatide Acts in conjuction Adenylyl cyclase Bone Disorders; Fracture prevention;
    (CAS-52232- with calcitonin to stimulation in rat Hypercalcemia; Malignant
    67-4) control calcium and osteosarcoma cells, hypercalcemia; Osteoporosis; Paget's
    phosphate ovariectomized rat disease; Osteopenia, Osteoclastogenesis;
    metabolism; elevates model of osteoporosis: osteolysis; osteomyelitis; osteonecrosis;
    blood calcium level; IUBMB Life 2000 periodontal bone loss; osteoarthritis;
    stimulates the activity Feb; 49(2): 131-5 rheumatoid arthritis; osteopetrosis;
    of osteocytes; periodontal, lytic, or metastatic bone
    enhances absorption disease; osteoclast differentiation
    of Ca+/Pi from small inhibition; bone disorders; bone healing
    intestine into blood; and regeneration.
    promotes
    reabsorption of Ca+
    and inhibits Pi by
    kidney tubules.
    Terlipressin Analog of Terlipressin activity Variceal hemorrhage; cirrhosis; portal
    (triglycyl vasopressin; induces can be measured using hypertension; hepatorenal syndrome;
    lycine vasoconstriction. assays of Blood-related disorders
    vasopressin) vasoconstriction, such
    (CAS-14636- as the isolated arterial
    12-5) ring preparation.
    (Landstrom et al., Hum
    Reprod 1999
    Jan; 14(1): 151-5).
    Ularitide Stimulates Ularitide activity can be Excretory disorders; Acute renal failure;
    (CAS-118812- natriuresis, diuresis, assessed by measuring asthma; congestive heart failure;
    69-4) and vasodilation. cGMP accumulation in hypertension; pulmonary hypertension;
    rat renal cells. cardiovascular disorders
    (Valentin et al.,
    Hypertension 1993
    Apr; 21(4): 432-8).
    Aprotinin Serine protease Inhibition of thrombin- Inhibition of fibrinolysis; reduction of
    (Trasylol) inhibitor; attenuates induced platelet blood loss during surgery; Treatment of
    (CAS-9087- Systemic aggregation can be Inflammation and Immune Disorders.
    70-1; CAS- Inflammatory measured using
    11061-94-2; Response, methods known in the
    CAS-12407- fibrinolysis and art. (Poullis et al., J
    79-3) thrombin-induced Thorac Cardiovasc
    platelet aggregation. Surg 2000
    Aug; 120(2): 370-8).
    Aspartocin Antibacteria Aspartocin activity can Treatment of Infectious Diseases;
    (CAS-4117- be assessed using in treatment of bacterial infections.
    65-1; CAS- vitro antibacterial
    1402-89-7) assays known in the art.
    (Zasloff et al.,
    Antimicrobial Agents
    and Chemotherapy
    1999, 43: 782-788).
    Calcitonin Regulates levels of Hypocalcemic Rat Musculoskeletal; Osteroporosis; Paget's
    (Calcimar) calcium and Bioassay, bone disease; hypercalcemia;
    (CAS-21215- phosphate in serum; resorbing assay and the Bone Disorders; Fracture prevention;
    62-3) causes a reduction in pit assay, CT receptor Malignant hypercalcemia; Osteopenia,
    serum calcium--an binding assay, CAMP Osteoclastogenesis; osteolysis;
    effect opposite to that stimulation assay: J osteomyelitis; osteonecrosis; periodontal
    of human parathyroid Bone Miner Res 1999 bone loss; osteoarthritis; rheumatoid
    hormone. Aug; 14(8): 1425-31 arthritis; osteopetrosis; periodontal, lytic,
    or metastatic bone disease; osteoclast
    differentiation inhibition; bone disorders;
    bone healing and regeneration.
    Carperitide Stimulates Carperitide activity can Treatment of Heart Failure;
    (HANP; natriuresis, diuresis, be assessed in vitro by Cardiovascular disorders; Respiratory
    recombinant and vasodilation. measuring cGMP disorders; Acute respiratory distress
    human atrial accumulation in a syndrome.
    natriuretic number of cell lines,
    peptide) including PC12 cells
    (CAS-89213- and cultured human
    87-6) glomerular cells.
    (Medvede et al., Life
    Sci 2001 Aug
    31; 69(15): 1783-90;
    Green et al., J Am Soc
    Nephrol 1994
    Oct; 5(4): 1091-8).
    Desirudin Inhibits thrombin; Desirudin activity can Blood-related disorder; Thrombosis;
    (recombinant inhibits blood be assessed using blood thrombocytopenia; hemorrhages.
    hirudin; clotting. clotting assays known
    Revasc) in the art, such as in
    (CAS-120993- vitro platelet
    53-5) aggragation assays.
    (Glusa, Haemostasis
    1991; 21 Suppl 1: 116-20).
    Emoctakin proinflammatory Treatment of Inflammation, Immune
    (interleukin 8) cytokine disorders, RSV infection.
    (CAS-142298-
    00-8)
    Felypressin Derivative of Felypressin Treatment of pain; to induce local
    (CAS-56-59-7) Vasopressin; vasoconstriction anesthesia.
    Stimulates activity can be
    vasoconstriction; measured using assays
    Induces local of vasoconstriction,
    anesthesia. such as the isolated
    arterial ring
    preparation.
    (Landstrom et al., Hum
    Reprod 1999
    Jan; 14(1): 151-5).
    Glucagon Induces Glucagon activity may Hypoglycemia; Diabetes; Diabetes
    (CAS-16941- hyperglycemia. be assayed in vitro Insipidus; Diabetes mellitus; Type 1
    32-5) using a [3-H]-glucose diabetes; Type 2 diabetes; Insulin
    uptake assay. (J Biol resistance; Insulin deficiency;
    Chem 1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    274(43): 30864-30873). insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X;
    Endocrine disorders.
    Nagrestipen Inflammation; Immune
    (CAS-166089-
    33-4)
    Pentigetide Respiratory; Allergy; Immune
    (Pentyde)
    (CAS-62087-
    72-3)
    Proinsulin Stimulates glucose Insulin activity may be Hyperglycemia; Diabetes; Diabetes
    (CAS-67422- uptake and promotes assayed in vitro using a Insipidus; Diabetes mellitus; Type 1
    14-4) glycogenesis and [3-H]-glucose uptake diabetes; Type 2 diabetes; Insulin
    lipogenesis. assay. (J Biol Chem resistance; Insulin deficiency;
    1999 Oct 22; Hyperlipidemia; Hyperketonemia; Non-
    274(43): 30864-30873). insulin dependent Diabetes Mellitus
    (NIDDM); Insulin-dependent Diabetes
    Mellitus (IDDM); A Condition
    Associated With Diabetes Including, But
    Not Limited To Obesity, Heart Disease,
    Hyperglycemia, Infections, Retinopathy,
    And/Or Ulcers; Metabolic Disorders;
    Immune Disorders; Obesity; Vascular
    Disorders; Suppression of Body Weight;
    Suppression of Appetite; Syndrome X.
    Becaplermin Promotes wound Becaplermin activity Stimulate Epithelial Cell Proliferation;
    (Regranex; healing. can be assessed using Stimulate Basal Keratinocytes; Promote
    recombinant animal wound healing Wound Healing; Stimulate Hair Follicle
    PDGF-BB) models known in the Production; Healing Of Dermal Wounds.
    (CAS-165101- art. (Saba et al., Ann Wound Healing; Eye Tissue Wounds,
    51-9) Plast Surg 2002 Dental Tissue Wounds, Oral Cavity
    Jul; 49(1): 62-6). Wounds, Diabetic Ulcers, Dermal
    Ulcers, Cubitus Ulcers, Arterial Ulcers,
    Venous Stasis Ulcers, Burns Resulting
    From Heat Exposure Or Chemicals, or
    Other Abnormal Wound Healing
    Conditions such as Uremia,
    Malnutrition, Vitamin Deficiencies or
    Complications Associated With
    Systemic Treatment With Steroids,
    Radiation Therapy or Antineoplastic
    Drugs or Antimetabolites; Promote
    Dermal Reestablishment Subsequent To
    Dermal Loss; Increase the Adherence Of
    Skin Grafts To A Wound Bed; Stimulate
    Re-Epithelialization from The Wound
    Bed; To Promote Skin Strength;
    Improve The Appearance Of Aged Skin;
    Proliferate Hepatocytes, Lung, Breast,
    Pancreas, Stomach, Bladder, Small
    Intestine, Large Intestine; Sebocytes,
    Hair Follicles, Type II Pneumocytes,
    Mucin-Producing Goblet Cells, or Other
    Epithelial Cells, Endothelial Cells,
    Keratinocytes, or Basal Keratinocytes
    (and Their Progenitors) Contained
    Within The Skin, Lung, Liver, Bladder,
    Eye, Salivary Glands, or Gastrointestinal
    Tract; Reduce The Side Effects Of Gut
    Toxicity That Result From Radiation,
    Chemotherapy Treatments Or Viral
    Infections; Cytoprotector, especially of
    the Small Intestine Mucosa or Bladder;
    Mucositis (Mouth Ulcers); Regeneration
    Of Skin; Full and/or Partial Thickness
    Skin Defects, including Burns, (e.g.,
    Repopulation Of Hair Follicles, Sweat
    Glands, And Sebaceous Glands);
    Psoriasis; Epidermolysis Bullosa;
    Blisters; Gastric and/or Doudenal Ulcers;
    Reduce Scarring; Inflamamatory Bowel
    Diseases; Crohn's Disease; Ulcerative
    Colitis; Gut Toxicity; Lung Damage;
    Repair Of Alveoli And/or Brochiolar
    Epithelium; Acute Or Chronic Lung
    Damage; Emphysema, ARDS; Inhalation
    Injuries; Hyaline Membrane Diseases;
    Infant Respiratory Distress Syndrome;
    Bronchopulmonary Displasia In
    Premature Infants; Fulminant Liver
    Failure; Cirrhosis, Liver Damage caused
    by Viral Hepatitis and/or Toxic
    Substances; Diabetes Mellitus;
    Inflammation; Cancer; Digestive
    disorders.
    Ghrelin Stimulates release of Appetite and food Endocrine; loss of body weight; loss of
    (Genbank growth hormone intake can be can be body weight associated with cancer or
    Accession No. from anterior measured by methods anorexia nervosa; loss of appetite;
    AB029434) pituitary. Stimulates known in the art excessive appetite; body weight gain;
    appetite and reduces (Batterham et al. Obesity; Diabetes; Acromegaly; Growth
    fat burning. Nature 2002; failure; Growth hormone deficiency;
    418: 650654) Growth failure and growth retardation
    Prader-Willi syndrome in children 2
    years or older; Growth deficiencies;
    Growth failure associated with chronic
    renal insufficiency; Postmenopausal
    osteoporosis; burns; cachexia; cancer
    cachexia; dwarfism; metabolic disorders;
    obesity; renal failure; Turner's
    Syndrome, pediatric and adult;
    fibromyalgia; fracture treatment; frailty,
    AIDS wasting
    Ghrelin - Inhibits growth Appetite and food Endocrine; Obesity; Diabetes; body
    binding hormone release in intake can be can be weight gain; excessive appetite; loss of
    antibody response to Ghrelin; measured by methods appetite; loss of body weight.
    including inhibits increase in known in the art
    antibody appetite. (Batterham et al.
    fragment, or Nature 2002;
    dominant- 418: 650654)
    negative form
    of Ghrelin
    receptor
    NOGO-66 Neurodegenerative disorders; spinal cord
    peptide injury; neuronal injury; brain trauma;
    fragment stroke; multiple sclerosis; demyelinating
    (Genbank disorders; neural activity and
    Accession No. neurological diseases; neural cell (e.g.,
    NP_008939 neuron, glial cell, and schwann cell)
    (amino acids regeneration and/or growth
    62-101))
    Gastric Increases nutrient Nutrient uptake and Most preferred: loss of body weight,
    inhibitory uptake and tryglyceride AIDS wasting, cachexia, loss of apetite.
    polypeptide tryglyceride accumulation can be Other: Obesity; Diabetes; insulin
    (GIP), accumulation in measured by methods resistance; body weight gain; excessive
    including GIP adipocytes, which desribed in Miyawaki appetite.
    fragments leads to obesity and et al., Nat. Medicine,
    (Genbank insulin resistance. 2002, Vol 8(7): 738-742.
    Accession No.
    NM_004123)
    Gastric Increased use of fat Fat utilization as an Obesity; Diabetes; Insulin resistance;
    inhibitory as predominant energy source can be body weight gain.
    polypeptide energy source; measured as described
    antibody, or decreased in Miyawaki et al., Nat.
    antibody accumulation of fat Medicine, 2002, Vol
    fragments in adipocytes. 8(7): 738-742.
    Gastric Increased use of fat Fat utilization as an Most preferred: Obesity; Diabetes; body
    inhibitory as predominant energy source can be weight gain; excessive appetite; insulin
    peptide energy source; measured as described resistance. Other: loss of body weight,
    receptor or decreased in Miyawaki et al., Nat. AIDS wasting, loss of appetite.
    receptor accumulation of fat Medicine, 2002, Vol
    fragments or in adipocytes. 8(7): 738-742.
    variants
    including
    soluble
    fragments or
    variants
    (Genbank
    Accession
    Number
    NM_000164)
    POMC Activity of POMC- Preferred: resistance to stress; anti-
    (proopiomelanocortin), derived fragments are inflammatory activity; analgesic activity;
    including diverse, and well- increased skin pigmentation; increased
    fragments or known in the art. protein catabolism; increased
    variants (such See, for example, gluconeogenesis; obesity; diabetes.
    as, for Hadley et al., Ann N Other: decreased protein catabolism,
    example, Y Acad Sci 1999 Oct decreased skin pigmentation, Addison's
    alpha- 20; 885: 1-21; Dores, disease, Cushing's syndrome
    melanocyte Prog Clin Biol Res
    stimulating 1990; 342: 22-7;
    hormone, Blalock, Ann N Y
    αMSH, Acad Sci. 1999 Oct
    gamma 20; 885: 161-72).
    melanocyte
    stimulating
    hormone,
    γMSH, beta-
    melanocyte
    stimulating
    hormone,
    βMSH,
    adrenocorticotropin,
    ACTH,
    beta-
    endorphin,
    met-
    enkephalin)
    (Genbank
    Accession No.
    NM_000930)
    HP 467, See U.S. Pat. No. See U.S. Pat. No. Resistance to stress; anti-inflammatory
    HP228 6,350,430 6,350,430 activity; analgesic activity; increased
    (U.S. Pat. No. skin pigmentation; increased protein
    6,350,430) catabolism; increased gluconeogenesis.
    NDP See U.S. Pat. No. See U.S. Pat. No. Resistance to stress; anti-inflammatory
    (U.S. Pat. No. 6,350,430 6,350,430 activity; analgesic activity; increased
    6,350,430) skin pigmentation; increased protein
    catabolism; increased gluconeogenesis.
    Interleukin-21 Immunomodulator; IL-21 activity can be Autoimmune disorders; Inflammatory
    (IL-21) inhibits interferon assessed by measuring disorders; Treatment of Psoriasis;
    gamma production by interferon gamma Rheumatoid Arthritis; Inflammatory
    Th1 cells, production in Th1 cells. bowel disease.
    (Wurster et al.,: J Exp
    Med 2002 Oct
    7; 196(7): 969-77)
    Interleukin-4 Immunomodulator; IL-4 activity can be Treatment of Psoriasis; Autoimmune
    (IL-4) promotes the assessed by measuring disorders; Rheumatoid Arthritis;
    differentiation of T Th1/Th2 cytokine Inflammatory bowel disease;
    cells into Th2 responses of isolated Inflammatory disorders.
    phenotype. spleen cells in vitro.
    (Waltz et al., Horm
    Metab Res 2002
    Oct; 34(10): 561-9).
    Osteoclast Inhibits osteoclast Osteoclast Inhibitory Treatment of Bone Disorders;
    Inhibitory formation. Lectin activity can be Osteoporosis; Fracture prevention;
    Lectin assessed using Hypercalcemia; Malignant
    (OCIL) osteoclast formation hypercalcemia; Paget's disease;
    assays known in the art. Osteopenia, Osteoclastogenesis;
    (Zhou et al., J Biol osteolysis; osteomyelitis; osteonecrosis;
    Chem 2002 Dec periodontal bone loss; osteoarthritis;
    13; 277(50): 48808-15) rheumatoid arthritis; osteopetrosis;
    periodontal, lytic, or metastatic bone
    disease; osteoclast differentiation
    inhibition; bone healing and
    regeneration.
    Therapeutic Therapeutic
    Protein: X Construct ID Protein: Z
    EPO 1772, 1774, 1781, See Table 2,
    (Erythropoietin; 1783, 1793, 1794, SEQ ID
    Epoetin 1925, 1926, 1966, NO: Z for
    alfa; Epoetin 1969, 1980, 1981, particular
    beta; Gene- 1994, 1995, 1996, construct.
    activated 1997, 2047, 2102,
    erythropoietin; 2283, 2284, 2287,
    Darbepoetin- 2289, 2294, 2298,
    alpha; NESP; 2310, 2311, 2325,
    Epogen; 2326, 2344, 2363,
    Procrit; Eprex; 2373, 2387, 2414,
    Erypo; Espo; 2441, 2603, 2604,
    Epoimmun; 2605, 3194, 3195,
    EPOGIN; 3196,
    NEORECORMON;
    HEMOLINK;
    Dynepo;
    ARANESP)
    G-CSF 1642, 1643, 2363, See Table 2,
    (Granulocyte 2373, 2387, 2414, SEQ ID
    colony- 2441, 2702, 2637, NO: Z for
    stimulating 2700, 2701, 2703, particular
    factor; 2886, 2887, 2888, construct.
    Granulokine; 2889, 2890,
    KRN 8601;
    Filgrastim;
    Lenograstim;
    Meograstim;
    Nartograstim;
    Neupogen;
    NOPIA; Gran;
    GRANOCYTE;
    Granulokine;
    Neutrogin;
    Neu-up;
    Neutromax)
    GM-CSF 1697, 1699, 2066, and See Table 2,
    (Granulocyte- 2067. SEQ ID
    macrophage NO: Z for
    colony- particular
    stimulating construct.
    factor; rhuGM-
    CSF; BI
    61012;
    Prokine;
    Molgramostim;
    Sargramostim;
    GM-CSF/IL 3
    fusion;
    Milodistim;
    Leucotropin;
    PROKINE;
    LEUKOMAX;
    Interberin;
    Leukine;
    Leukine
    Liquid;
    Pixykine)
    Human growth 3163, 2983, See Table 2,
    hormone SEQ ID
    (Pegvisamont; NO: Z for
    Somatrem; particular
    Somatropin; construct.
    TROVERT;
    PROTROPIN;
    BIO-TROPIN;
    HUMATROPE;
    NUTROPIN;
    NUTROPINAQ;
    NUTROPHIN;
    NORDITROPIN;
    GENOTROPIN;
    SAIZEN;
    SEROSTIM)
    Insulin 2250, 2255, 2276, See Table 2,
    (Human 2278, 2656, 2668, SEQ ID
    insulin; Insulin 2669, 2671, 2821, NO: Z for
    aspart; Insulin 2822, 2832, 2877, particular
    Glargine; 2878, 2882, 2885, construct.
    Insulin lispro; 2891, 2897, 2930,
    Lys-B28 Pro- 2931, 2942, 2986,
    B29; lyspro; 3025, 3133, 3134,
    LY 275585; 3197, 3198, 2726,
    diarginylinsulin; 2727, 2784, 2789
    Des-B26-
    B30-insulin-
    B25-amide;
    Insulin
    detemir;
    LABI;
    NOVOLIN;
    NOVORAPID;
    HUMULIN;
    NOVOMIX
    30;
    VELOSULIN;
    NOVOLOG;
    LANTUS;
    ILETIN;
    HUMALOG;
    MACRULIN;
    EXUBRA;
    INSUMAN;
    ORALIN;
    ORALGEN;
    HUMAHALE;
    HUMAHALIN)
    Interferon alfa 2249, 2343, 2366, See Table 2,
    (Interferon 2381, 2382, 2410, and SEQ ID
    alfa-2b; 3165. NO: Z for
    recombinant; particular
    Interferon alfa- construct.
    n1; Interferon
    alfa-n3;
    Peginterferon
    alpha-2b;
    Ribavirin and
    interferon alfa-
    2b; Interferon
    alfacon-1;
    interferon
    consensus;
    YM 643;
    CIFN;
    interferon -
    alpha
    consensus;
    recombinant
    methionyl
    consensus
    interferon;
    recombinant
    consensus
    interferon;
    CGP 35269;
    RO 253036;
    RO 258310;
    INTRON A;
    PEG-
    INTRON;
    OIF;
    OMNIFERON;
    PEG-
    OMNIFERON;
    VELDONA;
    PEG-
    REBETRON;
    ROFERON A;
    WELLFERON;
    ALFERON
    N/LDO;
    REBETRON;
    ALTEMOL;
    VIRAFERON
    PEG;
    PEGASYS;
    VIRAFERON;
    VIRAFON;
    AMPLIGEN;
    INFERGEN;
    INFAREX;
    ORAGEN)
    Calcitonin 1833, 1834, 1835, See Table 2,
    (Salmon 1836, 2447, 2513, SEQ ID
    Calcitonin 2806, 2915 NO: Z for
    (Salcatonin); particular
    Calcitonin construct.
    human-salmon
    hybrid;
    Forcaltonin;
    Fortical;
    Calcitonin; Calcitonina
    Almirall;
    Calcitonina
    Hubber;
    Calcimar; Calsynar;
    Calogen;
    Miacalcic;
    Miacalcin;
    SB205614;
    Macritonin;
    Cibacalcin;
    Cibacalcina;
    Cibacalcine;
    Salmocalcin;
    PowderJect
    Calcitonin)
    (CAS-21215-
    62-3)
    Interferon beta 1778, 1779, 2011, See Table 2,
    (Interferon 2013, 2053, 2054, SEQ ID
    beta-1a; 2492, 2580, 2795, NO: Z for
    Interferon beta 2796, 2797. particular
    1b; Interferon- construct.
    beta-serine;
    SH 579; ZK
    157046;
    BCDF; beta-2
    IF; Interferon-
    beta-2; rhIL-6;
    SJ0031; DL
    8234; FERON;
    IFNbeta;
    BETASERON;
    AVONEX;
    REBIF;
    BETAFERON;
    SIGOSIX)
    Growth 1747 and 1748. See Table 2,
    hormone SEQ ID
    releasing NO: Z for
    factor; Growth particular
    hormone construct.
    releasing
    hormone
    (Sermorelin
    acetate;
    Pralmorelin;
    Somatorelin;
    Somatoliberin;
    Geref; Gerel;
    Groliberin)
    IL-2 1757, 1758, 1812, See Table 2,
    (Aldesleukin; 1813, 1952, 1954, SEQ ID
    interleukin-2 2030, and 2031. NO: Z for
    fusion toxin; T particular
    cell growth construct.
    factor;
    PROLEUKIN;
    IMMUNACE;
    CELEUK;
    ONCOLIPIN
    2;
    MACROLIN)
    Parathyroid 1749, 1750, 1853, See Table 2,
    hormone; 1854, 1889, 1906, SEQ ID
    parathyrin 1907, 1914, 1932, NO: Z for
    (PTH; 1938, 1941, 1949, particular
    Ostabolin; 2021, 2022, 2023, construct.
    ALX1-11; 2428, 2714, 2791,
    hPTH 1-34; 2965, 2966.
    LY 333334;
    MN 10T;
    parathyroid
    hormone (1-31);
    FORTEO;
    PARATHAR)
    Resistin 2295, 2296, 2297, See Table 2,
    2300, and 2309. SEQ ID
    NO: Z for
    particular
    construct.
    TR6 (DcR3; 1520, 1537, 1545, See Table 2,
    Decoy 1546, 1568, 1570, SEQ ID
    Receptor 3; 1622, 1623, 1645, NO: Z for
    FASTR) 1700, 1702, 1703, particular
    1704, 1891, 1892, construct.
    1912, and 1913.
    DeCAF (D- 1657. See Table 2,
    SLAM; SEQ ID
    BCM-like NO: Z for
    membrane particular
    protein; construct.
    BLAME (B
    lymphocyte
    activator
    macrophage
    expressed))
    BLyS (B 1680, 2095, and 2096. See Table 2,
    Lymphocyte SEQ ID
    Stimulator; NO: Z for
    Neutrokine particular
    alpha; TL7; construct.
    BAFF;
    TALL-1;
    THANK;
    radiolabeled
    BLyS)
    Anti-BLyS 1821, 1956, 2501, See Table 2,
    single chain 2502, 2638. SEQ ID
    antibody (scFvI116A01, NO: Z for
    scFvI050B11, particular
    scFvI006D08) construct.
    and others.
    MPIF-1 1681, 3166, 3167, See Table 2,
    (Myeloid 3168, SEQ ID
    Progenitor NO: Z for
    Inhibitory particular
    Factor; CK construct.
    beta-8;
    Mirostipen)
    KDI 1746. See Table 2,
    (Keratinocyte SEQ ID
    Derived NO: Z for
    Interferon; particular
    Interferon construct.
    Kappa
    Precursor)
    TNFR2 (p75) 1777 and 1784. See Table 2,
    (ENBREL) SEQ ID
    NO: Z for
    particular
    construct.
    Keratinocyte 1785, 1786, 1916, See Table 2,
    growth factor 2 1917, 2498, 2499, SEQ ID
    (Repifermin; 2552, 2553, 2584, NO: Z for
    KGF-2; 2607, 2608, 2606, particular
    Fibroblast 2630 construct.
    Growth
    Factor-10;
    FGF-10)
    TR2 (and 1788 and 2129. See Table 2,
    TR2sv1, SEQ ID
    TR2SV2; NO: Z for
    TNFRSF14; particular
    HVEM; construct.
    Herpes Virus
    Entry
    Mediator;
    ATAR)
    Macrophage 1809, 2137, 2474, See Table 2,
    derived 2475, 2476, and 2477. SEQ ID
    chemokine, NO: Z for
    MDC particular
    (Ckbeta-13) construct.
    HAGDG59 1830 and 1831. See Table 2,
    (Retinal SEQ ID
    short-chain NO: Z for
    dehydrogenase) particular
    construct.
    GnRH 1862 and 1863. See Table 2,
    (Gonadotropin SEQ ID
    Releasing NO: Z for
    Hormone) particular
    construct.
    Teprotide 1866, 1867, 2025, See Table 2,
    and 2026. SEQ ID
    NO: Z for
    particular
    construct.
    Human 1933, 1934, 1947, See Table 2,
    chemokine 1948, 1955, 1998, SEQ ID
    HCC-1 2355, 2412, 2449, NO: Z for
    (ckBeta-1; 2837, 2838, 2839, particular
    HWFBD) 2840, 2841, 2842, construct.
    2843, 2844, 2845,
    2849, 2947, 3066,
    3105, 3124, 3125,
    3139, 3152, 3153,
    3154, 3155, 3156,
    3169, 3170, 3202,
    3203, 3204, 3205,
    3206, 3207, 3272
    ACE2 1989, 2000, 2001, and See Table 2,
    inhibitor 2002. SEQ ID
    (DX512) NO: Z for
    particular
    construct.
    TR1 (OCIF; 2016, 2017, 2085, See Table 2,
    Osteoclastogenesis 2086, 2529, 2530, SEQ ID
    inhibitory 2531, 2532, 2555, NO: Z for
    factor; 2556, 2557, and 2558. particular
    osteoprotegerin, construct.
    OPG;
    tumor
    necrosis
    factor
    receptor
    superfamily
    member 11B
    precursor;)
    Human 2101, 2240, 2241, See Table 2,
    chemokine 2245, 2246, 2247, and SEQ ID
    Ckbeta-7 2248. NO: Z for
    particular
    construct.
    CKbeta4 2141, 2330, 2335, See Table 2,
    (HGBAN46; 2336, 2337, 2338, SEQ ID
    HE9DR66) and 2348. NO: Z for
    particular
    construct.
    Leptin 2146, 2184, 2186, See Table 2,
    and 2187. SEQ ID
    NO: Z for
    particular
    construct.
    IL-1 receptor 2181, 2182, 2183, and See Table 2,
    antagonist 2185. SEQ ID
    (Anakinra; NO: Z for
    soluble particular
    interleukin-1 construct.
    receptor;
    IRAP;
    KINERET;
    ANTRIL)
    TREM-1 2226 and 2230. See Table 2,
    (Triggering SEQ ID
    Receptor NO: Z for
    Expressed on particular
    Monocytes construct.
    1)
    HCNCA73 2244 and 2365. See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    VEGF-2 2251, 2252, 2256, and See Table 2,
    (Vascular 2257. SEQ ID
    Endothelial NO: Z for
    Growth particular
    Factor-2; construct.
    VEGF-C)
    HCHNF25 2271, 2280, and 2320. See Table 2,
    (jumping SEQ ID
    translocation NO: Z for
    breakpoint) particular
    construct.
    HLDOU18 2328, 2340, 2350, See Table 2,
    (Bone 2351, 22359, 2362, SEQ ID NO: Z
    Morphogenic 2367, 2369, 22370, or particular
    Protein 9 2473, construct.
    (BMP9); 2623, 2624,
    Growth 2625, 2631,
    differentiation 2632, 2633.
    factor-2
    precursor
    (GDF-2
    precursor))
    Glucagon- 2448, 2455, 2456, See Table 2,
    Like-Peptide 1 2457, 2803, 2804, SEQ ID
    (GLP1; 2900, 2904, 2945, NO: Z for
    Insulinotropin) 2964, 2982, 3070, particular
    2802, 3027, 3028, construct.
    3045, 3046, 3069,
    3071, 3072, 3085,
    3086, 3087, 3140, 3309
    Exendin-4 2469 and 2470. See Table 2,
    (AC-2993) SEQ ID
    NO: Z for
    particular
    construct.
    T20 (T20 HIV 7777, 2672, 2673 See Table 2,
    inhibitory SEQ ID
    peptide, NO: Z for
    DP178; DP178 particular
    HIV inhibitory construct.
    peptide)
    T1249 (T1249 9999, 2667, 2670, 2946 See Table 2,
    HIV inhibitory SEQ ID
    peptide; T1249 NO: Z for
    anti-HIV particular
    peptide) construct.
    Interferon 2875, 2872, 2876, See Table 2,
    Hybrids, 2874, 2873. SEQ ID
    specifically NO: Z for
    preferred: particular
    IFNalpha A/D construct.
    hybrid (BgIII
    version)
    IFNalpha A/D
    hybrid (PvuII
    version)
    IFNalpha A/F
    hybrid
    IFNalpha A/B
    hybrid
    IFNbeta
    1/alpha D
    hybrid
    (IFNbeta-
    1/alpha-1
    hybrid)
    IFNalpha/beta
    hybrid
    B-type 3119, 8888. See Table 2,
    natriuretic SEQ ID
    peptide (BNP, NO: Z for
    brain particular
    natriuretic construct.
    peptide)
    α-defensin, 3208, 3209, 3210. See Table 2,
    including SEQ ID
    alpha 1 NO: Z for
    defensin, alpha particular
    2 defensin, construct.
    alpha 3
    defensin
    (myeloid-
    related
    defensin;
    DEFA1;
    neutrophil-
    specific
    defensin;
    CAF)
    Phosphatonin 3238. See Table 2,
    (matrix SEQ ID
    extracellular NO: Z for
    phosphoglycoprotein; particular
    MEPE) construct.
    P1pal-12 3274. See Table 2,
    (pepducin, SEQ ID
    PAR1-based NO: Z for
    pepducin) particular
    construct.
    P4pal-10 3275. See Table 2,
    (pepducin, SEQ ID
    PAR4-based NO: Z for
    pepducin) particular
    construct.
    HRDFD27 2361 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    HWHGZ51 2407, 2408 See Table 2,
    (CD59; SEQ ID
    Metastasis- NO: Z for
    associated particular
    GPI-adhered construct.
    protein
    homolog)
    C17 (cytokine- 2489, 2490 See Table 2,
    like protein SEQ ID
    C17) NO: Z for
    particular
    construct.
    HDPBQ71 2515, 2545 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    Oscar 2571, 2749 See Table 2,
    (osteoclast- SEQ ID
    associated NO: Z for
    receptor particular
    isoform-3) construct.
    Tumstatin (T5, 2647, 2648, 2649, See Table 2,
    T7 or T8 2650, 2943, 2944, SEQ ID
    peptide; 3047, 3048 NO: Z for
    α3(IV)NC1) particular
    construct.
    CNTF (Ciliary 2724, 2725, 3171, 3172 See Table 2,
    neurotrophic SEQ ID
    factor) NO: Z for
    particular
    construct.
    Somatostatin 2798, 2825, 2830, See Table 2,
    (Octreotide; 2831, 2902 SEQ ID
    octreotide NO: Z for
    acetate; particular
    Sandostating construct.
    LAR ®)
    IL-22 (IL22, 2901, 2903 See Table 2,
    interleukin-22; SEQ ID
    IL17D, IL27) NO: Z for
    particular
    construct.
    HCE1P80 2908, 3049, 3050, See Table 2,
    3051, 3052 SEQ ID
    NO: Z for
    particular
    construct.
    HDRMI82 2909 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    HDALV07 3053, 3055, 3056 See Table 2,
    (adiponectin; SEQ ID
    gelatin-binding NO: Z for
    28k protein particular
    precurson; construct.
    adipose most
    abundant gene
    transcript;
    APM-1;
    GBP28;
    ACRP30;
    ADIPOQ)
    C Peptide 3088, 3149 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    HCBOG68 3106, 3270 See Table 2,
    (enteric SEQ ID
    adipokine; Fat NO: Z for
    SID; proline particular
    rich acidic construct.
    protein)
    PYY (Peptide 3108, 3109, 3281, See Table 2,
    YY), including 3117, 3118, 3282. SEQ ID
    PYY3-36 NO: Z for
    (amino acid particular
    residues 31-64 construct.
    of full length
    PYY, amino
    acid residues
    3-36 of mature
    PYY)
    WNT10b 3141 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    WNT11 3142 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    Herstatin 3143 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    Adrenomedullin 3144 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    Nogo Receptor 3184, 3185 See Table 2,
    SEQ ID
    NO: Z for
    particular
    construct.
    CART 3232 See Table 2,
    (Cocaine- and SEQ ID
    Amphetamine- NO: Z for
    Regulated particular
    Transcript) construct.
    RegIV (Colon 2910. See Table 2,
    Specific Gene; SEQ ID
    Colon Specific NO: Z for
    Protein) particular
    construct.
    Cosyntropin SEQ ID:
    (Cortrosyn) NO: 2198
    (CAS-16960-
    16-0)
    Pexiganan SEQ ID NO:
    Acetate 2199
    (CAS-172820-
    23-4)
    Pramlintide SEQ ID NO:
    (Amylin) 2200
    (CAS-151126-
    32-8)
    Teriparatide SEQ ID NO:
    (CAS-52232- 2201
    67-4)
    Terlipressin SEQ ID NO:
    (triglycyl 2202
    lycine
    vasopressin)
    (CAS-14636-
    12-5)
    Ularitide SEQ ID NO:
    (CAS-118812- 2203
    69-4)
    Aprotinin SEQ ID NO:
    (Trasylol) 2204
    (CAS-9087-
    70-1; CAS-
    11061-94-2;
    CAS-12407-
    79-3)
    Aspartocin SEQ ID NO:
    (CAS-4117- 2205
    65-1; CAS-
    1402-89-7)
    Calcitonin SEQ ID NO:
    (Calcimar) 2206
    (CAS-21215-
    62-3)
    Carperitide SEQ ID NO:
    (HANP; 2207
    recombinant
    human atrial
    natriuretic
    peptide)
    (CAS-89213-
    87-6)
    Desirudin SEQ ID NO:
    (recombinant 2208
    hirudin;
    Revasc)
    (CAS-120993-
    53-5)
    Emoctakin SEQ ID NO:
    (interleukin 8) 2209
    (CAS-142298-
    00-8)
    Felypressin SEQ ID NO:
    (CAS-56-59-7) 2210
    Glucagon SEQ ID NO:
    (CAS-16941- 2211
    32-5)
    Nagrestipen SEQ ID NO:
    (CAS-166089- 2212
    33-4)
    Pentigetide SEQ ID NO:
    (Pentyde) 2213
    (CAS-62087-
    72-3)
    Proinsulin SEQ ID NO:
    (CAS-67422- 2214
    14-4)
    Becaplermin SEQ ID NO:
    (Regranex; 2215
    recombinant
    PDGF-BB)
    (CAS-165101-
    51-9)
    Ghrelin SEQ ID NO:
    (Genbank 2216
    Accession No.
    AB029434)
    Ghrelin -
    binding
    antibody
    including
    antibody
    fragment, or
    dominant-
    negative form
    of Ghrelin
    receptor
    NOGO-66 SEQ ID NO:
    peptide 2217
    fragment
    (Genbank
    Accession No.
    NP_008939
    (amino acids
    62-101))
    Gastric SEQ ID NO:
    inhibitory 2218
    polypeptide
    (GIP),
    including GIP
    fragments
    (Genbank
    Accession No.
    NM_004123)
    Gastric
    inhibitory
    polypeptide
    antibody, or
    antibody
    fragments
    Gastric SEQ ID NO:
    inhibitory 2219
    peptide
    receptor or
    receptor
    fragments or
    variants
    including
    soluble
    fragments or
    variants
    (Genbank
    Accession
    Number
    NM_000164)
    POMC SEQ ID NO:
    (proopiomelanocortin), 2220
    including
    fragments or
    variants (such
    as, for
    example,
    alpha-
    melanocyte
    stimulating
    hormone,
    αMSH,
    gamma
    melanocyte
    stimulating
    hormone,
    γMSH, beta-
    melanocyte
    stimulating
    hormone,
    βMSH,
    adrenocorticotropin,
    ACTH,
    beta-
    endorphin,
    met-
    enkephalin)
    (Genbank
    Accession No.
    NM_000930)
    HP 467, SEQ ID NO:
    HP228 2221
    (U.S. Pat. No.
    6,350,430)
    NDP SEQ ID NO:
    (U.S. Pat. No. 2222
    6,350,430)
    Interleukin-21 3298 SEQ ID NO:
    (IL-21) 2177
    Interleukin-4 3307 SEQ ID NO:
    (IL-4) 2178
    Osteoclast 3312 SEQ ID NO:
    Inhibitory 2181
    Lectin
    (OCIL)
  • [0000]
    TABLE 2
    Expression SEQ ID SEQ ID SEQ ID Leader
    Fusion No. Construct ID Construct Name Description Vector SEQ ID NO: Y SEQ ID NO: X NO: Z NO: A NO: B Sequence
    1 1520 pC4:HSA/TR6.V30-H300 Amino acids V30 to H300 of TR6 pC4 217 1 433 649 650 HSA
    (fragment shown as V1 to H271 of
    SEQ ID NO: 433) fused downstream
    of HSA.
    2 1537 pYPG:HSA.TR6coV30-E294 Amino acids V30 to E294 of TR6 pYPGaf 218 2 434 651 652 HSA
    (fragment shown as V1 to E265 of
    SEQ ID NO: 434) fused downstream
    of HSA. DNA encoding TR6 has
    been codon optimized.
    3 1545 pYPG:HSA.TR6coV30-L288 Amino acids V30 to L288 of TR6 pYPGaf 219 3 435 653 654 HSA
    (fragment shown as V1 to L259 of
    SEQ ID NO: 435) fused downstream
    of HSA. DNA encoding TR6 has
    been codon optimized.
    4 1546 pYPG:HSA.TR6coV30-R284 Amino acids V30 to R284 of TR6 pYPGaf 220 4 436 655 656 HSA
    (fragment shown as V1 to R255 of
    SEQ ID NO: 436) fused downstream
    of HSA. DNA encoding TR6 has
    been codon optimized.
    5 1568 pSAC35:HSA-yTR6 TR6 fused downstream of HSA. pSAC35 221 5 437 657 658 HSA/kex2
    DNA encoding TR6 has been codon
    optimized.
    6 1570 pSAC35:TR6-HSA Mature TR6 fused downstream of the pSAC35 222 6 438 659 660 HSA/kex2
    HSA/kex2 leader and upstream of the
    mature HSA.
    7 1622 pC4:synTR6.M1-H300. Synthetic TR6 fused upstream of pC4 223 7 439 661 662 Native
    HSA mature HSA, with 2 extra amino TR6
    acids between the TR6 and HSA
    portions.
    8 1623 pC4:HSA.synTR6.V30-H300 Synthetic mature TR6 fused pC4 224 8 440 663 664 HSA
    downstream of FL HSA. Last amino
    acid HSA sequence is missing at
    BSU36I site.
    9 1642 pSAC35:GCSF.T31-P204. Mature GCSF cloned downstream of pSAC35 225 9 441 665 666 HSA/kex2
    HSA the HSA/kex2 leader and upstream of
    the mature HSA
    10 1643 pSAC35:HSA.GCSF. Mature GCSF cloned downstream of pSAC35 226 10 442 667 668 HSA/kex2
    T31-P204 the mature HSA and HSA/kex2
    leader sequence.
    11 1645 pSAC35:yTR6(N173Q). Mutant mature TR6 cloned upstream pSAC35 227 11 443 669 670 HSA/kex2
    HSA of mature HSA and downstream of
    the HSA/kex2 leader sequence.
    12 1657 pC4.HSA:DeCAF.A23-D233 Amino acids A23 to D233 of DeCAF pC4 228 12 444 671 672 HSA
    fused downstream of full length
    HSA.
    13 1680 pYPG:HSA.BLyS.A134-L285 Amino acids A134 to L285 of BLyS pYPGaf 229 13 445 673 674 HSA
    fused downstream of FL HSA. Two
    extra amino acids (Leu, Glu) have
    been added between the therapeutic
    protein and HSA portions.
    14 1681 pYPG.HSA.MPIF.D45-N120 Amino acids D45 to N120 of MPIF pYPGaf 230 14 446 675 676 HSA
    fused downstream of FL HSA. Two
    additional amino acids (L and E)
    have been added between HSA and
    MPIF.
    15 1697 pSAC35:HSA.GM- Amino acids A18 to E144 of GM- pSAC35 231 15 447 677 678 HSA
    CSF.A18-E144 CSF fused downstream of FL HSA.
    16 1699 pSAC35:GM- Amino acids A18 to E144 of GM- pSAC35 232 16 448 679 680 HSA/kex2
    CSF.A18-E144:HSA CSF fused upstream of mature HSA
    and downstream of HSA/kex2 leader.
    17 1700 pSAC35:HSA- Mutant TR6 fused downstream of pSAC35 233 17 449 681 682 HSA/kex2
    yTR6(N173Q) mature HSA with HSA/kex2 leader
    sequence.
    18 1702 pYPG:HSA.ek.TR6co Amino acids V30 to L288 of TR6 pYPGaf 234 18 450 683 684 HSA
    V30-L288 (fragment shown as V1 to L259 of
    SEQ ID NO: 450) fused downstream
    of FL HSA with an enterokinase site
    in between. DNA encoding TR6 has
    been codon optimized.
    19 1703 pYPG:HSA.ek.TR6co Amino acids V30 to R284 of TR6 pYPGaf 235 19 451 685 686 HSA
    V30-R284 (fragment shown as V1 to R255 of
    SEQ ID NO: 451) fused downstream
    of HSA with an enterokinase site in
    between. DNA encoding TR6 has
    been codon optimized.
    20 1704 pYPG:HSA.TR6.V30-E294 Amino acids V30 to E294 of TR6 pYPGaf 236 20 452 687 688 HSA
    fused downstream of HSA. Two
    additional amino acids (Leu, Glu) are
    in between HSA and TR6.
    21 1746 pYPG:HSA.ek.KDI.L28-K207 Amino acids L28 to K207 of KDI pYPGaf 237 21 453 689 690 HSA
    fused downstream of HSA with an
    enterokinase site in between.
    22 1747 pSAC35.HSA.hGHRF. Amino acids Y32 to L75 of hGHRF pSAC35 238 22 454 691 692 HSA
    Y32-L75 fused downstream of HSA.
    23 1748 pSAC35.hGHRF.Y32-L75. Amino acids Y32 to L75 of hGHRF pSAC35 239 23 455 693 694 HSA/kex2
    HSA (see also SEQ IDNO: 454) fused
    upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    24 1749 pSAC35:HSA.PTH.S1-F3 FL HSA fused upstream of amino pSAC35 240 24 456 695 696 HSA
    acids S1-F34 of PTH
    25 1750 pSAC35:PTH.S1-F34. Amino acids 1-34 of PTH fused pSAC35 241 25 457 697 698 HSA/kex2
    HSA upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    26 1757 pSAC35:IL2.A21-T153. Mature human IL-2 with a single pSAC35 242 26 458 699 700 HSA/kex2
    145C/S.HSA amino acid mutation (C to S at
    position 145) cloned downstream of
    the HSA/KEX2 leader and upstream
    of mature HSA
    27 1758 pSAC35:HSA.IL2.A21-T153. Mature human IL-2 with a single pSAC35 243 27 459 701 702 HSA/kex2
    145C/S amino acid mutation (C to S at
    position 145) cloned downstream of
    HSA with HSA/kex2 leader
    sequence.
    28 1772 pSAC:EPOco.A28-D192. Amino acids A28-D192 of EPO pSAC35 244 28 460 703 704 HSA/kex2
    HSA variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused upstream of mature
    HSA and downstream of HSA/kex2
    leader sequence. DNA encoding EPO
    has been codon optimized.
    29 1774 pSAC:HSA.EPOco.A28-D192. Amino acids A28-D192 of EPO pSAC35 245 29 461 705 706 HSA/kex2
    variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused downstream of HSA
    with HSA/kex2 leader sequence.
    DNA encoding EPO has been codon
    optimized.
    30 1777 pSAC35:TNFR2.L23-D257. Mature TNFR2 fused downstream of pSAC35 246 30 462 707 708 HSA/kex2
    HSA the HSA/kex2 signal and upstream of
    mature HSA.
    31 1778 pSAC35:IFNβ.M22-N187: Residues M22-N187 of full-length pSAC35 247 31 463 709 710 HSA/kex2
    HSA IFNb (shown as M1 to N166 of SEQ
    ID NO: 463) fused upstream of
    mature HSA and downstream of
    HSA/kex2 leader sequence.
    32 1779 pSAC35:HSA:IFNβ. Residues M22-N187 of full-length pSAC35 248 32 464 HSA/kex2
    M22-N187 IFNb (shown as M1 to N166 of SEQ
    ID NO: 464) fused downstream of
    HSA with HSA/kex2 leader
    sequence.
    33 1781 pSAC:EPOcoA28-D192. Amino acids A28-D192 of EPO pSAC35 249 33 465 711 712 HSA/kex2
    HSA variant (where glycine at amino acid
    51N/S, 65N/S, 110N/s 140 has been replaced with an
    arginine) fused upstream of mature
    HSA and downstream of HSA/kex2
    leader sequence. Glycosylation sites
    at amino acid 51, 65, 110 are mutated
    from N to S residue. DNA encoding
    EPO has been codon optimized.
    34 1783 pSAC:HSA.EPOcoA28-D192. Amino acids A28-D192 of EPO pSAC35 250 34 466 713 714 HSA/kex2
    51N/S, 65N/S, 110N/s variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused downstream of HSA
    with HSA/kex2 leader sequence.
    Glycosylation sites at amino acids 51,
    65, 110 are mutated from N to S
    residue. DNA encoding EPO has
    been codon optimized.
    35 1784 pSAC35:HSA.TNFR2. Mature TNFR2 fused downstream of pSAC35 251 35 467 715 716 HSA
    L23-D257 FL HSA.
    36 1785 pSAC35:KGF2Δ28.A63-S208: Amino acids A63 to S208 of KGF2 pSAC35 252 36 468 717 718 HSA/kex2
    HSA fused upstream of mature HSA and
    downstream of the HSA/kex2 signal
    peptide.
    37 1786 pSAC35:HSA.KGF2 Amino acids A63 to S208 of KGF2 pSAC35 253 37 469 719 720 HSA
    {D}28.A63-S208 fused downstream of HSA.
    38 1788 pSAC35:HSA.TR2.P37-A192 Amino acids P37 to A192 of TR2 pSAC35 254 38 470 721 722 HSA/kex2
    fused downstream of HSA with
    HSA/kex2 leader sequence.
    39 1793 pSAC35:HSA.EPO.A28-D192 Amino acids A28-D192 of EPO pSAC35 255 39 471 HSA/kex2
    (N51A, N65A, N110A) variant (where glycine at amino acid
    140 has been replaced with an
    arginine; see, for example, SEQ ID
    NO: 499) fused downstream of HSA
    with HSA/kex2 leader sequence.
    Glycosylation sites at amino acids
    51, 65, 110 are mutated from N to A
    residue.
    40 1794 pSAC35:HSA.EPO.A28-D192 Amino acids A28-D192 of the EPO pSAC35 256 40 472 HSA/kex2
    variant (where glycine at amino acid
    140 has been replaced with an
    arginine; see, for example, SEQ ID
    NO: 499) fused downstream of HSA
    with HSA/kex2 leader sequence.
    41 1809 pSAC35.MDC.G25-Q93. Amino acids P26 to Q93 of MDC pSAC35 257 41 473 723 724 HSA/kex2
    HSA with an N-terminal methionine, fused
    downstream of the HSA/kex2 leader
    and upstream of mature HSA.
    42 1812 pSAC35:IL2.A21-T153. Amino acids A21 to T153 of IL-2 pSAC35 258 42 474 725 726 HSA/kex2
    HSA fused downstream of the HSA/kex2
    leader and upstream of mature HSA.
    43 1813 pSAC35:HSA.IL2.A21-T153 Amino acids A21 to T153 of IL-2 pSAC35 259 43 475 727 728 HSA/kex2
    fused downstream of HSA with
    HSA/kex2 leader sequence.
    44 1821 pSAC35:scFv116A01. BLyS antibody fused upstream of pSAC35 260 44 476 729 730 Modified
    HSA mature HSA which lacks the first 8 HSA/kex2,
    amino acids and downstream from lacking
    the HSA/kex2 signal sequence which the last
    lacks the last two amino acids. two amino
    acids
    45 1830 pSAC35:HSA.KEX2. Amino acids L19-Q300 of pSAC35 261 45 477 731 732 HSA/kex2
    HAGDG59.L19-Q300 HAGDG59 fused downstream of the
    HSA/kex2 signal, mature HSA and
    KEX2 cleavage site.
    46 1831 pSAC35:HAGDG59. HSA/kex2 signal peptide followed by pSAC35 262 46 478 733 734 HSA/kex2
    L19-Q300.HSA amino acids L19-Q300 of HAGDG59
    followed by mature HSA.
    47 1833 pSAC35:humancalcitonin. Human Calcitonin (amino acids C98-G130 pSAC35 263 47 479 735 736 HSA/kex2
    C1-G33:HSA of SEQ ID NO: 479) fused
    upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    48 1834 pSAC35:HSA.humancalcitonin. Human Calcitonin (amino acids C98-G130 pSAC35 264 48 480 737 738 HSA
    C1-G33 of SEQ ID NO: 480) fused
    downstream of FL HSA.
    49 1835 pSAC35:salmoncalcitonin. Salmon Calcitonin amino acids C1-G33 pSAC35 265 49 481 739 740 HSA/kex2
    C1-G33:HSA fused upstream of mature HSA
    and downstream of HSA/kex2 leader
    sequence.
    50 1836 pSAC35:HSA.salmon Salmon Calcitonin amino acids C1-G33 pSAC35 266 50 482 741 742 HSA
    calcitonin. C1-G33 fused downstream of HSA.
    51 1853 pSAC35:PTH(1-34) Amino acids 1 to 34 of PTH fused pSAC35 267 51 483 743 744 HSA/kex2
    N26.HSA upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence. Amino acid K26 of PTH
    mutated to N26.
    52 1854 pSAC35:HSA.PTH(1-34) Amino acids 1 to 34 of PTH fused pSAC35 268 52 484 745 746 HSA
    N26 downstream of HSA. Amino acid
    K26 of PTH mutated to N26.
    53 1862 pSAC35:HSA.GnRH. Amino acids Q24-G33 of human pSAC35 269 53 485 747 748 HSA/kex2
    Q24-G33 gonadotropin releasing hormone
    fused downstream of HSA with
    HSA/kex2 leader sequence.
    54 1863 pSAC35:GnRHQ24-G33. Amino acids Q24-G33 of human pSAC35 270 54 486 749 750 HSA/kex2
    HSA gonadotropin releasing hormone
    fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    55 1866 pSAC35:teprotide.HSA Teprotide fused upstream of mature pSAC35 271 55 487 751 752
    HSA.
    56 1867 pSAC35:HSA.teprotide. Teprotide fused downstream of FL pSAC35 272 56 488 753 754 HSA
    HSA.
    57 1889 pC4:HSA.PTH.S1-F34 PTH(1-34) fused downstream of pC4 273 57 489 755 756 HSA
    HSA.
    58 1891 pEE12:HSA.sTR6 Soluble mature TR6 fused pEE12.1 274 58 490 757 758 HSA
    downstream of HSA.
    59 1892 pEE12:sTR6.HSA Synthetic full length TR6 fused pEE12.1 275 59 491 759 760 TR6
    upstream of mature HSA.
    60 1906 pC4:PTH.S1-F34. Amino acids S1 to F34 of PTH fused pC4 276 60 492 761 762 MPIF
    HSA (junctioned) upstream of mature HSA and
    downstream of MPIF leader
    sequence. There are two cloning
    junction amino acids (T, S) between
    PTH and HSA.
    61 1907 pC4:HSA.PTH.S1-F34 Amino acids S1 to F34 fused pC4 277 61 493 763 764 HSA
    (junctioned) downstream of FL HSA. The last C-
    terminal amino acid (L) residue is
    missing for HSA in the cloning
    junction between HSA and PTH.
    62 1912 pC4:sTR6.HSA Synthetic full length TR6 fused pC4 278 62 494 765 766 Native
    upstream of mature HSA. TR6
    leader
    63 1913 pC4:HSA.synTR6.V30-H300 Amino acids V30 to H300 of pC4 279 63 495 767 768 HSA
    (seamless) synthetic TR6 (shown as V1 to H271
    of SEQ ID NO: 495) fused
    downstream of full-length HSA.
    64 1914 pC4:PTH.S1-F34. Amino acids S1 to F34 of PTH fused pC4 280 64 496 769 770 MPIF
    HSA (seamless) downstream of MPIF leader sequence
    and upstream of mature HSA.
    65 1916 pC4:HSA.KGF2D28. Amino acids A63 to S208 of full pC4 281 65 497 771 772 HSA
    A63-S208 length KGF2 fused downstream of
    HSA.
    66 1917 pC4:KGF2D28.A63-S208: Amino acids A63 to S208 of KGF2 pC4 282 66 498 773 774 HSA/kex2
    HSA fused upstream of mature HSA.
    67 1925 pcDNA3.EPO M1-D192. Amino acids M1 to D192 of EPO pcDNA3 283 67 499 775 776 Native
    HSA variant (where glycine at amino acid EPO
    140 has been replaced with an leader
    arginine) fused upstream of HSA. peptide
    D192 of EPO and D1 of mature HSA
    are the same amino acids in this
    construct.
    68 1926 pcDNA3:SPHSA.EPO Amino acids A28 to D192 of EPO pcDNA3 284 68 500 777 778 MPIF
    A28-D192 variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused upstream of mature
    HSA and downstream of the MPIF
    leader peptide.
    69 1932 pEE12.1:HSA.PTH.S1-F34 Amino acids 1 to 34 of PTH fused pEE12.1 285 69 501 779 780 HSA
    downstream of full length HSA.
    70 1933 pSAC35:HCC-1.T20-N93: Amino acids T20 to N93 of HCC-1 pSAC35 286 70 502 781 782 HSA/kex2
    HSA fused upstream of mature HSA and
    downstream of the HSA/kex2 leader
    sequence.
    71 1934 pSAC35:HCC- Amino acids T20 to N93 of HCC-1 pSAC35 287 71 503 783 784 HSA/kex2
    1C.O.T20-N93:HSA fused upstream of mature HSA and
    downstream of the HSA/kex2 leader
    sequence. DNA sequence is codon
    optimized for yeast expression.
    72 1938 pEE12.1:PTH.S1-F34. Amino acids S1 to F34 of PTH fused pEE12.1 288 72 504 785 786 MPIF
    HSA upstream of mature HSA and
    downstream of MPIF leader
    sequence.
    73 1941 pC4:HSA/PTH84 PTH fused downstream of full length pC4 289 73 505 787 788 HSA
    (junctioned) HSA. The last amino acid of HSA
    (Leu) has been deleted.
    74 1947 pSAC35:d8HCC- Amino acids G28 to N93 of HCC-1 pSAC35 290 74 506 789 790 HSA/kex2
    1.G28-N93:HSA fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    75 1948 pSAC35:d8HCC- Amino acids G28 to N93 of HCC-1 pSAC35 291 75 507 791 792 HSA/kex2
    1C.O.G28-N93:HSA fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence. DNA sequence is codon
    optimized for yeast expression.
    76 1949 pC4:PTH.S1-Q84/ PTH fused downstream of the MPIF pC4 292 76 508 793 794 MPIF
    HSA (junctioned) leader sequence and upstream of
    mature HSA. There are two
    additional amino acids between
    PTH84 and HSA as a result of the
    cloning site.
    77 1952 pcDNA3.1:IL2.HSA Full length human IL-2, having a pCDNA3.1 293 77 509 795 796 Native IL-
    Cysteine to Serine mutation at amino 2 leader
    acid 145, fused upstream of mature
    HSA.
    78 1954 pC4:IL2.HSA Full length human IL-2, having a pC4 294 78 510 797 798 Native IL-
    Cysteine to Serine mutation at amino 2 leader
    acid 145, fused upstream of mature
    HSA.
    79 1955 pSAC35:t9HCC- Amino acids G28 to N93 of HCC-1 pSAC35 295 79 511 799 800 HSA/kex2
    1.G28-N93:spcHSA fused upstream of a 16 amino acid
    spacer and mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    80 1956 pSAC35:HSA.scFv116A01 Single chain BLyS antibody fused pSAC35 296 80 512 801 802 HSA/kex2
    downstream of HSA with HSA/kex2
    leader sequence. This construct also
    contains a His tag at the 3′ end.
    81 1966 pC4:EPO.M1-D192. Amino acids M1 to D192 of EPO pC4 297 81 513 Native
    HSA variant (where glycine at amino acid EPO
    Construct is also 140 has been replaced with an leader
    named pC4:EPOM1-D192. arginine) fused upstream of mature peptide
    HSA HSA.
    82 1969 pC4:MPIFsp.HSA.EPO. Amino acids A28 to D192 of EPO pC4 298 82 514 MPIF
    A28-D192 variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused downstream of MPIF
    leader sequence and upstream of
    mature HSA.
    83 1980 pC4:EPO.A28-D192. Amino acids A28 to D192 of EPO pC4 299 83 515 803 804 HSA
    HSA variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused downstream of the
    HSA leader peptide and upstream of
    mature HSA.
    84 1981 pC4.HSA-EPO.A28-D192. Amino acids A28 to D192 of EPO pC4 300 84 516 805 806 HSA
    variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused downstream of the
    full length HSA.
    85 1989 pSAC35:activeAC2inhibitor: Active inhibitor of ACE2 (DX512) pSAC35 301 85 517 807 808 HSA/kex2
    HSA fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    86 1994 pEE12.1.HSA- Amino acids A28 to D192 of EPO pEE12.1 302 86 518 HSA
    EPO.A28-D192. variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused downstream of full
    length HSA.
    87 1995 pEE12.1:EPO.A28-D192. Amino acids A28 to D192 of EPO pEE12.1 303 87 519 HSA
    HSA variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused downstream of the
    HSA leader peptide and upstream of
    mature HSA.
    88 1996 pEE12.1:MPIFsp.HSA. Amino acids A28 to D192 of EPO pEE12.1 304 88 520 MPIF
    EPO.A28-D192 variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused downstream of MPIF
    leader sequence and upstream of
    mature HSA.
    89 1997 pEE12.1:EPO M1-D192. Amino acids M1 to D192 of EPO pEE12.1 305 89 521 Native
    HSA variant (where glycine at amino acid EPO
    140 has been replaced with an leader
    arginine) fused upstream of mature
    HSA.
    90 1998 pC4:CKB1.G28-N93. Amino acids G28 to N93 of CkBeta1 pC4 306 90 522 809 810 HSA
    HSA fused upstream of mature HSA and
    downstream of the HSA leader
    sequence.
    91 2000 pSAC35:HSA:activeAC2 Active inhibitor of ACE2 (DX512) pSAC35 307 91 523 811 812 HSA
    inhibitor fused downstream of HSA.
    92 2001 pSAC35:inactiveAC2inhibitor: Inactive inhibitor of ACE2 (DX510) pSAC35 308 92 524 813 814 HSA/kex2
    HSA fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    93 2002 pSAC35:HSA.inactive Inactive inhibitor of ACE2 (DX510) pSAC35 309 93 525 815 816 HSA
    AC2inhibitor fused downstream of HSA.
    94 2011 pC4:IFNb-HSA Full length IFNb fused upstream of pC4 310 94 526 817 818 Native
    mature HSA. IFNb
    leader
    95 2013 pC4:HSA-IFNb.M22-N187 Amino acids M22 to N187 of IFNb pC4 311 95 527 HSA
    (fragment shown as amino acids M1
    to N166 of SEQ ID NO: 527) fused
    downstream of HSA.
    96 2016 pC4:TR1.M1-L401. Amino acids M1 to L401 of TR1 pC4 312 96 528 819 820 Native
    HSA fused upstream of mature HSA. TR1
    Native TR1 signal sequence used. A
    Kozak sequence was added.
    97 2017 pC4:HSA.TR1.E22-L401 Amino acids E22 to L401 of TR1 pC4 313 97 529 821 822 HSA
    fused downstream of HSA.
    98 2021 pC4:PTH.S1-Q84/ Amino acids 1-84 of PTH fused pC4 314 98 530 823 824 HSA
    HSA (seamless) upstream of mature HSA and
    downstream of native HSA leader
    sequence.
    99 2022 pEE12.1:PTH.S1-Q84. Amino acids 1-84 of PTH fused pEE12.1 315 99 531 HSA
    HSA upstream of mature HSA and
    downstream of native HSA leader
    sequence.
    100 2023 pSAC35.PTH.S1-Q84. Amino acids 1-84 of PTH fused pSAC35 316 100 532 825 826 HSA/kex2
    HSA upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    101 2025 pSAC35:teprotide.spacer. Teprotide fused upstream of a linker pSAC35 317 101 533 827 828
    HSA and mature HSA.
    102 2026 pSAC35:HSA.spacer.teprotide Teprotide fused downstream of HSA pSAC35 318 102 534 829 830 HSA
    and a linker.
    103 2030 pSAC35.ycoIL-2.A21-T153. Amino acids A21 to T153 of IL-2 pSAC35 319 103 535 831 832 HSA/kex2
    HSA fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence. DNA encoding IL-2 has
    been codon optimized.
    104 2031 pSAC35.HSA.ycoIL- Amino acids A21 to T153 of IL-2 pSAC35 320 104 536 833 834 HSA/kex2
    2.A21-T153 fused downstream of HSA with the
    HSA/kex2 leader sequence. DNA
    encoding IL-2 has been codon
    optimized.
    105 2047 pC4HSA:SP.EPO Amino acids A28 to D192 of EPO pSAC35 321 105 537 835 836 MPIF
    A28-D192.HSA variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused upstream of mature
    HSA and downstream of MPIF leader
    peptide.
    106 2053 pEE12:IFNb-HSA Full length IFNb fused upstream of pEE12.1 322 106 538 Native
    also named mature HSA. IFNb
    pEE12.1:IFNβ-HSA leader
    107 2054 pEE12:HSA-IFNb Mature IFNb fused downstream of pEE12.1 323 107 539 HSA
    HSA.
    108 2066 pC4:GM-CSF.M1-E144. Amino acids M1 to E144 of GM- pC4 324 108 540 837 838 Native
    HSA CSF fused upstream of mature HSA. GM-CSF
    109 2067 pC4:HSA.GM- Amino acids A18 to E144 of GM- pC4 325 109 541 839 840 HSA
    CSF.A18-E144 CSF fused downstream of HSA.
    110 2085 pEE12.1:TR1.M1-L401. Amino acids M1 to L401 of TR1 pEE12.1 326 110 542 Native
    HSA fused upstream of mature HSA. TR-1
    111 2086 pEE12.1:HSA.TR1.E22-L401 Amino acids E22 to L401 (fragment pEE12.1 327 111 543 HSA
    shown as amino acids E1 to L380 of
    SEQ ID NO: 543) of TR1 fused
    downstream of HSA.
    112 2095 pC4:HSA-BLyS.A134 Amino acids A134 to L285 of BLyS pC4 328 112 544 841 842 HSA
    fused downstream of HSA.
    113 2096 pC4:sp.BLyS.A134-L285. Amino acids A134 to L285 of BLyS pC4 329 113 545 843 844 Native
    HSA (fragment shown as amino acids A1 CKβ8
    to L152 of SEQ ID NO: 545) fused
    upstream of mature HSA and
    downstream of the CKb8 signal
    peptide.
    114 2101 pcDNA3:SP.Ck7 N-terminal Methionine fused to pcDNA3 330 114 546 845 846 MPIF
    Q22-A89.HSA. amino acids Q22 to A89 of Ckβ7
    fused upstream of mature HSA and
    downstream of MPIF signal peptide.
    115 2102 pEE12.1:SP.EPO Amino acids A28 to D192 of EPO pEE12.1 331 115 547 MPIF
    A28-D192.HSA variant (where glycine at amino acid
    140 has been replaced with an
    arginine) fused upstream of mature
    HSA and downstream of MPIF leader
    peptide.
    116 2129 pC4:TR2.M1-A192. Amino acids M1-A192 of TR2 fused pC4 332 116 548 847 848 Native
    HSA upstream of HSA. TR2
    117 2137 pSAC35.MDC.G25-Q93. Amino acids G25 to Q93 of MDC pSAC35 333 117 549 849 850 HSA/kex2
    HSA. fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    118 2141 HSA-CK-Beta4 Full length CK-beta4 fused pSAC35 334 118 550 851 852 HSA
    downstream of HSA.
    119 2146 pC4:Leptin.HSA Full length Leptin fused upstream of pC4 335 119 551 853 854 Native
    mature HSA. leptin
    120 2181 pC4:HSA.IL1Ra(R8-E159) Amino acids R8 to E159 of IL1Ra pC4 336 120 552 855 856 HSA
    (plus an added methionine at N-
    terminus) fused downstream of HSA.
    121 2182 pC4:MPIFsp(M1-A21). Amino acids R8 to E159 of IL1Ra pC4 337 121 553 857 858 MPIF
    IL1Ra(R8-E159). (plus an added methionine at N-
    HSA terminus) fused downstream of the
    MPIF leader sequence and upstream
    of mature HSA.
    122 2183 pSAC35:HSA.IL1Ra Amino acids R8 to E159 of IL1Ra pSAC35 338 122 554 859 860 HSA
    (R8-E159) (plus an added methionine at N-
    terminus) fused downstream of HSA.
    123 2184 pC4:HSA.Leptin.V22-C166 Amino acids V22 to C167 of Leptin pC4 339 123 555 861 862 HSA
    fused downstream of HSA.
    124 2185 pSAC35:IL1Ra(R8-E159). Amino acids R8 to E159 of IL1Ra pSAC35 340 124 556 863 864 HSA/kex2
    HSA (plus an added methionine at N-
    terminus) fused upstream of mature
    HSA and downstream of HSA/kex2
    leader sequence.
    125 2186 pSAC35:Leptin.V22-C166. Amino acids V22 to C167 of Leptin pSAC35 341 125 557 865 866 HSA/kex2
    HSA fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    126 2187 pSAC35:HSA.Leptin. Amino acids V22 to C167 of Leptin pSAC35 342 126 558 867 868 HSA/kex2
    V22-C166 fused downstream of HSA with
    HSA/kex2 leader sequence.
    127 2226 pcDNA3(+):TREM- Amino acids A21 to P202 of TREM- pCDNA3.1 343 127 559 869 870 MPIF
    1(21-202)-HSA 1 fused upstream of mature HSA and
    downstream of the MPIF leader
    sequence.
    128 2230 pC4:TREM-1.M1-P202. Amino acids M1 to P202 of TREM-1 pC4 344 128 560 871 872 Native
    HSA fused upstream of mature HSA. TREM-1
    129 2240 pC4:SP.Ck7 Q22-A89. N-terminal Methionine fused to pC4 345 129 561 873 874 MPIF
    HSA. amino acids Q22 to A89 of Ckβ7
    fused upstream of mature HSA and
    downstream of the MPIF leader
    sequence. Contains a linker sequence
    between Ckβ7 and HSA.
    130 2241 pC4:HSA.Ck7metQ22-A89. N-terminal Methionine fused to pC4 346 130 562 875 876 HSA/kex2
    amino acids Q22 to A89 of
    Chemokine beta 7 (Ckbeta 7 or CK7)
    fused downstream of HSA with
    HSA/kex2 leader sequence. Contains
    a linker sequence between CkB7 and
    HSA.
    131 2244 pC4.HCNCA73.HSA HCNCA73 fused upstream of mature pC4 347 131 563 877 878 HCNCA73
    HSA.
    132 2245 pScNHSA:CK7.Q22-A89 Amino acids Q22 to A89 of Ckβ7 pScNHSA 348 132 564 879 880 HSA/kex2
    fused downstream of HSA with
    HSA/kex2 leader sequence. Contains
    a linker sequence between Ckβ7 and
    HSA.
    133 2246 pScCHSA.CK7metQ22-A89 N-terminal Methionine fused to pScCHSA 349 133 565 881 882 HSA/kex2
    amino acids Q22 to A89 of Ckβ7
    fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    134 2247 pSAC35:CK7metQ22-A89. N-terminal Methionine fused to pSAC35 350 134 566 883 884 HSA/kex2
    HSA. amino acids Q22 to A89 of Ckβ7
    fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    135 2248 pSAC35:HSA.CK7met N-terminal Methionine fused to pSAC35 351 135 567 885 886 HSA/kex2
    Q22-A89. amino acids Q22 to A89 of Ckβ7
    fused downstream of HSA with
    HSA/kex2 leader sequence. Contains
    a linker sequence between Ckβ7 and
    HSA.
    136 2249 pSAC35:IFNa2-HSA Mature IFNa2 fused upstream of pSAC35 352 136 568 887 888 HSA/kex2
    also named: mature HSA and downstream of
    pSAC23:IFNα2-HSA HSA/kex2 leader sequence.
    137 2250 pSAC35:HSA.INSULIN Mature Insulin wherein the C-peptide pSAC35 353 137 569 889 890 HSA
    (GYG) is replaced by the C-domain of IGF-1
    also named: fused downstream of HSA. DNA
    pSAC35.HSA.INSULING encoding Insulin was codon
    (GYG).F1-N62 optimized.
    138 2251 pScCHSA:VEGF2.T103-R227. Amino acids T103 to R227 of pScCHSA 354 138 570 891 892 HSA/kex2
    VEGF2 fused upstream of mature
    HSA and downstream of HSA/kex2
    leader sequence.
    139 2252 pScNHSA:VEGF2.T103-R227. Amino acids T103 to R227 of pScNHSA 355 139 571 893 894 HSA/kex2
    VEGF2 fused downstream of HSA
    with HSA/kex2 leader sequence.
    140 2255 pSAC35:INSULIN(GYG). Mature Insulin wherein the C-peptide pSAC35 356 140 572 895 896 HSA/kex2
    HSA is replaced by the C-domain of IGF-1
    also named fused upstream of mature HSA and
    pSAC35.INSULING downstream of HSA/kex2 leader.
    (GYG).F1-N62.HSA DNA encoding Insulin was codon
    optimized.
    141 2256 pSAC35:VEGF2.T103-R227. Amino acids T103 to R227 of pSAC35 357 141 573 897 898 HSA/kex2
    HSA VEGF2 fused upstream of mature
    HSA and downstream of HSA/kex2
    leader sequence.
    142 2257 pSAC35:HSA.VEGF2. Amino acids T103 to R227 of VEGF- pSAC35 358 142 574 899 900 HSA/kex2
    T103-R227 2 fused downstream of HSA with
    HSA/kex2 leader sequence.
    143 2271 pEE12.1:HCHNF25M1-R104. Amino acids M1 to R104 of pEE12.1 359 143 575 Native
    HSA HCHNF25 fused upstream of mature HCHNF25
    HSA.
    144 2276 pSAC35:HSA.INSULIN Mature Insulin wherein the C-peptide pSAC35 360 144 576 901 902 HSA
    (GGG) is replaced by a synthetic linker fused
    also named: downstream of HSA. DNA encoding
    pSAC35.HSA.INSULING Insulin was codon optimized.
    (GGG).F1-N58
    145 2278 pSAC35:insulin(GGG). Mature Insulin wherein the C-peptide pSAC35 361 145 577 903 904 HSA/kex2
    HSA is replaced by a synthetic linker fused
    downstream of HSA/kex2 leader and
    upstream of mature HSA. DNA
    encoding Insulin was codon
    optimized.
    146 2280 pC4:HCHNF25.HSA HCHNF25 fused upstream of mature pC4 362 146 578 905 906 Native
    HSA. HCHNF25
    147 2283 pScCHSA:EPOcoA28-D192. Amino acids A28 to D192 of EPO pScCHSA 363 147 579 907 908 HSA/kex2
    51N/Q, 65N/Q, variant (where glycine at amino acid
    110N/Q EPO 140 has been replaced with an
    arginine) are fused upstream of
    mature HSA and downstream of
    HSA/kex2 leader sequence.
    Glycosylation sites at amino acids 51,
    65 and 110 are mutated from N to Q
    residue. DNA encoding EPO is
    codon optimized.
    148 2284 pScNHSA:EPOcoA28-D192. Amino acids A28 to D192 of EPO pScNHSA 364 148 580 909 910 HSA/kex2
    51N/Q, 65N/Q, variant (where glycine at amino acid
    110N/Q EPO 140 has been replaced with an
    arginine) fused downstream of
    mature HSA and HSA/kex2 leader
    sequence. Glycosylation sites at
    amino acids 51, 65 and 110 are
    mutated from N to Q residue. DNA
    encoding EPO is codon optimized.
    149 2287 pSAC35:EPOcoA28-D192. Amino acids A28 to D192 of EPO pSAC35 365 149 581 911 912 HSA/kex2
    51N/Q, 65N/Q, 110N/Q. variant (where glycine at amino acid
    HSA. 140 has been replaced with an
    arginine) fused upstream of mature
    HSA and downstream of HSA/kex2
    leader sequence. Glycosylation sites
    at amino acid 51, 65 and 110 are
    mutated from N to Q residue. DNA
    encoding EPO is codon optimized.
    150 2289 pSAC35:HSA.EPOco Amino acids A28 to D192 of EPO pSAC35 366 150 582 913 914 HSA/kex2
    A28-D192. variant (where glycine at amino acid
    51N/Q, 65N/Q, 110N/Q. 140 has been replaced with an
    arginine) fused downstream of
    mature HSA and HSA/kex2 leader
    sequence. Glycosylation sites at
    amino acid 51, 65 and 110 are
    mutated from N to Q residue. DNA
    encoding EPO is codon optimized.
    151 2294 pC4:EPO.R140G.HSA Amino acids M1-D192 of EPO fused pC4 367 151 587 915 916 Native
    also named upstream of mature HSA. The EPO EPO
    pC4.EPO.R1406.HSA sequence included in construct 1997
    was used to generate this construct,
    mutating arginine at EPO amino acid
    140 to glycine. This mutated
    sequence matches the wildtype EPO
    sequence.
    152 2295 pSAC35:humanresistin. Amino acids K19 to P108 of Resistin pSAC35 368 152 584 917 918 HSA/kex2
    K19-P108:HSA fused upstream of mature HSA and
    downstream of HSA/kex2 leader
    sequence.
    153 2296 pSAC35:HSA:humanresistin. Amino acids K19 to P108 of Resistin pSAC35 369 153 585 919 920 HSA
    K19-P108 fused downstream of HSA.
    154 2297 pSAC35:humanresistin. Amino acids K19 to P108 of Resistin pSAC35 370 154 586 921 922 HSA/kex2
    K19-P108.stop:HSA</