U.S. patent application number 14/919328 was filed with the patent office on 2016-05-05 for therapeutic agents comprising elastin-like peptides.
The applicant listed for this patent is DUKE UNIVERSITY. Invention is credited to Ashutosh CHILKOTI.
Application Number | 20160120952 14/919328 |
Document ID | / |
Family ID | 41445383 |
Filed Date | 2016-05-05 |
United States Patent
Application |
20160120952 |
Kind Code |
A1 |
CHILKOTI; Ashutosh |
May 5, 2016 |
THERAPEUTIC AGENTS COMPRISING ELASTIN-LIKE PEPTIDES
Abstract
The present invention provides therapeutic agents and
compositions comprising elastin-like peptides (ELPs) and
therapeutic proteins. In some embodiments, the therapeutic protein
is a GLP-1 receptor agonist, insulin, or Factor VII/VIIa, including
functional analogs. The present invention further provides encoding
polynucleotides, as well as methods of making and using the
therapeutic agents. The therapeutic agents have improvements in
relation to their use as therapeutics, including, inter alia, one
or more of half-life, clearance and/or persistance in the body,
solubility, and bioavailability.
Inventors: |
CHILKOTI; Ashutosh; (Durham,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DUKE UNIVERSITY |
Durham |
NC |
US |
|
|
Family ID: |
41445383 |
Appl. No.: |
14/919328 |
Filed: |
October 21, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14822512 |
Aug 10, 2015 |
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14919328 |
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13524812 |
Jun 15, 2012 |
9127047 |
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14822512 |
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13445979 |
Apr 13, 2012 |
9200083 |
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13524812 |
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12493912 |
Jun 29, 2009 |
8178495 |
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13445979 |
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61076221 |
Jun 27, 2008 |
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Current U.S.
Class: |
514/6.2 ;
530/399 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
3/10 20180101; A61K 45/06 20130101; C07K 19/00 20130101; A61K
38/4846 20130101; A61K 38/28 20130101; A61K 38/2278 20130101; A61K
47/6435 20170801; A61K 47/65 20170801; A61P 3/08 20180101; C07K
14/575 20130101; A61P 43/00 20180101; C07K 14/605 20130101; C07K
14/78 20130101; C07K 2319/31 20130101; A61K 38/26 20130101; A61K
38/16 20130101; A61P 7/04 20180101 |
International
Class: |
A61K 38/28 20060101
A61K038/28; A61K 38/16 20060101 A61K038/16 |
Claims
1-100. (canceled)
101. A therapeutic agent comprising an insulin A chain and an
insulin B chain joined by one or more disulfide bonds and produced
by peptidase processing of proinsulin, wherein said insulin A chain
is a recombinant fusion protein with an elastin-like peptide (ELP)
comprising 120 repeats of VPGXG (SEQ ID NO: 3), where X is V, G, or
A at a ratio of 5:3:2.
102. The therapeutic agent of claim 101, wherein the insulin A
chain amino acid sequence is positioned at the N-terminal end of
the ELP.
103. The therapeutic agent of claim 101, wherein the Insulin A
chain is SEQ ID NO: 15.
104. The therapeutic agent of claim 101, wherein the Insulin B
chain is SEQ ID NO: 16.
105. The therapeutic agent of claim 101, wherein the Insulin A
chain is SEQ ID NO: 15 and the Insulin B chain is SEQ ID NO:
16.
106. The therapeutic agent of claim 101, wherein the insulin A
chain sequence comprises an amino acid sequence having about 5
amino acid insertions, deletions, and/or substitutions relative to
SEQ ID NO: 15 and the insulin B chain sequence comprises an amino
acid sequence having about 1 to 10 amino acid insertions,
deletions, and/or substitutions relative to SEQ ID NO: 16.
107. The therapeutic agent of claim 101, wherein the therapeutic
agent is formulated with a pharmaceutically acceptable carrier
and/or excipient.
108. The therapeutic agent of claim 107, wherein the therapeutic
agent is formulated for parenteral administration.
109. A therapeutic agent comprising the amino acid sequences of SEQ
ID NOs: 15 and 16 united by one or more disulfide bonds and
produced by peptidase processing of proinsulin, wherein the amino
acid sequence of SEQ ID NO: 15 is a recombinant fusion protein with
an elastin-like peptide (ELP) comprising 120 repeats of VPGXG (SEQ
ID NO: 3), where each X is V, G, or A at a ratio of 5:3:2.
110. The therapeutic agent of claim 109, wherein the amino acid
sequence of SEQ ID NO: 15 is positioned at the N-terminal side of
the ELP.
111. The therapeutic agent of claim 109, wherein the therapeutic
agent is formulated with a pharmaceutically acceptable carrier
and/or excipient.
112. The therapeutic agent of claim 109 wherein the peptidase
processing comprises trypsin processing and carboxypeptidase B
processing.
113. The therapeutic agent of claim 111, wherein the therapeutic
agent is formulated for parenteral administration.
Description
PRIORITY
[0001] This application claims priority to U.S. Provisional
Application No. 61/076,221, filed Jun. 27, 2008, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This application discloses therapeutic agents comprising
elastin-like-peptides, and is related to PCT/US2007/077767
(published as WO 2008/030968 on Mar. 13, 2008) having an
International Filing Date of Sep. 6, 2007. This application is also
related to PCT/US2006/048572 (published as WO 2007/073486 on Jun.
28, 2007) having an International Filing Date of Dec. 20, 2006. WO
2008/030968 and WO 2007/073486 are each hereby incorporated by
reference in their entireties.
Description of the Text File Submitted Electronically
[0003] The contents of the text file submitted electronically
herewith are incorporated herein by reference in their entirety: A
computer readable format copy of the Sequence Listing (filename:
PHAS_010_01 US_SeqList_ST25.txt, date recorded: Jun. 26, 2009, file
size 50 kb).
BACKGROUND OF THE INVENTION
[0004] Therapeutic proteins or peptides in their native state or
when recombinantly produced can be labile molecules exhibiting,
inter alia, short periods of serum stability, serum half-life
(i.e., circulatory half-life), or limited persistance in the body.
Such molecules can also be extremely labile when formulated, such
as when formulated in aqueous solutions.
[0005] In some instances, polyethylene glycol (PEG) conjugated to a
proteinaceous molecule results in a longer-acting, sustained
activity of the molecule. PEG attachment, however, can often
substantially reduce or even destroy the protein's therapeutic
activity. Therapeutic proteins and/or peptides have also been
stabilized by fusion to certain proteins that are capable of
extending serum half-life. For example, in some instances,
therapeutic proteins fused to albumin, transferrin, and antibody
fragments exhibit extended serum half-life when compared to the
therapeutic protein in the unfused state. See U.S. Pat. No.
7,238,667 (particularly with respect to albumin conjugates), U.S.
Pat. No. 7,176,278 (particularly with respect to transferrin
conjugates), and U.S. Pat. No. 5,766,883, which are each hereby
incorporated by reference in their entireties.
[0006] There remains a need in the art for more stable, longer
acting, and/or effective proteinaceous molecules.
SUMMARY OF THE INVENTION
[0007] The present invention provides therapeutic agents comprising
an elastin-like peptide (ELP) component and a therapeutic
proteinacious component. The ELP component contains structural
peptide units, which may be repeating units, structurally related
to, or derived from, sequences of the elastin protein. Such ELP
components provide certain therapeutic advantages to the
therapeutic agent, such as comparatively better stability,
solubility, bioavailability, half-life, persistance, and/or
biological action of the therapeutic proteinaceous component. Such
properties may be determined, for example, with respect to the
therapeutic component's unfused or unconjugated counterpart. In
some embodiments, the ELP components may undergo a reversible
inverse phase transition, which may impart additional practical
and/or therapeutic advantages. The invention further provides
polynucleotides encoding the therapeutic agents of the invention,
as well as methods of treatment or prophylaxis for certain
biological conditions.
[0008] In a first aspect, the invention provides a therapeutic
agent comprising an elastin-like peptide (ELP) component and a
therapeutic proteinacious component, as well as pharmaceutical
compositions containing the same for delivery to a subject or
patient in need. The therapeutic component may be selected from
active portions of the therapeutic proteins listed in Table 1, or
functional analogs thereof. In certain embodiments, the therapeutic
component is a GLP-1 receptor agonist, such as GLP-1, exendin-4, or
a functional analog thereof. Such therapeutic components are
generally effective for, among other things, increasing insulin
secretion from the pancreas in a glucose-dependent manner. In other
embodiments, the therapeutic component is an insulin or functional
analog thereof, which is generally effective for promoting glucose
uptake from the blood and storage within cells. In still other
embodiments, the therapeutic component is a Factor VII/VIIa or
functional analog thereof, which is generally effective for
promoting coagulation by activation of Factor X or Factor IX.
[0009] The ELP and therapeutic components may be covalently coupled
by various means, including chemical coupling (e.g., conjugation)
and recombinant fusion technology. In addition, the number of ELP
or therapeutic components per molecule, and their respective
positions within the molecule, may vary as needed. The therapeutic
agent may further include one or more spacer or linker moieties,
which in addition to providing the desired functional independence
of the ELP and therapeutic components, may optionally provide for
additional functionalities, such as a protease-sensitive feature to
allow for proteolytic release or activation of the therapeutic
component. The therapeutic agent may further include one or more
targeting components such as, for example, a peptide or protein to
target the therapeutic agent to a particular cell type, e.g., a
cancer cell, or to a particular organ.
[0010] In a second aspect, the invention provides polynucleotides,
such polynucleotides comprising a nucleotide sequence encoding a
therapeutic agent of the invention. For example, the nucleotide
sequence encodes an ELP fusion with a functional portion of at
least one therapeutic protein listed in Table 1 (or functional
analog thereof). In certain embodiments, the therapeutic component
is a GLP-1 receptor agonist (including GLP-1 and exendin-4),
insulin, Factor VII/VIIa, or functional analog thereof. Such
polynucleotides may further comprise additional control element(s)
operably linked to the nucleotide sequence, such as promoter
elements and/or other transcription or expression-related signals.
The polynucleotide may be inserted into various vectors, which may
be useful for production of the therapeutic agent in host cells,
including, for example, bacterial and eukaryotic host cells.
[0011] In a third aspect, the invention provides a method for
treating or preventing a disease, disorder, or condition in a
subject, such as in a mammalian patient, including a human patient.
The method comprises administering an effective amount of the
therapeutic agent of the invention (or pharmaceutical composition
containing the same) to a subject or patient in need thereof. For
example, the patient may be in need of an agent having a biological
activity or preferred indication listed in Table 1. In certain
embodiments employing a GLP-1 receptor agonist/ELP compound or
employing an insulin/ELP compound, the invention provides a method
for treating one or more disorders including type 1 or type 2
diabetes, hyperglycemia, and impaired glucose tolerance. In certain
other embodiments employing Factor VII/VIIa/ELP compound, the
invention provides a method for treating one or more disorders
including hemophilia, post-surgical bleeding,
anticoagulation-induced bleeding, thrombocytopenia, factor VII
deficiency, factor XI deficiency, and intracranial hemorrhage.
[0012] Various other aspects, features and embodiments of the
invention will be more fully apparent from the following disclosure
and appended claims.
BRIEF DESCRIPTION OF THE FIGURES
[0013] FIG. 1 depicts plasmid pET24d-ELP1-90, encoding an ELP
component with a 10 unit VPGXG (SEQ ID NO: 3) repeat motif, where
guest position X is V, G, and A in the ratio of 5:3:2. This motif
is repeated eight times with a final C-terminal 10-unit repeat
where X is V, G, A, and W in the ratio 4:3:2:1. This ELP component
is represented generally as [(VPGXG).sub.10].sub.9.
[0014] FIG. 2A depicts plasmid pET24d-Ex-4 ELP1-90 encoding an ELP
component with VPGXG (SEQ ID NO: 3) repeat motif (as in FIG. 1)
cloned in frame with an N-terminal exendin-4 component. FIG. 2B
depicts the nucleotide and amino acid sequence of the exendin-4/ELP
fusion (SEQ ID NOS: 23 and 24). Primer sequences are indicated (SEQ
ID NOS:35-40).
[0015] FIG. 3A depicts the nucleotide and amino acid sequence of an
exendin-4 construct having an N-terminal Tev (Tobacco Etch Virus
cysteine protease) cleavage site (SEQ ID NOS: 25 and 26). Primer
sequences are indicated (SEQ ID NOS:38, 41, 42). FIG. 3B also
depicts the nucleotide and amino acid sequence of an exendin-4
construct having an N-terminal Tev cleavage site, but with an
additional sequence N-terminal to the Tev cleavage site to provide
a better target for the protease (SEQ ID NOS: 27 and 28). Primer
sequences are indicated (SEQ ID NOS:38, 43,44).
[0016] FIG. 4A depicts the nucleotide and amino acid sequence of an
exendin-4/ELP fusion as in FIGS. 1-3, but with a DsbA leader
sequence to direct secretion into the periplasmic space (SEQ ID
NOS: 29 and 30). Primer sequences are indicated (SEQ ID NOS:38, 45,
46). FIG. 4B depicts plasmid pET24d-DsbA-Ex-4 ELP1-90 encoding the
fusion of FIG. 4A.
[0017] FIG. 5A depicts pPB0868, which encodes
GLP-1(A8G,7-37)ELP1-90.
[0018] FIG. 5B depicts the nucleotide and amino acid sequence of
the encoded fusion protein (SEQ ID NOS: 53 and 54,
respectively).
[0019] FIG. 6A depicts pPB1022, which encodes
GLP-1(A8G,7-37)ELP1-120.
[0020] FIG. 6B depicts the nucleotide and amino acid sequence of
the encoded fusion protein (SEQ ID NOS: 55 and 56,
respectively).
[0021] FIG. 7A depicts pPB0788, which encodes Factor VII-ELP1-90.
FIG. 7B depicts the nucleotide and amino acid sequence of the
encoded fusion protein (SEQ ID NOS: 57 and 58, respectively).
[0022] FIG. 8A depicts the nucleotide and amino acid sequence of an
insulin (B, C, and A chains) having the ELP component cloned in
frame (SEQ ID NOS: 31 and 32). Primer sequences are indicated (SEQ
ID NOS: 47 and 48). FIG. 8B depicts plasmid pET24d Insulin-ELP1-90
expressing the insulin/ELP fusion of FIG. 8A.
[0023] FIG. 9 is a Western blot for FVII-ELP1-90 from transient
transfection of Freestyle HEK293, detected with mouse anti-human
FVII monoclonal antibody. Lanes are: (1) culture media; (2) FVII
ELP1-90 after purification by phase transition; and FVII
control.
[0024] FIG. 10 is an SDS-PAGE showing recombinant production of an
Exendin-4/ELP4-60 fusion. Lanes are: (M) Protein markers; (1)
Exendin-4 ELP4-60 from total lysate; (2) Exendin-4 ELP4-60 from
insoluble lysate; (3) Exendin-4 ELP4-60 from soluble lysate; (4)
Exendin-4 ELP4-60 from 1st transition (equal volume); (5) Exendin-4
ELP4-60 from 2nd transition (concentrated); (6) Exendin-4 ELP4-60
from 3rd transition (concentrated).
[0025] FIG. 11 shows the activation of Factor X by
FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. As shown,
FactorVIIa-ELP retains full activity.
[0026] FIG. 12 shows that Factor VIIa-ELP1-90 has a long PK when
administered by i.v. in rats. FactorVIIa has a T.sub.1/2 of about
690 min. as compared to about 45-60 min. for Factor VIIa.
[0027] FIG. 13 shows the high in vitro activity of GLP1-ELP and
Exendin-4-ELP, when compared to the activity of Exendin
peptide.
[0028] FIG. 14 shows that GLP1-ELP has a T.sub.1/2 of about 12.9
hours when administered by i.v. to rats, and a T.sub.1/2 of about
8.6 hours when administered subcutaneously (SQ).
[0029] FIG. 15 shows that GLP-1 ELP has a long half-life in rabbits
of about 20 hours when administered i.v., and about 24 hours when
administered sub-cutaneously.
[0030] FIG. 16 shows sustained glycemic control in diabetic mice
with GLP-1-ELP.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The present invention provides therapeutic agents comprising
an elastin-like peptide (ELP) ("the ELP component") and a
therapeutic component. The therapeutic component may be selected
from Table 1 (e.g., selected from a Therapeutic Protein, or
functional portion or functional analog thereof, listed in Table
1). In certain embodiments, the therapeutic component is a GLP-1
receptor agonist, such as GLP-1 or exendin-4, or may be insulin,
Factor VII/VIIa, or functional analog thereof. The ELP component
contains structural units related to, or derived from, sequences of
the elastin protein, which provides certain therapeutic advantages,
such as comparatively better persistence, stability, solubility,
bioavailability, half-life, and/or biological action of the
therapeutic component. Such properties may be determined with
respect to, for example, an unfused or unconjugated counterpart of
the therapeutic component. The invention further provides
polynucleotides encoding the therapeutic agents of the invention,
as well as methods of treatment or prophylaxis for certain
biological conditions, including the preferred indications listed
in Table 1, and including diabetes (e.g., Type I and Type II),
hyperglycemia, bleeding, hemophilia, and hemorrhage, among
others.
[0032] For ease of reference in the ensuing discussion, set out
below are definitions of some terms appearing in the
discussion.
[0033] As used herein, the term "therapeutic agent" or "therapeutic
component" refers to an agent or component capable of inducing a
biological effect in vivo and/or in vitro. The biological effect
may be useful for treating and/or preventing a condition, disorder,
or disease in a subject or patient.
[0034] As used herein, the term "coupled" means that the specified
components are either directly covalently bonded to one another
(e.g., via chemical conjugation or recombinant fusion technology),
or indirectly covalently joined to one another (e.g., via chemical
conjugation or recombinant fusion technology) through an
intervening moiety or moieties, such as a bridge, spacer, or
linker.
[0035] As used herein, "half-life" (which generally refers to in
vivo half-life or circulatory half-life) is the period of time that
is required for a 50% diminution of bioactivity of the active agent
to occur. Such term is to be contrasted with "persistence," which
is the overall temporal duration of the active agent in the body,
and "rate of clearance" as being a dynamically changing variable
that may or may not be correlative with the numerical values of
half-life and persistence.
[0036] The term "functional analog" refers to a protein that is an
active analog (e.g., either chemical or protein analog),
derivative, fragment, truncation isoform or the like of a native
protein. For example, the functional analog may be a functional
analog of a therapeutic protein listed in Table 1, or may be a
functional analog of a GLP-1 receptor agonist (e.g., GLP-1,
exendin), insulin, or Factor VII/VIIa. A polypeptide is active when
it retains some or all of the biological activity of the
corresponding native polypeptide, as determined in vivo or in one
or more indicative in vitro assays. Exemplary activity assays for
certain therapeutic proteins, which are determinative of activity,
are listed Table 1. Further, such biological activities and assays
for GLP-1 receptor agonists, insulin, and Factor VII/VIIa, which
are determinative of whether a given molecule is a "functional
analog," are described in detail elsewhere herein.
[0037] As used herein, the term "native," as used in reference to
an amino acid sequence, indicates that the amino acid sequence is
found in a naturally-occurring protein.
[0038] As used herein, the term "spacer" refers to any moiety,
peptide or other chemical entity, that may be interposed between
the ELP component and the therapeutic component. For example, the
spacer may be a divalent group that is covalently bonded at one
terminus to the ELP component, and covalently bonded at the other
terminus to the therapeutic component. The therapeutic agents may
therefore be open to the inclusion of additional chemical structure
that does not preclude the efficacy of the agent for its intended
purpose. The spacer may, for example, be a protease-sensitive
spacer moiety that is provided to control the pharmacokinetics of
the agent, or the spacer may be a protease-resistant moiety.
[0039] The therapeutic component and the ELP component may be
coupled with one another in any suitable covalent manner, including
chemical coupling and recombinant technology, such that the
therapeutic agent is efficacious for its intended purpose, and such
that the presence of the ELP component enhances the therapeutic
component in some functional, therapeutic or physiological aspect.
For example, the ELP-coupled therapeutic component may be enhanced
in, e.g., its bioavailability, bio-unavailability, therapeutically
effective dose, biological action, formulation compatibility,
resistance to proteolysis or other degradative modality,
solubility, half-life or other measure of persistence in the body
subsequent to administration, rate of clearance from the body
subsequent to administration, etc. Such enhancement may be
determined, for example, in relation to a corresponding
unconjugated or unfused counterpart therapeutic (e.g., determined
relative to native GLP-1, exendin, insulin, or Factor VII/VIIa, or
a therapeutic protein listed in Table 1).
[0040] In some embodiments, the therapeutic agent of the invention
circulates or exists in the body in a soluble form, and escapes
filtration by the kidney thereby persisting in the body in an
active form. In some embodiments, the therapeutic agents of the
invention have a molecular weight of less than the generally
recognized cut-off for filtration through the kidney, such as less
than about 60 kD, or in some embodiments less than about 55, 50,
45, 40, 30, or 20 kDa, and persist in the body by at least 2-fold,
3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold longer than
an uncoupled (e.g., unfused or unconjugated) therapeutic
counterpart.
[0041] The number of ELP and/or therapeutic components per
molecule, and their respective positions within the molecule, may
vary among embodiments of the invention. For example, in
embodiments where the agent is a recombinant fusion, at least one
ELP component may be placed at one or both of the N-terminus and
the C-terminus. Where the ELP component is at both the N-terminus
and C-terminus of the fusion, the ELP components will flank the
therapeutic component. Alternatively, the therapeutic component may
be positioned at either or both of the N-terminus and C-terminus.
Where the therapeutic component is at both the N-terminus and
C-terminus, the therapeutic component will flank the ELP component.
In a further embodiment, different therapeutic components are
positioned at the N-terminus and C-terminus of the molecule. As
discussed in detail herein, in certain embodiments, such
therapeutic component(s) may be released by proteolysis of a spacer
moiety separating the ELP and therapeutic components. In certain
embodiments, the therapeutic component may be inactive in the fused
state, and becoming active upon proteolytic release from the ELP
component(s). Alternatively, the therapeutic component remains
active in the fused state, making proteolytic processing of the
therapeutic agent unnecessary for biological activity.
[0042] When prepared as recombinant fusions, the therapeutic agent
can be prepared by known recombinant expression techniques. For
example, to recombinantly produce the therapeutic agent, a nucleic
acid sequence encoding the chimeric gene is operatively linked to a
suitable promoter sequence such that the nucleic acid sequence
encoding such fusion protein will be transcribed and/or translated
into the desired fusion protein in the host cells. Preferred
promoters are those useful for expression in E. coli, such as the
T7 promoter. Any commonly used expression system may be used,
including eukaryotic or prokaryotic systems. Specific examples
include yeast (e.g., Saccharomyces spp., Pichia spp.), baculovirus,
mammalian, and bacterial systems, such as E. coli, and
Caulobacter.
[0043] The various aspects and embodiments of the invention are
described in greater detail in the following sections.
Elastin-Like Peptide (ELP) Component
[0044] The therapeutic agent of the invention may comprise one or
more ELP components. The ELP components comprise or consist of
structural peptide units or sequences that are related to, or
derived from, the elastin protein. Such sequences are useful for
improving the properties of therapeutic proteins, such as those
listed in Table 1, as well as GLP-1 receptor agonists (e.g., GLP-1
or exendin-4), insulin, and Factor VII/VIIa in one or more of
bioavailability, therapeutically effective dose, biological action,
formulation compatibility, resistance to proteolysis, solubility,
half-life or other measure of persistence in the body subsequent to
administration, and/or rate of clearance from the body.
[0045] The ELP component is constructed from structural units of
from three to about twenty amino acids, or in some embodiments,
from four to ten amino acids, such as five or six amino acids. The
length of the individual structural units, in a particular ELP
component, may vary or may be uniform. In certain embodiments, the
ELP component is constructed of a polytetra-, polypenta-,
polyhexa-, polyhepta-, polyocta, and polynonapeptide motif of
repeating structural units. Exemplary structural units include
units defined by SEQ ID NOS: 1-12 (below), which may be employed as
repeating structural units, including tandem-repeating units, or
may be employed in some combination, to create an ELP effective for
improving the properties of the therapeutic component. Thus, the
ELP component may comprise or consist essentially of structural
unit(s) selected from SEQ ID NOS: 1-12, as defined below.
[0046] The ELP component, comprising such structural units, may be
of varying sizes. For example, the ELP component may comprise or
consist essentially of from about 10 to about 500 structural units,
or in certain embodiments about 15 to about 150 structural units,
or in certain embodiments from about 20 to about 100 structural
units, or from about 50 to about 90 structural units, including one
or a combination of units defined by SEQ ID NOS: 1-12. Thus, the
ELP component may have a length of from about 50 to about 2000
amino acid residues, or from about 100 to about 600 amino acid
residues, or from about 200 to about 500 amino acid residues, or
from about 200 to about 400 amino acid residues.
[0047] In some embodiments, the ELP component, or in some cases the
therapeutic agent, has a size of less than about 65 kDa, or less
than about 60 kDa, or less than about 55 kDa, or less than about 50
kDa, or less than about 40 kDa, or less than about 30 or 25 kDa.
Three major blood proteins, Human Serum Albumin (HSA), Transferrin
(Tf) and IgG, or the Fc portion of IgGs in their glycosylated form,
have been exploited to extend the half-lives of proteins and
peptides for improved therapeutic use. These molecules are 585, 679
and 480 amino acids in length giving molecular weights of about 66,
77, and .about.75 kDa (including glycosylations), respectively.
They are each globular and relatively compact. The half life of
these molecules is determined by a number of factors, including
charge distribution, rescue of molecules by the neonatal Fc
receptor (FcRn) (HSA and Fc) or cycling of Tf through the Tf
receptor (TfR), and their size which prevents filtering through the
kidney glomerulus. HSA is slightly below the generally regarded
cut-off for filtration through the kidney (.about.70 kDa) but its
charge distribution helps prevent this. It would be anticipated
that, in order to achieve half-life extension of the same order as
that achieved with HSA, Tf and Fc, a protein of at least this
molecular weight range would be required or desirable, i.e. having
over 550 amino acids and being over 65 kDa. However, an ELP with a
small number of amino acids relative to HSA, Tf and Fc (e.g., in
the range of about 300 to 400) and around 30 to 40 kDa may have a
half life that matches and/or exceeds that of HSA, Tf, and Fc.
[0048] In some embodiments, the ELP component in the untransitioned
state may have an extended, relatively unstructured and
non-globular form, and thus such molecules may have a large
expanded structure in comparison to HSA, Tf and Fc, so as to escape
kidney filtration. In such embodiments, the therapeutic agents of
the invention have a molecular weight of less than the generally
recognized cut-off for filtration through the kidney, such as less
than about 60 kD, or in some embodiments less than about 55, 50,
45, 40, 30, or 25 kDa, and persist in the body by at least 2-fold,
3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold longer than
an uncoupled (e.g., unfused or unconjugated) therapeutic
counterpart.
[0049] In certain embodiments, the ELP component undergoes a
reversible inverse phase transition. That is, the ELP components
are structurally disordered and highly soluble in water below a
transition temperature (Tt), but exhibit a sharp (2-3.degree. C.
range) disorder-to-order phase transition when the temperature is
raised above the Tt, leading to desolvation and aggregation of the
ELP components. For example, the ELP forms insoluble polymers, when
reaching sufficient size, which can be readily removed and isolated
from solution by centrifugation. Such phase transition is
reversible, and isolated insoluble ELPs can be completely
resolubilized in buffer solution when the temperature is returned
below the Tt of the ELPs. Thus, the therapeutic agents of the
invention can, in some embodiments, be separated from other
contaminating proteins to high purity using inverse transition
cycling procedures, e.g., utilizing the temperature-dependent
solubility of the therapeutic agent, or salt addition to the
medium. Successive inverse phase transition cycles can be used to
obtain a high degree of purity. In addition to temperature and
ionic strength, other environmental variables useful for modulating
the inverse transition of the therapeutic agents include pH, the
addition of inorganic and organic solutes and solvents, side-chain
ionization or chemical modification, and pressure.
[0050] In certain embodiments, the ELP component does not undergo a
reversible inverse phase transition, or does not undergo such a
transition at a biologically relevant Tt, and thus the improvements
in the biological and/or physiological properties of the molecule
(as described elsewhere herein), may be entirely or substantially
independent of any phase transition properties. Nevertheless, such
phase transition properties may impart additional practical
advantages, for example, in relation to the recovery and
purification of such molecules.
[0051] In certain embodiments, the ELP component(s) may be formed
of structural units, including but not limited to: [0052] (a) the
tetrapeptide Val-Pro-Gly-Gly, or VPGG (SEQ ID NO: 1); [0053] (b)
the tetrapeptide Ile-Pro-Gly-Gly, or IPGG (SEQ ID NO: 2); [0054]
(c) the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO: 3), or VPGXG,
where X is any natural or non-natural amino acid residue, and where
X optionally varies among polymeric or oligomeric repeats; [0055]
(d) the pentapeptide Ala-Val-Gly-Val-Pro, or AVGVP (SEQ ID NO: 4);
[0056] (e) the pentapeptide Ile-Pro-Gly-X-Gly, or IPGXG (SEQ ID NO:
5), where X is any natural or non-natural amino acid residue, and
where X optionally varies among polymeric or oligomeric repeats;
[0057] (e) the pentapeptide Ile-Pro-Gly-Val-Gly, or IPGVG (SEQ ID
NO: 6); [0058] (f) the pentapeptide Leu-Pro-Gly-X-Gly, or LPGXG
(SEQ ID NO: 7), where X is any natural or non-natural amino acid
residue, and where X optionally varies among polymeric or
oligomeric repeats; [0059] (g) the pentapeptide
Leu-Pro-Gly-Val-Gly, or LPGVG (SEQ ID NO: 8); [0060] (h) the
hexapeptide Val-Ala-Pro-Gly-Val-Gly, or VAPGVG (SEQ ID NO: 9);
[0061] (I) the octapeptide Gly-Val-Gly-Val-Pro-Gly-Val-Gly, or
GVGVPGVG (SEQ ID NO: 10); [0062] (J) the nonapeptide
Val-Pro-Gly-Phe-Gly-Val-Gly-Ala-Gly, or VPGFGVGAG (SEQ ID NO: 11);
and [0063] (K) the nonapeptides
Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Gly, or VPGVGVPGG (SEQ ID NO: 12).
Such structural units defined by SEQ ID NOS:1-12 may form
structural repeat units, or may be used in combination to form an
ELP component in accordance with the invention. In some
embodiments, the ELP component is formed entirely (or almost
entirely) of one or a combination of (e.g., 2, 3 or 4) structural
units selected from SEQ ID NOS: 1-12. In other embodiments, at
least 75%, or at least 80%, or at least 90% of the ELP component is
formed from one or a combination of structural units selected from
SEQ ID NOS: 1-12, and which may be present as repeating units.
[0064] In certain embodiments, the ELP component(s) contain repeat
units, including tandem repeating units, of the pentapeptide
Val-Pro-Gly-X-Gly (SEQ ID NO:3), where X is as defined above, and
where the percentage of Val-Pro-Gly-X-Gly (SEQ ID NO:3)
pentapeptide units taken with respect to the entire ELP component
(which may comprise structural units other than VPGXG (SEQ ID
NO:3)) is greater than about 75%, or greater than about 85%, or
greater than about 95% of the ELP component. The ELP component may
contain motifs having a 5 to 15-unit repeat (e.g. about 10-unit
repeat) of the pentapeptide of SEQ ID NO: 3, with the guest residue
X varying among at least 2 or at least 3 of the units. The guest
residues may be independently selected, such as from the amino
acids V, I, L, A, G, and W (and may be selected so as to retain a
desired inverse phase transition property). The repeat motif itself
may be repeated, for example, from about 5 to about 12 times, such
as about 8 to 10 times, to create an exemplary ELP component. The
ELP component as described in this paragraph may of course be
constructed from any one of the structural units defined by SEQ ID
NOS: 1-12, or a combination thereof.
[0065] In some embodiments, the ELP component may include a
.beta.-turn structure. Exemplary peptide sequences suitable for
creating a .beta.-turn structure are described in International
Patent Application PCT/US96/05186, which is hereby incorporated by
reference in its entirety. For example, the fourth residue (X) in
the elastin pentapeptide sequence, VPGXG (SEQ ID NO:3), can be
altered without eliminating the formation of a .beta.-turn.
Alternatively, the ELP component may lack a .beta.-turn, or
otherwise have a different conformation and/or folding
character.
[0066] In certain embodiments, the ELP components include polymeric
or oligomeric repeats of the pentapeptide VPGXG (SEQ ID NO: 3),
where the guest residue X is any amino acid. X may be a naturally
occurring or non-naturally occurring amino acid. In some
embodiments, X is selected from alanine, arginine, asparagine,
aspartic acid, cysteine, glutamic acid, glutamine, glycine,
histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
serine, threonine, tryptophan, tyrosine and valine. In some
embodiments, X is a natural amino acid other than proline or
cysteine.
[0067] The guest residue X (e.g., with respect to SEQ ID NO: 3, or
other ELP structural unit) may be a non-classical (non-genetically
encoded) amino acid. Examples of non-classical amino acids include:
D-isomers of the common amino acids, 2,4-diaminobutyric acid,
.alpha.-amino isobutyric acid, A-aminobutyric acid, Abu, 2-amino
butyric acid, .gamma.-Abu, .epsilon.-Ahx, 6-amino hexanoic acid,
Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine,
norleucine, norvaline, hydroxyproline, sarcosine, citrulline,
homocitrulline, cysteic acid, t-butylglycine, t-butylalanine,
phenylglycine, cyclohexylalanine, .beta.-alanine, fluoro-amino
acids, designer amino acids such as .beta.-methyl amino acids,
Ca-methyl amino acids, Na-methyl amino acids, and amino acid
analogs in general.
[0068] Selection of X is independent in each ELP structural unit
(e.g., for each structural unit defined herein having a guest
residue X). For example, X may be independently selected for each
structural unit as an amino acid having a positively charged side
chain, an amino acid having a negatively charged side chain, or an
amino acid having a neutral side chain, including in some
embodiments, a hydrophobic side chain.
[0069] In still other embodiments, the ELP component(s) may include
polymeric or oligomeric repeats of the pentapeptides VPGXG (SEQ ID
NO:3), IPGXG (SEQ ID NO:5) or LPGXG (SEQ ID NO:7), or a combination
thereof, where X is as defined above.
[0070] In each embodiment, the structural units, or in some cases
polymeric or oligomeric repeats, of the ELP sequences may be
separated by one or more amino acid residues that do not eliminate
the overall effect of the molecule, that is, in imparting certain
improvements to the therapeutic component as described. In certain
embodiments, such one or more amino acids also do not eliminate or
substantially affect the phase transition properties of the ELP
component (relative to the deletion of such one or more amino
acids).
[0071] In each repeat, X is independently selected. The structure
of the resulting ELP components may be described using the notation
ELPk [X.sub.iY.sub.j-n], where k designates a particular ELP repeat
unit, the bracketed capital letters are single letter amino acid
codes and their corresponding subscripts designate the relative
ratio of each guest residue X in the structural units (where
applicable), and n describes the total length of the ELP in number
of the structural repeats. For example, ELP1
[V.sub.5A.sub.2G.sub.3-10] designates an ELP component containing
10 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X
is valine, alanine, and glycine at a relative ratio of 5:2:3; ELP1
[K.sub.1V.sub.2F.sub.1-4] designates an ELP component containing 4
repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is
lysine, valine, and phenylalanine at a relative ratio of 1:2:1;
ELP1 [K.sub.1V.sub.7F.sub.1-9] designates a polypeptide containing
9 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X
is lysine, valine, and phenylalanine at a relative ratio of 1:7:1;
ELP1 [V-5] designates a polypeptide containing 5 repeating units of
the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively
valine; ELP1 [V-20] designates a polypeptide containing 20
repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is
exclusively valine; ELP2 [5] designates a polypeptide containing 5
repeating units of the pentapeptide AVGVP (SEQ ID NO:4); ELP3 [V-5]
designates a polypeptide containing 5 repeating units of the
pentapeptide IPGXG (SEQ ID NO:5), where X is exclusively valine;
ELP4 [V-5] designates a polypeptide containing 5 repeating units of
the pentapeptide LPGXG (SEQ ID NO:7), where X is exclusively
valine. Such ELP components as described in this paragraph may be
used in connection with the present invention to increase the
therapeutic properties of the therapeutic component.
[0072] Further, the Tt is a function of the hydrophobicity of the
guest residue. Thus, by varying the identity of the guest
residue(s) and their mole fraction(s), ELPs can be synthesized that
exhibit an inverse transition over a 0-100.degree. C. range. Thus,
the Tt at a given ELP length may be decreased by incorporating a
larger fraction of hydrophobic guest residues in the ELP sequence.
Examples of suitable hydrophobic guest residues include valine,
leucine, isoleucine, phenyalanine, tryptophan and methionine.
Tyrosine, which is moderately hydrophobic, may also be used.
Conversely, the Tt may be increased by incorporating residues, such
as those selected from the group consisting of: glutamic acid,
cysteine, lysine, aspartate, alanine, asparagine, serine,
threonine, glycine, arginine, and glutamine; preferably selected
from alanine, serine, threonine and glutamic acid.
[0073] The ELP component in some embodiments is selected or
designed to provide a Tt ranging from about 10 to about 80.degree.
C., such as from about 35 to about 60.degree. C., or from about 38
to about 45.degree. C. In some embodiments, the Tt is greater than
about 40.degree. C. or greater than about 42.degree. C., or greater
than about 45.degree. C., or greater than about 50.degree. C. The
transition temperature, in some embodiments, is above the body
temperature of the subject or patient (e.g., >37.degree. C.)
thereby remaining soluble in vivo, or in other embodiments, the Tt
is below the body temperature (e.g., <37.degree. C.) to provide
alternative advantages, such as in vivo formation of a drug depot
for sustained release of the therapeutic agent.
[0074] The Tt of the ELP component can be modified by varying ELP
chain length, as the Tt generally increases with decreasing MW. For
polypeptides having a molecular weight >100,000, the
hydrophobicity scale developed by Urry et al. (PCT/US96/05186,
which is hereby incorporated by reference in its entirety) is
preferred for predicting the approximate Tt of a specific ELP
sequence. However, in some embodiments, ELP component length can be
kept relatively small, while maintaining a target Tt, by
incorporating a larger fraction of hydrophobic guest residues
(e.g., amino acid residues having hydrophobic side chains) in the
ELP sequence. For polypeptides having a molecular weight
<100,000, the Tt may be predicted or determined by the following
quadratic function: Tt=M.sub.0+M.sub.1X+M.sub.2X.sup.2 where X is
the MW of the fusion protein, and M.sub.0=116.21; M.sub.1=-1.7499;
M.sub.2=0.010349.
[0075] While the Tt of the ELP component, and therefore of the ELP
component coupled to a therapeutic component, is affected by the
identity and hydrophobicity of the guest residue, X, additional
properties of the molecule may also be affected. Such properties
include, but are not limited to solubility, bioavailability,
persistence, and half-life of the molecule.
[0076] As described in PCT/US2007/077767 (published as WO
2008/030968), which is hereby incorporated by reference in its
entrety, the ELP-coupled therapeutic component can retain the
therapeutic component's biological activity. Additionally, ELPs
themselves can exhibit long half-lives. Therefore, ELP components
in accordance with the present invention substantially increase
(e.g. by greater than 10%, 20%, 30%, 50%, 100%, 200%, 500% or more,
in specific embodiments) the half-life of the therapeutic component
when conjugated thereto. Such half-life (or in some embodiments
persistance or rate of clearance) is determined in comparison to
the half-life of the free (unconjugated or unfused) form of the
therapeutic component. Furthermore, ELPs may target high blood
content organs, when administered in vivo, and thus, can partition
in the body, to provide a predetermined desired corporeal
distribution among various organs or regions of the body, or a
desired selectivity or targeting of a therapeutic agent. In sum,
the therapeutic agents contemplated by the invention are
administered or generated in vivo as active compositions having
extended half-lives (e.g., circulatory half-life), among other
potential benefits described herein.
[0077] The invention thus provides various agents for therapeutic
(in vivo) application, where the therapeutic component is
biologically active. Such therapeutic components include those
listed in Table 1 (e.g., full length or functional portions or
functional analogs thereof), as well as GLP-1 receptor agonists
such as GLP-1 or exendin-4, insulin, or Factor VII/VIIa, and
functional analogs thereof. The structure and activity of such
therapeutic components are described in detail below. In some forms
of the therapeutic agent, the coupling of the therapeutic component
to the ELP component is effected by direct covalent bonding or
indirect (through appropriate spacer groups) bonding (as described
elsewhere herein). Further, the therapeutic component(s) and the
ELP component(s) can be structurally arranged in any suitable
manner involving such direct or indirect covalent bonding, relative
to one another.
Glucaqon-Like Peptide (GLP)-1 Receptor Agonists
[0078] In certain embodiments of the invention, the therapeutic
agent comprises an ELP component fused or conjugated to a GLP-1
receptor agonist, such as GLP-1, exendin-4, or functional analogs
thereof.
[0079] Human GLP-1 is a 37 amino acid residue peptide originating
from preproglucagon which is synthesized in the L-cells in the
distal ileum, in the pancreas, and in the brain. Processing of
preproglucagon to give GLP-1 (7-36)amide, GLP-1 (7-37) and GLP-2
occurs mainly in the L-cells. A simple system is used to describe
fragments and analogs of this peptide. For example, Gly.sup.8-GLP-1
(7-37) designates a fragment of GLP-1 formally derived from GLP-1
by deleting the amino acid residues Nos. 1 to 6 and substituting
the naturally occurring amino acid residue in position 8 (Ala) by
Gly. Similarly, Lys.sup.34 (N.sup.E-tetradecanoyl)-GLP-1(7-37)
designates GLP-1 (7-37) wherein the .epsilon.-amino group of the
Lys residue in position 34 has been tetradecanoylated. Where
reference in this text is made to C-terminally extended GLP-1
analogues, the amino acid residue in position 38 is Arg unless
otherwise indicated, the optional amino acid residue in position 39
is also Arg unless otherwise indicated and the optional amino acid
residue in position 40 is Asp unless otherwise indicated. Also, if
a C-terminally extended analogue extends to position 41, 42, 43, 44
or 45, the amino acid sequence of this extension is as in the
corresponding sequence in human preproglucagon unless otherwise
indicated.
[0080] The parent peptide of GLP-1, proglucagon (PG), has several
cleavage sites that produce various peptide products dependent on
the tissue of origin including glucagon (PG[32-62]) and
GLP-1[7-36]NH.sub.2 (PG[72-107]) in the pancreas, and GLP-1[7-37]
(PG[78-108]) and GLP-1[7-36]NH.sub.2 (PG [78-107]) in the L cells
of the intestine where GLP-1[7-36]NH.sub.2 (78-107 PG) is the major
product. The GLP-1 component in accordance with the invention may
be any biologically active product or deivative of proglocagon, or
functional analog thereof, including: GLP-1 (1-35), GLP-1(1-36),
GLP-1 (1-36)amide, GLP-1 (1-37), GLP-1 (1-38), GLP-1 (1-39), GLP-1
(1-40), GLP-1 (1-41), GLP-1 (7-35), GLP-1 (7-36), GLP-1
(7-36)amide, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40)
and GLP-1 (7-41), or a analog of the foregoing. Generally, the
GLP-1 component in some embodiments may be expressed as GLP-1
(A-B), where A is an integer from 1 to 7 and B is an integer from
38 to 45, optionally with one or more amino acid substitutions as
defined below.
[0081] As an overview, after processing in the intestinal L-cells,
GLP-1 is released into the circulation, most notably in response to
a meal. The plasma concentration of GLP-1 rises from a fasting
level of approximately 15 pmol/L to a peak postprandial level of 40
pmol/L. For a given rise in plasma glucose concentration, the
increase in plasma insulin is approximately threefold greater when
glucose is administered orally compared with intravenously
(Kreymann et al., 1987, Lancet 2(8571): 1300-4). This alimentary
enhancement of insulin release, known as the incretin effect, is
primarily humoral and GLP-1 is now thought to be the most potent
physiological incretin in humans. GLP-1 mediates insulin production
via binding to the GLP-1 receptor, known to be expressed in
pancreatic .beta. cells. In addition to the insulinotropic effect,
GLP-1 suppresses glucagon secretion, delays gastric emptying
(Wettergen et al., 1993, Dig Dis Sci 38: 665-73) and may enhance
peripheral glucose disposal (D'Alessio et al., 1994, J. Clin Invest
93: 2293-6).
[0082] A combination of actions gives GLP-1 unique therapeutic
advantages over other agents currently used to treat
non-insulin-dependent diabetes mellitus (NIDDM). First, a single
subcutaneous dose of GLP-1 can completely normalize post prandial
glucose levels in patients with NIDDM (Gutniak et al., 1994,
Diabetes Care 17: 1039-44). This effect may be mediated both by
increased insulin release and by a reduction in glucagon secretion.
Second, intravenous infusion of GLP-1 can delay postprandial
gastric emptying in patients with NIDDM (Williams et al., 1996, J.
Clin Endo Metab 81: 327-32). Third, unlike sulphonylureas, the
insulinotropic action of GLP-1 is dependent on plasma glucose
concentration (Holz et al., 1993, Nature 361:362-5). Thus, the loss
of GLP-1-mediated insulin release at low plasma glucose
concentration protects against severe hypoglycemia.
[0083] When given to healthy subjects, GLP-1 potently influences
glycemic levels as well as insulin and glucagon concentrations
(Orskov, 1992, Diabetologia 35:701-11), effects which are glucose
dependent (Weir et al., 1989, Diabetes 38: 338-342). Moreover, it
is also effective in patients with diabetes (Gutniak, M., 1992, N.
Engl J Med 226: 1316-22), normalizing blood glucose levels in type
2 diabetic subjects and improving glycemic control in type 1
patients (Nauck et al., 1993, Diabetologia 36: 741-4, Creutzfeldt
et al., 1996, Diabetes Care 19:580-6).
[0084] GLP-1 is, however, metabolically unstable, having a plasma
half-life (t.sub.1/2) of only 1-2 minutes in vivo. Moreover,
exogenously administered GLP-1 is also rapidly degraded (Deacon et
al., 1995, Diabetes 44: 1126-31). This metabolic instability has
limited the therapeutic potential of native GLP-1.
[0085] GLP-1[7-36]NH.sub.2 has the following amino acid sequence:
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 13), which may be
employed as the GLP-1 component in accordance with the invention.
Alternatively, the GLP-1 component may contain glycine (G) at the
second position, giving, for example, the sequence
HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 17). The GLP-1 component
may be a biologically active fragment of GLP-1, for example, as
disclosed in US 2007/0041951, which is hereby incorporated by
reference in its entirety. Other fragments and modified sequences
of GLP-1 are known in the art (U.S. Pat. No. 5,614,492; U.S. Pat.
No. 5,545,618; European Patent Application, Publication No. EP
0658568 A1; WO 93/25579, which are hereby incorporated by reference
in their entireties). Such fragments and modified sequences may be
used in connection with the present invention, as well as those
described below.
[0086] Certain structural and functional analogs of GLP-1 have been
isolated from the venom of the Gila monster lizards (Heloderma
suspectum and Heloderma horridum) and have shown clinical utility.
Such molecules find use in accordance with the present invention.
In particular, exendin-4 is a 39 amino acid residue peptide
isolated from the venom of Heloderma suspectum and shares
approximately 52% homology with human GLP-1. Exendin-4 is a potent
GLP-1 receptor agonist that stimulates insulin release, thereby
lowering blood glucose levels. Exendin-4 has the following amino
acid sequence: HGEGTFTSDLSKQMEEEAVRLFEWLKNGGPSSGAPPPS (SEQ ID NO:
14). A synthetic version of exendin-4 known as exenatide (marketed
as Byetta.RTM.) has been approved for the treatment of Type-2
Diabetes. Although exenatide is structurally analogous to native
GLP-1, it has a longer half-life after injection.
[0087] While exenatide has the ability to lower blood glucose
levels on its own, it can also be combined with other medications
such as metformin, a thiozolidinedione, a sulfonylureas, and/or
insulin to improve glucose control. Exenatide is administered by
injection subcutaneously twice per day using a pre-filled pen
device. Typical human responses to exenatide include improvements
in the initial rapid release of endogenous insulin, an increase in
.beta.-cell growth and replication, suppression of pancreatic
glucagon release, delayed gastric emptying, and reduced
appetite--all of which function to lower blood glucose. Unlike
sulfonylureas and meglitinides, exenatide increases insulin
synthesis and secretion in the presence of glucose only, thus
lessening the risk of hypoglycemia. Despite the therapeutic utility
of exenatide, it has certain undesirable traits, including the
requirement of twice daily injections, gastrointestional side
effects, and similar to native GLP-1, a relatively short half-life
(i.e. approximately 2 hr).
[0088] Various functional analogs of GLP-1 and exendin-4 are known,
and which find use in accordance with the invention. These include
liraglutide (Novo Nordisk, WO98/008871), R1583/taspoglutide (Roche,
WO00/034331), CJC-1131 (ConjuChem, WO00/069911), ZP-10/AVE0010
(Zealand Pharma, Sanofi-Aventis, WO01/004156), and LY548806 (Eli
Lilly, WO03/018516).
[0089] Liraglutide, also known as NN2211, is a GLP-1 receptor
agonist analog that has been designed for once-daily injection
(Harder et al., 2004, Diabetes Care 27: 1915-21). Liraglutide has
been tested in patients with type-2 diabetes in a number of studies
and has been shown to be effective over a variety of durations. In
one study, treatment with liraglutide improved glycemic control,
improved .beta.-cell function, and reduced endogenous glucose
release in patients with type-2 diabetes after one week of
treatment (Degn et al., 2004, Diabetes 53: 1187-94). In a similar
study, eight weeks of 0.6-mg liraglutide therapy significantly
improved glycemic control without increasing weight in subjects
with type 2 diabetes compared with those on placebo (Harder et al.,
2004, Diabetes Care 27: 1915-21).
[0090] Thus, in certain embodiments, the GLP-1 receptor agonist in
accordance with the invention is as described in WO98/008871, which
is hereby incorporated by reference in its entirety. The GLP-1
receptor agonist may have at least one lipophilic substituent, in
addition to one, two, or more amino acid substitutions with respect
to native GLP-1. For example, the lipophilic substituent may be an
acyl group selected from CH.sub.3(CH.sub.2).sub.nCO--, wherein n is
an integer from 4 to 38, such as an integer from 4 to 24. The
lipophilic substituent may be an acyl group of a straight-chain or
branched alkyl or fatty acid (for example, as described in
WO98/008871, which description is hereby incorporated by
reference).
[0091] In certain embodiments, the GLP-1 component is
Arg.sup.26-GLP-1 (7-37), Arg.sup.34-GLP-1 (7-37), Lys.sup.36-GLP-1
(7-37), Arg.sup.26,34Lys.sup.36-GLP-I (7-37),
Arg.sup.26,34Lys.sup.38-GLP-I (7-38), Arg.sup.28,34
Lys.sup.39-GLP-1 (7-39), Arg.sup.26,34Lys.sup.40-GLP-1(7-40),
Arg.sup.26Lys.sup.36-GLP-1(7-37), Arg.sup.34Lys.sup.36-GLP-1(7-37),
Arg.sup.26Lys.sup.39-GLP-1(7-39), Arg.sup.34Lys.sup.40-GLP-1(7-40),
Arg.sup.26,34Lys.sup.36,39-GLP-I (7-39),
Arg.sup.26,34Lys.sup.36,40-GLP-1(7-40),
Gly.sup.8Arg.sup.26-GLP-1(7-37); Gly.sup.8Arg.sup.34-GLP-1(7-37);
Gly.sup.8Lys.sup.38-GLP-1(7-37);
Gly.sup.8Arg.sup.26,34Lys.sup.36-GLP-1(7-37),
Gly.sup.8Arg.sup.26,34Lys.sup.39-GLP-1(7-39),
Gly.sup.8Arg.sup.26,34Lys.sup.40-GLP-1(7-40),
Gly.sup.8Arg.sup.26Lys.sup.36-GLP-1(7-37),
Gly.sup.8Arg.sup.34Lys.sup.36-GLP-1(7-37),
Gly.sup.8Arg.sup.26Lys.sup.39-GLP-1(7-39);
Gly.sup.8Arg.sup.34Lys.sup.40-GLP-1(7-40),
Gly.sup.8Arg.sup.28,34Lys.sup.36,39-GLP-1(7-39) and
Gly.sup.8Arg.sup.26,34Lys.sup.35,40-GLP-1(7-40), each optionally
having a lipophilic substituent. For example, the GLP-1 receptor
agonist may have the sequence/structure
Arg.sup.34Lys.sup.26-(N-.epsilon.-(.gamma.-Glu(N-.alpha.-hexadecanoyl)))--
GLP-I(7-37).
[0092] Taspoglutide, also known as R1583 or BIM 51077, is a GLP-1
receptor agonist that has been shown to improve glycemic control
and lower body weight in subjects with type 2 diabetes mellitus
treated with metformin (Abstract No. A-1604, Jun. 7, 2008, 68th
American Diabetes Association Meeting, San Francisco, Calif.).
[0093] Thus, in certain embodiments, the GLP-1 receptor agonist is
as described in WO00/034331, which is hereby incorporated by
reference in its entirety. In certain exemplary embodiments, the
GLP-1 receptor agonist has the sequence
[Aib.sup.8,35]hGLP-1(7-36)NH.sub.2 (e.g. taspoglutide), wherein Aib
is alpha-aminoisobutyric acid.
[0094] CJC-1131 is a GLP-1 analog that consists of a
DPP-IV-resistant form of GLP-1 joined to a reactive chemical linker
group that allows GLP-1 to form a covalent and irreversible bond
with serum albumin following subcutaneous injection (Kim et al.,
2003, Diabetes 52: 751-9). In a 12-week, randomized, double-blind,
placebo-controlled multicenter study, CJC-1131 and metformin
treatment was effective in reducing fasting blood glucose levels in
type 2 diabetes patients (Ratner et al., Abstract No. 10-OR, June
10-14th, 2005, 65th American Diabetes Association Meeting, San
Francisco, Calif.).
[0095] Thus, in certain embodiments, the GLP-1 receptor agonist is
as described in WO00/069911, which is hereby incorporated by
reference in its entirety. In some embodiments, the GLP-1 receptor
agonist is modified with a reactive group which reacts with amino
groups, hydroxyl groups or thiol groups on blood components to form
a stable covalent bond. In certain embodiments, the GLP-1 receptor
agonist is modified with a reactive group selected from the group
consisting of succinimidyl and maleimido groups. In certain
exemplary embodiments, the GLP-1 receptor agonist has the
sequence/structure:
D-Ala.sup.8Lys.sup.37-(2-(2-(2-maleimidopropionamido(ethoxy)ethoxy)acetam-
ide))-GLP-1(7-37) (e.g. CJC-1131).
[0096] AVE0010, also known as ZP-10, is a GLP-1 receptor agonist
that may be employed in connection with the invention. In a recent
double-blind study, patients treated with once daily dosing of
AVE0010 demonstrated significant reductions in HbA1c levels (Ratner
et al., Abstract No. 433-P, 68th American Diabetes Association
Meeting, San Francisco, Calif.). At the conclusion of the study,
the percentages of patients with HbA1c <7% ranged from 47-69%
for once daily dosing compared to 32% for placebo. In addition,
AVE0010 treated patients showed dose-dependent reductions in weight
and post-prandial plasma glucose.
[0097] Thus, in certain embodiments, the GLP-1 receptor agonist is
as described in WO01/004156, which is hereby incorporated by
reference in its entirety. For example, the GLP-1 receptor agonist
may have the sequence:
TABLE-US-00001 (SEQ ID NO: 18)
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2 (e.g.
AVE0010).
[0098] LY548806 is a GLP-1 derivative designed to be resistant to
proteolysis by dipeptidase-peptidyl IV (DPP-IV) (Jackson et al.,
Abstract No. 562, Jun. 10-14, 2005, 65th American Diabetes
Association Meeting, San Francisco, Calif.). In an animal model of
hyperglycemia, LY548806 has been shown to produce a significant
lowering of blood glucose levels during the hyperglycemic phase
(Saha et al., 2006, J. Pharm. Exp. Ther. 316: 1159-64). Moreover,
LY548806 was shown to produce a significant increase in insulin
levels consistent with its known mechanism of action, namely
stimulation of insulin release in the presence of
hyperglycemia.
[0099] Thus, in certain embodiments, the GLP-1 receptor agonist is
as described in WO03/018516, which is hereby incorporated by
reference in its entirety. In some embodiments, the therapeutic
agents of the present invention comprise GLP-1 analogs wherein the
backbone for such analogs or fragments contains an amino acid other
than alanine at position 8 (position 8 analogs). The backbone may
also include L-histidine, D-histidine, or modified forms of
histidine such as desamino-histidine, 2-amino-histidine,
.beta.-hydroxy-histidine, homohistidine,
.alpha.-fluoromethyl-histidine, or .alpha.-methyl-histidine at
position 7. In some embodiments, these position 8 analogs may
contain one or more additional changes at positions 12, 16, 18, 19,
20, 22, 25, 27, 30, 33, and 37 compared to the corresponding amino
acid of native GLP-1. In other embodiments, these position 8
analogs may contain one or more additional changes at positions 16,
18, 22, 25 and 33 compared to the corresponding amino acid of
native GLP-1. In certain exemplary embodiments, the GLP-1 receptor
agonist has the sequence: HVEGTFTSDVSSYLEEQAAKEFIAWLIKGRG-OH (SEQ
ID NO: 19) (e.g. LY548806).
[0100] Thus, the present invention provides therapeutic agents
comprising an elastin-like peptide (ELP) and a GLP-1 receptor
agonist. For example, in certain embodiments, the GLP-1 receptor
agonist is GLP-1 (SEQ ID NO:13, 17, or 59) or a functional analog
thereof. In other embodiments, the GLP-1 receptor agonist is
exendin-4 (SEQ ID NO:14) or a functional analog thereof. Such
functional analogs of GLP-1 or exendin-4 include functional
fragments truncated at the C-terminus by from 1 to 10 amino acids,
including by 1, 2, 3, or up to about 5 amino acids (with respect to
SEQ ID NOS: 13, 14, 17, or 59). Such functional analogs may contain
from 1 to 10 amino acid insertions, deletions, and/or substitutions
(collectively) with respect to the native sequence (e.g., SEQ ID
NOS 13, 14, and 59), and in each case retaining the activity of the
peptide. For example, the functional analog of GLP-1 or exendin-4
may have from 1 to about 3, 4, or 5 insertions, deletions and/or
substitutions (collectively) with respect to SEQ ID NOS: 13, 59 and
14, and in each case retaining the activity of the peptide. Such
activity may be confirmed or assayed using any available assay,
including those described herein. In these or other embodiments,
the GLP-1 receptor agonist component has at least about 50%, 75%,
80%, 85%, 90%, or 95% identity with the native sequence (SEQ ID
NOS: 13, 59, and 14). The determination of sequence identity
between two sequences (e.g., between a native sequence and a
functional analog) can be accomplished using any alignment tool,
including Tatusova et al., Blast 2 sequences--a new tool for
comparing protein and nucleotide sequences, FEMS Microbiol Lett.
174:247-250 (1999). Such functional analogs may further comprise
additional chemical modifications, such as those described in this
section and/or others known in the art.
[0101] In certain embodiments, the GLP1-ELP fusion has a sequence
exemplified herein as SEQ ID NOS: 54 and 56. When processed, the
mature form of such fusion protein will begin with the His.sup.7 of
GLP.
[0102] In another aspect, the present invention provides methods
for the treatment or prevention of type 2 diabetes, impaired
glucose tolerance, type 1 diabetes, hyperglycemia, obesity, binge
eating, bulimia, hypertension, syndrome X, dyslipidemia, cognitive
disorders, atheroschlerosis, non-fatty liver disease, myocardial
infarction, coronary heart disease and other cardiovascular
disorders. The method comprises administering the therapeutic agent
comprising the elastin-like peptide (ELP) and the GLP-1 receptor
agonist (as described above) to a patient in need of such
treatment. In these or other embodiments, the present invention
provides methods for decreasing food intake, decreasing .beta.-cell
apoptosis, increasing .beta.-cell function and .beta.-cell mass,
and/or for restoring glucose sensitivity to .beta.-cells.
Generally, the patient may be a human or non-human animal patient
(e.g., dog, cat, cow, or horse). Preferably, the patient is
human.
[0103] The treatment with a ELP/GLP-1 receptor agonist compound
according to the present invention may also be combined with one or
more pharmacologically active substances, e.g. selected from
antidiabetic agents, antiobesity agents, appetite regulating
agents, antihypertensive agents, agents for the treatment and/or
prevention of complications resulting from or associated with
diabetes and agents for the treatment and/or prevention of
complications and disorders resulting from or associated with
obesity. In the present context, the expression "antidiabetic
agent" includes compounds for the treatment and/or prophylaxis of
insulin resistance and diseases wherein insulin resistance is the
pathophysiological mechanism.
[0104] The ability of a GLP-1 or exendin-4 analog, or an GLP-1
receptor agonist/ELP compound, to bind the GLP-1 receptor may be
determined by standard methods, for example, by receptor-binding
activity screening procedures which involve providing appropriate
cells that express the GLP-1 receptor on their surface, for
example, insulinoma cell lines such as RINmSF cells or INS-1 cells.
In addition to measuring specific binding of tracer to membrane
using radioimmunoassay methods, cAMP activity or glucose dependent
insulin production can also be measured. In one method, a
polynucleotide encoding the GLP-1 receptor is employed to transfect
cells to thereby express the GLP-1 receptor protein. Thus, these
methods may be employed for testing or confirming whether a
suspected GLP-1 receptor agonist is active. An exemplary assay is
described in greater detail herein.
[0105] In addition, known methods can be used to measure or predict
the level of biologically activity of a GLP-1 receptor agonist or
GLP-1 receptor agonist/ELP in vivo (See e.g. Siegel, et al., 1999,
Regul Pept 79(2-3): 93-102). In particular, GLP-1 receptor agonists
or GLP-1 receptor agonist/ELP compounds can be assessed for their
ability to induce the production of insulin in vivo using a variety
of known assays for measuring GLP-1 activity. For example, an
ELP/GLP-1 receptor agonist compound can be introduced into a cell,
such as an immortalized .beta.-cell, and the resulting cell can be
contacted with glucose. If the cell produces insulin in response to
the glucose, then the modified GLP-1 is generally considered
biologically active in vivo (Fehmann et al., 1992, Endocrinology
130: 159-166). An exemplary assay is described in greater detail
herein.
[0106] The ability of an GLP-1 receptor agonist/ELP compound to
enhance .beta.-cell proliferation, inhibit .beta.-cell apoptosis,
and regulate islet growth may also be measured using known assays.
Pancreatic .beta.-cell proliferation may be assessed by
.sup.3H-tymidine or BrdU incorporation assays (See e.g. Buteau et
al., 2003, Diabetes 52: 124-32), wherein pancreatic .beta.-cells
such as INS(832/13) cells are contacted with an ELP/GLP-1 receptor
agonist compound and analyzed for increases in .sup.3H-thymidine or
BrdU incorporation. The antiapoptotic activity of an ELP/GLP-1
receptor agonist compound can be measured in cultured
insulin-secreting cells and/or in animal models where diabetes
occurs as a consequence of an excessive rate of beta-cell apoptosis
(See e.g. Bulotta et al., 2004, Cell Biochem Biophys 40(3 suppl):
65-78).
[0107] In addition to GLP-1, other peptides of this family, such as
those derived from processing of the pro-glucagon gene, such as
GLP-2, GIP, and oxyntomodulin, could be conjugated or fused to the
ELP component (as described herein) to enhance the therapeutic
potential.
Insulin
[0108] In other embodiments, the present invention provides a
therapeutic agent comprising an ELP component coupled to insulin
(e.g., via fusion or conjugation). Insulin injections, e.g. of
human insulin, can be used to treat diabetes. The insulin-making
cells of the body are called .beta.-cells, and they are found in
the pancreas gland. These cells clump together to form the "islets
of Langerhans", named for the German medical student who described
them.
[0109] The synthesis of insulin begins at the translation of the
insulin gene, which resides on chromosome 11. During translation,
two introns are spliced out of the mRNA product, which encodes a
protein of 110 amino acids in length. This primary translation
product is called preproinsulin and is inactive. It contains a
signal peptide of 24 amino acids in length, which is required for
the protein to cross the cell membrane.
[0110] Once the preproinsulin reaches the endoplasmic reticulum, a
protease cleaves off the signal peptide to create proinsulin.
Proinsulin consists of three domains: an amino-terminal B chain, a
carboxyl-terminal A chain, and a connecting peptide in the middle
known as the C-peptide. Insulin is composed of two chains of amino
acids named chain A (21 amino acids--GIVEQCCASVCSLYQLENYCN) (SEQ ID
NO: 15) and chain B (30 amino acids FVNQHLCGSHLVEALYLVCGERGFFYTPKA)
(SEQ ID NO: 16) that are linked together by two disulfide bridges.
There is a 3rd disulfide bridge within the A chain that links the
6th and 11th residues of the A chain together. In most species, the
length and amino acid compositions of chains A and B are similar,
and the positions of the three disulfide bonds are highly
conserved. For this reason, pig insulin can replace deficient human
insulin levels in diabetes patients. Today, porcine insulin has
largely been replaced by the mass production of human proinsulin by
bacteria (recombinant insulin).
[0111] Insulin molecules have a tendency to form dimers in
solution, and in the presence of zinc ions, insulin dimers
associate into hexamers. Whereas monomers of insulin readily
diffuse through the blood and have a rapid effect, hexamers diffuse
slowly and have a delayed onset of action. In the design of
recombinant insulin, the structure of insulin can be modified in a
way that reduces the tendency of the insulin molecule to form
dimers and hexamers but that does not interrupt binding to the
insulin receptor. In this way, a range of preparations are made,
varying from short acting to long acting.
[0112] Within the endoplasmic reticulum, proinsulin is exposed to
several specific peptidases that remove the C-peptide and generate
the mature and active form of insulin. In the Golgi apparatus,
insulin and free C-peptide are packaged into secretory granules,
which accumulate in the cytoplasm of the .beta.-cells. Exocytosis
of the granules is triggered by the entry of glucose into the beta
cells. The secretion of insulin has a broad impact on
metabolism.
[0113] There are two phases of insulin release in response to a
rise in glucose. The first is an immediate release of insulin. This
is attributable to the release of preformed insulin, which is
stored in secretory granules. After a short delay, there is a
second, more prolonged release of newly synthesized insulin.
[0114] Once released, insulin is active for a only a brief time
before it is degraded by enzymes. Insulinase found in the liver and
kidneys breaks down insulin circulating in the plasma, and as a
result, insulin has a half-life of only about 6 minutes. This short
duration of action results in rapid changes in the circulating
levels of insulin.
[0115] Insulin analogs have been developed with improved
therapeutic properties (Owens et al., 2001, Lancet 358: 739-46;
Vajo et al., 2001, Endocr Rev 22: 706-17), and such analogs may be
employed in connection with the present invention. Various
strategies, including elongation of the COOH-terminal end of the
insulin B-chain and engineering of fatty acid-acylated insulins
with substantial affinity for albumin are used to generate
longer-acting insulin analogs. However, in vivo treatments with
available longer-acting insulin compounds still result in a high
frequency of hypo- and hyperglycemic excursions and modest
reduction in HbA.sub.1c. Accordingly, development of a truly
long-acting and stable human insulin analog still remains an
important task.
[0116] Functional analogs of insulin that may be employed in
accordance with the invention include rapid acting analogs such as
lispro, aspart and glulisine, which are absorbed rapidly (<30
minutes) after subcutaneous injection, peak at one hour, and have a
relatively short duration of action (3 to 4 hours). In addition,
two long acting insulin analogs have been developed: glargine and
detemir, and which may be employed in connection with the
invention. The long acting insulin analogs have an onset of action
of approximately two hours and reach a plateau of biological action
at 4 to 6 hours, and may last up to 24 hours.
[0117] Thus, in one embodiment, the insulin component may contain
the A and/or B chain of lispro (also known as Humalog, Eli Lilly).
Insulin lispro differs from human insulin by the substitution of
proline with lysine at position 28 and the substitution of lysine
with proline at position 29 of the insulin B chain. Although these
modifications do not alter receptor binding, they help to block the
formation of insulin dimers and hexamers, allowing for larger
amounts of active monomeric insulin to be available for
postprandial injections.
[0118] In another embodiment, the insulin may contain an A and/or B
chain of aspart (also known as Novolog, Novo Nordisk). Insulin
aspart is designed with the single replacement of the amino acid
proline by aspartic acid at position 28 of the human insulin B
chain. This modification helps block the formation for insulin
hexamers, creating a faster acting insulin.
[0119] In yet another embodiment, the insulin may contain an A
and/or B chain of glulisine (also known as Apidra, Sanofi-Aventis).
Insulin glulisine is a short acting analog created by substitution
of asparagine at position 3 by lysine and lysine at position 29 by
glutamine of human insulin B chain. Insulin glulisine has more
rapid onset of action and shorter duration of action compared to
regular human insulin.
[0120] In another embodiment, the insulin may contain an A and/or B
chain of glargine (also known as Lantus, Sanofi-Aventis). Insulin
glargine differs from human insulin in that the amino acid
asparagine at position 21 of the A chain is replaced by glycine and
two arginines are added to the C-terminus of the B-chain. Compared
with bedtime neutral protamine Hagedorn (NPH) insulin (an
intermediate acting insulin), insulin glargine is associated with
less nocturnal hypoglycemia in patients with type 2 diabetes.
[0121] In yet another embodiment, the insulin may contain an A
and/or B chain from detemir (also known as Levemir, Novo Nordisk).
Insulin detemir is a soluble (at neutral pH) long-acting insulin
analog, in which the amino acid threonine at B30 is removed and a
14-carbon, myristoyl fatty acid is acetylated to the epsilon-amino
group of LysB29. After subcutaneous injection, detemir dissociates,
thereby exposing the free fatty acid which enables reversible
binding to albumin molecules. So at steady state, the concentration
of free unbound insulin is greatly reduced resulting in stable
plasma glucose levels.
[0122] In some embodiments, the insulin may be a single-chain
insulin analog (SIA) (e.g. as described in U.S. Pat. No. 6,630,438
and WO08/019368, which are hereby incorporated by reference in
their entirety). Single-chain insulin analogs encompass a group of
structurally-related proteins wherein the A and B chains are
covalently linked by a polypeptide linker. The polypeptide linker
connects the C-terminus of the B chain to the N-terminus of the A
chain. The linker may be of any length so long as the linker
provides the structural conformation necessary for the SIA to have
a glucose uptake and insulin receptor binding effect. In some
embodiments, the linker is about 5-18 amino acids in length. In
other embodiments, the linker is about 9-15 amino acids in length.
In certain embodiments, the linker is about 12 amino acids long. In
certain exemplary embodiments, the linker has the sequence
KDDNPNLPRLVR (SEQ ID NO.: 20) or GAGSSSRRAPQT (SEQ ID NO.: 21).
However, it should be understood that many variations of this
sequence are possible such as in the length (both addition and
deletion) and substitutions of amino acids without substantially
compromising the effectiveness of the produced SIA in glucose
uptake and insulin receptor binding activities. For example,
several different amino acid residues may be added or removed from
either end without substantially decreasing the activity of the
produced SIA.
[0123] An exemplary single-chain insulin analog currently in
clinical development is albulin (Duttaroy et al., 2005, Diabetes
54: 251-8). Albulin can be produced in yeast or in mammalian cells.
It consists of the B and A chain of human insulin (100% identity to
native human insulin) linked together by a dodecapeptide linker and
fused to the NH.sub.2 terminals of the native human serum albumin.
For expression and purification of albulin, Duttaroy et al.
constructed a synthetic gene construct encoding a single-chain
insulin containing the B- and A-chain of mature human insulin
linked together by a dodecapeptide linker using four overlapping
primers and PCR amplification. The resulting PCR product was
ligated in-frame between the signal peptide of human serum albumin
(HSA) and the NH.sub.2 terminus of mature HSA, contained within a
pSAC35 vector for expression in yeast. In accordance with the
present invention, the HSA component of abulin may be replaced with
an ELP component as described herein.
[0124] Thus, in one aspect, the present invention provides
therapeutic agents comprising an elastin-like peptide (ELP) and an
insulin or functional analog thereof. For example, in certain
embodiments, the insulin is a mammalian insulin, such as human
insulin or porcine insulin. In accordance with the invention, the
ELP component may be coupled (e.g., via recombinant fusion or
chemical conjugation) to the insulin A chain, or B chain, or both.
The insulin may comprise each of chains A, B, and C (SEQ ID NOS: 51
and 52), or may contain a processed form, containing only chains A
and B. In some embodiments, chains A and B are connected by a short
linking peptide, to create a single chain insulin. The insulin may
be a functional analog of human insulin, including functional
fragments truncated at the N-terminus and/or C-terminus (of either
or both of chains A and B) by from 1 to 10 amino acids, including
by 1, 2, 3, or about 5 amino acids. Functional analogs may contain
from 1 to 10 amino acid insertions, deletions, and/or substitutions
(collectively) with respect to the native sequence (e.g., SEQ ID
NOS 15 and 16), and in each case retaining the activity of the
peptide. For example, functional analogs may have 1, 2, 3, 4, or 5
amino acid insertions, deletions, and/or substitutions
(collectively) with respect to the native sequence (which may
contain chains A and B, or chains A, B, and C). Such activity may
be confirmed or assayed using any available assay, including those
described herein. In these or other embodiments, the insulin
component has at least about 75%, 80%, 85%, 90%, 95%, or 98%
identity with each of the native sequences for chains A and B (SEQ
ID NOS:15 and 16). The determination of sequence identity between
two sequences (e.g., between a native sequence and a functional
analog) can be accomplished using any alignment tool, including
Tatusova et al., Blast 2 sequences--a new tool for comparing
protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250
(1999). The insulin component may contain additional chemical
modifications known in the art.
[0125] In another aspect, the present invention provides methods
for the treatment or prevention of diabetes, including type I and
II diabetes. The method comprises administering an effective amount
of the therapeutic agent comprising an elastin-like peptide (ELP)
component and an insulin (or functional analog thereof) component
to a patient in need thereof. Generally, the patient may be a human
or non-human animal (e.g., dog, cat, cow, or horse) patient.
Preferably, the patient is human.
[0126] To characterize the in vitro binding properties of an
insulin analog or an ELP-containing insulin analog, competition
binding assays may be performed in various cell lines that express
the insulin receptor (Jehle et al., 1996, Diabetologia 39:
421-432). For example, competition binding assays using CHO cells
overexpressing the human insulin receptor may be employed. Insulin
can also bind to the IGF-1 receptor with a lower affinity than the
insulin receptor. To determine the binding affinity of an
ELP-containing insulin analog, a competition binding assay can be
performed using .sup.125I-labeled IGF-1 in L6 cells.
[0127] The activities of insulin include stimulation of peripheral
glucose disposal and inhibition of hepatic glucose production. The
ability of an ELP-containing insulin analog to mediate these
biological activities can be assayed in vitro using known
methodologies. For example, the effect of an ELP-containing analog
on glucose uptake in 3T3-L1 adipocytes can be measured and compared
with that of insulin. Pretreatment of the cells with a biologically
active analog will generally produce a dose-dependent increase in
2-deoxyglucose uptake. The ability of an ELP-containing insulin
analog to regulate glucose production may be measured in any number
of cells types, for example, H4IIe hepatoma cells. In this assay,
pretreatment with a biologically active analog will generally
result in a dose-dependent inhibition of the amount of glucose
released.
Factor VII (VIIa)
[0128] In certain embodiments, the invention provides therapeutic
agents comprising an ELP component coupled (e.g., via fusion or
conjugation) to a Factor VII/VIIa. Coagulation is the biological
process of blood clot formation involving many different serine
proteases as well as their essential cofactors and inhibitors. It
is initiated by exposure of Factor VII (FVII) and Factor VIIa
(FVIIa) to its membrane bound cofactor, tissue factor (TF),
resulting in production of Factor Xa (FXa) and more FVIIa. The
process is propagated upon production of Factor IXa (FIXa) and
additional FXa that, upon binding with their respective cofactors
FVIIIa and FVa, form platelet bound complexes, ultimately resulting
in the formation of thrombin and a fibrin clot. Thrombin also
serves to further amplify coagulation by activation of cofactors
such as FV and FVII and zymogens such as Factor XI. Moreover,
thrombin activates platelets leading to platelet aggregation, which
is necessary for the formation of a hemostatic plug.
[0129] Factor VII circulates in the blood in a zymogen form, and is
converted to its active form, Factor VIIa, by either factor IXa,
factor Xa, factor XIIa, or thrombin by minor proteolysis. Factor
VIIa is a two-chain, 50 kilodalton (kDa) plasma serine protease.
The active form of the enzyme comprises a heavy chain (254 amino
acid residues) containing a catalytic domain and a light chain (152
residues) containing 2 epidermal growth factor (EGF)-like domains.
The mature factor VII/VIIa that circulates in plasma is composed of
406 amino acid residues (SEQ ID NO: 33). The light and heavy chains
are held together by a disulfide bond.
[0130] As noted above, Factor VIIa is generated by proteolysis of a
single peptide bond from its single chain zymogen, Factor VII,
which is present at approximately 0.5 .mu.g/ml in plasma. The
conversion of zymogen Factor VII into the activated two-chain
molecule occurs by cleavage of an internal peptide bond. In human
Factor VII, the cleavage site is at Arg152-Ile153 (Hagen et al.,
1986, PNAS USA 83: 2412-6).
[0131] "Factor VII/VIIa" as used in this application means a
product consisting of either the unactivated form (factor VII) or
the activated form (factor VIIa) or mixtures thereof. "Factor
VII/VIIa" within the above definition includes proteins that have
an amino acid sequence of native human factor VII/VIIa. It also
includes proteins with a slightly modified amino acid sequence, for
instance, a modified N-terminal end including N-terminal amino acid
deletions or additions so long as those proteins substantially
retain the activity of factor VIIa. "Factor VII" within the above
definition also includes natural allelic variations that may exist
and occur from one individual to another. Also, degree and location
of glycosylation or other post-translation modifications may vary
depending on the chosen host cells and the nature of the host
cellular environment.
[0132] In the presence of calcium ions, Factor VIIa binds with high
affinity to TF. TF is a 263 amino acid residue glycoprotein
composed of a 219 residue extracellular domain, a single
transmembrane domain, and a short cytoplasmic domain (Morrissey et
al., 1987, Cell 50: 129-35). The TF extracellular domain is
composed of two fibronectin type III domains of about 105 amino
acids each. The binding of FVIIa is mediated entirely by the TF
extracellular domain (Muller et al., 1994, Biochem. 33:10864-70).
Residues in the area of amino acids 16-26 and 129-147 contribute to
the binding of FVIIa as well as the coagulant function of the
molecule. Residues Lys20, Trp45, Asp58, Tyr94, and Phe140 make a
large contribution (1 kcal/mol) to the free energy (.DELTA.G) of
binding to FVIIa.
[0133] TF is expressed constitutively on cells separated from
plasma by the vascular endothelium. Its expression on endothelial
cells and monocytes is induced by exposure to inflammatory
cytokines or bacterial lipopolysaccharides (Drake et al., 1989, J.
Cell Biol. 109: 389). Upon tissue injury, the exposed extracellular
domain of TF forms a high affinity, calcium dependent complex with
FVII. Once bound to TF, FVII can be activated by peptide bond
cleavage to yield serine protease FVIIa. The enzyme that catalyzes
this step in vivo has not been elucidated, but in vitro FXa,
thrombin, TF:FVIIa and FIXa can catalyze this cleavage. FVIIa has
only weak activity upon its physiological substrates FX and FIX
whereas the TF:FVIIa complex rapidly activates FX and FIX.
[0134] The TF:FVIIa complex constitutes the primary initiator of
the extrinsic pathway of blood coagulation. The complex initiates
the extrinsic pathway by activation of FX to Factor Xa (FXa), FIX
to Factor IXa (FIXa), and additional FVII to FVIIa. The action of
TF:FVIIa leads ultimately to the conversion of prothrombin to
thrombin, which carries out many biological functions. Among the
most important activities of thrombin is the conversion of
fibrinogen to fibrin, which polymerizes to form a clot. The
TF:FVIIa complex also participates as a secondary factor in
extending the physiological effects of the contact activation
system.
[0135] The initiation and subsequent regulation of coagulation is
complex, since maintenance of hemostasis is crucial for survival.
There is an exquisite balance between hemostasis (normal clot
formation and dissolution) and thrombosis (pathogenic clot
formation). Serious clinical conditions involving aberrations in
coagulation include deep vein thrombosis, myocardial infarction,
pulmonary embolism, stroke and disseminated intravascular
coagulation (in sepsis). There are also many bleeding
coagulopathies where there is insufficient clot formation. These
include hemophilia A (FVIII deficiency) or hemophilia B (FIX
deficiency), where procoagulant therapy is required. The challenge
in this therapeutic area is to operate in the narrow window between
too much and too little coagulation.
[0136] The use of exogenous FVIIa as a therapeutic agent has been
shown to induce hemostasis in patients with hemophilia A and B
(Hedner, 2001, Seminars Hematol. 38 (suppl. 12): 43-7; Hedner,
2004, Seminars Hematol. 41 (suppl. 1): 35-9). It also has been used
to treat bleeding in patients with liver disease,
anticoagulation-induced bleeding, surgery, thrombocytopenia,
thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease,
and other bleeding disorders (See e.g. Roberts et al., 2004, Blood
104: 3858-64).
[0137] Commercial preparations of human recombinant FVIIa are sold
as NovoSeven.TM. NovoSeven.TM. is indicated for the treatment of
bleeding episodes in hemophilia A or B patients and is the only
recombinant FVIIa effective for bleeding episodes currently
available. A circulating recombinant FVIIa half-life of 2.3 hours
was reported in "Summary Basis for Approval for NovoSeven.TM." FDA
reference number 96-0597. Moreover, the half-life of recombinant
FVIIa is shorter in pediatric patients (.about.1.3 hours),
suggesting that higher doses of recombinaint FVIIa may be required
in this population (Roberts et al., 2004, Blood 104: 3858-64).
Accordingly, relatively high doses and frequent administration are
necessary to reach and sustain the desired therapeutic or
prophylactic effect. As a consequence, adequate dose regulation is
difficult to obtain and the need of frequent intravenous
administrations imposes restrictions on the patient's way of
living.
[0138] A molecule with a longer circulation half-life would
decrease the number of necessary administrations. Given the
frequent injections associated with currently available FVIIa
therapy and the potential for obtaining more optimal therapeutic
FVIIa levels with concomitant enhanced therapeutic effect, there is
a clear need for improved FVII or FVIIa-like molecules with a
longer half-life in vivo.
[0139] Recombinant human coagulation factor VIIa (rFVIIa,
NovoSeven; Novo Nordisk NS, Copenhagen, Denmark) has proven to be
efficacious for the treatment of bleeding episodes in hemophilia
patients with inhibitors. A small fraction of patients may be
refractory to rFVIIa treatment and could potentially benefit from
genetically modified FVIIa molecules with increased potencies. To
this end, FVIIa analogs with increased intrinsic activity have been
investigated that exhibit superior hemostatic profiles in vitro
(see e.g. WO02/077218 or WO05/074975, which are hereby incorporated
by reference in their entirety, and Tranholm et al., 2003, Blood
102(10): 3615-20, which is also incorporated by reference). These
analogs may also be used as more efficacious hemostatic agents in
other indications where efficacy of rFVIIa has been observed,
including in thrombocytopenia and trauma.
[0140] Thus, in some embodiments, the Factor VIIa analog that may
be used in accordance with the invention is as described in
WO02/077218 or WO05/074975. For example, the FVIIa analog may have
a glutamine substituted for methionine at position 298 (i.e.
M298Q-FVIIa). In certain exemplary embodiments, the FVIIa analog
contains two additional mutations, valine at position 158 replaced
by aspartic acid and glutamic acid at position 296 replaced by
valine (i.e. V158D/E296V/M298Q-FVIIa). Additionally or
alternatively, the Factor VIIa analog may have an alanine residue
substitution for lysine at position 337 (i.e.
V158D/E296V/M298Q/K337A-FVIIa). In still other embodiments, the
Factor VIIa analog has a substitution or insertion selected from
Q250C; P406C; and 407C, wherein a cysteine has also been introduced
in the C-terminal sequence (see, e.g. U.S. Pat. No. 7,235,638,
which is hereby incorporated by reference in its entirety). The
Factor VIIa analog may further comprise a substitution or insertion
at one or more of positions 247, 260, 393, 396, and/or 405.
[0141] In these or other embodiments, the Factor VIIa analog
comprises a substitution relative to the sequence of native Factor
VIIa selected from: (a) a substitution of Lys157 with an amino acid
selected from the group consisting of Gly, Val, Ser, Thr, Asp, and
Glu; (b) a substitution of Lys337 with an amino acid selected from
the group consisting of Ala, Gly, Val, Ser, Thr, Gln, Asp, and Glu;
(c) a substitution of Asp334 with any amino acid other than Ala or
Asn; and (d) a substitution of Ser336 with any amino acid other
than Ala or Cys (see e.g. U.S. Pat. No. 7,176,288, which is hereby
incorporated by reference in its entirety). Additionally or
alternatively, the Factor VIIa analog comprises a substitution of
the Leu at position 305 of Factor VII with an amino acid residue
selected from the group consisting of Val, Ile, Met, Phe, Trp, Pro,
Gly, Ser, Thr, Cys, Tyr, Asn, Glu, Lys, Arg, His, Asp and Gln (see
e.g. U.S. Pat. No. 6,905,683, which is hereby incorporated by
reference in its entirety).
[0142] Thus, in one aspect, the present invention provides
therapeutic agents comprising an elastin-like peptide (ELP) and a
Factor VII/VIIa, or functional analog thereof. For example, in
certain embodiments, the Factor VII/VIIa is human Factor VII/VIIa
(e.g., SEQ ID NO: 33). The Factor VII/VIIa may be a functional
analog of human Factor VII/VIIa, including functional fragments
truncated at the N-terminus and/or C-terminus by from 1 to 10 amino
acids, including by 1, 2, 3, or about 5 amino acids. Functional
analogs may contain from 1 to 10 amino acid insertions, deletions,
and/or substitutions (collectively) with respect to the native
sequence (e.g., SEQ ID NO: 33), and in each case retaining the
activity of the peptide. For example, such analogs may have from 1
to about 5 amino acid insertions, deletions, and/or substitutions
(collectively) with respect to the native full length sequence, or
with respect to one or both of the heavy and light chains. Such
activity may be confirmed or assayed using any available assay,
including those described herein. In these or other embodiments,
the Factor VII/VIIa component has at least about 75%, 80%, 85%,
90%, 95%, or 98% identity with the native sequence (SEQ ID NO:33).
The determination of sequence identity between two sequences (e.g.,
between a native sequence and a functional analog) can be
accomplished using any alignment tool, including Tatusova et al.,
Blast 2 sequences--a new tool for comparing protein and nucleotide
sequences, FEMS Microbiol Lett. 174:247-250 (1999).
[0143] In exemplary embodiments, the FactorVII-ELP fusion has the
amino acid sequence of SEQ ID NO:58. SEQ ID NO:58 further comprises
a TEV protease cleavage site between the FactorVII and ELP
sequences, which may be beneficial for removing the ELP sequence
post expression where desired. However, in accordance with the
invention, the tev sequence may be entirely removed, or replaced
with another linking sequence as disclosed herein.
[0144] In another aspect, the present invention provides methods
for the treatment or prevention of bleeding-related disorders. The
method comprises administering an effective amount of the
therapeutic agent comprising an elastin-like peptide (ELP) and a
Factor VII/VIIa or functional analog thereof to a patient in need.
In certain embodiments, the bleeding-related disorder is one or
more of hemophilia (A or B), post-surgical bleeding,
anticoagulation-induced bleeding, thrombocytopenia, Factor VII
deficiency, Factor XI deficiency, bleeding in patients with liver
disease, thrombasthenia, Bemard-Soulier syndrome, von Willebrand
disease, and intracranial hemorrhage. Generally, the patient is a
human or non-human animal (e.g., dog, cat, cow, or horse) patient.
Preferably, the patient is human.
[0145] To characterize the in vitro binding properties of a
suspected Factor VII/VIIa analog, or an ELP-containing Factor VIIa
analog, TF binding assays can be performed as described previously
(See, e.g., Chaing et al., 1994, Blood 83(12): 3524-35). Briefly,
recombinant human TF can be coated onto Immulon II plates in
carbonate antigen buffer overnight at 4.degree. C. BSA is also
coated onto the plates for use as a control. ELP-containing Factor
VIIa analogs may be added at various concentrations in TBS-T
buffer. After several washes, monospecific polyclonal rabbit
anti-human FVIIa sera is added and incubated for approximately an
hour at room temperature. Next, goat anti-rabbit IgG conjugated to
alkaline phosphatase is added, followed by the alkaline phosphatase
substrate PNPP, which is used for detection. After subtraction of
background, the absorbance at .about.405 nm is taken to be directly
proportional to the degree of Factor VIIa binding to the
immobilized TF. These values can then be compared to control plasma
containing Factor VIIa.
[0146] The clotting ability of a Factor VII/VIIa analog or an
ELP-containing Factor VIIa analog can be measured in human FVII
deficient plasma. In this assay, the ELP-containing Factor VIIa
analog diluted to varying concentrations directly into FVII
deficient plasma. In a coagulometer, one part plasma.+-.a FVIIa
analog can be mixed with 2 parts Innovin.TM. (Dade, Miami, Fla.)
prothrombin time reagent (recombinant human tissue factor with
phospholipids and CaCl.sub.2). Clot formation is detected optically
and time to clotting measured. Clotting time (seconds) is compared
to the mean clotting time of FVII-deficient plasma alone and
plotted as the fractional clotting time versus FVIIa analog
concentration.
Therapeutic Proteins
[0147] The present invention further provides therapeutic agents
comprising an ELP component and at least one therapeutic protein
selected from Table 1. The ELP component and therapeutic protein
may be coupled by recombinant fusion or chemical conjugation as
described herein. Such therapeutic proteins are listed in Table 1
by protein name and GeneSeq Accession No. The amino acid sequence
of each Therapeutic Protein, which is known in the art, is hereby
incorporated by reference for each Therapeutic Protein listed in
Table 1. Such therapeutic proteins are further described in US
patent or PCT publications that are also listed in Table 1, and
such US patent and PCT publications are hereby incorporated by
reference, especially with respect to the structure of such
therapeutic proteins and described functional analogs.
[0148] Table 1 further describes the biological activity of each
listed Therapeutic Protein, as well as an exemplary assay for
determining the activity of functional analogs or agents of the
invention (e.g., fusion with an ELP component). Generally,
functional analogs of therapeutic proteins listed in Table 1 may
include functional fragments truncated at the N-terminus and/or
C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, 4 or
about 5 amino acids. Functional analogs may contain from 1 to 10
amino acid insertions, deletions, and/or substitutions
(collectively) with respect to the base sequence (e.g., as listed
in Table 1), and in each case retaining the full or partial
biological activity (as listed in Table 1) of the therapeutic
protein. For example, functional analogs may have 1, 2, 3, 4, or 5
amino acid insertions, deletions, and/or substitutions
(collectively) with respect to the base sequence. Such activity may
be confirmed or assayed using any available assay, including those
described in the Table. In these or other embodiments, the
therapeutic protein has at least about 75%, 80%, 85%, 90%, 95%, or
98% identity with the corresponding base sequence. The molecules
may further comprise additional chemical modifications known for
each in the art.
[0149] In some embodiments, the therapeutic protein (e.g., as
selected from Table 1) has a size of less than about 25 kDa, or
less than about 10 kDa, or less than about 5 kDa, and the
corresponding therapeutic agent of the invention (e.g., comprising
the ELP component) has a molecular weight of less than about 60
kDa, 55 kDa, 50 kDa, or 40 kDa.
[0150] Table 1 further lists preferred indications for each
therapeutic protein, for which the corresponding therapeutic agent
finds use, such as in a method for treatment or prevention related
to such indication.
TABLE-US-00002 TABLE 1 Exemplary Identifier PCT/Patent Reference
Exemplary Activity Assay (the sequences (the patents and publica-
(the publications listed in this column tions listed in this column
listed in this column are each hereby incor- are each hereby incor-
are each hereby incor- Therapeutic Protein X porated by reference)
porated by reference) Biological Activity porated by reference)
Preferred Indication Y BMP-1 GeneSeq WO8800205 BMP1 belongs to the
transforming growth BMP-1 activity can be determined Induction of
Cartilage, Tissue Acession factor-beta (TGFB) superfamily. Bone
using the following assays known in and Bone Growth, and Diabetes
P80618 morphogenic proteins induce cartilage and the art: Nat
Genet. 2001 January; bone formation, play important role in 27(1):
84-8; Eur J Biochem 1996 nephrogesis, and play an important role in
Apr. 1; 237(1): 295-302; J Biol the development of many organs,
including Chem, Vol. 274, Issue 16, 10897- lung, heart, teeth, gut,
skin, and 10902, Apr. 16, 1999; and Hogan, particularly the kidney.
B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-2 GeneSeq WO8800205
BMP-2 belongs to the transforming growth BMP-2 activity can be
determined Induction of Cartilage, Tissue Accession factor-beta
(TGFB) superfamily. Bone using the following assays known in and
Bone Growth, and Diabetes P80619 morphogenic protein induces bone
the art: Nat Genet. 2001 January; formation. 27(1): 84-8; Eur J
Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue
16, 10897- 10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes
Dev. 10, 1580-1594. BMP-2B GeneSeq U.S. Pat. No. BMP-2b belongs to
the transforming growth BMP-2b activity can be determined Induction
of Cartilage, Tissue Accession 5,631,142 factor-beta (TGFB)
superfamily. Bone using the following assays known in and Bone
Growth, and Diabetes W24850 morphogenic protein induces bone the
art: Nat Genet. 2001 January; formation. 27(1): 84-8; Eur J Biochem
1996 Apr. 1; 237(1): 295-302; I Biol Cbcre, Vol. 274, Issue 16,
10897- 10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev.
10, 1580-1594. BMP-4 GeneSeq WO0020591 BMP-4 belongs to the
transforming growth BMP-4 activity can be determined Induction of
Cartilage, Tissue Accession factor-beta (TGFB) superfamily. Bone
using the following assays known in and Bone Growth, and Diabetes
B02796 morphogenic protein induces bone the art: Nat Genet. 2001
January; formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1):
295-302; J Biol Chem, Vol. 274, Issue 16, 10897- 10902, Apr. 16,
1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-5
GeneSeq WO0020591 BMP-5 belongs to the transforming growth BMP-5
activity can be determined Induction of Cartilage, Tissue Accession
factor-beta (TGFB) superfamily. Bone using the following assays
known in and Bone Growth, and Diabetes B02797 morphogenic protein
induces bone the art: Nat Genet. 2001 January; formation. 27(1):
84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol.
274, Issue 16, 10897- 10902, Apr. 16, 1999; and Hogan, B. L. M.
(1996) Genes Dev. 10, 1580-1594. BMP-6 GeneSeq U.S. Pat. No. BMP-6
belongs to the transforming growth BMP-6 activity can be determined
Induction of Cartilage, Tissue Accession 5,187,076 factor-beta
(TGFB) superfamily. Bone using the following assays known in and
Bone Growth, and Diabetes R32904 morphogenic protein induces bone
the art: Nat Genet. 2001 January; formation. 27(1): 84-8; Eur J
Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue
16, 10897- 10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes
Dev. 10, 1580-1594. Osteo- GeneSeq WO973462 OP-1 belongs to the
transforming growth OP-1 activity can be determined Induction of
Cartilage, Tissue genic Accession factor-beta (TGFB) superfamily.
Bone using the following assays known in and Bone Growth, and
Diabetes Protein-1; W34783 morphogenic protein induces bone the
art: Nat Genet. 2001 January; OP-1; formation. 27(1): 84-8; Eur J
Biochem 1996 BMP-7 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274,
Issue 16, 10897- 10902, Apr. 16, 1999; and Hogan, B. L. M. (1996)
Genes Dev. 10, 1580-1594. Osteo- GeneSeq WO9406399 OP-2 belongs to
the transforming growth OP-2 activity can be determined Induction
of Cartilage, Tissue genic Accession factor-beta (TGFB)
superfamily. Bone using the following assays known in and Bone
Growth, and Diabetes Protein-2 R57973 morphogenic protein induces
bone the art: Nat Genet. 2001 January; formation. 27(1): 84-8; Eur
J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274,
Issue 16, 10897- 10902, Apr. 16, 1999; and Hogan, B. L. M. (1996)
Genes Dev. 10, 1580-1594. GDP-1 GeneSeq WO9406449 Members of the
TGF-beta The effect of GDF-1 on signaling Developmental disorders,
Accession family of proteins can be assayed by treating Primary
Induction of Cartilage, Tissue R60961 initiate cell signaling by
binding to BAECs transferred with a construct and Bone Growth, and
Diabetes heteromeric receptor complexes of type I called p3TP-Lux,
containing a TGF- (TbetaRI) and type II (TbetaRII) beta responsive
promoter fused to a serine/threonine kinase receptors (reviewed
reporter gene, and measuring by Massague, J. et al. (1994) Trends
Cell luciferase gene expression (Wrana et Biol. 4: 172 178;
Miyazono, K. et al. (1994) al., 1994, Nature 370: 341-347). Adv.
Immunol. 55: 181-220). Activation of this heteromeric receptor
complex occurs when TGF-beta binds to TbetaRII, which then recruits
and phosphorylates TbetaRI. Activated TbetaRI then propagates the
signal to downstream targets (Chen, F. and Weinberg, R. A. (1995)
PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341 347).
BMP-9 GeneSeq WO9533830 BMP-9 belongs to the transforming growth
BMP-9 activity can be determined Induction of Cartilage, Tissue
Accession factor-beta (TGFB) superfamily. Bone using the following
assays known in and Bone Growth, and Diabetes R86903 morphogenic
protein induces bone the art: Nat Genet. 2001 January; formation.
27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol
Chem, Vol. 274, Issue 16, 10897- 10902, Apr. 16, 1999; and Hogan,
B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-10 GeneSeq WO9426893
BMP-10 belongs to the transforming growth BMP-10 activity can be
determined Induction of Cartilage, Tissue Accession factor-beta
(TGFB) superfamily. Bone using the following assays known in and
Bone Growth, and Diabetes R66202 morphogenic protein induces bone
the art: Nat Genet. 2001 January; formation. 27(1): 84-8; Eur J
Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue
16, 10897- 10902, Apr. 16, 1999; and Hogan, B. L. M (1996) Genes
Dev. 10, 1580-1594. BMP-12 GeneSeq WO9516035 BMP-12 belongs to the
transforming growth BMP-12 activity can be determined Induction of
Cartilage, Tissue Accession factor-beta (TGFB) superfamily. Bone
using the following assays known in and Bone Growth, and Diabetes
R78734 morphogenic protein induces bone the art: Nat Genet. 2001
January; formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1):
295-302; J Biol Chem, Vol. 274, Issue 16, 10897- 10902, Apr. 16,
1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-15
GeneSeq W09636710 BMP-15 belongs to the transforming growth BMP-15
activity can be determined Induction of Cartilage, Tissue Accession
factor-beta (TGFB) superfamily. Bone using the following assays
known in and Bone Growth, and Diabetes W11261 morphogenic protein
induces bone the art: Nat Genet. 2001 January; formation. 27(1):
84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol.
274, Issue 16, 10897- 10902, Apr. 16, 1999; and Hogan, B. L. M.
(1996) Genes Dev. 10, 1580-1594. BMP-17 GeneSeq WO9929718 BMP-17
belongs to the transforming growth BMP-17 activity can be
determined Induction of Cartilage, Tissue Accession factor-beta
(TGFB) superfamily. Bone using the following assays known in and
Bone Growth, and Diabetes Y17870 morphogenic protein induces bone
the art: Nat Genet. 2001 January; formation. 27(1): 84-8; Eur J
Biochem 1996 Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue
16, 10897- 10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes
Dev. 10, 1580-1594. BMP-18 GeneSeq WO9929718 BMP-18 belongs to the
transforming growth BMP-18 activity can be determined Induction of
Cartilage, Tissue Accession factor-beta (TGFB) superfamily. Bone
using the following assays known in and Bone Growth, and Diabetes
Y17871 morphogenic protein induces bone the art: Nat Genet. 2001
January; formation. 27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1):
295-302; J Biol Chem, Vol. 274, Issue 16, 10897- 10902, Apr. 16,
1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Inhibin
GeneSeq WO0020591 The inhibin beta A subunit joins the alpha Tumor
suppressor activity of inhibin Tumor suppression. alpha Accession
subunit to form a pituitary FSH secretion can be determined using
assays B02806 inhibitor. Inhibin has been shown to known in the
art: Matzuk et al., regulate gonadal stromal cell proliferation
Nature 1992 Nov. 26: 360 negatively and to have tumour-suppressor
(6402); 313-9. activity. In addition, serum levels of inhibin have
been shown to reflect the size of granulosa-cell tumors and can
therefore be used as a marker for primary as well as recurrent
disease. Inhibin GeneSeq WO0020591 The inhibin beta A subunit joins
the alpha Tumor suppressor activity of inhibin Tumor suppression.
beta Accession subunit to form a pituitary FSH secretion can be
determined using assays H02808 inhibitor. Inhibin has been shown to
known in the art: Matzuk et al., regulate gonadal stromal cell
proliferation Nature 1992 Nov. 26: 360 negatively and to have
tumour-suppressor (6402); 313-9. activity. In addition, serum
levels of inhibin have been shown to reflect the size of
granulosa-cell tumors and can therefore be used as a marker for
primary as well as recurrent disease. Cerebus GeneSeq WO9849296
Cerebus is believed to be involved in the BMP activity, in the
presence of the BMP Antagonist useful for Protein Accession
inhibition of BMP activity antagonist Cerebus, can be Osteosarcoma,
abnormal bone W86032 determined using the following growth. assays
known in the art: Nat Genet. 2001 January; 27(1): 84-8; Eur J
Biochem 1996 Apr. 1; 237(1): 295- 302; J Biol Chem, Vol. 274, Issue
16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes
Dev. 10, 1580-1594. Soluble GeneSeq WO9614579 Soluble BMP receptor
kinase protein-3 is BMP activity, in the presence of the BMP
Antagonist useful for BMP Accession involved in the binding of
BMPs. Soluble soluble antagonist BMP receptor Osteosarcoma,
abnormal bone Receptor R95227 BMP receptor kinase protein-3 is
useful as kinase protein-3, can be determined growth. Kinase an
antagonist for the inhibition of BMP using the following assays
known in Protein-3 activity. the art: Nat Genet. 2001 January;
27(1): 84-8; Eur J Biochem 1996 Apr. 1; 237(1): 295-302; J Biol
Chem, Vol. 274, Issue 16, 10897- 10902, Apr. 16, 1999; and Hogan,
B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP GeneSeq WO9741250
BMPs belong to the transforming growth BMP activity, in the
presence of the Bone formation or Pro- Accession factor-beta (TGFB)
superfamily. Bone Furin, can be determined using the Regeneration
Abnormalities cessing W36099 morphogenic protein induces bone
following assays known in the art: Enzyme formation. Nat Genet.
2001 January; 27(1): 84-8; Furin Eur J Biochem 1996 Apr. 1; 237(1):
295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16,
1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. TGF-
GeneSeq WO9216228 Members of the TGF-beta The effect of TGF betas
on signaling Useful for treating cancer and beta 1 Accession family
of proteins can be assayed by treating Primary to promote wound
healing. R29657 initiate cell signaling by binding to BAECs
transfected with a construct heteromeric receptor complexes of type
I called p3TP-Lux, containing a TGF- (TbetaRI) and type II
(TbetaRII) beta responsive promoter fused to a serine/threonine
kinase receptors (reviewed reporter gene, and measuring by
Massague, J. et al. (1994) Trends Cell luciferase gene expression
(Wrana et Biol. 4: 172 178; Miyazono, K. et al. (1994) al., 1994,
Nature 370: 341-347). Adv. Immunol. 55: 181-220). Activation of
this heteromeric receptor complex occurs when TGF-beta. binds to
TbetaRII, which then recruits and phosphorylates TbetaRI. Activated
TbetaRI then propagates the signal to downstream targets (Chen, F.
and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al.
(1994) Nature 370: 341. TGF- GeneSeq EP542679 Members of the
TGF-beta The effect of TGF betas on signaling Useful for treating
cancer and beta 2 Accession family of proteins can be assayed by
treating Primary to promote wound healing. R39659 initiate cell
signaling by binding to BAECs transfected with a construct
heteromeric receptor complexes of type I called p3TP-Lux,
containing a TGF- (TbetaRI) and type II (TbetaRII) beta responsive
promoter fused to a serine/threonine kinase receptors (reviewed
reporter gene, and measuring by Massague, J. et al. (1994) Trends
Cell luciferase gene expression (Wrana et Biol. 4: 172 178;
Miyazono, K. et al. (1994) al., 1994, Nature 370: 341-347). Adv.
Immunol. 55: 181-220). Activation of this heteromeric receptor
complex occurs when TGF-beta. binds to TbetaRII, which then
recruits and phosphorylates TbetaRI. Activated TbetaRI then
propagates the signal to downstream targets (Chen, F. and Weinberg.
R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature
370: 341. ZTGF- GeneSeq WO0015798 Members of the TGF-beta The
effect of TGF betas on signaling Useful for treating cancer and
beta 9 Accession family of proteins can be assayed by treating
Primary to promote wound healing. Y70654 initiate cell signaling by
binding to BAECs transfected with a construct heteromeric receptor
complexes of type I called p3TP-Lux, containing a TGF- (TbetaRI)
and type II (TbetaRII) beta responsive promoter fused to a
serine/threonine kinase receptors (reviewed reporter gene, and
measuring by Massague, J. et al. (1994) Trends Cell luciferase gene
expression (Wrana et Biol. 4: 172 178; Miyazono, K. et al. (1994)
al., 1994, Nature 370: 341-347). Adv. Immunol. 55: 181-220).
Activation of this heteromeric receptor complex occurs when
TGF-beta. binds to TbetaRII, which then recruits and phosphorylates
TbetaRI. Activated TbetaRI then propagates the signal to downstream
targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569;
Wrana, J. L. et al. (1994) Nature 370: 341. Anti-TGF GB2305921
Members of the TGF-beta The effect of TGF betas on signaling Useful
for control of fibrosis, beta family of proteins in the presence of
an anti-TGF beta immune, and inflammatory family initiate cell
signaling by binding to antibody, can be assayed by treating
disease. anti- heteromeric receptor complexes of type I Primary
BAECs transfected with a bodies (TbetaRI) and type II (TbetaRII)
construct called p3TP-Lux, serine/threonine kinase receptors
(reviewed containing a TGF-beta responsive by Massague, J. et al.
(1994) Trends Cell promoter fused to a reporter Biol. 4: 172 178;
Miyazono, K. et al. (1994) gene, and measuring luciferase gene Adv.
Immunol. 55: 181-220). Activation of expression (Wrana et al.,
1994, this heteromeric receptor complex occurs Nature 370:
341-347). when TGF-beta. binds to TbetaRII, which then recruits and
phosphorylates TbetaRI. Activated TbetaRI then propagates the
signal to downstream targets (Chen, F. and Weinberg. R. A. (1995)
PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341.
Latent GeneSeq WO0012551 Members of the TGF-beta The effect of TGF
betas on signaling Useful for inhibiting tissue or TGF beta
Accession family of proteins in the presence of a TGF beta tumor
growth. binding Y70552 initiate cell signaling by binding to
binding protein, can be assayed by protein heteromeric receptor
complexes of type I treating Primary BAECs transfected II (TbetaRI)
and type II (TbetaRII) with a construct called p3TP-Lux,
serine/threonine kinase receptors (reviewed containing a TGF-beta
responsive by Massague, J. et al. (1994) Trends Cell promoter fused
to a reporter gene, Biol. 4: 172 178; Miyazono, K. et al. (1994)
and measuring luciferase gene Adv. Immunol 55: 181-220). Activation
of expression (Wrana et al., 1994, this heteromeric receptor
complex occurs Nature 370: 341-347). when TGF-beta. binds to
TbetaRII, which then recruits and phosphorylates TbetaRI. Activated
TbetaRI then propagates the signal to downstream targets (Chen, F.
and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al.
(1994) Nature 370: 341. MP52 GeneSeq WO9741250 Members of the
TGF-beta The effect of TGF betas on signaling Bone formation or
Accession family of proteins can be assayed by treating Primary
Regeneration Abnormalities W36100 initiate cell signaling by
binding to BAECs transfected with a construct heteromeric receptor
complexes of type I called p3TP-Lux, containing a TGF- (TbetaRI)
and type II (TbetaRII) beta responsive promoter fused to a
serine/threonine kinase receptors (reviewed reporter gene, and
measuring by Massague, J. et al. (1994) Trends Cell luciferase gene
expression (Wrana et Biol. 4: 172 178; Miyazono, K. et al. (1994)
al., 1994, Nature 370: 341-347). Adv. Immunol. 55: 181-220).
Activation of this heteromeric receptor complex occurs when
TGF-beta. binds to TbetaRII, which then recruits and phosphorylates
TbetaRI. Activated TbetaRI then propagates the signal to downstream
targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569;
Wrana, J. L. et al. (1994) Nature 370: 341. b57 GeneSeq WO9837195
BMPs are involved in the induction of bone BMP activity, in the
presence of b57 BMP Antagonist useful for Protein Accession
formation. Specific antagonists are useful is protein, can be
determined using the Osteosarcoma, abnormal bone W69293 preventing
this activity from occurring. following assays known in the art:
growth. Nat Genet. 2001 January; 27(1): 84-8; Eur J Biochem 1996
Apr. 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16,
1089-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Deve.
10, 1580-1594. Resistin GeneSeq WO0064920 This gene belongs to the
family defined by Ability of resistin to influence type Type II
diabetes and Accession mouse FIZZI and FIZZ3/Resistin genes. The II
diabetes can be determined using Syndrome X. W69293 characteristic
feature of this family is the C- assays known in the art: Pontoglio
terminal stretch of 10 cys residues with et al., J Clin Invest 1998
May 15; identical spacing. The mouse homolog of 101(10): 2215-22.
this protein is secreted by adipocytes, may be the hormone
potantially linking obesity to type II diabetes. Galectin-4 GeneSeq
WO9703190 Galectins are a family of carbohydrate- Ability of
Galectin-4 polypeptides Lactose intolerance. Accession binding
proteins characterized by an affinity to bind lactose can be
determined W11841 for beta-galactoside containing using assays
known in the art: glycoconjugates. Wada, et al., J Biol Chem 1997
Feb. 28; 272(9): 6078-86. APM-I; GeneSeq W00026363 ACPR30 gene is
exclusively expressed in Ability of ACRP30 polypeptides to Obesity,
Metabolic disorders, ACRP-30; Accession adipose tissue. ACRP30 is
thought to influence obesity and fat oxidation Lipid Metabolism;
Hormone Famoxin Y71035 increase fatty acid oxidation by muscle can
be determined using assays Secretion. tissue. known in the art:
Fruebis et al., Proc Nat'l Acad Sci USA 2001 Feb. 13; 98(4):
2005-10. ACRP-30 GeneSeq WO0063376 ACPR30 gene is exclusively
expressed in Ability of ACRP30 homologue polypeptides to Obesity,
Metabolic disorders, Homologue; Accession adipose tissue. ACRP30 is
thought to influence obesity and fat oxidation Lipid Metabolism;
Hormone Complement B30234 increase fatty acid oxidation by muscle
can be determined using assays Secretion. Component tissue. known
in the art: Fruebis et al., Clq C Proc Nat'l Acad Sci USA 2001 Feb.
13; 98(4): 2005-10. Calpain-10a GeneSeq WO0023603 Calpain is
believed to play a role in insulin Ability of Calpain-10 to
influence Diabetes mellitus; Regulation Accession secretion and
insulin activity, and therefore type II diabetes can be determined
of Insulin secretory response; Y79567 may be useful in the
treatment of type II using assays known in the art: Insulin
mediated glucose diabetes. Pontoglio et al., J Clin Invest 1998
transport disorders. May 15; 101(10): 2215-22. Calpain-10b GeneSeq
WO0023603 Calpain is believed to play a role in insulin Ability of
Calpain-10 to influence Diabetes mellitus; Regulation Accession
secretion and insulin activity, and therefore type II diabetes can
be determined of Insulin secretory response; Y79568 may be useful
in the treatment of type II using assays known in the art: Insulin
mediated glucose diabetes. Pontoglio et al., J Clin Invest 1998
transport disorders. May 15; 101(10): 2215-22. Calpain-10c GeneSeq
WO0023603 Calpain is believed to play a role in insulin Ability of
Calpain-10 to influence Diabetes mellitus; Regulation Accession
secretion and insulin activity, and therefore type II diabetes can
be determined of Insulin secretory response; Y79569 may be useful
in the treatment of type II using assays known in the art: Insulin
mediated glucose diabetes. Pontoglio et al., J Clin Invest 1998
transport disorders. May 15; 101(10): 2215-22. PDGF-D GeneSeq
WO0027879 Vascular Endothelial Growth Factor. Proliferation assay
using NR6R- Wound Healing; Atherosclermis. Accession 3T3 cells
(Rizzino 1988 Cancer Y71130 Res. 48: 4266). FasL GeneSeq WO9936079
Activities associated with apoptosis and Activity can be determined
using Apoptosis-related disorders; Accession immune system
functions. Apoptosis assays known in the art: Autoimmune disorders;
Graft Y28594 Walczak et al. (1996) EMBOJ 16: v-Host disorders.
5386-5397. Chondro GeneSeq W00029579 Chondromodulin proteins are
cartilage Ability of Chondromodulin-like Antianglogenic agent;
modulin- Accession proteins thought to confer resistance to protein
to inhibit vascularization Osteoblast proliferation like Y71262
anglogeneis, and thus are useful as anti- can be determined
using assays stimulator; prevents protein angiogenic agents that
may have utility in known in the art: Hirakie et al.,
vascularization of cartilage combating cancer. J Biol Chem 1997
Dec. 19; tissue; Useful to treat cancer. 272(51): 32419-26. Patched
GeneSeq U.S. Pat. No. Patched is a tumour-suppressor Ability of
soluble Patched to bind Receptor for Hedgehog Accession 5,837,538
receptor for Sonic hedgehog (shh), which to and inhibit the
activities of shh cellular proliferation signaling W72969 is a
protein that controls developmental can be determined using assays
molecule. This receptor is patterning and growth. known in the art:
Stone et al., useful as a means of Nature 1996 Nov. 14; preventing
cellular 384(6605): 129-34. proliferation via the shh signaling
pathway, thus useful for cancers. Patched-2 GeneSeq WO9953058
Patched is a tumour-suppressor Ability of soluble Patched to bind
Receptor for Hedgehog Accession receptor for Sonic hedgehog (shh),
which to and inhibit the activities of shh cellular proliferation
signaling Y43261 is a protein that controls developmental can be
determined using assays molecule. This receptor is patterning and
growth. known in the art: Stone et al., useful as a means of Nature
1996 Nov. 14; preventing cellular 384(6605): 129-34. proliferation
via the shh signaling pathway, thus useful for cancers. Maspin;
GeneSeq WO9405804 Maspin is a member of the serpin family of The
inhibitory effects cf Maspin Tumor suppressor which is Protease
Accession serine protease inhibitors that is thought to and other
protease inhibitors can be down-regulated in breast Inhibitor
R50938 suppress tumor metastasis. assayed using methods known in
cancers. The maspin protein 5 the art such as a labeled protease
has tumour suppressing and substrate, for example, Universal
invasion suppressing activity. Protease Substrate (casein,
resorufin-labeled): Roche Molecular Biochemicals, Cat. No. 1080733.
Endostatin GeneSeq WO0064946 Endostatin is believed to inhibit
effects of The inhibitory effects of endostatin Anti-angiogenic
activity. Accession capillary endothelial cell proliferation. can
be assayed using assays Useful in the prevention and/or B28399
disclosed by Cao et al. (1996) J. treatment of cancers. Biol. Chem.
271 29461-29467. aFGF; GeneSeq EP298723 Fibroblast Growth Factor
Proliferation assay using NR6R- Promotion of growth and FGF-1
Accession 3T3 cells (Rizzino 1988 Cancer proliferation of cells,
such as P94037 Res. 48: 4266); Examples 23 and epithelial cells and
39 disclosed herein. keratinocytes. Antagonists may be useful as
anti-cancer agents. bFGF; GeneSeq FR2642086 Fibroblast Growth
Factor Proliferation assay using NR6R- Promotion of growth and
FGF-2 Accession 3T3 cells (Rizzino 1988 Cancer proliferation of
cells, such as R06685 Res. 48: 4266); Examples 23 and epithelial
cells and 39 disclosed herein. keratinocytes. Antagonists may be
useful as anti-cancer agents. FGF-3; GeneSeq WO9503831 Fibroblast
Growth Factor Proliferation assay using NR6R- Promotion of growth
and INT-2 Accession 3T3 cells (Rizzino 1988 Cancer proliferation of
cells, such as R07824 Res. 48: 4266); Examples 23 and epithelial
cells and 39 disclosed herein. keratinocytes. Antagonists may be
useful as anti-cancer agents. FGF-4; GeneSeq WO9503831 Fibroblast
Growth Factor Proliferation assay using NR6R- Promotion of growth
and HST-1; Accession 3T3 cells (Rizzino 1988 Cancer proliferation
of cells, such as HBGF-4 R07825 Res. 48: 4266); Examples 23 and
epithelial cells and 39 disclosed herein. keratinocytes.
Antagonists may be useful as anti-cancer agents. FGF-5 GeneSeq
WO9730155 Fibroblast Growth Factor Proliferation assay using NR6R-
Promotion of growth and Accession 3T3 cells (Rizzino 1988 Cancer
proliferation of cells, such as W22600 Res. 48: 4266); Examples 23
and epithelial cells and 39 disclosed herein. keratinocytes.
Antagonists may be useful as anti-cancer agents. FGF-6; GeneSeq
EP613946 Fibroblast Growth Factor Proliferation assay using NR6R-
Promotion of growth and Heparin Accession 3T3 cells (Rizzino 1988
Cancer proliferation of cells, such as binding R58555 Res. 48:
4266); Examples 23 and epithelial cells and secreted 39 disclosed
herein. keratinocytes. Antagonists trans- may be useful as
anti-cancer forming agents. factor-2 FGF-8 GeneSeq WO9524928
Fibroblast Growth Factor Proliferation assay using NR6R- Promotion
of growth and Accession 3T3 cells (Rizzino 1988 Cancer
proliferation of cells, such as R80783 Res. 48: 4266); Examples 23
and epithelial cells and 39 disclosed herein. keratinocytes.
Antagonists may be useful as anti-cancer agents. FGF-9; GeneSeq
WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-
Promotion of growth and Gila Accession 3T3 cells (Rizzino 1988
Cancer proliferation of cells, such as activating R70822 Res. 48:
4266); Examples 23 and epithelial cells and factor 39 disclosed
herein. keratinocytes. Antagonists may be useful as anti-cancer
agents. FGF-12; GeneSeq WO9635708 Fibroblast Growth Factor
Proliferation assay using NR6R- Promotion of growth and Fibroblast
Accession 3T3 cells (Rizzino 1988 Cancer proliferation of cells,
such as growth W06309 Res. 48: 4266); Examples 23 and epithelial
cells and factor 39 disclosed herein. keratinocytes. Antagonists
homologous may be useful as anti-cancer factor-1 agents. FGF-15
GeneSeq WO9927100 Fibroblast Growth Factor Proliferation assay
using NR6R- Promotion of growth and Accession 3T3 cells (Rizzino
1988 Cancer proliferation of cells, such as Y08582 Res. 48: 4266);
Examples 23 and epithelial cells and 39 disclosed herein.
keratinocytes. Antagonists may be useful as anti-cancer agents.
FGF-16 GeneSeq WO9918128 Fibroblast Growth Factor Proliferation
assay using NR6R- Promotion of growth and Accession 3T3 cells
(Rizzino 1988 Cancer proliferation of cells, such as Y05474 Res.
48: 4266); Examples 23 and epithelial cells and 39 disclosed
herein. keratinocytes. Antagonists may be useful as anti-cancer
agents. FGF-18 GeneSeq WO9927100 Fibroblast Growth Factor
Proliferation assay using NR6R- Promotion of growth and Accession
3T3 cells (Rizzino 1988 Cancer proliferation of cells, such as
Y08590 Res. 48: 4266); Examples 23 and epithelial cells and 39
disclosed herein. keratinocytes. Antagonists may be useful as
anti-cancer agents. fit-3 GeneSeq EP627487 Stem Cell Progenitor
Chemokine activities can be Promotion of immune cell ligand
Accession determined using assays known in growth and/or
differentiation. R67541 the art: Methods in 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.
VEGF-110 GeneSeq WO0013702 Promotes the growth and/or VEGF activity
can be determined Promotion of growth and Accession proliferation
of endothelial cells. using assays known in the art, such
proliferation of cells, such as Y69417 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGB-121
GeneSeq WO0071713 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as B50432 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-138
GeneSeq WO9940197 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as Y43483 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-145
GeneSeq WO0013702 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as Y69413 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-162
GeneSeq W09940197 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as Y43484 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-165
GeneSeq WO0013702 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as Y69414 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-182
GeneSeq W09940197 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as Y43483 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-189
GeneSeq WO0013702 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as Y69415 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-206
GeneSeq W00013702 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as Y69416 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-D
GeneSeq WO9807832 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and Accession proliferation of
endothelial cells. using assays known in the art, such
proliferation of cells, such as W53240 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF-E;
GeneSeq W09947677 Promotes the growth and/or VEGF activity can be
determined Promotion of growth and VEGF-X Accession proliferation
of endothelial cells. using assays known in the art, such
proliferation of cells, such as Y33679 as those disclosed in
International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. VEGF
GeneSeq WO9831794 Receptor for VEGF polypeptides VEGF activity, in
the presence of VEGF Receptor. Fusion Receptor; Accession flk-1
polypeptides, can be protein with the extracellular KDR; W69679
determined using assays known in domain is useful as an anti- flk-1
the art, such as those disclosed in angiogenic agent.
Antagonists
International Publication No. may be useful in the promotion
WO0045835, for example. of angiogenesis. Soluble GeneSeq U.S. Pat.
No. Receptor for VEGF polypeptides VEGF activity, in the presence
of VEGF Receptor. Fusion VEGF Accession 5,712,380 VEGF Receptor
polypeptides, can protein with the extracellular Receptor W47037 be
determined using assays known in domain is useful as an anti- the
art, such as those disclosed in angiogenic agent. Antagonists
International Publication No. may be useful in the promotion
WO0045835, for example. of angiogenesis. flt-1 GeneSeq WO0021560
Receptor for VEGF polypeptides VEGF activity, in the presence of
VEGF Receptor. Fusion Accession flt-1 polypeptides, can be protein
with the extracellular Y70751 determined using assays known in
domain is useful as an anti- the art, such as those disclosed in
angiogenic agent. Antagonists International Publication No. may be
useful in the promotion WO0045835, for example. of angiogenesis.
VEGF R-3; GeneSeq WO0058511 Receptor for VEGF polypeptides VEGF
activity, in the presence of VEGF Receptor. Fusion flt-4 Accession
flt-4 polypeptides, can be protein with the extracellular B29047
determined using assays known in domain is useful as an anti- the
art, such as those disclosed in angiogenic agent. Antagonists
International Publication No. may be useful in the promotion
WO0045835, for example. of angiogenesis. Neuro- GeneSeq WO9929858
Vascular Endothelial Growth Factor VEGF activity can be determined
Promotion of growth and pilin-1 Accession using assays known in the
art, such proliferation of cells, such as Y06319 as those disclosed
in International vascular endothelial cells. Publication No.
WO0045835, for Antagonists may be useful as example.
anti-angiogenic agents, and may be applicable for cancer. Neuro-
GeneSeq WO9929858 Vascular Endothelial Growth Factor VEGF activity
can be determined Promotion of growth and pilin-2 Accession using
assays known in the art, such proliferation of cells, such as
Y03618 as those disclosed in International vascular endothelial
cells. Publication No. WO0045835, for Antagonists may be useful as
example. anti-angiogenic agents, and may be applicable for cancer.
Human GeneSeq W09730085 Troponins are contractile proteins that are
Ability of soluble Troponins to Anti-angiogenesis fast Accession
thought to inhibit angiogenesis. High levels inhibit anglogenesis
can be twitch W22597 may contribute to the difficulty encountered
determined using assays known in skeletal in revascularizing the
ischemic myocardium the art: . Proc Natl Acad Sci USA muscle after
cardiovascular injury. 1999 Mar. 16; 96(6): 2645-50. troponin C
Human GeneSeq W09730085 Troponins are contractile proteins that are
Ability of soluble Troponins to Anti-angiogenesis fast Accession
thought to inhibit angiogenesis. High levels inhibit anglogenesis
can be twitch W18054 may contribute to the difficulty encountered
determined using assays known in skeletal in revascularizing the
ischemic myocardium the art: . Proc Natl Acad Sci USA muscle after
cardiovascular injury. 1999 Mar. 16; 96(6): 2645-50. troponin I
Human fast GeneSeq W09730085 Troponins are contractile proteins
that are Ability of soluble Troponins to Anti-angiogenesis twitch
Accession thought to inhibit angiogenesis. High levels inhibit
anglogenesis can be skeletal W22599 may contribute to the
difficulty encountered determined using assays known in muscle in
revascularizing the ischemic myocardium the art: . Proc Natl Acad
Sci USA troponin T after cardiovascular injury. 1999 Mar. 16;
96(6): 2645-50. fragment. GeneSeq W09719955 Troponins are
contractile proteins that are Ability of soluble Troponins to
Anti-angiogenesis myo- Accession thought to inhibit angiogenesis.
High levels inhibit anglogenesis can be fibrillar W18053 may
contribute to the difficulty encountered determined using assays
known in protein in revascularizing the ischemic myocardium the
art: . Proc Natl Acad Sci USA troponin I after cardiovascular
injury. 1999 Mar. 16; 96(6): 2645-50. myo- GeneSeq W09719955
Troponins are contractile proteins that are Ability of soluble
Troponins to Anti-angiogenesis fibrillar Accession thought to
inhibit angiogenesis. High levels inhibit anglogenesis can be
protein W18054 may contribute to the difficulty encountered
determined using assays known in troponin I in revascularizing the
ischemic myocardium the art: . Proc Natl Acad Sci USA after
cardiovascular injury. 1999 Mar. 16; 96(6): 2645-50. Troponin
GeneSeq WO9933874 Troponins are contractile proteins that are
Ability of soluble Troponins to Anti-angiogenesis peptides
Accessions thought to inhibit angiogenesis. High levels inhibit
anglogenesis can be Y29581, may contribute to the difficulty
encountered determined using assays known in Y29582, in
revascularizing the ischemic myocardium the art: . Proc Natl Acad
Sci USA Y29583, after cardiovascular injury. 1999 Mar. 16; 96(6):
2645-50. Y29584, Y29585, and Y29586 Human fast GeneSeq WO0054770
Troponins are contractile proteins that are Ability of soluble
Troponins to Anti-angiogenesis twitch Accession thought to inhibit
angiogenesis. High levels inhibit anglogenesis can be skeletal
B00134 may contribute to the difficulty encountered determined
using assays known in muscle in revascularizing the ischemic
myocardium the art: . Proc Natl Acad Sci USA Troponin after
cardiovascular injury. 1999 Mar. 16; 96(6): 2645-50. subunit C
Human fast GeneSeq WO0054770 Troponins are contractile proteins
that are Ability of soluble Troponins to Anti-angiogenesis twitch
Accession thought to inhibit angiogenesis. High levels inhibit
anglogenesis can be skeletal B00135 may contribute to the
difficulty encountered determined using assays known in muscle in
revascularizing the ischemic myocardium the art: . Proc Natl Acad
Sci USA Troponin after cardiovascular injury. 1999 Mar. 16; 96(6):
2645-50. subunit I Protein Human fast GeneSeq WO0054770 Troponins
are contractile proteins that are Ability of soluble Troponins to
Anti-angiogenesis twitch Accession thought to inhibit angiogenesis.
High levels inhibit anglogenesis can be skeletal B00136 may
contribute to the difficulty encountered determined using assays
known in muscle in revascularizing the ischemic myocardium the art:
. Proc Natl Acad Sci USA Troponin after cardiovascular injury. 1999
Mar. 16; 96(6): 2645-50. subunit T Activator GeneSeq WO9013648 PAIs
are believed to play a role Methods that measure plasminogen
Anti-angiogenesis; blood- In- Accession in cancer, and
cardiovascular disease activator inhibitor (PAI) activity clotting
disorders. hibitor-1; R08411 and blood-clotting disorders. are
known in the art, for example, PAI-1 assay the ability of PAI to
inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J
Biochem Biophys Methods 2000 Sep. 11; 45(2): 127-40, Breast Cancer
Res Treat 1996; 41(2): 141-6. Methods that measure
anti-angiogenesis activity are known in the art, for example, Proc
Natl Acad Sci USA 1999 Mar. 16; 96(6): 2645-50. Plasmin- GeneSeq
DE3722673 PAIs are believed to play a role Methods that measure
plasminogen Anti-angiogenesis; blood- ogen Accession in cancer, and
cardiovascular disease activator inhibitor (PAI) activity clotting
disorders. Activator P94160 and blood-clotting disorders. are known
in the art, for example, In- assay the ability of PAI to inhibit
hibitor-2; tissue plasminogen activator (tPA) PAI-2 or urokinase
(uPA): J Biochem Biophys Methods 2000 Sep. 11; 45(2): 127-40,
Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure
anti-angiogenesis activity are known in the art, for example, Proc
Natl Acad Sci USA 1999 Mar. 16; 96(6): 2645-50. Activator GeneSeq
WO9102057 PAIs are believed to play a role Methods that measure
plasminogen Anti-angiogenesis; blood- In- Accession in cancer, and
cardiovascular disease activator inhibitor (PAI) activity clotting
disorders. hibitor-2; R10921 and blood-clotting disorders. are
known in the art, for example, PAI-2 assay the ability of PAI to
inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J
Biochem Biophys Methods 2000 Sep. 11; 45(2): 127-40, Breast Cancer
Res Treat 1996; 41(2): 141-6. Methods that measure
anti-angiogenesis activity are known in the art, for example, Proc
Natl Acad Sci USA 1999 Mar. 16; 96(6): 2645-50. Human GeneSeq
WO9105048 PAIs are believed to play a role Methods that measure
plasminogen Anti-angiogenesis; blood- PAI-1 Accessions in cancer,
and cardiovascular disease activator inhibitor (PAI) activity
clotting disorders. mutants R11755, and blood-clotting disorders.
are known in the art, for example, R11756, assay the ability of PAI
to inhibit R11757, tissue plasminogen activator (tPA) R11758, or
urokinase (uPA): J Biochem R11759, Biophys Methods 2000 Sep. 11;
45(2): R11760, 127-40, Breast Cancer Res R11761, Treat 1996; 41(2):
141-6. Methods R11762 that measure anti-angiogenesis and activity
are known in the art, for R11763 example, Proc Natl Acad Sci USA
1999 Mar. 16; 96(6): 2645-50. CXCR3; GeneSeq WO0018431 Chemokines
are a family of related Chemokine activities can be Soluble CXCR3
polypeptides CXC Accession small, secreted proteins determined
using assays known in may be useful for inhibiting Y79372 involved
in biological processes the art: Methods in Molecular chemokine
activities and viral ranging from hematopoiesis, Biology, 2000,
vol. 138: infection. angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ. rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Modified GeneSeq WO9737005 Chemokines are a
family of related Chemokine activities can be Immune disorders.
Rantes Accession small, secreted proteins determined using assays
known in W38129 involved in biological processes the art: Methods
in Molecular ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ. rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. RANTES GeneSeq EP905240 Chemokines are a family of
related Chemokine activities can be Immune disorders. Accession
small, secreted proteins determined using assays known in Y05299
involved in biological processes the art: Methods in Molecular
ranging from hematopoiesis, Biology, 2000, vol. 138: angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ. rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors.
Over 40 human chemokines have been described, which bind to ~17
receptors thus far identified. MCI-Ia GeneSeq WO9509232 Chemokines
are a family of related Chemokine activities can be Immune
disorders. Accession small, secreted proteins determined using
assays known in R73914 involved in biological processes the art:
Methods in Molecular ranging from hematopoiesis, Biology, 2000,
vol. 138: angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ. rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. MCP-Ib GeneSeq WO9929728 Chemokines are a
family of related Chemokine activities can be Immune disorders.
Accession small, secreted proteins determined using assays known in
Y26176 involved in biological processes the art: Methods in
Molecular ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ. rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. MCP-I GeneSeq WO9519436 Chemokines are a family of
related Chemokine activities can be Soluble MCP-1 Receptor receptor
Accession small, secreted proteins determined using assays known in
polypeptides may be useful for R79165 involved in biological
processes the art: Methods in Molecular inhibiting chemokine
activities ranging from hematopoiesis, Biology, 2000, vol. 138: and
viral infection. angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ. rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. MCP-3 GeneSeq W09509232 Chemokines are a
family of related Chemokine activities can be Immune disorders.
Accession small, secreted proteins determined using assays known in
R73915 involved in biological processes the art: Methods in
Molecular ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ. rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. MCP-4 GeneSeq W09809171 Chemokines are a family of
related Chemokine activities can be Soluble MCP-4 Receptor receptor
Accession small, secreted proteins determined using assays known in
polypeptides may be useful for W56689 involved in biological
processes the art: Methods in Molecular inhibiting chemokine
activities ranging from hematopoiesis, Biology, 2000, vol. 138: and
viral infection. angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ. rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. RANTES GeneSeq U.S. Pat. No. Chemokines are a
family of related Chemokine activities can be Soluble RANTES
Receptor receptor Accession 5,652,133 small, secreted proteins
determined using assays known in polypeptides may be useful for
W29588 involved in biological processes the art: Methods in
Molecular inhibiting chemokine activities ranging from
hematopoiesis, Biology, 2000, vol. 138: and viral infection.
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ. rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. CCR5 GeneSeq WO9854317 Chemokines are a family of
related Chemokine activities can be Soluble CCR5 polypeptides
variant Accession small, secreted proteins determined using assays
known in may be useful for inhibiting W88238 involved in biological
processes the art: Methods in Molecular chemokine activities and
viral ranging from hematopoiesis, Biology, 2000, vol. 138:
infection. angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ. rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. CCR7 GeneSeq U.S. Pat. No. Chemokines are a
family of related Chemokine activities can be Soluble CCR7
polypeptides Accession 6,153,441 small, secreted proteins
determined using assays known in may be useful for inhibiting
B50859 involved in biological processes the art: Methods in
Molecular chemokine activities and viral ranging from
hematopoiesis, Biology, 2000, vol. 138: infection. angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ. rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. CXC3
GeneSeq WO9727299 Chemokines are a family of related Chemokine
activities can be Immune disorders. Accession small, secreted
proteins determined using assays known in W23345 involved in
biological processes the art: Methods in Molecular ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ.
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Eotaxin
GeneSeq WO9700960 Chemokines are a family of related Chemokine
activities can be Immune disorders. Accession small, secreted
proteins determined using assays known in W10099 involved in
biological processes the art: Methods in Molecular ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ.
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Neuro-
GeneSeq U.S. Pat. No. Neurotactin may play a role in chemotactic
Chemotactic leukocyte migration Immune disorders. tactin Accessions
6,013,257 leukocyte migration and brain inflammation assays are
known in the art, for Y77537, WO9742224 processes. example: J.
Immunol. Methods 33, W34307, ((1980)); Nature 1997 Jun. 5; Y53259,
387(6633): 611-7. and, Y77539 Human GeneSeq U.S. Pat. No.
Chemokines are a family of related chemokine activities can be
Immune disorders. CKbeta-9 Accession 6,153,441 small, secreted
proteins determined using assays known in B50860 involved in
biological processes the art: Methods in Molecular ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ.
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Lympho-
GeneSeq WO0073320 Chemokines are a family of related chemokine
activities can be Immune disorders. tactin Accession small,
secreted proteins involved in determined using assays known in
B50052 biological processes ranging from the art: Methods in
Molecular hematopoiesis, angiogenesis, and Biology, 2000, vol. 138:
leukocyte trafficking. Chemokine Protocols. Edited by: Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ.
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane G. MIP-3
GeneSeq WO9801557 Chemokines are a family of related chemokine
activities can be Immune disorders. alpha Accession small, secreted
proteins involved in determined using assays known in W44398
biological processes ranging from the art: Methods in Molecular
hematopoiesis, angiogenesis, and Biology, 2000, vol. 138: leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ.
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting
on a family of seven transmembrane G. MIP-3 GeneSeq WO9801557
Chemokines are a family of related Chemokine activities can be
Immune disorders. beta Accession small, secreted proteins involved
in determined using assays known in W44399 biological processes
ranging from the art: Methods in Molecular hematopoiesis,
angiogenesis, and Biology, 2000, vol. 138: leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ. rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G. MIP-Gamma GeneSeq WO9504158
Chemokines are a family of related Chemokine activities can be
Immune disorders. Accession small, secreted proteins involved in
determined using assays known in R70798 biological processes
ranging from the art: Methods in Molecular hematopoiesis,
angiogenesis, and Biology, 2000, vol. 138: leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ. rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G. Stem Cell GeneSeq WO9104274
Chemokines are a family of related Chemokine activities can be
Hematopoietic growth factors. Inhib- Accession small, secreted
proteins involved in determined using assays known in itory R11553
biological processes ranging from the art: Methods in Molecular
Factor hematopoiesis, angiogenesis, and Biology, 2000, vol. 138:
leukocyte trafficking. Chemokine Protocols. Edited by: Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ.
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane G.
thrombo- GeneSeq WO9521920 Thrombopoietin is involved in the
Thrombopoietin (TPO) can be Hematopoietic growth factors. poietin
Accession regulation of the growth and assayed to determine
regulation of R79905 differentiation of growth and differentiation
of megakaryocytes and preceptors thereof. megakaryocytes. Mol Cell
Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1):
51-8 and within. c-kit GeneSeq EP992579 and C-kit ligan is thought
to stimulate the Chemokine activities can be Hematopoietic growth
factors. ligand; Accession EP676470 proliferation of mast cells,
and is able to determined using assays known in SCF; Mast Y53284,
augment the proliferation of both myeloid the art: Methods in
Molecular cell R83978 and lymphoid hematopoietic progenitors in
Biology, 2000, vol. 138: growth and bone marrow culture. C-kit
ligand is also Chemokine Protocols. Edited by: factor; R83977
though to act synergistically with other A. E. I. Proudfoot, T. N.
C. Wells, MGF; cytokines. and C. A. Power. Humana Press Fibro-
Inc., Totowa, NJ. sarcoma- derived stem cell factor Platelet
GeneSeq WO0066736 Vascular Endothelial Growth Factor VEGF activity
can be determined Promotion of growth and derived Accession using
assays known in the art, such proliferation of cells, such as
growth B48653 as those disclosed in International vascular
endothelial cells. factor Publication No. WO0045835, for
Antagonists may be useful as example. anti-angiogenic agents, and
may be applicable for cancer. Melanoma GeneSeq WO9503328 Melanoma
inhibiting protein has melanoma- Tumor suppressor activity of
Cancer; melanoma inhibiting Accession inhibiting activity and can
be used to treat melanoma inhibiting protein can be protein R69811
cancer (melanoma, glioblastoma, determined using assays known in
neuroblastoma, small cell lung cancer, the art: Matzuk et al.,
Nature 1992 neuroectodermal tumors) or as an Nov. 26; 360(6402):
313-9. immunosuppressant (it inhibits IL-2 or phytohaemagglutinin
induced proliferation of peripheral blood lymphocytes. Glioma-
GeneSeq EP399816 Vascular Endothelial Growth Factor VEGF activity
can be determined Promotion of growth and derived Accession using
assays known in the art, such proliferation of cells, such as
growth R08120 as those disclosed in International vascular
endothelial cells. factor Publication No. WO0045835, for
Antagonists may be useful as example. anti-angiogenic agents, and
may be applicable for cancer. Platelet GeneSeq EP682110 Vascular
Endothelial Growth Factor VEGF activity can be determined Promotion
of growth and derived Accession using assays known in the art, such
proliferation of cells, such as growth R84759 as those disclosed in
International vascular endothelial cells. factor Publication No.
WO0045835, for Antagonists may be useful as pre- example.
anti-angiogenic agents, and cursor A may be applicable for cancer.
Platelet GeneSeq EP682110 Vascular Endothelial Growth Factor VEGF
activity can be determined Promotion of growth and derived
Accession using assays known in the art, such proliferation of
cells, such as growth R84760 as those disclosed in International
vascular endothelial cells. factor Publication No. WO0045835, for
Antagonists may be useful as pre- example. anti-angiogenic agents,
and cursor B may be applicable for cancer. Platelet GeneSeq
EP282317 Vascular Endothelial Growth Factor VEGF activity can be
determined Promotion of growth and derived Accession using assays
known in the art, such proliferation of cells, such as growth
P80595 as those disclosed in International vascular endothelial
cells. factor and Publication No. WO0045835, for Antagonists may be
useful as Bv-sis P80596 example. anti-angiogenic agents, and may be
applicable for cancer. Placental GeneSeq WO9206194 Vascular
Endothelial Growth Factor VEGF activity can be determined Promotion
of growth and Growth Accessions using assays known in the art, such
proliferation of cells, such as Factor R23059 as those disclosed in
International vascular endothelial cells. and Publication No.
WO0045835, for Antagonists may be useful as R23060 example.
anti-angiogenic agents, and may be applicable for cancer. Placental
GeneSeq DE19748734 Vascular Endothelial Growth Factor VEGF activity
can be determined Promotion of growth and Growth Accession using
assays known in the art, such proliferation of cells, such as
Factor-2 Y08289 as those disclosed in International vascular
endothelial cells. Publication No. WO0045835, for Antagonists may
be useful as example. anti-angiogenic agents, and may be applicable
for cancer. Thrombo- GeneSeq WO0000612 Thrombopoietin is involved
in the Thrombopoietin (TPO) can be Thrombocytopenia, cancer.
poietin Accession regulation of the growth and assayed to determine
regulation of deriv- Y77244 differentiation of growth and
differentiation of ative1 megakaryocytes and preceptors thereof.
megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp
Hematol 2001 January; 29(1): 51-8 and within. Thrombo- GeneSeq
WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO)
can be Thrombocytopenia, cancer. poietin Accession regulation of
the growth and assayed to determine regulation of deriv- Y77255
differentiation of growth and differentiation of ative2
megakaryocytes and preceptors thereof. megakaryocytes. Mol Cell
Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1):
51-8 and within. Thrombo- GeneSeq WO0000612 Thrombopoietin is
involved in the Thrombopoietin (TPO) can be Thrombocytopenia,
cancer. poietin Accession regulation of the growth and assayed to
determine regulation of deriv- Y77262 differentiation of growth and
differentiation of ative3 megakaryocytes and preceptors thereof.
megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp
Hematol 2001 January; 29(1): 51-8 and within. Thrombo- GeneSeq
WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO)
can be Thrombocytopenia, cancer. poietin Accession regulation of
the growth and assayed to determine regulation of deriv- Y77267
differentiation of growth and differentiation of ative4
megakaryocytes and preceptors thereof. megakaryocytes. Mol Cell
Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1):
51-8 and within. Thrombo- GeneSeq WO0000612 Thrombopoietin is
involved in the Thrombopoietin (TPO) can be Thrombocytopenia,
cancer. poietin Accession regulation of the growth and assayed to
determine regulation of deriv- Y77246 differentiation of growth and
differentiation of ative5 megakaryocytes and preceptors thereof.
megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp
Hematol 2001 January; 29(1): 51-8 and within. Thrombo- GeneSeq
WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO)
can be Thrombocytopenia, cancer. poietin Accession regulation of
the growth and assayed to determine regulation of deriv- Y77253
differentiation of growth and differentiation of ative6
megakaryocytes and preceptors thereof. megakaryocytes. Mol Cell
Biol 2001 April; 21(8): 2659-70; Exp Hematol 2001 January; 29(1):
51-8 and within. Thrombo- GeneSeq WO0000612 Thrombopoietin is
involved in the Thrombopoietin (TPO) can be Thrombocytopenia,
cancer. poietin Accession regulation of the growth and assayed to
determine regulation of deriv- Y77256 differentiation of growth and
differentiation of ative7 megakaryocytes and preceptors thereof.
megakaryocytes. Mol Cell Biol 2001 April; 21(8): 2659-70; Exp
Hematol 2001 January; 29(1): 51-8 and within. Fract- GeneSeq U.S.
Pat. No. Fractalkine is believed to play a role in Fractalkine
activity can be Immune disorders. alkine Accession 6,043,086
chemotactic leukocyte migration and determined using Chemotactic
Y53255 neurological disorders. leukocyte migration assays known in
the art, for example: J. Immunol. Methods 33, ((1980)); Nature 1997
Jun. 5; 387(6633): 611-7. CXC3 GeneSeq WO9757599 Chemokines are a
family of related Chemokine activities can be Immune disorders.
Accession small, secreted proteins determined using assays known in
W23345 involved in biological processes the art: Methods in
Molecular ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ. rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. CCR7 GeneSeq U.S. Pat. No. Chemokines are a family
of related Chemokine activities can be Soluble CCR7 polypeptides
Accession 6,153,441 small, secreted proteins determined using
assays known in may be useful for inhibiting B50859 involved in
biological processes the art: Methods in Molecular chemokine
activities and viral ranging from hematopoiesis, Biology, 2000,
vol. 138: infection. angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by:
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ. rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Nerve
GeneSeq EP414151 Nerve Growth Factor Proliferation assay using
NR6R- Neurological disorders, cancer Growth Accession 3T3 cells
(Rizzino 1988 Cancer Factor- R11474 Res. 48: 4266) beta Nerve
GeneSeq EP859056 Nerve Growth Factor Proliferation assay using NR6R
Neurological disorders, cancer Growth Accession 3T3 cells (Rizzino
1988 Cancer Factor- W69725 Res. 48: 4266 beta2 Neuro- GeneSeq
WO9821234 Neurotrophins regulate neuronal Trk tyrosine kinase
activation assays Neurological disorders, cancer trophin-3
Accession cell survival and synaptic known in the art can be used
to W8889 plasticity. assay for neurotrophin activity, for example,
Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. Neuro-
GeneSeq WO9325684 Neurotrophins regulate neuronal Trk tyrosine
kinase activation assays Neurological disorders, cancer trophin-3
Accession cell survival and synaptic known in the art can be used
to R47100 plasticity. assay for neurotrophin activity, for example,
Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. Neuro-
GeneSeq WO9325684 Neurotrophins regulate neuronal Trk tyrosine
kinase activation assays Neurological disorders, cancer trophin-4a
Accession cell survival and synaptic known in the art can be used
to R47101 plasticity. assay for neurotrophin activity, for example,
Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. 13; 98(6):
3555-3560 Neuro- GeneSeq WO9325684 Neurotrophins regulate neuronal
Trk tyrosine kinase activation assays Neurological disorders,
cancer trophin-4b Accession cell survival and synaptic known in the
art can be used to R47102 plasticity. tyrosine kinases. assay for
neurotrophin activity, for example, Proc Natl Acad Sci USA 2001
Mar. 13; 98(6): 3555-3560. Neuro- GeneSeq WO9325684 Neurotrophins
regulate neuronal Trk tyrosine kinase activation assays
Neurological disorders, cancer trophin-4c Accession cell survival
and synaptic known in the art can be used to R47103 plasticity.
tyrosine kinases. assay for neurotrophin activity, for example,
Proc Natl Acad Sci USA 2001 Mar. 13; 98(6): 3555-3560. Neuro-
GeneSeq WO9325684 Neurotrophins regulate neuronal Trk tyrosine
kinase activation assays Neurological disorders, cancer trophin-4d
Accession cell survival and synaptic known in the art can be used
to R47102 plasticity. tyrosine kinases. assay for neurotrophin
activity, for example, Proc Natl Acad Sci USA 2001 Mar. 13; 98(6):
3555-3560. Platelet- GeneSeq U.S. Pat. No. Vascular Endothelial
Growth Factor VEGF activity can be determined Promotion of growth
and Derived Accession 5,219,739 using assays known in the art, such
proliferation of cells, such as Growth R38918 as those disclosed in
International vascular endothelial cells. Factor Publication No.
W00045835, for Hematopoietic and immune A chain example. disorders.
Antagonists may be useful as anti-angiogenic agents, and may be
applicable for cancer Platelet- GeneSeq U.S. Pat. No. Vascular
Endothelial Growth Factor VEGF activity can be determined Promotion
of growth and Derived Accession 5,219,739 using assays known in the
art, such proliferation of cells, such as Growth R38919 as those
disclosed in International vascular endothelial cells. Factor
Publication No. W00045835, for Hematopoietic and immune B chain
example. disorders. Antagonists may be useful as anti-angiogenic
agents, and may be applicable for cancer Stromal GeneSeq WO9948528
Stromal Growth Factor Proliferation assay using NR6R-
Hematopoietic, immune Derived Accession 3T3 cells (Rizzino 1988
Cancer disorders, cancer Factor-1 Y39995 Res. 48: 4266) alpha
Stromal GeneSeq CA2117953 Stromal Growth Factor Proliferation assay
using NR6R- Hematopoietic, immune Derived Accession 3T3 cells
(Rizzino 1988 Cancer disorders, cancer Factor-1 R75420 Res. 48:
4266) beta Tarc GeneSeq WO9711969 Chemotactic for T lymphocytes.
May Chemotactic leukocyte migration Antiinflammatory. Immune
Accession play a role in T-cell development. assays are known in
the art, for disorders, cancer W14917 Thought to bind CCR8 and CCR4
example: J. Immunol. Methods 33 ((1980)) Pro- GeneSeq WO9521625
Prolactin is involved in immune cell Immune coil proliferation and
Reproductive system lactin Accession proliferation and apoptosis.
suppression of apoptosis by disorders, cancer. R78691 prolactin can
be assayed by methods well-known in the art, for example, Buckley,
A R and Buckley D J, Ann N Y Acad Sci 2000; 917: 522-33, and
within. Pro- GeneSeq U.S. Pat. No. Prolactin is involved in immune
cell Immune coil proliferation and Reproductive system lactin2
Accession 5,955,346 proliferation and apoptosis. suppression of
apoptosis by disorders, cancer. Y31764 prolactin can be assayed by
methods well-known in the art, for example, Buckley, A R and
Buckley D J, Ann NY Acad Sci 2000; 917: 522-33, and within.
Follicle GeneSeq EP974359 FSH stimulates secretion of interleukin-1
by FSH activities can be determined Reproductive system stimu-
Accession cells isolated from women in the follicular using assays
known in the art; J disorders, cancer. lating Y54160 phase Gend
Specif Med 1999 November- hormone December; 2(6): 30-4; Mol Cell
Alpha Endocrinol. 1997 Nov. 15; subunit 134(2): 109-18. Follicle
GeneSeq EP974359 FSH stimulates secretion of interleukin-1 by FSH
activities can be determined Reproductive system stimu- Accession
cells isolated from women in the follicular using assays known in
the art; J disorders, cancer. lating Y54161 phase Gend Specif Med
1999 November- hormone December; 2(6): 30-4; Mol Cell Beta
Endocrinol. 1997 Nov. 15; subunit 134(2): 109-18. Sub- GeneSeq
WO0054053 Substance P is associated with Immuneregulation and bone
diabetes mellitus, stance P Accession immunoregulation. marrow,
cell proliferation by hypertension, cancer (tachy- B23027 substance
P can be assayed by kinin) methods well-known in the art, for
example, Lai et al. Proc Natl Acad Sci USA 2001 Mar. 27; 98(7):
3970- 5; Jallat-Daloz et al. Allergy Asthma Proc 2001
January-February; 22(1): 17-23; Kahler et al. Exp Lung Res 2001
January-February; 27(1): 25-46; and Adamus M A and Dabrowski Z J. J
Cell Biochem 2001; 81(3)499-506. Ocytocin GeneSeq WO0053755
Oxytocin is involved in the induction of Oxytocin and prostaglandin
E(2) inflammatory disorders (Neuro- Accession prostaglandin (E2)
release as well as an release and Ocytocin (Ca2+) immunologic
disorders, physin I) B24085 increased amount of calcium release by
increase can be assayed by methods cancer and smooth muscle cells.
well-known in the art, for example, B24086 Pavan et al., AM J Obset
Gynecol 2000 July; 183(1): 76-82 and Holda et al., Cell Calcium
1996 July; 20(1): 43 51. Vaso- GeneSeq WO0053755 Vasopressinis
believed to have a direct Vasopressin activity can be inflammatory
disorders pressin Accession antidiuretic action on the kidney, and
it is determined using assays known in immunologic disorders,
(Neuro- B24085 thought to cause vasoconstriction of the the art,
for example, Endocr Regul cancer physin and peripheral vessels.
1996 March; 30(1): 13-17. II) B24086 IL-1 GeneSeq EP165654
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, Accession cytokines synthesized by
lymphocytes, determined using assays known in immunologic
disorders, P60326 monocytes, and macrophages. Known the art:
Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Orencole & of neutrophils and
T lymphocytes, Dinarclio (1989) Cytokine 1, 14-20. and/or
inhibition of interferons. IL-1 GeneSeq EP456332 Interleukins are a
group of multifunctional Interleukin activity can be inflammatory
disorders, mature Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, R14855
monocytes, and macrophages. Known the art: Matthews et al., in
cancer functions include stimulating Lymphokines and Interferens: A
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Orencole & of neutrophils and T lymphocytes, Dinarclio
(1989) Cytokine 1, 14-20. and/or inhibition of interferons. IL-1
GeneSeq WO9922763 Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, beta Accession
cytokines synthesized by lymphocytes, determined using assays known
in immunologic disorders, Y08322 monocytes, and macrophages. Known
the art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Orencole & of neutrophils and
T lymphocytes, Dinarclio (1989) Cytokine 1, 14-20. and/or
inhibition of interferons. IL-3 GeneSeq WO8806161 Interleukins are
a group of multifunctional Interleukin activity can be inflammatory
disorders, variants Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, P80382,
monocytes, and macrophages. Known the art: Matthews et al., in
cancer P80383, functions include stimulating Lymphokines and
Interferens: A P80384, proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., and T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. P80381 and
lymphocytes), chemotaxis 1987, pp. 221-225; and Kitamura of
neutrophils and T lymphocytes, et al (1989) J Cell Physiol. and/or
inhibition of interferons. 140 323-334. IL-4 GeneSeq WO8702990
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, Accession cytokines synthesized by
lymphocytes, determined using assays known in immunologic
disorders, P70615 monocytes, and macrophages. Known the art:
Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Siegel & of neutrophils and T
lymphocytes, Mostowski (1990) J Immunol and/or inhibition of
interferons. Methods 132, 287-295. IL-4 GeneSeq WO9747744
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, muteins Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, W52151 monocytes, and macrophages. Known the
art: Matthews et al., in cancer W52152 functions include
stimulating Lymphokines and Interferens: A W52153 proliferation of
immune cells (e.g., Practical Approach, Clemens et al., W52154 T
helper cells, B cells, eosinophils, eds, IRL Press, Washington,
D.C. W52155 and lymphocytes), chemotaxis 1987, pp. 221-225; and
Siegel & W52156 of neutrophils and T lymphocytes, Mostowski
(1990) J Immunol
W52157 and/or inhibition of interferons. Methods 132, 287-295.
W52158 W52159 W52160 W52161 W52162 W52163 W52164 and W52165 IL-1
GeneSeq EP324447 Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, alpha Accession
cytokines synthesized by lymphocytes, determined using assays known
in immunologic disorders, P90108 monocytes, and macrophages. Known
the art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Orencole & of neutrophils and
T lymphocytes, Dinarello (1989) Cytokine 1, 14-20. and/or
inhibition of interferons. IL-3 GeneSeq WO9307171 Interleukins are
a group of multifunctional Interleukin activity can be inflammatory
disorders, variants Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, R38561,
monocytes, and macrophages. Known the art: Matthews et al., in
cancer R38562, functions include stimulating Lymphokines and
Interferens: A R38563, proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., R38564, T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. R38565, and
lymphocytes), chemotaxis 1987, pp. 221-225; and Aarden R38566, of
neutrophils and T lymphocytes, et al (1987) Eur. J. Immunol 17,
R38567, and/or inhibition of interferons. 1411-16. R38568, R38569,
R38570, R38571, and R38572 IL-6 GeneSeq WO9402512 Interleukins are
a group of multifunctional Interleukin activity can be inflammatory
disorders, Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, R45717
monocytes, and macrophages. Known the art: Matthews et al., in
cancer and functions include stimulating Lymphokines and
Interferens: A R45718 proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Aarden of neutrophils and T
lymphocytes, et al (1987) Eur. J. Immunol 17, and/or inhibition of
interferons. 1411-16. IL-13 GeneSeq WO9404680 Interleukins are a
group of multifunctional Interleukin activity can be inflammatory
disorders, Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, R48624
monocytes, and macrophages. Known the art: Matthews et al., in
cancer functions include stimulating Lymphokines and Interferens: A
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Boutelier of neutrophils and T lymphocytes, et al (1995) J.
Immunol. Methods and/or inhibition of interferons. 181, 29. IL-4
GeneSeq DE4137333 Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, mutein
Accession cytokines synthesized by lymphocytes, determined using
assays known in immunologic disorders, R47182 monocytes, and
macrophages. Known the art: Matthews et al., in cancer functions
include stimulating Lymphokines and Interferens: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Siegel & of
neutrophils and T lymphocytes, Mostowski (1990) J Immunol and/or
inhibition of interferons. Methods 132, 287-295. IL-4 GeneSeq
DE4137333 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, mutein Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, Y124X R47183 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Siegel & of
neutrophils and T lymphocytes, Mostowski (1990) J Immunol and/or
inhibition of interferons. Methods 132, 287-295. IL-4 GeneSeq
DE4137333 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, mutein Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, Y124G R47184 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Siegel & of
neutrophils and T lymphocytes, Mostowski (1990) J Immunol and/or
inhibition of interferons. Methods 132, 287-295. Human GeneSeq
WO9317698 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, Inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-10 R41664 monocytes, and macrophages.
Known the art: Matthews et al., in cancer (precursor) functions
include stimulating Lymphokines and Interferens: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Thompson- of
neutrophils and T lymphocytes, Snipes et al (1991) J. Exp. Med.
and/or inhibition of interferons. 173, 507-510. Human GeneSeq
WO9318783-A Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, Inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-10 R42642 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Thompson- of
neutrophils and T lymphocytes, Snipes et al (1991) J. Exp. Med.
and/or inhibition of interferons. 173, 507-510. Human GeneSeq
EP569042 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-1 R42447 monocytes, and macrophages.
Known the art: Matthews et al., in cancer beta functions include
stimulating Lymphokines and Interferens: A precursor. proliferation
of immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Orencole & of
neutrophils and T lymphocytes, Dinarello (1989) Cytokine 1, 14-20.
and/or inhibition of interferons. Inter- GeneSeq EP578278
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, leukin- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, 1alpha R45364 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225. of neutrophils and T
lymphocytes, and/or inhibition of interferons. Human GeneSeq
JP04063595 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-3 R22814 monocytes, and macrophages.
Known the art: Matthews et al., in cancer variant functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Kitamura of
neutrophils and T lymphocytes, et al (1989) J Cell Physiol. 140
and/or inhibition of interferons. 323-334. IL-1i GeneSeq EP541920
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, fragments Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, R35484 monocytes, and macrophages. Known the
art: Matthews et al., in cancer and functions include stimulating
Lymphokines and Interferens: A R35485 proliferation of immune cells
(e.g., Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and of neutrophils and T lymphocytes,
Orencole & Dinarclio (1989) and/or inhibition of interferons.
Cytokine 1, 14-20. IL-1 GeneSeq EPS541920 Interleukins are a group
of multifunctional Interleukin activity can be inflammatory
disorders, inhibitor Accession cytokines synthesized by
lymphocytes, determined using assays known in immunologic
disorders, (IL-Ii) R35486 monocytes, and macrophages. Known the
art: Matthews et al., in cancer and functions include stimulating
Lymphokines and Interferens: A R35484 proliferation of immune cells
(e.g., Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and of neutrophils and T lymphocytes,
Orencole & Dinarelio (1989) and/or inhibition of interferons.
Cytokine 1, 14-20. ICE 22 kD GeneSeq EP533350 Interleukins are a
group of multifunctional Interleukin activity can be inflammatory
disorders, subunit. Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, R33780
monocytes, and macrophages. Known the art: Matthews et al., in
cancer functions include stimulating Lymphokines and Interferens: A
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225. of
neutrophils and T lymphocytes, and/or inhibition of interferons.
ICE 20 kD GeneSeq EP533350 Interleukins are a group of
multifunctional Interleukin activity can be inflammatory disorders,
subunit. Accession cytokines synthesized by lymphocytes, determined
using assays known in immunologic disorders, R33781 monocytes, and
macrophages. Known the art: Matthews et al., in cancer functions
include stimulating Lymphokines and Interferens: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225. of neutrophils and T
lymphocytes, and/or inhibition of interferons. ICE 10 kD GeneSeq
EP533350 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, subunit Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, R33782 monocytes, and macrophages. Known the
art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225. of neutrophils and T lymphocytes,
and/or inhibition of interferons. Human GeneSeq WO9317698
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, Inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-10 R41664 monocytes, and macrophages.
Known the art: Matthews et al., in cancer (precursor) functions
include stimulating Lymphokines and Interferens: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C.
and lymphocytes), chemotaxis 1987, pp. 221-225; and Thompson- of
neutrophils and T lymphocytes, Snipes et al (1991) J. Exp. Med.
and/or inhibition of interferons. 173, 507-510. Human GeneSeq
WO9318783 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, Inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-10 R42642 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Thompson- of
neutrophils and T lymphocytes, Snipes et al (1991) J. Exp. Med.
and/or inhibition of interferons. 173, 507-510. Human GeneSeq
EP569042 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, Inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-1 R42447 monocytes, and macrophages.
Known the art: Matthews et al., in cancer beta functions include
stimulating Lymphokines and Interferens: A precursor proliferation
of immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Kitamura of
neutrophils and T lymphocytes, et al (1989) J Cell Physiol. 140
and/or inhibition of interferons. 323-334. Human GeneSeq WO9403492
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-6 R49041 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Aarden et al of
neutrophils and T lymphocytes, (1987) Eur. J. Immunol 17, 1411-16.
and/or inhibition of interferons. Mutant GeneSeq WO9411402
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, Inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin 6 R54990 monocytes, and macrophages.
Known the art: Matthews et al., in cancer S176R functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Aarden et al of
neutrophils and T lymphocytes, (1987) Eur. J. Immunol 17, 1411-16.
and/or inhibition of interferons. Inter- GeneSeq JP06145063
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, leukin 6 Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, R55256 monocytes, and macrophages. Known the
art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Aarden et al of neutrophils and T
lymphocytes, (1987) Eur. J. Immunol 17, 1411-16. and/or inhibition
of interferons. Inter- GeneSeq JP06100595 Interleukins are a group
of multifunctional Interleukin activity can be Soluble IL-8 leukin
8 Accession cytokines synthesized by lymphocytes, determined using
assays known in receptor polypeptides (IL-8) R53932 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting receptor functions include stimulating Lymphokines and
Interferens: A interleukin activities. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Holmes et al of
neutrophils and T lymphocytes, (1991) Science 253, 1278-80. and/or
inhibition of interferons. Human GeneSeq U.S. Pat. No. Interleukins
are a group of multifunctional Interleukin activity can be
inflammatory disorders, inter- Accession 5,328,988 cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-7 R59919 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Park et al of
neutrophils and T lymphocytes, (1990) J. Exp. Med. 171, 1073-79.
and/or inhibition of interferons. IL-3 GeneSeq WO9521254
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, containing Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, fusion R79342 monocytes, and macrophages.
Known the art: Matthews et al., in cancer protein. and functions
include stimulating Lymphokines and Interferens: A R79344
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Kitamura of neutrophils and T lymphocytes, et al (1989) J Cell
Physiol. 140 323- and/or inhibition of interferons. 334. IL-3
GeneSeq ZA9402636 Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, mutant
Accession cytokines synthesized by lymphocytes, determined using
assays known in immunologic disorders, proteins R79254, monocytes,
and macrophages. Known the art: Matthews et al., in cancer R79255,
functions include stimulating Lymphokines and Interferens: A
R79256, proliferation of immune cells (e.g., Practical Approach,
Clemens et al., R79257, T helper cells, B cells, eosinophils, eds,
IRL Press, Washington, D.C. R79258, and lymphocytes), chemotaxis
1987, pp. 221-225; and Giri et al R79259, of neutrophils and T
lymphocytes, (1994) EMBO J. 13 2822-2830. R79260, and/or inhibition
of interferons. R79261, R79262, R79263, R79264, R79265, R79266,
R79267, R79268, R79269, R79270, R79271, R79272, R79273, R79274,
R79275, R79276, R79277, R79278, R79279, R79280, R79281, R79282,
R79283, R79284, and R79285 IL-12 p40 GeneSeq AU9466072 Interleukins
are a group of multifunctional Interleukin activity can be
inflammatory disorders, subunit. Accession cytokines synthesized by
lymphocytes, determined using assays known in immunologic
disorders, R63018 monocytes, and macrophages. Known the art:
Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225. of neutrophils and T lymphocytes,
and/or inhibition of interferons. AGF GeneSeq WO9429344
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, Accession cytokines synthesized by
lymphocytes, determined using assays known in immunologic
disorders, R64240 monocytes, and macrophages. Known the art:
Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225. of neutrophils and T lymphocytes,
and/or inhibition of interferons. Human GeneSeq WO9519786
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, laukin-12 R79187 monocytes, and macrophages.
Known the art: Matthews et al., in cancer 40 kD functions include
stimulating Lymphokines and Interferens: A subunit proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Hori et al of
neutrophils and T lymphocytes, (1987), Blood 70, 1069-1078. and/or
inhibition of interferons. Human GeneSeq WO9530695 Interleukins are
a group of multifunctional Interleukin activity can be Soluble IL-8
inter- Accession cytokines synthesized by lymphocytes, determined
using assays known in receptor polypeptides leukin-15 R90843
monocytes, and macrophages. Known the art: Matthews et al., in may
be useful for inhibiting receptor functions include stimulating
Lymphokines and Interferens: A interleukin activities. from
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., clone P1 T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Giri et al of neutrophils and T lymphocytes, (1994) EMBO J. 13
2822-2830. and/or inhibition of interferons. Human GeneSeq
WO9604306 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-7 R92796 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Park et al of
neutrophils and T lymphocytes, (1990) J. Exp. Med. 171, 1073-79.
and/or inhibition of interferons. inter- GeneSeq WO9604306
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, leukin-9 Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, R92797 monocytes, and macrophages. Known the
art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferens: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Yang et al of neutrophils and T
lymphocytes, (1989) Blood 74, 1880-84. and/or inhibition of
interferons. inter- GeneSeq WO9604306 Interleukins are a group of
multifunctional Interleukin activity can be inflammatory disorders,
leukin-3 Accession cytokines synthesized by lymphocytes, determined
using assays known in immunologic disorders, R92801 monocytes, and
macrophages. Known the art: Matthews et al., in cancer functions
include stimulating Lymphokines and Interferens: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Kitamura of
neutrophils and T lymphocytes, et al (1989) J Cell Physiol. 140
and/or inhibition of interferons. 323-334. Human GeneSeq WO9604306
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-5 R92802 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Kitamura of neutrophils and T lymphocytes, et al (1989) J Cell
Physiol. 140 and/or inhibition of interferons. 323-334. Recomb-
GeneSeq DEI9617202 Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, inant Accession
cytokines synthesized by lymphocytes, determined using assays known
in immunologic disorders, inter- W33373 monocytes, and macrophages.
Known the art: Matthews et al., in cancer leukin-16 functions
include stimulating Lymphokines and Interferens: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Lim et al of
neutrophils and T lymphocytes, (1996) J. Immunol. 156, 2566-70.
and/or inhibition of interferons. Human GeneSeq DE19617202
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, IL-16 Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, protein W33234 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Lim et al of
neutrophils and T lymphocytes, (1996) J. Immunol. 156, 2566-70.
and/or inhibition of interferons. ThrI 17 GeneSeq WO9708321
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, human Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, inter- W27521 monocytes, and macrophages.
Known the art: Matthews et al., in cancer leukin 9 functions
include stimulating Lymphokines and Interferens: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225. of neutrophils and T
lymphocytes, and/or inhibition of interferons. MetI 17 GeneSeq
WO9708321 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, human Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, inter- W27522 monocytes, and macrophages.
Known the art: Matthews et al., in cancer leukin 9 functions
include stimulating Lymphokines and Interferens: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Yang et al of
neutrophils and T lymphocytes, (1989) Blood 74, 1880-84. and/or
inhibition of interferons. Human GeneSeq EP86-4585 Interleukins are
a group of multifunctional Interleukin activity can be inflammatory
disorders, intra- Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, cellular
W77158 monocytes, and macrophages. Known the art: Matthews et al.,
in cancer IL-1 functions include stimulating Lymphokines and
Interferens: A receptor proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., antagonist. T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Orencole & of
neutrophils and T lymphocytes, Dinarello (1989) Cytokine 1, 14-20.
and/or inhibition of interferons. Human GeneSeq EP864585
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-18 W77158 monocytes, and macrophages.
Known the art: Matthews et al., in cancer protein functions include
stimulating Lymphokines and Interferens: A (IL-18) proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and USHIO et al of
neutrophils and T lymphocytes, (1996) J. Immunol. 156, 4274-79.
and/or inhibition of interferons. Human GeneSeq EP861663
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-18 W77077 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferens: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and USHIO et al of
neutrophils and T lymphocytes, (1996) J. Immunol. 156, 4274-79.
and/or inhibition of interferons. Human GeneSeq EP861663
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, inter- Accessions cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin 18 W77083, monocytes, and
macrophages. Known the art: Matthews et al., in cancer deriv-
W77084, functions include stimulating Lymphokines and Interferons:
A atives W77085, proliferation of immune cells (e.g., Practical
Approach, Clemens et al., W77086, T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. W77087, and
lymphocytes), chemotaxis 1987, pp. 221-225; and Ushio et al W77088,
of neutrophils and T lymphocytes, (1996) J. Immunol, 156, 4274-79.
and and/or inhibition of interferons. W77089 Inter- GeneSeq
WO9827997 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, leukin-9 Accession
cytokines synthesized by lymphocytes, determined using assays known
in immunologic disorders, (IL-9) W68158 monocytes, and macrophages.
Known the art: Matthews et al., in cancer mature functions include
stimulating Lymphokines and Interferons: A protein proliferation of
immune cells (e.g., Practical Approach, Clemens et al., (Thr117 T
helper cells, B cells, eosinophils, eds, IRL Press, Washington,
D.C. version). and lymphocytes), chemotaxis 1987, pp. 221-225; and
Yang et al of neutrophils and T lymphocytes, (1989) Blood 74,
1880-84. and/or inhibition of interferons. IL-9 GenSeq WO9827997
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, mature Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, protein W68157 monocytes, and macrophages.
Known the art: Matthews et al., in cancer variant functions include
stimulating Lymphokines and Interferons: A (Met117 proliferation of
immune cells (e.g., Practical Approach, Clemens et al., version) T
helper cells, B cells, eosinophils, eds, IRL Press, Washington,
D.C. and lymphocytes), chemotaxis 1987, pp. 221-225; and Yang et al
of neutrophils and T lymphocytes, (1989) Blood 74, 1880-84. and/or
inhibition of interferons. Human GeneSeq WO9824904 Interleukins are
a group of multifunctional Interleukin activity can be inflammatory
disorders, IL-9 Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, receptor
W64058 monocytes, and macrophages. Known the art: Matthews et al.,
in cancer protein functions include stimulating Lymphokines and
Interferons: A variant #3. proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Yang et al of neutrophils and T
lymphocytes, (1989) Blood 74, 1880-84. and/or inhibition of
interferons. Human GenSeq WO9824904 Interleukins are a group of
multifunctional Interleukin activity can be Soluble IL-9 IL-9
Accession cytokines synthesized by lymphocytes, determined using
assays known in receptor polypeptides receptor W64060 monocytes,
and macrophages. Known the art: Matthews et al., in may be useful
for inhibiting protein functions include stimulating Lymphokines
and Interferons: A interleukin activities. variant proliferation of
immune cells (e.g., Practical Approach, Clemens et al., fragment T
helper cells, B cells, eosinophils, eds, IRL Press, Washington,
D.C. and lymphocytes), chemotaxis 1987, pp. 221-225; and Yang et al
of neutrophils and T lymphocytes, (1989) Blood 74, 1880-84. and/or
inhibition of interferons. Human GeneSeq WO9824904 Interleukins are
a group of multifunctional Interleukin activity can be Soluble IL-9
IL-9 Accession cytokines synthesized by lymphocytes, determined
using assays known in receptor polypeptides receptor W64061
monocytes, and macrophages. Known the art: Matthews et al., in may
be useful for inhibiting protein functions include stimulating
Lymphokines and Interferons: A interleukin activities. variant #3.
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Yang et al of neutrophils and T lymphocytes, (1989) Blood 74,
1880-84. and/or inhibition of interferons. Human GeneSeq WO9817689
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, Inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-12 W51311 monocytes, and macrophages.
Known the art: Matthews et al., in cancer p40 functions include
stimulating Lymphokines and Interferons: A protein proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Hori et al of
neutrophils and T lymphocytes, (1987), Blood 70, 1069-1078. and/or
inhibition of interferons. Human GeneSeq WO9817689 Interleukins are
a group of multifunctional Interleukin activity can be inflammatory
disorders, inter- Accession cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, leukin-12
W51312 monocytes, and macrophages. Known the art: Matthews et al.,
in cancer p35 functions include stimulating Lymphokines and
Interferons: A protein proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Hori et al of neutrophils and T
lymphocytes, (1987), Blood 70, 1069-1078. and/or inhibition of
interferons. Human GeneSeq DE19649233- Interleukins are a group of
multifunctional Interleukin activity can be inflammatory disorders,
protein Accession cytokines synthesized by lymphocytes, determined
using assays known in immunologic disorders, with W63753 monocytes,
and macrophages. Known the art: Matthews et al., in cancer IL-16
functions include stimulating Lymphokines and Interferons: A
activity proliferation of immune cells (e.g., Practical Approach,
Clemens et al., T helper cells, B cells, eosinophils, eds, IRL
Press, Washington, D.C. and lymphocytes), chemotaxis 1987, pp.
221-225; and Lim et al of neutrophils and T lymphocytes, (1996) J.
Immunol. 156, 2566-70. and/or inhibition of interferons. Human
GeneSeq DE19649233- Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, protein
Accession cytokines synthesized by lymphocytes, determined using
assays known in immunologic disorders, with W59425 monocytes, and
macrophages. Known the art: Matthews et al., in cancer IL-16
functions include stimulating Lymphokines and Interferons: A
activity proliferation of immune cells (e.g., Practical Approach,
Clemens et al., T helper cells, B cells, eosinophils, eds, IRL
Press, Washington, D.C. and lymphocytes), chemotaxis 1987, pp.
221-225; and Lim et al of neutrophils and T lymphocytes, (1996) J.
Immunol. 156, 2566-70. and/or inhibition of interferons. Human
GeneSeq U.S. Pat. No. Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, inter-
Accession 5,747,024 cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, leukin-
W53878 monocytes, and macrophages. Known the art: Matthews et al.,
in cancer 15 functions include stimulating Lymphokines and
Interferons: A proliferation of immune cells (e.g., Practical
Approach, Clemens et al., T helper cells, B cells, eosinophils,
eds, IRL Press, Washington, D.C. and lymphocytes), chemotaxis 1987,
pp. 221-225; and Giri et al of neutrophils and T lymphocytes,
(1994) EMBO J. 13 2822-2830. and/or inhibition of interferons.
Human GeneSeq WO9747744 Interleukins are a group of
multifunctional
Interleukin activity can be inflammatory disorders, wild-type
Accession cytokines synthesized by lymphocytes, determined using
assays known in immunologic disorders, inter- W52149 monocytes, and
macrophages. Known the art: Matthews et al., in cancer leukin-4
functions include stimulating Lymphokines and Interferons: A
(hIL-4) proliferation of immune cells (e.g., Practical Approach,
Clemens et al., protein T helper cells, B cells, eosinophils, eds,
IRL Press, Washington, D.C. and lymphocytes), chemotaxis 1987, pp.
221-225; and Siegel & of neutrophils and T lymphocytes,
Mostowski (1990) J Immunol and/or inhibition of interferons.
Methods 132, 287-295. inter- GeneSeq WO9747744 Interleukins are a
group of multifunctional Interleukin activity can be inflammatory
disorders, leukin-4 Accessions cytokines synthesized by
lymphocytes, determined using assays known in immunologic
disorders, muteins W52150, monocytes, and macrophages. Known the
art: Matthews et al., in cancer W52151, functions include
stimulating Lymphokines and Interferons: A W52153, proliferation of
immune cells (e.g., Practical Approach, Clemens et al., W52154, T
helper cells, B cells, eosinophils, eds, IRL Press, Washington,
D.C. W52155, and lymphocytes), chemotaxis 1987, pp. 221-225; and
Siegel & W52156, of neutrophils and T lymphocytes, Mostowski
(1990) J Immunol W52157, and/or inhibition of interferons. Methods
132, 287-295. W52158, W52159, W52160, W52161, W52162, W52163,
W52164, W52165, W52166, and W52167 Human GeneSeq WO9935268
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin 1 Y28408 monocytes, and macrophages.
Known the art: Matthews et al., in cancer delta functions include
stimulating Lymphokines and Interferons: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Orencole & of
neutrophils and T lymphocytes, Dinarello (1989) Cytokine 1, 14-20.
and/or inhibition of interferons. Human GeneSeq WO9935268
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-1 Y24395 monocytes, and macrophages.
Known the art: Matthews et al., in cancer receptor functions
include stimulating Lymphokines and Interferons: A antagonist
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., beta T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Orencole & of neutrophils and T lymphocytes, Dinarello
(1989) Cytokine 1, 14-20. and/or inhibition of interferons. Human
GeneSeq WO9932632 Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, EDIRF II
Accession cytokines synthesized by lymphocytes, determined using
assays known in immunologic disorders, protein Y22199 monocytes,
and macrophages. Known the art: Matthews et al., in cancer sequence
functions include stimulating Lymphokines and Interferons: A
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225. of
neutrophils and T lymphocytes, and/or inhibition of interferons.
Human GeneSeq WO9932632 Interleukins are a group of multifunctional
Interleukin activity can be inflammatory disorders, EDIRF I
Accession cytokines synthesized by lymphocytes, determined using
assays known in immunologic disorders, protein Y22197 monocytes,
and macrophages. Known the art: Matthews et al., in cancer sequence
functions include stimulating Lymphokines and Interferons: A
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225. of
neutrophils and T lymphocytes, and/or inhibition of interferons.
Human GeneSeq WO9919480 Interleukins are a group of multifunctional
Interleukin activity can be Soluble IL-1RD10 IL-1RD10 Accession
cytokines synthesized by lymphocytes, determined using assays known
in receptor polypeptides protein Y14131 monocytes, and macrophages.
Known the art: Matthews et al., in may be useful for inhibiting
sequence functions include stimulating Lymphokines and Interferons:
A interleukin activites. proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Orencole & of neutrophils and
T lymphocytes, Dinarello (1989) Cytokine 1, 14-20. and/or
inhibition of interferons. Human GeneSeq WO9919480 Interleukins are
a group of multifunctional Interleukin activity can be Soluble
IL-1RD10 IL-1RD9 Accession cytokines synthesized by lymphocytes,
determined using assays known in receptor polypeptides Y14122
monocytes, and macrophages. Known the art: Matthews et al., in may
be useful for inhibiting functions include stimulating Lymphokines
and Interferons: A interleukin activites. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Orencole & of
neutrophils and T lymphocytes, Dinarello (1989) Cytokine 1, 14-20.
and/or inhibition of interferons. Human GeneSeq WO9919491
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, DNAX Accession cytokines synthesized
by lymphocytes, determined using assays known in immunologic
disorders, inter- Y09196 monocytes, and macrophages. Known the art:
Matthews et al., in cancer leukin-40 functions include stimulating
Lymphokines and Interferons: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225. of neutrophils and T lymphocytes,
and/or inhibition of interferons. (DIL-40) GeneSeq WO9919491
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, alternative Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, sequence Y09197 monocytes, and macrophages.
Known the art: Matthews et al., in cancer functions include
stimulating Lymphokines and Interferons: A proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225. of neutrophils and T
lymphocytes, and/or inhibition of interferons. IL-11 GeneSeq
WO9405318 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, R50176 monocytes, and macrophages. Known the
art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferons: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Lu et al of neutrophils and T
lymphocytes, (1994) J immunol. Methods 173, 19. and/or inhibition
of interferons. Human GeneSeq EP566410 Interleukins are a group of
multifunctional Interleukin activity can be inflammatory disorders,
adipo- Accession cytokines synthesized by lymphocytes, determined
using assays known in immunologic disorders, genesis R43260
monocytes, and macrophages. Known the art: Matthews et al., in
cancer inhibitory functions include stimulating Lymphokines and
Interferons: A factor proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225. of neutrophils and T lymphocytes,
and/or inhibition of interferons. IL-11 GeneSeq JP08127539
Interleukins are a group of multifunctional Interleukin activity
can be inflammatory disorders, Accession cytokines synthesized by
lymphocytes, determined using assays known in immunologic
disorders, W02202 monocytes, and macrophages. Known the art:
Matthews et al., in cancer functions include stimulating
Lymphokines and Interferons: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Lu et al of neutrophils and T
lymphocytes, (1994) J immunol. Methods 173, 19. and/or inhibition
of interferons. IL-14 GeneSeq WO9416074 Interleukins are a group of
multifunctional Interleukin activity can be inflammatory disorders,
Accession cytokines synthesized by lymphocytes, determined using
assays known in immunologic disorders, R55800 monocytes, and
macrophages. Known the art: Matthews et al., in cancer functions
include stimulating Lymphokines and Interferons: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Ambrus et al of
neutrophils and T lymphocytes, (1993) PNAS 90, 63330-34. and/or
inhibition of interferons. IL-17 GeneSeq U.S. Pat. No. Interleukins
are a group of multifunctional Interleukin activity can be Soluble
IL-17 receptor Accession 6,072,033 cytokines synthesized by
lymphocytes, determined using assays known in receptor polypeptides
B03807 monocytes, and macrophages. Known the art: Matthews et al.,
in may be useful for inhibiting functions include stimulating
Lymphokines and Interferons: A interleukin activities.
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Yao et al of neutrophils and T lymphocytes, (1995) J. Immunol.
155, 5483-86. and/or inhibition of interferons. IL-17 GeneSeq
WO9518826 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, R76573 monocytes, and macrophages. Known the
art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferons: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Yao et al of neutrophils and T
lymphocytes, (1995) J. Immunol. 155, 5483-86. and/or inhibition of
interferons. CTLA-8 GeneSeq WO9704097 Interleukins are a group of
multifunctional Interleukin activity can be inflammatory disorders,
Accession cytokines synthesized by lymphocytes, determined using
assays known in immunologic disorders, W13651 monocytes, and
macrophages. Known the art: Matthews et al., in cancer functions
include stimulating Lymphokines and Interferons: A proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225. of neutrophils and T
lymphocytes, and/or inhibition of interferons. IL-19 GeneSeq
WO9808870 Interleukins are a group of multifunctional Interleukin
activity can be inflammatory disorders, Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, W37935 monocytes, and macrophages. Known the
art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferons: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Gallagher et of neutrophils and T
lymphocytes, al (2000) Genes Immun. 1, 442-50. and/or inhibition of
interferons. IL-21 GeneSeq WO0024758 Interleukins are a group of
multifunctional
Interleukin activity can be inflammatory disorders, (TIF) Accession
cytokines synthesized by lymphocytes, determined using assays known
in immunologic disorders, Y92879 monocytes, and macrophages. Known
the art: Matthews et al., in cancer functions include stimulating
Lymphokines and Interferons: A proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Parrish- of neutrophils and T
lymphocytes, Novak et al (2000) Nature 408, and/or inhibition of
interferons. 57-63. IL-8 GeneSeq WO9306229 Interleukins are a group
of multifunctional Interleukin activity can be Soluble IL-8
receptor Accession cytokines synthesized by lymphocytes, determined
using assays known in receptor polypeptides R33420 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting functions include stimulating Lymphokines and
Interferons: A interleukin activities. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Holmes et al of
neutrophils and T lymphocytes, (1991) Science 253, 1278-80.. and/or
inhibition of interferons. Human GeneSeq U.S. Pat. No. Interleukins
are a group of multifunctional Interleukin activity can be Soluble
type II interleukin-1 type II Accession 5,464,937 cytokines
synthesized by lymphocytes, determined using assays known in
receptor polypeptides inter- R85480 monocytes, and macrophages.
Known the art: Matthews et al., in may be useful for inhibiting
leukin-1 functions include stimulating Lymphokines and Interferons:
A interleukin activities. receptor proliferation of immune cells
(e.g., Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Orencole & of neutrophils and
T lymphocytes, Dinarello (1989) Cytokine 1, 14-20. and/or
inhibition of interferons. Human GeneSeq EP638644 Interleukins are
a group of multifunctional Interleukin activity can be Soluble
IL-12 inter- Accession cytokines synthesized by lymphocytes,
determined using assays known in receptor polypeptides leukin-12
R69632 monocytes, and macrophages. Known the art: Matthews et al.,
in may be useful for inhibiting receptor functions include
stimulating Lymphokines and Interferons: A interleukin activities.
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Hori et al of neutrophils and T lymphocytes, (1987), Blood 70,
1069-1078. and/or inhibition of interferons. Inter- GeneSeq U.S.
Pat. No. Interleukins are a group of multifunctional Interleukin
activity can be Soluble IL-8 leukin 8 Accession 5,440,021 cytokines
synthesized by lymphocytes, determined using assays known in
receptor B polypeptides receptor R80758 monocytes, and macrophages.
Known the art: Matthews et al., in may be useful for inhibiting B
functions include stimulating Lymphokines and Interferons: A
interleukin activities. proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Holmes et al of neutrophils and T
lymphocytes, (1991) Science 253, 1278-80. and/or inhibition of
interferons. Human GeneSeq JP08103276 Interleukins are a group of
multifunctional Interleukin activity can be Soluble IL-8 IL-8
Accession cytokines synthesized by lymphocytes, determined using
assays known in receptor A polypeptides receptor B09989 monocytes,
and macrophages. Known the art: Matthews et al., in may be useful
for inhibiting protein functions include stimulating Lymphokines
and Interferons: A interleukin activities. hIL8RA proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Holmes et al of
neutrophils and T lymphocytes, (1991) Science 253, 1278-80. and/or
inhibition of interferons. Human GeneSeq JP08103276 Interleukins
are a group of multifunctional Interleukin activity can be Soluble
IL-8 IL-8 Accession cytokines synthesized by lymphocytes,
determined using asays known in receptor polypeptides receptor
B09990 monocytes, and macrophages. Known the art: Matthews et al.,
in may be useful for inhibiting protein functions include
stimulating Lymphokines and Interferons: A interleukin activities.
hIL8R proliferation of immune cells (e.g., Practical Approach,
Clemens et al., T helper cells, B cells, eosinophils, eds, IRL
Press, Washington, D.C. and lymphocytes), chemotaxis 1987, pp.
221-225; and Holmes et al of neutrophils and T lymphocytes, (1991)
Science 253, 1278-80. and/or inhibition of interferons. Inter-
GeneSeq WO9621732- Interleukins are a group of multifunctional
Interleukin activity can be Soluble IL-2 leukin-2 Accession
cytokines synthesized by lymphocytes, determined using assays known
in receptor polypeptides receptor R97569 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting associated functions include stimulating Lymphokines and
Interferons: A interleukin activities. protein proliferation of
immune cells (e.g., Practical Approach, Clemens et al., p43 T
helper cells, B cells, eosinophils, eds, IRL Press, Washington,
D.C. and lymphocytes), chemotaxis 1987, pp. 221-225; and Gillis et
al of neutrophils and T lymphocytes, (1978) J. Immunol. 120, 2027.
and/or inhibition of interferons. Human GeneSeq WO9629408
Interleukins are a group of multifunctional Interleukin activity
can be Soluble IL-17 inter- Accession cytokines synthesized by
lymphocytes, determined using assays known in receptor polypeptides
leukin-17 W04185 monocytes, and macrophages. Known the art:
Matthews et al., in may be useful for inhibiting receptor functions
include stimulating Lymphokines and Interferons: A interleukin
activities. proliferation of immune cells (e.g., Practical
Approach, Clemens et al., T helper cells, B cells, eosinophils,
eds, IRL Press, Washington, D.C. and lymphocytes), chemotaxis 1987,
pp. 221-225; and Yao et al of neutrophils and T lymphocytes, (1995)
J. Immunol. 155, 5483-86. and/or inhibition of interferons. Human
GeneSeq WO9619574 Interleukins are a group of multifunctional
Interleukin activity can be Soluble IL-11 inter- Accession
cytokines synthesized by lymphocytes, determined using assays known
in receptor polypeptides leukin-11 R99090 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting receptor functions include stimulating Lymphokines and
Interferons: A interleukin activities. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Lu et al of
neutrophils and T lymphocytes, (1994) J immunol. Methods 173, 19.
and/or inhibition of interferons. Human GeneSeq WO9623067
Interleukins are a group of multifunctional Interleukin activity
can be Inflammatory disorders, inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
immunologic disorders, leukin-1 W01911 monocytes, and macrophages.
Known the art: Matthews et al., in cancer receptor functions
include stimulating Lymphokines and Interferons: A accessory
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., protein T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Orencole & of neutrophils and T lymphocytes, Dinarello
(1989) Cytokine 1, 14- and/or inhibition of interferons. 20. AGF
GeneSeq U.S. Pat. No. Interleukins are a group of multifunctional
Interleukin activity can be Inflammatory disorders, Protein
Accession 5,488,032 cytokines synthesized by lymphocytes,
determined using assays known in immunologic disorders, R92749
monocytes, and macrophages. Known the art: Matthews et al., in
cancer functions include stimulating Lymphokines and Interferons: A
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225. of
neutrophils and T lymphocytes, and/or inhibition of interferons.
Human GeneSeq W09607739 Interleukins are a group of multifunctional
Interleukin activity can be Soluble IL-type-3 inter- Accession
cytokines synthesized by lymphocytes, determined using assays known
in receptor polypeptides leukin-1 R91064 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting type-3 functions include stimulating Lymphokines and
Interferons: A interleukin activities receptor proliferation of
immune cells (e.g., Practical Approach, Clemens et al., T helper
cells, B cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Orencole & of
neutrophils and T lymphocytes, Dinarello (1989) Cytokine 1, 14-
and/or inhibition of interferons. 20. Human GeneSeq WO9720926
Interleukins are a group of multifunctional Interleukin activity
can be Soluble IL-13 beta inter- Accession cytokines synthesized by
lymphocytes, determined using assays known in receptor polypeptides
leukin-13 W24972 monocytes, and macrophages. Known the art:
Matthews et al., in may be useful for inhibiting beta functions
include stimulating Lymphokines and Interferons: A interleukin
activities. receptor proliferation of immune cells (e.g., Practical
Approach, Clemens et al., T helper cells, B cells, eosinophils,
eds, IRL Press, Washington, D.C. and lymphocytes), chemotaxis 1987,
pp. 221-225; and Boutelier et al of neutrophils and T lymphocytes,
(1995) J. Immunol. Methods 181, 29. and/or inhibition of
interferons. Human GeneSeq WO9720926 Interleukins are a group of
multifunctional Interleukin activity can be Soluble IL-13 alpha
inter- Accession cytokines synthesized by lymphocytes, determined
using assays known in receptor polypeptides leukin-13 W24973
monocytes, and macrophages. Known the art: Matthews et al., in may
be useful for inhibiting alpha functions include stimulating
Lymphokines and Interferons: A interleukin activities. receptor
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Boutelier et al of neutrophils and T lymphocytes, (1995) J.
Immunol. Methods 181, 29. and/or inhibition of interferons. Human
GeneSeq U.S. Pat. No. Interleukins are a group of multifunctional
Interleukin activity can be Soluble IL-4 inter- Accession 5,599,905
cytokines synthesized by lymphocytes, determined using assays known
in receptor polypeptides leukin-4 W13499 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting receptor functions include stimulating Lymphokines and
Interferons: A interleukin activities. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Siegel & of
neutrophils and T lymphocytes, Mostowski (1990) J Immunol and/or
inhibition of interferons. Methods 132, 287-295. Human GeneSeq
EP759466 Interleukins are a group of multifunctional Interleukin
activity can be Soluble IL-12 beta-2 inter- Accession cytokines
synthesized by lymphocytes, determined using assays known in
receptor polypeptides leukin-12 W12771 monocytes, and macrophages.
Known the art: Matthews et al., in may be useful for inhibiting
beta-2 functions include stimulating Lymphokines and Interferons: A
interleukin activities. receptor proliferation of immune cells
(e.g., Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Hori et al of neutrophils and T
lymphocytes, (1987), Blood 70, 1069-1078. and/or inhibition of
interferons. Human GeneSeq EP759466 Interleukins are a group of
multifunctional Interleukin activity can be Soluble IL-12 beta-1
inter- Accession cytokines synthesized by lymphocytes, determined
using assays known in receptor polypeptides leukin-12 W12772
monocytes, and macrophages. Known the art: Matthews et al., in may
be useful for inhibiting beta-1 functions include stimulating
Lymphokines and Interferons: A interleukin activities. receptor.
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Hori et al of neutrophils and T lymphocytes, (1987), Blood 70,
1069-1078. and/or inhibition of interferons. Human IL-9 GeneSeq
WO9824904 Interleukins are a group of multifunctional
Interleukin activity can be Soluble IL-9 receptor receptor
Accessions cytokines synthesized by lymphocytes, determined using
assays known in polypeptides may be useful for protein W64055,
monocytes, and macrophages. Known the art: Matthews et al., in
inhibiting interleukin W64056, functions include stimulating
Lymphokines and Interferons: A activities. and proliferation of
immune cells (e.g., Practical Approach, Clemens et al., W64057 T
helper cells, B cells, eosinophils, eds, IRL Press, Washington,
D.C. and lymphocytes), chemotaxis 1987, pp. 221-225; and Yang et al
of neutrophils and T lymphocytes, (1989), Blood 74, 1880-84..
and/or inhibition of interferons. IL-10 GeneSeq U.S. Pat. No.
Interleukins are a group of multifunctional Interleukin activity
can be Soluble IL-10 receptor Accession 5,716,804 cytokines
synthesized by lymphocytes, determined using assays known in
receptor polypeptides W41804 monocytes, and macrophages. Known the
art: Matthews et al., in may be useful for inhibiting functions
include stimulating Lymphokines and Interferons: A interleukin
activities. proliferation of immune cells (e.g., Practical
Approach, Clemens et al., T helper cells, B cells, eosinophils,
eds, IRL Press, Washington, D.C. and lymphocytes), chemotaxis 1987,
pp. 221-225; and Thompson- of neutrophils and T lymphocytes, Snipes
et al (1991) J. Exp. Med. and/or inhibition of interferons. 173,
507-510. Human IL-6 GeneSeq JP11196867 Interleukins are a group of
multifunctional Interleukin activity can be Soluble IL-6 receptor
Accession cytokines synthesized by lymphocytes, determined using
assays known in receptor polypeptides Y30938 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting functions include stimulating Lymphokines and
Interferons: A interleukin activities. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Aarden et al of
neutrophils and T lymphocytes, (1987) Eur. J. Immunol 17, 1411-16.
and/or inhibition of interferons. Il-17 GeneSeq U.S. Pat. No.
Interleukins are a group of multifunctional Interleukin activity
can be Soluble IL-17 receptor Accession 6,096,305 cytokines
synthesized by lymphocytes, determined using assays known in
receptor polypeptides Y97181 monocytes, and macrophages. Known the
art: Matthews et al., in may be useful for inhibiting functions
include stimulating Lymphokines and Interferons: A interleukin
activities. proliferation of immune cells (e.g., Practical
Approach, Clemens et al., T helper cells, B cells, eosinophils,
eds, IRL Press, Washington, D.C. and lymphocytes), chemotaxis 1987,
pp. 221-225; and Yao et al of neutrophils and T lymphocytes, (1995)
J. Immunol. 155, 5483-86. and/or inhibition of interferons. Il-17
GeneSeq U.S. Pat. No. Interleukins are a group of multifunctional
Interleukin activity can be Soluble IL-17 receptor Accession
6,100,235 cytokines synthesized by lymphocytes, determined using
assays known in receptor polypeptides Y97131 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting functions include stimulating Lymphokines and
Interferons: A interleukin activities. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Yao et al of
neutrophils and T lymphocytes, (1995) J. Immunol. 155, 5483-86.
and/or inhibition of interferons. Human GeneSeq EP509826
Interleukins are a group of multifunctional Interleukin activity
can be Soluble IL-3 inter- Accession cytokines synthesized by
lymphocytes, determined using assays known in receptor polypeptides
leukin-3 R25300 monocytes, and macrophages. Known the art: Matthews
et al., in may be useful for inhibiting receptor functions include
stimulating Lymphokines and Interferons: A interleukin activities.
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Kitamura et al of neutrophils and T lymphocytes, (1989) J Cell
Physiol. 140 323-334. and/or inhibition of interferons. Human
GeneSeq WO9102063 Interleukins are a group of multifunctional
Interleukin activity can be Soluble GM-CSF GM-CSF Accession
cytokines synthesized by lymphocytes, determined using assays known
in receptor polypeptides receptor R10919 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting functions include stimulating Lymphokines and
Interferons: A interleukin activities. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225. of neutrophils and T
lymphocytes, and/or inhibition of interferons. Human GeneSeq
EP492214 Interleukins are a group of multifunctional Interleukin
activity can be Soluble IL-5 IL-5 Accession cytokines synthesized
by lymphocytes, determined using assays known in receptor alpha
polypeptides receptor R25064 monocytes, and macrophages. Known the
art: Matthews et al., in may be useful for inhibiting alpha
functions include stimulating Lymphokines and Interferons: A
interleukin activities. chain proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Kitamura et al of neutrophils and
T lymphocytes, (1989) J Cell Physiol. 140, 323-334. and/or
inhibition of interferons. Il-5 GeneSeq WO9847923 Interleukins are
a group of multifunctional Interleukin activity can be Soluble IL-5
receptor Accession cytokines synthesized by lymphocytes, determined
using assays known in receptor polypeptides W82842 monocytes, and
macrophages. Known the art: Matthews et al., in may be useful for
inhibiting functions include stimulating Lymphokines and
Interferons: A interleukin activities. proliferation of immune
cells (e.g., Practical Approach, Clemens et al., T helper cells, B
cells, eosinophils, eds, IRL Press, Washington, D.C. and
lymphocytes), chemotaxis 1987, pp. 221-225; and Kitamura et al of
neutrophils and T lymphocytes, (1989) J Cell Physiol. 140, 323-334.
and/or inhibition of interferons. Il-6 GeneSeq JP05091892
Interleukins are a group of multifunctional Interleukin activity
can be Soluble IL-6 receptor Accession cytokines synthesized by
lymphocytes, determined using assays known in receptor polypeptides
R37215 monocytes, and macrophages. Known the art: Matthews et al.,
in may be useful for inhibiting functions include stimulating
Lymphokines and Interferons: A interleukin activities.
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Aarden et al of neutrophils and T lymphocytes, (1987) Eur. J.
Immunol 17, 1411-16. and/or inhibition of interferons. Human
GeneSeq AU8928720 Interleukins are a group of multifunctional
Interleukin activity can be Soluble B cell stimulating B cell
Accession cytokines synthesized by lymphocytes, determined using
assays known in factor-2 receptor polypeptides stimu- P90525
monocytes, and macrophages. Known the art: Matthews et al., in may
be useful for inhibiting lating functions include stimulating
Lymphokines and Interferons: A interleukin activities. factor-2
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., receptor T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225. of
neutrophils and T lymphocytes, and/or inhibition of interferons.
IL-7 GeneSeq EP403114 Interleukins are a group of multifunctional
Interleukin activity can be Soluble IL-7 receptor Accession
cytokines synthesized by lymphocytes, determined using assays known
in receptor polypeptides clone R08330 monocytes, and macrophages.
Known the art: Matthews et al., in may be useful for inhibiting
functions include stimulating Lymphokines and Interferons: A
interleukin activities. proliferation of immune cells (e.g.,
Practical Approach, Clemens et al., T helper cells, B cells,
eosinophils, eds, IRL Press, Washington, D.C. and lymphocytes),
chemotaxis 1987, pp. 221-225; and Park et al of neutrophils and T
lymphocytes, (1990) J. Exp. Med. 171, 1073-79. and/or inhibition of
interferons. EPO GeneSeq WO9008822 EPO Receptor is involved in the
EPO Receptor activity can be Inflammatory disorders, receptor;
Accession proliferation and differentiation of determined using
assays known in immunologic disorders, EPOR R06512 erythroblasts.
the art, such as, J Biol Chem 2001 cancer, erythroblast Mar. 23;
276(12: 8995-9002; JAK2 proliferation and protein tyrosine kinase
activity: differentiation Blood 1994 Sep. 1; 84(5): 1501-7 and Mol
Cell Biol. 1994 October; 14(10: 6506-14. IL-15 GeneSeq WO9530695
Interleukins are a group of multifunctional Interleukin activity
can be Soluble IL-15 receptor Accession cytokines synthesized by
lymphocytes, determined using assays known in receptor polypeptides
R90843 monocytes, and macrophages. Known the art: Matthews et al.,
in may be useful for inhibiting functions include stimulating
Lymphokines and Interferons: A interleukin activities.
proliferation of immune cells (e.g., Practical Approach, Clemens et
al., T helper cells, B cells, eosinophils, eds, IRL Press,
Washington, D.C. and lymphocytes), chemotaxis 1987, pp. 221-225;
and Giri et al of neutrophils and T lymphocytes, (1994) EMBO J. 13
2822-2830. and/or inhibition of interferons. CD137; GeneSeq
WO9507984 Activities associated with apoptosis, NF-kB Apoptosis
activity, NF-kB Soluble 4-1BB 4-1BB Accession activation, and
co-stimulation of immune activation, and B and T cell co- receptor
polypeptides Receptor R70977 cells such as T and B cells.
stimulation can be determined using may be useful for inhibiting
Protein assays known in the art: Moore et apoptosis, NF-kB
activation, al., 1999, Science, 285(5425): 260-3; and/or
co-stimulation of immune Song H Y et al., 1997 Proc Natl cells such
as B and T cells. Acad Sci USA 94(18): 9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. BCMA GeneSeq WO0068378
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Soluble BCMA Accession activation, and co-stimulation of
immune activation, and B and T cell co- receptor polypeptides
Y71979 cells such as T and B cells. stimulation can be determined
using may be useful for inhibiting assays known in the art: Moore
et apoptosis, NF-kB activation, al., 1999, Science, 285(5425):
260-3; and/or co-stimulation of immune Song H Y et al., 1997 Proc
Natl cells such as B and T cells. Acad Sci USA 94(18): 9792-6;
Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD27 GeneSeq
WO9201049 Activities associated with apoptosis, NF-kB Apoptosis
activity, NF-kB Soluble CD27 polypeptides Accession activation, and
co-stimulation of immune activation, and B and T cell co- may be
useful for inhibiting R20814 cells such as T and B cells.
stimulation can be determined using apoptosis, NF-kB activation,
assays known in the art: Moore et and/or co-stimulation of immune
al., 1999, Science, 285(5425): 260-3; cells such as B and T cells.
Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6;
Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD30 GeneSeq
DE4200043 Activities associated with apoptosis, NF-kB Apoptosis
activity, NF-kB Soluble CD30 polypeptides Accession activation, and
co-stimulation of immune activation, and B and T cell co- may be
useful for inhibiting R35478 cells such as T and B cells.
stimulation can be determined using apoptosis, NF-kB activation,
assays known in the art: and/or co-stimulation of immune Moore et
al., 1999, Science, 285(5425): cells such as B and T cells. 260-3;
Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6;
Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD40 GeneSeq
WO9945944 Activities associated with apoptosis, NF-kB Apoptosis
activity, NF-kB Soluble CD40 polypeptides Accession activation, and
co-stimulation of immune activation, and B and T cell co- may be
useful for inhibiting Y33499 cells such as T and B cells.
stimulation can be determined using apoptosis, NF-kB activation,
assays known in the art: Moore et and/or co-stimulation of immune
al., 1999, Science 285(5425): 260-3; cells such as B and T
cells.
Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6;
Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. EDAR Genbank
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Immune Disorders, Accession activation, and co-stimulation of
immune activation, and B and T cell co- Lymphomas, X-linked
AAD50077 cells such as T and B cells. stimulation can be determined
using hypohidrotic ectodermal assays known in the art: Moore et
dysplasia al., 1999, Science, 285(5425): 260-3; Song H Y et al.,
1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. OX40; GeneSeq WO9512673
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Immune Disorders, ACT-4 Accession activation, and
co-stimulation of immune activation, and B and T cell co-
Lymphomas, R74737 cells such as T and B cells. stimulation can be
determined using T cell disorders assays known in the art: Moore et
al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc
Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer, 1986,
J. Immunol. Methods. TACI GeneSeq WO9839361 Activities associated
with apoptosis, NF-kB Apoptosis activity, NF-kB Soluble TACI
Accession activation, and co-stimulation of immune activation, and
B and T cell co- receptor polypeptides W75783 cells such as T and B
cells. stimulation can be determined using may be useful for
inhibiting assays known in the art: Moore et apoptosis, NF-kB
activation, al., 1999, Science, 285(5425): 260-3; and/or
co-stimulation of immune Song H Y et al., 1997 Proc Natl cells such
as B and T cells. Acad Sci USA 94(18): 9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. TNF-R GeneSeq AU9058976
Activities associates with apoptosis, NF-kB Apoptosis activity,
NF-kB Soluble TNF-R Accession activation, and co-stimulation of
immune activation, and B and T cell co- receptor polypeptides
R10986 cells such as T and B cells. stimulation can be determined
using may be useful for inhibiting assays known in the art: Moore
et apoptosis, NF-kB activation, al., 1999, Science, 285(5425):
260-3; and/or co-stimulation of immune Song H Y et al., 1997 Proc
Natl cells such as B and T cells. Acad Sci USA 94(18): 9792-6;
Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. TNF-RII;
GeneSeq EP418014 Activities associated with apoptosis, NF-kB
Apoptosis activity, NF-kB Soluble TNFR-II TNF Accession activation,
and co-stimulation of immune activation, and B and T cell co-
receptor polypeptides p75 R11141 cells such as T and B cells.
stimulation can be determined using may be useful for inhibiting
receptor; assays known in the art: Moore et apoptosis, NF-kB
activation, Death al., 1999, Science, 285(5425): 260-3; and/or
co-stimulation of immune Receptor Song H Y et al., 1997 Proc Natl
cells such as B and T cells. Acad Sci USA 94(18)9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. hAPO-4; GeneSeq WO9911791
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Immune Disorders, TROY Accession activation, and
co-stimulation of immune activation, and B and T cell co- Cancers
W93581 cells such as T and B cells. stimulation can be determined
using assays known in the art: Moore et al., 1999, Science,
285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA
94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.
Methods. TNF-alpha GeneSeq EP205038 Activities associated with
apoptosis, NF-kB Apoptosis activity, NF-kB Inflammatory disorders,
precursor Accession activation, and co-stimulation of immune
activation, and B and T cell co- immunologic disorders, P60074
cells such as T and B cells. stimulation can be determined using
cancer assays known in the art: Moore et al., 1999, Science,
285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA
94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.
Methods. Human GeneSeq EP619372 Activities associated with
apoptosis, NF-kB Apoptosis activity, NF-kB Inflammatory disorders,
TNF-alpha Accession activation, and co-stimulation of immune
activation, and B and T cell co- immunologic disorders, R62463
cells such as T and B cells stimulation can be determined using
cancer assays known in the art: Moore et al., 1999, Science,
285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA
94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.
Methods. Human GeneSeq EP563714 Activities associated with
apoptosis, NF-kB Apoptosis activity, NF-kB Inflammatory disorders,
TNF-alpha Accession activation, and co-stimulation of immune
activation, and B and T cell co- immunologic disorders, R42679
cells such as T and B cells. stimulation can be determined using
cancer assays known in the art: Moore et al., 1999, Science,
285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA
94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.
Methods. Human GeneSeq WO0064479 Activities associated with
apoptosis, NF-kB Apoptosis activity, NF-kB Inflammatory disorders,
TNF-beta Accession activation, and co-stimulation of immune
activation, and B and T cell co- immunologic disorders, (LT-alpha)
B37799 cells such as T and B cells. stimulation can be determined
using cancer assays known in the art: Moore et al., 1999, Science,
285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA
94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.
Methods. LT-alpha GeneSeq EP250000 Activities associated with
apoptosis, NF-kB Apoptosis activity, NF-kB Inflammatory disorders,
Accession activation, and co-stimulation of immune activation, and
B and T cell co- immunologic disorders, P70107 cells such as T and
B cells. stimulation can be determined using cancer assays known in
the art: Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et
al., 1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. LT-beta GeneSeq WO9413808
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Inflammatory disorders, Accession activation, and
co-stimulation of immune activation, and B and T cell co-
immunologic disorders, R56869 cells such as T and B cells.
stimulation can be determined using cancer assays known in the art:
Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al.,
1997 Proc Natl Acad Sci USA 94(18)9792-6; Epsevik and Nissen-Meyer,
1986, J. Immunol. Methods. OPGL GeneSeq WO9846751 Activities
associated with apoptosis, NF-kB Apoptosis activity, NF-kB
Inflammatory disorders, Accession activation, and co-stimulation of
immune activation, and B and T cell co- immunologic disorders,
W83195 cells such as T and B cells. stimulation can be determined
using cancer, assays known in the art: Moore et loss of bone mass
al., 1999, Science, 285(5425): 260-3; Song H Y et al., 1997 Proc
Natl Acad Sci USA 94(18)9792-6; Epsevik and Nissen-Meyer, 1986, J.
Immunol. Methods. FasL GeneSeq WO9903999 Activities associated with
apoptosis, NF-kB Apoptosis activity, NF-kB Inflammatory disorders,
Accession activation, and co-stimulation of immune activation, and
B and T cell co- immunologic disorders, W98071 cells such as T and
B cells. stimulation can be determined using cancer assays known in
the art: Moore, et al., 1999, Science, 285(5425): 260-3; Song H Y
et al., 1997 Proc Natl Acad Sci USA 94(18)9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. FasL GeneSeq WO9903998
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Inflammatory disorders, Accession activation, and
co-stimulation of immune activation, and B and T cell co-
immunologic disorders, W95041 cells such as T and B cells.
stimulation can be determined using cancer assays known in the art:
Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al.,
1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. CD27L GeneSeq WO9405691
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Inflammatory disorders, Accession activation, and
co-stimulation of immune activation, and B and T cell co-
immunologic disorders, R50121 cells such as T and B cells.
stimulation can be determined using cancer assays known in the art:
Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al.,
1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. CD30 GeneSeq WO9324135
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Inflammatory disorders, ligand Accession activation, and
co-stimulation of immune activation, and B and T cell co-
immunologic disorders, R45007 cells such as T and B cells.
stimulation can be determined using cancer assays known in the art:
Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al.,
1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. CD40L GeneSeq WO9529935
Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Inflammatory disorders, Accession activation, and
co-stimulation of immune activation, and B and T cell co-
immunologic disorders, R85486 cells such as T and B cells.
stimulation can be determined using cancer assays known in the art:
Moore, et al., 1999, Science, 285(5425): 260-3; Song H Y et al.,
1997 Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and
Nissen-Meyer, 1986, J. Immunol. Methods. 4-1BB GeneSeq U.S. Pat.
No. Activities associated with apoptosis, NF-kB Apoptosis activity,
NF-kB Inflammatory disorders, ligand Accession 5,674,704
activation, and co-stimulation of immune activation, and B and T
cell co- immunologic disorders, W26657 cells such as T and B cells.
stimulation can be determined using cancer assays known in the art:
Moore et al., 1999, Science, 285(5425): 260-3; Song H Y et al, 1997
Proc Natl Acad Sci USA 94(18): 9792-6; Epsevik and Nissen-Meyer,
1986, J. Immunol. Methods. FAS GeneSeq WO0058465 Activities
associated with apoptosis, NF-kB Apoptosis activity, NF-kB Soluble
DcR3 polypeptides Ligand Accession activation, and co-stimulation
of immune activation, and B and T cell co- may be useful for
inhibiting Inhibitory B19335 cells such as T and B cells.
stimulation can be determined using apoptosis, NF-kB activation,
Protein assays known in the art: Moore et and/or co-stimulation of
immune (DcR3) al., 1999, Science, 285(5425): 260-3; cells such as B
and T cells. Song H Y et al., 1997 Proc Natl Acad Sci USA 94(18):
9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods OX40L
GeneSeq WO9521915 Activities associated with apoptosis, NF-kB
Apoptosis activity, NF-kB Inflammatory disorders, Accession
activation, and co-stimulation of immune activation, and B and T
cell co- immunologic disorders,
R79903 cells such as T and B cells. stimulation can be determined
using cancer assays known in the art: Moore et al., 1999, Science,
285(5425): 260-3; Song H Y et al., 1997 Proc Natl Acad Sci USA
94(18): 9792-6; Epsevik and Nissen-Meyer, 1986, J. Immunol.
Methods. Protease GeneSeq WO9106561 Peptides that inhibit the HIV
protease activities are known in HIV, inflammatory disorders,
inhibitor Accessions function/binding of HIV the art: HIV protease
assays: immunologic disorders, peptides R12435, EP0387231. One can
modify the cancer, viral infections R12436, assay to look for
inhibition using R12437, any of the disclosed protease R12438,
inhibitor polypeptides. R12439, R12440, and R1244 Retro- GeneSeq
EP387231 Peptides that inhibit the HIV protease activities are
known in HIV, inflammatory disorders, viral Accessions
function/binding of HIV the art: HIV protease assays: immunologic
disorders, protease R06660, EP0387231. One can modify the cancer,
viral infections inhibitors R06661, assay to look for inhibition
using R06662, any of the disclosed protease R06663, inhibitor
polypeptides. R06664, R06665, R06666, R06667, R06668, R06669,
R06670, R06671, R06672, R06673, R06674, R06675, and R06676 HIV
GeneSeq WO9301828 Peptides that inhibit the HIV protease activities
are known in the HIV, inflammatory disorders, protease Accessions
function/binding of HIV art. HIV protease assays EP0387231.
immunologic disorders, inhibiting R59293, One can modify the assay
to look for cancer, viral infections peptides R59294, inhibition
using any of the disclosed R59295, protease inhibitor polypeptides.
R59296, R59297, R59298, R59299, R592300, R59301, R59302, R59301,
R59302, R59303, R59304, R59305, R59306, R59307, R59308, R59309,
R59310, R59311, R59312, R59313, R59314, R59315, R59316, R59317
R59318, R59319, R59320, R59321, R59322, R59323, R59324, R59325,
R59326, R59327, R59328, R59329, R59330, R59331, R59332, R59333,
R59334, R59335, R59336, R59337, R59338, R59339, R59340, R59341,
R59342, R59343, R59344, R59345, R59346, R59347, R59348, R59349, and
R59350 HIV-1 GeneSeq DE4412174 Peptides that inhibit the HIV
protease activities are known in the HIV, inflammatory disorders,
protease Accessions function/binding of HIV art: HIV protease
assays: EP0387231. immunologic disorders, hinibitors R86326, One
can modify the assay to look for cancer, viral infections R86327,
inhibition using any of the disclosed R86328, protease inhibitor
polypeptides. R86329, R86330, R86331, R86332, R86333, R86334,
R86335, R86336, R86337, R86338, R86339, R86340, R86341, R86342,
R86343, R86344, R86345, R86346, R86347, R86348, R86349, R86350,
R86351, R86352, R86353, R86354, R86355, R86356, R86357, R86358,
R86359, R86360, R86361, R86362, R86363, R86364, R86365, R86366,
R86367, R86368, R86369, R86370, and R86371 HIV GeneSeq WO9959615
Peptides that inhibit the HIV protease activities are known in HIV,
inflammatory disorders, Inhibitor Accession function/binding of HIV
the art: HIV protease assays: immunologic disorders, Peptide Y89687
EP0387231. One can modify the cancer, viral infections assay to
look for inhibition using any of the disclosed protease inhibitor
polypeptides. HIV GenSeq WO9948513 Peptides that inhibit the HIV
Protease activities are known HIV, inflammatory disorders,
Inhibitor Accession function/binding of HIV in the art; HIV
protease assays: immunologic disorders, Peptide Y31955 EP0387231.
One can modify the cancer, viral infections assay to look for
inhibition using any of the disclosed protease inhibitor
polypeptides. HIV www.sciencex- Peptides that inhibit the HIV
protease activities are known HIV, inflammatory disorders,
Inhibitor press.org; function/binding of HIV in the art: HIV
protease assays: immunologic disorders, Peptide Published
EP0387231. One can modify the cancer, viral infections online 12
assay to look for inhibition using Jan. 2001; any of the disclosed
protease 10.1126/sci- inhibitor polypeptides. ence.1057453 Human
GeneSeq WO9509232 Chemokines are a family of related Chemokine
activities can be Immune disorders, particularly monocyte Accession
small, secreted proteins determined using assays known in useful
for treating bacterial chemo- R73915 involved in biological
processes the art: Methods in Molecular and/or viral menigitis
attractant ranging from hematopoiesis, Biology, 2000, vol. 138:
factor angiogenesis, and leukocyte trafficking. Chemokine
Protocols, Edited by: hMCP-3 Members of this family are involved in
a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9509232 Chemokines are a
family of related Chemokine activities can be Immune disorders,
particularly monocyte Accession small, secreted proteins determined
using assays known in useful for treating bacterial chemo- R73914
involved in biological processes the art: Methods in Molecular
and/or viral menigitis attractant ranging from hematopoiesis,
Biology, 2000, vol. 138: factor angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: hMCP-1 Members of this
family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO9429341 Chemokines are a family of related Chemokine
activities can be Immune disorders, gro- Accessions small, secreted
proteins determined using assays known in inflammatory disorders,
beta R66699 involved in biological processes the art: Methods in
Molecular blood-related disorders, chemokine and ranging from
hematopoiesis, Biology, 2000, vol. 138: stem cell transplantation,
W17671 angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: cancer Members of this family are involved in
a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9429341 Chemokines are a
family of related Chemokine activities can be Immune disorders,
gro- Accessions small, secreted proteins determined using assays
known in inflammatory disorders,
gamma R66700 involved in biological processes the art: Methods in
Molecular blood-related disorders, chemokine and ranging from
hematopoiesis, Biology, 2000, vol. 138: stem cell transplantation,
W17672 angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: cancer Members of this family are involved in
a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9429341 Chemokines are a
family of related Chemokine activities can be Immune disorders,
gro- Accessions small, secreted proteins determined using assays
known in inflammatory disorders, alpha R66698 and involved in
biological processes the art: Methods in Molecular blood-related
disorders, chemokine W18024 ranging from hematopoiesis, Biology,
2000, vol. 138: stem cell transplantation, angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by: cancer
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO9632481 Chemokines are a family of related Chemokine
activities can be Immune disorders, particularly eosinophil-
Accession small, secreted proteins determined using assays known in
treatment of eosinophilia, expressed W05186 involved in biological
processes the art: Methods in Molecular inflammation, chemokine
ranging from hematopoiesis, Biology, 2000, vol. 138: allergies,
asthma, leukaemia (EEC) angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: and lymphoma Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Chemo- GeneSeq
WO9613587 Chemokines are a family of related Chemokine activities
can be Cancer and blood-related kine-like Accessions small,
secreted proteins determined using assasys known in disorders,
particularly protein R92318 involved in biological processes the
art: Methods in Molecular myelosuppression PF4-414 and ranging from
hematopoiesis, Biology, 2000, vol. 138: Full- R99809 angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Length
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, and similarly diverse range of pathologies and C. A.
Power. Humana Press Mature including inflammation, allergy, tissue
Inc., Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Chemo- GeneSeq WO9613587 Chemokines are a family of
related Chemokine activities can be Cancer and blood-related
kine-like Accession small, secreted proteins determined using
assays known in disorders, particularly protein R99812 involved in
biological processes the art: Methods in Molecular myelosuppression
IL-8M3 ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ; and Holmes et al rejection, viral
infection, and tumor (1991) Science 253, 1278-80. biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Human GeneSeq WO9613587 Chemokines are a family of
related Chemokine activities can be Cancer and blood-related inter-
Accession small, secreted proteins determined using assays known in
disorders, particularly leukin-8 R99814 involved in biological
processes the art: Methods in Molecular myelosuppression (IL-8)
ranging from hematopoiesis, Biology, 2000, vol. 138: angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ; and Holmes et al rejection, viral infection, and tumor (1991)
Science 253, 1278-80. biology. The chemokines exert their effects
by acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Chemo- GeneSeq WO9613587
Chemokines are a family of related Chemokine activities can be
Cancer and blood-related kine-like Accessions small, secreted
proteins determined using assays known in disorders, particularly
protein R99815 involved in biological processes the art: Methods in
Molecular myelosuppression IL-8M1 and ranging from hematopoiesis,
Biology, 2000, vol. 138: Full- R99803 angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Length Members of this
family are involved in a A. E. I. Proudfoot, T. N. C. Wells, and
similarly diverse range of pathologies and C. A. Power. Humana
Press Mature including inflammation, allergy, tissue Inc., Totowa,
NJ; and Holmes et al rejection, viral infection, and tumor (1991)
Science 253, 1278-80. biology. The chemokines exert their effects
by acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Chemo- GeneSeq WO9613587
Chemokines are a family of related Chemokine activities can be
Cancer and blood-related kine-like Accessions small, secreted
proteins determined using assays known in disorders, particularly
protein R99816 involved in biological processes the art: Methods in
Molecular myelosuppression. IL - 8M8 and ranging from
hematopoiesis, Biology, 2000, vol. 138: Full- R99805 angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Length
Members of this family are involved in a A. E. I. Proudfoot; T. N.
C. Wells, and similarly diverse range of pathologies and C. A.
Power. Humana Press Mature including inflammation, allergy, tissue
Inc., Totowa, NJ; and Holmes et al rejection, viral infection, and
tumor (1991) Science 253, 1278-80. biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Chemo-
GeneSeq WO9613587 Chemokines are a family of related Chemokine
activities can be Cancer and blood-related kine-like Accessions
small, secreted proteins determined using assays known in
disorders, particularly protein R99817 involved in biological
processes the art: Methods in Molecular myelosuppression. IL - 8M8
and ranging from hematopoiesis, Biology, 2000, vol. 138: Full-
R99806 angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Length Members of this family are involved in
a A. E. I. Proudfoot; T. N. C. Wells, and similarly diverse range
of pathologies and C. A. Power. Humana Press Mature including
inflammation, allergy, tissue Inc., Totowa, NJ; and Holmes et al
rejection, viral infection, and tumor (1991) Science 253, 1278-80.
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Chemo- GeneSeq WO9613587 Chemokines are a family of
related Chemokine activities can be Cancer and blood-related
kine-like Accessions small, secreted proteins determined using
assays known in disorders, particularly protein R99818 involved in
biological processes the art: Methods in Molecular
myelosuppression. IL - 8M8 and ranging from hematopoiesis, Biology,
2000, vol. 138: Full- R99804 angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Length Members of this
family are involved in a A. E. I. Proudfoot; T. N. C. Wells, and
similarly diverse range of pathologies and C. A. Power. Humana
Press Mature including inflammation, allergy, tissue Inc., Totowa,
NJ; and Holmes et al rejection, viral infection, and tumor (1991)
Science 253, 1278-80. biology. The chemokines exert their effects
by acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Chemo- GeneSeq WO9613587
Chemokines are a family of related Chemokine activities can be
Cancer and blood-related kine-like Accessions small, secreted
proteins determined using assays known in disorders, particularly
protein R99819 involved in biological processes the art: Methods in
Molecular myelosuppression. IL - 8M8 and ranging from
hematopoiesis, Biology, 2000, vol. 138: Full- R99807 angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Length
Members of this family are involved in a A. E. I. Proudfoot; T. N.
C. Wells, and similarly diverse range of pathologies and C. A.
Power. Humana Press Mature including inflammation, allergy, tissue
Inc., Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Chemo- GeneSeq WO9613587 Chemokines are a family of
related Chemokine activities can be Cancer and blood-related
kine-like Accessions small, secreted proteins determined using
assays known in disorders, particularly protein R99822 and involved
in biological processes the art: Methods in Molecular
myelosuppression. IL - 8M8 R9807 ranging from hematopoiesis,
Biology, 2000, vol. 138: Full- angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Length Members of this
family are involved in a A. E. I. Proudfoot; T. N. C. Wells, and
similarly diverse range of pathologies and C. A. Power. Humana
Press Mature including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17
receptors thus far identified. Human GeneSeq WO9622374 Chemokines
are a family of related Chemokine activities can be Immune
disorders foetal Accession small, secreted proteins determined
using assays known in spleen R98499 involved in biological
processes the art: Methods in Molecular expressed ranging from
hematopoiesis, Biology, 2000, vol. 138: chemokine, angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: FSEC
Members of this family are involved in a A. E. I. Proudfoot; T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Liver
GeneSeq WO9616979 Chemokines are a family of related Chemokine
activities can be Inflammation of the liver expressed Accession
small, secreted proteins determined using assasys known in
chemokine-1 R95689 involved in biological processes the art:
Methods in Molecular (LVEC-1) ranging from hematopoiesis, Biology,
2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot; T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Liver GeneSeq WO9616979 Chemokines are a
family of related Chemokine activities can be Inflammation of the
liver expressed Accession small, secreted proteins determined using
assasys known in chemokine-2 R95690 involved in biological
processes the art: Methods in Molecular (LVEC-2) ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot; T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Pituitary GeneSeq
WO9616979 Chemokines are a family of related Chemokine activities
can be Inflammation, particularly of expressed Accession small,
secreted proteins determined using assasys known in the liver
chemokine R95691 involved in biological processes the art: Methods
in Molecular (PGEC) ranging from hematopoiesis, Biology, 2000, vol.
138: angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot; T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Adenoid- GeneSeq WO9617868 Chemokines are a family
of related Chemokine activities can be Inflammation, angiogenesis,
expressed Accession small, secreted proteins determined using
assasys known in tumorigenesis, chemokine R97664 involved in
biological processes the art: Methods in Molecular musculoskeletal
disorders (ADEC) ranging from hematopoiesis, Biology, 2000, vol.
138: angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot; T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO9741230 Chemokines are a family of
related Chemokine activities can be Immune disorders, chemokineCC-
Accession small, secreted proteins determined using assays known in
cell migration, 2 W38170 involved in biological processes the art:
Methods in Molecular proliferation, and ranging from hematopoiesis,
Biology, 2000, vol. 138; differentiation disorders angiogenesis,
and leukocyte trafficking. Chemokine protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc. Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO9741230 Chemokines are a family of related Chemokine
activities can be Immune disorders, chemokine Accession small,
secreted proteins determined using assays known in cell migration,
HCC-1 W38171 involved in biological processes the art: Methods in
molecular proliferation, and ranging from hematopoiesis, Biology
2000, vol. 138: differentiation disorders angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells
similarly diverse range of pathologies and C. A. Power Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
WO9741230 Chemokines are a family of related Chemokine activities
can be Immune disorders, chemokine Accession small, secreted
proteins determined using assays known in cell migration, CC-3
W38172 involved in biological processes the art: Methods in
molecular proliferation and ranging from hematopiesis, Biology,
2000, vol. 138: differentiation disorders anglogenesis, and
leukocyte trafficking. Chemokine Protocols, Edited by Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Novel GeneSeq
WO9739126 Chemokines are a family of related Chemokine activities
can be Immune disorders, beta- Accession small, secreted proteins
determined using assays known in vascular disorders, chemokine
W27271 involved in biological processes the art: Methods in
molecular cancer designated ranging from hematopoiesis, Biology,
2000, vol. 138: PTEC anglogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9727299 Chemokines are a
family of related Chemokine activities can be Immune disorders,
CX3C Accession small, secreted proteins determined using assays
known in inflammatory diseases, 111 amino W23344 involved in
biological processes the art: Methods in molecular abnormal
proliferation, acid ranging from hematopoiesis, Biology, 2000, vol.
138: regeneration, chemokine anglogenesis, and leukocyte
trafficking. Chemokine Protocols, Edited by degeneration, and
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, atrophy similarly diverse range of pathologies and C. A.
Power Humana Press including inflammation, allergy, tissue Inc.,
Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Human GeneSeq WO9721812 Chemokines are a family of
related Chemokine activities can be Abnormal physiology and CCF18
Accession small, secreted proteins determined using assays known in
development disorders, chemokine W25942 involved in biological
processes the art: Methods in molecular can also be used as an
ranging from hematopoiesis, Biology, 2000, vol. 138: anti-viral
agent anglogenesis, and leukocyte trafficking. Chemokine Protocols,
Edited by Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO9725427 Chemokines are a family of
related Chemokine activities can be Chemotaxis, blood-related beta-
Accession small, secreted proteins determined using assays known in
disorders, viral infection, chemokine W26655 involved in biological
processes the art: Methods in molecular HIV, wound healing, cancer
H1305 ranging from hematopoiesis, Biology, 2000, vol. 138: (MCP-2)
anglogenesis, and leukocyte trafficking. Chemokine Protocols,
Edited by Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO9712914 Chemokines are a family of
related Chemokine activities can be Inflammatory and eosino-
Accession small, secreted proteins determined using assays known in
immune disorders cyte CC W14990 involved in biological processes
the art: Methods in molecular type ranging from hematopoiesis,
Biology, 2000, vol. 138:
chemokine anglogenesis, and leukocyte trafficking. Chemokine
Protocols, Edited by eotaxin Members of this family are involved in
a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9711969 Chemokines are a
family of related Chemokine activities can be Inflammatory and
immune thymus Accession small, secreted proteins determined using
assays known in disorders and W14018 involved in biological
processes the art: Methods in molecular activation ranging from
hematopoiesis, Biology, 2000, vol. 138: regulated anglogenesis, and
leukocyte trafficking. Chemokine Protocols, Edited by cytokine
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, (TARC) similarly diverse range of pathologies and C. A.
Power Humana Press including inflammation, allergy, tissue Inc.,
Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Human GeneSeq WO9712041 Chemokines are a family of
related Chemokine activities can be Cancer, chemokine Accession
small, secreted proteins determined using assays known in wound
healing, beta- W16315 involved in biological processes the art:
Methods in molecular immune disorders 8 short ranging from
hematopoiesis, Biology, 2000, vol. 138: forms anglogenesis, and
leukocyte trafficking. Chemokine Protocols, Edited by Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Microphage GeneSeq
WO9640923 Chemokines are a family of related Chemokine activities
can be Inflammatory diseases, derived Accession small, secreted
proteins determined using assays known in wound healin, chemokine,
W20058 involved in biological processes the art: Methods in
Molecular angiogenesis MDC ranging from hematopoiesis, Biology,
2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9844117 Chemokines are a
family of related Chemokine activities can be Inflammatory and
chemokine Accession small, secreted proteins determined using
assays known in immune diseases ZSIG-35 W30565 involved in
biological processes the art: Methods in Molecular ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Primate GeneSeq
WO98328658 Chemokines are a family of related Chemokine activities
can be Immune and CC Accesssion small, secreted proteins involved
in determined using assays known in inflammatory disorders,
chemokine W69990 biological processes ranging from the art: Methods
in Molecular abnormal proliferation, "ILINCK" hematopoiesis,
angiogenesis, and Biology, 2000, vol. 138: regeneration, leukocyte
trafficking. Chemokine Protocols. Edited by: generation and A. E.
I. Proudfoot, T. N. C. Wells, atrophy disorders and C. A. Power.
Humana Press Inc., Totowa, NJ Primate GeneSeq WO9832858 Chemokines
are a family of related Chemokine activities can be Immune and CXC
Accession small, secreted proteins determined using assays known in
inflammatory disorders, chemokine W69989 involved in biological
processes the art: Methods in Molecular abnormal proliferation,
"IBICK" ranging from hematopoiesis, Biology, 2000, vol. 138:
regeneration, angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Editd by. generation and Members of this family are
involved in a A. E. I. Proudfoot, T. N. C. Wells, atrophy disorders
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO9831809 Chemokines are a family of related Chemokine
activities can be Immune, CC-type Accession small, secreted
proteins determined using assays known in inflammatory, and
chemokine W69163 involved in biological processes the art: Methods
in Molecular infectious disorders, protein ranging from
hematopoiesis, Biology, 2000, vol. 138: cancer designated
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: SLC Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, (secondary similarly diverse range of
pathologies and C. A. Power. Humana Press lymphoid including
inflammation, allergy, tissue Inc., Totowa, NJ chemokine)
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO9826071 Chemokines are a family of related Chemokine
activities can be Cancer and CC Accession small, secreted proteins
determined using assays known in infectious diseases, chemokine
W62542 involved in biological processes the art: Methods in
Molecular particularly ELC ranging from hematopoiesis, Biology,
2000, vol. 138: herpes virus protein angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
Wo9823750 Chemokines are a family of related Chemokine activities
can be Abnormal proliferation, DVic-1 Accession small, secreted
proteins determined using assays known in regeneration, C-C W60649
involved in biological processes the art: Methods in Molecular
degeneration, and chemokine ranging from hematopoiesis, Biology,
2000, vol. 138: atrophy disorders, angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: including cancer
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO9823750 Chemokines are a family of related Chemokine
activities can be Immune disorders, C-C Accession small, secreted
proteins determined using assays known in cell proliferation
chemokine W60650 involved in biological processes the art: Methods
in Molecular disorders, cancer DGWCC ranging from hematopoiesis,
Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9824907 Chemokines are a
family of related Chemokine activities can be Immune disorders,
STCP-1 Accession small, secreted proteins determined using assays
known in particularly T cell W62783 involved in biological
processes the art: Methods in Molecular related disorders, ranging
from hematopoiesis, Biology, 2000, vol. 138: viral infection, and
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: inflammation, Members of this family are involved in a
A. E. I. Proudfoot, T. N. C. Wells, especially joint similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Exodua GeneSeq
WO9821330 Chemokines are a family of related Chemokine activities
can be Immune and protein Accession small, secreted proteins
determined using assays known in inflammatory disorders, W61279
involved in biological processes the art: Methods in Molecular
angiogenesis, cancer, ranging from hematopoiesis, Biology, 2000,
vol. 138: and proliferation angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders,
particularly Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, myeloproliferative similarly diverse
range of pathologies and C. A. Power. Humana Press diseases
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified.
Human GeneSeq WO9814581 Chemokines are a family of related
Chemokine activities can be Cancer and Chr19Kine Acession small,
secreted proteins determined using assays known in degenerative
protein W50887 involved in biological processes the art: Methods in
Molecular disorders ranging from hematopoiesis, Biology, 2000, vol.
138: angiogenesis, and leukocyte trafficking. Chemokine Protocols,
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq U.S. Pat. No. Chemokines are a family
of related Chemokine activities can be Immune, T cell Accession
5,780,268 small, secreted proteins determined using assays known in
inflammatory, and mixed W58703 involved in biological processes the
art: Mehtods of Molecular infectious disorders, lymphocyte ranging
from hematopoiesis, Biology, 2000, vol. 138: cancer reaction
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: expressed Members of this family are involved in a A. E.
I. Proudfoot, T. N. C. Wells, chemokine similarly diverse range of
pathologies and C. A. Power Humana Press (TMEC) including
inflammation, allergy, tissue Inc., Totowa, NJ rejection, viral
infection, and tumor biology. The chemokines exert their effects by
acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Human GeneSeq W09814581
Chemokines are a family of related Chemokine activities can be
Cancer and 6CKine Accession small, secreted proteins determined
using assays known in degenerative protein W50885 involved in
biological processes the art: Mehtods of Molecular disorders
ranging from hematopoiesis, Biology, 2000, vol. 138: angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. human
GeneSeq WO9817800 Chemokines are a family of related Chemokine
activities can be Immune, liver Accession small, secreted proteins
determined using assays known in inflammatory, and and W57475
involved in biological processes the art: Mehtods of Molecular
infectious disorders, activation ranging from hematopoiesis,
Biology, 2000, vol. 138: cancer regulated angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by: chemokine
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, (LARC) similarly diverse range of pathologies and C. A.
Power Humana Press including inflammation, allergy, tissue Inc.,
Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. RANTES GeneSeq WO9744462 Chemokines are a family of
related Chemokine activities can be Infectious diseases, peptide
Accession small, secreted proteins determined using assays known in
particularly HIV W29538 involved in biological processes the art:
Mehtods of Molecular ranging from hematopoiesis, Biology, 2000,
vol. 138: angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. RANTES GeneSeq WO9744462 Chemokines are a
family of related Chemokine activities can be Infectious diseases,
8-68 Accession small, secreted proteins determined using assays
known in particularly HIV W29529 involved in biological processes
the art: Mehtods of Molecular ranging from hematopoiesis, Biology,
2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. RANTES GeneSeq WO9744462 Chemokines are a
family of related Chemokine activities can be Infectious diseases,
9-68 Accession small, secreted proteins determined using assays
known in particularly HIV W29528 involved in biological processes
the art: Mehtods of Molecular ranging from hematopoiesis, Biology,
2000, vol. 138: angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9811226 Chemokines are a
family of related Chemokine activities can be Abnormal
proliferation, chemokine Accession small, secreted proteins
determined using assays known in regeneration, protein W59433
involved in biological processes the art: Mehtods of Molecular
degeneration or 331D5 ranging from hematopoiesis, Biology, 2000,
vol. 138: atrophy, including cancer angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power Humana Press including
inflammation, allergy, tissue Inc., Totowa, NJ rejection, viral
infection, and tumor biology. The chemokines exert their effects by
acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Human GeneSeq WO9811226
Chemokines are a family of related Chemokine activities can be
Abnormal proliferation, chemokine Accession small, secreted
proteins determined using assays known in regeneration, protein
W59430 involved in biological processes the art: Mehtods of
Molecular degeneration or 61164 ranging from hematopoiesis,
Biology, 2000, vol. 138: atrophy, including cancer angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Chemokine GeneSeq WO9809171 Chemokines are a family of related
Chemokine activities can be Immune, MCP-4 Accession small, secreted
proteins determined using assays known in Inflammatory, and W56690
involved in biological processes the art: Mehtods of Molecular
infectious diseases ranging from hematopoiesis, Biology, 2000, vol.
138: angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq FR2751658 Chemokines are a family of
related Chemokine activities can be HIV infections stromal
Accession small, secreted proteins determined using assays known in
cell- W50766 involved in biological processes the art: Methods in
Molecular derived ranging from hematopoiesis, Biology, 2000, vol.
138: chemokine, angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: SDF-1 Members of this family are involved in
a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Thymus GeneSeq WO9801557 Chemokines are a
family of related Chemokine activities can be Immune and expressed
Accession small, secreted proteins determined using assays known in
inflammatory chemokine W44397 involved in biological processes the
art: Methods in Molecular disorders (TECK) ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
WO9801557 Chemokines are a family of related Chemokine activities
can be Immune and inflammatory chemokine Accession small, secreted
proteins determined using assays known in disorders MIP- W44398
involved in biological processes the art: Methods in Molecular
3alpha ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO9801557 Chemokines are a family of related Chemokine
activities can be Immune and chemokine Accession small, secreted
proteins determined using assays known in inflammatory MIP- W44399
involved in biological processes the art: Methods in Molecular
disorders 3beta ranging from hematopoiesis, Biology, 2000, vol.
138: angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO9802459 Chemokines are a family of
related Chemokine activities can be Immune disorders, respiratory
monocyte Accession small, secreted proteins determined using assays
known in disorders, cancer chemotactic W42072 involved in
biological processes the art: Methods in Molecular proprotein
ranging from hematopoiesis, Biology, 2000, vol. 138: (MCPP)
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: sequence Members of this family are involved in a A. E.
I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Macrophage- GeneSeq U.S. Pat. No. Chemokines
are a family of related Chemokine activities can be Immune, and
derived Accessions 5,688,927/ small, secreted proteins determined
using assays known in inflammatory chemokine W40811 U.S. Pat. No.
involved in biological processes the art: Methods in Molecular
disorders, (MDC) and 5,932,703 ranging from hematopoiesis, Biology,
2000, vol. 138: cancer Y24414 angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Macrophage GeneSeq
U.S. Pat. No. Chemokines are a family of related Chemokine
activities can be Immune and derived Accession 5,932,703 small,
secreted proteins determined using assays known in inflammatory
chemokine Y24416 involved in biological processes the art: Methods
in Molecular disorders analogue ranging from hematopoiesis,
Biology, 2000, vol. 138: MDC-eyfy angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Macrophage GeneSeq
U.S. Pat. No. Chemokines are a family of related Chemokine
activities can be Immune and derived Accession 5,932,703 small,
secreted proteins determined using assays known in inflammatory
chemokine Y24413 involved in biological processes the art: Methods
in Molecular disorders analogue ranging from hematopoiesis,
Biology, 2000, vol. 138: MDC angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: (n + 1) Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Macrophage GeneSeq U.S. Pat. No. Chemokines are a family of related
Chemokine activities can be Immune and derived Accession 5,932,703
small, secreted proteins determined using assays known in
inflammatory chemokine Y24415 involved in biological processes the
art: Methods in Molecular disorders analogue ranging from
hematopoiesis, Biology, 2000, vol. 138: MDC-yl angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by: Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq JP11243960 Chemokines are a family of related Chemokine
activities can be Allergic diseases type CC Accession small,
secreted proteins determined using assays known in and HIV
chemokine Y43178 involved in biological processes the art: Methods
in Molecular infection eotaxin 3 ranging from hematopoiesis,
Biology, 2000, vol. 138: protein angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: sequence Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO9946392 Chemokines are a family of related Chemokine
activities can be Cancer and immune disorders, MCP-3 and Acession
small, secreted proteins determined using assays known in
particularly HIV infection human Y29893 involved in biological
processes the art: Methods in Molecular Muc-1 ranging from
hematopoiesis, Biology, 2000, vol. 138: core angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by: epitope
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, (VNT) similarly diverse range of pathologies and C. A.
Power. Humana Press fusion including inflammation, allergy, tissue
Inc., Totowa, NJ protein rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO9946392 Chemokines are a family of
related Chemokine activities can be Cancer and immune disorders,
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assays known in particularly HIV infection human Y29894 involved in
biological processes the art: Methods in Molecular Muc-1 ranging
from hematopoiesis, Biology, 2000, vol. 138: core angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by: epitope
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, (VNT) similarly diverse range of pathologies and C. A.
Power. Humana Press fusion including inflammation, allergy, tissue
Inc., Totowa, NJ protein rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq W09946392 Chemokines are a family of
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assays known in particularly HIV infection HIV-1 Y29897 involved in
biological processes the art: Methods in Molecular gp 120 ranging
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and leukocyte trafficking. Chemokine Protocols. Edited by: variable
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, region similarly diverse range of pathologies and C. A.
Power. Humana Press fusion including inflammation, allergy, tissue
Inc., Totowa, NJ protein rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO9936540 Chemokines are a family of
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known in cancer associated Y29092 and involved in biological
processes the art: Methods in Molecular chemokine Y29093 ranging
from hematopoiesis, Biology, 2000, vol. 138: (MACK) angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: protein
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C. Wells, Full- similarly diverse range of pathologies and C. A.
Power. Humana Press Length including inflammation, allergy, tissue
Inc., Totowa, NJ and rejection, viral infection, and tumor Mature
biology. The chemokines exert their effects by acting on a family
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chemokines have been described, which bind to ~17 receptors thus
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protein Accession small, secreted proteins determined using assays
known in such as heart attacks and Y28290 involved in biological
processes the art: Methods in Molecular stroke, infection, physical
ranging from hematopoiesis, Biology, 2000, vol. 138: trauma, UV or
ionizing angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: radiation, burns, frostbite or Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
corrosive chemicals similarly diverse range of pathologies and C.
A. Power. Humana Press including inflammation, allergy, tissue
Inc., Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
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and leukocyte trafficking. Chemokine Protocols. Edited by: Mature
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N. C. Wells, protein Y17275 similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. N-terminal GeneSeq WO9920759 Chemokines are a
family of related Chemokine activities can be Inhibit or stimulate
modified Accession small, secreted proteins determined using assays
known in angiogenesis, inhibit the chemokine Y05818 involved in
biological processes the art: Methods in Molecular binding of HIV
met- ranging from hematopoiesis, Biology, 2000, vol. 138: hSDF-1
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: alpha Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. N-terminal GeneSeq WO9920759 Chemokines are a
family of related Chemokine activities can be Inhibit or stimulate
modified Accession small, secreted proteins determined using assays
known in angiogenesis, inhibit the chemokine Y05819 involved in
biological processes the art: Methods in Molecular binding of HIV,
met- ranging from hematopoiesis, Biology, 2000, vol. 138:
antiinflammatory; hSDF-1 angiogenesis, and leukocyte trafficking.
chemokine Protocols. Edited by: immunosuppressant beta Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
N-terminal GeneSeq WO9920759 Chemokines are a family of related
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small, secreted proteins determined using assays known in
angiogenesis, inhibit the chemokine Y05820 involved in biological
processes the art: Methods in Molecular binding of HIV, GroHEK/
ranging from hematopoiesis, Biology, 2000, vol. 138:
antiinflammatory; hSDF- angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: immunosuppressant 1alpha Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
N-terminal GeneSeq WO9920759 Chemokines are a family of related
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small, secreted proteins determined using assays known in
angiogenesis, inhibit the chemokine Y05821 involved in biological
processes the art: Methods in Molecular binding of HIV, GroHEK/
ranging from hematopoiesis, Biology, 2000, vol. 138:
antiinflammatory; hSDF- angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: immunosuppressant 1beta. Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Chemokine GeneSeq WO9912968 Chemokines are a family of related
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inflammatory response, an Y14230 involved in biological processes
the art: Methods in Molecular immune response ranging from
hematopoiesis, Bilogy, 2000, vol. 138: orhaematopoietic cell-
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
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involved in a A. E. I. Proudfoot, T. N. C. Wells, vascular
indication; Cancer; similarly diverse range of pathologies and C.
A. Power. Humana Press enhance wound healing, to including
inflammation, allergy, tissue Inc., Totowa, NJ prevent or treat
asthma, rejection, viral infection, and tumor organ transplant
rejction, biology. The chemokines exert their rheumatoid arthritis
effects by acting on a family of seven or allergy transmembrane
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described, which bind to ~17 receptors thus far identified.
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disorders, Wound healing, Y14225 involved in biological processes
the art: Methods in Molecular cancer, prevent organ ranging from
hematopoiesis, Bilogy, 2000, vol. 138: transplant rejection,
Increase angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: or enhance an inflammatory Members of this
family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
response, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Chemokine GeneSeq WO9912968 Chemokines are a family of related
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disorders, Wound healing, Y14226 involved in biological processes
the art: Methods in Molecular cancer, prevent organ ranging from
hematopoiesis, Bilogy, 2000, vol. 138: transplant rejection,
Increase angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: or enhance an inflammatory Members of this
family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
response, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Chemokine GeneSeq WO9912968 Chemokines are a family of related
Chemokine activities can be Immune disorders, Vascular hSDF1b
Accession small, secreted proteins determined using assays known in
disorders, Wound healing, Y14228 involved in biological processes
the art: Methods in Molecular cancer, prevent organ ranging from
hematopoiesis, Bilogy, 2000, vol. 138: transplant rejection,
Increase angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: or enhance an inflammatory Members of this
family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
response, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Chemokine GeneSeq WO9912968 Chemokines are a family of related
Chemokine activities can be Immune disorders, Vascular hIL-8
Accession small, secreted proteins determined using assays known in
disorders, Wound healing, Y14229 involved in biological processes
the art: Methods in Molecular cancer, prevent organ ranging from
hematopoiesis, Bilogy, 2000, vol. 138: transplant rejection,
Increase angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: or enhance an inflammatory Members of this
family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
response, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ; and Holmes et al rejection, viral infection, and tumor (1991)
Science 253, 1278-80. biology. The chemokines exert their effects
by acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968
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cancer, prevent organ ranging from hematopoiesis, Bilogy, 2000,
vol. 138: transplant rejection, Increase angiogenesis, and
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an inflammatory Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, response, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a
family of related Chemokine activities can be Immune disorders,
Vascular hMCP2 Accession small, secreted proteins determined using
assays known in disorders, Wound healing, Y14223 involved in
biological processes the art: Methods in Molecular cancer, prevent
organ ranging from hematopoiesis, Bilogy, 2000, vol. 138:
transplant rejection, Increase angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: or enhance an
inflammatory Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, response, similarly diverse range of
pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Chemokine GeneSeq
WO9912968 Chemokines are a family of related Chemokine activities
can be Immune disorders, Vascular hMCP3 Accession small, secreted
proteins determined using assays known disorders, Wound healing,
Y14224 involved in biological processes in the art: Methods in
Molecular cancer, prevent organ ranging from hematopoiesis, Bilogy,
2000, vol. 138: transplant rejection, Increase angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by: or enhance
an inflammatory Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, response, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. C-C GeneSeq EP905240 Chemokines are a family
of related Chemokine activities can be Inflammatory, Immune and
chemokine, Accession small, secreted proteins involved in
determined using assays known in infectious diseases; pulmonary
MCP2 Y05300 biological processes ranging from the art: Methods in
Molecular diseases and skin hematopoiesis, angiogenesis, and
Bilogy, 2000, vol. 138: disorders; tumours, and leukocyte
trafficking. Chemokine Protocols. Edited by: angiogenesis-and
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, haematopoiesis-related similarly diverse range of
pathologies and C. A. Power. Humana Press diseases including
inflammation, allergy, tissue Inc., Totowa, NJ rejection, viralk
infection, and tumor biology. The chemokines exert their effects by
acting on a family of seven transmembrane G-protein-coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Wild type GeneSeq EP906954
Chemokines are a family of related Chemokine activities can be
Inflammatory, Immune and monocyte Accession small, secreted
proteins involved in determined using assays known in infectious
diseases; pulmonary chemotactic Y07233 biological processes ranging
from the art: Methods in Molecular diseases and skin disorders;
protein 2 hematopoiesis, angiogenesis, and Bilogy, 2000, vol. 138:
tumours, and angiogenesis- leukocyte trafficking. Chemokine
Protocols. Edited by: and haematopoiesis-related Members of this
family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
diseases similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viralk infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein-coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Truncated GeneSeq EP906954 Chemokines are a family of related
Chemokines activities can be Inflammatory, immune and monocyte
Accession small, secreted proteins determined using assays known in
infectious diseases; pulmonry chemotactic Y07234 involved in
biological processes the art: Methods in Molecular diseases and
skin disorders; protein 2 ranging from hematopoiesis, Biology,
2000, vol. 138: tumours, and angiogenesis-and (6-76) angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by:
haematopoiesis-related Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, diseases similarly diverse range
of pathologies and C. A. Power, Humana Press including
inflammation, allergy, tissue Inc., Totowa, NJ rejection, viral
infection, and tumor biology. The chemokines exert their effects by
acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Truncated GeneSeq EP905241;
Chemokines are a family of related Chemokines activities can be
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proteins determined using assays known in infectious diseases;
pulmonry protein Y07236 involved in biological processes the art:
Methods in Molecular diseases and skin disorders; (3-68) and
ranging from hematopoiesis, Biology, 2000, vol. 138: tumours, and
angiogenesis-and Y07232 angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: haematopoiesis-related Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
diseases similarly diverse range of pathologies and C. A. Power,
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Wild
type GeneSeq EP905241 Chemokines are a family of related Chemokines
activities can be Inflammatory, immune and monocyte Accession
small, secreted proteins determined using assays known in
infectious diseases; pulmonry chemotactic Y07237 involved in
biological processes the art: Methods in Molecular diseases and
skin disorders; protein 2 ranging from hematopoiesis, Biology,
2000, vol. 138: tumours, and angiogenesis-and angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by:
haematopoiesis-related Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, diseases similarly diverse range
of pathologies and C. A. Power, Humana Press including
inflammation, allergy, tissue Inc., Totowa, NJ rejection, viral
infection, and tumor biology. The chemokines exert their effects by
acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Truncated GeneSeq EP905241
Chemokines are a family of related Chemokines activities can be
Inflammatory, immune and monocyte Accession small, secreted
proteins determined using assays known in infectious diseases;
pulmonry chemotactic Y07238 involved in biological processes the
art: Methods in Molecular diseases and skin disorders; protein
ranging from hematopoiesis, Biology, 2000, vol. 138: tumours, and
angiogenesis-and 2 (6-76) angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: haematopoiesis-related Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
diseases similarly diverse range of pathologies and C. A. Power,
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. A
partial GeneSeq EP897980 Chemokines are a family of related
Chemokines activities can be Soluble CXCR4B receptor CXCR4B
Accession small, secreted proteins determined using assays known in
polypeptides may be useful for protein W97363 involved in
biological processes the art: Methods in Molecular inhibiting
chemokine activities ranging from hematopoiesis, Biology, 2000,
vol. 138: and viral infection. angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power, Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Interferon GeneSeq
U.S. Pat. No. Chemokines are a family of related Chemokines
activities can be Angiogenesis, Cancer, gamma- Accession 5,871,723
small, secreted proteins determined using assays known in
Inflammatory and Immune inducible W96709 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
protein ranging from hematopoiesis, Biology, 2000, vol. 138:
discorders, Musco-skeletal (IP-10) angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power, Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. A
GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokines
activities can be Angiogenesis, Cancer, monokine Accession
5,871,723 small, secreted proteins determined using assays known in
Inflammatory and Immune induced W96710 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
by gamma- ranging from hematopoiesis, Biology, 2000, vol. 138:
discorders, Musco-skeletal interferon angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders (MIG)
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power,
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Inter-
GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokines
activities can be Angiogenesis, Cancer, leukin-8 Accession
5,871,723 small, secreted proteins determined using assays known in
Inflammatory and Immune (IL-8) W96711 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
protein. ranging from hematopoiesis, Biology, 2000, vol. 138:
discorders, Musco-skeletal angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: disorders Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power, Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ; and
Holmes et al rejection, viral infection, and tumor (1991) Science
253, 1278-80. biology. The chemokines exert their effects by acting
on a family of seven transmembrane G-protein coupled receptors.
Over 40 human chemokines have been described, which bind to ~17
receptors thus far identified. Epithelial GeneSeq U.S. Pat. No.
Chemokines are a family of related Chemokines activities can be
Angiogenesis, Cancer, neutrophil Accession 5,871,723 small,
secreted proteins determined using assays known in Inflammatory and
Immune activating W96712 involved in biological processes the art:
Methods in Molecular disorders, Cardio-Vascular protein-78 ranging
from hematopoiesis, Biology, 2000, vol. 138: discorders,
Musco-skeletal (ENA-78) angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: disorders
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power,
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Growth
GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokines
activities can be Angiogenesis, Cancer, related Accession 5,871,723
small, secreted proteins determined using assays known in
Inflammatory and Immune oncogene- W96713 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
alpha ranging from hematopoiesis, Biology, 2000, vol. 138:
discorders, Musco-skeletal (GRO- angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders alpha).
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power,
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Growth
GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine
activities can be Angiogenesis, Cancer, related Accession 5,871,723
small, secreted proteins determined using assays known in
Inflammatory and Immune oncogene- W96714 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
beta ranging from hematopoiesis, Biology, 2000, vol. 138:
disorders, Musco-skeletal (GRO- angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders beta).
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power,
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Growth
GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine
activities can be Angiogenesis, Cancer, related Accession 5,871,723
small, secreted proteins determined using assays known in
Inflammatory and Immune oncogene- W96715 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
gamma ranging from hematopoiesis, Biology, 2000, vol. 138:
disorders, Musco-skeletal (GRO- angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders gamma)
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, similarly diverse range of pathologies and C. A. Power,
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. A
GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine
activities can be Angiogenesis, Cancer, platelet Accession
5,871,723 small, secreted proteins determined using assays known in
Inflammatory and Immune basic W96716 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
protein ranging from hematopoiesis, Biology, 2000, vol. 138:
disorders, Musco-skeletal (PBP) angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power, Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Connective GeneSeq U.S. Pat. No. Chemokines are a family of related
Chemokine activities can be Angiogenesis, Cancer, tissue Accession
5,871,723 small, secreted proteins determined using assays known in
Inflammatory and Immune activating S96717 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
protein-III ranging from hematopoiesis, Biology, 2000, vol. 138:
disorders, Musco-skeletal (CTAP-III) angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power, Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Beta-
GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine
activities can be Angiogenesis, Cancer, thrombo- Accession
5,871,723 small, secreted proteins determined using assays known in
Inflammatory and Immune globulin W96718 involved in biological
processes the art: Methods in Molecular disorders, Cardio-Vascular
protein ranging from hematopoiesis, Biology, 2000, vol. 138:
disorders, Musco-skeletal (beta-TG) angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power, Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Neutrophil GeneSeq U.S. Pat. No. Chemokines are a family of related
Chemokine activities can be Angiogenesis, Cancer, activating
Accession 5,871,723 small, secreted proteins determined using
assays known in Inflammatory and Immune peptide-2 W96719 involved
in biological processes the art: Methods in Molecular disorders,
Cardio-Vascular (NAP-2) ranging from hematopoiesis, Biology, 2000,
vol. 138: disorders, Musco-skeletal angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: disorders Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power, Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified.
Granulocyte GeneSeq U.S. Pat. No. Chemokines are a family of
related Chemokine activities can be Angiogenesis, Cancer,
chemotactic Accession 5,871,723 small, secreted proteins determined
using assays known in Inflammatory and Immune protein-2 W96720
involved in biological processes the art: Methods in Molecular
disorders, Cardio-Vascular (GCP-2) ranging from hematopoiesis,
Biology, 2000, vol. 138: disorders, Musco-skeletal angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by:
disorders Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power, Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq EP887409 Chemokines are a family of
related Chemokine activities can be Immune disorders, viral,
chemokine Accession small, secreted proteins determined using
assays known in parasitic, fungal or MIG-beta W90124 involved in
biological processes the art: Methods in Molecular bacterial
protein ranging from hematopoiesis, Biology, 2000, vol. 138:
infections, Cancer; angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: autoimmune diseases or Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
transplant rejection similarly diverse range of pathologies and C.
A. Power, Humana Press including inflammation, allergy, tissue
Inc., Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Human GeneSeq WO9854326 Chemokines are a family of
related Chemokine activities can be Immune disorders, cancer,
ZCHEMO-8 Accession small, secreted proteins determined using assays
known in myelopoietic disorders, W82716 involved in biological
processes the art: Methods in Molecular autoimmune ranging from
hematopoiesis, Biology, 2000, vol. 138: disorders and angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by:
immunodeficiencies, Members of this family are involved in a A. E.
I. Proudfoot, T. N. C. Wells, Inflammatory and infectious similarly
diverse range of pathologies and C. A. Power, Humana Press
diseases, Vascular including inflammation, allergy, tissue Inc.,
Totowa, NJ disorders, rejection, viral infection, and tumor wound
healing biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO9854326 Chemokines are a
family of related Chemokine activities can be Immune disorders,
cancer, Act-2 Accession small, secreted proteins determined using
assays known in myelopoietic disorders, protein W82717 involved in
biological processes the art: Methods in Molecular autoimmune
ranging from hematopoiesis, Biology, 2000, vol. 138: disorders and
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: immunodeficiencies, Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, Inflammatory and
infectious similarly diverse range of pathologies and C. A. Power,
Humana Press diseases, Vascular including inflammation, allergy,
tissue Inc., Totowa, NJ disorders, rejection, viral infection, and
tumor wound healing biology. The chemokines exert their effects by
acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Human GeneSeq WO9854326
Chemokines are a family of related Chemokine activities can be
Immune disorders, cancer, SISD Acession small, secreted proteins
determined using assays known in myelopoietic disorders, protein
W82720 involved in biological processes the art: Methods in
Molecular autoimmune ranging from hematopoiesis, Biology, 2000,
vol. 138: disorders and angiogenesis, and leukocyte trafficking.
Chemokine Protocols, Edited by: immunodeficiencies,
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, Inflammatory and infectious similarly diverse range of
pathologies and C. A. Power. Humana Press diseases, Vascular
including inflammation, allergy, tissue Inc., Totowa, NJ disorders,
rejection, viral infection, and tumor wound healing biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Human GeneSeq WO9854326 Chemokines are a family of
related Chemokine activities can be Immune disorders, cancer, M110
Accession small, secreted proteins determined using assays known in
myelopoietic disorders, protein W82721 involved in biological
processes the art: Mehtods of Molecular autoimmune ranging from
hematopoiesis, Biology, 2000, vol. 138: disorders and angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by:
immunodeficiencies, Members of this family are involved in a A. E.
I. Proudfoot, T. N. C. Wells, Inflammatory and infectious similarly
diverse range of pathologies and C. A. Power Humana Press diseases,
Vascular including inflammation, allergy, tissue Inc., Totowa, NJ
disorders, rejection, viral infection, and tumor wound healing
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq W09854326 Chemokines are a family of
related Chemokine activities can be Immune disorders, cancer, M11A
Accession small, secreted proteins determined using assays known in
myelopoietic disorders, protein W82722 involved in biological
processes the art: Mehtods of Molecular autoimmune ranging from
hematopoiesis, Biology, 2000, vol. 138: disorders and angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by:
immunodeficiencies, Members of this family are involved in a A. E.
I. Proudfoot, T. N. C. Wells, Inflammatory and infectious similarly
diverse range of pathologies and C. A. Power Humana Press diseases,
Vascular including inflammation, allergy, tissue Inc., Totowa, NJ
disorders, rejection, viral infection, and tumor wound healing
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO9854326 Chemokines are a family of
related Chemokine activities can be Immune disorders, cancer, CCC3
Accession small, secreted proteins determined using assays known in
myelopoietic disorders, protein W82723 involved in biological
processes the art: Mehtods of Molecular autoimmune ranging from
hematopoiesis, Biology, 2000, vol. 138: disorders and angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by:
immunodeficiencies, Members of this family are involved in a A. E.
I. Proudfoot, T. N. C. Wells, Inflammatory and infectious similarly
diverse range of pathologies and C. A. Power Humana Press diseases,
Vascular including inflammation, allergy, tissue Inc., Totowa, NJ
disorders, rejection, viral infection, and tumor wound healing
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. A human GeneSeq WO9856818 Chemokines are a family
of related Chemokine activities can be Cancer, wound healing L105
Accession small, secreted proteins determined using assays known in
chemokine W87588 involved in biological processes the art: Mehtods
of Molecular designated ranging from hematopoiesis, Biology, 2000,
vol. 138: huL105_3. angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. A human GeneSeq WO9856818 Chemokines are a
family of related Chemokine activities can be Cancer, wound healing
L105 Accession small, secreted proteins determined using assays
known in chemokine W87589 involved in biological processes the art:
Mehtods of Molecular designated ranging from hematopoiesis,
Biology, 2000, vol. 138: huL105_7. angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power Humana Press including
inflammation, allergy, tissue Inc., Totowa, NJ rejection, viral
infection, and tumor biology. The chemokines exert their effects by
acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Human GeneSeq WO9848828
Chemokines are a family of related Chemokine activities can be
Infectious diseases, mature Accession small, secreted proteins
determined using assays known in sepsis gro-alpha W81498 involved
in biological processes the art: Mehtods of Molecular poly- ranging
from hematopoiesis, Biology, 2000, vol. 138: peptide angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: used to
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, treat similarly diverse range of pathologies and C. A.
Power Humana Press sepsis including inflammation, allergy, tissue
Inc., Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Human GeneSeq WO9848828 Chemokines are a family of
related Chemokine activities can be Infectious diseases, mature
Accession small, secreted proteins determined using assays known in
sepsis gro-gamma W81500 involved in biological processes the art:
Mehtods of Molecular poly- ranging from hematopoiesis, Biology,
2000, vol. 138: peptide angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: used to Members of this family are
involved in a A. E. I. Proudfoot, T. N. C. Wells, treat similarly
diverse range of pathologies and C. A. Power Humana Press sepsis
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
WO0053635 Chemokines are a family of related Chemokine activities
can be Inflammatory disorders, thymus Accessions small, secreted
proteins determined using assays known in cancer, expressed B19607
involved in biological processes the art: Mehtods of Molecular
Immune and vascular chemokine and ranging from hematopoiesis,
Biology, 2000, vol. 138: disorders TECK and B19608 angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: TECK
Members of this family are involved in a A. E. I. Proudfoot, T. N.
C. Wells, variant similarly diverse range of pathologies and C. A.
Power Humana Press including inflammation, allergy, tissue Inc.,
Totowa, NJ rejection, viral infection, and tumor biology. The
chemokines exert their effects by acting on a family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified. Human GeneSeq WO0042071 Chemokines are a family of
related Chemokine activities can be Autoimmune disorders, chemokine
Accession small, secreted proteins determined using assays known in
Immune, Vascular and SDF1alpha B15791 involved in biological
processes the art: Mehtods of Molecular Inflammatory disorders
ranging from hematopoiesis, Biology, 2000, vol. 138: angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO0042071 Chemokines are a family of related Chemokine
activities can be Autoimmune disorders, chemokine Accession small,
secreted proteins determined using assays known in Immune, Vascular
and GROalpha B15793 involved in biological processes the art:
Methods in Molecular Inflammatory diorders ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot; T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
WO0042071 Chemokines are a family of related Chemokine activities
can be Autoimmune disorders, chemokine Accession small, secreted
proteins determined using assays known in Immune, Vascular and
eotaxin B15794 involved in biological processes the art: Methods in
Molecular Inflammatory disorders ranging from hematopoiesis,
Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot; T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO0042071 Chemokines are a
family of related Chemokine activities can be Autoimmune disorders,
chemokine Accession small, secreted proteins determined using
assays known in Immune, Vascular and MIG B15803 involved in
biological processes the art: Methods in Molecular Inflammatory
disorders ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot; T. N. C. Wells, similarly diverse range of pathologies
and C.A Power. Humana Press including inflammation, allergy, tissue
Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO0042071 Chemokines are a family of
related Chemokine activities can be Autoimmune disorders, chemokine
Accession small, secreted proteins determined using assays known in
Immune, Vascular and PF4 B15804 involved in biological processes
the art: Methods in Molecular Inflammatory disorders ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot; T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
WO0042071 Chemokines are a family of related Chemokine activities
can be Autoimmune disorders, chemokine Accession small, secreted
proteins determined using assays known in Immune, Vascular and
I-309 B15805 involved in biological processes the art: Methods in
Molecular Inflammatory disorders ranging from hematopoiesis,
Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot; T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO0042071 Chemokines are a
family of related Chemokine activities can be Autoimmune disorders,
chemokine Accession small, secreted proteins determined using
assays known in Immune, Vascular and HCC-1 B15806 involved in
biological processes the art: Methods in Molecular Inflammatory
disorders ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot; T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO0042071 Chemokines are a family of
related Chemokine activities can be Autoimmune disorders, chemokine
Accession small, secreted proteins determined using assays known in
Immune, Vascular and C10 B15807 involved in biological processes
the art: Methods in Molecular Inflammatory disorders ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot; T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
WO0042071 Chemokines are a family of related Chemokine activities
can be Autoimmune disorders, chemokine Accession small, secreted
proteins determined using assays known in Immune, Vascular and
CCR-2 B15808 involved in biological processes the art: Methods in
Molecular Inflammatory disorders ranging from hematopoiesis,
Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot; T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO0042071 Chemokines are a
family of related Chemokine activities can be Autoimmune disorders,
chemokine Accession small, secreted proteins determined using
assays known in Immune, Vascular and ENA-78 B15809 involved in
biological processes the art: Methods in Molecular Inflammatory
disorders ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot; T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO0042071 Chemokines are a family of
related Chemokine activities can be Autoimmune disorders, chemokine
Accession small, secreted proteins determined using assays known in
Immune, Vascular and GRObeta B15810 involved in biological
processes the art: Methods in Molecular Inflammatory disorders
ranging from hematopoiesis, Biology, 2000, vol. 138: angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot; T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO0042071 Chemokines are a family of related Chemokine
activities can be Autoimmune disorders, chemokine Accession small,
secreted proteins determined using assays known in Immune, Vascular
and IP-10 B15811 involved in biological processes the art: Methods
in Molecular Inflammatory disorders ranging from hematopoiesis,
Biology, 2000, vol. 138: angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO0042071 Chemokines are a
family of related Chemokine activities can be Autoimmune disorders,
chemokine Accession small, secreted proteins determined using
assays known in Immune, Vascular and SDF1beta B15812 involved in
biological processes the art: Methods in Molecular Inflammatory
disorders ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq WO0042071 Chemokines are a family of
related Chemokine activities can be Autoimmune disorders, chemokine
Accession small, secreted proteins determined using assays known in
Immune, Vascular and GRO alpha B15813 involved in biological
processes the art: Methods in Molecular Inflammatory disorders
ranging from hematopoiesis, Biology, 2000, vol. 138: angiogenesis,
and leukocyte trafficking. Chemokine Protocols. Edited by: Members
of this family are involved in a A. E. I. Proudfoot, T. N. C.
Wells, similarly diverse range of pathologies and C. A. Power.
Humana Press including inflammation, allergy, tissue Inc., Totowa,
NJ rejection, viral infection, and tumor biology. The chemokines
exert their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO0042071 Chemokines are a family of related Chemokine
activities can be Autoimmune disorders, chemokine Accession small,
secreted proteins determined using assays known in Immune, Vascular
and MIP1beta B15831 involved in biological processes the art:
Methods in Molecular Inflammatory disorders ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. A human GeneSeq
U.S. Pat. No. Chemokines are a family of related Chemokine
activities can be Cancer C-C Accession 6,096,300 small, secreted
proteins determined using assays known in chemokine B07939 involved
in biological processes the art: Methods in Molecular designated
ranging from hematopoiesis, Biology, 2000, vol. 138: exodus
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq U.S. Pat. No. Chemokines are a family
of related Chemokine activities can be Chemotaxis, Gene Therapy,
chemokine Accession 6,084,071 small, secreted proteins determined
using assays known in Wound healing L105_7 Y96922 involved in
biological processes the art: Methods in
Molecular ranging from hematopoiesis, Biology, 2000, vol. 138:
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq U.S. Pat. No. Chemokines are a family
of related Chemokine activities can be Chemotaxis, Gene Therapy,
chemokine Accession 6,084,071 small, secreted proteins determined
using assays known in Wound healing L105_3 Y96923 involved in
biological processes the art: Methods in Molecular ranging from
hematopoiesis, Biology, 2000, vol. 138: angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
WO0038706 Chemokines are a family of related Chemokine activities
can be Cancer, Vascular and Immune secondary Accession small,
secreted proteins determined using assays known in disorders
lymphoid B01434 involved in biological processes the art: Methods
in Molecular chemokine ranging from hematopoiesis, Biology, 2000,
vol. 138: (SLC) angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO0029439 Chemokines are a
family of related Chemokine activities can be Immune and
Inflammatory non-ELR Accession small, secreted proteins determined
using assays known in disorders, Cancer, Haemostatic CXC Y96310
involved in biological processes the art: Methods in Molecular and
thrombolytic chemokine ranging from hematopoiesis, Biology, 2000,
vol. 138: activity H174 angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO0029439 Chemokines are a
family of related Chemokine activities can be Immune and
Inflammatory non-ELR Accession small, secreted proteins determined
using assays known in disorders, Cancer, haemostatic CXC Y96311
involved in biological processes the art: Methods in Molecular and
thrombolytic activity chemokine ranging from hematopoiesis,
Biology, 2000, vol. 138: IP10 angiogenesis, and leukocyte
trafficking. Chemokine Protocols. Edited by: Members of this family
are involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly
diverse range of pathologies and C. A. Power. Humana Press
including inflammation, allergy, tissue Inc., Totowa, NJ rejection,
viral infection, and tumor biology. The chemokines exert their
effects by acting on a family of seven transmembrane G-protein
coupled receptors. Over 40 human chemokines have been described,
which bind to ~17 receptors thus far identified. Human GeneSeq
WO0029439 Chemokines are a family of related Chemokine activities
can be Immune and Inflammatory non-ELR Accession small, secreted
proteins determined using assays known in disorders, Cancer,
haemostatic CXC Y96313 involved in biological processes the art:
Methods in Molecular and thrombolytic activity chemokine ranging
from hematopoiesis, Biology, 2000, vol. 138: Mig angiogenesis, and
leukocyte trafficking. Chemokine Protocols. Edited by: Members of
this family are involved in a A. E. I. Proudfoot, T. N. C. Wells,
similarly diverse range of pathologies and C. A. Power. Humana
Press including inflammation, allergy, tissue Inc., Totowa, NJ
rejection, viral infection, and tumor biology. The chemokines exert
their effects by acting on a family of seven transmembrane
G-protein coupled receptors. Over 40 human chemokines have been
described, which bind to ~17 receptors thus far identified. Human
GeneSeq WO0028035 Chemokines are a family of related Chemokine
activities can be Cancer, wound healing, chemokine Accession small,
secreted proteins determined using assays known in inflammatory and
Ckbeta-7 Y96280 involved in biological processes the art: Methods
in Molecular immunoregulatory ranging from hematopoiesis, Biology,
2000, vol. 138: disorders angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GeneSeq WO0028035 Chemokines are a
family of related Chemokine activities can be Cancer, wound
healing, chemokine Accession small, secreted proteins determined
using assays known in inflammatory and MIP-1alpha Y96281 involved
in biological processes the art: Methods in Molecular
immunoregulatory ranging from hematopoiesis, Biology, 2000, vol.
138: disorders angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified. Human GenSeq WO0028035 Chemokines are a family
of related Chemokine activities can be Cancer, wound healing,
mature Accession small, secreted proteins determined using assays
known in inflammatory and chemokine Y96282 involved in biological
processes the art: Methods in Molecular immunoregulatory Ckbeta-7
ranging from hematopoiesis, Biology, 2000, vol. 138: disorders
(optionally angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: truncated) Members of this family are
involved in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse
range of pathologies and C. A. Power. Humana Press including
inflammation, allergy, tissue Inc., Totowa, NJ rejection, viral
infection, and tumor biology. The chemokines exert their effects by
acting on a family of seven transmembrane G-protein coupled
receptors. Over 40 human chemokines have been described, which bind
to ~17 receptors thus far identified. Human GeneSeq WO0018431
Chemokines are a family of related Chemokine activities can be
Soluble CXCR3 polypeptides chemokine Accession small, secreted
proteins determined using assays known in may be useful for
inhibiting receptor Y79372 involved in biological processes the
art: Methods in Molecular chemokine activities and viral CXCR3
ranging from hematopoiesis, Biology, 2000, vol. 138: infection.
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq U.S. Pat. No. Chemokines are a family
of related Chemokine activities can be Neurological disorders,
neuro- Accession 6,043,086 small, secreted proteins determined
using assays known in Immune and respiratory tactin Y53259 involved
in biological processes the art: Methods in Molecular disorders
chemokine ranging from hematopoiesis, Biology, 2000, vol. 138: like
angiogenesis, and leukocyte trafficking. Chemokine Protocols.
Edited by: domain Members of this family are involved in a A. E. I.
Proudfoot, T. N. C. Wells, similarly diverse range of pathologies
and C. A. Power. Humana Press including inflammation, allergy,
tissue Inc., Totowa, NJ rejection, viral infection, and tumor
biology. The chemokines exert their effects by acting on a family
of seven transmembrane G-protein coupled receptors. Over 40 human
chemokines have been described, which bind to ~17 receptors thus
far identified. Human GeneSeq JP11302298 Chemokines are a family of
related Chemokine activities can be Cancer and infectious CC type
Accession small, secreted proteins determined using assays known in
diseases chemokine Y57771 involved in biological processes the art:
Methods in Molecular inter- ranging from hematopoiesis, Biology,
2000, vol. 138: leukin C angiogenesis, and leukocyte trafficking.
Chemokine Protocols. Edited by: Members of this family are involved
in a A. E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven transmembrane G-protein coupled receptors. Over 40
human chemokines have been described, which bind to ~17 receptors
thus far identified Human GeneSeq U.S. Pat. No. Chemokines are a
family of related Chemokine activities can be Cancer, Auto-immune
and CKbeta-9 Accession 6,153,441 small, secreted proteins
determined using assays known in inflammatory disorders, B50860
involved in biological processes the art: Methods in Molecular
Cardiovascular disorders ranging from hematopoiesis, Biology, 2000,
vol. 138: angiogenesis, and leukocyte trafficking. Chemokine
Protocols. Edited by: Members of this family are involved in a A.
E. I. Proudfoot, T. N. C. Wells, similarly diverse range of
pathologies and C. A. Power. Humana Press including inflammation,
allergy, tissue Inc., Totowa, NJ rejection, viral infection, and
tumor biology. The chemokines exert their effects by acting on a
family of seven
transmembrane G-protein coupled receptors. Over 40 human chemokines
have been described, which bind to ~17 receptors thus far
identified Prepro- GeneSeq WO9637608 Apoa-1 participates in the
reverse Lipid binding activity can be Useful for cardiovascular
apolipo- Accession transport of cholesterol from tissues determined
using assays known in disorders, cholesterol protein W08602 to the
liver for excretion by the art, such as, for example, the
disorders, and "paris" promoting cholesterol efflux Cholesterol
Efflux Assays of Hyperlipidaemia variant from tissues and by acting
as a Takahaski et al., P.N.A.S., Vol. 96, cofactor for the lecithin
cholesterol Issue 20, 11358-11363, Sep. acyltransferase (lcat). 28,
1999. Prepro- 5,721,114 Apoa-1 participates in the reverse Lipid
binding activity can be Useful for cardiovascular apolipo-
transport of cholesterol from tissues determined using assays known
in disorders, cholesterol protein to the liver for excretion by the
art, such as, for example, the disorders, and "milano" promoting
cholesterol efflux Cholesterol Efflux Assays of Hyperlipidaemia
variant from tissues and by acting as a Takahaski et al., P.N.A.S.,
Vol. 96, cofactor for the lecithin cholesterol Issue 20,
11358-11363, Sep. acyltransferase (lcat). 28, 1999. Glyco- GeneSeq
WO9628169 Naturally produced female Glycodelin-A activity can be
Naturally derived delin-A; Accession contraceptive that is removed
determined using the hemizona contraceptive useful for the Pro-
W00289 rapidly from the body assay as described in Oehninger, S.,
prevention of pregnancy. gesterone- following 2-3 days production.
Coddington, C. C., Hodgen, G. D., and associated Uses include
contraception Seppala, M (1995) Fertil. endometrial Steril. 63,
377-383. protein NOGO-A Genbank NOGO polypeptides are potent
Inhibition of Neurite outgrowth. NOGO-A polypeptide Accession
inhibitors of neurite growth. Antagonists to NOGO polypeptides
antagonists are useful for the CAB99248 may promote the outgrowth
of promotion of neural growth, neurites, thus inducing which could
be useful in the regeneration of neurons. treatment of neural
disorders and dysfunction due to degenerative diseases or trauma;
useful in the treatment of neoplastic diseases of the CNS; induce
regeneration of neurons or to promote the structural plasticity of
the CNS. NOGO-B Genbank NOGO polypeptides are potent Inhibition of
Neurite outgrowth. NOGO-B polypeptide Accession inhibitors of
neurite growth. Antagonists to NOGO polypeptides antagonists are
useful for the CAB99249 may promote the outgrowth of promotion of
neural growth, neurites, thus inducing which could be useful in the
regeneration of neurons. treatment of neural disorders and
dysfunction due to degenerative diseases or trauma; useful in the
treatment of neoplastic diseases of the CNS; induce regeneration of
neurons or to promote the structural plasticity of the CNS. NOGO-C
Genbank NOGO polypeptides are potent Inhibition of Neurite
outgrowth. NOGO-C polypeptide Accession inhibitors of neurite
growth. Antagonists to NOGO polypeptides antagonists are useful for
the CAB99250 may promote the outgrowth of promotion of neural
growth, neurites, thus inducing which could be useful in the
regeneration of neurons. treatment of neural disorders and
dysfunction due to degenerative diseases or trauma; useful in the
treatment of neoplastic diseases of the CNS; induce regeneration of
neurons or to promote the structural plasticity of the CNS. NOGO-66
Genbank NOGO polypeptides are potent Inhibition of Neurite
outgrowth by NOGO-66 receptor Receptor Accession inhibitors of
neurite growth, mediating the biological effects of polypeptides
are useful for the AAG53612 and are thought to mediate NOGO
polypeptides. Soluble promotion of neural growth, their effects
through the NOGO-66 NOGO-66 receptor polypeptides which could be
useful in the Receptor. may promote the outgrowth of treatment of
neural disorders neurites, thus inducing and dysfunction due to
regeneration of neurons. degenerative diseases or trauma; useful in
the treatment of neoplastic diseases of the CNS; induce
regeneration of neurons or to promote the structural plasticity of
the CNS. Antibodies U.S. Pat. No. These antibodies are useful for
the Collapsin activity, which is thought Useful for the promotion
of specific 5,416,197 promotion of neurite outgrowth to inhibit the
outgrowth of neurites, neural growth, which could be for can be
assayed in the presence of useful in the treatment of collapsin
antibodies specific for collapsing neural disorders and using
assays known in the art, such dysfunction due to as, for example,
the collapse assay degenerative diseases or disclosed by Luo et
al., Cell 1993 trauma. Oct. 22; 75(2): 217-27 Humanized WO9845331
These agents have anti-inflammatory VEGF activity can be determined
Promotion of growth and Anti- and anti-cancer applications using
assays known in the art, such proliferation of cells, such as VEGF
as those disclosed in International vascular endothelial cells.
Antibodies, Publication No. WO0045835, for Antagonists may be
useful as and example. anti-angiogenic agents, and fragments may be
applicable for cancer thereof Humanized WO0029584 These agents have
anti-inflammatory VEGF activity can be determined Promotion of
growth and Anti- and anti-cancer applications using assays known in
the art, such proliferation of cells, such as VEGF as those
disclosed in International vascular endothelial cells. Antibodies,
Publication No. WO0045835, for Antagonists may be useful as and
example. anti-angiogenic agents, and fragments may be applicable
for cancer thereof Membrane GeneSeq. WO9963088 Cancer, Immune
Disorders These proteins can be used for Activities can be
determined bound Accession linking bioactive molecules to cells
using assay known in the art, proteins Y66631- and for modulating
biological such as, for example, the Y66765 activities of cells,
using the assays disclosed in polypeptides for specific targeting.
International Publication No. The polypeptide targeting can be
WO0121658. used to kill the target cells, e.g. for the treatment of
cancers. These proteins are useful for the treatment of immune
system disorders. Secreted GenSeq WO0053756 Cancer, Immune
Disorders These proteins can be used for Activities can be
determined and Accession linking bioactive molecules to cells using
assay known in the art, Trans- B44241- and for modulating
biological such as, for example, the membrane B44334 activities of
cells, using the assays disclosed in poly- polypeptides for
specific targeting. International Publication No. peptides The
polypeptide targeting can be WO0121658 used to kill the target
cells, e.g. for the treatment of cancers. These proteins are useful
for the treatment of immune system disorders. Secreted GeneSeq
WO9946281 Cancer, Immune Disorders These proteins can be used for
Activities can be determined and Accession linking bioactive
molecules to cells using assay known in the art, Trans- Y41685- and
for modulating biological such as, for example, the membrane Y41774
activities of cells, using the assays disclosed in poly-
polypeptides for specific targeting. International Publication No.
peptides The polypeptide targeting can be WO0121658 used to kill
the target cells, e.g. for the treatment of cancers. These proteins
are useful for the treatment of immune system disorders.
Conjugation and Coupling
[0151] The present invention provides therapeutic agents comprising
an ELP component and a therapeutic component, such as therapeutic
proteins listed in Table 1, as well as a GLP-1 receptor agonists,
insulin, Factor VII/VIIa, and functional analogs as described. Such
agents may be prepared by recombinant technology and/or chemical
coupling (e.g., conjugation).
[0152] A recombinantly-produced ELP fusion protein, in accordance
with certain embodiments of the invention, includes the ELP
component and the therapeutic component associated with one another
by genetic fusion. For example, the fusion protein may be generated
by translation of a polynucleotide encoding the therapeutic
component cloned in-frame with the ELP component (or vice versa).
Such an ELP fusion protein may contain one or more copies of the
therapeutic component attached to the N-terminus and/or the
C-terminus of the ELP component. In some embodiments, the
therapeutic proteinacious component is attached to both the N- and
C-terminus of the ELP component and the fusion protein may contain
one or more equivalents of the therapeutic component on either or
both ends of the ELP component.
[0153] In certain embodiments, the ELP component and the
therapeutic components can be fused using a linker peptide of
various lengths to provide greater physical separation and allow
more spatial mobility between the fused portions, and thus maximize
the accessibility of the therapeutic component, for instance, for
binding to its cognate receptor. The linker peptide may consist of
amino acids that are flexible or more rigid. For example, a
flexible linker may include amino acids having relatively small
side chains, and which may be hydrophilic. Without limitation, the
flexible linker may contain a stretch of glycine and/or serine
residues. More rigid linkers may contain, for example, more
sterically hindering amino acid side chains, such as (without
limitation) tyrosine or histidine. The linker may be less than
about 50, 40, 30, 20, 10, or 5 amino acid residues. The linker can
be covalently linked to and between an ELP component and a
therapeutic component, for example, via recombinant fusion.
[0154] The linker or peptide spacer may be protease-cleavable or
non-cleavable. By way of example, cleavable peptide spacers
include, without limitation, a peptide sequence recognized by
proteases (in vitro or in vivo) of varying type, such as Tev,
thrombin, factor Xa, plasmin (blood proteases), metalloproteases,
cathepsins (e.g., GFLG, etc.), and proteases found in other
corporeal compartments. In some embodiments employing cleavable
linkers, the fusion protein ("the therapeutic agent") may be
inactive, less active, or less potent as a fusion, which is then
activated upon cleavage of the spacer in vivo. Alternatively, where
the therapeutic agent is sufficiently active as a fusion, a
non-cleavable spacer may be employed. The non-cleavable spacer may
be of any suitable type, including, for example, non-cleavable
spacer moieties having the formula [(Gly)n-Ser]m (SEQ ID NO.: 22)
where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive.
Alternatively, a short ELP sequence different than the backbone ELP
could be employed instead of a linker or spacer, while
accomplishing the necessary effect.
[0155] In still other embodiments, the therapeutic agent is a
recombinant fusion having a therapeutic component flanked on each
terminus by an ELP component. At least one of said ELP components
may be attached via a cleavable spacer, such that the therapeutic
component is inactive, but activated in vivo by proteolytic removal
of a single ELP component. The resulting single ELP fusion being
active, and having an enhanced half-life (or other property
described herein) in vivo.
[0156] In other embodiments, the present invention provides
chemical conjugates of the ELP component and the therapeutic
component. The conjugates can be made by chemically coupling an ELP
component to a therapeutic component by any number of methods well
known in the art (See e.g. Nilsson et al., 2005, Ann Rev Biophys
Bio Structure 34: 91-118). In some embodiments, the chemical
conjugate can be formed by covalently linking the therapeutic
component to the ELP component, directly or through a short or long
linker moiety, through one or more functional groups on the
therapeutic proteinacious component, e. g., amine, carboxyl,
phenyl, thiol or hydroxyl groups, to form a covalent conjugate.
Various conventional linkers can be used, e. g., diisocyanates,
diisothiocyanates, carbodiimides, bis (hydroxysuccinimide) esters,
maleimide-hydroxysuccinimide esters, glutaraldehyde and the
like.
[0157] Non-peptide chemical spacers can additionally be of any
suitable type, including for example, by functional linkers
described in Bioconjugate Techniques, Greg T. Hermanson, published
by Academic Press, Inc., 1995, and those specified in the
Cross-Linking Reagents Technical Handbook, available from Pierce
Biotechnology, Inc. (Rockford, Ill.), the disclosures of which are
hereby incorporated by reference, in their respective entireties.
Illustrative chemical spacers include homobifunctional linkers that
can attach to amine groups of Lys, as well as heterobifunctional
linkers that can attach to Cys at one terminus, and to Lys at the
other terminus.
[0158] In certain embodiments, relatively small ELP components
(e.g., ELP components of less than about 30 kDa, 25 kDa, 20 kDa, 15
kDa, or 10 kDa), that do not transition at room temperature (or
human body temperature, e.g., Tt>37.degree. C.), are chemically
coupled or crosslinked. For example, two relatively small ELP
components, having the same or different properties, may be
chemically coupled. Such coupling, in some embodiments, may take
place in vivo, by the addition of a single cysteine residue at or
around the C-terminus of the ELP. Such ELP components may each be
fused to one or more therapeutic components, so as to increase
activity or avidity at the target.
Polynucleotides, Vectors, and Host Cells
[0159] In another aspect, the invention provides polynucleotides
comprising a nucleotide sequence encoding the therapeutic agent of
the invention. Such polynucleotides further comprise, in addition
to sequences encoding the ELP and therapeutic components, one or
more expression control elements. For example, the polynucleotide,
may comprise one or more promoters or transcriptional enhancers,
ribosomal binding sites, transcription termination signals, and
polyadenylation signals, as expression control elements. The
polynucleotide may be inserted within any suitable vector, which
may be contained within any suitable host cell for expression.
[0160] A vector comprising the polynucleotide can be introduced
into a cell for expression of the therapeutic agent. The vector can
remain episomal or become chromosomally integrated, as long as the
insert encoding the therapeutic agent can be transcribed. Vectors
can be constructed by standard recombinant DNA technology. Vectors
can be plasmids, phages, cosmids, phagemids, viruses, or any other
types known in the art, which are used for replication and
expression in prokaryotic or eukaryotic cells. It will be
appreciated by one of skill in the art that a wide variety of
components known in the art (such as expression control elements)
may be included in such vectors, including a wide variety of
transcription signals, such as promoters and other sequences that
regulate the binding of RNA polymerase onto the promoter. Any
promoter known to be effective in the cells in which the vector
will be expressed can be used to initiate expression of the
therapeutic agent. Suitable promoters may be inducible or
constitutive. Examples of suitable promoters include the SV.sub.40
early promoter region, the promoter contained in the 3' long
terminal repeat of Rous sarcoma virus, the HSV-1 (herpes simplex
virus-1) thymidine kinase promoter, the regulatory sequences of the
metallothionein gene, etc., as well as the following animal
transcriptional control regions, which exhibit tissue specificity
and have been utilized in transgenic animals: elastase I gene
control region which is active in pancreatic acinar cells; insulin
gene control region which is active in pancreatic beta cells,
immunoglobulin gene control region which is active in lymphoid
cells, mouse mammary tumor virus control region which is active in
testicular, breast, lymphoid and mast cells, albumin gene control
region which is active in liver, alpha-fetoprotein gene control
region which is active in liver, alpha 1-antitrypsin gene control
region which is active in the liver, beta-globin gene control
region which is active in erythroid cells, myelin basic protein
gene control region which is active in oligodendrocyte cells in the
brain, myosin light chain-2 gene control region which is active in
skeletal muscle, and gonadotropin releasing hormone gene control
region which is active in the hypothalamus.
Pharmaceutical Compositions
[0161] The present invention further provides pharmaceutical
compositions comprising the therapeutic agents of the invention (as
described above) together with a pharmaceutically acceptable
carrier or excipient. Such pharmaceutical compositions may be
employed in the methods of treatment as described above, for each
of the therapeutic proteins, e.g., the therapeutic proteins listed
in Table 1, GLP-1 receptor agonists, insulin, and Factor VII/VIIa
embodiments.
[0162] The therapeutic agents of the invention may overcome certain
deficiencies of peptide agents when administered (e.g.,
parenterally), including in some embodiments, the limitation that
such peptides may be easily metabolized by plasma proteases or
cleared from circulation by kidney filtration. Traditionally, the
oral route of administration of peptide agents may also be
problematic, because in addition to proteolysis in the stomach, the
high acidity of the stomach destroys such peptide agents before
they reach their intended target tissue. Peptides and peptide
fragments produced by the action of gastric and pancreatic enzymes
are cleaved by exo and endopeptidases in the intestinal brush
border membrane to yield di- and tripeptides, and even if
proteolysis by pancreatic enzymes is avoided, polypeptides are
subject to degradation by brush border peptidases. Any of the
peptide agents that survive passage through the stomach are further
subjected to metabolism in the intestinal mucosa where a
penetration barrier prevents entry into the cells. In certain
embodiments, the therapeutic agents of the invention may overcome
such deficiencies, and provide compositional forms having enhanced
efficacy, bioavailability, therapeutic half-life, persistence,
degradation assistance, etc. The therapeutic agents of the
invention thus include oral and parenteral dose forms, as well as
various other dose forms, by which peptide agents can be utilized
in a highly effective manner. For example, in some embodiments,
such agents may achieve high mucosal absorption, and the
concomitant ability to use lower doses to elicit an optimum
therapeutic effect.
[0163] The therapeutic agents of the present invention may be
administered in smaller doses and/or less frequently than unfused
or unconjugated counterparts. While one of skill in the art can
determine the desirable dose in each case, a suitable dose of the
therapeutic agent for achievement of therapeutic benefit, may, for
example, be in a range of about 1 microgram (.mu.g) to about 100
milligrams (mg) per kilogram body weight of the recipient per day,
preferably in a range of about 10 .mu.g to about 50 mg per kilogram
body weight per day and most preferably in a range of about 10
.mu.g to about 50 mg per kilogram body weight per day. The desired
dose may be presented as one dose or two or more sub-doses
administered at appropriate intervals throughout the day. These
sub-doses can be administered in unit dosage forms, for example,
containing from about 10 .mu.g to about 1000 mg, preferably from
about 50 .mu.g to about 500 mg, and most preferably from about 50
.mu.g to about 250 mg of active ingredient per unit dosage form.
Alternatively, if the condition of the recipient so requires, the
doses may be administered as a continuous infusion.
[0164] The mode of administration and dosage forms will of course
affect the therapeutic amount of the peptide active therapeutic
agent that is desirable and efficacious for a given treatment
application. For example, orally administered dosages can be at
least twice, e.g., 2-10 times, the dosage levels used in parenteral
administration methods.
[0165] The therapeutic agents of the invention may be administered
per se as well as in various forms including pharmaceutically
acceptable esters, salts, and other physiologically functional
derivatives thereof. The present invention also contemplates
pharmaceutical formulations, both for veterinary and for human
medical use, which include therapeutic agents of the invention. In
such pharmaceutical and medicament formulations, the therapeutic
agents can be used together with one or more pharmaceutically
acceptable carrier(s) therefore and optionally any other
therapeutic ingredients. The carrier(s) must be pharmaceutically
acceptable in the sense of being compatible with the other
ingredients of the formulation and not unduly deleterious to the
recipient thereof. The therapeutic agents are provided in an amount
effective to achieve the desired pharmacological effect, as
described above, and in a quantity appropriate to achieve the
desired daily dose.
[0166] The formulations of the therapeutic agent include those
suitable for parenteral as well as non-parenteral administration,
and specific administration modalities include oral, rectal,
buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular,
intravenous, transdermal, intrathecal, intra-articular,
intra-arterial, sub-arachnoid, bronchial, lymphatic, vaginal, and
intra-uterine administration. Formulations suitable for oral and
parenteral administration are preferred.
[0167] When the therapeutic agent is used in a formulation
including a liquid solution, the formulation advantageously can be
administered orally or parenterally. When the therapeutic agent is
employed in a liquid suspension formulation or as a powder in a
biocompatible carrier formulation, the formulation may be
advantageously administered orally, rectally, or bronchially.
[0168] When the therapeutic agent is used directly in the form of a
powdered solid, the active agent can be advantageously administered
orally. Alternatively, it may be administered bronchially, via
nebulization of the powder in a carrier gas, to form a gaseous
dispersion of the powder which is inspired by the patient from a
breathing circuit comprising a suitable nebulizer device.
[0169] The formulations comprising the therapeutic agent of the
present invention may conveniently be presented in unit dosage
forms and may be prepared by any of the methods well known in the
art of pharmacy. Such methods generally include the step of
bringing the therapeutic agents into association with a carrier
which constitutes one or more accessory ingredients. Typically, the
formulations are prepared by uniformly and intimately bringing the
therapeutic agent into association with a liquid carrier, a finely
divided solid carrier, or both, and then, if necessary, shaping the
product into dosage forms of the desired formulation.
[0170] Formulations suitable for oral administration may be
presented as discrete units such as capsules, cachets, tablets, or
lozenges, each containing a predetermined amount of the active
ingredient as a powder or granules; or a suspension in an aqueous
liquor or a non-aqueous liquid, such as a syrup, an elixir, an
emulsion, or a draught.
[0171] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine, with the therapeutic
agent being in a free-flowing form such as a powder or granules
which optionally is mixed with a binder, disintegrant, lubricant,
inert diluent, surface active agent, or discharging agent. Molded
tablets comprised of a mixture of the powdered peptide active
therapeutic agent-ELF construct(s) with a suitable carrier may be
made by molding in a suitable machine.
[0172] A syrup may be made by adding the peptide active therapeutic
agent-ELF construct(s) to a concentrated aqueous solution of a
sugar, for example sucrose, to which may also be added any
accessory ingredient(s). Such accessory ingredient(s) may include
flavorings, suitable preservative, agents to retard crystallization
of the sugar, and agents to increase the solubility of any other
ingredient, such as a polyhydroxy alcohol, for example glycerol or
sorbitol.
[0173] Formulations suitable for parenteral administration
conveniently comprise a sterile aqueous preparation of the
therapeutic agent, which preferably is isotonic with the blood of
the recipient (e.g., physiological saline solution). Such
formulations may include suspending agents and thickening agents or
other microparticulate systems which are designed to target the
peptide active therapeutic agent to blood components or one or more
organs. The formulations may be presented in unit-dose or
multi-dose form.
[0174] Nasal spray formulations comprise purified aqueous solutions
of the therapeutic agent with preservative agents and isotonic
agents. Such formulations are preferably adjusted to a pH and
isotonic state compatible with the nasal mucus membranes.
[0175] Formulations for rectal administration may be presented as a
suppository with a suitable carrier such as cocoa butter,
hydrogenated fats, or hydrogenated fatty carboxylic acid.
[0176] Topical formulations comprise the therapeutic agent
dissolved or suspended in one or more media, such as mineral oil,
petroleum, polyhydroxy alcohols, or other bases used for topical
pharmaceutical formulations.
[0177] In addition to the aforementioned ingredients, the
formulations of this invention may further include one or more
accessory ingredient(s) selected from diluents, buffers, flavoring
agents, disintegrants, surface active agents, thickeners,
lubricants, preservatives (including antioxidants), and the
like.
[0178] The features and advantages of the present invention are
more fully shown with respect to the following non-limiting
examples.
EXAMPLES
Example 1
Construction of Various ELP Component Constructs
[0179] Cloning steps were conducted in Escherichia coli strain
XL1-Blue (rec A1, endA1, gyrA96, thi-1, hsdR17 (r.sub.k.sup.-,
m.sub.k.sup.+), supE44, re/A1, lac[F', proAB,
/.alpha.cI.sup.qZ.DELTA.M15, Tn10 (Tet.sup.r)] (Stratagene La
Jolla, Calif.). pUC19 (NEB, Beverly, Mass.) was used as the cloning
vector for the ELP construction (Meyer and Chilkoti, Nat.
Biotechnol., 17(11):1112-5, 1999). Modified forms of pET15b and
pET24d vectors (Novagen) were used to express ELP and ELP-fusion
proteins in BL21 Star (DE3) strain (F.sup.-, ompT, hsdS.sub.B
(r.sub.B.sup.- m.sub.B.sup.-), gal, dcm, me131, (DE3)) (Invitrogen
Carlsbed, Calif.) or BLR(DE3) (F.sup.-, ompT, hsdS.sub.B
(r.sub.B.sup.-m.sub.B.sup.-), gal, dcm, .DELTA.(srl-recA)
306::Tn10(TcR)(DE3)) (Novagen Madison, Wis.). Synthetic DNA oligos
were purchased from Integrated DNA Technologies, Coralville, Iowa
All vector constructs were made using standard molecular biology
protocols (e.g., Current Protocols in Molecular Biology, ed.
Ausubel, et al., 1995).
Construction of ELP1 [V.sub.5A.sub.2G.sub.3] Gene Series
[0180] The ELP1 [V.sub.5A.sub.2G.sub.3] series designate
polypeptides containing multiple repeating units of the
pentapeptide VPGXG (SEQ ID NO: 3), where X is valine, alanine, and
glycine at a relative ratio of 5:2:3.
[0181] The ELP1 [V.sub.5A.sub.2G.sub.3] series monomer, ELP1
[V.sub.5A.sub.2G.sub.3-10], was created by annealing four 5'
phosphorylated, PAGE purified synthetic oligos to form double
stranded DNA with EcoRI and HindIII compatible ends (Meyer and
Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). The oligos were
annealed in a 1 .mu.M mixture of the four oligos in 50 .mu.l IX
ligase buffer (Invitrogen) to 95.degree. C. in a heating block than
the block was allowed to cool slowly to room temperature. The ELP1
[V.sub.5A.sub.2G.sub.3-10]/EcoRI-HindIII DNA segment was ligated
into a pUC19 vector digested with EcoRI and HindIII and CIAP
dephosphorylated (Invitrogen) to form pUC19-ELP1
[V.sub.5A.sub.2G.sub.3-10]. Building of the ELP1
[V.sub.5A.sub.2G.sub.3] series library began by inserting ELP1
[V.sub.5A.sub.2G.sub.3-10] PfIMI/BgII fragment from pUC19-ELP1
[V.sub.5A.sub.2G.sub.3-10] into pUC19-ELP1
[V.sub.5A.sub.2G.sub.3-10] linearized with PfIMI and
dephosphorylated with CIAP to create pUC19-ELP1
[V.sub.5A.sub.2G.sub.3-20]. pUC19-ELP1 [V.sub.5A.sub.2G.sub.3-20]
was then built up to pUC19-ELP1 [V.sub.5A.sub.2G.sub.3-30] and
pUC19-ELP1 [V.sub.5A.sub.2G.sub.3-40] by ligating ELP1
[V.sub.5A.sub.2G.sub.3-10] or ELP1 [V.sub.5A.sub.2G.sub.3-20]
PfIMI/BgII fragments respectively into PfIMI digested pUC 19-ELP1
[V.sub.5A.sub.2G.sub.3-20]. This procedure was used to expand the
ELP1 [V.sub.5A.sub.2G.sub.3] series to create pUC19-ELP1
[V.sub.5A.sub.2G.sub.3-60], pUC19-ELP1 [V.sub.5A.sub.2G.sub.3-90]
and pUC19-ELP1 [V.sub.5A.sub.2G.sub.3-180] genes.
Construction of ELP1 [K.sub.1V.sub.2F.sub.1] Gene Series
[0182] The ELP1 [K.sub.1V.sub.2F.sub.1] series designate
polypeptides containing multiple repeating units of the
pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and
phenylalanine at a relative ratio of 1:2:1.
[0183] The ELP1 [K.sub.1V.sub.2F.sub.1] series monomer, ELP1
[K.sub.1V.sub.2F.sub.1-4], was created by annealing two 5'
phosphorylated, PAGE purified synthetic oligos to form double
stranded DNA with EcoRI and HindIII compatible ends (Meyer and
Chilkoti, 1999). The oligos were annealed in a 1 .mu.M mixture of
the four oligos in 50 .mu.l 1.times. ligase buffer (Invitrogen) to
95.degree. C. in a heating block then the block was allowed to cool
slowly to room temperature. The ELP1
[K.sub.1V.sub.2F.sub.1-4]/EcoRI-HindIII DNA segment was ligated
into a pUC19 vector digested with EcoRI and HindIII and CIAP
dephosphorylated (Invitrogen) to form pUC19-ELP1
[K.sub.1V.sub.2F.sub.1-4]. Building of the ELP1
[K.sub.1V.sub.2F.sub.1] series library began by inserting ELP1
[K.sub.1V.sub.2F.sub.1-4] Pf1M1/BgI1 fragment from pUC19-ELP1
[K.sub.1V.sub.2F.sub.1-4] into pUC19-ELP1 [K.sub.1V.sub.2F.sub.1-4]
linearized with Pf/M1 and dephosphorylated with CIAP to create
pUC19-ELP1 [K.sub.1V.sub.2F.sub.1-8]. Using the same procedure the
ELP1 [K.sub.1V.sub.2F.sub.1] series was doubled at each ligation to
form pUC19-ELP1 [K.sub.1V.sub.2F.sub.1-I6], pUC19-ELP1
[K.sub.1V.sub.2F.sub.1-32], pUC19-ELP1 [K.sub.1V.sub.2F.sub.1-64]
and pUC19-ELP1 [K.sub.1V.sub.2F.sub.1-128].
Construction of ELP1 [K.sub.1V.sub.7F.sub.1] Gene Series
[0184] The ELP1 [K.sub.1V.sub.7F.sub.1] series designate
polypeptides containing multiple repeating units of the
pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and
phenylalanine at a relative ratio of 1:7:1.
[0185] The ELP1 [K.sub.1V.sub.7F.sub.1] series monomer, ELP1
[K.sub.1V.sub.7F.sub.1-9], was created by annealing four 5'
phosphorylated, PAGE purified synthetic oligos to form double
stranded DNA with PfIMI and HindIII compatible ends. The ELP1
[K.sub.1V.sub.7F.sub.1-9] DNA segment was than ligated into
PfIM1/HindIII dephosphorylated PUC19-ELP1
[V.sub.5A.sub.2G.sub.3-180] vector thereby substituting ELP1
[V.sub.5A.sub.2G.sub.3-180] for ELP1 [K.sub.1V.sub.7F.sub.1-9] to
create the pUC19-ELP1 [K.sub.1V.sub.7F.sub.1-9] monomer. The ELP1
[K.sub.1V.sub.7F.sub.1] series was expanded in the same manner as
the ELP1 [K.sub.1V.sub.2F.sub.1] series to create pUC19-ELP1
[K.sub.1V.sub.7F.sub.1-18], PUC19-ELP1 [K.sub.1V.sub.7F.sub.1-36],
pUC19-ELP1 [K.sub.1V.sub.7F.sub.1-72] and pUC19-ELP1
[K.sub.1V.sub.7F.sub.1-144].
Construction of ELP1 [V] Gene Series
[0186] The ELP1 [V] series designate polypeptides containing
multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3),
where X is exclusively valine.
[0187] The ELP1 [V] series monomer, ELP1 [V-5], was created by
annealing two 5' phosphorylated, PAGE purified synthetic oligos to
form double stranded DNA with EcoRI and HindIII compatible ends.
The ELP1 [V-5] DNA segment was than ligated into EcoRI/HindIII
dephosphorylated pUC19 vector to create the pUC19-ELP1 [V-5]
monomer. The ELP1 [V] series was created in the same manner as the
ELP1 [V.sub.5A.sub.2G.sub.3] series, ultimately expanding
pUC19-ELP1 [V-5] to pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120].
Construction of ELP2 Gene Series
[0188] The ELP2 series designate polypeptides containing multiple
repeating units of the pentapeptide AVGVP.
[0189] The ELP2 series monomer, ELP2 [5], was created by annealing
two 5' phosphorylated, PAGE purified synthetic oligos to form
double stranded DNA with EcoRI and HindIII compatible ends. The
ELP2 [5] DNA segment was than ligated into EcoRI/HindIII
dephosphorylated pUC19 vector to create the pUC19-ELP2[5] monomer.
The ELP2 series was expanded in the same manner as the ELP1
[K.sub.1V.sub.2F.sub.1] series to create pUC19-ELP2[10], pUC19-ELP2
[30], pUC 19-ELP2 [60] and pUC 19-ELP2 [120].
Construction of ELP3 [V] Gene Series
[0190] The ELP3 [V] series designate polypeptides containing
multiple repeating units of the pentapeptide IPGXG (SEQ ID NO: 5),
where X is exclusively valine.
[0191] The ELP3 [V] series monomer, ELP3 [V-5], was created by
annealing two 5' phosphorylated, PAGE purified synthetic oligos to
form double stranded DNA with PfLM1 amino terminal and GGC carboxyl
terminal compatible ends due to the lack of a convenient carboxyl
terminal restriction site but still enable seamless addition of the
monomer. The ELP3 [V-5] DNA segment was then ligated into
PfIM1/BgII dephosphorylated pUC19-ELP4[V-5], thereby substituting
ELP4 [V-5] for ELP3 [V-5] to create the pUC19-ELP3 [V-5] monomer.
The ELP3 [V] series was expanded by ligating the annealed ELP3
oligos into pUC19-ELP3[V-5] digested with PfIMI. Each ligation
expands the ELP3 [V] series by 5 to create ELP3 [V-10], ELP3
[V-15], etc.
Construction of the ELP4 [V] Gene Series
[0192] The ELP4 [V] series designate polypeptides containing
multiple repeating units of the pentapeptide LPGXG (SEQ ID NO: 7),
where X is exclusively valine.
[0193] The ELP4 [V] series monomer, ELP4 [V-5], was created by
annealing two 5' phosphorylated, PAGE purified synthetic oligos to
form double stranded DNA with EcoRI and HindIII compatible ends.
The ELP4 [V-5] DNA segment was than ligated into EcoRI/HindIII
dephosphorylated pUC19 vector to create the pUC19-ELP4[V-5]
monomer. The ELP4 [V] series was expanded in the same manner as the
ELP1 [K.sub.1V.sub.2F.sub.1] series to create pUC19-ELP4[V-10],
pUC19-ELP4[V-30], pUC19-ELP4[V-60] and pUC19-ELP4[V-120].
[0194] The ELP genes were also inserted into other vectors such as
pET15b-SD0, pET15b-SD3, pET15b-SD5, pET15b-SD6, and pET24d-SD21.
The pET vector series are available from Novagen, San Diego,
Calif.
[0195] The pET15b-SD0 vector was formed by modifying the pET15b
vector using SD0 double-stranded DNA segment containing the
multicloning restriction site (SacI-NdeI-NcoI-XhoI-SnaBI-BamHI).
The SD0 double-stranded DNA segment had XbaI and BamHI compatible
ends and was ligated into XbaI/BamHI linearized and
5'-dephosphorylated pET15b to form the pet15b-SD0 vector.
[0196] The pET15b-SD3 vector was formed by modifying the pET15b-SD0
vector using SD3 double-stranded DNA segment containing a SfiI
restriction site upstream of a hinge region-thrombin cleavage site
followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The
SD3 double-stranded DNA segment had SacI and NdeI compatible ends
and was ligated into SacI/NdeI linearized and 5'-dephosphorylated
pET15b-SD0 to form the pET15b-SD3 vector.
[0197] The pET15b-SD5 vector was formed by modifying the pET15b-SD3
vector using the SD5 double-stranded DNA segment containing a SfiI
restriction site upstream of a thrombin cleavage site followed by a
hinge and the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The
SD5 double-stranded DNA segment had SfiI and NdeI compatible ends
and was ligated into SfiI/NdeI linearized and 5'-dephosphorylated
pET15b-SD3 to form the pET15b-SD5 vector.
[0198] The pET15b-SD6 vector was formed by modifying the pET15b-SD3
vector using the SD6 double-stranded DNA segment containing a SfiI
restriction site upstream of a linker region-TEV cleavage site
followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The
SD6 double-stranded DNA segment had SfiI and NheI compatible ends
and was ligated into SfiI/NdeI linearized and 5'-dephosphorylated
pET15b-SD3 to form the pET15b-SD6 vector.
[0199] The pET24d-SD21 vector was formed by modifying the pET24d
vector using the SD21 double-stranded DNA segment with NcoI and
NheI compatible ends. The SD21 double-stranded DNA segment was
ligated into NcoI/NheI linearized and 5' dephosphorylated pET24d to
create the pET24d-SD21 vector, which contained a new multi-cloning
site NcoI-SfiI-NheI-BamHI-EcoRI-SacI-SaII-HindIII-NotI-XhoI with
two stop codons directly after the SfiI site for insertion and
expression of ELP with the minimum number of extra amino acids.
[0200] The pUC19-ELP1 [V.sub.5A.sub.2G.sub.3-60], pUC19-ELP1
[V.sub.5A.sub.2G.sub.3-90], and pUC19-ELP1
[V.sub.5A.sub.2G.sub.3-180] plasmids produced in XL1-Blue were
digested with PfIMI and BgII, and the ELP-containing fragments were
ligated into the SfiI site of the pET15b-SD3 expression vector as
described hereinabove to create pET15b-SD3-ELP1
[V.sub.5A.sub.2G.sub.3-60], pET15b-SD5-ELP1
[V.sub.5A.sub.2G.sub.3-90] and pET15b-SD5-ELP1
[V.sub.5A.sub.2G.sub.3-180], respectively.
[0201] The pUC19-ELP1 [V.sub.5A.sub.2G.sub.3-90], pUC19-ELP1
[V.sub.5A.sub.2G.sub.3-180], pUC19-ELP1 [V-60] and pUC19-ELP1
[V-120] plasmids produced in XL1-Blue were digested with PfIMI and
BgII, and the ELP-containing fragments were ligated into the SfiI
site of the pET15b-SD5 expression vector as described hereinabove
to create pET15b-SD5-ELP1 [V.sub.5A.sub.2G.sub.3-90],
pET15b-SD5-ELP1 [V.sub.5A.sub.2G.sub.3-180], pET15b-SD5-ELP1 [V-60]
and pET15b-SD5-ELP1 [V-120], respectively.
[0202] The pUC19-ELP1 [V.sub.5A.sub.2G.sub.3-90] plasmid produced
in XL1-Blue was digested with PfIMI and BgII, and the
ELP-containing fragment was ligated into the SfiI site of the
pET15b-SD6 expression vector as described hereinabove to create
pET15b-SD6-ELP1 [V.sub.5A.sub.2G.sub.3-90].
[0203] The pUC19-ELP1 [K.sub.1V.sub.2F.sub.1-64], and pUC19-ELP1
[K.sub.1V.sub.2F.sub.1-128] plasmids produced in XL1-Blue were
digested with PfIMI and BgII, and the ELP-containing fragments were
ligated into the SfiI site of the pET24d-SD21 expression vector as
described hereinabove to create pET24d-SD21-ELP1
[K.sub.1V.sub.2F.sub.1-64] and pET24d-SD21-ELP1
[K.sub.1V.sub.2F.sub.1-128], respectively.
[0204] The pUC19-ELP1 [K.sub.1V.sub.7F.sub.1-72] and pUC19-ELP1
[K.sub.1V.sub.7F.sub.1-144] plasmids produced in XL1-Blue were
digested with PfIMI and BgII, and the ELP-containing fragments were
ligated into the SfiI site of the pET24d-SD21 expression vector as
described hereinabove to create pET24d-SD21-ELP1
[K.sub.1V.sub.7F.sub.1-72], pET24d-SD21-ELP1
[K.sub.1V.sub.7F.sub.1-144], respectively.
[0205] The pUC19-ELP2[60] and pUC19-ELP2[120] plasmids produced in
XL1-Blue were digested with NcoI and HindIII, and the
ELP-containing fragments were ligated into the NcoI and HindIII
sites of the pET24d-SD21 expression vector as described hereinabove
to create pET24d-SD21-ELP2[60], pET24d-SD21-ELP2[120],
respectively.
[0206] The pUC19-ELP4[V-60] and pUC19-ELP4[V-120] plasmids produced
in XL1-Blue were digested with NcoI and HindIII, and the
ELP-containing fragments were ligated into the NcoI and HindIII
sites of the pET24d-SD21 expression vector as described hereinabove
to create pET24d-SD21-ELP4[V-60], pET24d-SD21-ELP4[V-120],
respectively.
Example 2
Isolation and Purification of Fusion Proteins Containing Insulin a
Peptide (InsA)
[0207] ELP-InsA fusion proteins included the following:
[0208] Insulin A peptide and ELP1 [V-60] polypeptide with an
enterokinase protease cleavage site therebetween.
[0209] Insulin A peptide and ELP1 [V.sub.5A.sub.2G.sub.3-90]
polypeptide with an enterokinase protease cleavage site
therebetween.
[0210] Insulin A peptide and ELP1 [V-120] polypeptide with an
enterokinase protease cleavage site therebetween.
[0211] Insulin A peptide and ELP1 [V.sub.5A.sub.2G.sub.3-180]
polypeptide with an enterokinase protease cleavage site
therebetween.
[0212] A single colony of E. coli strain BLR (DE3) (Novagen)
containing the respective ELP-InsA fusion protein was inoculated
into 5 ml CircleGrow (Q-BIOgene, San Diego, Calif.) supplemented
with 100 .mu.g/ml ampicillin (Sigma) and grown at 37.degree. C.
with shaking at 250 rpm for 5 hours. The 5 ml culture was then
inoculated into a 500 ml culture and allowed to grow at 25.degree.
C. for 16 hours before inducing with 1 mM IPTG for 4 hours at
25.degree. C. The culture was harvested and suspended in 40 ml 20
mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and 1 Complete EDTA free
Protease inhibitor pellet (Roche, Indianapolis, Ind.). Cells were
lysed by ultrasonic disruption on ice for 3 minutes, which
consisted of 10 seconds bursts at 35% power separated by 30 second
cooling down intervals. Cell debris was removed by centrifugation
at 20,000 g, 4.degree. C. for 30 minutes.
[0213] Inverse phase transition was induced by adding NaCl to the
cell lysate at room temperature to achieve a final concentration of
1.0 M therein, followed by centrifugation at 20,000 g for 15
minutes at room temperature. The resulting pellet contained the
respective ELP-InsA fusion protein and non-specifically NaCl
precipitated proteins.
[0214] The pellet was re-suspended in 40 ml ice-cold ml 20 mM
Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and re-centrifuged at 20,000
g, 4.degree. C. for 15 minutes to remove the non-specifically NaCl
precipitated proteins. The inverse transition cycle was repeated
two additional times to increase the purity of the respective
ELP-InsA fusion protein and reduce the final volume to 0.5 ml.
Example 3
Half-Life of ELP1
[0215] The pharmacokinetics of ELP1 were determined by
intravenously administering [.sup.14C]ELP1 to nude mice (Balb/c
nu/nu) bearing a leg/flank FaDu xenograft and collecting blood
samples at various time intervals after administration. The blood
pharmacokinetics exhibited a characteristic distribution and
elimination response for large macromolecules, which was well
described by a bi-exponential process.
[0216] The plasma concentration time-course curve was fit to the
analytical solution of a two-compartment model to approximate both
an elimination and distribution response. Certain pharmakinetic
parameters are shown in Table 1 below. The distribution volume of
the ELP (1.338 .mu.l) was nearly identical to the hypothetical
plasma volume of 1.363 .mu.l (Barbee, R. W., et al., Am. J. Physio.
263(3) (1992) R728-R733), indicating that the ELP did not rapidly
distribute or bind to specific organs and tissues directly after
administration. The AUC is a measure of the cumulative exposure to
ELP in the central compartment or the blood plasma. The body
clearance is defined as the rate of ELP elimination in the body
relative to its plasma concentration and is the summation of
clearance through all organs including the kidney, liver and
others.
TABLE-US-00003 TABLE 1 Pharmacokinetic parameters calculated for
[.sup.14C]ELP1 k.sub.1 k.sub.2 k.sub.e V.sub.d AUC Cl.sub.B
(hr.sup.-1) (hr.sup.-1) (hr.sup.-1) (.mu.L) (mg ELP hr/ml)
(.mu.L/hr) ELP1-150 3.54 1.99 0.24 1,338 7.1 317
[0217] The mass transfer rate constants are from a standard
two-compartment model (k.sub.1; from central to peripheral
compartment; k.sub.2, from peripheral to central compartment; and
k.sub.e, elimination from central compartment). The distribution
volume (V.sub.d), central compartment concentration time-course
area under the curve (AUC) and body clearance (Cl.sub.B) are
displayed. Data are shown as the mean values (n=5, except V.sub.d
and initial plasma concentration (C.sub.o) was calculated from a
similar cohort with n=3).
Example 4
Biodistribution of ELPs in Nude Mice
[0218] .sup.14C labeled ELP1-150 and/or .sup.14C labeled
ELP2-160
[0219] .sup.14C labeled ELP1-150 and/or .sup.14C labeled ELP2-160
were administered to nude mice with a FaDu tumor (mean+/-SD, n=6).
The tumor was heated post administration of the ELP in a water bath
at 41.5.degree. C. The distribution was highest to the organs with
the highest blood content: liver, kidneys, spleen, and lungs.
.sup.14C Labeled ELP2-[V.sub.1A.sub.6G.sub.7-160]
[0220] .sup.14C labeled ELP2-[V.sub.1A.sub.8G.sub.7-160]
(T.sub.t>60.degree. C.) was administered to nude mice for a
plasma concentration of 15 .mu.M. ELP concentrations were
determined following 1 hour of heating (41.degree. C.) of an
implanted FaDu tumor, located in the right hind leg of the nude
mouse. Data are shown as the mean, plus the 95% confidence
interval. N=6.
[0221] ELP concentration was measured 1.5 hours following systemic
administration of .sup.14C labeled
ELP2-[V.sub.1A.sub.8G.sub.7-160]. The highest distribution is seen
in organs with the highest blood content: liver, kidneys, spleen,
and lungs.
Example 5
Exendin-4 ELP Fusion
[0222] The DNA sequence for Exendin-4 (Ex-4) (SEQ ID NO: 14) was
reverse translated from the amino acid sequence using codons
optimized for E. coli expression. The DNA sequence encoding
Exendin-4 was constructed by annealing together synthetic
oligonucleotides with overhanging 5' and 3' ends compatible with
the restriction sites NdeI and XhoI in the plasmid pET24d-ELP1-90
(FIG. 1). This plasmid was digested with the restriction enzymes
NdeI and XhoI and the annealed DNA sequence was ligated into the
cut vector. Insertion was confirmed by restriction digest and DNA
sequencing. The resulting plasmid was designated as pET24d-Ex-4
ELP1-90 (FIG. 2A), and the sequence of the resulting Exendin-4-ELP
fusion shown in FIG. 2B. Primers for construction of the fusion are
also indicated.
[0223] pET24d-Ex-4 ELP1-90 was used to transform the E. coli strain
BRL (Invitrogen) and selected transformants were grown in media 3
(1.2% Tryptone Peptone, 2.4% yeast extract, 5 g/L casamino acids,
2% glycerol, 2.313 g Potassium phosphate dibasic/L, 12.541 g
Potassium phosphate monobasic/L) in shake flasks. Production
proceeded by autoinduction by inoculating 1 OD cells into 1 L of
media 3 and allowing growth to proceed for 17 hr at 37.degree. C.
without addition of inducer. The product was recovered by
collection of the cell pellet, sonicated to disrupt the cells and
recovered by thermal and/or salt induced transition modulated by
the ELP moiety (Improved Non-chromatographic Purification of a
Recombinant Protein by Cationic Elastin-like Polypeptides, Dong Woo
Lim, Kimberly Trabbic-Carlson, J. Andrew MacKay, and Ashutosh
Chilkoti. Biomacromolecules 2007, 8, 1417-1424).
[0224] This example is with the ELP designated 1-90. This is based
on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the
ratio 5:3:2 in a 10 unit repeat, repeated 8x with a final
(C-terminal) 10-unit repeat where X is a V, G, A and Win the ratio
4:3:2:1.
[0225] [(VPGXG)10].sub.9 where the X residue in the ten sequential
iterations of the repeat unit (numerical subscript) can be
described as [(V.sub.1, 4, 5, 6, 10G.sub.2, 7, 9A.sub.3, 8).sub.8
(V.sub.1, 4, 5, 6G.sub.2, 7, 9A.sub.3, 8 W.sub.10)].
[0226] The ELP may be any combination of VPGXG (SEQ ID NO: 3) units
where X is any of the 20 natural amino, acids, except proline, in
any combination of repeat units of any length. In addition, the
amino acid may be an unnatural amino acid for which the host strain
has been engineered to accept an engineered tRNA for incorporation
at specific codon (Wang L, Brock A, Herberich B, Schultz P G.
Expanding the genetic code of Escherichia coli. [2001]Science 292,
498-500).
[0227] This construct was produced in the cytosol with an
N-terminal methionine, which is normally removed by methionine
aminopeptidase. Complete and accurate processing of the methionine,
however, cannot be assumed; this enzyme may also remove the
N-terminal histidine of the Exendin-4 moiety. This could result in
a mixture of, unprocessed, processed and incorrectly processed
products. Consequently, further constructs were developed to
generate products with correctly processed N-termini.
[0228] Primers were designed to add a Tev protease (Tobacco Etch
Virus cysteine protease) cleavage site between the N-terminal
methionine and the histidine at the N-terminus of Exendin-4. This
allows for removal of the methionine and the Tev recognition
sequence to give the mature N-terminus of Exendin-4 (histidine).
This can be done post-production or the Tev protease can be
co-expressed to cleave the recognition sequence during production,
for instance, as an intein (Ge, X., Yang, D. S. C.,
Trabbic-Carlson, K., Kim, B., Chilkoti, A. and Filipe, C. D. M.
Self-Cleavable Stimulus Responsive Tags for Protein Purification
without Chromatography. J. Am. Chem. Soc. 127, 11228-11229, 2005).
The Tev Exendin-4 sequence is shown in FIG. 3A. FIG. 3B shows
additional sequences added, labeled as "Linker Tev," provide a
better target for the Tev protease.
[0229] An alternative route to obtaining a correctly processed
N-terminus for Ex-4 is to use a leader or signal sequence that
directs the product to the periplasm and which is cleaved by a
signal peptidase in the process. In this instance, a signal
sequence, DsbA, that directs the transcript to the signal
recognition particle for direct secretion of the polypeptide into
the periplasm is given. (See FIG. 4A). The plasmid pET24d-DsbA-Ex-4
ELP1-90 is shown in FIG. 4B.
[0230] While this example illustrates the preparation of
therapeutic agents with Exendin-4 sequences, such sequences can be
replaced with GLP-1, insulin, Factor VII/VIIa, or other therapeutic
protein listed in Table 1, generated in exactly or a similar manner
as detailed for Exendin-4.
Example 6
GLP1-ELP Fusion Protein
[0231] The ELP plasmid constructs were used to prepare two GLP1-ELP
fusion proteins, GLP1(A8G,7-37)ELP1-90 and GLP1(A8G,7-37)ELP1-120.
The plasmid contructs, fusion-encoding nucleotide sequence, as well
as the amino acid sequence of the resulting fusion proteins are
shown in FIGS. 5 and 6.
[0232] Both constructs contain an N-terminal Tev protease site to
allow processing to the mature form where His.sup.7 of GLP1 is at
the N-terminus. The processed fusion proteins have calculated
molecular weights of about 39,536 and about 50,828,
respectively.
Example 7
FVII ELP Fusion Protein
[0233] The coagulation factor VII (FVII) gene was modified by PCR
from a cDNA clone (Oragene) to add restriction sites at the 5' and
3' ends for cloning into the ELP-containing vector. At the 5' end
an NheI site was added and at the 3' end a NotI site was added. The
DNA and amino acid sequences of the Factor VII gene are shown in
the accompanying Sequence Listing as SEQ ID NOS: 34 and 33,
respectively. The DNA sequences of the 5' and 3' primers used to
PCR amplify the factor VII (FVII) gene were:
TABLE-US-00004 (SEQ ID NO.: 49) P13: CTAGCTAGCATGGTCTCCCAGGCCCTC
(SEQ ID NO.: 50) P14: TATTCTTGCGGCCGCGGGAAATGGGGCTCGCAG
[0234] The resulting PCR fragment was digested with the restriction
enzymes NheI and NotI and ligated into the plasmid pcDNA3.1+ELP1-90
previously digested with the restriction enzymes NheI and NotI
(FIG. 7A).
[0235] The resulting plasmid, pcDNA3.1+FVII-ELP1-90, was
transiently transfected into HEK293 cells and culture media
harvested. The ELP fusion was purified by phase transition (FIGS. 9
and 10).
[0236] The nucleotide and amino acid sequences of the FactorVII-ELP
fusion is shown in FIG. 7B. As shown, the FactorVII-ELP fusion
protein contains a Tev protease linker between the FactorVII
component and the ELP component. This linker is optional.
Example 8
Insulin ELP Fusion Protein
[0237] The cDNA for the human insulin gene is modified at the 5'
and 3' ends for insertion in to pET24d-ELP1-90. The 5' primer adds
an N-terminal methionine for bacterial expression and an NdeI
restriction enzyme site. The 3' primer adds an XhoI restriction
enzyme site. The PCR product and the plasmid are both digested with
the restriction enzymes NdeI and XhoI and ligated together. The
sequence of the insulin (Chains B, C, and A fused to ELP1 is shown
in FIG. 8A.
[0238] Correct insertion is determined by restriction digest and
DNA sequencing. The resulting plasmid, designated pET24d
Insulin-ELP1-90, is shown in FIG. 8B.
[0239] The native insulin form is generated after recovery from E.
coli by treatment with trypsin and carboxypeptidase B to remove the
C-peptide chain.
[0240] For correct processing of the N-terminus of the B-chain
similar modifications to those made for the Exendin-4 fusion
(protease cleavage site, signal sequence) can be implemented (see
Example 4). Alternatively, the first two residues can be Met-Arg,
which can also be removed by trypsin digestion in production of the
final material (R. M. Belagaje, S. G. Reams, S. C. Ly and W. F.
Prouty, Increased production of low molecular weight recombinant
proteins in Escherichia coli. Protein Sci. 6, 1953-1962, 1997).
[0241] Additional constructs would place the insulin cDNA at the 3'
end of the ELP for a C-terminal fusion, add linkers between the
Insulin and ELP sequences, and/or use modified forms of insulin
which have no C-peptide (single chain insulins as described)
removing the need for additional processing.
Example 9
Synthesis of the ELP Gene for Conjugation
[0242] A gene encoding a 50 amino acid sequence was constructed
from chemically-synthesized oligonucleotides using standard
molecular biology protocols. The 50 amino acid sequence contained
10 repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the
guest residues (V, G, and A in a 5:3:2 molar ratio) were selected
to provide a Tt of 40.degree. C. The gene was oligomerized
end-to-end by standard molecular biology techniques, to produce an
oligomeric ELP gene. Additionally a single 50 amino acid sequence
was constructed containing the 10 repeat pentapeptide VPGXG (SEQ ID
NO: 3) polypeptide where the guest residues were V, G, A and C in a
4:3:2:1 molar ratio. This sequence could be added at any cycle of
the oligomerization process to introduce a single cysteine residue
into the final construct at a chosen point along the length of the
construct.
[0243] The example given here is with the ELP designated 1-90. This
is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A
in the ratio 5:3:2 in a 10-unit repeat, repeated 8x with a final
(C-terminal) 10-unit repeat where X is a V, G, A and C in the ratio
4:3:2:1, i.e., [(VPGXG)10]9 (SEQ ID NO.: 3).
[0244] Alternatively, the residue could be one of either arginine,
lysine, aspartic acid or glutamic acid. The purpose of these amino
acids is to provide a reactive side chain for the chemical
conjugation of, for example, insulin. In this particular case the
use of an ELP would be to extend the circulating half-life of the
therapeutic protein (e.g., insulin) to provide prolonged basal
glucose control. Conjugated to an ELP that transitions at body
temperature, the insulin would form a precipitated depot at the
site of injection in a similar manner to Lantus.RTM. (Sanofi
Aventis) but without the requirement for formulation in acidic (pH
4.0) conditions with m-cresol for a more tolerable injection.
Example 10
Potency and Half-Life of Factor VII-ELP
[0245] FIG. 11 shows the activation of Factor X by
FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. Factor
VII-ELP was produced in HEK cells. Factor VIIa was derived from
human plasma. As shown, FactorVIIa-ELP retains full activity.
[0246] When administered to rats by i.v., Factor VII-ELP
demonstrated a half-life of about 690 minutes. In contrast, Factor
VII demonstrated a half-life of 45-60 minutes. Half-life in this
example was measured by sandwich ELISA for FactorVII. FIG. 12.
[0247] Also in contrast, the reported half-life for NovoSeven.TM.
is 45 minutes, the reported half-life for FactorVIIa-albumin fusion
is 263 minutes, and the reported half-life for Factor VIIa-PEG is
300 minutes in mice and 600 minutes in dog.
Example 11
GLP-1 (or Exendin-4) In Vitro Bioassay
[0248] Activation of the GLP-1 receptor (GLP1R) results in
production of cAMP secondary messenger within the cell. Therefore,
GLP-1 or Exendin-4 analogs and corresponding therapeutic agents may
be tested by their ability to activate GLP1R on the cell surface
and produce cAMP.
[0249] For this bioassay CHO cells transfected with cDNA coding for
GLP1R are used. These cells respond to stimulation by GLP-1 and
produce high levels of cAMP. Log phase growing cells are plated and
increasing concentrations of test compounds (e.g., therapeutic
agent of the invention, or GLP-1 or exendin-4 functional analog)
are added to the cells. After an appropriate incubation period
(usually 15-60 min) in physiological buffer at 37.degree. C. the
cAMP produced is measured using a CatchPoint cAMP assay kit from
Molecular Devices (Sunnyvale, Calif.). The EC.sub.50 of each test
compound as compared to GLP-1 peptide or Exendin-4 peptide (or as
compared to an unfused or unconjugated counterpart of a therapeutic
agent of the invention) is indicative of the changes in activity
due to a specific modifications introduced into the peptide, or due
to particular chemical or recombinant coupling to an ELP
component.
[0250] As shown in FIG. 13, both GLP1-ELP (PB0868) and
Exendin-4-ELP (PB 0859) maintain high activity in vitro, shown in
comparison to Exendin alone. It is of note that the specific
activity of Albugon.RTM. and Liraglutide.RTM. run 50-100 fold less
than the exendin peptide.
Example 12
GLP-1 (or Exendin-4) In Vivo Bioassay
[0251] The activity of GLP-1 or Exendin analogues or corresponding
therapeutic agents may be tested in animals. For this assay, normal
or diabetic animals may be used. Diabetic animals with blood
glucose concentration 300-500 mg/dl are injected with different
doses of GLP-1 or Exendin analogues or corresponding therapeutic
agent, and changes in blood glucose monitored with a glucometer.
The drop in glucose at different times points post administration
is compared to that resulting with standard amounts of GLP-1 or
Exendin-4 peptide, or compared to an unfused or unconjugated
counterpart of a therapeutic agent of the invention. Alternatively,
the blood glucose excursion in normal or diabetic animals during
specific time period after administration of exogenous glucose is
compared to GLP-1 or Exendin-4 (or to unfused or unconjugated
counterparts of therapeutic agents). In this way the activity of
the analogues and fusion proteins can be compared to the natural
peptides.
[0252] FIG. 14 shows the pharmacokinetics of GLP1-ELP1-120 in rats
administered both by i.v. and subcutaneously. Three rats were used
for each time point. The dose was .about.10 mg/kg. The T.sub.1/2
when administered by i.v. was about 12.9 hours. The T.sub.1/2 when
administered subcutaneously was about 8.6 hours.
[0253] FIG. 15 shows the pharmacokinetics of GLP1-ELP1-120 in
rabbits administered both by i.v. and subcutaneously. Three rabbits
were used for each time point. The dose was .about.1 mg/kg. The
T.sub.1/2 when administered by i.v. was about 20 hours. The
T.sub.1/2 when administered subcutaneously was about 24 hours.
[0254] FIG. 16 shows the sustained glycemic control in diabetic
mice with GLP1-ELP1-90.
[0255] All reference cited herein are hereby incorporated by
reference in their entireties. While the invention has been has
been described herein in reference to specific aspects, features
and illustrative embodiments of the invention, it will be
appreciated that the utility of the invention is not thus limited,
but rather extends to and encompasses numerous other variations,
modifications and alternative embodiments, as will suggest
themselves to those of ordinary skill in the field of the present
invention, based on the disclosure herein
Sequence CWU 1
1
6814PRTArtificial SequenceELP component sequence 1Val Pro Gly Gly 1
24PRTArtificial SequenceELP component sequence 2Ile Pro Gly Gly 1
35PRTArtificial SequenceELP component sequence 3Val Pro Gly Xaa Gly
1 5 45PRTArtificial SequenceELP component sequence 4Ala Val Gly Val
Pro 1 5 55PRTArtificial SequenceELP component sequence 5Ile Pro Gly
Xaa Gly 1 5 65PRTArtificial SequenceELP component sequence 6Ile Pro
Gly Val Gly 1 5 75PRTArtificial SequenceELP component sequence 7Leu
Pro Gly Xaa Gly 1 5 85PRTArtificial SequenceELP component sequence
8Leu Pro Gly Val Gly 1 5 96PRTArtificial SequenceELP component
sequence 9Val Ala Pro Gly Val Gly 1 5 108PRTArtificial SequenceELP
component sequence 10Gly Val Gly Val Pro Gly Val Gly 1 5
119PRTArtificial SequenceELP component sequence 11Val Pro Gly Phe
Gly Val Gly Ala Gly 1 5 129PRTArtificial SequenceELP component
sequence 12Val Pro Gly Val Gly Val Pro Gly Gly 1 5 1330PRTHomo
sapiens 13His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu
Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys
Gly Arg 20 25 30 1439PRTHomo sapiens 14His Gly Glu Gly Thr Phe Thr
Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu
Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Pro Ser 35 1521PRTHomo sapiens 15Gly Ile Val Glu Gln Cys
Cys Ala Ser Val Cys Ser Leu Tyr Gln Leu 1 5 10 15 Glu Asn Tyr Cys
Asn 20 1630PRTHomo sapiens 16Phe Val Asn Gln His Leu Cys Gly Ser
His Leu Val Glu Ala Leu Tyr 1 5 10 15 Leu Val Cys Gly Glu Arg Gly
Phe Phe Tyr Thr Pro Lys Ala 20 25 30 1730PRTHomo sapiens 17His Gly
Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 20 25 30
1844PRTUnknownGLP-1 receptor agonist 18His Gly Glu Gly Thr Phe Thr
Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu
Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala
Pro Pro Ser Lys Lys Lys Lys Lys Lys 35 40 1931PRTUnknownGLP-1
receptor agonist 19His Val Glu Gly Thr Phe Thr Ser Asp Val Ser Ser
Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu
Ile Lys Gly Arg Gly 20 25 30 2012PRTArtificial SequencePeptide
linker sequence 20Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg 1
5 10 2112PRTArtificial SequencePeptide linker sequence 21Gly Ala
Gly Ser Ser Ser Arg Arg Ala Pro Gln Thr 1 5 10 228PRTArtificial
SequenceNon-cleavable spacer sequence 22Gly Gly Gly Gly Ser Ser Ser
Ser 1 5 23300DNAArtificial SequenceExendin-4/ELP sequence
23aattaatacg actcactata ggggaattgt gagcggataa caattcccct ctagaaataa
60ttttgtttaa ctttaagaag gagatataca tatgcatggc gaaggcacct ttaccagcga
120tctgagcaaa cagatggaag aagaagcggt gcgcctgttt attgaatggc
tgaaaaacgg 180cggcccgagc agcggcgcgc cgccgccgag cctcgagggc
atgggtgggc cgggcgtggg 240tgttccgggc gtgggtgttc cgggtggcgg
tgtgccgggc gcaggtgttc ctggtgtagg 3002469PRTArtificial
SequenceExendin-4/ELP sequence 24Met His Gly Glu Gly Thr Phe Thr
Ser Asp Leu Ser Lys Gln Met Glu 1 5 10 15 Glu Glu Ala Val Arg Leu
Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro 20 25 30 Ser Ser Gly Ala
Pro Pro Pro Ser Leu Glu Gly Met Gly Gly Pro Gly 35 40 45 Val Gly
Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala 50 55 60
Gly Val Pro Gly Val 65 25140DNAArtificial SequenceExendin-4/ELP
sequence with N-terminal Tev cleavage site 25tatggaaaac ctgtatttcc
aacatggcga aggcaccttt accagcgatc tgagcaaaca 60gatggaagaa gaagcggtgc
gcctgtttat tgaatggctg aaaaacggcg gcccgagcag 120cggcgcgccg
ccgccgagcc 1402646PRTArtificial SequenceExendin-4/ELP sequence with
N-terminal Tev cleavage site 26Met Glu Asn Leu Tyr Phe Gln His Gly
Glu Gly Thr Phe Thr Ser Asp 1 5 10 15 Leu Ser Lys Gln Met Glu Glu
Glu Ala Val Arg Leu Phe Ile Glu Trp 20 25 30 Leu Lys Asn Gly Gly
Pro Ser Ser Gly Ala Pro Pro Pro Ser 35 40 45 27155DNAArtificial
SequenceExendin-4/ELP sequence with N-terminal Tev cleavage site
and additional N-terminal sequence 27tatggatatc ccaacgaccg
aaaacctgta tttccaacat ggcgaaggca cctttaccag 60cgatctgagc aaacagatgg
aagaagaagc ggtgcgcctg tttattgaat ggctgaaaaa 120cggcggcccg
agcagcggcg cgccgccgcc gagcc 1552851PRTArtificial
SequenceExendin-4/ELP sequence with N-terminal Tev cleavage site
and additional N-terminal sequence 28Met Asp Ile Pro Thr Thr Glu
Asn Leu Tyr Phe Gln His Gly Glu Gly 1 5 10 15 Thr Phe Thr Ser Asp
Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg 20 25 30 Leu Phe Ile
Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro 35 40 45 Pro
Pro Ser 50 29176DNAArtificial SequenceExendin-4/ELP sequence with
DsbA leader sequence 29tatgaaaaag atttggctgg cgctggctgg tttagtttta
gcgtttagcg catcggcgca 60tggcgaaggc acctttacca gcgatctgag caaacagatg
gaagaagaag cggtgcgcct 120gtttattgaa tggctgaaaa acggcggccc
gagcagcggc gcgccgccgc cgagcc 1763058PRTArtificial
SequenceExendin-4/ELP sequence with DsbA leader sequence 30Met Lys
Lys Ile Trp Leu Ala Leu Ala Gly Leu Val Leu Ala Phe Ser 1 5 10 15
Ala Ser Ala His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln 20
25 30 Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn
Gly 35 40 45 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 50 55
31400DNAArtificial SequenceInsulin/ELP sequence 31ctagaaataa
ttttgtttaa ctttaagaag gagatataca tatgtttgtg aaccaacacc 60tgtgcggctc
acacctggtg gaagctctct acctagtgtg cggggaacga ggcttcttct
120acacacccaa gacccgccgg gaggcagagg acctgcaggt ggggcaggtg
gagctgggcg 180ggggccctgg tgcaggcagc ctgcagccct tggccctgga
ggggtccctg cagaagcgtg 240gcattgtgga acaatgctgt accagcatct
gctccctcta ccagctggag aactactgca 300acctcgaggg catgggtggg
ccgggcgtgg gtgttccggg cgtgggtgtt ccgggtggcg 360gtgtgccggg
cgcaggtgtt cctggtgtag gtgtgccggg 40032119PRTArtificial
SequenceInsulin/ELP sequence 32Met Phe Val Asn Gln His Leu Cys Gly
Ser His Leu Val Glu Ala Leu 1 5 10 15 Tyr Leu Val Cys Gly Glu Arg
Gly Phe Phe Tyr Thr Pro Lys Thr Arg 20 25 30 Arg Glu Ala Glu Asp
Leu Gln Val Gly Gln Val Glu Leu Gly Gly Gly 35 40 45 Pro Gly Ala
Gly Ser Leu Gln Pro Leu Ala Leu Glu Gly Ser Leu Gln 50 55 60 Lys
Arg Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr 65 70
75 80 Gln Leu Glu Asn Tyr Cys Asn Leu Glu Gly Met Gly Gly Pro Gly
Val 85 90 95 Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
Gly Ala Gly 100 105 110 Val Pro Gly Val Gly Val Pro 115
33406PRTHomo sapiens 33Ala Asn Ala Phe Leu Glu Glu Leu Arg Pro Gly
Ser Leu Glu Arg Glu 1 5 10 15 Cys Lys Glu Glu Gln Cys Ser Phe Glu
Glu Ala Arg Glu Ile Phe Lys 20 25 30 Asp Ala Glu Arg Thr Lys Leu
Phe Trp Ile Ser Tyr Ser Asp Gly Asp 35 40 45 Gln Cys Ala Ser Ser
Pro Cys Gln Asn Gly Gly Ser Cys Lys Asp Gln 50 55 60 Leu Gln Ser
Tyr Ile Cys Phe Cys Leu Pro Ala Phe Glu Gly Arg Asn 65 70 75 80 Cys
Glu Thr His Lys Asp Asp Gln Leu Ile Cys Val Asn Glu Asn Gly 85 90
95 Gly Cys Glu Gln Tyr Cys Ser Asp His Thr Gly Thr Lys Arg Ser Cys
100 105 110 Arg Cys His Glu Gly Tyr Ser Leu Leu Ala Asp Gly Val Ser
Cys Thr 115 120 125 Pro Thr Val Glu Tyr Pro Cys Gly Lys Ile Pro Ile
Leu Glu Lys Arg 130 135 140 Asn Ala Ser Lys Pro Gln Gly Arg Ile Val
Gly Gly Lys Val Cys Pro 145 150 155 160 Lys Gly Glu Cys Pro Trp Gln
Val Leu Leu Leu Val Asn Gly Ala Gln 165 170 175 Leu Cys Gly Gly Thr
Leu Ile Asn Thr Ile Trp Val Val Ser Ala Ala 180 185 190 His Cys Phe
Asp Lys Ile Lys Asn Trp Arg Asn Leu Ile Ala Val Leu 195 200 205 Gly
Glu His Asp Leu Ser Glu His Asp Gly Asp Glu Gln Ser Arg Arg 210 215
220 Val Ala Gln Val Ile Ile Pro Ser Thr Tyr Val Pro Gly Thr Thr Asn
225 230 235 240 His Asp Ile Ala Leu Leu Arg Leu His Gln Pro Val Val
Leu Thr Asp 245 250 255 His Val Val Pro Leu Cys Leu Pro Glu Arg Thr
Phe Ser Glu Arg Thr 260 265 270 Leu Ala Phe Val Arg Phe Ser Leu Val
Ser Gly Trp Gly Gln Leu Leu 275 280 285 Asp Arg Gly Ala Thr Ala Leu
Glu Leu Met Val Leu Asn Val Pro Arg 290 295 300 Leu Met Thr Gln Asp
Cys Leu Gln Gln Ser Arg Lys Val Gly Asp Ser 305 310 315 320 Pro Asn
Ile Thr Glu Tyr Met Phe Cys Ala Gly Tyr Ser Asp Gly Ser 325 330 335
Lys Asp Ser Cys Lys Gly Asp Ser Gly Gly Pro His Ala Thr His Tyr 340
345 350 Arg Gly Thr Trp Tyr Leu Thr Gly Ile Val Ser Trp Gly Gln Gly
Cys 355 360 365 Ala Thr Val Gly His Phe Gly Val Tyr Thr Arg Val Ser
Gln Tyr Ile 370 375 380 Glu Trp Leu Gln Lys Leu Met Arg Ser Glu Pro
Arg Pro Gly Val Leu 385 390 395 400 Leu Arg Ala Pro Phe Pro 405
341218DNAHomo sapiens 34gccaacgcgt tcctggagga gctgcggccg ggctccctgg
agagggagtg caaggaggag 60cagtgctcct tcgaggaggc ccgggagatc ttcaaggacg
cggagaggac gaagctgttc 120tggatttctt acagtgatgg ggaccagtgt
gcctcaagtc catgccagaa tgggggctcc 180tgcaaggacc agctccagtc
ctatatctgc ttctgcctcc ctgccttcga gggccggaac 240tgtgagacgc
acaaggatga ccagctgatc tgtgtgaacg agaacggcgg ctgtgagcag
300tactgcagtg accacacggg caccaagcgc tcctgtcggt gccacgaggg
gtactctctg 360ctggcagacg gggtgtcctg cacacccaca gttgaatatc
catgtggaaa aatacctatt 420ctagaaaaaa gaaatgccag caaaccccaa
ggccgaattg tggggggcaa ggtgtgcccc 480aaaggggagt gtccatggca
ggtcctgttg ttggtgaatg gagctcagtt gtgtgggggg 540accctgatca
acaccatctg ggtggtctcc gcggcccact gtttcgacaa aatcaagaac
600tggaggaacc tgatcgcggt gctgggcgag cacgacctca gcgagcacga
cggggatgag 660cagagccggc gggtggcgca ggtcatcatc cccagcacgt
acgtcccggg caccaccaac 720cacgacatcg cgctgctccg cctgcaccag
cccgtggtcc tcactgacca tgtggtgccc 780ctctgcctgc ccgaacggac
gttctctgag aggacgctgg ccttcgtgcg cttctcattg 840gtcagcggct
ggggccagct gctggaccgt ggcgccacgg ccctggagct catggtgctc
900aacgtgcccc ggctgatgac ccaggactgc ctgcagcagt cacggaaggt
gggagactcc 960ccaaatatca cggagtacat gttctgtgcc ggctactcgg
atggcagcaa ggactcctgc 1020aagggggaca gtggaggccc acatgccacc
cactaccggg gcacgtggta cctgacgggc 1080atcgtcagct ggggccaggg
ctgcgcaacc gtgggccact ttggggtgta caccagggtc 1140tcccagtaca
tcgagtggct gcaaaagctc atgcgctcag agccacgccc aggagtcctc
1200ctgcgagccc catttccc 12183533DNAHomo sapiens 35tatgcatggc
gaaggcacct ttaccagcga tct 333662DNAHomo sapiens 36gagcaaacag
atggaagaag aagcggtgcg cctgtttatt gaatggctga aaaacggcgg 60cc
623727DNAHomo sapiens 37cgagcagcgg cgcgccgccg ccgagcc 273835DNAHomo
sapiens 38tcgaggctcg gcggcggcgc gccgctgctc gggcc 353963DNAHomo
sapiens 39gccgtttttc agccattcaa taaacaggcg caccgcttct tcttccatct
gtttgctcag 60atc 634026DNAHomo sapiens 40gctggtaaag gtgccttcgc
catgca 264151DNAArtificial SequencePrimer for Exendin-4/ELP
sequence with N-terminal Tev cleavage site 41tatggaaaac ctgtatttcc
aacatggcga aggcaccttt accagcgatc t 514244DNAArtificial
SequencePrimer for Exendin-4/ELP sequence with N-terminal Tev
cleavage site 42gctggtaaag gtgccttcgc catgttggaa atacaggttt tcca
444366DNAArtificial SequencePrimer for Exendin-4/ELP sequence with
N-terminal Tev cleavage site and additional N-terminal sequence
43tatggatatc ccaacgaccg aaaacctgta tttccaacat ggcgaaggca cctttaccag
60cgatct 664459DNAArtificial SequencePrimer for Exendin-4/ELP
sequence with N-terminal Tev cleavage site and additional
N-terminal sequence 44gctggtaaag gtgccttcgc catgttggaa atacaggttt
tcggtcgttg ggatatcca 594587DNAArtificial SequencePrimer for
Exendin-4/ELP sequence with DsbA leader sequence 45tatgaaaaag
atttggctgg cgctggctgg tttagtttta gcgtttagcg catcggcgca 60tggcgaaggc
acctttacca gcgatct 874680DNAArtificial SequencePrimer for
Exendin-4/ELP sequence with DsbA leader sequence 46gctggtaaag
gtgccttcgc catgcgccga tgcgctaaac gctaaaacta aaccagccag 60cgccagccaa
atctttttca 804739DNAArtificial SequencePrimer for Insulin/ELP
sequence 47gaaggagata tacatatgtt tgtgaaccaa cacctgtgc
394830DNAArtificial SequencePrimer for Insulin/ELP sequence
48cccatgccct cgaggttgca gtagttctcc 304927DNAHomo sapiens
49ctagctagca tggtctccca ggccctc 275033DNAHomo sapiens 50tattcttgcg
gccgcgggaa atggggctcg cag 3351261DNAHomo sapiens 51atgtttgtga
accaacacct gtgcggctca cacctggtgg aagctctcta cctagtgtgc 60ggggaacgag
gcttcttcta cacacccaag acccgccggg aggcagagga cctgcaggtg
120gggcaggtgg agctgggcgg gggccctggt gcaggcagcc tgcagccctt
ggccctggag 180gggtccctgc agaagcgtgg cattgtggaa caatgctgta
ccagcatctg ctccctctac 240cagctggaga actactgcaa c 2615287PRTHomo
sapiens 52Met Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu
Ala Leu 1 5 10 15 Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr
Pro Lys Thr Arg 20 25 30 Arg Glu Ala Glu Asp Leu Gln Val Gly Gln
Val Glu Leu Gly Gly Gly 35 40 45 Pro Gly Ala Gly Ser Leu Gln Pro
Leu Ala Leu Glu Gly Ser Leu Gln 50 55 60 Lys Arg Gly Ile Val Glu
Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr 65 70 75 80 Gln Leu Glu Asn
Tyr Cys Asn 85 531700DNAArtificial SequencepPB0868 DNA sequence
53taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt
60tgtttaactt taagaaggag atatacatat ggagaacctg tatttccaac atggcgaagg
120tacctttaca agcgatgtta gttcatatct ggagggccag gcggcaaagg
aattcattgc 180gtggctggtg aaaggccgcg gcctcgaggg catgggtggg
ccgggcgtgg gtgttccggg 240cgtgggtgtt ccgggtggcg gtgtgccggg
cgcaggtgtt cctggtgtag gtgtgccggg 300tgttggtgtg ccgggtgttg
gtgtaccagg tggcggtgtt ccgggtgcag gcgttccggg 360tggcggtgtg
ccgggcgtgg gtgttccggg cgtgggtgtt ccgggtggcg gtgtgccggg
420cgcaggtgtt cctggtgtag gtgtgccggg tgttggtgtg ccgggtgttg
gtgtaccagg 480tggcggtgtt ccgggtgcag gcgttccggg tggcggtgtg
ccgggcgtgg gtgttccggg 540cgtgggtgtt ccgggtggcg gtgtgccggg
cgcaggtgtt cctggtgtag gtgtgccggg 600tgttggtgtg ccgggtgttg
gtgtaccagg tggcggtgtt ccgggtgcag gcgttccggg 660tggcggtgtg
ccgggcgtgg gtgttccggg cgtgggtgtt ccgggtggcg gtgtgccggg
720cgcaggtgtt cctggtgtag gtgtgccggg tgttggtgtg ccgggtgttg
gtgtaccagg 780tggcggtgtt ccgggtgcag gcgttccggg tggcggtgtg
ccgggcgtgg gtgttccggg 840cgtgggtgtt ccgggtggcg gtgtgccggg
cgcaggtgtt cctggtgtag
gtgtgccggg 900tgttggtgtg ccgggtgttg gtgtaccagg tggcggtgtt
ccgggtgcag gcgttccggg 960tggcggtgtg ccgggcgtgg gtgttccggg
cgtgggtgtt ccgggtggcg gtgtgccggg 1020cgcaggtgtt cctggtgtag
gtgtgccggg tgttggtgtg ccgggtgttg gtgtaccagg 1080tggcggtgtt
ccgggtgcag gcgttccggg tggcggtgtg ccgggcgtgg gtgttccggg
1140cgtgggtgtt ccgggtggcg gtgtgccggg cgcaggtgtt cctggtgtag
gtgtgccggg 1200tgttggtgtg ccgggtgttg gtgtaccagg tggcggtgtt
ccgggtgcag gcgttccggg 1260tggcggtgtg ccgggcgtgg gtgttccggg
cgtgggtgtt ccgggtggcg gtgtgccggg 1320cgcaggtgtt cctggtgtag
gtgtgccggg tgttggtgtg ccgggtgttg gtgtaccagg 1380tggcggtgtt
ccgggtgcag gcgttccggg tggcggtgtg ccgggcgtgg gtgttccggg
1440cgtgggtgtt ccgggtggcg gtgtgccggg cgcaggtgtt cctggtgtag
gtgtgccggg 1500tgttggtgtg ccgggtgttg gtgtaccagg tggcggtgtt
ccgggtgcag gcgttccggg 1560tggcggtgtg ccgggctggc cgtgataagc
tagcatgact ggtggacagc aaatgggtcg 1620gatccgaatt cgagctccgt
cgagcaccac caccaccacc actgagatcc ggctgctaac 1680aaagcccgaa
aggaagctga 170054498PRTArtificial SequenceGLP-1(A8G,7-37)ELP1-90
amino acid sequence 54Met Glu Asn Leu Tyr Phe Gln His Gly Glu Gly
Thr Phe Thr Ser Asp 1 5 10 15 Val Ser Ser Tyr Leu Glu Gly Gln Ala
Ala Lys Glu Phe Ile Ala Trp 20 25 30 Leu Val Lys Gly Arg Gly Leu
Glu Gly Met Gly Gly Pro Gly Val Gly 35 40 45 Val Pro Gly Val Gly
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val 50 55 60 Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro 65 70 75 80 Gly
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly 85 90
95 Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
100 105 110 Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
Val Gly 115 120 125 Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
Gly Gly Gly Val 130 135 140 Pro Gly Val Gly Val Pro Gly Val Gly Val
Pro Gly Gly Gly Val Pro 145 150 155 160 Gly Ala Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly 165 170 175 Val Gly Val Pro Gly
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly 180 185 190 Gly Val Pro
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly 195 200 205 Val
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val 210 215
220 Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro
225 230 235 240 Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
Val Pro Gly 245 250 255 Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
Gly Val Pro Gly Val 260 265 270 Gly Val Pro Gly Val Gly Val Pro Gly
Gly Gly Val Pro Gly Ala Gly 275 280 285 Val Pro Gly Gly Gly Val Pro
Gly Val Gly Val Pro Gly Val Gly Val 290 295 300 Pro Gly Gly Gly Val
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro 305 310 315 320 Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly 325 330 335
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val 340
345 350 Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val
Gly 355 360 365 Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
Gly Gly Val 370 375 380 Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro
Gly Val Gly Val Pro 385 390 395 400 Gly Val Gly Val Pro Gly Gly Gly
Val Pro Gly Ala Gly Val Pro Gly 405 410 415 Val Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Gly 420 425 430 Gly Val Pro Gly
Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly 435 440 445 Val Pro
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val 450 455 460
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro 465
470 475 480 Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
Pro Gly 485 490 495 Trp Pro 552050DNAArtificial SequencepPB1022 DNA
sequence 55taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta
gaaataattt 60tgtttaactt taagaaggag atatacatat ggagaacctg tatttccaac
atggcgaagg 120tacctttaca agcgatgtta gttcatatct ggagggccag
gcggcaaagg aatttattgc 180gtggctggtg aaaggccgcg gcgtgccggg
cgtgggtgtt ccgggcgtgg gtgttccggg 240tggcggtgtg ccgggcgcag
gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg 300tgttggtgta
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg
360cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag
gtgttcctgg 420tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta
ccaggtggcg gtgttccggg 480tgcaggcgtt ccgggtggcg gtgtgccggg
cgtgggtgtt ccgggcgtgg gtgttccggg 540tggcggtgtg ccgggcgcag
gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg 600tgttggtgta
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg
660cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag
gtgttcctgg 720tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta
ccaggtggcg gtgttccggg 780tgcaggcgtt ccgggtggcg gtgtgccggg
cgtgggtgtt ccgggcgtgg gtgttccggg 840tggcggtgtg ccgggcgcag
gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg 900tgttggtgta
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg
960cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag
gtgttcctgg 1020tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta
ccaggtggcg gtgttccggg 1080tgcaggcgtt ccgggtggcg gtgtgccggg
cgtgggtgtt ccgggcgtgg gtgttccggg 1140tggcggtgtg ccgggcgcag
gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg 1200tgttggtgta
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg
1260cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag
gtgttcctgg 1320tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta
ccaggtggcg gtgttccggg 1380tgcaggcgtt ccgggtggcg gtgtgccggg
cgtgggtgtt ccgggcgtgg gtgttccggg 1440tggcggtgtg ccgggcgcag
gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg 1500tgttggtgta
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg
1560cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag
gtgttcctgg 1620tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta
ccaggtggcg gtgttccggg 1680tgcaggcgtt ccgggtggcg gtgtgccggg
cgtgggtgtt ccgggcgtgg gtgttccggg 1740tggcggtgtg ccgggcgcag
gtgttcctgg tgtaggtgtg ccgggtgttg gtgtgccggg 1800tgttggtgta
ccaggtggcg gtgttccggg tgcaggcgtt ccgggtggcg gtgtgccggg
1860cgtgggtgtt ccgggcgtgg gtgttccggg tggcggtgtg ccgggcgcag
gtgttcctgg 1920tgtaggtgtg ccgggtgttg gtgtgccggg tgttggtgta
ccaggtggcg gtgttccggg 1980tgcaggcgtt ccgggtggcg gtgtgccggg
ctggccgtga taagctagca tgactggtgg 2040acagcaaatg
205056643PRTArtificial SequenceGLP-1(A8G,7-37)ELP1-120 amino acid
sequence 56Met Glu Asn Leu Tyr Phe Gln His Gly Glu Gly Thr Phe Thr
Ser Asp 1 5 10 15 Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu
Phe Ile Ala Trp 20 25 30 Leu Val Lys Gly Arg Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly 35 40 45 Val Pro Gly Gly Gly Val Pro Gly
Ala Gly Val Pro Gly Val Gly Val 50 55 60 Pro Gly Val Gly Val Pro
Gly Val Gly Val Pro Gly Gly Gly Val Pro 65 70 75 80 Gly Ala Gly Val
Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly 85 90 95 Val Gly
Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val 100 105 110
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly 115
120 125 Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly
Val 130 135 140 Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala
Gly Val Pro 145 150 155 160 Gly Val Gly Val Pro Gly Val Gly Val Pro
Gly Val Gly Val Pro Gly 165 170 175 Gly Gly Val Pro Gly Ala Gly Val
Pro Gly Gly Gly Val Pro Gly Val 180 185 190 Gly Val Pro Gly Val Gly
Val Pro Gly Gly Gly Val Pro Gly Ala Gly 195 200 205 Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val 210 215 220 Pro Gly
Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro 225 230 235
240 Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly
245 250 255 Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
Gly Val 260 265 270 Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
Pro Gly Gly Gly 275 280 285 Val Pro Gly Val Gly Val Pro Gly Val Gly
Val Pro Gly Gly Gly Val 290 295 300 Pro Gly Ala Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro 305 310 315 320 Gly Val Gly Val Pro
Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly 325 330 335 Gly Gly Val
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly 340 345 350 Gly
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val Gly 355 360
365 Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val
370 375 380 Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
Val Pro 385 390 395 400 Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
Val Gly Val Pro Gly 405 410 415 Val Gly Val Pro Gly Val Gly Val Pro
Gly Gly Gly Val Pro Gly Ala 420 425 430 Gly Val Pro Gly Gly Gly Val
Pro Gly Val Gly Val Pro Gly Val Gly 435 440 445 Val Pro Gly Gly Gly
Val Pro Gly Ala Gly Val Pro Gly Val Gly Val 450 455 460 Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro 465 470 475 480
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly 485
490 495 Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly
Val 500 505 510 Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
Gly Gly Gly 515 520 525 Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
Pro Gly Val Gly Val 530 535 540 Pro Gly Val Gly Val Pro Gly Gly Gly
Val Pro Gly Ala Gly Val Pro 545 550 555 560 Gly Val Gly Val Pro Gly
Val Gly Val Pro Gly Val Gly Val Pro Gly 565 570 575 Gly Gly Val Pro
Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val 580 585 590 Gly Val
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly 595 600 605
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val 610
615 620 Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
Pro 625 630 635 640 Gly Trp Pro 573700DNAArtificial SequencepPB0788
DNA sequence 57gacggatcgg gagatctccc gatcccctat ggtgcactct
cagtacaatc tgctctgatg 60ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt
ggaggtcgct gagtagtgcg 120cgagcaaaat ttaagctaca acaaggcaag
gcttgaccga caattgcatg aagaatctgc 180ttagggttag gcgttttgcg
ctgcttcgcg atgtacgggc cagatatacg cgttgacatt 240gattattgac
tagttattaa tagtaatcaa ttacggggtc attagttcat agcccatata
300tggagttccg cgttacataa cttacggtaa atggcccgcc tggctgaccg
cccaacgacc 360cccgcccatt gacgtcaata atgacgtatg ttcccatagt
aacgccaata gggactttcc 420attgacgtca atgggtggag tatttacggt
aaactgccca cttggcagta catcaagtgt 480atcatatgcc aagtacgccc
cctattgacg tcaatgacgg taaatggccc gcctggcatt 540atgcccagta
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca
600tcgctattac catggtgatg cggttttggc agtacatcaa tgggcgtgga
tagcggtttg 660actcacgggg atttccaagt ctccacccca ttgacgtcaa
tgggagtttg ttttggcacc 720aaaatcaacg ggactttcca aaatgtcgta
acaactccgc cccattgacg caaatgggcg 780gtaggcgtgt acggtgggag
gtctatataa gcagagctct ctggctaact agagaaccca 840ctgcttactg
gcttatcgaa attaatacga ctcactatag ggagacccaa gctggctagc
900atggtctccc aggccctcag gctcctctgc cttctgcttg ggcttcaggg
ctgcctggct 960gcagtcttcg taacccagga ggaagcccac ggcgtcctgc
accggcgccg gcgcgccaac 1020gcgttcctgg aggagctacg gccgggctcc
ctggagaggg agtgcaagga ggagcagtgc 1080tccttcgagg aggcccggga
gatcttcaag gacgcggaga ggacgaagct gttctggatt 1140tcttacagtg
atggggacca gtgtgcctca agtccatgcc agaatggggg ctcctgcaag
1200gaccagctcc agtcctatat ctgcttctgc ctccctgcct tcgagggccg
gaactgtgag 1260acgcacaagg atgaccagct gatctgtgtg aacgagaacg
gcggctgtga gcagtactgc 1320agtgaccaca cgggcaccaa gcgctcctgt
cggtgccacg aggggtactc tctgctggca 1380gacggggtgt cctgcacacc
cacagttgaa tatccatgtg gaaaaatacc tattctagaa 1440aaaagaaatg
ccagcaaacc ccaaggccga attgtggggg gcaaggtgtg ccccaaaggg
1500gagtgtccat ggcaggtcct gttgttggtg aatggagctc agttgtgtgg
ggggaccctg 1560atcaacacca tctgggtggt ctccgcggcc cactgtttcg
acaaaatcaa gaactggagg 1620aacctgatcg cggtgctggg cgagcacgac
ctcagcgagc acgacgggga tgagcagagc 1680cggcgggtgg cgcaggtcat
catccccagc acgtacgtcc cgggcaccac caaccacgac 1740atcgcgctgc
tccgcctgca ccagcccgtg gtcctcactg accatgtggt gcccctctgc
1800ctgcccgaac ggacgttctc tgagaggacg ctggccttcg tgcgcttctc
attggtcagc 1860ggctggggcc agctgctgga ccgtggcgcc acggccctgg
agctcatggt cctcaacgtg 1920ccccggctga tgacccagga ctgcctgcag
cagtcacgga aggtgggaga ctccccaaat 1980atcacggagt acatgttctg
tgccggctac tcggatggca gcaaggactc ctgcaagggg 2040gacagtggag
gcccacatgc cacccactac cggggcacgt ggtacctgac gggcatcgtc
2100agctggggcc agggctgcgc aaccgtgggc cactttgggg tgtacaccag
ggtctcccag 2160tacatcgagt ggctgcaaaa gctcatgcgc tcagagccac
gcccaggagt cctcctgcga 2220gccccatttc ccgcggccgc tgaaaacctg
tattttcagg gtggggccgc tgggccgggc 2280gtgggagttc ccggcgtggg
agttcccgga ggcggagtgc ccggcgcagg agttcctgga 2340gtcggagtgc
ccggagttgg agtgcccgga gttggagtcc caggaggcgg agtccccgga
2400gcaggcgtcc ccggaggcgg agtgccgggc gtgggagttc ccggcgtggg
agttcccgga 2460ggcggagtgc ccggcgcagg agttcctgga gtcggagtgc
ccggagttgg agtgcccgga 2520gttggagtcc caggaggcgg agtccccgga
gcaggcgtcc ccggaggcgg agtgccgggc 2580gtgggagttc ccggcgtggg
agttcccgga ggcggagtgc ccggcgcagg agttcctgga 2640gtcggagtgc
ccggagttgg agtgcccgga gttggagtcc caggaggcgg agtccccgga
2700gcaggcgtcc ccggaggcgg agtgccgggc gtgggagttc ccggcgtggg
agttcccgga 2760ggcggagtgc ccggcgcagg agttcctgga gtcggagtgc
ccggagttgg agtgcccgga 2820gttggagtcc caggaggcgg agtccccgga
gcaggcgtcc ccggaggcgg agtgccgggc 2880gtgggagttc ccggcgtggg
agttcccgga ggcggagtgc ccggcgcagg agttcctgga 2940gtcggagtgc
ccggagttgg agtgcccgga gttggagtcc caggaggcgg agtccccgga
3000gcaggcgtcc ccggaggcgg agtgccgggc gtgggagttc ccggcgtggg
agttcccgga 3060ggcggagtgc ccggcgcagg agttcctgga gtcggagtgc
ccggagttgg agtgcccgga 3120gttggagtcc caggaggcgg agtccccgga
gcaggcgtcc ccggaggcgg agtgccgggc 3180gtgggagttc ccggcgtggg
agttcccgga ggcggagtgc ccggcgcagg agttcctgga 3240gtcggagtgc
ccggagttgg agtgcccgga gttggagtcc caggaggcgg agtccccgga
3300gcaggcgtcc ccggaggcgg agtgccgggc gtgggagttc ccggcgtggg
agttcccgga 3360ggcggagtgc ccggcgcagg agttcctgga gtcggagtgc
ccggagttgg agtgcccgga 3420gttggagtcc caggaggcgg agtccccgga
gcaggcgtcc ccggaggcgg agtgccgggc 3480gtgggagttc ccggcgtggg
agttcccgga ggcggagtgc ccggcgcagg agttcctgga 3540gtcggagtgc
ccggagttgg agtgcccgga gttggagtcc caggaggcgg agtccccgga
3600gcaggcgtcc ccggaggcgg agtgccgggc tggccttgat gactcgagtc
tagagggccc 3660gtttaaaccc gctgatcagc ctcgactgtg ccttctagtt
370058912PRTArtificial SequenceFactor VIP-ELP 1-90 amino acid
sequence 58Met Val Ser Gln Ala Leu Arg Leu Leu Cys Leu Leu Leu Gly
Leu Gln 1 5 10 15 Gly Cys Leu Ala Ala Val Phe Val Thr Gln Glu Glu
Ala His Gly Val 20 25 30 Leu His Arg Arg Arg Arg Ala Asn Ala Phe
Leu Glu Glu Leu Arg Pro 35 40 45 Gly Ser Leu Glu Arg Glu Cys Lys
Glu Glu Gln Cys Ser Phe Glu Glu 50 55 60 Ala Arg Glu Ile Phe Lys
Asp Ala Glu Arg Thr Lys Leu Phe Trp Ile 65 70 75 80 Ser Tyr Ser Asp
Gly Asp Gln Cys Ala Ser Ser Pro Cys Gln Asn Gly 85 90 95 Gly Ser
Cys Lys Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys Leu Pro
100 105 110 Ala Phe Glu Gly Arg Asn Cys Glu Thr His Lys Asp Asp Gln
Leu Ile 115 120 125 Cys Val Asn Glu Asn Gly Gly Cys Glu Gln Tyr Cys
Ser Asp His Thr 130 135 140 Gly Thr Lys Arg Ser Cys Arg Cys His Glu
Gly Tyr Ser Leu Leu Ala 145 150 155 160 Asp Gly Val Ser Cys Thr Pro
Thr Val Glu Tyr Pro Cys Gly Lys Ile 165 170 175 Pro Ile Leu Glu Lys
Arg Asn Ala Ser Lys Pro Gln Gly Arg Ile Val 180 185 190 Gly Gly Lys
Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Val Leu Leu 195 200 205 Leu
Val Asn Gly Ala Gln Leu Cys Gly Gly Thr Leu Ile Asn Thr Ile 210 215
220 Trp Val Val Ser Ala Ala His Cys Phe Asp Lys Ile Lys Asn Trp Arg
225 230 235 240 Asn Leu Ile Ala Val Leu Gly Glu His Asp Leu Ser Glu
His Asp Gly 245 250 255 Asp Glu Gln Ser Arg Arg Val Ala Gln Val Ile
Ile Pro Ser Thr Tyr 260 265 270 Val Pro Gly Thr Thr Asn His Asp Ile
Ala Leu Leu Arg Leu His Gln 275 280 285 Pro Val Val Leu Thr Asp His
Val Val Pro Leu Cys Leu Pro Glu Arg 290 295 300 Thr Phe Ser Glu Arg
Thr Leu Ala Phe Val Arg Phe Ser Leu Val Ser 305 310 315 320 Gly Trp
Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu Leu Met 325 330 335
Val Leu Asn Val Pro Arg Leu Met Thr Gln Asp Cys Leu Gln Gln Ser 340
345 350 Arg Lys Val Gly Asp Ser Pro Asn Ile Thr Glu Tyr Met Phe Cys
Ala 355 360 365 Gly Tyr Ser Asp Gly Ser Lys Asp Ser Cys Lys Gly Asp
Ser Gly Gly 370 375 380 Pro His Ala Thr His Tyr Arg Gly Thr Trp Tyr
Leu Thr Gly Ile Val 385 390 395 400 Ser Trp Gly Gln Gly Cys Ala Thr
Val Gly His Phe Gly Val Tyr Thr 405 410 415 Arg Val Ser Gln Tyr Ile
Glu Trp Leu Gln Lys Leu Met Arg Ser Glu 420 425 430 Pro Arg Pro Gly
Val Leu Leu Arg Ala Pro Phe Pro Ala Ala Ala Glu 435 440 445 Asn Leu
Tyr Phe Gln Gly Gly Ala Ala Gly Pro Gly Val Gly Val Pro 450 455 460
Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly 465
470 475 480 Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
Gly Gly 485 490 495 Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
Pro Gly Val Gly 500 505 510 Val Pro Gly Val Gly Val Pro Gly Gly Gly
Val Pro Gly Ala Gly Val 515 520 525 Pro Gly Val Gly Val Pro Gly Val
Gly Val Pro Gly Val Gly Val Pro 530 535 540 Gly Gly Gly Val Pro Gly
Ala Gly Val Pro Gly Gly Gly Val Pro Gly 545 550 555 560 Val Gly Val
Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala 565 570 575 Gly
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly 580 585
590 Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Gly Gly Val
595 600 605 Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly
Val Pro 610 615 620 Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Val
Gly Val Pro Gly 625 630 635 640 Val Gly Val Pro Gly Gly Gly Val Pro
Gly Ala Gly Val Pro Gly Gly 645 650 655 Gly Val Pro Gly Val Gly Val
Pro Gly Val Gly Val Pro Gly Gly Gly 660 665 670 Val Pro Gly Ala Gly
Val Pro Gly Val Gly Val Pro Gly Val Gly Val 675 680 685 Pro Gly Val
Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro 690 695 700 Gly
Gly Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly 705 710
715 720 Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly
Val 725 730 735 Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val Pro
Gly Ala Gly 740 745 750 Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
Pro Gly Val Gly Val 755 760 765 Pro Gly Gly Gly Val Pro Gly Ala Gly
Val Pro Gly Val Gly Val Pro 770 775 780 Gly Val Gly Val Pro Gly Val
Gly Val Pro Gly Gly Gly Val Pro Gly 785 790 795 800 Ala Gly Val Pro
Gly Gly Gly Val Pro Gly Val Gly Val Pro Gly Val 805 810 815 Gly Val
Pro Gly Gly Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly 820 825 830
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Gly Gly Val 835
840 845 Pro Gly Ala Gly Val Pro Gly Gly Gly Val Pro Gly Val Gly Val
Pro 850 855 860 Gly Val Gly Val Pro Gly Gly Gly Val Pro Gly Ala Gly
Val Pro Gly 865 870 875 880 Val Gly Val Pro Gly Val Gly Val Pro Gly
Val Gly Val Pro Gly Gly 885 890 895 Gly Val Pro Gly Ala Gly Val Pro
Gly Gly Gly Val Pro Gly Trp Pro 900 905 910 5931PRTUnknownGLP-1
receptor agonist 59His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser
Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu
Val Lys Gly Arg Gly 20 25 30 6031PRTHomo sapiens 60His Gly Glu Gly
Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala
Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro 20 25 30
6130PRTHomo sapiens 61His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser
Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp
Leu Lys Asn Gly Gly 20 25 30 6232PRTHomo sapiens 62His Gly Glu Gly
Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala
Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30
6333PRTHomo sapiens 63His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser
Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp
Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser 6434PRTHomo sapiens 64His
Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10
15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30 Ser Gly 6535PRTHomo sapiens 65His Gly Glu Gly Thr Phe Thr
Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu
Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala 35
6636PRTHomo sapiens 66His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser
Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp
Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro 6737PRTHomo
sapiens 67His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met
Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn
Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro 35 6838PRTHomo sapiens
68His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1
5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro
Ser 20 25 30 Ser Gly Ala Pro Pro Pro 35
* * * * *
References