U.S. patent application number 16/352465 was filed with the patent office on 2019-07-04 for passive vaccine for elimination of senescent cells.
The applicant listed for this patent is Buck Institute for Research on Aging, Kythera Biopharmaceuticals, Inc., Unity Biotechnology, Inc.. Invention is credited to Judith Campisi, Serge Lichtsteiner, Alain Philippe Vasserot.
Application Number | 20190201510 16/352465 |
Document ID | / |
Family ID | 50883944 |
Filed Date | 2019-07-04 |
United States Patent
Application |
20190201510 |
Kind Code |
A1 |
Vasserot; Alain Philippe ;
et al. |
July 4, 2019 |
PASSIVE VACCINE FOR ELIMINATION OF SENESCENT CELLS
Abstract
Provided herein are immunogenic compositions (vaccines) and
methods for immunizing a subject with the immunogenic compositions
for inducing an adaptive immune response directed specifically
against senescent cells for treatment and prophylaxis of
age-related diseases and disorders, and other diseases and
disorders associated with or exacerbated by the presence of
senescent cells. The immunogenic compositions provided herein
comprise at least one or more senescent cell-associated antigens,
polynucleotides encoding senescent cell-associated antigens, and
recombinant expression vectors comprising the polynucleotides for
use in administering to a subject in need thereof.
Inventors: |
Vasserot; Alain Philippe;
(Carlsbad, CA) ; Lichtsteiner; Serge; (Westlake,
CA) ; Campisi; Judith; (Berkeley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Unity Biotechnology, Inc.
Kythera Biopharmaceuticals, Inc.
Buck Institute for Research on Aging |
Brisbane
Calabasas
Novato |
CA
CA
CA |
US
US
US |
|
|
Family ID: |
50883944 |
Appl. No.: |
16/352465 |
Filed: |
March 13, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14649022 |
Sep 21, 2015 |
10279018 |
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PCT/US13/72938 |
Dec 3, 2013 |
|
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16352465 |
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61732746 |
Dec 3, 2012 |
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61747653 |
Dec 31, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 14/47 20130101;
A61K 2039/70 20130101; C07K 2317/56 20130101; A61K 39/39 20130101;
A61K 39/0005 20130101; C07K 16/28 20130101; C07K 16/18 20130101;
C07K 2317/64 20130101; A61P 37/00 20180101 |
International
Class: |
A61K 39/00 20060101
A61K039/00; C07K 16/18 20060101 C07K016/18; A61K 39/39 20060101
A61K039/39; C07K 14/47 20060101 C07K014/47; C07K 16/28 20060101
C07K016/28 |
Goverment Interests
STATEMENT OF FEDERALLY SPONSORED RESEARCH
[0002] This invention was made with government support under
AG009909 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A method of preparing a passive vaccine for administration to a
subject who has senescent cells in a tissue that are causing or
promoting adverse symptoms, wherein the senescent cells are defined
as p16 positive cells that are not cancer cells; wherein the method
comprises: (a) obtaining an antibody or antigen binding fragment
that contains at least one immunoglobulin variable region that is
specific for human p16INK4a protein; (b) determining an amount of
the antibody or antigen binding fragment and a formulation of the
antibody or antigen binding fragment with a pharmaceutically
acceptable excipient to produce a passive vaccine suitable for
human administration that is effective for removing senescent cells
from the tissue that are causing or promoting the adverse symptoms;
and (c) compounding the amount of the antibody or antigen binding
fragment in the formulation determined in step (b) to produce the
passive vaccine.
2. The method of claim 1, wherein the antibody or antigen binding
fragment is a human or humanized antibody that is specific for
human p16INK4a protein.
3. The method of claim 1, wherein the antibody or antigen binding
fragment is an immunoglobulin G.
4. The method of claim 1, further comprising packaging the passive
vaccine with an informational insert that describes the use and
attendant benefits of the passive vaccine in alleviating at least
some of the adverse symptoms.
5. A method for selectively removing senescent cells from a tissue
in a subject that are causing or promoting adverse symptoms,
wherein the senescent cells are defined as p16 positive cells that
are not cancer cells, wherein the method comprises: obtaining a
passive vaccine containing at least one immunoglobulin variable
region that is specific for human p16INK4a protein; and
administering the passive vaccine to the subject so as to remove
senescent cells from the tissue that are causing or promoting the
adverse symptoms; wherein the passive vaccine has been prepared
according to the method of claim 1.
6. The method of claim 5, wherein the antibody or antigen binding
fragment is a human or humanized antibody that is specific for
human p16INK4a protein.
7. The method of claim 5, wherein the antibody or antigen binding
fragment is an immunoglobulin G.
8. The method of claim 5, which further comprises monitoring at
least one component of a senescence associated secretory phenotype
(SASP) in the subject following administration of the passive
vaccine.
9. The method of claim 5, which further comprises monitoring the
adverse symptoms in the subject following administration of the
passive vaccine.
10. The method of claim 5, which further comprises assessing p16
positive cells in the tissue following administration of the
passive vaccine.
11. A unit dose of a pharmaceutical composition configured for
administration to a subject who has senescent cells that are
causing or promoting adverse symptoms in a tissue of the subject;
wherein the senescent cells are not cancer cells; wherein the
composition comprises a formulation of an antibody or
antigen-binding fragment that contains at least one immunoglobulin
variable region that is specific for human p16INK4a protein; and
wherein the amount of the antibody or antigen binding fragment and
the formulation of the pharmaceutical composition configure the
unit dose to be effective in removing senescent cells that are
causing or promoting the adverse symptoms in the tissue.
12. The unit dose according to claim 11, wherein the antibody or
antigen binding fragment is a human or humanized antibody that is
specific for human p16INK4a protein.
13. The unit dose according to claim 11, wherein the antibody or
antigen binding fragment is an immunoglobulin G.
14. The unit dose according to claim 11, packaged with an
informational insert that describes the use and attendant benefits
of the passive vaccine in alleviating at least some of the adverse
symptoms.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 14/649,022, filed Sep. 21, 2015, which is a U.S. national stage
entry under 35 USC .sctn. 371 of PCT/US2013/072938, filed Dec. 3,
2013, which claims the benefit of U.S. Provisional Application No.
61/732,746, filed Dec. 3, 2012 and U.S. Provisional Application No.
61/747,653, filed Dec. 31, 2012, the contents of which are herein
incorporated by reference in their entirety.
STATEMENT REGARDING SEQUENCE LISTING
[0003] The Sequence Listing associated with this application is
provided in text format in lieu of a paper copy, and is hereby
incorporated by reference into the specification. The name of the
text file containing the Sequence Listing is
44237-720-301-Sequence-Listing.txt. The text file is 1 KB, was
created on Mar. 12, 2019 and is being submitted electronically via
EFS-Web.
BACKGROUND
Technical Field
[0004] The disclosure herein relates generally to immunogenic
compositions (e.g., vaccines) and methods for using the immunogenic
compositions for inducing an immune response directed specifically
against senescent cells for treatment and prophylaxis of
age-related diseases and disorders, and other diseases and
disorders associated or exacerbated by the presence of senescent
cells.
Description of the Related Art
[0005] Senescent cells accumulate in tissues and organs of
individuals as they age and are found at sites of age-related
pathologies. While senescent cells are believed important to
inhibiting proliferation of dysfunctional or damaged cells and
particularly to constraining development of malignancy (see, e.g.,
Campisi, Curr. Opin. Genet. Dev. 21:107-12 (2011); Campisi, Trends
Cell Biol. 11:S27-31 (2001); Prieur et al., Curr. Opin. Cell Biol.
20:150-55 (2008)), the presence of senescent cells in an aging
individual may contribute to aging and aging-related dysfunction
(see, e.g., Campisi, Cell 120:513-22 (2005)). Given that senescent
cells have been causally implicated in certain aspects of
age-related decline in health and may contribute to certain
diseases, and are also induced as a result of necessary
life-preserving chemotherapeutic and radiation treatments, the
presence of senescent cells may have deleterious effects to
millions of patients worldwide (e.g., fatigue, weakness, loss of
physical agility, decrease in cognitive function). Accordingly,
treatments aimed at clearing aging-induced and therapy-induced
senescent cells and improving age-sensitive traits have the
potential to markedly improve the health, lifespan, and quality of
life for patients exposed to senescence-inducing stimuli. The
present disclosure addresses these needs and offers numerous
related advantages.
BRIEF SUMMARY
[0006] Disclosed herein are immunogenic compositions and methods of
using the compositions for inducing an immune response that is
specific for senescent cells (i.e., specific for senescent cell
associated antigens expressed by the senescent cells) and that
comprises clearance (i.e., removal, elimination) of senescent cells
from the subject receiving the immunogenic composition. The methods
include active and passive immunization. Provided herein are the
following embodiments.
[0007] In one embodiment, a method is provided for evoking an
immune response specific for a senescent cell in a subject, wherein
the immune response comprises clearance of the senescent cell by
the immune system of the subject, wherein the method comprises
administering to the subject an immunogenic composition comprising:
(a) a pharmaceutically acceptable excipient, and (b) an immunogen.
In particular embodiments, the immunogen is selected from (i) an
isolated senescent cell-associated antigen or an antigenic fragment
thereof, wherein the senescent cell-associated antigen is selected
from (A) p16INK4a, (B) a senescent cell-associated antigen selected
from Table 1, and (C) a senescent cell-associated antigen that is
encoded by a nucleic acid sequence selected from Table 2 or Table
3, and wherein the antigenic fragment comprises at least 20
contiguous amino acids of the senescent cell-associated antigen;
(ii) an isolated polynucleotide encoding at least two senescent
cell-associated antigens of (i) or antigenic fragments thereof;
(iii) at least two isolated polynucleotides, wherein a first
isolated polynucleotide encodes a first senescent cell-associated
antigen or an antigenic fragment thereof, and wherein the first
senescent cell-associated antigen is selected from (A) p16INK4a,
(B) a senescent cell-associated antigen selected from Table 1, and
(C) a senescent cell-associated antigen that is encoded by a
nucleic acid sequence selected from Table 2 or Table 3, and wherein
the antigenic fragment comprises at least 20 contiguous amino acids
of the first senescent cell-associated antigen, and a second
polynucleotide encodes a second senescent cell-associated antigen,
wherein the second senescent cell-associated antigen is selected
from (A) p16INK4a, (B) a senescent cell-associated antigen selected
from Table 1, and (C) a senescent cell-associated antigen that is
encoded by a nucleic acid sequence selected from Table 2 or Table
3, and wherein the antigenic fragment comprises at least 20
contiguous amino acids of the second senescent cell-associated
antigen; (iv) a recombinant expression vector that is a viral
vector comprising a polynucleotide that encodes the senescent
cell-associate antigen or antigenic fragment thereof of (i); (v) a
senescent cell membrane preparation, a senescent cell organelle
preparation, or an exosome; (vi) a fusion polypeptide comprising at
least two senescent cell-associated antigens, wherein each of the
at least two senescent cell-associated antigens are different and
each is selected from (A) p16INK4a, (B) a senescent cell-associated
antigen selected from Table 1, and (C) a senescent cell-associated
antigen that is encoded by a nucleic acid sequence selected from
Table 2 or Table 3; (vii) a fusion polypeptide comprising at least
two antigenic fragments wherein each of the at least two antigenic
fragments comprises at least 20 contiguous amino acids of a
senescent cell-associated antigen selected from (A) p16INK4a, (B) a
senescent cell-associated antigen selected from Table 1, and (C) a
senescent cell-associated antigen that is encoded by a nucleic acid
sequence selected from Table 2 or Table 3; (viii) a fusion
polypeptide comprising at least one senescent cell-associated
antigen of (i) or an antigenic fragment thereof and a
co-stimulatory polypeptide; and (ix) a modified dendritic cell
wherein a dendritic cell is isolated from the subject and is
modified by (A) introducing a senescent cell-associated antigen, or
an antigenic fragment that comprises at least 20 contiguous amino
acids of the senescent cell-associated antigen, wherein the
senescent cell-associated antigen is selected from (A) p16INK4a,
(B) a senescent cell-associated antigen selected from Table 1, and
(C) a senescent cell-associated antigen that is encoded by a
nucleic acid sequence selected from Table 2 or Table 3, or (B)
introducing a polynucleotide encoding the senescent cell-associated
antigen, or an antigenic fragment of (A), into the dendritic cell
ex vivo to provide a modified dendritic cell, and wherein the
modified dendritic cell is administered to the subject. In certain
particular embodiments for use in the methods described above and
herein, the senescent cell-associated antigen that is encoded by a
nucleic acid sequence selected from Table 2 is any one of ADAMTS7,
APLP2, ATP6V0D2, BCHE, C11orf87, CD46, CYB5D2, FBXL7, GPR137B,
IFI27L1, IL15RA, LAMP2, MYO10, NEU1, NHSL2, NPAS2, OR1F1, PEA15,
RAB23, RARB, RNPC3, SELO, SELT, SEMASB, SERP1, SERPINE1, SLC9A7,
SNX3, TBC1D1, TBRG1, TCEANC, TFPI, TNFAIP1, TUBG2, USP18, or ZNF419
(see Table 2). In other more specific embodiments, the senescent
cell-associated antigen that is encoded by a nucleic acid sequence
selected from Table 2 is any one of NEU1, SELO, SERP1, SERPINE1, or
SNX3. In other specific embodiments, the senescent cell-associated
antigen is p16INK4a. In other certain particular embodiments, the
at least first and the at least second senescent cell-associated
antigen encoded by a nucleic acid sequence selected from Table 2
are different and selected from any one of ADAMTS7, APLP2,
ATP6V0D2, BCHE, C11orf87, CD46, CYB5D2, FBXL7, GPR137B, IFI27L1,
IL15RA, LAMP2, MYO10, NEU1, NHSL2, NPAS2, OR1F1, PEA15, RAB23,
RARB, RNPC3, SELO, SELT, SEMASB, SERP1, SERPINE1, SLC9A7, SNX3,
TBC1D1, TBRG1, TCEANC, TFPI, TNFAIP1, TUBG2, USP18, and ZNF419 (see
Table 2). In other more specific embodiments, the at least first
and the at least second senescent cell-associated antigens encoded
by a nucleic acid sequence selected from Table 2 is selected from
any one of NEU1, SELO, SERP1, SERPINE1, and SNX3. In still other
particular embodiments, the at least first senescent
cell-associated antigen or the at least second senescent
cell-associated antigen is p16INK4a.
[0008] In certain other embodiments of the method described above
and herein, the immunogen comprises at least two isolated senescent
cell-associated antigens or antigenic fragments thereof, wherein
(a) a first isolated senescent cell-associated antigen, or an
antigenic fragment thereof that comprises at least 20 contiguous
amino acids of the first senescent cell-associated antigen, and (b)
a second isolated senescent cell-associated antigen or an antigenic
fragment thereof that comprises at least 20 contiguous amino acids
of the second senescent cell-associated antigen, are different and
each independently is selected from (A) p16INK4a, (B) a senescent
cell-associated antigen selected from Table 1, and (C) a senescent
cell-associated antigen that is encoded by a nucleic acid sequence
selected from Table 2 or Table 3. In certain particular
embodiments, the at least first and the at least second isolated
senescent cell-associated antigen are different and encoded by a
nucleic acid sequence selected from Table 2, wherein the at least
first and the at least second isolated senescent cell-associated
antigens are selected from ADAMTS7, APLP2, ATP6V0D2, BCHE,
C11orf87, CD46, CYB5D2, FBXL7, GPR137B, IFI27L1, IL15RA, LAMP2,
MYO10, NEU1, NHSL2, NPAS2, OR1F1, PEA15, RAB23, RARB, RNPC3, SELO,
SELT, SEMASB, SERP1, SERPINE1, SLC9A7, SNX3, TBC1D1, TBRG1, TCEANC,
TFPI, TNFAIP1, TUBG2, USP18, and ZNF419 (see Table 2). In other
more specific embodiments, the at least first and the at least
second isolated senescent cell-associated antigens encoded by a
nucleic acid sequence from Table 2 are selected from NEU1, SELO,
SERP1, SERPINE1, and SNX3. In still other particular embodiments,
the at least first senescent cell-associated antigen or the at
least second senescent cell-associated antigen is p16INK4a.
[0009] In a more particular embodiment, the senescent
cell-associated antigen is present on the cell surface of the
senescent cell. In still another embodiment, when the immunogen
comprises a first and the second senescent cell-associated antigen,
the first and the second senescent cell-associated antigen are each
present on the cell surface of the senescent cell.
[0010] In certain other embodiments, the immunogenic composition
comprises a recombinant expression vector that comprises the
polynucleotide of (b)(ii) operatively linked to at least one
regulatory expression sequence. In a more particular embodiment,
the recombinant expression vector is a viral vector. In still
another specific embodiment, the viral vector is selected from an
adenovirus vector, lentivirus vector, a herpes virus vector,
adenovirus-associated vector, or a poxvirus vector. In another
particular embodiment, the adenoviral vector is a
replication-defective adenovirus. In certain specific embodiment,
the replication-defective adenovirus is a recombinant human
adenovirus having a serotype selected from Ad11, Ad24, Ad26, Ad34,
Ad35, Ad48, Ad49, and Ad50.
[0011] In yet another embodiment of the method described above and
herein, the immunogen comprises at least one polynucleotide that
encodes (a) a first senescent cell-associated antigen, or an
antigenic fragment thereof that comprises at least 20 contiguous
amino acids of the first senescent cell-associated antigen, and (b)
a second senescent cell-associated antigen or an antigenic fragment
thereof that comprises at least 20 contiguous amino acids of the
second senescent cell-associated antigen, wherein the first and
second senescent cell-associated antigens are different and each
independently is selected from (A) p16INK4a, (B) a senescent
cell-associated antigen selected from Table 1, and (C) a senescent
cell-associated antigen that is encoded by a nucleic acid sequence
selected from Table 2 or Table 3. In certain particular
embodiments, the at least first and the at least second isolated
senescent cell-associated antigen are encoded by a nucleic acid
sequence selected from Table 2, wherein the at least first and the
at least second isolated senescent cell-associated antigens are
selected from ADAMTS7, APLP2, ATP6V0D2, BCHE, C11orf87, CD46,
CYB5D2, FBXL7, GPR137B, IFI27L1, IL15RA, LAMP2, MYO10, NEU1, NHSL2,
NPAS2, OR1F1, PEA15, RAB23, RARB, RNPC3, SELO, SELT, SEMASB, SERP1,
SERPINE1, SLC9A7, SNX3, TBC1D1, TBRG1, TCEANC, TFPI, TNFAIP1,
TUBG2, USP18, and ZNF419 (see Table 2). In other more specific
embodiments, the at least first and the at least second isolated
senescent cell-associated antigens encoded by a nucleic acid
sequence from Table 2 are selected independently from NEU1, SELO,
SERP1, SERPINE1, and SNX3. In still other particular embodiments,
the at least first senescent cell-associated antigen or the at
least second senescent cell-associated antigen is p16INK4a. In
still another embodiment, the immunogenic composition comprises a
recombinant expression vector that comprises the at least one
polynucleotide operatively linked to at least one regulatory
expression sequence. In certain embodiments, the recombinant
expression vector is a viral vector. In still another specific
embodiment, the viral vector is selected from an adenovirus vector,
lentivirus vector, a herpes virus vector, adenovirus-associated
vector, or a poxvirus vector. In another particular embodiment, the
adenoviral vector is a replication-defective adenovirus. In certain
specific embodiment, the replication-defective adenovirus is a
recombinant human adenovirus having a serotype selected from Ad11,
Ad24, Ad26, Ad34, Ad35, Ad48, Ad49, and Ad50.
[0012] In yet another embodiment of the method described above and
herein, the immunogen comprises at least two polynucleotides
wherein a first polynucleotide encodes the first senescent
cell-associated antigen, or an antigenic fragment thereof, and a
second polynucleotide encodes the second senescent cell-associated
antigen, or an antigenic fragment thereof. In a specific
embodiment, the immunogenic composition comprises (a) a recombinant
expression vector that comprising the at least two polynucleotides
wherein each of the at least two polynucleotides is operatively
linked to at least one regulatory expression sequence; or (b) a
first recombinant expression vector that comprises the first
polynucleotide operatively linked to at least one regulatory
expression sequence and a second recombinant expression vector that
comprises the first polynucleotide operatively linked to at least
one regulatory expression sequence. In certain embodiments, the
recombinant expression vector is a viral vector. In still more
particular embodiments, the recombinant expression vector of (a)
the first recombinant expression vector of (b) and the second
recombinant expression vector of (b) are each a viral vector. In
still another specific embodiment, the viral vector is selected
from an adenovirus vector, lentivirus vector, a herpes virus
vector, adenovirus-associated vector, or a poxvirus vector. In
another particular embodiment, the adenoviral vector is a
replication-defective adenovirus. In certain specific embodiment,
the replication-defective adenovirus is a recombinant human
adenovirus having a serotype selected from Ad11, Ad24, Ad26, Ad34,
Ad35, Ad48, Ad49, and Ad50. In one particular embodiment, the first
recombinant expression vector and the second recombinant expression
vector are each the same or different recombinant human adenoviral
vector having a serotype independently selected from Ad11, Ad24,
Ad26, Ad34, Ad35, Ad48, Ad49, and Ad50.
[0013] In yet another embodiment of the method described above and
herein, when the immunogen comprises a dendritic cell, the
dendritic cell is modified by introducing a recombinant expression
vector comprising the polynucleotide. In certain embodiments, the
recombinant expression vector is a viral vector selected from an
adenovirus vector, lentivirus vector, a herpes virus vector,
adenovirus-associated vector, or a poxvirus vector. In another
particular embodiment, the adenoviral vector is a
replication-defective adenovirus. In certain specific embodiment,
the replication-defective adenovirus is a recombinant human
adenovirus having a serotype selected from Ad11, Ad24, Ad26, Ad34,
Ad35, Ad48, Ad49, and Ad50.
[0014] In particular embodiments, with respect to the methods
described above and herein, the immunogenic composition further
comprises a pharmaceutically acceptable adjuvant. In other
particular embodiments, with respect to the methods described above
and herein, the immunogenic composition further comprises (a) a
co-stimulatory polypeptide that enhances the adaptive immune
response to the immunogen; (b) a polynucleotide encoding the
co-stimulatory polypeptide; or (c) a recombinant expression vector
that comprises the polynucleotide sequence, which is operatively
linked to at least one regulatory expression sequence. In still
other specific embodiments, the subject has or is at risk of
developing a disease or disorder treatable by clearing senescent
cells from a tissue of the subject. In still more specific
embodiments, of the methods described above and herein, the disease
or disorder is an age-related disease or disorder.
[0015] Also provided herein is an immunogenic composition that
comprises a pharmaceutically acceptable excipient and at least one
immunogenic preparation selected from: (a) an immunogenic
preparation comprising a first isolated senescent cell-associated
antigen, or an antigenic fragment thereof that comprises at least
20 contiguous amino acids of the first senescent cell-associated
antigen, and a second isolated senescent cell-associated antigen or
an antigenic fragment thereof that comprises at least 20 contiguous
amino acids of the second senescent cell-associated antigen,
wherein the first and second senescent cell-associated antigens are
different and selected independently from p16INK4a, a senescent
cell-associated antigen selected from Table 1, and a senescent
cell-associated antigen that is encoded by a nucleic acid sequence
selected from Table 2 or Table 3; (b) an immunogenic preparation
comprising at least one polynucleotide that encodes the first
senescent cell-associated antigen, or an antigenic fragment
thereof, and the second senescent cell-associated antigen or an
antigenic fragment thereof; (c) an immunogenic preparation
comprising at least two polynucleotides wherein a first
polynucleotide encodes the first senescent cell-associated antigen,
or an antigenic fragment thereof, and a second polynucleotide
encodes the second senescent cell-associated antigen, or an
antigenic fragment thereof; (d) an immunogenic preparation
comprising a senescent cell membrane preparation, a senescent cell
organelle preparation, or an exosome; (e) an immunogenic
preparation comprising a fusion polypeptide comprising at least two
senescent cell-associated antigens, wherein each of the at least
two senescent cell-associated antigens are different and selected
independently from p16INK4a, a senescent cell-associated antigen
selected from Table 1, and a senescent cell-associated antigen that
is encoded by a nucleic acid sequence selected from Table 2 or
Table 3; (0 an immunogenic preparation comprising a fusion
polypeptide comprising at least two antigenic fragments wherein
each of the at least two antigenic fragments comprises at least 20
contiguous amino acids of a senescent cell-associated antigen
selected from p16INK4a, a senescent cell-associated antigen
selected from Table 1, and a senescent cell-associated antigen that
is encoded by a nucleic acid sequence selected from Table 2 or
Table 3; and (g) an immunogenic preparation comprising a modified
dendritic cell wherein a dendritic cell is isolated from the
subject and is modified by (i) introducing a senescent
cell-associated antigen, or an antigenic fragment that comprises at
least 20 contiguous amino acids of the senescent cell-associated
antigen, wherein the senescent cell-associated antigen is selected
from (A) p16INK4a, (B) a senescent cell-associated antigen selected
from Table 1, and (C) a senescent cell-associated antigen that is
encoded by a nucleic acid sequence selected from Table 2 or Table
3, or (ii) introducing a polynucleotide encoding the senescent
cell-associated antigen, or an antigenic fragment of (i), into the
dendritic cell ex vivo to provide a modified dendritic cell, and
wherein the modified dendritic cell is administered to the subject.
In certain particular embodiments, the senescent cell-associated
antigen that is encoded by a nucleic acid sequence selected from
Table 2 is any one of ADAMTS7, APLP2, ATP6V0D2, BCHE, C11orf87,
CD46, CYB5D2, FBXL7, GPR137B, IFI27L1, IL15RA, LAMP2, MYO10, NEU1,
NHSL2, NPAS2, OR1F1, PEA15, RAB23, RARB, RNPC3, SELO, SELT, SEMASB,
SERP1, SERPINE1, SLC9A7, SNX3, TBC1D1, TBRG1, TCEANC, TFPI,
TNFAIP1, TUBG2, USP18, or ZNF419 (see Table 2). In other more
specific embodiments, the senescent cell-associated antigen that is
encoded by a nucleic acid sequence selected from Table 2 is any one
of NEU1, SELO, SERP1, SERPINE1, or SNX3. In other specific
embodiments, the senescent cell-associated antigen is p16INK4a. In
other certain particular embodiments, the at least first and the at
least second senescent cell-associated antigen encoded by a nucleic
acid sequence selected from Table 2 are different and selected from
any one of ADAMTS7, APLP2, ATP6V0D2, BCHE, C11orf87, CD46, CYB5D2,
FBXL7, GPR137B, IFI27L1, IL15RA, LAMP2, MYO10, NEU1, NHSL2, NPAS2,
OR1F1, PEA15, RAB23, RARB, RNPC3, SELO, SELT, SEMASB, SERP1,
SERPINE1, SLC9A7, SNX3, TBC1D1, TBRG1, TCEANC, TFPI, TNFAIP1,
TUBG2, USP18, and ZNF419 (see Table 2). In other more specific
embodiments, the at least first and the at least second senescent
cell-associated antigens encoded by a nucleic acid sequence
selected from Table 2 is selected from any one of NEU1, SELO,
SERP1, SERPINE1, and SNX3. In still other particular embodiments,
the at least first senescent cell-associated antigen or the at
least second senescent cell-associated antigen is p16INK4a.
[0016] In particular embodiments, with respect to the immunogenic
composition described above and herein, the senescent
cell-associated antigen is present on the cell surface of the
senescent cell. In another particular embodiment, the first and the
second senescent cell-associated antigen are each present on the
cell surface of the senescent cell. In yet another specific
embodiment, (i) a recombinant expression vector comprises the at
least one polynucleotide of (b) operatively linked to at least one
regulatory expression sequence; or (ii) a recombinant expression
vector comprises the at least two polynucleotides of (c), wherein
each polynucleotide is operatively linked to at least one
regulatory expression sequence; or (iii) the dendritic cell is
modified by introducing a recombinant expression vector comprising
the polynucleotide; or (iv) a first recombinant expression vector
comprises the first polynucleotide of (c) and a second recombinant
expression vector comprises the second polynucleotide of (c). In
particular embodiments, the recombinant expression vector of (i),
(ii), and (iii), and the first and second recombination vectors of
(iv) are each a viral vector. In certain embodiments, the
recombinant expression vector is a viral vector selected from an
adenovirus vector, lentivirus vector, a herpes virus vector,
adenovirus-associated vector, or a poxvirus vector. In another
particular embodiment, the adenoviral vector is a
replication-defective adenovirus. In certain specific embodiment,
the replication-defective adenovirus is a recombinant human
adenovirus having a serotype selected from Ad11, Ad24, Ad26, Ad34,
Ad35, Ad48, Ad49, and Ad50.
[0017] In certain particular embodiments described above and
herein, the immunogenic composition further comprises (a) a
co-stimulatory polypeptide that enhances the adaptive immune
response to the immunogen; (b) a polynucleotide encoding the
co-stimulatory polypeptide; or (c) a recombinant expression vector
that comprises the polynucleotide sequence encoding the
co-stimulatory polypeptide, which is operatively linked to at least
one regulatory expression sequence. In still other embodiments, the
immunogenic compositions described above and herein further
comprise a pharmaceutically acceptable adjuvant.
[0018] In yet another embodiment, a recombinant antibody is
provided that comprises (a) at least one immunoglobulin variable
region domain that specifically binds to a senescent
cell-associated antigen selected from (A) p16INK4a, (B) a senescent
cell-associated antigen selected from Table 1, and (C) a senescent
cell-associated antigen that is encoded by a nucleic acid sequence
selected from Table 2 or Table 3; and (b) a modified human Fc
region that exhibits enhanced affinity for an Fc.gamma. receptor.
In a particular embodiment, the recombinant antibody further
comprises a second immunoglobulin variable region (Fv), wherein the
second variable region specifically binds to the same or a
different senescent cell-associated antigen selected from p16INK4a,
a senescent cell-associated antigen selected from Table 1, and a
senescent cell-associated antigen that is encoded by a nucleic acid
sequence selected from Table 2 or Table 3. Also provided is an
immunogenic composition that comprises the recombinant antibody
described above and herein and a pharmaceutically acceptable
carrier. In still another embodiment, a method is provided for
facilitating clearance of a senescent cell from a subject,
comprising administering to the subject the immunogenic composition
comprising the recombinant antibody described above and herein. In
certain particular embodiments, the senescent cell-associated
antigen that is encoded by a nucleic acid sequence selected from
Table 2 is any one of ADAMTS7, APLP2, ATP6V0D2, BCHE, C11orf87,
CD46, CYB5D2, FBXL7, GPR137B, IFI27L1, IL15RA, LAMP2, MYO10, NEU1,
NHSL2, NPAS2, OR1F1, PEA15, RAB23, RARB, RNPC3, SELO, SELT, SEMASB,
SERP1, SERPINE1, SLC9A7, SNX3, TBC1D1, TBRG1, TCEANC, TFPI,
TNFAIP1, TUBG2, USP18, or ZNF419 (see Table 2); In other more
specific embodiments, the senescent cell-associated antigen that is
encoded by a nucleic acid sequence selected from Table 2 is any one
of NEU1, SELO, SERP1, SERPINE1, or SNX3. In still other specific
embodiments, the senescent cell-associated antigen is p16INK4a.
[0019] In one embodiment, a process is provided for formulating the
immunogenic composition described above and herein, comprising (a)
producing the immunogenic preparation that comprises the first
isolated senescent cell-associated antigen, or an antigenic
fragment thereof, and the second isolated senescent cell-associated
antigen or an antigenic fragment thereof, each as described above
and herein, by (i) culturing a first host cell into which a
recombinant expression vector comprising at least one regulatory
expression sequence operatively linked to a nucleotide sequence
that encodes the first senescent cell-associated antigen, or an
antigenic fragment thereof in a medium and for a time sufficient to
produce the first senescent cell-associated antigen; and (ii)
culturing a second host cell into which a recombinant expression
vector comprising at least one regulatory expression sequence
operatively linked to a nucleotide sequence that encodes the second
senescent cell-associated antigen, or an antigenic fragment thereof
in a medium and for a time sufficient to produce the second
senescent cell-associated antigen; (iii) isolating the first
senescent cell-associated antigen from the first host cell culture,
and isolating the second senescent cell-associated antigen from the
second host cell culture; and (c) formulating the first and the
second cell-associated antigens with a pharmaceutically acceptable
excipient. In a particular embodiment, the medium is a serum-free
medium.
[0020] Uses of the immunogenic compositions described above are
also provided for evoking an immune response specific for a
senescent cell in a subject, wherein the immune response comprises
clearance of the senescent cell by the immune system of the
subject, and for the manufacture of a medicament for evoking an
immune response specific for a senescent cell in a subject, wherein
the immune response comprises clearance of the senescent cell by
the immune system.
[0021] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
embodiments. However, one skilled in the art will understand that
the invention may be practiced without these details. In other
instances, well-known structures have not been shown or described
in detail to avoid unnecessarily obscuring descriptions of the
embodiments. Unless the context requires otherwise, throughout the
specification and claims which follow, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is, as "including, but
not limited to." In addition, the term "comprising" (and related
terms such as "comprise" or "comprises" or "having" or "including")
is not intended to exclude that in other certain embodiments, for
example, an embodiment of any composition of matter, composition,
method, or process, or the like, described herein, may "consist of"
or "consist essentially of" the described features. Headings
provided herein are for convenience only and do not interpret the
scope or meaning of the claimed embodiments.
[0022] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment. Thus, the appearances of the
phrases "in one embodiment" or "in an embodiment" in various places
throughout this specification are not necessarily all referring to
the same embodiment. Furthermore, the particular features,
structures, or characteristics may be combined in any suitable
manner in one or more embodiments.
[0023] Also, as used in this specification and the appended claims,
the singular forms "a," "an," and "the" include plural referents
unless the content clearly dictates otherwise. Thus, for example,
reference to "a non-human animal" may refer to one or more
non-human animals, or a plurality of such animals, and reference to
"a cell" or "the cell" includes reference to one or more cells and
equivalents thereof (e.g., plurality of cells) known to those
skilled in the art, and so forth. When steps of a method are
described or claimed, and the steps are described as occurring in a
particular order, the description of a first step occurring (or
being performed) "prior to" (i.e., before) a second step has the
same meaning if rewritten to state that the second step occurs (or
is performed) "subsequent" to the first step. The term "about" when
referring to a number or a numerical range means that the number or
numerical range referred to is an approximation within experimental
variability (or within statistical experimental error), and thus
the number or numerical range may vary between 1% and 15% of the
stated number or numerical range. It should also be noted that the
term "or" is generally employed in its sense including "and/or"
unless the content clearly dictates otherwise. The term, "at least
one," for example, when referring to at least one compound or to at
least one composition, has the same meaning and understanding as
the term, "one or more."
[0024] As used herein, the term "isolated" means that a material
(such as a senescent cell-associated antigen or a polynucleotide
encoding same) is removed from its original environment (e.g., the
natural environment if it is naturally occurring). For example, a
naturally occurring nucleic acid or polypeptide present in a living
animal is not isolated, but the same nucleic acid or polypeptide,
separated from some or all of the co-existing materials in the
natural system, is isolated. An "isolated" nucleic acid could be
part of a vector and/or such nucleic acid or polypeptide could be
part of a composition, and still be isolated in that the vector or
composition is not part of the natural environment for the nucleic
acid or polypeptide. The term "gene" means the segment of DNA
involved in producing a polypeptide chain; it includes regions
preceding and following the coding region "leader and trailer" as
well as intervening sequences (introns) between individual coding
segments (exons). Amino acids may be referred to herein according
to the single letter and three letter codes, which are understood
according to common textbook knowledge in the art, and therefore
with which a person skilled in the art is familiar. The term
"fusion polypeptide" used herein may also be used interchangeably
with "fusion protein," and unless specifically indicated otherwise,
the two terms are not meant to indicate molecules that have
distinguishable properties or characteristics.
DETAILED DESCRIPTION
[0025] Provided herein are immunogenic compositions (e.g.,
vaccines) and methods for using the immunogenic compositions for
inducing an immune response directed specifically against senescent
cells for treatment and prophylaxis of age-related diseases and
disorders, and other diseases and disorders associated or
exacerbated by the presence of senescent cells. The immune response
evoked by the immunogenic compositions described herein is specific
for one or more senescent cell-associated antigens, particularly
including one or more senescent cell-associated antigens (SCAAg)
present on the cell surface of the senescent cell (SC). This
specific immune response that comprises clearance (i.e., removal,
elimination, destruction) of senescent cells may include a humoral
or cellular immune response or both a humoral and cellular immune
response. The specific immune response may also mediate
antibody-dependent cell cytotoxicity (ADCC) or complement dependent
cytotoxicity (CDC) or both. The one or more senescent
cell-associated antigens that induce a specific immune response may
be presented to a subject by administering one or more different
immunogenic compositions as described in greater detail herein.
[0026] A subject in need of immunization with any one of the
immunogenic compositions described herein, in certain embodiments,
exhibits features of an age-related phenotype, age-related
disorder, or age-sensitive trait. In certain embodiments, the
age-related phenotype, age-related disorder, or age-sensitive trait
may result from contact with a senescence-inducing stimulus or may
result from factors that are presently considered part of the
normal aging process. In other certain embodiments, the subject has
been exposed to at least one senescence-inducing stimulus, which
may include, for example, one or more of a chemical stimulus, an
environmental stimulus, a genetic modification, a diet
modification, or a combination thereof. In certain specific
embodiments, the senescence-inducing stimulus comprises irradiation
treatment or treatment with one or more chemotherapeutic agents. In
other embodiments, the senescence-inducing stimulus is cigarette
smoking or other exposure to tobacco (e.g., secondary exposure to
cigarette smoke; smokeless tobacco), high fat or high sugar diet,
or other environmental insult.
Immunogenic Compositions
[0027] As described in detail herein, methods are provided for
evoking (i.e., inducing, stimulating, enhancing, boosting) an
immune response specific for a senescent cell and that comprises
clearance of the senescent cell by the immune system in a subject
by administering to the subject (i.e., immunizing) one or more of
the immunogenic compositions described herein. An immunogenic
composition may comprise any one of the senescent cell associated
antigens described herein, including but not limited to, a
polypeptide or protein, or immunogenic fragment thereof
glycoprotein or immunogenic fragment thereof a nucleic acid
encoding the polypeptide, protein, or glycoprotein, or immunogenic
fragment thereof; a glycolipid; a senescent cell associated
carbohydrate or carbohydrate comprising molecule; and a lipid
molecule. An immunogenic composition comprises one or more
pharmaceutically acceptable excipients and at least one (i.e., one
or more) immunogen which is a senescent cell-associated antigen, or
which may be an antigenic fragment of a senescent cell-associated
antigen. In a particular embodiment, two or more isolated senescent
cell-associated antigens (or antigenic fragment(s) thereof) are
included in an immunogenic composition, and in an even more
particular embodiment, a fusion polypeptide is provided that
comprises the two or more senescent cell-associated antigens (or
antigenic fragment of any one or more of the two or more senescent
cell-associated antigens). In another embodiment, the fusion
polypeptide includes at least one or at least two senescent
cell-associated antigens and a co-stimulatory polypeptide (such as
by way of non-limiting example, B-7.1, ICAM-1, LFA-3, GM-CSF). In
other certain embodiments, the immunogenic composition comprises a
polynucleotide that encodes at least one or at least two senescent
cell-associated antigens or encodes a fusion polypeptide comprising
same; a recombinant expression vector comprising the
polynucleotide; or an immune cell or other cell into which a
senescent cell-associated antigen or a polynucleotide encoding the
senescent cell-associated antigen has been introduced. Also
provided herein, are immunogenic compositions that comprise a
recombinant expression vector as an immunogen. In certain
embodiments, the recombinant expression vector is a viral vector
and comprises the polynucleotide that encodes a senescent cell
associated antigen or antigenic fragment thereof. In other
particular embodiments, the immunogen is a senescent cell membrane
preparation, a senescent cell organelle preparation, or an exosome
of a cell. Each of these immunogens and immunogenic compositions is
described in greater detail herein.
[0028] For ease of discussion when describing a composition or
immunogen comprising two or more senescent cell-associated
antigens, for example, one of the two or more antigens may be
called a first senescent cell-associated antigen and another of the
two or more antigens may be called a second senescent
cell-associated antigen, and another different antigen may be
called a third senescent cell-associated antigen, etc. Such
description may also be used in describing two or more
polynucleotides that may be used as an immunogen.
[0029] As described in greater detail herein, immunogenic
compositions may further comprise components that enhance an immune
response to the one or more SCAAgs. For example, immunogenic
compositions may further comprise a pharmaceutically acceptable
adjuvant. In other embodiments, an immunogenic composition may also
comprise a helper antigen or carrier protein.
Senescent Cell Associated Antigens
[0030] Cellular senescence is a stable and essentially permanent
arrest of cell proliferation, which is accompanied by extensive
changes in gene expression. Many types of cells, both normal cells
and tumor cells, undergo senescence in response to stress. As
described in the art, the phenotype of a senescence cell, such as
the phenotype referred to as senescence associated secretory
phenotype (SASP), is typified by secretion of numerous cytokines
(e.g., inflammatory cytokines), growth factors, extracellular
matrix components (ECM) and ECM-degrading enzymes, and proteases,
for example. While proliferative arrest poses a formidable barrier
to tumor progression (see, e.g., Campisi, Curr. Opin. Genet. Dev.
21:107-12 (2011); Campisi, Trends Cell Biol. 11:S27-31 (2001);
Prieur et al., Curr. Opin. Cell Biol. 20:150-55 (2008)), and
molecules secreted by senescent cells can stimulate tissue repair
(see, e.g., Adams, Molec. Cell 36:2-14 (2009); Rodier et al., J.
Cell Biol. 192:547-56 (2011)), senescent cells also secrete
molecules that can cause inflammation (see, e.g., Freund et al.,
Trends Mol. Med. 16:238-46 (2010); Davalos et al., Cancer
Metastasis Rev. 29:273-83 (2010)). Low-level, chronic inflammation
is a hallmark of aging tissues, and inflammation is a major cause
of, or contributor to, virtually every major age-related pathology,
including cancer (Ferrucci et al., 2004, Aging Clin. Exp. Res.
16:240-243; Franceschi et al., 2007, Mech. Ageing Dev. 128:192-105;
Chung et al., 2009, Ageing Res. Rev. 8:18-30; Davalos et al., 2010,
Cancer Metastasis Rev. 29:273-283; Freund et al., 2010, Trends
Molec. Med. 16:238-248). Thus, senescent cells, which increase with
age and at sites of age-related pathology, might stimulate local
chronic inflammation and tissue remodeling, thereby fueling both
the degenerative diseases of aging as well as age-related
cancer.
[0031] A senescent cell may exhibit any one or more of the
following characteristics. (1) Senescence growth arrest is
essentially permanent and cannot be reversed by known physiological
stimuli. (2) Senescent cells increase in size, sometimes enlarging
more than twofold relative to the size of nonsenescent
counterparts. (3) Senescent cells express a senescence-associated
.beta.-galactosidase (SA-.beta.-gal), which partly reflects the
increase in lysosomal mass. (4) Most senescent cells express
p16INK4a, which is not commonly expressed by quiescent or
terminally differentiated cells. (5) Cells that senesce with
persistent DDR signaling harbor persistent nuclear foci, termed DNA
segments with chromatin alterations reinforcing senescence
(DNA-SCARS). These foci contain activated DDR proteins and are
distinguishable from transient damage foci. DNA-SCARS include
dysfunctional telomeres or telomere dysfunction--induced foci
(TIF). (6) Senescent cells express and may secrete molecules
associated with senescence, which in certain instances may be
observed in the presence of persistent DDR signaling, which in
certain instances may be dependent on persistent DDR signaling for
their expression. (7) The nuclei of senescent cells lose structural
proteins such as Lamin B1 or chromatin-associated proteins such as
histones and HMGB1. See, e.g., Freund et al., Mol. Biol. Cell
23:2066-75 (2012); Davalos et al., J. Cell Biol. 201:613-29 (2013);
Ivanov et al., J. Cell Biol. DOI: 10.1083/jcb.201212110, page 1-15;
published online Jul. 1, 2013; Funayama et al., J. Cell Biol.
175:869-80 (2006)).
[0032] The presence of senescent cells can also be determined by
detection of senescent cell-associated molecules include growth
factors, proteases, cytokines (e.g., inflammatory cytokines),
chemokines, cell-related metabolites, reactive oxygen species
(e.g., H.sub.2O.sub.2), and other molecules that stimulate
inflammation and/or other biological effects or reactions that may
promote or exacerbate the underlying disease of the subject.
Senescent cell-associated molecules include those that are
described in the art as comprising the senescence-associated
secretory phenotype (SASP, i.e., which includes secreted factors
which may make up the pro-inflammatory phenotype of a senescent
cell), senescent-messaging secretome, and DNA damage secretory
program (DDSP). These groupings of senescent cell associated
molecules, as described in the art, contain molecules in common and
are not intended to describe three separate distinct groupings of
molecules. Senescent cell-associated molecules include certain
expressed and secreted growth factors, proteases, cytokines, and
other factors that may have potent autocrine and paracrine
activities. Without wishing to be bound by theory, the negative
effects of senescent cells are believed to be the result of, at
least in part, the secretion of pro-inflammatory cytokines,
chemokines, growth factors, and proteases that comprise the SASP of
a senescent cell (see, e.g., Coppe et al., PLoS Biol. 6:2853-68
(2008)). Senescent cell-associated molecules that comprise the SASP
can disrupt normal tissue structure and function and stimulate
malignant phenotypes in pre-malignant or non-aggressive cancer
cells (see, e.g., Coppe et al., supra; Coppe et al. J. Biol. Chem.
281:29568-74 (2006); Coppe et al. PLoS One 5:39188 (2010); Krtolica
et al. Proc. Natl. Acad. Sci. U.S.A. 98:12072-77 (2001); Parrinello
et al., J. Cell Sci. 118:485-96 (2005). ECM associated factors
include inflammatory proteins and mediators of ECM remodeling and
which are strongly induced in senescent cells (see, e.g., Kuilman
et al., Nature Reviews 9:81-94 (2009)). Other senescent
cell-associated molecules include extracellular polypeptides
(proteins) described collectively as the DNA damage secretory
program (DDSP) (see, e.g., Sun et al., Nature Medicine published
online 5 Aug. 2012; doi:10.1038/nm.2890).
[0033] Senescent cell-associated antigens include molecules that
are overexpressed in senescent cells compared to their quiescent or
non-senescent counterparts. Certain senescent cell-associated
antigens are tissue specific while others are ubiquitously
overexpressed in senescent cells. In particular embodiments of the
immunogenic compositions described herein, a senescent
cell-associated antigen is an antigen present on the cell surface
of a senescent cell (e.g., receptor proteins, channel forming
proteins, proteins that facilitate diffusion or active transport of
molecules and ion across the membrane, cell recognition proteins,
and enzymes). These antigens may be present on the cell surface of
a cell exclusively or at a greater level on senescent cells
compared with non-senescent cells and are therefore useful as
immunogens for evoking a specific immune response. Examples of
senescent cell-associated antigens include polypeptides and
proteins (including glycoproteins), lipids, glycolipids, and
carbohydrate molecules that contribute to or are markers of a
senescence cell.
[0034] Factors considered when selecting a senescent
cell-associated antigen include, for example, expression profile,
T-cell receptor threading and profiling, pre-existing tolerance,
commonality between subjects and cell types as well as the
potential to elicit both T-cell and B-cell immunity. Senescent
cell-associated antigens can be identified by differential gene
expression analysis using, for instance, gene chip profiling to
characterize gene products that are either uniquely expressed or
overexpressed in SC. The gene products identified from expression
profiling are then matched to proteins known to be part of the
surfaceome (see, e.g., Bavik et al., Cancer Res. January 15;
66:794-802 (2006)) to generate a subset of surface proteins
specifically expressed or overexpressed on the membrane of the
senescent cell. Similarly, other molecules that are specific to
senescent cells can be used as antigens, such as carbohydrates,
glycoproteins, lipids and gangliosides, or proteins with
senescence-specific posttranslational modifications. Such molecules
can be identified, for instance, by mass spectrometry analysis of
fractionated lysates from senescent vs. normal cells.
[0035] In one embodiment, an immunogenic composition comprises at
least 1 or at least 2, or more isolated senescent cell-associated
antigens. In other embodiments an immunogenic composition comprises
at least 3, 4, 5, 6, or more senescent cell-associated antigens.
Exemplary senescent cell-associated antigens useful as immunogens
in the immunogenic compositions described herein include any one or
more of the antigens provided in Table 1 (see, e.g., International
Patent Application Publication No. WO 2009/085216 (Table 1), which
is incorporated herein by reference in its entirety). Other
exemplary senescent cell-associated antigens useful as immunogens
in the immunogenic compositions described herein include any one or
more of the antigens encoded by a polynucleotide that comprises any
one of the polynucleotide sequences provided in Table 2 (see also
Table 2A that lists the GenBank sequences of Table 2). Non-limiting
examples of SCAAgs encoded by a polynucleotide comprising a
nucleotide sequence in Table 2 include ADAMTS7, APLP2, ATP6V0D2,
BCHE, C11orf87, CD46, CYB5D2, FBXL7, GPR137B, IFI27L1, IL15RA,
LAMP2, MYO10, NEU1, NHSL2, NPAS2, OR1F1, PEA15, RAB23, RARB, RNPC3,
SELO, SELT, SEMASB, SERP1, SERPINE1, SLC9A7, SNX3, TBC1D1, TBRG1,
TCEANC, TFPI, TNFAIP1, TUBG2, USP18, and ZNF419 (see for example
Table 2). Other examples of senescent cell-associated antigens are
named in Table 3 and are encoded by the polynucleotides provided in
Table 3 (see also, e.g., Sun et al., Nature Medicine published
online 5 Aug. 2012; doi:10.1038/nm.2890.)
[0036] In a particular embodiment, an immunogenic composition
comprises p16INK4a polypeptide, or an antigenic fragment thereof,
for use in immunizing a subject. Most senescent cells express the
tumor suppressor protein p16INK4a on the cell surface, independent
of cell type and senescence inducer (see, e.g., Ohtani et al., J.
Med. Invest. 51:146-53 (2004); Campisi et al., Nat. Rev. Med. Cell
Biol. 8:729-40 (2007)). Expression of p16INK4a expression is
typically undetectable until adulthood and the level of expression
increases with age (see, e.g., Zindy et al., Oncogene 15:203-11
(1997)). Moreover, p16INK4a null mice develop and mature normally
although they die of cancer in early middle age (see, e.g.,
Sharpless et al., Nature 413:86-91 (2001)). Without wishing to be
bound by theory, p16INK4a peptides may be displayed on the surface
of senescent cells in complexes with MHC (major histocompatibility)
class 1 molecules.
[0037] Evoking an immune response specific for senescent cells that
express a SCAAg, such as p16INK4a, wherein the immune response
comprises clearance of senescent cells can provide therapeutic
benefit. Results from transgenic animal model studies demonstrated
that clearance of senescent cells that express p16INK4a delayed
acquisition and/or progression of age related diseases (see, e.g.,
Baker et al., Nature, 479:232-36 (2011); Int'l Patent Application
Publication No. WO/2012/177927). Metastasis of tumor cells was
significantly inhibited in animals when senescent cells expressing
p16INK4a were killed (see, e.g., Int'l Patent Application
Publication No. WO 2013/090645).
[0038] Immunogenic compositions comprising a p16INK4a polypeptide,
or an antigenic fragment thereof, may be prepared using p16INK4a
polypeptide derived from a mammal, including but not limited to
mouse, rat, or human. Polypeptide sequences for p16INK4a
polypeptides from different species are available in public
databases, such as GenBank. Amino acid sequences for murine
p16INK4a polypeptide are available, for example, at GenBank Nos.
AAK83159.1; 158352; and AAA85453.1. Amino acid sequences for human
p16INK4a polypeptide are available, for example, at GenBank Nos.
P42771.2; NP 000068.1; NP 001182061.1 (see also, e.g., ABC47036.1).
Amino acid sequences for rat p16INK4a polypeptide are available,
for example, at GenBank Nos. Q9R0Z3.1; NP_113738.1; and
AAL76339.1.
[0039] An immunogen used in the immunogenic compositions described
herein may comprise at least one, or at least two, or at least 3,
4, 5, 6, 7, 8 or more antigenic fragments of a senescent
cell-associated antigen. Antigenic fragments may also be referred
to herein as immunogenic fragments or antigenic (or immunogenic)
peptides. An antigenic fragment of a senescent cell-associated
antigen that may be used in the immunogenic compositions described
herein comprises an immunogenic portion of a full-length senescent
cell-associated antigen, Such antigenic fragments may comprise at
least 5, 10, 20, 25, 30, 35, 40, 45, 50, 55, or 60 or more
contiguous amino acids (or any number of contiguous amino acids
between 5-60, including 5-10, 10-15, 15-20, 20-25, 25-30, 30-35,
35-40, 40-45, 45-50, 40-55, or 55-60, or more than 60 contiguous
amino acids) of a senescent cell-associated polypeptide. In a more
particular embodiment, an immunogen used in the immunogenic
compositions described herein comprises at least 20 contiguous
amino acids. An antigenic fragment of a mature or full-length
senescent cell-associated antigen has one or more epitopes that
induce a specific immune response, which includes production of
antibodies that specifically bind to the antigenic peptide and to
the immunogenic portion within the mature and full-length
polypeptide from which the antigenic peptide is derived, and to a
senescent cell that expresses the polypeptide.
[0040] The immunogenic compositions contemplated herein also
include those with a mixture of full-length senescent
cell-associated antigens (with a signal peptide sequence or without
all or a portion of a signal peptide sequence) and antigenic
fragments of the same or different senescent cell-associated
antigens. A polypeptide from which a signal peptide sequence has
been cleaved or removed may also be called a mature polypeptide. In
certain embodiments, immunogenic compositions comprise immunogen(s)
that comprise two or more antigenic fragments of the same senescent
cell-associated antigen. In other certain embodiments, the
immunogen(s) comprise at least two antigenic fragments wherein each
of the at least two antigenic fragments are derived from different
senescent cell-associated antigens. The senescent cell-associated
antigens described herein and the antigenic fragments thereof may
be produced recombinantly by using any one of a variety of
molecular biology and protein expression methods and techniques
routinely practiced in the art and described herein.
[0041] In other certain embodiments, immunogens for use in the
methods described herein comprise fusion polypeptides comprising
two or more senescent cell-associated antigens or antigenic
fragments thereof. The two or more senescent cell-associated
antigens or two or more antigenic fragments of the same or
different senescent cell-associated antigens may be linked in
tandem with or without spacer amino acids between each of the two
or more antigenic moieties. The spacer (or linker) may be a single
amino acid (such as for example a glycine residue) or may be two,
three, four, five, six, seven, eight, nine, or ten amino acids, or
may be any number of amino acids between 5 and 100 amino acids,
between 5 and 50, 5 and 30, or 5 and 20 amino acids. A polypeptide
linker may also include a short peptide linker that may comprise at
least two amino acids that are encoded by a nucleotide sequence
that is a restriction enzyme recognition site. Examples of such
restriction enzyme recognition sites include, for example, BamHI,
ClaI, EcoRI, HindIII, KpnI, NcoI, NheI, PmlI, PstI, SalI, and XhoI.
The fusion polypeptide may be designed with or without a spacer
peptide so long as the two or more antigenic moieties fold properly
to maintain antigenic properties of each of the moieties that is
observed when each particular antigenic moiety is not present in a
fusion polypeptide. If incorporated into a fusion polypeptide, the
spacer peptide separates the different antigenic moieties by a
distance sufficient to aid or ensure that each properly folds into
the secondary and tertiary structures necessary for the desired
immunogenic activity.
[0042] Surface amino acids in flexible protein regions and which
are useful as a linker include glycine (Gly), asparagine (Asn) and
serine (Ser). Virtually any permutation of amino acid sequences
containing Gly, Asn, and Ser would be expected to satisfy the above
criteria for a peptide linker sequence. Other near-neutral amino
acids, such as threonine (Thr) and alanine (Ala), may also be used
in the linker sequence. Suitable spacer peptides may comprise
between from 5 to 100 amino acids and in certain embodiments,
comprise between from 5 to 20 amino acids in length. Examples of
such linkers include, but are not limited to (Gly.sub.4 Ser (SEQ ID
NO:1)).sub.n (i.e., Gly-Gly-Gly-Gly-Ser).sub.n), wherein n=1-12, or
n=1-8, or n=1-4; Gly.sub.4 SerGly.sub.5 Ser (SEQ ID NO: 2) (i.e.,
Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Gly-Ser); and (Gly.sub.4
SerGly.sub.5 Ser (SEQ ID NO:2)).sub.m, (i.e.,
Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Gly-Ser).sub.m) wherein
m=2-4.
[0043] As described herein, an antigenic fragment comprises at
least one immunogenic epitope. In certain embodiments, the number
of contiguous amino acid residues in an antigen fragment is
sufficient to comprise a conformational epitope that may be formed
by non-contiguous portions of a senescent cell associated antigen.
Alternatively, a fusion polypeptide may comprise two fragments that
each comprise at least 5, 10, 20, 30, 40, or 50 contiguous amino
acids of a senescent cell associated antigen and together with or
without a spacer moiety properly fold to form a conformational
epitope.
[0044] In certain instances senescent cells may be used to screen
for the presence of senescent cell associated antigens and relevant
epitopes for use in preparing antigenic fragments. Such targets can
be prepared using random, or selected, synthetic peptide libraries.
Alternatively, synthetic peptides of approximately 10-20 amino
acids in length may be prepared from an identified senescent cell
associated antigen, overlapping by 5-10 residues, which are
characterized using any one of a number of immunoassays available
in the art. In certain instances, a T cell epitope may be
identified by preparing overlapping peptides of between 5-10
contiguous amino acids (e.g., 9 amino acids) of a senescence cell
associated antigen. Similarly, B cell epitopes may be identified by
preparing overlapping peptides. See, for example, Sturniolo at al.,
Nature Biotech. 17: 555-61 (1999); Jameson et al., Comput. Appl.
Biosci. 4:181-186 (1988); Nakai et al., Trends Biochem. Sci.
24:34-36 (1999); Hopp, Pept. Res. 6:183-90 (1993); Hofmann et al.,
Biomed. Biochim. Acta 46:855-66 (1987); Menendez et al., Comput.
Appl. Biosci. 6:101-105 (1990), which describe methods for
identifying antigenic epitopes.
[0045] A person skilled in the art would readily appreciate that
senescent cell-associated antigens such as p16INK4a, those listed
in Table 1, and those encoded by the nucleotide sequences provided
in Tables 2 and 3 are exemplary sequences and that variants of each
antigen may exist. These variants may have amino acid sequences
that are not identical to the exemplary sequences described herein
and in the art, yet the variants exhibit the same immunogenicity as
the antigens comprising the exemplary sequences (i.e., the
immunogenicity is not reduced in a statistically significant,
clinically significant, or biologically significant manner). These
variants (or species) of individual senescent cell-associated
antigens may include amino acid substitutions, deletions, or
additions from the exemplary amino acid sequences. A senescent
cell-associated antigen species includes antigens that comprise at
least 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% amino acid sequence
identity to the exemplary senescent cell-associated antigen amino
acid sequences provided herein, including those in Table 1 and the
amino acid sequences encoded by the nucleotide sequences provided
in each of Tables 2 and 3, and those described herein for p16INK4a.
Percent identity of one amino acid sequence to one or more
additional sequences may be determined using any one of the
alignment tools described herein and used in the art.
[0046] Often a variant will have an amino acid substituted with
another amino acid that is included within the same group, such as
the group of polar residues, charged residues, hydrophobic
residues, and/or small residues, and the like. The effect of any
amino acid substitution may be determined empirically merely by
testing the resulting modified peptide, polypeptide, or fusion
polypeptide for the ability to function in a biological assay, or
to bind to a cognate ligand or target molecule, such as a
monoclonal or polyclonal antibody.
[0047] Senescent cell-associated antigen variants also include
those that have amino acid substitutions, deletions or insertions,
which may be introduced during chemical synthesis or recombinant
production, whichever method is used to produce the particular
immunogen. Substitutions, insertions, and deletions of one or more
amino acids of the amino acid sequences described herein are those
that do not adversely affect or alter (i.e., decrease or reduce in
a statistically or biologically significant manner) the
immunogenicity of the antigen or antigenic fragment thereof in a
statistically, biologically, or clinically significant manner. As
described herein, retention of immunogenicity includes the
capability to evoke an immune response against a senescent cell,
such as production of antibodies that specifically bind to the
cognate antigen present on the senescent cell.
[0048] In general, an amino acid substitution that may be included
in a senescent cell-associated antigen is a conservative
substitution. Conservative substitutions of amino acids are well
known and may occur naturally or may be introduced when the
senescent cell-associated antigen or fusion polypeptide comprising
the antigen is recombinantly produced or when the polynucleotide
encoding the antigen is produced. A variety of criteria understood
by a person skilled in the art indicates whether an amino acid that
is substituted at a particular position in an immunogenic peptide
or polypeptide is conservative (or similar). For example, a similar
amino acid or a conservative amino acid substitution is one in
which an amino acid residue is replaced with an amino acid residue
having a similar side chain. Similar amino acids may be included in
the following categories: amino acids with basic side chains (e.g.,
lysine, arginine, histidine); amino acids with acidic side chains
(e.g., aspartic acid, glutamic acid); amino acids with uncharged
polar side chains (e.g., glycine, asparagine, glutamine, serine,
threonine, tyrosine, cysteine, histidine); amino acids with
nonpolar side chains (e.g., alanine, valine, leucine, isoleucine,
proline, phenylalanine, methionine, tryptophan); amino acids with
beta-branched side chains (e.g., threonine, valine, isoleucine),
and amino acids with aromatic side chains (e.g., tyrosine,
phenylalanine, tryptophan). Proline, which is considered more
difficult to classify, shares properties with amino acids that have
aliphatic side chains (e.g., leucine, valine, isoleucine, and
alanine). In certain circumstances, substitution of glutamine for
glutamic acid or asparagine for aspartic acid may be considered a
similar substitution in that glutamine and asparagine are amide
derivatives of glutamic acid and aspartic acid, respectively. As
understood in the art "similarity" between two polypeptides is
determined by comparing the amino acid sequence and conserved amino
acid substitutes thereto of the peptide or polypeptide to the
sequence of a second peptide or polypeptide, respectively, using
any one of the algorithms, such as Align or the BLAST algorithm, or
other algorithms described herein and practiced in the art.
[0049] Amino acid substitutions, deletions, and additions may be
introduced into an a senescent cell associated antigen or antigenic
fragment thereof during chemical synthesis of the polynucleotide
that encodes the peptide or fusion polypeptide. Alternatively,
amino acid substitutions, deletions, and additions may be
introduced into an immunogenic peptide or fusion polypeptide
recombinantly using well-known and routinely practiced mutagenesis
methods (see, e.g., Sambrook et al. Molecular Cloning: A Laboratory
Manual, 3d ed., Cold Spring Harbor Laboratory Press, N Y 2001)).
Oligonucleotide-directed site-specific (or segment specific)
mutagenesis procedures may be employed to provide an altered
polynucleotide that has particular codons altered according to the
substitution, deletion, or insertion desired. Alternatively, random
mutagenesis techniques, such as alanine scanning mutagenesis, error
prone polymerase chain reaction mutagenesis, and
oligonucleotide-directed mutagenesis may be used to prepare
immunogenic peptide and fusion polypeptide variants (see, e.g.,
Sambrook et al., supra).
[0050] Assays for assessing whether a respective senescent cell
associated antigen or an antigenic fragment thereof prepared for
immunization folds into a conformation comparable to the antigen as
expressed by a senescent cell include, for example, the ability of
the protein to react with mono- or polyclonal antibodies that are
specific for native or unfolded epitopes, the retention of
ligand-binding functions, and the sensitivity or resistance of the
mutant protein to digestion with proteases (see Sambrook et al.,
supra). Such variants can be identified, characterized, and/or made
according to methods described herein or other methods known in the
art, which are routinely practiced by persons skilled in the
art.
Polynucleotides and Recombinant Expression Vectors
[0051] In certain embodiments, the immunogenic composition useful
in a method for inducing an immune response specific for a
senescent cell comprises at least one polynucleotide that encodes a
senescent cell-associated antigens or antigenic fragment thereof as
an immunogen. In certain embodiments, the at least one
polynucleotide encodes at least two senescent cell-associated
antigens or antigenic fragments thereof. In other embodiments, the
immunogen comprises two polynucleotides, wherein each of the two
polynucleotides encodes a different senescent cell-associated
antigen or antigenic fragment thereof. In a more specific
embodiment, a polynucleotide useful in the immunogenic compositions
encodes at least or at least two or more senescent cell-associated
antigens wherein the polynucleotide(s) comprises a nucleic acid
sequence provided in either Table 2 or Table 3. In another
embodiment, the polynucleotide of the composition comprises a
nucleotide sequence that encodes a senescent cell-associated
antigen provided in Table 1. In still another specific embodiment,
the polynucleotide of the composition comprises a nucleotide
sequence that encodes p16INK4a (including but not limited to
murine, rat, non-human primate, and human p16INK4a).
[0052] A polynucleotide that is an immunogen may be administered as
a "naked polynucleotide" or may be incorporated into a recombinant
expression vector that is administered to the subject (see, e.g.,
Ulmer et al., Science 259:1745-49, 1993 and reviewed by Cohen,
Science 259:1691-1692, 1993). Also provided herein are recombinant
expression vectors that comprise the polynucleotide that encodes a
senescent cell associated antigen or antigenic fragment thereof. To
obtain efficient transcription and translation of the immunogen
(i.e., the senescent cell-associated antigen or antigenic fragment
thereof), the encoding polynucleotide sequences in each vector
should include at least one appropriate expression control sequence
(also called a regulatory expression sequence or feature) (e.g.,
promoter, enhancer, leader), which are described in greater detail
herein, that is operatively linked to the encoding polynucleotide
sequence(s). These recombinant expression vectors are thus provided
for expression of the senescent cell-associated antigen or
antigenic fragment thereof in any appropriate host cell that has
been transformed, transduced, or transfected with a recombinant
expression vector. The recombinant expression vector may also
include nucleotide sequences that encode a co-stimulatory molecule,
which provides transcription and translation of the senescent
cell-associated antigen (or fragment thereof) and the
co-stimulatory molecule in the same cell.
[0053] The recombinant expression vector may be a plasmid DNA or
cosmid DNA. Plasmid DNA or cosmid DNA that contains one or more
polynucleotides encoding an immunogen as described herein are
readily constructed using standard techniques well known in the
art. The vector genome may be typically constructed in a plasmid
form that can then be transfected into a packaging or producer cell
line. The plasmid generally comprises sequences useful for
replication of the plasmid in bacteria. Such plasmids are well
known in the art. In addition, vectors that include a prokaryotic
origin of replication may also include a gene whose expression
confers a detectable or selectable marker such as a drug
resistance. Typical bacterial drug resistance products are those
that confer resistance to ampicillin or tetracycline. For analysis
to confirm that the correct nucleotide sequences are incorporated
in plasmids, the plasmid may be replicated in E. coli, purified,
and analyzed by restriction endonuclease digestion and/or its
nucleotide sequence determined by conventional methods.
[0054] In other particular embodiments, the recombinant expression
vector is a viral vector. Exemplary recombinant expression viral
vectors include a lentiviral vector, poxvirus vector, adenovirus
vector, adenovirus-associated virus vector, or a herpes virus
vector. In other embodiments, the recombinant expression vector is
of prokaryotic origin, and includes recombinant bacteria and
recombinant expression vectors that are expressed in bacteria.
[0055] A number of suitable, available lentiviral genome based
vectors are available in the art, including those identified for
human gene therapy applications (see, e.g., Pfeifer et al., Annu.
Rev. Genomics Hum. Genet. 2:177-211 (2001)). Suitable lentiviral
vector genomes include those based on Human Immunodeficiency Virus
(HIV-1), HIV-2, feline immunodeficiency virus (FIV), equine
infectious anemia virus, Simian Immunodeficiency Virus (SIV) and
maedi/visna virus. A desirable characteristic of lentiviruses is
that they are able to infect both dividing and non-dividing cells.
Safety features of the vector genome are desirably incorporated.
Safety features include self-inactivating LTR and a non-integrating
genome. See, for example, U.S. Pat. No. 8,273,345 (describing
lentiviral vectors for targeted delivery to a dendritic cell); U.S.
Patent Application Publication No. 2010/0297168; Simmons et al.,
Virol. J. 3:8 (2006).
[0056] In certain embodiments, a recombinant expression vector is
an adenovirus vector. The adenovirus genome is well characterized
and the biology of the adenoviruses is known in the art in detail.
The adenovirus is not associated with severe human pathology in
immunocompetent individuals. Adenovirus particles may be used for
efficiently introducing a polynucleotide into a host cell, and the
virus is capable of infecting a large variety of cells.
[0057] The adenovirus has a double-stranded linear genome with
inverted terminal repeats at both ends. During viral replication,
the genome is packaged inside a viral capsid to form a virion. The
virus enters its target cell through viral attachment followed by
internalization (Hitt et al., Advances in Pharmacology 40:137-206,
1997.) Adenovirus vectors may be based on different adenoviruses
that are characterized as human or non-human animal or avian
serotypes. Examples of non-human animal adenoviruses include
bovine, porcine, simian, murine, canine, and avian adenoviruses.
Adenoviral vectors can contain regions from a single adenovirus or
from two or more adenovirus serotypes.
[0058] An adenovirus may be rendered replication defective by
deletion of the early-region 1 (E1) of the viral genome. Most
adenoviral vectors currently used in gene therapy have a deletion
in the E1 region, where genetic information of interest is
introduced. Human adenoviruses have been categorized into about six
different subgroups that encompass 51 distinct adenovirus
serotypes. A serotype is defined on the basis of its immunological
distinctiveness determined by quantitative neutralization assays
using animal antisera. Simian adenoviral vectors may also be used
in the methods described herein for evoking an immune response
specific for a SCAAg and that comprises clearance of senescent
cells. Adenoviral serotypes that may be used for constructing
recombinant expression vectors include human adenoserotypes, for
example, Ad1, Ad2, Ad6, Ad5, Ad11, Ad12, Ad24, Ad26, Ad34, Ad35,
Ad48, Ad49, and Ad50, and simian adenoserotypes, for example,
common chimpanzee adenovirus (Ch) subtypes ChAd55, ChAd73, ChAd83,
ChAd146, ChAd147, and ponobo chimpanzee adenovirus (Pan) subtypes,
PanAd1, PanAd2, and PanAd3.
[0059] Adenoviral vectors include recombinant vectors that are
either replication-defective or replication-competent.
Replication-defective adenoviral vectors typically lack the E1A
gene (required for induction of adenovirus expression and DNA
replication) and E1B genes (called E1) and instead contain an
expression cassette consisting of a promoter and pre-mRNA
processing signals that drive expression of a gene encoding a
non-adenoviral polypeptide, such as an immunogen of interest. E3
genes or portions thereof may also be deleted.
[0060] Historically, the usefulness of adenovirus as a vehicle for
transgene delivery has been limited by induction of neutralizing
anti-adenoviral immunity following an initial administration,
resulting in shorter-term and reduced levels of transgene
expression. Serotype Ad5 vectors, for example, were developed (see.
e.g., Chroboczek, et al., J. Virology 186:280-285 (1992)); however,
neutralizing antibodies to Ad5 are highly prevalent in humans. More
recently, serotype Ad5 vectors have been modified to provide more
effective immunization against an antigen of interest delivered by
the adenovirus. By way of example, adenoviral vectors that may be
used in the methods described herein for inducing an immune
response specific for a senescent cell include chimeric Ad5-based
constructs in which the hexons from Ad6 is incorporated in place of
the Ad5 hexon (see, e.g., Youil, et al., Human Gene Therapy 13(2):
311-320 (2002) (16:10.1089/10430340252769824). Other Ad5/Ad6
adenoviral vectors may be used for expressing a senescent cell
associated antigen for inducing an immune response against
senescent cells (see, e.g., U.S. Pat. No. 8,142,794 (U.S. Patent
Application Publication No. 2009/0233992).
[0061] In certain specific embodiments, the adenovirus vector used
in the immunogenic compositions described herein is a
replication-defective adenovirus and has a serotype that is less
likely to have induced pre-existing immunity to the serotype, such
as a serotype selected from Ad11, Ad24, Ad26, Ad34, Ad35, Ad48,
Ad49, and Ad50. In another particular embodiment, the serotype is
Ad11, AD35, or AD49. In a more particular embodiment, the serotype
is AD35. In certain embodiments, two or more recombination
expression vectors are used as immunogens for expression of two or
more senescent cell-associated antigens or two or more two or more
antigenic fragments of the same or different senescent
cell-associated antigens, and each recombination vector is
independently selected from an adenovirus serotype Ad11, Ad24,
Ad26, Ad34, Ad35, Ad48, Ad49, and Ad50. Exemplary adenoviral
vectors can be prepared according to Crucell AdVac.RTM. technology
(Crucell, Leiden, The Netherlands). See, for example, U.S. Pat.
Nos. 8,221,971; 8,202,723; 8,114,637; 8,052,967; 8,012,467;
7,820,440; 7,781,208; 7,749,493; 7,741,099.
[0062] A recombinant adenovirus that at least a deletion in the E1
region to accommodate insertion of genetic information related to
expression of the SCAAg(s) of interest may include sequences
encoding the E1B-55K gene product that increases the expression of
the pIX gene present in the adenovirus and which expresses a
non-functional E1B-55K gene product (see, e.g., U.S. Pat. No.
8,052,967). These adenoviruses appear more stable and/or can
incorporate more exogenous DNA than the corresponding adenovirus
that lacks all E1B-coding sequences. Alternatively, or in addition
to, the presence of E1B-55K sequences increasing the expression of
the pIX gene, the sequences preceding the pIX-coding sequence may
be changed into a stronger promoter, which may be a heterologous
promoter, to increase the expression of pIX, resulting in an
increase of the stability of a recombinant adenovirus and/or an
increase of the packaging capacity of the adenoviral particle
produced.
[0063] As described herein, exogenous genetic information that
encodes one or more SCAAgs of interest can be inserted into the
genome where adenoviral E1 sequences have been deleted. In addition
to the E1 region deletion, E3 sequences can also be deleted from
such adenoviral vectors to increase the capacity for SCAA genetic
information. For example, B-type adenovirus serotypes such as Ad34
and Ad35 have a different E3 region than other serotypes, which
region is involved in suppressing immune response to adenoviral
products.
[0064] Adenovirus capsid, in particular the penton and/or the hexon
proteins, may induce an immune response to the adenoviral vector.
Thus, the adenoviral vector may comprise the elements of at least
one capsid protein or functional part thereof, such as fiber,
penton and/or hexon proteins or a gene encoding at least one of
them from a less immunogenic subtype, such as Ad35. In other
certain embodiments, any one of the fiber, penton, and hexon
proteins may be encoded by a gene derived from a simian (e.g.,
chimpanzee) adenovirus. Other deletions and various combinations of
part or complete deletions of E2, E3, and E4 regions, combined with
the E1 deletion, can be used, if necessary, in combination with a
packaging cell comprising the genetic information lacking in the
adenoviral vector when necessary for replication of the adenoviral
vector. For delivery of the transgene, the adenoviral particle can
be targeted specifically to target cells of interest via binding to
that specific cell either through capsid-receptor binding or
through other means.
[0065] Targeting of adenoviruses can be performed in many different
ways to deliver the adenoviral vectors to the cells of interest
using methods routinely practiced in the art. By way of example,
capsid alterations (fiber, hexon and/or penton modifications, such
as deletions, swaps between fibers of different serotypes, and
additions of peptides and/or other binding moieties), wherein
chimeric fibers are produced that recognize a receptor present on
the cell of interest or wherein the binding of the penton-base is
used. Other possibilities are linking targeting moieties to the
capsid proteins wherein, for instance, binding peptides, known and
strong binding proteins, or antibodies or parts thereof, are linked
to the capsid proteins to achieve specific targeting.
[0066] In a particular embodiment, the adenovirus vector is a
recombinant adenovirus of adenovirus serotype 35 (Ad35) wherein at
least the Ad35 fiber knob has been replaced by the fiber knob of a
serotype that binds to the Coxsackievirus and Adenovirus Receptor
(CAR). The Ad35 fiber knob may be replaced with the sequence that
encodes the fiber knob from serotype Ad5 or the knob, shaft and
part of the tail may be replaced. The shaft and tail of the fiber
may be of the carrying backbone serotype, such as Ad35, whereas the
shaft domain is of the same serotype as fiber knob serotype. When
the tail region is derived from the backbone serotype, the
interaction of the adenovirus with the remaining part of the capsid
will more likely result in production of stable vectors in the
art.
[0067] In other certain embodiments, a recombinant expression
vector is an adenoviral vector that is a simian adenovirus vector
(see, e.g., Int'l Patent Application Publication Nos. WO 03/046124;
WO 03/000851; WO 2010/085984; WO 2012/089833; U.S. Patent
Application Publication Nos. 2011/0129498; 2013/0101618; U.S. Pat.
No. 6,083,716). By way of non-limiting example, the adenoviral
vector may be derived from a chimpanzee adenovirus, which may be a
common chimpanzee adenovirus (ChAd) or a bonobo chimpanzee
adenovirus (PanAd). By using a simian adenoviral vector, an adverse
effect associated with the preexisting immunity in humans to common
serotypes of human adenoviruses can be avoided. The adenovirus
types ChAd55, ChAd73, ChAd83, ChAd146, ChAd147, PanAd1, PanAd2, and
PanAd3 are characterized by a the absence of preexisting
neutralizing antibody in humans directed against these adenovirus
types (see, e.g., U.S. Patent Appl. Publ. No. 2011/012949, and
references cited therein).
[0068] Simian adenoviral vectors may contain one or more of the
fiber, hexon, and penton proteins of ChAd55, ChAd73, ChAd83,
ChAd146, ChAd147, PanAd1, PanAd2, and/or PanAd3. Fiber, hexon, and
penton proteins are adenovirus capsid proteins that represent the
most surface exposed adenovirus epitopes. The aforementioned
chimpanzee hexon, penton, and fiber protein sequences may also be
used to improve other adenoviruses by replacing one or more of
these major structural capsid proteins or functional fragments
thereof of any adenovirus, such as any of the human adenoviruses
described herein and known in the art, which provide recombinant
adenoviruses with a reduced seroprevalence in humans.
[0069] As with human adenoviral vectors, simian adenoviral vectors
are preferably replication defective, meaning that the adenovirus
is incapable of replication because it has been engineered to
comprise at least a functional deletion or a complete removal of a
gene product that is essential for viral replication. For example,
and as described herein, one or more genes selected from the group
consisting of E1A, E1B, E2A, E2B, E3 and E4 gene can be deleted,
rendered non-functional, and/or can be replaced with sequences that
includes appropriate expression control sequence(s) operatively
linked to the nucleotide sequence encoding one or more
SCAAg(s).
[0070] In still other embodiments, the recombinant viral vector is
an adenovirus-associated virus (AAV) vector. Adeno-associated virus
(AAV) is a replication-deficient parvovirus that is able to infect
a wide spectrum of cells without inducing any effects on cellular
growth, morphology, or differentiation. AAV is non-pathogenic. The
AAV genome has been sequenced and well characterized. The
single-stranded DNA genome is about 4.7 kb in length and includes
145 nucleotide inverted terminal repeat (ITRs). The ITRs play a
role in integration of the AAV DNA into the host cell genome. The
remainder of the genome is divided into two essential regions that
carry the encapsidation functions: the left-hand part of the
genome, which contains the rep gene involved in viral replication
and expression of the viral genes; and the right-hand part of the
genome, which contains the cap gene encoding the capsid proteins.
When AAV infects a host cell, the viral genome integrates into the
host's chromosome resulting in latent infection of the cell. In the
instances of recombinant AAV vectors having no Rep and/or Cap
genes, the AAV can be non-integrating and exists transiently, as an
episome. AAV depends upon a helper virus (for example, adenovirus
or herpesvirus) to provide genes that allow for production of AAV
in the infected cell. In the case of adenovirus, genes E1A, E1B,
E2A, E4 and VA provide helper functions. Upon infection with a
helper virus, the AAV provirus is rescued and amplified, and both
AAV and adenovirus are produced. To date, at least 11 serotypes of
AAV have been identified and isolated from humans or primates.
[0071] AAV vectors are designed such that all viral genes are
replaced by an expression cassette for the transgene encoding the
polypeptide of interest (e.g., an SCAAg), leaving intact the
essential cis elements of the genome, the inverted terminal repeats
(ITRs), DNA packaging signal, and the replication origin.
Replication and packaging of AAV vectors requires all AAV and
Adenovirus/HSV helper functions to be provided in trans. While
wild-type AAV is capable of integrating in a site-specific manner
into human chromosome 19, site-specific integration of recombinant
AAV does not occur to a significant extent because of the lack of
Rep protein expression. Onset of transgene expression is generally
delayed by 2-4 weeks.
[0072] The ability of AAV vectors to infect a broad host range,
transduce both dividing and non-dividing cells in vitro and in
vivo, and maintain high levels of expression of the transduced
genes in the absence of a significant immune response to the
transgene product in general have made AAV an attractive vector for
recombinant use. AAV vector particles are thought to be
non-pathogenic and are heat stable, resistant to solvents,
detergents, and changes in pH and temperature. The ITRs have been
shown to be the only cis elements required for replication and
packaging and may contain some promoter activities. Thus, no viral
genes are encoded by AAV vectors.
[0073] In another particular embodiment, the recombinant viral
vector is a Herpes Simplex vector, such as a Herpes Simplex I
(HSV1) or a Herpes Simplex II (HSV2) viral vector. The HSV1 genome
has been sequenced and comprises 152 kb encoding at least 80 gene
products, about half of which are essential for viral replication.
The HSV2 genome has also been sequenced and comprises 155 kb
encoding 74 gene products, corresponding closely to the HSV1
genome. The lytic pathway of HSV infection is characterized by the
regulated sequential expression of three ordered classes of viral
gene products: immediate early (IE or .alpha.), early (E or 13),
and late (L or .gamma.) genes. Upon release of the viral DNA into
the host cell nucleus, the viral genome circularizes and expression
of five IE genes (infected cell protein ICP4, ICP27, ICP0, ICP22,
and ICP47) is induced. V16 binds to an enhancer element present in
all IE promoters and activates transcription. The IE genes are
involved in transactivation of the E genes, which encode DNA
polymerase and other proteins involved in altering the
intracellular milieu to favor viral replication. Expression of the
L genes follows which mostly encode structural proteins of the
capsid, tegument, and envelope. A productive HSV infection results
in death of the host cell.
[0074] The HSV genome can also be grouped according to whether they
are essential or nonessential to viral replication. Essential genes
are required to produce new infectious viral particles in
permissive cell culture infections. Non-essential, or accessory,
genes encode proteins that are not required but are important for
optimum lytic replication or affect the life cycle of the virus in
vivo (e.g., host range, pathogenesis, latency). In the unique short
(US) region of the HSV genome, glycoprotein D is the only essential
gene. Large segments of viral sequence in the US region may be
replaced with a transgene of interest. The HSV genome may
accommodate up to 40-50 kb of exogenous sequence.
[0075] Several factors contribute to the interest in HSV based
vectors for vaccines. HSV sequences are known and well
characterized; HSV elicits strong and durable immune responses by
various routes of administration; HSV has a large cargo capacity
(>160 kb); the viral DNA persists in the host cell nucleus as an
episomal element; HSV genome carries the tk gene which can be
exploited to kill infected cells with appropriate drugs (e.g.,
gangcyclovir). The use of vectors derived from HSV type I and type
II is well known in the art and has been previously described (see,
e.g., U.S. Pat. Nos. 6,071,692; 6,613,892; 6,838,279;
WO2000/077167; WO1990/009441; U.S. Pat. Nos. 5,846,707; 5,288,641;
WO2005/092374; U.S. Pat. No. 6,613,892; WO2006/004878; and
US2011/0171257). Vectors based on HSV type I or type II include:
replication-defective viruses; amplicon vectors; and attenuated
viruses.
[0076] Attenuated, replication-competent viral vectors have
mutations or deletions of non-essential genes (see, e.g., Hu and
Coffin, 2003, Int. Rev. Neurobiol. 55:165-84; Todo, 2008, Front.
Biosci. 13:2060-4; Varghese and Rabkin, 2002, Cancer Gene Ther.
9:967-78; Hunter et al., 1999, J. Virol. 73:6319-6326; US Patent
Publication 20080089910;). Non-essential HSV genes, such as
thymidine kinase, ribonucleotide reductase, virion-host shut off,
and ICP34.5, are involved in replication, virulence, and immune
evasion and optimize viral growth in host cells. Deletion or
modification of non-essential genes may yield HSV mutants with
decreased pathogenicity, such as, reduced replication in normal
quiescent cells but replication ability in tumor or dividing cells.
ICP34.5 deleted HSV, either alone or in combination with deletion
of ribonucleotide reductase, replicate selectively in malignant
cells (see, e.g., Shah et al., 2003, J. Neurooncol. 65:203-226;
Post et al., 2004, Curr. Gene Ther. 4:41-51). HSV has been shown to
infect dendritic cells, suggesting that HSV may be used to deliver
transgenes to dendritic cells for vaccination (see, e.g., Kruse t
al., 2000, J. Virol. 74:7127-7136; Coffin et al., 1998, Gene Ther.
5:718-722; Mikloska et al, 2001, J. Virol. 75:5958-5964).
Attenuated HSV vectors for dendritic cells have been previously
described (U.S. Pat. No. 6,641,817).
[0077] Replication-defective (incompetent) vectors derive from
mutant HSV viruses with mutations or deletions in one or more genes
essential for the lytic cycle. A transgene may be inserted in the
viral genome so that it is packaged into the viral particle along
with HSV DNA. Replication defective HSV are grown in complementing
cell lines which provide the missing essential gene(s) in trans.
Replication-defective vectors, in which one or more of the IE genes
(ICP0, ICP4, ICP22, ICP27, and ICP47) are deleted in various
combinations, have been constructed (see, e.g., Kaplitt et al.,
1997, J. Neurosci. Methods 71:125-132; Krisky et al., 1998, Gene
Ther. 5:1593-1603; Krisky et al., Gene Ther. 1997, 4:1120-1125; Wu
et al., 1996, J. Virol. 70:6358-6369). Alternatively, HSV mutants
with inactivated VP16 may be used to circumvent the use of
complementing cell lines expression IE proteins. Inactivation of
VP16 to eliminate its IE gene transactivation function in HSV
vectors, combined with conditional mutations in ICP4 and ICP0 can
express foreign genes without killing the host cell (see, e.g.,
Preston et al., 1997, Virology 229:228-239). In yet another
example, deletion of virion host shutoff protein (VHS) from
replication incompetent HSV vectors allows activation of dendritic
cells and induction of antigen-specific T cell responses (see,
e.g., Samady et al., 2003, J. Virol. 77:3768-3776).
[0078] Amplicons are plasmid-derived vectors engineered to contain
both the origin of HSV DNA replication (ori) and HSV
cleavage/packaging signal (pac). Upon transfection into mammalian
cells with HSV helper functions, amplicons are replicated and
amplified as head-to-tail linked concatamers, which are then
packaged into viral particles. Several advantages of using amplicon
vectors for gene delivery include: a large transgene capacity;
ability to introduce multiple copies of the transgene per infected
cell; ability to infect wide variety of host cells; easy
construction; and limited toxicity.
[0079] There are several methods known in the art for producing
amplicon particles. One prepares amplicon vectors in cells
transfected with amplicon plasmid and infected with
replication-defective helper HSVs. However, the use of HSV as
helper virus may result in helper-contaminated vector stocks, which
can induce cytotoxicity and inflammation (see, e.g., Epstein et
al., 2005, Curr. Gene Ther. 5:445-458; Zhang et al., 2006, J.
Virol. Methods 137:177-183; Sia et al., 2007, J. Virol. Methods
139:166-174). Alternatively, conditional packaging helper viruses
using Cre/loxP-based site-specific recombination to remove the
packaging signal may be used (Logvinoff and Epstein, 2000, Virology
267:102-110; Zaupa et al., 2003, Human Gene Therapy 14:1049-1063).
Yet another option is provide a plasmid comprising the HSV genome,
without the packaging signals, e.g., by using pac-deleted
overlapping cosmids (see, e.g., Fraefel et al., 1996, J. Virol.
70:7190-7197) or a pac-deleted and ICP27-deleted BAC-HSV-1 (see,
e.g., Saeki et al., 2001, Mol. Ther. 3:591-601).
[0080] In other certain embodiments, the immunogenic composition
useful in a method for inducing an immune response specific for a
senescent cell comprises a bacterial delivery system that comprises
a recombinant bacterium into which a recombinant expression vector
has been introduced. In a certain particular embodiment, the
recombinant bacterium is a recombinant Listeria bacterium, which
may be attenuated (see, e.g., Bower et al., Proc. Natl. Acad. Sci.
USA 103:5102-107 (2006); Chamekh, Immunopharmacology and
Immunotoxicology 32:1-4 (2010); U.S. Pat. Nos. 7,695,725;
7,833,775; 7,927,606; 7,935,804; 8,287,883; 8,580,939). Listeria
has been used to stimulate cellular immunity because of its
intracellular life cycle. After the bacteria infect the host, the
bacteria are taken up by phagocytes into a phagolysosomal
compartment. The majority of the bacteria are subsequently
degraded, and peptides of the antigen of interest are presented as
MHC II-peptide complexes. The recombinant expression vector
introduced into the bacteria, such as Listeria, comprises a
nucleotide sequence that encodes at least one appropriate bacterial
expression control sequence (e.g., promoter, enhancer, leader) that
is operatively linked to the encoding polynucleotide sequence(s)
for a senescence cell-associated antigen(s). The polynucleotide
sequence encoding the senescence cell-associated antigen (SCAAg)
may also comprise a signal peptide sequence (e.g., a bacterial
signal peptide) fused in frame to the amino terminal end of the
SCAAg. In other embodiments, the polynucleotide encodes the SCAAg
fused in frame with a polypeptide that enhances expression and
processing of the SCAAg. In one embodiment, the SCAAg is fused in
frame with an autolysin. The autolysin polypeptide has been shown
useful for efficient expression and secretion of a heterologous
antigen in Listeria (see, e.g., U.S. Pat. No. 7,842,289).
[0081] Recombinant expression viral vectors may be incorporated
into a vector particle that comprises a recombinant expression
system that comprises one recombinant expression vector (also
called a first recombinant expression vector) comprising a
polynucleotide sequence encoding at least one senescent
cell-associated antigen or antigenic fragment thereof and a second
recombinant expression vector that includes a polynucleotide
sequence that encodes a second senescent cell-associated antigen or
antigenic fragment thereof. Alternatively the second recombinant
expression vector may encode a co-stimulatory molecule.
[0082] In certain embodiments, the recombinant expression vectors
or viral particles are engineered to be delivered to a target cell
using methods and techniques known to and practiced by persons
skilled in the art. In particular embodiments, the target cell is
an immune cell that is an antigen-presenting cell, such as a
dendritic cell. Such methods comprise contacting (i.e., permitting
interaction) of the target cell with a vehicle that delivers the
polynucleotide.
[0083] In yet another embodiment, recombinant viral vectors are
recombinant viruses that are senolytic and are replication
competent or conditionally replication competent. Virus replication
leads to amplification, killing of the senescent cell, and
introduction of the progeny virus into other senescent cells.
Because of the inherent cytotoxicity and efficiency with which
viruses can infect other cells, recombinant viruses may be prepared
that exhibit a high enough degree of senescent cell selectivity,
and hence safety, for treatment of a subject in need of removal of
senescent cells to treat or prevent a disease or disorder. The
viruses are constructions so that the viruses are attenuated in
normal cells but retain their ability to kill senescent cells. Such
engineering may include modifying the ability of viruses to bind
to, or replicate in senescent cells, while others have involved the
construction of replication-competent viruses encoding suicide
proteins. The SCAAgs described herein may be used to target
senescent cells replication competent or conditionally replication
competent viruses.
[0084] The SCAAgs described herein are useful for identifying
ligands, including antibodies, of the respective SCAAg, which may
be used for targeting a lytic virus to senescent cells. By way of
example, SCAAg as described herein may be used to prepare an
antibody that specifically binds to the SCAAg. Antigen binding
fragments (e.g., Fv, sFv, one or more CDRs with one or more
adjacent framework regions) of the antibody may be prepared either
synthetically or recombinantly according to methods routinely
practiced in the art. Mutant viral vectors may be prepared in which
the viral vector comprises on its surface a viral surface protein
(or portion thereof) that is fused in frame with an antigen binding
fragment that specifically binds to a SCAAg, such as a senescent
cell surface polypeptide, to target the viral vector to a senescent
cell. In other embodiments, the viral surface protein is fused in
frame with a ligand, or a senescent cell binding peptide of the
ligand, of a SCAAg. Senolytic viruses include by way of
non-limiting example, HSV, lentiviruses, pox viruses, adenoviruses,
rhabdoviruses, measles viruses, Newcastle Disease Virus (NDV),
rhabdoviruses (e.g., vesicular stomatitis virus), reovirus, and
Seneca Valley viruses. See, e.g., Dalba et al., Mol Ther. 2007
March; 15(3):457-66. Epub 2007 Jan. 23; U.S. Pat. Nos. 5,585,096;
5,728,379; 7,501,126; 7,749,745; Doronin et al., J. Virol.
74:6147-55 (2000); Sarkar et al., Cell Cycle 2006 July;
5(14):1531-6. Epub 2006 Jul. 17; Lorence et al. (eds):
Replication-Competent Viruses for Cancer Therapy.Monogr Virol.
Basel, Karger, 2001, vol 22, pp 160-182 (DOI: 10.1159/000061724);
Int'l Appl. Publ. No. WO 2002/053760).
[0085] Conditionally replication competent senolytic viruses also
include those from which at least one regulatory element for
expression of an essential viral gene is replaced with a regulatory
element, such as a p16 promoter, to ensure that the virus
replicates and subsequently kills only senescent cells (see, e.g.,
Int'l Appl. Publ. No. WO 2013/158664). A viral surface protein of
such a virus may be fused in frame with an antigen binding fragment
that specifically binds to a SCAAg or fused in frame with a ligand,
or peptide thereof, of the SCAAg for binding specifically to a
senescent cell.
[0086] In yet another embodiment, a virus such as rhabdovirus, may
be engineered to target and kill senescent cells and also express
an immunostimulatory molecule that promotes removal of the virus by
the immune system (see, e.g., Batenchuk et al., Blood Cancer
Journal (2013) 3, e123; doi:10.1038/bcj.2013.23; Published online
12 Jul. 2013). Without wishing to be bound by theory, the
destruction of the senescent cells evokes an immune response to
senescent cell associated antigens that promotes continued
clearance of senescent cells.
Exosomes, Senescent Cell Membranes, Senescent Cell Lysates
[0087] In certain embodiments, the immunogenic composition for
evoking an immune response specific for a senescent cell in a
subject is an exosome comprising at least one senescent
cell-associated antigen or antigenic fragment thereof. Exosomes are
nanovesicles of endosomal origin that are secreted in the
extracellular environment following fusion of late endosomal
multivesicular bodies with the plasma membrane (see, e.g., Garin et
al., 2001, J. Cell Biol. 152:165-80). Cells from various tissue
types have been shown to secrete exosomes, including dendritic
cells, immune cells (e.g., B-cells and T cells), tumor cells, mast
cells, and senescent cells. Exosomes from different cell types
exhibit discrete sets of proteins and lipid moieties that reflect
their cells of origin (see, e.g., Thery et al., 1999, 147:599-610;
Thery et al., 2001, J. Immunol. 166:7309-18). Exosomes display
proteins involved in antigen presentation (MHC Class I and MHC
Class II) (Iero et al., 2008, Cell Death Differ. 15:80-88). Their
main protein markers are tetraspanins (CD63, CD9), Alix, and
TSG101, and they are able to mediate immune response by activating
T cells (via antigen presentation); natural killer cells (via NKG2D
ligand binding); and dendritic cells (via antigen transfer) (see,
e.g., Thery et al., 2009, Nat. Rev. Immunol. 9:581-593). Though
their precise biological function and mechanism have yet to be
determined and without wishing to be bound by theory, exosomes are
thought to be involved in cell-cell communication, leading to
immune modulation. By way of example, exosomes from dendritic cells
pulsed with peptides derived from tumor antigens elicit anti-tumor
immune responses in an animal model having the matching tumor (see,
e.g., Wolfers et al., 2001, Nat. Med. 7:297-303; Zitvogel et al.,
1998, Nat. Med. 4:594-600). Accordingly, exosomes based
immunotherapy may be useful as a cell-free vaccine (see, e.g.,
Viaud et al., 2010, Cancer Res. 70:1281-5; Tan et al., 2010, Intl.
J. Nanomed. 5:889-900).
[0088] Exosome producing cells may be any cell, preferably of
mammalian origin, that produces and secretes membrane vesicles of
endosomal origin by fusion of late endosomal multivesicular bodies
with the plasma membrane. Endosomal producing cells include, for
example, dendritic cells, B cells, tumor cells, senescent cells, T
cells, and mast cells. In one embodiment, exosome-producing cells
are mammalian senescent cells, mammalian T cells, and mammalian
dendritic cells, typically murine (useful for preclinical studies)
or human. Dendritic cell exosomes are capable of activating T cells
and NK cells. In certain embodiments, exosomes may be obtained from
any autologous subject-derived cells, heterologous
haplotype-matched cells, or heterologous stem cells to reduce or
avoid the generation of an immune response in a subject to whom the
exosomes are administered. For evoking production of antibody(ies),
B cells may be used as exosome producing cells because the
resulting exosomes comprise accessory functions and molecules such
as MHC Class II molecules that facilitate antibody production.
Additionally, B cell exosomes are able to bind follicular dendritic
cells, which is a feature of antibody induction. Exosomes from
other cells types, such as non-antigen presenting cells, for
example, senescent cells, can spread antigens or peptide-loaded MHC
complexes to antigen presenting cells for more efficient
presentation. Recombinant exosomes comprising recombinant MHC
molecules have also been described (see, e.g., WO00/028001,
incorporated herein in its entirety). In some embodiments, exosomes
originating from one or more cell types may be used as an immunogen
for evoking an immune response specific for a senescent cell.
[0089] One or more senescent cell-associated antigens or antigenic
fragments thereof may be selected for loading of exosome producing
cells. If the exosome producing cell is a senescent cell, it is
naturally loaded with senescent-cell associated antigens or
antigenic fragments thereof. An exosome producing senescent cell
may also be modified with specific recombinant senescent
cell-associated antigens or antigenic fragments thereof,
co-stimulatory molecules, targeting moieties, or loaded with an
exogenous antigen (i.e., a helper antigen or carrier protein) to
enhance the immune response. A variety of methods known in the art
may be used to load antigen presenting cells with antigens,
including peptide pulsing (see, e.g., Macatonia et al., 1989, J.
Exp. Med. 169:1255; Takahashi et al., 1993, Int. Immunol. 5:849),
antigen pulsing (see, e.g., Inaba et al., 1990, J. Exp. Med.
172:631; Hsu et al., 1996, Nat. Med. 2:52); placing cells in
contact with one or more antigenic protein complexes; placing cells
in contact with cells or membranes of cells expressing antigens or
antigenic peptides ("direct transfer") (see, e.g., Zou et al.,
Cancer Immunol. Immunother. 15:1); placing cells in contact with
membrane vesicles containing antigens or antigenic peptides (e.g.,
exosomes from senescent cells) (see, e.g., U.S. Pat. No.
6,685,911); placing cells in contact with liposomes containing
antigens or antigenic peptides (see, e.g., Nair et al., 1992, J.
Exp. Med. 175:609); placing cells in contact with polynucleotides
encoding antigens or antigenic peptides (optionally incorporated in
vectors of plasmid, viral, or chemical type) (see, e.g., Boczkowsky
et al., 1996, J. Exp. Med. 184:465-472; Bhardwaj et al., 1994, J.
Clin. Invest. 94:797; Alijagie et al., 1995, Eur. J. Immunol.
25:3100). Methods of producing, purifying, or using exosomes for
therapeutic purposes or as research tools are known in the art and
have been described, for example, in U.S. Pat. Nos. 6,685,911;
7,625,573; PCT Publication Nos. WO99/03499; WO00/44389;
WO00/028001; and WO97/05900, each of which is incorporated by
reference herein in its entirety.
[0090] Exosomes produced by the exosome-producing cell may be
collected and/or purified using techniques known in the art, such
as differential centrifugation, chromatography, etc. (see, e.g.,
Thery et al., 1999, Cell Biol. 147:500-10; Lehmann et al., 2008,
Cancer Res. 68:7864; U.S. Patent Publication No. 2004/0241176; U.S.
Pat. No. 6,899,863; PCT Publication No. WO 2000/44389; each of
which is incorporated herein by reference in its entirety). Methods
for targeting expression of recombinant polypeptides to exosomes
using exosome-specific targeting domains (e.g., C1 and/or C2
domains from lactadherin) have been described in U.S. Pat. No.
7,704,964 and Rountree et al., 2011, Cancer Res. 71:5235, each
reference incorporated herein in its entirety. Such methods may be
used to deliver chimeric senescent cell-associated antigens to
exosomes if they are not naturally expressed in senescent cell
exosomes. Exosome producing cells may also be modified such that
exosomes include a targeting moiety on the surface. The exosomes
may be targeted to a selected tissue or cell type (see, e.g., PCT
Publication No. WO 2010/119256, incorporated herein in its
entirety).
[0091] In certain embodiments of the present disclosure, senescent
cell exosomes comprising one or more senescent-cell associated
antigens may be modified to lack one or more immunosuppressive
polypeptides normally found in the exosome. Such modifications may
be useful for senescent cell exosomes. While cancer cells have been
shown to release exosomes, cancer cell exosomes may circumvent
immunosurveillance and recognition of the tumor by the immune
system via inclusion of immunosuppressive polypeptides (e.g., Fas,
programmed death ligand-1, programmed death ligand-2) in the cancer
cell exosome (see, e.g., U.S. Patent Publication No. 2010/0092524;
Iero et al., supra). Likewise, senescent cell exosomes may
circumvent immunosurveillance and recognition of senescent cells by
the immune system via inclusion of immunosuppressive polypeptides.
Expression of immunosuppressive polypeptides may be inhibited using
methods known in the art, such as siRNA, antisense, and
modifications thereto (see, e.g., U.S. Patent Publication No.
2010/0092524, incorporated herein by reference in its
entirety).
[0092] In certain embodiments, the immunogenicity of senescent cell
exosomes may be enhanced by expressing exogenous antigens (e.g.,
superantigens) on the cell surface as described in U.S. Patent
Publication No. 2010/0092524, incorporated herein in its entirety.
Superantigens can bind directly to MHC complex without being
processed. Examples of superantigens that may be incorporated into
senescent cell exosomes as exogenous polypeptides include
Staphylococcal enterotoxins (SEs, e.g., Staphylococcal enterotoxin
A or Staphylococcal enterotoxin E); a Streptococcus pyogenes
exotoxin (SPE), a Staphylococcus aureus toxic shock syndrome toxin
(TSST-1); a Streptococcal mitogenic exotoxin (SME); and a
Streptococcal superantigen (SSA).
[0093] In other embodiments, an immunogen used in the immunogenic
compositions and methods described herein comprises a senescent
cell membrane preparation. In a particular embodiment, the
senescent cell preparation comprises the cell membrane (also called
the plasma cell membrane or cytoplasmic cell membrane), thereby
providing senescent cell associated antigens present on the cell
surface of the senescent cell. Senescent cell associated antigens
present on the cell membrane may include proteins and glycoproteins
that are channel forming proteins, proteins that facilitate
diffusion or active transport of molecules and ion across the
membrane, cell recognition proteins, receptor proteins, and
enzymes. In another embodiment, an organelle of a senescent cell
may be an immunogen. For example, an organelle that is involved in
processing, production, or transport of a cell surface molecule,
for example, in certain instances, a lysozome, endoplasmic
reticulum, Golgi apparatus, or an endosome, may be prepared from
senescent cells. Senescent cell membranes and cell organelles may
be prepared using methods known and practiced by the skilled person
(see, e.g., Current Protocols in Cell Biology, John Wiley &
Sons, 2009).
Dendritic Cell Immunogens (Vaccines)
[0094] In certain embodiments, the present disclosure provides
methods of evoking an immune response specific for a senescent cell
in a subject using an immunogen comprising antigen-presenting cells
(APCs), e.g., dendritic cells (DCs), that include senescent
cell-associated antigens, for example, by being presented on the
surface of the antigen-presenting cells.
[0095] Dendritic cells play a critical role in coordinating innate
and adaptive immune responses. DCs are bone-marrow derived cells
characterized by dendritic morphology and high mobility that are
seeded in all tissues. DCs are specialized antigen presenting cells
that are capable of capturing and processing antigens, migrating
from the periphery to a lymphoid organ, and presenting the antigens
in a MHC-restricted manner to naive T-cells (see, e.g., Banchereau
& Steinman, 1998, Nature 392:245-252; Steinman et al., 2003,
Ann. Rev. Immunol. 21:685-711). Immature DCs are capable of
processing and presenting antigens, which leads to immune
regulation and/or suppression. Maturation (activation) of DCs is
required to induce differentiation of antigen-specific T cells into
effector T cells (see, e.g., Palucka et al., 2012, Nat. Rev. Cancer
12:265-277). Mature DCs express high levels of MHC-antigen complex
and other co-stimulatory molecules, such as CD40, B7-1, B7-2, and
CD1a (see, e.g., Steinman, 1991, Ann. Rev. Immunol. 9:271-296;
Banchereau & Steinman, 1998, Nature 392:245-252). These
molecules play key roles in stimulating T cells. Due to their
properties, DC-based vaccination strategies have been developed in
cancer (see, e.g., Heiser et al., 2001, Cancer Res. 61:338; Heiser
et al., 2001, J. Immunol. 166:2953; Milazzo et al., 2002, Blood
101:977; Zu et al., 2003, Cancer Res. 63:2127;). Likewise, DC based
immunogens (vaccines) may be able to elicit CD8.sup.+ T cells
capable of recognizing peptide-MHC Class complexes on senescent
cells and target them for destruction.
[0096] Dendritic cells may be obtained from various sources using
methods known in the art. DC precursors may be purified from
peripheral blood (see, e.g., Fong et al., 2003, Annu Rev. Immunol.
15:138). DCs may be also be differentiated from peripheral blood
monocytes or CD34.sup.+ hematopoietic progenitor cells ex vivo
(see, e.g., Sallusto et al., 1994, J. Exp. Med. 179:1109;
Banchereau et al., 2001, Cancer Res. 61:6451; Makensen et al.,
2000, Int. J. Cancer 86:385). Methods for in vitro proliferation of
dendritic cells from DC precursors and their use as immunogens are
described in U.S. Pat. Nos. 5,851,756; 5,994,126; 6,475,483; and
8,283,163 each of which is incorporated herein by reference in its
entirety. A method for isolating DCs from human peripheral blood is
described in U.S. Pat. No. 5,643,786, incorporated herein by
reference in its entirety. U.S. Patent Publication 2006/0063255,
U.S. Patent Publication 2006/0057129, and U.S. Pat. No. 7,247,480,
each of which is incorporated herein by reference in its entirety,
describe methods for making dendritic cell vaccines from human
embryonic stem cells.
[0097] Methods of isolating APCs, such as dendritic cells, are
known in the art. Procedures such as repetitive density gradient
separation, fluorescence activated cell sorting techniques,
positive selection, negative selection, or a combination thereof
are routinely used to obtain enriched populations of DCs. Methods
for isolating DCs may be found in O'Doherty et al., 1993, J. Exp.
Med. 178:1067-78; Young and Steinman, 1990, J. Exp. Med.
171:1315-32; Freudenthal et al., 1990, Proc. Natl. Acad. Sci. USA
57:7698-7702; Markowicz and Engleman, 1990, J. Clin. Invest.
85:955-961; Mehta-Damani et al, 1994, J. Immunol. 153:996-1003;
Thomas et al., 1993, J. Immunol. 151:6840-6852.
[0098] Dendritic cells may be loaded with specific antigens ex vivo
and then administered to a subject (see, e.g., Banchereau et al.,
2005, Nat. Rev. Immunol. 5:296-306; Figdor et al., 2004, Nat. Med.
10:475-480, each of which is incorporated herein by reference in
its entirety). Various methods for loading antigens to DCs have
been described and are known in the art. RNA encoding a specific
antigen may be pulsed into dendritic cells before administration to
a subject by electroporation, cationic lipids, cationic peptides or
using dendrimers (see, e.g., Boczkwoski et al. 1996, J. Exp. Med.
184:465; Heiser et al., 2001, Cancer Res. 61:338; Heiser et al., J.
Immunol. 2001, 166:2953; U.S. Patent Publication 2006/0063255; Choi
et al., 2005, Cell Cycle 4:669). DCs may also be loaded with
protein or peptide that is purified or isolated from a target cell,
chemically synthesized, or recombinantly expressed. Nucleic acid
vectors encoding a specific antigen may also be used for DC loading
(see, e.g., Frolkis et al., 2003, Cancer Gene Ther. 10:239).
Exemplary vectors include plasmids, cationic lipid complexes, viral
vectors, cDNA encoding antigen loaded onto dendrimers, or other
small particulates that enhance uptake by phagocytic cells. U.S.
Pat. Nos. 6,300,090 and 6,455,299 describe using non-replicating
viral vectors comprising sequence encoding an antigen for infecting
dendritic cells, resulting in antigen presentation on the DC
surface.
[0099] Alternatively, DCs may be loaded with specific antigens in
vivo. Antigens may be delivered directly to DCs using chimeric
proteins that are comprised of a DC receptor-specific antibody
fused to a selected antigen (see, e.g., Bonifaz et al., 2004, J.
Exp. Med. 199:815-824; Bonifaz et al., 2004, J. Exp. Med.
196:1627-1638; Hawiger et al., 2001, J. Exp. Med. 194:769-780; each
of which is incorporated herein by reference in its entirety). U.S.
Patent Publication 2012/0070462, incorporated herein by reference
in its entirety, describes targeted antigen delivery to dendritic
cells using recombinant viral vectors comprising a polynucleotide
encoding the antigen and a targeting molecule, which binds to a
DC-specific surface marker (e.g., DC-SIGN).
[0100] In another variation on antigen loading, DCs may be fused
with whole senescent cells to express a broad array of senescent
cell-associated antigens. Dendritic cell fusion vaccines are known
in the art and have been described in Rosenblatt et al., 2005,
Expert Opin. Biol. Ther. 5:703-15; Rosenblatt et al., 2011, Blood
117:393-402; Gong et al., Proc. Natl. Acad. Sci. USA 97:2715-2718;
Gong et al., 1997, Nat. Med. 3:558-561; U.S. Patent Publication
2004/0115224; U.S. Patent Publication 2005/0238627; and U.S. Patent
Publication 2010/0278873, each of which is incorporated herein by
reference its entirety.
[0101] Antigenic peptides useful for presentation by DCs for
vaccination are peptides that stimulate a T cell mediated immune
response (e.g., cytotoxic T cell response) by presentation to T
cells on MHC molecules. Useful antigenic peptides and proteins for
use in the present disclosure include those derived from senescent
cells (e.g., senescent cell-associated antigens). Depending on the
method of DC loading utilized, a senescent cell-associated antigen
may be presented in a variety of forms. In some embodiments, a
senescent cell-associated antigen is presented as a senescent cell
lysate to DCs. In other embodiments, senescent cell-associated
antigens are obtained by acid elution of peptides presented on MHC
molecules of the senescent cell surface. For example, senescent
cells are washed with an isotonic solution to remove media
components. The cells are then treated with acid to dissociate
peptides from surface MHCs, and the cells are removed from the
solution containing the soluble peptides. Antigenic peptides may be
obtained by chemical synthesis or produced using recombinant
methods with host cells and vector expression systems. A senescent
cell associated antigen may also be delivered as a polynucleotides
(RNA or DNA) to a DC directly or indirectly (e.g., via a plasmid or
viral vector). The antigenic peptides presented on MHC molecules
are typically short peptides and may be 5, 6, 7, 8, 9, or 10 amino
acids, for example.
[0102] A senescent cell associated antigen introduced into DCs may
also be designed as a fusion peptide, wherein the antigen is joined
to a protein or peptide sequence that enhances transport into
endosomal and other intracellular compartments involved in Class II
histocompatibility loading. For example, the N-terminus of such a
fusion protein may comprise a suitable heterologous leader or
signal sequence for the endosomal compartment and the C-terminus
may comprise a transmembrane and luminal component of a member of
the LAMP family for lysosomal targeting (see, e.g., U.S. Pat. No.
5,633,234; WO 02/080851; Sawada et al., 1993, J. Biol. Chem.
268:9014; each of which is incorporated by reference herein in its
entirety). Endosomal and lysosomal sorting signals include tyrosine
based signals, dileucine-based signals, acidic clusters, and
transmembrane proteins labeled with ubiquitin (see, e.g.,
Bonifacino et al., 2003, Annu. Rev. Biochem. 72:395; U.S. Pat. No.
6,248,565).
Characterization of Immunogens
[0103] The immunogenicity of isolated senescent cell associated
antigens, antigenic fragments, and fusion polypeptides, exosomes,
cell membrane and organelle preparations, dendritic cell
immunogens, and the products encoded by the polynucleotides
described herein may be determined by using any one or more
immunogenicity, immunochemistry, and/or cellular immune response
assays, and non-human animal models routinely practiced in the art
and described herein. For characterizing the immunogens described
herein, use of polyclonal and/or monoclonal antibodies may be
desired. The antibody may be obtained from or derived from an
animal, for example, fowl (e.g., chicken) and mammals, which
include but are not limited to a mouse, rat, hamster, rabbit, or
other rodent, a cow, horse, sheep, goat, camel, human, or other
primate. Polyclonal antisera are obtained from an animal by
immunizing the animal with an immunogenic composition described
herein.
[0104] Immunogenic compositions and SCAAgs may also be
characterized in pre-clinical studies that evaluate the safety of
the immunogenic composition to be administered to a subject.
Ultimately, the safety and efficacy of immunogenic compositions
will be determined by clinical studies, which are monitored by
regulatory agencies.
[0105] Characterizing the immunogenic activity of an immunogen
described herein may also be determined in art-accepted animal
models. The capability of the immunogen to effectively induce an
immune response in a subject can also be assessed in an animal
model for the particular disease, disorder, or condition that is
being treated or prevented by immunization. The immunogenicity of
any one of the immunogens described herein may be determined by
administering the immunogenic composition comprising the immunogen
to a host (or subject, patient) according to immunization protocols
described herein and in the art. Typically, after administering an
initial dose of the immunogenic composition (also called the
primary immunization) to a host, one, two or more doses of the
immunogenic composition (also called boosting or booster doses) are
administered.
[0106] To evaluate the immunogenicity of any one of the immunogenic
compositions described herein, the immunogen may be administered to
an animal by a parenteral (e.g., intravenous), intraperitoneal,
intramuscular, intradermal, intraocular, or subcutaneous route. The
immunogenic composition may further comprise a suitable adjuvant to
enhance the immune response to the immunogen. See, e.g., Harlow et
al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory
(1988). Adjuvants typically used for immunization of non-human
animals include but are not limited to Freund's complete adjuvant,
Freund's incomplete adjuvant, montanide ISA, Ribi Adjuvant System
(RAS) (GlaxoSmithKline, Hamilton, Mont.), and
nitrocellulose-adsorbed antigen. In general, after the first
injection, animals receive one or more booster immunizations
according to a preferred schedule that may vary according to, inter
alia, the immunogen, the adjuvant (if any) and/or the particular
animal species. The B cell immune response may be monitored by
periodically bleeding the animal, separating the sera from the
collected blood, and analyzing the sera in an immunoassay, such as
an ELISA or Ouchterlony diffusion assay, or the like, to determine
the specific antibody titer. When an adequate antibody titer is
established, the animals may be bled periodically to accumulate the
polyclonal antisera.
[0107] In general, to monitor the immune response of an immunized
host during pre-clinical studies in animals, sera is obtained from
the animals prior to the first dose (i.e., pre-immune sera) and
obtained after the final boosting dose. Sera may also be obtained
after any one or more of the boosting doses between the primary
dose and final boosting dose. To monitor the immune response of an
immunized host during clinical studies or during post-marketing
studies, sera may also be obtained from humans before the first
immunization and after one or more administrations of the
immunogenic compositions.
[0108] Production of senescent cell associated antigen-specific
antibodies in an immunized host (including a human host) may
include production of any class of immunoglobulin, including IgG,
IgA, IgM, and/or IgE, and isotypes within the classes. The presence
of specific IgG, IgM, IgE, and IgA may be detected in a biological
sample (e.g., serum, nasal wash, lung lavage, or other tissues)
obtained from an immunized host. For detection of antibodies in an
immunoassay, the biological sample may be permitted to interact
with or contact an antigen that is purified, isolated, partially
isolated, or a fragment thereof, or to interact with or contact a
senescent cell, which may be fixed (such as with ethanol or
formaldehyde) or unfixed or non-denatured.
[0109] The immunogenicity of immunogens described herein may also
be characterized by any number of assays and techniques practiced
in the art, including immunoassays to evaluate binding and the
capability of the immunogen to induce an immune response. By way of
non-limiting example, immunoassays include ELISA, immunoblot,
radioimmunoassay, immunohistochemistry, fluorescence activated cell
sorting (FACS), Ouchterlony, and the like. Conditions for in vitro
assays include temperature, buffers (including salts, cations,
media), and other components that maintain the integrity of any
cell used in the assay and the compound, which a person skilled in
the art will be familiar and/or which can be readily determined. A
person skilled in the art also readily appreciates that appropriate
controls can be designed and included when performing the in vitro
methods and in vivo methods described herein.
[0110] In vitro assay methods typically comprise contacting the
biological sample with at least one source of the antigens
described above and herein (particularly, e.g., an isolated
senescence cell associated antigen or fragment thereof, a senescent
cell or a lysate, membrane preparation or exosome comprising the
antigen of interest) under conditions and for a time sufficient for
an antibody in the sample to interact with the antigen source
(i.e., mixing, combining, or in some manner permitting the
biological sample and the antigen to interact). An antibody present
in the biological sample that specifically binds to the antigen can
be detected using any one of the exemplary detection methods
described herein and in the art for detecting antibody-antigen
binding. By way of non-limiting example, antibody bound to the
antigen may be detected using a reagent specific for a conserved
region of the antibody, such as the Fc portion of the antibody,
which reagent is typically selected depending on the source of the
antibody (i.e., whether the antibody is from an animal, such as a
mouse, rat, goat, or sheep, etc. or whether the antibody is from a
human). Such reagents typically comprise a detectable label, for
example an enzyme, fluorescent label, luminescent label, or
radioactive label. Additional exemplary reagents include those that
detect a specific isotype or class of antibody. Many such reagents
may be obtained from commercial sources.
[0111] Whether an immune response includes the capability to kill
or clear senescent cells may be determined according to techniques
and methods described herein and practiced in the art. An immune
response that comprises selectively clearing a senescent cell or
facilitating selective clearance of a senescent cell kills,
removes, destroys, reduces viability, or decreases survival of a
senescent cell (i.e., in some manner reduces the quantity of viable
senescent cells in the animal or in the cell-based assay) in a
statistically significant or biologically significant manner when
compared with the immune response to kill, remove, clear, reduce
viability, or decrease survival of a non-senescent cell. Such an
immune response may therefore be useful for treating or preventing
an age-related disease or disorder or another disease associated
with or exacerbated by the presence of senescent cells. Transgenic
animal models as described herein and in the art may be used to
determine clearance of senescent cells (see, e.g., Baker et al.,
supra; Nature, 479:232-36 (2011); Int'l Patent Application
Publication No. WO/2012/177927; Int'l Patent Application
Publication No. WO 2013/090645). The transgenic animals by
determining the level of a detectable label or labels that is
expressed in senescent cells of the animal. Exemplary transgenic
animal models contain a transgene that includes a nucleic acid that
allows for controlled clearance of senescence cells (e.g.,
p16.sup.Ink4a positive senescent cells). The transgene also
nucleotide sequences includes a detectable label, for example, one
or more of a red fluorescent protein; a green fluorescent protein;
and one or more luciferases to detect clearance of senescent
cells.
[0112] Senescent cells and senescent cell associated molecules can
be detected by techniques and procedures described in the art. For
example, the presence of senescent cells in tissues can be analyzed
by histochemistry or immunohistochemistry techniques that detect
the senescence marker, SA-beta gal (SA-Bgal) (see, e.g., Dimri et
al., Proc. P Natl. Acad. Sci. USA 92: 9363-9367 (1995). The
presence of the senescent cell-associated polypeptide p16 can be
determined by any one of numerous immunochemistry methods practiced
in the art, such as immunoblotting analysis. Expression of p16 mRNA
in a cell can be measured by a variety of techniques practiced in
the art including quantitative PCR. The presence and level of
senescence cell associated polypeptides (e.g., polypeptides of the
SASP) can be determined by using automated and high throughput
assays, such as an automated Luminex array assay described in the
art (see, e.g., Coppe et al., PLoS Biol 6: 2853-68 (2008)).
[0113] The presence of senescent cells can also be determined by
detection of senescent cell-associated molecules include growth
factors, proteases, cytokines (e.g., inflammatory cytokines),
chemokines, cell-related metabolites, reactive oxygen species
(e.g., H.sub.2O.sub.2), and other molecules that stimulate
inflammation and/or other biological effects or reactions that may
promote or exacerbate the underlying disease of the subject.
Senescent cell-associated molecules include those that are
described in the art as comprising the senescence-associated
secretory phenotype (SASP, i.e., which includes secreted factors
which may make up the pro-inflammatory phenotype of a senescent
cell), senescent-messaging secretome, and DNA damage secretory
program (DDSP). These groupings of senescent cell associated
molecules, as described in the art, contain molecules in common and
are not intended to describe three separate distinct groupings of
molecules. Senescent cell-associated molecules include certain
expressed and secreted growth factors, proteases, cytokines, and
other factors that may have potent autocrine and paracrine
activities. (see, e.g., Coppe et al., supra; Coppe et al. J. Biol.
Chem. 281:29568-74 (2006); Coppe et al. PLoS One 5:39188 (2010);
Krtolica et al. Proc. Natl. Acad. Sci. U.S.A. 98:12072-77 (2001);
Parrinello et al., J. Cell Sci. 118:485-96 (2005). ECM associated
factors include inflammatory proteins and mediators of ECM
remodeling and which are strongly induced in senescent cells (see,
e.g., Kuilman et al., Nature Reviews 9:81-94 (2009)). Other
senescent cell-associated molecules include extracellular
polypeptides (proteins) described collectively as the DNA damage
secretory program (DDSP) (see, e.g., Sun et al., Nature Medicine
published online 5 Aug. 2012; doi:10.1038/nm.2890).
[0114] Determining the effectiveness of an immune response to clear
senescent cells as described herein in an animal model is typically
performed using one or more statistical analyses with which a
skilled person will be familiar. By way of example, statistical
analyses such as two-way analysis of variance (ANOVA) may be used
for determining the statistical significance of differences between
animal groups treated with an agent and those that are not treated
with the agent (i.e., negative control group). Statistical packages
such as SPSS, MINITAB, SAS, Statistika, Graphpad, GLIM, Genstat,
and BMDP are readily available and routinely used by a person
skilled in the animal art.
[0115] Conditions for a particular assay including temperature,
buffers (including salts, cations, media), and other components,
which maintain the integrity of the antibodies within the
pre-immune and immune sera and the integrity of the antigen (which
may be an immunogenic peptide, dimeric peptide, or fusion
polypeptide, M protein, Spa protein, or bacteria) used in the
assay, are familiar to a person skilled in the art and/or which can
be readily determined. A biological sample, such as serum, is
contacted (mixed, combined with, or in some manner permitted to
interaction) with the antigen, under conditions and for a time
sufficient to permit interaction between the antigen and antibodies
present in the sample. The interaction, or level of binding, of the
antigen to an antibody present in an immune serum sample (or other
biological sample) may be determined and compared to a level of
binding of the respective antigen to antibodies present in a
pre-immune sample (or an otherwise suitable negative control). An
increase in the level of binding of the antigen to the immune serum
sample compared with the pre-immune serum sample indicates that the
immunogenic composition evoked production of specific antibodies.
As noted herein, the level of binding of an immunogen to antibodies
present in a sample from an immunized host is typically referred to
in the art as the titer.
Adjuvants and Helper Antigens
[0116] The immunogenic compositions described herein may also
comprise a suitable adjuvant. An adjuvant is intended to enhance
(or improve, augment) the immune response to the immunogens
described herein, including antigenic fragments and fusion
polypeptides comprising the fragments (i.e., increase the level of
the specific immune response in a statistically, biologically, or
clinically significant manner compared with the level of the
specific immune response in the absence of administering the
adjuvant).
[0117] For administration in humans, a pharmaceutically acceptable
adjuvant is one that has been approved or is approvable for human
administration by pertinent regulatory bodies. For example, as
discussed herein and known in the art, Complete Freund's adjuvant
is not suitable for human administration. Desired adjuvants augment
the response to the immunogen without causing conformational
changes in the immunogen that might adversely affect the
qualitative immune response. Suitable adjuvants include aluminum
salts, such as alum (potassium aluminum sulfate), or other aluminum
containing adjuvants such as aluminum hydroxide, aluminum
phosphate, or aluminum sulfate. Other pharmaceutically suitable
adjuvants include nontoxic lipid A-related adjuvants such as, by
way of non-limiting example, nontoxic monophosphoryl lipid A (see,
e.g., Persing et al., Trends Microbiol. 10:s32-s37 (2002)), for
example, 3 De-O-acylated monophosphoryl lipid A (MPL) (see, e.g.,
United Kingdom Patent Application No. GB 2220211). Other useful
adjuvants include QS21 and QuilA that comprise a triterpene
glycoside or saponin isolated from the bark of the Quillaja
saponaria Molina tree found in South America (see, e.g., Kensil et
al., in Vaccine Design: The Subunit and Adjuvant Approach (eds.
Powell and Newman, Plenum Press, N Y, 1995); U.S. Pat. No.
5,057,540). Other suitable adjuvants include oil in water
emulsions, optionally in combination with immune stimulants, such
as monophosphoryl lipid A (see, e.g., Stoute et al., N Engl. J.
Med. 336, 86-91 (1997)). Other suitable adjuvants include polymeric
or monomeric amino acids such as polyglutamic acid or polylysine,
liposomes, and CpG (see, e.g., Klinman, Int. Rev. Immunol.
25(3-4):135-54 (2006); U.S. Pat. No. 7,402,572; European Patent No.
772 619). CpG is often an adjuvant of choice when administering a
polynucleotide that encodes a senescent cell associate antigen or
antigenic fragment thereof (or a vector comprising the
polynucleotide).
[0118] In another embodiment, the immunogenicity of an immunogen
described herein may be enhanced by combining the immunogen with a
helper antigen or carrier moiety. A helper antigen includes a T
cell helper antigen, which is an antigen that is recognized by a T
helper cell and evokes an immune response in a T helper cell. T
helper cells are lymphocytes that are involved in activating and
directing other immune cells such as cytotoxic T cells, B cells,
and/or macrophages. Carrier moieties have been long known in the
immunology art and include without limitation, keyhole limpet
hemocyanin, bovine serum albumin, cationized BSA, or ovalbumin. For
human use, toxoids of bacterial proteins (e.g., tetanus toxoid,
diphtheria toxoid, cholera toxoid, and the like) are typically
employed as carrier proteins.
[0119] In certain embodiments, the immunogen comprises at least one
senescent cell associated antigen or at least one antigenic
fragment thereof and a helper antigen or carrier moiety that is
linked, conjugated, or attached to the antigen or antigenic
fragment thereof. The helper antigen or carrier moiety may be
recombinantly expressed in frame and directly linked to a senescent
cell associated antigen or fragment thereof. In certain
embodiments, a fusion protein comprising at least two senescent
cell associated antigens or at least two antigenic fragments
thereof or a combination of same may also comprise a helper antigen
or carrier moiety. Alternatively, the helper antigen or carrier
moiety may be chemically conjugated, linked, or attached to the
senescent cell associated antigen or fragment thereof. In still
another embodiment, the helper antigen or carrier moiety may be
formulated together with any immunogen described herein but not
covalently or non-covalently bound to the immunogen to form an
immunogenic composition.
Co-Stimulatory Molecules
[0120] In another embodiment, the immunogenic compositions
described herein (including those described above and immunogenic
compositions comprising a recombinant antibody described below),
include a co-stimulatory polypeptide. In certain embodiments, the
immunogen comprises at least one senescent cell associated antigen
or at least one antigenic fragment thereof and a co-stimulatory
molecule that is linked, conjugated, or attached to the antigen or
antigenic fragment thereof. The co-stimulatory molecule may be
recombinantly expressed in frame and directly linked to a senescent
cell associated antigen or fragment thereof. In certain
embodiments, a fusion protein comprising at least two senescent
cell associated antigen or at least two antigenic fragments thereof
or a combination of same may also comprise a co-stimulatory
molecule. Alternatively, the co-stimulatory molecule may be
chemically conjugated, linked, or attached to the senescent cell
associated antigen or fragment thereof. In still another
embodiment, the co-stimulatory molecule may be formulated together
with any immunogen described herein but not covalently or
non-covalently bound to the immunogen to form the immunogenic
composition.
[0121] Exemplary co-stimulatory molecules include, by way of
example, GM-CSF, IL-2, IL-4, IL-6, IL-7, IL-15, IL-21, IL-23,
TNF.alpha., B7.1 (CD80), B7.2 (CD86), 41BB, CD40 ligand (CD40L),
drug-inducible CD40 (iCD40), and the like. When an immunogenic
composition comprises a polynucleotide encoding the co-stimulatory
molecule, or a recombinant expression virus comprising the
polynucleotide, expression of the co-stimulatory molecule is
typically under the control of one or more regulatory elements
selected to direct the expression of the coding sequences in a cell
of choice, such as a dendritic cell.
[0122] Recombinantly engineered antigen-presenting cells such as
dendritic cells, for example, may be modified by recombinant
technology to express increased levels of antigen presenting
machinery, adhesion and/or co-stimulatory molecules, including MHC
class I/antigen complexes, MHC class II/antigen complexes, CD1,
hsp70-90, CD9, CD63, CD81, CD11b, CD11c, CD40, CD54 (ICAM-1), CD63,
CD80, CD86, 41BBL, OX40L, chemokine receptor CCR1-10 and CXCR1-6,
mannose-rich C-type lectin receptor DEC205 and Toll-like receptors
TLR4 and TLR9 or membrane-bound TGF-.beta.. The exosomes derived
from these recombinantly engineered antigen presenting cells will
express these additional molecules and can transfer them to the T
helper cells, T regulatory cells, or dendritic cells upon
absorption.
Processes for Preparing Senescent Cell Associated Antigens,
Fragments, and Polynucleotides
[0123] Peptides and polypeptides may be chemically synthesized by
manual techniques or by automated procedures. By way of example,
solid phase polypeptide synthesis has been performed since the
early 1960's. Numerous improvements to synthesis methods have been
developed, and many methods have been automated and chemistries
have been developed to protect the terminal ends and other reactive
groups (see, e.g., Geysen et al., J. Immun. Meth. 102:259-274
(1987); Miranda et al., Proc. Natl. Acad. Sci. USA 96:1181-86
(1999); Frank et al., Tetrahedron 44:6031-6040 (1988); Hyrup et
al., Bioorg. Med. Chem. 4:5-23 (1996); Perry-O'Keefe et al., Proc.
Natl. Acad. Sci. USA 93:14670-675 (1996); Schnolzer, et al. Int. J.
Pept. Protein Res. 40, 180-193 (1992); Hackeng et al., Proc. Natl.
Acad. Sci. USA 94:7845-50 (1997); Creighton, T. E. Protein:
Structures and Molecular Properties, pp. 55-60, W. H. Freeman and
Co., New York, N.Y. (1984)). Equipment for automated synthesis of
polypeptides is commercially available and may be operated
according to the manufacturer's instructions. Synthesized peptides,
polypeptides, and fusion polypeptides may also be obtained from any
number of different custom peptide synthesizing manufacturers. If
required, synthesized peptides or polypeptides may be purified
using preparative reverse phase chromatography, affinity
chromatography partition chromatography, gel filtration, gel
electrophoresis, or ion-exchange chromatography or other methods
used in the art.
[0124] Polynucleotides may also be chemically synthesized or may be
constructed by recombinant methods familiar to a person skilled in
the art. Polynucleotides can also be synthesized using an automatic
synthesizer. The nucleotide sequence can be designed with the
appropriate codons for the particular amino acid sequence desired.
In general, preferred codons may be selected for the intended host
in which the nucleotide sequence will be expressed. One recombinant
method of preparing a polynucleotide includes assembly from
overlapping oligonucleotides prepared by standard methods to
provide a complete coding sequence (see, e.g., Au et al., Biochem.
Biophys. Res. Commun. 248:200-203 (1998); Stemmer et al., Gene
164:49-53 (1995); Ausubel et al. (eds.), Current Protocols in
Molecular Biology, (Greene Publ. Assoc. Inc. & John Wiley &
Sons, Inc., 1993)); Sambrook et al., et al. Molecular Cloning: A
Laboratory Manual, 3rd Ed., (Cold Spring Harbor Laboratory 2001;
and elsewhere). Methods for purifying polynucleotides after either
chemical synthesis or recombinant synthesis are known to persons
skilled in the art (see, e.g., Ausubel et al., supra; Sambrook et
al., supra).
[0125] Chemical synthesis of oligonucleotides for primers and
probes has long been practiced in the art. Improved methods for
synthesizing oligonucleotides and polynucleotides, which provide
more rapid results, greater yields, and longer polynucleotides,
have since been developed and automated (see, e.g., Gao et al.,
Biopolymers 73:579-96 (2004); Mueller et al., Chem. Biol. 16:337-47
(2009); Lee et al., Nucleic Acids Res. 38:2514-21 (2010)).
Polynucleotides that encode the senescent cell-associated antigen,
antigenic fragments thereof, and fusion polypeptides described
herein may be synthesized commercially (see, e.g., GENSCRIPT,
Piscataway, N.J.).
[0126] Polynucleotides that encode a senescent cell-associated
antigen, antigenic fragment thereof, or fusion polypeptide
described herein may be recombinantly expressed in a variety of
different host cells. Host cells containing recombinant expression
constructs may be genetically engineered (transduced, transformed,
or transfected) with the vectors and/or expression constructs (for
example, a cloning vector, a shuttle vector, or an expression
construct). The vector or construct may be in the form of a
plasmid, a viral particle, a phage, etc. The engineered host cells
can be cultured in conventional nutrient media modified as
appropriate for activating promoters, selecting transformants, or
amplifying particular genes or encoding-nucleotide sequences.
Selection and maintenance of culture conditions for particular host
cells, such as temperature, pH and the like, will be readily
apparent to the ordinarily skilled artisan. In general, the desired
host cell is one that can be adapted to sustained propagation in
culture to yield a stable cell line that can express sufficient
amount of the desired peptide, polypeptide, or fusion protein. In
certain embodiments, the cell line is an immortal cell line, which
refers to a cell line that can be repeatedly passaged (at least ten
times while remaining viable) in culture following log-phase
growth. In other embodiments the host cell used to generate a cell
line is a cell that is capable of unregulated growth, such as a
cancer cell, or a transformed cell, or a malignant cell.
[0127] Useful bacterial expression constructs are prepared by
inserting into an expression vector a structural DNA sequence
encoding the desired peptide, polypeptide, or fusion protein
together with suitable translation initiation and termination
signals in an operative reading phase with a functional promoter.
The construct may comprise one or more phenotypic selectable
markers and an origin of replication to ensure maintenance of the
vector construct and, if desirable, to provide amplification within
the host. Suitable prokaryotic hosts for transformation include E.
coli, Bacillus subtilis, Salmonella typhimurium and various species
within the genera Pseudomonas, Streptomyces, and Staphylococcus,
although others may also be employed as a matter of choice. Any
other plasmid or vector may be used as long as the plasmid or
vector is replicable and viable in the host. Thus, for example, the
polynucleotides as provided herein may be included in any one of a
variety of expression vector constructs as a recombinant expression
construct for expressing the senescent cell-associated antigen,
antigenic fragment thereof, or fusion polypeptide. Such vectors and
constructs include chromosomal, nonchromosomal, and synthetic DNA
sequences, e.g., bacterial plasmids; phage DNA; baculovirus; yeast
plasmids; vectors derived from combinations of plasmids and phage
DNA; viral DNA, such as vaccinia, adenovirus, fowl pox virus, and
pseudorabies.
[0128] The appropriate DNA sequence(s) may be inserted into the
vector by a variety of procedures with which the skilled person is
familiar. In certain instances, the DNA sequence is inserted into
an appropriate restriction endonuclease site(s) by procedures known
in the art. Omission of restriction sites and the amino acid
sequence encoded by the restriction site is contemplated herein and
is intended to remove the possibility that a desired immunogenic
epitope will be adversely altered or that an epitope will be
inadvertently added that may have an undesirable immunogenicity.
Standard techniques for cloning, DNA isolation, amplification and
purification, for enzymatic reactions involving DNA ligase, DNA
polymerase, restriction endonucleases and the like, and various
separation techniques are those known and commonly employed by
those skilled in the art. Numerous standard techniques are
described, for example, in Ausubel et al. (Current Protocols in
Molecular Biology (Greene Publ. Assoc. Inc. & John Wiley &
Sons, Inc., 1993)) and in Sambrook et al. (Molecular Cloning: A
Laboratory Manual, 3rd Ed., (Cold Spring Harbor Laboratory
2001)).
[0129] The DNA sequence encoding a peptide, polypeptide, or fusion
polypeptide in the expression vector is operatively linked to at
least one appropriate expression control sequences (e.g., a
promoter or a regulated promoter) to direct mRNA synthesis.
Representative examples of such expression control sequences
include LTR or SV40 promoter, E. coli lac or trp, the phage lambda
P.sub.L promoter, and other promoters known to control expression
of genes in prokaryotic or eukaryotic cells or their viruses.
Promoter regions can be selected from any desired gene using CAT
(chloramphenicol transferase) vectors or other vectors with
selectable markers. Particular bacterial promoters include lad,
lacZ, T3, T5, T7, gpt, lambda P.sub.R, P.sub.L, and trp. Eukaryotic
promoters include CMV immediate early, HSV thymidine kinase, early
and late SV40, LTRs from retroviruses, and mouse metallothionein-I.
Selection of the appropriate vector and promoter and preparation of
certain recombinant expression constructs comprising at least one
promoter or regulated promoter operatively linked to a
polynucleotide described herein is well within the level of
ordinary skill in the art.
[0130] Design and selection of inducible, regulated promoters
and/or tightly regulated promoters are known in the art and will
depend on the particular host cell and expression system. The pBAD
Expression System (Invitrogen Life Technologies, Carlsbad, Calif.)
is an example of a tightly regulated expression system that uses
the E. coli arabinose operon (P.sub.BAD or P.sub.ARA) (see Guzman
et al., J. Bacteriology 177:4121-30 (1995); Smith et al., J. Biol.
Chem. 253:6931-33 (1978); Hirsh et al., Cell 11:545-50 (1977)),
which controls the arabinose metabolic pathway. A variety of
vectors employing this system are commercially available. Other
examples of tightly regulated promoter-driven expression systems
include PET Expression Systems (see U.S. Pat. No. 4,952,496)
available from Stratagene (La Jolla, Calif.) or tet-regulated
expression systems (Gossen et al., Proc. Natl. Acad. Sci. USA
89:5547-51 (1992); Gossen et al., Science 268:1766-69 (1995)). The
pLP-TRE2 Acceptor Vector (BD Biosciences Clontech, Palo Alto,
Calif.) is designed for use with CLONTECH's Creator.TM. Cloning
Kits to rapidly generate a tetracycline-regulated expression
construct for tightly controlled, inducible expression of a gene of
interest using the site-specific Cre-lox recombination system (see,
e.g., Sauer, Methods 14:381-92 (1998); Furth, J. Mamm. Gland Biol.
Neoplas. 2:373 (1997)), which may also be employed for host cell
immortalization (see, e.g., Cascio, Artif. Organs 25:529
(2001)).
[0131] Processes for producing a senescent cell-associated antigen
in a host cell comprising a recombinant expression encoding the
antigen may be scaled to manufacture large amounts. In another
embodiment, a method of manufacture of the immunogenic compositions
described herein is provided. Methods of manufacture comprise
combining or mixing together the desired senescent cell-associated
antigen, antigenic fragment thereof, or fusion polypeptides,
polynucleotides, recombinant expression vectors, senescent cell
membrane preparation, a senescent cell organelle preparation,
exosome of the senescent cell, modified dendritic cell, or
recombinant antibody to provide the immunogenic compositions
described herein. The methods of manufacture may further comprise
combining or mixing one or more physiologically suitable (or
pharmaceutically suitable) excipients as described herein. The
methods may further comprise combining or mixing the immunogenic
composition comprising the desired immunogen with a
pharmaceutically suitable adjuvant. At least one pharmaceutically
suitable excipient may also be combined or mixed with the
immunogenic composition comprising an adjuvant. In still further
embodiments, a method of manufacture comprises chemical synthesis
or recombinant production of the desired peptides, polypeptides, or
fusion polypeptides. Chemical synthesis and recombinant production
of the senescent cell-associated antigen, antigenic fragment
thereof, and fusion polypeptides are described in detail herein.
During manufacture of each immunogen, appropriate manufactures
processes (such as Good Manufacturing Practices (GMP)) as required
by a regulatory agency are employed. In addition, persons skilled
in the art are familiar with techniques and steps to be taken for
maintaining stability and integrity of the peptides or fusion
polypeptides during manufacture of an immunogenic composition.
[0132] A process is provided herein for producing an immunogenic
composition (or vaccine) that comprises at least one senescent
cell-associated antigen. Into a first host cell a recombinant
expression vector is introduced (transfected, transduced,
transformed) wherein the vector comprising at least one regulatory
expression sequence operatively linked to a nucleotide sequence
that encodes a first senescent cell-associated antigen, or an
antigenic fragment thereof. If the immunogenic composition will
comprise a second senescent cell-associated antigen, a second host
cell is transfected, transduced, transformed with a second
recombinant expression vector comprising at least one regulatory
expression sequence operatively linked to a nucleotide sequence
that encodes a second senescent cell-associated antigen, or an
antigenic fragment thereof. Each host cell is separately cultured
in a medium for a time sufficient and under conditions appropriate
for maximizing production of the antigen. Such conditions, which
can readily be determined by a person skilled in the art, include
maintaining the proper temperature, nutrient level, carbon dioxide
level, cell density, atmospheric pressure, and removing waste in a
timely manner. The respective antigens are then isolated from the
host cell culture. Typically, the cells are harvested (i.e.,
separated) from the culture by methods practiced in the art such as
centrifugation or filtration or a combination thereof. If the
antigen is secreted by the host cell, the cell culture medium (also
called spent medium) may be concentrated, followed by isolation of
the antigen by any one of a number of isolation methods, including
any number of chromatography methods and gel electrophoresis.
Alternatively, if the antigen is not secreted by the host cell, the
cells may be fractionated or lysed or the antigen may form
inclusion bodies in the cell, which inclusion bodies are then
isolated according to techniques known in the art. Once the
senescent cell associated antigen is isolated, it may be formulated
with one or more pharmaceutically acceptable excipients. If the
immunogenic composition comprises more than one senescent cell
associated antigen or fragment thereof, each antigen may be
formulated separately with an excipient or the two antigens may be
formulated together in the same vessel with a pharmaceutically
acceptable excipient.
Passive Immunization--Recombinant Antibodies
[0133] Also provided herein are polyclonal and monoclonal
antibodies that specifically bind to a senescent cell associated
antigen for use in passive immunotherapeutic methods. An antibody
that specifically binds to a senescent cell associated antigen (or
antigenic fragment thereof, or fusion protein comprising same, or a
senescent cell expressing the antigen) may belong to any
immunoglobulin class, for example IgG, IgE, IgM, IgD, or IgA. The
antibody may be obtained from or derived from an animal, for
example, fowl (e.g., chicken) and mammals, which include but are
not limited to a mouse, rat, hamster, rabbit, or other rodent, a
cow, horse, sheep, goat, camel, human or other primate. The
antibody may be an internalising antibody. The antibody may be a
monoclonal antibody, which includes a monoclonal antibody derived
from any human or non-human animal, a chimeric antibody, humanized
antibody, or an antigen-binding fragment thereof.
[0134] In a particular embodiment, a recombinant antibody that
specifically binds to a senescent cell-associated antigen of
interest is provided. The recombinant antibody comprises at least
one immunoglobulin variable region domain that specifically binds
to a senescent cell-associated antigen. In certain embodiments, the
recombinant antibody further comprises a modified human Fc region
that exhibits enhanced affinity for an Fc.gamma. receptor. In one
embodiment the senescent cell-associated antigen is selected from
Table 1 provided below. In certain other embodiments, the senescent
cell-associated antigen is encoded by a nucleic acid sequence
selected from Table 2 or Table 3. In another specific embodiment,
the senescent cell-associated antigen is p16INK4a, for example,
murine, human, or rat p16INK4a.
[0135] A recombinant antibody as described herein comprises at
least one variable region domain. The at least one immunoglobulin
variable region domain may comprise either the heavy chain variable
region. The variable region domain may be of any size or amino acid
composition and will generally comprise at least one hypervariable
amino acid sequence responsible for antigen binding and which is
adjacent to or in frame with one or more framework sequences. In
general terms, the variable (V) region domain may be any suitable
arrangement of immunoglobulin heavy (V.sub.H) and/or light
(V.sub.L) chain variable domains. In other embodiments, the
recombinant antibodies described herein comprise (1) an Fv fragment
consisting of the variable regions of both the heavy and light
chains, (2) recombinant single chain polypeptide molecules in which
light and heavy variable regions are connected by a peptide linker
(scFv proteins); or (3) minimal recognition units consisting of the
amino acid residues that mimic the hypervariable region. An Fv
region is defined in the immunoglobulin art as the N-terminal
portion of an Fab fragment of the immunoglobulin and includes the
V.sub.H (variable heavy chain) and V.sub.L (variable light chain)
regions that are bound together by non-covalent interactions. Each
V.sub.H comprises three complementarity determining regions (CDRs;
heavy chain CDR1, CDR2, and CDR3) and each V.sub.L comprises three
CDRs (light chain CDR1, CDR2, and CDR3). Thus, for example, the V
region domain may be monomeric and be a V.sub.H or V.sub.L domain,
which is capable of independently binding antigen with acceptable
affinity. Alternatively, the V region domain may be dimeric and
contain V.sub.H--V.sub.H, V.sub.H--V.sub.L, or V.sub.L--V.sub.L,
dimers. Preferably, the V region dimer comprises at least one
V.sub.H and at least one V.sub.L chain that are non-covalently
associated (hereinafter referred to as F.sub.v). If desired, the
chains may be covalently coupled either directly, for example via a
disulfide bond between the two variable domains, or through a
linker, for example a peptide linker, to form a single chain Fv
(scF.sub.v).
[0136] An immunoglobulin variable region may be derived from a
monoclonal antibody or polyclonal antibody that specifically binds
to a senescent cell associated antigen. Monoclonal and polyclonal
antibodies may generally be prepared by any of a variety of
techniques known to persons having ordinary skill in the art. See,
e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring
Harbor Laboratory (1988); Peterson, ILAR J. 46:314-19 (2005));
Green et al., "Production of Polyclonal Antisera," in
Immunochemical Protocols (Manson, ed.), pages 1-5 (Humana Press
1992); Harlow et al., Antibodies: A Laboratory Manual, Cold Spring
Harbor Laboratory (1988); Williams et al., "Expression of foreign
proteins in E. coli using plasmid vectors and purification of
specific polyclonal antibodies," in DNA Cloning 2: Expression
Systems, 2nd Edition, Glover et al. (eds.), page 15 (Oxford
University Press 1995)). Suitable animals include, for example,
rabbits, sheep, goats, pigs, cattle, subhuman primates and may also
include smaller mammalian species, such as mice, rats, and
hamsters, or other species (see, e.g., International Patent
Application Publication No. WO 91/11465 (1991) and in Losman et
al., Int. J. Cancer 46:310, 1990). Monoclonal antibodies that
specifically bind to the senescent cell associated antigen of
interest and hybridomas, which are examples of immortal eukaryotic
cell lines, that produce monoclonal antibodies having the desired
binding specificity, may be prepared, for example, using the
technique of Kohler and Milstein (Nature, 256:495-97 (1976), Eur.
J. Immunol. 6:511-19 (1975)) and improvements thereto (see, e.g.,
Coligan et al. (eds.), Current Protocols in Immunology,
1:2.5.1-2.6.7 (John Wiley & Sons 1991); U.S. Pat. Nos.
4,902,614, 4,543,439, and 4,411,993; Monoclonal Antibodies,
Hybridomas: A New Dimension in Biological Analyses, Plenum Press,
Kennett et al. (eds.) (1980); and Antibodies: A Laboratory Manual,
Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press (1988);
see also, e.g., Brand et al., Planta Med. 70:986-92 (2004);
Pasqualini et al., Proc. Natl. Acad. Sci. USA 101:257-59
(2004)).
[0137] An antibody that specifically binds to the senescent cell
associated antigen of interest may be derived from a human
monoclonal antibody. Human monoclonal antibodies may be generated
by any number of techniques with which those having ordinary skill
in the art will be familiar. Such methods include, but are not
limited to, Epstein Barr Virus (EBV) transformation of human
peripheral blood cells (e.g., containing B lymphocytes) (see, e.g.,
U.S. Pat. No. 4,464,456; see also, e.g., Glasky et al., Hybridoma
8:377-89 (1989)); in vitro immunization of human B cells (see,
e.g., Boerner et al., J. Immunol. 147:86-95 (1991)); fusion of
spleen cells from immunized transgenic mice carrying inserted human
immunoglobulin genes (see, e.g., Green et al., Nature Genet. 7:13
(1994); Lonberg et al., Nature 368:856 (1994); Taylor et al., Int
Immun. 6:579 (1994); U.S. Pat. No. 5,877,397; Bruggemann et al.,
Curr. Opin. Biotechnol. 8:455-58 (1997); Jakobovits et al., Ann. N.
Y. Acad. Sci. 764:525-35 (1995)); isolation from human
immunoglobulin V region phage libraries; cloning the light chain
and heavy chain variable regions from a B cell that is producing an
anti-cellular polypeptide antibody (WO 92/02551; U.S. Pat. No.
5,627,052; Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-48
(1996)); or other procedures as known in the art and based on the
disclosure herein.
[0138] The Fv region may further comprise one or all of the
framework regions that comprise the variable region of an
immunoglobulin. If the Fv region is derived from a non-human
antibody, and framework regions are included in the recombinant
antibody, the antibody may be further genetically engineered to
create a "humanized" antibody. Such a humanized antibody may
comprise a plurality of CDRs derived from an immunoglobulin of a
non-human mammalian species, at least one human variable framework
region. Useful strategies for designing humanized antibodies
include, by way of illustration and not limitation, identification
of human variable framework regions that are most homologous to the
non-human framework regions of the chimeric antibody (see, e.g.,
Jones et al., Nature 321:522-25 (1986); Riechmann et al., Nature
332:323-27 (1988)). Designing a humanized variable region may
include determining CDR loop conformations and structural
determinants of the non-human variable regions, for example, by
computer modeling, and then comparing the CDR loops and
determinants to known human CDR loop structures and determinants
(see, e.g., Padlan et al., FASEB 9:133-39 (1995); Chothia et al.,
Nature, 342:377-83 (1989)). Computer modeling may also be used to
compare human structural templates selected by sequence homology
with the non-human variable regions (see, e.g., Bajorath et al.,
Ther. Immunol. 2:95-103 (1995); EP-0578515-A3; Davies et al., Ann.
Rev. Biochem. 59:439-73, (1990)). If humanization of the non-human
CDRs results in a decrease in binding affinity, computer modeling
may aid in identifying specific amino acid residues that could be
changed by site-directed or other mutagenesis techniques to
partially, completely, or supra-optimally (i.e., increase to a
level greater than that of the non-humanized antibody) restore
affinity. Those having ordinary skill in the art are familiar with
these techniques and will readily appreciate numerous variations
and modifications to such design strategies.
[0139] A minimal recognition unit is an antibody fragment
comprising a single complementarity-determining region (CDR). Such
CDR peptides can be obtained by constructing polynucleotides that
encode the CDR of an antibody of interest according to methods
practiced by persons of ordinary skill in the art (see, for
example, Larrick et al., Methods: A Companion to Methods in
Enzymology 2:106, (1991); Courtenay-Luck, "Genetic Manipulation of
Monoclonal Antibodies," in Monoclonal Antibodies: Production,
Engineering and Clinical Application, Ritter et al. (eds.), page
166 (Cambridge University Press 1995); and Ward et al., "Genetic
Manipulation and Expression of Antibodies," in Monoclonal
Antibodies: Principles and Applications, Birch et al., (eds.), page
137 (Wiley-Liss, Inc. 1995)). Alternatively, such CDR peptides and
other antibody fragment can be synthesized using an automated
peptide synthesizer.
[0140] In other embodiments, a minimal recognition unit may be
identified from a peptide library. Such peptides may be identified
and isolated from combinatorial libraries (see, e.g., International
Patent Application Nos. PCT/US91/08694 and PCT/US91/04666) and from
phage display peptide libraries (see, e.g., Scott et al., Science
249:386 (1990); Devlin et al., Science 249:404 (1990); Cwirla et
al., Science 276: 1696-99 (1997); U.S. Pat. Nos. 5,223,409;
5,733,731; 5,498,530; 5,432,018; 5,338,665; 1994; U.S. Pat. No.
5,922,545; International Application Publication Nos. WO 96/40987
and WO 98/15833). In phage display peptide libraries, random
peptide sequences are fused to a phage coat protein such that the
peptides are displayed on the external surface of a filamentous
phage particle.
[0141] A peptide that is a minimal recognition unit or a CDR (i.e.,
any one or more of three CDRs present in a heavy chain variable
region and/or one or more of three CDRs present in a light chain
variable region) may be identified by computer modeling techniques,
which can be used for comparing and predicting a peptide sequence
that will specifically bind the senescent cell-associated antigen
of interest (see, e.g., Bradley et al., Science 309:1868 (2005);
Schueler-Furman et al., Science 310:638 (2005)). Such
computer-assisted predictive modeling techniques may also be useful
for altering the binding affinity of an antibody. Amino acid
substitutions may be readily accomplished using any one of a number
of mutagenesis techniques described herein and used routinely in
the art for making polynucleotide and polypeptide variants.
[0142] According to certain embodiments, non-human, human, or
humanized heavy chain and light chain variable regions of any of
the immunoglobulin molecules described herein may be constructed as
scFv polypeptide fragments (single chain antibodies). See, e.g.,
Bird et al., Science 242:423-426 (1988); Huston et al., Proc. Natl.
Acad. Sci. USA 85:5879-83 (1988)). Multi-functional scFv fusion
proteins may be generated by linking a polynucleotide sequence
encoding an scFv polypeptide in-frame with at least one
polynucleotide sequence encoding any of a variety of known effector
proteins. These methods are known in the art, and are disclosed,
for example, in EP-B1-0318554, U.S. Pat. Nos. 5,132,405, 5,091,513,
and 5,476,786. By way of example, effector proteins may include
immunoglobulin constant region sequences. See, e.g., Hollenbaugh et
al., J. Immunol. Methods 188:1-7 (1995). Other examples of effector
proteins are enzymes. As a non-limiting example, such an enzyme may
provide a biological activity for therapeutic purposes (see, e.g.,
Siemers et al., Bioconjug. Chem. 8:510-19 (1997)), or may provide a
detectable activity, such as horseradish peroxidase-catalyzed
conversion of any of a number of well-known substrates into a
detectable product, for diagnostic uses.
[0143] Antibodies may also be identified and isolated from human
immunoglobulin phage libraries, from rabbit immunoglobulin phage
libraries, from mouse immunoglobulin phage libraries, and/or from
chicken immunoglobulin phage libraries (see, e.g., Winter et al.,
Annu. Rev. Immunol. 12:433-55 (1994); Burton et al., Adv. Immunol.
57:191-280 (1994); U.S. Pat. No. 5,223,409; Huse et al., Science
246:1275-81 (1989); Schlebusch et al., Hybridoma 16:47-52 (1997)
and references cited therein; Rader et al., J. Biol. Chem.
275:13668-76 (2000); Popkov et al., J. Mol. Biol. 325:325-35
(2003); Andris-Widhopf et al., J. Immunol. Methods 242:159-31
(2000)). Antibodies isolated from non-human species or non-human
immunoglobulin libraries may be genetically engineered according to
methods described herein and known in the art to humanize the
antibody or fragment thereof. Immunoglobulin variable region gene
combinatorial libraries may be created in phage vectors that can be
screened to select immunoglobulin fragments (Fab, Fv, scFv, or
multimers thereof) that bind specifically to the senescent cell
associated antigen of interest (see, e.g., U.S. Pat. No. 5,223,409;
Huse et al., Science 246:1275-81 (1989); Sastry et al., Proc. Natl.
Acad. Sci. USA 86:5728-32 (1989); Alting-Mees et al., Strategies in
Molecular Biology 3:1-9 (1990); Kang et al., Proc. Natl. Acad. Sci.
USA 88:4363-66 (1991); Hoogenboom et al., J. Molec. Biol.
227:381-388 (1992); Schlebusch et al., Hybridoma 16:47-52 (1997)
and references cited therein; U.S. Pat. No. 6,703,015).
[0144] In certain other embodiments, antibodies are multimeric
antibody fragments. Useful methodologies are described generally,
for example in Hayden et al., Curr Opin. Immunol. 9:201-12 (1997)
and Coloma et al., Nat. Biotechnol. 15:159-63 (1997). For example,
multimeric antibody fragments may be created by phage techniques to
form miniantibodies (U.S. Pat. No. 5,910,573) or diabodies
(Holliger et al., Cancer Immunol. Immunother. 45:128-30 (1997)).
Multimeric fragments may be generated that are multimers of a viral
coat protein-specific Fv. Multimeric antibodies include bispecific
and bifunctional antibodies comprising a first Fv specific for an
antigen (e.g., E-selectin) associated with a second Fv having a
different antigen specificity (see, e.g., Drakeman et al., Expert
Opin. Investig. Drugs 6:1169-78 (1997); Koelemij et al., J.
Immunother. 22:514-24 (1999); Marvin et al., Acta Pharmacol. Sin.
26:649-58 (2005); Das et al., Methods Mol. Med. 109:329-46 (2005)).
In an exemplary embodiment, the recombinant antibody comprises at
least two Fv regions (bivalent), and in other embodiments may
comprise 3 or more Fv regions (i.e., multivalent). In certain
embodiments, the bivalent and multivalent Fv regions each
specifically bind to different senescent cell associated antigens;
in other embodiments, the bivalent and multivalent regions each
bind to different epitopes of the same senescent cell associated
antigen. By way of non-limiting example, a bivalent recombinant
antibody comprises an Fv region specific for human or mouse
p16INK4a and a second Fv region that is specific for a different
SCAAg (e.g., a SCAAg listed in Table 1 or a SCAAg that is encoded
by a nucleotide sequence selected from Table 2 or Table 3).
[0145] Immunoglobulin framework and constant region sequences are
available in the art, for example, in Kabat et al. (in Sequences of
Proteins of Immunological Interest, 4th ed., (U.S. Dept. of Health
and Human Services, U.S. Government Printing Office, 1991); see
also Kabat databases available on the Internet). In a particular
embodiment, the recombinant antibody comprises an Fc (constant
region) derived from a human immunoglobulin. In a more specific
embodiment, the Fc regions is derived from an immunoglobulin class,
such as IgG, that mediates effector functions that facilitate
clearance of a senescence cell from a tissue of a subject immunized
with an immunogenic composition described herein,
[0146] Antibodies that bind to specific cell-surface antigens on
target cells (e.g., a senescent cell) can induce cytotoxicity via
effector functions of antibody-dependent cellular cytotoxicity
(ADCC), antibody-dependent cell-mediated phagocytosis, and
complement-dependent cytotoxicity (CDC) through the Fc region of
the antibody, and apoptosis of target cells directly (see, e.g.,
Shan et al., 2000, Cancer Immunol. Immunother. 48:673-683; Carter
et al., 2001, Nat. Rev. Cancer 1:118-129; Glennie et al., 2003,
Drug Discov. Today 8:503-510; Smith et al., 2003, Oncogene
22:7359-7368; Weiner and Carter, 2005, Nat. Biotechnol. 23:556-7).
The cell mediated reaction where non-specific cytotoxic cells that
express Fc.gamma. receptors recognize bound antibody on a target
cell and subsequently causes lysis of the target cell is known as
antibody dependent cell mediated cytotoxicity (ADCC) (see, e.g.,
Raghavan et al., 1996, Annu. Rev. Cell. Dev. Biol. 12:181-220).
Another important Fc ligand is the complement protein Clq, the
binding of which mediates complement dependent cytotoxicity (see,
e.g., Ward et al, 1995, Ther. Immunol. 2:77-94). Binding of C1q to
at least two IgGs is sufficient to activate the classical
complement cascade, causing osmotic lysis of target cells. Animal
models and clinical trials suggest an important role for Fc
receptors and ADCC in clinical efficacy of antibody therapies (see,
e.g., Clynes et al., 2000, Nat. Med. 6:443-446; de Haij et al.,
2010, Cancer Res. 70:3209-3217; Weng and Levy, 2003, J. Clin.
Oncol. 21:3940-3947). In certain embodiments, antibody therapies
specific for a senescent cell associated antigen may be modified to
enhance ADCC activity.
[0147] For IgG antibodies, ADCC and ADCP require the engagement of
the Fc region of an antibody that is bound to the surface of a
target cell with Fc.gamma. receptors (Fc.gamma.Rs) (see, e.g.,
Cohen-Solal et al., 2004, Immunol. Lett. 92:199-205). In humans,
Fc.gamma.Rs comprise Fc.gamma.RI (CD64); Fc.gamma.RII (CD32),
including Fc.gamma.RIIa, Fc.gamma.RIIb, and Fc.gamma.RIIc isoforms;
and Fc.gamma.RIII (CD16), including Fc.gamma.RIIIa and
Fc.gamma.RIIIb isoforms (see, e.g., Jefferis et al., 2002, Immunol.
Lett. 82:57-65; Raghavan et al., 1996, Annu. Rev. Cell Dev. Biol.
12:181-220). Fc.gamma.Rs are expressed on a variety of immune
cells. Binding of Fc/Fc.gamma.R complex recruits these cells to
sites of bound antigen, resulting in signaling and subsequent
immune responses such as release of inflammation mediators,
activation of B cells, endocytosis, phagocytosis, and cytoxicity.
Fc.gamma.Rs have varying affinity for the same Fc region
(Fc.gamma.RI high, Fc.gamma.RII and Fc.gamma.RIII low). While
Fc.gamma.RI, Fc.gamma.RIIa/c, and Fc.gamma.RIII are activating
receptors characterized by an intracellular immunoreceptor
tyrosine-based activation motif (ITAM), Fc.gamma.RIIb has an
intracellular immunoreceptor tyrosine-based inhibition motif (ITIM)
and is accordingly an inhibitor receptor.
[0148] IgG molecules comprise an N-linked oligosaccharide
covalently linked at a conserved N297 (EU numbering system, Kabat
et al., supra) residue of each of the CH2 domains of the Fc region.
The oligosaccharides found in the Fc region of serum IgGs are
mostly biantennary glycans of the complex type. Variations of IgG
glycosylation patterns include attachment of terminal sialic acid,
a third GlcNAc arm (bisecting GlcNAc), a terminal galactosylation,
and .alpha.-1, 6-linked core fucosylation. Oligosaccharides may
contain zero (G0), one (G1) or two (G2) galactoses. The precise
pattern of glycosylation depends on the structural properties of
IgG subcomponents, in particular, the CH2 and CH3 domains (see,
e.g., Lund et al., 2000, Eur. J. Biochem. 267:7246-7257). The cell
lines used for recombinant monoclonal antibody synthesis may also
influence oligosaccharide chain synthesis. The oligosaccharide
moiety of glycoproteins is initially synthesized by the cell from
lipid-linked oligosaccharides to form
Glc.sub.3Man.sub.9G1cNAc.sub.2-pyrophosphoryl-dolichol, which is
transferred to the protein in the endoplasmic reticulum. The
oligosaccharide portion is then sequentially processed. First, all
three glucose resides are removed by glucosidases I and II to yield
Man.sub.9G1cNAc.sub.2-protein. Further removal of a number of
mannose residues may occur. Initially, four .alpha.1,2-linked
mannoses are removed to yield a Man.sub.5G1cNAc.sub.2-protein,
which is then elongated by the addition of a N-acetylglucosamine
(GlcNAc) residue, producing GlcNAcMan.sub.5GlcNAc.sub.2-protein.
Mannosidase II then removes the .alpha.1,3- and .alpha.1,6-linked
mannoses. Then, other sugars, GlcNAc, galactose, and sialic acid,
are added sequentially to yield the complex structures often found
on glycoproteins.
[0149] Methods of enhancing Fc receptor binding include Fc amino
acid modification and modification of Fc carbohydrate structures.
For immunoglobulins, it has been demonstrated that the attachment
of an N-linked oligosaccharide to Asn-297 of the CH2 domain is
critical for ADCC activity. Removal of the N-linked oligosaccharide
through mutation of the N-linked consensus site or by enzymatic
means results in little or no ADCC activity. Removal of the core
.alpha.-1,6-fucose moiety from IgG1 Fc oligosaccharides has been
demonstrated to improve Fc.gamma.RIII binding and ADCC activity
(see, e.g., Carter, 2001, Nat. Rev. Cancer 1:118-129; Kanda et al.,
Glycobiology, 2006, 17:104-118; Shields et al., 2002, J. Biol.
Chem. 277:26733-26740; Shinkawa et al., 2003, J Biol. Chem., 2003,
278:3466-3473; Niwa et al., 2004, Cancer Res. 64:2127-2133). The
level of another glycoform, bisected N-linked carbohydrate, has
also been suggested to increase ADCC (see, e.g., Umana et al, 1999,
Nat. Biotechnol. 17:176-180; Hodoniczky et al., 2005, Biotechnol.
Prog. 21:1644-52)
[0150] Compositions and methods for producing antibody-based
therapies with modified glycosylation pattern of the Fc region are
known in the art. For example, inhibition or disruption of
glycoprotein processing may be used to modify Fc glycosylation to
enhance ADCC (see, e.g., Rothman et al., 1989, Mol. Immunol.
26:1113-23). Antibodies produced from castanospermine-treated
hybridomas also exhibited enhanced ADCC by NK cells (see, e.g.,
Kaushal and Elbein, 1995, Methods Enzymol. 230:316-329,
incorporated herein in its entirety). U.S. Pat. No. 8,071,336,
incorporated herein in its entirety, describes methods of producing
antibodies comprising oligomannose-type-N-glycans with enhanced
ADCC and higher binding affinity for Fc.gamma.RIIIA by culturing
hybridomas in the presence of kifunesine. Antibody producing cells
may be genetically modified to reduce/inhibit expression of enzymes
involved in glycoprotein processing. WO2009/114641, incorporated
herein in its entirety, describes antibody producing cells lacking
GlcNAc transferase I, yielding antibodies with enhanced ADCC.
Antibodies with lower fucosylated oligosaccharide and enhanced ADCC
have been produced using hybridomas expressing lower
.alpha.-1,6-fucosyltransferase (see, e.g., Shinkawa et al., 2003,
J. Biol. Chem. 278:3466-3473; European Patent Applic. Pub. No.
1176195, each of which is incorporated herein by reference in its
entirety). U.S. Pat. No. 7,931,895, incorporated herein in its
entirety, describes antibodies with bi-antennary glycan structures
with short chains, low degree of sialylation, and non-intercalated
terminal mannoses and/or terminal GlcNAcs that have enhanced ADCC
activity. U.S. Patent Publication 2011/0053223, incorporated herein
in its entirety, describes methods for making antibodies with Man5
glycans.
[0151] A variety of Fc sequence variants with optimized binding
affinity for Fc.gamma.Rs and/or enhanced ADCC have been described
and are known in the art. By way of example, Fc S239D/I332E double
mutants have been shown to have enhanced effector function (see,
e.g., Lazar et al., 2006, Proc. Natl. Acad. Sci. 103:4005-4010,
incorporated herein in its entirety). U.S. Patent Publication
2010/0297103, incorporated herein in its entirety, describes
constant region positions for cysteine substitutions for enhancing
ADCC. Lazar et al. described IgG1 Fc mutations of S298A, E333A, and
K334A with optimized Fc.gamma.R affinity and specificity (see,
e.g., Shields et al., J. Biol. Chem. 276:6591-6604 (2001),
incorporated herein in its entirety). U.S. Patent Publication
2006/0039904, incorporated herein by reference in its entirety,
describes an IgG1 Fc region high effector function amino acid
residue 332E, as well as a variety of other Fc residue
substitutions for enhancing ADCC. U.S. Pat. No. 8,192,737,
incorporated herein in its entirety, describes IgG Fc variants at
position 396 with increased ADCC activity.
[0152] Also provided herein are methods of manufacture for
producing an antibody, or antigen-binding fragment thereof, that
specifically binds to a senescent cell associated antigen of
interest. For example a process (or method) for manufacturing an
antibody may comprise determining the nucleotide sequence that
encodes the antibody by using standard molecular biology
techniques, including primer design, hybridization, nucleic acid
isolation, cloning, and amplification, and sequencing. A
polynucleotide comprising a nucleotide sequence encoding the
antibody, or antigen-binding fragment thereof, may be incorporated
into a recombinant expression construct (i.e., vector) according to
well-known methods and principles known in the molecular biology
art and described herein for preparing a recombinant expression
vector.
[0153] The nucleic acid molecules encoding the antibody or antigen
binding fragment, as described herein, may be propagated and
expressed according to any of a variety of routinely practiced
procedures for nucleic acid excision, ligation, transformation, and
transfection. Thus, in certain embodiments expression of the
antibody or antigen binding fragment may be preferred in a
prokaryotic host cell, such as Escherichia coli (see, e.g.,
Pluckthun et al., Methods Enzymol. 178:497-515 (1989)). In certain
other embodiments, the antibody may be expressed in a eukaryotic
host cell, including animal cells (including mammalian cells);
yeast (e.g., Saccharomyces cerevisiae, Schizosaccharomyces pombe,
and Pichia pastoris); or plant cells. Examples of suitable animal
cells include, but are not limited to, myeloma, HEK293, COS, or CHO
cells. Examples of plant cells include tobacco, corn, soybean, and
rice cells. By methods known to those having ordinary skill in the
art and based on the present disclosure, a nucleic acid vector may
be designed for expressing foreign sequences in a particular host
system, and then polynucleotide sequences encoding the cellular
polypeptide may be inserted. The regulatory elements will vary as
appropriate for the particular host.
Immune Response
[0154] An immune response that results in clearance (i.e., removal,
elimination, destruction) of senescent cells may include a humoral
or cellular immune response or both a humoral and cellular immune
response. A humoral immune response has been generally described as
a response in which antibodies (i.e., immunoglobulins) specific for
antigens are produced by differentiated B lymphocytes. The Fc
portion of the immunoglobulin mediates certain effector functions
including activation of the classical complement cascade;
interaction with effector cells; and compartmentalization of
immunoglobulins. Destruction of senescent cells may therefore
comprise antibody dependent cell-mediated cytotoxicity (ADCC) or
complement fixation and associated complement dependent
cytotoxicity (CDC).
[0155] Typically, ADCC involves activation of NK cells by
antibodies. An NK cell expresses CD16 which is an Fc receptor. This
receptor recognizes, and binds to, the Fc portion of an antibody,
such as an IgG, which has bound to the surface of a target cell.
The most common Fc receptor on the surface of an NK cell is called
CD16 or Fc.gamma.RIII. Once the Fc receptor binds to the Fc region
of IgG, the NK cell releases cytokines such as IFN-.gamma., and
cytotoxic granules containing perforin and granzymes that enter the
target cell and promote cell death by triggering apoptosis. This is
similar to, but independent of, responses by cytotoxic (CTLs).
[0156] Cell mediated responses involve various types of T
lymphocytes that eliminate antigens, and cells expressing the
antigens, by a variety of mechanisms. For example, CD4+ helper T
cells that are capable of recognizing specific antigens may release
soluble mediators such as cytokines to recruit additional cells of
the immune system to participate in an immune response. CD8+
cytotoxic T cells are also capable of recognizing specific antigens
and may bind to and destroy or damage an antigen-bearing cell or
particle. Cell mediated immune responses also include a cytotoxic T
lymphocyte (CTL) response and can be important for elimination of
senescent cells.
[0157] As described herein, the immune response evoked by any one
of the immunogens described herein may include a specific T cell
response, a specific B cell response (i.e., production of specific
antibodies), or both a specific T cell immune response and B cell
immune response in the immunized subject. As used herein, the
immune response is said to be "specific for," "specific to," or
"specifically against" a senescent cell (i.e., specific for one or
more senescence cell associated antigens) when the immune response
is detectable at a level greater than the level against a
non-senescent cell. Also as described herein, the immune response
evoked by any one of the immunogens described herein may include
production of specific antibodies in the immunized subject.
Interaction or binding of an antibody to a specific antigen
generally involves electrostatic interactions, hydrogen bonding,
Van der Waals interactions, and hydrophobic interactions. Any one
of these or any combination thereof can play a role in the binding
between an antibody and its antigen. As used herein, an antibody is
said to be "specific for" or to "specifically bind" its cognate
senescent cell associate antigen (or fragment thereof) or a
senescent cell that expresses the antigen when the antibody reacts
at a detectable level with the respective immunogen, preferably
with an affinity constant, K.sub.a, of greater than or equal to
about 10.sup.4 M.sup.-1, or greater than or equal to about 10.sup.5
M.sup.-1, greater than or equal to about 10.sup.6 M.sup.-1, greater
than or equal to about 10.sup.7 M.sup.-1, or greater than or equal
to 10.sup.8 M.sup.-1. The ability of the antibody to bind to its
cognate ligand may also be expressed as a dissociation constant
K.sub.D, and an antibody is said to specifically bind its cognate
ligand if it binds with a K.sub.D of less than or equal to
10.sup.-4 M, less than or equal to about 10.sup.-5 M, less than or
equal to about 10.sup.-6 M, less than or equal to 10.sup.-7 M, or
less than or equal to 10.sup.-8 M.
[0158] Affinities of an antibody for a senescent cell associate
antigen described herein, can be readily determined using
conventional techniques, for example, those described by Scatchard
et al. (Ann. N.Y. Acad. Sci. USA 51:660 (1949)) and by surface
plasmon resonance (SPR; BIAcore.TM., Biosensor, Piscataway, N.J.).
For surface plasmon resonance, target molecules are immobilized on
a solid phase and exposed to ligands in a mobile phase running
along a flow cell. If ligand binding to the immobilized target
occurs, the local refractive index changes, leading to a change in
SPR angle, which can be monitored in real time by detecting changes
in the intensity of the reflected light. The rates of change of the
surface plasmon resonance signal can be analyzed to yield apparent
rate constants for the association and dissociation phases of the
binding reaction. The ratio of these values gives the apparent
equilibrium constant (affinity) (see, e.g., Wolff et al., Cancer
Res. 53:2560-65 (1993)).
[0159] The immunological status, including the presence, level, or
extent of a specific immune response, of a subject before, during,
and after active immunization with an immunogen described herein or
passive immunization with a recombinant antibody described herein
(or composition comprising the immunogen or antibody) may be
monitored. Induction and production of cytokines and other immune
modulators can be determined by methods and techniques routinely
practiced in the art for determining the level of immune modulators
and cytokines in a biological sample obtained from the subject
before, during, and/or after treatment. An immune response,
including activation and proliferation of immune cells and level of
specific antibodies, in a subject may be determined by any number
of well-known immunological techniques and methods with which those
having ordinary skill in the art will be readily familiar. Such
assays include, but need not be limited to, in vivo or in vitro
determination of the presence or level of one or more cytokines
(e.g., IFN-.gamma., IL-2, IL-4, and IL-12, and also IL-6,
IL-1.beta., leukemia inhibitory factor, TNF-.alpha., IL-10),
lymphokines, chemokines, hormones, growth factors, and the like.
Cellular activation state changes may also be determined, for
example, by determining altered functional or structural properties
of cells of the immune system, for example cell proliferation,
altered motility, induction of specialized activities such as
specific gene expression or cytolytic behavior; cellular
differentiation by cells of the immune system, including altered
surface antigen expression profiles or the onset of apoptosis
(programmed cell death). Procedures for performing these and
similar assays may be found, for example, in Lefkovits (Immunology
Methods Manual: The Comprehensive Sourcebook of Techniques, 1998).
See also Current Protocols in Immunology; Weir, Handbook of
Experimental Immunology, Blackwell Scientific, Boston, Mass.
(1986); Mishell and Shigii (eds.) Selected Methods in Cellular
Immunology, Freeman Publishing, San Francisco, Calif. (1979); Green
and Reed, Science 281:1309 (1998)) and references cited therein.
Immunoassays to determine the level of specific anti-senescent cell
antigen antibodies in a subject are also routinely practiced in the
art and described herein.
[0160] A "biological sample" may include a sample from a subject,
and may be a blood sample (from which serum or plasma may be
prepared), a biopsy specimen, one or more body fluids (e.g., lung
lavage, ascites, mucosal washings, synovial fluid), bone marrow,
lymph nodes, tissue explant, organ culture, or any other tissue or
cell preparation from the subject or a biological source. A
biological sample may further refer to a tissue or cell preparation
in which the morphological integrity or physical state has been
disrupted, for example, by dissection, dissociation,
solubilization, fractionation, homogenization, biochemical or
chemical extraction, pulverization, lyophilization, sonication, or
any other means for processing a sample derived from a subject or
biological source. In certain embodiments, the subject or
biological source may be a human or non-human animal, a primary
cell culture (e.g., immune cells), or culture adapted cell line,
including but not limited to, genetically engineered cell lines
that may contain chromosomally integrated or episomal recombinant
nucleic acid sequences, immortalized or immortalizable cell lines,
somatic cell hybrid cell lines, differentiated or differentiatable
cell lines, transformed cell lines, and the like.
[0161] Animal models are also available for determining the effect
of the immunogens described herein on age-sensitive traits. Such
traits include for example T cell subset distribution, cataract
formation, spontaneous activity, motor coordination, and cognitive
capacity, physical function, body composition (e.g., sarcopenia,
osteoporosis, loss of fat mass) and cardiac function. In animal
models, physical function can be assessed, for example, by
measuring running time, distance and work using a motorized
treadmill, and grip strength using a grip meter, according to
previously described protocols (e.g., Zhang et al., Animal Models
of Inflammatory Pain, Neuromethods, Volume 49, Oct. 20, 2010,
23-40; Balkaya et al., Behavioral Testing in Mouse Models of
Stroke, Neuromethods, Volume 47, 2010, 179-197). Lean mass, fat
mass and bone mineral density can be assessed, for example, by QNMR
and/or dual-energy X-ray absorptiometry measurements as previously
described (e.g., Reed et al., Physiology & Behavior, Vol. 91,
2007, 593-600; Halldorsdottir et al., Int. J. Body Compos. Res.,
2009; 7(4), 147-154; Brommage et al., AJP--Endo, Sep. 1, 2003, Vol.
285, No. 3 E454-E459). Methods and techniques are also available
for assessing many of these traits in human subjects.
[0162] Spontaneous activity of individual mice can be measured, for
example, over a 48-hour period using comprehensive laboratory
animal monitoring systems equipped with photocells (e.g., Columbus
Instruments) as previously described (e.g., Handschin et al., J.
Biol. Chem., Vol. 282, 41, 30014, Oct. 12, 2007; Pack et al.,
Physiol. Genomics (Sep. 19, 2006)). Motor coordination can be
analyzed, for example, by performing an accelerating rotarod test.
For measuring cognitive capacity, a modified Stone T-maze, which is
sensitive to age-related changes in learning and memory, can be
used. In animal models, illustrative age-sensitive traits and the
benefit of immunization with an immunogenic composition described
herein can be measured using tissues and organs of test and control
mice, including fiber diameter analysis on gastrocnemius muscle,
DNA damage analysis, analysis of renal and glomerulosclerosis,
analysis for retinal atrophy, proteotoxic stress analysis,
oxidative stress analysis, analysis of the hematopoietic system,
and the like.
Methods of Treating Diseases, Disorders, and Conditions by
Immunization
[0163] The immunogens, immunogenic compositions, and methods
described herein are useful for treating diseases, disorders, and
conditions that are treatable or preventable by clearing (i.e.,
removing, destroying, eliminating) senescent cells from a tissue in
the subject receiving the immunization. Protocols for administering
an immunogenic composition described herein may be readily
established by a person skilled in the art. Typically, after
administering an initial dose of an immunogenic composition
comprising an immunogen (also called the primary immunization) to a
subject, one, two or more doses of the immunogenic composition
(also called boosting or booster doses) are administered.
Administration of one or more booster immunizations may vary
according to, inter alia, the immunogen, the adjuvant (if any), the
co-stimulatory molecule (if any) and/or the particular animal
species. As described herein, the level of an immune response (B
cell, T cell, or both) after the first and each administration of
an immunogen may be determined by methods described herein and in
the art.
[0164] In certain embodiments, the immunogenic composition
comprises a recombinant antibody(ies) that specifically bind to a
SCAAg. The pharmacokinetics and clearance of the antibody can be
monitored by using any one or more of the immunoassays described
herein and routinely practiced in the art. The immunogenicity of
the recombinant antibody can also be monitored to determine whether
the recombinant antibody is evoking an undesired anti-recombinant
antibody immune response.
[0165] As understood by a person skilled in the medical art, the
terms, "treat" and "treatment," refer to medical management of a
disease, disorder, or condition of a subject (i.e., patient) (see,
e.g., Stedman's Medical Dictionary). In general, an appropriate
dose and treatment regimen provide the immunogen in an amount
sufficient to provide therapeutic and/or prophylactic benefit.
Therapeutic and/or prophylactic benefit includes, for example, an
improved clinical outcome, both therapeutic treatment and
prophylactic or preventative measures, wherein the object is to
prevent or slow or retard (lessen) an undesired physiological
change or disorder, or to prevent or slow or retard (lessen) the
expansion or severity of such disease or disorder. Beneficial or
desired clinical results from treating a subject include, but are
not limited to, abatement, lessening, or alleviation of symptoms
that result from or are associated the disease or disorder to be
treated; decreased occurrence of symptoms; improved quality of
life; longer disease-free status (i.e., decreasing the likelihood
or the propensity that a subject will present symptoms on the basis
of which a diagnosis of a disease is made); diminishment of extent
of disease; stabilized (i.e., not worsening) state of disease;
delay or slowing of disease progression; amelioration or palliation
of the disease state; and remission (whether partial or total),
whether detectable or undetectable; and/or overall survival.
"Treatment" can also mean prolonging survival when compared to
expected survival if a subject were not receiving treatment.
Subjects in need of treatment include those who already have the
disease or disorder as well as subjects prone to have or at risk of
developing the disease or disorder, and those in which the disease,
condition, or disorder is to be prevented (i.e., decreasing the
likelihood of occurrence or recurrence of the disease or disorder).
A subject may have a genetic predisposition for developing a
disease or disorder that would benefit from clearance of senescent
cells or may be of a certain age wherein immunization would provide
clinical benefit to delay development or reduce severity of a
disease, such as an age-related disease or disorder.
[0166] A subject (i.e., patient, individual) in need of the
therapeutic methods described herein is a human or non-human
animal. The subject in need of medical therapies with enhanced
efficacy may exhibit symptoms or sequelae of a disease described
herein or may be at risk of developing the disease. Non-human
animals that may be treated include mammals, for example, non-human
primates (e.g., monkey, chimpanzee, gorilla, and the like), rodents
(e.g., rats, mice, gerbils, hamsters, ferrets, rabbits),
lagomorphs, swine (e.g., pig, miniature pig), equine, canine,
feline, bovine, and other domestic, farm, and zoo animals.
[0167] An age-related disorder or disease or an age-sensitive trait
may be associated with a senescence-inducing stimulus. The efficacy
of immunization as described herein may be manifested by reducing
the number of symptoms of an age-related disorder or age-sensitive
trait associated with a senescence-inducing stimulus, decreasing
the severity of one or more symptoms, or delaying the progression
of an age-related disorder or age-sensitive trait associated with a
senescence-inducing stimulus. In other particular embodiments,
preventing an age-related disorder or age-sensitive trait
associated with a senescence-inducing stimulus refers to preventing
or delaying onset of an age-related disorder or age-sensitive trait
associated with a senescence-inducing stimulus, or reoccurrence of
one or more age-related disorder or age-sensitive trait associated
with a senescence-inducing stimulus. The effectiveness of an
immunogenic composition described herein to evoke a beneficial
immune response against senescent cells can readily be determined
by a person skilled in the medical and clinical arts. One or any
combination of diagnostic methods, including physical examination,
assessment and monitoring of clinical symptoms, and performance of
analytical tests and methods described herein, may be used for
monitoring the health status of the subject. The effects of
immunization can be analyzed using techniques known in the art,
such as comparing symptoms of patients suffering from or at risk of
a particular disease or disorder that have received the immunogenic
composition with those of patients without such immunization or
with placebo treatment.
[0168] In one embodiment, methods are provided for treating or
preventing diseases or disorders related to, associated with, or
caused by cellular senescence including age-related diseases and
disorders. Exemplary diseases or disorders that may be treated or
prevented by administering an immunogenic composition described
herein include, without limitation, cognitive diseases (e.g.,
Alzheimer's disease and other dementias); cardiovascular disease;
diabetes; motor function diseases and disorders (e.g., Parkinson's
disease); cancer occurrence, cancer metastasis, cardiovascular
disease, cerebrovascular disease, emphysema, osteoarthritis,
peripheral vascular disease, cardiac diastolic dysfunction, benign
prostatic hypertrophy, aortic aneurysm, and emphysema. Evoking an
immune response that comprises clearance of senescence cells by
employing the immunization methods described herein may also be
useful for treating or reducing the likelihood of cancer or cancer
metastasis (exemplary cancers include melanoma, prostate cancer,
testicular cancer, breast cancer, brain cancer, pancreatic cancer,
colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian
cancer, Kaposi's sarcoma, skin cancer (including squamous cell skin
cancer), renal cancer, head and neck cancers, throat cancer,
squamous carcinomas that form on the moist mucosal linings of the
nose, mouth, throat, etc.), bladder cancer, osteosarcoma (bone
cancer), cervical cancer, endometrial cancer, esophageal cancer,
liver cancer, and kidney cancer; those that occur in blood, bone
marrow, and lymph nodes and include generally, leukemias (myeloid
and lymphocytic), lymphomas (e.g., Hodgkin lymphoma), and melanoma
(including multiple myeloma). Leukemias include for example, acute
lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic
lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and
hairy cell leukemia).
[0169] The efficacy of the immunization methods may be determined
and monitored by assessing one or more age-sensitive traits. Such
traits include for example T cell subset distribution, cataract
formation, spontaneous activity, motor coordination, and cognitive
capacity, physical function, body composition (e.g., sarcopenia,
osteoporosis, loss of fat mass) and cardiac function. These
exemplary age-sensitive traits can be assessed using standard
techniques known and available in the art. In a related embodiment,
the lean mass, fat mass and bone mineral density are measured by
QNMR, dual-energy X-ray absorptiometry, MRI, PET, or a combination
thereof. In another related embodiment, the physical function is a
measure of (1) running time, distance, and work using a motorized
treadmill, (2) grip strength using a grip meter, or (3) any
combination measure thereof. In another embodiment, the
age-sensitive trait is a measure of a tissue or organ, wherein the
measure is of fiber diameter on gastrocnemius muscle, DNA damage,
renal and glomerulosclerosis, retinal atrophy, proteotoxic stress,
oxidative stress, or hematopoietic system.
[0170] In certain embodiments, the immunogenic compositions
described herein are administered to a subject who has a cancer or
who is at risk of developing cancer. The immunogens and recombinant
antibodies described herein that evoke an immune response that
results in clearance of senescent cells may be used in combination
with chemotherapy, radiotherapy, or both to provide clinical
benefit to the subject. Therapeutic benefit includes any one or
more of reducing the size of the tumor(s), inhibiting tumor
progression, inhibiting tumor growth, delaying tumor colonization,
and/or inhibiting, preventing, or delaying metastasis of a tumor.
Enhancing the effectiveness of the chemotherapy or radiotherapy may
include preventing, slowing, or decreasing development of
resistance of the cancer (i.e., tumor or tumors) to the
chemotherapy or radiotherapy, thereby allowing additional cycles of
therapy and/or decreasing the time interval between cycles of
therapy.
[0171] An age-related disease or disorder includes diabetes and can
be associated with cellular senescence. Therefore, clearance of
senescent cells from a subject by administering an immunogenic
composition described herein may provide therapeutic benefit.
Subjects suffering from type 2 diabetes can be identified using
standard diagnostic methods known in the art for type 2 diabetes.
Generally, diagnosis of type 2 diabetes is based on symptoms (e.g.,
increased thirst and frequent urination, increased hunger, weight
loss, fatigue, blurred vision, slow-healing sores or frequent
infections, and/or areas of darkened skin), medical history, and/or
physical examination of a patient. Subjects at risk of developing
type 2 diabetes include those having a family history of type 2
diabetes and those having other risk factors such as weight, fat
distribution, inactivity, race, age, prediabetes, and/or
gestational diabetes. Clinical benefit and improvement of a subject
who has diabetes may be evaluated by stability of glucose levels.
For example, an increase in the length of time between doses of
insulin or a decrease in the dose of insulin required to maintain
proper glucose levels in patients who receive an immunogenic
composition described herein indicates improved effectiveness of
the insulin. Other clinical parameters that may be monitored
include level of insulin tolerance, energy expenditure, body
composition, fat tissue, skeletal muscle, liver inflammation,
lipotoxicity (muscle and liver lipid by imaging in vivo and muscle,
liver, bone marrow, and pancreatic .beta.-cell lipid accumulation
and inflammation by histology).
[0172] Other age-related diseases or disorders that may be
associated with cellular senescence are neurological diseases such
as Alzheimer's disease, Parkinson's disease, mild cognitive
impairment (MCI), and Motor Neuron Dysfunction (MND). Therefore,
clearance of senescent cells from a subject who has or who is at
risk of developing such a neurological disease may benefit by
receiving an immunogenic composition described herein.
[0173] Subjects suffering from Alzheimer's disease can be
identified using standard diagnostic methods known in the art for
Alzheimer's disease. Generally, diagnosis of Alzheimer's disease is
based on symptoms (e.g., progressive decline in memory function,
gradual retreat from and frustration with normal activities,
apathy, agitation or irritability, aggression, anxiety, sleep
disturbance, dysphoria, aberrant motor behavior, disinhibition,
social withdrawal, decreased appetite, hallucinations, dementia),
medical history, neuropsychological tests, neurological and/or
physical examination of a patient. Cerebrospinal fluid may also be
for tested for various proteins that have been associated with
Alzheimer pathology, including tau, amyloid beta peptide, and
AD7C-NTP. Genetic testing is also available for early-onset
familial Alzheimer disease (eFAD), an autosomal-dominant genetic
disease. Clinical genetic testing is available for individuals with
AD symptoms or at-risk family members of patients with early-onset
disease. In the U.S., mutations for PS2, and APP may be tested in a
clinical or federally approved laboratory under the Clinical
Laboratory Improvement Amendments. A commercial test for PS1
mutations is also available (Elan Pharmaceuticals).
[0174] Subjects at risk of developing Alzheimer's disease include
those of advanced age, those with a family history of Alzheimer's
disease, those with genetic risk genes (e.g., ApoE4) or
deterministic gene mutations (e.g., APP, PS1, or PS2), and those
with history of head trauma or heart/vascular conditions (e.g.,
high blood pressure, heart disease, stroke, diabetes, high
cholesterol).
[0175] Subjects suffering from MCI can be identified using standard
diagnostic methods known in the art for MCI. Criteria for an MCI
diagnosis typically include: an individual's report of his or her
own memory problems; measurable, greater-than-normal memory
impairment detected with standard memory assessment tests; normal
general thinking and reasoning skills; and ability to perform
normal daily activities. Generally, diagnosis of MCI is based on
medical history, assessment of independent function and daily
activities, assessment of mental status, neurological examination,
evaluation of mood, laboratory tests including blood tests and
imaging of the brain's structure of a patient. Exemplary
assessments include Clinical Dementia Rating (CDR) scores (a CDR
rating of about 0.5 or about 0.5 to 1.0 is often considered
clinically relevant MCI) and simple memory test (paragraph recall)
to establish an objective memory deficit in combination of a
measure of general cognition (mini-mental state exam) to exclude a
broader cognitive decline beyond memory (see, Grundman et al., Arch
Neurol. 61: 59-66, 2004). In certain embodiments, subjects
suffering from MCI may also suffer from Parkinson's disease or have
one or more symptoms commonly associated with Parkinson's
disease.
[0176] Preventing Parkinson's disease as used herein refers to
preventing or delaying onset of Parkinson's disease or reoccurrence
of one or more symptoms. Symptoms of Parkinson's disease are known
in the art and include, but are not limited to, difficulty starting
or finishing voluntary movements, jerky, stiff movements, muscle
atrophy, shaking (tremors), and changes in heart rate, but normal
reflexes, bradykinesia, and postural instability.
[0177] Subjects suffering from Parkinson's disease can be
identified using standard diagnostic methods known in the art for
Parkinson's disease. Generally, diagnosis of Parkinson's disease is
based on symptoms, medical history, and neurological and/or
physical examination of a patient. Subjects at risk of developing
Parkinson's disease include those having a family history of
Parkinson's disease and those exposed to pesticides (e.g., rotenone
or paraquat), herbicides (e.g., agent orange), or heavy metals.
[0178] Subjects suffering from MND exhibit weakness, wasting, and
loss of control of muscles. Some diseases affect all muscles
(amyotrophic lateralsclerosis), and other diseases cause weakness
and loss of function in particular muscles. Subjects develop
wasting, uncontrollable twitching, spasticity (stiffness), and
movements become slow and effortful. Subjects suffering from MND
can be identified using standard diagnostic methods known in the
art for MND. Subject are given a physical exam and neurological
exam, which assesses motor and sensory skills, nerve function,
hearing and speech, vision, coordination and balance, mental
status, and changes in mood or behavior. To measure muscle involves
the following may be performed: electromyography; laboratory tests
to assess the presence of inflammation and/or infection and to
measure protein creatine kinase; magnetic resonance imaging; muscle
or nerve biopsies; and transcranial magnetic stimulation. Subjects
at risk of developing MND include those who have genetic mutations
associated with a particular MND. In adults, MNDs occur more
commonly in men than in women, with symptoms appearing after age
40.
[0179] Cardiovascular disease includes high blood pressure,
coronary heart disease, and heart disease, and many factors
contribute to development of cardiovascular disease. These factors
include aging, smoking, high cholesterol, and calcification of the
cardiovascular tissue (Heart Disease and Stroke Statistics--2012
Update: A Report from the American Heart Association. Circulation
(2012), 125:e5-e220 ("Heart Disease Statistics")). Subjects
suffering from cardiovascular disease can be identified using
standard diagnostic methods known in the art for cardiovascular
disease. Generally, diagnosis of atherosclerosis and other
cardiovascular disease is based on symptoms (e.g., chest pain or
pressure (angina), numbness or weakness in arms or legs, difficulty
speaking or slurred speech, drooping muscles in face, leg pain,
high blood pressure, kidney failure and/or erectile dysfunction),
medical history, and/or physical examination of a patient. Subjects
at risk of developing cardiovascular disease include those having a
family history of cardiovascular disease and those having other
risk factors such as high blood pressure, high cholesterol,
diabetes, obesity and/or smoking.
[0180] Cardiovascular disease include angina, arrhythmia,
atherosclerosis, cardiomyopathy, congestive heart failure, coronary
artery disease (CAD), carotid artery disease, endocarditis, heart
attack (coronary thrombosis, myocardial infarction [MI]), high
blood pressure/hypertension, hypercholesterolemia/hyperlipidemia,
mitral valve prolapsed, peripheral artery disease (PAD) and stroke.
The benefit to a subject who received an immunogenic composition
described herein may be monitored using any known and established
techniques, illustrative examples of which include detection or
signs of narrowed, enlarged or hardened arteries during a physical
exam. These include a weak or absent pulse below the narrowed area
of an artery, decreased blood pressure in an affected limb,
whooshing sounds (bruits) over the arteries heard using a
stethoscope, signs of a pulsating bulge (aneurysm) in the abdomen
or behind the knee and/or evidence of poor wound healing in an area
where blood flow is restricted. Additional diagnostic tests for
monitoring the effectiveness of an immunization method described
herein may be performed, such as blood tests to detect cholesterol
levels and blood sugar levels, Doppler ultrasound, ankle-brachial
index testing, electrocardiogram (ECG), stress tests, cardiac
catheterization and angiograms and/or other imaging tests.
[0181] Another age-related disease that may be treated by
immunizing a subject in need with any one of the immunogenic
compositions described herein is pulmonary fibrosis. Symptoms of
pulmonary fibrosis are known in the art and include shortness of
breath, particularly during exercise; dry, hacking cough; fast,
shallow breathing; gradual unintended weight loss; tiredness;
aching joints and muscles; and clubbing (widening and rounding of
the tips of the fingers or toes). Subjects suffering from pulmonary
fibrosis can be identified and monitored using standard diagnostic
methods known in the art for pulmonary fibrosis. Generally,
diagnosis of pulmonary fibrosis is based on one or more of the
following exams or tests: physical exam, patient's medical history,
patient's family's medical history, chest X-ray, lung function
tests, blood test, bronchoalveolar lavage, lung biopsy, CT scan,
and exercise testing.
[0182] Subjects at risk of developing pulmonary fibrosis include
those exposed to environmental or occupational pollutants, such as
asbestosis and silicosis; who smokes cigarettes; having some
typical connective tissue diseases such as rheumatoid arthritis,
SLE and scleroderma; having other diseases that involve connective
tissue, such as sarcoidosis and Wegener's granulomatosis; having
infections; taking certain medications (e.g., amiodarone,
bleomycin, busufan, methotrexate, and nitrofurantoin); those
subject to radiation therapy to the chest; and those whose family
member has pulmonary fibrosis.
[0183] The immunization protocol used in the methods described
herein will be designed dependent upon the disease or disorder to
be treated, age of the subject, and on other factors with which a
person skilled in the art may use to determine suitability of a
subject for the immunization. For example, if a human subject is to
be immunized to prevent or treat an age-related disease or
disorder, an initial (i.e., primary) immunization may be
administered after age 40, 45, 50, 55, 60, or older. Immunization
to induce an immune response against senescent cells may also be
initiated at an earlier age when the subject's health indicates
initiating immunization independent of age is indicated. For
example, a subject who is at risk of developing diabetes includes a
subject who is overweight. By way of another example, a subject who
has been diagnosed with a cancer and will receive chemotherapy,
radiation, or both may benefit from the immunization methods
described herein.
Pharmaceutically Suitable Immunogenic Compositions
[0184] Also provided herein are pharmaceutically suitable
immunogenic compositions comprising any one or more of the
immunogens described herein or a recombinant antibody described
herein for evoking an immune response specific for a senescent
cell. Immunogenic compositions may also be called herein
immunogenic preparations, which preparations may comprise at least
one immunogen and a pharmaceutically acceptable excipient. The
immunogenic composition may be a sterile aqueous or non-aqueous
solution, suspension or emulsion, which additionally comprises a
physiologically acceptable excipient (pharmaceutically acceptable
or suitable excipient or carrier) (i.e., a non-toxic material that
does not interfere with the activity of the active ingredient). The
excipients described herein are merely exemplary and are in no way
limiting. An effective amount or therapeutically effective amount
refers to an amount of the immunogen or antibody administered to a
subject, either as a single dose or as part of a series of doses,
which is effective to produce a desired therapeutic effect.
[0185] Subjects may generally be monitored for therapeutic
effectiveness using assays suitable for the condition being treated
or prevented, which assays will be familiar to those having
ordinary skill in the art and are described herein. The level of an
immunogen or recombinant antibody that is administered to a subject
may be monitored by determining the level of the immunogen or
recombinant antibody, respectively, in a biological fluid, for
example, in the blood, blood fraction (e.g., serum), and/or in the
urine, and/or other biological sample from the subject. Any method
practiced in the art to detect the immunogen or recombinant
antibody may be used to measure the level of immunogen or
recombinant antibody, respectively, during the course of a
immunization regimen.
[0186] The dose of an immunogen or recombinant antibody described
herein for evoking a specific immune response may depend upon the
subject's condition, that is, stage of the disease if present,
severity of symptoms caused by the disease, general health status,
as well as age, gender, and weight, and other factors apparent to a
person skilled in the medical art. Immunogenic compositions may be
administered in a manner appropriate to the disease or disorder to
be treated or prevented as determined by persons skilled in the
medical arts. An appropriate dose and a suitable duration and
frequency of administration will be determined by such factors as
the condition of the patient, the type and severity of the
patient's disease, the particular form of the active ingredient,
and the method of administration. Optimal doses of an immunogen or
recombinant antibody may generally be determined using experimental
models and/or clinical trials. The optimal dose may depend upon the
body mass, weight, or blood volume of the subject. The use of the
minimum dose that is sufficient to provide an effective immune
response is usually preferred. Design and execution of pre-clinical
and clinical studies for an agent (including when administered for
prophylactic benefit) described herein are well within the skill of
a person skilled in the relevant art. For example, an amount of an
immunogen or recombinant antibody may be administered at a dose
between 0.01 mg/kg and 1000 mg/kg (e.g., about 0.1 to 1 mg/kg,
about 1 to 10 mg/kg, about 10-50 mg/kg, about 50-100 mg/kg, about
100-500 mg/kg, or about 500-1000 mg/kg) body weight.
[0187] The immunogenic compositions may be administered to a
subject in need thereof by any one of several routes that
effectively deliver an effective amount of the immunogen or
recombinant antibody. Such administrative routes include, for
example, oral, topical, parenteral, enteral, rectal, intranasal,
buccal, sublingual, intramuscular, transdermal, vaginal, rectal, or
by intracranial injection, or any combination thereof Such
compositions may be in the form of a solid, liquid, or gas
(aerosol). The administrative route is also determined by the type
of immunogen or if the recombinant antibody is being administered.
Immunogenic compositions comprising a senescent cell associated
antigen, antigenic fragment, or fusion polypeptide may be
administered intramuscularly, transdermally, intranasally, for
example. Recombinant antibodies are typically administered by a
parenteral route, such as intravenously.
[0188] Pharmaceutical acceptable excipients are well known in the
pharmaceutical art and described, for example, in Rowe et al.,
Handbook of Pharmaceutical Excipients: A Comprehensive Guide to
Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The
Science and Practice of Pharmacy (Gennaro, 21.sup.st Ed. Mack Pub.
Co., Easton, Pa. (2005)). Exemplary pharmaceutically acceptable
excipients include sterile saline and phosphate buffered saline at
physiological pH. Preservatives, stabilizers, dyes, buffers, and
the like may be provided in the immunogenic composition. In
addition, antioxidants and suspending agents may also be used. In
general, the type of excipient is selected based on the mode of
administration, as well as the chemical composition of the active
ingredient(s). Alternatively, compositions described herein may be
formulated as a lyophilizate, or the immunogen or recombinant
antibody may be encapsulated within liposomes using technology
known in the art. Immunogenic compositions may be formulated for
any appropriate manner of administration described herein and in
the art.
[0189] A composition (e.g., for oral administration or delivery by
injection) may be in the form of a liquid. A liquid immunogenic
composition may include, for example, one or more of the following:
a sterile diluent such as water for injection, saline solution,
preferably physiological saline, Ringer's solution, isotonic sodium
chloride, fixed oils that may serve as the solvent or suspending
medium, polyethylene glycols, glycerin, propylene glycol or other
solvents; antibacterial agents; antioxidants; chelating agents;
buffers and agents for the adjustment of tonicity such as sodium
chloride or dextrose. A parenteral preparation can be enclosed in
ampoules, disposable syringes or multiple dose vials made of glass
or plastic. The use of physiological saline is preferred, and an
injectable pharmaceutical composition is preferably sterile.
[0190] For oral formulations, an immunogen or recombinant antibody
described herein can be used alone or in combination with
appropriate additives to make tablets, powders, granules or
capsules, and if desired, with diluents, buffering agents,
moistening agents, preservatives, coloring agents, and flavoring
agents. An immunogen or recombinant antibody included in the
compositions may be formulated for oral delivery with a buffering
agent, flavoring agent, e.g., in a liquid, solid or semi-solid
formulation and/or with an enteric coating.
[0191] A composition comprising any one of the immunogens or
recombinant antibodies described herein may be formulated for
sustained or slow release. Such compositions may generally be
prepared using well known technology and administered by, for
example, oral, rectal or subcutaneous implantation, or by
implantation at the desired target site. Sustained-release
formulations may contain the immunogen or recombinant antibody
dispersed in a carrier matrix and/or contained within a reservoir
surrounded by a rate controlling membrane. Excipients for use
within such formulations are biocompatible, and may also be
biodegradable; preferably the formulation provides a relatively
constant level of active component release. The amount of active
agent contained within a sustained release formulation depends upon
the site of implantation, the rate and expected duration of
release, and the nature of the condition to be treated or
prevented.
[0192] For immunogenic compositions comprising a nucleic acid
molecule, the nucleic acid molecule may be present within any of a
variety of delivery systems known to those of ordinary skill in the
art, including nucleic acid, and bacterial, viral and mammalian
expression systems such as, for example, recombinant expression
constructs as provided herein. Techniques for incorporating DNA
into such expression systems are well known to those of ordinary
skill in the art. The DNA may also be "naked," as described, for
example, in Ulmer et al., Science 259:1745-49, 1993 and reviewed by
Cohen, Science 259:1691-1692, 1993. The uptake of naked DNA may be
increased by coating the DNA onto biodegradable beads, which are
efficiently transported into the cells.
[0193] Nucleic acid molecules may be delivered into a cell
according to any one of several methods described in the art (see,
e.g., Akhtar et al., Trends Cell Bio. 2:139 (1992); Delivery
Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar,
1995, Maurer et al., Mol. Membr. Biol. 16:129-40 (1999); Hofland
and Huang, Handb. Exp. Pharmacol. 137:165-92 (1999); Lee et al.,
ACS Symp. Ser. 752:184-92 (2000); U.S. Pat. No. 6,395,713;
International Patent Application Publication No. WO 94/02595);
Selbo et al., Int. J. Cancer 87:853-59 (2000); Selbo et al., Tumour
Biol. 23:103-12 (2002); U.S. Patent Application Publication Nos.
2001/0007666, and 2003/077829). Such delivery methods known to
persons having skill in the art, include, but are not restricted
to, encapsulation in liposomes, by iontophoresis, or by
incorporation into other vehicles, such as biodegradable polymers;
hydrogels; cyclodextrins (see, e.g., Gonzalez et al., Bioconjug.
Chem. 10:1068-74 (1999); Wang et al., International Application
Publication Nos. WO 03/47518 and WO 03/46185);
poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (also
useful for delivery of peptides and polypeptides and other
substances) (see, e.g., U.S. Pat. No. 6,447,796; U.S. Patent
Application Publication No. 2002/130430); biodegradable
nanocapsules; and bioadhesive microspheres, or by proteinaceous
vectors (International Application Publication No. WO 00/53722). In
another embodiment, the nucleic acid molecules for use in evoking
an immune response as described herein can also be formulated or
complexed with polyethyleneimine and derivatives thereof, such as
polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine
(PEI-PEG-GAL) or
polyethyleneimine-polyethyleneglycol-tri-N-acetylgalactosamine
(PEI-PEG-triGAL) derivatives (see also, e.g., U.S. Patent
Application Publication No. 2003/0077829).
[0194] Kits with unit doses of an immunogen or recombinant antibody
described herein, usually in oral or injectable doses, are
provided. Such kits may include a container containing the unit
dose, an informational package insert describing the use and
attendant benefits of the immunogen or antibody in treating
pathological condition of interest, and optionally an appliance or
device for delivery of the composition.
EXAMPLES
Example 1
Effect of Murine P16Ink4A Polypeptide Immunization on Tumor Growth
and Metastasis
[0195] Most senescent cells express the tumor suppressor protein
p16INK4a on the cell surface, and expression is independent of cell
type and senescence inducer (see, e.g., Ohtani et al., J. Med.
Invest. 51:146-53 (2004); Campisi et al., Nat. Rev. Med. Cell Biol.
8:729-40 (2007)). To characterize an immune response specific for
p16INK4a, groups of mice are immunized with isolated murine
p16INK4a according to procedures practiced in the art, which
include an initial immunization followed by at least one booster
immunization with murine p16INK4a. The presence and titer of immune
sera containing anti-murine p16INK4a antibodies are monitored by
periodic bleeding of the animals, preparation of sera, and
performance of an immunoassay to detect specific anti-murine
p16KINK4a antibodies in the murine sera. Animals that develop an
anti-murine p16INK4a immune response are then exposed to
chemotherapy or radiation to induce p16INK4a-positive senescent
cells. The presence of senescent cells expressing p16INK4a is
determined.
[0196] Animals that have an anti-murine p16INK4a immune response
and control animals are then engrafted with a tumor cell line. Size
of tumor(s) and metastasis are monitored in the immunized animals
and compared with control animals. Additional control animal groups
include p16-3MR or INK-ATTAC animals in which senescent cells are
eliminated by gancyclovir and AP20187, respectively, and which may
be engrafted with the tumor cell line.
[0197] Transgenic p16-3MR mice were prepared as follows. The
promoter, p16.sup.Ink4a, which is transcriptionally active in
senescent cells but not in non-senescent cells (see, e.g., Wang et
al., J. Biol. Chem. 276:48655-61 (2001); Baker et al., Nature,
supra) was engineered into a nucleic acid construct. A fragment of
the p16.sup.Ink4a gene promoter was introduced upstream of a
nucleotide sequence encoding a trimodal reporter fusion protein.
The trimodal reporter protein is termed 3MR and consists of renilla
luciferase (rLUC), monomeric red fluorescent protein (mRFP) and a
truncated herpes simplex virus thymidine kinase (tTK) (see, e.g.,
Ray et al., Cancer Res. 64:1323-30 (2004)). Thus, the expression of
3MR is driven by the p16.sup.Ink4a promoter in senescent cells
only. The polypeptide sequences and the encoding polynucleotides
for each of the three proteins are known in the art and are
available in public databases, such as GenBank. The detectable
markers, rLUC and mRFP permit detection of senescent cells by
bioluminescence and fluorescence, respectively. The expression of
tTK permits selective killing of senescent cells by exposure to the
pro-drug ganciclovir (GCV), which is converted to a cytotoxic
moiety by tTK. Transgenic founder animals, which have a C57B16
background, were established and bred using known procedures for
introducing transgenes into animals (see, e.g., Baker et al.,
Nature, 479:232-36 (2011); Int'l Patent Application Publication No.
WO/2012/177927).
[0198] INK-ATTAC (p16.sup.Ink4a apoptosis through targeted
activation of caspase) transgenic mice have an FK506-binding
protein (FKBP)-caspase 8 (Casp8) fusion polypeptide under the
control of the p16.sup.Ink4a promoter (see, e.g., Baker et al.,
Nature, supra; Int'l Patent Application Publication No.
WO/2012/177927). In the presence of AP20187, a synthetic drug that
induces dimerization of a membrane bound myristoylated FKBP-Casp8
fusion protein, senescent cells specifically expressing the
FKBP-Casp8 fusion protein via the p16.sup.Ink4a promoter undergo
programmed cell death (apoptosis) (see, e.g., Baker, Nature, supra,
FIG. 1 therein).
[0199] Senescent cells secret molecules that can cause inflammation
(see, e.g., Freund et al., Trends Mol. Med. 16:238-46 (2010)),
which, if chronic, will fuel various pathologies, including cancer
(see, e.g., Davalos et al., Cancer Metastasis Rev. 29:273-83
(2010)), which is often referred to as senescence-associated
secretory phenotype (SASP) as described herein. For example, IL-6
(interleukin-6) and MMP-3 (matrix metalloproteinase-3) are two
prominent SASP components. Hence, in animals immunized with
p16INK4a, RNA expression levels of various biomarkers associated
with SASP are examined, including p16INK4a (p16), IL-6, and MMP-3.
The level of expressed SASP components may also be monitored. In
addition, the level of the mRFP reporter is measured.
Example 2
Effect of Human P16Ink4a Polypeptide Immunization On Tumor Growth
and Metastasis
[0200] Murine p16INK4a and human p16INK4a share approximately 74%
sequence identity. Groups of mice that are murine p16INK4a null
mice and that are carrying the human p16INK4a gene are immunized
with isolated human p16INK4a according to procedures practiced in
the art, which include an initial immunization followed by at least
one booster immunization with human p16INK4a. The human p16INK4a
gene that is introduced into the animals may be under the control
of the murine p16INK4a promoter. The presence and titer of immune
sera containing anti-human p16INK4a antibodies are monitored by
periodic bleeding of the animals, isolation of sera, and
performance of an immunoassay to detect specific anti-human
p16KINK4a antibodies in the sera. Animals that develop an
anti-human p16INK4a immune response are then exposed to
chemotherapy or radiation to induce p16INK4a-positive senescent
cells. The presence of senescent cells expressing p16INK4a is
determined. The presence and level of mRNA encoding SASP components
is determined, and the level of expressed SASP components may also
be monitored.
[0201] Animals that that have an anti-human p16INK4a immune
response and control animals are then engrafted with a tumor cell
line. Size of tumor(s) and metastasis are monitored in the
immunized animals and compared with control animals. Additional
control animal groups include p16-3MR or INK-ATTAC animals
engrafted with the tumor cell line in which senescent cells are
eliminated by gancyclovir and AP20187, respectively (see Example
1).
Example 3
Preparation of Antibodies that Specifically Bind to P161NK4A
Polypeptide
[0202] Polyclonal antisera from mice immunized with murine p16INK4a
as described in Example 1 and antisera from mice immunized with
human p16INK4a are isolated. Mice are bled and the sera are
separated from the blood cells. To obtain a greater volume of
antisera, rabbits (such as New Zealand White) are immunized with
isolated murine or human p16INK4a. The animals are bled to monitor
titers before the first immunization (pre-bleed control) and after
the first immunization and after each subsequent immunization.
Antisera are collected. The antibodies in the sera may be purified
by affinity chromatography methods according to methods and
techniques routinely practiced in the art.
Example 4
Senescent Cell Associated Antigens
[0203] Polynucleotides comprising a nucleotide sequence that is
important for establishing and/or maintaining senescence of a cell
were identified. The GenBank accession numbers for these nucleotide
sequences are provided in Table 2 (with product annotations) and in
Table 2A. Polynucleotides comprising the nucleotide sequences that
encode all or a portion of a senescent cell associated antigen that
is important for cellular senescence (see Tables 2, 2A, and 3). The
encoded polypeptides may be used as immunogens in the methods and
compositions described herein. Certain polynucleotide sequences
listed in Table 2A that encode a portion of a SCCAg are ESTs. The
polypeptide encoded by a polynucleotide comprising these sequences
was determined by genome coordinates of the EST using UCSC Human
Genome annotation database version 19 (see Internet at
genome.ucsc.edu/cgi-bin/hgGateway (UCSC hg v19)) to identify unique
transcripts in those coordinates. The transcripts were mapped to
entrez gene identifiers and symbols. The EST coordinates were
determined from the all_ests table in hg19. The code to map the
refseq Ids was extended by using the refGene table or the kgXref
table.
[0204] Examplary SCAAgs encoded by polynucleotides comprising the
nucleotide sequences provided in Table 2 include but are not
limited to ADAMTS7, APLP2, ATP6V0D2, BCHE, C11orf87, CD46, CYB5D2,
FBXL7, GPR137B, IFI27L1, IL15RA, LAMP2, MYO10, NEU1, NHSL2, NPAS2,
OR1F1, PEA15, RAB23, RARB, RNPC3, SELO, SELT, SEMASB, SERP1,
SERPINE1, SLC9A7, SNX3, TBC1D1, TBRG1, TCEANC, TFPI, TNFAIP1,
TUBG2, USP18, and ZNF419. Senescent cells in which expression of
the each of these polypeptides was suppressed decreased viability
of senescent cells. Methods for evoking an immune response specific
for a senescent cell in a subject, wherein the immune response
comprises clearance of the senescent cell by the immune system of
the subject, comprises evoking an immune response to one or more of
ADAMTS7, APLP2, ATP6V0D2, BCHE, C11orf87, CD46, CYB5D2, FBXL7,
GPR137B, IFI27L1, IL15RA, LAMP2, MYO10, NEU1, NHSL2, NPAS2, OR1F1,
PEA15, RAB23, RARB, RNPC3, SELO, SELT, SEMASB, SERP1, SERPINE1,
SLC9A7, SNX3, TBC1D1, TBRG1, TCEANC, TFPI, TNFAIP1, TUBG2, USP18,
and ZNF419. Certain polypeptides (e.g., CD46, LAMP2, NPAS2, TBRG1,
TFPI, and C11orf87, and ZNF419) are represented more than once in
the tables herein). Senescent cell associated antigens are also
provided in Table 1.
Tables: Senescent Cell-Associated Antigens and Polynucleotide
Sequences Encoding Senescent Cell-Associated Antigens
TABLE-US-00001 [0205] TABLE 1 SENESCENT CELL-ASSOCIATED ANTIGENS
Senescent Cell-Associated Antigens GI Reference Number Mutant
beta-actin (ACTB) protein 28336 Beta actin (ACTB) 15277503 drug
resistance-related protein LRP 1097308 major vault protein (MVP)
19913410 (see also GenBank Acc. No. NM_017458) thyroid hormone
binding protein 339647 precursor prolyl 4-hydroxylase beta subunit
20070125 precursor, beta polypeptide (P4HB) chain A, human protein
disulfide 159162689 isomerase (PDI) electron-transfer-flavoprotein,
beta 4503609 (see also GenBank polypeptide (ETFB) Acc. No.
NM_001985) ATP synthase, H+ transporting, 4757810 mitochondrial F
complex, alpha subunit precursor cathepsin B (CTSB) 4503139 (see
also GenBank Acc. No. NM_001908) Un-named product 1 35655 Un-named
product 2 158257194 Un-named product 3 158259937
TABLE-US-00002 TABLE 2 GenBank No. Encoded Polypeptide AA004279
C6orf89 hypothetical protein LOC221477 AA012883 RSU1 ras suppressor
protein 1 isoform 1 AA020826 CTSB cathepsin B preproprotein
AA022510 APLP2 amyloid beta (A4) precursor-like protein 2 AA029155
unknown AA034012 RORA RAR-related orphan receptor A isoform b
AA037766 TRNP1 TMF regulated nuclear protein AA043348 unknown
AA044835 unknown AA044921 GEMIN8 gem (nuclear organelle) associated
protein 8 AA045247 FREQ frequenin homolog isoform 1 AA045527 AGBL5
ATP/GTP binding protein-like 5 isoform 1 AA056548 PARP14 poly
(ADP-ribose) polymerase family, member 14 AA081349 IVD isovaleryl
Coenzyme A dehydrogenase isoform 1 AA083483 BEST1 bestrophin 1
isoform 1 AA088857 unknown AA088873 unknown AA099357 ABCA6
ATP-binding cassette, sub-family A, member 6 AA102600 BET3L BET3
like AA115933 TRIM35 tripartite motif-containing 35 isoform 2
AA121673 unknown AA128261 SHBG sex hormone-binding globulin isoform
1 AA130982 C20orf3 chromosome 20 open reading frame 3 AA131041
IFIT2 interferon-induced protein with AA133285 unknown AA133962
C16orf72 hypothetical protein LOC29035 AA133989 IFNAR1
interferon-alpha receptor 1 precursor AA148534 PAPPA
pregnancy-associated plasma protein A AA149644 JAM3 junctional
adhesion molecule 3 precursor AA149745 TRIM2 tripartite
motif-containing 2 isoform 1 AA150242 ARID5B AT rich interactive
domain 5B (MRF1-like) AA150460 unknown AA156605 unknown AA156721
ALCAM activated leukocyte cell adhesion molecule AA156723 VAT1L
vesicle amine transport protein 1 homolog (T. AA156754 unknown
AA156961 ASCC3 activating signal cointegrator 1 complex subunit
AA160474 unknown AA169752 YIPF5 Yip1 domain family, member 5
AA195009 TWSG1 twisted gastrulation precursor AA196034 unknown
AA196245 EXT2 exostosin 2 isoform 1 AA203365 PIGV
phosphatidylinositol glycan class V AA205660 unknown AA209239 ABHD6
abhydrolase domain containing 6 AA209487 CMBL
carboxymethylenebutenolidase AA215738 unknown AA228366 ITGAV
integrin alpha-V isoform 1 precursor AA243427 MDGA1 MAM domain
containing AA279958 GOPC golgi associated PDZ and coiled-coil motif
AA284248 ROR1 receptor tyrosine kinase-like orphan receptor 1
AA284829 ZNF79 zinc finger protein 79 AA329676 unknown AA372349
FAM171B KIAA1946 AA393484 PLCB1 phosphoinositide-specific
phospholipase C beta 1 AA398658 DYX1C1 dyslexia susceptibility 1
candidate 1 isoform a AA398740 SMYD3 SET and MYND domain containing
3 AA401703 TMEM231 transmembrane protein 231 isoform 3 AA404269
PRICKLE1 prickle homolog 1 AA418028 unknown AA418074 unknown
AA418816 MRAP2 melanocortin 2 receptor accessory protein 2 AA429615
ZNF419 zinc finger protein 419 isoform 1 AA432267 AK3 adenylate
kinase 3 AA459699 ANKRD55 ankyrin repeat domain 55 isoform 1
AA461080 PPARA peroxisome proliferative activated receptor,
AA476916 unknown AA481560 unknown AA482478 unknown AA482548 WDR26
WD repeat domain 26 isoform b AA496034 BAIAP2L1 BAI1-associated
protein 2-like 1 AA496213 C14orf28 hypothetical protein LOC122525
AA514384 PHPT1 phosphohistidine phosphatase 1 isoform 2 AA514634
VPS53 vacuolar protein sorting 53 isoform 1 AA521080 unknown
AA522514 SEL1L3 sel-1 suppressor of lin-12-like 3 AA523543 MFSD3
major facilitator superfamily domain containing AA523733 CCDC132
coiled-coil domain containing 132 isoform a AA523958 KIAA1468
hypothetical protein LOC57614 AA524669 unknown AA526844 MYLK myosin
light chain kinase isoform 1 AA532640 ZBTB47 zinc finger protein
651 AA532655 LOC100286793 AA534198 CHPF2 chondroitin polymerizing
factor 2 AA535917 unknown AA543030 ASPH aspartate beta-hydroxylase
isoform a AA545764 HBMSF1D5-REV Human Bone Marrow Stromal
Fibroblast AA551075 KCTD12 potassium channel tetramerisation domain
AA554833 MAP1B microtubule-associated protein 1B AA563621 HSPB6
heat shock protein, alpha-crystallin-related, AA565715 SPAG8 sperm
associated antigen 8 isoform 2 AA565852 unknown AA572675 AFF3
AF4/FMR2 family, member 3 isoform 2 AA573452 EDNRA endothelin
receptor type A isoform a precursor AA573523 EPB41L1 erythrocyte
membrane protein band 4.1-like 1 AA576961 PHLDA1 pleckstrin
homology-like domain, family A, AA582404 unknown AA583044 BMP2 bone
morphogenetic protein 2 preproprotein AA594609 unknown AA599017
DOCK1 dedicator of cytokinesis 1 AA602532 TPP1
tripeptidyl-peptidase I preproprotein AA603472 unknown AA609053
ENPP5 ectonucleotide pyrophosphatase/phosphodiesterase AA628051
STX12 syntaxin 12 AA628398 unknown AA629286 unknown AA631103
unknown AA631254 MAN1B1 alpha 1,2-mannosidase AA633992 C11orf87
hypothetical protein LOC399947 precursor (see also Table 3)
AA634220 NFASC neurofascin isoform 1 precursor AA639752 DNAJC3 DnaJ
(Hsp40) homolog, subfamily C, member 3 AA653300 ZKSCAN1 zinc finger
protein 36 AA654142 CERCAM cerebral endothelial cell adhesion
molecule 1 AA675892 unknown AA678047 MMAA RecName: Full = Putative
L-type amino acid transporter 1-like protein MMAA; AltName: Full =
hLAT1 3-transmembrane protein MMAA; Short = hLAT1 3TM MMAA;
AA678241 SCD stearoyl-CoA desaturase 1 AA683481 CYBASC3 cytochrome
b, ascorbate dependent 3 isoform 1 AA683501 SUMF1 sulfatase
modifying factor 1 isoform 1 AA683602 MIR548N AA699809 MBNL1
muscleblind-like 1 isoform a AA702143 unknown AA703280 SERPINE2
plasminogen activator inhibitor type 1, member 2 AA706658 unknown
AA707125 UQCC basic FGF-repressed Zic binding protein isoform
AA716107 SVEP1 polydom AA721252 ADAM23 ADAM metallopeptidase domain
23 preproprotein AA722799 DCBLD2 discoidin, CUB and LCCL domain
containing 2 AA724665 unknown AA732007 ATP6V1G1 vacuolar H+ ATPase
G1 AA736604 unknown AA747309 ZFP90 zinc finger protein 90 AA761181
TTTY14 AA767440 unknown AA768884 unknown AA778684 unknown AA805633
DCBLD2 discoidin, CUB and LCCL domain containing 2 AA806283 unknown
AA806349 unknown AA810263 unknown AA810788 unknown AA811138 IFNAR1
interferon-alpha receptor 1 precursor AA811509 unknown AA812232
TXNIP thioredoxin interacting protein AA814140 REEP5 receptor
accessory protein 5 AA815089 unknown AA827865 C17orf39 hypothetical
protein LOC79018 AA827878 MALAT1 AA831438 MXD4 MAD4 AA831769 ULBP2
UL16 binding protein 2 precursor AA832474 unknown AA833832 unknown
AA836340 unknown AA843132 LZTFL1 leucine zipper transcription
factor-like 1 AA847654 TCEAL3 transcription elongation factor A
(SII)-like 3 AA853175 SLC16A3 solute carrier family 16, member 3
AA861784 RUFY3 RUN and FYVE domain containing 3 isoform 1 AA872727
FDFT1 squalene synthase AA883074 NRBF2 nuclear receptor binding
factor 2 AA886870 ANKRD37 ankyrin repeat domain 37 AA889628 ZNF219
zinc finger protein 219 AA889952 COL4A3BP alpha 3 type IV collagen
binding protein isoform AA890010 SEC22B SEC22 vesicle trafficking
protein homolog B AA897514 CPD carboxypeptidase D precursor
AA902480 MDM2 mouse double minute 2 homolog isoform MDM2 AA904430
WDR69 WD repeat domain 69 AA907927 DTWD1 DTW domain containing 1
AA910945 PPARA peroxisome proliferative activated receptor,
AA913146 PKP4 plakophilin 4 isoform a AA916831 UBE2H
ubiquitin-conjugating enzyme E2H isoform 1 AA917672 ATP5L ATP
synthase, H+ transporting, mitochondrial F0 AA917899 unknown
AA927870 unknown AA928542 unknown AA933779 WIPI2 WD repeat domain,
phosphoinositide interacting 2 AA969194 SP110 SP110 nuclear body
protein isoform c AA971753 BBS12 Bardet-Biedl syndrome 12 AA988241
RAB3A RAB3A, member RAS oncogene family AA988323 VEPH1 ventricular
zone expressed PH domain homolog 1 AA993518 unknown AA995925 NFASC
neurofascin isoform 1 precursor AB000888 SKIV2L2 superkiller
viralicidic activity 2-like 2 AB002282 EDF1 endothelial
differentiation-related factor 1 AB002301 MAST4 microtubule
associated serine/threonine kinase AB002323 DYNC1H1 cytoplasmic
dynein 1 heavy chain 1 AB002347 UBR2 ubiquitin protein ligase E3
component n-recognin AB002354 PLEKHM1 pleckstrin homology domain
containing, family M AB002365 unknown AB002391 HERC2P2 AB004574
DNASE2 deoxyribonuclease II, lysosomal precursor AB005043 SOCS1
suppressor of cytokine signaling 1 AB006756 PCDH7 protocadherin 7
isoform c precursor AB006757 PCDH7 protocadherin 7 isoform c
precursor AB007457 P53TG1-C AB007458 P53TG1-D AB007875 KIAA0415
hypothetical protein LOC9907 AB007877 unknown AB007900 SIPA1L1
signal-induced proliferation-associated 1 like AB007923 unknown
AB009598 glucuronyltransferase I AB011161 unknown AB014511 ATP9A
ATPase, class II, type 9A AB014600 unknown AB015656 PDE5A
phosphodiesterase 5A isoform 1 AB017269 TMEFF2 transmembrane
protein with EGF-like and two AB017445 XRCC4 X-ray repair cross
complementing protein 4 AB017498 Lipoprotein Receptor Related
Protein 5 AB018283 unknown AB018322 TMCC1 transmembrane and
coiled-coil domain family 1 AB018580 AKR1C3 aldo-keto reductase
family 1, member C3 AB019691 AKAP9 A-kinase anchor protein 9
isoform 3 AB020335 unknown AB020635 AHCYL2 S-adenosylhomocysteine
hydrolase-like 2 isoform AB020645 GLS glutaminase precursor
AB020657 IVNS1ABP influenza virus NS1A binding protein AB020663
DMXL2 Dmx-like 2 AB020712 SEC31A SEC31 homolog A isoform 1 AB020717
SYNJ1 synaptojanin 1 isoform b AB022663 RNF14 ring finger protein
14 isoform 1 AB022918 alpha2,3-sialyltransferase ST3Gal VI AB023147
C22orf9 hypothetical protein LOC23313 isoform a AB023179 unknown
AB024518 IL33 interleukin 33 precursor AB024703 RNF11 ring finger
protein 11 AB029040 DOPEY1 dopey family member 1 AB029290 MACF1
microfilament and actin filament cross-linker AB030655 EFEMP2
EGF-containing fibulin-like extracellular matrix AB030710 unknown
AB032261 SCD stearoyl-CoA desaturase 1 AB032987 unknown AB032996
FAM40B hypothetical protein LOC57464 isoform a AB033007 ERGIC1
endoplasmic reticulum-golgi intermediate AB033010 PNKD
myofibrillogenesis regulator 1 isoform 1 AB033055 unknown AB033080
PIGB phosphatidylinositol glycan, class B AB033832 PDGFD platelet
derived growth factor D isoform 2 AB034747 LITAF
lipopolysaccharide-induced TNF-alpha factor
AB036063 p53R2 ribonucleotide reductase AB037738 KCTD16 potassium
channel tetramerisation domain AB037791 KIAA1370 hypothetical
protein LOC56204 AB037813 unknown AB037823 unknown AB037853
KIAA1432 connexin 43-interacting protein 150 isoform a AB037925
NFKBIZ nuclear factor of kappa light polypeptide gene AB039327 CASK
calcium/calmodulin-dependent serine protein AB039947 XB51
X11L-binding protein 51 AB046692 hAO aldeyde oxidase AB046809
unknown AB046842 PPP4R4 HEAT-like repeat-containing protein isoform
1 AB046844 GPR107 G protein-coupled receptor 107 isoform 1 AB047360
SNX 3A sorting nexin 3A AB049654 MRPL36 mitochondrial ribosomal
protein L36 precursor AB051486 EXOC4 SEC8 protein isoform a
AB053318 NBEAL1 neurobeachin-like 1 isoform 3 AB053319 NBEAL1
neurobeachin-like 1 isoform 3 AB056106 ABI3BP ABI gene family,
member 3 (NESH) binding protein AC004770 unknown AC004997 unknown
AC005339 unknown AC007182 unknown AD000092 unknown AF001602 PON2
paraoxonase 2 isoform 2 AF003934 GDF15 growth differentiation
factor 15 AF005774 CFLAR CASP8 and FADD-like apoptosis regulator
isoform AF006516 ABI1 abl-interactor 1 isoform a AF007162 CRYAB
crystallin, alpha B AF009616 CFLAR CASP8 and FADD-like apoptosis
regulator isoform AF010314 ENC1 ectodermal-neural cortex (with
BTB-like domain) AF010446 MHC class I related protein 1 isoform B
(MR1B) AF011466 LPAR2 lysophosphatidic acid receptor 2 AF014403
SKIV2L2 superkiller viralicidic activity 2-like 2 AF015186 SFRS2
splicing factor, arginine/serine-rich 2 AF017987 SFRP1 secreted
frizzled-related protein 1 precursor AF019214 HBP1 HMG-box
transcription factor 1 AF021834 TFPI tissue factor pathway
inhibitor isoform a AF026071 TNFRSF25 tumor necrosis factor
receptor superfamily, AF029674 CREB3 cAMP responsive element
binding protein 3 AF029750 tapasin (NGS-17) AF031469 MR1 major
histocompatibility complex, class AF033026 PAPSS1
3'-phosphoadenosine 5'-phosphosulfate synthase AF039217 INVS
inversin isoform b AF039690 SDCCAG8 serologically defined colon
cancer antigen 8 AF040704 TUSC4 tumor suppressor candidate 4
AF041459 CFLAR CASP8 and FADD-like apoptosis regulator isoform
AF043732 PDE5A phosphodiesterase 5A isoform 1 AF043977 CLCA2
chloride channel accessory 2 precursor AF045451 NAB1 NGFI-A binding
protein 1 AF047020 AMACR alpha-methylacyl-CoA racemase isoform 1
AF047338 SLC12A4 solute carrier family 12, member 4 isoform a
AF052059 SEL1L sel-1 suppressor of lin-12-like precursor AF052094
EPAS1 endothelial PAS domain protein 1 AF052151 FAM89B family with
sequence similarity 89, member B AF053453 TSPAN6 transmembrane 4
superfamily member 6 AF056322 SP100 nuclear antigen Sp100 isoform 1
AF060922 BNIP3L BCL2/adenovirus E1B 19 kD-interacting protein
AF061731 ACIN1 apoptotic chromatin condensation inducer 1 AF061735
ATP5H ATP synthase, H+ transporting, mitochondrial F0 AF062483 SNX3
sorting nexin 3 isoform a AF063591 CD200 CD200 antigen isoform b
AF064243 ITSN1 intersectin 1 isoform ITSN-1 AF064484 natural
resistance-associated macrophage protein 2 non-IRE form (NRAMP2)
AF064771 DGKA diacylglycerol kinase, alpha 80 kDa AF065214 PLA2G4C
phospholipase A2, group IVC isoform 1 precursor AF065385 P2RX6
purinergic receptor P2X6 isoform 1 AF065854 unknown AF067286 TAPBP
tapasin isoform 1 precursor AF070524 CNIH3 cornichon homolog 3
AF070569 C17orf91 hypothetical protein LOC84981 AF070571 unknown
AF070596 DNAH3 dynein, axonemal, heavy chain 3 AF072098 TPT1 tumor
protein, translationally-controlled 1 AF073890 CTSZ cathepsin Z
preproprotein AF078844 DDX42 DEAD box polypeptide 42 protein
AF082283 BCL10 B-cell CLL/lymphoma 10 AF083068 PARP3 poly
(ADP-ribose) polymerase family, member 3 AF086256 unknown AF086333
MOSPD1 motile sperm domain containing 1 AF087847 GABA-A
receptor-associated protein like 1 (GABARAPL1) AF090891 TAX1BP1
Tax1 (human T-cell leukemia virus type I) AF092128 ITM2B integral
membrane protein 2B AF092137 MIR548N AF094754 GLRB glycine
receptor, beta isoform A precursor AF095727 MPZL1 myelin protein
zero-like 1 isoform a AF095771 BBS9 parathyroid hormone-responsive
B1 isoform 2 AF096296 thymic stroma chemokine-1 precursor AF096304
TM7SF2 transmembrane 7 superfamily member 2 AF097493 GLS
glutaminase precursor AF098951 ABCG2 ATP-binding cassette,
sub-family G, member 2 AF101051 senescence-associated epithelial
membrane protein (SEMP1) AF105974 HBA1 alpha 1 globin AF106069
deubiquitinating enzyme (UNPH4) AF109681 integrin alpha-11 subunit
precursor (ITGA11) AF112216 CMPK1 UMP-CMP kinase 1 isoform a
AF113211 unknown AF114488 intersectin short isoform (ITSN) AF115512
DNAJB9 DnaJ (Hsp40) homolog, subfamily B, member 9 AF116574
astrotactin2 (ASTN2) AF116616 SCD stearoyl-CoA desaturase 1
AF116827 COG6 RecName: Full = Conserved oligomeric Golgi complex
subunit 6; Short = COG complex subunit 6; AltName: Full = Component
of oligomeric Golgi complex 6; AF118274 SLC45A1 DNB5 AF118887 VAV3
vav 3 guanine nucleotide exchange factor isoform AF119835 KITLG KIT
ligand isoform b precursor AF119863 MEG3 Homo sapiens MEG3 mRNA,
partial sequence, imprinted gene. AF121856 SNX6 sorting nexin 6
isoform b AF123758 CLN8 ceroid-lipofuscinosis, neuronal 8 AF123759
CLN8 ceroid-lipofuscinosis, neuronal 8 AF126782 DHRS7
dehydrogenase/reductase (SDR family) member 7 AF127481 AKAP13
A-kinase anchor protein 13 isoform 1 AF130089 C14orf45 hypothetical
protein LOC80127 AF130090 NRIP1 nuclear receptor interacting
protein 1 AF130104 unknown AF131743 LOC100302652 hypothetical
protein LOC100302652 AF131747 ENDOD1 endonuclease domain containing
1 precursor AF131801 ATL1 atlastin GTPase 1 isoform b AF132203 SCD
stearoyl-CoA desaturase 1 AF133207 HSPB8 heat shock 22 kDa protein
8 AF133425 TSPAN1 tetraspan 1 AF134149 KCNK6 potassium channel,
subfamily K, member 6 AF134715 TNFSF13B tumor necrosis factor
superfamily, member 13b AF135266 NUPR1 p8 protein isoform a
AF135593 VPS41 vacuolar protein sorting 41 isoform 1 AF139131 CNTD1
cyclin N-terminal domain containing 1 AF144488 SPATA7
spermatogenesis-associated protein 7 isoform a AF151074 2-Mar
membrane-associated ring finger (C3HC4) 2 AF151810 STARD10 START
domain containing 10 AF151861 CGI-103 protein AF153415 C9orf5
hypothetical protein LOC23731 AF153820 inwardly-rectifying
potassium channel Kir2.1 (KCNJ2) AF155158 MCM7 minichromosome
maintenance complex component 7 AF157324 RER1 RER1 retention in
endoplasmic reticulum 1 AF158185 POLH DNA-directed DNA polymerase
eta AF158555 GLS glutaminase precursor AF159570 RGS5 regulator of
G-protein signalling 5 AF161526 TMBIM4 transmembrane BAX inhibitor
motif containing 4 AF162769 GLRX glutaredoxin (thioltransferase)
AF164794 SERINC1 serine incorporator 1 AF165187 AGTRAP angiotensin
II receptor-associated protein AF165520 phorbolin I protein (PBI)
AF169312 ANGPTL4 angiopoietin-like 4 protein isoform a precursor
AF169676 FLRT2 fibronectin leucine rich transmembrane protein 2
AF172398 F11R F11 receptor precursor AF176518 FBXL2 F-box and
leucine-rich repeat protein 2 AF178532 aspartyl protease (BACE2)
AF179281 IDS iduronate-2-sulfatase isoform a precursor AF180519
GABARAPL3 Homo sapiens GABA-A receptor-associated protein mRNA,
complete cds. AF182273 CYP3A4 cytochrome P450, family 3, subfamily
A, AF182414 TMBIM4 transmembrane BAX inhibitor motif containing 4
AF183417 MAP1LC3B microtubule-associated proteins 1A/1B light
AF183419 AK3 adenylate kinase 3 AF186773 DYRK3 dual-specificity
tyrosine-(Y)-phosphorylation AF188298 DAB2 disabled homolog 2
AF197952 PRDX5 peroxiredoxin 5 isoform a precursor AF201370 MDM2
mouse double minute 2 homolog isoform MDM2 AF205218 IVNS1ABP
influenza virus NS1A binding protein AF212995 CUL4B cullin 4B
isoform 1 AF216292 HSPA5 heat shock 70 kDa protein 5 AF216962 CNNM2
cyclin M2 isoform 1 AF217974 ADAMTSL4 thrombospondin repeat
containing 1 isoform 1 AF217990 HERPUD1 homocysteine-inducible,
endoplasmic reticulum AF218365 Ets transcription factor TEL2E
(TEL2) AF220026 TRIM5 tripartite motif protein TRIMS isoform alpha
AF225981 calcium transport ATPase ATP2C1 (ATP2C1) AF228422 C15orf48
normal mucosa of esophagus specific 1 AF229179 Collectrin AF230398
TRIM23 ADP-ribosylation factor domain protein 1 isoform AF230411
PML promyelocytic leukemia protein isoform 2 AF230904 SH3KBP1
SH3-domain kinase binding protein 1 isoform a AF230924 CUTA cutA
divalent cation tolerance homolog isoform AF232772 HAS3 hyaluronan
synthase 3 isoform b AF232905 C1QTNF1 C1q and tumor necrosis factor
related protein 1 AF237813 ABAT 4-aminobutyrate aminotransferase
precursor AF239756 MPZL1 myelin protein zero-like 1 isoform a
AF240468 COPA coatomer protein complex, subunit alpha isoform
AF246144 CCNDBP1 cyclin D-type binding-protein 1 isoform 1 AF247168
C1orf63 hypothetical protein LOC57035 AF248966 unknown AF250226
ADCY6 adenylate cyclase 6 isoform b AF251025 ZFYVE1 zinc finger,
FYVE domain containing 1 isoform 1 AF251054 NDRG3 N-myc downstream
regulated gene 3 isoform a AF257659 CALU calumenin isoform b
precursor AF263293 SH3GLB1 SH3-containing protein SH3GLB1 AF267855
ERGIC1 endoplasmic reticulum-golgi intermediate AF267856 unknown
AF274948 C20orf24 Homo sapiens putative Rab5-interacting protein
mRNA, complete cds. AF276658 MAP1LC3A microtubule-associated
protein 1 light chain 3 AF278532 beta-netrin AF280094 SP110 SP110
nuclear body protein isoform c AF285119 PHPT1 phosphohistidine
phosphatase 1 isoform 2 AF288208 B3GNT2 UDP-G1cNAc:betaGal AF288391
FAM129A niban protein isoform 2 AF295039 CABYR calcium-binding
tyrosine AF302786 GNPTG N-acetylglucosamine-1-phosphotransferase,
gamma AF303378 TBRG1 transforming growth factor beta regulator 1
AF313413 C5orf62 putative small membrane protein NID67 AF315325
cytochrome P450 variant 3A7 (CYP3A7) AF316824 CENPP centromere
protein P AF316873 PINK1 PTEN induced putative kinase 1 precursor
AF325213 TSPAN10 tetraspanin 10 AF327923 TMEM120A transmembrane
protein 120A AF329088 C4orf49 ovary-specific acidic protein
AF330205 SCOC short coiled-coil protein isoform 4 AF348078 SUCNR1
succinate receptor 1 AF353618 RSPH3 radial spoke 3 homolog AF353992
TM2D3 TM2 domain containing 3 isoform a AF355465 ZMAT3 p53 target
zinc finger protein isoform 1 AF356193 caspase recruitment domain
protein 6 AF380356 XG XG glycoprotein isoform 2 precursor AF478446
NR1H4 nuclear receptor subfamily 1, group H, member 4 AF493931 RGS7
regulator of G-protein signaling 7 AF495383 ADAM9 Homo sapiens
disintegrin/metalloproteinase domain 9 short protein precursor
(ADAM9) mRNA, complete cds; alternatively spliced. AF513360 Enverin
AF542051 SH3KBP1 SH3-domain kinase binding protein 1 isoform a
(AFFX- HUMISGF3A)/ M97935_3 AFFX- HUMISGF3A/ M97935_5 AFFX-
HUMISGF3A/ M97935_MA AFFX- HUMISGF3A/ M97935_MB AI003763 LMF1
lipase maturation factor 1 AI022882 PAM peptidylglycine
alpha-amidating monooxygenase AI023433 GALNT5
N-acetylgalactosaminyltransferase 5 AI023774 LETM2 leucine
zipper-EF-hand containing
transmembrane AI038737 unknown AI040029 B4GALT7 xylosylprotein beta
1,4-galactosyltransferase 7 AI040305 CDH11 cadherin 11, type 2
preproprotein AI040324 unknown AI041217 unknown AI051046 unknown
AI051127 unknown AI052003 VPS13B vacuolar protein sorting 13B
isoform 5 AI052103 C6orf170 hypothetical protein LOC221322 AI052536
SNX1 sorting nexin 1 isoform a AI056692 unknown AI074333 RALGPS1
Ral GEF with PH domain and SH3 binding motif 1 AI077660 unknown
AI079540 YIF1B Yip1 interacting factor homolog B isoform 7 AI081779
SGSM3 small G protein signaling modulator 3 AI091079 unknown
AI092511 DPP4 dipeptidylpeptidase IV AI092770 unknown AI092931
SERF2 small EDRK-rich factor 2 AI096389 MAST4 microtubule
associated serine/threonine kinase AI096706 unknown AI097463
GALNTL1 UDP-N-acetyl-alpha-D- galactosamine:polypeptide AI110886
PAPPA pregnancy-associated plasma protein A AI122754 STS
steryl-sulfatase precursor AI123348 unknown AI125204 TMEM217
transmembrane protein 217 isoform 1 AI125670 unknown AI129626 DCLK1
doublecortin-like kinase 1 AI129628 unknown AI133137 C20orf108
hypothetical protein LOC116151 AI139993 LOC651250 Homo sapiens cDNA
FLJ33831 fis, clone CTONG2003937. AI147621 C10orf32 hypothetical
protein LOC119032 AI150000 LAMP2 lysosomal-associated membrane
protein 2 isoform AI150117 TOPORS topoisomerase I binding,
arginine/serine-rich AI160126 LOC728855 Homo sapiens mRNA,
chromosome 1 specific transcript KIAA0493. AI160339 unknown
AI160540 KLHDC8B kelch domain containing 8B AI167292 SYTL4
synaptotagmin-like 4 AI183997 RGS5 regulator of G-protein
signalling 5 AI187364 unknown AI188104 unknown AI188161 FLRT2
fibronectin leucine rich transmembrane protein 2 AI188389 TMEM9B
TMEM9 domain family, member B precursor AI190413 unknown AI200538
unknown AI200555 unknown AI202327 CPEB2 cytoplasmic polyadenylation
element binding AI202969 OSBPL3 oxysterol-binding protein-like
protein 3 isoform AI215102 RAB11A Ras-related protein Rab-11A
AI218542 unknown AI222435 unknown AI223870 DNAJC21 DnaJ homology
subfamily A member 5 isoform 1 AI224105 PLCB4 phospholipase C beta
4 isoform a AI243677 ARSK arylsulfatase K precursor AI247763 GALNT5
N-acetylgalactosaminyltransferase 5 AI248598 LAMP1
lysosomal-associated membrane protein 1 AI254547 PDLIM4 PDZ and LIM
domain 4 isoform 1 AI261321 FAM82A1 family with sequence similarity
82, member A1 AI262560 CNPY3 trinucleotide repeat containing 5
precursor AI264121 PLXDC2 plexin domain containing 2 precursor
AI268315 GFPT1 glucosamine-fructose-6-phosphate AI270356 unknown
AI275162 DLGAP1 discs large homolog-associated protein 1 isoform
AI276880 ETNK1 ethanolamine kinase 1 isoform A AI278445 unknown
AI279062 SLC22A15 solute carrier family 22, member 15 AI290475
RAB23 Ras-related protein Rab-23 AI291123 MEG3 Homo sapiens MEG3
mRNA, partial sequence, imprinted gene. AI291989 GBA2 bile acid
beta-glucosidase AI307750 C5orf41 luman-recruiting factor AI307760
MRPS22 mitochondrial ribosomal protein S22 AI307802 ANKRD29 ankyrin
repeat domain 29 AI312083 unknown AI313324 unknown AI332407 SFRP1
secreted frizzled-related protein 1 precursor AI333326 11-Sep
septin 11 AI334015 ABCB5 ATP-binding cassette, sub-family B, member
5 AI337304 GOPC golgi associated PDZ and coiled-coil motif AI341146
E2F7 E2F transcription factor 7 AI341234 unknown AI341246 TRAP1 TNF
receptor-associated protein 1 precursor AI341602 C4orf48
hypothetical protein LOC401115 AI342246 unknown AI346026 PLEKHA1
pleckstrin homology domain containing, family A AI348009 unknown
AI348094 unknown AI354864 GPC1 glypican 1 precursor AI356412 LYN
Yamaguchi sarcoma viral (v-yes-1) oncogene AI359676 unknown
AI361227 NFE2L1 nuclear factor erythroid 2-like 1 AI363270 TRIM38
tripartite motif-containing 38 AI369073 LOC283788 Homo sapiens cDNA
FLJ31053 fis, clone HSYRA2000640, highly similar to Homo sapiens
FRG1 mRNA. AI373299 unknown AI374756 LOC400927 Homo sapiens cDNA
FLJ34950 fis, clone NT2RP7017284, highly similar to Casein kinase I
isoform epsilon (EC 2.7.11.1). AI376997 C5orf44 hypothetical
protein LOC80006 isoform 2 AI378035 unknown AI378788 DCBLD2
discoidin, CUB and LCCL domain containing 2 AI379338 ASAH1
N-acylsphingosine amidohydrolase 1 isoform b AI380156 unknown
AI382026 MUC12 SubName: Full = MUC12 protein; Flags: Fragment;
AI391633 unknown AI393091 KIAA1632 hypothetical protein LOC57724
AI393706 unknown AI393725 unknown AI418538 FLJ44606 AI418892 TM9SF4
transmembrane 9 superfamily protein member 4 AI420817 unknown
AI421559 RALGDS ral guanine nucleotide dissociation stimulator
AI422414 unknown AI431643 RRAS2 related RAS viral (r-ras) oncogene
homolog 2 AI433463 MME membrane metallo-endopeptidase AI435399
unknown AI435514 unknown AI439556 TXNIP thioredoxin interacting
protein AI446414 KITLG KIT ligand isoform b precursor AI446756
MALAT1 AI453452 ZNF654 zinc finger protein 654 AI457817 JAG1 jagged
1 precursor AI458439 unknown AI459140 unknown AI460037 NAPEPLD
N-acyl phosphatidylethanolamine phospholipase D AI469425 unknown
AI472310 KCNRG potassium channel regulator isoform 2 AI472339 TMED4
transmembrane emp24 protein transport domain AI473891 unknown
AI474054 DRAM2 transmembrane protein 77 AI475544 MALAT1 AI478147
ATP10D ATPase, class V, type 10D AI479082 GAS6 growth
arrest-specific 6 isoform 1 precursor AI479419 unknown AI493587
ZFP106 zinc finger protein 106 homolog AI498144 C20orf194
hypothetical protein LOC25943 AI498395 unknown AI522053 unknown
AI523391 unknown AI525212 APLP2 amyloid beta (A4) precursor-like
protein 2 AI537887 STOM stomatin isoform a AI559300 SPATA18
spermatogenesis associated 18 homolog AI569974 unknown AI571796
SEC14L2 SEC14-like 2 isoform 1 AI582773 unknown AI613010 unknown
AI623211 LOC645166 Homo sapiens cDNA, FLJ18771. AI625741 UBE2W
ubiquitin-conjugating enzyme E2W (putative) AI631210 unknown
AI632212 RNPC3 RNA-binding region (RNP1, RRM) containing 3 AI632728
unknown AI633503 GALNT5 N-acetylgalactosaminyltransferase 5
AI633523 GNPTAB N-acetylglucosamine-1-phosphate transferase
AI634046 CFLAR CASP8 and FADD-like apoptosis regulator isoform
AI634580 SYNPO2 synaptopodin 2 isoform c AI636233 TMEM8A
transmembrane protein 8 (five membrane- spanning AI638405 MEG3 Homo
sapiens MEG3 mRNA, partial sequence, imprinted gene. AI638420 CLIC4
chloride intracellular channel 4 AI638768 unknown AI638771 unknown
AI650285 unknown AI650819 CUL4B cullin 4B isoform 1 AI651603
unknown AI651786 unknown AI652452 unknown AI652681 unknown AI653037
CSTF3 cleavage stimulation factor subunit 3 isoform 1 AI653117
unknown AI653327 unknown AI654636 unknown AI655057 RIT1 Ras-like
without CAAX 1 AI655524 PAQR8 progestin and adipoQ receptor family
member AI655763 NHLRC3 NHL repeat containing 3 isoform a AI656232
OTUB2 OTU domain, ubiquitin aldehyde binding 2 AI656481 unknown
AI658662 SYNPO2 synaptopodin 2 isoform c AI659225 CASK
calcium/calmodulin-dependent serine protein AI659456 USP9X
ubiquitin specific protease 9, X-linked isoform AI659800 C13orf31
hypothetical protein LOC144811 AI668610 unknown AI668625 unknown
AI669498 ZBTB4 zinc finger and BTB domain containing 4 AI670852
PTPRB protein tyrosine phosphatase, receptor type, B AI671049 CCNE1
cyclin E1 isoform 1 AI671186 unknown AI672159 unknown AI672432
DUSP28 dual specificity phosphatase 28 AI674647 SPPL2A signal
peptide peptidase-like 2A AI675453 PLXNA3 plexin A3 precursor
AI675682 SLC2A12 solute carrier family 2 (facilitated glucose
AI676022 ACCS 1-aminocyclopropane-1-carboxylate synthase AI677701
RBM24 RNA binding motif protein 24 isoform 1 AI683805 unknown
AI689225 unknown AI690274 PYROXD2 pyridine nucleotide-disulphide
oxidoreductase AI693193 unknown AI693862 unknown AI694303 APBB2
amyloid beta A4 precursor protein-binding, AI700633 SERINC5
developmentally regulated protein TPO1 AI701428 GLRB glycine
receptor, beta isoform A precursor AI703142 ZNF814 zinc finger
protein 814 AI703496 unknown AI718223 PRDX5 peroxiredoxin 5 isoform
a precursor AI719655 unknown AI732587 unknown AI733041 CTTNBP2NL
CTTNBP2 N-terminal like AI733474 GPR155 G protein-coupled receptor
155 isoform 9 AI735261 DRAM2 transmembrane protein 77 AI738556
TNFRSF10D tumor necrosis factor receptor superfamily, AI738896
TNFAIP3 tumor necrosis factor, alpha-induced protein 3 AI740460
unknown AI740589 C22orf23 hypothetical protein LOC84645 AI741056
SELPLG selectin P ligand AI741110 ARSD arylsulfatase D isoform a
precursor AI742029 unknown AI742434 unknown AI743115 NDUFA11 NADH
dehydrogenase (ubiquinone) 1 alpha AI743534 ARHGAP24 Rho GTPase
activating protein 24 isoform 1 AI743744 unknown AI743792 ST6GAL1
ST6 beta-galactosamide AI743979 unknown AI744658 TSPAN16
transmembrane 4 superfamily member 16 AI753143 unknown AI753792
RRAS2 related RAS viral (r-ras) oncogene homolog 2 AI754693 unknown
AI760252 HAPLN1 hyaluronan and proteoglycan link protein 1 AI761250
unknown AI761561 HK2 hexokinase 2 AI761947 ARHGAP24 Rho GTPase
activating protein 24 isoform 1 AI762782 IDUA alpha-L-iduronidase
precursor AI765327 unknown AI768122 EIF4G3 eukaryotic translation
initiation factor 4 AI783924 PLSCR3 phospholipid scramblase 3
AI793200 TRIM45 tripartite motif-containing 45 isoform 1 AI793340
unknown AI795908 PHLDA1 pleckstrin homology-like domain, family A,
AI795923 RHBDD1 rhomboid domain containing 1 AI796536 unknown
AI797353 KIAA1324L hypothetical protein LOC222223 isoform 1
AI797678 unknown AI797684 RCN3 reticulocalbin 3, EF-hand calcium
binding
domain AI801013 HCCS holocytochrome c synthase AI803010 unknown
AI803088 ADAMTSL1 ADAMTS-like 1 isoform 4 precursor AI803181 TMEM47
transmembrane protein 47 AI805050 RAB6B RAB6B, member RAS oncogene
family AI805301 unknown AI806169 unknown AI806583 LYPLAL1
lysophospholipase-like 1 AI806674 HS2ST1 heparan sulfate
2-O-sulfotransferase 1 isoform AI806905 unknown AI806927 unknown
AI807023 RAB8B RAB8B, member RAS oncogene family AI807532 EPHX4
abhydrolase domain containing 7 AI807917 CCDC149 coiled-coil domain
containing 149 isoform 2 AI809404 unknown AI810266 unknown AI810572
PGPEP1 pyroglutamyl-peptidase I AI810669 unknown AI810767 unknown
AI811298 OSR2 odd-skipped related 2 isoform a AI814116 LOC100130691
AI814274 SBSN suprabasin isoform 2 precursor AI814587 KIAA1715
Lunapark AI816071 FAM174A family with sequence similarity 174,
member A AI816243 STX12 syntaxin 12 AI817448 LOC100130522 Homo
sapiens cDNA FLJ31742 fis, clone NT2RI2007214. AI819386 unknown
AI821404 PAPSS2 3'-phosphoadenosine 5'-phosphosulfate synthase 2
AI821935 FBXL7 F-box and leucine-rich repeat protein 7 AI823600
unknown AI823980 RBKS ribokinase AI824013 unknown AI825800 PDIA3
protein disulfide-isomerase A3 precursor AI825987 unknown AI828035
GLS glutaminase precursor AI829920 UBE2H ubiquitin-conjugating
enzyme E2H isoform 1 AI830201 unknown AI832193 GNB1L guanine
nucleotide binding protein AI859242 unknown AI860341 DLEC1 deleted
in lung and esophageal cancer 1 isoform AI860764 XPO1 exportin 1
AI860874 WDR63 WD repeat domain 63 AI861942 LDLR low density
lipoprotein receptor precursor AI862120 MAMDC2 MAM domain
containing 2 precursor AI862255 ATP6V0E1 ATPase, H+ transporting,
lysosomal 9 kDa, V0 AI862559 ANGPTL6 angiopoietin-like 6 precursor
AI867198 SLC5A3 solute carrier family 5 (inositol transporters),
AI868167 EFHA2 EF-hand domain family, member A2 AI869717 SLC38A10
solute carrier family 38, member 10 isoform a AI870615 PDK2
pyruvate dehydrogenase kinase 2 precursor AI870617 unknown AI879064
unknown AI884858 TUSC3 tumor suppressor candidate 3 isoform a
AI885170 C9orf16 hypothetical protein LOC79095 AI885178 MAPRE3
microtubule-associated protein, RP/EB family, AI886656 AQP11
aquaporin 11 AI888786 ZNF449 zinc finger protein 449 AI889160
CABLES1 Cdk5 and Abl enzyme substrate 1 isoform 2 AI889584 BOD1L
biorientation of chromosomes in cell division AI890529 POLH
DNA-directed DNA polymerase eta AI890761 unknown AI911687 CLN5
ceroid-lipofuscinosis, neuronal 5 AI911972 unknown AI912583 GLIPR1
GLI pathogenesis-related 1 precursor AI912976 RNU5E Homo sapiens
RNA, U5E small nuclear (RNU5E), non-coding RNA. AI913533 LOC283267
Homo sapiens cDNA FLJ30003 fis, clone 3NB691000113. AI913749
PLEKHH2 pleckstrin homology domain containing, family H AI915827
unknown AI916555 COPZ2 coatomer protein complex, subunit zeta 2
AI921238 CDC14B CDC14 homolog B isoform 3 AI921586 ALDOA
fructose-bisphosphate aldolase A AI922855 CPE carboxypeptidase E
preproprotein AI922968 MAST4 microtubule associated
serine/threonine kinase AI923675 SLFN5 schlafen family member 5
AI924150 GLT25D1 glycosyltransferase 25 domain containing 1
AI924426 ELL2 elongation factor, RNA polymerase II, 2 AI927770
SEL1L sel-1 suppressor of lin-12-like precursor AI928387 unknown
AI929792 unknown AI932310 C14orf4 chromosome 14 open reading frame
4 AI933861 C11orf17 chromosome 11 open reading frame 17 AI934569
ASAH1 N-acylsphingosine amidohydrolase 1 isoform b AI935115 TMEM188
transmembrane protein 188 AI935162 unknown AI935415 TAX1BP1 Tax1
(human T-cell leukemia virus type I) AI935917 PRKAA1 protein
kinase, AMP-activated, alpha 1 catalytic AI936560 ARHGAP20 Rho
GTPase activating protein 20 AI936769 unknown AI939544 unknown
AI950273 MEG3 Homo sapiens MEG3 mRNA, partial sequence, imprinted
gene. AI951454 SPR sepiapterin reductase AI952357 MDM2 mouse double
minute 2 homolog isoform MDM2 AI955001 unknown AI955713 unknown
AI961401 KLHL24 DRE1 protein AI962377 PPFIBP1 PTPRF interacting
protein binding protein 1 AI970061 GPR155 G protein-coupled
receptor 155 isoform 9 AI970289 MEG3 Homo sapiens MEG3 mRNA,
partial sequence, imprinted gene. AI970972 unknown AI971519 DTWD1
DTW domain containing 1 AI982754 CLU clusterin isoform 2 AI983904
unknown AI984136 NENF neuron derived neurotrophic factor precursor
AI989567 ST3GAL6 alpha2,3-sialyltransferase VI AI989799 unknown
AI991033 HSPG2 heparan sulfate proteoglycan 2 precursor AI992095
ZNF771 zinc finger protein 771 AI992283 TRAF4 TNF
receptor-associated factor 4 AJ131212 RNASE7 ribonuclease, RNase A
family, 7 precursor AJ227860 COTL1 coactosin-like 1 AJ243951
deafness locus associated putative guanine nucleotide exchange
factor (DelGEF gene, splice variant DelGEF 2) AJ245600 DEPDC7 novel
58.3 KDA protein isoform 1 AJ251830 PERP PERP, TP53 apoptosis
effector AJ252246 GRIK2 glutamate receptor, ionotropic, kainate 2
AJ276395 FN1 fibronectin 1 isoform 1 preproprotein AJ276888 MDM2
mouse double minute 2 homolog isoform MDM2 AJ301610 GRIK2 glutamate
receptor, ionotropic, kainate 2 AJ406928 keratin associated protein
1.5 (KRTAP1.5 gene) AJ406929 keratin associated protein 2.1b
(KRTAP2.1B gene) AJ406932 keratin associated protein 3.2 (KRTAP3.2
gene) AJ422148 LRRC25 leucine rich repeat containing 25 precursor
AJ457063 high tyrosine glycine keratin associated protein
7.1(partial) (KRTAP7.1 gene) AK000162 ACSS2 acyl-CoA synthetase
short-chain family member 2 AK000168 KIAA1919 sodium-dependent
glucose transporter 1 AK000345 DHRS2 dehydrogenase/reductase member
2 isoform 2 AK000684 TMEM135 transmembrane protein 135 AK000778
NR3C2 nuclear receptor subfamily 3, group C, member 2 AK000826
RAB7A RAB7, member RAS oncogene family AK000938 ZNF691 zinc finger
protein 691 AK001007 unknown AK001029 UBQLN2 ubiquilin 2 AK001619
PDE4DIP phosphodiesterase 4D interacting protein isoform AK001684
ATP2C1 calcium-transporting ATPase 2C1 isoform 1c AK001821 unknown
AK001913 LOC100302652 hypothetical protein LOC100302652 AK002054
COBLL1 COBL-like 1 AK002207 SPG20 spartin AK021433 YIPF3 natural
killer cell-specific antigen KLIP1 AK021539 DSEL dermatan sulfate
epimerase-like AK021586 AGRN agrin precursor AK021925 SLC41A3
solute carrier family 41, member 3 isoform 1 AK022198 unknown
AK022459 PIGB phosphatidylinositol glycan, class B AK022566 B4GALT7
xylosylprotein beta 1,4-galactosyltransferase 7 AK022644 DBNDD1
dysbindin (dystrobrevin binding protein 1) AK022817 NAPB
N-ethylmaleimide-sensitive factor attachment AK022871 TOLLIP toll
interacting protein AK022883 TMEM30A transmembrane protein 30A
isoform 1 AK022885 C9orf16 hypothetical protein LOC79095 AK023113
RNF213 ring finger protein 213 AK023116 SP140L SP140 nuclear body
protein-like AK023166 unknown AK023230 TTC23 tetratricopeptide
repeat domain 23 AK023297 MOV10 Mov10, Moloney leukemia virus 10,
homolog AK023343 unknown AK023348 GRN granulin precursor AK023679
DISP1 dispatched A AK023743 unknown AK023778 WDTC1 WD and
tetratricopeptide repeats 1 AK023817 KIAA1632 hypothetical protein
LOC57724 AK024029 MOAP1 modulator of apoptosis 1 AK024050 UBE2W
ubiquitin-conjugating enzyme E2W (putative) AK024064 AK024256
CACHD1 cache domain containing 1 AK024446 ABCC10 ATP-binding
cassette, sub-family C, member 10 AK024712 CHSY3 chondroitin
sulfate synthase 3 AK024724 LYPLA2 lysophospholipase II AK024845
RAB4B ras-related GTP-binding protein 4b AK024846 unknown AK024896
SLC5A3 solute carrier family 5 (inositol transporters), AK024898
unknown AK025063 FAM84A family with sequence similarity 84, member
A AK025253 unknown AK025301 USP53 ubiquitin specific protease 53
AK025432 KIAA0564 hypothetical protein LOC23078 isoform a AK025464
TPRG1L tumor protein p63 regulated 1-like AK025608 C22orf9
hypothetical protein LOC23313 isoform a AK025872 unknown AK026026
unknown AK026106 TLL2 tolloid-like 2 precursor AK026195 unknown
AK026392 unknown AK026498 CYP2U1 cytochrome P450, family 2,
subfamily U, AK026577 ALDOA fructose-bisphosphate aldolase A
AK026697 CDS1 CDP-diacylglycerol synthase 1 AK026720 unknown
AK026747 PION pigeon homolog AK026784 unknown AK026808 HERC4 hect
domain and RLD 4 isoform a AK026921 unknown AK026966 unknown
AK027151 LAMA4 laminin, alpha 4 isoform 2 precursor AK027199
unknown AK027246 SC5DL sterol-C5-desaturase AK054668 SLFN5 schlafen
family member 5 AK075503 P4HB prolyl 4-hydroxylase, beta subunit
precursor AK075558 C1orf187 chromosome 1 open reading frame 187
precursor AK090412 unknown AK090434 unknown AK091691 unknown
AK091716 LOC728190 Homo sapiens cDNA FLJ34397 fis, clone
HCHON2001110. AK091986 unknown AK092855 AP1G2 adaptor-related
protein complex 1, gamma 2 AK095719 FLJ42709 Homo sapiens cDNA
FLJ38400 fis, clone FEBRA2008159. AK096921 unknown AK097618
C19orf51 hypothetical protein LOC352909 AK097652 unknown AK097997
LZTS2 leucine zipper, putative tumor suppressor 2 AK098058 MAPK12
mitogen-activated protein kinase 12 AK098125 unknown AK098337
unknown AK098354 PACS2 phosphofurin acidic cluster sorting protein
2 AK098414 SNRK SNF related kinase AK098812 PVR poliovirus receptor
isoform alpha AL008583 unknown AL021366 unknown AL022165 unknown
AL031177 unknown AL031178 unknown AL031295 unknown AL031429 unknown
AL031651 unknown AL031667 unknown AL034418 unknown AL034550 unknown
AL035413 unknown AL035541 unknown AL037339 PTK2 PTK2 protein
tyrosine kinase 2 isoform b AL038787 unknown AL039447 UBAP1
ubiquitin associated protein 1 AL039706 IFI27L1 interferon,
alpha-inducible protein 27-like 1 AL039811 unknown AL039831 RAVER2
ribonucleoprotein, PTB-binding 2 AL040222 unknown AL040341 TTC14
tetratricopeptide repeat domain 14 isoform a AL041747 unknown
AL042483 SPATA18 spermatogenesis associated 18 homolog AL044019
SNX29 sorting nexin 29 AL044056 MRVI1 JAW1-related protein isoform
b
AL044126 unknown AL044170 NBR1 neighbor of BRCA1 gene 1 AL044570
unknown AL045717 ERO1LB endoplasmic reticulum oxidoreductin 1-Lbeta
AL046017 FAM46C hypothetical protein LOC54855 AL046979 TNS1 tensin
AL048423 unknown AL049226 FAM63B hypothetical protein LOC54629
isoform b AL049369 RCAN1 calcipressin 1 isoform b AL049548 unknown
AL049646 unknown AL049699 unknown AL049709 unknown AL049923 OSBPL8
oxysterol-binding protein-like protein 8 isoform AL049933 GNAI1
guanine nucleotide binding protein (G protein), AL049942 unknown
AL050022 TCTN3 tectonic 3 isoform a precursor AL050069 DOK5 docking
protein 5 AL050154 unknown AL050217 unknown AL050332 unknown
AL050374 unknown AL050388 SOD2 manganese superoxide dismutase
isoform A AL078596 unknown AL080081 unknown AL080214 IFFO1
intermediate filament family orphan isoform 4 AL080220 unknown
AL096732 unknown AL096740 UBE3B ubiquitin protein ligase E3B
AL109824 unknown AL110115 unknown AL110191 unknown AL110209 PLA2G15
lysophospholipase 3 (lysosomal phospholipase A2) AL117354 unknown
AL117381 unknown AL117468 unknown AL117598 unknown AL118520 unknown
AL118571 REEP3 receptor accessory protein 3 AL118843 LOC100286793
AL119957 DNAJC3 DnaJ (Hsp40) homolog, subfamily C, member 3
AL120021 KLHL24 DRE1 protein AL120354 ZNF654 zinc finger protein
654 AL121829 unknown AL121883 unknown AL132665 BNIP3L
BCL2/adenovirus E1B 19 kD-interacting protein AL133001 SULF2
sulfatase 2 isoform b precursor AL133084 ERCC6 excision repair
cross-complementing rodent AL133580 SCOC short coiled-coil protein
isoform 4 AL134420 unknown AL134489 RPP38 ribonuclease P/MRP 38
subunit AL134724 LOC151162 Homo sapiens clone 24711 mRNA sequence.
AL135342 ZNF561 zinc finger protein 561 AL136561 SGIP1 SH3-domain
GRB2-like (endophilin) interacting AL136597 KLHL7 kelch-like 7
isoform 2 AL136629 TSPYL1 TSPY-like 1 AL136653 RASSF4 Ras
association domain family 4 AL136658 C14orf1 ergosterol
biosynthetic protein 28 AL136680 GBP3 guanylate binding protein 3
AL136693 CYBRD1 cytochrome b reductase 1 isoform 1 AL136733 UBAP1
ubiquitin associated protein 1 AL136797 AHI1 Abelson helper
integration site 1 isoform a AL136807 SERP1 stress-associated
endoplasmic reticulum protein AL136829 unknown AL136835 unknown
AL136944 unknown AL137370 LMBRD2 LMBR1 domain containing 2 AL137432
SUSD1 sushi domain containing 1 precursor AL138104 KIAA1432
connexin 43-interacting protein 150 isoform a AL138349 PRUNE2 prune
homolog 2 AL139228 unknown AL157430 unknown AL157437 unknown
AL157473 KIAA1217 sickle tail isoform 1 AL157485 unknown AL161958
THY1 Thy-1 cell surface antigen preproprotein AL161999 CYFIP2
cytoplasmic FMR1 interacting protein 2 AL162047 NCOA4 nuclear
receptor coactivator 4 isoform 1 AL162060 unknown AL353132 unknown
AL354872 unknown AL355532 unknown AL355685 unknown AL355815 unknown
AL357536 C20orf30 hypothetical protein LOC29058 isoform 1 AL359052
ITGBL1 integrin, beta-like 1 (with EGF-like repeat AL359601 ELMOD1
ELMO/CED-12 domain containing 1 isoform 1 AL359605 unknown AL359622
ANKRD34A ankyrin repeat domain 34 AL365347 unknown AL365404 GPR108
G protein-coupled receptor 108 isoform 2 AL389942 MIR146A unknown
AL389956 FBXO32 F-box only protein 32 isoform 1 AL390186 unknown
AL390216 STOX2 storkhead box 2 AL391688 unknown AL512687 NOMO1
nodal modulator 1 precursor AL512694 NADSYN1 NAD synthetase 1
AL512737 SLC22A23 solute carrier family 22, member 23 isoform b
AL512766 FAM54B hypothetical protein LOC56181 isoform a AL513583
GM2A GM2 ganglioside activator precursor AL515318 SH3BGRL SH3
domain binding glutamic acid-rich protein AL515916 LMF1 lipase
maturation factor 1 AL520200 ABHD14B abhydrolase domain containing
14B AL520774 MDH2 mitochondrial malate dehydrogenase precursor
AL520900 TMEM219 transmembrane protein 219 AL522395 SHISA4 shisa
homolog 4 precursor AL522667 C5orf32 hypothetical protein LOC84418
AL523076 MAP1B microtubule-associated protein 1B AL523860 unknown
AL524093 unknown AL529434 unknown AL530264 CEP68 centrosomal
protein 68 kDa AL533234 unknown AL535113 PLCB4 phospholipase C beta
4 isoform a AL536553 unknown AL537457 NEFL neurofilament, light
polypeptide 68 kDa AL540260 PIK3IP1 HGFL protein isoform 1 AL547782
DHRSX dehydrogenase/reductase (SDR family) X-linked AL551046 HSPB6
heat shock protein, alpha-crystallin-related, AL552450 SYNPO2
synaptopodin 2 isoform c AL553774 KIAA1462 hypothetical protein
LOC57608 AL555086 JAK1 janus kinase 1 AL560266 FCRLA Fc
receptor-like and mucin-like 1 AL561930 PI4K2A phosphatidylinositol
4-kinase type 2 alpha AL562686 EXOC2 Sec5 protein AL564683 CEBPB
CCAAT/enhancer binding protein beta AL565238 C5orf41
luman-recruiting factor AL565449 TPT1 tumor protein,
translationally-controlled 1 AL565741 C5orf30 hypothetical protein
LOC90355 AL565767 CIRBP cold inducible RNA binding protein AL566172
ATP6V0D1 ATPase, H+ transporting, lysosomal, V0 subunit AL566528
NEFL neurofilament, light polypeptide 68 kDa AL567779 MCFD2
multiple coagulation factor deficiency 2 AL569506 FLJ43663 Homo
sapiens cDNA FLJ43663 fis, clone SYNOV4005989. AL569575 ANTXR1
anthrax toxin receptor 1 isoform 1 precursor AL569601 DKK3 dickkopf
homolog 3 precursor AL570661 CD46 CD46 antigen, complement
regulatory protein AL571375 SCD5 stearoyl-CoA desaturase 5 isoform
a AL572206 C18orf32 hypothetical protein LOC497661 AL573201 ENDOD1
endonuclease domain containing 1 precursor AL573637 UXS1
UDP-glucuronate decarboxylase 1 AL573722 TMEM150A transmembrane
protein 150A isoform 1 AL574319 PDK2 pyruvate dehydrogenase kinase
2 precursor AL583909 KIAA1539 hypothetical protein LOC80256
AL589603 SYNPO2 synaptopodin 2 isoform c AL832227 unknown AL833204
ABI3BP ABI gene family, member 3 (NESH) binding protein AL833762
unknown AU118882 EDNRA endothelin receptor type A isoform a
precursor AU121431 FAM63B hypothetical protein LOC54629 isoform b
AU134977 NEAT1 Human MEN1 region clone epsilon/beta mRNA, 3'
fragment. AU135154 ADAM10 ADAM metallopeptidase domain 10 precursor
AU138166 STS steryl-sulfatase precursor AU143929 FANK1 fibronectin
type III and ankyrin repeat domains AU144083 ARSD arylsulfatase D
isoform a precursor AU144243 PIGB phosphatidylinositol glycan,
class B AU144247 CLIP4 CAP-GLY domain containing linker protein
family, AU145361 CBLB Cas-Br-M (murine) ecotropic retroviral
AU145941 CDC14B CDC14 homolog B isoform 3 AU146771 SNX18 sorting
nexin 18 isoform c AU150078 unknown AU150319 TAPBPL TAP binding
protein-like precursor AU151560 unknown AU152410 C15orf17
hypothetical protein LOC57184 AU153366 IKBKB inhibitor of nuclear
factor kappa B kinase beta AU153583 unknown AU154125 SEC22B SEC22
vesicle trafficking protein homolog B AU154469 SLC11A2 solute
carrier family 11 (proton-coupled AU155376 unknown AU156421 unknown
AU156721 PAPPA pregnancy-associated plasma protein A AU157541
OBFC2A oligonucleotide/oligosaccharide-binding fold AU157716
unknown AU160004 IGF2BP3 insulin-like growth factor 2 mRNA binding
AU160685 GPR180 G protein-coupled receptor 180 precursor AV648367
TMEM66 transmembrane protein 66 precursor AV661099 NF1
neurofibromin isoform 1 AV661152 UGP2 UDP-glucose pyrophosphorylase
2 isoform a AV681975 unknown AV682252 GLIPR1 GLI
pathogenesis-related 1 precursor AV682567 KTELC1 KTEL
(Lys-Tyr-Glu-Leu) containing 1 precursor AV691323 UGT1A7 UDP
glycosyltransferase 1 family, polypeptide A7 AV692127 GALNT1
polypeptide N-acetylgalactosaminyltransferase 1 AV693216 PLXNB1
plexin B1 precursor AV694039 LOC90110 Homo sapiens mRNA; cDNA
DKFZp564O2364 (from clone DKFZp564O2364). AV696976 LYNX1 Ly-6
neurotoxin-like protein 1 isoform a AV697515 RDH10 retinol
dehydrogenase 10 AV700174 C14orf182 hypothetical protein LOC283551
AV700323 unknown AV700415 unknown AV700514 CLN5
ceroid-lipofuscinosis, neuronal 5 AV700626 unknown AV701177 ARRDC4
arrestin domain containing 4 AV701283 unknown AV701750 unknown
AV702575 unknown AV703259 IDS iduronate-2-sulfatase isoform a
precursor AV703555 unknown AV704551 COMMD6 COMM domain containing 6
isoform a AV704962 SC4MOL sterol-C4-methyl oxidase-like isoform 1
AV705559 LPIN1 lipin 1 AV707142 unknown AV708945 CATSPER2
sperm-associated cation channel 2 isoform 2 AV712413 unknown
AV712912 TMEM167B transmembrane protein 167B precursor AV713913
unknown AV714268 PLA2G12A phospholipase A2, group XIIA precursor
AV714462 unknown AV717561 ATP6V0E1 ATPase, H+ transporting,
lysosomal 9 kDa, V0 AV722628 unknown AV722990 PCDHB15 protocadherin
beta 15 precursor AV723308 NTNG1 netrin G1 isoform 1 AV724329
PGM2L1 phosphoglucomutase 2-like 1 AV725328 PRNP prion protein
preproprotein AV725364 IQCK IQ motif containing K AV728606 PDCD4
programmed cell death 4 isoform 2 AV734793 ZDBF2 zinc finger,
DBF-type containing 2 AV734843 unknown AV741657 LUZP1 leucine
zipper protein 1 AV751731 TOM1L2 target of myb1-like 2 isoform 3
AV756141 CSF2RB colony stimulating factor 2 receptor, beta AV756532
MTCH2 mitochondrial carrier 2 AV757675 OPTN optineurin AV758342
LOC100131801 AV760596 MED31 mediator of RNA polymerase II
transcription, AV762892 SNHG9 Homo sapiens mRNA; cDNA
DKFZp686N06141 (from clone DKFZp686N06141). AW000928 NPAS2 neuronal
PAS domain protein 2 AW001777 unknown AW001847 APLP2 amyloid beta
(A4) precursor-like protein 2 AW003508 C3orf23 hypothetical protein
LOC285343 isoform 1 AW003889 unknown AW004076 unknown AW005237
unknown AW005535 RAP2B RAP2B, member of RAS oncogene family
precursor AW005545 unknown AW006123 FBXO32 F-box only protein 32
isoform 1 AW006185 unknown AW006345 SSR1 signal sequence receptor,
alpha precursor AW006750 KLHL24 DRE1 protein AW007289 ADAMTS7 ADAM
metallopeptidase with thrombospondin
type 1 AW008051 AGRN agrin precursor AW008976 SNX25 sorting nexin
25 AW009436 FDPS farnesyl diphosphate synthase isoform a AW009747
SYNPO2 synaptopodin 2 isoform c AW015537 ZNF469 zinc finger protein
469 AW021673 unknown AW024350 unknown AW026241 unknown AW028100
MTMR7 myotubularin related protein 7 AW029619 CKAP4
cytoskeleton-associated protein 4 AW043602 unknown AW043859 unknown
AW050627 ADAP1 centaurin, alpha 1 AW051365 SLC35E1 solute carrier
family 35, member E1 AW052044 HSPA5 heat shock 70 kDa protein 5
AW052084 unknown AW052179 COL4A5 type IV collagen alpha 5 isoform 2
precursor AW058459 TMEM171 transmembrane protein 171 isoform 2
AW071793 MXD1 MAX dimerization protein 1 AW080618 unknown AW080999
NR3C2 nuclear receptor subfamily 3, group C, member 2 AW086021
unknown AW089415 SFRP4 secreted frizzled-related protein 4
precursor AW090182 TMEM79 transmembrane protein 79 AW090529 MOXD1
monooxygenase, DBH-like 1 isoform 2 AW102637 NFASC neurofascin
isoform 1 precursor AW105337 unknown AW118878 SVIL supervillin
isoform 2 AW129145 POLI DNA polymerase iota AW130600 unknown
AW131553 unknown AW134492 unknown AW135176 CCDC146 coiled-coil
domain containing 146 AW136198 unknown AW138767 ELOVL7 elongation
of very long chain fatty acids-like AW139131 DLG1 discs, large
homolog 1 isoform 1 AW139393 unknown AW139538 unknown AW149492
GOSR2 golgi SNAP receptor complex member 2 isoform B AW150720 RDH10
retinol dehydrogenase 10 AW150953 DHCR7 7-dehydrocholesterol
reductase AW151360 unknown AW157619 CES2 carboxylesterase 2 isoform
2 AW166562 unknown AW167727 unknown AW167793 GNS glucosamine
(N-acetyl)-6-sulfatase precursor AW168154 ZBTB1 zinc finger and BTB
domain containing 1 isoform AW168942 unknown AW169973 METTL8
methyltransferase like 8 AW170015 PLCXD2
phosphatidylinositol-specific phospholipase C, X AW172311 unknown
AW173623 SERINC3 tumor differentially expressed protein 1 AW182938
MCART6 mitochondrial carrier triple repeat 6 AW183074 SDHC
succinate dehydrogenase complex, subunit C AW188464 USP53 ubiquitin
specific protease 53 AW189467 unknown AW190479 unknown AW190565
LOXL4 lysyl oxidase-like 4 precursor AW193531 CDK6 cyclin-dependent
kinase 6 AW194730 STK17A serine/threonine kinase 17a AW194947 ENPP4
ectonucleotide pyrophosphatase/phosphodiesterase AW195071 unknown
AW195928 SMURF2 SMAD specific E3 ubiquitin protein ligase 2
AW204088 unknown AW205616 unknown AW205686 unknown AW206037 unknown
AW206234 FLJ42709 Homo sapiens cDNA FLJ38400 fis, clone
FEBRA2008159. AW206414 unknown AW206419 unknown AW235061 SLC1A1
solute carrier family 1, member 1 AW236958 ASAP1 development and
differentiation enhancing factor AW237258 APH1B presenilin
stabilization factor-like isoform 1 AW241549 unknown AW241832
ATXN10 ataxin 10 AW242315 PTGER3 Homo sapiens PTGER3 mRNA for
prostaglandin E receotor EP3 subtype 3 isoform, partial cds, clone:
FLJ80357SAAF. AW242973 RAB4B ras-related GTP-binding protein 4b
AW245401 unknown AW264036 BCL6 B-cell lymphoma 6 protein isoform 1
AW264082 FAM110B hypothetical protein LOC90362 AW268365 ERO1L
ERO1-like precursor AW268719 unknown AW269686 RAP2B RAP2B, member
of RAS oncogene family precursor AW270037 unknown AW270170 unknown
AW271409 DCBLD1 discoidin, CUB and LCCL domain containing 1
AW272255 unknown AW273796 unknown AW274503 unknown AW274856 SAP18
Sin3A-associated protein, 18 kDa AW275049 unknown AW276078
LOC387763 hypothetical protein LOC387763 AW290940 unknown AW291402
unknown AW291696 TBRG1 transforming growth factor beta regulator 1
AW293849 unknown AW294630 unknown AW294729 GRIA3 glutamate
receptor, ionotrophic, AMPA 3 isoform AW294765 FBXO22 F-box only
protein 22 isoform a AW296788 MAP1A microtubule-associated protein
1A AW299226 CD36 CD36 antigen AW299245 CEP290 centrosomal protein
290 kDa AW299452 unknown AW300004 unknown AW300140 ZNF599 zinc
finger protein 599 AW300953 unknown AW300959 MMAA RecName: Full =
Putative L-type amino acid transporter 1-like protein MMAA;
AltName: Full = hLAT1 3-transmembrane protein MMAA; Short = hLAT1
3TM MMAA; AW301861 MAT2A methionine adenosyltransferase II, alpha
AW303865 PYGB brain glycogen phosphorylase AW304174 SPATA1
spermatogenesis associated 1 AW338089 MED31 mediator of RNA
polymerase II transcription, AW339310 DTNA dystrobrevin alpha
isoform 2 AW340588 unknown AW341649 unknown AW364693 CCDC30
coiled-coil domain containing 30 AW392551 unknown AW411259 unknown
AW418882 UST uronyl-2-sulfotransferase AW439843 LOC285550
hypothetical protein LOC285550 AW449728 GPR155 G protein-coupled
receptor 155 isoform 9 AW449754 LYNX1 Ly-6 neurotoxin-like protein
1 isoform a AW450035 NAV2 neuron navigator 2 isoform 1 AW452022
ODF2L outer dense fiber of sperm tails 2-like isoform AW452620
LYSMD4 LysM, putative peptidoglycan-binding, domain AW452656
unknown AW452681 unknown AW468201 B3GNTL1 UDP-GlcNAc:betaGal
AW469351 CLVS1 AW469523 DGAT2 diacylglycerol O-acyltransferase 2
AW469790 unknown AW471181 unknown AW511227 MIB2 mindbomb homolog 2
AW511319 unknown AW511595 unknown AW513227 ZNF285A zinc finger
protein 285 AW513612 CPXM2 carboxypeptidase X (M14 family), member
2 AW514038 unknown AW514401 SEPW1 selenoprotein W, 1 AW515704 SCYL1
SCY1-like 1 isoform A AW516297 unknown AW517464 ORAI3 ORAI calcium
release-activated calcium modulator AW517686 ATP2B4 plasma membrane
calcium ATPase 4 isoform 4a AW518714 unknown AW571715 DDX49 DEAD
(Asp-Glu-Ala-Asp) box polypeptide 49 AW575245 FCRLA Fc
receptor-like and mucin-like 1 AW575493 GRAMD3 GRAM domain
containing 3 isoform 2 AW575737 unknown AW576457 unknown AW591809
unknown AW593996 3-Mar membrane-associated ring finger (C3HC4) 3
AW611550 unknown AW612657 LYPLAL1 lysophospholipase-like 1 AW628045
CXorf23 hypothetical protein LOC256643 AW628835 unknown AW629527
TPRG1 tumor protein p63 regulated 1 AW665086 unknown AW665155 POLH
DNA-directed DNA polymerase eta AW665748 unknown AW665758 Unknown
AW665892 Unknown AW771007 ZNF862 SubName: Full = Putative
uncharacterized protein ENSP00000353120; AW771190 unknown AW771590
RHOQ ras-like protein TC10 precursor AW779916 Unknown AW850158
ADAM19 ADAM metallopeptidase domain 19 preproprotein AW954107
MAN2B2 mannosidase, alpha, class 2B, member 2 AW955612 FBN1
fibrillin 1 precursor AW958475 RPS27L ribosomal protein S27-like
AW960707 Unknown AW962850 SLFN5 schlafen family member 5 AW963328
Unknown AW970888 Unknown AW975183 Unknown AW978375 OSBPL8
oxysterol-binding protein-like protein 8 isoform AW979182 Unknown
AW979271 PDE4D phosphodiesterase 4D isoform 2 AY007239 MOXD1
monooxygenase, DBH-like 1 isoform 2 AY008268 GTP-binding protein
SAR1 (SAR1) AY008372 oxysterol binding protein-related protein 3
(ORP3) AY009128 ISCU iron-sulfur cluster assembly enzyme isoform
AY014180 SMURF2 SMAD specific E3 ubiquitin protein ligase 2
AY028632 CAT catalase AY079172 ATP6V0D2 ATPase, H+ transporting,
lysosomal 38 kDa, V0 AY090780 Unknown AY099509 C3orf34 hypothetical
protein LOC84984 AY134855 smooth muscle myosin heavy chain 11
isoform SM1-like protein AY185496 SERPINA9 serine (or cysteine)
proteinase inhibitor, clade BC000019 CDH6 cadherin 6, type 2
preproprotein BC000027 TMED3 transmembrane emp24 domain containing
3 BC000102 COL4A3BP alpha 3 type IV collagen binding protein
isoform BC000182 ANXA4 annexin IV BC000196 CCNG1 cyclin G1 BC000232
receptor accessory protein 5 BC000296 OSBPL2 oxysterol-binding
protein-like protein 2 isoform BC000314 RTN1 reticulon 1 isoform A
BC000324 Granulin BC000351 PCYT2 phosphate cytidylyltransferase 2,
ethanolamine BC000353 MYOD1 myogenic differentiation 1 BC000373
APLP2 amyloid beta (A4) precursor-like protein 2 BC000419 TXNRD2
thioredoxin reductase 2 precursor BC000474 TP53I3 tumor protein p53
inducible protein 3 BC000580 P4HTM hypoxia-inducible factor prolyl
4-hydroxylase BC000596 RPL23AP7 Homo sapiens ribosomal protein L23a
pseudogene 7, mRNA (cDNA clone IMAGE: 3346366). BC000638 ORM1-like
3 BC000686 EPDR1 ependymin related protein 1 precursor BC000687
TRAM1 translocation associated membrane protein 1 BC000704 TSPAN3
transmembrane 4 superfamily member 8 isoform 1 BC000737 RGS4
regulator of G-protein signaling 4 isoform 1 BC000836 YPEL5
yippee-like 5 BC000856 Unknown BC000899 BET1 blocked early in
transport 1 BC000905 RAB1A RAB1A, member RAS oncogene family
isoform 1 BC000961 degenerative spermatocyte homolog 1, lipid
desaturase (Drosophila) BC001001 VPS8 vacuolar protein sorting 8
homolog isoform b BC001099 SELO selenoprotein O BC001207 MAGED4
melanoma antigen family D, 4 BC001255 NCBP2 nuclear cap binding
protein subunit 2, 20 kDa BC001281 TNFRSF10B tumor necrosis factor
receptor superfamily, BC001364 SEC22B SEC22 vesicle trafficking
protein homolog B BC001387 PLA2G16 HRAS-like suppressor 3 BC001467
ADI1 acireductone dioxygenase 1 BC001595 NT5C2 5'-nucleotidase,
cytosolic II BC001689 SLC25A20 carnitine/acylcarnitine translocase
BC001727 ANKRD10 ankyrin repeat domain 10 BC001745 D4S234E brain
neuron cytoplasmic protein 1 BC001805 Unknown BC001867 ATPIF1
ATPase inhibitory factor 1 isoform 2 precursor BC001875 MFI2 Homo
sapiens, clone IMAGE: 4858804, mRNA. BC002480 SRD5A3 steroid 5
alpha-reductase 3 BC002510 RAB6B RAB6B, member RAS oncogene family
BC002571 ABHD14A abhydrolase domain containing 14A BC002637 TRIB2
tribbles homolog 2
BC002660 TMOD1 tropomodulin 1 BC002704 STAT1 signal transducer and
activator of transcription BC002709 Unknown BC002713 MXD4 MAD4
BC002752 Unknown BC002794 TNFRSF14 tumor necrosis factor receptor
superfamily, BC002842 HIST1H2BD histone cluster 1, H2bd BC003064
DAB2 disabled homolog 2 BC003096 PDLIM4 PDZ and LIM domain 4
isoform 1 BC003128 ZDHHC9 zinc finger, DHHC domain containing 9
BC003143 dual specificity phosphatase 6 BC003164 MBOAT7 membrane
bound O-acyltransferase domain BC003170 UBAP2L ubiquitin associated
protein 2-like isoform a BC003177 CALCOCO1 coiled-coil
transcriptional coactivator isoform BC003358 RPL10 ribosomal
protein L10 BC003503 RNA binding motif protein 4B BC003561 AP1S1
adaptor-related protein complex 1, sigma 1 BC003564 ATP6V1G1
vacuolar H+ ATPase G1 BC003602 H2AFJ Homo sapiens cDNA FLJ10903
fis, clone OVARC1000006, highly similar to HISTONE H2A.1. BC003610
milk fat globule-EGF factor 8 protein BC003614 DAPK1
death-associated protein kinase 1 BC003637 DDIT3
DNA-damage-inducible transcript 3 BC003658 SAR1A SAR1a gene homolog
1 BC003660 DPH5 diphthine synthase isoform b BC003667 RPS27L
ribosomal protein S27-like BC003686 SNAP23 synaptosomal-associated
protein 23 isoform BC004108 immunoglobulin superfamily, member 8
BC004130 CALCOCO2 calcium binding and coiled-coil domain 2 BC004153
GPR62 G protein-coupled receptor 62 BC004162 PPARA peroxisome
proliferative activated receptor, BC004180 keratin associated
protein 4-12 BC004191 dynactin 5 (p25) BC004241 LAMA4 laminin,
alpha 4 isoform 2 precursor BC004269 FAM167B hypothetical protein
LOC84734 BC004276 TMEM8A transmembrane protein 8 (five membrane-
spanning BC004283 AHNAK2 AHNAK nucleoprotein 2 BC004331 HSDL2
hydroxysteroid dehydrogenase like 2 BC004371 APLP2 amyloid beta
(A4) precursor-like protein 2 BC004395 APOL2 apolipoprotein L2
BC004443 ATP6V1E1 vacuolar H+ ATPase E1 isoform a BC004446 C20orf24
Homo sapiens putative Rab5-interacting protein mRNA, complete cds.
BC004535 ZDHHC16 Abl-philin 2 isoform 1 BC004566 MRPS21
mitochondrial ribosomal protein S21 BC004818 Unknown BC004911 BSCL2
seipin isoform 1 BC004936 SCD5 stearoyl-CoA desaturase 5 isoform a
BC004942 PGPEP1 pyroglutamyl-peptidase I BC004948 LRRC41 MUF1
protein BC005009 yippee-like 3 (Drosophila) BC005047 DUSP6 dual
specificity phosphatase 6 isoform a BC005050 NICN1 nicolin 1
BC005056 DNAJC30 DnaJ (Hsp40) homolog subfamily C member 30
BC005073 CYHR1 cysteine/histidine-rich 1 isoform 1 BC005078
coiled-coil domain containing 93 BC005127 PLIN2 adipose
differentiation-related protein BC005147 FKBP1A FK506 binding
protein 1A, 12 kDa BC005193 UFM1 ubiquitin-fold modifier 1
precursor BC005247 C10orf110 Homo sapiens uncharacterized
hypothalamus protein HT009 mRNA, complete cds. BC005259 XRCC4 X-ray
repair cross complementing protein 4 BC005334 CETN2 caltractin
BC005374 ERP44 thioredoxin domain containing 4 (endoplasmic
BC005807 SCD stearoyl-CoA desaturase 1 BC005810 CLEC11A stem cell
growth factor precursor BC005876 ATP6V0B ATPase, H+ transporting,
lysosomal 21 kDa, V0 BC005884 Unknown BC005896 HYAL3
hyaluronoglucosaminidase 3 precursor BC005903 POLR2L DNA directed
RNA polymerase II polypeptide L BC005924 PSG3 pregnancy specific
beta-1-glycoprotein 3 BC005931 hemoglobin, alpha 1 BC005980 UBE2D1
ubiquitin-conjugating enzyme E2D 1 BC006088 SERINC3 tumor
differentially expressed protein 1 BC006110 C7orf70 hypothetical
protein LOC84792 BC006163 dynactin 1 (p150, glued homolog,
Drosophila) BC006164 Unknown BC006211 SDF4 stromal cell derived
factor 4 isoform 2 BC006249 GUK1 guanylate kinase 1 isoform b
BC006270 Unknown BC006279 ZNF627 zinc finger protein 627 BC006362
PPAPDC3 phosphatidic acid phosphatase type 2 domain BC006373 SRD5A1
steroid-5-alpha-reductase 1 BC006374 ROR1 receptor tyrosine
kinase-like orphan receptor 1 BC006405 TXNDC17 thioredoxin-like 5
BC006422 PFKL RecName: Full = 6-phosphofructokinase, liver type; EC
= 2.7.1.11; AltName: Full = Phosphofructokinase 1; AltName: Full =
Phosphohexokinase; AltName: Full = Phosphofructo-1-kinase isozyme
B; Short = PFK-B; BC008034 CUEDC1 CUE domain-containing 1 BC008300
PCNXL2 pecanex-like 2 BC008410 PMS1 postmeiotic segregation 1
isoform a BC008745 CRTAP cartilage associated protein precursor
BC008992 docking protein 5 BC009735 Unknown BC010024 HKR1
GLI-Kruppel family member HKR1 BC010942 ACAT1 acetyl-Coenzyme A
acetyltransferase 1 precursor BC011002 Unknown BC012344 ZNF333 zinc
finger protein 333 BC012846 IDH1 isocitrate dehydrogenase 1
(NADP+), soluble BC013633 Unknown BC014207 ELMO2 engulfment and
cell motility 2 BC014579 AKR1C1 aldo-keto reductase family 1,
member C1 BC014974 YIF1B Yip1 interacting factor homolog B isoform
7 BC015232 transmembrane protein 136 BC015390 hypothetical protein
LOC644242 BC015429 Unknown BC015449 Unknown BC016291 Unknown
BC016828 ASAH1 N-acylsphingosine amidohydrolase 1 isoform b
BC017771 CCDC90B coiled-coil domain containing 90B precursor
BC017927 ERAP2 endoplasmic reticulum aminopeptidase 2 BC018336
HSD11B1L short-chain dehydrogenase/reductase 10 isoform BC018681
NDST2 heparan glucosaminyl BC018756 MOXD1 monooxygenase, DBH-like 1
isoform 2 BC019064 FAM40B hypothetical protein LOC57464 isoform a
BC020925 SLC38A10 solute carrier family 38, member 10 isoform a
BC021286 C1orf187 chromosome 1 open reading frame 187 precursor
BC021680 C5orf46 hypothetical protein LOC389336 precursor BC021861
LOC554202 Homo sapiens cDNA FLJ42400 fis, clone ASTRO2003581.
BC022066 ARMCX5 armadillo repeat containing, X-linked 5 BC022487
GCLC glutamate-cysteine ligase, catalytic subunit BC022967 DCAF5 WD
repeat domain 22 BC025250 METTL8 methyltransferase like 8 BC028703
LASS3 LAG1 longevity assurance homolog 3 BC029051 ARSB
arylsulfatase B isoform 1 precursor BC029442 Unknown BC029828
B4GALNT1 beta-1,4-N-acetyl-galactosaminyl transferase 1 BC030005
MCTP1 multiple C2 domains, transmembrane 1 isoform L BC030130 WFS1
wolframin BC031620 SNX19 sorting nexin 19 BC031811 Unknown BC032004
GRIA3 glutamate receptor, ionotrophic, AMPA 3 isoform BC032406
WDR78 WD repeat domain 78 isoform 1 BC033311 HAS1 hyaluronan
synthase 1 BC033513 TEX261 testis expressed sequence 261 BC033663
LAMA3 laminin alpha 3 subunit isoform 1 BC034236 hypothetical
protein MGC39821 BC034248 NBR2 Homo sapiens cDNA, FLJ17910.
BC034275 ASPHD1 aspartate beta-hydroxylase domain containing 1
BC035749 C13orf31 hypothetical protein LOC144811 BC036225
coiled-coil domain containing 147 BC036405 KIAA1908 Homo sapiens
mRNA for KIAA1908 protein, partial cds. BC036453 PHYHIPL
phytanoyl-CoA 2-hydroxylase interacting BC037317 KIAA1107
hypothetical protein LOC23285 BC037359 ZNF846 zinc finger protein
846 BC039509 hypothetical protein LOC340109 BC040924 SYT16
synaptotagmin XIV-like BC040952 PIK3C2A phosphoinositide-3-kinase,
class 2 alpha BC040965 RORA RAR-related orphan receptor A isoform b
BC041127 ALCAM activated leukocyte cell adhesion molecule BC041355
C3orf52 TPA-induced transmembrane protein BC041482 Unknown BC041664
BEST1 bestrophin 1 isoform 1 BC042510 CEL carboxyl ester lipase
precursor BC042953 Unknown BC043411 Unknown BE042976 PIK3IP1 HGFL
protein isoform 1 BE043477 ATP6V0E1 ATPase, H+ transporting,
lysosomal 9 kDa, V0 BE044272 DYNLL1 dynein light chain 1 BE044480
CYB5D2 cytochrome b5 domain containing 2 BE045549 MIB2 mindbomb
homolog 2 BE046443 CYLD ubiquitin carboxyl-terminal hydrolase CYLD
BE048525 Unknown BE048919 Unknown BE092211 CHID1 chitinase domain
containing 1 isoform b BE138888 Unknown BE147896 VPS53 vacuolar
protein sorting 53 isoform 1 BE217875 Unknown BE219277 HDAC11
histone deacetylase 11 isoform 1 BE220330 C7orf46 hypothetical
protein LOC340277 isoform 1 BE221817 Unknown BE222746 DUSP22 dual
specificity phosphatase 22 BE251303 Unknown BE262551 APC2
adenomatosis polyposis coli 2 BE271644 CDH23 cadherin-like 23
isoform 1 precursor BE301252 FLJ23867 SubName: Full = cDNA FLJ23867
fis, clone LNG09729; BE302191 STK38L serine/threonine kinase 38
like BE326919 SAT1 Synthetic construct DNA, clone: pF1KB8373, Homo
sapiens SAT1 gene for spermidine/spermine N1-acetyltransferase 1,
without stop codon, in Flexi system. BE328850 TLCD1 TLC domain
containing 1 isoform 2 BE348597 C3orf58 hypothetical protein
LOC205428 isoform a BE348679 NHSL2 NHS-like 2 BE349022 SUMF2
sulfatase modifying factor 2 isoform b BE349147 CPD
carboxypeptidase D precursor BE379006 CD59 CD59 antigen
preproprotein BE408081 C1orf122 hypothetical protein LOC127687
isoform 1 BE439489 XPR1 xenotropic and polytropic retrovirus
receptor BE465475 KLHL29 RecName: Full = Kelch-like protein 29;
AltName: Full = Kelch repeat and BTB domain-containing protein 9;
BE466675 IBSP integrin-binding sialoprotein precursor BE466825
ZNF565 zinc finger protein 565 BE501385 C12orf60 hypothetical
protein LOC144608 BE501464 TRIM4 tripartite motif protein TRIM4
isoform alpha BE501976 Unknown BE502785 ALCAM activated leukocyte
cell adhesion molecule BE502982 YPEL2 yippee-like 2 BE503425 LOX
lysyl oxidase preproprotein BE504180 STK10 serine/threonine kinase
10 BE541641 SLC38A10 solute carrier family 38, member 10 isoform a
BE547542 DCBLD1 discoidin, CUB and LCCL domain containing 1
BE549656 RCN1 reticulocalbin 1 precursor BE549937 FGF14 fibroblast
growth factor 14 isoform 1B BE550486 SLC2A3 SubName: Full = Solute
carrier family 2 (Facilitated glucose transporter), member 3,
isoform CRA_a; SubName: Full = cDNA, FLJ92716, Homo sapiens solute
carrier family 2 (facilitated glucosetransporter), member 3
(SLC2A3), mRNA; BE551877 FBXW7 F-box and WD repeat domain
containing 7 isoform BE565675 FAM45A hypothetical protein LOC404636
BE568660 CHURC1 churchill domain containing 1 BE615277 PVR
poliovirus receptor isoform alpha BE622627 PIK3R3
phosphoinositide-3-kinase, regulatory subunit 3 BE644809 PCDH7
protocadherin 7 isoform c precursor BE644818 SPPL2B signal peptide
peptidase-like 2B isoform 3 BE645771 GFPT1
glucosamine-fructose-6-phosphate BE646146 LOC729678 Homo sapiens
cDNA FLJ37851 fis, clone BRSSN2014294. BE646573 NFKBIZ nuclear
factor of kappa light polypeptide gene BE669858 SAMD9L sterile
alpha motif domain containing 9-like BE671156 Unknown BE671224
STK11 serine/threonine protein kinase 11 BE672313 FAM110B
hypothetical protein LOC90362 BE672499 MIR548F5 BE672676 Unknown
BE673226 Unknown BE673587 SLC14A1 solute carrier family 14 (urea
transporter), BE674089 LHFP lipoma HMGIC fusion partner precursor
BE674460 MAN1A1 mannosidase, alpha, class 1A, member 1 BE674466
Unknown BE675337 Unknown BE675516 NEAT1 Human MEN1 region clone
epsilon/beta mRNA, 3' fragment. BE677131 ANKRD6 ankyrin repeat
domain 6 BE740761 Unknown BE741920 NDUFA11 NADH dehydrogenase
(ubiquinone) 1 alpha BE744389 RNASEK ribonuclease kappa BE787063
Unknown
BE813017 SHC3 src homology 2 domain-containing transforming
BE856341 LAYN layilin BE857601 MAP1LC3A microtubule-associated
protein 1 light chain 3 BE869583 PRDX6 peroxiredoxin 6 BE875567
AGTRAP angiotensin II receptor-associated protein BE877420 Unknown
BE877796 MIR548G BE877955 Unknown BE880245 GNS glucosamine
(N-acetyl)-6-sulfatase precursor BE880828 MCFD2 multiple
coagulation factor deficiency 2 BE882538 TBC1D1 TBC1 (tre-2/USP6,
BUB2, cdc16) domain family, BE883841 Unknown BE886225 SAMD9L
sterile alpha motif domain containing 9-like BE888744 IFIT2
interferon-induced protein with BE889628 ERAP2 endoplasmic
reticulum aminopeptidase 2 BE890745 ARL1 ADP-ribosylation
factor-like 1 BE892293 Unknown BE892574 LACTB lactamase, beta
isoform a BE893893 MAP1LC3B microtubule-associated proteins 1A/1B
light BE895437 TK2 thymidine kinase 2, mitochondrial BE897886 RHOQ
ras-like protein TC10 precursor BE904551 CASC4 cancer
susceptibility candidate 4 isoform a BE906233 C1orf183 hypothetical
protein LOC55924 isoform 2 BE930512 MDM2 mouse double minute 2
homolog isoform MDM2 BE958291 MTAP 5'-methylthioadenosine
phosphorylase BE961916 FBXO18 F-box only protein, helicase, 18
isoform 1 BE962027 Unknown BE962299 C7orf42 hypothetical protein
LOC55069 BE962354 TCTN3 tectonic 3 isoform a precursor BE962615
Unknown BE963444 LYRM1 LYR motif containing 1 BE965311 METRN
meteorin, glial cell differentiation regulator BE966604 SAMD9L
sterile alpha motif domain containing 9-like BE966768 MXRA7
transmembrane anchor protein 1 isoform 2 BE967275 Unknown BE967311
Unknown BE967331 ALG2 alpha-1,3-mannosyltransferase ALG2 BE967532
Unknown BE971383 SAT1 Synthetic construct DNA, clone: pF1KB8373,
Homo sapiens SAT1 gene for spermidine/spermine N1-acetyltransferase
1, without stop codon, in Flexi system. BF000155 TRAF4 TNF
receptor-associated factor 4 BF001267 DOCK7 dedicator of
cytokinesis 7 BF002195 Unknown BF002844 COBLL1 COBL-like 1 BF003134
CLCA2 chloride channel accessory 2 precursor BF030331 LRRC8A
leucine rich repeat containing 8 family, member BF033242 CES2
carboxylesterase 2 isoform 2 BF035563 KIAA1324L hypothetical
protein LOC222223 isoform 1 BF055311 Unknown BF055343 GALNTL2
UDP-N-acetyl-alpha-D- galactosamine:polypeptide BF055474 PHF11 PHD
finger protein 11 isoform b BF056746 PAX8 paired box 8 isoform
PAX8A BF061003 KCNC4 Shaw-related voltage-gated potassium channel
BF061543 Unknown BF062384 SLC39A11 solute carrier family 39, member
11 isoform 1 BF062886 VRK3 vaccinia related kinase 3 isoform 1
BF063896 Unknown BF107618 PAPPA pregnancy-associated plasma protein
A BF108666 LOC375190 hypothetical protein LOC375190 BF108695
LOC285550 hypothetical protein LOC285550 BF109303 Unknown BF109660
OXR1 oxidation resistance 1 isoform 1 BF109854 ST7L suppression of
tumorigenicity 7-like isoform 1 BF111214 ADAMTSL1 ADAMTS-like 1
isoform 4 precursor BF111326 KCNJ2 potassium inwardly-rectifying
channel J2 BF111651 PPAPDC1B phosphatidic acid phosphatase type 2
domain BF112171 Unknown BF114745 Unknown BF116042 Unknown BF125756
GABARAPL1 GABA(A) receptor-associated protein like 1 BF130943
PPAPDC1A phosphatidic acid phosphatase type 2 domain BF195608
Unknown BF196943 USP53 ubiquitin specific protease 53 BF197222
PHF10 PHD finger protein 10 isoform a BF203664 Unknown BF215644
Unknown BF218115 HIPK2 homeodomain interacting protein kinase 2
isoform BF218804 ATP13A3 ATPase type 13A3 BF218922 VCAN versican
isoform 1 precursor BF221525 ROR1 receptor tyrosine kinase-like
orphan receptor 1 BF221547 PDE5A phosphodiesterase 5A isoform 1
BF222826 Unknown BF222867 Unknown BF240286 TOB1 transducer of
ERBB2, 1 BF242905 ALCAM activated leukocyte cell adhesion molecule
BF244081 C4orf3 hypothetical protein LOC401152 BF244402 FBXO32
F-box only protein 32 isoform 1 BF246115 MT1F metallothionein 1F
BF304759 LRP1 low density lipoprotein-related protein 1 BF308548
TUSC2 tumor suppressor candidate 2 BF337528 ORMDL3 ORM1-like 3
BF340123 RFK riboflavin kinase BF340635 ATP6V1G2 ATPase, H+
transporting, lysosomal, V1 subunit BF342661 MAP2
microtubule-associated protein 2 isoform 1 BF343672 DCPS mRNA
decapping enzyme BF344265 PBXIP1 pre-B-cell leukemia homeobox
interacting protein BF346014 IDS iduronate-2-sulfatase isoform a
precursor BF382281 BLOC1S2 biogenesis of lysosome-related
organelles BF382393 NAPEPLD N-acyl phosphatidylethanolamine
phospholipase D BF431309 LOC100130987 Homo sapiens cDNA FLJ38836
fis, clone MESAN2002519, weakly similar to Mus musculus cell cycle
checkpoint control protein Mrad9 gene. BF431973 ZNF397 zinc finger
protein 397 isoform 2 BF432276 Unknown BF432376 GALNTL2
UDP-N-acetyl-alpha-D- galactosamine:polypeptide BF432478 PINK1 PTEN
induced putative kinase 1 precursor BF432956 SCN2A sodium channel,
voltage-gated, type II, alpha BF433005 HGSNAT
heparan-alpha-glucosaminide N-acetyltransferase BF433180 Unknown
BF433475 ERCC6 excision repair cross-complementing rodent BF435617
Unknown BF435852 ACOX1 acyl-Coenzyme A oxidase 1 isoform b BF437602
ZNF561 zinc finger protein 561 BF438014 Unknown BF438386 Unknown
BF439451 CEBPZ CCAAT/enhancer binding protein zeta BF439488 EDEM3
ER degradation enhancer, mannosidase alpha- like BF445273 SLC3A1
solute carrier family 3, member 1 BF446673 HMCN1 hemicentin 1
precursor BF448048 SETD3 SET domain containing 3 isoform a BF476080
Unknown BF507342 PPM1K protein phosphatase 1K (PP2C domain
containing) BF508244 AKR1C2 aldo-keto reductase family 1, member C2
BF508344 Unknown BF510490 WDR26 WD repeat domain 26 isoform b
BF510581 BTBD11 BTB (POZ) domain containing 11 isoform a BF510588
TSHZ3 zinc finger protein 537 BF511231 Unknown BF512162 C3orf55
hypothetical protein LOC152078 isoform 1 BF512190 Unknown BF515031
KIFC2 kinesin family member C2 BF570193 MGAT4B
alpha-1,3-mannosyl-glycoprotein BF570412 ABHD12 abhydrolase domain
containing 12 isoform a BF575213 SOD2 manganese superoxide
dismutase isoform A BF575514 NAMPT nicotinamide
phosphoribosyltransferase BF589322 RSPO3 R-spondin 3 precursor
BF590274 TBCK TBC domain-containing protein kinase-like BF593252
ADSSL1 adenylosuccinate synthase like 1 isoform 2 BF593917 Unknown
BF663461 SLC38A10 solute carrier family 38, member 10 isoform a
BF666293 KDSR 3-ketodihydrosphingosine reductase precursor BF670447
RHOQ ras-like protein TC10 precursor BF672306 Unknown BF676462 SHC4
rai-like protein BF676980 GCLC glutamate-cysteine ligase, catalytic
subunit BF680588 STEAP2 six transmembrane epithelial antigen of the
BF691045 Unknown BF692332 SELT selenoprotein T precursor BF696757
Unknown BF699855 GALNT7 polypeptide
N-acetylgalactosaminyltransferase 7 BF718769 PPP1R7 protein
phosphatase 1, regulatory subunit 7 BF723626 MKLN1 muskelin 1,
intracellular mediator containing BF724137 C7orf58 hypothetical
protein LOC79974 isoform 1 BF724210 Unknown BF724944 MCART1 Homo
sapiens cDNA FLJ34088 fis, clone FCBBF3005698. BF726934 CPXM2
carboxypeptidase X (M14 family), member 2 BF732712 GPRASP2 G
protein-coupled receptor associated sorting BF792631 CDC14B CDC14
homolog B isoform 3 BF797381 CAMK2D calcium/calmodulin-dependent
protein kinase II BF939176 MYOZ2 myozenin 2 BF939292 STX4 syntaxin
4 BF939365 CALU calumenin isoform b precursor BF939833 DLEU2
BF939919 MAPKAP1 mitogen-activated protein kinase associated
BF940211 CCDC148 coiled-coil domain containing 148 BF940276 RFNG
radical fringe BF956762 MEG3 Homo sapiens MEG3 mRNA, partial
sequence, imprinted gene. BF966015 ZNF18 zinc finger protein 18
BF968134 MXRA7 transmembrane anchor protein 1 isoform 2 BF968960
TM2D1 beta-amyloid binding protein precursor BF969982 KCNC4
Shaw-related voltage-gated potassium channel BF970829 OSBPL8
oxysterol-binding protein-like protein 8 isoform BF973568 Unknown
BF974389 FAM89B family with sequence similarity 89, member B
BF977145 Unknown BF978611 MPZL1 myelin protein zero-like 1 isoform
a BF978689 RHOQ ras-like protein TC10 precursor BF982174 SDPR serum
deprivation response protein BF982927 SLC5A3 solute carrier family
5 (inositol transporters), BF983379 CD59 CD59 antigen preproprotein
BF983948 SRPRB signal recognition particle receptor, beta BF984227
SYNPO2 synaptopodin 2 isoform c BG027926 Unknown BG030576 BTBD8 BTB
(POZ) domain containing 8 BG031974 IGF2R insulin-like growth factor
2 receptor precursor BG054844 RND3 ras homolog gene family, member
E precursor BG107203 RABGAP1L RAB GTPase activating protein 1-like
isoform A BG107676 Unknown BG111808 Unknown BG112359 Unknown
BG122789 ARHGAP22 Rho GTPase activating protein 2 BG149557 RORA
RAR-related orphan receptor A isoform b BG163267 HSP90AB1 SubName:
Full = Heat shock protein 90 kDa alpha (Cytosolic), class B member
1, isoform CRA_a; SubName: Full = cDNA, FLJ92550, Homo sapiens heat
shock 90 kDa protein 1, beta (HSPCB), mRNA; BG163756 Unknown
BG164365 MAP1B microtubule-associated protein 1B BG167841 MOBKL2C
MOB1, Mps One Binder kinase activator-like 2C BG169689 SLC41A2
solute carrier family 41, member 2 BG170130 C6orf89 hypothetical
protein LOC221477 BG177759 WDR26 WD repeat domain 26 isoform b
BG200452 BANK1 B-cell scaffold protein with ankyrin repeats 1
BG230614 CD47 CD47 antigen isoform 1 precursor BG231932 TPP1
tripeptidyl-peptidase I preproprotein BG236006 Unknown BG250310
ZFP36L1 butyrate response factor 1 BG250585 Unknown BG251175 DLG1
discs, large homolog 1 isoform 1 BG252490 DNAJB4 DnaJ (Hsp40)
homolog, subfamily B, member 4 BG252899 Unknown BG260394 SNCA
alpha-synuclein isoform NACP140 BG260623 ZNF319 zinc finger protein
319 BG284890 Unknown BG285881 PRICKLE2 prickle-like 2 BG289443
Unknown BG290577 SPAG9 sperm associated antigen 9 isoform 1
BG291039 Unknown BG292040 Unknown BG292389 ERAP2 endoplasmic
reticulum aminopeptidase 2 BG292405 BG326045 BHLHE40 basic
helix-loop-helix family, member e40 BG326897 EXD3 exonuclease 3'-5'
domain containing 3 BG327863 TTTY14 BG339064 Unknown BG340967
TRAPPC1 trafficking protein particle complex 1 BG341906 ARF3
ADP-ribosylation factor 3 BG354573 PSG8 pregnancy specific
beta-1-glycoprotein 8 isoform BG386566 H2AFJ Homo sapiens cDNA
FLJ10903 fis, clone OVARC1000006, highly similar to HISTONE H2A.1.
BG427393 APLP2 amyloid beta (A4) precursor-like protein 2 BG432350
C20orf108 hypothetical protein LOC116151 BG434272 PAPPA
pregnancy-associated plasma protein A BG469257 MMP24 matrix
metalloproteinase 24 preproprotein BG475299 CTTN cortactin isoform
a BG501219 TMEM167A transmembrane protein 167A precursor BG534245
Unknown
BG537190 FTL ferritin, light polypeptide BG537255 Unknown BG538564
Unknown BG620958 Unknown BG913589 DNAJC3 DnaJ (Hsp40) homolog,
subfamily C, member 3 BI438189 Purified pancreatic islet BM128432
IGFBP5 insulin-like growth factor binding protein 5 BM677498
MGC23284 Homo sapiens hypothetical protein MGC23284, mRNA (cDNA
clone IMAGE: 4637796), partial cds. BM992214 Unknown BQ007522
Unknown BQ183759 Unknown BQ187042 Unknown BQ876971 CRTAP cartilage
associated protein precursor BU069195 C2orf74 hypothetical protein
LOC339804 isoform 1 BU074567 C14orf37 hypothetical protein
LOC145407 precursor BU078629 ZFYVE16 zinc finger, FYVE domain
containing 16 BU430052 FGD2 FYVE, RhoGEF and PH domain containing 2
CA431092 Unknown D10537 major structural protein of myelin D13287
MTX1 metaxin 1 isoform 1 D17391 COL4A4 alpha 4 type IV collagen
precursor D21089 XPC xeroderma pigmentosum, complementation group C
D29810 DCBLD2 discoidin, CUB and LCCL domain containing 2 D31421
SGMS2 sphingomyelin synthase 2 D38299 PTGER3 Homo sapiens PTGER3
mRNA for prostaglandin E receotor EP3 subtype 3 isoform, partial
cds, clone: FLJ80357SAAF. D43967 RUNX1 runt-related transcription
factor 1 isoform D45864 PRKG1 protein kinase, cGMP-dependent, type
I isoform D50579 CES2 carboxylesterase 2 isoform 2 D50683 TGFBR2
transforming growth factor, beta receptor II D63807 Unknown D79994
KANK1 KN motif and ankyrin repeat domains 1 isoform a D80010 LPIN1
lipin 1 D83485 PDIA3 protein disulfide-isomerase A3 precursor
D84105 CD46 CD46 antigen, complement regulatory protein D86586
CLEC11A stem cell growth factor precursor D86985 KIAA0232
hypothetical protein LOC9778 D87292 Rhodanese H04482 OSTM1
osteopetrosis associated transmembrane protein 1 H05023 RGS7BP
regulator of G-protein signaling 7 binding H05025 C5orf53
IgA-inducing protein precursor H07095 Unknown H10659 MMAA RecName:
Full = Putative L-type amino acid transporter 1-like protein MMAA;
AltName: Full = hLAT1 3-transmembrane protein MMAA; Short = hLAT1
3TM MMAA; H10766 GTF2F2 general transcription factor IIF,
polypeptide 2, H11075 HEATR7A HEAT repeat containing 7A isoform 1
H14241 SLC48A1 heme-responsive gene 1 H23979 CD200 CD200 antigen
isoform b H24398 C11orf87 hypothetical protein LOC399947 precursor
(see also AA633992 herein and Table 3) H25097 USP53 ubiquitin
specific protease 53 H27948 C17orf103 transcript expressed during
hematopoiesis 2 H72927 TMEM179B transmembrane protein 179B H84390
Unknown H89790 MEG3 Homo sapiens MEG3 mRNA, partial sequence,
imprinted gene. H93077 Unknown H97567 Unknown H98105 Unknown H98994
PLEKHA8 pleckstrin homology domain containing, family A J03202
LAMC1 laminin, gamma 1 precursor J03225 TFPI tissue factor pathway
inhibitor isoform a J04183 LAMP2 lysosomal-associated membrane
protein 2 isoform J04755 ferritin H processed pseudogene K02920 GBA
glucocerebrosidase precursor L06633 CYTIP cytohesin 1 interacting
protein L08835 Unknown L11315 DDR1 discoidin domain receptor
family, member 1 L11669 MFSD10 major facilitator superfamily domain
containing L12002 ITGA4 integrin alpha 4 precursor L12711 TKT
transketolase isoform 1 L13720 GAS6 growth arrest-specific 6
isoform 1 precursor L13852 UBA7 ubiquitin-like modifier activating
enzyme 7 L14611 RORA RAR-related orphan receptor A isoform b L16895
lysyl oxidase (LOX) L20817 DDR1 discoidin domain receptor family,
member 1 L27489 PTGER3 Homo sapiens PTGER3 mRNA for prostaglandin E
receotor EP3 subtype 3 isoform, partial cds, clone: FLJ80357SAAF.
L38019 ITPR1 inositol 1,4,5-triphosphate receptor, type 1 L38969
THBS3 thrombospondin 3 precursor L41690 TRADD TNFRSF1A-associated
via death domain L42374 PPP2R5B beta isoform of regulatory subunit
B56, protein M10943 metallothionein-If M11734 CSF2 colony
stimulating factor 2 precursor M14016 UROD uroporphyrinogen
decarboxylase M15329 IL1A interleukin 1, alpha proprotein M15330
interleukin 1-beta (IL1B) M22921 B4GALT1 UDP-Gal:betaGlcNAc beta
1,4- M25915 CLU clusterin isoform 2 M27968 FGF2 fibroblast growth
factor 2 M28880 ANK1 ankyrin 1 isoform 9 M31125 PSG6 pregnancy
specific beta-1-glycoprotein 6 isoform M32221 PSAP prosaposin
isoform a preproprotein M33376 pseudo-chlordecone reductase M33653
COL13A1 alpha 1 type XIII collagen isoform 1 M34421 PSG9 pregnancy
specific beta-1-glycoprotein 9 M34715 pregnancy-specific
beta-1-glycoprotein M55580 SAT1 Synthetic construct DNA, clone:
pF1KB8373, Homo sapiens SAT1 gene for spermidine/spermine
N1-acetyltransferase 1, without stop codon, in Flexi system. M55983
DNASE1 deoxyribonuclease I precursor M59916 SMPD1 sphingomyelin
phosphodiesterase 1, acid M59917 acid sphingomyelinase (ASM) M65062
IGFBP5 insulin-like growth factor binding protein 5 M68874 PLA2G4A
cytosolic phospholipase A2, group IVA M76453 CSF1 colony
stimulating factor 1 isoform c precursor M76477 GM2A GM2
ganglioside activator precursor M79321 LYN Yamaguchi sarcoma viral
(v-yes-1) oncogene M79462 PML promyelocytic leukemia protein
isoform 2 M81635 STOM stomatin isoform a M81768 SLC9A1 solute
carrier family 9, isoform A1 M83248 SPP1 secreted phosphoprotein 1
isoform a M87507 interleukin-1 beta convertase M95548 SLC3A1 solute
carrier family 3, member 1 M98399 CD36 CD36 antigen M98478 TGM2
transglutaminase 2 isoform a M98528 Unknown N20923 neuron-specific
protein; protein phosphatase inhibitor N20927 RAP2B RAP2B, member
of RAS oncogene family precursor N21202 Unknown N21643 Unknown
N22918 PPM1M protein phosphatase 1M isoform a N30152 Unknown N30169
PSG5 pregnancy specific beta-1-glycoprotein 5 N30209 CLVS1 N30649
SQSTM1 sequestosome 1 isoform 2 N33403 MYO10 myosin X N34514
Unknown N35896 PPFIBP1 PTPRF interacting protein binding protein 1
N36085 Unknown N36759 C6orf225 hypothetical protein LOC619208
N36762 Unknown N39536 NOMO3 nodal modulator 3 precursor N45228
GABBR1 gamma-aminobutyric acid (GABA) B receptor 1 N45309 PCYOX1
prenylcysteine oxidase 1 precursor N48315 PPARA peroxisome
proliferative activated receptor, N49852 NALCN voltage gated
channel like 1 N51370 Unknown N51413 Unknown N51708 Unknown N51836
Unknown N52532 SECISBP2L SECIS binding protein 2-like N52767 GTF2F2
general transcription factor IIF, polypeptide 2, N58363 Unknown
N63706 Unknown N63748 ZBTB4 zinc finger and BTB domain containing 4
N66571 Unknown N66633 LHFPL2 lipoma HMGIC fusion partner-like 2
N71074 SEC22A SEC22 vesicle trafficking protein homolog A N71923
Unknown N79662 GSTA4 glutathione S-transferase alpha 4 N90755 CAP2
adenylyl cyclase-associated protein 2 N92494 ARL6IP5
ADP-ribosylation-like factor 6 interacting N95414 ITGA2 integrin
alpha 2 precursor N95437 LMCD1 LIM and cysteine-rich domains 1
NM_000034 ALDOA fructose-bisphosphate aldolase A NM_000043 FAS
tumor necrosis factor receptor superfamily, NM_000046 ARSB
arylsulfatase B isoform 1 precursor NM_000049 ASPA aspartoacylase
NM_000055 BCHE butyrylcholinesterase precursor NM_000060 BTD
biotinidase precursor NM_000062 SERPING1 serpin peptidase
inhibitor, clade G, member 1 NM_000064 C3 complement component 3
precursor NM_000072 CD36 CD36 antigen NM_000077 CDKN2A
cyclin-dependent kinase inhibitor 2A isoform 3 NM_000081 LYST
lysosomal trafficking regulator NM_000099 CST3 cystatin C precursor
NM_000100 CSTB cystatin B NM_000107 DDB2 damage-specific DNA
binding protein 2 NM_000120 EPHX1 epoxide hydrolase 1 NM_000123
ERCC5 XPG-complementing protein NM_000124 ERCC6 excision repair
cross-complementing rodent NM_000132 F8 coagulation factor VIII
isoform a precursor NM_000137 FAH fumarylacetoacetase NM_000147
FUCA1 fucosidase, alpha-L-1, tissue precursor NM_000156 GAMT
guanidinoacetate N-methyltransferase isoform a NM_000161 GCH1 GTP
cyclohydrolase 1 isoform 1 NM_000163 GHR growth hormone receptor
precursor NM_000169 GLA alpha-galactosidase A precursor NM_000175
GPI glucose phosphate isomerase NM_000177 GSN gelsolin isoform c
NM_000183 HADHB mitochondrial trifunctional protein, beta NM_000191
HMGCL 3-hydroxy-3-methylglutaryl CoA lyase isoform 1 NM_000202 IDS
iduronate-2-sulfatase isoform a precursor NM_000203 IDUA
alpha-L-iduronidase precursor NM_000227 LAMA3 laminin alpha 3
subunit isoform 1 NM_000235 LIPA lipase A precursor NM_000247 MICA
RecName: Full = MHC class I polypeptide-related sequence A; Short =
MIC-A; Flags: Precursor; NM_000281 PCBD1 pterin-4
alpha-carbinolamine NM_000291 PGK1 phosphoglycerate kinase 1
NM_000297 PKD2 polycystin 2 NM_000305 PON2 paraoxonase 2 isoform 2
NM_000311 PRNP prion protein preproprotein NM_000376 VDR vitamin D
(1,25-dihydroxyvitamin D3) receptor NM_000381 MID1 midline 1
NM_000389 CDKN1A cyclin-dependent kinase inhibitor 1A NM_000391
TPP1 tripeptidyl-peptidase I preproprotein NM_000396 CTSK cathepsin
K preproprotein NM_000401 EXT2 exostosin 2 isoform 1 NM_000404 GLB1
galactosidase, beta 1 isoform b NM_000407 GP1BB glycoprotein Ib,
beta polypeptide precursor NM_000413 HSD17B1 hydroxysteroid
(17-beta) dehydrogenase 1 NM_000428 LTBP2 latent transforming
growth factor beta binding NM_000449 RFX5 regulatory factor X, 5
NM_000459 TEK TEK tyrosine kinase, endothelial precursor NM_000476
AK1 adenylate kinase 1 NM_000480 AMPD3 adenosine monophosphate
deaminase 3 isoform 1A NM_000484 APP amyloid beta A4 protein
isoform a precursor NM_000487 ARSA arylsulfatase A isoform b
NM_000501 ELN elastin isoform a precursor NM_000512 GALNS
galactosamine (N-acetyl)-6-sulfate sulfatase NM_000521 HEXB
hexosaminidase B preproprotein NM_000527 LDLR low density
lipoprotein receptor precursor NM_000558 HBA1 alpha 1 globin
NM_000576 IL1B interleukin 1, beta proprotein NM_000581 GPX1
glutathione peroxidase 1 isoform 1 NM_000584 IL8 interleukin 8
precursor NM_000585 IL15 interleukin 15 preproprotein NM_000593
TAP1 transporter 1, ATP-binding cassette, sub-family NM_000596
IGFBP1 insulin-like growth factor binding protein 1 NM_000599
IGFBP5 insulin-like growth factor binding protein 5 NM_000600 IL6
interleukin 6 precursor NM_000602 SERPINE1 plasminogen activator
inhibitor-1 isoform 1 NM_000611 CD59 CD59 antigen preproprotein
NM_000617 SLC11A2 solute carrier family 11 (proton-coupled
NM_000638 VTN vitronectin precursor NM_000640 IL13RA2 interleukin
13 receptor, alpha 2 precursor NM_000662 NAT1 N-acetyltransferase 1
isoform b NM_000679 ADRA1B alpha-1B-adrenergic receptor NM_000711
bone gamma-carboxyglutamate (gla) protein (replaced by (BGLAP)
NM_199173.4) NM_000714 TSPO translocator protein isoform PBR
NM_000717 CA4 carbonic anhydrase IV precursor NM_000722 CACNA2D1
calcium channel, voltage-dependent, alpha NM_000757 CSF1 colony
stimulating factor 1 isoform c precursor NM_000765 CYP3A7
cytochrome P450, family 3, subfamily A, NM_000786 CYP51A1
cytochrome P450, family 51, subfamily A, NM_000801 FKBP1A FK506
binding protein 1A, 12 kDa
NM_000804 FOLR3 folate receptor 3 precursor NM_000817 GAD1
glutamate decarboxylase 1 isoform GAD67 NM_000820 GAS6 growth
arrest-specific 6 isoform 1 precursor NM_000824 GLRB glycine
receptor, beta isoform A precursor NM_000852 GSTP1 glutathione
transferase NM_000876 IGF2R insulin-like growth factor 2 receptor
precursor NM_000885 ITGA4 integrin alpha 4 precursor NM_000899
KITLG KIT ligand isoform b precursor NM_000901 NR3C2 nuclear
receptor subfamily 3, group C, member 2 NM_000916 OXTR oxytocin
receptor NM_000919 PAM peptidylglycine alpha-amidating
monooxygenase NM_000930 PLAT plasminogen activator, tissue isoform
1 NM_000933 PLCB4 phospholipase C beta 4 isoform a NM_000942 PPIB
peptidylprolyl isomerase B precursor NM_000965 RARB retinoic acid
receptor, beta isoform 1 NM_001001548 CD36 CD36 antigen
NM_001001669 FLJ41603 hypothetical protein LOC389337 NM_001001713
SH3BGR SH3-binding domain and glutamic acid-rich NM_001017974 P4HA2
prolyl 4-hydroxylase, alpha II subunit isoform 2 NM_001030050 KLK3
prostate specific antigen isoform 5 NM_001031702 SEMA5B semaphorin
5B isoform 1 NM_001032409 OAS1 2',5'-oligoadenylate synthetase 1
isoform 3 NM_001033053 NLRP1 NLR family, pyrin domain containing 1
isoform 1 NM_001047 SRD5A1 steroid-5-alpha-reductase 1 NM_001055
SULT1A1 sulfotransferase family, cytosolic, 1A, NM_001083 PDE5A
phosphodiesterase 5A isoform 1 NM_001108 acylphosphatase 2, muscle
type (ACYP2), (replaced by NM_138448.3) NM_001110 ADAM10 ADAM
metallopeptidase domain 10 precursor NM_001124 ADM adrenomedullin
precursor NM_001146 ANGPT1 angiopoietin 1 precursor NM_001151
SLC25A4 adenine nucleotide translocator 1 NM_001153 ANXA4 annexin
IV NM_001154 ANXA5 annexin 5 NM_001159 AOX1 aldehyde oxidase 1
NM_001174 unknown NM_001183 ATP6AP1 ATPase, H+ transporting,
lysosomal accessory NM_001196 BID BH3 interacting domain death
agonist isoform 2 NM_001200 BMP2 bone morphogenetic protein 2
preproprotein NM_001216 CA9 carbonic anhydrase IX precursor
NM_001251 CD68 CD68 antigen isoform B NM_001252 CD70 tumor necrosis
factor ligand superfamily, member NM_001257 CDH13 cadherin 13
preproprotein NM_001259 CDK6 cyclin-dependent kinase 6 NM_001268
RCBTB2 regulator of chromosome condensation and BTB NM_001283 AP1S1
adaptor-related protein complex 1, sigma 1 NM_001304 CPD
carboxypeptidase D precursor NM_001330 CTF1 cardiotrophin 1 isoform
1 NM_001343 DAB2 disabled homolog 2 NM_001344 DAD1 defender against
cell death 1 NM_001345 DGKA diacylglycerol kinase, alpha 80 kDa
NM_001346 DGKG diacylglycerol kinase gamma isoform 1 NM_001353
AKR1C1 aldo-keto reductase family 1, member C1 NM_001355 DDT
D-dopachrome tautomerase NM_001360 DHCR7 7-dehydrocholesterol
reductase NM_001386 DPYSL2 dihydropyrimidinase-like 2 NM_001397
ECE1 endothelin converting enzyme 1 isoform 4 NM_001442 FABP4 fatty
acid binding protein 4, adipocyte NM_001448 GPC4 glypican 4
precursor NM_001458 FLNC gamma filamin isoform a NM_001478 B4GALNT1
beta-1,4-N-acetyl-galactosaminyl transferase 1 NM_001498 GCLC
glutamate-cysteine ligase, catalytic subunit NM_001511 CXCL1
chemokine (C--X--C motif) ligand 1 NM_001518 GTF2I general
transcription factor IIi isoform 1 NM_001531 MR1 major
histocompatibility complex, class NM_001540 HSPB1 heat shock
protein beta-1 NM_001547 IFIT2 interferon-induced protein with
NM_001548 IFIT1 interferon-induced protein with NM_001549 IFIT3
interferon-induced protein with NM_001552 IGFBP4 insulin-like
growth factor binding protein 4 NM_001553 IGFBP7 insulin-like
growth factor binding protein 7 NM_001565 CXCL10 small inducible
cytokine B10 precursor NM_001611 ACP5 acid phosphatase 5, tartrate
resistant NM_001628 AKR1B1 aldo-keto reductase family 1, member B1
NM_001642 APLP2 amyloid beta (A4) precursor-like protein 2
NM_001647 APOD apolipoprotein D precursor NM_001660 ARF4
ADP-ribosylation factor 4 NM_001684 ATP2B4 plasma membrane calcium
ATPase 4 isoform 4a NM_001724 BPGM bisphosphoglycerate mutase
NM_001752 CAT catalase NM_001780 CD63 CD63 antigen isoform A
NM_001792 CDH2 cadherin 2, type 1 preproprotein NM_001797 CDH11
cadherin 11, type 2 preproprotein NM_001807 CEL carboxyl ester
lipase precursor NM_001823 CKB brain creatine kinase NM_001846
COL4A2 alpha 2 type IV collagen preproprotein NM_001860 SLC31A2
solute carrier family 31 (copper transporters), NM_001873 CPE
carboxypeptidase E preproprotein NM_001893 CSNK1D casein kinase 1,
delta isoform 2 NM_001908 CTSB cathepsin B preproprotein NM_001909
CTSD cathepsin D preproprotein NM_001913 CUX1 cut-like homeobox 1
isoform b NM_001914 CYB5A cytochrome b-5 isoform 2 NM_001920 DCN
decorin isoform a preproprotein NM_001924 GADD45A growth arrest and
DNA-damage-inducible, alpha NM_001954 DDR1 discoidin domain
receptor family, member 1 NM_001957 EDNRA endothelin receptor type
A isoform a precursor NM_001967 EIF4A2 eukaryotic translation
initiation factor 4A2 NM_001985 ETFB
electron-transfer-flavoprotein, beta polypeptide NM_001999 FBN2
fibrillin 2 precursor NM_002004 farnesyl diphosphate synthase
(FDPS) NM_002006 FGF2 fibroblast growth factor 2 NM_002016 FLG
filaggrin NM_002032 FTH1 ferritin, heavy polypeptide 1 NM_002056
GFPT1 glucosamine-fructose-6-phosphate NM_002064 GLRX glutaredoxin
(thioltransferase) NM_002081 GPC1 glypican 1 precursor NM_002087
GRN granulin precursor NM_002133 HMOX1 heme oxygenase (decyclizing)
1 NM_002162 ICAM3 intercellular adhesion molecule 3 precursor
NM_002184 IL6ST interleukin 6 signal transducer isoform 1 NM_002189
IL15RA interleukin 15 receptor, alpha isoform 2 NM_002197 ACO1
aconitase 1 NM_002198 IRF1 interferon regulatory factor 1 NM_002203
ITGA2 integrin alpha 2 precursor NM_002204 ITGA3 integrin alpha 3
isoform a precursor NM_002205 ITGA5 integrin alpha 5 precursor
NM_002213 ITGB5 integrin, beta 5 precursor NM_002227 JAK1 janus
kinase 1 NM_002231 CD82 CD82 antigen isoform 1 NM_002254 KIF3C
kinesin family member 3C NM_002275 KRT15 keratin 15 NM_002290 LAMA4
laminin, alpha 4 isoform 2 precursor NM_002291 LAMB1 laminin, beta
1 precursor NM_002294 LAMP2 lysosomal-associated membrane protein 2
isoform NM_002309 LIF leukemia inhibitory factor (cholinergic
NM_002317 LOX lysyl oxidase preproprotein NM_002332 LRP1 low
density lipoprotein-related protein 1 NM_002337 LRPAP1 low density
lipoprotein receptor-related protein NM_002350 LYN Yamaguchi
sarcoma viral (v-yes-1) oncogene NM_002357 MXD1 MAX dimerization
protein 1 NM_002372 MAN2A1 mannosidase, alpha, class 2A, member 1
NM_002389 CD46 CD46 antigen, complement regulatory protein
NM_002392 MDM2 mouse double minute 2 homolog isoform MDM2 NM_002395
ME1 SubName: Full = Cadherin; Flags: Fragment; NM_002406 MGAT1
mannosyl (alpha-1,3-)-glycoprotein NM_002407 SCGB2A1 secretoglobin,
family 2A, member 1 precursor NM_002408 MGAT2 mannosyl
(alpha-1,6-)-glycoprotein NM_002425 MMP10 matrix metalloproteinase
10 preproprotein NM_002426 MMP12 matrix metalloproteinase 12
preproprotein NM_002448 MSX1 msh homeobox 1 NM_002450
metallothionein 1L (gene/pseudogene) (MT1L NM_002463 MX2 myxovirus
resistance protein 2 NM_002477 MYL5 myosin regulatory light chain 5
NM_002513 NME3 nucleoside diphosphate kinase 3 NM_002517 NPAS1
neuronal PAS domain protein 1 NM_002518 NPAS2 neuronal PAS domain
protein 2 NM_002527 NTF3 neurotrophin 3 isoform 1 preproprotein
NM_002555 SLC22A18 tumor suppressing subtransferable candidate 5
NM_002560 P2RX4 purinergic receptor P2X4 NM_002575 SERPINB2 serine
(or cysteine) proteinase inhibitor, clade NM_002581 PAPPA
pregnancy-associated plasma protein A NM_002589 PCDH7 protocadherin
7 isoform c precursor NM_002626 PFKL RecName: Full =
6-phosphofructokinase, liver type; EC = 2.7.1.11; AltName: Full =
Phosphofructokinase 1; AltName: Full = Phosphohexokinase; AltName:
Full = Phosphofructo-1-kinase isozyme B; Short = PFK-B; NM_002631
PGD phosphogluconate dehydrogenase NM_002647 PIK3C3 catalytic
phosphatidylinositol 3-kinase 3 NM_002675 PML promyelocytic
leukemia protein isoform 2 NM_002676 PMM1 phosphomannomutase 1
NM_002778 PSAP prosaposin isoform a preproprotein NM_002780 PSG4
pregnancy specific beta-1-glycoprotein 4 isoform NM_002781 PSG5
pregnancy specific beta-1-glycoprotein 5 NM_002782 PSG6 pregnancy
specific beta-1-glycoprotein 6 isoform NM_002783 PSG7 pregnancy
specific beta-1-glycoprotein 7 NM_002784 PSG9 pregnancy specific
beta-1-glycoprotein 9 NM_002830 PTPN4 protein tyrosine phosphatase,
non-receptor type NM_002845 PTPRM protein tyrosine phosphatase,
receptor type, M NM_002848 PTPRO receptor-type protein tyrosine
phosphatase O NM_002849 PTPRR protein tyrosine phosphatase,
receptor type, R NM_002870 RAB13 RAB13, member RAS oncogene family
NM_002886 RAP2B RAP2B, member of RAS oncogene family precursor
NM_002923 RGS2 regulator of G-protein signaling 2 NM_002924 RGS7
regulator of G-protein signaling 7 NM_002963 S100A7 S100 calcium
binding protein A7 NM_002970 SAT1 Synthetic construct DNA, clone:
pF1KB8373, Homo sapiens SAT1 gene for spermidine/spermine
N1-acetyltransferase 1, without stop codon, in Flexi system.
NM_002975 CLEC11A stem cell growth factor precursor NM_002977 SCN9A
sodium channel, voltage-gated, type IX, alpha NM_002979 SCP2 sterol
carrier protein 2 isoform 1 proprotein NM_002985 CCL5 small
inducible cytokine A5 precursor NM_003009 SEPW1 selenoprotein W, 1
NM_003012 SFRP1 secreted frizzled-related protein 1 precursor
NM_003014 SFRP4 secreted frizzled-related protein 4 precursor
NM_003022 SH3BGRL SH3 domain binding glutamic acid-rich protein
NM_003038 SLC1A4 solute carrier family 1, member 4 isoform 1
NM_003059 SLC22A4 solute carrier family 22 member 4 NM_003060
SLC22A5 solute carrier family 22 member 5 NM_003134 SRP14 signal
recognition particle 14 kDa (homologous NM_003144 SSR1 signal
sequence receptor, alpha precursor NM_003151 STAT4 signal
transducer and activator of transcription NM_003165 STXBP1 syntaxin
binding protein 1 isoform a NM_003172 SURF1 surfeit 1 NM_003174
SVIL supervillin isoform 2 NM_003236 TGFA transforming growth
factor, alpha isoform 1 NM_003238 TGFB2 transforming growth factor,
beta 2 isoform 1 NM_003242 TGFBR2 transforming growth factor, beta
receptor II NM_003244 TGIF1 TG-interacting factor isoform c
NM_003246 THBS1 thrombospondin 1 precursor NM_003254 TIMP1 tissue
inhibitor of metalloproteinase 1 NM_003265 TLR3 toll-like receptor
3 precursor NM_003272 GPR137B G protein-coupled receptor 137B
NM_003275 TMOD1 tropomodulin 1 NM_003289 TPM2 tropomyosin 2 (beta)
isoform 2 NM_003326 TNFSF4 tumor necrosis factor (ligand)
superfamily, NM_003330 TXNRD1 thioredoxin reductase 1 isoform 3
NM_003344 UBE2H ubiquitin-conjugating enzyme E2H isoform 1
NM_003433 ZNF132 zinc finger protein 132 NM_003451 ZNF177 zinc
finger protein 177 NM_003469 SCG2 secretogranin II precursor
NM_003475 RASSF7 Ras association (RalGDS/AF-6) domain family
NM_003492 TMEM187 transmembrane protein 187 NM_003494 DYSF
dysferlin isoform 12 NM_003516 HIST2H2AA3 histone cluster 2, H2aa3
NM_003517 HIST2H2AC histone cluster 2, H2ac NM_003528 HIST2H2BE
histone cluster 2, H2be NM_003543 HIST1H4H histone cluster 1, H4h
NM_003548 HIST2H4A histone cluster 2, H4a NM_003588 CUL4B cullin 4B
isoform 1 NM_003595 TPST2 tyrosylprotein sulfotransferase 2
NM_003596 TPST1 tyrosylprotein sulfotransferase 1 NM_003619 PRSS12
neurotrypsin precursor NM_003620 PPM1D protein phosphatase 1D
NM_003622 PPFIBP1 PTPRF interacting protein binding protein 1
NM_003633 ENC1 ectodermal-neural cortex (with BTB-like domain)
NM_003635 NDST2 heparan glucosaminyl NM_003641 IFITM1 interferon
induced transmembrane protein 1 NM_003670 BHLHE40 basic
helix-loop-helix family, member e40 NM_003676 DEGS1 degenerative
spermatocyte homolog 1, lipid NM_003688 CASK
calcium/calmodulin-dependent serine protein NM_003725 HSD17B6
hydroxysteroid (17-beta) dehydrogenase 6 NM_003730 RNASET2
ribonuclease T2 precursor NM_003733 OASL 2'-5'-oligoadenylate
synthetase-like isoform a NM_003744 NUMB numb homolog isoform 1
NM_003746 DYNLL1 dynein light chain 1 NM_003748 ALDH4A1 aldehyde
dehydrogenase 4A1 isoform a precursor NM_003768 PEA15
phosphoprotein enriched in astrocytes 15 NM_003784 SERPINB7 serine
(or cysteine) proteinase inhibitor, clade NM_003789 TRADD
TNFRSF1A-associated via death domain NM_003790 TNFRSF25 tumor
necrosis factor receptor superfamily, NM_003793 CTSF cathepsin F
precursor NM_003811 TNFSF9 tumor necrosis factor (ligand)
superfamily,
NM_003812 ADAM23 ADAM metallopeptidase domain 23 preproprotein
NM_003813 ADAM21 ADAM metallopeptidase domain 21 preproprotein
NM_003825 SNAP23 synaptosomal-associated protein 23 isoform
NM_003851 CREG1 cellular repressor of E1A-stimulated genes
NM_003878 GGH gamma-glutamyl hydrolase precursor NM_003879 CFLAR
CASP8 and FADD-like apoptosis regulator isoform NM_003896 ST3GAL5
ST3 beta-galactoside alpha-2,3-sialyltransferase NM_003900 SQSTM1
sequestosome 1 isoform 2 NM_003928 Unknown NM_003945 ATP6V0E1
ATPase, H+ transporting, lysosomal 9 kDa, V0 NM_003992 CLK3
CDC-like kinase 3 isoform a NM_004010 DMD dystrophin Dp427p1
isoform NM_004030 Unknown NM_004045 ATOX1 antioxidant protein 1
NM_004048 B2M beta-2-microglobulin precursor NM_004059 CCBL1
kynurenine aminotransferase I isoform a NM_004073 PLK3 polo-like
kinase 3 NM_004110 FDXR ferredoxin reductase isoform 2 precursor
NM_004138 KRT33A keratin 33A NM_004148 NINJ1 ninjurin 1 NM_004161
RAB1A RAB1A, member RAS oncogene family isoform 1 NM_004163 RAB27B
RAB27B, member RAS oncogene family NM_004165 RRAD Ras-related
associated with diabetes NM_004170 SLC1A1 solute carrier family 1,
member 1 NM_004221 IL32 interleukin 32 isoform A NM_004233 CD83
CD83 antigen isoform b NM_004265 FADS2 fatty acid desaturase 2
NM_004290 RNF14 ring finger protein 14 isoform 1 NM_004318 ASPH
aspartate beta-hydroxylase isoform a NM_004327 BCR Homo sapiens
breakpoint cluster region, mRNA (cDNA clone IMAGE: 4500154).
NM_004339 PTTG1IP pituitary tumor-transforming gene 1 NM_004343
CALR calreticulin precursor NM_004346 CASP3 caspase 3 preproprotein
NM_004356 CD81 CD81 antigen NM_004357 CD151 CD151 antigen NM_004381
ATF6B activating transcription factor 6 beta isoform NM_004388 CTBS
chitobiase, di-N-acetyl-precursor NM_004403 DFNA5 deafness,
autosomal dominant 5 protein isoform NM_004411 DYNC1I1 dynein,
cytoplasmic 1, intermediate chain 1 NM_004414 RCAN1 calcipressin 1
isoform b NM_004490 GRB14 growth factor receptor-bound protein 14
NM_004508 IDI1 isopentenyl-diphosphate delta isomerase NM_004509
SP110 SP110 nuclear body protein isoform c NM_004542 NDUFA3 NADH
dehydrogenase (ubiquinone) 1 alpha NM_004545 NDUFB1 NADH
dehydrogenase (ubiquinone) 1 beta NM_004546 NDUFB2 NADH
dehydrogenase (ubiquinone) 1 beta NM_004556 NFKBIE nuclear factor
of kappa light polypeptide gene NM_004591 CCL20 chemokine (C-C
motif) ligand 20 isoform 1 NM_004614 TK2 thymidine kinase 2,
mitochondrial NM_004642 CDK2AP1 CDK2-associated protein 1 NM_004649
C21orf33 es1 protein isoform Ia precursor NM_004657 SDPR serum
deprivation response protein NM_004668 MGAM maltase-glucoamylase
NM_004688 NMI N-myc and STAT interactor NM_004696 SLC16A4 solute
carrier family 16, member 4 NM_004710 SYNGR2 synaptogyrin 2
NM_004734 DCLK1 doublecortin-like kinase 1 NM_004748 CCPG1 cell
cycle progression 1 isoform 2 NM_004751 GCNT3 glucosaminyl
(N-acetyl) transferase 3, mucin NM_004753 DHRS3
dehydrogenase/reductase (SDR family) member 3 NM_004791 ITGBL1
integrin, beta-like 1 (with EGF-like repeat NM_004815 ARHGAP29
PTPL1-associated RhoGAP 1 NM_004862 LITAF
lipopolysaccharide-induced TNF-alpha factor NM_004899 BRE brain and
reproductive organ-expressed (TNFRSF1A NM_004905 PRDX6
peroxiredoxin 6 NM_004932 CDH6 cadherin 6, type 2 preproprotein
NM_004934 CDH18 cadherin 18, type 2 preproprotein NM_004938 DAPK1
death-associated protein kinase 1 NM_005010 NRCAM neuronal cell
adhesion molecule isoform A NM_005019 PDE1A phosphodiesterase 1A
isoform 1 NM_005020 PDE1C phosphodiesterase 1C NM_005044 PRKX
protein kinase, X-linked NM_005065 SEL1L sel-1 suppressor of
lin-12-like precursor NM_005098 MSC musculin NM_005101 ISG15 ISG15
ubiquitin-like modifier precursor NM_005103 FEZ1 zygin 1 isoform 1
NM_005113 GOLGA5 Golgi autoantigen, golgin subfamily a, 5 NM_005123
NR1H4 nuclear receptor subfamily 1, group H, member 4 NM_005125 CCS
copper chaperone for superoxide dismutase NM_005167 PPM1J protein
phosphatase 1J (PP2C domain containing) NM_005168 RND3 ras homolog
gene family, member E precursor NM_005195 CEBPD CCAAT/enhancer
binding protein delta NM_005200 paraplegia 7 (pure and complicated
autosomal (replaced by recessive) (SPG7) NM_003119.2) NM_005204
MAP3K8 mitogen-activated protein kinase kinase kinase NM_005213
CSTA cystatin A NM_005245 FAT1 FAT tumor suppressor 1 precursor
NM_005319 HIST1H1C histone cluster 1, H1c NM_005326 HAGH
hydroxyacylglutathione hydrolase isoform 2 NM_005340 HINT1 Homo
sapiens cDNA: FLJ22904 fis, clone KAT05632. NM_005345 HSPA1A heat
shock 70 kDa protein 1A NM_005346 HSPA1B heat shock 70 kDa protein
1B NM_005354 JUND jun D proto-oncogene NM_005393 PLXNB3 plexin B3
isoform 2 NM_005419 STAT2 signal transducer and activator of
transcription NM_005505 SCARB1 scavenger receptor class B, member 1
isoform 2 NM_005506 SCARB2 scavenger receptor class B, member 2
NM_005512 LRRC32 leucine rich repeat containing 32 precursor
NM_005525 HSD11B1 11-beta-hydroxysteroid dehydrogenase 1 NM_005528
DNAJC4 DnaJ (Hsp40) homolog, subfamily C, member 4 NM_005532 IFI27
interferon, alpha-inducible protein 27 isoform NM_005533 IFI35
interferon-induced protein 35 NM_005541 INPP5D SH2 containing
inositol phosphatase isoform a NM_005547 IVL involucrin NM_005557
KRT16 keratin 16 NM_005561 LAMP1 lysosomal-associated membrane
protein 1 NM_005567 LGALS3BP galectin 3 binding protein NM_005569
LIMK2 LIM domain kinase 2 isoform 2a NM_005575 LNPEP
leucyl/cystinyl aminopeptidase isoform 1 NM_005584 MAB21L1
mab-21-like protein 1 NM_005625 SDCBP syntenin isoform 3 NM_005642
TAF7 TATA box-binding protein-associated factor 2F NM_005645 TAF13
TBP-associated factor 13 NM_005665 EVI5 ecotropic viral integration
site 5 NM_005667 RNF103 ring finger protein 103 NM_005713 COL4A3BP
alpha 3 type IV collagen binding protein isoform NM_005715 UST
uronyl-2-sulfotransferase NM_005720 ARPC1B actin related protein
2/3 complex subunit 1B NM_005724 TSPAN3 transmembrane 4 superfamily
member 8 isoform 1 NM_005745 BCAP31 B-cell receptor-associated
protein 31 isoform a NM_005755 EBI3 Epstein-Barr virus induced 3
precursor NM_005756 GPR64 G protein-coupled receptor 64 isoform 1
NM_005765 ATP6AP2 ATPase, H+ transporting, lysosomal accessory
NM_005780 LHFP lipoma HMGIC fusion partner precursor NM_005794
DHRS2 dehydrogenase/reductase member 2 isoform 2 NM_005817 PLIN3
mannose 6 phosphate receptor binding protein 1 NM_005824 LRRC17
leucine rich repeat containing 17 isoform 2 NM_005875 EIF1B
translation factor sui1 homolog NM_005896 IDH1 isocitrate
dehydrogenase 1 (NADP+), soluble NM_005899 NBR1 neighbor of BRCA1
gene 1 NM_005907 MAN1A1 mannosidase, alpha, class 1A, member 1
NM_005908 MANBA mannosidase, beta A, lysosomal precursor NM_005926
MFAP1 microfibrillar-associated protein 1 NM_005935 AFF1
myeloid/lymphoid or mixed-lineage leukemia NM_005950 MT1G
metallothionein 1G NM_005951 MT1H metallothionein 1H NM_005952 MT1X
metallothionein 1X NM_005965 Unknown NM_005979 S100A13 S100 calcium
binding protein A13 NM_006002 UCHL3 ubiquitin carboxyl-terminal
esterase L3 NM_006005 WFS1 wolframin NM_006010 MANF mesencephalic
astrocyte-derived neurotrophic NM_006019 TCIRG1 T-cell, immune
regulator 1 isoform a NM_006024 TAX1BP1 Tax1 (human T-cell leukemia
virus type I) NM_006033 LIPG endothelial lipase precursor NM_006038
SPATA2 spermatogenesis associated 2 NM_006058 TNIP1 TNFAIP3
interacting protein 1 NM_006096 NDRG1 N-myc downstream regulated 1
NM_006102 carboxypeptidase Q (CPQ) (replaced by NM_016134.3)
NM_006106 YAP1 Yes-associated protein 1, 65 kDa isoform 1 NM_006113
VAV3 vav 3 guanine nucleotide exchange factor isoform NM_006134
TMEM50B transmembrane protein 50B NM_006141 DYNC1LI2 dynein,
cytoplasmic, light intermediate NM_006145 DNAJB1 DnaJ (Hsp40)
homolog, subfamily B, member 1 NM_006200 PCSK5 proprotein
convertase subtilisin/kexin type 5 NM_006223 PIN4 protein
(peptidyl-prolyl cis/trans isomerase) NM_006227 PLTP phospholipid
transfer protein isoform a NM_006244 PPP2R5B beta isoform of
regulatory subunit B56, protein NM_006255 PRKCH protein kinase C,
eta NM_006256 PKN2 protein kinase N2 NM_006258 PRKG1 protein
kinase, cGMP-dependent, type I isoform NM_006260 DNAJC3 DnaJ
(Hsp40) homolog, subfamily C, member 3 NM_006285 TESK1
testis-specific protein kinase 1 NM_006290 TNFAIP3 tumor necrosis
factor, alpha-induced protein 3 NM_006307 SRPX
sushi-repeat-containing protein, X-linked NM_006315 PCGF3 ring
finger protein 3 NM_006332 IFI30 interferon, gamma-inducible
protein 30 NM_006349 ZNHIT1 zinc finger, HIT domain containing 1
NM_006369 LRRC41 MUF1 protein NM_006384 CIB1 calcium and integrin
binding 1 NM_006404 PROCR endothelial protein C receptor precursor
NM_006406 PRDX4 peroxiredoxin 4 NM_006407 ARL6IP5
ADP-ribosylation-like factor 6 interacting NM_006416 SLC35A1 solute
carrier family 35 (CMP-sialic acid NM_006423 RABAC1 Rab acceptor 1
NM_006426 DPYSL4 dihydropyrimidinase-like 4 NM_006462 RBCK1
RanBP-type and C3HC4-type zinc finger containing NM_006472 TXNIP
thioredoxin interacting protein NM_006493 CLN5
ceroid-lipofuscinosis, neuronal 5 NM_006505 PVR poliovirus receptor
isoform alpha NM_006517 SLC16A2 solute carrier family 16, member 2
NM_006520 DYNLT3 dynein, light chain, Tctex-type 3 NM_006526 ZNF217
zinc finger protein 217 NM_006536 CLCA2 chloride channel accessory
2 precursor NM_006542 SPHAR S-phase response (cyclin-related)
NM_006547 IGF2BP3 insulin-like growth factor 2 mRNA binding
NM_006577 B3GNT2 UDP-GlcNAc:betaGal NM_006608 PHTF1 putative
homeodomain transcription factor 1 NM_006634 VAMP5
vesicle-associated membrane protein 5 NM_006642 SDCCAG8
serologically defined colon cancer antigen 8 NM_006670 TPBG
trophoblast glycoprotein precursor NM_006675 TSPAN9 tetraspanin 9
NM_006676 USP20 ubiquitin specific protease 20 NM_006682 FGL2
fibrinogen-like 2 precursor NM_006698 BLCAP bladder cancer
associated protein NM_006702 PNPLA6 neuropathy target esterase
isoform b NM_006720 ABLIM1 actin-binding LIM protein 1 isoform c
NM_006727 CDH10 cadherin 10, type 2 preproprotein NM_006730
DNASE1L1 deoxyribonuclease I-like 1 precursor NM_006755 TALDO1
transaldolase 1 NM_006759 UGP2 UDP-glucose pyrophosphorylase 2
isoform a NM_006763 BTG2 B-cell translocation gene 2 NM_006767
LZTR1 leucine-zipper-like transcription regulator 1 NM_006803 AP3M2
adaptor-related protein complex 3, mu 2 subunit NM_006810 PDIA5
protein disulfide isomerase A5 precursor NM_006822 RAB40B RAB40B,
member RAS oncogene family NM_006823 PKIA cAMP-dependent protein
kinase inhibitor alpha NM_006829 C10orf116 adipose specific 2
NM_006830 UQCR ubiquinol-cytochrome c reductase, 6.4 kDa NM_006851
GLIPR1 GLI pathogenesis-related 1 precursor NM_006876 B3GNT1
UDP-GlcNAc:betaGal NM_006905 PSG1 pregnancy specific
beta-1-glycoprotein 1 NM_006918 SC5DL sterol-C5-desaturase
NM_007034 DNAJB4 DnaJ (Hsp40) homolog, subfamily B, member 4
NM_007036 ESM1 endothelial cell-specific molecule 1 isoform a
NM_007048 BTN3A1 butyrophilin, subfamily 3, member A1 isoform d
NM_007076 FICD Huntingtin interacting protein E NM_007167 ZMYM6
zinc finger protein 258 NM_007168 ABCA8 ATP-binding cassette,
sub-family A member 8 NM_007173 PRSS23 protease, serine, 23
precursor NM_007213 PRAF2 PRAT domain family, member 2 NM_007260
LYPLA2 lysophospholipase II NM_007271 STK38 serine/threonine kinase
38 NM_007274 ACOT7 acyl-CoA thioesterase 7 isoform hBACHd NM_007278
GABARAP GABA(A) receptor-associated protein NM_007287 MME membrane
metallo-endopeptidase NM_007315 STAT1 signal transducer and
activator of transcription NM_007325 GRIA3 glutamate receptor,
ionotrophic, AMPA 3 isoform NM_007341 SH3BGR SH3-binding domain and
glutamic acid-rich NM_007350 PHLDA1 pleckstrin homology-like
domain, family A, NM_012067 AKR7A3 aldo-keto reductase family 7,
member A3 NM_012081 ELL2 elongation factor, RNA polymerase II, 2
NM_012090 MACF1 microfilament and actin filament cross-linker
NM_012093 AK5 adenylate kinase 5 isoform 1 NM_012105 BACE2
beta-site APP-cleaving enzyme 2 isoform A NM_012155 EML2 echinoderm
microtubule associated protein like NM_012168 FBXO2 F-box only
protein 2 NM_012193 FZD4 frizzled 4 precursor NM_012200 B3GAT3
beta-1,3-glucuronyltransferase 3
NM_012201 GLG1 golgi apparatus protein 1 isoform 1 NM_012213 MLYCD
malonyl-CoA decarboxylase precursor NM_012215 MGEA5 meningioma
expressed antigen 5 (hyaluronidase) NM_012228 MSRB2 methionine
sulfoxide reductase B2 precursor NM_012243 SLC35A3 solute carrier
family 35 member 3A NM_012249 RHOQ ras-like protein TC10 precursor
NM_012250 RRAS2 related RAS viral (r-ras) oncogene homolog 2
NM_012252 TFEC transcription factor EC isoform a NM_012268 PLD3
phospholipase D3 NM_012281 KCND2 potassium voltage-gated channel,
Shal-related NM_012328 DNAJB9 DnaJ (Hsp40) homolog, subfamily B,
member 9 NM_012329 MMD monocyte to macrophage NM_012342 BAMBI BMP
and activin membrane-bound inhibitor NM_012360 OR1F1 olfactory
receptor, family 1, subfamily F, NM_012396 PHLDA3 pleckstrin
homology-like domain, family A, NM_012413 QPCT glutaminyl-peptide
cyclotransferase precursor NM_012419 RGS17 regulator of G-protein
signalling 17 NM_012429 SEC14L2 SEC14-like 2 isoform 1 NM_012430
SEC22A SEC22 vesicle trafficking protein homolog A NM_012431 SEMA3E
semaphorin 3E precursor NM_012434 SLC17A5 sialin NM_012449 STEAP1
six transmembrane epithelial antigen of the NM_013229 APAF1
apoptotic peptidase activating factor 1 isoform NM_013231 FLRT2
fibronectin leucine rich transmembrane protein 2 NM_013281 FLRT3
fibronectin leucine rich transmembrane protein 3 NM_013312 HOOK2
hook homolog 2 isoform 1 NM_013314 BLNK B-cell linker isoform 1
NM_013325 ATG4B APG4 autophagy 4 homolog B isoform a NM_013335
GMPPA GDP-mannose pyrophosphorylase A NM_013343 Unknown NM_013352
DSE dermatan sulfate epimerase precursor NM_013379 DPP7 dipeptidyl
peptidase 7 preproprotein NM_013381 TRHDE thyrotropin-releasing
hormone degrading enzyme NM_013390 TMEM2 transmembrane protein 2
isoform a NM_013399 C16orf5 cell death inducing protein NM_013943
CLIC4 chloride intracellular channel 4 NM_013959 NRG1 neuregulin 1
isoform ndf43b NM_013960 NRG1 neuregulin 1 isoform ndf43b NM_014015
DEXI dexamethasone-induced protein NM_014028 OSTM1 osteopetrosis
associated transmembrane protein 1 NM_014045 LRP10 Homo sapiens
LRP10 mRNA for low density lipoprotein receptor-related protein 10,
complete cds. NM_014068 PSORS1C1 SEEK1 protein NM_014145 C20orf30
hypothetical protein LOC29058 isoform 1 NM_014158 C1GALT1-specific
chaperone 1 (C1GALT1C1) (replaced by NM_152692.4) NM_014182 ORMDL2
ORMDL2 NM_014244 ADAMTS2 ADAM metallopeptidase with thrombospondin
type 1 NM_014266 HCST hematopoietic cell signal transducer isoform
2 NM_014268 MAPRE2 microtubule-associated protein, RP/EB family,
NM_014278 HSPA4L heat shock 70 kDa protein 4-like NM_014294 TRAM1
translocation associated membrane protein 1 NM_014297 ETHE1 ETHE1
protein precursor NM_014298 QPRT quinolinate
phosphoribosyltransferase NM_014314 DDX58 DEAD/H
(Asp-Glu-Ala-Asp/His) box polypeptide NM_014350 TNFAIP8 tumor
necrosis factor, alpha-induced protein 8 NM_014391 ANKRD1 cardiac
ankyrin repeat protein NM_014392 D4S234E brain neuron cytoplasmic
protein 1 NM_014396 VPS41 vacuolar protein sorting 41 isoform 1
NM_014399 TSPAN13 tetraspan NET-6 NM_014454 SESN1 sestrin 1
NM_014548 TMOD2 neuronal tropomodulin isoform a NM_014556 Unknown
NM_014563 TRAPPC2 trafficking protein particle complex 2 isoform
NM_014584 ERO1L ERO1-like precursor NM_014646 LPIN2 lipin 2
NM_014650 ZNF432 zinc finger protein 432 NM_014652 IPO13 importin
13 NM_014668 GREB1 growth regulation by estrogen in breast cancer 1
NM_014713 LAPTM4A lysosomal protein transmembrane 4 alpha NM_014723
SNPH syntaphilin NM_014730 MLEC malectin precursor NM_014734
KIAA0247 hypothetical protein LOC9766 precursor NM_014751 MTSS1
metastasis suppressor 1 NM_014774 KIAA0494 hypothetical protein
LOC9813 NM_014799 HEPH hephaestin isoform c NM_014804 KIAA0753
hypothetical protein LOC9851 NM_014840 NUAK1 AMPK-related protein
kinase 5 NM_014844 TECPR2 tectonin beta-propeller repeat containing
2 NM_014845 FIG4 Sac domain-containing inositol phosphatase 3
NM_014888 FAM3C family with sequence similarity 3, member C
NM_014890 FILIP1L filamin A interacting protein 1-like isoform 1
NM_014900 COBLL1 COBL-like 1 NM_014905 GLS glutaminase precursor
NM_014934 DZIP1 DAZ interacting protein 1 isoform 2 NM_014936 ENPP4
ectonucleotide pyrophosphatase/phosphodiesterase NM_014942 ANKRD6
ankyrin repeat domain 6 NM_014943 ZHX2 zinc fingers and homeoboxes
2 NM_014945 ABLIM3 actin binding LIM protein family, member 3
NM_014950 ZBTB1 zinc finger and BTB domain containing 1 isoform
NM_014951 ZNF365 zinc finger protein 365 isoform C NM_015000 STK38L
serine/threonine kinase 38 like NM_015271 TRIM2 tripartite
motif-containing 2 isoform 1 NM_015364 LY96 MD-2 protein precursor
NM_015392 NPDC1 neural proliferation, differentiation and NM_015415
BRP44 brain protein 44 NM_015516 TSKU tsukushin precursor NM_015556
SIPA1L1 signal-induced proliferation-associated 1 like NM_015654
NAT9 N-acetyltransferase 9 NM_015705 SGSM3 small G protein
signaling modulator 3 NM_015865 SLC14A1 solute carrier family 14
(urea transporter), NM_015878 AZIN1 ornithine decarboxylase
antizyme inhibitor NM_015917 GSTK1 glutathione S-transferase kappa
1 isoform a NM_015919 ZNF226 zinc finger protein 226 isoform b
NM_015920 RPS27L ribosomal protein S27-like NM_015967 PTPN22
protein tyrosine phosphatase, non-receptor type NM_015976 SNX7
sorting nexin 7 isoform a NM_015987 HEBP1 heme binding protein 1
NM_015996 NM_016040 TMED5 transmembrane emp24 protein transport
domain NM_016061 YPEL5 yippee-like 5 NM_016109 NM_016127 TMEM66
transmembrane protein 66 precursor NM_016134 PGCP plasma glutamate
carboxypeptidase precursor NM_016142 HSD17B12 hydroxysteroid
(17-beta) dehydrogenase 12 NM_016151 TAOK2 TAO kinase 2 isoform 1
NM_016152 RARB retinoic acid receptor, beta isoform 1 NM_016154
RAB4B ras-related GTP-binding protein 4b NM_016162 ING4 inhibitor
of growth family, member 4 isoform 1 NM_016219 MAN1B1 alpha
1,2-mannosidase NM_016226 VPS29 vacuolar protein sorting 29 isoform
2 NM_016227 C1orf9 chromosome 1 open reading frame 9 protein
NM_016235 GPRC5B G protein-coupled receptor, family C, group 5,
NM_016243 CYB5R1 cytochrome b5 reductase 1 NM_016255 FAM8A1 family
with sequence similarity 8, member A1 NM_016275 SELT selenoprotein
T precursor NM_016303 WBP5 WW domain binding protein 5 NM_016311
ATPIF1 ATPase inhibitory factor 1 isoform 2 precursor NM_016352
CPA4 carboxypeptidase A4 preproprotein NM_016399 TRIAP1
p53-inducible cell-survival factor NM_016422 RNF141 ring finger
protein 141 NM_016423 ZNF219 zinc finger protein 219 NM_016429
COPZ2 coatomer protein complex, subunit zeta 2 NM_016437 TUBG2
tubulin, gamma 2 NM_016530 RAB8B RAB8B, member RAS oncogene family
NM_016547 SDF4 stromal cell derived factor 4 isoform 2 NM_016557
CCRL1 chemokine (C-C motif) receptor-like 1 NM_016577 RAB6B RAB6B,
member RAS oncogene family NM_016582 SLC15A3 solute carrier family
15, member 3 NM_016588 NRN1 neuritin precursor NM_016599 MYOZ2
myozenin 2 NM_016608 ARMCX1 armadillo repeat containing, X-linked 1
NM_016621 PHF21A BRAF35/HDAC2 complex isoform b NM_016651 DACT1
dapper 1 isoform 1 NM_016656 RRAGB Ras-related GTP binding B long
isoform NM_016657 KDELR3 KDEL receptor 3 isoform a NM_016830 VAMP1
vesicle-associated membrane protein 1 isoform 1 NM_016938 EFEMP2
EGF-containing fibulin-like extracellular matrix NM_017414 USP18
ubiquitin specific protease 18 NM_017415 KLHL3 kelch-like 3
NM_017423 GALNT7 polypeptide N-acetylgalactosaminyltransferase 7
NM_017445 unknown NM_017458 MVP major vault protein NM_017514
PLXNA3 plexin A3 precursor NM_017554 PARP14 poly (ADP-ribose)
polymerase family, member 14 NM_017567 NAGK N-Acetylglucosamine
kinase NM_017627 HECT, UBA and WWE domain containing 1, E3
(replaced by ubiquitin protein ligase (HUWE1) NM_031407.6)
NM_017649 CNNM2 cyclin M2 isoform 1 NM_017655 GIPC2 PDZ domain
protein GIPC2 NM_017661 ZNF280D suppressor of hairy wing homolog 4
isoform 1 NM_017679 BCAS3 breast carcinoma amplified sequence 3
isoform 1 NM_017680 ASPN asporin precursor NM_017684 VPS13C
vacuolar protein sorting 13C protein isoform 2A NM_017692 APTX
aprataxin isoform a NM_017706 WDR55 WD repeat domain 55 NM_017712
PGPEP1 pyroglutamyl-peptidase I NM_017733 PIGG phosphatidylinositol
glycan anchor biosynthesis, NM_017739 POMGNT1 SubName: Full =
Protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase;
NM_017742 ZCCHC2 zinc finger, CCHC domain containing 2 NM_017750
RETSAT all-trans-13,14-dihydroretinol saturase NM_017784 OSBPL10
oxysterol-binding protein-like protein 10 NM_017814 TMEM161A
transmembrane protein 161A precursor NM_017836 SLC41A3 solute
carrier family 41, member 3 isoform 1 NM_017837 PIGV
phosphatidylinositol glycan class V NM_017856 GEMIN8 gem (nuclear
organelle) associated protein 8 NM_017870 TMEM132A transmembrane
protein 132A isoform a NM_017901 TPCN1 two pore segment channel 1
isoform 1 NM_017935 BANK1 B-cell scaffold protein with ankyrin
repeats 1 NM_017938 FAM70A hypothetical protein LOC55026 isoform 1
NM_017947 MOCOS molybdenum cofactor sulfurase NM_017983 WIPI1 WD
repeat domain, phosphoinositide interacting NM_017992 ER
degradation enhancer, mannosidase alpha- (replaced by like 3
(EDEM3) NM_025191.3) NM_018042 SLFN12 schlafen family member 12
NM_018046 AGGF1 angiogenic factor VG5Q NM_018075 ANO10
transmembrane protein 16K NM_018113 LMBR1L lipocalin-interacting
membrane receptor NM_018129 PNPO pyridoxine 5'-phosphate oxidase
NM_018153 ANTXR1 anthrax toxin receptor 1 isoform 1 precursor
NM_018161 NADSYN1 NAD synthetase 1 NM_018191 RCBTB1 regulator of
chromosome condensation (RCC1) and NM_018217 EDEM2 ER degradation
enhancer, mannosidase alpha- like NM_018229 MUDENG Mu-2 related
death-inducing protein NM_018267 NM_018291 FGGY FGGY carbohydrate
kinase domain containing NM_018293 ZNF654 zinc finger protein 654
NM_018295 TMEM140 transmembrane protein 140 NM_018334 LRRN3 leucine
rich repeat neuronal 3 precursor NM_018357 LARP6 La
ribonucleoprotein domain family, member 6 NM_018368 LMBRD1 liver
regeneration p-53 related protein NM_018370 DRAM1 DNA-damage
regulated autophagy modulator 1 NM_018371 CSGALNACT1 chondroitin
sulfate NM_018381 C19orf66 hypothetical protein LOC55337 NM_018418
SPATA7 spermatogenesis-associated protein 7 isoform a NM_018447
TMEM111 transmembrane protein 111 NM_018490 LGR4 leucine-rich
repeat-containing G protein-coupled NM_018494 LRDD leucine rich
repeat and death domain containing NM_018530 GSDMB gasdermin B
isoform 1 NM_018584 CAMK2N1 calcium/calmodulin-dependent protein
kinase II NM_018638 ETNK1 ethanolamine kinase 1 isoform A NM_018639
WSB2 WD SOCS-box protein 2 NM_018648 NOP10 nucleolar protein family
A, member 3 NM_018656 SLC35E3 solute carrier family 35, member E2
NM_018835 RC3H2 ring finger and CCCH-type zinc finger domains 2
NM_018840 C20orf24 Homo sapiens putative Rab5-interacting protein
mRNA, complete cds. NM_018973 DPM3 dolichyl-phosphate
mannosyltransferase NM_018999 FAM190B granule cell antiserum
positive 14 NM_019059 TOMM7 translocase of outer mitochondrial
membrane 7 NM_019099 C1orf183 hypothetical protein LOC55924 isoform
2 NM_019114 EPB41L4B erythrocyte membrane protein band 4.1 like 4B
NM_019555 ARHGEF3 Rho guanine nucleotide exchange factor 3 isoform
NM_019556 MOSPD1 motile sperm domain containing 1 NM_019885 CYP26B1
cytochrome P450, family 26, subfamily b, NM_020127 TUFT1 tuftelin 1
isoform 1 NM_020139 BDH2 3-hydroxybutyrate dehydrogenase, type 2
NM_020154 C15orf24 chromosome 15 open reading frame 24 precursor
NM_020166 MCCC1 methylcrotonoyl-Coenzyme A carboxylase 1 (alpha)
NM_020182 PMEPA1 transmembrane prostate androgen-induced protein
NM_020199 C5orf15 keratinocytes associated transmembrane protein 2
NM_020215 Unknown NM_020224 Unknown NM_020234 DTWD1 DTW domain
containing 1 NM_020299 AKR1B10 aldo-keto reductase family 1, member
B10 NM_020347 LZTFL1 leucine zipper transcription factor-like 1
NM_020353 PLSCR4 phospholipid scramblase 4 isoform a NM_020372
SLC22A17 solute carrier family 22, member 17 isoform b NM_020375
C12orf5 TP53-induced glycolysis and apoptosis regulator NM_020379
MAN1C1 mannosidase, alpha, class 1C, member 1 NM_020399 GOPC golgi
associated PDZ and coiled-coil motif NM_020448 NIPAL3 NIPA-like
domain containing 3 NM_020524 PBXIP1 pre-B-cell leukemia homeobox
interacting protein NM_020639 RIPK4 ankyrin repeat domain 3
NM_020644 TMEM9B TMEM9 domain family, member B precursor NM_020650
RCN3 reticulocalbin 3, EF-hand calcium binding domain NM_020663
RHOJ ras homolog gene family, member J precursor NM_020689 SLC24A3
solute carrier family 24 NM_020755 SERINC1 serine incorporator 1
NM_020760 HECW2 HECT, C2 and WW domain containing E3 ubiquitin
NM_020815 PCDH10 protocadherin 10 isoform 1 precursor NM_020841
OSBPL8 oxysterol-binding protein-like protein 8 isoform NM_021007
SCN2A sodium channel, voltage-gated, type II, alpha NM_021013 KRT34
keratin 34 NM_021016 PSG3 pregnancy specific beta-1-glycoprotein 3
NM_021035 ZNFX1 zinc finger, NFX1-type containing 1 NM_021070 LTBP3
latent transforming growth factor beta binding NM_021101 CLDN1
claudin 1 NM_021106 RGS3 regulator of G-protein signalling 3
isoform 6 NM_021127 PMAIP1 phorbol-12-myristate-13-acetate-induced
protein NM_021136 RTN1 reticulon 1 isoform A NM_021137 TNFAIP1
tumor necrosis factor, alpha-induced protein 1 NM_021151 CROT
peroxisomal carnitine O-octanoyltransferase NM_021173 POLD4
DNA-directed DNA polymerase delta 4 NM_021199 SQRDL sulfide
dehydrogenase like precursor NM_021203 SRPRB signal recognition
particle receptor, beta NM_021219 JAM2 junctional adhesion molecule
2 precursor NM_021229 NTN4 netrin 4 precursor NM_021244 RRAGD
Ras-related GTP binding D NM_021249 SNX6 sorting nexin 6 isoform b
NM_021616 TRIM34 tripartite motif protein 34 isoform 2 NM_021622
PLEKHA1 pleckstrin homology domain containing, family A NM_021626
SCPEP1 serine carboxypeptidase 1 precursor NM_021637 TMEM35
transmembrane protein 35 NM_021643 TRIB2 tribbles homolog 2
NM_021727 FADS3 fatty acid desaturase 3 NM_021731 C19orf28
hypothetical protein LOC126321 isoform a NM_021783 EDA2R X-linked
ectodysplasin receptor NM_021825 CCDC90B coiled-coil domain
containing 90B precursor NM_021827 CCDC81 coiled-coil domain
containing 81 isoform 1 NM_021980 OPTN optineurin NM_021994 ZNF277
zinc finger protein (C2H2 type) 277 NM_021999 ITM2B integral
membrane protein 2B NM_022001 unknown NM_022060 ABHD4 abhydrolase
domain containing 4 NM_022083 sequence similarity 129, member A
(FAM129A) (replaced by NM_052966.3) NM_022087 GALNT11
N-acetylgalactosaminyltransferase 11 NM_022117 TSPYL2 TSPY-like 2
NM_022121 PERP PERP, TP53 apoptosis effector NM_022128 RBKS
ribokinase NM_022129 PBLD MAWD binding protein isoform a NM_022135
POPDC2 popeye protein 2 NM_022147 RTP4 28 kD interferon responsive
protein NM_022152 TMBIM1 transmembrane BAX inhibitor motif
containing 1 NM_022168 IFIH1 interferon induced with helicase C
domain 1 NM_022171 TCTA T-cell leukemia translocation altered
NM_022338 C11orf24 hypothetical protein LOC53838 precursor
NM_022350 ERAP2 endoplasmic reticulum aminopeptidase 2 NM_022368
PJA1 praja 1 isoform c NM_022450 RHBDF1 rhomboid family 1 NM_022464
SIL1 SIL1 protein precursor NM_022470 ZMAT3 p53 target zinc finger
protein isoform 1 NM_022473 ZFP106 zinc finger protein 106 homolog
NM_022477 NDRG3 N-myc downstream regulated gene 3 isoform a
NM_022736 MFSD1 major facilitator superfamily domain containing
NM_022742 CCDC136 coiled-coil domain containing 136 NM_022743 SMYD3
SET and MYND domain containing 3 NM_022748 TNS3 tensin 3 NM_022750
PARP12 poly ADP-ribose polymerase 12 NM_022765 MICAL1 microtubule
associated monoxygenase, calponin NM_022772 EPS8L2 epidermal growth
factor receptor pathway NM_022783 DEPDC6 DEP domain containing 6
NM_022837 unknown NM_022902 SLC30A5 solute carrier family 30 (zinc
transporter), NM_023034 WHSC1L1 WHSC1L1 protein isoform long
NM_023037 FRY furry homolog NM_023039 ANKRA2 ankyrin repeat, family
A (RFXANK-like), 2 NM_023073 C5orf42 hypothetical protein LOC65250
NM_023112 OTUB2 OTU domain, ubiquitin aldehyde binding 2 NM_023915
GPR87 G protein-coupled receptor 87 NM_023928 AACS acetoacetyl-CoA
synthetase NM_024006 VKORC1 vitamin K epoxide reductase complex,
subunit 1 NM_024028 PCYOX1L prenylcysteine oxidase 1 like precursor
NM_024042 METRN meteorin, glial cell differentiation regulator
NM_024047 NUDT9 nudix-type motif 9 isoform a NM_024056 TMEM106C
transmembrane protein 106C isoform a NM_024064 protein kinase C,
eta (PRKCH) (replaced by NM_006255.3) NM_024097 C1orf50
hypothetical protein LOC79078 NM_024105 ALG12
alpha-1,6-mannosyltransferase ALG12 NM_024112 C9orf16 hypothetical
protein LOC79095 NM_024292 UBL5 ubiquitin-like 5 NM_024315 C7orf23
chromosome 7 open reading frame 23 NM_024324 CRELD2 cysteine-rich
with EGF-like domains 2 isoform a NM_024341 ZNF557 zinc finger
protein 557 isoform a NM_024430 PSTPIP2 proline-serine-threonine
phosphatase interacting NM_024500 unknown NM_024512 LRRC2 leucine
rich repeat containing 2 NM_024523 GCC1 Golgi coiled-coil protein 1
NM_024532 SPAG16 sperm associated antigen 16 isoform 1 NM_024536
CHPF chondroitin polymerizing factor NM_024539 RNF128 ring finger
protein 128 isoform 1 NM_024549 TCTN1 tectonic family member 1
isoform 3 NM_024564 Unknown NM_024574 C4orf31 hypothetical protein
LOC79625 precursor NM_024577 SH3TC2 SH3 domain and
tetratricopeptide repeats 2 NM_024599 RHBDF2 rhomboid, veinlet-like
6 isoform 2 NM_024602 HECTD3 HECT domain containing 3 NM_024617
ZCCHC6 zinc finger, CCHC domain containing 6 NM_024620 ZNF329 zinc
finger protein 329 NM_024649 BBS1 Bardet-Biedl syndrome 1 NM_024691
ZNF419 zinc finger protein 419 isoform 1 NM_024728 C7orf10 dermal
papilla derived protein 13 NM_024763 WDR78 WD repeat domain 78
isoform 1 NM_024766 C2orf34 hypothetical protein LOC79823 NM_024770
METTL8 methyltransferase like 8 NM_024801 Unknown NM_024806
C11orf63 hypothetical protein LOC79864 isoform 1 NM_024819 DCAKD
dephospho-CoA kinase domain containing NM_024825 PODNL1
podocan-like 1 isoform 2 NM_024837 ATP8B4 ATPase class I type 8B
member 4 NM_024841 PRR5L protor-2 isoform a NM_024843 CYBRD1
cytochrome b reductase 1 isoform 1 NM_024887 DHDDS dehydrodolichyl
diphosphate synthase isoform a NM_024913 C7orf58 hypothetical
protein LOC79974 isoform 1 NM_024924 Unknown NM_024935 Unknown
NM_025000 DCAF17 DDB1 and CUL4 associated factor 17 isoform 1
NM_025024 Unknown NM_025076 UXS1 UDP-glucuronate decarboxylase 1
NM_025133 FBXO11 F-box only protein 11 isoform 1 NM_025139 ARMC9
armadillo repeat containing 9 NM_025140 CCDC92 coiled-coil domain
containing 92 NM_025149 ACSF2 acyl-CoA synthetase family member 2
precursor NM_025165 ELL3 elongation factor RNA polymerase II-like 3
NM_025182 KIAA1539 hypothetical protein LOC80256 NM_025202 EFHD1
EF-hand domain family, member D1 NM_025208 PDGFD platelet derived
growth factor D isoform 2 NM_025217 ULBP2 UL16 binding protein 2
precursor NM_025226 Unknown NM_030641 APOL6 apolipoprotein L6
NM_030778 cytoplasmic FMR1 interacting protein 2 (replaced by
(CYFIP2) NM_014376.2) NM_030790 ITFG1 integrin alpha FG-GAP repeat
containing 1 NM_030799 YIPF5 Yip1 domain family, member 5 NM_030801
MAGED4B melanoma antigen family D, 4B isoform 1 NM_030802 FAM117A
family with sequence similarity 117, member A NM_030810 TXNDC5
thioredoxin domain containing 5 isoform 3 NM_030882 APOL2
apolipoprotein L2 NM_030911 CDADC1 cytidine and dCMP deaminase
domain containing 1 NM_030952 NUAK2 NUAK family, SNF1-like kinase,
2 NM_030963 RNF146 ring finger protein 146 NM_030967 KRTAP1-1
keratin associated protein 1-1 NM_030975 KRTAP9-9 keratin
associated protein 9-9 NM_030977 unknown NM_031244 SIRT5 sirtuin 5
isoform 2 NM_031246 PSG2 pregnancy specific beta-1-glycoprotein 2
NM_031285 tetraspanin 9 (TSPAN9), transcript variant 1 (replaced by
NM_006675.4) NM_031286 SH3BGRL3 SH3 domain binding glutamic
acid-rich protein NM_031301 APH1B presenilin stabilization
factor-like isoform 1 NM_031305 ARHGAP24 Rho GTPase activating
protein 24 isoform 1 NM_031458 PARP9 poly (ADP-ribose) polymerase
family, member 9 NM_031961 KRTAP9-2 keratin associated protein 9.2
NM_032211 LOXL4 lysyl oxidase-like 4 precursor NM_032412 C5orf32
hypothetical protein LOC84418 NM_032591 SLC9A7 solute carrier
family 9, member 7 NM_032623 C4orf49 ovary-specific acidic protein
NM_032784 RSPO3 R-spondin 3 precursor NM_032789 PARP10 poly
(ADP-ribose) polymerase family, member 10 NM_032812 PLXDC2 plexin
domain containing 2 precursor NM_032866 CGNL1 cingulin-like 1
NM_033255 EPSTI1 epithelial stromal interaction 1 isoform 1
NM_033405 PRIC285 PPAR-alpha interacting complex protein 285
NM_033407 DOCK7 dedicator of cytokinesis 7 NM_037370 CCNDBP1 cyclin
D-type binding-protein 1 isoform 1 NM_052822 unknown NM_052839
PANX2 pannexin 2 isoform 2 NM_052866 ADAMTSL1 ADAMTS-like 1 isoform
4 precursor NM_052885 SLC2A13 solute carrier family 2 (facilitated
glucose NM_052889 CARD16 caspase-1 dominant-negative inhibitor
pseudo- ICE NM_052941 GBP4 guanylate binding protein 4 NM_052958
C8orf34 hypothetical protein LOC116328 NM_053056 CCND1 cyclin D1
NM_078474 TM2D3 TM2 domain containing 3 isoform a NM_078483 SLC36A1
solute carrier family 36 member 1 NM_078487 CDKN2B cyclin-dependent
kinase inhibitor 2B isoform 2 NM_080657 RSAD2 radical S-adenosyl
methionine domain containing NM_080669 SLC46A1 proton-coupled
folate transporter NM_133477 SYNPO2 synaptopodin 2 isoform c
NM_138924 GAMT guanidinoacetate N-methyltransferase isoform a
NM_139266 STAT1 signal transducer and activator of transcription
NM_144657 HDX highly divergent homeobox NM_144717 IL20RB
interleukin 20 receptor beta precursor NM_144724 MARVELD2 MARVEL
domain containing 2 isoform 1 NM_144974 CCDC122 coiled-coil domain
containing 122 NM_144975 SLFN5 schlafen family member 5 NM_145058
RILPL2 Rab interacting lysosomal protein-like 2 NM_145259 ACVR1C
activin A receptor, type IC isoform 2 NM_145301 FAM18B2
hypothetical protein LOC201158 isoform 2 NM_145316 TMEM217
transmembrane protein 217 isoform 1 NM_145731 SYNGR1 synaptogyrin 1
isoform 1a NM_152282 ACPL2 acid phosphatase-like 2 precursor
NM_152532 Unknown NM_152565 ATP6V0D2 ATPase, H+ transporting,
lysosomal 38 kDa, V0 NM_152597 FSIP1 fibrous sheath interacting
protein 1 NM_152634 TCEANC TFIIS central domain-containing protein
1 NM_152701 ABCA13 ATP binding cassette, sub-family A (ABC1),
NM_152703 SAMD9L sterile alpha motif domain containing 9-like
NM_152748 KIAA1324L hypothetical protein LOC222223 isoform 1
NM_152757 C20orf200 hypothetical protein LOC253868 NM_152791 ZNF555
zinc finger protein 555 NM_152910 DGKH diacylglycerol kinase, eta
isoform 2 NM_153218 C13orf31 hypothetical protein LOC144811
NM_153487 MDGA1 MAM domain containing NM_170753 PGBD3 hypothetical
protein LOC267004 NM_171846 LACTB lactamase, beta isoform a
NM_172037 RDH10 retinol dehydrogenase 10 NM_173217 ST6GAL1 ST6
beta-galactosamide NM_173354 SIK1 salt-inducible kinase 1 NM_173617
Unknown NM_176821 NLRP10 NLR family, pyrin domain containing 10
NM_177424 STX12 syntaxin 12 NM_177974 CASC4 cancer susceptibility
candidate 4 isoform a NM_178550 C1orf110 hypothetical protein
LOC339512 NM_178821 WDR69 WD repeat domain 69 NM_181597 UPP1
uridine phosphorylase 1 NM_181782 NCOA7 nuclear receptor
coactivator 7 isoform 2 NM_182752 TPRG1L tumor protein p63
regulated 1-like NM_183079 PRNP prion protein preproprotein
NM_198183 UBE2L6 ubiquitin-conjugating enzyme E2L 6 isoform 2
NM_198576 AGRN agrin precursor NM_199139 XAF1 XIAP associated
factor 1 isoform 1 NM_206833 CTXN1 cortexin 1 NM_207380 C15orf52
hypothetical protein LOC388115 NM_213589 RAPH1 Ras association and
pleckstrin homology domains
NR_001568 BCYRN1 Homo sapiens brain cytoplasmic RNA 1 (non- protein
coding) (BCYRN1), non-coding RNA. R14890 HECW2 HECT, C2 and WW
domain containing E3 ubiquitin R22891 Unknown R24779 Unknown R32065
PSG3 pregnancy specific beta-1-glycoprotein 3 R34841 SOD2 manganese
superoxide dismutase isoform A R38084 GIT2 G protein-coupled
receptor kinase interacting R44930 Unknown R49343 SEC14L2
SEC14-like 2 isoform 1 R52665 Unknown R62907 DAB2 disabled homolog
2 R78604 IPP intracisternal A particle-promoted polypeptide R79120
DAB2 disabled homolog 2 R98767 CAMK2D calcium/calmodulin-dependent
protein kinase II S57296 ERBB2 erbB-2 isoform b S68290 AKR1C1
aldo-keto reductase family 1, member C1 S69189 ACOX1 acyl-Coenzyme
A oxidase 1 isoform b S69738 CCL2 small inducible cytokine A2
precursor S70123 LDLR low density lipoprotein receptor precursor
S81491 Stat2 type (partial) S81545 EDNRA endothelin receptor type A
isoform a precursor S81916 PGK1 phosphoglycerate kinase 1 T03492
Unknown T17299 CACNA2D2 calcium channel, voltage-dependent, alpha
T30183 BCR Homo sapiens breakpoint cluster region, mRNA (cDNA clone
IMAGE: 4500154). T50399 HBA2 alpha 2 globin T63497 Unknown T70087
EPAS1 endothelial PAS domain protein 1 T78402 Unknown T84558 NIPAL3
NIPA-like domain containing 3 T94585 ACOT13 acyl-CoA thioesterase
13 isoform 2 U04897 RORA RAR-related orphan receptor A isoform b
U05598 dihydrodiol dehydrogenase U10473 B4GALT1 UDP-Gal:betaGlcNAc
beta 1,4- U11058 KCNMA1 large conductance calcium-activated
potassium U13698 CASP1 caspase 1 isoform alpha precursor U13699
CASP1 caspase 1 isoform alpha precursor U13700 CASP1 caspase 1
isoform alpha precursor U16307 GLIPR1 GLI pathogenesis-related 1
precursor U17714 putative tumor suppressor ST13 U19599 BAX Homo
sapiens bax epsilon mRNA, complete cds. U24267
pyrroline-5-carboxylate dehydrogenase (P5CDh) U25147 SLC25A1 solute
carrier family 25 (mitochondrial carrier; U27143 HINT1 Homo sapiens
cDNA: FLJ22904 fis, clone KAT05632. U36190 CRIP2 cysteine-rich
protein 2 U36501 SP100 nuclear antigen Sp100 isoform 1 U37283 MFAP5
microfibrillar associated protein 5 precursor U37546 BIRC3
baculoviral IAP repeat-containing protein 3 U38321 MMP19 matrix
metalloproteinase 19 isoform rasi-1 U40053 lanosterol 14-alpha
demethylase (CYP51P2) pseudogene U40372 3',5' cyclic nucleotide
phosphodiesterase (HSPDE1C3A) U42349 TUSC3 tumor suppressor
candidate 3 isoform a U43559 RDH5 retinol dehydrogenase 5 (11-cis
and 9-cis) U47674 ASAH1 N-acylsphingosine amidohydrolase 1 isoform
b U48437 APLP1 amyloid precursor-like protein 1 isoform 2 U48705
receptor tyrosine kinase DDR U49188 SERINC3 tumor differentially
expressed protein 1 U49396 ionotropic ATP receptor P2X5b U50529
BRCA2 region U55936 SNAP23 synaptosomal-associated protein 23
isoform U58111 VEGFC vascular endothelial growth factor C U61276
JAG1 jagged 1 precursor U62325 APBB2 amyloid beta A4 precursor
protein-binding, U62858 IL13RA1 interleukin 13 receptor, alpha 1
precursor U67280 CALU calumenin isoform b precursor U72937 ATRX
transcriptional regulator ATRX isoform 1 U73936 JAG1 jagged 1
precursor U76833 FAP fibroblast activation protein, alpha subunit
U77706 LAMA4 laminin, alpha 4 isoform 2 precursor U77914 JAG1
jagged 1 precursor U77917 PTPRR protein tyrosine phosphatase,
receptor type, R U79277 Unknown U79297 Unknown U82671 Unknown
U83508 ANGPT1 angiopoietin 1 precursor U84138 RAD51L1 RAD51-like 1
isoform 3 U84246 NEU1 neuraminidase precursor U85995 BBS9
parathyroid hormone-responsive B1 isoform 2 U89281 HSD17B6
hydroxysteroid (17-beta) dehydrogenase 6 U89330 MAP2
microtubule-associated protein 2 isoform 1 U89386 PAFAH2
platelet-activating factor acetylhydrolase 2 U90552 BTN3A1
butyrophilin, subfamily 3, member A1 isoform d U92268 MAPK11
mitogen-activated protein kinase 11 U92816 c33.6 unnamed HERV-H
protein U94831 multispanning membrane protein V00489 alpha-globin
W01715 NAPEPLD N-acyl phosphatidylethanolamine phospholipase D
W03103 ASAP1 development and differentiation enhancing factor
W15435 NIPAL3 NIPA-like domain containing 3 W46388 Unknown W46994
STAU2 staufen homolog 2 isoform e W61007 NFAT5 nuclear factor of
activated T-cells 5 isoform a W65310 Unknown W67995 FXC1
mitochondrial import inner membrane translocase W72466 Unknown
W72564 LOC100134259 Homo sapiens cDNA FLJ35178 fis, clone
PLACE6014043. W73272 PDE8A phosphodiesterase 8A isoform 1 W73431
FN1 fibronectin 1 isoform 1 preproprotein W73788 TTC14
tetratricopeptide repeat domain 14 isoform a W74476 Unknown W74640
Unknown W81648 CSGALNACT2 chondroitin sulfate W87466 Unknown W91876
Unknown W92744 ZNF84 zinc finger protein 84 W93554 SH3PXD2A SH3
multiple domains 1 W93695 CLN8 ceroid-lipofuscinosis, neuronal 8
X06989 APP amyloid beta A4 protein isoform a precursor X15132 SOD2
manganese superoxide dismutase isoform A X15306 heavy neurofilament
subunit (NF-H) X16354 transmembrane carcinoembryonic antigen BGPa
(formerly TM1-CEA) X16447 CD59 CD59 antigen preproprotein X56841
HLA-E major histocompatibility complex, class I, E X61094 GM2A GM2
ganglioside activator precursor X63338 HB2B gene for high sulfur
keratin X64116 PVR gene for poliovirus receptor (exon 1) X65232
ZNF79 zinc finger protein 79 X68742 ITGA1 integrin, alpha 1
precursor X74039 PLAUR plasminogen activator, urokinase receptor
X76775 HLA-DMA X79683 beta2 laminin X83858 PTGER3 Homo sapiens
PTGER3 mRNA for prostaglandin E receotor EP3 subtype 3 isoform,
partial cds, clone: FLJ80357SAAF. X90579 CYP3A5 cytochrome P450,
family 3, subfamily A, XM_042066 mitogen-activated protein kinase
kinase kinase 1, (replaced by E3 ubiquitin protein ligase (MAP3K1)
NM_005921.1) XM_290629 AHNAK nucleoprotein 2 (AHNAK2) (replaced by
NM_138420.2) XM_371461 Unknown XM_379298 Unknown XM_927270 Unknown
XM_927532 Unknown XM_930405 Unknown XM_934030 Unknown XM_936467
Unknown XM_937514 Unknown XM_940706 Unknown XM_943119 transcription
elongation factor A (SII), 1 (replaced by NM_201437.1) (TCEA1)
XM_943477 Unknown Y09846 shc pseudogene, p66 isoform Z21533 HHEX
hematopoietically expressed homeobox Z38765 Unknown Z97053
Unknown
TABLE-US-00003 TABLE 2A POLYNUCLEOTIDES ENCODING SENESCENT
CELL-ASSOCIATED ANTIGENS AA004279 AA012883 AA020826 AA022510
AA029155 AA034012 AA037766 AA043348 AA044835 AA044921 AA045247
AA045527 AA056548 AA081349 AA083483 AA088857 AA088873 AA099357
AA102600 AA115933 AA121673 AA128261 AA130982 AA131041 AA133285
AA133962 AA133989 AA148534 AA149644 AA149745 AA150242 AA150460
AA156605 AA156721 AA156723 AA156754 AA156961 AA160474 AA169752
AA195009 AA196034 AA196245 AA203365 AA205660 AA209239 AA209487
AA215738 AA228366 AA243427 AA279958 AA284248 AA284829 AA329676
AA372349 AA393484 AA398658 AA398740 AA401703 AA404269 AA418028
AA418074 AA418816 AA429615 AA432267 AA459699 AA461080 AA476916
AA481560 AA482478 AA482548 AA496034 AA496213 AA514384 AA514634
AA521080 AA522514 AA523543 AA523733 AA523958 AA524669 AA526844
AA532640 AA532655 AA534198 AA535917 AA543030 AA545764 AA551075
AA554833 AA563621 AA565715 AA565852 AA572675 AA573452 AA573523
AA576961 AA582404 AA583044 AA594609 AA599017 AA602532 AA603472
AA609053 AA628051 AA628398 AA629286 AA631103 AA631254 AA633992
AA634220 AA639752 AA653300 AA654142 AA675892 AA678047 AA678241
AA683481 AA683501 AA683602 AA699809 AA702143 AA703280 AA706658
AA707125 AA716107 AA721252 AA722799 AA724665 AA732007 AA736604
AA747309 AA761181 AA767440 AA768884 AA778684 AA805633 AA806283
AA806349 AA810263 AA810788 AA811138 AA811509 AA812232 AA814140
AA815089 AA827865 AA827878 AA831438 AA831769 AA832474 AA833832
AA836340 AA843132 AA847654 AA853175 AA861784 AA872727 AA883074
AA886870 AA889628 AA889952 AA890010 AA897514 AA902480 AA904430
AA907927 AA910945 AA913146 AA916831 AA917672 AA917899 AA927870
AA928542 AA933779 AA969194 AA971753 AA988241 AA988323 AA993518
AA995925 AB000888 AB002282 AB002301 AB002323 AB002347 AB002354
AB002365 AB002391 AB004574 AB005043 AB006756 AB006757 AB007457
AB007458 AB007875 AB007877 AB007900 AB007923 AB009598 AB011161
AB014511 AB014600 AB015656 AB017269 AB017445 AB017498 AB018283
AB018322 AB018580 AB019691 AB020335 AB020635 AB020645 AB020657
AB020663 AB020712 AB020717 AB022663 AB022918 AB023147 AB023179
AB024518 AB024703 AB029040 AB029290 AB030655 AB030710 AB032261
AB032987 AB032996 AB033007 AB033010 AB033055 AB033080 AB033832
AB034747 AB036063 AB037738 AB037791 AB037813 AB037823 AB037853
AB037925 AB039327
AB039947 AB046692 AB046809 AB046842 AB046844 AB047360 AB049654
AB051486 AB053318 AB053319 AB056106 AC004770 AC004997 AC005339
AC007182 AD000092 AF001602 AF003934 AF005774 AF006516 AF007162
AF009616 AF010314 AF010446 AF011466 AF014403 AF015186 AF017987
AF019214 AF021834 AF026071 AF029674 AF029750 AF031469 AF033026
AF039217 AF039690 AF040704 AF041459 AF043732 AF043977 AF045451
AF047020 AF047338 AF052059 AF052094 AF052151 AF053453 AF056322
AF060922 AF061731 AF061735 AF062483 AF063591 AF064243 AF064484
AF064771 AF065214 AF065385 AF065854 AF067286 AF070524 AF070569
AF070571 AF070596 AF072098 AF073890 AF078844 AF082283 AF083068
AF086256 AF086333 AF087847 AF090891 AF092128 AF092137 AF094754
AF095727 AF095771 AF096296 AF096304 AF097493 AF098951 AF101051
AF105974 AF106069 AF109681 AF112216 AF113211 AF114488 AF115512
AF116574 AF116616 AF116827 AF118274 AF118887 AF119835 AF119863
AF121856 AF123758 AF123759 AF126782 AF127481 AF130089 AF130090
AF130104 AF131743 AF131747 AF131801 AF132203 AF133207 AF133425
AF134149 AF134715 AF135266 AF135593 AF139131 AF144488 AF151074
AF151810 AF151861 AF153415 AF153820 AF155158 AF157324 AF158185
AF158555 AF159570 AF161526 AF162769 AF164794 AF165187 AF165520
AF169312 AF169676 AF172398 AF176518 AF178532 AF179281 AF180519
AF182273 AF182414 AF183417 AF183419 AF186773 AF188298 AF197952
AF201370 AF205218 AF212995 AF216292 AF216962 AF217974 AF217990
AF218365 AF220026 AF225981 AF228422 AF229179 AF230398 AF230411
AF230904 AF230924 AF232772 AF232905 AF237813 AF239756 AF240468
AF246144 AF247168 AF248966 AF250226 AF251025 AF251054 AF257659
AF263293 AF267855 AF267856 AF274948 AF276658 AF278532 AF280094
AF285119 AF288208 AF288391 AF295039 AF302786 AF303378 AF313413
AF315325 AF316824 AF316873 AF325213 AF327923 AF329088 AF330205
AF348078 AF353618 AF353992 AF355465 AF356193 AF380356 AF478446
AF493931 AF495383 AF513360 AF542051 AFFX- HUMISGF3A/M 97935_3 AFFX-
HUMISGF3A/M 97935_5 AFFX- HUMISGF3A/M 97935_MA AFFX- HUMISGF3A/M
97935_MB AI003763 AI022882 AI023433 AI023774 AI038737 AI040029
AI040305 AI040324 AI041217 AI051046 AI051127 AI052003 AI052103
AI052536 AI056692 AI074333 AI077660 AI079540 AI081779 AI091079
AI092511 AI092770 AI092931 AI096389 AI096706 AI097463 AI110886
AI122754 AI123348 AI125204 AI125670 AI129626
AI129628 AI133137 AI139993 AI147621 AI150000 AI150117 AI160126
AI160339 AI160540 AI167292 AI183997 AI187364 AI188104 AI188161
AI188389 AI190413 AI200538 AI200555 AI202327 AI202969 AI215102
AI218542 AI222435 AI223870 AI224105 AI243677 AI247763 AI248598
AI254547 AI261321 AI262560 AI264121 AI268315 AI270356 AI275162
AI276880 AI278445 AI279062 AI290475 AI291123 AI291989 AI307750
AI307760 AI307802 AI312083 AI313324 AI332407 AI333326 AI334015
AI337304 AI341146 AI341234 AI341246 AI341602 AI342246 AI346026
AI348009 AI348094 AI354864 AI356412 AI359676 AI361227 AI363270
AI369073 AI373299 AI374756 AI376997 AI378035 AI378788 AI379338
AI380156 AI382026 AI391633 AI393091 AI393706 AI393725 AI418538
AI418892 AI420817 AI421559 AI422414 AI431643 AI433463 AI435399
AI435514 AI439556 AI446414 AI446756 AI453452 AI457817 AI458439
AI459140 AI460037 AI469425 AI472310 AI472339 AI473891 AI474054
AI475544 AI478147 AI479082 AI479419 AI493587 AI498144 AI498395
AI522053 AI523391 AI525212 AI537887 AI559300 AI569974 AI571796
AI582773 AI613010 AI623211 AI625741 AI631210 AI632212 AI632728
AI633503 AI633523 AI634046 AI634580 AI636233 AI638405 AI638420
AI638768 AI638771 AI650285 AI650819 AI651603 AI651786 AI652452
AI652681 AI653037 AI653117 AI653327 AI654636 AI655057 AI655524
AI655763 AI656232 AI656481 AI658662 AI659225 AI659456 AI659800
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NM_002631
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NM_004509 NM_004542 NM_004545 NM_004546 NM_004556 NM_004591
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NM_004791 NM_004815 NM_004862 NM_004899 NM_004905 NM_004932
NM_004934 NM_004938 NM_005010 NM_005019 NM_005020 NM_005044
NM_005065 NM_005098 NM_005101 NM_005103 NM_005113 NM_005123
NM_005125 NM_005167 NM_005168 NM_005195 NM_005200 NM_005204
NM_005213 NM_005245 NM_005319 NM_005326 NM_005340 NM_005345
NM_005346 NM_005354 NM_005393 NM_005419 NM_005505 NM_005506
NM_005512 NM_005525 NM_005528 NM_005532 NM_005533 NM_005541
NM_005547 NM_005557 NM_005561 NM_005567 NM_005569 NM_005575
NM_005584 NM_005625 NM_005642 NM_005645 NM_005665 NM_005667
NM_005713 NM_005715 NM_005720 NM_005724 NM_005745 NM_005755
NM_005756 NM_005765 NM_005780 NM_005794 NM_005817 NM_005824
NM_005875 NM_005896 NM_005899 NM_005907 NM_005908 NM_005926
NM_005935 NM_005950 NM_005951 NM_005952 NM_005965 NM_005979
NM_006002 NM_006005 NM_006010 NM_006019 NM_006024 NM_006033
NM_006038 NM_006058 NM_006096 NM_006102 NM_006106 NM_006113
NM_006134 NM_006141 NM_006145 NM_006200 NM_006223 NM_006227
NM_006244 NM_006255 NM_006256 NM_006258 NM_006260 NM_006285
NM_006290 NM_006307 NM_006315 NM_006332 NM_006349
NM_006369 NM_006384 NM_006404 NM_006406 NM_006407 NM_006416
NM_006423 NM_006426 NM_006462 NM_006472 NM_006493 NM_006505
NM_006517 NM_006520 NM_006526 NM_006536 NM_006542 NM_006547
NM_006577 NM_006608 NM_006634 NM_006642 NM_006670 NM_006675
NM_006676 NM_006682 NM_006698 NM_006702 NM_006720 NM_006727
NM_006730 NM_006755 NM_006759 NM_006763 NM_006767 NM_006803
NM_006810 NM_006822 NM_006823 NM_006829 NM_006830 NM_006851
NM_006876 NM_006905 NM_006918 NM_007034 NM_007036 NM_007048
NM_007076 NM_007167 NM_007168 NM_007173 NM_007213 NM_007260
NM_007271 NM_007274 NM_007278 NM_007287 NM_007315 NM_007325
NM_007341 NM_007350 NM_012067 NM_012081 NM_012090 NM_012093
NM_012105 NM_012155 NM_012168 NM_012193 NM_012200 NM_012201
NM_012213 NM_012215 NM_012228 NM_012243 NM_012249 NM_012250
NM_012252 NM_012268 NM_012281 NM_012328 NM_012329 NM_012342
NM_012360 NM_012396 NM_012413 NM_012419 NM_012429 NM_012430
NM_012431 NM_012434 NM_012449 NM_013229 NM_013231 NM_013281
NM_013312 NM_013314 NM_013325 NM_013335 NM_013343 NM_013352
NM_013379 NM_013381 NM_013390 NM_013399 NM_013943 NM_013959
NM_013960 NM_014015 NM_014028 NM_014045 NM_014068 NM_014145
NM_014158 NM_014182 NM_014244 NM_014266 NM_014268 NM_014278
NM_014294 NM_014297 NM_014298 NM_014314 NM_014350 NM_014391
NM_014392 NM_014396 NM_014399 NM_014454 NM_014548 NM_014556
NM_014563 NM_014584 NM_014646 NM_014650 NM_014652 NM_014668
NM_014713 NM_014723 NM_014730 NM_014734 NM_014751 NM_014774
NM_014799 NM_014804 NM_014840 NM_014844 NM_014845 NM_014888
NM_014890 NM_014900 NM_014905 NM_014934 NM_014936 NM_014942
NM_014943 NM_014945 NM_014950 NM_014951 NM_015000 NM_015271
NM_015364 NM_015392 NM_015415 NM_015516 NM_015556 NM_015654
NM_015705 NM_015865 NM_015878 NM_015917 NM_015919 NM_015920
NM_015967 NM_015976 NM_015987 NM_015996 NM_016040 NM_016061
NM_016109 NM_016127 NM_016134 NM_016142 NM_016151 NM_016152
NM_016154 NM_016162 NM_016219 NM_016226 NM_016227 NM_016235
NM_016243 NM_016255 NM_016275 NM_016303 NM_016311 NM_016352
NM_016399 NM_016422 NM_016423 NM_016429 NM_016437 NM_016530
NM_016547 NM_016557 NM_016577 NM_016582 NM_016588 NM_016599
NM_016608 NM_016621 NM_016651 NM_016656 NM_016657 NM_016830
NM_016938 NM_017414 NM_017415 NM_017423 NM_017445 NM_017514
NM_017554 NM_017567 NM_017627 NM_017649 NM_017655 NM_017661
NM_017679 NM_017680 NM_017684 NM_017692 NM_017706 NM_017712
NM_017733 NM_017739 NM_017742 NM_017750 NM_017784 NM_017814
NM_017836 NM_017837 NM_017856 NM_017870 NM_017901 NM_017935
NM_017938 NM_017947 NM_017983 NM_017992 NM_018042
NM_018046 NM_018075 NM_018113 NM_018129 NM_018153 NM_018161
NM_018191 NM_018217 NM_018229 NM_018267 NM_018291 NM_018293
NM_018295 NM_018334 NM_018357 NM_018368 NM_018370 NM_018371
NM_018381 NM_018418 NM_018447 NM_018490 NM_018494 NM_018530
NM_018584 NM_018638 NM_018639 NM_018648 NM_018656 NM_018835
NM_018840 NM_018973 NM_018999 NM_019059 NM_019099 NM_019114
NM_019555 NM_019556 NM_019885 NM_020127 NM_020139 NM_020154
NM_020166 NM_020182 NM_020199 NM_020215 NM_020224 NM_020234
NM_020299 NM_020347 NM_020353 NM_020372 NM_020375 NM_020379
NM_020399 NM_020448 NM_020524 NM_020639 NM_020644 NM_020650
NM_020663 NM_020689 NM_020755 NM_020760 NM_020815 NM_020841
NM_021007 NM_021013 NM_021016 NM_021035 NM_021070 NM_021101
NM_021106 NM_021127 NM_021136 NM_021137 NM_021151 NM_021173
NM_021199 NM_021203 NM_021219 NM_021229 NM_021244 NM_021249
NM_021616 NM_021622 NM_021626 NM_021637 NM_021643 NM_021727
NM_021731 NM_021783 NM_021825 NM_021827 NM_021980 NM_021994
NM_021999 NM_022001 NM_022060 NM_022083 NM_022087 NM_022117
NM_022121 NM_022128 NM_022129 NM_022135 NM_022147 NM_022152
NM_022168 NM_022171 NM_022338 NM_022350 NM_022368 NM_022450
NM_022464 NM_022470 NM_022473 NM_022477 NM_022736 NM_022742
NM_022743 NM_022748 NM_022750 NM_022765 NM_022772 NM_022783
NM_022837 NM_022902 NM_023034 NM_023037 NM_023039 NM_023073
NM_023112 NM_023915 NM_023928 NM_024006 NM_024028 NM_024042
NM_024047 NM_024056 NM_024064 NM_024097 NM_024105 NM_024112
NM_024292 NM_024315 NM_024324 NM_024341 NM_024430 NM_024500
NM_024512 NM_024523 NM_024532 NM_024536 NM_024539 NM_024549
NM_024564 NM_024574 NM_024577 NM_024599 NM_024602 NM_024617
NM_024620 NM_024649 NM_024691 NM_024728 NM_024763 NM_024766
NM_024770 NM_024801 NM_024806 NM_024819 NM_024825 NM_024837
NM_024841 NM_024843 NM_024887 NM_024913 NM_024924 NM_024935
NM_025000 NM_025024 NM_025076 NM_025133 NM_025139 NM_025140
NM_025149 NM_025165 NM_025182 NM_025202 NM_025208 NM_025217
NM_025226 NM_030641 NM_030778 NM_030790 NM_030799 NM_030801
NM_030802 NM_030810 NM_030882 NM_030911 NM_030952 NM_030963
NM_030967 NM_030975 NM_030977 NM_031244 NM_031246 NM_031285
NM_031286 NM_031301 NM_031305 NM_031458 NM_031961 NM_032211
NM_032412 NM_032591 NM_032623 NM_032784 NM_032789 NM_032812
NM_032866 NM_033255 NM_033405 NM_033407 NM_037370 NM_052822
NM_052839 NM_052866 NM_052885 NM_052889 NM_052941 NM_052958
NM_053056 NM_078474 NM_078483 NM_078487 NM_080657 NM_080669
NM_133477 NM_138924 NM_139266 NM_144657 NM_144717 NM_144724
NM_144974 NM_144975 NM_145058 NM_145259 NM_145301
NM_145316 NM_145731 NM_152282 NM_152532 NM_152565 NM_152597
NM_152634 NM_152701 NM_152703 NM_152748 NM_152757 NM_152791
NM_152910 NM_153218 NM_153487 NM_170753 NM_171846 NM_172037
NM_173217 NM_173354 NM_173617 NM_176821 NM_177424 NM_177974
NM_178550 NM_178821 NM_181597 NM_181782 NM_182752 NM_183079
NM_198183 NM_198576 NM_199139 NM_206833 NM_207380 NM_213589
NR_001568 R14890 R22891 R24779 R32065 R34841 R38084 R44930 R49343
R52665 R62907 R78604 R79120 R98767 S57296 S68290 S69189 S69738
S70123 S81491 S81545 S81916 T03492 T17299 T30183 T50399 T63497
T70087 T78402 T84558 T94585 U04897 U05598 U10473 U11058 U13698
U13699 U13700 U16307 U17714 U19599 U24267 U25147 U27143 U36190
U36501 U37283 U37546 U38321 U40053 U40372 U42349 U43559 U47674
U48437 U48705 U49188 U49396 U50529 U55936 U58111 U61276 U62325
U62858 U67280 U72937 U73936 U76833 U77706 U77914 U77917 U79277
U79297 U82671 U83508 U84138 U84246 U85995 U89281 U89330 U89386
U90552 U92268 U92816 U94831 V00489 W01715 W03103 W15435 W46388
W46994 W61007 W65310 W67995 W72466 W72564 W73272 W73431 W73788
W74476 W74640 W81648 W87466 W91876 W92744 W93554 W93695 X06989
X15132 X15306 X16354 X16447 X56841 X61094 X63338 X64116 X65232
X68742 X74039 X76775 X79683 X83858 X90579 XM_042066 XM_290629
XM_371461 XM_379298 XM_927270 XM_927532 XM_930405 XM_934030
XM_936467 XM_937514 XM_940706 XM_943119 XM_943477 Y09846 Z21533
Z38765 Z97053
TABLE-US-00004 TABLE 3 POLYNUCLEOTIDES ENCODING SENESCENT
CELL-ASSOCIATED ANTIGENS GENE SYMBOL GENE PRODUCT DESCRIPTION
GENBANK # PUBMED # LOGFC CLCA2 CLCA family member 2, chloride
channel regulator BF003134 10362588, 10437792 4.79 CLCA2 CLCA
family member 2, chloride channel regulator NM_006536 10362588,
10437792 4.51 IL33 interleukin 33 AB024518 10566975, 12477932 4.24
CLCA2 CLCA family member 2, chloride channel regulator AF043977
10362588, 10437792 4.22 CLCA2 CLCA family member 2, chloride
channel regulator NM_006536 10362588, 10437792 3.87 RP4-692D3.1
hypothetical protein LOC728621 AW364693 16710767 3.75 SYNPO2
synaptopodin2 AI634580 8593614, 11076863, 3.74 GLS glutaminase
AF097493 3531404, 6682827, 6 3.53 AB13BP ABI gene family, member 3
(NESH) binding protein NM_024801 11501947, 12477932 3.52 BCHE
butyrylcholinesterase NM_000055 1769657, 1769658, 2 3.51 LOC727770
similar to ankyrin repeat domain 20 family, member A1 A1359676 3.51
OSAP ovary-specific acidic protein AF329088 12477932 3.44 PLAT
plasminogen activator, tissue NM_000930 1301152, 1310033, 1 3.42
IL1A interleukin 1, alpha M15329 1548758, 1584804, 1 3.42 IFIT2
interferon-induced protein with tetratricopeptide repeats 2
AA131041 1377167, 245816, 3 3.39 CDH10 cadherin 10, type 2
(T2-cadherin) NM_006727 2059658, 10386616 3.37 IL1B interleukin 1,
beta NM_000576 1548758, 1753956, 1 3.33 SPATA18 spermatogenesis
associated 18 homolog (rat) AI559300 12477932, 14702039 3.31
AI422414 3.29 IL1B interleukin 1, beta M15330 1548758, 173956, 1
3.29 PAPPA pregnancy-associated plasma protein A, poppalysin 1
AI110886 1721035, 2422961, 2 3.25 GLS glutaminase NM_014905
3531404, 6682827, 6 3.23 ABI38P ABI gene family, member 3 (NESH)
binding protein AB056106 11501947, 12477932 3.2 SYNPO2 synaptopodin
2 AW009747 8593614, 11076863, 3.16 PAPPA pregnancy-associated
plasma protein A, pappalysin 1 BF107618 1721035, 2422961, 2 3.14
C11orf87 chromosome 11 open reading frame 87 AA633992 12477932 3.12
PAPPA pregnancy-associated plasma protein A, pappalysin 1 BF107618
1721035, 2422961, 2 3.11 SLC16A4 solute carrier family 16, member 4
(monocarboxylic acid NM_004696 8125298, 9373149, 9 3.1 transporter
5) SCN2A sodium channel, voltage-gated, type II, alpha subunit
BF432956 1317301, 1325650, 1 3.09 RNF128 ring finger protein 128
NM_024539 12477932, 12705856 3.07 AKR1C3 adlo-keto reductace family
1, member C3 (3-alpha AB018580 762489, 7650035, 7 3.03
hydroxysteroid dehydrogenase, type II) IL13RA2 interleukin 13
receptor, alpha 2 NM_000640 8663118, 9083087, 9 2.99 GDF15 growth
differentiation factor 15 AF003934 8125298, 9326641, 9 2.93 SULF2
sulfatase 2 AL133001 10574462, 11549316 2.92 KRT34 keratin 34
NM_021013 2431943, 7686952, 9 2.89 FBX032 F-box protein 32 BF244402
11679633, 11717410 2.89 AA594609 2.88 BC043411 2.88 ESM1
endothelial cell-specific molecule 1 NM_007036 8702785, 11025405
2.85 PAPPA pregnancy-associated plasma protein A, pappalysin 1
AA148534 1721035, 2422961, 2 2.81 MEG3 maternally expressed 3
(non-protein coding) AI291123 8619474, 9110174, 1 2.8 C15orf48
chromosome 15 open reading frame 48 AF228422 12209954, 12477932
2.79 AK022198 2.77 USP53 ubiquitin specific peptidase 53 H25097
10718198, 12477932 2.75 SDPR serum deprivation response
(phosphatidylserine binding BF982174 2390065, 8012384, 8 2.71
protein) MAP2 microtubule-associated protein 2 BF342661 1494913,
1708129, 2 2.69 RDH10 retinol dehydrogenase 10 (all-trans) AW150720
12407145, 12477932 2.68 BMP2 bone morphogenetic protein 2 AA583044
1487246, 2004788, 2 2.64 CRYAB crystalline, alpha B AF007162
838078, 1407707, 15 2.64 PAPPA pregnancy-associated plasma protein
A, pappalysin 1 BG434272 1721035, 2422961, 2 2.64 USP53 ubiquitin
specific peptidase 53 AW188464 10718198, 12477932 2.63 KRTAP1-5
keratin associated protein 1-5 AJ406928 11279113, 12228244 2.63
HSD11B1 hydroxysteroid (11-beta) dehydrogenase 1 NM_00525 1885595,
3034894, 7 2.62 GLS glutaminase AB020645 3531404, 6682827, 6 2.6
ARRDC4 arrestin domain containing 4 AV701177 12477932, 14702039
2.59 CCRL1 chemokine (C-C motif) receptor-like 1 NM_016557 8125298,
9373149, 9 2.58 MAMDC2 MAM domain containing 2 AI82120 11076863,
11256614 2.54 RTN1 reticulon 1 NM_021136 7515034, 7685762, 7 2.52
PAPPA pregnancy-associated plasma protein A, pappalysin 1 BG620958
1721035, 2422961, 2 2.49 FBX032 F-box protein 32 BF244402 11679633,
11717410 2.48
[0206] This application claims the benefit under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application No. 61/732,746 filed Dec. 3,
2012 and U.S. Provisional Application No. 61/747,653, filed Dec.
31, 2013, which applications are incorporated by reference herein
in their entirety.
[0207] The various embodiments described above can be combined to
provide further embodiments. All the U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet are incorporated herein by reference, in their entirety.
Aspects of the embodiments can be modified, if necessary to employ
concepts of the various patents, applications and publications to
provide yet further embodiments.
[0208] These and other changes can be made to the embodiments in
light of the above-detailed description. In general, in the
following claims, the terms used should not be construed to limit
the claims to the specific embodiments disclosed in the
specification and the claims, but should be construed to include
all possible embodiments along with the full scope of equivalents
to which such claims are entitled. Accordingly, the claims are not
limited by the disclosure.
Sequence CWU 1
1
215PRTArtificial SequenceLinker sequence 1Gly Gly Gly Gly Ser1
5211PRTArtificial SequenceLinker sequence 2Gly Gly Gly Gly Ser Gly
Gly Gly Gly Gly Ser1 5 10
* * * * *