U.S. patent application number 17/085027 was filed with the patent office on 2021-07-01 for treatment methods.
The applicant listed for this patent is Genocea Biosciences, Inc.. Invention is credited to Wendy Jane Broom, Pamela M. Carroll, Jessica Baker Flechtner, Hubert Lam, Marie Lossky-Elias, Lisa K. McNeil.
Application Number | 20210199644 17/085027 |
Document ID | / |
Family ID | 1000005459065 |
Filed Date | 2021-07-01 |
United States Patent
Application |
20210199644 |
Kind Code |
A1 |
Flechtner; Jessica Baker ;
et al. |
July 1, 2021 |
TREATMENT METHODS
Abstract
Methods and compositions for identifying tumor antigens of human
lymphocytes, and for identifying subjects for cancer therapy, are
provided herein.
Inventors: |
Flechtner; Jessica Baker;
(Sudbury, MA) ; Lossky-Elias; Marie; (Cambridge,
MA) ; Carroll; Pamela M.; (Boston, MA) ; Lam;
Hubert; (Quincy, MA) ; McNeil; Lisa K.;
(Watertown, MA) ; Broom; Wendy Jane; (Arlington,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genocea Biosciences, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005459065 |
Appl. No.: |
17/085027 |
Filed: |
October 30, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15927067 |
Mar 20, 2018 |
10859566 |
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17085027 |
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62583233 |
Nov 8, 2017 |
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62484258 |
Apr 11, 2017 |
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62473899 |
Mar 20, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 33/5011 20130101;
C40B 30/06 20130101; G01N 33/57484 20130101; G01N 2800/52 20130101;
C12Q 2600/158 20130101; A61K 2039/505 20130101; G01N 33/5044
20130101; C40B 30/04 20130101; G01N 33/5032 20130101; C40B 40/10
20130101; C12Q 2600/136 20130101; A61K 39/00117 20180801; A61K
39/001186 20180801; G01N 33/505 20130101; A61P 35/00 20180101; C07K
16/2818 20130101; C12Q 2600/106 20130101; C07K 2317/24 20130101;
G16H 50/20 20180101; G01N 33/5023 20130101; G16H 50/30 20180101;
C12Q 1/6886 20130101 |
International
Class: |
G01N 33/50 20060101
G01N033/50; C07K 16/28 20060101 C07K016/28; C12Q 1/6886 20060101
C12Q001/6886; A61P 35/00 20060101 A61P035/00; A61K 39/00 20060101
A61K039/00; G16H 50/30 20060101 G16H050/30; G16H 50/20 20060101
G16H050/20; G01N 33/574 20060101 G01N033/574 |
Claims
1-282. (canceled)
283. An immunogenic composition comprising one or more antigens or
immunogenic fragments thereof; wherein the one or more antigens are
selected by a method comprising: a) obtaining, providing, or
generating a library comprising bacterial cells or beads comprising
a plurality of tumor antigens, wherein each bacterial cell or bead
of the library comprises a different tumor antigen; b) contacting
the bacterial cells or beads with antigen presenting cells (APCs)
from a subject, wherein the APCs internalize the bacterial cells or
beads; c) contacting the APCs with lymphocytes from the subject,
under conditions suitable for activation of lymphocytes by a tumor
antigen presented by one or more APCs; d) determining whether one
or more lymphocytes are activated by one or more tumor antigens
presented by one or more APCs by assessing a level of expression
and/or secretion of one or more immune mediators; e) identifying
each activating tumor antigen as (i) an antigen that stimulates the
level of expression and/or secretion of one or more immune
mediators, or (ii) an antigen that inhibits and/or suppresses the
level of expression and/or secretion of one or more immune
mediators; and f) selecting from among the identified tumor
antigens (i) one or more antigens that increase a level of
expression and/or secretion of one or more immune mediators
associated with at least one beneficial response to cancer, (ii)
one or more tumor antigens that inhibit and/or suppress a level of
expression and/or secretion of one or more immune mediators
associated with at least one deleterious and/or non-beneficial
response to cancer, (iii) one or more antigens that increase a
level of expression and/or secretion of one or more immune
mediators associated with at least one deleterious and/or
non-beneficial response to cancer, and/or (iv) one or more tumor
antigens that inhibit and/or suppress a level of expression and/or
secretion of one or more immune mediators associated with at least
one beneficial response to cancer.
284. The immunogenic composition of claim 283, wherein the
immunogenic composition does not comprise: (iii) one or more tumor
antigens that increase level of expression and/or secretion of one
or more immune mediators associated with at least one deleterious
and/or non-beneficial response to cancer, and/or (iv) one or more
tumor antigens that inhibit and/or suppress level of expression
and/or secretion of one or more immune mediators associated with at
least one beneficial response to cancer, or immunogenic fragments
thereof.
285. The immunogenic composition of claim 283, wherein the
immunogenic composition comprises: (i) one or more antigens that
increase a level of expression and/or secretion of one or more
immune mediators associated with at least one beneficial response
to cancer, and/or (ii) one or more tumor antigens that inhibit
and/or suppress a level of expression and/or secretion of one or
more immune mediators associated with at least one deleterious
and/or non-beneficial response to cancer, or immunogenic fragments
thereof.
286. A method of manufacturing an immunogenic composition, the
method comprising: combining one or more selected antigens or
immunogenic fragments thereof and a carrier; wherein the one or
more selected antigens are selected by a method comprising: a)
obtaining, providing, or generating a library comprising bacterial
cells or beads comprising a plurality of tumor antigens, wherein
each bacterial cell or bead of the library comprises a different
tumor antigen; b) contacting the bacterial cells or beads with
antigen presenting cells (APCs) from a subject, wherein the APCs
internalize the bacterial cells or beads; c) contacting the APCs
with lymphocytes from the subject, under conditions suitable for
activation of lymphocytes by a tumor antigen presented by one or
more APCs; d) determining whether one or more lymphocytes are
activated by one or more tumor antigens presented by one or more
APCs by assessing a level of expression and/or secretion of one or
more immune mediators; e) identifying each activating tumor antigen
as (i) an antigen that stimulates the level of expression and/or
secretion of one or more immune mediators, or (ii) an antigen that
inhibits and/or suppresses the level of expression and/or secretion
of one or more immune mediators; and f) selecting from among the
identified tumor antigens (i) one or more antigens that increase a
level of expression and/or secretion of one or more immune
mediators associated with at least one beneficial response to
cancer, (ii) one or more tumor antigens that inhibit and/or
suppress a level of expression and/or secretion of one or more
immune mediators associated with at least one deleterious and/or
non-beneficial response to cancer, (iii) one or more antigens that
increase a level of expression and/or secretion of one or more
immune mediators associated with at least one deleterious and/or
non-beneficial response to cancer, and/or (iv) one or more tumor
antigens that inhibit and/or suppress a level of expression and/or
secretion of one or more immune mediators associated with at least
one beneficial response to cancer.
287. The method of claim 286, wherein the APCs are human APCs
isolated from the subject.
288. The method of claim 286, wherein the APCs and lymphocytes are
isolated from peripheral blood.
289. The method of claim 286, wherein the lymphocytes are derived
from a cancer or tumor.
290. The method of claim 286, wherein lymphocyte activation is
determined by (i) assessing a level of one or more expressed or
secreted immune mediators that is at least about 20% higher or
lower than a control level; (ii) assessing a level of one or more
expressed or secreted immune mediators that is at least two
standard deviations greater or lower than the mean of a control
level; and/or (iii) assessing a level of one or more expressed or
secreted immune mediators that is at least 2 median absolute
deviations (MADs) greater or lower than a median response level to
a control.
291. The method of claim 286, wherein lymphocyte non-responsiveness
is determined by (i) assessing a level of one or more expressed or
secreted immune mediators that is within about 20% of a control
level; (ii) assessing a level of one or more expressed or secreted
immune mediators that is less than one standard deviation higher or
lower than the mean of a control level; and/or (iii) assessing a
level of one or more expressed or secreted immune mediators that is
less than one median absolute deviation (MAD) higher or lower than
a median response level to a control.
292. The method of claim 286, wherein the APCs are provided in an
array, and wherein the APCs in each location of the array are
contacted with a set of bacterial cells, each set comprising a
different tumor antigen.
293. A method of identifying a subject as a candidate for cancer
therapy, the method comprising: 1) obtaining a subject response
profile, wherein the subject response profile is generated by: a)
obtaining, providing, or generating a library comprising bacterial
cells or beads comprising a plurality of tumor antigens, wherein
each bacterial cell or bead of the library comprises a different
tumor antigen; b) contacting the bacterial cells or beads with
antigen presenting cells (APCs) from a subject, wherein the APCs
internalize the bacterial cells or beads; c) contacting the APCs
with lymphocytes from the subject, under conditions suitable for
activation of lymphocytes by a tumor antigen presented by one or
more APCs; d) determining whether one or more lymphocytes are
activated by one or more tumor antigens presented by one or more
APCs by assessing a level of expression and/or secretion of one or
more immune mediators; e) identifying each activating tumor antigen
as (i) an antigen that stimulates the level of expression and/or
secretion of one or more immune mediators, or (ii) an antigen that
inhibits and/or suppresses the level of expression and/or secretion
of one or more immune mediators, to obtain or generate a subject
response profile; and 2) determining, based on one or more
characteristics of the subject response profile, whether the
subject is a candidate subject for initiation, continuation,
modification, discontinuation or non-initiation of a cancer
therapy.
294. The method of claim 293, wherein the subject response profile
comprises a representation of the level of expression and/or
secretion of the one or more immune mediators associated with the
plurality of tumor antigens.
295. The method of claim 293, wherein the one or more
characteristics of the subject response profile include: (i) number
of activating tumor antigens identified; (ii) number of antigens
that stimulate the level of expression and/or secretion of one or
more immune mediators; and/or (iii) number of antigens that inhibit
and/or suppress the level of expression and/or secretion of one or
more immune mediators.
296. The method of claim 293, wherein the subject response profile
is in the form of a report in paper and/or electronic form.
297. The method of claim 293, wherein the report also contains
information on prognosis, resistance, or potential or suggested
therapeutic options; information on the likely effectiveness of a
therapeutic option; the acceptability of a therapeutic option; the
advisability of applying the therapeutic option to a cancer
patient; and/or a recommendation on the administration of a cancer
therapy (e.g., the administration of a pre-selected dosage or in a
preselected treatment regimen e.g., in combination with one or more
alternative cancer therapies).
298. The method of claim 293, wherein the subject suffers from a
tumor.
299. The method of claim 298, wherein the tumor is or comprises a
solid tumor selected from a breast carcinoma, a squamous cell
carcinoma, a colon cancer, a head and neck cancer, ovarian cancer,
a lung cancer, mesothelioma, a genitourinary cancer, a rectal
cancer, a gastric cancer, or an esophageal cancer.
300. The method of claim 293, wherein the cancer therapy comprises
an immunogenic composition comprising: (i) one or more antigens
that increase a level of expression and/or secretion of one or more
immune mediators associated with at least one beneficial response
to cancer, and/or (ii) one or more tumor antigens that inhibit
and/or suppress a level of expression and/or secretion of one or
more immune mediators associated with at least one deleterious
and/or non-beneficial response to cancer, or immunogenic fragments
thereof.
301. The method of claim 293, wherein the cancer therapy further
comprises at least one immune checkpoint inhibitor.
302. The method of claim 293, wherein the immunogenic composition
does not comprise (iii) one or more tumor antigens that increase
level of expression and/or secretion of one or more immune
mediators associated with at least one deleterious and/or
non-beneficial response to cancer, and/or (iv) one or more tumor
antigens that inhibit and/or suppress level of expression and/or
secretion of one or more immune mediators associated with at least
one beneficial response to cancer, or immunogenic fragments
thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional U.S. application Ser. No.
15/927,067, filed Mar. 20, 2018, now U.S. Pat. No. 10,859,566,
which claims the benefit of U.S. Provisional Application No.
62/583,233, filed Nov. 8, 2017, U.S. Provisional Application No.
62/484,258, filed Apr. 11, 2017 and U.S. Provisional Application
No. 62/473,899, filed Mar. 20, 2017, the contents of each of which
are hereby incorporated by reference herein in their entirety.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which
has been submitted electronically in ASCII format and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Mar. 22, 2021, is named 2007781-0274_SL.txt and is 2,106,037
bytes in size.
BACKGROUND
[0003] Cancer is characterized by proliferation of abnormal cells.
Many treatments include costly and painful surgeries and
chemotherapies. Although there is a growing interest in cancer
therapies that target cancerous cells using a patient's own immune
system, such therapies have had limited success.
SUMMARY
[0004] The present invention features, inter alia, methods of
identifying tumor antigens and potential tumor antigens of human
lymphocytes, methods of selecting tumor antigens and potential
tumor antigens, as well as compositions including the tumor
antigens and potential tumor antigens, methods of making such
compositions, and methods of using the tumor antigens and potential
tumor antigens. The invention also features methods of evaluating
an immune response in a cancer subject, e.g., for identifying
and/or selecting a cancer subject for initiation, continuation,
modification, and/or discontinuation of a cancer therapy
[0005] Accordingly, in one aspect the disclosure features a method
of obtaining or generating a subject response profile. In some
embodiments, the method comprises: a) obtaining, providing, or
generating a library comprising bacterial cells or beads comprising
a plurality of tumor antigens, wherein each bacterial cell or bead
of the library comprises a different tumor antigen; b) contacting
the bacterial cells or beads of the library with antigen presenting
cells (APCs) from a subject, wherein the APCs internalize the
bacterial cells or beads; c) contacting the APCs with lymphocytes
from the subject, under conditions suitable for activation of
lymphocytes by a tumor antigen presented by one or more APCs; d)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more tumor antigens presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control) of expression and/or secretion of one or more immune
mediators; and e) identifying one or more tumor antigens that
stimulate, inhibit and/or suppress, and/or have minimal effect on a
level of expression and/or secretion of one or more immune
mediators, to obtain or generate a subject response profile.
[0006] In some embodiments, the subject response profile comprises
a representation of the level of expression and/or secretion of the
one or more immune mediators associated with the plurality of tumor
antigens.
[0007] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0008] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0009] In another aspect, the disclosure features a method of
obtaining or generating a target response profile. In some
embodiments, the method comprises: a) obtaining, providing, or
generating a library comprising bacterial cells or beads comprising
a plurality of tumor antigens, wherein each bacterial cell or bead
of the library comprises a different tumor antigen; b) contacting
the bacterial cells or beads of the library with antigen presenting
cells (APCs) from a subject who exhibits or previously exhibited a
response to cancer, wherein the APCs internalize the bacterial
cells or beads; c) contacting the APCs with lymphocytes from the
subject, under conditions suitable for activation of lymphocytes by
a tumor antigen presented by one or more APCs; d) determining
whether one or more lymphocytes are activated by, or not responsive
to, one or more tumor antigens presented by one or more APCs, e.g.,
by assessing (e.g., detecting or measuring) a level (e.g., an
increased or decreased level, relative to a control) of expression
and/or secretion of one or more immune mediators; and e)
identifying one or more tumor antigens that stimulate, inhibit
and/or suppress, and/or have a minimal effect on a level of
expression and/or secretion of one or more immune mediators, to
obtain or generate a target response profile.
[0010] In some embodiments, the subject exhibits or previously
exhibited at least one beneficial response to cancer. In some
embodiments, the beneficial response comprises a positive clinical
response, e.g., one or more positive clinical endpoints, to a
cancer therapy or combination of therapies. In some embodiments,
the beneficial response comprises a spontaneous response to a
cancer. In some embodiments, the beneficial response comprises
clearance of a cancer, e.g., a level of one or more clinical
measures associated with clearance of a cancer. In some
embodiments, the beneficial response comprises a lack of a relapse,
recurrence, and/or metastasis of a cancer, e.g., over a defined
period of time (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12 weeks, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months,
or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years). In some
embodiments, the beneficial response comprises a positive cancer
prognosis. In some embodiments, the beneficial response comprises a
lack of measurable toxic responses or side effects to a cancer
therapy or combination of therapies.
[0011] In some embodiments, the subject exhibits or previously
exhibited at least one deleterious or non-beneficial response to
cancer. In some embodiments, the deleterious response comprises a
negative clinical response and/or a failure to respond, to a cancer
therapy or combination of therapies. In some embodiments, the
deleterious response comprises a lack of clearance of a cancer,
e.g., a level of one or more clinical measures associated with lack
of clearance of a cancer. In some embodiments, the deleterious
response comprises at least one relapse, recurrence, and/or
metastasis of a cancer. In some embodiments, the deleterious
response comprises a negative cancer prognosis. In some
embodiments, the deleterious response comprises one or more toxic
responses or side effects (e.g., one or more measurable toxic
responses or side effects) to a cancer therapy or combination of
therapies.
[0012] In some embodiments, the library used to obtain the target
response profile is the same library used to obtain a subject
response profile.
[0013] In some embodiments, the method further comprises the step
of repeating steps a) through e) with antigen presenting cells
(APCs) and/or lymphocytes from additional subjects, to obtain a
population-based or composite target response profile.
[0014] In some embodiments, the target response profile comprises a
representation of the level of expression and/or secretion of the
one or more immune mediators associated with the plurality of tumor
antigens.
[0015] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0016] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0017] In another aspect, the disclosure features a method of
identifying a subject as a candidate for cancer therapy. In some
embodiments, the method comprises: a) obtaining, providing, or
generating a library comprising bacterial cells or beads comprising
a plurality of tumor antigens, wherein each bacterial cell or bead
of the library comprises a different tumor antigen; b) contacting
the bacterial cells or beads with antigen presenting cells (APCs)
from the subject, wherein the APCs internalize the bacterial cells
or beads; c) contacting the APCs with lymphocytes from the subject,
under conditions suitable for activation of lymphocytes by a tumor
antigen presented by one or more APCs; d) determining whether one
or more lymphocytes are activated by, or not responsive to, one or
more tumor antigens presented by one or more APCs, e.g., by
assessing (e.g., detecting or measuring) a level (e.g., an
increased or decreased level, relative to a control), of expression
and/or secretion of one or more immune mediators; e) identifying
one or more tumor antigens that stimulate, inhibit and/or suppress,
and/or have a minimal effect on a level of expression and/or
secretion of one or more immune mediators, to obtain or generate a
subject response profile; and f) comparing the subject response
profile to a target response profile to select the subject as a
candidate subject for initiation, continuation, modification,
discontinuation or non-initiation of a cancer therapy. In some
embodiments, the subject response profile comprises a
representation of the level of expression and/or secretion of the
one or more immune mediators associated with the plurality of tumor
antigens.
[0018] In some embodiments, the method further comprises generating
the target response profile by a method comprising: g) contacting
the bacterial cells or beads with antigen presenting cells (APCs)
from a target subject, wherein the APCs internalize the bacterial
cells or beads; h) contacting the APCs with lymphocytes from the
target subject, under conditions suitable for activation of
lymphocytes by a tumor antigen presented by one or more APCs; i)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more tumor antigens presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control), of expression and/or secretion of one or more immune
mediators; and j) identifying one or more tumor antigens that
stimulate, inhibit and/or suppress, and/or have a minimal effect on
a level of expression and/or secretion of one or more immune
mediators, to obtain or generate the target response profile. In
some embodiments, the target response profile comprises a
representation of the level of expression and/or secretion of the
one or more immune mediators associated with the plurality of tumor
antigens.
[0019] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited at
least one beneficial response to cancer. In some embodiments, the
beneficial response comprises a positive clinical response to a
cancer therapy or combination of therapies. In some embodiments,
the beneficial response comprises a spontaneous response to a
cancer. In some embodiments, the beneficial response comprises
clearance of a cancer, e.g., a level of one or more clinical
measures associated with clearance of a cancer. In some
embodiments, the beneficial response comprises a lack of a relapse,
recurrence, and/or metastasis of a cancer, e.g., over a defined
period of time (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12 weeks, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months,
or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years). In some
embodiments, the beneficial response comprises a positive cancer
prognosis. In some embodiments, the beneficial response comprises a
lack of one or more toxic responses and/or side effects (e.g., one
or more measurable toxic responses or side effects) to a cancer
therapy or combination of therapies.
[0020] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited one or
more deleterious and/or non-beneficial response to cancer. In some
embodiments, the deleterious and/or non-beneficial response
comprises a negative clinical response and/or a failure to respond,
to a cancer therapy or combination of therapies. In some
embodiments, the deleterious and/or non-beneficial response
comprises a lack of clearance of a cancer, e.g., a level of one or
more clinical measures associated with lack of clearance of a
cancer. In some embodiments, the deleterious and/or non-beneficial
response comprises at least one relapse, recurrence, and/or
metastasis of a cancer. In some embodiments, the deleterious and/or
non-beneficial response comprises a negative cancer prognosis. In
some embodiments, the deleterious and/or non-beneficial response
comprises one or more toxic responses and/or side effects (e.g.,
one or more measurable toxic responses and/or side effects) to a
cancer therapy or combination of therapies.
[0021] In some embodiments, the method further comprises selecting
the candidate subject for initiation of a cancer therapy or
combination of cancer therapies. In some embodiments, the method
further comprises selecting the candidate subject for continuation
of a cancer therapy or combination of cancer therapies. In some
embodiments, the method comprises selecting the subject as a
candidate subject (i) if the subject response profile is similar to
the target response profile from a target subject who exhibits or
previously exhibited one or more beneficial responses to the cancer
therapy or combination, and/or (ii) if the subject response profile
is dissimilar to the target response profile from a target subject
who exhibits or previously exhibited one or more deleterious
responses to the cancer therapy or combination. In some
embodiments, the method further comprises administering the cancer
therapy or combination of cancer therapies to the candidate
subject.
[0022] In some embodiments, the method further comprises selecting
the candidate subject for modification of a cancer therapy. In some
embodiments, the method further comprises selecting the candidate
subject for discontinuation or non-initiation of a cancer therapy.
In some embodiments, the method further comprises selecting the
subject as a candidate subject for modification, discontinuation,
and/or non-initiation of a cancer therapy (i) if the subject
response profile is similar to the target response profile from a
target subject who exhibits or previously exhibited one or more
deleterious responses to the cancer therapy, and/or (ii) if the
subject response profile is dissimilar to the target response
profile from a target subject who exhibits or previously exhibited
one or more beneficial responses to the cancer therapy. In some
embodiments, the method further comprises modifying the cancer
therapy administered to the candidate subject. In some embodiments,
the method further comprises discontinuing or not initiating the
cancer therapy to the candidate subject.
[0023] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0024] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0025] In another aspect, the disclosure features a method of
selecting tumor antigens. In some embodiments, the, method
comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads comprising a plurality of tumor
antigens, wherein each bacterial cell or bead of the library
comprises a different tumor antigen; b) contacting the bacterial
cells or beads with antigen presenting cells (APCs) from a subject,
wherein the APCs internalize the bacterial cells or beads; c)
contacting the APCs with lymphocytes from the subject, under
conditions suitable for activation of lymphocytes by a tumor
antigen presented by one or more APCs; d) determining whether one
or more lymphocytes are activated by, or not responsive to, one or
more tumor antigens presented by one or more APCs, e.g., by
assessing (e.g., detecting or measuring) a level) e.g., an
increased or decreased level, relative to a control), of expression
and/or secretion of one or more immune mediators; e) identifying
one or more tumor antigens that stimulate, inhibit and/or suppress,
and/or have minimal effect on a level of expression and/or
secretion of one or more immune mediators, to obtain or generate a
subject response profile; f) comparing the subject response profile
to a target response profile; and g) selecting one or more tumor
antigens based on the comparison. In some embodiments, the subject
response profile comprises a representation of the level of
expression and/or secretion of the one or more immune mediators
associated with the plurality of tumor antigens.
[0026] In some embodiments, the method further comprises generating
the target response profile by a method comprising: h) contacting
the bacterial cells or beads with antigen presenting cells (APCs)
from a target subject, wherein the APCs internalize the bacterial
cells or beads; i) contacting the APCs with lymphocytes from the
target subject, under conditions suitable for activation of
lymphocytes by a tumor antigen presented by one or more APCs; j)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more tumor antigens presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control), of expression and/or secretion of one or more immune
mediators; and k) identifying one or more tumor antigens that
stimulate, inhibit and/or suppress, and/or have a minimal effect on
a level of expression and/or secretion of one or more immune
mediators, to obtain or generate the target response profile. In
some embodiments, the target response profile comprises a
representation of the level of expression and/or secretion of the
one or more immune mediators associated with the plurality of tumor
antigens.
[0027] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited one or
more beneficial response to cancer. In some embodiments, the
beneficial response comprises a positive clinical response to a
cancer therapy or combination of therapies. In some embodiments,
the beneficial response comprises a spontaneous response to a
cancer. In some embodiments, the beneficial response comprises
clearance of a cancer, e.g., a level of one or more clinical
measures associated with clearance of a cancer. In some
embodiments, the beneficial response comprises a relapse,
recurrence, and/or metastasis of a cancer e.g., over a defined
period of time (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12 weeks, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months,
or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years). In some
embodiments, the beneficial response comprises a positive cancer
prognosis. In some embodiments, the beneficial response comprises a
lack of one or more toxic responses and/or side effects (e.g., one
or more measurable toxic responses and/or side effects) to a cancer
therapy or combination of therapies.
[0028] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited one or
more deleterious or non-beneficial response to cancer. In some
embodiments, the deleterious and/or non-beneficial response
comprises a negative clinical response and/or a failure to respond,
to a cancer therapy or combination of therapies. In some
embodiments, the deleterious and/or non-beneficial response
comprises a lack of clearance of a cancer, e.g., a level of one or
more clinical measures associated with lack of clearance of a
cancer. In some embodiments, the deleterious and/or non-beneficial
response comprises at least one relapse, recurrence, and/or
metastasis of a cancer. In some embodiments, the deleterious and/or
non-beneficial response comprises a negative cancer prognosis. In
some embodiments, the deleterious and/or non-beneficial response
comprises one or more toxic responses and/or side effects (e.g.,
one or more measurable toxic responses and/or side effects) to a
cancer therapy or combination of therapies.
[0029] In some embodiments, the method further comprises selecting
(i) one or more tumor antigens that increase level of expression
and/or secretion of one or more immune mediators associated with a
beneficial response to cancer, and/or (ii) one or more tumor
antigens that inhibit and/or suppress level of expression and/or
secretion of one or more immune mediators associated with
deleterious or not beneficial responses to cancer. In some
embodiments, the method further comprises administering to the
subject an immunogenic composition comprising one or more of the
selected antigens or immunogenic fragments thereof. In some
embodiments, the method further comprises administering to the
subject a cancer therapy or combination of therapies.
[0030] In some embodiments, the method further comprises selecting
(i) one or more tumor antigens that increase level of expression
and/or secretion of one or more immune mediators associated with
deleterious or not beneficial responses to cancer, and/or (ii) one
or more tumor antigens that inhibit and/or suppress level of
expression and/or secretion of one or more immune mediators
associated with beneficial responses to cancer. In some
embodiments, the method further comprises administering to the
subject an immunogenic composition that does not comprise one or
more of the selected antigens or immunogenic fragments thereof. In
some embodiments, the method further comprises administering to the
subject a cancer therapy or combination of therapies.
[0031] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0032] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0033] In another aspect, the disclosure features a method of
inducing an immune response in a subject. In some embodiments, the
method comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads comprising a plurality of tumor
antigens, wherein each bacterial cell or bead of the library
comprises a different tumor antigen; b) contacting the bacterial
cells or beads with antigen presenting cells (APCs) from a subject,
wherein the APCs internalize the bacterial cells or beads; c)
contacting the APCs with lymphocytes from the subject, under
conditions suitable for activation of lymphocytes by a tumor
antigen presented by one or more APCs; d) determining whether one
or more lymphocytes are activated by, or not responsive to, one or
more tumor antigens presented by one or more APCs, e.g., by
assessing (e.g., detecting or measuring) a level (e.g., an
increased level or decreased level, relative to a control) of
expression and/or secretion of one or more immune mediators; e)
identifying one or more tumor antigens that stimulate, inhibit
and/or suppress, and/or have a minimal effect on a level of
expression and/or secretion of one or more immune mediators, to
obtain or generate a subject response profile; f) comparing the
subject response profile to a target response profile; g) selecting
one or more tumor antigens based on the comparison; and h)
administering to the subject an immunogenic composition comprising
one or more of the selected antigens or immunogenic fragment
thereof. In some embodiments, the subject response profile
comprises a representation of the level of expression and/or
secretion of the one or more immune mediators associated with the
plurality of tumor antigens.
[0034] In some embodiments, the method further comprises generating
the target response profile by a method comprising: i) contacting
the bacterial cells or beads with antigen presenting cells (APCs)
from a target subject, wherein the APCs internalize the bacterial
cells or beads; j) contacting the APCs with lymphocytes from the
target subject, under conditions suitable for activation of
lymphocytes by a tumor antigen presented by one or more APCs; k)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more tumor antigens presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control), of expression and/or secretion of one or more immune
mediators; and l) identifying one or more tumor antigens that
stimulate, inhibit and/or suppress, and/or have a minimal effect on
a level of expression and/or secretion of one or more immune
mediators, to obtain or generate the target response profile. In
some embodiments, the target response profile comprises a
representation of the level of expression and/or secretion of the
one or more immune mediators associated with the plurality of tumor
antigens.
[0035] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited at
least one beneficial response to cancer. In some embodiments, the
beneficial response comprises a positive clinical response to a
cancer therapy or combination of therapies. In some embodiments,
the beneficial response comprises a spontaneous response to a
cancer. In some embodiments, the beneficial response comprises
clearance of a cancer, e.g., a level of one or more clinical
measures associated with clearance of a cancer. In some
embodiments, the beneficial response comprises a lack of a relapse,
recurrence, and/or metastasis of a cancer, e.g., over a defined
period of time (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12 weeks, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months,
or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years). In some
embodiments, the beneficial response comprises a positive cancer
prognosis. In some embodiments, the beneficial response comprises a
lack of one or more toxic responses and/or side effects (e.g., one
or more measurable toxic responses or side effects) to a cancer
therapy or combination of therapies.
[0036] In some embodiments, the method further comprises selecting
and administering to the subject (i) one or more tumor antigens
that increase level of expression and/or secretion of one or more
immune mediators associated with one or more beneficial responses
to cancer, and/or (i) one or more tumor antigens that inhibit
and/or suppress level of expression and/or secretion of one or more
immune mediators associated with one or more deleterious or not
beneficial responses to cancer.
[0037] In some embodiments, the method further comprises
administering to the subject a cancer therapy or combination of
therapies.
[0038] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0039] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0040] In another aspect, the disclosure features a method of
inducing an immune response in a subject. In some embodiments, the
method comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads comprising a plurality of tumor
antigens, wherein each bacterial cell or bead of the library
comprises a different tumor antigen; b) contacting the bacterial
cells or beads with antigen presenting cells (APCs) from a subject,
wherein the APCs internalize the bacterial cells or beads; c)
contacting the APCs with lymphocytes from the subject, under
conditions suitable for activation of lymphocytes by a tumor
antigen presented by one or more APCs; d) determining whether one
or more lymphocytes are activated by, or not responsive to, one or
more tumor antigens presented by one or more APCs, e.g., by
assessing (e.g., detecting or measuring) a level (e.g., an
increased or decreased level, relative to a control) of expression
and/or secretion of one or more immune mediators; e) identifying
one or more tumor antigens that stimulate, inhibit and/or suppress,
and/or have a minimal effect on a level of expression and/or
secretion of one or more immune mediators, to obtain or generate a
subject response profile; f) comparing the subject response profile
to a target response profile; g) selecting one or more tumor
antigens based on the comparison; and h) administering to the
subject an immunogenic composition that does not comprise one or
more of the selected antigens or immunogenic fragment thereof. In
some embodiments, the subject response profile comprises a
representation of the level of expression and/or secretion of the
one or more immune mediators associated with the plurality of tumor
antigens.
[0041] In some embodiments, the method further comprises generating
the target response profile by a method comprising: i) contacting
the bacterial cells or beads with antigen presenting cells (APCs)
from a target subject, wherein the APCs internalize the bacterial
cells or beads; j) contacting the APCs with lymphocytes from the
target subject, under conditions suitable for activation of
lymphocytes by a tumor antigen presented by one or more APCs; k)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more tumor antigens presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control), of expression and/or secretion of one or more immune
mediators; and l) identifying one or more tumor antigens that
stimulate, inhibit and/or suppress, and/or have a minimal effect on
a level of expression and/or secretion of one or more immune
mediators, to obtain or generate the target response profile. In
some embodiments, the target response profile comprises a
representation of the level of expression and/or secretion of the
one or more immune mediators associated with the plurality of tumor
antigens.
[0042] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited one or
more deleterious and/or non-beneficial response to cancer. In some
embodiments, the deleterious and/or non-beneficial response
comprises a negative clinical response and/or a failure to respond,
to a cancer therapy or combination of therapies. In some
embodiments, the deleterious and/or non-beneficial response
comprises a lack of clearance of a cancer, e.g., a level of one or
more clinical measures associated with lack of clearance of a
cancer. In some embodiments, the deleterious and/or non-beneficial
response comprises at least one relapse, recurrence, and/or
metastasis of a cancer. In some embodiments, the deleterious and/or
non-beneficial response comprises a negative cancer prognosis. In
some embodiments, the deleterious and/or non-beneficial response
comprises one or more toxic responses and/or side effects (e.g.,
one or more measurable toxic responses and/or side effects) to a
cancer therapy or combination of therapies.
[0043] In some embodiments, the method further comprises selecting
one or more tumor antigens that increase expression or secretion of
immune mediators associated with deleterious or not beneficial
responses to cancer, and/or one or more tumor antigens that inhibit
and/or suppress expression or secretion of immune mediators
associated with beneficial responses to cancer.
[0044] In some embodiments, the method further comprises
administering to the subject a cancer therapy or combination of
therapies.
[0045] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0046] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0047] In another aspect, the disclosure features a method of
selecting tumor antigens. In some embodiments, the method
comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads comprising a plurality of tumor
antigens, wherein each bacterial cell or bead of the library
comprises a different tumor antigen; b) contacting the bacterial
cells or beads with antigen presenting cells (APCs) from a subject,
wherein the APCs internalize the bacterial cells or beads; c)
contacting the APCs with lymphocytes from the subject, under
conditions suitable for activation of lymphocytes by a tumor
antigen presented by one or more APCs; d) determining whether one
or more lymphocytes are activated by one or more tumor antigens
presented by one or more APCs by assessing (e.g., detecting or
measuring) a level (e.g., an increased or decreased level, relative
to a control) of expression and/or secretion of one or more immune
mediators; e) identifying one or more tumor antigens that
stimulate, inhibit and/or suppress, and/or have a minimal effect on
a level of expression and/or secretion of one or more immune
mediators, to obtain a subject response profile; and f) selecting
from among the identified tumor antigens one or more antigens that
increase a level of expression and/or secretion of one or more
immune mediators associated with at least one beneficial response
to cancer, and/or selecting one or more tumor antigens that inhibit
and/or suppress a level of expression and/or secretion of one or
more immune mediators associated with at least one deleterious
and/or non-beneficial response to cancer.
[0048] In some embodiments, the method further comprises comparing
the subject response profile to a target response profile, e.g., a
target response profile generated using a method described herein,
and selecting one or more tumor antigens based on the
comparison.
[0049] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited at
least one beneficial response to cancer. In some embodiments, the
beneficial response comprises a positive clinical response to a
cancer therapy or combination of therapies. In some embodiments,
the beneficial response comprises a spontaneous response to a
cancer. In some embodiments, the beneficial response comprises
clearance of a cancer, e.g., a level of one or more clinical
measures associated with clearance of a cancer. In some
embodiments, the beneficial response comprises a lack of a relapse,
recurrence, and/or metastasis of a cancer, e.g., over a defined
period of time (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12 weeks, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months,
or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years). In some
embodiments, the beneficial response comprises a positive cancer
prognosis. In some embodiments, the beneficial response comprises a
lack of one or more toxic responses and/or side effects (e.g., one
or more measurable toxic responses or side effects) to a cancer
therapy or combination of therapies.
[0050] In some embodiments, the method further comprises
administering to the subject an immunogenic composition comprising
one or more of the selected antigens or immunogenic fragments
thereof.
[0051] In some embodiments, the method further comprises
administering to the subject a cancer therapy or combination of
therapies.
[0052] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0053] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0054] In another aspect, the disclosure features a method of
selecting tumor antigens. In some embodiments, the method comprises
a) obtaining, providing, or generating a library comprising
bacterial cells or beads comprising a plurality of tumor antigens,
wherein each bacterial cell or bead of the library comprises a
different tumor antigen; b) contacting the bacterial cells or beads
with antigen presenting cells (APCs) from a subject, wherein the
APCs internalize the bacterial cells or beads; c) contacting the
APCs with lymphocytes from the subject, under conditions suitable
for activation of lymphocytes by a tumor antigen presented by one
or more APCs; d) determining whether one or more lymphocytes are
activated by one or more tumor antigens presented by one or more
APCs by assessing (e.g., detecting or measuring) a level (e.g., an
increased or decreased level, relative to a control) of expression
and/or secretion of one or more immune mediators; e) identifying
one or more tumor antigens that stimulate, inhibit and/or suppress,
and/or have a minimal effect on a level of expression and/or
secretion of one or more immune mediators, to obtain a subject
response profile; and f) selecting from among the identified tumor
antigens (i) one or more antigens that increase a level of
expression and/or secretion of one or more immune mediators
associated with at least one deleterious and/or non-beneficial
response to cancer, and/or (ii) one or more tumor antigens that
inhibit and/or suppress a level of expression and/or secretion of
one or more immune mediators associated with at least one
beneficial response to cancer.
[0055] In some embodiments, the method further comprises comparing
the subject response profile to a target response profile, e.g., a
target response profile generated using a method described herein,
and selecting one or more tumor antigens based on the
comparison.
[0056] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited one or
more deleterious and/or non-beneficial response to cancer. In some
embodiments, the deleterious and/or non-beneficial response
comprises a negative clinical response and/or a failure to respond,
to a cancer therapy or combination of therapies. In some
embodiments, the deleterious and/or non-beneficial response
comprises a lack of clearance of a cancer, e.g., a level of one or
more clinical measures associated with lack of clearance of a
cancer. In some embodiments, the deleterious and/or non-beneficial
response comprises at least one relapse, recurrence, and/or
metastasis of a cancer. In some embodiments, the deleterious and/or
non-beneficial response comprises a negative cancer prognosis. In
some embodiments, the deleterious and/or non-beneficial response
comprises one or more toxic responses and/or side effects (e.g.,
one or more measurable toxic responses and/or side effects) to a
cancer therapy or combination of therapies.
[0057] In some embodiments, the method further comprises
administering to the subject an immunogenic composition that does
not comprise one or more of the selected antigens or immunogenic
fragments thereof.
[0058] In some embodiments, the method further comprises
administering to the subject a cancer therapy or combination of
therapies.
[0059] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0060] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0061] In another aspect, the disclosure features a method of
inducing an immune response in a subject. In some embodiments, the
method comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads comprising a plurality of tumor
antigens, wherein each bacterial cell or bead of the library
comprises a different tumor antigen; b) contacting the bacterial
cells or beads with antigen presenting cells (APCs) from a subject,
wherein the APCs internalize the bacterial cells or beads; c)
contacting the APCs with lymphocytes from the subject, under
conditions suitable for activation of lymphocytes by a tumor
antigen presented by one or more APCs; d) determining whether one
or more lymphocytes are activated by, or not responsive to, one or
more tumor antigens presented by one or more APCs, e.g., by
assessing (e.g., detecting or measuring) a level (e.g., an
increased or decreased level, relative to a control), of expression
and/or secretion of one or more immune mediators; e) identifying
one or more tumor antigens that stimulate, inhibit and/or suppress,
and/or have a minimal effect on a level of expression and/or
secretion of one or more immune mediators, to obtain a subject
response profile; f) selecting from among the identified tumor
antigens (i) one or more antigens that increase level of expression
and/or secretion of one or more immune mediators associated with at
least one beneficial response to cancer, and/or (ii) one or more
tumor antigens that inhibit and/or suppress level of expression
and/or secretion of one or more immune mediators associated with at
least one deleterious or non-beneficial response to cancer; and g)
administering to the subject an immunogenic composition comprising
one or more of the selected antigens or immunogenic fragment
thereof.
[0062] In some embodiments, the method further comprises comparing
the subject response profile to a target response profile, e.g., a
target response profile generated using a method described herein,
and selecting one or more tumor antigens based on the comparison,
prior to administration of the immunogenic composition.
[0063] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited at
least one beneficial response to cancer. In some embodiments, the
beneficial response comprises a positive clinical response to a
cancer therapy or combination of therapies. In some embodiments,
the beneficial response comprises a spontaneous response to a
cancer. In some embodiments, the beneficial response comprises
clearance of a cancer, e.g., a level of one or more clinical
measures associated with clearance of a cancer. In some
embodiments, the beneficial response comprises a lack of a relapse,
recurrence, and/or metastasis of a cancer, e.g., over a defined
period of time (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12 weeks, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months,
or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years). In some
embodiments, the beneficial response comprises a positive cancer
prognosis. In some embodiments, the beneficial response comprises a
lack of one or more toxic responses and/or side effects (e.g., one
or more measurable toxic responses or side effects) to a cancer
therapy or combination of therapies.
[0064] In some embodiments, the method further comprises
administering to the subject a cancer therapy or combination of
therapies.
[0065] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0066] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0067] In another aspect, the disclosure features a method of
inducing an immune response in a subject. In some embodiments, the
method comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads comprising a plurality of tumor
antigens, wherein each bacterial cell or bead of the library
comprises a different tumor antigen; b) contacting the bacterial
cells or beads with antigen presenting cells (APCs) from a subject,
wherein the APCs internalize the bacterial cells or beads; c)
contacting the APCs with lymphocytes from the subject, under
conditions suitable for activation of lymphocytes by a tumor
antigen presented by one or more APCs; d) determining whether one
or more lymphocytes are activated by, or not responsive to, one or
more tumor antigens presented by one or more APCs, e.g., by
assessing e.g., detecting or measuring) a level (e.g., an increased
or decreased level, relative to a control). of expression and/or
secretion of one or more immune mediators; e) identifying one or
more tumor antigens that stimulate, inhibit and/or suppress, and/or
have a minimal effect on level of expression and/or secretion of
one or more immune mediators, to obtain a subject response profile;
f) comparing the subject response profile to a target response
profile, e.g., a target response profile generated using a method
described herein; g) selecting from among the identified tumor
antigens (i) one or more antigens that increase level of expression
and/or secretion of one or more immune mediators associated with at
least one deleterious and/or non-beneficial response to cancer,
and/or (ii) one or more tumor antigens that inhibit and/or suppress
level of expression and/or secretion of one or more immune
mediators associated with at least one beneficial response to
cancer; and h) administering to the subject an immunogenic
composition that does not comprise one or more of the selected
antigens or immunogenic fragment thereof.
[0068] In some embodiments, the method further comprises comparing
the subject response profile to a target response profile e.g., a
target response profile generated using a method described herein,
and selecting one or more tumor antigens based on the
comparison.
[0069] In some embodiments, the target response profile is from one
or more target subjects who exhibit or previously exhibited one or
more deleterious and/or non-beneficial response to cancer. In some
embodiments, the deleterious and/or non-beneficial response
comprises a negative clinical response and/or a failure to respond,
to a cancer therapy or combination of therapies. In some
embodiments, the deleterious and/or non-beneficial response
comprises a lack of clearance of a cancer, e.g., a level of one or
more clinical measures associated with lack of clearance of a
cancer. In some embodiments, the deleterious and/or non-beneficial
response comprises at least one relapse, recurrence, and/or
metastasis of a cancer. In some embodiments, the deleterious and/or
non-beneficial response comprises a negative cancer prognosis. In
some embodiments, the deleterious and/or non-beneficial response
comprises one or more toxic responses and/or side effects (e.g.,
one or more measurable toxic responses and/or side effects) to a
cancer therapy or combination of therapies.
[0070] In some embodiments, the method further comprises
administering to the subject a cancer therapy or combination of
therapies.
[0071] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0072] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0073] In another aspect, the disclosure features a method of
identifying tumor antigens. In some embodiments, the method
comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads, wherein each bacterial cell or
bead of the library comprises a different heterologous polypeptide
comprising one or more mutations, splice variants, or
translocations expressed in a cancer or tumor cell of a subject; b)
contacting the bacterial cells or beads with antigen presenting
cells (APCs) from the subject, wherein the APCs internalize the
bacterial cells or beads; c) contacting the APCs with lymphocytes
from the subject, under conditions suitable for activation of
lymphocytes by a polypeptide presented by one or more APCs; d)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more polypeptides presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control) of expression and/or secretion of one or more immune
mediators; and e) identifying one or more polypeptides that
stimulate, inhibit and/or suppress, and/or have a minimal effect on
level of expression and/or secretion of one or more immune
mediators, wherein stimulation, inhibition and/or suppression
indicate that the polypeptide is a tumor antigen.
[0074] In another aspect, the disclosure features a method of
selecting tumor antigens. In some embodiments, the method
comprises: a) providing a library comprising bacterial cells or
beads, wherein each bacterial cell or bead of the library comprises
a different heterologous polypeptide comprising one or more
mutations, splice variants, or translocations expressed in a cancer
or tumor cell expressed in a cancer or tumor cell of a subject; b)
contacting the bacterial cells or beads with antigen presenting
cells (APCs) from the subject, wherein the APCs internalize the
bacterial cells or beads; c) contacting the APCs with lymphocytes
from the subject, under conditions suitable for activation of
lymphocytes by a polypeptide presented by one or more APCs; d)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more polypeptides presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control), of expression and/or secretion of one or more immune
mediators; e) identifying one or more polypeptides that stimulate,
inhibit and/or suppress, and/or have a minimal effect on level of
expression and/or secretion of one or more immune mediators,
wherein stimulation, inhibition and/or suppression indicate that
the polypeptide is a tumor antigen; and f) selecting from among the
identified tumor antigens (i) one or more tumor antigens that
increase level of expression and/or secretion of one or more immune
mediators associated with at least one beneficial response to
cancer, and/or (ii) one or more tumor antigens that inhibit and/or
suppress level of expression and/or secretion of one or more immune
mediators associated with at least one deleterious and/or
non-beneficial response to cancer.
[0075] In some embodiments, the method further comprises selecting
from among the identified polypeptides one of more polypeptides
that have a minimal effect on level of expression and/or secretion
of one of more immune mediators.
[0076] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0077] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0078] In another aspect, the disclosure features a method of
selecting potential tumor antigens. In some embodiments, the method
comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads, wherein each bacterial cell or
bead of the library comprises a heterologous polypeptide comprising
one or more mutations, splice variants, or translocations expressed
in a cancer or tumor cell expressed in a cancer or tumor cell of a
subject; b) contacting the bacterial cells or beads with antigen
presenting cells (APCs) from the subject, wherein the APCs
internalize the bacterial cells or beads; c) contacting the APCs
with lymphocytes from the subject, under conditions suitable for
activation of lymphocytes by a polypeptide presented by one or more
APCs; d) determining whether one or more lymphocytes are activated
by, or not responsive to, one or more polypeptides presented by one
or more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control) of expression and/or secretion of one or more immune
mediators; e) identifying one or more polypeptides that stimulate,
inhibit and/or suppress, and/or have a minimal effect on level of
expression and/or secretion of one or more immune mediators, and
identifying one or more polypeptides that stimulate, inhibit,
and/or suppress as a tumor antigen; and f) selecting from among the
identified polypeptides one or more polypeptides that have a
minimal effect on level of expression and/or secretion of one or
more immune mediators.
[0079] In some embodiments, the method further comprises repeating
steps b) through e), or steps c) through e), with lymphocytes from
the subject that have undergone one or more previous rounds of
exposure to APCs.
[0080] In some embodiments, the method further comprises selecting
from among the identified tumor antigens (i) one or more tumor
antigens that increase level of expression and/or secretion of one
or more immune mediators associated with at least one beneficial
response to cancer, and/or (ii) one or more tumor antigens that
inhibit and/or suppress level of expression and/or secretion of one
or more immune mediators associated with at least one deleterious
and/or non-beneficial responses to cancer.
[0081] In some embodiments, the method further comprises
administering to the subject an immunogenic composition comprising
one or more of the selected tumor antigens or selected
polypeptides, or immunogenic fragments thereof. In some
embodiments, the method further comprises administering to the
subject an immunogenic composition comprising a combination of one
or more of the selected tumor antigens and selected polypeptides,
or immunogenic fragments thereof. In some embodiments, the method
further comprises administering to the subject a cancer therapy or
combination of therapies.
[0082] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0083] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0084] In another aspect, the disclosure features a method of
selecting tumor antigens. In some embodiments, the method
comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads, wherein each bacterial cell or
bead of the library comprises a different heterologous polypeptide
comprising one or more mutations, splice variants, or
translocations expressed in a cancer or tumor cell expressed in a
cancer or tumor cell of a subject; b) contacting the bacterial
cells or beads with antigen presenting cells (APCs) from the
subject, wherein the APCs internalize the bacterial cells or beads;
c) contacting the APCs with lymphocytes from the subject, under
conditions suitable for activation of lymphocytes by a polypeptide
presented by one or more APCs; d) determining whether one or more
lymphocytes are activated by, or not responsive to, one or more
polypeptides presented by one or more APCs, e.g., by assessing
(e.g., detecting or measuring) a level (e.g., an increased or
decreased level, relative to a control), of expression and/or
secretion of one or more immune mediators; e) identifying one or
more polypeptides that stimulate, inhibit and/or suppress, and/or
have a minimal effect on level of expression and/or secretion of
one or more immune mediators, and identifying one or more
polypeptides that stimulate, inhibit, and/or suppress as a tumor
antigen; and f) selecting from among the identified tumor antigens
(i) one or more tumor antigens that increase level of expression
and/or secretion of one or more immune mediators associated with at
least one deleterious and/or non-beneficial response to cancer,
and/or (ii) one or more tumor antigens that inhibit and/or suppress
level of expression and/or secretion of one or more immune
mediators associated with at least one beneficial response to
cancer.
[0085] In some embodiments, the method further comprises
administering to the subject an immunogenic composition that does
not comprise one or more of the selected tumor antigens or
immunogenic fragments thereof. In some embodiments, the method
further comprises administering to the subject a cancer therapy or
combination of therapies.
[0086] In some embodiments, the APCs are human APCs isolated from
the subject; and/or the bacterial cells further comprise a
cytolysin polypeptide; and/or the cytolysin polypeptide is
listeriolysin O (LLO); and/or the APCs are provided in an array,
and/or the APCs in each location of the array are contacted with a
set of bacterial cells, each set comprising a different tumor
antigen; and/or the APCs and lymphocytes are isolated from
peripheral blood; and/or the APCs comprise immortalized cells;
and/or the lymphocytes are derived from a cancer or tumor.
[0087] In some embodiments, the tumor antigens comprise full length
polypeptides encoding mutations, splice variants, or translocations
present in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides
encoding mutations, splice variants, or translocations present in a
cancer or tumor; and/or the tumor antigens comprise full length
polypeptides encoded by a virus or other infectious agent present
in a cancer or tumor; and/or the tumor antigens comprise
polypeptides that are fragments of full length polypeptides encoded
by a virus or other infectious agent present in a cancer or tumor;
and/or the tumor antigens comprise full length polypeptides
encoding autoantigens associated with a cancer or tumor; and/or the
tumor antigens comprise polypeptides that are fragments of full
length polypeptides encoding autoantigens associated with a cancer
or tumor.
[0088] In another aspect, the disclosure features a method of
inducing an immune response in a subject. In some embodiments, the
method comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads, wherein each bacterial cell or
bead of the library comprises a different heterologous polypeptide
comprising one or more mutations, splice variants, or
translocations expressed in a cancer or tumor cell of a subject; b)
contacting the bacterial cells or beads with antigen presenting
cells (APCs) from the subject, wherein the APCs internalize the
bacterial cells or beads; c) contacting the APCs with lymphocytes
from the subject, under conditions suitable for activation of
lymphocytes by a polypeptide presented by one or more APCs; d)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more polypeptides presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control) of expression and/or secretion of one or more immune
mediators; e) identifying one or more polypeptides that stimulate,
inhibit and/or suppress, and/or have a minimal effect on level of
expression and/or secretion of one or more immune mediators, and
identifying a polypeptide that stimulates, inhibits and/or
suppresses as a tumor antigen; f) selecting from among the
identified tumor antigens (i) one or more tumor antigens that
increase level of expression and/or secretion of one or more immune
mediators associated with at least one beneficial response to
cancer, and/or (ii) one or more tumor antigens that inhibit and/or
suppress level of expression and/or secretion of one or more immune
mediators associated with at least one deleterious and/or
non-beneficial responses to cancer; and g) administering to the
subject an immunogenic composition comprising one or more of the
selected antigens or immunogenic fragment thereof.
[0089] In another aspect, the disclosure features a method of
inducing an immune response in a subject. In some embodiments, the
method comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads, wherein each bacterial cell or
bead of the library comprises a different heterologous polypeptide
comprising one or more mutations, splice variants, or
translocations expressed in a cancer or tumor cell of a subject; b)
contacting the bacterial cells or beads with antigen presenting
cells (APCs) from the subject, wherein the APCs internalize the
bacterial cells or beads; c) contacting the APCs with lymphocytes
from the subject, under conditions suitable for activation of
lymphocytes by a polypeptide presented by one or more APCs; d)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more polypeptides presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control), of expression and/or secretion of one or more immune
mediators; e) identifying one or more polypeptides that stimulate,
inhibit and/or suppress, and/or have a minimal effect on level of
expression and/or secretion of one or more immune mediators,
wherein stimulation, inhibition and/or suppression indicate that
the polypeptide is a tumor antigen; f) selecting from among the
identified polypeptides one or more polypeptides that have a
minimal effect on level of expression and/or secretion of one or
more immune mediators; and g) administering to the subject an
immunogenic composition comprising one or more of the selected
polypeptides or immunogenic fragment thereof.
[0090] In another aspect, the disclosure features a method of
inducing an immune response in a subject. In some embodiments, the
method comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads, wherein each bacterial cell or
bead of the library comprises a different heterologous polypeptide
comprising one or more mutations, splice variants, or
translocations expressed in a cancer or tumor cell of a subject; b)
contacting the bacterial cells or beads with antigen presenting
cells (APCs) from the subject, wherein the APCs internalize the
bacterial cells or beads; c) contacting the APCs with lymphocytes
from the subject, under conditions suitable for activation of
lymphocytes by a polypeptide presented by one or more APCs; d)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more polypeptides presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control), of expression and/or secretion of one or more immune
mediators; e) identifying one or more polypeptides that stimulate,
inhibit and/or suppress, and/or have a minimal effect on level of
expression and/or secretion of one or more immune mediators,
wherein stimulation, inhibition and/or suppression indicate that
the polypeptide is a tumor antigen; f) selecting from among the
identified tumor antigens and polypeptides (i) one or more
polypeptides that have a minimal effect on level of expression
and/or secretion of one or more immune mediators, (ii) one or more
tumor antigens that increase level of expression and/or secretion
of one or more immune mediators associated with at least one
beneficial response to cancer; and/or (iii) one or more tumor
antigens that inhibit and/or suppress level of expression and/or
secretion of one or more immune mediators associated with at least
one deleterious and/or non-beneficial response to cancer; and g)
administering to the subject an immunogenic composition comprising
one or more of the selected tumor antigens and polypeptides, or
immunogenic fragments thereof.
[0091] In some embodiments, the method further comprises
administering to the subject a cancer therapy or combination of
therapies.
[0092] In another aspect, the disclosure features a method of
inducing an immune response in a subject. In some embodiments, the
method comprises: a) obtaining, providing, or generating a library
comprising bacterial cells or beads, wherein each bacterial cell or
bead of the library comprises a different heterologous polypeptide
comprising one or more mutations, splice variants, or
translocations expressed in a cancer or tumor cell of a subject; b)
contacting the bacterial cells or beads with antigen presenting
cells (APCs) from the subject, wherein the APCs internalize the
bacterial cells or beads; c) contacting the APCs with lymphocytes
from the subject, under conditions suitable for activation of
lymphocytes by a polypeptide presented by one or more APCs; d)
determining whether one or more lymphocytes are activated by, or
not responsive to, one or more polypeptides presented by one or
more APCs, e.g., by assessing (e.g., detecting or measuring) a
level (e.g., an increased or decreased level, relative to a
control) of expression and/or secretion of one or more immune
mediators; e) identifying one or more polypeptides that stimulate,
inhibit and/or suppress, and/or have a minimal effect on level of
expression and/or secretion of one or more immune mediators, and
identifying a polypeptide that stimulates, inhibits and/or
suppresses as a tumor antigen; f) selecting from among the
identified tumor antigens (i) one or more tumor antigens that
increase level of expression and/or secretion of one or more immune
mediators associated with at least one deleterious and/or
non-beneficial response to cancer, and/or (ii) one or more tumor
antigens that inhibit and/or suppress level of expression and/or
secretion of one or more immune mediators associated with at least
one beneficial response to cancer; and g) administering to the
subject an immunogenic composition that does not comprise one or
more of the selected antigens or immunogenic fragment thereof.
[0093] In some embodiments, the method further comprises
administering to the subject a cancer therapy or combination of
therapies.
[0094] In any of the aspects described herein, the plurality of
tumor antigens comprises at least 1, 3, 5, 10, 15, 20, 25, 30, 50,
100, 150, 250, 500, 750, 1000 or more different tumor antigens, or
portions thereof; and/or determining whether one or more
lymphocytes are activated by, or not responsive to, one or more
tumor antigens comprises measuring a level of one or more immune
mediators; and/or the one or more immune mediators are selected
from the group consisting of cytokines, soluble mediators, and cell
surface markers expressed by the lymphocytes; and/or the one or
more immune mediators are cytokines; and/or the one or more
cytokines are selected from the group consisting of TRAIL,
IFN-gamma, IL-12p70, IL-2, TNF-alpha, MIP1-alpha, MIP1-beta, CXCL9,
CXCL10, MCP1, RANTES, IL-1 beta, IL-4, IL-6, IL-8, IL-9, IL-10,
IL-13, IL-15, CXCL11, IL-3, IL-5, IL-17, IL-18, IL-21, IL-22,
IL-23A, IL-24, IL-27, IL-31, IL-32, TGF-beta, CSF, GM-CSF, TRANCE
(also known as RANK L), MIP3-alpha, and fractalkine; and/or the one
or more immune mediators are soluble mediators; and/or the one or
more soluble mediators are selected from the group consisting of
granzyme A, granzyme B, sFas, sFasL, perform, and granulysin;
and/or the one or more immune mediators are cell surface markers;
and/or the one or more cell surface markers are selected from the
group consisting of CD107a, CD107b, CD25, CD69, CD45RA, CD45RO,
CD137 (4-1BB), CD44, CD62L, CD27, CCR7, CD154 (CD40L), KLRG-1,
CD71, HLA-DR, CD122 (IL-2RB), CD28, IL7Ra (CD127), CD38, CD26,
CD134 (OX-40), CTLA-4 (CD152), LAG-3, TIM-3 (CD366), CD39, PD1
(CD279), FoxP3, TIGIT, CD160, BTLA, 2B4 (CD244), and KLRG1; and/or
the lymphocytes comprise CD4+ T cells; and/or the lymphocytes
comprise CD8+ T cells; and/or the lymphocytes comprise NKT cells,
gamma-delta T cells, or NK cells; and/or the lymphocytes comprise
any combination of CD4+ T cells, CD8+ T cells, NKT cells,
gamma-delta T cells, and NK cells; and/or lymphocyte activation is
determined by assessing a level of one or more expressed or
secreted immune mediators that is at least 20%, 40%, 60%, 80%,
100%, 120%, 140%, 160%, 180%, or 200% higher or lower than a
control level; and/or lymphocyte activation is determined by
assessing a level of one or more expressed or secreted immune
mediators that is at least one, two, or three standard deviations
greater or lower than the mean of a control level; and/or
lymphocyte activating is determined by assessing a level of one or
more expressed or secreted immune mediators that is at least 1, 2,
3, 4 or 5 median absolute deviations (MADs) greater or lower than a
median response level to a control; and/or lymphocyte
non-responsiveness is determined by assessing a level of one or
more expressed or secreted immune mediators that is within 5%, 10%,
15%, or 20% of a control level; and/or lymphocyte
non-responsiveness is determined by assessing a level of one or
more expressed or secreted immune mediators that is less than one
or two standard deviation higher or lower than the mean of a
control level; and/or lymphocyte non-responsiveness is determined
by assessing a level of one or more expressed or secreted immune
mediators that is less than one or two median absolute deviation
(MAD) higher or lower than a median response level to a control;
and/or the subject response profile comprises one or more different
tumor antigens that increase level of expression and/or secretion
of one or more immune mediators; and/or the subject response
profile comprises one or more different tumor antigens that inhibit
and/or suppress level of expression and/or secretion of one or more
immune mediators; and/or the subject response profile comprises one
or more different tumor antigens that have a minimal effect on
level of expression and/or secretion of one or more immune
mediators; and/or the subject response profile comprises a
combination of one or more different tumor antigens that stimulate,
inhibit and/or suppress, and/or have a minimal effect on level of
expression and/or secretion of one or more immune mediators; and/or
the target response profile comprises one or more different tumor
antigens that increase level of expression and/or secretion of one
or more immune mediators; and/or the target response profile
comprises one or more different tumor antigens that inhibit and/or
suppress level of expression and/or secretion of one or more immune
mediators; and/or the target response profile comprises one or more
different tumor antigens that have a minimal effect on level of
expression and/or secretion of one or more immune mediators; and/or
the target response profile comprises a combination of one or more
different tumor antigens that stimulate, inhibit and/or suppress,
and/or have a minimal effect on level of expression and/or
secretion of one or more immune mediators; and/or the target
response profile comprises an average number of different tumor
antigens that increase level of expression and/or secretion of one
or more immune mediators, from a population of subjects who respond
clinically to the cancer therapy, or from subjects who fail to
respond clinically to the cancer therapy; and/or the target
response profile comprises an average number of different tumor
antigens that inhibit and/or suppress level of expression and/or
secretion of one or more immune mediators, from a population of
subjects who respond clinically to the cancer therapy, or from
subjects who fail to respond clinically to the cancer therapy;
and/or the target response profile comprises an average number of
different tumor antigens that have a minimal effect on level of
expression and/or secretion of one or more immune mediators, from a
population of subjects who respond clinically to the cancer
therapy, or from subjects who fail to respond clinically to the
cancer therapy; and/or the target response profile comprises a
combination of different tumor antigens that stimulate, inhibit
and/or suppress, and/or have a minimal effect on level of
expression and/or secretion of one or more immune mediators, from a
population of subjects who respond clinically to the cancer
therapy, or from a population of subjects who fail to respond
clinically to the cancer therapy; and or the subject response
profile is similar to the target response profile if the number of
tumor antigens of the subject response profile differs by no more
than 1, 2, 3, 4, 5, or 10 from the number of antigens of the target
response profile; and/or the subject response profile comprises the
number of different tumor antigens for each of a plurality of
cytokines expressed and/or secreted by activated and/or
non-responsive lymphocytes; and/or the target response profile
comprises the number of antigens for each of the corresponding
plurality of cytokines; and/or the target response profile
comprises an average number of antigens for each of the
corresponding plurality of cytokines expressed and/or secreted by
activated and/or non-responsive lymphocytes from a population of
subjects who respond clinically to the cancer therapy; and/or the
target response profile comprises an average number of antigens for
each of the corresponding plurality of cytokines expressed and/or
secreted by activated and/or non-responsive lymphocytes from a
population of subjects who fail to respond clinically to the cancer
therapy; and/or the target response profile comprises a combination
of antigens for each of the corresponding plurality of cytokines
expressed and/or secreted by activated and/or non-responsive
lymphocytes from a population of subjects who respond clinically to
the cancer therapy, or from a population of subjects who fail to
respond clinically to the cancer therapy; and/or the subject
response profile is similar to the target response profile if the
number of tumor antigens for at least two of the plurality of
cytokines of the subject response profile differs by no more than
1, 2, 3, 4, 5, or 10 from the number of antigens for the
corresponding plurality of cytokines of the target response
profile; and/or a subject exhibits at least one measure or
indication of clinical responsiveness to the cancer therapy; and/or
a subject exhibits at least one measure or indication of failure of
clinical responsiveness to the cancer therapy; and/or the cancer
therapy comprises immune checkpoint blockade therapy; and/or the
immune checkpoint blockade therapy comprises administration of
pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab,
durvalumab, tremelimumab, or cemiplimab; and/or the immune
checkpoint blockade therapy comprises administration of two or more
immune checkpoint inhibitors; and/or the cancer therapy comprises
immune suppression blockade therapy; and/or the immune suppression
blockade therapy comprises administration of Vista (B7-H5, v-domain
Ig suppressor of T cell activation) inhibitors, Lag-3
(lymphocyte-activation gene 3, CD223) inhibitors, IDO
(indolemamine-pyrrole-2,3,-dioxygenase-1,2) inhibitors, or KIR
receptor family (killer cell immunoglobulin-like receptor)
inhibitors, CD47 inhibitors, or Tigit (T cell immunoreceptor with
Ig and ITIM domain) inhibitors; and/or the immune suppression
blockade therapy comprises administration of two or more immune
suppression inhibitors; and/or the cancer therapy comprises immune
activation therapy; and/or the immune activation therapy comprises
administration of CD40 agonists, GITR (glucocorticoid-induced
TNF-R-related protein, CD357) agonists, OX40 (CD134) agonists,
4-1BB (CD137) agonists, ICOS (inducible T cell stimulator, CD278)
agonists, IL-2 (interleukin 2) agonists, or interferon agonists;
and/or immune activation comprises administration of two or more
immune activators; and/or the cancer therapy comprises adjuvant
therapy; and/or the adjuvant therapy comprises administration of a
TLR agonist (e.g., CpG or Poly I:C), STING agonist, non-specific
stimulus of innate immunity, dendritic cells, GM-CSF, IL-12, IL-7,
Flt-3, or other cytokines; and/or the cancer therapy comprises
oncolytic virus therapy; and/or the oncolytic viral therapy
comprises administration of talimogene leherparepvec; and/or the
cancer therapy comprises administration of one or more
chemotherapeutic agents; and/or the cancer therapy comprises
radiation; and/or the cancer therapy comprises surgical excision;
and/or the cancer therapy comprises cell-based therapy; and/or the
cell-based therapy comprises administration of dendritic cells,
chimeric antigen receptor T (CAR-T) cells, T cell
receptor-transduced cells, tumor infiltrating lymphocytes (TIL), or
natural killer (NK) cells; and/or the cancer therapy comprises
localized hyperthermia or hypothermia; and/or the cancer therapy
comprises administration of one or more anti-tumor antibodies;
and/or the anti-tumor antibodies comprise bi-specific antibodies;
and/or the cancer therapy comprises administration of one or more
anti-angiogenic agents; and/or the cancer therapy comprises any
combination of immune checkpoint blockade, immune suppression
blockade, immune activation, adjuvant, oncolytic virus,
chemotherapeutic, radiation, surgical, cell-based, hyperthermia,
hypothermia, anti-tumor antibody, and anti-angiogenic
therapies.
[0095] In another aspect, the disclosure features a method of
inducing an immune response in a subject with one or more selected
antigens, the method comprising: a) obtaining, providing or
generating a library comprising bacterial cells or beads comprising
a plurality of tumor antigens, wherein each bacterial cell or bead
of the library comprises a different tumor antigen; b) contacting
the bacterial cells or beads with antigen presenting cells (APCs)
from a first subject, wherein the APCs internalize the bacterial
cells or beads; c) contacting the APCs with lymphocytes from the
first subject, under conditions suitable for stimulation or
inhibition and/or suppression of lymphocytes by a tumor antigen
presented by one or more APCs; d) identifying one or more
stimulatory tumor antigens that stimulate lymphocytes and
identifying one or more non-stimulatory tumor antigens that do not
stimulate lymphocytes, to produce a subject response profile; e)
comparing the subject response profile to a target response
profile, wherein the target response profile is from a second
subject who responds clinically to a cancer therapy, and wherein
the target response profile comprises one or more identified
stimulatory tumor antigens that stimulate lymphocytes and comprises
one or more identified non-stimulatory tumor antigens that do not
stimulate lymphocytes; f) selecting one or more antigens, wherein
the one or more antigens are identified as non-stimulatory in the
subject response profile and the same one or more antigens are
identified as stimulatory in the target response profile; and g)
administering to the first subject an immunogenic composition
comprising one or more of the selected antigens.
[0096] In some embodiments, the method further comprises
administering a cancer therapy to the subject. In some embodiments,
the subject response profile comprises a representation of the
level of expression and/or secretion of the one or more immune
mediators associated with the plurality of tumor antigens.
[0097] In another aspect, the disclosure features an immunogenic
composition of the invention, comprising one or more antigens of
the target response profile obtained or generated according to any
of the methods described herein.
[0098] In another aspect, the disclosure features an immunogenic
composition of the invention, comprising one or more antigens
selected according to any of the methods described herein.
[0099] In another aspect, the disclosure features an immunogenic
composition comprising (i) one or more heparanase polypeptides or
immunogenic fragments thereof and (ii) a SMAD4 polypeptide or
immunogenic fragment thereof.
[0100] In some embodiments, the one or more heparanase polypeptides
or fragments and the SMAD4 polypeptide or fragment are each 8-29
amino acids in length. In some embodiments, the heparanase
polypeptides comprise the amino acid sequence of SEQ ID NO:6 or SEQ
ID NO:7. In some embodiments, the SMAD4 polypeptide comprises the
amino acid sequence of SEQ ID NO:8. In some embodiments, the one or
more immunogenic fragments consist of about 70%, 75%, 80%, 85%,
90%, 95%, 96%, 97%, 98%, or 99% of the total number of amino acids
of SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:8. In some embodiments,
the one or more immunogenic fragments consist of SEQ ID NO:6, SEQ
ID NO:7, or SEQ ID NO:8 lacking about 1, 2, 3, 4, 5, 10, 15, 20,
25, 30, 35, 40, 45, 50, or more amino acids. In some embodiments,
the one or more heparanse polypeptides comprise an amino acid
sequence at least 85%, 90%, 95%, 97%, or 99% identical to SEQ ID
NO:6 or SEQ ID NO:7. In some embodiments, the SMAD4 polypeptide
comprises an amino acid sequence at least 85%, 90%, 95%, 97%, or
99% identical to SEQ ID NO:8.
[0101] In another aspect, the disclosure features an immunogenic
composition comprising a heparanase isoform 1 polypeptide or
immunogenic fragment, a heparanase isoform 2 polypeptide or
immunogenic fragment, and a SMAD4 polypeptide or immunogenic
fragment.
[0102] In some embodiments, the heparanase isoform 1 polypeptide or
immunogenic fragment, the heparanase isoform 2 polypeptide or
immunogenic fragment and the SMAD4 polypeptide or immunogenic
fragment are each 8-29 amino acids in length. In some embodiments,
the heparanase isoform 1 polypeptide comprises the amino acid
sequence of SEQ ID NO:1 and the heparanase isoform 2 polypeptide
comprises the amino acid sequence of SEQ ID NO:2. In some
embodiments, the SMAD4 polypeptide comprises the amino acid
sequence of SEQ ID NO:3. In some embodiments, the one or more
immunogenic fragments consist of about 70%, 75%, 80%, 85%, 90%,
95%, 96%, 97%, 98%, or 99% of the total number of amino acids of
SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:8. In some embodiments, one
or more immunogenic fragments consist of SEQ ID NO:6, SEQ ID NO:7,
or SEQ ID NO:8 lacking about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35,
40, 45, 50, or more amino acids. In some embodiments, the
heparanase isoform 1 polypeptide comprises an amino acid sequence
at least 85%, 90%, 95%, 97%, or 99% identical to SEQ ID NO:6 and
wherein the heparanase isoform 1 polypeptide comprises an amino
acid sequence at least 85%, 90%, 95%, 97%, or 99% identical to SEQ
ID NO:7. In some embodiments, the SMAD4 polypeptide comprises an
amino acid sequence at least 85%, 90%, 95%, 97%, or 99% identical
to SEQ ID NO:8. In some embodiments, the compositions further
comprises an adjuvant.
[0103] In another aspect of the invention, methods of treating
cancer comprises administering to a subject the immunogenic
compositions described herein. In some embodiments, the subject has
or is at risk of cancer, and/or exhibits one or more signs or
symptoms of cancer, and/or exhibits one or more risk factors for
cancer. In some embodiments, the cancer is colorectal cancer,
melanoma, or lung cancer.
[0104] In another aspect of the invention, methods of inducing an
immune response in a subject, comprise administering to a subject
the immunogenic compositions described herein. In some embodiment,
the immune response comprises activation of one or more
lymphocytes. In some embodiments, the one or more lymphocytes
comprise CD4+ T cells. In some embodiments, the one or more
lymphocytes comprise CD8+ T cells. In some embodiments, the one or
more lymphocytes comprise NKT cells, gamma-delta T cells, or NK
cells. In some embodiments, the one or more lymphocytes comprise
any combination of CD4+ T cells, CD8+ T cells, NKT cells,
gamma-delta T cells, and NK cells. In some embodiments, the immune
response comprises an increased expression and/or secretion of one
or more immune mediators relative to a control. In some
embodiments, the lymphocyte signaling molecule is selected from
among immune mediators. In some embodiments, the one or more immune
mediators are cytokines. In some embodiments, the one or more
cytokines are selected from TRAIL, IFN-gamma, IL-12p70, IL-2,
TNF-alpha, MIP1-alpha, MIP1-beta, CXCL9, CXCL10, MCP1, RANTES, IL-1
beta, IL-4, IL-6, IL-8, IL-9, IL-10, IL-13, IL-15, CXCL11, IL-3,
IL-5, IL-17, IL-18, IL-21, IL-22, IL-23A, IL-24, IL-27, IL-31,
IL-32, TGF-beta, CSF, GM-CSF, TRANCE (also known as RANK L),
MIP3-alpha, MCP1, and fractalkine. In some embodiments, the one or
more immune mediators are soluble mediators. In some embodiments,
the one or more soluble mediators are selected from granzyme A,
granzyme B, sFas, sFasL, perforin, and granulysin. In some
embodiments, the one or more immune mediators are cell surface
markers. In some embodiments, the one or more cell surface markers
are selected from CD107a, CD107b, CD25, CD69, CD45RA, CD45RO, CD137
(4-1BB), CD44, CD62L, CD27, CCR7, CD154 (CD40L), KLRG-1, CD71,
HLA-DR, CD122 (IL-2RB), CD28, IL7Ra (CD127), CD38, CD26, CD134
(OX-40), CTLA-4 (CD152), LAG-3, TIM-3 (CD366), CD39, PD1 (CD279),
FoxP3, TIGIT, CD160, BTLA, 2B4 (CD244), and KLRG1. In some
embodiments, a level of one or more expressed or secreted immune
mediators that is at least 20%, 40%, 60%, 80%, 100%, 120%, 140%,
160%, 180%, or 200% higher than a control level. In some
embodiments, a level of one or more expressed or secreted immune
mediators that is at least one, two, or three standard deviations
higher than the mean of a control level indicates lymphocyte
activation. In some embodiments, a level of one or more expressed
or secreted immune mediators that is at least 1, 2, 3, 4 or 5
median absolute deviations (MADs) higher or lower than a median
response level to a control indicates lymphocyte activation. In
some embodiments, the immune response comprises a humoral response
and/or a cellular response. In some embodiments, humoral response
comprises an increase in magnitude of response or fold rise from
baseline of antigen specific immunoglobulin G (IgG) levels and/or
of antigen specific neutralizing antibody levels. In some
embodiments, the humoral response comprises a 4-fold or greater
rise in IgG titer from baseline. In some embodiments, the humoral
response comprises a 2-fold or greater rise in 50% neutralizing
antibody titer from baseline. In some embodiments, the cellular
response comprises secretion of granzyme B (GrB). In some
embodiments, the cellular response comprises an increase in
magnitude of response or fold rise from baseline of granzyme B
(GrB) levels. In some embodiments, the cellular response comprises
an increase in IFN-gamma secretion for T cells. In some
embodiments, the subject has or is at risk of cancer, and/or
exhibits one or more signs or symptoms of cancer, and/or exhibits
one or more risk factors for cancer. In some embodiments, the
cancer is colorectal cancer, melanoma, or lung cancer.
[0105] In another aspect, the disclosure features a method for
manufacturing an immunogenic composition, the method comprising
combining one or more antigens identified by any method described
herein and a carrier.
[0106] In some embodiments, the antigen is produced using
recombinant DNA technology in a suitable host cell. In some
embodiments, the method comprises formulating the immunogenic
composition as a pharmaceutical composition.
[0107] In another aspect, the disclosure features a method for
manufacturing an immunogenic composition for administration to a
subject in need thereof, the method comprising: a. providing,
preparing, or obtaining a plurality of antigenic compositions
comprising a plurality of antigens, each composition comprising a
different antigen; b. providing, preparing, or obtaining a target
response profile, wherein the target response profile comprises a
representation of the level of expression and/or secretion of one
or more immune mediators associated (e.g., determined, measured,
observed) with the plurality of antigens; c. providing, preparing,
or obtaining a subject response profile, wherein the subject
response profile comprises a representation of the level of
expression and/or secretion of one or more immune mediators
associated (e.g., determined, measured, observed) with the
plurality of antigens; d. comparing the target response profile to
the subject response profile; e. selecting one or more antigens
based on the comparison; and f. formulating at least a portion of
one or more antigenic compositions comprising the one or more
selected antigens as a pharmaceutical composition.
[0108] In some embodiments, the selecting step comprises selecting
one or more antigens that increase expression or secretion of
immune mediators associated with a beneficial response to cancer,
and/or one or more antigens that inhibit and/or suppress expression
or secretion of immune mediators associated with deleterious or not
beneficial responses to cancer. In some embodiments, the plurality
of antigenic compositions are in solution, lyophilized, or on a
synthetic matrix.
[0109] In another aspect, the disclosure features a method of
manufacturing an immunogenic composition for administration to a
subject in need thereof, the method comprising: preparing one or
more antigens, or fragments thereof, identified by any of the
method described herein; combining one or more antigens, or
fragments thereof, wherein the one or more antigens or fragments
thereof are selected according to the subject's response profile;
and formulating the immunogenic composition as a pharmaceutical
composition.
[0110] In another aspect, the disclosure features a method of
manufacturing an immunogenic composition for administration to a
subject in need thereof, the method comprising: preparing one or
more antigens, or fragments thereof, identified by any method
described herein; combining one or more antigens, or fragments
thereof, wherein the one or more antigens or fragments thereof are
selected according to whether or not the one or more antigens have
been shown to stimulate, inhibit and/or suppress and/or have
minimal effect on level of expression and/or secretion of one or
more immune mediators by the subject's lymphocytes; and formulating
the immunogenic composition as a pharmaceutical composition.
[0111] In another aspect, the disclosure features a method of
manufacturing an immunogenic composition for administration to a
subject in need thereof, the method comprising: preparing one or
more antigens, or fragments thereof, identified by any method
described herein;
[0112] combining one or more antigens, or fragments thereof,
wherein the one or more antigens or fragments thereof are selected
according to the subject's response profile; and formulating the
immunogenic composition as a pharmaceutical composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0113] The present teachings described herein will be more fully
understood from the following description of various illustrative
embodiments, when read together with the accompanying drawings. It
should be understood that the drawings described below are for
illustration purposes only and are not intended to limit the scope
of the present teachings in any way.
[0114] FIG. 1 is a graph showing IFN.gamma. secreted in
supernatants by T cells from a representative melanoma patient who
received immune checkpoint blockade therapy. The T cells were
co-cultured with autologous antigen presenting cells pulsed with E.
coli expressing various tumor-associated antigens.
[0115] FIG. 2 is a graph showing the number of T cell antigens that
stimulated cytokine secretion in supernatants by CD4.sup.+ T cells
from melanoma patients who were non-responders or responders to
immune checkpoint blockade therapy. The T cells were co-cultured
with autologous antigen presenting cells pulsed with E. coli
expressing various tumor associated antigens.
[0116] FIG. 3 is a graph showing the number of T cell antigens that
stimulated cytokine secretion in supernatants by CD8.sup.+ T cells
from melanoma patients who were non-responders or responders to
immune checkpoint blockade therapy. The T cells were co-cultured
with autologous antigen presenting cells pulsed with E. coli
expressing various tumor-associated antigens.
[0117] FIG. 4 is a scatter plot showing good alignment between
replicate measurements for cytokines secreted by T cells from a
representative NSCLC patient after stimulation by autologous
antigen presenting cells pulsed with E. coli expressing putative
neoantigens.
[0118] FIG. 5 is a graph showing results for IFN.gamma. and
TNF.alpha. secretion from CD8.sup.+ T cells from a representative
NSCLC patient, collected pre- and post-checkpoint blockade therapy,
after co-culture with autologous antigen presenting cells pulsed
with E. coli expressing putative neoantigens.
[0119] FIG. 6 is a graph showing results for IFN.gamma. and
TNF.alpha. secretion from CD4.sup.+ T cells from a representative
NSCLC patient, collected pre- and post-checkpoint blockade therapy,
after co-culture with autologous antigen presenting cells pulsed
with E. coli expressing putative neoantigens.
[0120] FIG. 7 is a Venn diagram showing limited overlap between
CD8.sup.+-specific T cell neoantigens from a representative NSCLC
patient, identified using methods of the disclosure and epitope
prediction algorithms.
[0121] FIG. 8 is a schematic showing epitope predictions had a high
false positive rate, missed relevant antigens and failed to
identify suppressive and/or inhibitory neoantigens.
[0122] FIG. 9 is a graph showing IFN.gamma. and TNF-.alpha.
secreted in supernatants by T cells from a representative patient
with colorectal cancer. The T cells were co-cultured with
autologous antigen presenting cells pulsed with E. coli expressing
various tumor-associated antigens. NG=neon green.
[0123] FIG. 10 is a graph showing the percentage of colorectal
cancer patients who responded to each TAA, as measured by
IFN.gamma. secretion that exceeded three standard deviations of the
mean negative control response.
[0124] FIG. 11 is a graph showing results for IFN.gamma. and
TNF-.alpha. secretion from CD8.sup.+ T cells from a patient with
colorectal carcinoma after co-culture with antigen presenting cells
pulsed with E. coli expressing 31 mutations unique to the
patient.
[0125] FIGS. 12A and 12B are Venn diagrams representing the limited
overlap between CD8.sup.+-specific T cell neoantigens identified by
ATLAS and epitope prediction algorithms. FIG. 12A represents
epitopes predicted that had binding affinity projected to be below
500 nM for the mutant peptide (neoantigen) but not for its
wild-type counterpart, and an IEDB percentile rank of .ltoreq.1 for
the mutant peptide but not for wild-type. FIG. 12B represents
epitopes predicted to have binding affinity below 500 nM or an IEDB
percentile rank of .ltoreq.1, irrespective of the wild-type
counterpart predictions.
[0126] FIGS. 13A and 13B are Venn diagrams representing the limited
overlap between CD8.sup.+-specific T cell inhibitory and/or
suppressive neoantigens identified by ATLAS and epitope prediction
algorithms. FIG. 13A represents epitopes predicted that had binding
affinity projected to be below 500 nM for the mutant peptide
(neoantigen) but not for its wild-type counterpart, and an IEDB
percentile rank of .ltoreq.1 for the mutant peptide but not for
wild-type. FIG. 13B represents epitopes predicted to have binding
affinity below 500 nM or an IEDB percentile rank of .ltoreq.1,
irrespective of the wild-type counterpart predictions.
[0127] FIG. 14 is a graph showing response profiles to 25
CRC-associated TAAs across CRC patients with all stages of disease
using TNF-.alpha. and IFN-.gamma. secretion as an indicator for a
recall response to a putative antigen.
[0128] FIGS. 15A and 15B are graphs showing the high frequency of T
cell stimulatory responses to three novel ATLAS-identified TAAs in
comparison to three TAAs that are or were in clinical development
as a therapeutic vaccine.
[0129] FIG. 16 is a graph showing stimulatory response rates to 4
selected TAAs for both CD4.sup.+ and CD8.sup.+ T cell subsets from
CRC patients with early or late stage disease and TNF-.alpha. and
IFN-.gamma. cytokine release.
[0130] FIG. 17 is a graph showing normalized cytokine
concentrations released in response to 4 selected TAAs in healthy
individuals and donors with various disease states (polyps or CRC)
for CD4.sup.+ and CD8.sup.+ T cell subsets and for TNF-.alpha. and
IFN-.gamma. release.
[0131] FIG. 18 is a graph showing an exemplary empirical
determination of T cell responses to profiled TAAs. Exemplary data
is shown for a single lung cancer patient. T cell responses are
reported as natural log concentrations extrapolated from the MSD
standard curve and normalized to the patient's response to a
negative control protein.
[0132] FIG. 19 is a graph showing shows frequent CD4.sup.+ T cell
responses to two novel TAAs compared to previously described TAAs
(NY-ESO-1, MUC1, and MAGEA3). Each point represents a patient's
response to that TAA, normalized to the patient's response to a
negative control protein. Stimulatory responses are colored
black.
[0133] FIG. 20 is a graph showing CD4.sup.+ and CD8.sup.+ T cell
responses to a broad range of TAAs from lung cancer patients.
[0134] FIG. 21 is a graph showing inhibitory and/or suppressive T
cell responses detected in most profiled TAAs across lung cancer
patients.
[0135] FIG. 22 is a graph showing a neoantigen screen with ATLAS
identifying patient-specific CD4.sup.+ and CD8.sup.+ T cell
responses. Each dot represents a technical replicate. Horizontal
dotted lines indicate the cutoffs used to define stimulatory
neoantigens and inhibitory and/or suppressive neoantigens at +3 and
-3 Median Absolute Deviations (MADs), respectively.
[0136] FIGS. 23A, 23B, 23C, and 23D show that algorithm prediction
of MHC Class I binding does not accurately predict CD8.sup.+ T cell
responses or types of response. FIGS. 23A and 23C show the total
numbers and overlap of neoantigens predicted by algorithm and
observed in ATLAS. FIGS. 23B and 23D show the break-down of
predictions by strong binding (<150 nM), weak binding (<500
nM), or non-binding (>=500 nM). There is no enrichment of either
stimulatory or inhibitory and/or suppressive responses in CD8.sup.+
T cells across binding prediction groups.
[0137] FIGS. 24A and 24B are graphs showing that CD8.sup.+ T cell
responses identified by ATLAS to candidate neoantigens are not
enriched for any mutation type.
[0138] FIGS. 25A and 25B are graphs showing DNA mutant allele
frequency is not associated with CD8.sup.+ T cell response
frequency.
[0139] FIGS. 26A and 26B are graphs showing detection of a mutation
in RNA does not predict whether the candidate neoantigen elicits a
recall response in CD8.sup.+ T cells.
[0140] FIGS. 27A and 27B are graphs showing that CD8+ T cell
responses identified by ATLAS to candidate neoantigens do not
correlate with gene expression.
[0141] FIG. 28 is a graph illustrating the different cytokine
response profiles elicited by 6 representative neoantigens in a
screen of CD8.sup.+ T cells from a single patient.
[0142] FIG. 29 is a graph showing CD8+ T cell data for healthy
donors and cancer patients. When analyzed by IFN.gamma. secretion,
there was a large inhibitory response in the healthy donor cohort,
that greatly exceeded the inhibitory responses in the cancer
patient cohort. Conversely, there was a greater median inhibitory
response in the cancer cohort when TNF.alpha. secretion was
considered.
DEFINITIONS
[0143] Activate: As used herein, a peptide presented by an antigen
presenting cell (APC) "activates" a lymphocyte if lymphocyte
activity is detectably modulated after exposure to the peptide
presented by the APC under conditions that permit antigen-specific
recognition to occur. Any indicator of lymphocyte activity can be
evaluated to determine whether a lymphocyte is activated, e.g., T
cell proliferation, phosphorylation or dephosphorylation of a
receptor, calcium flux, cytoskeletal rearrangement, increased or
decreased expression and/or secretion of immune mediators such as
cytokines or soluble mediators, increased or decreased expression
of one or more cell surface markers.
[0144] Administration: As used herein, the term "administration"
typically refers to the administration of a composition to a
subject or system. Those of ordinary skill in the art will be aware
of a variety of routes that may, in appropriate circumstances, be
utilized for administration to a subject, for example a human. For
example, in some embodiments, administration may be systemic or
local. In some embodiments, administration may be enteral or
parenteral. In some embodiments, administration may be by injection
(e.g., intramuscular, intravenous, or subcutaneous injection). In
some embodiments, injection may involve bolus injection, drip,
perfusion, or infusion. In some embodiments administration may be
topical. Those skilled in the art will be aware of appropriate
administration routes for use with particular therapies described
herein, for example from among those listed on www.fda.gov, which
include auricular (otic), buccal, conjunctival, cutaneous, dental,
endocervical, endosinusial, endotracheal, enteral, epidural,
extra-amniotic, extracorporeal, interstitial, intra-abdominal,
intra-amniotic, intra-arterial, intra-articular, intrabiliary,
intrabronchial, intrabursal, intracardiac, intracartilaginous,
intracaudal, intracavernous, intracavitary, intracerebral,
intracisternal, intracorneal, intracoronal, intracorporus
cavernosum, intradermal, intranodal, intradiscal, intraductal,
intraduodenal, intradural, intraepidermal, intraesophageal,
intragastic, intragingival, intralesional, intraluminal,
intralymphatic, intramedullary, intrameningeal, intramuscular,
intraocular, intraovarian, intrapericardial, intraperitoneal,
intrapleural, intraprostatic, intrapulmonary, intrasinal,
intraspinal, intrasynovial, intratendinous, intratesticular,
intrathecal, intrathoracic, intratubular, intratumor,
intratympanic, intrauterine, intravascular, intravenous,
intravenous bolus, intravenous drip, intraventricular,
intravitreal, laryngeal, nasal, nasogastric, ophthalmic, oral,
oropharyngeal, parenteral, percutaneous, periarticular, peridural,
perineural, periodontal, rectal, respiratory (e.g., inhalation),
retrobulbar, soft tissue, subarachnoid, subconjunctival,
subcutaneous, sublingual, submucosal, topical, transdermal,
transmucosal, transplacental, transtracheal, ureteral, urethral, or
vaginal. In some embodiments, administration may involve
electro-osmosis, hemodialysis, infiltration, iontophoresis,
irrigation, and/or occlusive dressing. In some embodiments,
administration may involve dosing that is intermittent (e.g., a
plurality of doses separated in time) and/or periodic (e.g.,
individual doses separated by a common period of time) dosing. In
some embodiments, administration may involve continuous dosing.
[0145] Antigen: The term "antigen", as used herein, refers to a
molecule (e.g., a polypeptide) that elicits a specific immune
response. Antigen-specific immunological responses, also known as
adaptive immune responses, are mediated by lymphocytes (e.g., T
cells, B cells, NK cells) that express antigen receptors (e.g., T
cell receptors, B cell receptors). In certain embodiments, an
antigen is a T cell antigen, and elicits a cellular immune
response. In certain embodiments, an antigen is a B cell antigen,
and elicits a humoral (i.e., antibody) response. In certain
embodiments, an antigen is both a T cell antigen and a B cell
antigen. As used herein, the term "antigen" encompasses both a
full-length polypeptide as well as a portion or immunogenic
fragment of the polypeptide, and a peptide epitope within the
polypeptides (e.g., a peptide epitope bound by a Major
Histocompatibility Complex (MHC) molecule (e.g., MHC class I, or
MHC class II)).
[0146] Antigen presenting cell: An "antigen presenting cell" or
"APC" refers to a cell that presents peptides on MHC class I and/or
MHC class II molecules for recognition by T cells. APC include both
professional APC (e.g., dendritic cells, macrophages, B cells),
which have the ability to stimulate naive lymphocytes, and
non-professional APC (e.g., fibroblasts, epithelial cells,
endothelial cells, glial cells). In certain embodiments, APC are
able to internalize (e.g., endocytose) members of a library (e.g.,
cells of a library of bacterial cells) that express heterologous
polypeptides as candidate antigens.
[0147] Autolysin polypeptide: An "autolysin polypeptide" is a
polypeptide that facilitates or mediates autolysis of a cell (e.g.,
a bacterial cell) that has been internalized by a eukaryotic cell.
In some embodiments, an autolysin polypeptide is a bacterial
autolysin polypeptide. Autolysin polypeptides include, and are not
limited to, polypeptides whose sequences are disclosed in
GenBank.RTM. under Acc. Nos. NP 388823.1, NP 266427.1, and
POAGC3.1.
[0148] Cancer: As used herein, the term "cancer" refers to a
disease, disorder, or condition in which cells exhibit relatively
abnormal, uncontrolled, and/or autonomous growth, so that they
display an abnormally elevated proliferation rate and/or aberrant
growth phenotype characterized by a significant loss of control of
cell proliferation. In some embodiments, a cancer may be
characterized by one or more tumors. Those skilled in the art are
aware of a variety of types of cancer including, for example,
adrenocortical carcinoma, astrocytoma, basal cell carcinoma,
carcinoid, cardiac, cholangiocarcinoma, chordoma, chronic
myeloproliferative neoplasms, craniopharyngioma, ductal carcinoma
in situ, ependymoma, intraocular melanoma, gastrointestinal
carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational
trophoblastic disease, glioma, histiocytosis, leukemia (e.g., acute
lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic
lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),
hairy cell leukemia, myelogenous leukemia, myeloid leukemia),
lymphoma (e.g., Burkitt lymphoma [non-Hodgkin lymphoma], cutaneous
T cell lymphoma, Hodgkin lymphoma, mycosis fungoides, Sezary
syndrome, AIDS-related lymphoma, follicular lymphoma, diffuse large
B-cell lymphoma), melanoma, merkel cell carcinoma, mesothelioma,
myeloma (e.g., multiple myeloma), myelodysplastic syndrome,
papillomatosis, paraganglioma, pheochromacytoma, pleuropulmonary
blastoma, retinoblastoma, sarcoma (e.g., Ewing sarcoma, Kaposi
sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, vascular
sarcoma), Wilms' tumor, and/or cancer of the adrenal cortex, anus,
appendix, bile duct, bladder, bone, brain, breast, bronchus,
central nervous system, cervix, colon, endometrium, esophagus, eye,
fallopian tube, gall bladder, gastrointestinal tract, germ cell,
head and neck, heart, intestine, kidney (e.g., Wilms' tumor),
larynx, liver, lung (e.g., non-small cell lung cancer, small cell
lung cancer), mouth, nasal cavity, oral cavity, ovary, pancreas,
rectum, skin, stomach, testes, throat, thyroid, penis, pharynx,
peritoneum, pituitary, prostate, rectum, salivary gland, ureter,
urethra, uterus, vagina, or vulva.
[0149] Cytolysin polypeptide: A "cytolysin polypeptide" is a
polypeptide that has the ability to form pores in a membrane of a
eukaryotic cell. A cytolysin polypeptide, when expressed in host
cell (e.g., a bacterial cell) that has been internalized by a
eukaryotic cell, facilitates release of host cell components (e.g.,
host cell macromolecules, such as host cell polypeptides) into the
cytosol of the internalizing cell. In some embodiments, a cytolysin
polypeptide is bacterial cytolysin polypeptide. In some
embodiments, a cytolysin polypeptide is a cytoplasmic cytolysin
polypeptide. Cytolysin polypeptides include, and are not limited
to, polypeptides whose sequences are disclosed in U.S. Pat. No.
6,004,815, and in GenBank.RTM. under Acc. Nos. NP_463733.1,
NP_979614, NP_834769, YP_084586, YP_895748, YP_694620, YP_012823,
NP_346351, YP_597752, BAB41212.2, NP_561079.1, YP_001198769, and
NP_359331.1.
[0150] Cytoplasmic cytolysin polypeptide: A "cytoplasmic cytolysin
polypeptide" is a cytolysin polypeptide that has the ability to
form pores in a membrane of a eukaryotic cell, and that is
expressed as a cytoplasmic polypeptide in a bacterial cell. A
cytoplasmic cytolysin polypeptide is not significantly secreted by
a bacterial cell. Cytoplasmic cytolysin polypeptides can be
provided by a variety of means. In some embodiments, a cytoplasmic
cytolysin polypeptide is provided as a nucleic acid encoding the
cytoplasmic ccytolysin polypeptide. In some embodiments, a
cytoplasmic cytolysin polypeptide is provided attached to a bead.
In some embodiments, a cytoplasmic cytolysin polypeptide has a
sequence that is altered relative to the sequence of a secreted
cytolysin polypeptide (e.g., altered by deletion or alteration of a
signal sequence to render it nonfunctional). In some embodiments, a
cytoplasmic cytolysin polypeptide is cytoplasmic because it is
expressed in a secretion-incompetent cell. In some embodiments, a
cytoplasmic cytolysin polypeptide is cytoplasmic because it is
expressed in a cell that does not recognize and mediate secretion
of a signal sequence linked to the cytolysin polypeptide. In some
embodiments, a cytoplasmic cytolysin polypeptide is a bacterial
cytolysin polypeptide.
[0151] Heterologous: The term "heterologous", as used herein to
refer to genes or polypeptides, refers to a gene or polypeptide
that does not naturally occur in the organism in which it is
present and/or being expressed, and/or that has been introduced
into the organism by the hand of man. In some embodiments, a
heterologous polypeptide is a tumor antigen described herein.
[0152] Immune mediator: As used herein, the term "immune mediator"
refers to any molecule that affects the cells and processes
involved in immune responses. Immune mediators include cytokines,
chemokines, soluble proteins, and cell surface markers.
[0153] Improve, increase, inhibit, stimulate, suppress, or reduce:
As used herein, the terms "improve", "increase", "inhibit",
"stimulate", "suppress", "reduce", or grammatical equivalents
thereof, indicate values that are relative to a baseline or other
reference measurement. In some embodiments, an appropriate
reference measurement may be or comprise a measurement in a
particular system (e.g., in a single individual) under otherwise
comparable conditions absent presence of (e.g., prior to and/or
after) a particular agent or treatment, or in presence of an
appropriate comparable reference agent. The effect of a particular
agent or treatment may be direct or indirect. In some embodiments,
an appropriate reference measurement may be or may comprise a
measurement in a comparable system known or expected to respond in
a particular way, in presence of the relevant agent or treatment.
In some embodiments, a peptide presented by an antigen presenting
cell (APC) "stimulates" or is "stimulatory" to a lymphocyte if the
lymphocyte is activated to a phenotype associated with beneficial
responses, after exposure to the peptide presented by the APC under
conditions that permit antigen-specific recognition to occur, as
observed by, e.g., T cell proliferation, phosphorylation or
dephosphorylation of a receptor, calcium flux, cytoskeletal
rearrangement, increased or decreased expression and/or secretion
of immune mediators such as cytokines or soluble mediators,
increased or decreased expression of one or more cell surface
markers, relative to a control. In some embodiments, a peptide
presented by an antigen presenting cell "suppresses", "inhibits" or
is "inhibitory" to a lymphocyte if the lymphocyte is activated to a
phenotype associated with deleterious or non-beneficial responses,
after exposure to the peptide presented by the APC under conditions
that permit antigen-specific recognition to occur, as observed by,
e.g., phosphorylation or dephosphorylation of a receptor, calcium
flux, cytoskeletal rearrangement, increased or decreased expression
and/or secretion of immune mediators such as cytokines or soluble
mediators, increased or decreased expression of one or more cell
surface markers, relative to a control.
[0154] Invasin polypeptide: An "invasin polypeptide" is a
polypeptide that facilitates or mediates uptake of a cell (e.g., a
bacterial cell) by a eukaryotic cell. Expression of an invasin
polypeptide in a noninvasive bacterial cell confers on the cell the
ability to enter a eukaryotic cell. In some embodiments, an invasin
polypeptide is a bacterial invasin polypeptide. In some
embodiments, an invasin polypeptide is a Yersinia invasin
polypeptide (e.g., a Yersinia invasin polypeptide comprising a
sequence disclosed in GenBank.RTM. under Acc. No. YP_070195.1).
[0155] Listeriolysin O (LLO): The terms "listeriolysin O" or "LLO"
refer to a listeriolysin O polypeptide of Listeria monocytogenes
and truncated forms thereof that retain pore-forming ability (e.g.,
cytoplasmic forms of LLO, including truncated forms lacking a
signal sequence). In some embodiments, an LLO is a cytoplasmic LLO.
Exemplary LLO sequences are shown in Table 1, below.
[0156] Polypeptide: The term "polypeptide", as used herein,
generally has its art-recognized meaning of a polymer of at least
three amino acids. Those of ordinary skill in the art will
appreciate, however, that the term "polypeptide" is intended to be
sufficiently general as to encompass not only polypeptides having
the complete sequence recited herein (or in a reference or database
specifically mentioned herein), but also to encompass polypeptides
that represent functional fragments (i.e., fragments retaining at
least one activity) and immunogenic fragments of such complete
polypeptides. Moreover, those of ordinary skill in the art
understand that protein sequences generally tolerate some
substitution without destroying activity. Thus, any polypeptide
that retains activity and shares at least about 30-40% overall
sequence identity, often greater than about 50%, 60%, 70%, or 80%,
and further usually including at least one region of much higher
identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%
in one or more highly conserved regions, usually encompassing at
least 3-4 and often up to 20 or more amino acids, with another
polypeptide of the same class, is encompassed within the relevant
term "polypeptide" as used herein. Other regions of similarity
and/or identity can be determined by those of ordinary skill in the
art by analysis of the sequences of various polypeptides.
[0157] Primary cells: As used herein, "primary cells" refers to
cells from an organism that have not been immortalized in vitro. In
some embodiments, primary cells are cells taken directly from a
subject (e.g., a human). In some embodiments, primary cells are
progeny of cells taken from a subject (e.g., cells that have been
passaged in vitro). Primary cells include cells that have been
stimulated to proliferate in culture.
[0158] Response: As used herein, in the context of a subject (a
patient or experimental organism), "response", "responsive", or
"responsiveness" refers to an alteration in a subject's condition
that occurs as a result of, or correlates with, treatment. In
certain embodiments, a response is a beneficial response. In
certain embodiments, a beneficial response can include
stabilization of a subject's condition (e.g., prevention or delay
of deterioration expected or typically observed to occur absent the
treatment), amelioration (e.g., reduction in frequency and/or
intensity) of one or more symptoms of the condition, and/or
improvement in the prospects for cure of the condition, etc. In
certain embodiments, for a subject who has cancer, a beneficial
response can include: the subject has a positive clinical response
to cancer therapy or a combination of therapies; the subject has a
spontaneous response to a cancer; the subject is in partial or
complete remission from cancer; the subject has cleared a cancer;
the subject has not had a relapse, recurrence or metastasis of a
cancer; the subject has a positive cancer prognosis; the subject
has not experienced toxic responses or side effects to a cancer
therapy or combination of therapies. In certain embodiments, for a
subject who had cancer, the beneficial responses occurred in the
past, or are ongoing.
[0159] In certain embodiments, a response is a deleterious or
non-beneficial response. In certain embodiments, a deleterious or
non-beneficial response can include deterioration of a subject's
condition, lack of amelioration (e.g., no reduction in frequency
and/or intensity) of one or more symptoms of the condition, and/or
degradation in the prospects for cure of the condition, etc. In
certain embodiments, for a subject who has cancer, a deleterious or
non-beneficial response can include: the subject has a negative
clinical response to cancer therapy or a combination of therapies;
the subject is not in remission from cancer; the subject has not
cleared a cancer; the subject has had a relapse, recurrence or
metastasis of a cancer; the subject has a negative cancer
prognosis; the subject has experienced toxic responses or side
effects to a cancer therapy or combination of therapies. In certain
embodiments, for a subject who had cancer, the deleterious or
non-beneficial responses occurred in the past, or are ongoing.
[0160] As used herein, in the context of a cell, organ, tissue, or
cell component, e.g., a lymphocyte, "response", "responsive", or
"responsiveness" refers to an alteration in cellular activity that
occurs as a result of, or correlates with, administration of or
exposure to an agent, e.g. a tumor antigen. In certain embodiments,
a beneficial response can include increased expression and/or
secretion of immune mediators associated with positive clinical
responses or outcomes in a subject. In certain embodiments, a
beneficial response can include decreased expression and/or
secretion of immune mediators associated with negative clinical
response or outcomes in a subject. In certain embodiments, a
deleterious or non-beneficial response can include increased
expression and/or secretion of immune mediators associated with
negative clinical responses or outcomes in a subject. In certain
embodiments, a deleterious or non-beneficial response can include
decreased expression and/or secretion of immune mediators
associated with positive clinical responses or outcomes in a
subject. In certain embodiments, a response is a clinical response.
In certain embodiments, a response is a cellular response. In
certain embodiments, a response is a direct response. In certain
embodiments, a response is an indirect response. In certain
embodiments, "non-response", "non-responsive", or
"non-responsiveness" mean minimal response or no detectable
response. In certain embodiments, a "minimal response" includes no
detectable response. In certain embodiments, presence, extent,
and/or nature of response can be measured and/or characterized
according to particular criteria. In certain embodiments, such
criteria can include clinical criteria and/or objective criteria.
In certain embodiments, techniques for assessing response can
include, but are not limited to, clinical examination, positron
emission tomography, chest X-ray, CT scan, MM, ultrasound,
endoscopy, laparoscopy, presence or level of a particular marker in
a sample, cytology, and/or histology. Where a response of interest
is a response of a tumor to a therapy, ones skilled in the art will
be aware of a variety of established techniques for assessing such
response, including, for example, for determining tumor burden,
tumor size, tumor stage, etc. Methods and guidelines for assessing
response to treatment are discussed in Therasse et al., J. Natl.
Cancer Inst., 2000, 92(3):205-216; and Seymour et al., Lancet
Oncol., 2017, 18:e143-52. The exact response criteria can be
selected in any appropriate manner, provided that when comparing
groups of tumors, patients or experimental organism, and/or cells,
organs, tissues, or cell components, the groups to be compared are
assessed based on the same or comparable criteria for determining
response rate. One of ordinary skill in the art will be able to
select appropriate criteria.
[0161] Tumor: As used herein, the term "tumor" refers to an
abnormal growth of cells or tissue. In some embodiments, a tumor
may comprise cells that are precancerous (e.g., benign), malignant,
pre-metastatic, metastatic, and/or non-metastatic. In some
embodiments, a tumor is associated with, or is a manifestation of,
a cancer. In some embodiments, a tumor may be a disperse tumor or a
liquid tumor. In some embodiments, a tumor may be a solid
tumor.
DETAILED DESCRIPTION
[0162] Recent advances in immune checkpoint inhibitor therapies
such as ipilimumab, nivolumab, and pembrolizumab for cancer
immunotherapy have resulted in dramatic efficacy in subjects
suffering from NSCLC, among other indications. Nivolumab and
pembroluzimab have been approved by the Food and Drug
Administration (FDA) and European Medicines Agency (EMA) for use in
patients with advanced NSCLC who have previously been treated with
chemotherapy. They have solidified the importance of T cell
responses in control of tumors. Neoantigens, potential cancer
rejection antigens that are entirely absent from the normal human
genome, are postulated to be relevant to tumor control; however,
attempts to define them and their role in tumor clearance has been
hindered by the paucity of available tools to define them in a
biologically relevant and unbiased way (Schumacher and Schreiber,
2015 Science 348:69-74, Gilchuk et al., 2015 Curr Opin Immunol
34:43-51)
[0163] Taking non-small cell lung carcinoma (NSCLC) as an example,
whole exome sequencing of NSCLC tumors from patients treated with
pembrolizumab showed that higher non-synonymous mutation burden in
tumors was associated with improved objective response, durable
clinical benefit, and progression-free survival (Rizvi et al.,
(2015) Science 348(6230): 124-8). In this study, the median
non-synonymous mutational burden of the discovery cohort was 209
and of the validation cohort was 200. However, simply because a
mutation was identified by sequencing, does not mean that the
epitope it creates can be recognized by a T cell or serves as a
protective antigen for T cell responses (Gilchuk et al., 2015 Curr
Opin Immunol 34:43-51), making the use of the word neoantigen
somewhat of a misnomer. With 200 or more potential targets of T
cells in NSCLC, it is not feasible to test every predicted epitope
to determine which of the mutations serve as neoantigens, and which
neoantigens are associated with clinical evidence of tumor control.
Recently, a study by McGranahan et al., showed that clonal
neoantigen burden and overall survival in primary lung
adenocarcinomas are related. However, even enriching for clonal
neoantigens results in potential antigen targets ranging from 50 to
approximately 400 (McGranahan et al., 2016 Science 351:1463-69).
Similar findings have been described for melanoma patients who have
responded to ipilimumab therapy (Snyder et al., 2015 NEJM; Van
Allen et al., 2015 Science) and in patients with mismatch-repair
deficient colorectal cancer who were treated with pembrolizumab (Le
et al., 2015 NEJM).
[0164] The present disclosure provides methods and systems for the
rapid identification of tumor antigens (e.g., tumor specific
antigens (TSAs, or neoantigens), tumor associated antigens (TAAs),
or cancer/testis antigens (CTAs)) that elicit T cell responses and
particularly that elicit human T cell responses, as well as
polypeptides that are potential tumor antigens. For purposes of
this disclosure, "tumor antigens" includes both tumor antigens and
potential tumor antigens. As described herein, methods of the
present disclosure identified stimulatory tumor antigens that were
not identified by known algorithms. Further, methods of the present
disclosure identified suppressive and/or inhibitory tumor antigens
that are not identifiable by known algorithms. Methods of the
present disclosure also identified polypeptides that are potential
tumor antigens, i.e., polypeptides that activate T cells of
non-cancerous subjects, but not T cells of subjects suffering from
cancer. The present disclosure also provides methods of selecting
tumor antigens and potential tumor antigens, methods of using the
selected tumor antigens and potential tumor antigens, immunogenic
compositions comprising the selected tumor antigens and potential
tumor antigens, and methods of manufacturing immunogenic
compositions. The present disclosure also provides methods of
evaluating an immune response in a cancer subject, e.g., for
identifying or selecting subjects for initiation, continuation,
modification, and/or discontinuation of cancer therapy.
Library Generation
[0165] A library is a collection of members (e.g., cells or
non-cellular particles, such as virus particles, liposomes, or
beads (e.g., beads coated with polypeptides, such as in vitro
translated polypeptides, e.g., affinity beads, e.g., antibody
coated beads, or NTA-Ni beads bound to polypeptides of interest).
According to the present disclosure, members of a library include
(e.g., internally express or carry) polypeptides of interest
described herein. In some embodiments, members of a library are
cells that internally express polypeptides of interest described
herein. In some embodiments, members of a library which are
particles carry, and/or are bound to, polypeptides of interest. Use
of a library in an assay system allows simultaneous evaluation in
vitro of cellular responses to multiple candidate antigens.
According to the present disclosure, a library is designed to be
internalized by human antigen presenting cells so that peptides
from library members, including peptides from internally expressed
polypeptides of interest, are presented on MEW molecules of the
antigen presenting cells for recognition by T cells.
[0166] Libraries can be used in assays that detect peptides
presented by human MHC class I and MHC class II molecules.
Polypeptides expressed by the internalized library members are
digested in intracellular endocytic compartments (e.g., phagosomes,
endosomes, lysosomes) of the human cells and presented on MHC class
II molecules, which are recognized by human CD4.sup.+ T cells. In
some embodiments, library members include a cytolysin polypeptide,
in addition to a polypeptide of interest. In some embodiments,
library members include an invasin polypeptide, in addition to the
polypeptide of interest. In some embodiments, library members
include an autolysin polypeptide, in addition to the polypeptide of
interest. In some embodiments, library members are provided with
cells that express a cytolysin polypeptide (i.e., the cytolysin and
polypeptide of interest are not expressed in the same cell, and an
antigen presenting cell is exposed to members that include the
cytolysin and members that include the polypeptide of interest,
such that the antigen presenting cell internalizes both, and such
that the cytolysin facilitates delivery of polypeptides of interest
to the MHC class I pathway of the antigen presenting cell). A
cytolysin polypeptide can be constitutively expressed in a cell, or
it can be under the control of an inducible expression system
(e.g., an inducible promoter). In some embodiments, a cytolysin is
expressed under the control of an inducible promoter to minimize
cytotoxicity to the cell that expresses the cytolysin.
[0167] Once internalized by a human cell, a cytolysin polypeptide
perforates intracellular compartments in the human cell, allowing
polypeptides expressed by the library members to gain access to the
cytosol of the human cell. Polypeptides released into the cytosol
are presented on MHC class I molecules, which are recognized by
CD8.sup.+ T cells.
[0168] A library can include any type of cell or particle that can
be internalized by and deliver a polypeptide of interest (and a
cytolysin polypeptide, in applications where a cytolysin
polypeptide is desirable) to, antigen presenting cells for use in
methods described herein. Although the term "cell" is used
throughout the present specification to refer to a library member,
it is understood that, in some embodiments, the library member is a
non-cellular particle, such as a virus particle, liposome, or bead.
In some embodiments, members of the library include polynucleotides
that encode the polypeptide of interest (and cytolysin
polypeptide), and can be induced to express the polypeptide of
interest (and cytolysin polypeptide) prior to, and/or during
internalization by antigen presenting cells.
[0169] In some embodiments, the cytolysin polypeptide is
heterologous to the library cell in which it is expressed, and
facilitates delivery of polypeptides expressed by the library cell
into the cytosol of a human cell that has internalized the library
cell. Cytolysin polypeptides include bacterial cytolysin
polypeptides, such as listeriolysin O (LLO), streptolysin O (SLO),
and perfringolysin O (PFO). Additional cytolysin polypeptides are
described in U.S. Pat. No. 6,004,815. In certain embodiments,
library members express LLO. In some embodiments, a cytolysin
polypeptide is not significantly secreted by the library cell
(e.g., less than 20%, 10%, 5%, or 1% of the cytolysin polypeptide
produced by the cell is secreted). For example, the cytolysin
polypeptide is a cytoplasmic cytolysin polypeptide, such as a
cytoplasmic LLO polypeptide (e.g., a form of LLO which lacks the
N-terminal signal sequence, as described in Higgins et al., Mol.
Microbiol. 31(6):1631-1641,1999). Exemplary cytolysin polypeptide
sequences are shown in Table 1. The listeriolysin O (43-25)
sequence shown in the second row of Table 1 has a deletion of
residues 3-25, relative to the LLO sequence in shown in the first
row of Table 1, and is a cytoplasmic LLO polypeptide. In some
embodiments, a cytolysin is expressed constitutively in a library
host cell. In other embodiments, a cytolysin is expressed under the
control of an inducible promoter. Cytolysin polypeptides can be
expressed from the same vector, or from a different vector, as the
polypeptide of interest in a library cell.
TABLE-US-00001 TABLE 1 Exemplary Cytolysin Polypeptides Polypeptide
Polypeptide Name Accession No. (species) GI No. Polypeptide
Sequence listeriolysin O NP_463733.1
MKKIMLVFITLILVSLPIAQQTEAKDASAFNKENSISSMAPPASP (Listeria GI:
16802248 PASPKTPIEKKHADEIDKYIQGLDYNKNNVLVYHGDAVTNVPPRK
monocytogenes) GYKDGNEYIVVEKKKKSINQNNADIQVVNAISSLTYPGALVKANS
ELVENQPDVLPVKRDSLILSIDLPGMTNQDNKIVVKNATKSNVNN
AVNTLVERWNEKYAQAYPNVSAKIDYDDEMAYSESQLIAKFGTAF
KAVNNSLNVNFGAISEGKMQEEVISFKQIYYNVNVNEPTRPSRFF
GKAVTKEQLQALGVNAENPPAYISSVAYGRQVYLKLSTNSHSTKV
KAAFDAAVSGKSVSGDVELTNIIKNSSFKAVIYGGSAKDEVQIID
GNLGDLRDILKKGATFNRETPGVPIAYTTNFLKDNELAVIKNNSE
YIETTSKAYTDGKINIDHSGGYVAQFNISWDEVNYDPEGNEIVQH
KNWSENNKSKLAHFTSSIYLPGNARNINVYAKECTGLAWEWWRTV
IDDRNLPLVKNRNISIWGTTLYPKYSNKVDNPIE (SEQ ID NO: 1) listeriolysin O
MKDASAFNKENSISSMAPPASPPASPKTPIEKKHADEIDKYIQGL (.DELTA.3-25)
DYNKNNVLVYHGDAVTNVPPRKGYKDGNEYIVVEKKKKSINQNNA
DIQVVNAISSLTYPGALVKANSELVENQPDVLPVKRDSLTLSIDL
PGMTNQDNKIVVKNATKSNVNNAVNTLVERWNEKYAQAYPNVSAK
IDYDDEMAYSESQLIAKEGTAFKAVNNSLNVNFGAISEGKMQEEV
ISFKQIYYNVNVNEPTRPSRFFGKAVTKEQLQALGVNAENPPAYI
SSVAYGRQVYLKLSTNSHSTKVKAAFDAAVSGKSVSGDVELTNII
KNSSFKAVIYGGSAKDEVQIIDGNLGDLRDILKKGATFNRETPGV
PIAYTTNFLKDNELAVIKNNSEYIETTSKAYTDGKINIDHSGGYV
AQFNISWDEVNYDPEGNEIVQHKNWSENNKSKLAHFTSSIYLPGN
ARNINVYAKECTGLAWEWWRTVIDDRNLPLVKNRNISIWGTTLYP KYSNKVDNPIE(SEQ ID
NO: 2) streptolysin O BAB41212.2
MSNKKTFKKYSRVAGLLTAALIIGNLVTANAESNKQNTASTETTT (Streptococcus GI:
71061060 TSEQPKPESSELTIEKAGQKMDDMLNSNDMIKLAPKEMPLESAEK pyogenes)
EEKKSEDKKKSEEDHTEEINDKIYSLNYNELEVLAKNGETIENFV
PKEGVKKADKFIVIERKKKNINTTPVDISIIDSVTDRTYPAALQL
ANKGFTENKPDAVVTKRNPQKIHIDLPGMGDKATVEVNDPTYANV
STAIDNLVNQWHDNYSGGNTLPARTQYTESMVYSKSQIEAALNVN
SKILDGTLGIDFKSISKGEKKVMIAAYKQIFYTVSANLPNNPADV
FDKSVTFKDLQRKGVSNEAPPLFVSNVAYGRTVFVKLETSSKSND
VEAAFSAALKGTDVKTNGKYSDILENSSFTAVVLGGDAAEHNKVV
TKDFDVIRNVIKDNATFSRKNPAYPISYTSVFLKNNKIAGVNNRT
EYVETTSTEYTSGKINLSHQGAYVAQYEILWDEINYDDKGKEVIT
KRRWDNNWYSKTSPFSTVIPLGANSRNIRIMARECTGLAWEWWRK
VIDERDVKLSKEINVNISGSTLSPYGSITYK (SEQ ID NO: 3) perfringolysin O
NP_561079.1 MIRFKKTKLIASIAMALCLFSQPVISFSKDITDKNQSIDSGISSL
(Clostridium GI: 18309145
SYNRNEVLASNGDKIESFVPKEGKKTGNKFIVVERQKRSLTTSPV perfringens)
DISIIDSVNDRTYPGALQLADKAFVENRPTILMVKRKPININIDL
PGLKGENSIKVDDPTYGKVSGAIDELVSKWNEKYSSTHTLPARTQ
YSESMVYSKSQISSALNVNAKVLENSLGVDFNAVANNEKKVMILA
YKQIFYTVSADLPKNPSDLFDDSVTFNDLKQKGVSNEAPPLMVSN
VAYGRTIYVKLETTSSSKDVQAAFKALIKNTDIKNSQQYKDIYEN
SSFTAVVLGGDAQEHNKVVTKDFDEIRKVIKDNATFSTKNPAYPI
SYTSVFLKDNSVAAVHNKTDYIETTSTEYSKGKINLDHSGAYVAQ
FEVAWDEVSYDKEGNEVLTHKTWDGNYQDKTAHYSTVIPLEANAR
NIRIKARECTGLAWEWWRDVISEYDVPLTNNINVSIWGTTLYPGS SITYN (SEQ ID NO: 4)
Pneumolysin NP_359331.1
MANKAVNDFILAMNYDKKKLLTHQGESIENRFIKEGNQLPDEFVV (Streptococcus GI:
933687 IERKKRSLSTNTSDISVTATNDSRLYPGALLVVDETLLENNPTLL pneumoniae)
AVDRAPMTYSIDLPGLASSDSFLQVEDPSNSSVRGAVNDLLAKWH
QDYGQVNNVPARMQYEKITAHSMEQLKVKFGSDFEKTGNSLDIDF
NSVHSGEKQIQIVNFKQIYYTVSVDAVKNPGDVFQDTVTVEDLKQ
RGISAERPLVYISSVAYGRQVYLKLETTSKSDEVEAAFEALIKGV
KVAPQTEWKQILDNTEVKAVILGGDPSSGARVVTGKVDMVEDLIQ
EGSRFTADHPGLPISYTTSFLRDNVVATFQNSTDYVETKVTAYRN
GDLLLDHSGAYVAQYYITWDELSYDHQGKEVLTPKAWDRNGQDLT
AHFTTSIPLKGNVRNLSVKIRECTGLAWEWWRTVYEKTDLPLVRK RTISIWGTTLYPQVEDKVEND
(SEQ ID NO: 5)
[0170] In some embodiments, a library member (e.g., a library
member which is a bacterial cell) includes an invasin that
facilitates uptake by the antigen presenting cell. In some
embodiments, a library member includes an autolysin that
facilitates autolysis of the library member within the antigen
presenting cell. In some embodiments, a library member includes
both an invasin and an autolysin. In some embodiments, a library
member which is an E. coli cell includes an invasin and/or an
autolysin. In various embodiments, library cells that express an
invasin and/or autolysin are used in methods that also employ
non-professional antigen presenting cells or antigen presenting
cells that are from cell lines. Isberg et al. (Cell, 1987,
50:769-778), Sizemore et al. (Science, 1995, 270:299-302) and
Courvalin et al. (C.R. Acad. Sci. Paris, 1995, 318:1207-12)
describe expression of an invasin to effect endocytosis of bacteria
by target cells. Autolysins are described by Cao et al., Infect.
Immun. 1998, 66(6): 2984-2986; Margot et al., J. Bacteriol. 1998,
180(3):749-752; Buist et al., Appl. Environ. Microbiol., 1997,
63(7):2722-2728; Yamanaka et al., FEMS Microbiol. Lett., 1997,
150(2): 269-275; Romero et al., FEMS Microbiol. Lett., 1993,
108(1):87-92; Betzner and Keck, Mol. Gen. Genet., 1989, 219(3):
489-491; Lubitz et al., I Bacteriol., 1984, 159(1):385-387; and
Tomasz et al., I Bacteriol., 1988, 170(12): 5931-5934. In some
embodiments, an autolysin has a feature that permits delayed lysis,
e.g., the autolysin is temperature-sensitive or time-sensitive
(see, e.g., Chang et al., 1995, 1 Bact. 177, 3283-3294; Raab et
al., 1985, J Mol. Biol. 19, 95-105; Gerds et al., 1995, Mol.
Microbiol. 17, 205-210). Useful cytolysins also include addiction
(poison/antidote) autolysins, (see, e.g., Magnuson R, et al., 1996,
J Biol. Chem. 271(31), 18705-18710; Smith A S, et al., 1997, Mol.
Microbiol. 26(5), 961-970).
[0171] In some embodiments, members of the library include
bacterial cells. In certain embodiments, the library includes
non-pathogenic, non-virulent bacterial cells. Examples of bacteria
for use as library members include E. coli, mycobacteria, Listeria
monocytogenes, Shigella flexneri, Bacillus subtilis, or
Salmonella.
[0172] In some embodiments, members of the library include
eukaryotic cells (e.g., yeast cells). In some embodiments, members
of the library include viruses (e.g., bacteriophages). In some
embodiments, members of the library include liposomes. Methods for
preparing liposomes that include a cytolysin and other agents are
described in Kyung-Dall et al., U.S. Pat. No. 5,643,599. In some
embodiments, members of the library include beads. Methods for
preparing libraries comprised of beads are described, e.g., in Lam
et al., Nature 354: 82-84, 1991, U.S. Pat. Nos. 5,510,240 and
7,262,269, and references cited therein.
[0173] In certain embodiments, a library is constructed by cloning
polynucleotides encoding polypeptides of interest, or portions
thereof, into vectors that express the polypeptides of interest in
cells of the library. The polynucleotides can be synthetically
synthesized. The polynucleotides can be cloned by designing primers
that amplify the polynucleotides. Primers can be designed using
available software, such as Primer3Plus (available the following
URL: bioinformatics.nl/cgi-bin/primer3plus/primer3plus.cgi; see
Rozen and Skaletsky, In: Krawetz S, Misener S (eds) Bioinformatics
Methods and Protocols: Methods in Molecular Biology. Humana Press,
Totowa, N.J., pp. 365-386, 2000). Other methods for designing
primers are known to those of skill in the art. In some
embodiments, primers are constructed so as to produce polypeptides
that are truncated, and/or lack hydrophobic regions (e.g., signal
sequences or transmembrane regions) to promote efficient
expression. The location of predicted signal sequences and
predicted signal sequence cleavage sites in a given open reading
frame (ORF) sequence can be determined using available software,
see, e.g., Dyrlov et al., J. Mol. Biol., 340:783-795, 2004, and the
following URL: cbs.dtu.dk/services/SignalP/). For example, if a
signal sequence is predicted to occur at the N-terminal 20 amino
acids of a given polypeptide sequence, a primer is designed to
anneal to a coding sequence downstream of the nucleotides encoding
the N-terminal 20 amino acids, such that the amplified sequence
encodes a product lacking this signal sequence.
[0174] Primers can also be designed to include sequences that
facilitate subsequent cloning steps. ORFs can be amplified directly
from genomic DNA (e.g., genomic DNA of a tumor cell), or from
polynucleotides produced by reverse transcription (RT-PCR) of mRNAs
expressed by the tumor cell. RT-PCR of mRNA is useful, e.g., when
the genomic sequence of interest contains intronic regions.
PCR-amplified ORFs are cloned into an appropriate vector, and size,
sequence, and expression of ORFs can be verified prior to use in
immunological assays.
[0175] In some embodiments, a polynucleotide encoding a polypeptide
of interest is linked to a sequence encoding a tag (e.g., an
N-terminal or C-terminal epitope tag) or a reporter protein (e.g.,
a fluorescent protein). Epitope tags and reporter proteins
facilitate purification of expressed polypeptides, and can allow
one to verify that a given polypeptide is properly expressed in a
library host cell, e.g., prior to using the cell in a screen.
Useful epitope tags include, for example, a polyhistidine (His)
tag, a V5 epitope tag from the P and V protein of paramyxovirus, a
hemagglutinin (HA) tag, a myc tag, and others. In some embodiments,
a polynucleotide encoding a polypeptide of interest is fused to a
sequence encoding a tag which is a known antigenic epitope (e.g.,
an MHC class I- and/or MHC class II-restricted T cell epitope of a
model antigen such as an ovalbumin), and which can be used to
verify that a polypeptide of interest is expressed and that the
polypeptide-tag fusion protein is processed and presented in
antigen presentation assays. In some embodiments a tag includes a T
cell epitope of a murine T cell (e.g., a murine T cell line). In
some embodiments, a polynucleotide encoding a polypeptide of
interest is linked to a tag that facilitates purification and a tag
that is a known antigenic epitope. Useful reporter proteins include
naturally occurring fluorescent proteins and their derivatives, for
example, Green Fluorescent Protein (Aequorea Victoria) and Neon
Green (Branchiostoma lanceolatum). Panels of synthetically derived
fluorescent and chromogenic proteins are also available from
commercial sources.
[0176] Polynucleotides encoding a polypeptide of interest are
cloned into an expression vector for introduction into library host
cells. Various vector systems are available to facilitate cloning
and manipulation of polynucleotides, such as the Gateway.RTM.
Cloning system (Invitrogen). As is known to those of skill in the
art, expression vectors include elements that drive production of
polypeptides of interest encoded by a polynucleotide in library
host cells (e.g., promoter and other regulatory elements). In some
embodiments, polypeptide expression is controlled by an inducible
element (e.g., an inducible promoter, e.g., an IPTG- or
arabinose-inducible promoter, or an IPTG-inducible phage T7 RNA
polymerase system, a lactose (lac) promoter, a tryptophan (trp)
promoter, a tac promoter, a trc promoter, a phage lambda promoter,
an alkaline phosphatase (phoA) promoter, to give just a few
examples; see Cantrell, Meth. in Mol. Biol., 235:257-276, Humana
Press, Casali and Preston, Eds.). In some embodiments, polypeptides
are expressed as cytoplasmic polypeptides. In some embodiments, the
vector used for polypeptide expression is a vector that has a high
copy number in a library host cell. In some embodiments, the vector
used for expression has a copy number that is more than 25, 50, 75,
100, 150, 200, or 250 copies per cell. In some embodiments, the
vector used for expression has a ColE1 origin of replication.
Useful vectors for polypeptide expression in bacteria include pET
vectors (Novagen), Gateway.RTM. pDEST vectors (Invitrogen), pGEX
vectors (Amersham Biosciences), pPRO vectors (BD Biosciences), pBAD
vectors (Invitrogen), pLEX vectors (Invitrogen), pMAL.TM. vectors
(New England BioLabs), pGEMEX vectors (Promega), and pQE vectors
(Qiagen). Vector systems for producing phage libraries are known
and include Novagen T7Select.RTM. vectors, and New England Biolabs
Ph.D..TM. Peptide Display Cloning System.
[0177] In some embodiments, library host cells express (either
constitutively, or when induced, depending on the selected
expression system) a polypeptide of interest to at least 10%, 20%,
30%, 40%, 50%, 60%, or 70% of the total cellular protein. In some
embodiments, the level a polypeptide available in or on a library
member (e.g., cell, virus particle, liposome, bead) is such that
antigen presenting cells exposed to a sufficient quantity of the
library members are presented on MHC molecules polypeptide epitopes
at a density that is comparable to the density presented by antigen
presenting cells pulsed with purified peptides.
[0178] Methods for efficient, large-scale production of libraries
are available. For example, site-specific recombinases or
rare-cutting restriction enzymes can be used to transfer
polynucleotides between expression vectors in the proper
orientation and reading frame (Walhout et al., Meth. Enzymol.
328:575-592, 2000; Marsischky et al., Genome Res. 14:2020-202,
2004; Blommel et al., Protein Expr. Purif. 47:562-570, 2006).
[0179] For production of liposome libraries, expressed polypeptides
(e.g., purified or partially purified polypeptides) can be
entrapped in liposomal membranes, e.g., as described in Wassef et
al., U.S. Pat. No. 4,863,874; Wheatley et al., U.S. Pat. No.
4,921,757; Huang et al., U.S. Pat. No. 4,925,661; or Martin et al.,
U.S. Pat. No. 5,225,212.
[0180] A library can be designed to include full length
polypeptides and/or portions of polypeptides. Expression of full
length polypeptides maximizes epitopes available for presentation
by a human antigen presenting cell, thereby increasing the
likelihood of identifying an antigen. However, in some embodiments,
it is useful to express portions of polypeptides, or polypeptides
that are otherwise altered, to achieve efficient expression. For
example, in some embodiments, polynucleotides encoding polypeptides
that are large (e.g., greater than 1,000 amino acids), that have
extended hydrophobic regions, signal peptides, transmembrane
domains, or domains that cause cellular toxicity, are modified
(e.g., by C-terminal truncation, N-terminal truncation, or internal
deletion) to reduce cytotoxicity and permit efficient expression a
library cell, which in turn facilitates presentation of the encoded
polypeptides on human cells. Other types of modifications, such as
point mutations or codon optimization, may also be used to enhance
expression.
[0181] The number of polypeptides included in a library can be
varied. For example, in some embodiments, a library can be designed
to express polypeptides from at least 5%, 10%, 15%, 20%, 25%, 35%,
40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%,
99%, or more, of ORFs in a target cell (e.g., tumor cell). In some
embodiments, a library expresses at least 10, 15, 20, 25, 30, 40,
50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650,
700, 750, 800, 850, 900, 950, 1000, 2500, 5000, 10,000, or more
different polypeptides of interest, each of which may represent a
polypeptide encoded by a single full length polynucleotide or
portion thereof.
[0182] In some embodiments, assays may focus on identifying
antigens that are secreted polypeptides, cell surface-expressed
polypeptides, or virulence determinants, e.g., to identify antigens
that are likely to be targets of both humoral and cell mediated
immune responses.
[0183] In addition to polypeptides of interest, libraries can
include tags or reporter proteins that allow one to easily purify,
analyze, or evaluate MHC presentation, of the polypeptide of
interest. In some embodiments, polypeptides expressed by a library
include C-terminal tags that include both an MHC class I and an MHC
class II-restricted T cell epitope from a model antigen, such as
chicken ovalbumin (OVA). Library protein expression and MHC
presentation is validated using these epitopes. In some
embodiments, the epitopes are OVA.sub.247-265 and OVA.sub.258-265
respectfully, corresponding to positions in the amino acid sequence
found in GenBank.RTM. under Acc. No. NP_990483. Expression and
presentation of linked ORFs can be verified with antigen
presentation assays using T cell hybridomas (e.g., B3Z T hybridoma
cells, which are H2-K.sup.b restricted, and KZO T hybridoma cells,
which are H2-A.sup.k restricted) that specifically recognize these
epitopes.
[0184] Sets of library members (e.g., bacterial cells) can be
provided on an array (e.g., on a solid support, such as a 96-well
plate) and separated such that members in each location express a
different polypeptide of interest, or a different set of
polypeptides of interest.
[0185] Methods of using library members for identifying T cell
antigens are described in detail below. In addition to these
methods, library members also have utility in assays to identify B
cell antigens. For example, lysate prepared from library members
that include polypeptides of interest can be used to screen a
sample comprising antibodies (e.g., a serum sample) from a subject
(e.g., a subject who has been exposed to an infectious agent of
interest, a subject who has cancer, and/or a control subject), to
determine whether antibodies present in the subject react with the
polypeptide of interest. Suitable methods for evaluating antibody
reactivity are known and include, e.g., ELISA assays.
Polypeptides of Interest
[0186] In some embodiments, methods and compositions described
herein can be used to identify and/or detect immune responses to a
polypeptide of interest. In some embodiments, a polypeptide of
interest is encoded by an ORF from a target tumor cell, and members
of a library include (e.g., internally express or carry) ORFs from
a target tumor cell. In some such embodiments, a library can be
used in methods described herein to assess immune responses to one
or more polypeptides of interest encoded by one or more ORFs. In
some embodiments, methods of the disclosure identify one or more
polypeptides of interest as stimulatory antigens (e.g., that
stimulate an immune response, e.g., a T cell response, e.g.,
expression and/or secretion of one or more immune mediators). In
some embodiments, methods of the disclosure identify one or more
polypeptides of interest as antigens or potential antigens that
have minimal or no effect on an immune response (e.g., expression
and/or secretion of one or more immune mediators). In some
embodiments, methods of the disclosure identify one or more
polypeptides of interest as inhibitory and/or suppressive antigens
(e.g., that inhibit, suppress, down-regulate, impair, and/or
prevent an immune response, e.g., a T cell response, e.g.,
expression and/or secretion of one or more immune mediators). In
some embodiments, methods of the disclosure identify one or more
polypeptides of interest as tumor antigens or potential tumor
antigens, e.g., tumor specific antigens (TSAs, or neoantigens),
tumor associated antigens (TAAs), or cancer/testis antigens
(CTAs).
[0187] In some embodiments, a polypeptide of interest is a putative
tumor antigen, and methods and compositions described herein can be
used to identify and/or detect immune responses to one or more
putative tumor antigens. For example, members of a library include
(e.g., internally express or carry) putative tumor antigens (e.g.,
a polypeptide previously identified (e.g., by a third party) as a
tumor antigen, e.g., identified as a tumor antigen using a method
other than a method of the present disclosure). In some
embodiments, a putative tumor antigen is a tumor antigen described
herein. In some such embodiments, such libraries can be used to
assess whether and/or the extent to which such putative tumor
antigen mediates an immune response. In some embodiments, methods
of the disclosure identify one or more putative tumor antigens as
stimulatory antigens. In some embodiments, methods of the
disclosure identify one or more putative tumor antigens as antigens
that have minimal or no effect on an immune response. In some
embodiments, methods of the disclosure identify one or more
putative tumor antigens as inhibitory and/or suppressive
antigens.
[0188] In some embodiments, a polypeptide of interest is a
pre-selected tumor antigen, and methods and compositions described
herein can be used to identify and/or detect immune responses to
one or more pre-selected tumor antigens. For example, in some
embodiments, members of a library include (e.g., internally express
or carry) one or more polypeptides identified as tumor antigens
using a method of the present disclosure and/or using a method
other than a method of the present disclosure. In some such
embodiments, such libraries can be used to assess whether and/or
the extent to which such tumor antigens mediate an immune response
by an immune cell from one or more subjects (e.g., a subject who
has cancer and/or a control subject) to obtain one or more response
profiles described herein. In some embodiments, methods of the
disclosure identify one or more pre-selected tumor antigens as
stimulatory antigens for one or more subjects. In some embodiments,
methods of the disclosure identify one or more pre-selected tumor
antigens as antigens that have minimal or no effect on an immune
response for one or more subjects. In some embodiments, methods of
the disclosure identify one or more pre-selected tumor antigens as
inhibitory and/or suppressive antigens for one or more
subjects.
[0189] In some embodiments, a polypeptide of interest is a known
tumor antigen, and methods and compositions described herein can be
used to identify and/or detect immune responses to one or more
known tumor antigens. For example, in some embodiments, members of
a library include (e.g., internally express or carry) one or more
polypeptides identified as a tumor antigen using a method of the
present disclosure and/or using a method other than a method of the
present disclosure. In some such embodiments, such libraries can be
used to assess whether and/or the extent to which such tumor
antigens mediate an immune response by an immune cell from one or
more subjects (e.g., a subject who has cancer and/or a control
subject) to obtain one or more response profiles described herein.
In some embodiments, methods of the disclosure identify one or more
known tumor antigens as stimulatory antigens for one or more
subjects. In some embodiments, methods of the disclosure identify
one or more known tumor antigens as antigens that have minimal or
no effect on an immune response for one or more subjects. In some
embodiments, methods of the disclosure identify one or more known
tumor antigens as inhibitory and/or suppressive antigens for one or
more subjects.
[0190] In some embodiments, a polypeptide of interest is a
potential tumor antigen, and methods and compositions described
herein can be used to identify and/or detect immune responses to
one or more potential tumor antigens. For example, in some
embodiments, members of a library include (e.g., internally express
or carry) one or more polypeptides identified as being of interest,
e.g., encoding mutations associated with a tumor, using a method of
the present disclosure and/or using a method other than a method of
the present disclosure. In some such embodiments, such libraries
can be used to assess whether and/or the extent to which such
polypeptides mediate an immune response by an immune cell from one
or more subjects (e.g., a subject who has cancer and/or a control
subject) to obtain one or more response profiles described herein.
In some embodiments, methods of the disclosure identify one or more
polypeptides as stimulatory antigens for one or more subjects. In
some embodiments, methods of the disclosure identify one or more
polypeptides as antigens that have minimal or no effect on an
immune response for one or more subjects. In some embodiments,
methods of the disclosure identify one or more polypeptides as
inhibitory and/or suppressive antigens for one or more
subjects.
Tumor Antigens
[0191] Polypeptides of interest used in methods and systems
described herein include tumor antigens amd potential tumor
antigens, e.g., tumor specific antigens (TSAs, or neoantigens),
tumor associated antigens (TAAs), and/or cancer/testis antigens
(CTAs). Exemplary tumor antigens include, e.g., MART-1/MelanA
(MART-I or MLANA), gp100 (Pmel 17 or SILV), tyrosinase, TRP-1,
TRP-2, MAGE-1, MAGE-3 (also known as HIP8), BAGE, GAGE-1, GAGE-2,
p15, Calcitonin, Calretinin, Carcinoembryonic antigen (CEA),
Chromogranin, Cytokeratin, Desmin, Epithelial membrane protein
(EMA), Factor VIII, Glial fibrillary acidic protein (GFAP), Gross
cystic disease fluid protein (GCDFP-15), HMB-45, Human chorionic
gonadotropin (hCG), inhibin, lymphocyte marker, MART-1 (Melan-A),
Myo D1, muscle-specific actin (MSA), neurofilament, neuron-specific
enolase (NSE), placental alkaline phosphatase (PLAP),
prostate-specific antigen, PTPRC (CD45), S100 protein, smooth
muscle actin (SMA), synaptophysin, thyroglobulin, thyroid
transcription factor-1, Tumor M2-PK, vimentin, p53, Ras, HER-2/neu,
BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus
antigens (e.g., EBNA1), human papillomavirus (HPV) antigen E6 or E7
(HPV_E6 or HPV_E7), TSP-180, MAGE-4, MAGE-5, MAGE-6, RAGE, NY-ESO-1
(also known as CTAG1B), erbB, p185erbB2, p180erbB-3, c-met,
nm-23H1, PSA, TAG-72, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras,
beta-Catenin, CDK4, Mum-1, p 15, p 16, 43-9F, 5T4, 791Tgp72,
alpha-fetoprotein (AFP), beta-HCG, BCA225, BTAA, CA 125, CA 15-3\CA
27.29\BCAA, CA 195, CA 242, CA-50, CAM43, CD68\P1, CO-029, FGF-5,
G250, Ga733\EpCAM, HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K,
NY-CO-1, RCAS1, SDCCAG16, TA-90\Mac-2 binding protein\cyclophilin
C-associated protein, TAAL6, TAG72, TLP, MUC16, IL13Ra2, FRa,
VEGFR2, Lewis Y, FAP, EphA2, CEACAM5, EGFR, CA6, CA9, GPNMB, EGP1,
FOLR1, endothelial receptor, STEAP1, SLC44A4, Nectin-4, AGS-16,
guanalyl cyclase C, MUC-1, CFC1B, integrin alpha 3 chain (of a3b1,
a laminin receptor chain), TPS, CD19, CD20, CD22, CD30, CD31, CD72,
CD180, CD171 (L1CAM), CD123, CD133, CD138, CD37, CD70, CD79a,
CD79b, CD56, CD74, CD166, CD71, CD34, CD99, CD117, CD80, CD28,
CD13, CD15, CD25, CD10, CLL-1/CLEC12A, ROR1, Glypican 3 (GPC3),
Mesothelin, CD33/IL3Ra, c-Met, PSCA, PSMA, Glycolipid F77,
EGFRvIII, BCMA, GD-2, PSAP, prostein (also known as P501S), PSMA,
Survivin (also known as BIRC5), and MAGE-A3, MAGEA2, MAGEA4,
MAGEA6, MAGEA9, MAGEA10, MAGEA12, BIRC5, CDH3, CEACAM3, CGB
isoform2, ELK4, ERBB2, HPSE1, HPSE2, KRAS_isoform1, KRAS_isoform2,
MUC1, SMAD4, TERT.2. TERT.3, TGFBR2, EGAG9_isoform1, TP53, CGB
isoforml, IMPDH2, LCK, angiopoietin-1 (Ang1) (also known as
ANGPT1), XIAP (also known as BIRC4), galectin-3 (also known as
LGALS3), VEGF-A (also known as VEGF), ATP6S1 (also known as
ATP6AP1), MAGE-A1, cIAP-1 (also known as BIRC2), macrophage
migration inhibitory factor (MIF), galectin-9 (also known as
LGALS9), progranulin PGRN (also known as granulin), OGFR, MLIAP
(also known as BIRC7), TBX4 (also known as ICPPS, SPS or T-Box4),
secretory leukocyte protein inhibitor (Slpi) (also known as
antileukoproteinase), Ang2 (also known as ANGPT2), galectin-1 (also
known as LGALS1), TRP-2 (also known as DCT), hTERT (telomerase
reverse transcriptase) tyrosinase-related protein 1 (TRP-1, TYRP1),
NOR-90/UBF-2 (also known as UBTF), LGMN, SPA17, PRTN3, TRRAP_1,
TRRAP_2, TRRAP_3, TRRAP_4, MAGEC2, PRAME, SOX10, RAC1, HRAS, GAGE4,
AR, CYP1B1, MMP8, TYR, PDGFRB, KLK3, PAX3, PAXS, ST3GAL5, PLAC1,
RhoC, MYCN, REG3A, CSAG2, CTAG2-1a, CTAG2-1b, PAGE4, BRAF, GRM3,
ERBB4, KIT, MAPK1, MFI2, SART3, ST8SIA1, WDR46, AKAP-4, RGSS,
FOSL1, PRM2, ACRBP, CTCFL, CSPG4, CCNB1, MSLN, WT1, SSX2, KDR,
ANKRD30A, MAGED1, MAP3K9, XAGE1B, PREX2, CD276, TEK, AIM1, ALK,
FOLH1, GRIN2A MAP3K5 and one or more isoforms of any preceding
tumor antigens. Exemplary tumor antigens are provided in the
accompanying list of sequences.
[0192] Tumor specific antigens (TSAs, or neoantigens) are tumor
antigens that are not encoded in normal host genome (see, e.g.,
Yarchoan et al., Nat. Rev. Cancer. 2017 Feb. 24. doi:
10.1038/nrc.2016.154; Gubin et al., J. Clin. Invest. 125:3413-3421
(2015)). In some embodiments, TSAs arise from somatic mutations
and/or other genetic alterations. In some embodiments, TSAs arise
from missense or in-frame mutations. In some embodiments, TSAs
arise from frame-shift mutations or loss-of-stop-codon mutations.
In some embodiments, TSAs arise from insertion or deletion
mutations. In some embodiments, TSAs arise from duplication or
repeat expansion mutations. In some embodiments, TSAs arise from
splice variants or improper splicing. In some embodiments, TSAs
arise from gene fusions. In some embodiments, TSAs arise from
translocations. In some embodiments, TSAs include oncogenic viral
proteins. For example, as with Merkel cell carcinoma (MCC)
associated with the Merkel cell polyomavirus (MCPyV) and cancers of
the cervix, oropharynx and other sites associated with the human
papillomavirus (HPV), TSAs include proteins encoded by viral open
reading frames. For purposes of this disclosure, the terms
"mutation" and "mutations" encompass all mutations and genetic
alterations that may give rise to an antigen encoded in the genome
of a cancer or tumor cell of a subject, but not in a normal or
non-cancerous cell of the same subject. In some embodiments, TSAs
are specific (personal) to a subject. In some embodiments, TSAs are
shared by more than one subject, e.g., less than 1%, 1-3%, 1-5%,
1-10%, or more of subjects suffering from a cancer. In some
embodiments, TSAs shared by more than one subject may be known or
pre-selected.
[0193] In some embodiments, a TSA is encoded by an open reading
frame from a virus. For example, a library can be designed to
express polypeptides from one of the following viruses: an
immunodeficiency virus (e.g., a human immunodeficiency virus (HIV),
e.g., HIV-1, HIV-2), a hepatitis virus (e.g., hepatitis B virus
(HBV), hepatitis C virus (HCV), hepatitis A virus, non-A and non-B
hepatitis virus), a herpes virus (e.g., herpes simplex virus type I
(HSV-1), HSV-2, Varicella-zoster virus, Epstein Barr virus, human
cytomegalovirus, human herpesvirus 6 (HHV-6), HHV-7, HHV-8), a
poxvirus (e.g., variola, vaccinia, monkeypox, Molluscum contagiosum
virus), an influenza virus, a human papilloma virus, adenovirus,
rhinovirus, coronavirus, respiratory syncytial virus, rabies virus,
coxsackie virus, human T cell leukemia virus (types I, II and III),
parainfluenza virus, paramyxovirus, poliovirus, rotavirus,
rhinovirus, rubella virus, measles virus, mumps virus, adenovirus,
yellow fever virus, Norwalk virus, West Nile virus, a Dengue virus,
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV),
bunyavirus, Ebola virus, Marburg virus, Eastern equine encephalitis
virus, Venezuelan equine encephalitis virus, Japanese encephalitis
virus, St. Louis encephalitis virus, Junin virus, Lassa virus, and
Lymphocytic choriomeningitis virus. Libraries for other viruses can
also be produced and used according to methods described
herein.
[0194] Tumor specific antigens are known in the art, any of which
can be used in methods described herein. In some embodiments, gene
sequences encoding polypeptides that are potential or putative
neoantigens are determined by sequencing the genome and/or exome of
tumor tissue and healthy tissue from a subject having cancer using
next generation sequencing technologies. In some embodiments, genes
that are selected based on their frequency of mutation and ability
to encode a potential or putative neoantigen are sequenced using
next-generation sequencing technology. Next-generation sequencing
applies to genome sequencing, genome resequencing, transcriptome
profiling (RNA-Seq), DNA-protein interactions (ChIP-sequencing),
and epigenome characterization (de Magalhaes et al. (2010) Ageing
Research Reviews 9 (3): 315-323; Hall N (2007) J. Exp. Biol. 209
(Pt 9): 1518-1525; Church (2006) Sci. Am. 294 (1): 46-54; ten Bosch
et al. (2008) Journal of Molecular Diagnostics 10 (6): 484-492;
Tucker T et al. (2009) The American Journal of Human Genetics 85
(2): 142-154). Next-generation sequencing can be used to rapidly
reveal the presence of discrete mutations such as coding mutations
in individual tumors, e.g., single amino acid changes (e.g.,
missense mutations, in-frame mutations) or novel stretches of amino
acids generated by frame-shift insertions, deletions, gene fusions,
read-through mutations in stop codons, duplication or repeat
expansion mutations, and translation of splice variants or
improperly spliced introns, and translocations (e.g.,
"neoORFs").
[0195] Another method for identifying potential or putative
neoantigens is direct protein sequencing. Protein sequencing of
enzymatic digests using multidimensional MS techniques (MSn)
including tandem mass spectrometry (MS/MS)) can also be used to
identify neoantigens. Such proteomic approaches can be used for
rapid, highly automated analysis (see, e.g., Gevaert et al.,
Electrophoresis 21:1145-1154 (2000)). High-throughput methods for
de novo sequencing of unknown proteins can also be used to analyze
the proteome of a subject's tumor to identify expressed potential
or putative neoantigens. For example, meta shotgun protein
sequencing may be used to identify expressed potential or putative
neoantigens (see e.g., Guthals et al. (2012) Molecular and Cellular
Proteomics 11(10):1084-96).
[0196] Potential or putative neoantigens may also be identified
using MHC multimers to identify neoantigen-specific T cell
responses. For example, high-throughput analysis of
neoantigen-specific T cell responses in patient samples may be
performed using MHC tetramer-based screening techniques (see e.g.,
Hombrink et al. (2011) PLoS One; 6(8): e22523; Hadrup et al. (2009)
Nature Methods, 6(7):520-26; van Rooij et al. (2013) Journal of
Clinical Oncology, 31:1-4; and Heemskerk et al. (2013) EMBO
Journal, 32(2):194-203).
[0197] In some embodiments, one or more known or pre-selected tumor
specific antigens, or one or more potential or putative tumor
specific antigens identified using one of these methods, can be
included in a library described herein.
[0198] Tumor associated antigens (TAAs) include proteins encoded in
a normal genome (see, e.g., Ward et al., Adv. Immunol. 130:25-74
(2016)). In some embodiments, TAAs are either normal
differentiation antigens or aberrantly expressed normal proteins.
Overexpressed normal proteins that possess
growth/survival-promoting functions, such as Wilms tumor 1 (WT1)
(Ohminami et al., Blood 95:286-293 (2000)) or Her2/neu (Kawashima
et al., Cancer Res. 59:431-435 (1999)), are TAAs that directly
participate in the oncogenic process. Post-translational
modifications, such as phosphorylation, of proteins may also lead
to formation of TAAs (Doyle, J. Biol. Chem. 281:32676-32683 (2006);
Cobbold, Sci. Transl. Med. 5:203ra125 (2013)). TAAs are generally
shared by more than one subject, e.g., less than 1%, 1-3%, 1-5%,
1-10%, 1-20%, or more of subjects suffering from a cancer. In some
embodiments, TAAs are known or pre-selected tumor antigens. In some
embodiments, with respect to an individual subject, TAAs are
potential or putative tumor antigens.Cancer/testis antigens (CTAs)
are expressed by various tumor types and by reproductive tissues
(for example, testes, fetal ovaries and trophoblasts) but have
limited or no detectable expression in other normal tissues in the
adult and are generally not presented on normal reproductive cells,
because these tissues do not express MHC class I molecules (see,
e.g., Coulie et al., Nat. Rev. Cancer 14:135-146 (2014); Simpson et
al., Nat. Rev. Cancer 5:615-625 (2005); Scanlan et al., Immunol.
Rev. 188:22-32 (2002)). Library Screens
[0199] Human Cells for Antigen Presentation
[0200] The present invention provides, inter alia, compositions and
methods for identifying tumor antigens recognized by human immune
cells. Human antigen presenting cells express ligands for antigen
receptors and other immune activation molecules on human
lymphocytes. Given differences in MHC peptide binding specificities
and antigen processing enzymes between species, antigens processed
and presented by human cells are more likely to be physiologically
relevant human antigens in vivo than antigens identified in
non-human systems. Accordingly, methods of identifying these
antigens employ human cells to present candidate tumor antigen
polypeptides. Any human cell that internalizes library members and
presents polypeptides expressed by the library members on MHC
molecules can be used as an antigen presenting cell according to
the present disclosure. In some embodiments, human cells used for
antigen presentation are primary human cells. The cells can include
peripheral blood mononuclear cells (PBMC) of a human. In some
embodiments, peripheral blood cells are separated into subsets
(e.g., subsets comprising dendritic cells, macrophages, monocytes,
B cells, or combinations thereof) prior to use in an antigen
presentation assay. In some embodiments, a subset of cells that
expresses MHC class II is selected from peripheral blood. In one
example, a cell population including dendritic cells is isolated
from peripheral blood. In some embodiments, a subset of dendritic
cells is isolated (e.g., plasmacytoid, myeloid, or a subset
thereof). Human dendritic cell markers include CD1c, CD1a, CD303,
CD304, CD141, and CD209. Cells can be selected based on expression
of one or more of these markers (e.g., cells that express CD303,
CD1c, and CD141).
[0201] Dendritic cells can be isolated by positive selection from
peripheral blood using commercially available kits (e.g., from
Miltenyi Biotec Inc.). In some embodiments, the dendritic cells are
expanded ex vivo prior to use in an assay. Dendritic cells can also
be produced by culturing peripheral blood cells under conditions
that promote differentiation of monocyte precursors into dendritic
cells in vitro. These conditions typically include culturing the
cells in the presence of cytokines such as GM-CSF and IL-4 (see,
e.g., Inaba et al., Isolation of dendritic cells, Curr. Protoc.
Immunol. May; Chapter 3: Unit 3.7, 2001). Procedures for in vitro
expansion of hematopoietic stem and progenitor cells (e.g., taken
from bone marrow or peripheral blood), and differentiation of these
cells into dendritic cells in vitro, is described in U.S. Pat. No.
5,199,942, and U.S. Pat. Pub. 20030077263. Briefly, CD34.sup.+
hematopoietic stem and progenitor cells are isolated from
peripheral blood or bone marrow and expanded in vitro in culture
conditions that include one or more of Flt3-L, IL-1, IL-3, and
c-kit ligand.
[0202] In some embodiments, immortalized cells that express human
MHC molecules (e.g., human cells, or non-human cells that are
engineered to express human MHC molecules) are used for antigen
presentation. For example, assays can employ COS cells transfected
with human MHC molecules or HeLa cells.
[0203] In some embodiments, both the antigen presenting cells and
immune cells used in the method are derived from the same subject
(e.g., autologous T cells and APC are used). In these embodiments,
it can be advantageous to sequentially isolate subsets of cells
from peripheral blood of the subject, to maximize the yield of
cells available for assays. For example, one can first isolate
CD4.sup.+ and CD8.sup.+ T cell subsets from the peripheral blood.
Next, dendritic cells (DC) are isolated from the T cell-depleted
cell population. The remaining T- and DC-depleted cells are used to
supplement the DC in assays, or are used alone as antigen
presenting cells. In some embodiments, DC are used with T- and
DC-depleted cells in an assay, at a ratio of 1:2, 1:3, 1:4, or 1:5.
In some embodiments, the antigen presenting cells and immune cells
used in the method are derived from different subjects (e.g.,
heterologous T cells and APC are used).
[0204] Antigen presenting cells can be isolated from sources other
than peripheral blood. For example, antigen presenting cells can be
taken from a mucosal tissue (e.g., nose, mouth, bronchial tissue,
tracheal tissue, the gastrointestinal tract, the genital tract
(e.g., vaginal tissue), or associated lymphoid tissue), peritoneal
cavity, lymph nodes, spleen, bone marrow, thymus, lung, liver,
kidney, neuronal tissue, endocrine tissue, or other tissue, for use
in screening assays. In some embodiments, cells are taken from a
tissue that is the site of an active immune response (e.g., an
ulcer, sore, or abscess). Cells may be isolated from tissue removed
surgically, via lavage, or other means.
[0205] Antigen presenting cells useful in methods described herein
are not limited to "professional" antigen presenting cells. In some
embodiments, non-professional antigen presenting cells can be
utilized effectively in the practice of methods of the present
disclosure. Non-professional antigen presenting cells include
fibroblasts, epithelial cells, endothelial cells, neuronal/glial
cells, lymphoid or myeloid cells that are not professional antigen
presenting cells (e.g., T cells, neutrophils), muscle cells, liver
cells, and other types of cells.
[0206] Antigen presenting cells are cultured with library members
that express a polypeptide of interest (and, if desired, a
cytolysin polypeptide) under conditions in which the antigen
presenting cells internalize, process and present polypeptides
expressed by the library members on WIC molecules. In some
embodiments, library members are killed or inactivated prior to
culture with the antigen presenting cells. Cells or viruses can be
inactivated by any appropriate agent (e.g., fixation with organic
solvents, irradiation, freezing). In some embodiments, the library
members are cells that express ORFs linked to a tag (e.g., a tag
which comprises one or more known T cell epitopes) or reporter
protein, expression of which has been verified prior to the
culturing.
[0207] In some embodiments, antigen presenting cells are incubated
with library members at 37.degree. C. for between 30 minutes and 5
hours (e.g., for 45 min. to 1.5 hours). After the incubation, the
antigen presenting cells can be washed to remove library members
that have not been internalized. In certain embodiments, the
antigen presenting cells are non-adherent, and washing requires
centrifugation of the cells. The washed antigen presenting cells
can be incubated at 37.degree. C. for an additional period of time
(e.g., 30 min. to 2 hours) prior to exposure to lymphocytes, to
allow antigen processing. In some embodiments, it is desirable to
fix and kill the antigen presenting cells prior to exposure to
lymphocytes (e.g., by treating the cells with 1%
paraformaldehyde).
[0208] The antigen presenting cell and library member numbers can
be varied, so long as the library members provide quantities of
polypeptides of interest sufficient for presentation on WIC
molecules. In some embodiments, antigen presenting cells are
provided in an array, and are contacted with sets of library cells,
each set expressing a different polypeptide of interest. In certain
embodiments, each location in the array includes
1.times.10.sup.3-1.times.10.sup.6 antigen presenting cells, and the
cells are contacted with 1.times.10.sup.3-1.times.10.sup.8 library
cells which are bacterial cells.
[0209] In any of the embodiments described herein, antigen
presenting cells can be freshly isolated, maintained in culture,
and/or thawed from frozen storage prior to incubation with library
cells, or after incubation with library cells.
[0210] Human Lymphocytes
[0211] In methods of the present disclosure, human lymphocytes are
tested for antigen-specific reactivity to antigen presenting cells,
e.g., antigen presenting cells that have been incubated with
libraries expressing polypeptides of interest as described above.
The methods of the present disclosure permit rapid identification
of human antigens using pools of lymphocytes isolated from an
individual, or progeny of the cells. The detection of
antigen-specific responses does not rely on laborious procedures to
isolate individual T cell clones. In some embodiments, the human
lymphocytes are primary lymphocytes. In some embodiments, human
lymphocytes are NKT cells, gamma-delta T cells, or NK cells. Just
as antigen presenting cells may be separated into subsets prior to
use in antigen presentation assays, a population of lymphocytes
having a specific marker or other feature can be used. In some
embodiments, a population of T lymphocytes is isolated. In some
embodiments, a population of CD4.sup.+ T cells is isolated. In some
embodiments, a population of CD8.sup.+ T cells is isolated.
CD8.sup.+ T cells recognize peptide antigens presented in the
context of MHC class I molecules. Thus, in some embodiments, the
CD8.sup.+ T cells are used with antigen presenting cells that have
been exposed to library host cells that co-express a cytolysin
polypeptide, in addition to a polypeptide of interest. T cell
subsets that express other cell surface markers may also be
isolated, e.g., to provide cells having a particular phenotype.
These include CLA (for skin-homing T cells), CD25, CD30, CD69,
CD154 (for activated T cells), CD45RO (for memory T cells), CD294
(for Th2 cells), .gamma./.delta. TCR-expressing cells, CD3 and CD56
(for NK T cells). Other subsets can also be selected.
[0212] Lymphocytes can be isolated, and separated, by any means
known in the art (e.g., using antibody-based methods such as those
that employ magnetic bead separation, panning, or flow cytometry).
Reagents to identify and isolate human lymphocytes and subsets
thereof are well known and commercially available.
[0213] Lymphocytes for use in methods described herein can be
isolated from peripheral blood mononuclear cells, or from other
tissues in a human. In some embodiments, lymphocytes are taken from
tumors, lymph nodes, a mucosal tissue (e.g., nose, mouth, bronchial
tissue, tracheal tissue, the gastrointestinal tract, the genital
tract (e.g., vaginal tissue), or associated lymphoid tissue),
peritoneal cavity, spleen, thymus, lung, liver, kidney, neuronal
tissue, endocrine tissue, peritoneal cavity, bone marrow, or other
tissues. In some embodiments, cells are taken from a tissue that is
the site of an active immune response (e.g., an ulcer, sore, or
abscess). Cells may be isolated from tissue removed surgically, via
lavage, or other means.
[0214] Lymphocytes taken from an individual can be maintained in
culture or frozen until use in antigen presentation assays. In some
embodiments, freshly isolated lymphocytes can be stimulated in
vitro by antigen presenting cells exposed to library cells as
described above. In some embodiments, these lymphocytes exhibit
detectable stimulation without the need for prior non-antigen
specific expansion. However, primary lymphocytes also elicit
detectable antigen-specific responses when first stimulated
non-specifically in vitro. Thus, in some embodiments, lymphocytes
are stimulated to proliferate in vitro in a non-antigen specific
manner, prior to use in an antigen presentation assay. Lymphocytes
can also be stimulated in an antigen-specific manner prior to use
in an antigen presentation assay. In some embodiments, cells are
stimulated to proliferate by a library (e.g., prior to use in an
antigen presentation assay that employs the library). Expanding
cells in vitro provides greater numbers of cells for use in assays.
Primary T cells can be stimulated to expand, e.g., by exposure to a
polyclonal T cell mitogen, such as phytohemagglutinin or
concanavalin, by treatment with antibodies that stimulate
proliferation, or by treatment with particles coated with the
antibodies. In some embodiments, T cells are expanded by treatment
with anti-CD2, anti-CD3, and anti-CD28 antibodies. In some
embodiments, T cells are expanded by treatment with interleukin-2.
In some embodiments, lymphocytes are thawed from frozen storage and
expanded (e.g., stimulated to proliferate, e.g., in a non-antigen
specific manner or in an antigen-specific manner) prior to
contacting with antigen presenting cells. In some embodiments,
lymphocytes are thawed from frozen storage and are not expanded
prior to contacting with antigen presenting cells. In some
embodiments, lymphocytes are freshly isolated and expanded (e.g.,
stimulated to proliferate, e.g., in a non-antigen specific manner
or in an antigen-specific manner) prior to contacting with antigen
presenting cells.
[0215] Antigen Presentation Assays
[0216] In antigen presentation assays, T cells are cultured with
antigen presenting cells prepared according to the methods
described above, under conditions that permit T cell recognition of
peptides presented by MHC molecules on the antigen presenting
cells. In some embodiments, T cells are incubated with antigen
presenting cells at 37.degree. C. for between 12-48 hours (e.g.,
for 24 hours). In some embodiments, T cells are incubated with
antigen presenting cells at 37.degree. C. for 3, 4, 5, 6, 7, or 8
days. Numbers of antigen presenting cells and T cells can be
varied. In some embodiments, the ratio of T cells to antigen
presenting cells in a given assay is 1:10, 1:5, 1:2, 1:1, 2:1, 5:1,
10:1, 20:1, 25:1, 30:1, 32:1, 35:1 or 40:1. In some embodiments,
antigen presenting cells are provided in an array (e.g., in a
96-well plate), wherein cells in each location of the array have
been contacted with sets of library cells, each set including a
different polypeptide of interest. In certain embodiments, each
location in the array includes 1.times.10.sup.3-1.times.10.sup.6
antigen presenting cells, and the cells are contacted with
1.times.10.sup.3-1.times.10.sup.6 T cells.
[0217] After T cells have been incubated with antigen presenting
cells, cultures are assayed for activation. Lymphocyte activation
can be detected by any means known in the art, e.g., T cell
proliferation, phosphorylation or dephosphorylation of a receptor,
calcium flux, cytoskeletal rearrangement, increased or decreased
expression and/or secretion of immune mediators such as cytokines
or soluble mediators, increased or decreased expression of one or
more cell surface markers. In some embodiments, culture
supernatants are harvested and assayed for increased and/or
decreased expression and/or secretion of one or more polypeptides
associated with activation, e.g., a cytokine, soluble mediator,
cell surface marker, or other immune mediator. In some embodiments,
the one or more cytokines are selected from TRAIL, IFN-gamma,
IL-12p'70, IL-2, TNF-alpha, MIP1-alpha, MIP1-beta, CXCL9, CXCL10,
MCP1, RANTES, IL-1 beta, IL-4, IL-6, IL-8, IL-9, IL-10, IL-13,
IL-15, CXCL11, IL-3, IL-5, IL-17, IL-18, IL-21, IL-22, IL-23A,
IL-24, IL-27, IL-31, IL-32, TGF-beta, CSF, GM-CSF, TRANCE (also
known as RANK L), MIP3-alpha, and fractalkine. In some embodiments,
the one or more soluble mediators are selected from granzyme A,
granzyme B, sFas, sFasL, perforin, and granulysin. In some
embodiments, the one or more cell surface markers are selected from
CD107a, CD107b, CD25, CD69, CD45RA, CD45RO, CD137 (4-1BB), CD44,
CD62L, CD27, CCR7, CD154 (CD40L), KLRG-1, CD71, HLA-DR, CD122
(IL-2RB), CD28, IL7Ra (CD127), CD38, CD26, CD134 (OX-40), CTLA-4
(CD152), LAG-3, TIM-3 (CD366), CD39, PD1 (CD279), FoxP3, TIGIT,
CD160, BTLA, 2B4 (CD244), and KLRG1. Cytokine secretion in culture
supernatants can be detected, e.g., by ELISA, bead array, e.g.,
with a Luminex.RTM. analyzer. Cytokine production can also be
assayed by RT-PCR of mRNA isolated from the T cells, or by ELISPOT
analysis of cytokines released by the T cells. In some embodiments,
proliferation of T cells in the cultures is determined (e.g., by
detecting .sup.3H thymidine incorporation). In some embodiments,
target cell lysis is determined (e.g., by detecting T cell
dependent lysis of antigen presenting cells labeled with Na.sub.2
.sup.51CrO.sub.4). Target cell lysis assays are typically performed
with CD8.sup.+ T cells. Protocols for these detection methods are
known. See, e.g., Current Protocols In Immunology, John E. Coligan
et al. (eds), Wiley and Sons, New York, N.Y., 2007. One of skill in
the art understands that appropriate controls are used in these
detection methods, e.g., to adjust for non-antigen specific
background activation, to confirm the presenting capacity of
antigen presenting cells, and to confirm the viability of
lymphocytes.
[0218] In some embodiments, antigen presenting cells and
lymphocytes used in the method are from the same individual. In
some embodiments, antigen presenting cells and lymphocytes used in
the method are from different individuals.
[0219] In some embodiments, antigen presentation assays are
repeated using lymphocytes from the same individual that have
undergone one or more previous rounds of exposure to antigen
presenting cells, e.g., to enhance detection of responses, or to
enhance weak initial responses. In some embodiments, antigen
presentation assays are repeated using antigen presenting cells
from the same individual that have undergone one or more previous
rounds of exposure to a library, e.g., to enhance detection of
responses, or to enhance weak initial responses. In some
embodiments, antigen presentation assays are repeated using
lymphocytes from the same individual that have undergone one or
more previous rounds of exposure to antigen presenting cells, and
antigen presenting cells from the same individual that have
undergone one or more previous rounds of exposure to a library,
e.g., to enhance detection of responses, or to enhance weak initial
responses. In some embodiments, antigen presentation assays are
repeated using antigen presenting cells and lymphocytes from
different individuals, e.g., to identify antigens recognized by
multiple individuals, or compare reactivities that differ between
individuals.
Methods of Identifying Tumor Antigens
[0220] One advantage of methods described herein is their ability
to identify clinically relevant human antigens. Humans that have
cancer may have lymphocytes that specifically recognize tumor
antigens, which are the product of an adaptive immune response
arising from prior exposure. In some embodiments, these cells are
present at a higher frequency than cells from an individual who
does not have cancer, and/or the cells are readily reactivated when
re-exposed to the proper antigenic stimulus (e.g., the cells are
"memory" cells). Thus, humans that have or have had cancer are
particularly useful donors of cells for identifying antigens in
vitro. The individual may be one who has recovered from cancer. In
some embodiments, the individual has been recently diagnosed with
cancer (e.g., the individual was diagnosed less than one year,
three months, two months, one month, or two weeks, prior to
isolation of lymphocytes and/or antigen presenting cells from the
individual). In some embodiments, the individual was first
diagnosed with cancer more than three months, six months, or one
year prior to isolation of lymphocytes and/or antigen presenting
cells.
[0221] In some embodiments, lymphocytes are screened against
antigen presenting cells that have been contacted with a library of
cells whose members express or carry polypeptides of interest, and
the lymphocytes are from an individual who has not been diagnosed
with cancer. In some embodiments, such lymphocytes are used to
determine background (i.e., non-antigen-specific) reactivities. In
some embodiments, such lymphocytes are used to identify antigens,
reactivity to which exists in non-cancer individuals.
[0222] Cells from multiple donors (e.g., multiple subjects who have
cancer) can be collected and assayed in methods described herein.
In some embodiments, cells from multiple donors are assayed in
order to determine if a given tumor antigen is reactive in a broad
portion of the population, or to identify multiple tumor antigens
that can be later combined to produce an immunogenic composition
that will be effective in a broad portion of the population.
[0223] Antigen presentation assays are useful in the context of
both infectious and non-infectious diseases. The methods described
herein are applicable to any context in which a rapid evaluation of
human cellular immunity is beneficial. In some embodiments,
antigenic reactivity to polypeptides that are differentially
expressed by neoplastic cells (e.g., tumor cells) is evaluated.
Sets of nucleic acids differentially expressed by neoplastic cells
have been identified using established techniques such as
subtractive hybridization. Methods described herein can be used to
identify antigens that were functional in a subject in which an
anti-tumor immune response occurred. In other embodiments, methods
are used to evaluate whether a subject has lymphocytes that react
to a tumor antigen or set of tumor antigens.
[0224] In some embodiments, antigen presentation assays are used to
examine reactivity to autoantigens in cells of an individual, e.g.,
an individual predisposed to, or suffering from, an autoimmune
condition. Such methods can be used to provide diagnostic or
prognostic indicators of the individual's disease state, or to
identify autoantigens. For these assays, in some embodiments,
libraries that include an array of human polypeptides are prepared.
In some embodiments, libraries that include polypeptides from
infectious agents which are suspected of eliciting cross-reactive
responses to autoantigens are prepared. For examples of antigens
from infectious agents thought to elicit cross-reactive autoimmune
responses, see Barzilai et al., Curr Opin Rheumatol., 19(6):636-43,
2007; Ayada et al., Ann NY Acad Sci., 1108:594-602, 2007; Drouin et
al., Mol Immunol., 45(1):180-9, 2008; and Bach, J Autoimmun., 25
Supp1:74-80, 2005.
[0225] As discussed, the present disclosure includes methods in
which polypeptides of interest are included in a library (e.g.,
expressed in library cells or carried in or on particles or beads).
After members of the library are internalized by antigen presenting
cells, the polypeptides of interest are proteolytically processed
within the antigen presenting cells, and peptide fragments of the
polypeptides are presented on MEW molecules expressed in the
antigen presenting cells. The identity of the polypeptide that
stimulates a human lymphocyte in an assay described herein can be
determined from examination of the set of library cells that were
provided to the antigen presenting cells that produced the
stimulation. In some embodiments, it is useful to map the epitope
within the polypeptide that is bound by MEW molecules to produce
the observed stimulation. This epitope, or the longer polypeptide
from which it is derived (both of which are referred to as an
"antigen" herein) can form the basis for an immunogenic
composition, or for an antigenic stimulus in future antigen
presentation assays.
[0226] Methods for identifying peptides bound by MEW molecules are
known. In some embodiments, epitopes are identified by generating
deletion mutants of the polypeptide of interest and testing these
for the ability to stimulate lymphocytes. Deletions that lose the
ability to stimulate lymphocytes, when processed and presented by
antigen presenting cells, have lost the peptide epitope. In some
embodiments, epitopes are identified by synthesizing peptides
corresponding to portions of the polypeptide of interest and
testing the peptides for the ability to stimulate lymphocytes
(e.g., in antigen presentation assays in which antigen presenting
cells are pulsed with the peptides). Other methods for identifying
MEW bound peptides involve lysis of the antigen presenting cells
that include the antigenic peptide, affinity purification of the
MEW molecules from cell lysates, and subsequent elution and
analysis of peptides from the MHC (Falk, K. et al. Nature 351:290,
1991, and U.S. Pat. No. 5,989,565).
[0227] In other embodiments, it is useful to identify the clonal T
cell receptors that have been expanded in response to the antigen.
Clonal T cell receptors are identified by DNA sequencing of the T
cell receptor repertoire (Howie et al, 2015 Sci Trans Med 7:301).
By identifying TCR specificity and function, TCRs can be
transfected into other cell types and used in functional studies or
for novel immunotherapies.
In other embodiments, it is useful to identify and isolate T cells
responsive to a tumor antigen in a subject. The isolated T cells
can be expanded ex vivo and administered to a subject for cancer
therapy or prophylaxis.
Methods of Identifying Immune Responses of a Subject
[0228] The disclosure provides methods of identifying one or more
immune responses of a subject (e.g., a test subject, or a target
subject). In some embodiments, one or more immune responses of a
subject (e.g., a test subject or a target subject) are determined
by a) providing a library described herein that includes a panel of
tumor antigens (e.g., known tumor antigens, tumor antigens
described herein, or tumor antigens, potential tumor antigens,
and/or other polypeptides of interest identified using a method
described herein); b) contacting the library with antigen
presenting cells from the subject; c) contacting the antigen
presenting cells with lymphocytes from the subject; and d)
determining whether one or more lymphocytes are stimulated by,
inhibited and/or suppressed by, activated by, or non-responsive to
one or more tumor antigens presented by one or more antigen
presenting cells. In some embodiments, the library includes about
1, 3, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, or more
tumor antigens.
[0229] In some embodiments, a test subject is (i) a cancer subject
who has not received a cancer therapy; (ii) a cancer subject who
has not responded and/or is not responding and/or has responded
negatively, clinically to a cancer therapy; or (iii) a subject who
has not been diagnosed with a cancer.
[0230] In some embodiments, a target subject is (i) a cancer
subject who responds or has responded positively clinically
("responsive subject") to a cancer therapy; (ii) a cancer subject
who has not responded and/or is not responding and/or has responded
negatively, clinically ("non-responsive subject") to a cancer
therapy; (iii) a cancer subject who responds or has responded
spontaneously to a cancer ("spontaneous target subject"); or (vi) a
subject who has not been diagnosed with a cancer ("normal
subject").
[0231] In some embodiments, lymphocyte stimulation,
non-stimulation, inhibition and/or suppression, activation, and/or
non-responsiveness is determined by assessing levels of one or more
expressed or secreted cytokines or other immune mediators described
herein. In some embodiments, levels of one or more expressed or
secreted cytokines that is at least 20%, 40%, 60%, 80%, 100%, 120%,
140%, 160%, 180%, 200% or more, higher than a control level
indicates lymphocyte stimulation. In some embodiments, a level of
one or more expressed or secreted cytokines that is at least 1, 2,
3, 4 or 5 standard deviations greater than the mean of a control
level indicates lymphocyte stimulation. In some embodiments, a
level of one or more expressed or secreted cytokines that is at
least 1, 2, 3, 4 or 5 median absolute deviations (MADs) greater
than a median response level to a control indicates lymphocyte
stimulation. In some embodiments, a control is a negative control,
for example, a clone expressing Neon Green (NG). In some
embodiments, a level of one or more expressed or secreted cytokines
that is at least 20%, 40%, 60%, 80%, 100%, 120%, 140%, 160%, 180%,
200% or more, lower than a control level indicates lymphocyte
inhibition and/or suppression. In some embodiments, a level of one
or more expressed or secreted cytokines that is at least 1, 2, 3, 4
or 5 standard deviations lower than the mean of a control level
indicates lymphocyte inhibition and/or suppression. In some
embodiments, a level of one or more expressed or secreted cytokines
that is at least 1, 2, 3, 4 or 5 median absolute deviations (MADs)
lower than a median response level to a control indicates
lymphocyte inhibition and/or suppression. In some embodiments, a
control is a negative control, for example, a clone expressing Neon
Green (NG). In some embodiments, levels of one or more expressed or
secreted cytokines that is at least 20%, 40%, 60%, 80%, 100%, 120%,
140%, 160%, 180%, 200% or more, higher or lower than a control
level indicates lymphocyte activation. In some embodiments, a level
of one or more expressed or secreted cytokines that is at least 1,
2, 3, 4 or 5 standard deviations greater or lower than the mean of
a control level indicates lymphocyte activation. In some
embodiments, a level of one or more expressed or secreted cytokines
that is at least 1, 2, 3, 4 or 5 median absolute deviations (MADs)
greater or lower than a median response level to a control
indicates lymphocyte activation. In some embodiments, a control is
a negative control, for example, a clone expressing Neon Green
(NG). In some embodiments, a level of one or more expressed or
secreted cytokines that is within about 20%, 15%, 10%, 5%, or less,
of a control level indicates lymphocyte non-responsiveness or
non-stimulation. In some embodiments, a level of one or more
expressed or secreted cytokines that is less than 1 or 2 standard
deviations higher or lower than the mean of a control level
indicates lymphocyte non-responsiveness or non-stimulation. In some
embodiments, a level of one or more expressed or secreted cytokines
that is less than 1 or 2 median absolute deviations (MADs) higher
or lower than a median response level to a control indicates
lymphocyte non-responsiveness or non-stimulation. In some
embodiments, a subject response profile can include a
quantification, identification, and/or representation of a panel of
different cytokines (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14,
16, 18, 20, or more cytokines) and of the total number of tumor
antigens (e.g., of all or a portion of different tumor antigens
from the library) that stimulate, do not stimulate, inhibit and/or
suppress, activate, or have no or minimal effect on production,
expression or secretion of each member of the panel of
cytokines.
Method of Obtaining a Subject Response Profile
[0232] The disclosure provides methods for obtaining a subject
response profile from a test subject (a "subject response
profile").
[0233] In some embodiments, the subject response profile of a test
subject is obtained by a) providing a library described herein that
includes a panel of tumor antigens (e.g., known tumor antigens,
tumor antigens described herein, or tumor antigens, potential tumor
antigens, and/or other polypeptides of interest identified using a
method described herein); b) contacting the library with antigen
presenting cells from the test subject; c) contacting the antigen
presenting cells with lymphocytes from the test subject; and d)
determining whether one or more lymphocytes are stimulated by,
inhibited and/or suppressed by, activated by, or non-responsive to
one or more tumor antigens presented by one or more antigen
presenting cells, to obtain the subject response profile. In some
embodiments, the library includes about 1, 3, 5, 10, 15, 20, 25,
30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 500, 1000, or more
tumor antigens.
[0234] The subject response profile can include a quantification,
identification, and/or representation of all or a portion of the
panel of tumor antigens, identified by the methods of the
disclosure, that stimulate lymphocytes, that do not stimulate
lymphocytes, that inhibit and/or suppress lymphocytes, that
activate lymphocytes, or to which lymphocytes are non-responsive.
In some embodiments, the subject response profile further includes
a quantification, identification, and/or representation of the
level of expression or secretion of one or more immune mediators,
e.g., one or more cytokines.
[0235] In some embodiments, the subject response profile includes a
quantification, identification, and/or representation of all or a
portion of the panel of tumor antigens, identified by the methods
of the disclosure, that stimulate expression or secretion of one or
more immune mediators, that inhibit and/or suppress expression or
secretion of one or more immune mediators, and/or which do not, or
minimally, affect expression or secretion of immune mediators. In
some embodiments, the subject response profile further includes a
quantification, identification, and/or representation of the level
of expression or secretion of one or more immune mediators, e.g.,
one or more cytokines.
Methods of Obtaining a Target Response Profile
[0236] In some embodiments, a subject response profile is compared
to a corresponding response profile from a target subject, e.g. a
cancer subject who responds and/or has responded clinically to a
cancer therapy; a cancer subject who does not and/or has not
responded clinically to a cancer therapy; a subject who has, or has
had, spontaneous response to a cancer; or a subject who has not
been diagnosed with a cancer (a "target response profile" of a
target subject).
[0237] The disclosure provides methods for obtaining a target
response profile from a target subject. The target response profile
of a target subject is obtained by a) providing a library described
herein that includes all or a portion of the same panel of tumor
antigens (e.g., known tumor antigens, tumor antigens described
herein, or tumor antigens, potential tumor antigens, and/or other
polypeptides of interest identified using a method described
herein) used to generate the subject response profile; b)
contacting the library with antigen presenting cells from the
target subject; c) contacting the antigen presenting cells with
lymphocytes from the target subject; and d) determining whether one
or more lymphocytes are stimulated by, inhibited and/or suppressed
by, activated by, or non-responsive to, one or more tumor antigens
presented by one or more antigen presenting cells, to obtain the
target response profile.
[0238] The target response profile includes a quantification,
identification, and/or representation of the immune response of
cells from the target subject to the same panel of tumor antigens
included in the subject response profile.
[0239] In some embodiments, the target response profile includes a
quantification, identification, and/or representation of all or a
portion of the panel of tumor antigens that stimulate lymphocytes,
that do not stimulate lymphocytes, that inhibit and/or suppress
lymphocytes, that activate lymphocytes, and/or to which lymphocytes
are non-responsive. In some embodiments, the subject response
profile further includes a quantification, identification, and/or
representation of the level of expression or secretion of one or
more immune mediators, e.g., one or more cytokines.
[0240] In some embodiments, the target response profile includes a
quantification, identification, and/or representation of all or a
portion of the panel of tumor antigens identified by the methods of
the disclosure, that stimulate expression and/or secretion of one
or more immune mediators, that inhibit and/or suppress expression
or secretion of one or more immune mediators, and/or which do not,
or minimally, affect expression and/or secretion of immune
mediators. In some embodiments, the subject response profile
further includes a quantification, identification, and/or
representation of the level of expression or secretion of one or
more immune mediators, e.g., one or more cytokines.
Comparison of a Subject Response Profile to a Target Response
Profile
Lymphocytes
[0241] In some embodiments, a subject response profile is similar
to the target response profile if the identified tumor antigens
that stimulate lymphocytes in the subject response profile differ
by no more than 1, 2, 3, 4, 5, 10, 15, 20, or 25 from the
identified tumor antigens that stimulate lymphocytes in the target
response profile; if the identified tumor antigens that do not
stimulate lymphocytes in the subject response profile differ by no
more than 1, 2, 3, 4, 5, 10, 15, 20, or 25 from the identified
tumor antigens that do not stimulate lymphocytes in the target
response profile; if the identified tumor antigens that inhibit
and/or suppress lymphocytes in the subject response profile differ
by no more than 1, 2, 3, 4, 5, 10, 15, 20, or 25 from the
identified tumor antigens that inhibit and/or suppress lymphocytes
in the target response profile; if the identified tumor antigens
that activate lymphocytes in the subject response profile differ by
no more than 1, 2, 3, 4, 5, 10, 15, 20, or 25 from the identified
tumor antigens that activate lymphocytes in the target response
profile; and/or if the identified tumor antigens that do not
stimulate lymphocytes or to which lymphocytes are non-responsive in
the subject response profile differ by no more than 1, 2, 3, 4, 5,
10, 15, 20, or 25 from the identified tumor antigens to which
lymphocytes are not, or are minimally, responsive in the target
response profile.
[0242] In some embodiments, a subject response profile is
dissimilar from the target response profile if the identified tumor
antigens that stimulate lymphocytes in the subject response profile
differ by more than 5, 6, 7, 8, 9, 10, 20, or more, from the
identified tumor antigens that stimulate lymphocytes in the target
response profile; if the identified tumor antigens that do not
stimulate lymphocytes in the subject response profile differ by
more than 5, 6, 7, 8, 9, 10, 20, or more, from the identified tumor
antigens that do not stimulate lymphocytes in the target response
profile; if the identified tumor antigens that inhibit and/or
suppress lymphocytes in the subject response profile differ by more
than 5, 6, 7, 8, 9, 10, 20, or more, from the identified tumor
antigens that inhibit and/or suppress lymphocytes in the target
response profile; if the identified tumor antigens that activate
lymphocytes in the subject response profile differ by more than 5,
6, 7, 8, 9, 10, 20, or more, from the identified tumor antigens
that activate lymphocytes in the target response profile; and/or if
the identified tumor antigens that do not stimulate lymphocytes or
to which lymphocytes are non-responsive in the subject response
profile differ by more than 5, 6, 7, 8, 9, 10, 20, or more, from
the identified tumor antigens to which lymphocytes are not, or are
minimally, responsive in the target response profile.
[0243] In some embodiments, a subject response profile is similar
to the target response profile if the identified tumor antigens
that stimulate lymphocytes in the subject response profile differ
by no more than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, or 25% from the
identified tumor antigens that stimulate lymphocytes in the target
response profile; if the identified tumor antigens that do not
stimulate lymphocytes in the subject response profile differ by no
more than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, or 25% from the
identified tumor antigens that do not stimulate lymphocytes in the
target response profile; if the identified tumor antigens that
inhibit and/or suppress lymphocytes in the subject response profile
differ by no more than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, or 25%
from the identified tumor antigens that inhibit and/or suppress
lymphocytes in the target response profile; if the identified tumor
antigens that activate lymphocytes in the subject response profile
differ by no more than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, or 25%
from the identified tumor antigens that activate lymphocytes in the
target response profile; and/or if the identified tumor antigens
that do not stimulate lymphocytes or to which lymphocytes are
non-responsive in the subject response profile differ by no more
than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, or 25% from the identified
tumor antigens to which lymphocytes are not, or are minimally,
responsive in the target response profile.
[0244] In some embodiments, a subject response profile is
dissimilar from the target response profile if the identified tumor
antigens that stimulate lymphocytes in the subject response profile
differ by more than 5%, 6%, 7%, 8%, 9%, 10%, 20%, or more, from the
identified tumor antigens that stimulate lymphocytes in the target
response profile if the identified tumor antigens that do not
stimulate lymphocytes in the subject response profile differ by
more than 5%, 6%, 7%, 8%, 9%, 10%, 20%,or more, from the identified
tumor antigens that do not stimulate lymphocytes in the target
response profile; and/or if the identified tumor antigens that
inhibit and/or suppress lymphocytes in the subject response profile
differ by more than 5%, 6%, 7%, 8%, 9%, 10%, 20%, or more, from the
identified tumor antigens that inhibit and/or suppress lymphocytes
in the target response profile; if the identified tumor antigens
that activate lymphocytes in the subject response profile differ by
more than 5%, 6%, 7%, 8%, 9%, 10%, 20%, or more, from the
identified tumor antigens that activate lymphocytes in the target
response profile; and/or if the identified tumor antigens that do
not stimulate lymphocytes or to which lymphocytes are
non-responsive in the subject response profile differ by more than
5%, 6%, 7%, 8%, 9%, 10%, 20%, or more, from the identified tumor
antigens to which lymphocytes are not, or are minimally, responsive
in the target response profile.
Cytokines
[0245] In some embodiments, the target response profile can include
a quantification, identification, and/or representation of one or
more cytokines and the total number of tumor antigens (e.g., of the
same tumor antigens included in the subject response profile) that
stimulate, do not stimulate, inhibit and/or suppress, or have no or
minimal effect on cytokine production, expression and/or secretion.
In some embodiments, the target response profile can include a
quantification, identification, and/or representation of a panel of
different cytokines (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14,
16, 18, 20, or more (e.g., all) of the cytokines included in the
subject response profile) and the total number of tumor antigens
(e.g., of the same tumor antigens included in the subject response
profile) that stimulate, do not stimulate, inhibit and/or suppress,
or have no or minimal effect on production, expression and/or
secretion of the panel of cytokines.
[0246] In some embodiments, a subject response profile is similar
to the target response profile if the total number of antigens that
stimulate expression and/or secretion of one or more cytokines
included in the subject response profile differs by no more than 1,
2, 3, 4, 5, 10, 15, 20, or 25 from the total number of antigens
that stimulate the same one or more cytokines included in the
target response profile; if the total number of antigens that do
not stimulate expression and/or secretion of one or more cytokines
included in the subject response profile differs by no more than 1,
2, 3, 4, 5, 10, 15, 20, or 25 from the total number of antigens
that do not stimulate the same one or more cytokines included in
the target response profile; if the total number of antigens that
inhibit and/or suppress one or more cytokines included in the
subject response profile differs by no more than 1, 2, 3, 4, 5, 10,
15, 20, or 25 from the total number of antigens that inhibit and/or
suppress expression and/or secretion of the same one or more
cytokines included in the target response profile; and/or if the
total number of antigens that have no or minimal effect on
expression and/or secretion of one or more cytokines included in
the subject response profile differs by no more than 1, 2, 3, 4, 5,
10, 15, 20, or 25 from the total number of antigens that that have
no or minimal effect on the same one or more cytokines included in
the target response profile.
[0247] In some embodiments, a subject response profile is
dissimilar from the target response profile if the total number of
antigens that stimulate expression and/or secretion of one or more
cytokines included in the subject response profile differs by more
than 5, 6, 7, 8, 9, 10, 20, or more, from the total number of
antigens that stimulate the same one or more cytokines included in
the target response profile; if the total number of antigens that
do not stimulate expression and/or secretion of one or more
cytokines included in the subject response profile differs by more
than 5, 6, 7, 8, 9, 10, 20, or more, from the total number of
antigens that do not stimulate the same one or more cytokines
included in the target response profile; if the total number of
antigens that inhibit and/or suppress expression and/or secretion
of one or more cytokines included in the subject response profile
differs by more than 5, 6, 7, 8, 9, 10, 20, or more, from the total
number of antigens that inhibit and/or suppress the same one or
more cytokines included in the target response profile; and/or if
the total number of antigens that have no or minimal effect on
expression and/or secretion of one or more cytokines included in
the subject response profile differs by more than 5, 6, 7, 8, 9,
10, 20, or more, from the total number of antigens that that have
no or minimal effect on the same one or more cytokines included in
the target response profile.
[0248] The foregoing methods apply to subject response profiles and
target response profiles obtained with libraries encoding
polypeptides that are potential tumor antigens, as well as tumor
antigens.
Methods of Identifying/Selecting Subjects for Cancer Therapy
[0249] The disclosure provides methods of identifying a test
subject, e.g., a cancer subject, for initiation, continuation,
modification, and/or discontinuation or in some cases
non-initiation of a cancer therapy (e.g., a cancer therapy
described herein). Generally, such methods include comparing one or
more immune responses of a cancer subject who has not received a
cancer therapy (or who has not responded and/or is not responding
and/or has responded negatively, clinically to a cancer therapy) to
one or more immune responses of a target subject, who may be: (i) a
cancer subject who responds or has responded positively clinically
("responsive subject") to the cancer therapy; (ii) a cancer subject
who has not responded and/or is not responding and/or has responded
negatively, clinically ("non-responsive subject") to the cancer
therapy; (iii) a cancer subject who responds or has responded
spontaneously to a cancer ("spontaneous subject"); and/or (vi) a
subject who has not been diagnosed with a cancer ("normal
subject").
[0250] One or more immune responses of the test subject that are
the same or similar to one or more immune responses of a responsive
subject and/or dissimilar to one or more immune responses of a
non-responsive subject indicates that the test subject should
initiate and/or continue and/or modify (e.g., increase and/or
combine with one or more other modalities) the cancer therapy. One
or more immune responses of the test subject that are dissimilar to
one or more immune responses of a responsive subject and/or similar
to (or same as) one or more immune responses of a non-responsive
subject indicates that the cancer subject should not initiate
and/or should discontinue and/or should modify (e.g., reduce and/or
combine with one or more other modalities) the cancer therapy,
and/or should initiate an alternative cancer therapy, or in some
cases, no cancer therapy.
[0251] In some embodiments, a subject response profile that is
similar to a target response profile (of a responsive subject)
indicates the test subject should initiate and/or continue and/or
modify (e.g., increase and/or combine with one or more other
modalities) the cancer therapy. In some embodiments, methods
described herein include selecting a test subject for initiation
and/or continuation and/or modification (e.g., increase and/or
combine with one or more other modalities) of the cancer therapy if
the subject response profile is similar to a target response
profile (of a responsive subject). In some embodiments, methods
described herein include initiating and/or continuing and/or
modifying (e.g., increasing and/or combining with one or more other
modalities) administration of the cancer therapy to a test subject
if the subject response profile is similar to a target response
profile (of a responsive subject). In some embodiments, methods
described herein include administering the cancer therapy to a test
subject if the subject response profile is similar to a target
response profile (of a responsive subject). In some embodiments,
methods described herein include modifying (e.g., increasing and/or
combining with one or more other modalities) administration of the
cancer therapy to a test subject if the subject response profile is
similar to a target response profile (of a responsive subject).
[0252] In some embodiments, a subject response profile that is
dissimilar to a target response profile (of a responsive subject)
indicates the test subject should not initiate and/or should modify
(e.g., reduce and/or combine with one or more other modalities)
and/or should discontinue the cancer therapy, and/or should
initiate an alternative cancer therapy. In some embodiments,
methods described herein include not selecting a test subject for
initiation and/or selecting a test subject for modification (e.g.,
reduction and/or combination with one or more other modalities)
and/or discontinuation of the cancer therapy and/or initiation of
an alternative cancer therapy, if the subject response profile is
dissimilar to a target response profile (of a responsive subject).
In some embodiments, methods described herein include not
initiating and/or modifying (e.g., reducing and/or combining with
one or more other modalities) and/or discontinuing administration
of the cancer therapy to a test subject and/or initiation of an
alternative cancer therapy, if the subject response profile is
dissimilar to a target response profile (of a responsive subject).
In some embodiments, methods described herein include not
administering the cancer therapy to a test subject if the subject
response profile is dissimilar to a target response profile (of a
responsive subject). In some embodiments, methods described herein
include modifying (e.g., reducing and/or combining with one or more
other modalities) administration of the cancer therapy to a test
subject if the subject response profile is dissimilar to a target
response profile (of a responsive subject). In some embodiments,
methods described herein include administering an alternative
cancer therapy to a test subject if the subject response profile is
dissimilar to a target response profile (of a responsive
subject).
[0253] In some embodiments, a subject response profile is compared
to a corresponding response profile from a cancer subject who has
not responded and/or is not responding and/or responds negatively,
clinically to the cancer therapy (a "target response profile" of a
non-responsive subject). In some embodiments, the target response
profile (of a non-responsive subject) is obtained by providing a
library described herein that includes all or a portion of the same
panel of tumor antigens (e.g., known tumor antigens, tumor antigens
described herein or identified using a method described herein)
used to generate the subject response profile; contacting the
library with antigen presenting cells from the non-responsive
subject; contacting the antigen presenting cells with lymphocytes
from the non-responsive subject; and determining whether one or
more lymphocytes are stimulated, inhibited and/or suppressed by, or
non-responsive to, one or more tumor antigens presented by one or
more antigen presenting cells. The target response profile (of a
non-responsive subject) includes a quantification, identification,
and/or representation of the immune response of cells from the
non-responsive cancer subject to the same panel of tumor antigens
included in the subject response profile.
[0254] Methods for comparing a subject response profile to a target
response profile, and parameters for determining similarity and
dissimilarily of a subject response profile to a target response
profile are provided in the disclosure.
[0255] In some embodiments, the target response profile (of a
non-responsive subject) includes a quantification, identification,
and/or representation of all or a portion of the panel of tumor
antigens that stimulate lymphocytes, that do not stimulate
lymphocytes, and/or that inhibit and/or suppress lymphocytes. In
some embodiments, a subject response profile is similar to the
target response profile (of a nonresponsive subject) if the
identified tumor antigens that stimulate lymphocytes in the subject
response profile differ by no more than 1, 2, 3, 4, 5, 10, 15, 20,
or 25 from the identified tumor antigens that stimulate lymphocytes
in the target response profile (of a nonresponsive subject); if the
identified tumor antigens that do not stimulate lymphocytes in the
subject response profile differ by no more than 1, 2, 3, 4, 5, 10,
15, 20, or 25 from the identified tumor antigens that do not
stimulate lymphocytes in the target response profile (of a
nonresponsive subject); and/or if the identified tumor antigens
that inhibit and/or suppress lymphocytes in the subject response
profile differ by no more than 1, 2, 3, 4, 5, 10, 15, 20, or 25
from the identified tumor antigens that inhibit and/or suppress
lymphocytes in the target response profile (of a nonresponsive
subject). In some embodiments, a subject response profile is
dissimilar from the target response profile if the identified tumor
antigens that stimulate lymphocytes in the subject response profile
differ by more than 5, 6, 7, 8, 9, 10, 20, or more, from the
identified tumor antigens that stimulate lymphocytes in the target
response profile (of a nonresponsive subject); if the identified
tumor antigens that do not stimulate lymphocytes in the subject
response profile differ by more than 5, 6, 7, 8, 9, 10, 20, or
more, from the identified tumor antigens that do not stimulate
lymphocytes in the target response profile (of a nonresponsive
subject); and/or if the identified tumor antigens that inhibit
and/or suppress lymphocytes in the subject response profile differ
by more than 5, 6, 7, 8, 9, 10, 20, or more, from the identified
tumor antigens that inhibit and/or suppress lymphocytes in the
target response profile (of a nonresponsive subject). In some
embodiments, a subject response profile is similar to the target
response profile (of a nonresponsive subject) if the identified
tumor antigens that stimulate lymphocytes in the subject response
profile differ by no more than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%,
or 25% from the identified tumor antigens that stimulate
lymphocytes in the target response profile (of a nonresponsive
subject); if the identified tumor antigens that do not stimulate
lymphocytes in the subject response profile differ by no more than
1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, or 25% from the identified tumor
antigens that do not stimulate lymphocytesin the target response
profile (of a nonresponsive subject); and/or if the identified
tumor antigens that inhibit and/or suppress lymphocytes in the
subject response profile differ by no more than 1%, 2%, 3%, 4%, 5%,
10%, 15%, 20%, or 25% from the identified tumor antigens that
inhibit and/or suppress lymphocytes in the target response profile
(of a non-responsive subject). In some embodiments, a subject
response profile is dissimilar from the target response profile (of
a non-responsive subject) if the identified tumor antigens that
stimulate lymphocytes in the subject response profile differ by
more than 5%, 6%, 7%, 8%, 9%, 10%, 20%, or more, from the
identified tumor antigens that stimulate lymphocytes in the target
response profile (of a non-responsive subject); if the identified
tumor antigens that do not stimulate lymphocytes in the subject
response profile differ by more than 5%, 6%, 7%, 8%, 9%, 10%, 20%,
or more, from the identified tumor antigens that do not stimulate
lymphocytes in the target response profile (of a nonresponsive
subject); and/or if the identified tumor antigens that inhibit
and/or suppress lymphocytes in the subject response profile differ
by more than 5%, 6%, 7%, 8%, 9%, 10%, 20%, or more, from the
identified tumor antigens that inhibit and/or suppress lymphocytes
in the target response profile (of a non-responsive subject).
[0256] In some embodiments, the target response profile (of a
non-responsive subject) can include a quantification,
identification, and/or representation of one or more cytokines and
the total number of tumor antigens (e.g., of the same tumor
antigens included in the subject response profile) that stimulate,
do not stimulate, and/or inhibit and/or suppress cytokine
production, expression and/or secretion. In some embodiments, the
target response profile (of a nonresponsive subject) can include a
quantification, identification, and/or representation of a panel of
different cytokines (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14,
16, 18, 20, or more (e.g., all), of the cytokines included in the
subject response profile) and the total number of tumor antigens
(e.g., of the same tumor antigens included in the subject response
profile) that stimulate, do not stimulate, and/or inhibit and/or
suppress production, expression and/or secretion of the panel of
cytokines. In some embodiments, a subject response profile is
similar to the target response profile (of a nonresponsive subject)
if the total number of antigens that stimulate one or more
cytokines included in the subject response profile differs by no
more than 1, 2, 3, 4, 5, 10, 15, 20, or 25 from the total number of
antigens that stimulate the same one or more cytokines included in
the target response profile (of a non-responsive subject); if the
total number of antigens that do not stimulate one or more
cytokines included in the subject response profile differs by no
more than 1, 2, 3, 4, 5, 10, 15, 20, or 25 from the total number of
antigens that do not stimulate the same one or more cytokines
included in the target response profile (of a nonresponsive
subject); and/or if the total number of antigens that inhibit
and/or suppress one or more cytokines included in the subject
response profile differs by no more than 1, 2, 3, 4, 5,10, 15, 20,
or 25 from the total number of antigens that inhibit and/or
suppress the same one or more cytokines included in the target
response profile (of a non-responsive subject). In some
embodiments, a subject response profile is dissimilar from the
target response profile (of a non-responsive subject) if the total
number of antigens that stimulate one or more cytokines included in
the subject response profile differs by more than 5, 6, 7, 8, 9,
10, or more, from the total number of antigens that stimulate the
same one or more cytokines included in the target response profile
(of a non-responsive subject); if the total number of antigens that
not stimulate one or more cytokines included in the subject
response profile differs by more than 5, 6, 7, 8, 9, 10, or more,
from the total number of antigens that do not stimulate the same
one or more cytokines included in the target response profile (of a
non-responsive subject); and/or if the total number of antigens
that inhibit and/or suppress one or more cytokines included in the
subject response profile differs by more than 5, 6, 7, 8, 9, 10,
20, or more, from the total number of antigens that inhibit and/or
suppress the same one or more cytokines included in the target
response profile (of a non-responsive subject).
[0257] In some embodiments, a subject response profile that is
dissimilar to a target response profile (of a non-responsive
subject) indicates the test subject should initiate and/or continue
and/or modify (e.g., increase and/or combine with one or more other
modalities) the cancer therapy. In some embodiments, methods
described herein include selecting a test subject for initiation
and/or continuation and/or modification of (e.g., increasing and/or
combining with one or more other modalities) the cancer therapy if
the subject response profile is dissimilar to a target response
profile (of a non-responsive subject). In some embodiments, methods
described herein include initiating and/or continuing and/or
modifying (e.g., increasing and/or combining with one or more other
modalities) administration of the cancer therapy to a test subject
if the subject response profile is dissimilar to a target response
profile (of a non-responsive subject). In some embodiments, methods
described herein include administering the cancer therapy to a test
subject if the subject response profile is dissimilar to a target
response profile (of a non-responsive subject). In some
embodiments, methods described herein include modifying (e.g.,
increasing and/or combining with one or more other modalities)
administration of the cancer therapy to a test subject if the
subject response profile is dissimilar to a target response profile
(of a non-responsive subject).
[0258] In some embodiments, a subject response profile that is
similar to a target response profile (of a non-responsive subject)
indicates the test subject should not initiate, and/or should
modify (e.g., reduce and/or combine with one or more other
modalities), and/or should discontinue the cancer therapy, and/or
should initiate an alternative cancer therapy. In some embodiments,
methods described herein include not selecting a test subject for
initiation and/or selecting a test subject for modification (e.g.,
reduction and/or combination with one or more other modalities)
and/or discontinuation of the cancer therapy and/or initiation of
an alternative cancer therapy, if the subject response profile is
similar to a target response profile (of a non-responsive subject).
In some embodiments, methods described herein include not
initiating and/or modifying (e.g., reducing and/or combining with
one or more other modalities) and/or discontinuing administration
of the cancer therapy to a test subject and/or initiating an
alternative cancer therapy, if the subject response profile is
similar to a target response profile (of a non-responsive subject).
In some embodiments, methods described herein include not
administering the cancer therapy to a test subject if the subject
response profile is similar to a target response profile (of a
non-responsive subject). In some embodiments, methods described
herein include modifying (e.g., reducing and/or combining with one
or more other modalities) administration of the cancer therapy to a
test subject if the subject response profile is similar to a target
response profile (of a non-responsive subject). In some
embodiments, methods described herein include administering an
alternative cancer therapy to a test subject if the subject
response profile is similar to a target response profile (of a
non-responsive subject).
[0259] In some embodiments, a subject response profile described
herein is compared to one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, or more) target response profiles of one or more responsive
subjects and/or of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, or more) non-responsive subjects. In some embodiments, a target
response profile described herein (e.g., of a responsive subject or
non-responsive subject) includes an average of one or more immune
responses (described herein) from a population of responsive or
non-responsive subjects, respectively. In some embodiments, one or
more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) subject
response profiles of the test subject are obtained (e.g., before,
during, and/or after initiation, modification, and/or
discontinuation of administration of the cancer therapy).
Methods of Selecting Tumor Antigens and Methods of Inducing an
Immune Response in a Subject
[0260] In general, immune responses can be usefully defined in
terms of their integrated, functional end-effects. Dhabar et al.
(2014) have proposed that immune responses can be categorized as
being immunoprotective, immunopathological, and
immunoregulatory/inhibitory. While these categories provide useful
constructs with which to organize ideas, an overall in vivo immune
response is likely to consist of several types of responses with
varying amounts of dominance from each category. Immunoprotective
or beneficial responses are defined as responses that promote
efficient wound healing, eliminate infections and cancer, and
mediate vaccine-induced immunological memory. These responses are
associated with cytokines and mediators such as IFN-gamma, IL-12,
IL-2, Granzyme B, CD107, etc. Immunopathological or deleterious
responses are defined as those that are directed against self
(autoimmune disease like multiple sclerosis, arthritis, lupus) or
innocuous antigens (asthma, allergies) and responses involving
chronic, non-resolving inflammation. These responses can also be
associated with molecules that are implicated in immunoprotective
responses, but also include immune mediators such as TNF-alpha,
IL-10, IL-13, IL-17, IL-4, IgE, histamine, etc. Immunoregulatory
responses are defined as those that involve immune cells and
factors that regulate (mostly down-regulate) the function of other
immune cells. Recent studies suggest that there is an arm of the
immune system that functions to inhibit immune responses. For
example, regulatory CD4.sup.+CD25+FoxP3.sup.+ T cells, IL-10, and
TGF-beta, among others have been shown to have
immunoregulatory/inhibitory functions. The physiological function
of these factors is to keep pro-inflammatory, allergic, and
autoimmune responses in check, but they may also suppress
anti-tumor immunity and be indicative of negative prognosis for
cancer. In the context of tumors, the expression of co-stimulatory
molecules often decreases, and the expression of co-inhibitory
ligands increases. MEW molecules are often down-regulated on tumor
cells, favoring their escape. The tumor micro-environment,
including stromal cells, tumor associated immune cells, and other
cell types, produce many inhibitory factors, such as, IL-10,
TGF-.beta., and IDO. Inhibitory immune cells, including T regs, Tr1
cells, immature DCs (iDCs), pDCs, and MDSC can be found in the
tumor microenvironment. (Y Li UT GSBS Thesis 2016). Examples of
mediators and their immune effects are shown in Table 2.
TABLE-US-00002 TABLE 2 Immune Mediators Beneficial Outcomes
Deleterious Outcomes Cytokine Function Secreted by Cancer ID Al
Cancer ID Al TRAIL Induces apoptosis of Most cells X X ? X ? ?
tumor cells, induces immune suppressor cells IFN- Critical for
innate T cells, NK X X ? X ? X gamma and adaptive cells, NKT
immunity to cells pathogens, inhibits viral replication, increases
MHC Class I expression IL-12 Th1 differentiation; DCs, macro- X X ?
X ? X stimulates T cell phages, growth, induces IFN- neutron-
gamma/TNF-alpha phils secretion from T cells, enhances CTLs IL-2 T
cell proliferation, T cells, APCs X X X ? ? ? differentiation into
effector and memory T cells and regulatory T cells TNF- Induces
fevers, Macro- X X ? X ? X alpha apoptosis, phages, inflammation,
APCs inhibits viral replication MIP-1 Chemotactic/pro- Macro- X X ?
? ? X alpha inflammatory phages, DCs, effects, activates T cells
granulocytes, induces secretion of IL-1/IL6/TNF-alpha MIP-1
Chemotactic/pro- Macro- X X ? ? ? X beta inflammatory phages, DCs,
effects, activates T cells granulocytes, induces secretion of
IL-1/IL6/TNF-alpha CXCL9 T cell APCs X X ? X ? X chemoattractant,
induced by IFN-gamma CXCL10 Chemoattractant for APCs X X ? ? ? X T
cells, macrophages, NK and DCs, promotes T cell adhesion to
endothelial cells MCP-1 Recruits monocytes, most cells X X ? X ? X
memory T cells and DCS RANTES Recruits T cells, T cells X X ? ? ? X
eosinophils, basophils, induces proliferation/activation of NK
cells, T cell activation marker CXCL11 Chemoattractant for APCs X X
? ? ? X activated T cells IL-3 Stimulates T cells, APCs X X ? ? ? ?
proliferation of myeloid cells, induces growth of T cells IL-17I
Produced by Th17 T cells X X ? X ? X cells, induces production of
IL6, GCSF, GMCSF, IL1b, TGF-beta, TNF-alpha, chemokines IL-18
Pro-inflammatory, Macro- X X ? X ? X induces cell- phages mediated
immunity, production of IFN- gamma IL-21 Induces CD4 T cells X X X
X ? ? proliferation, upregulated in Th2/Th17 TFh IL-22
Cell-mediated NK cells, T X X ? X ? X immunity, pro- cells
inflammatory IL-23 Pro-inflammatory APCs X X ? X ? X IL-24 Controls
survival and Monocytes- X X ? ? ? X proliferation macro- phages,
Th2 cells IL-27 Induces APCs, T cells X X X X ? X differentiation
of T cells, upregulates IL- 10, can be pro-or anti-inflammatory;
promotes Th1/Tr1, inhibits Th2/Th17/ regulatory T cells IL-32
Pro-inflammatory, T cells, NK X X ? X ? X increases secretion cells
of inflammatory cytokines and chemokines CSF Induces myeloid APCs X
X X ? ? ? cells to proliferate and differentiate GM-CSF Promotes T
cells, X X ? ? ? X macrophage and macro- Eosinophil phages
proliferation and maturation, growth factor TRANCE Helps DC T cells
? X ? X ? ? maturation/survival, T cell activation marker, anti-
apoptotic, stimulates osteoclast activity MIP-3 Chemotactic for T X
X ? ? ? X alpha cells, DCs fractalkine Chemotactic for T
Endothelial X X ? ? ? X cells and monocytes cells IL-4 Stimulates B
cells, Th2 cells, ? X ? X X X Th2 proliferation, basophils plasma
cell differentiation, IgE, upregulates MHC Class II expression,
decreases IFN- gamma production IL-10 Down regulates Th1 Monocytes
X ? X X X X cytokines/MHC Class Th2 cells, II expression/Co-
regulatory T stimulatory molecule cells expression IL-5 Stimulates
B cells, Ig Th2 cells, ? X ? X X X secretion, eosinophil mast cells
activation IL-13 Similar to IL4, Th2 cells, NK ? X ? X X X induces
IgE cells, mast production, Th2 cells, cytokine eosinophils,
basophils TGF-beta Inhibits T cell regulatory T ? ? X X X ?
proliferation, cells activity, function; blocks effects of pro-
inflammatory cytokines IL-1 beta Induces fevers, pro- Macro- X X ?
X ? X inflammatory phages IL-6 Pro-inflammatory, T cells, ? X ? X X
X drives osteoclast macro- formation, drives phages Th17 IL-8
Recruits neutrophils Macro- ? X ? X ? X to site of infection
phages, epithelial cells IL-31 Cell-mediated Th2 cells, X X ? X ? X
immunity, pro- macro- inflammatory phages, DCs IL-15 T cell
proliferation T cells, NK X X X ? ? ? and survival cells IL-9 Th2
proliferation, T cells, ? ? X X X ? cytokine secretion neutrophils,
mast cells ID = Infectious disease IA = Autoimmune disease
[0261] In some embodiments, a tumor antigen stimulates one or more
lymphocyte responses that are beneficial to the subject. In some
embodiments, a tumor antigen inhibits and/or suppresses one or more
lymphocyte responses that are deleterious or non-beneficial to the
subject. Examples of immune responses that may lead to beneficial
anti-tumor responses include but are not limited to 1) cytotoxic
CD8.sup.+ T cells which can effectively kill cancer cells and
release the mediators perforin and/or granzymes to drive tumor cell
death; and 2) CD4.sup.+ Th1 T cells which play an important role in
host defense and can secrete IL-2, IFN-gamma and TNF-alpha. These
are induced by IL-12, IL-2, and IFN gamma among other
cytokines.
[0262] In some embodiments, a tumor antigen stimulates one or more
lymphocyte responses that are deleterious or non-beneficial to the
subject. In some embodiments, a tumor antigen inhibits and/or
suppresses one or more lymphocyte responses that are beneficial to
the subject. Examples of immune responses that may lead to
deleterious or non-beneficial anti-tumor responses include but are
not limited to 1) T regulatory cells which are a population of T
cells that can suppress an immune response and secrete
immunosuppressive cytokines such as TGF-beta and IL-10 and express
the molecules CD25 and FoxP3; and 2) Th2 cells which target
responses against allergens but are not productive against cancer.
These are induced by increased IL-4 and IL-10 and can secrete IL-4,
IL-5, IL-6, IL-9 and IL-13.
[0263] The disclosure provides methods and systems for identifying
and selecting tumor antigens. In some embodiments, methods and
systems described herein can identify and select one or more tumor
antigens to which one or more immune responses are stimulated in a
cancer subject who has not received a cancer therapy (or who has
not responded and/or is not responding, clinically to a cancer
therapy). In some embodiments, methods and systems described herein
can identify and select one or more tumor antigens to which one or
more immune responses are not stimulated in a cancer subject who
has not received a cancer therapy (or who has not responded and/or
is not responding, clinically to a cancer therapy). In some
embodiments, methods and systems described herein can identify and
select one or more tumor antigens to which one or more immune
responses are inhibited and/or suppressed in a cancer subject who
has not received a cancer therapy (or who has not responded and/or
is not responding, clinically to a cancer therapy). In some
embodiments, methods and systems described herein can identify and
select one or more tumor antigens which elicit no or minimal immune
responses in a cancer subject who has not received a cancer therapy
(or who has not responded and/or is not responding, clinically to a
cancer therapy).
[0264] In some embodiments, a composition comprising the one or
more selected tumor antigens is administered to a cancer subject
before, during, and/or after administration of a cancer
therapy.
[0265] The disclosure provides methods for selecting tumor antigens
identified by the methods herein based on comparison of a subject
response profile to a target response profile. The disclosure also
provides methods for selecting (or de-selecting) tumor antigens
identified by the methods herein, based on association with
desirable or beneficial responses. The disclosure also provides
methods for selecting (or de-selecting) tumor antigens identified
by the methods herein, based on association with undesirable,
deleterious or non-beneficial responses. In some embodiments, the
methods for selecting tumor antigens are combined. The methods may
be combined in any order, e.g. selection may be carried out by
comparison of a subject response profile to a target response
profile, followed by selection based on association with a
desirable (or undesirable) response; or, selection may be carried
out based on association with a desirable (or undesirable)
response, followed by comparison of the subject response profile to
a target response profile.
[0266] Methods for identifying tumor antigens and potential tumor
antigens are provided herein. Methods for generating or obtaining a
subject response profile are provided herein. Methods for
generating or obtaining a target response profile, e.g. a
population-based or composite target response profile, are provided
herein. Methods for comparison of a subject response profile to a
target response profile are provided herein. Methods for
determining whether a subject response profile is similar to a
target response profile are provided herein.
[0267] In some embodiments, a subject response profile and target
response profile are generated or obtained using the same plurality
of polypeptides of interest. In some embodiments, a subject
response profile and target response profile are generated or
obtained using the same plurality of tumor antigens.
[0268] The target response profile includes a quantification,
identification, and/or representation of one or more tumor antigens
that stimulate lymphocytes, that do not stimulate lymphocytes, that
inhibit and/or suppress lymphocytes, that activate lymphocytes,
and/or to which lymphocytes are non-responsive.
[0269] In some embodiments, one or more tumor antigens are
identified as inhibiting and/or suppressing lymphocytes in the test
subject (e.g., identified from the subject response profile), and
the same one or more tumor antigens are identified as stimulating
lymphocytes in the target subject (e.g., identified from the target
response profile). In some embodiments, one or more tumor antigens
are identified as stimulating lymphocytes in the test subject
(e.g., identified from the subject response profile) and the same
one or more tumor antigens are identified as inhibiting and/or
suppressing lymphocytes in the target subject (e.g., identified
from the target response profile). In some embodiments, one or more
tumor antigens or potential tumor antigens are identified as
eliciting minimal or no response from lymphocytes in the test
subject (e.g., identified from the subject response profile), and
the same one or more tumor antigens are identified as stimulating,
or inhibiting and/or suppressing lymphocytes in the target subject
(e.g., identified from the target response profile). In some
embodiments, one or more tumor antigens are identified as
stimulating, or inhibiting and/or suppressing, lymphocytes in the
test subject (e.g., identified from the subject response profile),
and the same one or more tumor antigens are identified as eliciting
minimal or no response from lymphocytes in the target subject
(e.g., identified from the target response profile).
[0270] Tumor antigens may be identified and/or selected on the
basis of similarity or dissimilarity of a subject response profile
to a target response profile. Tumor antigens may be identified
and/or selected (or de-selected) based on association with
desirable or beneficial responses. Tumor antigens may be identified
and/or selected (or de-selected) based on association with
undesirable, deleterious or non-beneficial responses. Tumor
antigens may be identified and/or selected (or de-selected) based
on a combination of the preceding methods, applied in any
order.
All Positive Responders
[0271] In some embodiments, a subject response profile is compared
to a corresponding response profile from a cancer subject who
responds and/or has responded clinically to a cancer therapy (a
"target response profile" of a responsive subject described
herein). In some embodiments, a subject response profile is
compared to a target response profile from a target subject who has
not been diagnosed with cancer. In some embodiments, a subject
response profile is compared to a target response profile from a
target subject who has (or had) a beneficial response to cancer. In
some embodiments, the subject has (or had) a positive clinical
response to a cancer therapy or combination of therapies. In some
embodiments, the subject had a spontaneous response to a cancer. In
some embodiments, the subject is in partial or complete remission
from cancer. In some embodiments, the subject has cleared a cancer.
In some embodiments, the subject has not had a relapse, recurrence
or metastasis of a cancer. In some embodiments, the subject has a
positive cancer prognosis. In some embodiments, the subject has not
experienced toxic responses or side effects to a cancer therapy or
combination of therapies.
[0272] In some embodiments, one or more tumor antigens of the
subject response profile which elicit responses that are different
from, or dissimilar to, responses elicited by the same tumor
antigens of the target response profile are selected. In some
embodiments, one or more tumor antigens are selected (or
de-selected) based on association with desirable or beneficial
immune responses. In some embodiments, one or more tumor antigens
are selected (or de-selected) based on association with
undesirable, deleterious, or non-beneficial immune responses.
[0273] Responses whereby tumor antigens or immunogenic fragments
thereof (i) stimulate lymphocyte responses that are beneficial to
the subject, (ii) stimulate expression of cytokines that are
beneficial to the subject, (iii) inhibit and/or suppress lymphocyte
responses that are deleterious or non-beneficial to the subject, or
(iv) inhibit and/or suppress expression of cytokines that are
deleterious or non-beneficial to the subject, are termed
"beneficial responses".
[0274] In some embodiments, a selected tumor antigen stimulates one
or more lymphocyte responses that are beneficial to the subject. In
some embodiments, a selected tumor antigen inhibits and/or
suppresses one or more lymphocyte responses that are deleterious or
non-beneficial to the subject.
[0275] In some embodiments, a selected tumor antigen increases
expression and/or secretion of cytokines that are beneficial to the
subject. In some embodiments, a selected tumor antigen inhibits
and/or suppresses expression of cytokines that are deleterious or
non-beneficial to the subject.
[0276] In some embodiments, administration of one or more selected
tumor antigens to the subject elicits an immune response of the
subject. In some embodiments, administration of one or more
selected tumor antigens to the subject elicits a beneficial immune
response of the subject. In some embodiments, administration of one
or more selected tumor antigens to the subject elicits a beneficial
response of the subject. In some embodiments, administration of one
or more selected tumor antigens to the subject improves clinical
response of the subject to a cancer therapy.
All Negative Responders
[0277] In some embodiments, a subject response profile is compared
to a corresponding response profile from a cancer subject who does
not respond and/or has not responded clinically to a cancer therapy
(a "target response profile" of a non-responsive subject described
herein). In some embodiments, a subject response profile is
compared to a target response profile from a target subject who has
(or had) a deleterious or non-beneficial response to cancer. In
some embodiments, the subject has (or had) a negative clinical
response to a cancer therapy or combination of therapies. In some
embodiments, the subject has not cleared a cancer. In some
embodiments, the subject has had a relapse, recurrence or
metastasis of a cancer. In some embodiments, the subject has a
negative cancer prognosis. In some embodiments, the subject has
experienced toxic responses or side effects to a cancer therapy or
combination of therapies.
[0278] Responses whereby tumor antigens or immunogenic fragments
thereof (i) stimulate lymphocyte responses that are deleterious or
not beneficial to the subject, (ii) stimulate expression of
cytokines that are deleterious or not beneficial to the subject,
(iii) inhibit and/or suppress lymphocyte responses that are
beneficial to the subject, or (iv) inhibit and/or suppress
expression of cytokines that are beneficial to the subject, are
termed "deleterious or non-beneficial responses".
[0279] In some embodiments, one or more tumor antigens of the
subject response profile which elicit responses that are the same
as, or similar to, responses elicited by the same tumor antigens of
the target response profile are selected. In some embodiments, one
or more tumor antigens are selected (or de-selected) based on
association with desirable or beneficial immune responses. In some
embodiments, one or more tumor antigens are selected (or
de-selected) based on association with undesirable, deleterious, or
non-beneficial immune responses.
[0280] In some embodiments, a selected tumor antigen stimulates one
or more lymphocyte responses that are deleterious or non-beneficial
to the subject. In some embodiments, a selected tumor antigen
inhibits and/or suppresses one or more lymphocyte responses that
are beneficial to the subject.
[0281] In some embodiments, a selected tumor antigen increases
expression and/or secretion of cytokines that are deleterious or
non-beneficial to the subject. In some embodiments, a selected
tumor antigen inhibits and/or suppresses expression of cytokines
that are beneficial to the subject.
[0282] In some embodiments, the one or more tumor antigens are
de-selected by the methods herein.
[0283] In some embodiments, the one or more selected tumor antigens
are excluded from administration to a subject.
Methods of Selecting Potential Tumor Antigens
[0284] In well-established tumors, activation of endogenous
anti-tumor T cell responses is often insufficient to result in
complete tumor regression. Moreover, T cells that have been
educated in the context of the tumor microenvironment sometimes are
sub-optimally activated, have low avidity, and ultimately fail to
recognize the tumor cells that express antigen. In addition, tumors
are complex and comprise numerous cell types with varying degrees
of expression of mutated genes, making it difficult to generate
polyclonal T cell responses that are adequate to control tumor
growth. As a result, researchers in the field have proposed that it
is important in cancer subjects to identify the mutations that are
"potential tumor antigens" in addition to those that are confirmed
in the cancer subject to be recognized by their T cells.
[0285] There are currently no reliable methods of identifying
potential tumor antigens in a comprehensive way. Computational
methods have been developed in an attempt to predict what is an
antigen, however there are many limitations to these approaches.
First, modeling epitope prediction and presentation needs to take
into account the greater than 12,000 HLA alleles encoding MHC
molecules, with each subject expressing as many as 14 of them, all
with different epitope affinities. Second, the vast majority of
predicted epitopes fail to be found presented by tumors when they
are evaluated using mass spectrometry. Third, the predictive
algorithms do not take into account T cell recognition of the
antigen, and the majority of predicted epitopes are incapable of
eliciting T cell responses even when they are present. Finally, the
second arm of cellular immunity, the CD4+ T cell subset, is often
overlooked; the majority of in silico tools focus on MHC class I
binders. The tools for predicting MHC class II epitopes are
under-developed and more variable.
[0286] The present disclosure provides methods to a) identify
polypeptides that are potential tumor antigens in antigen
presentation assays of the disclosure, and b) select polypeptides
on the basis of their antigenic potential. The methods are
performed without making predictions about what could be a target
of T cell responses or presented by MHC, and without the need for
deconvolution. The methods can be expanded to explore antigenic
potential in healthy subjects who share the same MHC alleles as a
subject, to identify those potential tumor antigens that would be
most suitable to include in an immunogenic composition or vaccine
formulation. The methods ensure that the potential tumor antigen is
processed and presented in the context of subject MHC molecules,
and that T cells can respond to the potential tumor antigen if they
are exposed to the potential tumor antigen under the right
conditions (e.g., in the context of a vaccine with a strong danger
signal from an adjuvant or delivery system).
[0287] The preceding methods for selection of tumor antigens may be
applied to selection of potential tumor antigens, that is,
polypeptides encoding one or more mutations present or expressed in
a cancer or tumor cell of a subject.
Immunogenic Compositions and Uses thereof
[0288] The present disclosure provides compositions that include a
tumor antigen or tumor antigens identified or selected by methods
described herein, nucleic acids encoding the tumor antigens, and
methods of using the compositions. In some embodiments, a
composition includes tumor antigens that are peptides 8-40 amino
acids, 8-60 amino acids, 8-100. 8-150,or 8-200 amino acids in
length (e.g., MHC binding peptides, e.g., peptides 23-29, 24-28,
25-27, 8-30, 8-29, 8-28, 8-27, 8-26, 8-25, 8-24, 8-23, 8-22, 8-21,
8-20, 8-15, 8-12 amino acids in length). In some embodiments, a
composition includes one or more tumor antigens that are about 70%,
75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the length
of the full-length polypeptides. In some embodiments, a composition
includes one or more tumor antigens that are truncated by about 1,
2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more amino
acids, relative to the full-length polypeptides. The compositions
can include tumor antigens that are, or that comprise, MHC class
I-binding peptides, MHC class II-binding peptides, or both MHC
class I and MHC class II-binding peptides. Compositions can include
a single tumor antigen, or multiple tumor antigens. In some
embodiments, a composition includes a set of two, three, four,
five, six, seven, eight, nine, ten, or more tumor antigens. In some
embodiments, a composition includes ten, fifteen, twenty,
twenty-five, thirty, or more tumor antigens. In some embodiments,
the tumor antigens or peptides are provided as one or more fusion
proteins. In some embodiments, a composition comprises nucleic
acids encoding the tumor antigens or peptides. In some embodiments,
the nucleic acids encoding the tumor antigens or peptides are
provided as one or more fusion constructs.
[0289] The present disclosure provides immunogenic compositions
comprising any combination of two or three TAAs: HPSE1 (SEQ ID NO:
6), HPSE2 (SEQ ID NO: 7), and/or SMAD4 (SEQ ID NO: 8).
[0290] HPSE encodes Heparinase, an endoglycosidase that cleaves
heparan sulfate proteoglycans (HSPGs) into heparan sulfate side
chains and core proteoglycans. HPSE participates in extracellular
matrix (ECM) degradation and remodeling. There is a single
functional heparinase: HPSE isoform 1 (HPSE1), a 543 amino acid
protein. The splice variant HPSE isoform 2 (HPSE2) has no enzymatic
activity, but may regulate HPSE1 activity. The active protein form
of HPSE1 is a heterodimer of 8 and 50 kDa subunits which are
non-covalently linked. The TIM barrel fold domain contains the
active site, and the C-terminal domain of the protein is involved
in nonenzymatic signaling and secretory functions. Potential T-cell
epitopes within HPSE have been described (Tang. In vitro and ex
vivo evaluation of a multi-epitope heparinase vaccine for various
malignancies. Cancer Sci 105 (2014) 9-17). The protein sequences of
HPSE1 and HPSE2 may be found by searching in the publicly available
database, UniProt (on the World Wide Web, at
http://www.uniprot.org/uniprot/Q9Y251) and
http://www.uniprot.org/uniprot/Q8WWQ2 respectively). The DNA
sequence of HPSE1 and HPSE2 may be found by searching in the
publicly available database, Entrez (on the World Wide Web
https://www.ncbi.nlm.nih.gov/gene/10855 and
https://www.ncbi.nlm.nih.gov/gene/60495 respectively).
[0291] SMAD4 encodes Mothers against decapentaplegic homolog 4, a
signal transduction protein and tumor suppressor gene, which is a
central mediator of downstream transcriptional output in TGFb
signaling pathways. SMAD4 is a 552 amino acid, 60.4 KDa protein.
SMAD4 exists as a monomer in the absence of TGF-beta activation,
and a heterodimer on TGF-beta activation. SMAD4 is composed of two
molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2
or SMAD3, and one molecule of SMAD4 to form the transcriptional
active SMAD2/SMAD3-SMAD4 complex. SMAD4 regulates transcription of
a number of target genes through binding to DNA, recognizing an
8-bp palindromic sequence (GTCTAGAC) called the Smad-binding
element (SBE). The protein acts as a tumor suppressor and inhibits
epithelial cell proliferation. The protein and DNA sequences of
SMAD4 may be found by searching in the publicly available
databases, UniProt and Entrez (on the World Wide Web, at
http://www.uniprot.org/uniprot/Q13485 and
https://www.ncbi.nlm.nih.gov/gene/4089 respectively).
[0292] The disclosure also provides nucleic acids encoding the
tumor antigens. The nucleic acids can be used to produce expression
vectors, e.g., for recombinant production of the tumor antigens, or
for nucleic acid-based administration in vivo (e.g., DNA
vaccination).
[0293] In some embodiments, tumor antigens are used in diagnostic
assays. For these assays, compositions including the tumor antigens
can be provided in kits, e.g., for detecting antibody reactivity,
or cellular reactivity, in a sample from an individual.
[0294] In some embodiments, tumor antigen compositions are used to
induce an immune response in a subject. In some embodiments, the
subject is a human. In some embodiments, the subject is a non-human
animal. The tumor antigen compositions can be used to raise
antibodies (e.g., in a non-human animal, such as a mouse, rat,
hamster, or goat), e.g., for use in diagnostic assays, and for
therapeutic applications. For an example of a therapeutic use, a
tumor antigen discovered by a method described herein may be a
potent T cell and/or B cell antigen. Preparations of antibodies may
be produced by immunizing a subject with the tumor antigen and
isolating antiserum from the subject. Methods for eliciting high
titers of high affinity, antigen-specific antibodies, and for
isolating the tumor antigen-specific antibodies from antisera, are
known in the art. In some embodiments, the tumor antigen
compositions are used to raise monoclonal antibodies, e.g., human
monoclonal antibodies.
[0295] In some embodiments, a tumor antigen composition is used to
induce an immune response in a human subject to provide a
therapeutic response. In some embodiments, a tumor antigen
composition is used to induce an immune response in a human subject
that redirects an undesirable immune response. In some embodiments,
a tumor antigen composition elicits an immune response that causes
the subject to have a positive clinical response described herein,
e.g., as compared to a subject who has not been administered the
tumor antigen composition. In some embodiments, a tumor antigen
composition elicits an immune response that causes the subject to
have an improved clinical response, e.g., as compared to a subject
who has not been administered the tumor antigen composition. In
some embodiments, a tumor antigen composition is used to induce an
immune response in a human subject for palliative effect. The
response can be complete or partial therapy.
[0296] In some embodiments, a tumor antigen composition is used to
induce an immune response in a human subject to provide a
prophylactic response. The response can be complete or partial
protection.
[0297] In some embodiments, immunogenicity of a tumor antigen is
evaluated in vivo. In some embodiments, humoral responses to a
tumor antigen are evaluated (e.g., by detecting antibody titers to
the administered tumor antigen). In some embodiments, cellular
immune responses to a tumor antigen are evaluated, e.g., by
detecting the frequency of antigen-specific cells in a sample from
the subject (e.g., by staining T cells from the subject with
WIC/peptide tetramers containing the antigenic peptide, to detect
antigen-specific T cells, or by detecting antigen-specific cells
using an antigen presentation assay such as an assay described
herein). In some embodiments, the ability of a tumor antigen or
antigens to elicit protective or therapeutic immunity is evaluated
in an animal model. In some embodiments, the ability of a tumor
antigen or antigens to stimulate or to suppress and/or inhibit
immunity is evaluated in an animal model.
[0298] In some embodiments, the composition includes a
pharmaceutically acceptable carrier or excipient. An immunogenic
composition may also include an adjuvant for enhancing the
immunogenicity of the formulation, (e.g., oil in water, incomplete
Freund's adjuvant, aluminum phosphate, aluminum hydroxide, saponin
adjuvants, toll-like receptor agonists, or muramyl dipeptides).
Other adjuvants are known in the art.
[0299] In some embodiments, an immunogenic composition includes a
tumor antigen linked to a carrier protein. Examples of carrier
proteins include, e.g., toxins and toxoids (chemical or genetic),
which may or may not be mutant, such as anthrax toxin, PA and DNI
(PharmAthene, Inc.), diphtheria toxoid (Massachusetts State
Biological Labs; Serum Institute of India, Ltd.) or CRM 197,
tetanus toxin, tetanus toxoid (Massachusetts State Biological Labs;
Serum Institute of India, Ltd.), tetanus toxin fragment Z, exotoxin
A or mutants of exotoxin A of Pseudomonas aeruginosa, bacterial
flagellin, pneumolysin, an outer membrane protein of Neisseria
meningitidis (strain available from the ATCC (American Type Culture
Collection, Manassas, Va.)), Pseudomonas aeruginosa Hcp1 protein,
E. coli heat labile enterotoxin, shiga-like toxin, human LTB
protein, a protein extract from whole bacterial cells, and any
other protein that can be cross-linked by a linker. Other useful
carrier proteins include high density lipoprotein (HDL), bovine
serum albumin (BSA), P40, and chicken riboflavin. Many carrier
proteins are commercially available (e.g., from Sigma
Aldrich.).
[0300] In some embodiments, an immunogenic composition including a
tumor antigen identified by a method described herein is used in
conjunction with an available vaccine. For example, an antigen
identified as described herein can be used as a supplemental
component of a vaccine formulation, or as a boosting antigen in a
vaccination protocol.
[0301] In some embodiments, an immunogenic composition is in a
volume of about 0.5 mL for subcutaneous injection, 0.1 mL for
intradermal injection, or 0.002-0.02 mL for percutaneous
administration. A 0.5 ml dose of the composition may contain
approximately 2-500 ug of the tumor antigen.
[0302] In some embodiments an immunogenic composition is
administered parenterally (for instance, by subcutaneous,
intramuscular, intravenous, or intradermal injection). In some
embodiments, delivery by a means that physically penetrates the
dermal layer is used (e.g., a needle, airgun, or abrasion).
[0303] In some embodiments, an immunogenic composition is
administered to a subject, e.g., by intramuscular injection,
intradermal injection, or transcutaneous immunization with
appropriate immune adjuvants. Compositions can be administered, one
or more times, often including a second administration designed to
boost an immune response in a subject. The frequency and quantity
of dosage of the composition can vary depending on the specific
activity of the composition and clinical response of the subject,
and can be determined by routine experimentation.
[0304] The formulations of immunogenic compositions can be provided
in unit-dose or multi-dose containers, for example, sealed ampoules
and vials and may be stored in a freeze-dried (lyophilized)
condition requiring only the addition of the sterile liquid carrier
immediately prior to use.
Production of Tumor Antigens
[0305] A tumor antigen suitable for use in any method or
composition of the disclosure may be produced by any available
means, such as recombinantly or synthetically (see, e.g., Jaradat
Amino Acids 50:39-68 (2018); Behrendt et al., J. Pept. Sci. 22:4-27
(2016)). For example, a tumor antigen may be recombinantly produced
by utilizing a host cell system engineered to express a tumor
antigen-encoding nucleic acid. Alternatively or additionally, a
tumor antigen may be produced by activating endogenous genes.
Alternatively or additionally, a tumor antigen may be partially or
fully prepared by chemical synthesis.
[0306] Where proteins are recombinantly produced, any expression
system can be used. To give but a few examples, known expression
systems include, for example, E. coli, egg, baculovirus, plant,
yeast, or mammalian cells.
[0307] In some embodiments, recombinant tumor antigen suitable for
the present invention are produced in mammalian cells. Non-limiting
examples of mammalian cells that may be used in accordance with the
present invention include BALB/c mouse myeloma line (NSO/1, ECACC
No: 85110503); human retinoblasts (PER.C6, CruCell, Leiden, The
Netherlands); monkey kidney CV1 line transformed by SV40 (COS-7,
ATCC CRL 1651); human embryonic kidney line (HEK293 or 293 cells
subcloned for growth in suspension culture, Graham et al., J. Gen
Virol., 36:59,1977); human fibrosarcoma cell line (e.g., HT1080);
baby hamster kidney cells (BHK21, ATCC CCL 10); Chinese hamster
ovary cells+/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci.
USA, 77:4216, 1980); mouse sertoli cells (TM4, Mather, Biol.
Reprod., 23:243-251, 1980); monkey kidney cells (CV1 ATCC CCL 70);
African green monkey kidney cells (VERO-76, ATCC CRL-1 587); human
cervical carcinoma cells (HeLa, ATCC CCL 2); canine kidney cells
(MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL
1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep
G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI
cells (Mather et al., Annals N.Y. Acad. Sci., 383:44-68, 1982); MRC
5 cells; FS4 cells; and a human hepatoma line (Hep G2).
[0308] In some embodiments, the present invention provides
recombinant tumor antigen produced from human cells. In some
embodiments, the present invention provides recombinant tumor
antigen produced from CHO cells or HT1080 cells.
[0309] Typically, cells that are engineered to express a
recombinant tumor antigen may comprise a transgene that encodes a
recombinant tumor antigen described herein. It should be
appreciated that the nucleic acids encoding recombinant tumor
antigen may contain regulatory sequences, gene control sequences,
promoters, non-coding sequences and/or other appropriate sequences
for expressing the recombinant tumor antigen. Typically, the coding
region is operably linked with one or more of these nucleic acid
components.
[0310] The coding region of a transgene may include one or more
silent mutations to optimize codon usage for a particular cell
type. For example, the codons of a tumor antigen transgene may be
optimized for expression in a vertebrate cell. In some embodiments,
the codons of a tumor antigen transgene may be optimized for
expression in a mammalian cell. In some embodiments, the codons of
a tumor antigen transgene may be optimized for expression in a
human cell.
Methods of Manufacturing Immunogenic Compositions
[0311] In some embodiments, the disclosure provides methods of
manufacturing an immunogenic composition for administration to a
subject in need thereof, the method comprising: a) providing,
preparing, or obtaining a plurality of antigenic compositions
comprising a plurality of antigens, each composition comprising a
different antigen; b) providing, preparing, or obtaining a target
response profile, wherein the target response profile comprises a
representation of the level of expression and/or secretion of one
or more immune mediators associated (e.g., determined, measured,
observed) with the plurality of antigens; c) providing, preparing,
or obtaining a subject response profile, wherein the subject
response profile comprises a representation of the level of
expression and/or secretion of one or more immune mediators
associated (e.g., determined, measured, observed) with the
plurality of antigens; d) comparing the target response profile to
the subject response profile; e) selecting one or more antigens
based on the comparison; and f) formulating at least a portion of
one or more antigenic compositions comprising the one or more
selected antigens as a pharmaceutical composition.
[0312] In some instances, about 1, 2, 5, 10, 20, 40, 60, 80, 100,
150, 200 or more, antigenic compositions are provided, prepared, or
obtained. For example, a plurality of antigens can be produced
using a method described herein, e.g., recombinantly or
synthetically. The antigens can be provided in a suitable
composition, such as a solution or lyophilized composition. In some
instances, the antigens are synthetically produced. In some
instances, a synthetically produced antigen remains attached to a
solid support. In some instances, formulating an antigen includes
aliquoting a portion of the antigenic composition, reconstituting
at least a portion of a lyophilized antigenic composition, and/or
releasing a synthetically produced antigen from a solid
support.
[0313] Antigenic compositions may be prepared or obtained and
stored in a variety of forms, such as in a suspension, in solution,
or lyophilized. Antigenic compositions may be stored at a
temperature ranging from less than -80.degree. C. to about room
temperature, for example at about -80.degree. C., about -20.degree.
C., about -15.degree. C., about -10.degree. C., about 4.degree. C.
or at about room temperature. In some embodiments, antigenic
compositions may include a carrier, excipient, stabilizer,
preservative and/or adjuvant.
[0314] A plurality of antigens can be derived from a target
response profile wherein the target response profile comprises a
representation of the level of expression and/or secretion of one
or more immune mediators associated with (e.g., determined,
measured, observed) with the plurality of antigens.
[0315] A plurality of antigens can be derived from a subject
response profile wherein the subject response profile comprises a
representation of the level of expression and/or secretion of one
or more immune mediators associated with (e.g., determined,
measured, observed) with the plurality of antigens.
[0316] In some embodiments, a target response profile and subject
response profile are compared and one or more antigens are selected
based on the comparision. In some embodiments, one or more antigens
are selected that increase expression or secretion of immune
mediators associated with a beneficial response to cancer, and/or
one or more antigens that inhibit and/or suppress expression or
secretion of immune mediators associated with deleterious or not
beneficial responses to cancer. The selected antigens, or a portion
of the selected antigens may be formulated as a pharmaceutical
composition.
Cancer and Cancer Therapy
[0317] The present disclosure provides methods and systems related
to subjects having or diagnosed with cancer, such as a tumor. In
some embodiments, a tumor is or comprises a hematologic malignancy,
including but not limited to, acute lymphoblastic leukemia, acute
myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous
leukemia, hairy cell leukemia, AIDS-related lymphoma, Hodgkin
lymphoma, non-Hodgkin lymphoma, Langerhans cell histiocytosis,
multiple myeloma, or myeloproliferative neoplasms.
[0318] In some embodiments, a tumor is or comprises a solid tumor,
including but not limited to breast carcinoma, a squamous cell
carcinoma, a colon cancer, a head and neck cancer, ovarian cancer,
a lung cancer, mesothelioma, a genitourinary cancer, a rectal
cancer, a gastric cancer, or an esophageal cancer.
[0319] In some particular embodiments, a tumor is or comprises an
advanced tumor, and/or a refractory tumor. In some embodiments, a
tumor is characterized as advanced when certain pathologies are
observed in a tumor (e.g., in a tissue sample, such as a biopsy
sample, obtained from a tumor) and/or when cancer patients with
such tumors are typically considered not to be candidates for
conventional chemotherapy. In some embodiments, pathologies
characterizing tumors as advanced can include tumor size, altered
expression of genetic markers, invasion of adjacent organs and/or
lymph nodes by tumor cells. In some embodiments, a tumor is
characterized as refractory when patients having such a tumor are
resistant to one or more known therapeutic modalities (e.g., one or
more conventional chemotherapy regimens) and/or when a particular
patient has demonstrated resistance (e.g., lack of responsiveness)
to one or more such known therapeutic modalities.
[0320] In some embodiments, the present disclosure provides methods
and systems related to cancer therapy. The present disclosure is
not limited to any specific cancer therapy, and any known or
developed cancer therapy is encompassed by the present disclosure.
Known cancer therapies include, e.g., administration of
chemotherapeutic agents, radiation therapy, surgical excision,
chemotherapy following surgical excision of tumor, adjuvant
therapy, localized hypothermia or hyperthermia, anti-tumor
antibodies, and anti-angiogenic agents. In some embodiments, cancer
and/or adjuvant therapy includes a TLR agonist (e.g., CpG, Poly
I:C, etc., see, e.g., Wittig et al., Crit. Rev. Oncol. Hematol.
94:31-44 (2015); Huen et al., Curr. Opin. Oncol. 26:237-44 (2014);
Kaczanowska et al., J. Leukoc. Biol. 93:847-863 (2013)), a STING
agonist (see, e.g., US20160362441; US20140329889; Fu et al., Sci.
Transl. Med. 7:283ra52 (2015); and WO2014189805), a non-specific
stimulus of innate immunity, and/or dendritic cells, or
administration of GM-CSF, Interleukin-12, Interleukin-7, Flt-3, or
other cytokines. In some embodiments, the cancer therapy is or
comprises oncolytic virus therapy, e.g., talimogene leherparepvec.
(see, e.g., Fukuhara et al., Cancer Sci. 107:1373-1379 (2016)). In
some embodiments, the cancer therapy is or comprises bi-specific
antibody therapy (e.g., Choi et al., 2011 Expert Opin Biol Ther;
Huehls et al., 2015, Immunol and Cell Biol). In some embodiments,
the cancer therapy is or comprises cellular therapy such as
chimeric antigen receptor T (CAR-T) cells, TCR-transduced T cells,
dendritic cells, tumor infiltrating lymphocytes (TIL), or natural
killer (NK) cells (e.g., as reviewed in Sharpe and Mount, 2015, Dis
Model Mech 8:337-50).
[0321] Anti-tumor antibody therapies (i.e., therapeutic regimens
that involve administration of one or more anti-tumor antibody
agents) are rapidly becoming the standard of care for treatment of
many tumors. Antibody agents have been designed or selected to bind
to tumor antigens, particularly those expressed on tumor cell
surfaces. Various review articles have been published that describe
useful anti-tumor antibody agents (see, for example, Adler et al.,
Hematol. Oncol. Clin. North Am. 26:447-81 (2012); Li et al., Drug
Discov. Ther. 7:178-84 (2013); Scott et al., Cancer Immun. 12:14
(2012); and Sliwkowski et al., Science 341:1192-1198 (2013)). The
below Table 8 presents a non-comprehensive list of certain human
antigens targeted by known, available antibody agents, and notes
c
[0322] Certain cancer indications for which the antibody agents
have been proposed to be useful:
TABLE-US-00003 TABLE 8 Human Antibody (commercial Antigen or
scientific name) Cancer indication CD2 Siplizumab Non-Hodgkin's
Lymphoma CD3 UCHT1 Peripheral or CD4 HuMax-CD4 Cutaneous T-cell
Lymphoma CD19 SAR3419, MEDI-551 Diffuse Large B-cell Lymphoma CD19
and Bispecific antibodies Non-Hodgkin's CD3 or such as
Blinatumomab, Lymphoma CD22 DT2219ARL CD20 Rituximab, Veltuzumab, B
cell malignancies Tositumomab, (Non-Hodgkin's Ofatumumab, lymphoma,
Chronic Ibritumomab, lymphocytic leukemia) Obinutuzumab, CD22
Inotuzumab, tetraxetan, Chemotherapy-resistant (SIGLEC2) CAT-8015,
hairy cell leukemia, DCDT2980S, Hodgkin's lymphoma Bectumomab CD30
Brentuximab vedotin CD33 Gemtuzumab Acute myeloid ozogamicin
leukemia (Mylotarg) CD37 16 Chronic lymphocytic leukemia CD38 mumab
Multiple myeloma, hematological tumors CD40 mumab Non-Hodgkin's
lymphoma CD52 Alemtuzumab Chronic lymphocytic (Campath) leukemia
CD56 Lorvotuzumab Small Cell Lung (NCAM1) Cancer CD66e (CEA)
Labetuzumab Breast, colon and lung tumors CD70 SGN-75 Non-Hodgkin's
lymphoma CD74 Milatuzumab Non-Hodgkin's lymphoma CD138 (SYND1)
BT062 Multiple Myeloma CD152 (CTLA-4) Ipilimumab Metastatic
melanoma CD221 (IGF1R) AVE1642, IMC-A12, Glioma, lung, breast,
MK-0646, head and neck, R150, CP 751871 prostate and thyroid cancer
CD254 (RANKL) Denosumab Breast and prostate carcinoma CD261
(TRAILR1) Mapatumumab Colon, lung and CD262 (TRAILR2) HGS-ETR2,
pancreas tumors and CS-1008 haematological malignancies CD326
(Epcam) Edrecolomab, Colon and rectal cancer, 17-1A, IGN101,
malignant ascites, Catumaxomab, epithelial tumors Adecatumumab
(breast, colon, lung) CD309 (VEGFR2) IM-2C6, CDP791
Epithelium-derived solid tumors CD319 (SLAMF7) HuLuc63 Multiple
myeloma CD340 (HER2) Trastuzumab, Breast cancer Pertuzumab, Ado-
trastuzumab emtansine CAIX (CA9) cG250 Renal cell carcinoma EGFR
(c-erbB) Cetuximab, Solid tumors including Panitumumab, glioma,
lung, breast, nimotuzumab and 806 colon, and head and neck tumors
EPHA3 (HEK) KB004, IIIA4 Lung, kidney and colon tumors, melanoma,
glioma and haematological malignancies Episialin Epitumomab
Epithelial ovarian tumors FAP Sibrotuzumab Colon, breast, lung, and
F19 pancreas, and head and neck tumors HLA-DR beta Apolizumab
Chronic lymphocytic leukemia, non- Hodkin's lymphoma FOLR-1
Farletuzumab Ovarian tumors 5T4 Anatumomab Non-small cell lung
cancer GD3/GD2 3F8, ch14.18, Neuroectodermal and KW-2871 epithelial
tumors gpA33 huA33 Colorectal carcinoma GPNMB Glembatumumab Breast
cancer HER3 (ERBB3) MM-121 Breast, colon, lung, ovarian, and
prostate tumors Integrin .alpha.V.beta.3 Etaracizumab Tumor
vasculature Integrin .alpha.5.beta.1 Volociximab Tumor vasculature
Lewis-Y antigen hu3S193, IgN311 Breast, colon, lung and prostate
tumors MET (HGFR) AMG 102, METMAB, Breast, ovary and SCH900105 lung
tumors Mucin-1/CanAg Pemtumomab, Breast, colon, lung oregovomab,
and ovarian tumors Cantuzumab PSMA ADC, J591 Prostate Cancer
Phosphatidylserine Bavituximab Solid tumors TAG-72 Minretumomab
Breast, colon and lung tumors Tenascin 81C6 Glioma, breast and
prostate tumours VEGF Bevacizumab Tumor vasculature PD-L1 Avelumab
Non-small cell lung cancer, MCC CD274 Durvalumab Non-small cell
lung cancer IDO enzyme IDO inhibitors Multiple
[0323] In some embodiments, a cancer therapy is or comprises immune
checkpoint blockade therapy (see, e.g., Martin-Liberal et al.,
Cancer Treat. Rev. 54:74-86 (2017); Menon et al., Cancers (Basel)
8:106 (2016)), or immune suppression blockade therapy. Certain
cancer cells thrive by taking advantage of immune checkpoint
pathways as a major mechanism of immune resistance, particularly
with respect to T cells that are specific for tumor antigens. For
example, certain cancer cells may overexpress one or more immune
checkpoint proteins responsible for inhibiting a cytotoxic T cell
response. Thus, immune checkpoint blockade therapy may be
administered to overcome the inhibitory signals and permit and/or
augment an immune attack against cancer cells. Immune checkpoint
blockade therapy may facilitate immune cell responses against
cancer cells by decreasing, inhibiting, or abrogating signaling by
negative immune response regulators (e.g., CTLA-4). In some
embodiments, a cancer therapy or may stimulate or enhance signaling
of positive regulators of immune response (e.g., CD28).
[0324] Examples of immune checkpoint blockade and immune
suppression blockade therapy include agents targeting one or more
of A2AR, B7-H4, BTLA, CTLA-4, CD28, CD40, CD137, GITR, IDO, KIR,
LAG-3, PD-1, PD-L1, OX40, TIM-3, and VISTA. Specific examples of
immune checkpoint blockade agents include the following monoclonal
antibodies: ipilimumab (targets CTLA-4); tremelimumab (targets
CTLA-4); atezolizumab (targets PD-L1); pembrolizumab (targets
PD-1); nivolumab (targets PD-1); avelumab; durvalumab; and
cemiplimab.
[0325] Specific examples of immune suppression blockade agents
include: Vista (B7-H5, v-domain Ig suppressor of T cell activation)
inhibitors; Lag-3 (lymphocyte-activation gene 3, CD223) inhibitors;
IDO (indolemamine-pyrrole-2,3,-dioxygenase-1,2) inhibitors; KIR
receptor family (killer cell immunoglobulin-like receptor)
inhibitors; CD47 inhibitors; and Tigit (T cell immunoreceptor with
Ig and ITIM domain) inhibitors.
[0326] In some embodiments, a cancer therapy is or comprises immune
activation therapy. Specific examples of immune activators include:
CD40 agonists; GITR (glucocorticoid-induced TNF-R-related protein,
CD357) agonists; OX40 (CD134) agonists; 4-1BB (CD137) agonists;
ICOS (inducible T cell stimulator); CD278 agonists; IL-2
(interleukin 2) agonists; and interferon agonists.
[0327] In some embodiments, cancer therapy is or comprises a
combination of one or more immune checkpoint blockade agents,
immune suppression blockade agents, and/or immune activators, or a
combination of one or more immune checkpoint blockade agents,
immune suppression blockade agents, and/or immune activators, and
other cancer therapies.
[0328] As discussed herein, in some embodiments, the present
disclosure provides methods and systems related to subjects who do
not respond and/or have not responded; or respond and/or have
responded (e.g., clinically responsive, e.g., clinically positively
responsive or clinically negatively responsive) to a cancer
therapy. In some embodiments, subjects respond and/or have
responded positively clinically to a cancer therapy. In some
embodiments, subjects respond and/or have responded negatively
clinically to a cancer therapy. In some embodiments, subjects do
not respond and/or have not responded (e.g., clinically
non-responsive) to a cancer therapy.
[0329] Whether a subject responds positively, responds negatively,
and/or fails to respond to a cancer therapy can be measured and/or
characterized according to particular criteria. In certain
embodiments, such criteria can include clinical criteria and/or
objective criteria. In certain embodiments, techniques for
assessing response can include, but are not limited to, clinical
examination, positron emission tomography, chest X-ray, CT scan,
MM, ultrasound, endoscopy, laparoscopy, presence or level of a
particular marker in a sample, cytology, and/or histology. A
positive response, a negative response, and/or no response, of a
tumor to a therapy can be assessed by ones skilled in the art using
a variety of established techniques for assessing such response,
including, for example, for determining one or more of tumor
burden, tumor size, tumor stage, etc. Methods and guidelines for
assessing response to treatment are discussed in Therasse et al.,
J. Natl. Cancer Inst., 2000, 92(3):205-216; and Seymour et al.,
Lancet Oncol., 2017, 18:e143-52.
[0330] In some embodiments, a responsive subject exhibits a
decrease in tumor burden, tumor size, and/or tumor stage upon
administration of a cancer therapy. In some embodiments, a
non-responsive subject does not exhibit a decrease in tumor burden,
tumor size, or tumor stage upon administration of a cancer therapy.
In some embodiments, a non-responsive subject exhibits an increase
in tumor burden, tumor size, or tumor stage upon administration of
a cancer therapy.
[0331] In some embodiments, a cancer subject is identified and/or
selected for administration of a cancer therapy as described
herein. In some embodiments, the cancer therapy is administered to
the subject. In some embodiments, upon administration of the cancer
therapy, the subject exhibits a positive clinical response to the
cancer therapy, e.g., exhibits an improvement based on one or more
clinical and/or objective criteria (e.g., exhibits a decrease in
tumor burden, tumor size, and/or tumor stage). In some embodiments,
the clinical response is more positive than a clinical response to
the cancer therapy administered to a cancer subject who is
identified (using a method described herein) as a cancer subject
who should not initiate, and/or should modify (e.g., reduce and/or
combine with one or more other modalities), and/or should
discontinue the cancer therapy, and/or should initiate an
alternative cancer therapy.
[0332] Methods described herein can include preparing and/or
providing a report, such as in electronic, web-based, or paper
form. The report can include one or more outputs from a method
described herein, e.g., a subject response profile described
herein. In some embodiments, a report is generated, such as in
paper or electronic form, which identifies the presence or absence
of one or more tumor antigens (e.g., one or more stimulatory and/or
inhibitory and/or suppressive tumor antigens, or tumor antigens to
which lymphocytes are not responsive, described herein) for a
cancer patient, and optionally, a recommended course of cancer
therapy. In some embodiments, the report includes an identifier for
the cancer patient. In one embodiment, the report is in web-based
form.
[0333] In some embodiments, additionally or alternatively, a report
includes information on prognosis, resistance, or potential or
suggested therapeutic options. The report can include information
on the likely effectiveness of a therapeutic option, the
acceptability of a therapeutic option, or the advisability of
applying the therapeutic option to a cancer patient, e.g.,
identified in the report. For example, the report can include
information, or a recommendation, on the administration of a cancer
therapy, e.g., the administration of a pre-selected dosage or in a
pre-selected treatment regimen, e.g., in combination with one or
more alternative cancer therapies, to the patient. The report can
be delivered, e.g., to an entity described herein, within 7, 14,
21, 30, or 45 days from performing a method described herein. In
some embodiments, the report is a personalized cancer treatment
report.
[0334] In some embodiments, a report is generated to memorialize
each time a cancer subject is tested using a method described
herein. The cancer subject can be reevaluated at intervals, such as
every month, every two months, every six months or every year, or
more or less frequently, to monitor the subject for responsiveness
to a cancer therapy and/or for an improvement in one or more cancer
symptoms, e.g., described herein. In some embodiments, the report
can record at least the treatment history of the cancer
subject.
[0335] In one embodiment, the method further includes providing a
report to another party. The other party can be, for example, the
cancer subject, a caregiver, a physician, an oncologist, a
hospital, clinic, third-party payor, insurance company or a
government office.
[0336] All publications, patent applications, patents, and other
references mentioned herein are incorporated by reference in their
entirety. In addition, the materials, methods, and examples are
illustrative only and not intended to be limiting. Unless otherwise
defined, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the
art to which this invention belongs. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present invention, suitable methods and
materials are described herein.
[0337] The disclosure is further illustrated by the following
examples. The examples are provided for illustrative purposes only.
They are not to be construed as limiting the scope or content of
the disclosure in any way.
EXAMPLES
Example 1. Immune Responses to the ATLAS Melanoma Tumor Associated
Antigen (TAA) Library--Single Patient Responses
Generation of the ATLAS Melanoma TAA Library
[0338] 23 full-length genes (labelled as Un001-023, encoding known
TAAs as shown below in Table 3) were obtained from the DNA Resource
Core at Harvard Medical School, recloned into the ATLAS expression
vector (Genocea Biosciences), and sequence-verified. Each TAA was
recombinantly expressed in E. coli. Protein expression was verified
using a surrogate T cell assay (the B3Z hybridoma) which recognizes
the C57BL/6 mouse T cell epitope SIINFEKL (SEQ ID NO: 452), which
is inserted at the C-terminus of each open reading frame, upstream
of the stop codon. Proteins that induced B3Z responses that
exceeded 5% of the positive control (the minimal SIINFEKL (SEQ ID
NO: 452) epitope pulsed onto antigen presenting cells) were
considered expressed.
TABLE-US-00004 TABLE 3 ATLAS melanoma TAA library Antigen Code Name
Alias Long Name OMIM GeneID Un001 MAGEA3 HIP8; HYPD; MAGE family
member A3 300174 4102 CT1.3; MAGE3; MAGEA6, MAGE-A3 (G-2544) Un002
NY-ESO-1 CTAG; ESO1; cancer/testis antigen 1B 300156 1485 CT6.1;
CTAG1; LAGE-2; LAGE2B; NY- ESO-1 Un003 ANGPT1 AGP1, AGPT,
Angiopoietin-1 601667 284 ANG1 Un004 XIAP API3; ILP1; X-linked
inhibitor of 300079 331 MIHA; XLP2; apoptosis BIRC4; IAP-3; hIAP3;
hIAP-3 Un005 LGALS3 L31; GAL3; Galectin-3 153619 3958 MAC2; CBP35;
GALBP; GALIG; LGALS2 Un006 VEGF-A VPF; VEGF; vascular endothelial
growth 192240 7422 MVCD1 factor A Un007 ATP6AP1 16A; CF2; ATPase H+
transporting 300197 537 Ac45; XAP3; accessory protein 1 XAP-3;
ATP6S1; VATPS1; ATP6IP1 Un008 MAGEA1 CT1.1; MAGE1 MAGE family
member A1 300016 4100 Un009 BIRC2 API1; MIHB; baculoviral IAP
repeat 601712 329 HIAP2; RNF48; containing 2 cIAP1; Hiap-2; c-IAP1
Un010 MIF GIF; GLIF; Macrophage migration 153620 4282 MMIF, MIF
inhibitory factor Un011 LGALS9 HUAT; Galectin-9 601879 3965 LGALS9A
Un012 PMEL P1; SI; SIL; premelanosome protein 155550 6490 ME20;
P100; SILV; ME20M; gp100; ME20- M; PMEL17; D12S53E Un013 GRN GEP;
GP88; Progranulin 138945 2896 PEPI; PGRN; CLN11; PCDGF Un014 OGFR
opioid growth factor receptor 606459 11054 Un015 BIRC5 API4; EPR-1;
Surviving 603352 332 survivin, BIRC5 Un016 BIRC7 KIAP; LIVIN;
baculoviral IAP repeat 79444 MLIAP; containing 7 RNF50; ML- IAP
Un017 TBX4 SPS T-box 4 601719 9496 Un018 SLPI ALP; MPI; Secretory
leukocyte protein 107285 6590 ALK1; BLPI; inhibitor HUSI; WAP4;
WFDC4; HUSI- I Un019 ANGPT2 AGPT2, ANG2 Angiopoietin-2 601922 285
Un020 LGALS1 GBP; GAL1 Galectin-1 150570 3956 Un021 DCT TRP-2;
TYRP2, , dopachrome tautomerase 191275 1638 Un100 TYRP-2 Un022
MLANA MART1; Melan-A 605513 2315 MART-1 Un023 TERT TP2; TRT;
telomerase reverse 187270 7015 CMM9; EST2; transcriptase TCS1;
hTRT; DKCA2; DKCB4; hEST2; PFBMFT1 Un024 LGMN AEP; LGMN1; legumain
602620 5641 PRSC1 Un025 SPA17 CT22; SP17; sperm surface protein
Sp17 608621 53340 SP17-1 Un026 HPV_E7 HPV E7 oncoprotein 1489079
Un027 TP53 P53; BCC7; cellular tumor antigen p53 191170 7157 LFS1;
TRP53 Un028 CEACAM3 CEA; CGM1; carcinoembryonic antigen- 609142
1084 W264; W282; related cell adhesion molecule CD66D 3 Un029 PRTN3
MBN; MBT; myeloblastin precursor 177020 5657 NP4; P29; PR3; ACPA;
AGP7; NP-4; PR-3; CANCA; C- ANCA Un030 TRRAP PAF350/400,
transformation/transcription 603015 8295 Un031 PAF400, domain
associated protein Un046 STAF40, TR- Un092 AP, Tra1 Un032 MAGEA12
CT1.12; melanoma-associated antigen 300177 4111 MAGE12 12 Un033
MAGEA2 CT1.2; melanoma-associated antigen 300173 4101 MAGE2; 2
MAGEA2A Un034 MAGEA9 CT1.9; MAGE9 melanoma-associated antigen
300342 4108 9 Un035 MAGEC2 CT10; melanoma-associated antigen 300468
51438 HCA587; C2 MAGEE1 Un036 PRAME MAPE; OIP4; melanoma antigen
606021 23532 CT130; O1P-4 preferentially expressed in tumors Un037
SOX10 DOM; WS4; transcription factor SOX-10 602229 6663 PCWH; WS2E;
WS4C Un038 MUC1 EMA; MCD; mucin-1 158340 4582 PEM; RUM; KL-6; MAM6;
MCKD; PEMT; CD227; H23AG; MCKD1; MUC- 1; ADMCKD; ADMCKD1; CA 15-3;
MUC- 1/X; MUC1/ZD; MUC-1/SEC Un039 RAC1 MIG5; Rac-1; ras-related C3
botulinum 602048 5879 TC-25; p21- toxin substrate 1 isoform Rac1
Rac1b Un040 HRAS CTLO; GTPase HRas 190020 3265 HAMSV; HRAS1; RASH1;
p21ras; C-H-RAS; H- RASIDX; C- BAS/HAS; C- HA-RAS1 Un041 GAGE4
CT4.4 G antigen 12I 300597 2576 Un042 BAGE BAGE1; CT2.1 B melanoma
antigen 1 605167 574 precursor Un043 AR KD; AIS; AR8; androgen
receptor 313700 367 TFM; DHTR; SBMA; HYSP1; NR3C4; SMAX1; HUMARA
Un044 CYP1B1 CP1B; GLC3A; cytochrome P450 1B1 601771 1545 CYPIB1;
P4501B1 Un045 CA9 MN; CAIX carbonic anhydrase 9 603179 768
precursor Un047 MMP8 HNC; CLG1; neutrophil collagenase 120355 4317
MMP-8; PMNL-CL Un048 GAGE1 CT4.1; GAGE-1 G antigen 1 300594 2543
Un049 TYR ATN; CMM8; tyrosinase precursor 606933 7299 OCA1; OCA1A;
OCAIA; SHEP3 Un050 HPV_E6 HPV E6 oncoprotein 1489078 Un051 Bcr-abl
BCR/ABL fusion protein 107963955 e14a5, (peptide atlas A6MFJ9)
Un052 PDGFRB IMF1; IBGC4; platelet-derived growth factor 173410
5159 JTK12; receptor beta PDGFR; CD140B; PDGFR1; PDGFR-1 Un053 KLK3
KLKB1, KLK3, Plasma kallikrein 176820 354 PSA Un054 PAX5 ALL3; BSAP
paired box protein Pax-5 167414 5079 Un055 ST3GAL5 SATI; SIAT9;
lactosylceramide alpha-2,3- 604402 8869 ST3GalV; sialyltransferase
SIATGM3S Un056 PLAC1 CT92; OOSP2L placenta-specific protein 1
300296 10761 precursor Un057 PSCA PRO232 prostate stem cell antigen
602470 8000 preproprotein Un058 RhoC H9; ARH9; rho-related
GTP-binding 165380 389 ARHC; RHOH9 protein RhoC precursor Un059
MYCN NMYC; ODED; N-myc proto-oncogene 164840 4613 MODED; N- protein
myc; bHLHe37 Un060 EpCAM ESA; KSA; epithelial cell adhesion 185535
4072 M4S1; MK-1; molecule DIAR5; EGP-2; EGP40; KS1/4; MIC18; TROP1;
EGP314; HNPCC8; TACSTD1 Un061 REG3A HIP; PAP; regenerating
islet-derived 167805 5068 PAP1; REG3; protein 3-alpha precursor
INGAP; PAP- H; PBCGF; HIP/PAP; REG- III Un062 EphA2 ECK; CTPA;
ephrin type-A receptor 2 176946 1969 ARCC2; CTPP1; CTRCT6 Un063
CSAG2 TRAG3; chondrosarcoma-associated 102723547 CSAG3B; gene 2/3
protein CT24.2; TRAG- 3 Un064 CTAG2-1a CT2; ESO2; cancer/testis
antigen 2 isoform 30848 CAMEL; LAGE-1a CT6.2; CT6.2a; CT6.2b; LAGE-
1; LAGE2B Un065 PAGE4 JM27; JM-27; P antigen family member 4 300287
9506 CT16.7; GAGE- 9; GAGEC1; PAGE-1; PAGE-4 Un066 BRAF NS7; BRAF1;
serine/threonine-protein 164757 673 RAFB1; B- kinase B-raf RAF1
Un067 FAP FAPA; SIMP; prolyl endopeptidase FAP 600403 2191 DPPIV
Un068 GRM3 GLUR3; metabotropic glutamate 601115 2913 mGlu3;
receptor 3 GPRC1C; MGLUR3 Un069 ERBB4 HER4; ALS19; receptor
tyrosine-protein 600543 2066 p180erbB4 kinase erbB-4 Un070 KIT PBT;
SCFR; C- mast/stem cell growth factor 164920 3815 Kit; CD117
receptor Kit Un071 LCK LSK; YT16; tyrosine-protein kinase Lck
153390 3932 IMD22; p56lck; pp58lck Un072 MAGEA10 CT1.10;
melanoma-associated antigen 300343 4109 MAGE10 10 Un073 MAGEA4
CT1.4; melanoma-associated antigen 300175 4103 MAGE4; 4 MAGE4A;
MAGE4B; MAGE-41; MAGE-X2 Un074 MAGEA6 CT1.6; melanoma-associated
antigen 300176 4105 MAGE6; 6 MAGE3B; MAGE-3b
Un075 MAPK1 ERK; p38; p40; mitogen-activated protein 176948 5594
p41; ERK2; kinase 1 ERT1; ERK-2; MAPK2; PRKM1; PRKM2; P42MAPK;
p41mapk; p42- MAPK Un076 MFI2 MTf; MTF1; melanotransferrin 155750
4241 CD228; MAP97 Un077 SART3 P100; p110; squamous cell carcinoma
611684 9733 DSAP1; antigen recognized by T-cells TIP110; 3
p110(nrb); RP11-13G14 Un078 ST8SIA1 GD3S; SIAT8;
alpha-N-acetylneuraminide 601123 6489 SIAT8A;
alpha-2,8-sialyltransferase SIAT8-A; ST8SiaI Un079 WDR46 UTP7;
BING4; WD repeat-containing protein 611440 9277 FP221; C6orf11 46
Un080 AKAP-4 AKAP 82, A-kinase anchoring protein 4 300185 8852
AKAP-4, AKAP82, CT99, FSC1, HI, PRKA4, hAKAP82, p8, AKAP4 Un081
RGS5 MST092; regulator of G-protein 603276 8490 MST106; signaling 5
MST129; MSTP032; MSTP092; MSTP106; MSTP129 Un082 CTAG2-1b CT2;
ESO2; cancer/testis antigen 2 isoform CAMEL; LAGE-1b CT6.2; CT6.2a;
CT6.2b; LAGE- 1; LAGE2B Un083 FOSL1 FRA; FRA1; fos-related antigen
1 136515 8061 fra-1 Un084 PRM2 MAD-CT-1; protamine-2 182890 5620
CT94.2 Un085 ACRBP CT23; SP32; acrosin-binding protein 608352 84519
OY-TES-1 precursor Un086 AFP AFPD, FETA, alpha-fetoprotein 104150
174 HPAFP Un087 CTCFL CT27; BORIS; transcriptional repressor 607022
140690 CTCF-T; CTCFL HMGB1L1; dJ579F20.2 Un088 CSPG4 NG2; MCSP;
chondroitin sulfate 601172 1464 MCSPG; proteoglycan 4 precursor
MSK16; HMW- MAA; MEL- CSPG Un089 PAX3 WS1; WS3; paired box protein
Pax-3 606597 5077 CDHS; HUP2 Un090 CCNB1 CCNB G2/mitotic-specific
cyclin-B1 123836 891 Un091 MSLN Mesotheline; mesothelin 601051
10232 MPF; SMRP Un093 EGFR ERBB; HER1; epidermal growth factor
131550 1956 mENA; receptor ERBB1; PIG61; NISBD2 Un094 WT1 GUD;
AWT1; Wilms tumor protein 607102 7490 WAGR; WT33; NPHS4; WIT-2;
EWS-WT1 Un095 SSX2 SSX; HD21; protein SSX2 300192 6757 CT5.2;
CT5.2A; HOM-MEL-40 Un096 KDR FLK1; CD309; vascular endothelial
growth 191306 3791 VEGFR; factor receptor 2 precursor VEGFR2 Un097
ANKRD30A NY-BR-1 ankyrin repeat domain- 610856 91074 containing
protein 30A Un098 MAGED1 NRAGE; melanoma-associated antigen 300224
9500 DLXIN-1 D1 Un099 CEACAM5 CEA; CD66e carcinoembryonic antigen-
114890 1048 related cell adhesion molecule 5 Un101 MAP3K9 MLK1;
mitogen-activated protein 600136 4293 MEKK9; kinase kinase kinase 9
PRKE1 Un102 XAGE1B CTP9; XAGE1; X antigen family member 1 300742
653220 CT12.1; GAGED2; XAGE-1; XAGE1A; CT12.1A; CT12.1B Un103 PREX2
DEP.2; phosphatidylinositol 3,4,5- 612139 80243 DEPDC2; P-
trisphosphate-dependent Rac REX2; exchanger 2 protein PPP1R129;
6230420N16Rik Un104 ERBB2 NEU; NGL; receptor tyrosine-protein
164870 2064 HER2; TKR1; kinase erbB-2 CD340; HER-2; MLN 19; HER-
2/neu Un105 CD276 B7H3; B7-H3; CD276 antigen 605715 80381 B7RP-2;
4Ig- B7-H3 Un106 TEK TIE2; VMCM; angiopoietin-1 receptor 600221
7010 TIE-2; VMCM1; CD202B Un107 AIM1 ST4; CRYBG1 absent in melanoma
1 protein 601797 202 Un108 ALK CD246; ALK tyrosine kinase receptor
613014 238 NBLST3 Un109 PSMA FOLH1 Glutamate carboxypeptidase 2
600934 2346 Un110 GRIN2A LKS; EPND; glutamate receptor ionotropic,
138253 2903 FESD; NR2A; NMDA 2A GluN2A; NMDAR2A Un111 MAP3K5 ASK1;
mitogen-activated protein 602448 4217 MEKK5; kinase kinase kinase 5
MAPKKK5 Un112 HPSE1 heparanase isoform 1 604724 10855 Un113 HPSE2
heparanase isoform 2 604724 10855 Un114 SAGE CT14 sarcoma antigen 1
300359 55511 OMIM = Online Mendelian Inheritance in Man database
GeneID = NCBI database
ATLAS Library Screening
[0339] A peripheral blood sample was collected from a consented
melanoma patient who had previously undergone therapy with a
checkpoint inhibitor (pembrolizumab) and responded to therapy.
Peripheral blood mononuclear cells (PBMC) were enriched by density
gradient centrifugation. CD4.sup.+ and CD8.sup.+ T cells were
sorted using antibody-conjugated magnetic beads and
non-specifically expanded with anti-CD3 and anti-CD28 stimulation.
Monocytes were differentiated into dendritic cells (MDDC).
[0340] Library clones were screened in replicates using 5,000 MDDC
and 80,000 T cells, at an E. coli:MDDC ratio of 100:1. After 24
hours incubation, assay supernatants were harvested and stored at
-80.degree. C. Supernatant cytokines were analyzed using a Meso
Scale Discovery V-PLEX Proinflammatory Panel 1 (human) Kit.
Data Analysis
[0341] Clones that induced mean IFN.gamma. responses that were
statistically different from background (Wilcoxon Rank Sum,
p<0.05) and exceeded 3 standard deviations (SD) of the mean of
the negative control GFP clones (N=10) were considered
antigens.
[0342] FIG. 1 shows representative results for a single melanoma
patient. Clones that induced mean IFN.gamma. responses that were
statistically different from background (Wilcoxon Rank Sum,
p<0.05) and exceeded 3 standard deviations (SD) of the mean of
the negative control GFP clones (N=10) were considered antigens
(indicated by horizontal dotted line). CEF=positive control peptide
pool. GFP=green fluorescent protein. Each symbol represents an
individual measurement, horizontal line=mean. Un022 & Un023
were not included in the CD8.sup.+ library.
Example 2. Cohort-Specific T Cell Responses to TAAs Associated with
Protective Immunity in Melanoma Patients after Checkpoint Blockade
Therapy
[0343] Dozens of subjects were recruited into the study and
cohorted based upon their clinical outcome after checkpoint
inhibitor therapy. Subjects who had stable disease or tumor
regression were considered protected; those who had worsening
disease (tumor growth) were considered not protected. Clinical
determinations were made by tumor imaging scans.
[0344] Briefly, blood samples were collected from 32 consented
melanoma patients who had previously undergone checkpoint inhibitor
therapy (one subject had two separate collections). Peripheral
blood mononuclear cells (PBMC) were enriched by density gradient
centrifugation. CD4.sup.+ and CD8.sup.+ T cells were sorted and
non-specifically expanded using anti-CD3 and anti-CD28-coated
microbeads, and CD14.sup.+ monocytes were differentiated into
dendritic cells (MDDC). Library clones comprising known TAAs
(labelled as Un001-023, as shown above in Table 3) were screened in
duplicate using 5,000 MDDC and 80,000 T cells, at an E. coli:MDDC
ratio of 100:1; ten replicates of E. coli expressing GFP were
included as negative controls. Assay supernatants were harvested at
24 hours and stored at -80.degree. C. Supernatant cytokines were
analyzed using Meso Scale Discovery V-PLEX Proinflammatory Panel 1
(human) Kit.
Data Analysis
[0345] Clones that induced mean cytokine responses that were
statistically different from background (Wilcoxon Rank Sum,
p<0.05) and exceeded 3 standard deviations (SD) of the mean
responses to the negative control GFP clones (N=10) were considered
antigens. The mean number of antigens to which each cohort
responded with each cytokine were compared to determine if
differences existed between protected (Responder) and non-protected
(Non-responder) cohort.
[0346] FIG. 2 shows cohort data for the CD4.sup.+ T cell subset.
Subjects were cohorted into "Responder" (gray bars) or
"Non-Responder" (black bars) groups based on clinical evaluation of
disease. Using a cutoff of 3 SD above the mean of the negative
control response per patient for each cytokine evaluated, the
number of TAAs to which each subject responded with their CD4.sup.+
T cell subset is represented. In contrast to the Responder cohort,
the Non-Responder group had minimal discernable CD4.sup.+ T cell
responses, by the majority of cytokines evaluated, to any of the
TAAs included in the library. Data are shown as the mean number
(.+-.SE) of TAAs to which each cohort responded with each cytokine
measured.
[0347] FIG. 3 shows cohort data for the CD8.sup.+ T cell subset.
Subjects were cohorted into "Responder" (gray bars) or
"Non-Responder" (black bars) groups based on clinical evaluation of
disease. Using a cutoff of 3 SD above the mean of the negative
control response per patient for each cytokine evaluated, the
number of TAAs to which each subject responded with their CD8.sup.+
T cell subset is represented. CD8.sup.+ T cells secreting
IFN.gamma. were undetectable in Non-Responders, but Responders had
responses to a mean of .about.two TAAs. Data are shown as the mean
number (.+-.SE) of TAAs to which each cohort responded with each
cytokine measured.
Example 3. Immune Responses to Neoantigens Identified Using ATLAS
in a Non-Small Cell Lung Cancer (NSCLC) Patient
Generation of the ATLAS Neoantigen Library
[0348] ATLAS (Genocea Biosciences) was applied to screen the entire
complement of mutations identified in the tumor of a consented
NSCLC patient who was successfully treated with pembrolizumab
(.alpha.PD-1 antibody (Ab), every other week starting on day 0). An
ATLAS library was built that expressed 201 of 202 mutations unique
to this patient. Each clone contained 113 amino acids with the
mutation positioned near the center of the construct and
sequence-verified. Each clone was recombinantly expressed in E.
coli. Protein expression was verified using a surrogate T cell
assay (the B3Z hybridoma) which recognizes the C57BL/6 mouse T cell
epitope SIINFEKL (SEQ ID NO: 452), which is inserted at the
C-terminus of each open reading frame, upstream of the stop codon.
Proteins that induced B3Z responses that exceeded 5% of the
positive control (the minimal SIINFEKL (SEQ ID NO: 452) epitope
pulsed onto antigen presenting cells) were considered
expressed.
ATLAS Library Screening
[0349] Peripheral blood samples were collected from the NSCLC
patient before and after checkpoint blockade therapy. Peripheral
blood mononuclear cells (PBMC) were enriched by density gradient
centrifugation. CD4.sup.+ and CD8.sup.+ T cells were sorted using
antibody-conjugated magnetic beads and non-specifically expanded
with anti-CD3 and anti-CD28 stimulation. Monocytes were
differentiated into dendritic cells (MDDC).
[0350] CD4.sup.+ and CD8.sup.+ T cells from Day 0 and Day 42 (after
3.sup.rd injection) of treatment were screened, respectively,
against 195 and 201 of the 201 library clones, as well as against
20 negative control clones expressing Neon Green (NG). Library
clones were screened in duplicate using 2,000 MDDC and 80,000 T
cells, at an E. coli:MDDC ratio of 250:1. After 24h incubation,
assay supernatants were harvested and stored at -80.degree. C.
Supernatant cytokines were analyzed using a Meso Scale Discovery
V-PLEX Proinflammatory Panel 1 (human) Kit.
Data Analysis
[0351] Clones that induced mean cytokine responses that were
statistically different from background (Wilcoxon Rank Sum,
p<0.05) and exceeded 3 standard deviations (SD) of the mean
responses to the negative control Neon Green clones (N=20) were
considered antigens (indicated by horizontal dotted line).
[0352] FIG. 4 shows good alignment between duplicate measurements
of the cytokines IFN.gamma. and TNF.alpha. for CD8.sup.+ T cell
response, with over 74% of replicates falling within 1.5-fold of
one another.
[0353] FIG. 5 shows results for IFN.gamma. and TNF.alpha. for
CD8.sup.+ T cells pre- and post-treatment (left and right panels
respectively). In this NSCLC patient, 5% of mutations screened (9
of 201) were identified as neoantigens recognized by his/her
peripheral blood CD8.sup.+ T cells taken pre- and post-treatment.
Only 1% of the identified neoantigens were found both pre- and
post-treatment. Points above the top dotted line indicate
neoantigens that stimulate CD8.sup.+ T cell responses. Points below
the lower dotted line indicate neoantigens that suppress and/or
inhibit CD8.sup.+ T cell responses.
[0354] FIG. 6 shows results for IFN.gamma. and TNF.alpha. for
CD4.sup.+ T cells pre- and post-treatment (left and right panels
respectively). In this NSCLC patient, 10% of mutations screened (20
of 195) were identified as neoantigens recognized by his/her
peripheral blood CD4.sup.+ T cells taken pre-treatment, increasing
to 17% of mutations screened (33 of 195) post-treatment. Five
percent of the identified neoantigens were found both pre- and
post-treatment. Points above the top dotted line indicate
neoantigens that stimulate CD4.sup.+ T cell responses. Points below
the lower dotted line indicate neoantigens that suppress and/or
inhibit CD4.sup.+ T cell responses. These results show increased
breadth of CD4.sup.+ T cell responses to neoantigens following
checkpoint inhibitor therapy, particularly with respect to
IFN.gamma..
TABLE-US-00005 TABLE 4 summarizes results shown in FIGS. 5 and 6. T
cell responses Pre-treatment Post-treatment Both CD8.sup.+ 5% 5% 1%
CD4.sup.+ 10% 17% 5%
[0355] FIG. 7 shows the limited overlap between CD8.sup.+-specific
T cell neoantigens identified by ATLAS and epitope prediction
algorithms. MEW class I epitopes were predicted for all screened
neoantigens from the NSCLC patient using three commonly used
algorithms: NetMHC, NetCTLpan and IEDB, and using patient-specific
haplotypes HLA-A*02:01/*32:01, HLA-B*40:01:02/*45:01:01,
HLAC*06:02/*03:041 (see Rizvi et al., (2015) Science. 348(6230):
124-8). Eight of the antigens identified by ATLAS were not
predicted by any of NetMHC, NetCTLpan, or IEDB. (Note that MEW
class II epitopes cannot be effectively predicted using currently
available algorithms.)
[0356] FIG. 8 further shows that epitope predictions have a high
false positive rate, miss relevant stimulatory neoantigens, and are
not able to identify suppressive and/or inhibitory neoantigens. Of
the 137 neoantigens predicted by at least one algorithm, only 15
(or 11%) were confirmed by ATLAS to effect a CD8.sup.+ T cell
response in the NSCLC patient. Six of these 15 neoantigens were
found to be suppressive and/or inhibitory. Altogether, ATLAS
identified 9+8 stimulatory neoantigens, and 6+3 suppressive and/or
inhibitory neoantigens. Thus, 47% of stimulatory antigens found by
ATLAS were missed by algorithms, and 33% of suppressive and/or
inhibitory neoantigens found by ATLAS failed to be identified by
algorithms.
Example 4. Immune Responses to the ATLAS Colorectal Cancer (CRC)
Tumor Associated Antigen (TAA) Library--Single Patient Response
Generation of the ATLAS Colorectal Cancer TAA Library
[0357] Twenty-six TAA genes (representing 23 unique genes; labelled
as "taa1-26" and shown below in Table 5) were cloned into the ATLAS
expression vector (Genocea Biosciences), and sequence-verified.
Each TAA was recombinantly expressed in E. coli. Protein expression
was verified using a surrogate T cell assay (the B3Z hybridoma)
which recognizes the C57BL/6 mouse T cell epitope SIINFEKL (SEQ ID
NO: 452), which is inserted at the C-terminus of each open reading
frame, upstream of the stop codon. Proteins that induced B3Z
responses that exceeded 5% of the positive control (the minimal
SIINFEKL (SEQ ID NO: 452) epitope pulsed onto antigen presenting
cells) were considered expressed.
ATLAS Library Screening
[0358] A frozen peripheral blood mononuclear cell (PBMC) vial was
purchased from Bioreclamation IVT. The PBMC were derived from a 50
year-old Caucasian male who had stage IV colorectal cancer.
CD8.sup.+ T cells were sorted using antibody-conjugated magnetic
beads and non-specifically expanded with anti-CD3 and anti-CD28
stimulation. Monocytes were differentiated into dendritic cells
(MDDC).
[0359] Library clones were screened in replicates using 5,000 MDDC
and 80,000 T cells, at an E. coli:MDDC ratio of 100:1. After 24h
incubation, assay supernatants were harvested and stored at
-80.degree. C. Negative controls included 13 replicates of E. coli
expressing neon green (NG). Supernatant cytokines were analyzed
using a Meso Scale Discovery V-PLEX Proinflammatory Panel 1 (human)
Kit.
Data Analysis
[0360] Measurements that were below the lower limit of detection
for the standard curve of each cytokine were masked. Clones that
induced mean IFN.gamma. or TNF.alpha. responses that exceeded 3
standard deviations (SD) of the mean of the negative control neon
green (NG) clones (N=13) were considered antigens.
[0361] FIG. 9 shows representative results for a single CRC
patient. Clones that induced mean IFN.gamma. and/or TNF.alpha.
responses that exceeded 3 standard deviations (SD) of the mean of
the negative control NG clones (N=10) were considered antigens
(indicated by horizontal dotted line, black symbols). NG=neon
green. Each symbol represents an individual measurement, small
horizontal line=mean of duplicate measurements. TAA coding
conventions are shown in Table 5 below.
Example 5. T Cell Responses to CRC TAAs in a Cohort of CRC
Patients
[0362] PBMC from 21 CRC patients were screened against a library of
26 known TAAs (shown in Table 5). CD4.sup.+ and CD8.sup.+ T cells
were sorted and non-specifically expanded using anti-CD3 and
anti-CD28-coated microbeads, and CD14.sup.+ monocytes were
differentiated into dendritic cells (MDDC). Library clones were
screened in duplicate using 5,000 MDDC and 80,000 T cells, at an E.
coli:MDDC ratio of 100:1; 13 replicates of E. coli expressing neon
green (NG) were included as negative controls. Assay supernatants
were harvested at 24 hours and stored at -80.degree. C. Supernatant
cytokines were analyzed using Meso Scale Discovery V-PLEX
Proinflammatory Panel 1 (human) Kit.
Data Analysis
[0363] Clones that induced mean cytokine responses that exceeded 3
standard deviations (SD) of the mean responses to the negative
control NG clones (N=10) were considered antigens.
[0364] FIG. 10 shows data for both the CD4.sup.+ (grey bars) and
CD8.sup.+ (black bars) T cell subsets. The percentage of subjects
who responded to each TAA, as measured by IFN.gamma. secretion that
exceeded three standard deviations of the mean negative control
(NG) response, is represented. Overall, nine of 26 antigens induced
a CD8.sup.+ T cell response from at least one of the CRC patients.
Three TAAs (HPSE1, HPSE2, SMAD4) were antigens for CD8.sup.+ T
cells from nearly all subjects screened; two TAAs (HPSE1, HPSE2)
were also antigens for each subject's CD4.sup.+ T cell subset.
Results are summarized in Table 5 below.
TABLE-US-00006 TABLE 5 Summary of T cell response rates to TAAs in
the ATLAS colorectal cancer library Code TAA CD4 CD8 taa1 BIRC5 0 0
taa2 CDH3 0 0 taa3 CEACAM3 0 0 taa4 CEACAM5 0 0 taa5 CGB_5 0 0 taa6
COA1 0 0 taa7 EBAG9 0 0 taa8 EGFR 0 0 taa9 ELK4 0 0 taa10 ERBB2 0 0
taa11 EpCAM 0 8% taa12 HPSE1 100% 92% taa13 HPSE2 100% 77% taa14
KRAS_isoform1 0 31% taa15 KRAS_isoform2 0 0 taa16 MAGEA3 0 0 taa17
MUC1 0 0 taa18 SMAD4 0 100% taa19 TERT.2 0 31% taa20 TERT.3 0 31%
taa21 TGFBR2 0 8% taa22 EBAG9_isoform1 0 0 taa23 TP53 0 15% taa24
CGB_3 0 0 taa25 IMPDH2 0 0 taa26 LCK 0 0
Example 6. Immune Responses to Neoantigens Identified Using ATLAS
in a Colorectal Cancer (CRC) Patient
Generation of the ATLAS Neoantigen Library
[0365] ATLAS was applied to screen the entire complement of
mutations identified in the tumor of a consented colorectal cancer
patient. An ATLAS library was built that expressed 31 mutations
unique to this patient. Each clone contained 113 amino acids with
the mutation positioned near the center of the construct and
sequence-verified. Each clone was recombinantly expressed in E.
coli and protein expression was verified using Western Blot.
ATLAS Library Screening
[0366] Frozen peripheral blood mononuclear cells (PBMC) were
purchased from Conversant Bio. After thaw, CD8.sup.+ T cells were
sorted using antibody-conjugated magnetic beads and
non-specifically expanded with anti-CD3 and anti-CD28 stimulation.
CD14+ monocytes were also sorted using antibody-conjugated magnetic
beads and differentiated in vitro into dendritic cells (MDDC).
[0367] CD8.sup.+ T cells were screened against the 31 library
clones, as well as against 2 negative control clones expressing
Neon Green (NG). Library clones were screened using 1,500 MDDC and
80,000 T cells, at an E. coli:MDDC ratio of 333:1. After 24h
incubation, assay supernatants were harvested and stored at
-80.degree. C. Supernatant cytokines were analyzed using a Meso
Scale Discovery custom plate.
Data Analysis
[0368] Clones that induced median cytokine responses that exceeded
3 median absolute deviations (MAD) of the median responses to the
negative control Neon Green clones (N=2) (indicated by horizontal
dotted line in FIG. 11) were considered antigens. Clones that
reduced median cytokine responses to 3 MAD below the median
negative control responses were considered inhibitory and/or
suppressive antigens.
[0369] FIG. 11 shows results for IFN.gamma. and TNF.alpha. from the
patient's CD8.sup.+ T cells. The X indicates the median response to
the negative controls. Points above the top dotted line indicate
neoantigens that stimulate CD8.sup.+ T cell responses (black
circles). Points below the lower dotted line indicate neoantigens
that inhibit and/or suppress CD8.sup.+ T cell responses (black
squares). In this patient, 16% of mutations screened (5 of 31) were
identified as neoantigens recognized by his/her peripheral blood
CD8.sup.+ T cells. Additionally, 13% (4 of 31) of mutations
screened were identified as inhibitory and/or suppressive
neoantigens. There was no overlap of the neoantigens that induced
IFN.gamma. compared with TNF.alpha., but two of the inhibitory
neoantigens suppressed both IFN.gamma. and TNF.alpha..
[0370] FIGS. 12A and 12B show Venn diagrams representing the
limited overlap between CD8.sup.+-specific T cell neoantigens
identified by ATLAS and epitope prediction algorithms. MHC class I
epitopes were predicted for all screened neoantigens using three
commonly used algorithms: NetMHC, NetCTLpan and IEDB, and using
patient-specific haplotypes HLA-A*30:02/*32:01, B*18:01/*14:01,
C*05:01/*08:02. FIG. 12A represents epitopes predicted that had
binding affinity projected to be below 500 nM for the mutant
peptide (neoantigen) but not for its wild-type counterpart, and an
IEDB percentile rank of .ltoreq.1 for the mutant peptide but not
for wild-type. FIG. 12B represents epitopes predicted to have
binding affinity below 500 nM or an IEDB percentile rank of
.ltoreq.1, irrespective of the wild-type counterpart predictions.
In the former case, none of the neoantigens that were identified by
ATLAS were predicted by algorithms, and there were six epitopes
predicted that were not identified empirically (100% false positive
and 100% false negative rate). For the latter, there was one
neoantigen that was identified using ATLAS that was also predicted
by all three algorithms used. The remaining four neoantigens were
not predicted by any algorithm. There were 26 epitopes predicted
that could not be confirmed by ATLAS (therefore the algorithms had
a 96% false positive rate and an 80% false negative rate).
[0371] FIGS. 13A and 13B show Venn diagrams representing the
limited overlap between CD8.sup.+-specific T cell inhibitory and/or
suppressive neoantigens identified by ATLAS and epitope prediction
algorithms. Epitope predictions do not discriminate between
stimulatory or inhibitory and/or suppressive antigens, therefore
the same MHC predictions used for FIGS. 12A and 12B were applied
for the inhibitory and/or suppressive, rather than stimulatory
neoantigens. FIG. 13A represents epitopes predicted that had
binding affinity projected to be below 500 nM for the mutant
peptide (neoantigen) but not for its wild-type counterpart, and an
IEDB percentile rank of .ltoreq.1 for the mutant peptide but not
for wild-type. FIG. 13B represents epitopes predicted to have
binding affinity below 500 nM or an IEDB percentile rank of
.ltoreq.1, irrespective of the wild-type counterpart predictions.
In the former case, none of the inhibitory and/or suppressive
neoantigens that were identified by ATLAS were predicted by
algorithms, and there were six epitopes predicted that were not
identified empirically (100% false positive and 100% false negative
rate). For the latter, there was one neoantigen that was identified
using ATLAS that was also predicted by one of the three algorithms
(netMHCpan_MT). The remaining three neoantigens identified
empirically with ATLAS were not predicted by any algorithm. Once
again, there were 26 epitopes predicted that could not be confirmed
by ATLAS.
Example 7. T Cell Response Profiling in Colorectal Carcinoma
Patients Reveals an Enrichment in Responses to Specific
Tumor-Associated Antigens
[0372] Generation of an ATLAS Tumor Associated Antigen library
[0373] ATLAS.TM. was applied to profile T cell recall responses to
a set of Tumor Associated Antigens (TAAs) in 34 subjects with
various stages of CRC and pre-malignant lesions in an
HLA-independent manner. Twenty-six TAA genes (representing 23
unique genes, shown in Table 5) were cloned into the ATLAS
expression vector and sequence verified. Each TAA was recombinantly
expressed in E. coli, with expression verified using Western Blot
analysis.
TABLE-US-00007 TABLE 6 ATLAS colorectal cancer TAA library Antigen
Name Alias long name OMIM GeneID CDH3 CDHP, HJMD, PCAD cadherin 3
114021 1001 CEACAM3 CEA; CGM1; W264; carcinoembryonic antigen-
609142 1084 W282; CD66D related cell adhesion molecule 3 CEACAM5
CEA; CD66e carcinoembryonic antigen- 114890 1048 related cell
adhesion molecule 5 CGB_3 CGB, CGB5, CGB7, chorionic gonadotropin
118860 1082 CGB8, hCGB beta subunit 3 CGB_5 CGB, HCG, hCGB
chorionic gonadotropin 608825 93659 beta subunit 5 COA1 C7orf44,
MITRAC15 cytochrome c oxidase 614769 55744 assembly factor 1
homolog EBAG9 EB9, PDAF estrogen receptor binding 605772 9166 site
associated, antigen, 9 EGFR ERBB; HER1; mENA; epidermal growth
factor 131550 1956 ERBB1; PIG61; NISBD2 receptor ELK4 SAP1 ETS
transcription factor 600246 2005 EpCAM ESA; KSA; M4S1; MK-
epithelial cell adhesion 185535 4072 1; DIAR5; EGP-2; molecule
precursor EGP40; KS1/4; MIC18; TROP1; EGP314; HNPCC8; TACSTD1 ERBB2
NEU; NGL; HER2; receptor tyrosine-protein 164870 2064 TKR1; CD340;
HER-2; kinase erbB-2 MLN 19; HER-2/neu HPSE1 heparanase isoform 1
604724 10855 HPSE2 heparanase isoform 2 IMPDH2 IMPD2, IMPDH-II
inosine monophosphate 146691 3615 dehydrogenase 2 KRAS C-K-RAS,
CFC2, K- KRAS proto-oncogene, 190070 3845 RAS2A, K-RAS2B, K- GTPase
RAS4A, K-RAS4B, K- Ras, K LCK LSK; YT16; IMD22; tyrosine-protein
kinase 153390 3932 p56lck; pp58lck Lck MAGEA3 HIP8; HYPD; CT1.3;
MAGE family member A3 300174 4102 MAGE3; MAGEA6, MAGE-A3 (G-2544)
MUC1 EMA; MCD; PEM; mucin-1 isoform 14 158340 4582 PUM; KL-6; MAM6;
precursor MCKD; PEMT; CD227; H23AG; MCKD1; MUC- 1; ADMCKD; ADMCKD1;
CA 15-3; MUC-1/X; MUC1/ZD; MUC-1/SEC SMAD4 DPC4, JIP, MADH4, SMAD
family member 4 600993 4089 MYHRS BIRC5 API4; EPR-1; survivin,
survivin 603352 332 BIRC5 TERT TP2; TRT; CMM9; telomerase reverse
187270 7015 EST2; TCS1; hTRT; transcriptase DKCA2; DKCB4; hEST2;
PFBMFT1 TGFBR2 AAT3, FAA3, LDS1B, transforming growth factor 190182
7048 LDS2, LDS2B, MFS2, beta receptor 2 RTIC, TAAD2, TGFR-2, TP53
P53; BCC7; LFS1; cellular tumor antigen p53 191170 7157 TRP53 OMIM
= Online Mendelian Inheritance in Man database GeneID = NCBI
database
ATLAS Library Screening
[0374] Frozen peripheral blood mononuclear cells (PBMC) were
purchased from Conversant Bio (Alabama) or obtained from a
collaborator at Mayo Clinic. After thaw, CD8.sup.+ T cells were
sorted using antibody-conjugated magnetic beads and
non-specifically expanded with anti-CD3 and anti-CD28 stimulation.
CD14+ monocytes were also sorted using antibody-conjugated magnetic
beads and differentiated in vitro into dendritic cells (MDDCs).
[0375] Frozen peripheral blood mononuclear cells (PBMC) were
purchased from Conversant Bio (Alabama) or obtained from a
collaborator at Mayo Clinic. After thaw, CD8.sup.+ T cells were
sorted using antibody-conjugated magnetic beads and
non-specifically expanded with anti-CD3 and anti-CD28 stimulation.
CD14+ monocytes were also sorted using antibody-conjugated magnetic
beads and differentiated in vitro into dendritic cells (MDDCs).
[0376] CD4.sup.+ and CD8.sup.+ T cells were screened against the 26
library clones, as well as against 10 negative control clones
expressing Neon Green (NG). Library clones were screened using
1,000-5,000 MDDCs and 80,000 T cells, at an E. coli:MDDC ratio of
333:1. After 24h incubation, assay supernatants were harvested and
stored at -80.degree. C. Supernatant cytokines levels were analyzed
using a Meso Scale Discovery custom plate.
Data Analysis
[0377] Clones that induced median cytokine responses that exceeded
2 median absolute deviations (MAD) of the median responses to the
negative control Neon Green (NG) clones (N=10) (indicated by a
vertical dotted line in FIG. 14 and a horizontal dotted line in
FIG. 17) were considered antigens. Clones that reduced median
cytokine responses to 2 MAD below the median negative control
responses were considered inhibitory and/or suppressive antigens.
In CRC patients, the breadth of recall responses to the 26 tested
TAAs varied, but there was a strong enrichment of CD4.sup.+ and
CD8.sup.+ T cell responses to a subset of 3 TAAs, which was absent
in healthy individuals.
[0378] FIG. 14 shows response profiles to 25 CRC-associated TAAs
across CRC patients. CD4.sup.+ and CD8.sup.+ T cells from CRC
patients across all stages of disease were profiled for responses
to 25 TAAs, using TNF-.alpha. and IFN-.gamma. secretion as an
indicator for a recall response to a putative antigen.
Distributions of normalized cytokine concentrations released in
response to each antigen are shown, each row represents one
antigen. Dashed vertical lines indicate 2 MADs from median cytokine
release in response to the NG negative control antigen. Positive
values, indicated by a shift toward the right side of the plot,
indicate stimulatory T cell recall responses. Negative values,
indicated by a shift toward the left side of the plot, indicate
inhibitory and/or suppressive T cell recall responses.
[0379] FIGS. 15A and 15B shows the high frequency of T cell
responses to three TAAs not previously identified by algorithm.
Response rates in individuals with CRC to three ATLAS-identified
TAAs in comparison to three TAAs that are or were in clinical
development as a therapeutic vaccine. FIG. 15A shows response rate
of CD4.sup.+ and CD8.sup.+ T cells for HPSE1 and HPSE2, in
comparison to MUC1, MAGEA3, and TP53. FIG. 15B shows response rate
of CD8.sup.+ T cells for HPSE1, HPSE2 and SMAD4, in comparison to
MUC1, MAGEA3, and TP53. Stimulatory (top panels) and inhibitory
and/or suppressive (bottom panels) T cell recall responses are
shown.
[0380] FIG. 16 shows T cell responses to selected TAAs in CRC
patients with early or late stage disease (NR, no responders).
Stimulatory response rates to four selected TAAs are shown for both
CD4.sup.+ and CD8.sup.+ T cell subsets and TNF-.alpha. and
IFN-.gamma. cytokine release (Panel A=HPSE1; Panel B=HPSE2; Panel
C=TP53; Panel D=MAGEA3). Patients were grouped by stage of disease
with early stage representing stages I and II, i.e., locoregional
disease, and late stage representing stages III and IV, i.e., with
metastasis to lymph nodes or distant sites. There was no
significant difference between response rates in early and late
disease for either stimulatory responses (shown) or inhibitory
and/or suppressive responses (not shown). Stage of cancer did not
impact the T cell response signature.
[0381] FIG. 17 shows T cell responses to selected TAAs in healthy
individuals and donors with various disease states. Normalized
cytokine concentrations released in response to the four selected
TAAs in the three cohorts are shown for CD4.sup.+ and CD8.sup.+ T
cell subsets and for TNF-.alpha. and IFN-.gamma. release (Panel
A=HPSE1; Panel B=HPSE2; Panel C=TP53; Panel D=MAGEA3). Each data
point represents one individual. IFN-.gamma. release in different
cohorts was compared using a Wilcoxon rank sum test. Asterisks
indicate statistical significance in comparison to cytokine release
in healthy donors unless otherwise indicated. * p<0.05; **
p<0.01; *** p<0.001. Significant differences based on
TNF-.alpha. levels were detected across the same groups (not
shown). Importantly, T cell responses to a subset of TAAs (HPSE1,
HPSE2, SMAD4) in individuals with pre-malignant adenomatous polyps
were similar to those in CRC patients and clearly distinguishable
from the rare responses in healthy individuals. This pattern was
not observed for responses to TAAs currently or previously
investigated as therapeutic vaccines (MUC1, TP53, MAGEA3).
Example 8. Profiling of T Cell Responses to Tumor-Associated
Antigens in Lung Cancer Patients Treated with Checkpoint
Inhibitors
Generation of an ATLAS Tumor Associated Antigen Library
[0382] ATLAS was applied to characterize and profile T cell
responses to Tumor Associated Antigens (TAAs) in a diverse sample
of lung cancer patients undergoing ICI therapy. Seventy-six TAA
genes (representing 74 unique genes, shown in Table 7) were cloned
into the ATLAS expression vector and sequence verified. Each TAA
was recombinantly expressed in E. coli, with expression verified
using Western Blot analysis.
TABLE-US-00008 TABLE 7 ATLAS lung cancer TAA library Gene Name
Alias Long Name OMIM GeneID ACTN4 ACTININ-4, FSGS, actinin alpha 4
604638 81 FSGS1 ACVR1 ACTRIA, ACVRLK2, activin A receptor type 1
102576 90 ALK2, FOP, SKR1, TSRI, ACVR1, ACTIVIN ADH1C ADH3 alcohol
dehydrogenase 1C 103730 126 (class I), gamma polypeptide ADORA2A
A2aR, ADORA2, RDC8, adenosine A2a receptor 102776 135 A2AR AKAP-4
AKAP82, AKAP-4, A-kinase anchoring protein 300185 8852 AKAP82,
CT99, FSC1, 4 HI, PRKA4, hAKAP82, p8, AKAP4 ARHGEF16 GEF16, NBR Rho
guanine nucleotide 27237 exchange factor 16 BAGE BAGE1; CT2.1 B
melanoma antigen 1 605167 574 precursor BLNK AGM4, BASH-S, LY57,
B-cell linker 604515 29760 SLP-65, SLP65, bca, BLNK BNC1 BNC, BSN1,
HsT19447 basonuclin 1 601930 646 BPIFA1 LUNX, NASG, PLUNC, BPI fold
containing family 607412 51297 SPLUNC1, SPURT, A member 1 bA49G10.5
CACNB3 CAB3, CACNLB3 calcium voltage-gated 601958 784 channel
auxiliary subunit beta 3 CASP3 CPP32, CPP32B, SCA-1, caspase 3
600636 836 CASPASE-3 CAV1 BSCL3, CGL3, LCCNS, caveolin 1 601047 857
MSTP085, PPH3, VIP21 CDH1 Arc-1, BCDS1, CD324, cadherin 1 192090
999 CDHE, ECAD, LCAM, UVO COX8C COX8-3 cytochrome c oxidase 616855
341947 subunit 8C CPT1A CPT1, CPT1-L, L-CPT1 carnitine 600528 1374
palmitoyltransferase 1A CTAG1A CT6.1, ESO1, LAGE-2, cancer/testis
antigen 1A 300657 246100 LAGE2A, NY-ESO-1 CTCFL CT27; BORIS;
CTCF-T; transcriptional repressor 607022 140690 HMGB1L1; dJ579F20.2
CTCFL CXCL13 ANGIE, ANGIE2, BCA- C-X-C motif chemokine 605149 10563
1, BCA1, BLC, BLR1L, ligand 13 SCYB13 DGKH DGKeta diacylglycerol
kinase eta 604071 160851 EEF2 EEF-2, EF-2, EF2, eukaryotic
translation 130610 1938 SCA26 elongation factor 2 EGFR ERBB; HER1;
mENA; epidermal growth factor 131550 1956 ERBB1; PIG61; receptor
NISBD2 E1F5A EIF-5A1, eIF5AI, EIF5A eukaryotic translation 600187
1984 initiation factor 5A FN1 CIG, ED-B, FINC, FN, fibronectin 1
135600 2335 FNZ, GFND, GFND2, LETS, MSF, Fibronectin GAGE1 CT4.1;
GAGE-1 G antigen 1 300594 2543 GAGE4 CT4.4 G antigen 12I 300597
2576 HLA-DRB1 major histocompatibility 142857 3123 complex, class
II, DR beta 1 HLA-DRB5 major histocompatibility 604776 3127
complex, class II, DR beta 5 HPSE1 heparanase isoform 1 604724
10855 HPSE2 heparanase isoform 2 HSD17B3 EDH17B3, SDR12C2
hydroxysteroid 17-beta 605573 3293 dehydrogenase 3 IDE INSULYSIN
insulin degrading enzyme 146680 3416 IDO1 IDO, IDO-1, INDO
indoleamine 2,3- 147435 3620 dioxygenase 1 IGFBP5 IBP5 insulin like
growth factor 146734 3488 binding protein 5 IGFBP7 AGM, FSTL2,
IBP-7, insulin like growth factor 602867 3490 IGFBP-7, IGFBP-7v,
binding protein 7 IGFBPRP1, MAC25, PSF, KCNK1 DPK, HOHO, K2P1,
potassium two pore 601745 3775 K2p1.1, KCNO1, TWIK- domain channel
subfamily 1, TWIK1 K member 1 LAMP3 CD208, DC LAMP, DC- lysosomal
associated 605883 27074 LAMP, DCLAMP, membrane protein 3 LAMP,
LAMP-3, TSC403 MAGEA1 CT1.1; MAGE1 MAGE family member A1 300016
4100 MAGEA3 HIP8; HYPD; CT1.3; MAGE family member A3 300174 4102
MAGE3; MAGEA6, MAGE-A3 (G-2544) MAGEB2 CT3.2, DAM6, MAGE- MAGE
family member B2 300098 4113 XP-2 MAPK13 MAPK 13, MAPK-13,
mitogen-activated protein 602899 5603 PRKM13, SAPK4, kinase 13
p38delta MARCO SCARA2, SR-A6 macrophage receptor with 604870 8685
collagenous structure ME1 HUMNDME, MES malic enzyme 1 154250 4199
MIIP IIP45, IGFBP-2 migration and invasion 608772 60672 inhibitory
protein MMP12 HME, ME, MME, MMP- matrix metallopeptidase 12 601046
4321 12 MMP7 MMP-7, MPSL1, matrix metallopeptidase 7 178990 4316
PUMP-1 MPZL1 MPZL1b, PZR, PZR1b, myelin protein zero like 1 604376
9019 PZRa, PZRb MSR1 CD204, SCARA1, SR-A, macrophage scavenger
153622 4481 SR-AI, SR-AII, SR-AIII, receptor 1 SRA, phSR1, ph MUC1
EMA; MCD; PEM; mucin-1 isoform 14 158340 4582 PUM; KL-6; MAM6;
precursor MCKD; PEMT; CD227; H23AG; MCKD1; MUC-1; ADMCKD; ADMCKD1;
CA 15-3; MUC-1/X; MUC1/ZD; MUC-1/SEC MYNN OSZF, SBBIZ1, myoneurin
606042 55892 ZBTB31, ZNF902 NAGK GNK, HSA242910 N-acetylglucosamine
606828 55577 kinase NAPSA KAP, Kdap, NAP1, napsin A aspartic
peptidase 605631 9476 NAPA, SNAPA NFYC CBF-C, CBFC, nuclear
transcription factor 605344 4802 H1TF2A, HAP5, HSM, Y subunit gamma
NF-YC NKRF ITBA4, NRF NFKB repressing factor 300440 55922 PLAU ATF,
BDPLT5, QPD, plasminogen activator, 191840 5328 UPA, URK, u-PA
urokinase ROR1 NTRKR1, dJ537F10.1 receptor tyrosine kinase 602336
4919 like orphan receptor 1 RUNX1 AML1, AML1-EVI-1, runt related
transcription 151385 861 AMLCR1, CBF2alpha, factor 1 CBFA2, EVI-1,
PEBP2aB, SFTPA1 COLEC4, PSAP, PSP-A, surfactant protein A1 178630
653509 PSPA, SFTP1B, SP-A, SP-A1, SPA, SPA1, SFTPA2 COLEC5, PSAP,
PSP-A, surfactant protein A2 178642 729238 PSPA, SFTP1B, SP-2A,
SP-A, SPA2, SPAII SFTPB PSP-B, SFTB3, SFTP3, surfactant protein B
178640 6439 SMDP1, SP-B SFTPC BRICD6, PSP-C, SFTP2, surfactant
protein C 178620 6440 SMDP2, SP-C SFTPD COLEC7, PSP-D, surfactant
protein D 178635 6441 SFTP4, SP-D SLC2A5 GLUT-5, GLUT5, SGT1 solute
carrier family 2 138230 6518 member 5 SPAG9 CT89, HLC-6, HLC4,
sperm associated antigen 9 605430 9043 HLC6, JIP-4, JIP4, JLP,
PHET, PIG6 SSX2 SSX; HD21; CT5.2; protein SSX2 300192 6757 CT5.2A;
HOM-MEL-40 SUGT1 SGT1 SGT1 homolog, MIS12 604098 10910 kinetochore
complex assembly cochaperone SULT1C2 ST1C1, ST1C2, sulfotransferase
family 1C 602385 6819 SULT1C1, humSULTC2 member 2 TGFBR2 AAT3,
FAA3, LDS1B, transforming growth factor 190182 7048 LDS2, LDS2B,
MFS2, beta receptor 2 RTIC, TAAD2, TGFR-2, TMEM52B transmembrane
protein 120939 52B TP53 P53; BCC7; LFS1; cellular tumor antigen p53
191170 7157 TRP53 isoform a VEGF-A VPF; VEGF; MVCD1 vascular
endothelial 192240 7422 growth factor A XPO7 EXP7, RANBP16 exportin
7 606140 23039 YES1 HsT441, P61-YES, Yes, YES proto-oncogene 1,
164880 7525 c-yes Src family tyrosine kinase CCDC80 DRO1, SSG1,
URB, coiled-coil domain 608298 151887 okuribin containing 80 OMIM =
Online Mendelian Inheritance in Man database GeneID = NCBI
database
ATLAS Library Screening
[0383] Blood samples were collected from 13 consenting patients
undergoing ICI therapy. Frozen peripheral blood mononuclear cells
(PBMC) were purchased from Bioreclamation (New York). After thaw,
CD4.sup.+ and CD8.sup.+ T cells were sorted using
antibody-conjugated magnetic beads and non-specifically expanded
with anti-CD3 and anti-CD28 stimulation. CD14.sup.+ monocytes were
also sorted using antibody-conjugated magnetic beads and
differentiated in vitro into dendritic cells (MDDCs).
[0384] CD4.sup.+ and CD8.sup.+ T cells were screened against the 76
library clones, as well as against 10 negative control clones
expressing Neon Green (NG). Library clones were screened using
1,000-5,000 MDDCs and 80,000 T cells, at an E. coli:MDDC ratio of
333:1. After 24h incubation, assay supernatants were harvested and
stored at -80.degree. C. Supernatant cytokines levels were analyzed
using a Meso Scale Discovery custom plate.
Data Analysis
[0385] Clones that induced median cytokine responses that exceeded
2 median absolute deviations (MADs) of the median responses to the
negative control Neon Green clones (N=10) (indicated by a
horizontal dotted line in FIG. 18 and FIG. 19) were considered
antigens. Clones that reduced median cytokine responses to two MADs
below the median negative control responses were considered
inhibitory and/or suppressive antigens.
[0386] FIG. 18 shows an exemplary empirical determination of T cell
responses to profiled TAAs. Exemplary data is shown for a single
lung cancer patient. T cell responses were reported as natural log
concentrations back-calculated from the MSD standard curve and
normalized to the patient's response to a negative control protein.
A stimulatory response was defined as a TAA with a median
concentration greater than two MADs above the median of the
negative control replicates. This threshold is shown as the upper
dashed horizontal line, and stimulatory responses are shown as
filled circles. An inhibitory and/or suppressive response was
defined as a TAA with a median concentration greater than two MADs
of the negative control replicates below the median of the negative
control replicates. This threshold is shown as the lower dashed
horizontal line, and inhibitory and/or suppressive responses are
shown as filled triangles.
[0387] FIG. 19 shows frequent CD4.sup.+ T cell responses to novel
TAAs compared to previously described TAAs. Across patients,
IFN-.gamma. CD4.sup.+ T cell responses to two novel TAAs (Novel
TAA1=HPSE1; Novel TAA2=HPSE2) appeared to be stronger than
responses to NY-ESO-1, MUC1, and MAGEA3, three TAAs that have been
utilized in cancer vaccines in clinical trials for treatment of
lung cancer patients. Each point represents a patient's response to
that TAA, normalized to the patient's response to an irrelevant
negative control protein. Stimulatory responses, those that fall
above the 2.times.MAD cutoff indicated by the upper horizontal
dotted line, are colored black. Both the median normalized
concentration and the proportion of stimulatory responses to these
two TAAs were higher than those of the three other TAAs. CD8+
responses to these five TAAs were more similar across patients (not
shown).
[0388] FIG. 20 shows that lung cancer patients develop CD4.sup.+
and CD8.sup.+ T cell responses to a broad range of TAAs. Across
lung cancer patients, stimulatory CD4.sup.+ and/or CD8.sup.+ T cell
responses were observed in at least one individual to a clear
majority of the 76 profiled TAAs. The percent of patients that
developed a stimulatory T cell response to each TAA is shown
separately for CD4.sup.+ (grey bars) and CD8.sup.+ (black bars) T
cells. IFN-.gamma. responses are displayed in the top two panels,
and TNF-.alpha. responses are displayed in the bottom two panels.
Antigens to which patients developed both a CD4.sup.+ and a
CD8.sup.+ T cell response (left panels) were differentiated from
antigens to which patients developed either a CD4.sup.+ or a
CD8.sup.+ T cell response (right panels).
[0389] FIG. 21 shows that inhibitory and/or suppressive T cell
responses were detected in most profiled TAAs. Inhibitory and/or
suppressive T cell responses to TAAs were observed frequently
across the profiled lung cancer patients. For each profiled TAA,
the percent of patients that developed an inhibitory and/or
suppressive T cell response, defined as a response that is two MADs
lower than the response to the negative control protein, are shown
for CD4.sup.+ (white bars) and CD8.sup.+ (grey bars) T cells.
IFN-.gamma. responses are displayed in the top two panels, and
TNF-.alpha. responses are displayed in the bottom two panels.
Antigens to which patients developed both a CD4.sup.+ and a
CD8.sup.+ T cell response (left panels) were differentiated from
antigens to which patients developed either a CD4.sup.+ or a
CD8.sup.+ T cell response (right panels).
Example 9. Neoantigen Identification Using ATLAS.sup.T Across
Multiple Tumor Types
Generation of the ATLAS Neoantigen Library
[0390] ATLAS was applied to characterize and profile pre-existing T
cell responses to tumor specific mutations in a diverse set of
cancer patients. Tumor biopsy and normal tissue samples were
collected from 19 consenting patients. Whole exome and RNA
sequencing of the tumor sample and whole exome sequencing of the
matched normal sample identified mutations which are unique to the
tumor and not present in the germline of the patient. Each somatic
protein altering mutation was expressed as individual clones in the
ATLAS expression vector and sequence verified. Each clone was
recombinantly expressed in E. coli, with expression verified using
Western Blot analysis.
ATLAS Library Screening
[0391] Blood samples were collected from 19 consenting patients and
PBMCs isolated using standard procedures. Frozen peripheral blood
mononuclear cells (PBMCs) were purchased from Conversant (Alabama)
or obtained from collaborators. After thaw, CD4.sup.+ and CD8.sup.+
T cells were sorted using antibody-conjugated magnetic beads and
non-specifically expanded with anti-CD3 and anti-CD28 stimulation.
CD14.sup.+ monocytes were also sorted using antibody-conjugated
magnetic beads and differentiated in vitro into myeloid derived
dendritic cells (MDDCs).
[0392] CD4.sup.+ and CD8.sup.+ T cells were screened against the
individuals' specific library clones, as well as against multiple
negative control clones expressing Neon Green (NG). Library clones
were screened using 1,000-5,000 MDDCs and 80,000 T cells, at an E.
coli:MDDC ratio of 333:1. After 24h incubation, assay supernatants
were harvested and stored at -80.degree. C. Supernatant cytokines
levels were analyzed using a Meso Scale Discovery custom plate.
Data Analysis
[0393] Clones that induced median cytokine responses that exceeded
2 median absolute deviations (MADs) of the median responses to the
negative control Neon Green clones (indicated by horizontal dotted
line in FIG. 22) were considered stimulatory neoantigens. Clones
that reduced median cytokine responses to 2 MADs below the median
negative control responses were considered inhibitory and/or
suppressive neoantigens.
[0394] FIG. 22 shows an exemplary neoantigen screen with ATLAS
identifying patient-specific CD4.sup.+ and CD8.sup.+ T cell
responses. For one pancreatic cancer subject, displayed are the
CD4+ and CD8+ T cell responses observed in response to each
candidate neoantigen. Each dot represents a technical replicate.
Horizontal dotted lines indicate the cutoffs used to define
stimulatory neoantigens and inhibitory and/or suppressive
neoantigens at +3 and -3 Median Absolute Deviations (MADs),
respectively.
[0395] FIGS. 23A, 23B, 23C, and 23D show that an algorithm
predicting MHC Class I binding did not accurately predict CD8.sup.+
T cell responses or type of response. The diagrams compare MHC
class I algorithm-based binding predictions (NetMHCpan predictions
with binding affinity cutoff of <500 nM) and T cell responses
observed in ATLAS across 11 initial subjects and across all 19
subjects. FIGS. 23A and 23C show the total numbers and overlap of
neoantigens predicted by algorithm and observed in ATLAS for the 11
initial subjects and for all 19 subjects, respectively. FIGS. 23B
and 23D show the break-down of predictions by strong binding
(<150 nM), weak binding (<500 nM), or non-binding (>=500
nM) for the 11 initial subjects and for all 19 subjects,
respectively. There was no enrichment of either stimulatory or
inhibitory and/or suppressive responses in CD8.sup.+ T cells across
binding prediction groups.
[0396] FIGS. 24A and 24B show that CD8.sup.+ T cell responses
identified by ATLAS to candidate stimulatory neoantigens were not
enriched for any mutation type. In FIG. 24A, mutation types for the
11 initial subjects were defined as missense, in-frame, or
frameshift. In FIG. 24B, mutation types for all 19 subjects were
defined as short variant (a combination of missense and in-frame
mutations resulting in 1-2 amino acid changes relative to wild-type
gene sequence) and neoORF (a combination of frameshift and
loss-of-stop-codon mutations resulting in 3 or more amino acid
changes relative to wild-type gene sequence). In this example,
candidate inhibitory and/or suppressive neoantigens were somewhat
more frequently associated with missense or short variant
mutations.
[0397] FIGS. 25A and 25B show that lower DNA mutant allele
frequency has a moderate association with CD8.sup.+ T cell response
frequency (P-value=0.037). Mutant DNA allele frequency was derived
from whole exome sequencing and compared to response type observed.
FIG. 25A shows results for the 11 initial subjects. FIG. 25B shows
results for all 19 subjects.
[0398] FIGS. 26A and 26B show that detection of a mutation in RNA
did not predict whether the candidate stimulatory or
inhibitory/suppressive antigen has a recall response in CD8.sup.+ T
cells. RNA-seq was performed on the tumor material. Somatic
mutations were identified via whole exome sequencing, and the
RNA-seq data was interrogated for the presence or absence of
mutations identified in DNA. FIG. 26A shows results for 8 of the 11
initial subjects. FIG. 26B shows results for all 19 subjects.
[0399] FIGS. 27A and 27B show that CD8+ T cell responses identified
by ATLAS to candidate neoantigens did not correlate with gene
expression. RNA-seq was performed on the tumor material;
quantitative gene expression values were calculated for each gene
harboring a candidate neoantigen and compared to normalized
cytokine measurements. FIG. 27A shows results for 10 of the 11
initial subjects. FIG. 27B shows results for all 19 subjects.
Example 10. Different Cytokine Responses to Different Neoantigens
Identified Using ATLAS in a Pancreatic Cancer Patient
Generation of the ATLAS Neoantigen Library
[0400] ATLAS was applied to screen the entire complement of
mutations identified in the tumor of a consented pancreatic cancer
patient. An ATLAS library was built that expressed 22 mutations
unique to this patient. Each clone contained 113 amino acids with
the mutation positioned near the center of the construct and
sequence-verified. Each clone was recombinantly expressed in E.
coli and protein expression was verified using Western Blot.
[0401] ATLAS Library Screening
[0402] Frozen peripheral blood mononuclear cells (PBMC) were
purchased from Conversant Bio. After thaw, CD8.sup.+ T cells were
sorted using antibody-conjugated magnetic beads and
non-specifically expanded with anti-CD3 and anti-CD28 stimulation.
CD14+ monocytes were also sorted using antibody-conjugated magnetic
beads and differentiated in vitro into dendritic cells (MDDC).
[0403] CD8.sup.+ T cells were screened against the 22 library
clones, as well as against a negative control clones expressing
Neon Green (NG). Library clones were screened using 5,000 MDDC and
80,000 T cells, at an E. coli:MDDC ratio of 333:1. After 19.5 h
incubation, assay supernatants were harvested and stored at
-80.degree. C. Supernatant cytokines CM-CSF, IFN.gamma., IL-10,
MIF, TNF.alpha., and TRAIL were analyzed using a Meso Scale
Discovery custom plate.
Data Analysis
[0404] FIG. 28 shows the different CM-CSF, IFN.gamma., IL-10, MIF,
TNF.alpha., and TRAIL response profiles elicited by six
representative neoantigens in a screen of CD8.sup.+ T cells from
the patient. Each panel corresponds to one neoantigen (denoted
G-3618, G-3624, G-3620, G-3627, G-3617, and G-3632). The horizontal
line in each panel indicates the median response to the negative
controls. Bars above the horizontal line indicate stimulation of
cytokine secretion. Bars below the horizontal line indicate
inhibition and/or suppression of cytokine secretion. The panels
illustrate the different cytokine responses elicited by each
neoantigen.
Example 11. T Cell Responses to VEGF in a Cohort of Cancer Patients
and Healthy Donors
[0405] PBMC from eight cancer patients (seven lung cancer, one
colorectal cancer) and 13 healthy donors were screened in duplicate
against VEGF, a known TAA. CD8.sup.+ T cells were sorted and
non-specifically expanded using anti-CD3 and anti-CD28-coated
microbeads, and CD14.sup.+ monocytes were differentiated into
dendritic cells (MDDC). Library clones were screened in duplicate
using 5,000 MDDC and 80,000 T cells, at an E. coli:MDDC ratio of
100:1; replicates of E. coli expressing neon green (NG) were
included as negative controls. Assay supernatants were harvested at
24 hr and stored at -80.degree. C. Supernatant cytokines were
analyzed using Meso Scale Discovery V-PLEX Proinflammatory Panel 1
(human) Kit.
Data Analysis
[0406] Clones that induced mean cytokine responses that exceeded 2
median average deviations (MAD) of the median responses to the
negative control NG clones (N=10) were considered antigens. FIG. 29
shows CD8.sup.+ T cell data for healthy donors (black bars) and
cancer patients (white bars). The median log cytokine response
normalized to neon green are indicated for each subject cohort.
When analyzed by IFN.gamma. secretion, there was a large inhibitory
response in the healthy donor cohort, that greatly exceeded the
inhibitory responses in the cancer patient cohort. Conversely,
there was a greater median inhibitory response in the cancer cohort
when TNF.alpha. secretion was considered.
Example 12. In Vitro Immunization Using Combination of 3 TAAs
Protocol for In Vitro Immunization
[0407] PBMCs from healthy donors are enriched using standard
protocols. Washed PBMCs are resuspended in supplemented RPMI-1640
medium. 100 .mu.L cells (2.times.10.sup.6cell/mL) are added into
each well of a 96-well flat-bottom assay plate. Overlapping
peptides corresponding to TAAs HPSE1, HPSE2, SMAD4, MUC1, MAGEA3,
and TP53 were added to cultures at a final concentration of 50
.mu.g/mL. Cultures are incubated for 5 days, the peptide-containing
medium removed, then cultures provided with human IL-2 (10 U/mL)
for 11 days, with IL-2-containing medium being replenished every 3
days. The incubation time of 5 days with peptide plus 11 days with
IL-2 constitutes one cycle. Primary cultures are subsequently
restimulated with the same peptides (50 ng/mL) on day 16 to begin
the next cycle. Irradiated (4000 rad) autologous peripheral blood
mononuclear cells (5.times.10.sup.5) are added in a volume of 50
.mu.L in complete medium as APCs. An ELISPOT is performed on an
aliquot of cells at the end of each cycle to observe de novo
responses to the peptides.
TABLE-US-00009 LISTING OF SEQUENCES Heparanase isoform 1,
preproprotein, NP_001092010.1, NP_006656.2 (SEQ ID NO: 6) 1
mllrskpalp pplmllllgp lgplspgalp rpaqaqdvvd ldfftqeplh lvspsflsvt
61 idanlatdpr flillgspkl rtlarglspa ylrfggtktd flifdpkkes
tfeersywqs 121 qvngdickyg sippdveekl rlewpyqeql llrehyqkkf
knstysrssv dvlytfancs 181 gldlifglna llrtadlqwn ssnaqllldy
csskgynisw elgnepnsfl kkadifings 241 qlgedfiqlh kllrkstfkn
aklygpdvgq prrktakmlk sflkaggevi dsvtwhhyyl 301 ngrtatkedf
lnpdvldifi ssvqkvfqvv estrpgkkvw lgetssaygg gapllsdtfa 361
agfmwldklg lsarmgievv mrqvffgagn yhlvdenfdp lpdywlsllf kklvgtkvlm
421 asvqgskrrk lrvylhctnt dnprykegdl tlyainlhnv tkylrlpypf
snkqvdkyll 481 rplgphglls ksvqlngltl kmvddqtlpp lmekplrpgs
slglpafsys ffvirnakva 541 aci Heparanase isoform 2, preproprotein,
NP_001159970.1 (SEQ ID NO: 7) 1 mllrskpalp pplmllllgp lgplspgalp
rpaqaqdvvd ldfftqeplh lvspsflsvt 61 idanlatdpr flillgspkl
rtlarglspa ylrfggtktd flifdpkkes tfeersywqs 121 qvngdickyg
sippdveekl rlewpyqeql llrehyqkkf knstysrssv dvlytfancs 181
gldlifglna llrtadlqwn ssnaqllldy csskgynisw elgnepnsfl kkadifings
241 qlgedfiqlh kllrkstfkn aklygpdvgq prrktakmlk sflkaggevi
dsvtwhhyyl 301 ngrtatkedf lnpdvldifi ssvqkvfqdy wlsllfkklv
gtkvlmasvq gskrrklrvy 361 lhctntdnpr ykegdltlya inlhnvtkyl
rlpypfsnkq vdkyllrplg phgllsksvq 421 lngltlkmvd dqtlpplmek
plrpgsslgl pafsysffvi rnakvaaci SMAD family member 4 , mothers
against decapentaplegic homolog 4, NP_005350.1 (SEQ ID NO: 8) 1
mdnmsitntp tsndaclsiv hslmchrqgg esetfakrai eslvkklkek kdeldslita
61 ittngahpsk cvtiqrtldg rlqvagrkgf phviyarlwr wpdlhknelk
hvkycqyafd 121 lkcdsvcvnp yhyervvspg idlsgltlqs napssmmvkd
eyvhdfegqp slsteghsiq 181 tiqhppsnra stetystpal lapsesnats
tanfpnipva stsqpasilg gshsegllqi 241 asgpqpgqqq ngftgqpaty
hhnstttwtg srtapytpnl phhqnghlqh hppmpphpgh 301 ywpvhnelaf
qppisnhpap eywcsiayfe mdvqvgetfk vpsscpivtv dgyvdpsggd 361
rfclgqlsnv hrteaierar lhigkgvqle ckgegdvwvr clsdhavfvq syyldreagr
421 apgdavhkiy psayikvfdl rqchrqmqqq aataqaaaaa qaaavagnip
gpgsvggiap 481 aislsaaagi gvddlrrlci lrmsfvkgwg pdyprqsike
tpcwieihlh ralqlldevl 541 htmpiadpqp ld Cadherin 3, isoform 1
preproprotein, NP_001784.2 (SEQ ID NO: 9) 1 mglprgplas llllqvcwlq
caaseperav freaevtlea ggaegepgqa lgkvfmgcpg 61 qepalfstdn
ddftvrnget vqerrslker nplkifpskr ilrrhkrdwv vapisvpeng 121
kgpfpqrlnq lksnkdrdtk ifysitgpga dsppegvfav eketgwllln kpldreeiak
181 yelfghavse ngasvedpmn isiivtdqnd hkpkftqdtf rgsvlegvlp
gtsvmqvtat 241 deddaiytyn gvvaysihsq epkdphdlmf tihrstgtis
vissgldrek vpeytltiqa 301 tdmdgdgstt tavavveild andnapmfdp
qkyeahvpen avghevqrlt vtdldapnsp 361 awratylimg gddgdhftit
thpesnqgil ttrkgldfea knqhtlyvev tneapfvlkl 421 ptstativvh
vedvneapvf vppskvvevq egiptgepvc vytaedpdke nqkisyrilr 481
dpagwlamdp dsgqvtavgt ldredeqfvr nniyevmvla mdngsppttg tgtllltlid
541 vndhgpvpep rqiticnqsp vrqvlnitdk dlsphtspfq aqltddsdiy
wtaevneegd 601 tvvlslkkfl kqdtydvhls lsdhgnkeql tviratvcdc
hghvetcpgp wkggfilpvl 661 gavlallfll lvllllvrkk rkikeplllp
eddtrdnvfy ygeegggeed qdyditqlhr 721 glearpevvl rndvaptiip
tpmyrprpan pdeignfiie nlkaantdpt appydtllvf 781 dyegsgsdaa
slssltssas dqdqdydyln ewgsrfkkla dmygggedd Cadherin 3, isoform 2
precursor, NP_001304124.1 (SEQ ID NO: 10) 1 mglprgplas llllqvcwlq
caasepcrav freaevtlea ggaeqepgqa lgkvfmgcpg 61 qepalfstdn
ddftvrnget vqerrslker nplkifpskr ilrrhkrdwv vapisvpeng 121
kgpfpqrlnq lksnkdrdtk ifysitgpga dsppegvfav eketgwllln kpldreeiak
181 yelfghavse ngasvedpmn isiivtdqnd hkpkftqdtf rgsvlegvlp
gtsvmqvtat 241 deddaiytyn gvvaysihsq epkdphdlmf tihrstgtis
vissgldrek vpeytltiqa 301 tdmdgdgstt tavavveild andnapmfdp
qkyeahvpen avghevqrlt vtdldapnsp 361 awratylimg gddgdhftit
thpesnqgil ttrkgldfea knqhtlyvev tneapfvlkl 421 ptstativvh
vedvneapvf vppskvvevq egiptgepvc vytaedpdke nqkisyrilr 481
dpagwlamdp dsgqvtavgt ldredeqfvr nniyevmvla mdngsppttg tgtllltlid
541 vndhgpvpep rqiticnqsp vrqvlnitdk dlsphtspfq aqltddsdiy
wtaevneegd 601 tvvlslkkfl kqdtydvhls lsdhgnkeql tviratvcdc
hghvetcpgp wkggfilpvl 661 gavlallfll lvllllvrkk rkikeplllp
eddtrdnvfy ygeegggeed qdyditqlhr 721 glearpevvl rndvaptiip
tpmyrprpan pdeignfiie grgergsqrg ngglqlargr 781 trrs Cadherin 3,
isoform 3, NP_001304125.1 (SEQ ID NO: 11) 1 mgcpgqepal fstdnddftv
rngetvgerr slkernplki fpskrilrrh krdwvvapis 61 vpengkgpfp
qrlnqlksnk drdtkifysi tgpgadsppe gvfaveketg wlllnkpldr 121
eeiakyelfg havsengasv edpmnisiiv tdqndhkpkf tqdtfrgsvl egvlpgtsvm
181 qvtatdedda iytyngvvay sihsqepkdp hdlmftihrs tgtisvissg
ldrekvpeyt 241 ltiqatdmdg dgstttavav veildandna pmfdpqkyea
hvpenavghe vqrltvtdld 301 apnspawrat ylimggddgd hftitthpes
nqgilttrkg ldfeaknqht lyvevtneap 361 fvlklptsta tivvhvedvn
eapvfvppsk vvevqegipt gepvcvytae dpdkenqkis 421 yrilrdpagw
lamdpdsgqv tavgtldred eqfvrnniye vmvlamdngs ppttgtgtll 481
ltlidvndhg pvpeprqiti cnqspvrqvl nitdkdlsph tspfqaqltd dsdiywtaev
541 neegdtvvls lkkflkqdty dvhlslsdhg nkeqltvira tvcdchghve
tcpgpwkggf 601 ilpvlgavla llflllvlll lvrkkrkike plllpeddtr
dnvfyygeeg ggeedqdydi 661 tqlhrglear pevvlrndva ptiiptpmyr
prpanpdeig nfiienlkaa ntdptappyd 721 tllvfdyegs gsdaaslssl
tssasdqdqd ydylnewgsr fkkladmygg gedd Chorionic gonadotropin beta
subunit 3, precursor, NP_000728.1 (SEQ ID NO: 12) 1 memfqgllll
lllsmggtwa skeplrprcr pinatlavek egcpvcitvn tticagycpt 61
mtrvlqgvlp alpqvvcnyr dvrfesirlp gcprgvnpvv syavalscqc alcrrsttdc
121 ggpkdhpltc ddprfqdsss skapppslps psrlpgpsdt pilpq Chorionic
gonadotropin beta subunit 5, precursor, NP_149032.1 (SEQ ID NO: 13)
1 memfggllll lllsmggtwa skeplrprcr pinatlavek egcpvcitvn tticagycpt
61 mtrvlqgvlp alpqvvcnyr dvrfesirlp gcprgvnpvv syavalscqc
alcrrsttdc 121 ggpkdhpltc ddprfqdsss skapppslps psrlpgpsdt pilpq
Cytochrome c oxidase assembly factor 1 homolog, isoform a,
NP_001308126.1, NP_001308127.1, NP_001308128.1, NP_001308129.1,
NP_001337853.1, NP_001337854.1, NP_001337855.1, NP_001337856.1,
NP_060694.2 (SEQ ID NO: 14) 1 mmwqkyagsr rsmplgaril fhgvfyaggf
aivyyliqkf hsralyykla veqlqshpea 61 qealgppini hylklidren
fvdivdaklk ipvsgskseg llyvhssrgg pfqrwhldev 121 flelkdgqqi
pvfklsgeng devkke Cytochrome c oxidase assembly factor 1 homolog,
isoform b, NP_001308130.1 (SEQ ID NO: 15) 1 mplgarilfh gvfyaggfai
vyyliqkfhs ralyyklave qlqshpeaqe algpplnihy 61 lklidrenfv
divdaklkip vsgsksegll yvhssrggpf qrwhldevfl elkdgqqipv 121
fklsgengde vkke Cytochrome c oxidase assembly factor 1 homolog,
isoform c, NP_001308131.1, NP_001308132.1, NP_001308133.1,
NP_001308134.1 (SEQ ID NO: 16) 1 mmwqkyagsr rsmplgaril fhgvfyaggf
aivyyliqsk ypasrlrpdl llacscssir 61 gnt Cytochrome c oxidase
assembly factor 1 homolog, isoform d, NP_001337857.1 (SEQ ID NO:
17) 1 mqeaggqclw eqgsfstvcs mpgalplcit sfkfhsraly yklaveqlqs
hpeaqealgp 61 pinihylkli drenfvdivd aklkipvsgs ksegllyvhs
srggpfqrwh ldevflelkd 121 gqqipvfkls gengdevkke Estrogen receptor
binding site associated, antigen, 9, NP_001265867.1, NP_004206.1,
NP_936056.1, NP_001308129.1, (SEQ ID NO: 18) 1 maitqfrlfk
fctclatvfs flkrlicrsg rgrklsgdqi tlpttvdyss vpkqtdveew 61
tswdedapts vkieggngnv atqqnsleql epdyfkdmtp tirktqkivi kkreplnfgi
121 pdgstgfssr laatqdlpfi hqsselgdld twqentnawe eeedaawqae
evlrqqklad 181 rekraaeqqr kkmekeaqrl mkkeqnkigv kls ETS
transcription factor, isoform a, NP_001964.2 (SEQ ID NO: 19) 1
mdsaitlwqf llqllqkpqn khmicwtsnd gqfkllqaee varlwgirkn kpnmnydkls
61 ralryyyvkn iikkvngqkf vykfvsypei lnmdpmtvgr iegdceslnf
sevsssskdv 121 enggkdkppq pgaktssrnd yihsglyssf tlnslnssnv
klfklikten paeklaekks 181 pqeptpsvik fvttpskkpp vepvaatisi
gpsispssee tiqaletlvs pklpsleapt 241 sasnvmtafa ttppissipp
lqepprtpsp plsshpdidt didsvasqpm elpenlslep 301 kdqdsvllek
dkvnnssrsk kpkglelapt lvitssdpsp lgilspslpt asltpaffsq 361
tpiiltpspl lssihfwstl spvaplspar lqgantlfqf psvlnshgpf tlsgldgpst
421 pgpfspdlqk t ETS transcription factor, isoform b, NP_068567.1
(SEQ ID NO: 20) 1 mdsaitlwqf llqllqkpqn khmicwtsnd gqfkllqaee
varlwgirkn kpnmnydkls 61 ralryyyvkn iikkvngqkf vykfvsypei
lnmdpmtvgr iegdceslnf sevsssskdv 121 enggkdkppq pgaktssrnd
yihsglyssf tlnslnssnv klfklikten paeklaekks 181 pqeptpsvik
fvttpskkpp vepvaatisi gpsispssee tiqaletivs pklpsleapt 241
sasnvmtafa ttppissipp lqepprtpsp plsshpdidt didsvasqpm elpenlslep
301 kdqdsvllek dkvnnssrsk kpkglelapt lvitssdpsp lgilspslpt
asltpaffsq 361 vacslfmvsp llsficpfkq iqnlytqvcf lllrfvlerl cvtvm
Receptor tyrosine-protein kinase erbB-2, isoform a precursor,
NP_004439.2 (SEQ ID NO: 21) 1 melaalcrwg lllallppga astqvctgtd
mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflgdiqev
qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dplnnttpvt
gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181
ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc
241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt
fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar
vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta
plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga
ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph
qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541
veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc
601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp
ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl
tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv
aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql
mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn
vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901
hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm
961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle
dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt
lglepseeea prsplapseg 1081 agsdvfdgdl gmgaakglqs lpthdpsplq
rysedptvpl psetdgyvap ltcspqpeyv 1141 nqpdvrpqpp spregplpaa
rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq 1201 ggaapqphpp
pafspafdnl yywdqdpper gappstfkgt ptaenpeylg ldvpv Receptor
tyrosine-protein kinase erbB-2, isoform b, NP_001005862.1 (SEQ ID
NO: 22) 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas lsflqdiqev
qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng dplnnttpvt
gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk difhknnqla
ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc aggcarckgp
lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241 lvtyntdtfe
smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr 301
cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes fdgdpasnta
361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv irgrilhnga
ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv pwdqlfrnph
qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn csqflrgqec
veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe adqcvacahy
kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 thscvdlddk
gcpaeqrasp ltsiisavvg illvvvlgvv fgilikrrqq kirkytmrrl 661
lqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi pdgenvkipv
721 aikvlrents pkankeilde ayvmagvgsp yvsrllgicl tstvqlvtql
mpygclldhv 781 renrgrlgsq dllnwcmqia kgmsyledvr lvhrdlaarn
vlvkspnhvk itdfglarll 841 dideteyhad ggkvpikwma lesilrrrft
hqsdvwsygv tvwelmtfga kpydgipare 901 ipdllekger lpqppictid
vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq 961 nedlgpaspl
dstfyrslle dddmgdlvda eeylvpqqgf fcpdpapgag gmvhhrhrss 1021
strsgggdlt lglepseeea prsplapseg agsdvfdgdl gmgaakglqs lpthdpsplq
1081 rysedptvpl psetdgyvap ltcspqpeyv nqpdvrpqpp spregplpaa
rpagatlerp 1141 ktlspgkngv vkdvfafgga venpeyltpq ggaapqphpp
pafspafdnl yywdqdpper 1201 gappstfkgt ptaenpeylg ldvpv Receptor
tyrosine-protein kinase erbB-2, isoform c, NP_001276865.1 (SEQ ID
NO: 23) 1 mprgswkpqv ctgtdmklrl paspethldm lrhlyqgcqv vqgnleltyl
ptnaslsflq 61 diqevqgyvl iahnqvrqvp lqrlrivrgt qlfednyala
vldngdplnn ttpvtgaspg 121 glrelqlrsl teilkggvli qrnpqlcyqd
tilwkdifhk nnqlaltlid tnrsrachpc 181 spmckgsrcw gessedcqsl
trtvcaggca rckgplptdc cheqcaagct gpkhsdclac 241 lhfnhsgice
lhcpalvtyn tdtfesmpnp egrytfgasc vtacpynyls tdvgsctlvc 301
plhnqevtae dgtqrcekcs kpcarvcygl gmehlrevra vtsaniqefa gckkifgsla
361 flpesfdgdp asntaplqpe qlqvfetlee itgylyisaw pdslpdlsvf
qnlqvirgri 421 lhngaysltl gglgiswlgl rslrelgsgl alihhnthlc
fvhtvpwdql frnphqallh 481 tanrpedecv geglachqlc arghcwgpgp
tqcvncsqfl rgqecveecr vlqglpreyv 541 narhclpchp ecqpqngsvt
cfgpeadqcv acahykdppf cvarcpsgvk pdlsympiwk 601 fpdeegacqp
cpincthscv dlddkgcpae qraspltsii savvgillvv vlgvvfgili 661
krrqqkirky tmrrllqete lvepltpsga mpnqaqmril ketelrkvkv lgsgafgtvy
721 kgiwipdgen vkipvaikvl rentspkank eildeayvma gvgspyvsrl
lgicltstvq 781 lvtqlmpygc lldhvrenrg rlgsqdllnw cmqiakgmsy
ledvrlvhrd laarnvlvks 841 pnhvkitdfg larlldidet eyhadggkvp
ikwmalesil rrrfthqsdv wsygvtvwel 901 mtfgakpydg ipareipdll
ekgerlpqpp ictidvymim vkcwmidsec rprfrelvse 961 fsrmardpqr
fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp 1021
apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdv fdgdlgmgaa
1081 kglqslpthd psplqrysed ptvplpsetd gyvapltcsp qpeyvnqpdv
rpqppspreg 1141 plpaarpaga tlerpktlsp gkngvvkdvf afggavenpe
yltpqggaap qphpppafsp 1201 afdnlyywdq dppergapps tfkgtptaen
peylgldvpv Receptor tyrosine-protein kinase erbB-2, isoform d
precursor, NP_001276866.1 (SEQ ID NO: 24) 1 melaalcrwg lllallppga
astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas
lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121
dplnnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla
181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp
lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe
smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr
cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes
fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv
irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481
pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrggec
541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy
kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk
gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl
lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi
pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl
tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841
lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft
901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid
vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl
dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss
strnm
Receptor tyrosine-protein kinase erbB-2, isoform e, NP_001276867.1
(SEQ ID NO: 25) 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas
lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng
dplnnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk
difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc
aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241
lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr
301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes
fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv
irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv
pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn
csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe
adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 ths
Inosine monophosphate dehydrogenase 2 , NP_000875.2 (SEQ ID NO: 26)
1 madylisggt syvpddglta qqlfncgdgl tyndflilpg yidftadqvd ltsaltkkit
61 lktplvsspm dtvteagmai amaltggigf ihhnctpefq anevrkvkky
eqgfitdpvv 121 lspkdrvrdv feakarhgfc gipitdtgrm gsrlvgiiss
rdidflkeee hdcfleeimt 181 kredlvvapa gitlkeanei lqrskkgklp
ivneddelva iiartdlkkn rdyplaskda 241 kkqllcgaai gtheddkyrl
dllaqagvdv vvldssqgns ifqinmikyi kdkypnlqvi 301 ggnvvtaaqa
knlidagvda lrvgmgsgsi citqevlacg rpqatavykv seyarrfgvp 361
viadggiqnv ghiakalalg astvmmgsll aatteapgey ffsdgirlkk yrgmgsldam
421 dkhlssqnry fseadkikva qgvsgavqdk gsihkfvpyl iagiqhscqd
igaksltqvr 481 ammysgelkf ekrtssaqve ggvhslhsye krlf KRAS
proto-oncogene, GTPase, isoform a, NP_203524.1 (SEQ ID NO: 27) 1
mteyklvvvg aggvgksalt iqliqnhfvd eydptiedsy rkqvvidget clldildtag
61 qeeysamrdq ymrtgegflc vfainntksf edihhyreqi krvkdsedvp
mvlvgnkcdl 121 psrtvdtkqa qdlarsygip fietsaktrq rvedafytlv
reirqyrlkk iskeektpgc 181 vkikkciim KRAS proto-oncogene, GTPase,
isoform b, NP_004976.2 (SEQ ID NO: 28) 1 mteyklvvvg aggvgksalt
iqliqnhfvd eydptiedsy rkqvvidget clldildtag 61 qeeysamrdq
ymrtgegflc vfainntksf edihhyreqi krvkdsedvp mvlvgnkcdl 121
psrtvdtkqa qdlarsygip fietsaktrq gvddafytlv reirkhkekm skdgkkkkkk
181 sktkcvim Transforming growth factor beta receptor 2, isoform A
precursor, NP_001020018.1 (SEQ ID NO: 29) 1 mgrgllrglw plhivlwtri
astipphvqk sdvemeaqkd eiicpscnrt ahplrhinnd 61 mivtdnngav
kfpqlckfcd vrfstcdnqk scmsncsits icekpqevcv avwrkndeni 121
tletvchdpk lpyhdfiled aaspkcimke kkkpgetffm cscssdecnd niifseeynt
181 snpdlllvif qvtgisllpp lgvaisviii fycyrvnrqq klsstwetgk
trklmefseh 241 caiileddrs disstcanni nhntellpie ldtlvgkgrf
aevykaklkq ntseqfetva 301 vkifpyeeya swktekdifs dinlkhenil
qfltaeerkt elgkqywlit afhakgnlqe 361 yltrhviswe dlrklgssla
rgiahlhsdh tpcgrpkmpi vhrdlkssni lvkndltccl 421 cdfglslrld
ptlsvddlan sgqvgtarym apevlesrmn lenvesfkqt dvysmalvlw 481
emtsrcnavg evkdyeppfg skvrehpcve smkdnvlrdr grpeipsfwl nhqgiqmvce
541 tltecwdhdp earltaqcva erfselehld rlsgrscsee kipedgslnt tk
Transforming growth factor beta receptor 2, isoform B precursor,
NP_003233.4 (SEQ ID NO: 30) 1 mgrgllrglw plhivlwtri astipphvqk
svnndmivtd nngavkfpql ckfcdvrfst 61 cdnqkscmsn csitsicekp
qevcvavwrk ndenitletv chdpklpyhd filedaaspk 121 cimkekkkpg
etffmcscss decndniifs eeyntsnpdl llvifqvtgi sllpplgvai 181
sviiifycyr vnrqqklsst wetgktrklm efsehcaiil eddrsdisst canninhnte
241 llpieldtlv gkgrfaevyk aklkqntseq fetvavkifp yeeyaswkte
kdifsdinlk 301 henilqflta eerktelgkq ywlitafhak gnlqeyltrh
viswedlrkl gsslargiah 361 lhsdhtpcgr pkmpivhrdl kssnilvknd
ltcclcdfgl slrldptlsv ddlansgqvg 421 tarymapevl esrmnlenve
sfkqtdvysm alvlwemtsr cnavgevkdy eppfgskvre 481 hpcvesmkdn
vlrdrgrpei psfwlnhqgi qmvcetltec wdhdpearlt aqcvaerfse 541
lehldrlsgr scseekiped gslnttk Actinin alpha 4, isoform 1,
NP_004915.2 (SEQ ID NO: 31) 1 mvdyhaanqs yqygpssagn gaggggsmgd
ymaqeddwdr dllldpawek qqrktftawc 61 nshlrkagtq ienidedfrd
glklmlllev isgerlpkpe rgkmrvhkin nvnkaldfia 121 skgvklvsig
aeeivdgnak mtlgmiwtii lrfaiqdisv eetsakegll lwcqrktapy 181
knvnvqnfhi swkdglafna lihrhrpeli eydklrkddp vtnlnnafev aekyldipkm
241 ldaedivnta rpdekaimty vssfyhafsg aqkaetaanr ickvlavnqe
nehlmedyek 301 lasdllewir rtipwledrv pqktiqemqg kledfrdyrr
vhkppkvqek cqleinfntl 361 qtklrlsnrp afmpsegkmv sdinngwqhl
eqaekgyeew llneirrler ldhlaekfrq 421 kasiheawtd gkeamlkhrd
yetatlsdik alirkheafe sdlaahqdrv eqiaaiaqel 481 neldyydshn
vntrcqkicd qwdalgslth srrealekte kqleaidqlh leyakraapf 541
nnwmesamed lqdmfivhti eeieglisah dqfkstlpda drereailai hkeaqriaes
601 nhiklsgsnp yttvtpqiin skwekvqqlv pkrdhallee qskqqsnehl
rrqfasqanv 661 vgpwiqtkme eigrisiemn gtledqlshl kqyersivdy
kpnldlleqq hqliqealif 721 dnkhtnytme hirvgweqll ttiartinev
enqiltrdak gisqeqmqef rasfnhfdkd 781 hggalgpeef kaclislgyd
vendrqgeae fnrimslvdp nhsglvtfqa fidfmsrett 841 dtdtadqvia
sfkvlagdkn fitaeelrre lppdqaeyci armapyqgpd avpgaldyks 901
fstalygesd l Actinin alpha 4, isoform 2, NP_001308962.1 (SEQ ID NO:
32) 1 mvdyhaanqs yqygpssagn gaggggsmgd ymaqeddwdr dllldpawek
qqrktftawc 61 nshlrkagtq ienidedfrd glklmlllev isgerlpkpe
rgkmrvhkin nvnkaldfia 121 skgvklvsig aeeivdgnak mtlgmiwtii
lrfaiqdisv eetsakegll lwcqrktapy 181 knvnvqnfhi swkdglafna
lihrhrpeli eydklrkddp vtnlnnafev aekyldipkm 241 ldaedivgtl
rpdekaimty vscfyhafsg aqkaetaanr ickvlavnqe nehlmedyek 301
lasdllewir rtipwledrv pqktiqemqq kledfrdyrr vhkppkvqek cqleinfntl
361 qtklrlsnrp afmpsegkmv sdinngwqhl eqaekgyeew llneirrler
ldhlaekfrq 421 kasiheawtd gkeamlkhrd yetatlsdik alirkheafe
sdlaahqdrv eqiaaiaqel 481 neldyydshn vntrcqkicd qwdalgslth
srrealekte kqleaidqlh leyakraapf 541 nnwmesamed lqdmfivhti
eeieglisah dqfkstlpda drereailai hkeaqriaes 601 nhiklsgsnp
yttvtpqiin skwekvqqlv pkrdhallee qskqqsnehl rrqfasqanv 661
vgpwiqtkme eigrisiemn gtledqlshl kqyersivdy kpnldlleqq hqliqealif
721 dnkhtnytme hirvgweqll ttiartinev enqiltrdak gisqeqmqef
rasfnhfdkk 781 qtgsmdsddf rallistgys lgeaefnrim slvdpnhsgl
vtfqafidfm srettdtdta 841 dqviasfkvl agdknfitae elrrelppdq
aeyciarmap yqgpdavpga ldyksfstal 901 ygesdl Activin A receptor type
1, NP_001096.1, NP_001104537.1, NP_001334592.1, NP_001334593.1,
NP_001334594.1, NP_001334595.1, NP_001334596.1 (SEQ ID NO: 33) 1
mvdgvmilpv limialpsps medekpkvnp klymcvcegl scgnedhceg qqcfsslsin
61 dgfhvyqkgc fqvyeqgkmt cktppspgqa veccqgdwcn rnitaqlptk
gksfpgtqnf 121 hlevgliils vvfavcllac llgvalrkfk rrnqerlnpr
dveygtiegl ittnvgdstl 181 adlldhscts gsgsglpflv qrtvarqitl
lecvgkgryg evwrgswqge nvavkifssr 241 dekswfrete lyntvmlrhe
nilgfiasdm tsrhsstqlw lithyhemgs lydylqlttl 301 dtvsclrivl
siasglahlh ieifgtqgkp aiahrdlksk nilvkkngqc ciadlglavm 361
hsqstnqldv gnnprvgtkr ymapevldet iqvdcfdsyk rvdiwafglv lwevarrmvs
421 ngivedykpp fydvvpndps fedmrkvvcv dqqrpnipnr wfsdptltsl
aklmkecwyq 481 npsarltalr ikktltkidn sldklktdc Alcohol
dehydrogenase 1C (class I), gamma polypeptide, NP_000660.1 (SEQ ID
NO: 34) 1 mstagkvikc kaavlwelkk pfsieeveva ppkahevrik mvaagicrsd
ehvvsgnlvt 61 plpvilghea agivesvgeg vttvkpgdkv iplftpqcgk
cricknpesn yclkndlgnp 121 rgtlqdgtrr ftcsgkpihh fvgvstfsqy
tvvdenavak idaasplekv cligcgfstg 181 ygsavkvakv tpgstcavfg
lggvglsvvm gckaagaari iavdinkdkf akakelgate 241 cinpqdykkp
iqevlkemtd ggvdfsfevi grldtmmasl lccheacgts vivgvppdsq 301
nlsinpmlll tgrtwkgaif ggfkskesvp klvadfmakk fsldalitni lpfekinegf
361 dllrsgksir tvltf Adenosine A2a receptor, NP_000666.2,
NP_001265426.1, NP_001265427.1, NP_001265428.1, NP_ 001265429.1
(SEQ ID NO: 35) 1 mpimgssvyi tvelaiavla ilgnvlvcwa vwlnsnlqnv
tnyfvvslaa adiavgvlai 61 pfaitistgf caachgclfi acfvlvltqs
sifsllaiai dryiairipl rynglvtgtr 121 akgiiaicwv lsfaigltpm
lgwnncgqpk egknhsqgcg egqvaclfed vvpmnymvyf 181 nffacvlvpl
llmlgvylri flaarrqlkg mesqplpger arstlqkevh aakslaiivg 241
lfalcwlplh iincftffcp dcshaplwlm ylaivlshtn svvnpfiyay rirefrqtfr
301 kiirshvlrq qepfkaagts arvlaahgsd geqvslrlng hppgvwangs
aphperrpng 361 yalglvsggs aqesqgntgl pdvellshel kgvcpeppgl
ddplaqdgag vs Rho guanine nucleotide exchange factor 16,
NP_055263.2 (SEQ ID NO: 36) 1 magrhsdssl eekllghrfh selrldaggn
pasglpmvrg sprvrddaaf qpqvpappqp 61 rppgheepwp ivlstespaa
lklgtqqlip kslavaskak tparhqsfga avlsreaarr 121 dpkllpapsf
slddmdvdkd pggmlrrnlr nqsyraamkg lgkpggqgda iqlspklqal 181
aeepsqphtr spaknkktlg rkrghkgsfk ddpqlyqeiq erglntsqes dddildesss
241 pegtqkvdat ivvksyrpaq vtwsqlpevv elgildqlst eerkrqeamf
eiltsefsyq 301 hslsilveef lqskelratv tqmehhhlfs nildvlgasq
rffedleqrh kaqvlvedis 361 dileehaekh fhpyiaycsn evyqqrtlqk
lissnaafre alreierrpa cgglpmlsfl 421 ilpmqrvtrl pllmdtlclk
tqghseryka asralkaisk lvrqcnegah rmermeqmyt 481 lhtqldfskv
kslplisasr wllkrgelfl veetglfrki asrptcylfl fndvlvvtkk 541
kseesymvqd yaqmnhiqve kiepselplp gggnrsssvp hpfqvtllrn segrqeqlll
601 ssdsasdrar wivalthser qwqglsskgd lpqveitkaf fakqadevtl
qqadvvlvlq 661 qedgwlyger lrdgetgwfp edfarfitsr vavegnvrrm
erlrvetdv B-cell linker, isoform 1, NP_037446.1 (SEQ ID NO: 37) 1
mdklnkitvp asqklrqlqk mvhdiknneg gimnkikklk vkappsvprr dyasespade
61 eeqwsddfds dyenpdehsd semyvmpaee naddsyeppp veqetrpvhp
alpfargeyi 121 dnrssqrhsp pfsktlpskp swpsekarlt stlpaltalq
kpqvppkpkg lledeadyvv 181 pvedndenyi hptesssppp ekapmvnrst
kpnsstpasp pgtasgrnsg awetkspppa 241 apsplpragk kpttplkttp
vasqqnassv ceekpipaer hrgsshrqea vqspvfppaq 301 kqihqkpipl
prfteggnpt vdgplpsfss nstiseqeag vlckpwyaga cdrksaeeal 361
hrsnkdgsfl irkssghdsk qpytlvvffn krvynipvrf ieatkqyalg rkkngeeyfg
421 svaeiirnhq hsplvlidsq nntkdstrlk yavkvs B-cell linker, isoform
2, NP_001107566.1 (SEQ ID NO: 38) 1 mdklnkitvp asqklrqlqk
mvhdiknneg gimnkikklk vkappsvprr dyasespade 61 eeqwsddfds
dyenpdehsd semyvmpaee naddsyeppp veqetrpvhp alpfargeyi 121
dnrssqrhsp pfsktlpskp swpsekarlt stlpaltalq kpqvppkpkg lledeadyvv
181 pvedndenyi hptesssppp ekgrnsgawe tkspppaaps plpragkkpt
tplkttpvas 241 qqnassvcee kpipaerhrg sshrqeavqs pvfppaqkqi
hqkpiplprf teggnptvdg 301 plpsfssnst iseqeagvlc kpwyagacdr
ksaeealhrs nkdgsflirk ssghdskqpy 361 tivvffnkrv ynipvrfiea
tkqyalgrkk ngeeyfgsva eiirnhqhsp lvlidsqnnt 421 kdstrlkyav kvs
B-cell linker, isoform 3, NP_001245369.1 (SEQ ID NO: 39) 1
mdklnkitvp asqklrqlqk mvhdiknneg gimnkikklk vkappsvprr dyasespade
61 eeqwsddfds dyenpdehsd semyvmpaee naddsyeppp veqetrpvhp
alpfargeyi 121 dnrssqrhsp pfsktlpskp swpsekarlt stlpaltalq
kpqvppkpkg lledeadyvv 181 pvedndenyi hptesssppp ekapmvnrst
kpnsstpasp pgtasgrnsg awetkspppa 241 apsplpragk kpttplkttp
vasqqnassv ceekpipaer hrgsshrqea vqspvfppaq 301 kqihqkpipl
prfteggnpt vdgplpsfss nstiseqeag vlckpwyaga cdrksaeeal 361
hrsnkyfgsv aeiirnhqhs plvlidsqnn tkdstrlkya vkvs B-cell linker,
isoform 4, NP_001245370.1 (SEQ ID NO: 40) 1 mdklnkitvp asqklrqlqk
mvhdiknneg gimnkikklk vkappsvprr dyasespade 61 eeqwsddfds
dyenpdehsd semyvmpaee naddsyeppp veqetrpvhp alpfargeyi 121
dnrssqrhsp pfsktlpskp swpsekarlt stlpaltalq kpqvppkpkg lledeadyvv
181 pvedndenyi hptesssppp ekgrnsgawe tkspppaaps plpragkkpt
tplkttpvas 241 qqnassvcee kpipaerhrg sshrqeavqs pvfppaqkqi
hqkpiplprf teggnptvdg 301 plpsfssnst iseqeagvlc kpwyagacdr
ksaeealhrs nkyfgsvaei irnhqhsplv 361 lidsqnntkd strlkyavkv s B-cell
linker, isoform 5, NP_001245371.1 (SEQ ID NO: 41) 1 mdklnkitvp
asqklrqlqk mvhdiknneg gimnkikklk vkappsvprr dyasespade 61
eeqwsddfds dyenpdehsd semyvmpaee naddsyeppp veqetrpvhp alpfargtas
121 grnsgawetk spppaapspl pragkkpttp lkttpvasqq nassvceekp
ipaerhrgss 181 hrqeavqspv fppaqkqihq kpiplprfte ggnptvdgpl
psfssnstis eqeagvlckp 241 wyagacdrks aeealhrsnk yfgsvaeiir
nhqhsplvli dsqnntkdst rlkyavkvs Basonuclin 1, isoform a,
NP_001708.3 (SEQ ID NO: 42) 1 mrrrppsrgg rgaararetr rqprhrsgrr
maeaisctln cscqsfkpgk inhrqcdqck 61 hgwvahalsk lrippmypts
qveivqsnvv fdisslmlyg tqaipvrlki lldrlfsvlk 121 qdevlqilha
ldwtlqdyir gyvlqdasgk vldhwsimts eeevatlqqf lrfgetksiv 181
elmaiqekee qsiiippsta nvdirafies cshrssslpt pvdkgnpssi hpfenlisnm
241 tfmlpfqffn plppaligsl peqymleqgh dqsqdpkqev hgpfpdssfl
tssstpfqve 301 kdqclncpda itkkedsthl sdsssynivt kfertqlspe
akvkpernsl gtkkgrvfct 361 acektfydkg tlkihynavh lkikhkctie
gcnmvfsslr srnrhsanpn prlhmpmnrn 421 nrdkdlrnsl nlassenykc
pgftvtspdc rpppsypgsg edskgqpafp nigqngvlfp 481 nlktvqpvlp
fyrspatpae vantpgilps lpllsssipe qlisnempfd alpkkksrks 541
smpikiekea veianekrhn lssdedmplq vvsedeqeac spqshrvsee qhvqsgglgk
601 pfpegerpch resviessga isqtpeqath nsereteqtp alimvpreve
dgghehyftp 661 gmepqvpfsd ymelqqrlla gglfsalsnr gmafpcleds
kelehvgqha larqieenrf 721 qcdickktfk nacsvkihhk nmhvkemhtc
tvegcnatfp srrsrdrhss nlnlhqkals 781 qealessedh fraayllkdv
akeayqdvaf tqqasqtsvi fkgtsrmgsl vypitqvhsa 841 slesynsgpl
segtildlst tssmksesss hsswdsdgvs eegtvlmeds dgncegsslv 901
pgedeypicv lmekadqsla slpsglpitc hlcqktysnk gtfrahyktv hlrqlhkckv
961 pgcntmfssv rsrnrhsqnp nlhkslassp shlq Basonuclin 1, isoform b,
NP_001288135.1 (SEQ ID NO: 43) 1 mrcrnmffsf kaslcgcgaa tapsltaisc
tlncscqsfk pgkinhrqcd qckhgwvaha 61 lsklrippmy ptsqveivqs
nvvfdisslm lygtqaipvr lkilldrlfs vlkqdevlqi 121 lhaldwtlqd
yirgyvlqda sgkvldhwsi mtseeevatl qqflrfgetk sivelmaiqe 181
keeqsiiipp stanvdiraf iescshrsss lptpvdkgnp ssihpfenli snmtfmlpfq
241 ffnplppali gslpeqymle qghdqsqdpk cqvhgpfpds sfltssstpf
qvekdqclnc 301 pdaitkkeds thlsdsssyn ivtkfertql speakvkper
nslgtkkgrv fctacektfy 361 dkgtlkihyn avhlkikhkc tiegcnmvfs
slrsrnrhsa npnprlhmpm nrnnrdkdlr 421 nslnlassen ykcpgftvts
pdcrpppsyp gsgedskgqp afpnigqngv lfpnlktvqp 481 vlpfyrspat
paevantpgi lpslpllsss ipeqlisnem pfdalpkkks rkssmpikie 541
keaveianek rhnlssdedm plqvvsedeq eacspqshrv seeqhvqsgg lgkpfpeger
601 pchresvies sgaisqtpeq athnserete qtpalimvpr evedgghehy
ftpgmepqvp 661 fsdymelqqr llagglfsal snrgmafpcl edskelehvg
qhalarqiee nrfqcdickk 721 tfknacsvki hhknmhvkem htctvegcna
tfpsrrsrdr hssnlnlhqk alsqealess 781 edhfraayll kdvakeayqd
vaftqqasqt svifkgtsrm gslvypitqv hsaslesyns 841 gplsegtild
lsttssmkse ssshsswdsd gvseegtvlm edsdgncegs slvpgedeyp 901
icvlmekadq slaslpsglp itchlcqkty snkgtfrahy ktvhlrqlhk ckvpgcntmf
961 ssvrsrnrhs qnpnlhksla sspshlq BPI fold containing family A
member 1, precursor, NP_001230122.1, NP_057667.1, NP_570913.1 (SEQ
ID NO: 44) 1 mfqtgglivf ygllaqtmaq fgglpvpldq tlplnvnpal plsptglags
ltnalsngll 61 sggllgilen lplldilkpg ggtsggllgg llgkvtsvip
glnniidikv tdpqllelgl 121 vqspdghrly vtiplgiklq vntplvgasl
lrlavkldit aeilavrdkq erihlvlgdc 181 thspgslqis lldglgplpi
qglldsltgi lnkvlpelvq gnvcplvnev lrglditivh 241 divnmlihgl qfvikv
Calcium voltage-gated channel auxiliary subunit beta 3, isoform 1,
NP_000716.2 (SEQ ID NO: 45) 1 myddsyvpgf edseagsads ytsrpsldsd
vsleedresa rrevesqaqq qlerakhkpv 61 afavrtnvsy cgvldeecpv
qgsgvnfeak dflhikekys ndwwigrlvk eggdiafips 121 pqrlesirlk
qeqkarrsgn psslsdignr rspppslakq kqkqaehvpp ydvvpsmrpv 181
vlvgpslkgy evtdmmqkal fdflkhrfdg risitrvtad lslakrsvin npgkrtiier
241 ssarssiaev qseierifel akslqlvvld adtinhpaql aktslapiiv
fvkvsspkvl 301 qrlirsrgks qmkhltvqmm aydklvqcpp esfdvilden
qledacehla eylevywrat 361 hhpapgpgll gppsaipglq nqqllgerge
ehsplerdsl mpsdeasess rqawtgssqr 421 ssrhleedya dayqdlyqph
rqhtsglpsa nghdpqdrll aqdsehnhsd rnwqrnrpwp
481 kdsy Calcium voltage-gated channel auxiliary subunit beta 3,
isoform 2, NP_001193844.1 (SEQ ID NO: 46) 1 myddsyvpgf edseagsads
ytsrpsldsd vsleedresa rrevesqaqq qlerakkysn 61 dwwigrlvke
ggdiafipsp qrlesirlkq eqkarrsgnp sslsdignrr spppslakqk 121
qkqaehvppy dvvpsmrpvv lvgpslkgye vtdmmqkalf dflkhrfdgr isitrvtadl
181 slakrsvlnn pgkrtiiers sarssiaevq seierifela kslqlvvlda
dtinhpaqla 241 ktslapiivf vkvsspkvlq rlirsrgksq mkhltvqmma
ydklvqcppe sfdvildenq 301 ledacehlae ylevywrath hpapgpgllg
ppsaipglqn qqllgergee hsplerdslm 361 psdeasessr qawtgssqrs
srhleedyad ayqdlyqphr qhtsglpsan ghdpqdrlla 421 qdsehnhsdr
nwqrnrpwpk dsy Calcium voltage-gated channel auxiliary subunit beta
3, isoform 3, NP_001193845.1 (SEQ ID NO: 47) 1 msfsdssatf
llnegsadsy tsrpsldsdv sleedresar revesqaqqg lerakhkpva 61
favrtnvsyc gvldeecpvq gsgvnfeakd flhikekysn dwwigrlvke ggdiafipsp
121 qrlesirlkq eqkarrsgnp sslsdignrr spppslakqk qkqaehvppy
dvvpsmrpvv 181 lvgpslkgye vtdmmqkalf dflkhrfdgr isitrvtadl
slakrsvlnn pgkrtiiers 241 sarssiaevq seierifela kslqlvvlda
dtinhpaqla ktslapiivf vkvsspkvlq 301 rlirsrgksq mkhltvqmma
ydklvqcppe sfdvildenq ledacehlae ylevywrath 361 hpapgpgllg
ppsaipglqn qqllgergee hsplerdslm psdeasessr qawtgssqrs 421
srhleedyad ayqdlyqphr qhtsglpsan ghdpqdrlla qdsehnhsdr nwqrnrpwpk
481 dsy Calcium voltage-gated channel auxiliary subunit beta 3,
isoform 4, NP_001193846.1 (SEQ ID NO: 48) 1 megsadsyts rpsldsdvsl
eedresarre vesqaqqqle rakhkpvafa vrtnvsycgv 61 ldeecpvggs
gvnfeakdfl hikekysndw wigrlvkegg diafipspqr lesirlkqeq 121
karrsgnpss lsdignrrsp ppslakqkqk qaehvppydv vpsmrpvvlv gpslkgyevt
181 dmmqkalfdf lkhrfdgris itrvtadlsl akrsvlnnpg krtiierssa
rssiaevqse 241 ierifelaks lqlvvldadt inhpaglakt slapiivfvk
vsspkvlqrl irsrgksqmk 301 hltvqmmayd klvqcppesf dvildenqle
dacehlaeyl evywrathhp apgpgllgpp 361 saipglqnqq llgergeehs
plerdslmps deasessrqa wtgssqrssr hleedyaday 421 qdlyqphrqh
tsglpsangh dpqdrllaqd sehnhsdrnw qrnrpwpkds y Caspase 3,
preproprotein, NP_ 001341706.1, NP_001341707.1, NP_004346.3,
NP_116786.1 (SEQ ID NO: 49) 1 mentensvds ksiknlepki ihgsesmdsg
isldnsykmd ypemglciii nnknfhkstg 61 mtsrsgtdvd aanlretfrn
lkyevrnknd ltreeivelm rdvskedhsk rssfvcvlls 121 hgeegiifgt
ngpvdlkkit nffrgdrcrs ltgkpklfii qacrgteldc gietdsgvdd 181
dmachkipve adflyaysta pgyyswrnsk dgswfiqslc amlkqyadkl efmhiltrvn
241 rkvatefesf sfdatfhakk qipcivsmlt kelyfyh Caspase 3, isoform b,
NP_001341708.1, NP_001341709.1 (SEQ ID NO: 50) 1 mdsgisldns
ykmdypemgl ciiinnknfh kstgmtsrsg tdvdaanlre tfrnlkyevr 61
nkndltreei velmrdvske dhskrssfvc vllshgeegi ifgtngpvdl kkitnffrgd
121 rcrsltgkpk lfiiqacrgt eldcgietds gvdddmachk ipveadflya
ystapgyysw 181 rnskdgswfi qslcamlkqy adklefmhil trvnrkvate
fesfsfdatf hakkgipciv 241 smltkelyfy h Caspase 3, isoform c,
NP_001341710.1, NP_001341711.1 (SEQ ID NO: 51) 1 mentensvds
ksiknlepki ihgsesmdsg isldnsykmd ypemglciii nnknfhkstg 61
mtsrsgtdvd aanlretfrn lkyevrnknd ltreeivelm rdvskedhsk rssfvcvlls
121 hgeegiifgt ngpvdlkkit nffrgdrcrs ltgkpklfii qviilgeiqr
mapgsssrfv 181 pc Caspase 3, isoform d, NP_001341712.1 (SEQ ID NO:
52) 1 msdalikvsm entensvdsk siknlepkii hgsesmdsgi sldnsykmdy
pemglciiin 61 nknfhkstgm tsrsgtdvda anlretfrnl kyevrnkndl
treeivelmr dvskedhskr 121 ssfvcvllsh geegiifgtn gpvdlkkitn
ffrgdrcrsl tgkpklfiiq viilgeiqrm 181 apgsssrfvp c Caspase 3,
isoform e, NP_001341713.1 (SEQ ID NO: 53) 1 mdsgisldns ykmdypemgl
ciiinnknfh kstgmtsrsg tdvdaanlre tfrnlkyevr 61 nkndltreei
velmrdvske dhskrssfvc vllshgeegi ifgtngpvdl kkitnffrgd 121
rcrsltgkpk lfiiqviilg eiqrmapgss srfvpc Caveolin 1, isoform alpha,
NP_001744.2 (SEQ ID NO: 54) 1 msggkyvdse ghlytvpire qgniykpnnk
amadelsekq vydahtkeid lvnrdpkhln 61 ddvvkidfed viaepegths
fdgiwkasft tftvtkywfy rllsalfgip maliwgiyfa 121 ilsflhiwav
vpciksflie iqcisrvysi yvhtvcdplf eavgkifsnv rinlqkei Caveolin 1,
isoform beta, NP_001166366.1, NP_001166367.1, NP_001166368.1 (SEQ
ID NO: 55) 1 madelsekqv ydahtkeidl vnrdpkhlnd dvvkidfedv iaepegthsf
dgiwkasftt 61 ftvtkywfyr llsalfgipm aliwgiyfai lsflhiwavv
pciksfliei qcisrvysiy 121 vhtvcdplfe avgkifsnvr inlqkei Cadherin 1,
isoform 1 preproprotein, NP_004351.1 (SEQ ID NO: 56) 1 mgpwsrslsa
lllllqvssw logepepchp gfdaesytft vprrhlergr vlgrvnfedc 61
tgrqrtayfs ldtrfkvgtd gvitvkrplr fhnpqihflv yawdstyrkf stkvtlntvg
121 hhhrppphqa sysgiqaell tfpnsspglr rqkrdwvipp iscpenekgp
fpknlvqiks 181 nkdkegkvfy sitgqgadtp pvgvfiiere tgwlkvtepl
dreriatytl fshayssngn 241 avedpmeili tvtdqndnkp eftqevfkgs
vmegalpgts vmevtatdad ddvntynaai 301 aytilsqdpe lpdknmftin
rntgvisvvt tgldresfpt ytlvvqaadl qgeglsttat 361 avitvtdtnd
nppifnptty kgqvpenean vvittlkvtd adapntpawe avytilnddg 421
gqfvvttnpv nndgilktak gldfeakqqy ilhvavtnvv pfevslttst atvtvdvldv
481 neapifvppe krvevsedfg vggeitsyta qepdtfmeqk ityriwrdta
nwleinpdtg 541 aistraeldr edfehvknst ytaliiatdn gspvatgtgt
lllilsdvnd napipeprti 601 ffcernpkpq viniidadlp pntspftael
thgasanwti qyndptqesi ilkpkmalev 661 gdykinlklm dnqnkdqvtt
levsvcdceg aagvcrkaqp veaglqipai lgilggilal 721 lililllllf
lrrravvkep llppeddtrd nvyyydeegg geedqdfdls qlhrgldarp 781
evtrndvapt lmsvprylpr panpdeignf idenlkaadt dptappydsl lvfdyegsgs
841 eaaslsslns sesdkdqdyd ylnewgnrfk kladmyggge dd Cadherin 1,
isoform 2 precursor, NP_001304113.1 (SEQ ID NO: 57) 1 mgpwsrslsa
lllllqvssw lcqepepchp gfdaesytft vprrhlergr vlgrvnfedc 61
tgrqrtayfs ldtrfkvgtd gvitvkrplr fhnpqihflv yawdstyrkf stkvtlntvg
121 hhhrppphqa sysgiqaell tfpnsspglr rqkrdwvipp iscpenekgp
fpknlvqiks 181 nkdkegkvfy sitgqgadtp pvgvfiiere tgwlkvtepl
dreriatytl fshayssngn 241 avedpmeili tvtdqndnkp eftqevfkgs
vmegalpgts vmevtatdad ddvntynaai 301 aytilsqdpe lpdknmftin
rntgvisvvt tgldresfpt ytlvvqaadl qgeglsttat 361 avitvtdtnd
nppifnpttg ldfeakqqyi lhvavtnvvp fevslttsta tvtvdvldvn 421
eapifvppek rvevsedfgv gqeitsytaq epdtfmeqki tyriwrdtan wleinpdtga
481 istraeldre dfehvknsty taliiatdng spvatgtgtl llilsdvndn
apipeprtif 541 fcernpkpqv iniidadlpp ntspftaelt hgasanwtiq
yndptqesii lkpkmalevg 601 dykinlklmd nqnkdqvttl evsvcdcega
agvcrkaqpv eaglqipail gilggilall 661 ililllllfl rrravvkepl
lppeddtrdn vyyydeeggg eedqdfdlsq lhrgldarpe 721 vtrndvaptl
msvprylprp anpdeignfi denlkaadtd ptappydsll vfdyegsgse 781
aaslsslnss esdkdqdydy lnewgnrfkk ladmyggged d Cadherin 1, isoform
3, NP_001304114.1 (SEQ ID NO: 58) 1 meqkityriw rdtanwlein
pdtgaistra eldredfehv knstytalii atdngspvat 61 gtgtlllils
dvndnapipe prtiffcern pkpqviniid adlppntspf taelthgasa 121
nwtiqyndpt qesiilkpkm alevgdykin lklmdnqnkd qvttlevsvc dcegaagvcr
181 kaqpveaglq ipailgilgg ilallilill lllflrrrav vkepllpped
dtrdnvyyyd 241 eegggeedqd fdlsqlhrgl darpevtrnd vaptlmsvpr
ylprpanpde ignfidenlk 301 aadtdptapp ydsllvfdye gsgseaasls
slnssesdkd qdydylnewg nrfkkladmy 361 gggedd Cadherin 1, isoform 4,
NP_001304115.1 (SEQ ID NO: 59) 1 malevgdyki nlklmdnqnk dqvttlevsv
cdcegaagvc rkaqpveagl qipailgilg 61 gilallilil llllflrrra
vvkepllppe ddtrdnvyyy deegggeedq dfdlsqlhrg 121 ldarpevtrn
dvaptlmsvp rylprpanpd eignfidenl kaadtdptap pydsllvfdy 181
egsgseaasl sslnssesdk dqdydylnew gnrfkkladm ygggedd Cytochrome c
oxidase subunit 8C, NP_892016.1 (SEQ ID NO: 60) 1 mpllrgrcpa
rrhyrrlall glqpaprfah sgpprqrpls aaemavglvv ffttfltpaa 61
yvlgnlkqfr rn Carnitine palmitoyltransferase 1A, isoform 1,
NP_001867.2 (SEQ ID NO: 61) 1 maeahqavaf qftvtpdgid lrlshealrq
iylsglhswk kkfirfkngi itgvypasps 61 swlivvvgvm ttmyakidps
lgiiakinrt letancmssq tknvvsgvlf gtglwvaliv 121 tmryslkvll
syhgwmfteh gkmsratkiw mgmvkifsgr kpmlysfqts lprlpvpavk 181
dtvnrylqsv rplmkeedfk rmtalaqdfa vglgprlqwy lklkswwatn yvsdwweeyi
241 ylrgrgplmv nsnyyamdll yilpthiqaa ragnaihail lyrrkldree
ikpirllgst 301 iplcsaqwer mfntsripge etdtiqhmrd skhivvyhrg
ryfkvwlyhd grllkpreme 361 qqmqrildnt sepqpgearl aaltagdrvp
warcrqayfg rgknkqslda vekaaffvtl 421 deteegyrse dpdtsmdsya
ksllhgrcyd rwfdksftfv vfkngkmgln aehswadapi 481 vahlweyvms
idslqlgyae dghckgdinp nipyptrlqw dipgecqevi etslntanll 541
andvdfhsfp fvafgkgiik kcrtspdafv qlalqlahyk dmgkfcltye asmtrlfreg
601 rtetvrsctt escdfvramv dpaqtveqrl klfklasekh qhmyrlamtg
sgidrhlfcl 661 yvvskylave spflkevlse pwrlstsqtp qqqvelfdle
nnpeyvssgg gfgpvaddgy 721 gvsyilvgen linfhisskf scpetdshrf
grhlkeamtd iitlfglssn skk Carnitine palmitoyltransferase 1A,
isoform 2, NP_001027017.1 (SEQ ID NO: 62) 1 maeahqavaf qftvtpdgid
lrlshealrq iylsglhswk kkfirfkngi itgvypasps 61 swlivvvgvm
ttmyakidps lgiiakinrt letancmssq tknvvsgvlf gtglwvaliv 121
tmryslkvll syhgwmfteh gkmsratkiw mgmvkifsgr kpmlysfqts lprlpvpavk
181 dtvnrylqsv rplmkeedfk rmtalaqdfa vglgprlqwy lklkswwatn
yvsdwweeyi 241 ylrgrgplmv nsnyyamdll yilpthiqaa ragnaihail
lyrrkldree ikpirllgst 301 iplcsaqwer mfntsripge etdtiqhmrd
skhivvyhrg ryfkvwlyhd grllkpreme 361 qqmqrildnt sepqpgearl
aaltagdrvp warcrqayfg rgknkqslda vekaaffvtl 421 deteegyrse
dpdtsmdsya ksllhgrcyd rwfdksftfv vfkngkmgln aehswadapi 481
vahlweyvms idslqlgyae dghckgdinp nipyptrlqw dipgecqevi etslntanll
541 andvdfhsfp fvafgkgiik kcrtspdafv qlalqlahyk dmgkfcltye
asmtrlfreg 601 rtetvrsctt escdfvramv dpaqtveqrl klfklasekh
qhmyrlamtg sgidrhlfcl 661 yvvskylave spflkevlse pwrlstsqtp
qqqvelfdle nnpeyvssgg gfgpvaddgy 721 gvsyilvgen linfhisskf
scpetgiisq gpssdt Cancer/testis antigen 1A, NP_640343.1 (SEQ ID NO:
63) 1 mqaegrgtgg stgdadgpgg pgipdgpggn aggpgeagat ggrgprgaga
arasgpggga 61 prgphggaas glngccrcga rgpesrllef ylampfatpm
eaelarrsla qdapplpvpg 121 vllkeftvsg niltirltaa dhrqlqlsis
sclqqlsllm witqcflpvf laqppsgqrr C-X-C motif chemokine ligand 13,
NP_006410.1 (SEQ ID NO: 64) 1 mkfistslll mllvsslspv qgvlevyyts
lrcrcvqess vfiprrfidr iqilprgngc 61 prkeiivwkk nksivcvdpq
aewiqrmmev lrkrssstlp vpvfkrkip Diacylglycerol kinase eta, isoform
1, NP_001191433.1, NP_690874.2 (SEQ ID NO: 65) 1 magaggqhhp
pgaaggaaag agaavtsaaa sagpgedssd seaeqegpqk lirkvstsgq 61
irtktsikeg qllkqtssfq rwkkryfklr grtlyyakds kslifdevdl sdasvaeast
121 knannsftii tpfrrlmlca enrkemedwi sslksvqtre pyevaqfnve
hfsgmhnwya 181 csharptfcn vcreslsgvt shglscevck fkahkrcavr
atnnckwttl asigkdiied 241 edgvamphqw legnlpvsak cavcdktcgs
vlrlqdwkcl wcktmvhtac kdlyhpicpl 301 gqckvsiipp ialnstdsdg
fcratfsfcv spllvfvnsk sgdnqgvkfl rrfkqllnpa 361 qvfdlmnggp
hlglrlfqkf dnfrilvcgg dgsvgwvlse idklnlnkqc qlgvlplgtg 421
ndlarvlgwg gsydddtqlp qilekleras tkmldrwsim tyelklppka sllpgppeas
481 eefymtiyed svathltkil nsdehavvis saktlcetvk dfvakvekty
dktlenavva 541 davaskcsvl nekleqllqa lhtdsqaapv lpglsplive
edavesssee slgeskeqlg 601 ddvtkpssqk avkpreimlr anslkkavrq
vieeagkvmd dptvhpcepa nqssdydste 661 tdeskeeakd dgakesitvk
taprspdara syghsqtdsv pgpavaaske nlpvintrii 721 cpglraglaa
siagssiink mllanidpfg atpfidpdld svdgysekcv mnnyfgigld 781
akislefnnk reehpekcrs rtknlmwygv lgtrellqrs yknleqrvql ecdgqyiplp
841 slqgiavini psyaggtnfw ggtkeddifa apsfddkile vvaifdsmqm
aysrviklqh 901 hriaqcrtvk itifgdegvp vqvdgeawvq ppgiikivhk
nraqmltrdr afestlkswe 961 dkqkcdsgkp vlrthlyihh aidlateevs
qmqlcsqaae elitricdaa tihclleqel 1021 ahavnacsha lnkanprcpe
sltrdtatei ainvkalyne tesllvgrvp lqlespheer 1081 vsnalhsvev
elqklteipw lyyilhpned eeppmdctkr nnrstvfriv pkfkkekvqk 1141
qktssqpgsg dtesgscean spgn Diacylglycerol kinase eta, isoform 2,
NP_821077.1 (SEQ ID NO: 66) 1 magaggqhhp pgaaggaaag agaavtsaaa
sagpgedssd seaeqegpqk lirkvstsgq 61 irtktsikeg qllkqtssfq
rwkkryfklr grtlyyakds kslifdevdl sdasvaeast 121 knannsftii
tpfrrlmlca enrkemedwi sslksvqtre pyevaqfnve hfsgmhnwya 181
csharptfcn vcreslsgvt shglscevck fkahkrcavr atnnckwttl asigkdiied
241 edgvamphqw legnlpvsak cavcdktcgs vlrlqdwkcl wcktmvhtac
kdlyhpicpl 301 gqckvsiipp ialnstdsdg fcratfsfcv spllvfvnsk
sgdnqgvkfl rrfkqllnpa 361 qvfdlmnggp hlglrlfqkf dnfrilvcgg
dgsvgwvlse idklnlnkqc qlgvlplgtg 421 ndlarvlgwg gsydddtqlp
qilekleras tkmldrwsim tyelklppka sllpgppeas 481 eefymtiyed
svathltkil nsdehavvis saktlcetvk dfvakvekty dktlenavva 541
davaskcsvl nekleqllqa lhtdsqaapv lpglsplive edavesssee slgeskeqlg
601 ddvtkpssqk avkpreimlr anslkkavrq vieeagkvmd dptvhpcepa
nqssdydste 661 tdeskeeakd dgakesitvk taprspdara syghsqtdsv
pgpavaaske nlpvlntrii 721 cpglraglaa siagssiink mllanidpfg
atpfidpdld svdgysekcv mnnyfgigld 781 akislefnnk reehpekcrs
rtknlmwygv lgtrellqrs yknleqrvql ecdgqyiplp 841 slqgiavini
psyaggtnfw ggtkeddifa apsfddkile vvaifdsmqm aysrviklqh 901
hriaqcrtvk itifgdegvp vqvdgeawvq ppgiikivhk nraqmltrdr afestlkswe
961 dkqkcdsgkp vlrthlyihh aidlateevs qmqlcsqaae elitricdaa
tihclleqel 1021 ahavnacsha lnkanprcpe sltrdtatei ainvkalyne
tesllvgrvp lqlespheer 1081 vsnalhsvev elqklteipw lyyilhpned
eeppmdctkr nnrstvfriv pkfkkekvqk 1141 qktssqpvqk wgteevaawl
dllnlgeykd ifirhdirga ellhlerrdl kdlgipkvgh 1201 vkrilqgike
lgrstpqsev Diacylglycerol kinase eta, isoform 3, NP_001191434.1
(SEQ ID NO: 67) 1 mlcaenrkem edwisslksv qtrepyevaq fnvehfsgmh
nwyacsharp tfcnvcresl 61 sgvtshglsc evckfkahkr cavratnnck
wttlasigkd iiededgvam phqwlegnlp 121 vsakcavcdk tcgsvlrlqd
wkclwcktmv htackdlyhp icplgqckvs iippialnst 181 dsdgfcratf
sfcvspllvf vnsksgdnqg vkflrrfkql lnpaqvfdlm nggphlglrl 241
fqkfdnfril vcggdgsvgw vlseidklnl nkqcqlgvlp lgtgndlarv lgwggsyddd
301 tqlpqilekl erastkmldr wsimtyelkl ppkasllpgp peaseefymt
iyedsvathl 361 tkilnsdeha vvissaktic etvkdfvakv ektydktlen
avvadavask csvlnekleq 421 llqalhtdsq aapvlpglsp liveedaves
sseeslgesk eqlgddvtkp ssqkavkpre 481 imlranslkk avrqvieeag
kvmddptvhp cepanqssdy dstetdeske eakddgakes 541 itvktaprsp
darasyghsq tdsvpgpava askenlpvin triicpglra glaasiagss 601
iinkmllani dpfgatpfid pdldsvdgys ekcvmnnyfg igldakisle fnnkreehpe
661 kcrsrtknlm wygvlgtrel lqrsyknleq rvqlecdgqy iplpslqgia
vlnipsyagg 721 tnfwggtked difaapsfdd kilevvaifd smqmavsrvi
klqhhriaqc rtvkitifgd 781 egvpvqvdge awvqppgiik ivhknraqml
trdrafestl kswedkqkcd sgkpvlrthl 841 yihhaidlat eevsqmqlcs
qaaeelitri cdaatihcll eqelahavna cshalnkanp 901 rcpesltrdt
ateiainvka lynetesllv grvplqlesp heervsnalh svevelqklt 961
eipwlyyilh pnedeeppmd ctkrnnrstv frivpkfkke kvqkqktssq pvqkwgteev
1021 aawldllnlg eykdifirhd irgaellhle rrdlkntvge krdtkengkh
mdlgipkvgh 1081 vkrilqgike lgrstpqsev Diacylglycerol kinase eta,
isoform 4, NP_001191435.1 (SEQ ID NO: 68) 1 mlcaenrkem edwisslksv
qtrepyevaq fnvehfsgmh nwyacsharp tfcnvcresl 61 sgvtshglsc
evckfkahkr cavratnnck wttlasigkd iiededgvam phqwlegnlp 121
vsakcavcdk tcgsvlrlqd wkclwcktmv htackdlyhp icplgqckvs iippialnst
181 dsdgfcratf sfcvspllvf vnsksgdnqg vkflrrfkql lnpaqvfdlm
nggphlglrl 241 fqkfdnfril vcggdgsvgw vlseidklnl nkqcqlgvlp
lgtgndlarv lgwggsyddd 301 tqlpqilekl erastkmldr wsimtyelkl
ppkasllpgp peaseefymt iyedsvathl 361 tkilnsdeha vvissaktlc
etvkdfvakv ektydktlen avvadavask csvlnekleq 421 llqalhtdsq
aapvlpglsp liveedaves sseeslgesk eqlgddvtkp ssqkavkpre 481
imlranslkk avrqvieeag kvmddptvhp cepanqssdy dstetdeske eakddgakes
541 itvktaprsp darasyghsq tdsvpgpava askenlpvln triicpglra
glaasiagss
601 iinkmllani dpfgatpfid pdldsvdgys ekcvmnnyfg igldakisle
fnnkreehpe 661 kcrsrtknlm wygvlgtrel lqrsyknleq rvqlecdgqy
iplpslqgia vlnipsyagg 721 tnfwggtked difaapsfdd kilevvaifd
smqmavsrvi klqhhriaqc rtvkitifgd 781 egvpvqvdge awvqppgiik
ivhknraqml trdrafestl kswedkqkcd sgkpvlrthl 841 yihhaidlat
eevsgmqlcs qaaeelitri cdaatihcll eqelahavna cshalnkanp 901
rcpesltrdt ateiainvka lynetesllv grvplqlesp heervsnalh svevelqklt
961 eipwlyyilh pnedeeppmd ctkrnnrstv frivpkfkke kvqkqktssq
pvqkwgteev 1021 aawldllnlg eykdifirhd irgaellhle rrdlkdlgip
kvghvkrilq gikelgrstp 1081 qsev Diacylglycerol kinase eta, isoform
5, NP_001284358.1 (SEQ ID NO: 69) 1 mwnisqgctt gtpaptpdpp
svtcaervfl esppmacpak vhtackdlyh picplgqckv 61 siippialns
tdsdgfcrat fsfcvspllv fvnsksgdnq gvkflrrfkq llnpaqvfdl 121
mnggphlglr lfqkfdnfri lvcggdgsvg wvlseidkln lnkqcqlgvl plgtgndlar
181 vlgwggsydd dtqlpqilek lerastkmld rwsimtyelk lppkasllpg
ppeaseefym 241 tiyedsvath ltkilnsdeh avvissaktl cetvkdfvak
vektydktle navvadavas 301 kcsvlnekle qllqalhtds qaapvlpgls
pliveedave ssseeslges keqlgddvtk 361 pssqkavkpr eimlranslk
kavrqvieea gkvmddptvh pcepanqssd ydstetdesk 421 eeakddgake
sitvktaprs pdarasyghs qtdsvpgpav aaskenlpvl ntriicpglr 481
aglaasiags siinkmllan idpfgatpfi dpdldsvdgy sekcvmnnyf gigldakisl
541 efnnkreehp ekcrsrtknl mwygvlgtre llqrsyknle qrvqlecdgq
yiplpslqgi 601 avinipsyag gtnfwggtke ddifaapsfd dkilevvaif
dsmqmavsrv iklqhhriaq 661 crtvkitifg degvpvqvdg eawvqppgii
kivhknraqm ltrdrafest lkswedkqkc 721 dsgkpvlrth lyihhaidla
teevsqmqlc sqaaeelitr icdaatihcl leqelahavn 781 acshalnkan
prcpesltrd tateiainvk alynetesll vgrvplqles pheervsnal 841
hsvevelqkl teipwlyyil hpnedeeppm dctkrnnrst vfrivpkfkk ekvqkqktss
901 qpgsgdtesg sceanspgn Eukaryotic translation elongation factor
2, NP_001952.1 (SEQ ID NO: 70) 1 mvnftvdqir aimdkkanir nmsviahvdh
gkstltdslv ckagiiasar agetrftdtr 61 kdeqerciti kstaislfye
lsendlnfik qskdgagfli nlidspghvd fssevtaalr 121 vtdgalvvvd
cvsgvcvqte tvlrqaiaer ikpvlmmnkm drallelqle peelyqtfqr 181
ivenvnviis tygegesgpm gnimidpvlg tvgfgsglhg waftlkqfae myvakfaakg
241 egqlgpaera kkvedmmkkl wgdryfdpan gkfsksatsp egkklprtfc
qlildpifkv 301 fdaimnfkke etakliekld ikldsedkdk egkpllkavm
rrwlpagdal lqmitihlps 361 pvtaqkyrce llyegppdde aamgikscdp
kgplmmyisk mvptsdkgrf yafgrvfsgl 421 vstglkvrim gpnytpgkke
dlylkpiqrt ilmmgryvep iedvpcgniv glvgvdqflv 481 ktgtittfeh
ahnmrvmkfs vspvvrvave aknpadlpkl veglkrlaks dpmvqciiee 541
sgehiiagag elhleiclkd leedhacipi kksdpvvsyr etvseesnvl clskspnkhn
601 rlymkarpfp dglaedidkg evsarqelkq rarylaekye wdvaearkiw
cfgpdgtgpn 661 iltditkgvq ylneikdsvv agfqwatkeg alceenmrgv
rfdvhdvtlh adaihrgggq 721 iiptarrcly asvltaqprl mepiylveiq
cpeqvvggiy gvlnrkrghv feesqvagtp 781 mfvvkaylpv nesfgftadl
rsntggqafp qcvfdhwqil pgdpfdnssr psqvvaetrk 841 rkglkegipa ldnfldkl
Eukaryotic translation initiation factor 5A, isoform A,
NP_001137232.1 (SEQ ID NO: 71) 1 mcgtggtdsk trrpphrasf lkrleskplk
maddldfetg dagasatfpm qcsalrkngf 61 vvlkgrpcki vemstsktgk
hghakvhlvg idiftgkkye dicpsthnmd vpnikrndfq 121 ligiqdgyls
llqdsgevre dlrlpegdlg keieqkydcg eeilitvlsa mteeaavaik 181 amak
Eukaryotic translation initiation factor 5A, isoform B,
NP_001137233.1, NP_001137234.1, NP_001961.1 (SEQ ID NO: 72) 1
maddldfetg dagasatfpm qcsalrkngf vvlkgrpcki vemstsktgk hghakvhlvg
61 idiftgkkye dicpsthnmd vpnikrndfq ligiqdgyls llqdsgevre
dlrlpegdlg 121 keieqkydcg eeilitvlsa mteeaavaik amak Fibronectin 1,
isoform 1 precursor, NP_997647.1 (SEQ ID NO: 73) 1 mlrgpgpgll
llavqclgta vpstgasksk rqaqqmvqpq spvaysqskp gcydngkhyq 61
inqqwertyl gnalvctcyg gsrgfncesk peaeetcfdk ytgntyrvgd tyerpkdsmi
121 wdctcigagr grisctianr cheggqsyki gdtwrrphet ggymlecvcl
gngkgewtck 181 piaekcfdha agtsyvvget wekpyqgwmm vdctclgegs
gritctsrnr cndqdtrtsy 241 rigdtwskkd nrgnllqcic tgngrgewkc
erhtsvqtts sgsgpftdvr aavyqpqphp 301 qpppyghcvt dsgvvysvgm
qwlktqgnkq mlctclgngv scqetavtqt yggnsngepc 361 vlpftyngrt
fyscttegrq dghlwcstts nyeqdqkysf ctdhtvlvqt rggnsngalc 421
hfpflynnhn ytdctsegrr dnmkwcgttq nydadqkfgf cpmaaheeic ttnegvmyri
481 gdqwdkqhdm ghmmrctcvg ngrgewtcia ysqlrdqciv dditynvndt
fhkrheeghm 541 lnctcfgqgr grwkcdpvdq cqdsetgtfy qigdswekyv
hgvryqcycy grgigewhcq 601 plqtypsssg pvevfitetp sqpnshpiqw
napqpshisk yilrwrpkns vgrwkeatip 661 ghlnsytikg lkpgvvyegq
lisiqqyghq evtrfdfttt ststpvtsnt vtgettpfsp 721 lvatsesvte
itassfvvsw vsasdtvsgf rveyelseeg depqyldlps tatsvnipdl 781
lpgrkyivnv yqisedgeqs lilstsqtta pdappdptvd qvddtsivvr wsrpqapitg
841 yrivyspsve gsstelnlpe tansvtlsdl qpgvqyniti yaveengest
pvviqqettg 901 tprsdtvpsp rdlqfvevtd vkvtimwtpp esavtgyrvd
vipvnlpgeh gqrlpisrnt 961 faevtglspg vtyyfkvfav shgreskplt
aqqttkldap tnlqfvnetd stvlvrwtpp 1021 ragitgyrlt vgltrrgqpr
qynvgpsvsk yplrnlqpas eytvslvaik gnqespkatg 1081 vfttlqpgss
ippyntevte ttivitwtpa prigfklgvr psqggeapre vtsdsgsivv 1141
sgltpgveyv ytiqvlrdgq erdapivnkv vtplspptnl hleanpdtgv ltvswerstt
1201 pditgyritt tptngqqgns leevvhadqs sctfdnlspg leynvsvytv
kddkesvpis 1261 dtiipevpql tdlsfvditd ssiglrwtpl nsstiigyri
tvvaagegip ifedfvdssv 1321 gyytvtglep gidydisvit linggesapt
tltqqtavpp ptdlrftnig pdtmrvtwap 1381 ppsidltnfl vryspvknee
dvaelsisps dnavvltnll pgteyvvsys svyeqhestp 1441 lrgrqktgld
sptgidfsdi tansftvhwi apratitgyr irhhpehfsg rpredrvphs 1501
rnsitltnlt pgteyvvsiv alngreespl ligqqstvsd vprdlevvaa tptslliswd
1561 apavtvryyr itygetggns pvqeftvpgs kstatisglk pgvdytitvy
avtgrgdspa 1621 sskpisinyr teidkpsqmq vtdvqdnsis vkwlpssspv
tgyrvtttpk ngpgptktkt 1681 agpdqtemti eglqptveyv vsvyaqnpsg
esqplvqtav tnidrpkgla ftdvdvdsik 1741 iawespqgqv sryrvtyssp
edgihelfpa pdgeedtael qglrpgseyt vsvvalhddm 1801 esqpligtqs
taipaptdlk ftqvtptsls aqwtppnvql tgyrvrvtpk ektgpmkein 1861
lapdsssvvv sglmvatkye vsvyalkdtl tsrpaqgvvt tlenvspprr arvtdatett
1921 itiswrtkte titgfqvdav pangqtpiqr tikpdvrsyt itglqpgtdy
kiylytlndn 1981 arsspvvida staidapsnl rflattpnsl lvswqpprar
itgyiikyek pgspprevvp 2041 rprpgvteat itglepgtey tiyvialknn
qksepligrk ktdelpqlvt lphpnlhgpe 2101 ildvpstvqk tpfvthpgyd
tgngiqlpgt sgqgpsvgqq mifeehgfrr ttppttatpi 2161 rhrprpyppn
vgeeiqighi predvdyhly phgpglnpna stgqealsqt tiswapfqdt 2221
seyiischpv gtdeeplqfr vpgtstsatl tgltrgatyn iivealkdqq rhkvreevvt
2281 vgnsvnegln qptddscfdp ytvshyavgd ewermsesgf kllcqclgfg
sghfrcdssr 2341 wchdngvnyk igekwdrqge ngqmmsctcl gngkgefkcd
pheatcyddg ktyhvgeqwq 2401 keylgaicsc tcfggqrgwr cdncrrpgge
pspegttgqs ynqysqryhq rtntnvncpi 2461 ecfmpldvqa dredsre
Fibronectin 1, isoform 3 precursor, NP_002017.1 (SEQ ID NO: 74) 1
mlrgpgpgll llavqclgta vpstgasksk rqaqqmvqpq spvaysqskp gcydngkhyq
61 inqqwertyl gnalvctcyg gsrgfncesk peaeetcfdk ytgntyrvgd
tyerpkdsmi 121 wdctcigagr grisctianr cheggqsyki gdtwrrphet
ggymlecvcl gngkgewtck 181 piaekcfdha agtsyvvget wekpyqgwmm
vdctclgegs gritctsrnr cndqdtrtsy 241 rigdtwskkd nrgnllqcic
tgngrgewkc erhtsvqtts sgsgpftdvr aavyqpqphp 301 qpppyghcvt
dsgvvysvgm qwlktqgnkq mlctclgngv scqetavtqt yggnsngepc 361
vlpftyngrt fyscttegrq dghlwcstts nyeqdqkysf ctdhtvlvqt rggnsngalc
421 hfpflynnhn ytdctsegrr dnmkwcgttq nydadqkfgf cpmaaheeic
ttnegvmyri 481 gdqwdkqhdm ghmmrctcvg ngrgewtcia ysqlrdqciv
dditynvndt fhkrheeghm 541 lnctcfgqgr grwkcdpvdq cqdsetgtfy
qigdswekyv hgvryqcycy grgigewhcq 601 plqtypsssg pvevfitetp
sqpnshpiqw napqpshisk yilrwrpkns vgrwkeatip 661 ghlnsytikg
lkpgvvyegq lisiqqyghq evtrfdfttt ststpvtsnt vtgettpfsp 721
lvatsesvte itassfvvsw vsasdtvsgf rveyelseeg depqyldlps tatsvnipdl
781 lpgrkyivnv yqisedgeqs lilstsqtta pdappdptvd qvddtsivvr
wsrpqapitg 841 yrivyspsve gsstelnlpe tansvtlsdl qpgvqyniti
yaveenqest pvviqqettg 901 tprsdtvpsp rdlqfvevtd vkvtimwtpp
esavtgyrvd vipvnlpgeh gqrlpisrnt 961 faevtglspg vtyyfkvfav
shgreskplt aqqttkldap tnlqfvnetd stvlvrwtpp 1021 raqitgyrlt
vgltrrgqpr qynvgpsysk yplrnlqpas eytvslvaik gnqespkatg 1081
vfttlqpgss ippyntevte ttivitwtpa prigfklgvr psqggeapre vtsdsgsivv
1141 sgltpgveyv ytiqvlrdgq erdapivnkv vtplspptnl hleanpdtgv
ltvswerstt 1201 pditgyritt tptngqqgns leevvhadqs sctfdnlspg
leynvsvytv kddkesvpis 1261 dtiipavppp tdlrftnigp dtmrvtwapp
psidltnflv ryspvkneed vaelsispsd 1321 navvltnllp gteyvvsyss
vyeqhestpl rgrqktglds ptgidfsdit ansftvhwia 1381 pratitgyri
rhhpehfsgr predrvphsr nsitltnltp gteyvvsiva lngreespll 1441
igqqstvsdv prdlevvaat ptslliswda pavtvryyri tygetggnsp vqeftvpgsk
1501 statisglkp gvdytitvya vtgrgdspas skpisinyrt eidkpsqmqv
tdvgdnsisv 1561 kwlpssspvt gyrvtttpkn gpgptktkta gpdqtemtie
glqptveyvv svyaqnpsge 1621 sqplvqtavt nidrpkglaf tdvdvdsiki
awespqgqvs ryrvtysspe dgihelfpap 1681 dgeedtaelq glrpgseytv
svvalhddme sqpligtqst aipaptdlkf tqvtptslsa 1741 qwtppnvqlt
gyrvrvtpke ktgpmkeinl apdsssvvvs glmvatkyev svyalkdtlt 1801
srpaqgvvtt lenvspprra rvtdatetti tiswrtktet itgfqvdavp angqtpiqrt
1861 ikpdvrsyti tglqpgtdyk iylytlndna rsspvvidas taidapsnlr
flattpnsll 1921 vswqpprari tgyiikyekp gspprevvpr prpgvteati
tglepgteyt iyvialknnq 1981 ksepligrkk tdelpqlvtl phpnlhgpei
ldvpstvqkt pfvthpgydt gngiqlpgts 2041 gqqpsvgqqm ifeehgfrrt
tppttatpir hrprpyppnv gqealsqtti swapfqdtse 2101 yiischpvgt
deeplqfrvp gtstsatltg ltrgatynii vealkdqqrh kvreevvtvg 2161
nsvneglnqp tddscfdpyt vshyavgdew ermsesgfkl lcqclgfgsg hfrcdssrwc
2221 hdngvnykig ekwdrqgeng qmmsctclgn gkgefkcdph eatcyddgkt
yhvgeqwqke 2281 ylgaicsctc fggqrgwrcd ncrrpggeps pegttgqsyn
qysqryhqrt ntnvncpiec 2341 fmpldvqadr edsre Fibronectin 1, isoform
4 precursor, NP_997643.1 (SEQ ID NO: 75) 1 mlrgpgpgll llavqclgta
vpstgasksk rqaqqmvqpq spvavsqskp gcydngkhyq 61 inqqwertyl
gnalvctcyg gsrgfncesk peaeetcfdk ytgntyrvgd tyerpkdsmi 121
wdctcigagr grisctianr cheggqsyki gdtwrrphet ggymlecvcl gngkgewtck
181 piaekcfdha agtsyvvget wekpyqgwmm vdctclgegs gritctsrnr
cndqdtrtsy 241 rigdtwskkd nrgnllqcic tgngrgewkc erhtsvqtts
sgsgpftdvr aavyqpqphp 301 qpppyghcvt dsgvvysvgm qwlktqgnkq
mlctclgngv scqetavtqt yggnsngepc 361 vlpftyngrt fyscttegrq
dghlwcstts nyeqdqkysf ctdhtvlvqt rggnsngalc 421 hfpflynnhn
ytdctsegrr dnmkwcgttq nydadqkfgf cpmaaheeic ttnegvmyri 481
gdqwdkqhdm ghmmrctcvg ngrgewtcia ysqlrdqciv dditynvndt fhkrheeghm
541 lnctcfgqgr grwkcdpvdq cqdsetgtfy qigdswekyv hgvryqcycy
grgigewhcq 601 plqtypsssg pvevfitetp sqpnshpiqw napqpshisk
yilrwrpkns vgrwkeatip 661 ghlnsytikg lkpgvvyegq lisiqqyghq
evtrfdfttt ststpvtsnt vtgettpfsp 721 lvatsesvte itassfvvsw
vsasdtvsgf rveyelseeg depqyldlps tatsvnipdl 781 lpgrkyivnv
yqisedgeqs lilstsqtta pdappdptvd qvddtsivvr wsrpqapitg 841
yrivyspsve gsstelnlpe tansvtlsdl qpgvqyniti yaveenqest pvviqqettg
901 tprsdtvpsp rdlqfvevtd vkvtimwtpp esavtgyrvd vipvnlpgeh
gqrlpisrnt 961 faevtglspg vtyyfkvfav shgreskplt aqqttkldap
tnlqfvnetd stvlvrwtpp 1021 raqitgyrlt vgltrrgqpr qynvgpsvsk
yplrnlqpas eytvslvaik gnqespkatg 1081 vfttlqpgss ippyntevte
ttivitwtpa prigfklgvr psqggeapre vtsdsgsivv 1141 sgltpgveyv
ytiqvlrdgq erdapivnkv vtplspptnl hleanpdtgv ltvswerstt 1201
pditgyritt tptngqqgns leevvhadqs sctfdnlspg leynvsvytv kddkesvpis
1261 dtiipavppp tdlrftnigp dtmrvtwapp psidltnflv ryspvkneed
vaelsispsd 1321 navvltnllp gteyvvsyss vyeqhestpl rgrqktglds
ptgidfsdit ansftvhwia 1381 pratitgyri rhhpehfsgr predrvphsr
nsitltnitp gteyvvsiva lngreespll 1441 igqqstvsdv prdlevvaat
ptslliswda pavtvryyri tygetggnsp vqeftvpgsk 1501 statisglkp
gvdytitvya vtgrgdspas skpisinyrt eidkpsqmqv tdvqdnsisv 1561
kwlpssspvt gyrvtttpkn gpgptktkta gpdqtemtie glqptveyvv svyaqnpsge
1621 sqplvqtavt nidrpkglaf tdvdvdsiki awespqgqvs ryrvtysspe
dgihelfpap 1681 dgeedtaelq glrpgseytv svvalhddme sqpligtqst
aipaptdlkf tqvtptslsa 1741 qwtppnvqlt gyrvrvtpke ktgpmkeinl
apdsssvvvs glmvatkyev svyalkdtlt 1801 srpaqgvvtt lenvspprra
rvtdatetti tiswrtktet itgfqvdavp angqtpiqrt 1861 ikpdvrsyti
tglqpgtdyk iylytlndna rsspvvidas taidapsnlr flattpnsll 1921
vswqpprari tgyiikyekp gspprevvpr prpgvteati tglepgteyt iyvialknnq
1981 ksepligrkk tvqktpfvth pgydtgngiq lpgtsgqqps vgqqmifeeh
gfrrttpptt 2041 atpirhrprp yppnvgqeal sqttiswapf qdtseyiisc
hpvgtdeepl qfrvpgtsts 2101 atltgltrga tyniivealk dqqrhkvree
vvtvgnsvne glnqptddsc fdpytvshya 2161 vgdewermse sgfkllcgcl
gfgsghfrcd ssrwchdngv nykigekwdr qgengqmmsc 2221 tclgngkgef
kcdpheatcy ddgktyhvge qwgkeylgai csctcfggqr gwrcdncrrp 2281
ggepspegtt gqsynqysqr yhqrtntnvn cpiecfmpld vqadredsre Fibronectin
1, isoform 5 precursor, NP_997641.1 (SEQ ID NO: 76) 1 mlrgpgpgll
llavqclgta vpstgasksk rqaqqmvqpq spvaysqskp gcydngkhyq 61
inqqwertyl gnalvctcyg gsrgfncesk peaeetcfdk ytgntyrvgd tyerpkdsmi
121 wdctcigagr grisctianr cheggqsyki gdtwrrphet ggymlecvcl
gngkgewtck 181 piaekcfdha agtsyvvget wekpyqgwmm vdctclgegs
gritctsrnr cndqdtrtsy 241 rigdtwskkd nrgnllqcic tgngrgewkc
erhtsvqtts sgsgpftdvr aavyqpqphp 301 qpppyghcvt dsgvvysvgm
qwlktqgnkq mlctclgngv scqetavtqt yggnsngepc 361 vlpftyngrt
fyscttegrq dghlwcstts nyeqdqkysf ctdhtvlvqt rggnsngalc 421
hfpflynnhn ytdctsegrr dnmkwcgttq nydadqkfgf cpmaaheeic ttnegvmyri
481 gdqwdkqhdm ghmmrctcvg ngrgewtcia ysqlrdqciv dditynvndt
fhkrheeghm 541 lnctcfgqgr grwkcdpvdq cqdsetgtfy qigdswekyv
hgvryqcycy grgigewhcq 601 plqtypsssg pvevfitetp sqpnshpiqw
napqpshisk yilrwrpkns vgrwkeatip 661 ghlnsytikg lkpgvvyegq
lisiqqyghq evtrfdfttt ststpvtsnt vtgettpfsp 721 lvatsesvte
itassfvvsw vsasdtvsgf rveyelseeg depqyldlps tatsvnipdl 781
lpgrkyivnv yqisedgeqs lilstsqtta pdappdptvd qvddtsivvr wsrpqapitg
841 yrivyspsve gsstelnlpe tansvtlsdl qpgvqyniti yaveenqest
pvviqqettg 901 tprsdtvpsp rdlqfvevtd vkvtimwtpp esavtgyrvd
vipvnlpgeh gqrlpisrnt 961 faevtglspg vtyyfkvfav shgreskplt
aqqttkldap tnlqfvnetd stvlvrwtpp 1021 raqitgyrlt vgltrrgqpr
qynvgpsysk yplrnlqpas eytvslvaik gnqespkatg 1081 vfttlqpgss
ippyntevte ttivitwtpa prigfklgvr psqggeapre vtsdsgsivv 1141
sgltpgveyv ytiqvlrdgq erdapivnkv vtplspptnl hleanpdtgv ltvswerstt
1201 pditgyritt tptngqqgns leevvhadqs sctfdnlspg leynvsvytv
kddkesvpis 1261 dtiipavppp tdlrftnigp dtmrvtwapp psidltnflv
ryspvkneed vaelsispsd 1321 navvltnllp gteyvvsvss vyeqhestpl
rgrqktglds ptgidfsdit ansftvhwia 1381 pratitgyri rhhpehfsgr
predrvphsr nsitltnltp gteyvvsiva lngreespll 1441 igqqstvsdv
prdlevvaat ptslliswda pavtvryyri tygetggnsp vqeftvpgsk 1501
statisglkp gvdytitvya vtgrgdspas skpisinyrt eidkpsqmqv tdvgdnsisv
1561 kwlpssspvt gyrvtttpkn gpgptktkta gpdqtemtie glqptveyvv
svyaqnpsge 1621 sqplvqtavt tipaptdlkf tqvtptslsa qwtppnvqlt
gyrvrvtpke ktgpmkeinl 1681 apdsssvvvs glmvatkyev svyalkdtlt
srpaqgvvtt lenvspprra rvtdatetti 1741 tiswrtktet itgfqvdavp
angqtpiqrt ikpdvrsyti tglqpgtdyk iylytlndna 1801 rsspvvidas
taidapsnlr flattpnsll vswqpprari tgyiikyekp gspprevvpr 1861
prpgvteati tglepgteyt iyvialknnq ksepligrkk tdelpqlvtl phpnlhgpei
1921 ldvpstvqkt pfvthpgydt gngiqlpgts gqqpsvgqqm ifeehgfrrt
tppttatpir 1981 hrprpyppnv geeiqighip redvdyhlyp hgpglnpnas
tgqealsqtt iswapfqdts 2041 eyiischpvg tdeeplqfrv pgtstsatlt
gltrgatyni ivealkdqqr hkvreevvtv 2101 gnsvneglnq ptddscfdpy
tvshyavgde wermsesgfk llcqclgfgs ghfrcdssrw 2161 chdngvnyki
gekwdrqgen gqmmsctclg ngkgefkcdp heatcyddgk tyhvgeqwqk 2221
eylgaicsct cfggqrgwrc dncrrpggep spegttgqsy nqysqryhqr tntnvncpie
2281 cfmpldvqad redsre Fibronectin 1, isoform 6 precursor,
NP_997639.1 (SEQ ID NO: 77) 1 mlrgpgpgll llavqclgta vpstgasksk
rqaqqmvqpq spvaysqskp gcydngkhyq 61 inqqwertyl gnalvctcyg
gsrgfncesk peaeetcfdk ytgntyrvgd tyerpkdsmi 121 wdctcigagr
grisctianr cheggqsyki gdtwrrphet ggymlecvcl gngkgewtck 181
piaekcfdha agtsyvvget wekpyqgwmm vdctclgegs gritctsrnr cndqdtrtsy
241 rigdtwskkd nrgnllqcic tgngrgewkc erhtsvqtts sgsgpftdvr
aavyqpqphp 301 qpppyghcvt dsgvvysvgm qwlktqgnkq mlctclgngv
scqetavtqt yggnsngepc 361 vlpftyngrt fyscttegrq dghlwcstts
nyeqdqkysf ctdhtvlvqt rggnsngalc 421 hfpflynnhn ytdctsegrr
dnmkwcgttq nydadqkfgf cpmaaheeic ttnegvmyri 481 gdqwdkqhdm
ghmmrctcvg ngrgewtcia ysqlrdqciv dditynvndt fhkrheeghm 541
lnctcfgqgr grwkcdpvdq cqdsetgtfy qigdswekyv hgvryqcycy grgigewhcq
601 plqtypsssg pvevfitetp sqpnshpiqw napqpshisk yilrwrpkns
vgrwkeatip 661 ghlnsytikg lkpgvvyegq lisiqqyghq evtrfdfttt
ststpvtsnt vtgettpfsp 721 lvatsesvte itassfvvsw vsasdtvsgf
rveyelseeg depqyldlps tatsvnipdl 781 lpgrkyivnv yqisedgeqs
lilstsqtta pdappdptvd qvddtsivvr wsrpqapitg 841 yrivyspsve
gsstelnlpe tansvtlsdl qpgvqyniti yaveenqest pvviqqettg 901
tprsdtvpsp rdlqfvevtd vkvtimwtpp esavtgyrvd vipvnlpgeh gqrlpisrnt
961 faevtglspg vtyyfkvfav shgreskplt aqqttkldap tnlqfvnetd
stvlvrwtpp 1021 raqitgyrlt vgltrrgqpr qynvgpsvsk yplrnlqpas
eytvslvaik gnqespkatg 1081 vfttlqpgss ippyntevte ttivitwtpa
prigfklgvr psqggeapre vtsdsgsivv 1141 sgltpgveyv ytiqvlrdgq
erdapivnkv vtplspptnl hleanpdtgv ltvswerstt 1201 pditgyritt
tptngqqgns leevvhadqs sctfdnlspg leynvsvytv kddkesvpis 1261
dtiipavppp tdlrftnigp dtmrvtwapp psidltnflv ryspvkneed vaelsispsd
1321 navvltnllp gteyvvsyss vyeqhestpl rgrqktglds ptgidfsdit
ansftvhwia
1381 pratitgyri rhhpehfsgr predrvphsr nsitltnltp gteyvvsiva
lngreespll 1441 igqqstvsdv prdlevvaat ptslliswda pavtvryyri
tygetggnsp vqeftvpgsk 1501 statisglkp gvdytitvya vtgrgdspas
skpisinyrt eidkpsqmqv tdvqdnsisv 1561 kwlpssspvt gvrvtttpkn
gpgptktkta gpdqtemtie glqptveyvv svyaqnpsge 1621 sqplvqtavt
tipaptdlkf tqvtptslsa qwtppnvqlt gyrvrvtpke ktgpmkeinl 1681
apdsssvvvs glmvatkyev svyalkdtlt srpaqgvvtt lenvspprra rvtdatetti
1741 tiswrtktet itgfqvdavp angqtpiqrt ikpdvrsyti tglqpgtdyk
iylytlndna 1801 rsspvvidas taidapsnlr flattpnsll vswqpprari
tgyiikyekp gspprevvpr 1861 prpgvteati tglepgteyt iyvialknnq
ksepligrkk tgqealsqtt iswapfqdts 1921 eyiischpvg tdeeplqfrv
pgtstsatlt gltrgatyni ivealkdqqr hkvreevvtv 1981 gnsvneglnq
ptddscfdpy tvshyavgde wermsesgfk llcqclgfgs ghfrcdssrw 2041
chdngvnyki gekwdrqgen gqmmsctclg ngkgefkcdp heatcyddgk tyhvgeqwqk
2101 eylgaicsct cfggqrgwrc dncrrpggep spegttgqsy nqysqryhqr
tntnvncpie 2161 cfmpldvqad redsre Fibronectin 1, isoform 7
precursor, NP_473375.2 (SEQ ID NO: 78) 1 mlrgpgpgll llavqclgta
vpstgasksk rqaqqmvqpq spvaysqskp gcydngkhyq 61 inqqwertyl
gnalvctcyg gsrgfncesk peaeetcfdk ytgntyrvgd tyerpkdsmi 121
wdctcigagr grisctianr cheggqsyki gdtwrrphet ggymlecvcl gngkgewtck
181 piaekcfdha agtsyvvget wekpyqgwmm vdctclgegs gritctsrnr
cndqdtrtsy 241 rigdtwskkd nrgnllqcic tgngrgewkc erhtsvqtts
sgsgpftdvr aavyqpqphp 301 qpppyghcvt dsgvvysvgm qwlktqgnkq
mlctclgngv scqetavtqt yggnsngepc 361 vlpftyngrt fyscttegrq
dghlwcstts nyeqdqkysf ctdhtvlvqt rggnsngalc 421 hfpflynnhn
ytdctsegrr dnmkwcgttq nydadqkfgf cpmaaheeic ttnegvmyri 481
gdqwdkqhdm ghmmrctcvg ngrgewtcia ysqlrdqciv dditynvndt fhkrheeghm
541 lnctcfgqgr grwkcdpvdq cqdsetgtfy qigdswekyv hgvryqcycy
grgigewhcq 601 plqtypsssg pvevfitetp sqpnshpiqw napqpshisk
yilrwrpvsi pprnlgy Fibronectin 1, isoform 8 precursor,
NP_001293058.1 (SEQ ID NO: 79) 1 mlrgpgpgll llavqclgta vpstgasksk
rqaqqmvqpq spvaysqskp gcydngkhyq 61 inqqwertyl gnalvctcyg
gsrgfncesk peaeetcfdk ytgntyrvgd tyerpkdsmi 121 wdctcigagr
grisctianr cheggqsyki gdtwrrphet ggymlecvcl gngkgewtck 181
piaekcfdha agtsyvvget wekpyqgwmm vdctclgegs gritctsrnr cndqdtrtsy
241 rigdtwskkd nrgnllqcic tgngrgewkc erhtsvqtts sgsgpftdvr
aavyqpqphp 301 qpppyghcvt dsgvvysvgm qwlktqgnkq mlctclgngv
scqetavtqt yggnsngepc 361 vlpftyngrt fyscttegrq dghlwcstts
nyeqdqkysf ctdhtvlvqt rggnsngalc 421 hfpflynnhn ytdctsegrr
dnmkwcgttq nydadqkfgf cpmaaheeic ttnegvmyri 481 gdqwdkqhdm
ghmmrctcvg ngrgewtcia ysqlrdqciv dditynvndt fhkrheeghm 541
lnctcfgqgr grwkcdpvdq cqdsetgtfy qigdswekyv hgvryqcycy grgigewhcq
601 plqtypsssg pvevfitetp sqpnshpiqw napqpshisk yilrwrpkns
vgrwkeatip 661 ghlnsytikg lkpgvvyegq lisiqqyghq evtrfdfttt
ststpvtsnt vtgettpfsp 721 lvatsesvte itassfvvsw vsasdtvsgf
rveyelseeg depqyldlps tatsvnipdl 781 lpgrkyivnv yqisedgeqs
lilstsqtta pdappdptvd qvddtsivvr wsrpqapitg 841 yrivyspsve
gsstelnlpe tansvtlsdl qpgvqyniti yaveenqest pvviqqettg 901
tprsdtvpsp rdlqfvevtd vkvtimwtpp esavtgyrvd vipvnlpgeh gqrlpisrnt
961 faevtglspg vtyyfkvfav shgreskplt aqqttkldap tnlqfvnetd
stvlvrwtpp 1021 raqitgyrlt vgltrrgqpr qynvgpsysk yplrnlqpas
eytvslvaik gnqespkatg 1081 vfttlqpgss ippyntevte ttivitwtpa
prigfklgvr psqggeapre vtsdsgsivv 1141 sgltpgveyv ytiqvlrdgq
erdapivnkv vtplspptnl hleanpdtgv ltvswerstt 1201 pditgyritt
tptngqqgns leevvhadqs sctfdnlspg leynvsvytv kddkesvpis 1261
dtiipevpql tdlsfvditd ssiglrwtpl nsstiigyri tvvaagegip ifedfvdssv
1321 gyytvtglep gidydisvit linggesapt tltqqtavpp ptdlrftnig
pdtmrvtwap 1381 ppsidltnfl vryspvknee dvaelsisps dnavvltnll
pgteyvvsys svyeqhestp 1441 lrgrqktgld sptgidfsdi tansftvhwi
apratitgyr irhhpehfsg rpredrvphs 1501 rnsitltnlt pgteyvvsiv
alngreespl ligqqstvsd vprdlevvaa tptslliswd 1561 apavtvryyr
itygetggns pvqeftvpgs kstatisglk pgvdytitvy avtgrgdspa 1621
sskpisinyr teidkpsqmq vtdvqdnsis vkwlpssspv tgyrvtttpk ngpgptktkt
1681 agpdqtemti eglqptveyv vsvyaqnpsg esqplvqtav tnidrpkgla
ftdvdvdsik 1741 iawespqgqv sryrvtyssp edgihelfpa pdgeedtael
qglrpgseyt vsvvalhddm 1801 esqpligtqs taipaptdlk ftqvtptsls
aqwtppnvql tgyrvrvtpk ektgpmkein 1861 lapdsssvvv sglmvatkye
vsvyalkdtl tsrpaqgvvt tlenvspprr arvtdatett 1921 itiswrtkte
titgfqvdav pangqtpiqr tikpdvrsyt itglqpgtdy kiylytlndn 1981
arsspvvida staidapsnl rflattpnsl lvswqpprar itgyiikyek pgspprevvp
2041 rprpgvteat itglepgtey tiyvialknn qksepligrk ktdelpqlvt
lphpnlhgpe 2101 ildvpstvqk tpfvthpgyd tgngiqlpgt sgqqpsvgqq
mifeehgfrr ttppttatpi 2161 rhrprpyppn vgqealsqtt iswapfqdts
eyiischpvg tdeeplqfrv pgtstsatlt 2221 gltrgatyni ivealkdqqr
hkvreevvtv gnsvneglnq ptddscfdpy tvshyavgde 2281 wermsesgfk
llcqclgfgs ghfrcdssrw chdngvnyki gekwdrqgen gqmmsctclg 2341
ngkgefkcdp heatcyddgk tyhvgeqwqk eylgaicsct cfggqrgwrc dncrrpggep
2401 spegttgqsy nqysciryhqr tntnvncpie cfmpldvqad redsre
Fibronectin 1, isoform 9 precursor, NP_001293059.1 (SEQ ID NO: 80)
1 mlrgpgpgll llavqclgta vpstgasksk rqaqqmvqpq spvaysqskp gcydngkhyq
61 inqqwertyl gnalvctcyg gsrgfncesk peaeetcfdk ytgntyrvgd
tyerpkdsmi 121 wdctcigagr grisctianr cheggqsyki gdtwrrphet
ggymlecvcl gngkgewtck 181 piaekcfdha agtsyvvget wekpyqgwmm
vdctclgegs gritctsrnr cndqdtrtsy 241 rigdtwskkd nrgnllqcic
tgngrgewkc erhtsvqtts sgsgpftdvr aavyqpqphp 301 qpppyghcvt
dsgvvysvgm qwlktqgnkq mlctclgngv scqetavtqt yggnsngepc 361
vlpftyngrt fyscttegrq dghlwcstts nyeqdqkysf ctdhtvlvqt rggnsngalc
421 hfpflynnhn ytdctsegrr dnmkwcgttq nydadqkfgf cpmaaheeic
ttnegvmyri 481 gdqwdkqhdm ghmmrctcvg ngrgewtcia ysqlrdqciv
dditynvndt fhkrheeghm 541 lnctcfgqgr grwkcdpvdq cqdsetgtfy
qigdswekyv hgvryqcycy grgigewhcq 601 plqtypsssg pvevfitetp
sqpnshpiqw napqpshisk yilrwrpkns vgrwkeatip 661 ghlnsytikg
lkpgvvyegq lisiqqyghq evtrfdfttt ststpvtsnt vtgettpfsp 721
lvatsesvte itassfvvsw vsasdtvsgf rveyelseeg depqyldlps tatsvnipdl
781 lpgrkyivnv yqisedgeqs lilstsqtta pdappdptvd qvddtsivvr
wsrpqapitg 841 yrivyspsve gsstelnlpe tansvtlsdl qpgvqyniti
yaveenqest pvviqqettg 901 tprsdtvpsp rdlqfvevtd vkvtimwtpp
esavtgyrvd vipvnlpgeh gqrlpisrnt 961 faevtglspg vtyyfkvfav
shgreskplt aqqttkldap tnlqfvnetd stvlvrwtpp 1021 raqitgyrlt
vgltrrgqpr qynvgpsysk yplrnlqpas eytvslvaik gnqespkatg 1081
vfttlqpgss ippyntevte ttivitwtpa prigfklgvr psqggeapre vtsdsgsivv
1141 sgltpgveyv ytiqvlrdgq erdapivnkv vtplspptnl hleanpdtgv
ltvswerstt 1201 pditgyritt tptngqqgns leevvhadqs sctfdnlspg
leynvsvytv kddkesvpis 1261 dtiipevpql tdlsfvditd ssiglrwtpl
nsstiigyri tvvaagegip ifedfvdssv 1321 gyytvtglep gidydisvit
linggesapt tltqqtavpp ptdlrftnig pdtmrvtwap 1381 ppsidltnfl
vryspvknee dvaelsisps dnavvltnll pgteyvvsvs svyeqhestp 1441
lrgrqktgld sptgidfsdi tansftvhwi apratitgyr irhhpehfsg rpredrvphs
1501 rnsitltnit pgteyvvsiv alngreespl ligqqstvsd vprdlevvaa
tptslliswd 1561 apavtvryyr itygetggns pvqeftvpgs kstatisglk
pgvdytitvy avtgrgdspa 1621 sskpisinyr teidkpsqmq vtdvqdnsis
vkwlpssspv tgyrvtttpk ngpgptktkt 1681 agpdqtemti eglqptveyv
vsvyagnpsg esqplvqtav ttipaptdlk ftqvtptsls 1741 aqwtppnvql
tgyrvrvtpk ektgpmkein lapdsssvvv sglmvatkye vsvyalkdtl 1801
tsrpaqgvvt tlenvspprr arvtdatett itiswrtkte titgfqvdav pangqtpiqr
1861 tikpdvrsyt itglqpgtdy kiylytlndn arsspvvida staidapsnl
rflattpnsl 1921 lvswqpprar itgyiikyek pgspprevvp rprpgvteat
itglepgtey tiyvialknn 1981 qksepligrk ktgqealsqt tiswapfqdt
seyiischpv gtdeeplqfr vpgtstsatl 2041 tgltrgatyn iivealkdqq
rhkvreevvt vgnsvnegln qptddscfdp ytvshyavgd 2101 ewermsesgf
kllcqclgfg sghfrcdssr wchdngvnyk igekwdrqge ngqmmsctcl 2161
gngkgefkcd pheatcyddg ktyhvgeqwq keylgaicsc tcfggqrgwr cdncrrpgge
2221 pspegttgqs ynqysqryhq rtntnvncpi ecfmpldvqa dredsre
Fibronectin 1, isoform 10 precursor, NP_001293060.1 (SEQ ID NO: 81)
1 mlrgpgpgll llavqclgta vpstgasksk rqaqqmvqpq spvaysqskp gcydngkhyq
61 inqqwertyl gnalvctcyg gsrgfncesk peaeetcfdk ytgntyrvgd
tyerpkdsmi 121 wdctcigagr grisctianr cheggqsyki gdtwrrphet
ggymlecvcl gngkgewtck 181 piaekcfdha agtsyvvget wekpyqgwmm
vdctclgegs gritctsrnr cndqdtrtsy 241 rigdtwskkd nrgnllqcic
tgngrgewkc erhtsvqtts sgsgpftdvr aavyqpqphp 301 qpppyghcvt
dsgvvysvgm qwlktqgnkq mlctclgngv scqetavtqt yggnsngepc 361
vlpftyngrt fyscttegrq dghlwcstts nyeqdqkysf ctdhtvlvqt rggnsngalc
421 hfpflynnhn ytdctsegrr dnmkwcgttq nydadqkfgf cpmaaheeic
ttnegvmyri 481 gdqwdkqhdm ghmmrctcvg ngrgewtcia ysqlrdqciv
dditynvndt fhkrheeghm 541 lnctcfgqgr grwkcdpvdq cqdsetgtfy
qigdswekyv hgvryqcycy grgigewhcq 601 plqtypsssg pvevfitetp
sqpnshpiqw napqpshisk yilrwrpkns vgrwkeatip 661 ghlnsytikg
lkpgvvyegq lisiqqyghq evtrfdfttt ststpvtsnt vtgettpfsp 721
lvatsesvte itassfvvsw vsasdtvsgf rveyelseeg depqyldlps tatsvnipdl
781 lpgrkyivnv yqisedgeqs lilstsqtta pdappdptvd qvddtsivvr
wsrpqapitg 841 yrivyspsve gsstelnlpe tansvtlsdl qpgvqyniti
yaveenqest pvviqqettg 901 tprsdtvpsp rdlqfvevtd vkvtimwtpp
esavtgyrvd vipvnlpgeh gqrlpisrnt 961 faevtglspg vtyyfkvfav
shgreskplt aqqttkldap tnlqfvnetd stvlvrwtpp 1021 raqitgyrlt
vgltrrgqpr qynvgpsysk yplrnlqpas eytvslvaik gnqespkatg 1081
vfttlqpgss ippyntevte ttivitwtpa prigfklgvr psqggeapre vtsdsgsivv
1141 sgltpgveyv ytiqvlrdgq erdapivnkv vtplspptnl hleanpdtgv
ltvswerstt 1201 pditgyritt tptngqqgns leevvhadqs sctfdnlspg
leynvsvytv kddkesvpis 1261 dtiipavppp tdlrftnigp dtmrvtwapp
psidltnflv ryspvkneed vaelsispsd 1321 navvltnllp gteyvvsyss
vyeqhestpl rgrqktglds ptgidfsdit ansftvhwia 1381 pratitgyri
rhhpehfsgr predrvphsr nsitltnitp gteyvvsiva lngreespll 1441
igqqstvsdv prdlevvaat ptslliswda pavtvryyri tygetggnsp vqeftvpgsk
1501 statisglkp gvdytitvya vtgrgdspas skpisinyrt eidkpsqmqv
tdvqdnsisv 1561 kwlpssspvt gyrvtttpkn gpgptktkta gpdqtemtie
glqptveyvv svyaqnpsge 1621 sqplvqtavt tipaptdlkf tqvtptslsa
qwtppnvqlt gyrvrvtpke ktgpmkeinl 1681 apdsssvvvs glmvatkyev
svyalkdtlt srpaqgvvtt lenvspprra rvtdatetti 1741 tiswrtktet
itgfqvdavp angqtpiqrt ikpdvrsyti tglqpgtdyk iylytlndna 1801
rsspvvidas taidapsnlr flattpnsll vswqpprari tgyiikyekp gspprevvpr
1861 prpgvteati tglepgteyt iyvialknnq ksepligrkk tdelpqlvtl
phpnlhgpei 1921 ldvpstvqkt pfvthpgydt gngiqlpgts gqqpsvgqqm
ifeehgfrrt tppttatpir 1981 hrprpyppnv gqealsqtti swapfqdtse
yiischpvgt deeplqfrvp gtstsatltg 2041 ltrgatynii vealkdqqrh
kvreevvtvg nsvneglnqp tddscfdpyt vshyavgdew 2101 ermsesgfkl
lcqclgfgsg hfrcdssrwc hdngvnykig ekwdrqgeng qmmsctclgn 2161
gkgefkcdph eatcyddgkt yhvgeqwqke ylgaicsctc fggqrgwrcd ncrrpggeps
2221 pegttgqsyn gysqryhqrt ntnvncpiec fmpldvqadr edsre Fibronectin
1, isoform 11 precursor, NP_001293061.1 (SEQ ID NO: 82) 1
mlrgpgpgll llavqclgta vpstgasksk rqaqqmvqpq spvaysqskp gcydngkhyq
61 inqqwertyl gnalvctcyg gsrgfncesk peaeetcfdk ytgntyrvgd
tyerpkdsmi 121 wdctcigagr grisctianr cheggqsyki gdtwrrphet
ggymlecvcl gngkgewtck 181 piaekcfdha agtsyvvget wekpyqgwmm
vdctclgegs gritctsrnr cndqdtrtsy 241 rigdtwskkd nrgnllqcic
tgngrgewkc erhtsvqtts sgsgpftdvr aavyqpqphp 301 qpppyghcvt
dsgvvysvgm qwlktqgnkq mlctclgngv scqetavtqt yggnsngepc 361
vlpftyngrt fyscttegrq dghlwcstts nyeqdqkysf ctdhtvlvqt rggnsngalc
421 hfpflynnhn ytdctsegrr dnmkwcgttq nydadqkfgf cpmaaheeic
ttnegvmyri 481 gdqwdkqhdm ghmmrctcvg ngrgewtcia ysqlrdqciv
dditynvndt fhkrheeghm 541 lnctcfgqgr grwkcdpvdq cqdsetgtfy
qigdswekyv hgvryqcycy grgigewhcq 601 plqtypsssg pvevfitetp
sqpnshpiqw napqpshisk yilrwrpkns vgrwkeatip 661 ghlnsytikg
lkpgvvyegq lisiqqyghq evtrfdfttt ststpvtsnt vtgettpfsp 721
lvatsesvte itassfvvsw vsasdtvsgf rveyelseeg depqyldlps tatsvnipdl
781 lpgrkyivnv yqisedgeqs lilstsqtta pdappdptvd qvddtsivvr
wsrpqapitg 841 yrivyspsve gsstelnlpe tansvtlsdl qpgvqyniti
yaveenqest pvviqqettg 901 tprsdtvpsp rdlqfvevtd vkvtimwtpp
esavtgyrvd vipvnlpgeh gqrlpisrnt 961 faevtglspg vtyyfkvfav
shgreskplt aqqttkldap tnlqfvnetd stvlvrwtpp 1021 raqitgyrlt
vgltrrgqpr qynvgpsysk yplrnlqpas eytvslvaik gnqespkatg 1081
vfttlqpgss ippyntevte ttivitwtpa prigfklgvr psqggeapre vtsdsgsivv
1141 sgltpqveyv ytiqvlrdgq erdapivnkv vtplspptnl hleanpdtgv
ltvswerstt 1201 pditgyritt tptngqqgns leevvhadqs sctfdnlspg
leynvsvytv kddkesvpis 1261 dtiipavppp tdlrftnigp dtmrvtwapp
psidltnflv ryspvkneed vaelsispsd 1321 navvltnllp gteyvvsvss
vyeqhestpl rgrqktglds ptgidfsdit ansftvhwia 1381 pratitgyri
rhhpehfsgr predrvphsr nsitltnltp gteyvvsiva lngreespll 1441
igqqstvsdv prdlevvaat ptslliswda pavtvryyri tygetggnsp vqeftvpgsk
1501 statisglkp gvdytitvya vtgrgdspas skpisinyrt eidkpsqmqv
tdvqdnsisv 1561 kwlpssspvt gyrvtttpkn gpgptktkta gpdqtemtie
glqptveyvv svyaqnpsge 1621 sqplvqtavt tipaptdlkf tqvtptslsa
qwtppnvqlt gyrvrvtpke ktgpmkeinl 1681 apdsssvvvs glmvatkyev
svyalkdtlt srpaqgvvtt lenvspprra rvtdatetti 1741 tiswrtktet
itgfqvdavp angqtpiqrt ikpdvrsyti tglqpgtdyk iylytlndna 1801
rsspvvidas taidapsnlr flattpnsll vswqpprari tgyiikyekp gspprevvpr
1861 prpgvteati tglepgteyt iyvialknnq ksepligrkk tvqktpfvth
pgydtgngiq 1921 lpgtsgqqps vgqqmifeeh gfrrttpptt atpirhrprp
yppnvgqeal sqttiswapf 1981 qdtseyiisc hpvgtdeepl qfrvpgtsts
atltgltrga tyniivealk dqqrhkvree 2041 vvtvgnsvne glnqptddsc
fdpytvshya vgdewermse sgfkllcqcl gfgsghfrcd 2101 ssrwchdngv
nykigekwdr qgengqmmsc tclgngkgef kcdpheatcy ddgktyhvge 2161
qwgkeylgai csctcfggqr gwrcdncrrp ggepspegtt gqsynqysqr yhqrtntnvn
2221 cpiecfmpld vqadredsre Major histocompatibility complex, class
II, DR beta 1, precursor, NP_001230894.1 (SEQ ID NO: 83) 1
mvclrlpggs cmavltvtlm vlssplalag dtrprfleys tsechffngt ervryldrvf
61 hnqeenvrfd sdvgefravt elgrpdaeyw nsqkdlleqk rgrvdnycrh
nygvvesftv 121 qrrvhpkvtv ypsktqplqh hnllvcsysg fypgsievrw
frngqeektg vvstglihng 181 dwtfqtlvml etvprsgevy tcqvehpsvt
spltvewrar sesaqskmls gvggfvlgll 241 flgaglfiyf rnqkghsglq prgfls
Major histocompatibility complex, class II, DR beta 1, precursor,
NP_001346122.1 (SEQ ID NO: 84) 1 mvclklpggs cmaaltvtlm vlssplalag
dtqprflwqg kykchffngt ervqflerlf 61 ynqeefvrfd sdvgeyravt
elgrpvaesw nsqkdiledr rgqvdtvcrh nygvgesftv 121 qrrvhpevtv
ypaktqplqh hnllvcsysg fypgsievrw frngqeekag vvstgliqng 181
dwtfqtlvml etvprsgevy tcqvehpsvm spltvewrar sesaqskmls gvggfvlgll
241 flgaglfiyf rnqkghsglq ptgfls Major histocompatibility complex,
class II, DR beta 1, precursor, NP_001346123.1 (SEQ ID NO: 85) 1
mvclkfpggs cmaaltvtlm vlssplalag dtrprfleqv khechffngt ervrfldrvf
61 yhqeeyvrfd sdvgeyravt elgrpdaeyw nsqkdlleqr raevdtycrh
nygvvesftv 121 qrrvypevtv ypaktqplqh hnllvcsvng fypgsievrw
frngqeektg vvstgliqng 181 dwtfqtlvml etvprsgevy tcqvehpslt
spltvewrar sesaqskmls gvggfvlgll 241 flgaglfiyf rnqkghsglq ptgfls
Major histocompatibility complex, class II, DR beta 1, precursor,
NP_002115.2 (SEQ ID NO: 86) 1 mvclklpggs cmtaltvtlm vlssplalsg
dtrprflwqp krechffngt ervrfldrvf 61 ynqeesvrfd sdvgefravt
elgrpdaeyw nsqkdileqa raavdtycrh nygvvesftv 121 qrrvqpkvtv
ypsktqplqh hnllvcsysg fypgsievrw flngqeekag mvstgliqng 181
dwtfqtlvml etvprsgevy tcqvehpsvt spltvewrar sesaqskmls gvggfvlgll
241 flgaglfiyf rnqkghsglq ptgfls Major histocompatibility complex,
class II, DR beta 5, precursor, NP_002116.2 (SEQ ID NO: 87) 1
mvclklpggs ymakltvtlm vlssplalag dtrprflqqd kyechffngt ervrflhrdi
61 ynqeedlrfd sdvgeyravt elgrpdaeyw nsqkdfledr raavdtycrh
nygvgesftv 121 qrrvepkvtv ypartqtlqh hnllvcsvng fypgsievrw
frnsqeekag vvstgliqng 181 dwtfqtlvml etvprsgevy tcqvehpsvt
spltvewraq sesaqskmls gvggfvlgll 241 flgaglfiyf knqkghsglh ptglvs
Hydroxysteroid 17-beta dehydrogenase 3, NP_000188.1 (SEQ ID NO: 88)
1 mgdvleqffi ltgllvclac lakcvrfsrc vllnywkvlp ksflrsmgqw avitgagdgi
61 gkaysfelak rglnvvlisr tlekleaiat eierttgrsv kiiqadftkd
diyehikekl 121 agleigilvn nvgmlpnllp shflnapdei qslihcnits
vvkmtqlilk hmesrqkgli 181 lnissgialf pwplysmysa skafvcafsk
alqeeykake viiqvltpya vstamtkyln 241 tnvitktade fvkeslnyvt
iggetcgcla heilagflsl ipawafysga fqrlllthyv 301 aylklntkvr Insulin
degrading enzyme, isoform 1, NP_004960.2 (SEQ ID NO: 89) 1
mryrlawllh palpstfrsv lgarlppper lcgfqkktys kmnnpaikri gnhitksped
61 kreyrglela ngikvllisd pttdkssaal dvhigslsdp pniaglshfc
ehmlflgtkk 121 ypkeneysqf lsehagssna ftsgehtnyy fdvshehleg
aldrfaqffl cplfdesckd 181 revnavdseh eknvmndawr lfqlekatgn
pkhpfskfgt gnkytletrp nqegidvrqe 241 llkfhsayys snlmavcvlg
reslddltnl vvklfseven knvplpefpe hpfqeehlkq 301 lykivpikdi
rnlyvtfpip dlqkyyksnp ghylghligh egpgsllsel kskgwvntlv 361
ggqkegargf mffiinvdlt eegllhvedi ilhmfqyiqk lraegpqewv fqeckdlnav
421 afrfkdkerp rgytskiagi lhyypleevl taeylleefr pdliemvldk
lrpenvrvai 481 vsksfegktd rteewygtqy kqeaipdevi kkwqnadlng
kfklptknef iptnfeilpl
541 ekeatpypal ikdtamsklw fkqddkfflp kaclnfeffs pfayvdplhc
nmaylylell 601 kdslneyaya aelaglsydl qntiygmyls vkgyndkqpi
llkkiiekma tfeidekrfe 661 iikeaymrsl nnfraeqphq hamyylrllm
tevawtkdel kealddvtlp rlkafipqll 721 srlhieallh gnitkqaalg
imqmvedtli ehahtkpllp sqlvryrevq lpdrgwfvyq 781 qrnevhnncg
ieiyyqtdmq stsenmflel fcqiisepcf ntlrtkeqlg yivfsgprra 841
ngiqglrfii qsekpphyle srveaflitm eksiedmtee afqkhiqala irrldkpkkl
901 saecakywge iisqqynfdr dntevaylkt ltkediikfy kemlavdapr
rhkvsvhvla 961 remdscpvvg efpcqndinl sqapalpqpe viqnmtefkr
glplfplvkp hinfmaakl Insulin degrading enzyme, isoform 2,
NP_001159418.1 (SEQ ID NO: 90) 1 msklwfkqdd kfflpkacln feffspfayv
dplhcnmayl ylellkdsln eyayaaelag 61 lsydlqntiy gmylsvkgyn
dkqpillkki iekmatfeid ekrfeiikea ymrslnnfra 121 eqphqhamyy
lrllmtevaw tkdelkeald dvtlprlkaf ipqllsrlhi eallhgnitk 181
qaalgimqmv edtliehaht kpllpsqlvr yrevqlpdrg wfvyqqrnev hnncgieiyy
241 qtdmqstsen mflelfcqii sepcfntlrt keqlgyivfs gprrangiqg
lrfiiqsekp 301 phylesrvea flitmeksie dmteeafqkh iqalairrld
kpkklsaeca kywgeiisqq 361 ynfdrdntev aylktltked iikfykemla
vdaprrhkvs vhvlaremds cpvvgefpcq 421 ndinlsqapa lpqpeviqnm
tefkrglplf plvkphinfm aakl Insulin degrading enzyme, isoform 3,
NP_001309722.1 (SEQ ID NO: 91) 1 mryrlawllh palpstfrsv lgarlppper
lcgfqkktys kmnnpaikri gnhitksped 61 kreyrglela ngikvllisd
pttdkssaal dvhigslsdp pniaglshfc ehmlflgtkk 121 ypkeneysqf
lsehagssna ftsgehtnyy fdvshehleg aldrfaqffl cplfdesckd 181
revnavdseh eknvmndawr lfqlekatgn pkhpfskfgt gnkytletrp nqegidvrqe
241 llkfhsayys snlmavcvlg reslddltnl vvklfseven knvplpefpe
hpfqeehlkq 301 lykivpikdi rnlyvtfpip dlqkyyksnp ghylghligh
egpgsllsel kskgwvntlv 361 ggqkegargf mffiinvdlt eegllhvedi
ilhmfqyiqk lraegpqewv fqeckdlnav 421 afrfkdkerp rgytskiagi
lhyypleevl taeylleefr pdliemvldk lrpenvrvai 481 vsksfegktd
rteewygtqy kqeaipdevi kkwqnadlng kfklptknef iptnfeilpl 541
ekeatpypal ikdtamsklw fkqddkfflp kaclnfeffs ryiyadplhc nmtylfirll
601 kddlkeytya arlsglsygi asgmnaills vkgyndkqpi llkkiiekma
tfeidekrfe 661 iikeaymrsl nnfraeqphq hamyylrllm tevawtkdel
kealddvtlp rlkafipqll 721 srlhieallh gnitkqaalg imqmvedtli
ehahtkpllp sqlvryrevq lpdrgwfvyq 781 qrnevhnncg ieiyyqtdmq
stsenmflel fcqiisepcf ntlrtkeqlg yivfsgprra 841 ngiqglrfii
qsekpphyle srveaflitm eksiedmtee afqkhigala irrldkpkkl 901
saecakywge iisqqynfdr dntevaylkt ltkediikfy kemlavdapr rhkvsvhvla
961 remdscpvvg efpcqndinl sqapalpqpe viqnmtefkr glplfplvkp
hinfmaakl Insulin degrading enzyme, isoform 4, NP_001309723.1 (SEQ
ID NO: 92) 1 mryrlawllh palpstfrsv lgarlppper lcgfqkktys kmnnpaikri
gnhitksped 61 kreyrglela ngikvllisd pttdkssaal dvhigslsdp
pniaglshfc ehmlflgtkk 121 ypkeneysqf lsehagssna ftsgehtnyy
fdvshehleg aldrfaqffl cplfdesckd 181 revnavdseh eknvmndawr
lfqlekatgn pkhpfskfgt greslddltn lvvklfseve 241 nknvplpefp
ehpfqeehlk qlykivpikd irnlyvtfpi pdlqkyyksn pghylghlig 301
hegpgsllse lkskgwvntl vggqkegarg fmffiinvdl teegllhved iilhmfqyiq
361 klraegpqew vfqeckdlna vafrfkdker prgytskiag ilhyypleev
ltaeylleef 421 rpdliemvld klrpenvrva ivsksfegkt drteewygtq
ykqeaipdev ikkwqnadln 481 gkfklptkne fiptnfeilp lekeatpypa
likdtamskl wfkqddkffl pkaclnfeff 541 spfayvdplh cnmaylylel
lkdslneyay aaelaglsyd lqntiygmyl svkgyndkqp 601 illkkiiekm
atfeidekrf eiikeaymrs lnnfraeqph qhamyylrll mtevawtkde 661
lkealddvtl prlkafipql lsrlhieall hgnitkqaal gimqmvedtl iehahtkpll
721 psqlvryrev qlpdrgwfvy qqrnevhnnc gieiyyqtdm qstsenmfle
lfcqiisepc 781 fntlrtkeql gyivfsgprr angiqglrfi iqsekpphyl
esrveaflit meksiedmte 841 eafqkhiqal airrldkpkk lsaecakywg
eiisqqynfd rdntevaylk tltkediikf 901 ykemlavdap rrhkvsvhvl
aremdscpvv gefpcqndin lsqapalpqp eviqnmtefk 961 rglplfplvk
phinfmaakl Insulin degrading enzyme, isoform 5, NP_001309724.1,
NP_001309725.1 (SEQ ID NO: 93) 1 mnnpaikrig nhitkspedk reyrglelan
gikvllisdp ttdkssaald vhigslsdpp 61 niaglshfce hmlflgtkky
pkeneysqfl sehagssnaf tsgehtnyyf dvshehlega 121 ldrfaqfflc
plfdesckdr evnavdsehe knvmndawrl fqlekatgnp khpfskfgtg 181
nkytletrpn qegidvrqel lkfhsayyss nlmavcvlgr eslddltnlv vklfsevenk
241 nvplpefpeh pfqeehlkql ykivpikdir nlyvtfpipd lqkyyksnpg
hylghlighe 301 gpgsllselk skgwvntlvg gqkegargfm ffiinvdlte
egllhvedii lhmfqyiqkl 361 raegpgewvf qeckdlnava frfkdkerpr
gytskiagil hyypleevlt aeylleefrp 421 dliemvldkl rpenvrvaiv
sksfegktdr teewygtqyk qeaipdevik kwqnadlngk 481 fklptknefi
ptnfeilple keatpypali kdtamsklwf kqddkfflpk aclnfeffsp 541
fayvdplhcn maylylellk dslneyayaa elaglsydlq ntiygmylsv kgyndkqpil
601 lkkiiekmat feidekrfei ikeaymrsln nfraeqphqh amyylrllmt
evawtkdelk 661 ealddvtlpr lkafipqlls rlhieallhg nitkqaalgi
mqmvedtlie hahtkpllps 721 qlvryrevql pdrgwfvyqq rnevhnncgi
eiyyqtdmqs tsenmflelf cqiisepcfn 781 tlrtkeqlgy ivfsgprran
giqglrfiiq sekpphyles rveaflitme ksiedmteea 841 fqkhiqalai
rrldkpkkls aecakywgei isqqynfdrd ntevaylktl tkediikfyk 901
emlavdaprr hkvsvhvlar emdscpvvge fpcqndinls qapalpqpev iqnmtefkrg
961 lplfplvkph infmaakl Insulin degrading enzyme, isoform 6,
NP_001309726.1 (SEQ ID NO: 94) 1 msklwfkqdd kfflpkacln feffsryiya
dplhcnmtyl firllkddlk eytyaarlsg 61 lsygiasgmn aillsvkgyn
dkqpillkki iekmatfeid ekrfeiikea ymrslnnfra 121 eqphqhamyy
lrllmtevaw tkdelkeald dvtlprlkaf ipqllsrlhi eallhgnitk 181
qaalgimqmv edtliehaht kpllpsqlvr yrevqlpdrg wfvyqqrnev hnncgieiyy
241 qtdmqstsen mflelfcqii sepcfntlrt keqlgyivfs gprrangiqg
lrfiiqsekp 301 phylesrvea flitmeksie dmteeafqkh iqalairrld
kpkklsaeca kywgeiisqq 361 ynfdrdntev aylktltked iikfykemla
vdaprrhkvs vhvlaremds cpvvgefpcq 421 ndinlsqapa lpqpeviqnm
tefkrglplf plvkphinfm aakl Indoleamine 2,3-dioxygenase 1,
NP_002155.1 (SEQ ID NO: 95) 1 mahamenswt iskeyhidee vgfalpnpqe
nlpdfyndwm fiakhlpdli esgqlrerve 61 klnmlsidhl tdhksqrlar
lvlgcitmay vwgkghgdvr kvlprniavp ycqlskklel 121 ppilvyadcv
lanwkkkdpn kpltyenmdv lfsfrdgdcs kgfflvsllv eiaaasaikv 181
iptvfkamqm qerdtllkal leiascleka lqvfhqihdh vnpkaffsvl riylsgwkgn
241 pqlsdglvye gfwedpkefa ggsagqssvf qcfdvllgiq qtaggghaaq
flqdmrrymp 301 pahrnflcsl esnpsvrefv lskgdaglre aydacvkalv
slrsyhlqiv tkyilipasq 361 qpkenktsed pskleakgtg gtdlmnflkt
vrstteksll keg Insulin like growth factor binding protein 5,
precursor, NP_000590.1 (SEQ ID NO: 96) 1 mvlltavlll laayagpaqs
lgsfvhcepc dekalsmcpp splgcelvke pgcgccmtca 61 laegqscgvy
tercaqglrc lprqdeekpl hallhgrgvc lneksyreqv kierdsrehe 121
epttsemaee tyspkifrpk htriselkae avkkdrrkkl tqskfvggae ntahpriisa
181 pemrqeseqg pcrrhmeasl qelkasprmv pravylpncd rkgfykrkqc
kpsrgrkrgi 241 cwcvdkygmk lpgmeyvdgd fqchtfdssn ve Insulin like
growth factor binding protein 7, isoform 1 precursor, NP_001544.1
(SEQ ID NO: 97) 1 merpslrall lgaaglllll lplssssssd tcgpcepasc
pplpplgcll getrdacgcc 61 pmcargegep cggggagrgy capgmecvks
rkrrkgkaga aaggpgvsgv cvcksrypvc 121 gsdgttypsg cqlraasqra
esrgekaitq vskgtceqgp sivtppkdiw nvtgaqvyls 181 cevigiptpv
liwnkvkrgh ygvqrtellp gdrdnlaiqt rggpekhevt gwvlvsplsk 241
edageyecha snsqggasas akitvvdalh eipvkkgega el Insulin like growth
factor binding protein 7, isoform 2 precursor, NP_001240764.1 (SEQ
ID NO: 98) 1 merpslrall lgaaglllll lplssssssd tcgpcepasc pplpplgcll
getrdacgcc 61 pmcargegep cggggagrgy capgmecvks rkrrkgkaga
aaggpgvsgv cvcksrypvc 121 gsdgttypsg cqlraasqra esrgekaitq
vskgtceqgp sivtppkdiw nvtgaqvyls 181 cevigiptpv liwnkvkrgh
ygvqrtellp gdrdnlaiqt rggpekhevt gwvlvsplsk 241 edageyecha
snsqgqasas akitvvdalh eipvkkgtq Potassium two pore domain channel
subfamily K member 1, NP_002236.1 (SEQ ID NO: 99) 1 mlqslagssc
vrlverhrsa wcfgflvlgy llylvfgavv fssvelpyed llrqelrklk 61
rrfleehecl seqqleqflg rvleasnygv svlsnasgnw nwdftsalff astvlsttgy
121 ghtvplsdgg kafciiysvi gipftllflt avvqritvhv trrpvlyfhi
rwgfskqvva 181 ivhavllgfv tvscfffipa avfsvleddw nflesfyfcf
islstiglgd yvpgegynqk 241 frelykigit cylllgliam lvvletfcel
helkkfrkmf yvkkdkdedq vhiiehdqls 301 fssitdqaag mkedqkqnep
fvatqssacv dgpanh Lysosomal associated membrane protein 3,
precursor, NP_055213.2 (SEQ ID NO: 100) 1 mprqlsaaaa lfaslavilh
dgsqmrakaf petrdysqpt aaatvqdikk pvqqpakqap 61 hqtlaarfmd
ghitfqtaat vkiptttpat tkntattspi tytlvttqat pnnshtappv 121
tevtvgpsla pyslpptitp pahttgtsss tvshttgntt gpsnqttlpa tlsialhkst
181 tgqkpvqpth apgttaaahn ttrtaapast vpgptlapqp ssvktgiyqv
lngsrlcika 241 emgiqlivqd kesvfsprry fnidpnatqa sgncgtrksn
lllnfqggfv nltftkdees 301 yyisevgayl tvsdpetiyq gikhavvmfq
tavghsfkcv seqslqlsah lqvkttdvql 361 qafdfeddhf gnvdecssdy
tivlpvigai vvglclmgmg vykirlrcqs sgyqri MAGE family member B2,
NP_002355.2 (SEQ ID NO: 101) 1 mprgqksklr arekrrkard etrglnvpqv
teaeeeeapc csssysggaa ssspaagipq 61 epqrapttaa aaaagvsstk
skkgakshqg eknasssqas tstkspsedp ltrksgslvq 121 fllykykikk
svtkgemlki vgkrfrehfp eilkkasegl svvfglelnk vnpnghtytf 181
idkvdltdee sllsswdfpr rkllmpllgv iflngnsate eeiweflnml gvydgeehsv
241 fgepwklitk dlvqekyley kqvpssdppr fqflwgpray aetskmkvle
flakvngttp 301 cafpthyeea lkdeekagv Mitogen-activated protein
kinase 13, NP_002745.1 (SEQ ID NO: 102) 1 mslirkkgfy kqdvnktawe
lpktyvspth vgsgaygsvc saidkrsgek vaikklsrpf 61 qseifakray
rellllkhmq henviglldv ftpasslrnf ydfylvmpfm qtdlqkimgm 121
efseekigyl vyqmlkglky ihsagvvhrd lkpgnlavne dcelkildfg larhadaemt
181 gyvvtrwyra pevilswmhy nqtvdiwsvg cimaemltgk tlfkgkdyld
qltqilkvtg 241 vpgtefvqkl ndkaaksyiq slpqtprkdf tqlfpraspq
aadllekmle ldvdkrltaa 301 qalthpffep frdpeeetea qqpfddsleh
ekltvdewkq hiykeivnfs piarkdsrrr 361 sgmkl Macrophage receptor with
collagenous structure, NP_006761.1 (SEQ ID NO: 103) 1 mrnkkilked
ellsetqqaa fhqiamepfe invpkpkrrn gvnfslavvv iylilltaga 61
gllvvqvlnl qarlrvlemy flndtlaaed spsfsllqsa hpgehlaqga srlqvlqaql
121 twvrvshehl lqrvdnftqn pgmfrikgeq gapglqghkg amgmpgapgp
pgppaekgak 181 gamgrdgatg psgpqgppgv kgeaglqgpq gapgkqgatg
tpgpqgekgs kgdggligpk 241 getgtkgekg dlglpgskgd rgmkgdagvm
gppgaqgskg dfgrpgppgl agfpgakgdg 301 gqpglqgvpg ppgavghpga
kgepgsagsp graglpgspg spgatglkgs kgdtglqgqq 361 grkgesgvpg
pagvkgeqgs pglagpkgap gqagqkgdqg vkgssgeqgv kgekgergen 421
sysvrivgss nrgraevyys gtwgticdde wqnsdaivfc rmlgyskgra lykvgagtgq
481 iwldnvqcrg testlwsctk nswghhdcsh eedagvecsv Malic enzyme 1,
NADP-dependent malic enzyme, NP_002386.1 (SEQ ID NO: 104) 1
mepeaprrrh thqrgylltr nphlnkdlaf tleerqqlni hgllppsfns qeiqvlrvvk
61 nfehlnsdfd rylllmdlqd rneklfyrvl tsdiekfmpi vytptvglac
qqyslvfrkp 121 rglfitihdr ghiasvinaw pedvikaivv tdgerilglg
dlgcngmgip vgklalytac 181 ggmnpqeclp vildvgtene ellkdplyig
lrqrrvrgse yddfldefme aysskygmnc 241 liqfedfanv nafrllnkyr
nqyctfnddi qgtasvavag llaalritkn klsdqtilfq 301 gageaalgia
hlivmaleke glpkekaikk iwlvdskgli vkgrasltqe kekfahehee 361
mknleaivqe ikptaligva aiggafseqi lkdmaafner piifalsnpt skaecsaeqc
421 ykitkgraif asgspfdpvt lpngqtlypg qgnnsyvfpg valgvvacgl
rqitdniflt 481 taeviaqqvs dkhleegrly pplntirdvs lkiaekivkd
ayqektatvy pepqnkeafv 541 rsqmystdyd qilpdcyswp eevqkiqtkv dq
Migration and invasion inhibitory protein, NP_068752.2 (SEQ ID NO:
105) 1 mveaeelaql rllnlellrq lwvgqdavrr svaraasess lessssynse
tpstpetsst 61 slstscprgr ssvwgppdac rgdlrdvars gvaslppakc
qhqeslgrpr phsapslgts 121 slrdpepsgr lgdpgpqeaq tprsilaqqs
klskprvtfs eesavpkrsw rlrpylgydw 181 iagsldtsss itsqpeaffs
klqefretnk eecicshpep qlpglressg sgveedhecv 241 ycyrvnrrlf
pvpvdpgtpc rlcrtprdqq gpgtlaqpah vrvsiplsil epphryhihr 301
rksfdasdtl alprhcllgw difppkseks saprnldlws sysaeaqhqk lsgtsspfhp
361 aspmqmlppt ptwsvpqvpr phvprqkp Matrix metallopeptidase 12,
macrophage metalloelastase preproprotein, NP_002417.2 (SEQ ID NO:
106) 1 mkfllilllq atasgalpln sstsleknnv lfgerylekf ygleinklpv
tkmkysgnlm 61 kekiqemqhf lglkvtgqld tstlemmhap rcgvpdvhhf
rempggpvwr khyityrinn 121 ytpdmnredv dyairkafqv wsnvtplkfs
kintgmadil vvfargahgd fhafdgkggi 181 lahafgpgsg iggdahfded
efwtthsggt nlfltavhei ghslglghss dpkavmfpty 241 kyvdintfrl
saddirgiqs lygdpkenqr lpnpdnsepa lcdpnlsfda vttvgnkiff 301
fkdrffwlkv serpktsvnl isslwptlps gieaayeiea rnqvflfkdd kywlisnlrp
361 epnypksihs fgfpnfvkki daavfnprfy rtyffvdnqy wryderrqmm
dpgypklitk 421 nfqgigpkid avfysknkyy yffqgsnqfe ydfllqritk
tlksnswfgc Matrix metallopeptidase 7, matrilysin preproprotein,
NP_002414.1 (SEQ ID NO: 107) 1 mrltvlcavc llpgslalpl pqeaggmsel
qweqaqdylk rfylydsetk nansleaklk 61 emqkffglpi tgmlnsrvie
imqkprcgvp dvaeyslfpn spkwtskvvt yrivsytrdl 121 phitvdrlvs
kalnmwgkei plhfrkvvwg tadimigfar gahgdsypfd gpgntlahaf 181
apgtglggda hfdederwtd gsslginfly aathelghsl gmghssdpna vmyptygngd
241 pqnfklsqdd ikgigklygk rsnsrkk Myelin protein zero like 1,
myelin protein zero-like protein 1 isoform a precursor, NP_003944.1
(SEQ ID NO: 108) 1 maasagagav iaapdsrrwl wsvlaaalgl ltagvsalev
ytpkeifvan gtqgkltckf 61 kststtgglt syswsfqpeg adttvsffhy
sqgqvylgny ppfkdriswa gdldkkdasi 121 nienmqfihn gtyicdvknp
pdivvqpghi rlyvvekenl pvfpvwvvvg ivtavvlglt 181 llismilavl
yrrknskrdy tgcstsesls pvkqaprksp sdteglvksl psgshqgpvi 241
yaqldhsggh hsdkinkses vvyadirkn Myelin protein zero like 1, myelin
protein zero-like protein 1 isoform b precursor, NP_078845.3 (SEQ
ID NO: 109) 1 maasagagav iaapdsrrwl wsvlaaalgl ltagvsalev
ytpkeifvan gtqgkltckf 61 kststtgglt syswsfqpeg adttvsffhy
sqgqvylgny ppfkdriswa gdldkkdasi 121 nienmqfihn gtyicdvknp
pdivvqpghi rlyvvekenl pvfpvwvvvg ivtavvlglt 181 llismilavl
yrrknskrdy tgaqsymhs Myelin protein zero like 1, myelin protein
zero-like protein 1 isoform c precursor, NP_001139663.1 (SEQ ID NO:
110) 1 maasagagav iaapdsrrwl wsvlaaalgl ltagvsalev ytpkeifvan
gtqgkltckf 61 kststtgglt syswsfqpeg adttvsgpvi yaqldhsggh
hsdkinkses vvyadirkn Macrophage scavenger receptor 1, macrophage
scavenger receptor types I and II isoform type 1, NP_619729.1 (SEQ
ID NO: lll) 1 meqwdhfhnq qedtdscses vkfdarsmta llppnpknsp
slqeklksfk aalialyllv 61 favlipligi vaaqllkwet kncsvsstna
nditqsltgk gndseeemrf qevfmehmsn 121 mekriqhild meanlmdteh
fqnfsmttdq rfndillqls tlfssvqghg naideisksl 181 islnttlldl
qlnienlngk iqentfkqqe eiskleervy nvsaeimamk eeqvhleqei 241
kgevkvlnni tndlrlkdwe hsqtlrnitl iqgppgppge kgdrgptges gprgfpgpig
301 ppglkgdrga igfpgsrglp gyagrpgnsg pkgqkgekgs gntltpftkv
rlvggsgphe 361 grveilhsgq wgticddrwe vrvgqvvcrs lgypgvqavh
kaahfgqgtg piwlnevfcf 421 gressieeck irqwgtracs hsedagvtct l
Macrophage scavenger receptor 1, macrophage scavenger receptor
types I and II isoform type 2, NP_002436.1 (SEQ ID NO: 112) 1
meqwdhfhnq qedtdscses vkfdarsmta llppnpknsp slqeklksfk aalialyllv
61 favlipligi vaaqllkwet kncsysstna nditqsltgk gndseeemrf
qevfmehmsn 121 mekriqhild meanlmdteh fqnfsmttdq rfndillqls
tlfssvqghg naideisksl
181 islnttlldl qlnienlngk iqentfkqqe eiskleervy nvsaeimamk
eegvhleqei 241 kgevkvlnni tndlrlkdwe hsqtlrnitl iqgppgppge
kgdrgptges gprgfpgpig 301 ppglkgdrga igfpgsrglp gyagrpgnsg
pkgqkgekgs gntlrpvqlt dhiragps Macrophage scavenger receptor 1,
macrophage scavenger receptor types I and II isoform type 3,
NP_619730.1 (SEQ ID NO: 113) 1 meqwdhfhnq qedtdscses vkfdarsmta
llppnpknsp slqeklksfk aalialyllv 61 favlipligi vaaqllkwet
kncsvsstna nditqsltgk gndseeemrf qevfmehmsn 121 mekriqhild
meanlmdteh fqnfsmttdq rfndillqls tlfssvqghg naideisksl 181
islnttlldl qlnienlngk iqentfkqqe eiskleervy nvsaeimamk eeqvhleqei
241 kgevkvlnni tndlrlkdwe hsqtlrnitl iqgppgppge kgdrgptges
gprgfpgpig 301 ppglkgdrga igfpgsrglp gyagrpgnsg pkgqkgekgs
gntlstgpiw lnevfcfgre 361 ssieeckirq wgtracshse dagvtctl Myoneurin,
isoform A, NP_001172047.1, NP_061127.1 (SEQ ID NO: 114) 1
mqyshhcehl lerlnkqrea gflcdctivi gefqfkahrn vlasfseyfg aiyrstsenn
61 vfldqsqvka dgfqkllefi ytgtlnldsw nvkeihqaad ylkveevvtk
ckikmedfaf 121 ianpssteis sitgnielnq qtclltlrdy nnreksevst
dliqanpkqg alakkssqtk 181 kkkkafnspk tgqnktvqyp sdilenasve
lfldanklpt pvveqvaqin dnseleltsv 241 ventfpaqdi vhtvtvkrkr
gksqpncalk ehsmsniasv kspyeaensg eeldqryska 301 kpmcntcgkv
fseasslrrh mrihkgvkpy vchlcgkaft qcnqlkthvr thtgekpykc 361
elcdkgfaqk cqlvfhsrmh hgeekpykcd vcnlqfatss nlkiharkhs gekpyvcdrc
421 gqrfaqastl tyhvrrhtge kpyvcdtcgk afavssslit hsrkhtgekp
yicgicgksf 481 issgelnkhf rshtgerpfi celcgnsytd iknlkkhktk
vhsgadktld ssaedhtlse 541 qdsiqkspls etmdvkpsdm tlplalplgt
edhhmllpvt dtqsptsdtl lrstvngyse 601 pqliflqqly Myoneurin, isoform
B, NP_001172048.1 (SEQ ID NO: 115) 1 mqyshhcehl lerlnkqrea
gflcdctivi gefqfkahrn vlasfseyfg aiyrstsenn 61 vfldqsqvka
dgfqkllefi ytgtlnldsw nvkeihqaad ylkveevvtk ckikmedfaf 121
ianpssteis sitgnielnq qtclltlrdy nnreksevst dliqanpkqg alakkssqtk
181 kkkkafnspk tgqnktvqyp sdilenasve lfldanklpt pvveqvaqin
dnseleltsv 241 ventfpaqdi vhtvtvkrkr gksqpncalk ehsmsniasv
kspyeaensg eeldqryska 301 kpmcntcgkv fseasslrrh mrihkgvkpy
vchlcgkaft qcnqlkthvr thtgekpykc 361 elcdkgfaqk cqlvfhsrmh
hgeekpykcd vcnlqfatss nlkiharkhs gekpyvcdrc 421 gqrfaqastl
tyhvrrhtge kpyvcdtcgk afayssslit hsrkhtgekp yicgicgksf 481
issgelnkhf rshtgadktl dssaedhtls eqdsiqkspl setmdvkpsd mtlplalplg
541 tedhhmllpv tdtqsptsdt llrstvngys epqliflqql y
N-acetylglucosamine kinase, isoform 1, NP_060037.3 (SEQ ID NO: 116)
1 mrtrtgsqla arevtgsgav prqlegrrcq agrdanggts sdgsssmaai yggvegggtr
61 sevllvsedg kilaeadgls tnhwligtdk cverinemvn rakrkagvdp
lvplrslgls 121 lsggdqedag rilieelrdr fpylsesyli ttdaagsiat
atpdggvvli sgtgsncrli 181 npdgsesgcg gwghmmgdeg saywiahqav
kivfdsidnl eaaphdigyv kqamfhyfqv 241 pdrlgilthl yrdfdkcrfa
gfcrkiaega qqgdplsryi frkagemlgr hivavlpeid 301 pvlfqgkigl
pilcvgsvwk swellkegfl laltqgreiq aqnffssftl mklrhssalg 361
gaslgarhig hllpmdysan aiafysytfs N-acetylglucosamine kinase,
isoform 2, NP_001317354.1, NP_001317355.1 (SEQ ID NO: 117) 1
mvnrakrkag vdplvplrsl glslsggdqe dagrilieel rdrfpylses ylittdaags
61 iatatpdggv vlisgtgsnc rlinpdgses gcggwghmmg degsaywiah
qavkivfdsi 121 dnleaaphdi gyvkqamfhy fqvpdrlgil thlyrdfdkc
rfagfcrkia egaqqgdpls 181 ryifrkagem lgrhivavlp eidpvlfqgk
iglpilcvgs vwkswellke gfllaltqgr 241 eiqaqnffss ftlmklrhss
alggaslgar highllpmdy sanaiafysy tfs Napsin A aspartic peptidase,
preproprotein, NP_004842.1 (SEQ ID NO: 118) 1 mspppllqpl llllpllnve
psgatlirip lhrvqpgrri lnllrgwrep aelpklgaps 61 pgdkpifvpl
snyrdvqyfg eiglgtppqn ftvafdtgss nlwvpsrrch ffsvpcwlhh 121
rfdpkasssf qangtkfaiq ygtgrvdgil sedkltiggi kgasvifgea lwepslvfaf
181 ahfdgilglg fpilsvegvr ppmdvlveqg lldkpvfsfy lnrdpeepdg
gelvlggsdp 241 ahyippltfv pvtvpaywqi hmervkvgpg ltlcakgcaa
ildtgtslit gpteeiralh 301 aaiggiplla geyiilcsei pklpavsfll
ggvwfnltah dyviqttrng vrlclsgfqa 361 ldvpppagpf wilgdvflgt
yvavfdrgdm kssarvglar artrgadlgw getaqaqfpg Nuclear transcription
factor Y subunit gamma, isoform 1, NP_001136060.1 (SEQ ID NO: 119)
1 msteggfggt sssdaqqslq sfwprvmeei rnltvkdfrv qelplarikk imkldedvkm
61 isaeapvlfa kaaqifitel tlrawihted nkrrtlqrnd iamaitkfdq
fdflidivpr 121 delkppkrqe evrqsvtpae pvqyyftlaq qptavqvqgq
qqgqqttsst ttiqpgqiii 181 aqpqqgqttp vtmqvgegqq vqivqaqpqg
qaqqaqsgtg qtmqvmqqii tntgeiqqip 241 vqlnagqlqy irlaqpvsgt
qvvqgqiqtl atnaqqgqrn asqgkprrcl ketlqitqte 301 vqqgqqqfsq
ftdgqqlyqi qqvtmpagqd laqpmfiqsa nqpsdgqapq vtgd Nuclear
transcription factor Y subunit gamma, isoform 2, NP_055038.2 (SEQ
ID NO: 120) 1 msteggfggt sssdaqqslq sfwprvmeei rnltvkdfrv
qelplarikk imkldedvkm 61 isaeapvlfa kaaqifitel tlrawihted
nkrrtlqrnd iamaitkfdq fdflidivpr 121 delkppkrqe evrqsvtpae
pvqyyftlaq qptavqvqgq qqgqqttsst ttiqpgqiii 181 aqpqqgqttp
vtmqvgegqq vqivqaqpqg qaqqaqsgtg qtmqvmqqii tntgeiqqip 241
vqlnagqlqy irlaqpvsgt qvvqgqiqtl atnaqqitqt evqqgqqqfs qftdgqqlyq
301 iqqvtmpagq dlaqpmfigs anqpsdgqap qvtgd Nuclear transcription
factor Y subunit gamma, isoform 3, NP_001136059.1 (SEQ ID NO: 121)
1 msteggfggt sssdaqqslq sfwprvmeei rnltvkdfrv qelplarikk imkldedvkm
61 isaeapvlfa kaaqifitel tlrawihted nkrrtlqrnd iamaitkfdq
fdflidivpr 121 delkppkrqe evrqsvtpae pvqyyftlaq qptavqvqgq
qqgqqttsst ttiqpgqiii 181 aqpqqgqttp vtmqvgegqq vqivqaqpqg
qaqqaqsgtg qtmqvmqqii tntgeiggip 241 vqlnagqlqy irlaqpvsgt
qvvqgqiqtl atnaqqitqt evqqgqqqfs qftdgqlyqi 301 qqvtmpagqd
laqpmfiqsa nqpsdgqapq vtgd Nuclear transcription factor Y subunit
gamma, isoform 4, NP_001136061.1 (SEQ ID NO: 122) 1 msteggfggt
sssdaqqslq sfwprvmeei rnltvkdfrv qelplarikk imkldedvkr 61
ndiamaitkf dqfdflidiv prdelkppkr qeevrqsvtp aepvqyyftl aqqptavqvq
121 gqqqgqqtts stttiqpgqi iiaqpqqgqt tpvtmqvgeg qqvqivqaqp
qgqaqqaqsg 181 tgqtmqvmqq iitntgeiqq ipvqlnagql gyirlaqpvs
gtqvvqgqiq tlatnaqqit 241 qtevqqgqqq fsqftdgqql yqiqqvtmpa
gqdlaqpmfi qsanqpsdgq apqvtgd Nuclear transcription factor Y
subunit gamma, isoform 5, NP_001136062.1 (SEQ ID NO: 123) 1
msteggfggt sssdaqqslq sfwprvmeei rnltvkdfrv qelplarikk imkldedvkm
61 isaeapvlfa kaaqifitel tlrawihted nkrrtlqrnd iamaitkfdq
fdflidivpr 121 delkppkrqe evrqsvtpae pvqyyftlaq qptavqvqgq
qqgqqttsst ttiqpgqiii 181 aqpqqgqtmq vmqqiitntg eiqqipvqln
agqlqyirla qpvsgtqvvg gqiqtlatna 241 qqitqtevqq gqqqfsqftd
gqqlyqiqqv tmpagqdlaq pmfiqsanqp sdgqapqvtg 301 d Nuclear
transcription factor Y subunit gamma, isoform 6, NP_001295043.1
(SEQ ID NO: 124) 1 msteggfggt sssdaqqslq sfwprvmeei rnltvkdfrv
qelplarikk imkldedvkm 61 isaeapvlfa kaaqifitel tlrawihted
nkrrtlqrnd iamaitkfdq fdflidivpr 121 delkppkrqe evrqsvtpae
pvqyyftlaq qptavqvqgq qqgqqttsst ttiqpgqiii 181 aqpqqgqttp
vtmqvgegqq vqivqaqpqg qaqqaqsgtg qtmqvmqqii tntgeiqqip 241
vqlnagqlqy irlaqpvsgt qvvqgqiqtl atnaqqgqrn asqgkprrcl ketlqitqte
301 vqqgqqqfsq ftdgqrnsvq qarvseltge aeprevkatg nstpctsslp
tthppshrag 361 ascvccsqpq qsstspppsd alqwvvvevs gtpnqlethr
elhaplpgmt slsplhpsqq 421 lyqiqqvtmp agqdlaqpmf iqsanqpsdg qapqvtgd
Nuclear transcription factor Y subunit gamma, isoform 7,
NP_001295044.1 (SEQ ID NO: 125) 1 msteggfggt sssdaqqslq sfwprvmeei
rnltvkdfrv qelplarikk imkldedvkm 61 isaeapvlfa kaaqifitel
tlrawihted nkrrtlqrnd iamaitkfdq fdflidivpr 121 delkppkrqe
evrqsvtpae pvqyyftlaq qptavqvqgq qqgqqttsst ttiqpgqiii 181
aqpqqgqttp vtmqvgegqq vqivqaqpqg qaqqaqsgtg qtmqvmqqii tntgeiqqip
241 vqlnagqlqy irlaqpvsgt qvvqgqiqtl atnaqqitqt evqqgqqqfs
qftdgqrnsv 301 qqarvseltg eaeprevkat gnstpctssl ptthppshra
gascvccsqp qqsstsppps 361 dalqwvvvev sgtpngleth relhaplpgm
tslsplhpsq qlyqiqqvtm pagqdlaqpm 421 fiqsanqpsd gqapqvtgd NFKB
repressing factor, isoform 1, NP_001166958.1 (SEQ ID NO: 126) 1
mgfmlplifr ysprlmekil qmaegidige mpsydlvlsk pskgqkrhls tcdgqnppkk
61 qagskfharp rfepvhfvas sskderqedp ygpqtkevne qthfasmprd
iygdytqdsf 121 siqdgnsqyc dssgfiltkd qpvtanmyfd sgnpapstts
qqansqstpe pspsqtfpes 181 vvaekqyfie kltatiwknl snpemtsgsd
kinytymltr ciqacktnpe yiyaplkeip 241 padipknkkl ltdgyacevr
cqniylttgy agskngsrdr atelavkllq krievrvvrr 301 kfkhtfgedl
vvcqigmssy efppalkppe dlvvlgkdas gqpifnasak hwtnfviten 361
andaigilnn sasfnkmsie ykyemmpnrt wrcrvflqdh claegygtkk tskhaaadea
421 lkilqktqpt ypsvkssqch tgssprgsgk kkdikdlvvy enssnpvctl
ndtaqfnrmt 481 veyvyermtg lrwkckvile seviaeavgv kktvkyeaag
eavktlkktq ptvinnlkkg 541 avedvisrne iqgrsaeeay kqqikednig
nqllrkmgwt ggglgksgeg irepisvkeq 601 hkreglgldv ervnkiakrd
ieqiirnyar seshtdltfs reltnderkq ihqiaqkygl 661 kskshgvghd
rylvvgrkrr kedlldqlkq egqvghyelv mpqan NFKB repressing factor,
isoform 2, NP_001166959.1, NP_060014.2 (SEQ ID NO: 127) 1
mekilqmaeg idigempsyd lvlskpskgq krhlstcdgq nppkkqagsk fharprfepv
61 hfvassskde rqedpygpqt kevneqthfa smprdiyqdy tqdsfsiqdg
nsqycdssgf 121 iltkdqpvta nmyfdsgnpa psttsqqans qstpepspsq
tfpesvvaek qyfiekltat 181 iwknlsnpem tsgsdkinyt ymltrciqac
ktnpeyiyap lkeippadip knkklltdgy 241 acevrcqniy lttgyagskn
gsrdratela vkllqkriev rvvrrkfkht fgedlvvcqi 301 gmssyefppa
lkppedlvvl gkdasgqpif nasakhwtnf vitenandai gilnnsasfn 361
kmsieykyem mpnrtwrcrv flqdhclaeg ygtkktskha aadealkilq ktqptypsvk
421 ssqchtgssp rgsgkkkdik dlvvyenssn pvctlndtaq fnrmtveyvy
ermtglrwkc 481 kvilesevia eavgvkktvk yeaageavkt lkktqptvin
nlkkgavedv isrneiqgrs 541 aeeaykqqik ednignqllr kmgwtggglg
ksgegirepi svkeqhkreg lgldvervnk 601 iakrdieqii rnyarsesht
dltfsreltn derkqihqia qkyglksksh gvghdrylvv 661 grkrrkedll
dqlkqegqvg hyelvmpqan Plasminogen activator, urokinase,
urokinase-type plasminogen activator isoform 1 preproprotein,
NP_002649.1 (SEQ ID NO: 128) 1 mrallarlll cvlvvsdskg snelhqvpsn
cdclnggtcv snkyfsnihw cncpkkfggq 61 hceidksktc yegnghfyrg
kastdtmgrp clpwnsatvl qqtyhahrsd alqlglgkhn 121 ycrnpdnrrr
pwcyvqvglk plvqecmvhd cadgkkpssp peelkfqcgq ktlrprfkii 181
ggefttienq pwfaaiyrrh rggsvtyvcg gslispcwvi sathcfidyp kkedyivylg
241 rsrinsntqg emkfevenli lhkdysadtl ahhndiallk irskegrcaq
psrtiqticl 301 psmyndpqfg tsceitgfgk enstdylype qlkmtvvkli
shrecqqphy ygsevttkml 361 caadpqwktd scqgdsggpl vcslqgrmtl
tgivswgrgc alkdkpgvyt rvshflpwir 421 shtkeengla l Plasminogen
activator, urokinase, urokinase-type plasminogen activator isoform
2, NP_001138503.1 (SEQ ID NO: 129) 1 mvfhlrtrye qancdclngg
tcvsnkyfsn ihwcncpkkf ggqhceidks ktcyegnghf 61 yrgkastdtm
grpclpwnsa tvlqqtyhah rsdalqlglg khnycrnpdn rrrpwcyvqv 121
glkplvqecm vhdcadgkkp ssppeelkfq cgqktlrprf kiiggeftti enqpwfaaiy
181 rrhrggsvty vcggslispc wvisathcfi dypkkedyiv ylgrsrlnsn
tqgemkfeve 241 nlilhkdysa dtlahhndia llkirskegr caqpsrtiqt
iclpsmyndp qfgtsceitg 301 fgkenstdyl ypeqlkmtvv klishrecqq
phyygsevtt kmlcaadpqw ktdscqgdsg 361 gplvcslqgr mtltgivswg
rgcalkdkpg vytrvshflp wirshtkeen glal Plasminogen activator,
urokinase, urokinase-type plasminogen activator isoform 3,
NP_001306120.1 (SEQ ID NO: 130) 1 mgrpclpwns atvlqqtyha hrsdalqlgl
gkhnycrnpd nrrrpwcyvq vglkplvqec 61 mvhdcadgkk pssppeelkf
qcgqktlrpr fkiiggeftt ienqpwfaai yrrhrggsvt 121 yvcggslisp
cwvisathcf idypkkedyi vylgrsrlns ntqgemkfev enlilhkdys 181
adtlahhndi allkirskeg rcaqpsrtiq ticlpsmynd pqfgtsceit gfgkenstdy
241 lypeqlkmtv vklishrecq qphyygsevt tkmlcaadpq wktdscqgds
ggplvcslqg 301 rmtltgivsw grgcalkdkp gvytrvshfl pwirshtkee nglal
Receptor tyrosine kinase like orphan receptor 1, inactive
tyrosine-protein kinase transmembrane receptor ROR1 isoform 1
precursor, NP_005003.2 (SEQ ID NO: 131) 1 mhrprrrgtr ppllallaal
llaargaaaq etelsysael vptsswniss elnkdsyltl 61 depmnnitts
lgqtaelhck vsgnppptir wfkndapvvq eprrlsfrst iygsrlrirn 121
ldttdtgyfq cvatngkevv sstgvlfvkf gppptaspgy sdeyeedgfc qpyrgiacar
181 fignrtvyme slhmqgeien qitaaftmig tsshlsdkcs qfaipslchy
afpycdetss 241 vpkprdlcrd eceilenvlc qteyifarsn pmilmrlklp
ncedlpqpes peaancirig 301 ipmadpinkn hkcynstgvd yrgtvsvtks
grqcqpwnsq yphthtftal rfpelngghs 361 ycrnpgnqke apwcftlden
fksdlcdipa cdskdskekn kmeilyilvp svaiplaial 421 lffficvcrn
nqksssapvq rqpkhvrgqn vemsmlnayk pkskakelpl savrfmeelg 481
ecafgkiykg hlylpgmdha qlvaiktlkd ynnpqqwtef qqeaslmael hhpnivcllg
541 avtqeqpvcm lfeyinqgdl heflimrsph sdvgcssded gtvkssldhg
dflhiaiqia 601 agmeylsshf fvhkdlaarn iligeqlhvk isdlglsrei
ysadyyrvqs ksllpirwmp 661 peaimygkfs sdsdiwsfgv vlweifsfgl
qpyygfsnqe viemvrkrql lpcsedcppr 721 myslmtecwn eipsrrprfk
dihvrlrswe glsshtsstt psggnattqt tslsaspvsn 781 lsnprypnym
fpsqgitpqg qiagfigppi pqnqrfipin gypippgyaa fpaahyqptg 841
pprviqhcpp pksrspssas gststghvts lpssgsnqea nipllphmsi pnhpggmgit
901 vfgnksqkpy kidskqasll gdanihghte smisael Receptor tyrosine
kinase like orphan receptor 1, inactive tyrosine-protein kinase
transmembrane receptor ROR1 isoform 2 precursor, NP_001077061.1
(SEQ ID NO: 132) 1 mhrprrrgtr ppllallaal llaargaaaq etelsvsael
vptsswniss elnkdsyltl 61 depmnnitts lgqtaelhck vsgnppptir
wfkndapvvq eprrlsfrst iygsrlrirn 121 ldttdtgyfq cvatngkevv
sstgvlfvkf gppptaspgy sdeyeedgfc qpyrgiacar 181 fignrtvyme
slhmqgeien qitaaftmig tsshlsdkcs qfaipslchy afpycdetss 241
vpkprdlcrd eceilenvlc qteyifarsn pmilmrlklp ncedlpqpes peaancirig
301 ipmadpinkn hkcynstgvd yrgtvsvtks grqcqpwnsq yphthtftal
rfpelngghs 361 ycrnpgnqke apwcftlden fksdlcdipa cgk Runt related
transcription factor 1, runt-related transcription factor 1 isoform
AML1a, NP_00lll6079.1 (SEQ ID NO: 133) 1 mripvdasts rrftppstal
spgkmsealp lgapdagaal agklrsgdrs mvevladhpg 61 elvrtdspnf
lcsvlpthwr cnktlpiafk vvalgdvpdg tlvtvmagnd enysaelrna 121
taamknqvar fndlrfvgrs grgksftlti tvftnppqva tyhraikitv dgpreprrhr
181 qklddqtkpg slsfserlse leqlrrtamr vsphhpaptp npraslnhst
afnpqpqsqm 241 qeedtapwrc Runt related transcription factor 1,
runt-related transcription factor 1 isoform AML1b, NP_001001890.1
(SEQ ID NO: 134) 1 mripvdasts rrftppstal spgkmsealp lgapdagaal
agklrsgdrs mvevladhpg 61 elvrtdspnf lcsvlpthwr cnktlpiafk
vvalgdvpdg tlvtvmagnd enysaelrna 121 taamknqvar fndlrfvgrs
grgksftlti tvftnppqva tyhraikitv dgpreprrhr 181 qklddqtkpg
slsfserlse leqlrrtamr vsphhpaptp npraslnhst afnpqpqsqm 241
qdtrqiqpsp pwsydqsyqy lgsiaspsvh patpispgra sgmttlsael ssrlstapdl
301 tafsdprqfp alpsisdprm hypgaftysp tpvtsgigig msamgsatry
htylpppypg
361 ssqaqggpfq asspsyhlyy gasagsyqfs mvggersppr ilppctnast
gsallnpslp 421 nqsdvveaeg shsnsptnma psarleeavw rpy Runt related
transcription factor 1, runt-related transcription factor 1 isoform
AML1c, NP_001745.2 (SEQ ID NO: 135) 1 masdsifesf psypqcfmre
cilgmnpsrd vhdastsrrf tppstalspg kmsealplga 61 pdagaalagk
lrsgdrsmve vladhpgelv rtdspnflcs vlpthwrcnk tlpiafkvva 121
lgdvpdgtlv tvmagndeny saelrnataa mknqvarfnd lrfvgrsgrg ksftltitvf
181 tnppqvatyh raikitvdgp reprrhrqkl ddqtkpgsls fserlseleq
lrrtamrvsp 241 hhpaptpnpr aslnhstafn pqpqsqmqdt rqiqpsppws
ydqsyqylgs iaspsvhpat 301 pispgrasgm ttlsaelssr lstapdltaf
sdprqfpalp sisdprmhyp gaftysptpv 361 tsgigigmsa mgsatryhty
lpppypgssq aqggpfqass psyhlyygas agsyqfsmvg 421 gerspprilp
pctnastgsa llnpslpnqs dvveaegshs nsptnmapsa rleeavwrpy Surfactant
protein A1, pulmonary surfactant-associated protein A1 isoform 1
precursor, NP_001158116.1, NP_001158119.1, NP_005402.3 (SEQ ID NO:
136) 1 mwlcplalnl ilmaasgavc evkdvcvgsp gipgtpgshg lpgrdgrdgl
kgdpgppgpm 61 gppgempcpp gndglpgapg ipgecgekge pgergppglp
ahldeelqat lhdfrhqilq 121 trgalslqgs imtvgekvfs sngqsitfda
iqeacaragg riavprnpee neaiasfvkk 181 yntyayvglt egpspgdfry
sdgtpvnytn wyrgepagrg keqcvemytd gqwndrncly 241 srlticef Surfactant
protein A1, pulmonary surfactant-associated protein A1 isoform 2
precursor, NP_001087239.2 (SEQ ID NO: 137) 1 mrpcqvpgaa tgpramwlcp
lalnlilmaa sgavcevkdv cvgspgipgt pgshglpgrd 61 grdglkgdpg
ppgpmgppge mpcppgndgl pgapgipgec gekgepgerg ppglpahlde 121
elqatlhdfr hqilqtrgal slqgsimtvg ekvfssngqs itfdaiqeac araggriavp
181 rnpeeneaia sfvkkyntya yvgltegpsp gdfrysdgtp vnytnwyrge
pagrgkeqcv 241 emytdgqwnd rnclysrlti cef Surfactant protein A1,
pulmonary surfactant-associated protein A1 isoform 3 precursor,
NP_001158117.1 (SEQ ID NO: 138) 1 mrpcqvpgaa tgpramwlcp lalnlilmaa
sgavcevkdv cvgtpgipge cgekgepger 61 gppglpahld eelqatlhdf
rhqilqtrga lslqgsimtv gekvfssngq sitfdaiqea 121 caraggriav
prnpeeneai asfvkkynty ayvgltegps pgdfrysdgt pvnytnwyrg 181
epagrgkeqc vemytdgqwn drnclysrlt icef Surfactant protein A1,
pulmonary surfactant-associated protein A1 isoform 4 precursor,
NP_001158118.1 (SEQ ID NO: 139) 1 mwlcplalnl ilmaasgavc evkdvcvgtp
gipgecgekg epgergppgl pahldeelqa 61 tlhdfrhqil qtrgalslqg
simtvgekvf ssngqsitfd aiqeacarag griavprnpe 121 eneaiasfvk
kyntyayvgl tegpspgdfr ysdgtpvnyt nwyrgepagr gkeqcvemyt 181
dgqwndrncl ysrlticef Surfactant protein A2, pulmonary
surfactant-associated protein A2 isoform 1 precursor,
NP_001092138.1, NP_001307742.1 (SEQ ID NO: 140) 1 mwlcplaltl
ilmaasgaac evkdvcvgsp gipgtpgshg lpgrdgrdgv kgdpgppgpm 61
gppgetpcpp gnnglpgapg vpgergekge agergppglp ahldeelqat lhdfrhqilq
121 trgalslqgs imtvgekvfs sngqsitfda iqeacaragg riavprnpee
neaiasfvkk 181 yntyayvglt egpspgdfry sdgtpvnytn wyrgepagrg
keqcvemytd gqwndrncly 241 srlticef Surfactant protein A2, pulmonary
surfactant-associated protein A2 isoform 2 precursor,
NP_001307743.1 (SEQ ID NO: 141) 1 mpgaatgpra mwlcplaltl ilmaasgaac
evkdvcvgsp gipgtpgshg lpgrdgrdgv 61 kgdpgppgpm gppgetpcpp
gnnglpgapg vpgergekge agergppglp ahldeelqat 121 lhdfrhqilq
trgalslqgs imtvgekvfs sngqsitfda iqeacaragg riavprnpee 181
neaiasfvkk yntyayvglt egpspgdfry sdgtpvnytn wyrgepagrg keqcvemytd
241 gqwndrncly srlticef Surfactant protein B, pulmonary
surfactant-associated protein B precursor, NP_000533.3, NP_942140.2
(SEQ ID NO: 142) 1 mhqagypgcr gamaeshllq wlllllptlc gpgtaawtts
slacaqgpef wcgsleqalq 61 cralghclqe vwghvgaddl cqecedivhi
lnkmakeaif qdtmrkfleq ecnvlplkll 121 mpqcnqvldd yfplvidyfq
nqtdsngicm hlglcksrqp epeqepgmsd plpkplrdpl 181 pdplldklvl
pvlpgalqar pgphtqdlse qqfpiplpyc wlcralikri qamipkgala 241
vavaqvcrvv plvaggicqc laerysvill dtllgrmlpq lvcrlvlrcs mddsagprsp
301 tgewlprdse chlcmsvttq agnsseqaip qamlqacvgs wldrekckqf
veghtpqllt 361 lvprgwdaht tcgalgvcgt mssplqcihs pdl Surfactant
protein C, pulmonary surfactant-associated protein C isoform 1
precursor, NP_001165881.1, NP_003009.2 (SEQ ID NO: 143) 1
mdvgskevlm esppdysaap rgrfgipccp vhlkrllivv vvvvlivvvi vgallmglhm
61 sqkhtemvle msigapeagq rlalsehlvt tatfsigstg lvvydyqqll
iaykpapgtc 121 cyimkiapes ipslealtrk vhnfqmecsl qakpavptsk
lgqaegrdag sapsggdpaf 181 lgmaysticg evplyyi Surfactant protein C,
pulmonary surfactant-associated protein C isoform 2 precursor,
NP_001165828.1, NP_001304707.1, NP_001304709.1 (SEQ ID NO: 144) 1
mdvgskevlm esppdysaap rgrfgipccp vhlkrllivv vvvvlivvvi vgallmglhm
61 sqkhtemvle msigapeaqq rlalsehlvt tatfsigstg lvvydyqqll
iaykpapgtc 121 cyimkiapes ipslealtrk vhnfqakpav ptsklgqaeg
rdagsapsgg dpaflgmavs 181 ticgevplyy i Surfactant protein C,
pulmonary surfactant-associated protein C isoform 3 precursor,
NP_001304708.1 (SEQ ID NO: 145) 1 mdvgskevlm esppvlemsi gapeaqqrla
lsehlvttat fsigstglvv ydyqqlliay 61 kpapgtccyi mkiapesips
lealtrkvhn fqmecslqak pavptsklgq aegrdagsap 121 sggdpaflgm
aysticgevp lyyi Surfactant protein D, pulmonary
surfactant-associated protein D precursor, NP_003010.4 (SEQ ID NO:
146) 1 mllfllsalv lltqplgyle aemktyshrt mpsactlvmc ssvesglpgr
dgrdgregpr 61 gekgdpglpg aagqagmpgq agpvgpkgdn gsvgepgpkg
dtgpsgppgp pgvpgpagre 121 gplgkqgnig pqgkpgpkge agpkgevgap
gmqgsagarg lagpkgergv pgergvpgnt 181 gaagsagamg pqgspgargp
pglkgdkgip gdkgakgesg lpdvaslrqg vealqgqvqh 241 lqaafsqykk
velfpngqsv gekifktagf vkpfteaqll ctqaggqlas prsaaenaal 301
qqlvvaknea aflsmtdskt egkftyptge slvysnwapg epnddggsed cveiftngkw
361 ndracgekrl vvcef Solute carrier family 2 member 5, solute
carrier family 2, facilitated glucose transporter member 5 isoform
1, NP_001315548.1, NP_003030.1 (SEQ ID NO: 147) 1 meqqdqsmke
grltlvlala tliaafgssf qygynvaavn spallmqqfy netyygrtge 61
fmedfpltll wsvtvsmfpf ggfigsllvg plvnkfgrkg allfnnifsi vpailmgcsr
121 vatsfeliii srllvgicag vssnvvpmyl gelapknlrg algvvpqlfi
tvgilvaqif 181 glrnllanvd gwpillgltg vpaalqllll pffpespryl
liqkkdeaaa kkalqtlrgw 241 dsvdrevaei rqedeaekaa gfisvlklfr
mrslrwqlls iivlmggqql sgvnaiyyya 301 dqiylsagvp eehvqyvtag
tgavnvvmtf cavfvvellg rrlllllgfs icliaccvlt 361 aalalqdtvs
wmpyisivcv isyvighalg pspipallit eiflqssrps afmvggsvhw 421
lsnftvglif pfigeglgpy sfivfavicl lttiyifliv petkaktfie inqiftkmnk
481 vsevypekee lkelppvtse q Solute carrier family 2 member 5,
solute carrier family 2, facilitated glucose transporter member 5
isoform 2, NP_001129057.1 (SEQ ID NO: 148) 1 meqqdqsmke grltlvlala
tliaafgssf qygynvaavn spallmqqfy netyygrtge 61 fmedfpltll
wsvtvsmfpf ggfigsllvg plvnkfgrkg allfnnifsi vpailmgcsr 121
vatsfeliii srllvgicag vssnvvpmyl gelapknlrg algvvpqlfi tvgilvaqif
181 glrnllanvd gefrtsrehp hpftttlgpl lvfqshhhrt glsadwsllt
gwmslggpsc 241 pept Solute carrier family 2 member 5, solute
carrier family 2, facilitated glucose transporter member 5 isoform
3, NP_001315549.1 (SEQ ID NO: 149) 1 mgttwllstp qhwtgefmed
fpltllwsvt vsmfpfggfi gsllvgplvn kfgrkgallf 61 nnifsivpai
lmgcsrvats feliiisrll vgicagvssn vvpmylgela pknlrgalgv 121
vpqlfitvgi lvaqifglrn llanvdgwpi llgltgvpaa lqllllpffp esprylliqk
181 kdeaaakkal qtlrgwdsvd revaeirqed eaekaagfis vlklfrmrsl
rwqllsiivl 241 mggqqlsgvn aiyyyadqiy lsagvpeehv qyvtagtgav
nvvmtfcavf vvellgrrll 301 lllgfsicli accvltaala lqdtvswmpy
isivcvisyv ighalgpspi palliteifl 361 qssrpsafmv ggsvhwlsnf
tvglifpfiq eglgpysfiv faviclltti yiflivpetk 421 aktfieinqi
ftkmnkvsev ypekeelkel ppvtseq Solute carrier family 2 member 5,
solute carrier family 2, facilitated glucose transporter member 5
isoform 4, NP_001315550.1 (SEQ ID NO: 150) 1 mylgelapkn lrgalgvvpq
lfitvgilva qifglrnlla nvdgwpillg ltgvpaalql 61 lllpffpesp
rylliqkkde aaakkalqtl rgwdsvdrev aeirqedeae kaagfisvlk 121
lfrmrslrwq llsiivlmgg qqlsgvnaiy yyadqiylsa gvpeehvgyv tagtgavnvv
181 mtfcavfvve llgrrlllll gfsicliacc vltaalalqd tvswmpyisi
vcvisyvigh 241 algpspipal liteiflqss rpsafmvggs vhwlsnftvg
lifpfiqegl gpysfivfav 301 icllttiyif livpetkakt fieinqiftk
mnkvsevype keelkelppv tseq Sperm associated antigen 9,
C-Jun-amino-terminal kinase-interacting protein 4 isoform 1,
NP_001124000.1 (SEQ ID NO: 151) 1 meledgvvyq eepggsgavm servsglags
iyreferlig rydeevvkel mplvvavlen 61 ldsvfaqdqe hqvelellrd
dneqlitqye rekalrkhae ekfiefedsq eqekkdlqtr 121 veslesqtrq
lelkaknyad qisrleerea elkkeynalh qrhtemihny mehlertklh 181
qlsgsdqles tahsrirker pislgifplp agdglltpda qkggetpgse qwkfgelsqp
241 rshtslkvsn spepqkaveq edelsdvsqg gskattpast ansdvatipt
dtplkeeneg 301 fvkvtdapnk seiskhievq vaqetrnvst gsaeneekse
vqaiiestpe ldmdkdlsgy 361 kgsstptkgi enkafdrnte slfeelssag
sgligdvdeg adllgmgrev enlilentql 421 letknalniv kndliakvde
ltcekdvlqg eleavkqakl kleeknrele eelrkaraea 481 edarqkakdd
ddsdiptaqr krftrvemar vlmernqyke rlmelqeavr wtemirasre 541
npamgekkrs siwqffsrlf ssssnttkkp eppvnlkyna ptshvtpsvk krsstlsqlp
601 gdkskafdfl seeteaslas rreqkreqyr qvkahvqked grvqafgwsl
pqkykqvtng 661 qgenkmknlp vpvylrplde kdtsmklwca vgvnlsggkt
rdggsvvgas vfykdvagld 721 tegskqrsas gssldkldge lkeqqkelkn
qeelsslvwi ctsthsatkv liidavqpgn 781 ildsftvcns hvlciasvpg
aretdypage dlsesgqvdk aslcgsmtsn ssaetdsllg 841 gitvvgcsae
gvtgaatsps tngaspvmdk ppemeaense vdenvptaee ateategnag 901
saedtvdisq tgvytehvft dplgvqiped lspvyqssnd sdaykdqisv lpneqdlvre
961 eaqkmssllp tmwlgaqngc lyvhssvaqw rkclhsiklk dsilsivhvk
givlvaladg 1021 tlaifhrgvd gqwdlsnyhl ldlgrphhsi rcmtvvhdkv
wcgyrnkiyv vqpkamkiek 1081 sfdahprkes qvrqlawvgd gvwvsirlds
tlrlyhahty qhlqdvdiep yvskmlgtgk 1141 lgfsfvrita lmvscnrlwv
gtgngviisi pltetnktsg vpgnrpgsvi rvygdensdk 1201 vtpgtfipyc
smahaqlcfh ghrdavkffv avpgqvispq ssssgtdltg dkagpsaqep 1261
gsqtplksml visggegyid frmgdegges ellgedlple psvtkaersh livwqvmygn
1321 e Sperm associated antigen 9, C-Jun-amino-terminal
kinase-interacting protein 4 isoform 2, NP_001123999.1 (SEQ ID NO:
152) 1 meledgvvyq eepggsgavm servsglags iyreferlig rydeevvkel
mplvvavlen 61 ldsvfaqdqe hqvelellrd dneqlitqye rekalrkhae
ekfiefedsq eqekkdlqtr 121 veslesqtrq lelkaknyad qisrleerea
elkkeynalh qrhtemihny mehlertklh 181 qlsgsdqles tahsrirker
pislgifplp agdglltpda qkggetpgse qwkfgelsqp 241 rshtslkdel
sdvsqggska ttpastansd vatiptdtpl keenegfvkv tdapnkseis 301
khievqvaqe trnvstgsae neeksevqai iestpeldmd kdlsgykgss tptkgienka
361 fdrnteslfe elssagsgli gdvdegadll gmgrevenli lentqlletk
nalnivkndl 421 iakvdeltce kdvlqgelea vkqaklklee knreleeelr
karaeaedar qkakddddsd 481 iptaqrkrft rvemarvlme rnqykerlme
lqeavrwtem irasrenpam qekkrssiwq 541 fvptrfsrlf ssssnttkkp
eppvnlkyna ptshvtpsvk krsstlsqlp gdkskafdfl 601 seeteaslas
rreqkreqyr qvkahvqked grvqafgwsl pqkykqvtng qgenkmknlp 661
vpvylrplde kdtsmklwca vgvnlsggkt rdggsvvgas vfykdvagld tegskqrsas
721 qssldkldqe lkeqqkelkn qeelsslvwi ctsthsatkv liidavqpgn
ildsftvcns 781 hvlciasvpg aretdypage dlsesgqvdk aslcgsmtsn
ssaetdsllg gitvvgcsae 841 gvtgaatsps tngaspvmdk ppemeaense
vdenvptaee ateategnag saedtvdisq 901 tgvytehvft dplgvqiped
lspvyqssnd sdaykdqisv lpneqdlvre eaqkmssllp 961 tmwlgaqngc
lyvhssvaqw rkclhsiklk dsilsivhvk givlvaladg tlaifhrgvd 1021
gqwdlsnyhl ldlgrphhsi rcmtvvhdkv wcgyrnkiyv vqpkamkiek sfdahprkes
1081 qvrqlawvgd gvwvsirlds tlrlyhahty qhlqdvdiep yvskmlgtgk
lgfsfvrita 1141 lmvscnrlwv gtgngviisi pltetnktsg vpgnrpgsvi
rvygdensdk vtpgtfipyc 1201 smahaqlcfh ghrdavkffv avpgqvispq
ssssgtdltg dkagpsaqep gsqtplksml 1261 visggegyid frmgdegges
ellgedlple psvtkaersh livwqvmygn e Sperm associated antigen 9,
C-Jun-amino-terminal kinase-interacting protein 4 isoform 3,
NP_003962.3 (SEQ ID NO: 153) 1 meledgvvyq eepggsgavm servsglags
iyreferlig rydeevvkel mplvvavlen 61 ldsvfaqdqe hqvelellrd
dneqlitqye rekalrkhae ekfiefedsq eqekkdlqtr 121 veslesqtrq
lelkaknyad qisrleerea elkkeynalh qrhtemihny mehlertklh 181
qlsgsdqles tahsrirker pislgifplp agdglltpda qkggetpgse qwkfgelsqp
241 rshtslkdel sdvsqggska ttpastansd vatiptdtpl keenegfvkv
tdapnkseis 301 khievqvaqe trnvstgsae neeksevqai iestpeldmd
kdlsgykgss tptkgienka 361 fdrnteslfe elssagsgli gdvdegadll
gmgrevenli lentqlletk nalnivkndl 421 iakvdeltce kdvlqgelea
vkqaklklee knreleeelr karaeaedar qkakddddsd 481 iptaqrkrft
rvemarvlme rnqykerlme lqeavrwtem irasrenpam qekkrssiwq 541
ffsrlfssss nttkkpeppv nlkynaptsh vtpsvkkrss tlsqlpgdks kafdflseet
601 easlasrreq kreqyrqvka hvqkedgrvq afgwslpqky kqvtngqgen
kmknlpvpvy 661 lrpldekdts mklwcavgvn lsggktrdgg svvgasvfyk
dvagldtegs kqrsasgssl 721 dkldqelkeq qkelknqeel sslvwictst
hsatkvliid avqpgnilds ftvcnshvlc 781 iasvpgaret dypagedlse
sgqvdkaslc gsmtsnssae tdsllggitv vgcsaegvtg 841 aatspstnga
spvmdkppem eaensevden vptaeeatea tegnagsaed tvdisqtgvy 901
tehvftdplg vqipedlspv yqssndsday kdqisvlpne qdlvreeaqk mssllptmwl
961 gaqngclyvh ssvaqwrkcl hsiklkdsil sivhvkgivl valadgtlai
fhrgvdgqwd 1021 lsnyhlldlg rphhsircmt vvhdkvwcgy rnkiyvvqpk
amkieksfda hprkesqvrq 1081 lawvgdgvwv sirldstlrl yhahtyqhlq
dvdiepyvsk mlgtgklgfs fvritalmvs 1141 cnrlwvgtgn gviisiplte
tnktsgvpgn rpgsvirvyg densdkvtpg tfipycsmah 1201 aqlcfhghrd
avkffvavpg qvispqssss gtdltgdkag psaqepgsqt plksmlvisg 1261
gegyidfrmg deggesellg edlplepsvt kaershlivw qvmygne Sperm
associated antigen 9, C-Jun-amino-terminal kinase-interacting
protein 4 isoform 4, NP_001238900.1 (SEQ ID NO: 154) 1 mspgcmllfv
fgfvggavvi nsailvslsv lllvhfsist gvpaltqnlp rilrkerpis 61
lgifplpagd glltpdaqkg getpgseqwk fqelsqprsh tslkdelsdv sqggskattp
121 astansdvat iptdtplkee negfvkvtda pnkseiskhi evqvaqetrn
vstgsaenee 181 ksevqaiies tpeldmdkdl sgykgsstpt kgienkafdr
nteslfeels sagsgligdv 241 degadllgmg revenlilen tqlletknal
nivkndliak vdeltcekdv lqgeleavkq 301 aklkleeknr eleeelrkar
aeaedarqka kddddsdipt aqrkrftrve marvlmernq 361 ykerlmelqe
avrwtemira srenpamqek krssiwqffs rlfssssntt kkpeppvnlk 421
ynaptshvtp svkkrsstls qlpgdkskaf dflseeteas lasrreqkre qyrqvkahvq
481 kedgrvqafg wslpqkykqv tngqgenkmk nlpvpvylrp ldekdtsmkl
wcavgvnlsg 541 gktrdggsvv gasvfykdva gldtegskqr sasqssldkl
dqelkeqqke lknqeelssl 601 vwictsthsa tkvliidavq pgnildsftv
cnshvlcias vpgaretdyp agedlsesgq 661 vdkaslcgsm tsnssaetds
llggitvvgc saegvtgaat spstngaspv mdkppemeae 721 nsevdenvpt
aeeateateg nagsaedtvd isqtgvyteh vftdplgvqi pedlspvyqs 781
sndsdaykdq isvlpneqdl vreeaqkmss llptmwlgaq ngclyvhssv aqwrkclhsi
841 klkdsilsiv hvkgivlval adgtlaifhr gvdgqwdlsn yhlldlgrph
hsircmtvvh 901 dkvwcgyrnk iyvvqpkamk ieksfdahpr kesqvrqlaw
vgdgvwvsir ldstlrlyha 961 htyqhlqdvd iepyvskmlg tgklgfsfvr
italmvscnr lwvgtgngvi isipltetvi 1021 lhqgrllglr anktsgvpgn
rpgsvirvyg densdkvtpg tfipycsmah aqlcfhghrd
1081 avkffvavpg qvispqssss gtdltgdkag psaqepgsqt plksmlvisg
gegyidfrmg 1141 deggesellg edlplepsvt kaershlivw qvmygne SGT1
homolog, MIS12 kinetochore complex assembly cochaperone, protein
SGT1 homolog isoform A, NP_006695.1 (SEQ ID NO: 155) 1 maaaaagtat
sqrffqsfsd alidedpqaa leeltkaleq kpddaqyycq raychillgn 61
ycvavadakk slelnpnnst amlrkgicey heknyaaale tftegqklds adanfsvwik
121 rcqeaqngse sevwthqski kydwyqtesq vvitlmiknv qkndvnvefs
ekelsalvkl 181 psgedynlkl ellhpiipeq stfkvlstki eiklkkpeav
rweklegqgd vptpkqfvad 241 vknlypsssp ytrnwdklvg eikeeeknek
legdaalnrl fqqiysdgsd evkramnksf 301 mesggtvlst nwsdvgkrkv
einppddmew kky SGT1 homolog, MIS512 kinetochore complex assembly
cochaperone, protein SGT1 homolog isoform B, NP_001124384.1 (SEQ ID
NO: 156) 1 maaaaagtat sqrffqsfsd alidedpqaa leeltkaleq kpddaqyycq
raychillgn 61 ycvavadakk slelnpnnst amlrkgicey heknyaaale
tftegqkldi etgfhrvgqa 121 glqlltssdp paldsqsagi tgadanfsvw
ikrcqeaqng sesevwthqs kikydwyqte 181 sqvvitlmik nvqkndvnve
fsekelsalv klpsgedynl klellhpiip eqstfkvlst 241 kieiklkkpe
avrweklegq gdvptpkqfv advknlypss spytrnwdkl vgeikeeekn 301
eklegdaaln rlfqqiysdg sdevkramnk sfmesggtvl stnwsdvgkr kveinppddm
361 ewkky SGT1 homolog, MIS12 kinetochore complex assembly
cochaperone, protein SGT1 homolog isoform C, NP_001307760.1 (SEQ ID
NO: 157) 1 mlsqkevava dakkslelnp nnstamlrkg iceyheknya aaletftegq
kldsadanfs 61 vwikrcqeaq ngsesevwth qskikydwyq tesqvvitlm
iknvqkndvn vefsekelsa 121 lvklpsgedy nlklellhpi ipeqstfkvl
stkieiklkk peavrwekle gqgdvptpkq 181 fvadvknlyp ssspytrnwd
klvgeikeee kneklegdaa lnrlfqqiys dgsdevkram 241 nksfmesggt
vlstnwsdvg krkveinppd dmewkky Sulfotransferase family 1C member 2,
sulfotransferase 1C2 isoform a, NP_001047.1 (SEQ ID NO: 158) 1
maltsdlgkq iklkevegtl lqpatvdnws qiqsfeakpd dllictypka gttwiqeivd
61 mieqngdvek cqraiiqhrh pfiewarppq psgvekakam psprilkthl
stqllppsfw 121 ennckflyva rnakdcmvsy yhfqrmnhml pdpgtweeyf
etfingkvvw gswfdhvkgw 181 wemkdrhqil flfyedikrd pkheirkvmq
fmgkkvdetv ldkivqetsf ekmkenpmtn 241 rstvsksild qsissfmrkg
tvgdwknhft vaqnerfdei yrrkmegtsi nfcmel Sulfotransferase family 1C
member 2, sulfotransferase 1C2 isoform b, NP_789795.1 (SEQ ID NO:
159) 1 maltsdlgkq iklkevegtl lqpatvdnws qiqsfeakpd dllictypka
gttwiqeivd 61 mieqngdvek cqraiiqhrh pfiewarppq psetgfhhva
qaglkllsss nppastsqsa 121 kitdllppsf wennckflyv arnakdcmvs
yyhfqrmnhm lpdpgtweey fetfingkvv 181 wgswfdhvkg wwemkdrhqi
lflfyedikr dpkheirkvm qfmgkkvdet vldkivqets 241 fekmkenpmt
nrstvsksil dqsissfmrk gtvgdwknhf tvaqnerfde iyrrkmegts 301 infcmel
Transmembrane protein 52B, isoform 1, NP_694567.1 (SEQ ID NO: 160)
1 mswrpqpcci sscclttdwv hlwyiwllvv igallllcgl tslcfrcccl srqqngedgg
61 pppcevtvia fdhdstlqst itslqsvfgp aarrilavah shsslgqlps
sldtlpgyee 121 alhmsrftva mcgqkapdlp pvpeekqlpp tekestrivd swn
Transmembrane protein 52B, isoform 2 precursor, NP_001073283.1 (SEQ
ID NO: 161) 1 mgvrvhvvaa sallyfills gtrceencgn pehclttdwv
hlwyiwllvv igallllcgl 61 tslcfrcccl srqqngedgg pppcevtvia
fdhdstlqst itslqsvfgp aarrilavah 121 shsslgqlps sldtlpgyee
alhmsrftva mcgqkapdlp pvpeekqlpp tekestrivd 181 swn Exportin 7,
NP_055839.3 (SEQ ID NO: 162) 1 madhvqslaq lenlckqlye ttdtttrlqa
ekalveftns pdclskcqll lergsssysq 61 llaatcltkl vsrtnnplpl
eqridirnyv lnylatrpkl atfvtqaliq lyaritklgw 121 fdcqkddyvf
rnaitdvtrf lqdsveycii gvtilsqltn einqadtthp ltkhrkiass 181
frdsslfdif tlscnllkqa sgknlnlnde sqhgllmqll klthnclnfd figtstdess
241 ddlctvqipt swrsafldss tlqlffdlyh sippsfsplv lsclvqiasv
rrslfnnaer 301 akflshlvdg vkrilenpqs lsdpnnyhef crllarlksn
yqlgelvkve nypevirlia 361 nftvtslqhw efapnsvhyl lslwqrlaas
vpyvkateph mletytpevt kayitsrles 421 vhiilrdgle dpledtglvq
qqldqlstig rceyektcal lvqlfdqsaq syqellqsas 481 aspmdiavqe
grltwlvyii gaviggrvsf astdeqdamd gelvcrvlql mnltdsrlaq 541
agneklelam lsffeqfrki yigdqvqkss klyrrlsevl glndetmvls vfigkiitnl
601 kywgrcepit sktlqllndl sigyssvrkl vklsavqfml nnhtsehfsf
lginnqsnlt 661 dmrcrttfyt algrllmvdl gededqyeqf mlpltaafea
vaqmfstnsf neqeakrtlv 721 glvrdlrgia fafnaktsfm mlfewiypsy
mpilqraiel wyhdpacttp vlklmaelvh 781 nrsqrlqfdv sspngillfr
etskmitmyg nriltlgevp kdqvyalklk gisicfsmlk 841 aalsgsyvnf
gvfrlygdda ldnalqtfik lllsiphsdl ldypklsqsy ysllevltqd 901
hmnfiaslep hvimyilssi segltaldtm vctgccscld hivtylfkql srstkkrttp
961 lngesdrflh imqqhpemiq qmlstvinii ifedcrnqws msrpllglil
lnekyfsdlr 1021 nsivnsqppe kqqamhlcfe nlmegiernl ltknrdrftq
nlsafrrevn dsmknstygv 1081 nsndmms YES proto-oncogene 1, Src family
tyrosine kinase, tyrosine-protein kinase Yes, NP_005424.1 (SEQ ID
NO: 163) 1 mgcikskenk spaikyrpen tpepvstsvs hygaepttvs pcpsssakgt
avnfsslsmt 61 pfggssgvtp fggasssfsv vpssypaglt ggvtifvaly
dyearttedl sfkkgerfqi 121 inntegdwwe arsiatgkng yipsnyvapa
dsiqaeewyf gkmgrkdaer lllnpgngrg 181 iflvresett kgayslsird
wdeirgdnvk hykirkldng gyyittraqf dtlqklvkhy 241 tehadglchk
lttvcptvkp qtqglakdaw eipreslrle vklgqgcfge vwmgtwngtt 301
kvaiktlkpg tmmpeaflqe aqimkklrhd klvplyavvs eepiyivtef mskgslldfl
361 kegdgkylkl pqlvdmaaqi adgmayierm nyihrdlraa nilvgenlvc
kiadfglarl 421 iedneytarq gakfpikwta peaalygrft iksdvwsfgi
lqtelvtkgr vpypgmvnre 481 vleqvergyr mpcpqgcpes lhelmnlcwk
kdpderptfe yiqsfledyf tatepqyqpg 541 enl Coiled-coil domain
containing 80, coiled-coil domain-containing 80 precursor,
NP_955805.1, NP_955806.1 (SEQ ID NO: 164) 1 mtwrmgprft mllamwlvcg
sephphatir gshggrkvpl vspdssrpar flrhtgrsrg 61 ierstleepn
lqplqrrrsv pvlrlarpte pparsdinga avrpeqrpaa rgspremird 121
egssarsrml rfpsgssspn ilasfagknr vwvisaphas egyyrlmmsl lkddvycela
181 erhiqqivlf hqageeggkv rritsegqil eqpldpslip klmsflklek
gkfgmvllkk 241 tlqveerypy pvrleamyev idqgpirrie kirqkgfvqk
ckasgvegqv vaegndgggg 301 agrpslgsek kkedprraqv pptresrvkv
lrklaatapa lpqppstpra ttlppapatt 361 vtrstsravt vaarpmttta
fpttqrpwtp spshrppttt evitarrpsv senlyppsrk 421 dqhrerpqtt
rrpskatsle sftnapptti sepstraagp grfrdnrmdr rehghrdpnv 481
vpgppkpake kppkkkaqdk ilsneyeeky dlsrptasql edelqvgnvp lkkakeskkh
541 eklekpekek kkkmknenad kllksekqmk ksekkskqek ekskkkkggk
teqdgyqkpt 601 nkhftqspkk svadllgsfe gkrrlllita pkaennmyvq
qrdeylesfc kmatrkisvi 661 tifgpvnnst mkidhfqldn ekpmrvvdde
dlvdqrlise lrkeygmtyn dffmvltdvd 721 lrvkqyyevp itmksvfdli
dtfqsrikdm ekqkkegivc kedkkqslen flsrfrwrrr 781 llvisapnde
dwaysqqlsa lsgqacnfgl rhitilkllg vgeevggvle lfpingssvv 841
eredvpahlv kdirnyfqvs peyfsmllvg kdgnvkswyp spmwsmvivy dlidsmqlrr
901 qemaiqqslg mrcpedeyag ygyhsyhqgy qdgyqddyrh hesyhhgypy
Acrosin-binding protein precursor NP_115878.2 (SEQ ID NO: 165) 1
mrkpaagflp sllkvlllpl apaaaqdstq astpgsplsp teyerffall tptwkaettc
61 rlrathgcrn ptlvqldqye nhglvpdgav csnlpyaswf esfcqfthyr
csnhvyyakr 121 vlcsqpvsil spntlkeiea saevspttmt spisphftvt
erqtfqpwpe rlsnnveell 181 qsslslggqe qapehkqeqg vehrqeptqe
hkqeegqkqe eqeeeqeeeg kqeegqgtke 241 greaysqlqt dsepkfhses
lssnpssfap rvrevestpm imeniqelir saqeidemne 301 iydensywrn
qnpgsllqlp hteallvlcy siventciit ptakawkyme eeilgfgksv 361
cdslgrrhms tcalcdfcsl kleqchseas lqrqqcdtsh ktpfvsplla sqslsignqv
421 gspesgrfyg ldlygglhmd fwcarlatkg cedvrvsgwl qteflsfqdg
dfptkicdtd 481 yiqypnycsf ksqqclmrnr nrkvsrmrcl qnetysalsp
gksedvvlrw sqefstltlg 541 qfg Alpha-fetoprotein, isoform 1
NP_001125.1 (SEQ ID NO: 166) 1 mkwvesifli fllnftesrt lhrneygias
ildsyqctae isladlatif faqfvqeaty 61 kevskmvkda ltaiekptgd
eqssgclenq lpafleelch ekeilekygh sdccsqseeg 121 rhncflahkk
ptpasiplfq vpepvtscea yeedretfmn kfiyeiarrh pflyaptill 181
waarydkiip scckaenave cfqtkaatvt kelresslln qhacavmknf gtrtfqaitv
241 tklsqkftkv nfteiqklvl dvahvhehcc rgdvldclqd gekimsyics
qqdtlsnkit 301 eccklttler gqciihaend ekpeglspnl nrflgdrdfn
qfssgeknif lasfvheysr 361 rhpqlavsvi lrvakgyqel lekcfqtenp
lecqdkgeee lqkyiqesqa lakrscglfq 421 klgeyylqna flvaytkkap
qltsselmai trkmaataat ccqlsedkll acgegaadii 481 ighlcirhem
tpvnpgvgqc ctssyanrrp cfsslvvdet yvppafsddk fifhkdlcqa 541
qgvalqtmkg eflinlvkqk pqiteeqlea viadfsglle kccqgqeqev cfaeegqkli
601 sktraalgv Alpha-fetoprotein, isoform 2 NP_001341646.1 (SEQ ID
NO: 167) 1 mnkfiyeiar rhpflyapti llwaarydki ipscckaena vecfqtkaat
vtkelressl 61 lnqhacavmk nfgtrtfqai tvtklsqkft kvnfteiqkl
vldvahvheh ccrgdvldcl 121 qdgerimsyi csqqdtlsnk iteccklttl
ergqciihae ndekpeglsp nlnrflgdrd 181 fnqfssgekn iflasfvhey
srrhpqlavs vilrvakgyq ellekcfqte nplecqdkge 241 eelqkyiqes
qalakrscgl fqklgeyylq naflvaytkk apqltsselm aitrkmaata 301
atccqlsedk llacgegaad iiighlcirh emtpvnpgvg qcctssyanr rpcfsslvvd
361 etyvppafsd dkfifhkdlc qaqgvalqtm kqeflinlvk qkpqiteeql
eaviadfsgl 421 lekccqgqeq evcfaeegqk lisktraalg v Absent in
melanoma 1 protein NP_001615.2 (SEQ ID NO: 168) 1 mplsppaqgd
pgepsperpp kkhttfhlwr skkkqqpapp dcgvfvphpl papagearal 61
dvvdgkyvvr dsqefplhcg esqffhttse algslllesg ifkksraqpp ednrrkpvlg
121 klgtlftagr rrnsrngles ptrsnakpls pkdvvaspkl peresersrs
qssqlkqtdt 181 seegsprenp reaegelpes ggpaappdae lsprwsssaa
avavqqchen dspqleplea 241 egepfpdatt takqlhsspg nssrqenaet
parspgedas pgagheqeaf lgvrgapgsp 301 tqerpagglg eapngapsvc
aeegslgprn arsqppkgas dlpgeppaeg aahtassaqa 361 dctarpkgha
hpakvltldi ylsktegaqv depvvitpra edcgdwddme krssgrrsgr 421
rrgsqkstds pgadaelpes aarddavfdd evapnaasdn asaekkvksp raaldggvas
481 aaspeskpsp gtkgqlrges drskqpppas sptkrkgrsr aleavpappa
sgprapakes 541 ppkrvpdpsp vtkgtaaesg eeaaraipre lpvksssllp
eikpehkrgp lpnhfngrae 601 ggrsrelgra agapgasdad glkprnhfgv
grstvttkvt lpakpkhvel nlktpknlds 661 lgnehnpfsq pvhkgntatk
islfenkrtn ssprhtdirg qrntpasskt fvgraklnla 721 kkakemeqpe
kkvmpnspqn gvlvketaie tkvtvseeei lpatrgmngd ssenqalgpq 781
pnqddkadvq tdagclsepv asalipvkdh kllekedsea adskslvlen vtdtaqdipt
841 tvdtkdlppt ampkpqhtfs dsqspaessp gpslslsapa pgdvpkdtcv
qspissfpct 901 dlkvsenhkg cvlpvsrqnn ekmpllelgg ettpplster
speavgsecp srvlvqvrsf 961 vlpvestqdv ssqvipesse vrevqlptch
snepevvsva scappqeevl gnehshctae 1021 laaksgpqvi ppasektlpi
qaqsqgsrtp lmaessptns pssgnhlatp qrpdqtvtng 1081 qdspasllni
sagsddsvfd sssdmekfte iikqmdsavc mpmkrkkarm pnspaphfam 1141
ppihedhlek vfdpkvftfg lgkkkesqpe mspalhlmqn ldtksklrpk rasaeqsvlf
1201 kslhtntngn seplvmpein dkenrdvtng gikrsrleks alfssllssl
pqdkifspsv 1261 tsvntmttaf stsqngslsq ssysqptteg appcglnkeq
snllpdnslk vfnfnsssts 1321 hsslkspshm ekypqkektk edldsrsnlh
lpetkfsels klknddmeka nhiesviksn 1381 lpncansdtd fmglfkssry
dpsisfsgms lsdtmtlrgs vqnklnprpg kvviysepdv 1441 sekcievfsd
iqdcsswsls pvilikvvrg cwilyeqpnf eghsipleeg elelsglwgi 1501
edilerheea esdkpvvigs irhvvqdyrv shidlftepe glgilssyfd dteemqgfgv
1561 mqktcsmkvh wgtwliyeep gfqgvpfile pgeypdlsfw dteeayigsm
rplkmggrkv 1621 efptdpkvvv yekpffegkc veletgmcsf vmeggeteea
tgddhlpfts vgsmkvlrgi 1681 wvayekpgft ghqylleege yrdwkawggy
ngelqslrpi lgdfsnahmi myseknfgsk 1741 gssidvlgiv anlketgygv
ktqsinvlsg vwvayenpdf tgeqyildkg fytsfedwgg 1801 knckissvqp
icldsftgpr rrnqihlfse pqfqghsqsf eettsqidds fstkscrvsg 1861
gswvvydgen ftgnqyvlee ghypclsamg cppgatfksl rfidvefsep tiilferedf
1921 kgkkielnae tvnlrslgfn tqirsvqvig giwvtyeygs yrgrqfllsp
aevpnwyefs 1981 gcrqigslrp fvqkriyfrl rnkatglfms tngnledlkl
lriqvmedvg addqiwiyqe 2041 gcikcriaed ccltivgslv tsgsklglal
dqnadsqfws lksdgriysk lkpnlvldik 2101 ggtqydqnhi ilntvskekf
tqvweamvly t A-kinase anchoring protein 4, isoform 1 NP_003877.2
(SEQ ID NO: 169) 1 mmaysdttmm sddidwlrsh rgvckvdlyn pegqqdqdrk
vicfvdvstl nvedkdykda 61 assssegnln lgsleekeii vikdtekkdq
sktegsvclf kqapsdpvsv lnwllsdlqk 121 yalgfqhals pststckhkv
gdtegeyhra ssencysvya dqvnidylmn rpqnlrlemt 181 aakntnnnqs
psappakpps tqravispdg ecsiddlsfy vnrlsslviq mahkeikekl 241
egkskclhhs icpspgnker isprtpaski asemayeave ltaaemrgtg eesreggqks
301 flyselsnks ksgdkqmsqr eskefadsis kglmvyanqv asdmmvslmk
tlkvhssgkp 361 ipasvvlkrv llrhtkeivs dlidscmknl hnitgvlmtd
sdfvsavkrn lfnqwkqnat 421 dimeamlkrl vsaligeeke tksqslsyas
lkagshdpkc rnqslefstm kaemkerdkg 481 kmksdpcksl tsaekvgehi
lkegltiwnq kqgnsckvat kacsnkdekg ekinastdsl 541 akdlivsalk
liqyhltqqt kgkdtceedc pgstmgymaq stqyekcggg qsakalsvkq 601
leshrapgps tcqkenqhld sqkmdmsniv lmliqkllne npfkcedpce genkcsepra
661 skaasmsnrs dkaeeqcqeh qeldctsgmk qangqfidkl vesvmklcli
makysndgaa 721 laeleeqaas ankpnfrgtr cihsgampqn yqdslghevi
vnnqcstnsl qkqlqavlqw 781 iaasqfnvpm lyfmgdkdgq leklpqvsak
aaekgysvgg llqevmkfak erqpdeavgk 841 varkqlldwl lanl A-kinase
anchoring protein 4, isoform 2 NP_647450.1 (SEQ ID NO: 170) 1
msddidwlrs hrgvckvdly npegqqdqdr kvicfvdvst lnvedkdykd aassssegnl
61 nlgsleekei ivikdtekkd qsktegsvcl fkqapsdpvs vlnwllsdlq
kyalgfqhal 121 spststckhk vgdtegeyhr assencysvy adqvnidylm
nrpqnlrlem taakntnnnq 181 spsappakpp stqravispd gecsiddlsf
yvnrlsslvi qmahkeikek legkskclhh 241 sicpspgnke risprtpask
iasemayeav eltaaemrgt geesreggqk sflyselsnk 301 sksgdkqmsq
reskefadsi skglmvyanq vasdmmvslm ktlkvhssgk pipasvvlkr 361
vllrhtkeiv sdlidscmkn lhnitgvlmt dsdfvsavkr nlfnqwkqna tdimeamlkr
421 lvsaligeek etksqslsya slkagshdpk crnqslefst mkaemkerdk
gkmksdpcks 481 ltsaekvgeh ilkegltiwn qkqgnsckva tkacsnkdek
gekinastds lakdlivsal 541 kliqyhltqq tkgkdtceed cpgstmgyma
qstqyekcgg gqsakalsvk qleshrapgp 601 stcqkenqhl dsqkmdmsni
vlmliqklln enpfkcedpc egenkcsepr askaasmsnr 661 sdkaeeqcqe
hqeldctsgm kqangqfidk lvesvmklcl imakysndga alaeleeqaa 721
sankpnfrgt rcihsgampq nyqdslghev ivnnqcstns lqkqlqavlq wiaasqfnvp
781 mlyfmgdkdg qleklpqvsa kaaekgysvg gllqevmkfa kerqpdeavg
kvarkqlldw 841 llanl ALK tryrosine kinase receptor, isoform 1
NP_004295.2 (SEQ ID NO: 171) 1 mgaigllwll plllstaavg sgmgtgqrag
spaagpplqp replsysrlq rkslavdfvv 61 pslfrvyard lllppsssel
kagrpeargs laldcapllr llgpapgvsw tagspapaea 121 rtlsrvlkgg
svrklrrakq lvlelgeeai legcvgppge aavgllqfnl selfswwirq 181
gegrlrirlm pekkasevgr egrlsaaira sqprllfqif gtghsslesp tnmpspspdy
241 ftwnltwimk dsfpflshrs ryglecsfdf pceleysppl hdlrnqswsw
rripseeasq 301 mdlldgpgae rskemprgsf lllntsadsk htilspwmrs
ssehctlays vhrhlqpsgr 361 yiaqllphne aareillmpt pgkhgwtvlq
grigrpdnpf rvaleyissg nrslsavdff 421 alkncsegts pgskmalqss
ftcwngtvlq lgqacdfhqd caqgedesqm crklpvgfyc 481 nfedgfcgwt
qgtlsphtpq wqvrtlkdar fqdhqdhall lsttdvpase satvtsatfp 541
apiksspcel rmswlirgvl rgnvslvlve nktgkeqgrm vwhvaayegl slwqwmvlpl
601 ldvsdrfwlq mvawwgqgsr aivafdnisi sldcyltisg edkilqntap
ksrnlfernp 661 nkelkpgens prqtpifdpt vhwlfttcga sgphgptqaq
cnnayqnsnl svevgsegpl 721 kgiqiwkvpa tdtysisgyg aaggkggknt
mmrshgvsvl gifnlekddm lyilvgqqge 781 dacpstnqli qkvcigennv
ieeeirvnrs vhewaggggg gggatyvfkm kdgvpvplii 841 aaggggrayg
aktdtfhper lennssvlgl ngnsgaaggg ggwndntsll wagkslqega 901
tgghscpqam kkwgwetrgg fggggggcss ggggggyigg naasnndpem dgedgvsfis
961 plgilytpal kvmeghgevn ikhylncshc evdechmdpe shkvicfcdh
gtvlaedgvs 1021 civsptpeph lplslilsvv tsalvaalvl afsgimivyr
rkhqelqamq melqspeykl 1081 sklrtstimt dynpnycfag ktssisdlke
vprknitlir glghgafgev yegqvsgmpn 1141 dpsplqvavk tlpevcseqd
eldflmeali iskfnhqniv rcigvslqsl prfillelma 1201 ggdlksflre
trprpsqpss lamldllhva rdiacgcqyl eenhfihrdi aarnclltcp 1261
gpgrvakigd fgmardiyra syyrkggcam lpvkwmppea fmegiftskt dtwsfgvllw
1321 eifslgympy psksnqevle fvtsggrmdp pkncpgpvyr imtqcwqhqp
edrpnfaiil 1381 erieyctqdp dvintalpie ygplveeeek vpvrpkdpeg
vppllvsqqa kreeerspaa 1441 ppplpttssg kaakkptaae isvrvprgpa
vegghvnmaf sqsnppselh kvhgsrnkpt 1501 slwnptygsw ftekptkknn
piakkephdr gnlglegsct vppnvatgrl pgasllleps
1561 sltanmkevp lfrlrhfpcg nvnygyqqqg lpleaatapg aghyedtilk
sknsmnqpgp ALK tyrosin kinese receptor, isoform 2 NP_001340694.1
(SEQ ID NO: 172) 1 mqmelqspey klsklrtsti mtdynpnycf agktssisdl
kevprknitl irglghgafg 61 evyegqvsgm pndpsplqva vktlpevcse
qdeldflmea liiskfnhqn ivrcigvslq 121 slprfillel maggdlksfl
retrprpsqp sslamldllh vardiacgcq yleenhfihr 181 diaarncllt
cpgpgrvaki gdfgmardiy rasyyrkggc amlpvkwmpp eafmegifts 241
ktdtwsfgvl lweifslgym pypsksnqev lefvtsggrm dppkncpgpv yrimtqcwqh
301 qpedrpnfai ilerieyctq dpdvintalp ieygplveee ekvpvrpkdp
egvppllvsq 361 qakreeersp aappplptts sgkaakkpta aeisvrvprg
pavegghvnm afsqsnppse 421 lhkvhgsrnk ptslwnptyg swftekptkk
nnpiakkeph drgnlglegs ctvppnvatg 481 rlpgasllle pssltanmke
vplfrlrhfp cgnvnygyqq qglpleaata pgaghyedti 541 lksknsmnqp gp
Angiopoietin-2, isoform a NP_001138.1 (SEQ ID NO: 173) 1 mwqivfftls
cdlvlaaayn nfrksmdsig kkgyqvghgs csytfllpem dncrsssspy 61
vsnavqrdap leyddsvqrl qvlenimenn tqwlmkleny iqdnmkkemv eiqqnavqnq
121 tavmieigtn llnqtaeqtr kltdveaqvl nqttrlelql lehslstnkl
ekqildqtse 181 inklqdknsf lekkvlamed khiiqlqsik eekdqlqvlv
skqnsiieel ekkivtatvn 241 nsvlqkqqhd lmetvnnllt mmstsnsakd
ptvakeeqis frdcaevfks ghttngiytl 301 tfpnsteeik aycdmeaggg
gwtiiqrred gsvdfqrtwk eykvgfgnps geywlgnefv 361 sqltnqqryv
lkihlkdweg neayslyehf ylsseelnyr ihlkgltgta gkissisqpg 421
ndfstkdgdn dkcickcsqm ltggwwfdac gpsnlngmyy pqrqntnkfn gikwyywkgs
481 gyslkattmm irpadf Angiopoietin-2, isoform b NP_00lll2359.1 (SEQ
ID NO: 174) 1 mwqivfftls cdlvlaaayn nfrksmdsig kkqyqvghgs
csytfllpem dncrsssspy 61 vsnavqrdap leyddsvqrl qvlenimenn
tqwlmkleny iqdnmkkemv eiqqnavqnq 121 tavmieigtn llnqtaeqtr
kltdveaqvl nqttrlelql lehslstnkl ekqildqtse 181 inklqdknsf
lekkvlamed khiiqlqsik eekdqlqvlv skqnsiieel ekkivtatvn 241
nsvlqkqqhd lmetvnnllt mmstsnskdp tvakeeqisf rdcaevfksg httngiytlt
301 fpnsteeika ycdmeagggg wtiiqrredg svdfqrtwke ykvgfgnpsg
eywlgnefvs 361 qltnqqryvl kihlkdwegn eayslyehfy lsseelnyri
hlkgltgtag kissisqpgn 421 dfstkdgdnd kcickcsqml tggwwfdacg
psnlngmyyp qrqntnkfng ikwyywkgsg 481 yslkattmmi rpadf
Angiopoietin-2, isoform c NP_00lll2360.1 (SEQ ID NO: 175) 1
mwqivfftls cdlvlaaayn nfrksmdsig kkgyqvqhgs csytfllpem dncrsssspy
61 vsnavqrdap leyddsvqrl qvlenimenn tqwlmkvlnq ttrlelqlle
hslstnklek 121 qildqtsein klqdknsfle kkvlamedkh iiqlqsikee
kdqlqvlvsk qnsiieelek 181 kivtatvnns vlqkqqhdlm etvnnlltmm
stsnsakdpt vakeeqisfr dcaevfksgh 241 ttngiytltf pnsteeikay
cdmeaggggw tiiqrredgs vdfqrtwkey kvgfgnpsge 301 ywlgnefvsq
ltnqqryvlk ihlkdwegne ayslyehfyl sseelnyrih lkgltgtagk 361
issisqpgnd fstkdgdndk cickcsqmlt ggwwfdacgp snlngmyypq rqntnkfngi
421 kwyywkgsgy slkattmmir padf Angiopoietin-1, isoform 1 precursor
NP_001137.2 (SEQ ID NO: 176) 1 mtvflsfafl aailthigcs nqrrspensg
rrynriqhgq caytfilpeh dgncresttd 61 gyntnalqrd aphvepdfss
qklqhlehvm enytqwlqkl enyivenmks emaqiqqnav 121 qnhtatmlei
gtsllsqtae qtrkltdvet qvlnqtsrle iqllenslst yklekqllqq 181
tneilkihek nsllehkile megkhkeeld tlkeekenlq glvtrqtyii qelekqlnra
241 ttnnsvlqkq qlelmdtvhn lvnlctkegv llkggkreee kpfrdcadvy
gagfnksgiy 301 tiyinnmpep kkvfcnmdvn gggwtviqhr edgsldfqrg
wkeykmgfgn psgeywlgne 361 fifaitsqrq ymlrielmdw egnraysqyd
rfhignekqn yrlylkghtg tagkqsslil 421 hgadfstkda dndncmckca
lmltggwwfd acgpsnlngm fytagqnhgk lngikwhyfk 481 gpsyslrstt mmirpldf
Angiopoietin-1, isoform 2 precursor NP_001186788.1 (SEQ ID NO: 177)
1 mtvflsfafl aailthigcs nqrrspensg rrynriqhgq caytfilpeh dgncresttd
61 gyntnalqrd aphvepdfss qklqhlehvm enytqwlqkl enyivenmks
emaqiqqnav 121 qnhtatmlei gtsllsqtae qtrkltdvet qvlnqtsrle
iqllenslst yklekqllqq 181 tneilkihek nsllehkile megkhkeeld
tlkeekenlq glvtrqtyii qelekqlnra 241 ttnnsvlqkq qlelmdtvhn
lvnlctkevl lkggkreeek pfrdcadvyq agfnksgiyt 301 iyinnmpepk
kvfcnmdvng ggwtviqhre dgsldfqrgw keykmgfgnp sgeywlgnef 361
ifaitsqrqy mlrielmdwe gnraysqydr fhignekqny rlylkghtgt agkqsslilh
421 gadfstkdad ndncmckcal mltggwwfda cgpsnlngmf ytagqnhgkl
ngikwhyfkg 481 psyslrsttm mirpldf Angiopoietin-1, isoform 3
precursor NP_001300980.1 (SEQ ID NO: 178) 1 megkhkeeld tlkeekenlq
glvtrqtyii qelekqlnra ttnnsvlqkq qlelmdtvhn 61 lvnlctkegv
llkggkreee kpfrdcadvy qagfnksgiy tiyinnmpep kkvfcnmdvn 121
gggwtviqhr edgsldfqrg wkeykmgfgn psgeywlgne fifaitsqrq ymlrielmdw
181 egnraysqyd rfhignekqn yrlylkghtg tagkqsslil hgadfstkda
dndncmckca 241 lmltggwwfd acgpsnlngm fytagqnhgk lngikwhyfk
gpsyslrstt mmirpldf Ankyrin repeat domain-containing protein 30A
NP_443723.2 (SEQ ID NO: 179) 1 mtkrkktinl niqdaqkrta lhwacvnghe
evvtflvdrk cqldvldgeh rtplmkalqc 61 hqeacanili dsgadinlvd
vygntalhya vyseilsvva kllshgavie vhnkasltpl 121 llsitkrseq
ivefllikna nanavnkykc talmlavchg sseivgmllq qnvdvfaadi 181
cgvtaehyav tcgfhhiheq imeyirklsk nhqntnpegt sagtpdeaap laertpdtae
241 slvektpdea aplvertpdt aeslvektpd eaaslvegts dkiqclekat
sgkfeqsaee 301 tpreitspak etsekftwpa kgrprkiawe kkedtpreim
spaketsekf twaakgrprk 361 iawekketpv ktgcvarvts nktkvlekgr
skmiacptke sstkasandq rfpseskqee 421 deeyscdsrs lfessakiqv
cipesiyqkv meinreveep pkkpsafkpa iemqnsvpnk 481 afelknegtl
radpmfppes kqkdyeensw dseslcetvs qkdvclpkat hqkeidking 541
kleespnkdg llkatcgmkv siptkalelk dmqtfkaepp gkpsafepat emqksvpnka
601 lelkneqtlr adeilpsesk qkdyeenswd teslcetvsq kdvclpkaah
qkeidkingk 661 legspvkdgl lkancgmkvs iptkalelmd mqtfkaeppe
kpsafepaie mqksvpnkal 721 elkneqtlra deilpseskq kdyeesswds
eslcetvsqk dvclpkathq keidkingkl 781 eespdndgfl kapermkvsi
ptkalelmdm qtfkaeppek psafepaiem qksvpnkale 841 lkneqtlrad
qmfpseskqk kveenswdse slretvsqkd vcvpkathqk emdkisgkle 901
dstslskild tvhscerare lqkdhceqrt gkmeqmkkkf cvlkkklsea keiksqlenq
961 kvkweqelcs vrltlnqeee krrnadilne kireelgrie eqhrkelevk
qqleqalriq 1021 dielksvesn lnqvshthen enyllhencm lkkeiamlkl
eiatlkhqyq ekenkyfedi 1081 kilkeknael qmtlklkees ltkrasqysg
qlkvliaent mltsklkekq dkeileaeie 1141 shhprlasav qdhdqivtsr
ksqepafhia gdaclqrkmn vdvsstiynn evlhqplsea 1201 qrkskslkin
lnyagdalre ntlvsehaqr dqretqcqmk eaehmyqneq dnvnkhteqq 1261
esldqklfql qsknmwlqqq lvhahkkadn kskitidihf lerkmqhhll kekneeifny
1321 nnhlknriyq yekekaeten s Androgen receptor, isoform 1
NP_000035.2 (SEQ ID NO: 180) 1 mevqlglgrv yprppsktyr gafqnlfqsv
reviqnpgpr hpeaasaapp gasllllqqq 61 qqqqqqqqqq qqqqqqqqqq
etsprqqqqq qgedgspqah rrgptgylvl deeqqpsqpq 121 salechperg
cvpepgaava askglpqqlp appdeddsaa pstlsllgpt fpglsscsad 181
lkdilseast mqllqqqqqe aysegsssgr areasgapts skdnylggts tisdnakelc
241 kaysysmglg vealehlspg eqlrgdcmya pllgvppavr ptpcaplaec
kgsllddsag 301 kstedtaeys pfkggytkgl egeslgcsgs aaagssgtle
lpstlslyks galdeaaayq 361 srdyynfpla lagppppppp phpharikle
npldygsawa aaaaqcrygd laslhgagaa 421 gpgsgspsaa assswhtlft
aeegqlygpc gggggggggg gggggggggg gggeagavap 481 ygytrppqgl
agqesdftap dvwypggmvs rvpypsptcv ksemgpwmds ysgpygdmrl 541
etardhvlpi dyyfppqktc licgdeasgc hygaltcgsc kvffkraaeg kqkylcasrn
601 dctidkfrrk ncpscrlrkc yeagmtlgar klkklgnlkl qeegeasstt
spteettqkl 661 tvshiegyec qpiflnvlea iepgvvcagh dnnqpdsfaa
llsslnelge rqlvhvvkwa 721 kalpgfrnlh vddgmaviqy swmglmvfam
gwrsftnvns rmlyfapdlv fneyrmhksr 781 mysqcvrmrh lsqefgwlqi
tpqeflcmka lllfsiipvd glknqkffde lrmnyikeld 841 riiackrknp
tscsrrfyql tklldsvqpi arelhqftfd llikshmvsv dfpemmaeii 901
svqvpkilsg kvkpiyfhtq Androgen receptor, isoform 2 NP_001011645.1
(SEQ ID NO: 181) 1 milwlhslet ardhvlpidy yfppqktcli cgdeasgchy
galtcgsckv ffkraaegkq 61 kylcasrndc tidkfrrknc pscrlrkcye
agmtlgarkl kklgnlklqe egeassttsp 121 teettqkltv shiegyecqp
iflnvleaie pgvvcaghdn nqpdsfaall sslnelgerq 181 lvhvvkwaka
lpgfrnlhvd dqmaviqysw mglmvfamgw rsftnvnsrm lyfapdlvfn 241
eyrmhksrmy sqcvrmrhls qefgwlqitp qeflcmkall lfsiipvdgl knqkffdelr
301 mnyikeldri iackrknpts csrrfyqltk lldsvqpiar elhqftfdll
ikshmvsvdf 361 pemmaeiisv qvpkilsgkv kpiyfhtq Androgen receptor,
isoform 3 NP_001334990.1 (SEQ ID NO: 182) 1 mevqlglgrv yprppsktyr
gafqnlfqsv reviqnpgpr hpeaasaapp gasllllqqq 61 qqqqqqqqqq
qqqqqqqqqq etsprqqqqq qgedgspqah rrgptgylvl deeqqpsqpq 121
salechperg cvpepgaava askglpqqlp appdeddsaa pstlsllgpt fpglsscsad
181 lkdilseast mqllqqqqqe aysegsssgr areasgapts skdnylggts
tisdnakelc 241 kaysysmglg vealehlspg eqlrgdcmya pllgvppavr
ptpcaplaec kgsllddsag 301 kstedtaeys pfkggytkgl egeslgcsgs
aaagssgtle lpstlslyks galdeaaayq 361 srdyynfpla lagppppppp
phpharikle npldygsawa aaaaqcrygd laslhgagaa 421 gpgsgspsaa
assswhtlft aeegqlygpc gggggggggg gggggggggg gggeagavap 481
ygytrppqgl agqesdftap dvwypggmvs rvpypsptcv ksemgpwmds ysgpygdmrl
541 etardhvlpi dyyfppqktc licgdeasgc hygaltcgsc kvffkraaeg
kqkylcasrn 601 dctidkfrrk ncpscrlrkc yeagmtlgek frvgnckhlk mtrp
Androgen receptor, isoform 4 NP_001334992.1 (SEQ ID NO: 183) 1
mevqlglgrv yprppsktyr gafqnlfqsv reviqnpgpr hpeaasaapp gasllllqqq
61 qqqqqqqqqq qqqqqqqqqq etsprqqqqq qgedgspqah rrgptgylvl
deeqqpsqpq 121 salechperg cvpepgaava askglpqqlp appdeddsaa
pstlsllgpt fpglsscsad 181 lkdilseast mqllqqqqqe aysegsssgr
areasgapts skdnylggts tisdnakelc 241 kaysvsmglg vealehlspg
eqlrgdcmya pllgvppavr ptpcaplaec kgsllddsag 301 kstedtaeys
pfkggytkgl egeslgcsgs aaagssgtle lpstlslyks galdeaaayq 361
srdyynfpla lagppppppp phpharikle npldygsawa aaaaqcrygd laslhgagaa
421 gpgsgspsaa assswhtlft aeegqlygpc gggggggggg gggggggggg
gggeagavap 481 ygytrppqgl agqesdftap dvwypggmvs rvpypsptcv
ksemgpwmds ysgpygdmrl 541 etardhvlpi dyyfppqktc licgdeasgc
hygaltcgsc kvffkraaeg kqkylcasrn 601 dctidkfrrk ncpscrlrkc
yeagmtlgaa vvvserilry fgvsewlp Androgen receptor, isoform 5
NP_001334993.1 (SEQ ID NO: 184) 1 mevqlglgrv yprppsktyr gafqnlfqsv
reviqnpgpr hpeaasaapp gasllllqqq 61 qqqqqqqqqq qqqqqqqqqq
etsprqqqqq qgedgspqah rrgptgylvl deeqqpsqpq 121 salechperg
cvpepgaava askglpqqlp appdeddsaa pstlsllgpt fpglsscsad 181
lkdilseast mqllqqqqqe aysegsssgr areasgapts skdnylggts tisdnakelc
241 kaysysmglg vealehlspg eqlrgdcmya pllgvppavr ptpcaplaec
kgsllddsag 301 kstedtaeys pfkggytkgl egeslgcsgs aaagssgtle
lpstlslyks galdeaaayq 361 srdyynfpla lagppppppp phpharikle
npldygsawa aaaaqcrygd laslhgagaa 421 gpgsgspsaa assswhtlft
aeegqlygpc gggggggggg gggggggggg gggeagavap 481 ygytrppqgl
agqesdftap dvwypggmvs rvpypsptcv ksemgpwmds ysgpygdmrn 541
trrkrlwkli irsinscics pretevpvrq qk ATPase H+ transporting
accessory protein 1 NP_001174.2 (SEQ ID NO: 185) 1 mmaamatarv
rmgprcaqal wrmpwlpvfl slaaaaaaaa aeqqvplvlw ssdrdlwapa 61
adtheghits dlqlstyldp alelgprnvl lflqdklsie dftayggvfg nkqdsafsnl
121 enaldlapss lvlpavdwya vstlttylqe klgasplhvd latlrelkln
aslpalllir 181 lpytassglm aprevltgnd evigqvlstl ksedvpytaa
ltavrpsrva rdvavvaggl 241 grqllqkqpv spvihppvsy ndtaprilfw
aqnfsvaykd qwedltpltf gvqelnltgs 301 fwndsfarls ltyerlfgtt
vtfkfilanr lypvsarhwf tmerlevhsn gsvayfnasq 361 vtgpsiysfh
ceyvsslskk gsllvartqp spwqmmlqdf qiqafnvmge qfsyasdcas 421
ffspgiwmgl ltslfmlfif tyglhmilsl ktmdrfddhk gptisltqiv B melanoma
antigen 1 precursor NP_001178.1 (SEQ ID NO: 186) 1 maaravflal
saqllqarlm keespvvswr lepedgtalc fif BCR/ABL fusion protein e14ab
NP_050673.1 (SEQ ID NO: 187) 1 gcacctgcag ggagggcagg cagctagcct
gaaggctgat ccccccttcc tgttagcact 61 tttgatggga ctagtggact
ttggttcaga aggaagagct atgcttgtta gggcctcttg 121 tctcctccca
ggagtggaca aggtgggtta ggagcagttt ctccctgagt ggctgctgct 181
gggtggttga ggagatgcac ggcttctgtt cctagtcaca aggctgcagc agacgctcct
241 cagatgctct gtgccttgga tctggcccca ctcccgtcct cccagccctc
ctctcctcca 301 gctacctgcc agccggcact tttggtcaag ctgttttgca
ttcactgttg cacatatgct 361 cagtcacaca cacagcatac gctatgcaca
tgtgtccaca cacaccccac ccacatccca 421 catcaccccg accccctctg
ctgtccttgg aaccttatta cacttcgagt cactggtttg 481 cctgtattgt
gaaaccagct ggatcctgag atccccaaga cagaaatcat gatgagtatg 541
tttttggccc atgacactgg cttaccttgt gccaggcaga tggcagccac acagtgtcca
601 ccggatggtt gattttgaag cagagttagc ttgtcacctg cctccctttc
ccgggacaac 661 agaagctgac ctctttgatc tcttgcgcag atgatgagtc
tccggggctc tatgggtttc 721 tgaatgtcat cgtccactca gccactggat
ttaagcagag ttcaagtaag tactggtttg 781 gggaggaggg ttgcagcggc
cgagccaggg tctccaccca ggaaggactc atcgggcagg 841 gtgtggggaa
acagggaggt tgttcagatg accacgggac acctttgacc ctggccgctg 901
tggagtgttt gtgctggttg atgccttctg ggtgtggaat tgtttttccc ggagtggcct
961 ctgccctctc ccctagcctg tctcagatcc tgggagctgg tgagctgccc
cctgcaggtg 1021 gatcgagtaa ttgcaggggt ttggcaagga ctttgacaga
catccccagg ggtgcccggg 1081 agtgtggggt ccaagccagg agggctgtca
gcagtgcacc ttcaccccac agcagagcag 1141 atttggctgc tctgtcgagc
tggatggata ctactttttt tttcctttcc ctctaagtgg 1201 gggtctcccc
cagctactgg agctgtcaga acagtgaagg ctggtaacac atgagttgca 1261
ctgtgtaagt ttctcgaggc cgggcgcagt ggctcatgcc tgtaatccca gcactttggg
1321 aggctgaggc aggtggatcg cttgagctca ggagttggag accagcctga
ccaacatggt 1381 gaaaccctgt gtctactaaa aatacaaaga ttagccgggc
taggcagtgg gcacctgtaa 1441 tcacaactgc ttgggaggct gagggaagag
aatcgcttga acccaggagg cggaggttgc 1501 agtgagccga gcttgtgcca
ctgcattcca gcctgggcga cagagcaaga ctccgcctca 1561 aaaaaaaaaa
aaaaaagttc ctagaaacag caaaatgtgg agacagaaag cttaccaggg 1621
attgttgggg aatggggttg ggagagagga ctaactgcag atgaacccaa gggggacttt
1681 ttaggtgaga gcagtgtcgt gaaaagactg tggtgctgtt tgcgctcaca
tttacatttc 1741 ctaaaattct ttaaacccta cacttggaat ggatgaatta
catgacatgc agattgcacc 1801 ttcataacat aatctttctc ctgggcccct
gtctctggct gcctcataaa cgctggtgtt 1861 tccctcgtgg gcctccctgc
atccctgcat ctcctcccgg gtcctgtctg tgagcaatac 1921 agcgtgacac
cctacgctgc cccgtggtcc cgggcttgtc tctccttgcc tccctgttac 1981
ctttctttct atctcttcct tgccccgtgc actcaacctt gcatccccaa accaaaccta
2041 ttattcatgg accccaaact tgttcctctt atgtcctgtc cctttgaggg
gcaccaccat 2101 ccacccgcat ggccaagcca gaaaccgtgg tctgctctcc
ctccgttaaa tgccattctc 2161 catcagtgag gcttcttagt catctctggc
tgcctggcca ggccctggct gtggcctcct 2221 ccctggtctt tgtagctctg
gatatccctg cagaaagggt ccccactacc aggcctctcc 2281 atccccagtc
tcaggtagtt tttctaaaat gcaaacccca ccctgcaact taccgcccac 2341
agcccagccc actcttctcc aggcctcgcc tccctccctt ccccctgcac cccacgactt
2401 ctccagcact gagctgcttc ctgtgcccca cagtggcctg gagtcccctt
tgccttaact 2461 ctttgcccca tagtacagcg gggtctgctc tgattgtagg
ggcttcccac atcccccagg 2521 atggctgccc tctgctgtgg catcactgtg
taacaatggc gtgtacacct ctctgtcccc 2581 accagtgcag ggcccttctc
atcgtagggg ctttagctgg ggtttgtgga tcgactgagt 2641 gaacgaatgt
tgtgggaagt cccgtttccc agccgcaccc agggaaattc cacagagcgg 2701
gcaggggcat cgcatgaggt gctggtgttc acgccagacc acaattaggt gtttaatttt
2761 taaaaagaaa gttacaacct ttttttttta tttttatttt ttctgattct
gcaaataaca 2821 cctgctctta cagaccatgt gggtgatgtg gaaaagacct
gtgaccttct ccatgtccac 2881 ttctccccac agatctgtac tgcaccctgg
aggtggattc ctttgggtat tttgtgaata 2941 aagcaaagac gcgcgtctac
agggacacag ctgagcca Serine/threonine-protein kinase B-raf, isoform
1 NP_004324.2 (SEQ ID NO: 188) 1 maalsggggg gaepgqalfn gdmepeagag
agaaassaad paipeevwni kqmikltqeh 61 iealldkfgg ehnppsiyle
ayeeytskld alqqreqqll eslgngtdfs vsssasmdtv 121 tsssssslsv
lpsslsvfqn ptdvarsnpk spqkpivrvf lpnkqrtvvp arcgvtvrds 181
lkkalmmrgl ipeccavyri qdgekkpigw dtdiswltge elhvevlenv pltthnfvrk
241 tfftlafcdf crkllfqgfr cqtcgykfhq rcstevplmc vnydqldllf
vskffehhpi 301 pqeeaslaet altsgsspsa pasdsigpqi ltspspsksi
pipqpfrpad edhrnqfgqr 361 drsssapnvh intiepvnid dlirdqgfrg
dggsttglsa tppaslpgsl tnvkalqksp 421 gpqrerksss ssedrnrmkt
lgrrdssddw eipdgqitvg qrigsgsfgt vykgkwhgdv 481 avkmlnvtap
tpqqlqafkn evgvlrktrh vnillfmgys tkpqlaivtg wcegsslyhh 541
lhiietkfem iklidiarqt aqgmdylhak siihrdlksn niflhedltv kigdfglatv
601 ksrwsgshqf eqlsgsilwm apevirmqdk npysfqsdvy afgivlyelm
tgqlpysnin 661 nrdqiifmvg rgylspdlsk vrsncpkamk rlmaeclkkk
rderplfpqi lasiellars 721 lpkihrsase pslnragfqt edfslyacas
pktpiqaggy gafpvh Serine/threonine-protein kinase B-raf, isoform 2
NP_001341538.1 (SEQ ID NO: 189) 1 maalsggggg gaepgqalfn gdmepeagag
agaaassaad paipeevwni kqmikltqeh 61 iealldkfgg ehnppsiyle
ayeeytskld alqqreqqll eslgngtdfs vsssasmdtv
121 tsssssslsv lpsslsvfqn ptdvarsnpk spqkpivrvf lpnkqrtvvp
arcgvtvrds 181 lkkalmmrgl ipeccavyri qdgekkpigw dtdiswltge
elhvevlenv pltthnfvrk 241 tfftlafcdf crkllfqgfr cqtcgykfhq
rcstevplmc vnydqldllf vskffehhpi 301 pqeeaslaet altsgsspsa
pasdsigpqi ltspspsksi pipqpfrpad edhrnqfgqr 361 drsssapnvh
intiepvnid dlirdqgfrg dggsttglsa tppaslpgsl tnvkalqksp 421
gpqrerksss ssedrnrmkt lgrrdssddw eipdgqitvg qrigsgsfgt vykgkwhgdv
481 avkmlnvtap tpqqlqafkn evgvlrktrh vnillfmgys tkpqlaivtq
wcegsslyhh 541 lhiietkfem iklidiarqt aqgmdylhak siihrdlksn
niflhedltv kigdfglatv 601 ksrwsgshqf eqlsgsilwm apevirmqdk
npysfqsdvy afgivlyelm tgqlpysnin 661 nrdqiifmvg rgylspdlsk
vrsncpkamk rlmaeclkkk rderplfpqi lasiellars 721 lpkihrsase
pslnragfqt edfslyacas pktpiqaggy gefaafk Carbonic anhydrase 9
precursor NP_001207.2 (SEQ ID NO: 190) 1 maplcpspwl pllipapapg
ltvqlllsll llvpvhpqrl prmqedsplg ggssgeddpl 61 geedlpseed
spreedppge edlpgeedlp geedlpevkp kseeegslkl edlptveapg 121
dpqepqnnah rdkegddqsh wryggdppwp rvspacagrf qspvdirpql aafcpalrpl
181 ellgfqlppl pelrlrnngh svqltlppgl emalgpgrey ralqlhlhwg
aagrpgseht 241 veghrfpaei hvvhlstafa rvdealgrpg glavlaafle
egpeensaye qllsrleeia 301 eegsetqvpg ldisallpsd fsryfqyegs
lttppcaqgv iwtvfnqtvm lsakqlhtls 361 dtlwgpgdsr lqlnfratqp
lngrvieasf pagvdsspra aepvqlnscl aagdilalvf 421 gllfavtsva
flvqmrrqhr rgtkggvsyr paevaetga G/mitotic-specific cyclin-B1,
isoform 1 NP_114172.1 (SEQ ID NO: 191) 1 malrvtrnsk inaenkakin
magakrvpta paatskpglr prtalgdign kvseqlqakm 61 pmkkeakpsa
tgkvidkklp kplekvpmlv pvpvsepvpe pepepepepv keeklspepi 121
lvdtaspspm etsgcapaee dlcqafsdvi lavndvdaed gadpnlcsey vkdiyaylrq
181 leeeqavrpk yllgrevtgn mrailidwlv qvqmkfrllq etmymtvsii
drfmqnncvp 241 kkmlqlvgvt amfiaskyee myppeigdfa fvtdntytkh
girqmemkil ralnfglgrp 301 lplhflrras kigevdveqh tlakylmelt
mldydmvhfp psqiaagafc lalkildnge 361 wtptlqhyls yteesllpvm
qhlaknvvmv nqgltkhmtv knkyatskha kistlpqlns 421 alvqdlakav akv
G/mitotic-specific cyclin-B1, isoform 2 NP_001341773.1 (SEQ ID NO:
192) 1 malrvtrnsk inaenkakin magakrvpta paatskpglr prtalgdign
kvseqlqakm 61 pmkkeakpsa tgkvidkklp kplekvpmlv pvpvsepvpe
pepepepepv keeklspepi 121 lvdtaspspm etsgcapaee dlcqafsdvi
lavndvdaed gadpnlcsey vkdiyaylrq 181 leeeqavrpk yllgrevtgn
mrailidwlv qvqmkfrllq etmymtvsii drfmqnncvp 241 kkmlqlvgvt
amfiaskyee myppeigdfa fvtdntytkh qirqmemkil ralnfglgrp 301
lplhflrras kigevdveqh tlakylmelt mldydmvhfp psqiaagafc lalkildnge
361 wtvknkyats khakistlpq lnsalvqdla kavakv G/mitotic-specific
cyclin-B1, isoform 3 NP_001341774.1 (SEQ ID NO: 193) 1 malrvtrnsk
inaenkakin magakrvpta paatskpglr prtalgdign kvseqlqakm 61
pmkkeakpsa tgkvidkklp kplekvpmlv pvpvsepvpe pepepepepv keeklspepi
121 lvdtaspspm etsgcapaee dlcqafsdvi lavndvdaed gadpnlcsey
vkdiyaylrq 181 lenncvpkkm lqlvgvtamf iaskyeemyp peigdfafvt
dntytkhqir qmemkilral 241 nfglgrplpl hflrraskig evdveqhtla
kylmeltmld ydmvhfppsq iaagafclal 301 kildngewtp tlqhylsyte
esllpvmghl aknvvmvnqg ltkhmtvknk yatskhakis 361 tlpqlnsalv
qdlakavakv CD276, isoform a precursor NP_001019907.1 (SEQ ID NO:
194) 1 mlrrrgspgm gvhvgaalga lwfcltgale vqvpedpvva lvgtdaticc
sfspepgfsl 61 aqlnliwqlt dtkqlvhsfa egqdqgsaya nrtalfpdll
aqgnaslrlq rvrvadegsf 121 tcfvsirdfg saayslqvaa pyskpsmtle
pnkdlrpgdt vtitcssyqg ypeaevfwqd 181 gqgvpltgnv ttsqmaneqg
lfdvhsilrv vlgangtysc lvrnpvlqqd ahssvtitpq 241 rsptgavevq
vpedpvvalv gtdatlrcsf spepgfslaq lnliwqltdt kqlvhsfteg 301
rdqgsayanr talfpdllaq gnaslrlqrv rvadegsftc fvsirdfgsa ayslqvaapy
361 skpsmtlepn kdlrpgdtvt itcssyrgyp eaevfwqdgq gvpltgnvtt
sqmaneqglf 421 dvhsvlrvvl gangtysclv rnpvlqqdah gsvtitgqpm
tfppealwvt vglsvclial 481 lvalafvcwr kikqsceeen agaedqdgeg
egsktalqpl khsdskeddg qeia CD276, isoform b precursor
NP_001316557.1, NP_079516.1 (SEQ ID NO: 195) 1 mlrrrgspgm
gvhvgaalga lwfcltgale vqvpedpvva lvgtdatlcc sfspepgfsl 61
aqlnliwqlt dtkqlvhsfa egqdqgsaya nrtalfpdll aqgnaslrlq rvrvadegsf
121 tcfvsirdfg saayslqvaa pyskpsmtle pnkdlrpgdt vtitcssyrg
ypeaevfwqd 181 gqgvpltgnv ttsqmaneqg lfdvhsvlrv vlgangtysc
lvrnpvlqqd ahgsvtitgq 241 pmtfppealw vtvglsvcli allvalafvc
wrkikqscee enagaedqdg egegsktalq 301 plkhsdsked dgqeia CD276,
isoform c NP_001316558.1 (SEQ ID NO: 196) 1 mtlepnkdlr pgdtvtitcs
syqgypeaev fwqdgqgvpl tgnvttsqma neqglfdvhs 61 ilrvvlgang
tysclvrnpv lqqdahssvt itpqrsptga vevqvpedpv valvgtdatl 121
rcsfspepgf slaqlnliwq ltdtkqlvhs ftegrdqgsa yanrtalfpd llaqgnaslr
181 lqrvrvadeg sftcfvsird fgsaayslqv aapyskpsmt lepnkdlrpg
dtvtitcssy 241 rgypeaevfw qdgqgvpltg nvttsqmane qglfdvhsvl
rvvlgangty sclvrnpvlq 301 qdahgsvtit gqpmtfppea lwvtvglsvc
liallvalaf vcwrkikqsc eeenagaedq 361 dgegegskta lqplkhsdsk eddgqeia
Carcinoembryonic antigen-related cell adhesion molecule 3, isoform
1 precursor NP_001806.2 (SEQ ID NO: 197) 1 mgppsasphr ecipwqglll
tasllnfwnp pttaklties mplsvaegke vlllvhnlpq 61 hlfgyswykg
ervdgnsliv gyvigtqqat pgaaysgret iytnaslliq nvtqndigfy 121
tlqviksdlv neeatgqfhv yqenapglpv gavagivtgv lvgvalvaal vcflllaktg
181 rtsiqrdlke qqpqalapgr gpshssafsm splstaqapl pnprtaasiy
eellkhdtni 241 ycrmdhkaev as Carcinoembryonic antigen-related cell
adhesion molecule 3, isoform 2 precursor NP_001264092.1 (SEQ ID NO:
198) 1 mgppsasphr ecipwqglll tasllnfwnp pttaklties mplsvaegke
vlllvhnlpq 61 hlfgyswykg ervdgnsliv gyvigtqqat pgaaysgret
iytnaslliq nvtqndigfy 121 tlqviksdlv neeatgqfhv yqenapglpv
gavagivtgv lvgvalvaal vcflllaktg 181 rpwslpqlcl ldvpslhcpg
pptqpqdssf hl Carcinoembryonic antigen-related cell adhesion
molecule 5, isoform 1 preprotein NP_001278413.1, NP_004354.3 (SEQ
ID NO: 199) 1 mespsapphr wcipwqrlll taslltfwnp pttaklties
tpfnvaegke vlllvhnlpq 61 hlfgyswykg ervdgnrqii gyvigtqqat
pgpaysgrei iypnaslliq niiqndtgfy 121 tlhviksdlv neeatgqfrv
ypelpkpsis snnskpvedk davaftcepe tqdatylwwv 181 nnqslpvspr
lqlsngnrtl tlfnvtrndt asykcetqnp vsarrsdsvi lnvlygpdap 241
tisplntsyr sgenlnlsch aasnppaqys wfvngtfqqs tqelfipnit vnnsgsytcq
301 ahnsdtglnr ttvttitvya eppkpfitsn nsnpvededa valtcepeiq
nttylwwvnn 361 qslpvsprlq lsndnrtltl lsvtrndvgp yecgiqnels
vdhsdpviln vlygpddpti 421 spsytyyrpg vnlslschaa snppaqyswl
idgniqghtq elfisnitek nsglytcqan 481 nsasghsrtt vktitvsael
pkpsissnns kpvedkdava ftcepeaqnt tylwwvngqs 541 lpvsprlqls
ngnrtltlfn vtrndarayv cgiqnsvsan rsdpvtldvl ygpdtpiisp 601
pdssylsgan lnlschsasn pspqyswrin gipqqhtqvl fiakitpnnn gtyacfvsnl
661 atgrnnsivk sitvsasgts pglsagatvg imigvlvgva li Carcinoembryonic
antigen-related cell adhesion molecule 5, isoform 2 preprotein
NP_001295327.1 (SEQ ID NO: 200) 1 mespsapphr wcipwqrlll taslltfwnp
pttaklties tpfnvaegke vlllvhnlpq 61 hlfgyswykg ervdgnrqii
gyvigtqqat pgpaysgrei iypnaslliq niiqndtgfy 121 tlhviksdlv
neeatgqfrv ypelpkpsis snnskpvedk davaftcepe tqdatylwwv 181
nnqslpvspr lqlsngnrtl tlfnvtrndt asykcetqnp vsarrsdsvi lnvlygpdap
241 tispintsyr sgenlnlsch aasnppaqys wfvngtfqqs tqelfipnit
vnnsgsytcq 301 ahnsdtglnr ttvttitvye ppkpfitsnn snpvededav
altcepeiqn ttylwwvnnq 361 slpvsprlql sndnrtltll svtrndvgpy
ecgiqnelsv dhsdpvilnv lygpddptis 421 psytyyrpgv nlslschaas
nppaqyswli dgniqqhtqe lfisnitekn sglytcqann 481 sasghsrttv
ktitvsaelp kpsissnnsk pvedkdavaf tcepeaqntt ylwwvngqsl 541
pvsprlqlsn gnrtltlfnv trndarayvc giqnsysanr sdpvtldvly gpdtpiispp
601 dssylsganl nlschsasnp spqyswring ipqqhtqvlf iakitpnnng
tyacfvsnla 661 tgrnnsivks itvsasgtsp glsagatvgi migvlvgval i
Baculoviral IAP repeat containing 2, isoform 1 NP_001157.1,
NP_001243092.1 (SEQ ID NO: 201) 1 mhktasqrlf pgpsyqniks imedstilsd
wtnsnkqkmk ydfscelyrm stystfpagv 61 pvserslara gfyytgvndk
vkcfccglml dnwklgdspi qkhkqlypsc sfiqnlvsas 121 lgstskntsp
mrnsfahsls ptlehsslfs gsysslspnp lnsravedis ssrtnpysya 181
msteearflt yhmwpltfls pselaragfy yigpgdrvac facggklsnw epkddamseh
241 rrhfpncpfl ensletlrfs isnlsmqtha armrtfmywp ssvpvqpeql
asagfyyvgr 301 nddvkcfccd gglrcwesgd dpwvehakwf prceflirmk
gqefvdeiqg ryphlleqll 361 stsdttgeen adppiihfgp gesssedavm
mntpvvksal emgfnrdlvk qtvqskiltt 421 genyktvndi vsallnaede
kreeekekqa eemasddlsl irknrmalfq qltcvlpild 481 nllkanvink
qehdiikqkt qiplqareli dtilvkgnaa anifknclke idstlyknlf 541
vdknmkyipt edvsglslee qlrrlqeert ckvcmdkevs vvfipcghlv vcqecapslr
601 kcpicrgiik gtvrtfls Baculoviral IAP repeat containing 2,
isoform 2 NP_001243095.1 (SEQ ID NO: 202) 1 mstystfpag vpvserslar
agfyytgvnd kvkcfccglm ldnwklgdsp iqkhkqlyps 61 csfiqnlvsa
slgstsknts pmrnsfahsl sptlehsslf sgsysslspn plnsravedi 121
sssrtnpysy amsteearfl tyhmwpltfl spselaragf yyigpgdrva cfacggklsn
181 wepkddamse hrrhfpncpf lensletlrf sisnlsmqth aarmrtfmyw
pssvpvqpeq 241 lasagfyyvg rnddvkcfcc dgglrcwesg ddpwvehakw
fprceflirm kgqefvdeiq 301 gryphlleql lstsdttgee nadppiihfg
pgesssedav mmntpvvksa lemgfnrdlv 361 kqtvqskilt tgenyktvnd
ivsallnaed ekreeekekq aeemasddls lirknrmalf 421 qqltcvlpil
dnllkanvin kqehdiikqk tqiplqarel idtilvkgna aanifknclk 481
eidstlyknl fvdknmkyip tedvsglsle eqlrrlqeer tckvcmdkev svvfipcghl
541 vvcqecapsl rkcpicrgii kgtvrtfls Chondrosarcoma-associated gene
2/3 protein, isoform X1 XP_006724920.1 (SEQ ID NO: 203) 1
mwmgliqlve gvkrkdqgfl ekefyhktni kmrceflacw paftvlgeaw rdqvdwsrll
61 rdtglvkmsr kprassplsn nhpptpkrrg sgrhpinpgp ealskfprqp
grekgpikev 121 pgtkgsp Chondrosarcoma-associated gene 2/3 protein,
isoform X2 XP_016885512.1 (SEQ ID NO: 204) 1 mwmgliqlve gvkrkdqgfl
ekefyhktni kmrceflacw paftvlgeaw rdqvdwsrll 61 rdtglvkmsr
kprassplsn nhpptpkrfp rqpgrekgpi kevpgtkgsp Chondroitin sulfate
proteoglycan 4 precursor NP_001888.2 (SEQ ID NO: 205) 1 mqsgprpplp
apglalaltl tmlarlasaa sffgenhlev pvataltdid lqlqfstsqp 61
eallllaagp adhlllqlys grlqvrlvlg qeelrlqtpa etllsdsiph tvvltvvegw
121 atlsvdgfln assavpgapl evpyglfvgg tgtlglpylr gtsrplrgcl
haatlngrsl 181 lrpltpdvhe gcaeefsasd dvalgfsgph slaafpawgt
qdegtleftl ttqsrqapla 241 fqaggrrgdf iyvdifeghl ravvekgqgt
vllhnsvpva dgqphevsvh inahrleisv 301 dqypthtsnr gvlsyleprg
slllggldae asrhlqehrl gltpeatnas llgcmedlsv 361 ngqrrglrea
lltrnmaagc rleeeeyedd ayghyeafst lapeawpame lpepcvpepg 421
lppvfanftq lltisplvva eggtawlewr hvqptldlme aelrksqvlf svtrgarhge
481 leldipgaqa rkmftlldvv nrkarfihdg sedtsdqlvl evsvtarvpm
psclrrgqty 541 llpiqvnpvn dpphiifphg slmvilehtq kplgpevfqa
ydpdsacegl tfqvlgtssg 601 lpverrdqpg epatefscre leagslvyvh
rggpaqdltf rvsdglqasp patlkvvair 661 paiqihrstg lrlaqgsamp
ilpanlsvet navgqdvsvl frvtgalqfg elqkqgaggv 721 egaewwatqa
fhqrdveqgr vrylstdpqh haydtvenla levqvgqeil snlsfpvtiq 781
ratvwmlrle plhtqntqqe tlttahleat leeagpsppt fhyevvqapr kgnlqlqgtr
841 lsdgqgftqd diqagrvtyg ataraseave dtfrfrvtap pyfsplytfp
ihiggdpdap 901 vltnvllvvp eggegvlsad hlfvkslnsa sylyevmerp
rhgrlawrgt qdkttmvtsf 961 tnedllrgrl vyqhddsett eddipfvatr
qgessgdmaw eevrgvfrva iqpvndhapv 1021 qtisrifhva rggrrllttd
dvafsdadsg fadaqlvltr kdllfgsiva vdeptrpiyr 1081 ftqedlrkrr
vlfvhsgadr gwiqlqvsdg qhqatallev qasepylrva ngsslvvpqg 1141
gqgtidtavl hldtnldirs gdevhyhvta gprwgqlvra gqpatafsqq dlldgavlys
1201 hngslsprdt mafsveagpv htdatlqvti alegplaplk lvrhkkiyvf
qgeaaeirrd 1261 qleaaqeavp padivfsvks ppsagylvmv srgaladepp
sldpvqsfsq eavdtgrvly 1321 lhsrpeawsd afsldvasgl gaplegvlve
levlpaaipl eaqnfsvpeg gsltlappll 1381 rvsgpyfptl lglslqvlep
pqhgalqked gpqartlsaf swrmveeqli ryvhdgsetl 1441 tdsfvlmana
semdrqshpv aftvtvlpvn dqppilttnt glqmwegata pipaealrst 1501
dgdsgsedlv ytieqpsngr vvlrgapgte vrsftqaqld gglvlfshrg tldggfrfrl
1561 sdgehtspgh ffrvtaqkqv llslkgsqtl tvcpgsvqpl ssqtlrasss
agtdpqllly 1621 rvvrgpqlgr lfhaqqdstg ealvnftqae vyagnilyeh
emppepfwea hdtlelqlss 1681 ppardvaatl avavsfeaac pqrpshlwkn
kglwvpegqr aritvaalda snllasvpsp 1741 qrsehdvlfq vtqfpsrgql
lvseeplhag qphflqsqla agqlvyahgg ggtqqdgfhf 1801 rahlqgpaga
svagpqtsea faitvrdvne rppqpqasvp lrltrgsrap israqlsvvd 1861
pdsapgeiey evqraphngf lslvggglgp vtrftqadvd sgrlafvang ssvagifqls
1921 msdgaspplp mslavdilps aievqlrapl evpqalgrss lsqqqlrvvs
dreepeaayr 1981 liqgpqyghl lvggrptsaf sqfqidqgev vfaftnfsss
hdhfrvlala rgvnasavvn 2041 vtvrallhvw aggpwpqgat lrldptvlda
gelanrtgsv prfrllegpr hgrvvrvpra 2101 rtepggsqlv eqftqqdled
grlglevgrp egrapgpagd sltlelwaqg vppavasldf 2161 atepynaarp
ysvallsvpe aarteagkpe sstptgepgp masspepava kggflsflea 2221
nmfsviipmc lvllllalil pllfylrkrn ktgkhdvqvl takprnglag dtetfrkvep
2281 gqaipltavp gqgpppggqp dpellqfcrt pnpalkngqy wv Cancer/testis
antigen 2 isoform LAGE-1a NP_758965.2 (SEQ ID NO: 206) 1 mqaegrgtgg
stgdadgpgg pgipdgpggn aggpgeagat ggrgprgaga arasgprgga 61
prgphggaas aqdgrcpcga rrpdsrllel hitmpfsspm eaelvrrils rdaaplprpg
121 avlkdftvsg nllfirltaa dhrqlqlsis sclqqlsllm witqcflpvf
laqapsgqrr Cancer/testis antigen 2 isoform LAGE-1b NP_066274.2 (SEQ
ID NO: 207) 1 mqaegrgtgg stgdadgpgg pgipdgpggn aggpgeagat
ggrgprgaga arasgprgga 61 prgphggaas aqdgrcpcga rrpdsrllel
hitmpfsspm eaelvrrils rdaaplprpg 121 avlkdftvsg nllfmsvrdq
dregagrmrv vgwglgsasp egqkardlrt pkhkvseqrp 181 gtpgppppeg
aqgdgcrgva fnvmfsaphi Transcriptional repressor CTCFL, isoform 1
NP_001255969.1, NP_001255970.1, NP_542185.2 (SEQ ID NO: 208) 1
maateisvls eqftkikele lmpekglkee ekdgvcrekd hrspseleae rtsgafqdsv
61 leeevelvla pseesekyil tlqtvhftse avelqdmsll siqqqegvqv
vvqqpgpgll 121 wleegprqsl qqcvaisiqq elyspqemev lqfhaleenv
mvasedskla vslaettgli 181 kleeeqeknq llaertkeql ffvetmsgde
rsdeivltvs nsnveeqedq ptagqadaek 241 akstknqrkt kgakgtfhcd
vcmftssrms sfnrhmktht sekphlchlc lktfrtvtll 301 rnhvnthtgt
rpykcndcnm afvtsgelvr hrrykhthek pfkcsmckya sveasklkrh 361
vrshtgerpf qccqcsyasr dtyklkrhmr thsgekpyec hichtrftqs gtmkihilqk
421 hgenvpkyqc phcatiiark sdlrvhmrnl haysaaelkc rycsavfher
yaliqhqkth 481 knekrfkckh csyackqerh mtahirthtg ekpftclscn
kcfrqkqlln ahfrkyhdan 541 fiptvykcsk cgkgfsrwin lhrhsekcgs
geaksaasgk grrtrkrkqt ilkeatkgqk 601 eaakgwkeaa ngdeaaaeea
sttkgeqfpg emfpvacret tarvkeevde gvtcemllnt 661 mdk Transcriptional
repressor CTCFL, isoform 2 NP_001255971.1 (SEQ ID NO: 209) 1
maateisvls eqftkikele lmpekglkee ekdgvcrekd hrspseleae rtsgafqdsv
61 leeevelvla pseesekyil tlqtvhftse avelqdmsll siqqqegvqv
vvqqpgpgll 121 wleegprqsl qqcvaisiqq elyspqemev lqfhaleenv
mvasedskla vslaettgli 181 kleeeqeknq llaertkeql ffvetmsgde
rsdeivltvs nsnveeqedq ptagqadaek 241 akstknqrkt kgakgtfhcd
vcmftssrms sfnrhmktht sekphlchlc lktfrtvtll 301 rnhvnthtgt
rpykcndcnm afvtsgelvr hrrykhthek pfkcsmckya sveasklkrh 361
vrshtgerpf qccqcsyasr dtyklkrhmr thsgekpyec hichtrftqs gtmkihilqk
421 hgenvpkyqc phcatiiark sdlrvhmrnl haysaaelkc rycsavfher
yaliqhqkth 481 knekrfkckh csyackqerh mtahirthtg ekpftclscn
kcfrqkqlln ahfrkyhdan 541 fiptvykcsk cgkgfsrwin lhrhsekcgs
geaksaasgk grrtrkrkqt ilkeatkgqk 601 eaakgwkeaa ngdaaaeeas
ttkgeqfpge mfpvacrett arvkeevdeg vtcemllntm 661 dk Transcriptional
repressor CTCFL, isoform 3 NP_001255972.1 (SEQ ID NO: 210) 1
maateisvls eqftkikele lmpekglkee ekdgvcrekd hrspseleae rtsgafqdsv
61 leeevelvla pseesekyil tlqtvhftse avelqdmsll siqqqegvqv
vvqqpgpgll
121 wleegprqsl qqcvaisiqq elyspqemev lqfhaleenv mvasedskla
vslaettgli 181 kleeeqeknq llaertkeql ffvetmsgde rsdeivltvs
nsnveeqedq ptagqadaek 241 akstknqrkt kgakgtfhcd vcmftssrms
sfnrhmktht sekphlchlc lktfrtvtll 301 rnhvnthtgt rpykcndcnm
afvtsgelvr hrrykhthek pfkcsmckya sveasklkrh 361 vrshtgerpf
qccqcsyasr dtyklkrhmr thsgekpyec hichtrftqs gtmkihilqk 421
hgenvpkyqc phcatiiark sdlrvhmrnl haysaaelkc rycsavfher yaliqhqkth
481 knekrfkckh csyackqerh mtahirthtg ekpftclscn kcfrqkqlln
ahfrkyhdan 541 fiptvykcsk cgkgfsrwin lhrhsekcgs geaksaasgk
grrtrkrkqt ilkeatkgqk 601 eaakgwkeaa ngdeaaaeea sttkgeqfpg
emfpvacret tarvkeevde gvtcemllnt 661 mdnsagctgr mmlvsawllg
rpqetynqgr rrrgsrrvtw Transcriptional repressor CTCFL, isoform 4
NP_001255973.1 (SEQ ID NO: 211) 1 maateisvls eqftkikele lmpekglkee
ekdgvcrekd hrspseleae rtsgafqdsv 61 leeevelvla pseesekyil
tlqtvhftse avelqdmsll siqqqegvqv vvqqpgpgll 121 wleegprqsl
qqcvaisiqq elyspqemev lqfhaleenv mvasedskla vslaettgli 181
kleeeqeknq llaertkeql ffvetmsgde rsdeivltvs nsnveeqedq ptagqadaek
241 akstknqrkt kgakgtfhcd vcmftssrms sfnrhmktht sekphlchlc
lktfrtvtll 301 rnhvnthtgt rpykcndcnm afvtsgelvr hrrykhthek
pfkcsmckya sveasklkrh 361 vrshtgerpf qccqcsyasr dtyklkrhmr
thsgekpyec hichtrftqs gtmkihilqk 421 hgenvpkyqc phcatiiark
sdlrvhmrnl haysaaelkc rycsavfher yaliqhqkth 481 knekrfkckh
csyackqerh mtahirthtg ekpftclscn kcfrqkqlln ahfrkyhdan 541
fiptvykcsk cgkgfsrwin lhrhsekcgs geaksaasgk grrtrkrkqt ilkeatkgqk
601 eaakgwkeaa ngdgvisahr nlcllgssds hasysgagit darhhawliv
llflvemgfy 661 hvshs Transcriptional repressor CTCFL, isoform 5
NP_001255974.1 (SEQ ID NO: 212) 1 maateisvls eqftkikele lmpekglkee
ekdgvcrekd hrspseleae rtsgafqdsv 61 leeevelvla pseesekyil
tlqtvhftse avelqdmsll siqqqegvqv vvqqpgpgll 121 wleegprqsl
qqcvaisiqq elyspqemev lqfhaleenv mvasedskla vslaettgli 181
kleeeqeknq llaertkeql ffvetmsgde rsdeivltvs nsnveeqedq ptagqadaek
241 akstknqrkt kgakgtfhcd vcmftssrms sfnrhmktht sekphlchlc
lktfrtvtll 301 rnhvnthtgt rpykcndcnm afvtsgelvr hrrykhthek
pfkcsmckya sveasklkrh 361 vrshtgerpf qccqcsyasr dtyklkrhmr
thsgekpyec hichtrftqs gtmkihilqk 421 hgenvpkyqc phcatiiark
sdlrvhmrnl haysaaelkc rycsavfher yaliqhqkth 481 knekrfkckh
csyackqerh mtahirthtg ekpftclscn kcfrqkqlln ahfrkyhdan 541
fiptvykcsk cgkgfsrwil wvgnsevael ggpgsgpllr lqsgcppglh hpkaglgped
601 plpgqlrhtt agtglssllq gplcraa Transcriptional repressor CTCFL,
isoform 6 NP_001255975.1 (SEQ ID NO: 213) 1 maateisvls eqftkikele
lmpekglkee ekdgvcrekd hrspseleae rtsgafqdsv 61 leeevelvla
pseesekyil tlqtvhftse avelqdmsll siqqqegvqv vvqqpgpgll 121
wleegprqsl qqcvaisiqq elyspqemev lqfhaleenv mvasedskla vslaettgli
181 kleeeqeknq llaertkeql ffvetmsgde rsdeivltvs nsnveeqedq
ptagqadaek 241 akstknqrkt kgakgtfhcd vcmftssrms sfnrhmktht
sekphlchlc lktfrtvtll 301 rnhvnthtgt rpykcndcnm afvtsgelvr
hrrykhthek pfkcsmckya sveasklkrh 361 vrshtgerpf qccqcsyasr
dtyklkrhmr thsgvhmrnl haysaaelkc rycsavfher 421 yaliqhqkth
knekrfkckh csyackqerh mtahirthtg ekpftclscn kcfrqkqlln 481
ahfrkyhdan fiptvykcsk cgkgfsrwin lhrhsekcgs geaksaasgk grrtrkrkqt
541 ilkeatkgqk eaakgwkeaa ngdeaaaeea sttkgeqfpg emfpvacret
tarvkeevde 601 gvtcemllnt mdk Transcriptional repressor CTCFL,
isoform 7 NP_001255976.1 (SEQ ID NO: 214) 1 maateisvls eqftkikele
lmpekglkee ekdgvcrekd hrspseleae rtsgafqdsv 61 leeevelvla
pseesekyil tlqtvhftse avelqdmsll siqqqegvqv vvqqpgpgll 121
wleegprqsl qqcvaisiqq elyspqemev lqfhaleenv mvasedskla vslaettgli
181 kleeeqeknq llaertkeql ffvetmsgde rsdeivltvs nsnveeqedq
ptagqadaek 241 akstknqrkt kgakgtfhcd vcmftssrms sfnrhmktht
sekphlchlc lktfrtvtll 301 rnhvnthtgt rpykcndcnm afvtsgelvr
hrrykhthek pfkcsmckya sveasklkrh 361 vrshtgerpf qccqcsyasr
dtyklkrhmr thsgekpyec hichtrftqs gtmkihilqk 421 hgenvpkyqc
phcatiiark sdlrvhmrnl haysaaelkc rycsavfher yaliqhqkth 481
knekrfkckh csyackqerh mtahirthtg ekpftclscn kcfrqkqlln ahfrkyhdan
541 fiptvykcsk cgkgfsrwit skwsglkpqt fit Transcriptional repressor
CTCFL, isoform 8 NP_001255977.1 (SEQ ID NO: 215) 1 maateisvls
eqftkikele lmpekglkee ekdgvcrekd hrspseleae rtsgafqdsv 61
leeevelvla pseesekyil tlqtvhftse avelqdmsll siqqqegvqv vvqqpgpgll
121 wleegprqsl qqcvaisiqq elyspqemev lqfhaleenv mvasedskla
vslaettgli 181 kleeeqeknq llaertkeql ffvetmsgde rsdeivltvs
nsnveeqedq ptagqadaek 241 akstknqrkt kgakgtfhcd vcmftssrms
sfnrhmktht sekphlchlc lktfrtvtll 301 rnhvnthtgt rpykcndcnm
afvtsgelvr hrrykhthek pfkcsmckya sveerhmtah 361 irthtgekpf
tclscnkcfr qkqllnahfr kyhdanfipt vykcskcgkg fsrwilwvgn 421
sevaelggpg sgpllrlqsg cppglhhpka glgpedplpg qlrhttagtg lssllqgplc
481 raa Transcriptional repressor CTCFL, isoform 9 NP_001255978.1
(SEQ ID NO: 216) 1 msgdersdei vltvsnsnve eqedqptagq adaekakstk
nqrktkgakg tfhcdvcmft 61 ssrmssfnrh mkthtsekph lchlclktfr
tvtllrnhvn thtgtrpykc ndcnmafvts 121 gelvrhrryk hthekpfkcs
mckyasveas klkrhvrsht gerpfqccqc syasrdtykl 181 krhmrthsge
kpyechicht rftqsgtmki hilqkhgenv pkyqcphcat iiarksdlrv 241
hmrnlhaysa aelkcrycsa vfheryaliq hqkthknekr fkckhcsyac kqerhmtahi
301 rthtgekpft clscnkcfrq kqllnahfrk yhdanfiptv ykcskcgkgf
srwinlhrhs 361 ekcgsgeaks aasgkgrrtr krkqtilkea tkgqkeaakg
wkeaangdgv isahrnlcll 421 gssdshasvs gagitdarhh awlivllflv
emgfyhvshs Transcriptional repressor CTCFL, isoform 10
NP_001255979.1 (SEQ ID NO: 217) 1 msgdersdei vltvsnsnve eqedqptagq
adaekakstk nqrktkgakg tfhcdvcmft 61 ssrmssfnrh mkthtsekph
lchlclktfr tvtllrnhvn thtgtrpykc ndcnmafvts 121 gelvrhrryk
hthekpfkcs mckyasveas klkrhvrsht gerpfqccqc syasrdtykl 181
krhmrthsge kpyechicht rftqsgtmki hilqkhgenv pkyqcphcat iiarksdlrv
241 hmrnlhaysa aelkcrycsa vfheryaliq hqkthknekr fkckhcsyac
kqerhmtahi 301 rthtgekpft clscnkcfrq kqllnahfrk yhdanfiptv
ykcskcgkgf srwilwvgns 361 evaelggpgs gpllrlqsgc ppglhhpkag
lgpedplpgq lrhttagtgl ssllqgplcr 421 aa Transcriptional repressor
CTCFL, isoform 11 NP_001255980.1, NP_001255981.1 (SEQ ID NO: 218) 1
maateisvls eqftkikele lmpekglkee ekdgvcrekd hrspseleae rtsgafqdsv
61 leeevelvla pseesekyil tlqtvhftse avelqdmsll siqqqegvqv
vvqqpgpgll 121 wleegprqsl qqcvaisiqq elyspqemev lqfhaleenv
mvasedskla vslaettgli 181 kleeeqeknq llaertkeql ffvetmsgde
rsdeivltvs nsnveeqedq ptagqadaek 241 akstknqrkt kgakgtfhcd
vcmftssrms sfnrhmktht sekphlchlc lktfrtvtll 301 rnhvnthtgt
rpykcndcnm afvtsgelvr hrrykhthek pfkcsmckya svevkpfldl 361
klhgilveaa vqvtpsvtns ricykqafyy sykiyagnnm hsll Transcriptional
repressor CTCFL, isoform 12 NP_001255983.1 (SEQ ID NO: 219) 1
mftssrmssf nrhmkthtse kphlchlclk tfrtvtllrn hvnthtgtrp ykcndcnmaf
61 vtsgelvrhr rykhthekpf kcsmckyasv easklkrhvr shtgerpfqc
cqcsyasrdt 121 yklkrhmrth sgekpyechi chtrftqsgt mkihilqkhg
envpkyqcph catiiarksd 181 lrvhmrnlha ysaaelkcry csavfherya
liqhqkthkn ekrfkckhcs yackqerhmt 241 ahirthtgek pftclscnkc
frqkqllnah frkyhdanfi ptvykcskcg kgfsrwinlh 301 rhsekcgsge
aksaasgkgr rtrkrkqtil keatkgqkea akgwkeaang dgvisahrnl 361
cllgssdsha sysgagitda rhhawlivll flvemgfyhv shs Transcriptional
repressor CTCFL, isoform 13 NP_001255984.1 (SEQ ID NO: 220) 1
mftssrmssf nrhmkthtse kphlchlclk tfrtvtllrn hvnthtgtrp ykcndcnmaf
61 vtsgelvrhr rykhthekpf kcsmckyasv easklkrhvr shtgerpfqc
cqcsyasrdt 121 yklkrhmrth sgekpyechi chtrftqsgt mkihilqkhg
envpkyqcph catiiarksd 181 lrvhmrnlha ysaaelkcry csavfherya
liqhqkthkn ekrfkckhcs yackqerhmt 241 ahirthtgek pftclscnkc
frqkqllnah frkyhdanfi ptvykcskcg kgfsrwvly Cytochrome P450 1B1
NP_000095.2 (SEQ ID NO: 221) 1 mgtslspndp wplnplsiqq ttlllllsvl
atvhvgqrll rqrrrqlrsa ppgpfawpli 61 gnaaavgqaa hlsfarlarr
ygdvfqirlg scpivvlnge raihqalvqq gsafadrpaf 121 asfrvvsggr
smafghyseh wkvqrraahs mmrnfftrqp rsrqvleghv lsearelval 181
lvrgsadgaf ldprpltvva vanvmsavcf gcryshddpe frellshnee fgrtvgagsl
241 vdvmpwlqyf pnpvrtvfre feqlnrnfsn fildkflrhc eslrpgaapr
dmmdafilsa 301 ekkaagdshg ggarldlenv patitdifga sqdtlstalq
wllllftryp dvqtrvqael 361 dqvvgrdrlp cmgdqpnlpy vlaflyeamr
fssfvpvtip hattantsvl gyhipkdtvv 421 fvnqwsvnhd plkwpnpenf
dparfldkdg linkdltsrv mifsvgkrrc igeelskmql 481 flfisilahq
cdfranpnep akmnfsyglt ikpksfkvnv tlresmelld savqnlqake 541 tcq
Epidermal growth factor receptor, isoform a precursor NP_005219.2
(SEQ ID NO: 222) 1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq
lgtfedhfls lqrmfnncev 61 vlgnleityv qrnydlsflk tiqevagyvl
ialntverip lenlqiirgn myyensyala 121 vlsnydankt glkelpmrnl
qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf 181 qnhlgscqkc
dpscpngscw gageencqkl tkiicaqqcs grcrgkspsd cchnqcaagc 241
tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv
301 vtdhgscvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls
inatnikhfk 361 nctsisgdlh ilpvafrgds fthtppldpq eldilktvke
itgflliqaw penrtdlhaf 421 enleiirgrt kqhgqfslav vslnitslgl
rslkeisdgd viisgnknlc yantinwkkl 481 fgtsgqktki isnrgensck
atgqvchalc spegcwgpep rdcvscrnvs rgrecvdkcn 541 llegeprefv
enseciqchp eclpqamnit ctgrgpdnci qcahyidgph cvktcpagvm 601
genntlvwky adaghvchlc hpnctygctg pglegcptng pkipsiatgm vgalllllvv
661 algiglfmrr rhivrkrtlr rllqerelve pltpsgeapn qallrilket
efkkikvlgs 721 gafgtvykgl wipegekvki pvaikelrea tspkankeil
deayvmasvd nphvcrllgi 781 cltstvqlit qlmpfgclld yvrehkdnig
sqyllnwcvq iakgmnyled rrlvhrdlaa 841 rnvlvktpqh vkitdfglak
llgaeekeyh aeggkvpikw malesilhri ythqsdvwsy 901 gvtvwelmtf
gskpydgipa seissilekg erlpqppict idvymimvkc wmidadsrpk 961
freliiefsk mardpqrylv iqgdermhlp sptdsnfyra lmdeedmddv vdadeylipq
1021 qgffsspsts rtpllsslsa tsnnstvaci drnglqscpi kedsflqrys
sdptgalted 1081 siddtflpvp eyinqsvpkr pagsvqnpvy hnqplnpaps
rdphyqdphs tavgnpeyln 1141 tvqptcvnst fdspahwaqk gshqisldnp
dyqqdffpke akpngifkgs taenaeylry 1201 apqssefiga Epidermal growth
factor receptor, isoform b precursor NP_958439.1 (SEQ ID NO: 223) 1
mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq lgtfedhfls lqrmfnncev
61 vlgnleityv qrnydlsflk tiqevagyvl ialntverip lenlqiirgn
myyensyala 121 vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve
siqwrdivss dflsnmsmdf 181 qnhlgscqkc dpscpngscw gageencqkl
tkiicaqqcs grcrgkspsd cchnqcaagc 241 tgpresdclv crkfrdeatc
kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv 301 vtdhgscvra
cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls inatnikhfk 361
nctsisgdlh ilpvafrgds fthtppldpq eldilktvke itgflliqaw penrtdlhaf
421 enleiirgrt kqhgqfslav vslnitslgl rslkeisdgd viisgnknlc
yantinwkkl 481 fgtsgqktki isnrgensck atgqvchalc spegcwgpep
rdcvscrnvs rgrecvdkcn 541 llegeprefv enseciqchp eclpqamnit
ctgrgpdnci qcahyidgph cvktcpagvm 601 genntlvwky adaghvchlc hpnctygs
Epidermal growth factor receptor, isoform c precursor NP_958440.1
(SEQ ID NO: 224) 1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq
lgtfedhfls lqrmfnncev 61 vlgnleityv qrnydlsflk tiqevagyvl
ialntverip lenlqiirgn myyensyala 121 vlsnydankt glkelpmrnl
qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf 181 qnhlgscqkc
dpscpngscw gageencqkl tkiicaqqcs grcrgkspsd cchnqcaagc 241
tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv
301 vtdhgscvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls
inatnikhfk 361 nctsisgdlh ilpvafrgds fthtppldpq eldilktvke itgls
Epidermal growth factor receptor, isoform d precursor NP_958441.1
(SEQ ID NO: 225) 1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq
lgtfedhfls lqrmfnncev 61 vlgnleityv qrnydlsflk tiqevagyvl
ialntverip lenlqiirgn myyensyala 121 vlsnydankt glkelpmrnl
qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf 181 qnhlgscqkc
dpscpngscw gageencqkl tkiicaqqcs grcrgkspsd cchnqcaagc 241
tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn pegkysfgat cvkkcprnyv
301 vtdhgscvra cgadsyemee dgvrkckkce gpcrkvcngi gigefkdsls
inatnikhfk 361 nctsisgdlh ilpvafrgds fthtppldpq eldilktvke
itgflliqaw penrtdlhaf 421 enleiirgrt kqhgqfslav vslnitslgl
rslkeisdgd viisgnknlc yantinwkkl 481 fgtsgqktki isnrgensck
atgqvchalc spegcwgpep rdcvscrnvs rgrecvdkcn 541 llegeprefv
enseciqchp eclpqamnit ctgrgpdnci qcahyidgph cvktcpagvm 601
genntlvwky adaghvchlc hpnctygpgn eslkamlfcl fklsscnqsn dgsyshqsgs
661 paaqesclgw ipsllpsefq lgwggcshlh awpsasviit assch Epidermal
growth factor receptor, isoform e precursor NP_001333826.1 (SEQ ID
NO: 226) 1 mrpsgtagaa llallaalcp asraleekkv cqgtsnkltq lgtfedhfls
lqrmfnncev 61 vlgnleityv qrnydlsflk tiqevagyvl ialntverip
lenlqiirgn myyensyala 121 vlsnydankt glkelpmrnl qgqkcdpscp
ngscwgagee ncqkltkiic aqqcsgrcrg 181 kspsdcchnq caagctgpre
sdclvcrkfr deatckdtcp plmlynptty qmdvnpegky 241 sfgatcvkkc
prnyvvtdhg scvracgads yemeedgvrk ckkcegpcrk vcngigigef 301
kdslsinatn ikhfknctsi sgdlhilpva frgdsfthtp pldpqeldil ktvkeitgfl
361 liqawpenrt dlhafenlei irgrtkqhgq fslavvslni tslglrslke
isdgdviisg 421 nknlcyanti nwkklfgtsg qktkiisnrg ensckatgqv
chalcspegc wgpeprdcvs 481 crnvsrgrec vdkcnllege prefvensec
iqchpeclpq amnitctgrg pdnciqcahy 541 idgphcvktc pagvmgennt
lvwkyadagh vchlchpnct ygctgpgleg cptngpkips 601 iatgmvgall
lllvvalgig lfmrrrhivr krtlrrllqe relvepltps geapnqallr 661
ilketefkki kvlgsgafgt vykglwipeg ekvkipvaik elreatspka nkeildeayv
721 masvdnphvc rllgicltst vqlitqlmpf gclldyvreh kdnigsqyll
nwcvqiakgm 781 nyledrrlvh rdlaarnvlv ktpqhvkitd fglakllgae
ekeyhaeggk vpikwmales 841 ilhriythqs dvwsygvtvw elmtfgskpy
dgipaseiss ilekgerlpq ppictidvym 901 imvkcwmida dsrpkfreli
iefskmardp qrylviqgde rmhlpsptds nfyralmdee 961 dmddvvdade
ylipqqgffs spstsrtpll sslsatsnns tvacidrngl qscpikedsf 1021
lqryssdptg altedsiddt flpvpgewlv wkqscsstss thsaaaslqc psqvlppasp
1081 egetvadlqt q Epidermal growth factor receptor, isoform f
precursor NP_001333827.1 (SEQ ID NO: 227) 1 mrpsgtagaa llallaalcp
asraleekkv cqgtsnkltq lgtfedhfls lqrmfnncev 61 vlgnleityv
qrnydlsflk tiqevagyvl ialntverip lenlqiirgn myyensyala 121
vlsnydankt glkelpmrnl qeilhgavrf snnpalcnve siqwrdivss dflsnmsmdf
181 qnhlgscqkc dpscpngscw gageencqkl tkiicaqqcs grcrgkspsd
cchnqcaagc 241 tgpresdclv crkfrdeatc kdtcpplmly npttyqmdvn
pegkysfgat cvkkcprnyv 301 vtdhgscvra cgadsyemee dgvrkckkce
gpcrkvcngi gigefkdsls inatnikhfk 361 nctsisgdlh ilpvafrgds
fthtppldpq eldilktvke itgflliqaw penrtdlhaf 421 enleiirgrt
kqhgqfslav vslnitslgl rslkeisdgd viisgnknlc yantinwkkl 481
fgtsgqktki isnrgensck atgqvchalc spegcwgpep rdcvscrnvs rgrecvdkcn
541 llegeprefv enseciqchp eclpqamnit ctgrgpdnci qcahyidgph
cvktcpagvm 601 genntivwky adaghvchlc hpnctygctg pglegcptng
pkipsiatgm vgalllllvv 661 algiglfmrr rhivrkrtlr rllqerelve
pltpsgeapn qallrilket efkkikvlgs 721 gafgtvykgl wipegekvki
pvaikelrea tspkankeil deayvmasvd nphvcrllgi 781 cltstvqlit
qlmpfgclld yvrehkdnig sqyllnwcvq iakgmnyled rrlvhrdlaa 841
rnvlvktpqh vkitdfglak llgaeekeyh aeggkvpikw malesilhri ythqsdvwsy
901 gvtvwelmtf gskpydgipa seissilekg erlpqppict idvymimvkc
wmidadsrpk
961 freliiefsk mardpqrylv iqgdermhlp sptdsnfyra lmdeedmddv
vdadeylipq 1021 qgffsspsts rtpllsslsa tsnnstvaci drnglqscpi
kedsflqrys sdptgalted 1081 siddtflpvp gewlvwkqsc sstssthsaa
aslqcpsqvl ppaspegetv adlqtq Epidermal growth factor receptor,
isoform g precursor NP_001333828.1 (SEQ ID NO: 228) 1 mrpsgtagaa
llallaalcp asraleekkv cqgtsnkltq lgtfedhfls lqrmfnncev 61
vlgnleityv qrnydlsflk tiqevagyvl ialntverip lenlqiirgn myyensyala
121 vlsnydankt glkelpmrnl qgqkcdpscp ngscwgagee ncqkltkiic
aqqcsgrcrg 181 kspsdcchnq caagctgpre sdclvcrkfr deatckdtcp
plmlynptty qmdvnpegky 241 sfgatcvkkc prnyvvtdhg scvracgads
yemeedgvrk ckkcegperk vcngigigef 301 kdslsinatn ikhfknctsi
sgdlhilpva frgdsfthtp pldpqeldil ktvkeitgfl 361 liqawpenrt
dlhafenlei irgrtkqhgq fslavvslni tslglrslke isdgdviisg 421
nknlcyanti nwkklfgtsg qktkiisnrg ensckatgqv chalcspegc wgpeprdcvs
481 crnvsrgrec vdkcnllege prefvensec iqchpeclpq amnitctgrg
pdnciqcahy 541 idgphcvktc pagvmgennt lvwkyadagh vchlchpnct
ygctgpgleg cptngpkips 601 iatgmvgall lllvvalgig lfmrrrhivr
krtlrrllqe relvepltps geapnqallr 661 ilketefkki kvlgsgafgt
vykglwipeg ekvkipvaik elreatspka nkeildeayv 721 masvdnphvc
rllgicltst vqlitqlmpf gclldyvreh kdnigsqyll nwcvqiakgm 781
nyledrrlvh rdlaarnvlv ktpqhvkitd fglakllgae ekeyhaeggk vpikwmales
841 ilhriythqs dvwsygvtvw elmtfgskpy dgipaseiss ilekgerlpq
ppictidvym 901 imvkcwmida dsrpkfreli iefskmardp qrylviqgde
rmhlpsptds nfyralmdee 961 dmddvvdade ylipqqgffs spstsrtpll
sslsatsnns tvacidrngl qscpikedsf 1021 lqryssdptg altedsiddt
flpvpeyinq svpkrpagsv qnpvyhnqpl npapsrdphy 1081 qdphstavgn
peylntvqpt cvnstfdspa hwaqkgshqi sldnpdyqqd ffpkeakpng 1141
ifkgstaena eylrvapqss efiga Epidermal growth factor receptor,
isoform h NP_001333829.1 (SEQ ID NO: 229) 1 mfnncevvlg nleityvqrn
ydlsflktiq evagyvlial ntveriplen lqiirgnmyy 61 ensyalavls
nydanktglk elpmrnlqei lhgavrfsnn palcnvesiq wrdivssdfl 121
snmsmdfqnh lgscqkcdps cpngscwgag eencqkltki icaqqcsgrc rgkspsdcch
181 nqcaagctgp resdclvcrk frdeatckdt cpplmlynpt tyqmdvnpeg
kysfgatcvk 241 kcprnyvvtd hgscvracga dsyemeedgv rkckkcegpc
rkvcngigig efkdslsina 301 tnikhfknct sisgdlhilp vafrgdsfth
tppldpqeld ilktvkeitg flliqawpen 361 rtdlhafenl eiirgrtkqh
gqfslavvsl nitslglrsl keisdgdvii sgnknlcyan 421 tinwkklfgt
sgqktkiisn rgensckatg qvchalcspe gcwgpeprdc vscrnvsrgr 481
ecvdkcnlle geprefvens eciqchpecl pqamnitctg rgpdnciqca hyidgphcvk
541 tcpagvmgen ntlvwkyada ghvchlchpn ctygctgpgl egcptngpki
psiatgmvga 601 lllllvvalg iglfmrrrhi vrkrtlrrll qerelveplt
psgeapnqal lrilketefk 661 kikvlgsgaf gtvykglwip egekvkipva
ikelreatsp kankeildea yvmasvdnph 721 vcrllgiclt stvqlitqlm
pfgclldyvr ehkdnigsqy llnwcvqiak gmnyledrrl 781 vhrdlaarnv
lvktpqhvki tdfglakllg aeekeyhaeg gkvpikwmal esilhriyth 841
qsdvwsygvt vwelmtfgsk pydgipasei ssilekgerl pqppictidv ymimvkcwmi
901 dadsrpkfre liiefskmar dpqrylviqg dermhlpspt dsnfyralmd
eedmddvvda 961 deylipqqgf fsspstsrtp llsslsatsn nstvacidrn
glqscpiked sflqryssdp 1021 tgaltedsid dtflpvpeyi nqsvpkrpag
svqnpvyhnq plnpapsrdp hyqdphstav 1081 gnpeylntvq ptcvnstfds
pahwaqkgsh qisldnpdyq qdffpkeakp ngifkgstae 1141 naeylrvapq ssefiga
Epidermal growth factor receptor, isoform i precursor
NP_001333870.1 (SEQ ID NO: 230) 1 mrpsgtagaa llallaalcp asraleekkg
nyvvtdhgsc vracgadsye meedgvrkck 61 kcegperkvc ngigigefkd
slsinatnik hfknctsisg dlhilpvafr gdsfthtppl 121 dpqeldilkt
vkeitgflli qawpenrtdl hafenleiir grtkqhgqfs lavvslnits 181
lglrslkeis dgdviisgnk nlcyantinw kklfgtsgqk tkiisnrgen sckatgqvch
241 alcspegcwg peprdcvscr nvsrgrecvd kcnllegepr efvenseciq
chpeclpqam 301 nitctgrgpd nciqcahyid gphcvktcpa gvmgenntlv
wkyadaghvc hlchpnctyg 361 ctgpglegcp tngpkipsia tgmvgallll
lvvalgiglf mrrrhivrkr tlrrllqere 421 lvepltpsge apnqallril
ketefkkikv lgsgafgtvy kglwipegek vkipvaikel 481 reatspkank
eildeayvma svdnphvcrl lgicltstvq litqlmpfgc lldyvrehkd 541
nigsqyllnw cvqiakgmny ledrrlvhrd laarnvlvkt pqhvkitdfg lakllgaeek
601 eyhaeggkvp ikwmalesil hriythqsdv wsygvtvwel mtfgskpydg
ipaseissil 661 ekgerlpqpp ictidvymim vkcwmidads rpkfreliie
fskmardpqr ylviqgderm 721 hlpsptdsnf yralmdeedm ddvvdadeyl
ipqqgffssp stsrtpllss lsatsnnstv 781 acidrnglqs cpikedsflq
ryssdptgal tedsiddtfl pvpeyingsv pkrpagsvqn 841 pvyhnqplnp
apsrdphyqd phstavgnpe ylntvqptcv nstfdspahw aqkgshqisl 901
dnpdyqqdff pkeakpngif kgstaenaey lrvapqssef iga Epithelial cell
adhesion molecule NP_002345.2 (SEQ ID NO: 231) 1 mappqvlafg
lllaaatatf aaaqeecvce nyklavncfv nnnrqcqcts vgaqntvics 61
klaakclvmk aemngsklgr rakpegalqn ndglydpdcd esglfkakqc ngtsmcwcvn
121 tagvrrtdkd teitcservr tywiiielkh karekpydsk slrtalqkei
ttryqldpkf 181 itsilyennv itidlvqnss qktqndvdia dvayyfekdv
kgeslfhskk mdltvngeql 241 dldpgqtliy yvdekapefs mqglkagvia
vivvvviavv agivvlvisr kkrmakyeka 301 eikemgemhr elna Ephrin type-A
receptor 2, isoform 1 precursor NP_004422.2 (SEQ ID NO: 232) 1
melqaaracf allwgcalaa aaaaqgkevv lldfaaagge lgwlthpygk gwdlmqnimn
61 dmpiymysvc nvmsgdqdnw lrtnwvyrge aerifielkf tvrdcnsfpg
gasscketfn 121 lyyaesdldy gtnfqkrlft kidtiapdei tvssdfearh
vklnveersv gpltrkgfyl 181 afqdigacva llsvrvyykk cpellqglah
fpetiagsda pslatvagtc vdhavvppgg 241 eeprmhcavd gewlvpigqc
lcqagyekve dacqacspgf fkfeasespc lecpehtlps 301 pegatscece
egffrapqdp asmpctrpps aphyltavgm gakvelrwtp pqdsggredi 361
vysvtceqcw pesgecgpce asvrysepph gltrtsvtvs dlephmnytf tvearngvsg
421 lvtsrsfrta sysinqtepp kvrlegrstt slsvswsipp pqqsrvwkye
vtyrkkgdsn 481 synvrrtegf svtlddlapd ttylvqvgal tqegqgagsk
vhefqtlspe gsgnlavigg 541 vavgvvlllv lagvgffihr rrknqrarqs
pedvyfskse qlkplktyvd phtyedpnqa 601 vlkftteihp scvtrqkvig
agefgevykg mlktssgkke vpvaiktlka gytekqrvdf 661 lgeagimgqf
shhniirleg viskykpmmi iteymengal dkflrekdge fsvlqlvgml 721
rgiaagmkyl anmnyvhrdl aarnilvnsn lvckvsdfgl srvleddpea tyttsggkip
781 irwtapeais yrkftsasdv wsfgivmwev mtygerpywe lsnhevmkai
ndgfrlptpm 841 dcpsaiyqlm mqcwqqerar rpkfadivsi ldklirapds
lktladfdpr vsirlpstsg 901 segvpfrtvs ewlesikmqq ytehfmaagy
taiekvvqmt nddikrigvr lpghqkriay 961 sllglkdqvn tvgipi Ephrin
type-A receptor 2, isoform 2 NP_001316019.1 (SEQ ID NO: 233) 1
mqnimndmpi ymysvcnvms gdqdnwlrtn wvyrgeaeri fielkftvrd cnsfpggass
61 cketfnlyya esdldygtnf qkrlftkidt iapdeitvss dfearhvkln
veersvgplt 121 rkgfylafqd igacvallsv rvyykkcpel lqglahfpet
iagsdapsla tvagtcvdha 181 vvppggeepr mhcavdgewl vpigqclcqa
gyekvedacq acspgffkfe asespclecp 241 ehtlpspega tsceceegff
rapqdpasmp ctrppsaphy ltavgmgakv elrwtppqds 301 ggredivysv
tceqcwpesg ecgpceasvr ysepphgltr tsvtvsdlep hmnytftvea 361
rngvsglvts rsfrtasysi nqteppkvrl egrsttslsv swsipppqqs rvwkyevtyr
421 kkgdsnsynv rrtegfsvtl ddlapdttyl vqvqaltqeg qgagskvhef
qtlspegsgn 481 laviggvavg vvlllvlagv gffihrrrkn qrarqspedv
yfskseqlkp lktyvdphty 541 edpnqavlkf tteihpscvt rqkvigagef
gevykgmlkt ssgkkevpva iktlkagyte 601 kqrvdflgea gimgqfshhn
iirlegvisk ykpmmiitey mengaldkfl rekdgefsvl 661 qlvgmlrgia
agmkylanmn yvhrdlaarn ilvnsnlvck vsdfglsrvl eddpeatytt 721
sggkipirwt apeaisyrkf tsasdvwsfg ivmwevmtyg erpywelsnh evmkaindgf
781 rlptpmdcps aiyqlmmqcw qgerarrpkf adivsildkl irapdslktl
adfdprvsir 841 lpstsgsegv pfrtvsewle sikmqqyteh fmaagytaie
kvvqmtnddi krigvrlpgh 901 qkriaysllg lkdqvntvgi pi
Receptor-tyrosine-protein kinase erbB-2, isoform a precursor
NP_004439.2 (SEQ ID NO: 234) 1 melaalcrwg lllallppga astqvctgtd
mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas lsflqdiqev
qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121 dpinnttpvt
gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla 181
ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp lptdccheqc
241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe smpnpegryt
fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr cekcskpcar
vcyglgmehl revravtsan 361 iqefagckki fgslaflpes fdgdpasnta
plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv irgrilhnga
ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481 pwdqlfrnph
qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec 541
veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy kdppfcvarc
601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk gcpaeqrasp
ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl lqetelvepl
tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi pdgenvkipv
aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl tstvqlvtql
mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841 lvhrdlaarn
vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft 901
hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid vymimvkcwm
961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl dstfyrslle
dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strsgggdlt
lglepseeea prsplapseg 1081 agsdvfdgdl gmgaakglqs lpthdpsplq
rysedptvpl psetdgyvap ltcspqpeyv 1141 nqpdvrpqpp spregplpaa
rpagatlerp ktlspgkngv vkdvfafgga venpeyltpq 1201 ggaapqphpp
pafspafdnl yywdqdpper gappstfkgt ptaenpeylg ldvpv
Receptor-tyrosine-protein kinase erbB-2, isoform b NP_001005862.1
(SEQ ID NO: 235) 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas
lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng
dpinnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk
difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc
aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241
lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr
301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes
fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv
irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv
pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn
csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe
adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601
thscvdlddk gcpaeqrasp ltsiisavvg illvvvlgvv fgilikrrqq kirkytmrrl
661 lqetelvepl tpsgampnqa qmrilketel rkvkvlgsga fgtvykgiwi
pdgenvkipv 721 aikvlrents pkankeilde ayvmagvgsp yvsrllgicl
tstvqlvtql mpygclldhv 781 renrgrlgsq dllnwcmqia kgmsyledvr
lvhrdlaarn vlvkspnhvk itdfglarll 841 dideteyhad ggkvpikwma
lesilrrrft hqsdvwsygv tvwelmtfga kpydgipare 901 ipdllekger
lpqppictid vymimvkcwm idsecrprfr elvsefsrma rdpqrfvviq 961
nedlgpaspl dstfyrslle dddmgdlvda eeylvpqqgf fcpdpapgag gmvhhrhrss
1021 strsgggdlt lglepseeea prsplapseg agsdvfdgdl gmgaakglqs
lpthdpsplq 1081 rysedptvpl psetdgyvap ltcspqpeyv nqpdvrpqpp
spregplpaa rpagatlerp 1141 ktlspgkngv vkdvfafgga venpeyltpq
ggaapqphpp pafspafdnl yywdqdpper 1201 gappstfkgt ptaenpeylg ldvpv
Receptor-tyrosine-protein kinase erbB-2, isoform c NP_001276865.1
(SEQ ID NO: 236) 1 mprgswkpqv ctgtdmklrl paspethldm lrhlyqgcqv
vqgnleltyl ptnaslsflq 61 diqevqgyvl iahnqvrqvp lqrlrivrgt
qlfednyala vldngdpinn ttpvtgaspg 121 glrelqlrsl teilkggvli
grnpqlcyqd tilwkdifhk nnqlaltlid tnrsrachpc 181 spmckgsrcw
gessedcqsl trtvcaggca rckgplptdc cheqcaagct gpkhsdclac 241
lhfnhsgice lhcpalvtyn tdtfesmpnp egrytfgasc vtacpynyls tdvgsctlvc
301 plhnqevtae dgtqrcekcs kpcarvcygl gmehlrevra vtsaniqefa
gckkifgsla 361 flpesfdgdp asntaplqpe qlqvfetlee itgylyisaw
pdslpdlsvf qnlqvirgri 421 lhngaysltl qglgiswlgl rslrelgsgl
alihhnthlc fvhtvpwdql frnphqallh 481 tanrpedecv geglachqlc
arghcwgpgp tqcvncsqfl rgqecveecr vlqglpreyv 541 narhclpchp
ecqpqngsvt cfgpeadqcv acahykdppf cvarcpsgvk pdlsympiwk 601
fpdeegacqp cpincthscv dlddkgcpae qraspltsii savvgillvv vlgvvfgili
661 krrqqkirky tmrrllqete lvepltpsga mpnqaqmril ketelrkvkv
lgsgafgtvy 721 kgiwipdgen vkipvaikvl rentspkank eildeayvma
gvgspyvsrl lgicltstvq 781 lvtqlmpygc lldhvrenrg rlgsqdllnw
cmqiakgmsy ledvrlvhrd laarnvlvks 841 pnhvkitdfg larlldidet
eyhadggkvp ikwmalesil rrrfthqsdv wsygvtvwel 901 mtfgakpydg
ipareipdll ekgerlpqpp ictidvymim vkcwmidsec rprfrelvse 961
fsrmardpqr fvviqnedlg paspldstfy rslledddmg dlvdaeeylv pqqgffcpdp
1021 apgaggmvhh rhrssstrsg ggdltlglep seeeaprspl apsegagsdv
fdgdlgmgaa 1081 kglqslpthd psplqrysed ptvplpsetd gyvapltcsp
qpeyvnqpdv rpqppspreg 1141 plpaarpaga tlerpktlsp gkngvvkdvf
afggavenpe yltpqggaap qphpppafsp 1201 afdnlyywdq dppergapps
tfkgtptaen peylgldvpv Receptor-tyrosine-protein kinase erbB-2,
isoform d NP_001276866.1 (SEQ ID NO: 237) 1 melaalcrwg lllallppga
astqvctgtd mklrlpaspe thldmlrhly qgcqvvqgnl 61 eltylptnas
lsflqdiqev qgyvliahnq vrqvplqrlr ivrgtqlfed nyalavldng 121
dpinnttpvt gaspgglrel qlrslteilk ggvliqrnpq lcyqdtilwk difhknnqla
181 ltlidtnrsr achpcspmck gsrcwgesse dcqsltrtvc aggcarckgp
lptdccheqc 241 aagctgpkhs dclaclhfnh sgicelhcpa lvtyntdtfe
smpnpegryt fgascvtacp 301 ynylstdvgs ctlvcplhnq evtaedgtqr
cekcskpcar vcyglgmehl revravtsan 361 iqefagckki fgslaflpes
fdgdpasnta plqpeqlqvf etleeitgyl yisawpdslp 421 dlsvfqnlqv
irgrilhnga ysltlqglgi swlglrslre lgsglalihh nthlcfvhtv 481
pwdqlfrnph qallhtanrp edecvgegla chqlcarghc wgpgptqcvn csqflrgqec
541 veecrvlqgl preyvnarhc lpchpecqpq ngsvtcfgpe adqcvacahy
kdppfcvarc 601 psgvkpdlsy mpiwkfpdee gacqpcpinc thscvdlddk
gcpaeqrasp ltsiisavvg 661 illvvvlgvv fgilikrrqq kirkytmrrl
lqetelvepl tpsgampnqa qmrilketel 721 rkvkvlgsga fgtvykgiwi
pdgenvkipv aikvlrents pkankeilde ayvmagvgsp 781 yvsrllgicl
tstvqlvtql mpygclldhv renrgrlgsq dllnwcmqia kgmsyledvr 841
lvhrdlaarn vlvkspnhvk itdfglarll dideteyhad ggkvpikwma lesilrrrft
901 hqsdvwsygv tvwelmtfga kpydgipare ipdllekger lpqppictid
vymimvkcwm 961 idsecrprfr elvsefsrma rdpqrfvviq nedlgpaspl
dstfyrslle dddmgdlvda 1021 eeylvpqqgf fcpdpapgag gmvhhrhrss strnm
Receptor-tyrosine-protein kinase erbB-2, isoform e NP_001276867.1
(SEQ ID NO: 238) 1 mklrlpaspe thldmlrhly qgcqvvqgnl eltylptnas
lsflqdiqev qgyvliahnq 61 vrqvplqrlr ivrgtqlfed nyalavldng
dpinnttpvt gaspgglrel qlrslteilk 121 ggvliqrnpq lcyqdtilwk
difhknnqla ltlidtnrsr achpcspmck gsrcwgesse 181 dcqsltrtvc
aggcarckgp lptdccheqc aagctgpkhs dclaclhfnh sgicelhcpa 241
lvtyntdtfe smpnpegryt fgascvtacp ynylstdvgs ctlvcplhnq evtaedgtqr
301 cekcskpcar vcyglgmehl revravtsan iqefagckki fgslaflpes
fdgdpasnta 361 plqpeqlqvf etleeitgyl yisawpdslp dlsvfqnlqv
irgrilhnga ysltlqglgi 421 swlglrslre lgsglalihh nthlcfvhtv
pwdqlfrnph qallhtanrp edecvgegla 481 chqlcarghc wgpgptqcvn
csqflrgqec veecrvlqgl preyvnarhc lpchpecqpq 541 ngsvtcfgpe
adqcvacahy kdppfcvarc psgvkpdlsy mpiwkfpdee gacqpcpinc 601 ths
Receptor tyrosine-protein kinase erbB-4, isoform JM-a/CVT-1
precursor NP_005226.1 (SEQ ID NO: 239) 1 mkpatglwvw vsllvaagtv
qpsdsqsvca gtenklssls dleqqyralr kyyencevvm 61 gnleitsieh
nrdlsflrsv revtgyvlva lnqfrylple nlriirgtkl yedryalaif 121
lnyrkdgnfg lqelglknit eilnggvyvd qnkflcyadt ihwqdivrnp wpsnltivst
181 ngssgcgrch ksctgrcwgp tenhcqtltr tvcaeqcdgr cygpyvsdcc
hrecaggcsg 241 pkdtdcfacm nfndsgacvt qcpqtfvynp ttfqlehnfn
akytygafcv kkcphnfvvd 301 ssscvracps skmeveengi kmckpctdic
pkacdgigtg slmsaqtvds snidkfinct 361 kingnliflv tgihgdpyna
ieaidpekln vfrtvreitg flniqswppn mtdfsvfsnl 421 vtiggrvlys
glsllilkqq gitslqfqsl keisagniyi tdnsnlcyyh tinwttlfst 481
inqrivirdn rkaenctaeg mvcnhlcssd gcwgpgpdqc lscrrfsrgr iciescnlyd
541 gefrefengs icvecdpqce kmedglltch gpgpdnctkc shfkdgpncv
ekcpdglqga 601 nsfifkyadp drechpchpn ctqgcngpts hdciyypwtg
hstlpqhart pliaagvigg 661 lfilvivglt favyvrrksi kkkralrrfl
etelvepltp sgtapnqaql rilketelkr 721 vkvlgsgafg tvykgiwvpe
getvkipvai kilnettgpk anvefmdeal imasmdhphl 781 vrllgvclsp
tiqlvtqlmp hgclleyvhe hkdnigsqll lnwcvqiakg mmyleerrlv 841
hrdlaarnvl vkspnhvkit dfglarlleg dekeynadgg kmpikwmale cihyrkfthq
901 sdvwsygvti welmtfggkp ydgiptreip dllekgerlp qppictidvy
mvmvkcwmid 961 adsrpkfkel aaefsrmard pqrylviqgd drmklpspnd
skffqnllde edledmmdae 1021 eylvpqafni pppiytsrar idsnrseigh
spppaytpms gnqfvyrdgg faaeqgvsvp 1081 yraptstipe apvaqgatae
ifddsccngt lrkpvaphvq edsstqrysa dptvfapers 1141 prgeldeegy
mtpmrdkpkq eylnpveenp fvsrrkngdl qaldnpeyhn asngppkaed
1201 eyvneplyln tfantlgkae ylknnilsmp ekakkafdnp dywnhslppr
stlqhpdylq 1261 eystkyfykq ngrirpivae npeylsefsl kpgtvlpppp
yrhrntvv Receptor tyrosine-protein kinase erbB-4, isoform
JM-a/CVT-2 precursor NP_001036064.1 (SEQ ID NO: 240) 1 mkpatglwvw
vsllvaagtv qpsdsqsvca gtenklssls dleqqyralr kyyencevvm 61
gnleitsieh nrdlsflrsv revtgyvlva lnqfrylple nlriirgtkl yedryalaif
121 lnyrkdgnfg lqelglknit eilnggvyvd qnkflcyadt ihwqdivrnp
wpsnltlvst 181 ngssgcgrch ksctgrcwgp tenhcqtltr tvcaeqcdgr
cygpyvsdcc hrecaggcsg 241 pkdtdcfacm nfndsgacvt qcpqtfvynp
ttfqlehnfn akytygafcv kkcphnfvvd 301 ssscvracps skmeveengi
kmckpctdic pkacdgigtg slmsaqtvds snidkfinct 361 kingnliflv
tgihgdpyna ieaidpekln vfrtvreitg flniqswppn mtdfsvfsnl 421
vtiggrvlys glsllilkqq gitslqfqsl keisagniyi tdnsnlcyyh tinwttlfst
481 inqrivirdn rkaenctaeg mvcnhlcssd gcwgpgpdqc lscrrfsrgr
iciescnlyd 541 gefrefengs icvecdpqce kmedglltch gpgpdnctkc
shfkdgpncv ekcpdglqga 601 nsfifkyadp drechpchpn ctqgcngpts
hdciyypwtg hstlpqhart pliaagvigg 661 lfilvivglt favyvrrksi
kkkralrrfl etelvepltp sgtapnqaql rilketelkr 721 vkvlgsgafg
tvykgiwvpe getvkipvai kilnettgpk anvefmdeal imasmdhphl 781
vrllgvclsp tiqlvtqlmp hgclleyvhe hkdnigsqll lnwcvqiakg mmyleerrlv
841 hrdlaarnvl vkspnhvkit dfglarlleg dekeynadgg kmpikwmale
cihyrkfthq 901 sdvwsygvti welmtfggkp ydgiptreip dllekgerlp
qppictidvy mvmvkcwmid 961 adsrpkfkel aaefsrmard pqrylviqgd
drmklpspnd skffqnllde edledmmdae 1021 eylvpqafni pppiytsrar
idsnrnqfvy rdggfaaeqg vsvpyrapts tipeapvaqg 1081 ataeifddsc
cngtlrkpva phvqedsstq rysadptvfa persprgeld eegymtpmrd 1141
kpkqeylnpv eenpfvsrrk ngdlqaldnp eyhnasngpp kaedeyvnep lylntfantl
1201 gkaeylknni lsmpekakka fdnpdywnhs lpprstlqhp dylqeystky
fykqngrirp 1261 ivaenpeyls efslkpgtvl ppppyrhrnt vv Prolyl
endopeptidase FAP, isoform 1 NP_004451.2 (SEQ ID NO: 241) 1
mktwvkivfg vatsavlall vmcivlrpsr vhnseentmr altlkdilng tfsyktffpn
61 wisgqeylhq sadnnivlyn ietgqsytil snrtmksvna snyglspdrq
fvylesdysk 121 lwrysytaty yiydlsngef vrgnelprpi qylcwspvgs
klayvyqnni ylkqrpgdpp 181 fqitfngren kifngipdwv yeeemlatky
alwwspngkf layaefndtd ipviaysyyg 241 deqyprtini pypkagaknp
vvrifiidtt ypayvgpqev pvpamiassd yyfswltwvt 301 dervclqwlk
rvqnvsvlsi cdfredwqtw dcpktqehie esrtgwaggf fvstpvfsyd 361
aisyykifsd kdgykhihyi kdtvenaiqi tsgkweaini frvtqdslfy ssnefeeypg
421 rrniyrisig syppskkcvt chlrkercqy ytasfsdyak yyalvcygpg
ipistlhdgr 481 tdqeikilee nkelenalkn iqlpkeeikk levdeitlwy
kmilppqfdr skkyplliqv 541 yggpcsqsvr svfavnwisy laskegmvia
lvdgrgtafq gdkllyavyr klgvyevedq 601 itavrkfiem gfidekriai
wgwsyggyvs slalasgtgl fkcgiavapv ssweyyasvy 661 terfmglptk
ddnlehykns tvmaraeyfr nvdyllihgt addnvhfqns aqiakalvna 721
qvdfqamwys dqnhglsgls tnhlythmth flkqcfslsd Prolyl endopeptidase
FAP, isoform 2 NP_001278736.1 (SEQ ID NO: 242) 1 mktwvkivfg
vatsavlall vmcivlrpsr vhnseentmr altlkdilng tfsyktffpn 61
wisgqeylhq sadnnivlyn ietgqsytil snrtmlwrys ytatyyiydl sngefvrgne
121 lprpiqylcw spvgsklayv yqnniylkqr pgdppfqitf ngrenkifng
ipdwvyeeem 181 latkyalwws pngkflayae fndtdipvia ysyygdeqyp
rtinipypka gaknpvvrif 241 iidttypayv gpqevpvpam iassdyyfsw
ltwvtdervc lqwlkrvqnv svlsicdfre 301 dwqtwdcpkt qehieesrtg
waggffvstp vfsydaisyy kifsdkdgyk hihyikdtve 361 naiqitsgkw
eainifrvtq dslfyssnef eeypgrrniy risigsypps kkcvtchlrk 421
ercqyytasf sdyakyyalv cygpgipist lhdgrtdqei kileenkele nalkniqlpk
481 eeikklevde itlwykmilp pqfdrskkyp lliqvyggpc sqsvrsvfav
nwisylaske 541 gmvialvdgr gtafqgdkll yavyrklgvy evedqitavr
kfiemgfide kriaiwgwsy 601 ggyvsslala sgtglfkcgi avapvsswey
yasvyterfm glptkddnle hyknstvmar 661 aeyfrnvdyl lihgtaddnv
hfqnsaqiak alvnaqvdfq amwysdqnhg lsglstnhly 721 thmthflkqc fslsd
Glutamate carboxypeptidase 2, isoform 1 NP_004467.1 (SEQ ID NO:
243) 1 mwnllhetds avatarrprw lcagalvlag gffllgflfg wfikssneat
nitpkhnmka 61 fldelkaeni kkflynftqi phlagteqnf qlakqiqsqw
kefgldsvel ahydvllsyp 121 nkthpnyisi inedgneifn tslfeppppg
yenvsdivpp fsafspqgmp egdlvyvnya 181 rtedffkler dmkincsgki
viarygkvfr gnkvknaqla gakgvilysd padyfapgvk 241 sypdgwnlpg
ggvqrgniln lngagdpltp gypaneyayr rgiaeavglp sipvhpigyy 301
daqkllekmg gsappdsswr gslkvpynvg pgftgnfstq kvkmhihstn evtriynvig
361 tlrgavepdr yvilgghrds wvfggidpqs gaavvheivr sfgtlkkegw
rprrtilfas 421 wdaeefgllg stewaeensr llqergvayi nadssiegny
tlrvdctplm yslvhnitke 481 lkspdegfeg kslyeswtkk spspefsgmp
risklgsgnd fevffqrlgi asgrarytkn 541 wetnkfsgyp lyhsvyetye
lvekfydpmf kyhltvaqvr ggmvfelans ivlpfdcrdy 601 avvlrkyadk
iysismkhpq emktysysfd slfsavknft eiaskfserl qdfdksnpiv 661
lrmmndqlmf lerafidplg lpdrpfyrhv iyapsshnky agesfpgiyd alfdieskvd
721 pskawgevkr qiyvaaftvq aaaetlseva Glutamate carboxypeptidase 2,
isoform 2 NP_001014986.1 (SEQ ID NO: 244) 1 mwnllhetds avatarrprw
lcagalvlag gffllgflfg wfikssneat nitpkhnmka 61 fldelkaeni
kkflynftqi phlagteqnf qlakqiqsqw kefgldsvel ahydvllsyp 121
nkthpnyisi inedgneifn tslfeppppg yenvsdivpp fsafspqgmp egdlvyvnya
181 rtedffkler dmkincsgki viarygkvfr gnkvknaqla gakgvilysd
padyfapgvk 241 sypdgwnlpg ggvqrgniln lngagdpltp gypaneyayr
rgiaeavglp sipvhpigyy 301 daqkllekmg gsappdsswr gslkvpynvg
pgftgnfstq kvkmhihstn evtriynvig 361 tlrgavepdr yvilgghrds
wvfggidpqs gaavvheivr sfgtlkkegw rprrtilfas 421 wdaeefgllg
stewaeensr llqergvayi nadssiegny tlrvdctplm yslvhnitke 481
lkspdegfeg kslyeswtkk spspefsgmp risklgsgnd fevffqrlgi asgrarytkn
541 wetnkfsgyp lyhsvyetye lvekfydpmf kyhltvaqvr ggmvfelans
ivlpfdcrdy 601 avvlrkyadk iysismkhpq emktysysfd slfsavknft
eiaskfserl qdfdkskhvi 661 yapsshnkya gesfpgiyda lfdieskvdp
skawgevkrq iyvaaftvqa aaetlseva Glutamate carboxypeptidase 2,
isoform 3 NP_001180400.1 (SEQ ID NO: 245) 1 mtagssyplf laayactgcl
aerlgwfiks sneatnitpk hnmkafldel kaenikkfly 61 nftqiphlag
teqnfqlakq iqsqwkefgl dsvelahydv llsypnkthp nyisiinedg 121
neifntslfe ppppgyenvs divppfsafs pqgmpegdlv yvnyartedf fklerdmkin
181 csgkiviary gkvfrgnkvk naqlagakgv ilysdpadyf apgvksypdg
wnlpgggvqr 241 gnilnlngag dpltpgypan eyayrrgiae avglpsipvh
pigyydaqkl lekmggsapp 301 dsswrgslkv pynvgpgftg nfstqkvkmh
ihstnevtri ynvigtlrga vepdryvilg 361 ghrdswvfgg idpqsgaavv
heivrsfgtl kkegwrprrt ilfaswdaee fgllgstewa 421 eensrllqer
gvayinadss iegnytlrvd ctplmyslvh nitkelkspd egfegkslye 481
swtkkspspe fsgmpriskl gsgndfevff qrlgiasgra rytknwetnk fsgyplyhsv
541 yetyelvekf ydpmfkyhlt vaqvrggmvf elansivlpf dcrdyavvlr
kyadkiysis 601 mkhpqemkty sysfdslfsa vknfteiask fserlqdfdk
snpivlrmmn dqlmfleraf 661 idplglpdrp fyrhviyaps shnkyagesf
pgiydalfdi eskvdpskaw gevkrqiyva 721 aftvqaaaet lseva Glutamate
carboxypeptidase 2, isoform 4 NP_001180401.1 (SEQ ID NO: 246) 1
mtagssyplf laayactgcl aerlgwfiks sneatnitpk hnmkafldel kaenikkfly
61 nftqiphlag teqnfqlakq iqsqwkefgl dsvelahydv llsypnkthp
nyisiinedg 121 neifntslfe ppppgyenvs divppfsafs pqgmpegdlv
yvnyartedf fklerdmkin 181 csgkiviary gkvfrgnkvk naqlagakgv
ilysdpadyf apgvksypdg wnlpgggvqr 241 gnilnlngag dpltpgypan
eyayrrgiae avglpsipvh pigyydaqkl lekmggsapp 301 dsswrgslkv
pynvgpgftg nfstqkvkmh ihstnevtri ynvigtlrga vepdryvilg 361
ghrdswvfgg idpqsgaavv heivrsfgtl kkegwrprrt ilfaswdaee fgllgstewa
421 eensrllqer gvayinadss iegnytlrvd ctplmyslvh nitkelkspd
egfegkslye 481 swtkkspspe fsgmpriskl gsgndfevff qrlgiasgra
rytknwetnk fsgyplyhsv 541 yetyelvekf ydpmfkyhlt vaqvrggmvf
elansivlpf dcrdyavvlr kyadkiysis 601 mkhpqemkty sysfdslfsa
vknfteiask fserlqdfdk skhviyapss hnkyagesfp 661 giydalfdie
skvdpskawg evkrqiyvaa ftvqaaaetl seva Glutamate carboxypeptidase 2,
isoform 5 NP_001180402.1 (SEQ ID NO: 247) 1 mggsappdss wrgslkvpyn
vgpgftgnfs tqkvkmhihs tnevtriynv igtlrgavep 61 dryvilgghr
dswvfggidp qsgaavvhei vrsfgtlkke gwrprrtilf aswdaeefgl 121
lgstewaeen srllqergva yinadssieg nytlrvdctp lmyslvhnit kelkspdegf
181 egkslyeswt kkspspefsg mprisklgsg ndfevffqrl giasgraryt
knwetnkfsg 241 yplyhsvyet yelvekfydp mfkyhltvaq vrggmvfela
nsivlpfdcr dyavvlrkya 301 dkiysismkh pqemktysvs fdslfsavkn
fteiaskfse rlqdfdksnp ivlrmmndql 361 mflerafidp lglpdrpfyr
hviyapsshn kyagesfpgi ydalfdiesk vdpskawgev 421 krqiyvaaft
vqaaaetlse va Glutamate carboxypeptidase 2, isoform 6
NP_001338165.1 (SEQ ID NO: 248) 1 mkafldelka enikkflynf tqiphlagte
qnfqlakqiq sqwkefglds velahydvll 61 sypnkthpny isiinedgne
ifntslfepp ppgyenvsdi vppfsafspq gmpegdlvyv 121 nyartedffk
lerdmkincs gkiviarygk vfrgnkvkna qlagakgvil ysdpadyfap 181
gvksypdgwn lpgggvqrgn ilnlngagdp ltpgypaney ayrrgiaeav glpsipvhpi
241 gyydaqklle kmggsappds swrgslkvpy nvgpgftgnf stqkvkmhih
stnevtriyn 301 vigtlrgave pdryvilggh rdswvfggid pqsgaavvhe
ivrsfgtlkk egwrprrtil 361 faswdaeefg llgstewaee nsrllqergv
ayinadssie gnytlrvdct plmyslvhnl 421 tkelkspdeg fegkslyesw
tkkspspefs gmprisklgs gndfevffqr lgiasgrary 481 tknwetnkfs
gyplyhsvye tyelvekfyd pmfkyhltva qvrggmvfel ansivlpfdc 541
rdyavvlrky adkiysismk hpqemktysv sfdslfsavk nfteiaskfs erlqdfdksk
601 hviyapsshn kyagesfpgi ydalfdiesk vdpskawgev krqiyvaaft
vqaaaetlse 661 va Fos-related antigen 1, isoform 1 NP_005429.1 (SEQ
ID NO: 249) 1 mfrdfgepgp ssgngggygg paqppaaaqa aqqkfhlvps
intmsgsqel qwmvqphflg 61 pssyprplty pqysppqprp gviralgppp
gvrrrpceqi speeeerrrv rrernklaaa 121 kcrnrrkelt dflqaetdkl
edeksglqre ieelqkqker lelvleahrp ickipegake 181 gdtgstsgts
sppapcrpvp cislspgpvl epealhtptl mttpsltpft pslvftypst 241
pepcasahrk sssssgdpss dplgsptlla l Fos-related antigen 1, isoform 2
NP_001287773.1 (SEQ ID NO: 250) 1 mfrdfgepgp ssgngggygg paqppaaaqa
aqqkfhlvps intmsgsqel qwmvqphflg 61 pssyprplty pqysppqprp
gviralgppp gvrrrpceqe tdkledeksg lqreieelqk 121 qkerlelvle
ahrpickipe gakegdtgst sgtssppapc rpvpcislsp gpvlepealh 181
tptlmttpsl tpftpslvft ypstpepcas ahrksssssg dpssdplgsp tllal
Fos-related antigen 1, isoform 3 NP_001287784.1 (SEQ ID NO: 251) 1
mfrdfgepgp ssgngggygg paqppaaaqa aqqkfhlvps intmsgsqel qwmvqphflg
61 pssyprplty pqysppqprp gviralgppp gvrrrpceqp ggrgappska
raeqagcgqv 121 gepeegtdrl paggd Fos-related antigen 1, isoform 4
NP_001287785.1 (SEQ ID NO: 252) 1 mfrdfgepgp ssgngggygg paqppaaaqa
aqqispeeee rrrvrrernk laaakcrnrr 61 keltdflqae tdkledeksg
lqreieelqk qkerlelvle ahrpickipe gakegdtgst 121 sgtssppapc
rpvpcislsp gpvlepealh tptlmttpsl tpftpslvft ypstpepcas 181
ahrksssssg dpssdplgsp tllal Fos-related antigen 1, isoform 5
NP_001287786.1 (SEQ ID NO: 253) 1 mfrdfgepgp ssgngggygg paqppaaaqa
aqqetdkled eksglqreie elqkqkerle 61 lvleahrpic kipegakegd
tgstsgtssp paperpvpci slspgpvlep ealhtptlmt 121 tpsltpftps
lvftypstpe pcasahrkss sssgdpssdp lgsptllal G antigen 1
NP_001035753.1 (SEQ ID NO: 254) 1 mswrgrstyy wprprryvqp pemigpmrpe
qfsdevepat peegepatqr qdpaaaqege 61 degasagqgp kpeadsqeqg
hpqtgceced gpdgqemdpp npeevktpee gegqsqc G antigen 12I NP_001465.1
(SEQ ID NO: 255) 1 mswrgrstyy wprprryvqp pemigpmrpe qfsdevepat
peegepatqr qdpaaaqege 61 degasagqgp kpeadsqeqg hpqtgceced
gpdgqemdpp npeevktpee gekqsqc Galectin-1 NP_002296.1 (SEQ ID NO:
256) 1 macglvasnl nlkpgeclrv rgevapdaks fvinlgkdsn nlclhfnprf
nahgdantiv 61 cnskdggawg teqreavfpf qpgsvaevci tfdqanltvk
lpdgyefkfp nrlnleainy 121 maadgdfkik cvafd Galectin-3 isoform 1
NP_002297.2 (SEQ ID NO: 257) 1 madnfslhda lsgsgnpnpq gwpgawgnqp
agaggypgas ypgaypgqap pgaypgqapp 61 gaypgapgay pgapapgvyp
gppsgpgayp ssgqpsatga ypatgpygap agplivpynl 121 plpggvvprm
litilgtvkp nanrialdfq rgndvafhfn prfnennrrv ivcntkldnn 181
wgreerqsvf pfesgkpfki qvlvepdhfk vavndahllq ynhrvkklne isklgisgdi
241 dltsasytmi Galectin-3, isoform 3 NP_001344607.1 (SEQ ID NO:
258) 1 mhsktpcgcf kpwkmadnfs lhdalsgsgn pnpqgwpgaw gnqpagaggy
pgasypgayp 61 gqappgaypg qappgaypga pgaypgapap gvypgppsgp
gaypssgqps atgaypatgp 121 ygapagpliv pynlplpggv vprmlitilg
tvkpnanria ldfqrgndva fhfnprfnen 181 nrrvivcntk ldnnwgreer
qsvfpfesgk pfkiqvlvep dhfkvavnda hllqynhrvk 241 klneisklgi
sgdidltsas ytmi Galectin-9 short NP_002299.2 (SEQ ID NO: 259) 1
mafsgsqapy lspavpfsgt iqgglqdglq itvngtvlss sgtrfavnfq tgfsgndiaf
61 hfnprfedgg yvvcntrqng swgpeerkth mpfqkgmpfd lcflvqssdf
kvmvngilfv 121 qyfhrvpfhr vdtisvngsv qlsyisfqpp gvwpanpapi
tqtvihtvqs apgqmfstpa 181 ippmmyphpa ypmpfittil gglypsksil
lsgtvlpsaq rfhinlcsgn hiafhlnprf 241 denavvrntq idnswgseer
slprkmpfvr gqsfsvwilc eahclkvavd gqhlfeyyhr 301 lrnlptinrl
evggdiqlth vqt Galectin-9 long NP_033665.1 (SEQ ID NO: 260) 1
mafsgsqapy lspavpfsgt iqgglqdglq itvngtvlss sgtrfavnfq tgfsgndiaf
61 hfnprfedgg yvvcntrqng swgpeerkth mpfqkgmpfd lcflvqssdf
kvmvngilfv 121 qyfhrvpfhr vdtisvngsv qlsyisfqnp rtvpvqpafs
tvpfsqpvcf pprprgrrqk 181 ppgvwpanpa pitqtvihtv qsapgqmfst
paippmmyph paypmpfitt ilgglypsks 241 illsgtvlps aqrfhinlcs
gnhiafhlnp rfdenavvrn tqidnswgse erslprkmpf 301 vrgqsfsvwi
lceahclkva vdgqhlfeyy hrlrnlptin rlevggdiql thvqt Galectin-9
isoform 3 NP_001317092.1 (SEQ ID NO: 261) 1 mafsgsqapy lspavpfsgt
iqgglqdglq itvngtvlss sgtrfavnfq tgfsgndiaf 61 hfnprfedgg
yvvcntrqng swgpeerkth mpfqkgmpfd lcflvqssdf kvmvngilfv 121
qyfhrvpfhr vdtisvngsv qlsyisfqpp gvwpanpapi tqtvihtvqs apgqmfstpa
181 ippmmyphpa ypmpfittil gglypsksil lsgtvlpsaq rcgscvklta
srwpwmvstc 241 lnttia Premelanosome protein, isoform 1 preprotein
NP_001186983.1 (SEQ ID NO: 262) 1 mdlvlkrcll hlavigalla vgatkvprnq
dwlgvsrqlr tkawnrqlyp ewteaqrldc 61 wrggqvslkv sndgptliga
nasfsialnf pgsqkvlpdg qviwvnntii ngsqvwggqp 121 vypqetddac
ifpdggpcps gswsqkrsfv yvwktwgqyw qvlggpvsgl sigtgramlg 181
thtmevtvyh rrgsrsyvpl ahsssaftit dqvpfsysvs qlraldggnk hflrnqpltf
241 alqlhdpsgy laeadlsytw dfgdssgtli sralvvthty lepgpvtaqv
vlqaaiplts 301 cgsspvpgtt dghrptaeap nttagqvptt evvgttpgqa
ptaepsgtts vqvpttevis 361 tapvqmptae stgmtpekvp vsevmgttla
emstpeatgm tpaevsivvl sgttaaqvtt 421 tewvettare lpipepegpd
assimstesi tgslgplldg tatlrlvkrq vpldcvlyry 481 gsfsvtldiv
qgiesaeilq avpsgegdaf eltvscqggl pkeacmeiss pgcqppaqrl 541
cqpvlpspac qlvlhqilkg gsgtyclnvs ladtnslavv stqlimpvpg illtgqeagl
601 gqvplivgil lvlmavvlas liyrrrlmkq dfsvpqlphs sshwlrlpri
fcscpigens 661 pllsgqqv Premelanosome protein, isoform 2 precursor
NP_001186982.1 (SEQ ID NO: 263) 1 mdlvlkrcll hlavigalla vgatkgsqvw
ggqpvypqet ddacifpdgg pcpsgswsqk 61 rsfvyvwktw gqywqvlggp
vsglsigtgr amlgthtmev tvyhrrgsrs yvplahsssa 121 ftitdqvpfs
vsysqlrald ggnkhflrnq pltfalqlhd psgylaeadl sytwdfgdss 181
gtlisralvv thtylepgpv taqvvlqaai pltscgsspv pgttdghrpt aeapnttagq
241 vpttevvgtt pgqaptaeps gttsvqvptt evistapvqm ptaestgmtp
ekvpvsevmg 301 ttlaemstpe atgmtpaevs ivvlsgttaa qvtttewvet
tarelpipep egpdassims 361 tesitgslgp lldgtatlrl vkrqvpldcv
lyrygsfsvt ldivqgiesa eilqavpsge 421 gdafeltvsc qgglpkeacm
eisspgcqpp aqrlcqpvlp spacqlvlhq ilkggsgtyc 481 lnvsladtns
lavvstqlim pgqeaglgqv plivgillvl mavvlasliy rrrlmkqdfs 541
vpqlphsssh wlrlprifcs cpigenspll sgqqv Premelanosome protein,
isoform 3 preprotein NP_008859.1 (SEQ ID NO: 264) 1 mdlvlkrcll
hlavigalla vgatkvprnq dwlgvsrqlr tkawnrqlyp ewteaqrldc 61
wrggqvslkv sndgptliga nasfsialnf pgsqkvlpdg qviwvnntii ngsqvwggqp
121 vypqetddac ifpdggpcps gswsqkrsfv yvwktwgqyw qvlggpvsgl
sigtgramlg
181 thtmevtvyh rrgsrsyvpl ahsssaftit dqvpfsvsvs qlraldggnk
hflrnqpltf 241 alqlhdpsgy laeadlsytw dfgdssgtli sralvvthty
lepgpvtaqv vlqaaiplts 301 cgsspvpgtt dghrptaeap nttagqvptt
evvgttpgqa ptaepsgtts vqvpttevis 361 tapvqmptae stgmtpekvp
vsevmgttla emstpeatgm tpaevsivvl sgttaaqvtt 421 tewvettare
lpipepegpd assimstesi tgslgplldg tatlrlvkrq vpldcvlyry 481
gsfsvtldiv qgiesaeilq avpsgegdaf eltvscqggl pkeacmeiss pgcqppaqrl
541 cqpvlpspac qlvlhqilkg gsgtyclnvs ladtnslavv stqlimpgqe
aglgqvpliv 601 gillvlmavv lasliyrrrl mkqdfsvpql phssshwlrl
prifcscpig enspllsgqq 661 v Premelanosome protein, isoform 4
preprotein NP_001307050.1 (SEQ ID NO: 265) 1 mdlvlkrcll hlavigalla
vgatkvprnq dwlgvsrqlr tkawnrqlyp ewteaqrldc 61 wrggqvslkv
sndgptliga nasfsialnf pgsqkvlpdg qviwvnntii ngsqvwggqp 121
vypqetddac ifpdggpcps gswsqkrsfv yvwktwgqyw qvlggpvsgl sigtgramlg
181 thtmevtvyh rrgsrsyvpl ahsssaftit dqvpfsvsvs qlraldggnk
hflrnqpltf 241 alqlhdpsgy laeadlsytw dfgdssgtli sralvvthty
lepgpvtaqv vlqaaiplts 301 cgsspvpgtt dghrptaeap nttagqvptt
evvgttpgqa ptaepsgtts vqvpttevis 361 tapvqmptae staaqvttte
wvettarelp ipepegpdas simstesitg slgplldgta 421 tlrlvkrqvp
ldcvlyrygs fsvtldivqg iesaeilqav psgegdafel tvscqgglpk 481
eacmeisspg cqppaqrlcq pvlpspacql vlhqilkggs gtyclnvsla dtnslavvst
541 qlimpvpgil ltgqeaglgq vplivgillv lmavvlasli yrrrlmkqdf
svpqlphsss 601 hwlrlprifc scpigenspl lsgqqv Premelanosome protein,
isoform 5 preprotein NP_001307051.1 (SEQ ID NO: 266) 1 mdlvlkrcll
hlavigalla vgatkvprnq dwlgvsrqlr tkawnrqlyp ewteaqrldc 61
wrggqvslkv sndgptliga nasfsialnf pgsqkvlpdg qviwvnntii ngsqvwggqp
121 vypqetddac ifpdggpcps gswsqkrsfv yvwktwgqyw qvlggpvsgl
sigtgramlg 181 thtmevtvyh rrgsrsyvpl ahsssaftit dqvpfsvsvs
qlraldggnk hflrnqpltf 241 alqlhdpsgy laeadlsytw dfgdssgtli
sralvvthty lepgpvtaqv vlqaaiplts 301 cgsspvpgtt dghrptaeap
nttagqvptt evvgttpgqa ptaepsgtts vqvpttevis 361 tapvqmptae
staaqvttte wvettarelp ipepegpdas simstesitg slgplldgta 421
tlrlvkrqvp ldcvlyrygs fsvtldivqg iesaeilqav psgegdafel tvscqgglpk
481 eacmeisspg cqppaqrlcq pvlpspacql vlhqilkggs gtyclnvsla
dtnslavvst 541 qlimpgqeag lgqvplivgi llvlmavvla sliyrrrlmk
qdfsvpqlph ssshwlrlpr 601 ifcscpigen spllsgqqv Glutamate receptor
ionotropic,NMDA 2A, isoform 1 precursor NP_000824.1, NP_001127879.1
(SEQ ID NO: 267) 1 mgrvgywtll vlpallvwrg papsaaaekg ppalniavml
ghshdvtere lrtlwgpeqa 61 aglpldvnvv allmnrtdpk slithvcdlm
sgarihglvf gddtdqeava qmldfissht 121 fvpilgihgg asmimadkdp
tstffqfgas iqqqatvmlk imqdydwhvf slvttifpgy 181 refisfvktt
vdnsfvgwdm qnvitldtsf edaktqvglk kihssvilly cskdeavlil 241
searslgltg ydffwivpsl vsgntelipk efpsglisvs yddwdyslea rvrdgigilt
301 taassmlekf syipeakasc ygqmerpevp mhtlhpfmvn vtwdgkdlsf
teegyqvhpr 361 lvvivinkdr ewekvgkwen htlslrhavw pryksfsdce
pddnhlsivt leeapfvive 421 didpltetcv rntvpcrkfv kinnstnegm
nvkkcckgfc idilkklsrt vkftydlylv 481 tngkhgkkvn nvwngmigev
vyqravmavg sltineerse vvdfsvpfve tgisvmvsrs 541 ngtvspsafl
epfsasvwvm mfvmllivsa iavfvfeyfs pvgynrnlak gkaphgpsft 601
igkaiwllwg lvfnnsvpvq npkgttskim vsvwaffavi flasytanla afmiqeefvd
661 qvtglsdkkf qrphdysppf rfgtvpngst ernirnnypy mhqymtkfnq
kgvedalvsl 721 ktgkldafiy daavinykag rdegcklvti gsgyifattg
ygialqkgsp wkrqidlall 781 qfvgdgemee letlwltgic hneknevmss
qldidnmagv fymlaaamal slitfiwehl 841 fywklrfcft gvcsdrpgll
fsisrgiysc ihgvhieekk kspdfnitgs qsnmlkllrs 901 aknissmsnm
nssrmdspkr aadfiqrgsl imdmvsdkgn lmysdnrsfq gkesifgdnm 961
nelqtfvanr qkdnlnnyvf qgqhpltlne snpntvevav steskansrp rqlwkksvds
1021 irqdslsqnp vsqrdeatae nrthslkspr ylpeemahsd isetsnratc
hrepdnsknh 1081 ktkdnfkrsv askypkdcse vertylktks ssprdkiyti
dgekepgfhl dppqfvenvt 1141 lpenvdfpdp yqdpsenfrk gdstlpmnrn
plhneeglsn ndqyklyskh ftlkdkgsph 1201 setseryrqn sthcrsclsn
mptysghftm rspfkcdacl rmgnlydide dqmlqetgnp 1261 atgeqvyqqd
waqnnalqlq knklrisrqh sydnivdkpr eldlsrpsrs islkdrerll 1321
egnfygslfs vpssklsgkk sslfpqgled skrsksllpd htsdnpflhs hrddqrlvig
1381 rcpsdpykhs lpsqavndsy lrsslrstas ycsrdsrghn dvyisehvmp
yaanknnmys 1441 tprvlnscsn rrvykkmpsi esdv Glutamate receptor
ionotropic,NMDA 2A, isoform 2 precursor NP_001127880.1 (SEQ ID NO:
268) 1 mgrvgywtll vlpallvwrg papsaaaekg ppalniavml ghshdvtere
lrtlwgpeqa 61 aglpldvnvv allmnrtdpk slithvcdlm sgarihglvf
gddtdqeava qmldfissht 121 fvpilgihgg asmimadkdp tstffqfgas
iqqqatvmlk imqdydwhvf slvttifpgy 181 refisfvktt vdnsfvgwdm
qnvitldtsf edaktqvqlk kihssvilly cskdeavlil 241 searslgltg
ydffwivpsl vsgntelipk efpsglisvs yddwdyslea rvrdgigilt 301
taassmlekf syipeakasc ygqmerpevp mhtlhpfmvn vtwdgkdlsf teegyqvhpr
361 lvvivlnkdr ewekvgkwen htlslrhavw pryksfsdce pddnhlsivt
leeapfvive 421 didpltetcv rntvpcrkfv kinnstnegm nvkkcckgfc
idilkklsrt vkftydlylv 481 tngkhgkkvn nvwngmigev vyqravmavg
sltineerse vvdfsvpfve tgisvmvsrs 541 ngtvspsafl epfsasvwvm
mfvmllivsa iavfvfeyfs pvgynrnlak gkaphgpsft 601 igkaiwllwg
lvfnnsvpvg npkgttskim vsvwaffavi flasytanla afmiqeefvd 661
qvtglsdkkf qrphdysppf rfgtvpngst ernirnnypy mhqymtkfnq kgvedalvsl
721 ktgkldafiy daavlnykag rdegcklvti gsgyifattg ygialqkgsp
wkrqidlall 781 qfvgdgemee letlwltgic hneknevmss qldidnmagv
fymlaaamal slitfiwehl 841 fywklrfcft gvcsdrpgll fsisrgiysc
ihgvhieekk kspdfnltgs qsnmlkllrs 901 aknissmsnm nssrmdspkr
aadfiqrgsl imdmvsdkgn lmysdnrsfq gkesifgdnm 961 nelqtfvanr
qkdnlnnyvf qgqhpltlne snpntvevav steskansrp rqlwkksvds 1021
irqdslsqnp vsqrdeatae nrthslkspr ylpeemahsd isetsnratc hrepdnsknh
1081 ktkdnfkrsv askypkdcse vertylktks ssprdkiyti dgekepgfhl
dppqfvenvt 1141 lpenvdfpdp yqdpsenfrk gdstlpmnrn plhneeglsn
ndqyklyskh ftlkdkgsph 1201 setseryrqn sthcrsclsn mptysghftm
rspfkcdacl rmgnlydide dgmlqetgmt 1261 nawllgdapr tltntrchpr r
Metabotropic glutamate receptor 3 precursor NP_000831.2 (SEQ ID NO:
269) 1 mkmltrlqvl tlalfskgfl lslgdhnflr reikiegdlv lgglfpinek
gtgteecgri 61 nedrgiqrle amlfaidein kddyllpgvk lgvhildtcs
rdtyaleqsl efvrasltkv 121 deaeymcpdg syaiqenipl liagviggsy
ssysiqvanl lrlfqipgis yastsaklsd 181 ksrydyfart vppdfyqaka
maeilrffnw tyvstvaseg dygetgieaf eqearlrnic 241 iataekvgrs
nirksydsvi rellqkpnar vvvlfmrsdd sreliaaasr anasftwvas 301
dgwgaqesii kgsehvayga itlelasqpv rqfdryfqsl npynnhrnpw frdfweqkfq
361 cslqnkrnhr rvcdkhlaid ssnyeqeski mfvvnavyam ahalhkmqrt
lcpnttklcd 421 amkildgkkl ykdyllkinf tapfnpnkda dsivkfdtfg
dgmgrynvfn fqnvggkysy 481 lkvghwaetl sldvnsihws rnsvptsqcs
dpcapnemkn mqpgdvccwi cipcepyeyl 541 adeftcmdcg sgqwptadlt
gcydlpedyi rwedawaigp vtiaclgfmc tcmvvtvfik 601 hnntplvkas
grelcyillf gvglsycmtf ffiakpspvi calrrlglgs sfaicysall 661
tktnciarif dgvkngaqrp kfispssqvf iclglilvqi vmvsvwlile apgtrrytla
721 ekretvilkc nvkdssmlis ltydvilvil ctvyafktrk cpenfneakf
igftmyttci 781 iwlaflpify vtssdyrvqt ttmcisysls gfvvlgclfa
pkvhiilfqp qknvvthrlh 841 lnrfsvsgtg ttysqssast yvptvcngre
vldsttssl HPV E6 concoprotein, NP_041325.1 (SEQ ID NO: 270) 1
mhqkrtamfq dpqerprklp qlctelqtti hdiilecvyc kqqllrrevy dfafrdlciv
61 yrdgnpyavc dkclkfyski seyrhycysl ygttleqqyn kplcdllirc
incqkplcpe 121 ekqrhldkkq rfhnirgrwt grcmsccrss rtrretql HPV E7
Oncoprotein, NP_041326.1 (SEQ ID NO: 271) 1 mhgdtptlhe ymldlqpett
dlycyeqlnd sseeedeidg pagqaepdra hynivtfcck 61 cdstlrlcvq
sthvdirtle dllmgtlgiv cpicsqkp GTPase HRas, isoform 1
NP_001123914.1, NP_005334.1 (SEQ ID NO: 272) 1 mteyklvvvg
aggvgksalt iqliqnhfvd eydptiedsy rkqvvidget clldildtag 61
qeeysamrdq ymrtgegflc vfainntksf edihqyreqi krvkdsddvp mvlvgnkcdl
121 aartvesrqa qdlarsygip yietsaktrq gvedafytlv reirqhklrk
lnppdesgpg 181 cmsckcvls GTPase HRas, isoform 3 NP_001304983.1 (SEQ
ID NO: 273) 1 mtcpwcwwgt svtwlhalwn lgrlrtspea tasptsrprp
rpgraaalal apapgpsgtp 61 rdpcdpaapr agvedafytl vreirqhklr
klnppdesgp gcmsckcvls GTPase HRas, isoform 2 NP_789765.1 (SEQ ID
NO: 274) 1 mteyklvvvg aggvgksalt iqliqnhfvd eydptiedsy rkqvvidget
clldildtag 61 qeeysamrdq ymrtgegflc vfainntksf edihqyreqi
krvkdsddvp mvlvgnkcdl 121 aartvesrqa qdlarsygip yietsaktrq
gsrsgsssss gtlwdppgpm Vascular endothelial growth factor receptor 2
precursor NP_002244.1 (SEQ ID NO: 275) 1 mqskvllava lwlcvetraa
svglpsvsld lprlsiqkdi ltikanttlq itcrgqrdld 61 wlwpnnqsgs
eqrvevtecs dglfcktlti pkvigndtga ykcfyretdl asviyvyvqd 121
yrspfiasvs dqhgvvyite nknktvvipc lgsisnlnvs lcarypekrf vpdgnriswd
181 skkgftipsy misyagmvfc eakindesyq simyivvvvg yriydvvlsp
shgielsvge 241 klvinctart elnvgidfnw eypsskhqhk klvnrdlktq
sgsemkkfls tltidgvtrs 301 dqglytcaas sglmtkknst fvrvhekpfv
afgsgmeslv eatvgervri pakylgyppp 361 eikwykngip lesnhtikag
hvltimevse rdtgnytvil tnpiskekqs hvvslvvyvp 421 pqigekslis
pvdsyqygtt qtltctvyai ppphhihwyw qleeecanep sqavsvtnpy 481
pceewrsved fqggnkievn knqfaliegk nktvstiviq aanvsalykc eavnkvgrge
541 rvisfhvtrg peitlqpdmq pteqesvslw ctadrstfen ltwyklgpqp
lpihvgelpt 601 pvcknldtlw klnatmfsns tndilimelk naslqdqgdy
vclaqdrktk krhcvvrqlt 661 vlervaptit gnlenqttsi gesievscta
sgnpppqimw fkdnetlved sgivlkdgnr 721 nitirrvrke deglytcqac
svlgcakvea ffiiegaqek tnleiiilvg taviamffwl 781 llviilrtvk
ranggelktg ylsivmdpde lpldehcerl pydaskwefp rdrlklgkpl 841
grgafgqvie adafgidkta tcrtvavkml kegathsehr almselkili highhlnvvn
901 llgactkpgg plmvivefck fgnlstylrs krnefvpykt kgarfrqgkd
yvgaipvdlk 961 rrldsitssq ssassgfvee kslsdveeee apedlykdfl
tlehlicysf qvakgmefla 1021 srkcihrdla arnillsekn vvkicdfgla
rdiykdpdyv rkgdarlplk wmapetifdr 1081 vytiqsdvws fgvllweifs
lgaspypgvk ideefcrrlk egtrmrapdy ttpemyqtml 1141 dcwhgepsqr
ptfselvehl gnllqanaqq dgkdyivlpi setlsmeeds glslptspvs 1201
cmeeeevcdp kfhydntagi sqylqnskrk srpvsvktfe dipleepevk vipddnqtds
1261 gmvlaseelk tledrtklsp sfggmvpsks resvasegsn qtsgyqsgyh
sddtdttvys 1321 seeaellkli eigvqtgsta qilqpdsgtt lssppv Mast/stem
cell growth acor receptor KIT, isoform 1 precursor NP_000213.1 (SEQ
ID NO: 276) 1 mrgargawdf lcvlllllrv qtgssqpsys pgepsppsih
pgksdlivrv gdeirllctd 61 pgfvkwtfei ldetnenkqn ewitekaeat
ntgkytctnk hglsnsiyvf vrdpaklflv 121 drslygkedn dtlvrcpltd
pevtnyslkg cqgkplpkdl rfipdpkagi miksvkrayh 181 rlclhcsvdq
egksvlsekf ilkvrpafka vpvvsyskas yllregeeft vtctikdvss 241
svystwkren sqtklqekyn swhhgdfnye rqatltissa rvndsgvfmc yanntfgsan
301 vtttlevvdk gfinifpmin ttvfvndgen vdliveyeaf pkpehqqwiy
mnrtftdkwe 361 dypksenesn iryvselhlt rlkgteggty tflvsnsdvn
aaiafnvyvn tkpeiltydr 421 lvngmlqcva agfpeptidw yfcpgteqrc
sasvlpvdvq tlnssgppfg klvvqssids 481 safkhngtve ckayndvgkt
sayfnfafkg nnkeqihpht lftplligfv ivagmmciiv 541 miltykylqk
pmyevqwkvv eeingnnyvy idptqlpydh kwefprnrls fgktlgagaf 601
gkvveatayg liksdaamtv avkmlkpsah lterealmse lkvlsylgnh mnivnllgac
661 tiggptlvit eyccygdlln flrrkrdsfi cskqedhaea alyknllhsk
esscsdstne 721 ymdmkpgvsy vvptkadkrr svrigsyier dvtpaimedd
elaldledll sfsyqvakgm 781 aflaskncih rdlaarnill thgritkicd
fglardiknd snyvvkgnar lpvkwmapes 841 ifncvytfes dvwsygiflw
elfslgsspy pgmpvdskfy kmikegfrml spehapaemy 901 dimktcwdad
plkrptfkqi vqliekqise stnhiysnla ncspnrqkpv vdhsvrinsv 961
gstasssqpl lvhddv Mast/stem cell growth acor receptor KIT, isoform
2 precursor NP_001087241.1 (SEQ ID NO: 277) 1 mrgargawdf lcvlllllrv
qtgssqpsys pgepsppsih pgksdlivrv gdeirllctd 61 pgfvkwtfei
ldetnenkqn ewitekaeat ntgkytctnk hglsnsiyvf vrdpaklflv 121
drslygkedn dtlvrcpltd pevtnyslkg cqgkplpkdl rfipdpkagi miksvkrayh
181 rlclhcsvdq egksvlsekf ilkvrpafka vpvvsvskas yllregeeft
vtctikdvss 241 svystwkren sqtklqekyn swhhgdfnye rqatltissa
rvndsgvfmc yanntfgsan 301 vtttlevvdk gfinifpmin ttvfvndgen
vdliveyeaf pkpehqqwiy mnrtftdkwe 361 dypksenesn iryvselhlt
rlkgteggty tflvsnsdvn aaiafnvyvn tkpeiltydr 421 lvngmlqcva
agfpeptidw yfcpgteqrc sasvlpvdvq tlnssgppfg klvvqssids 481
safkhngtve ckayndvgkt sayfnfafke qihphtlftp lligfvivag mmciivmilt
541 ykylqkpmye vqwkvveein gnnyvyidpt qlpydhkwef prnrlsfgkt
lgagafgkvv 601 eataygliks daamtvavkm lkpsahlter ealmselkvl
sylgnhmniv nllgactigg 661 ptiviteycc ygdllnflrr krdsficskq
edhaeaalyk nllhskessc sdstneymdm 721 kpgvsyvvpt kadkrrsvri
gsyierdvtp aimeddelal dledllsfsy qvakgmafla 781 skncihrdla
arnillthgr itkicdfgla rdikndsnyv vkgnarlpvk wmapesifnc 841
vytfesdvws ygiflwelfs lgsspypgmp vdskfykmik egfrmlspeh apaemydimk
901 tcwdadplkr ptfkqivqli ekqisestnh iysnlancsp nrqkpvvdhs
vrinsvgsta 961 sssqpllvhd dv Plasma kallikrein isoform 1 preprotein
NP_001639.1 (SEQ ID NO: 278) 1 mwvpvvfltl svtwigaapl ilsrivggwe
cekhsqpwqv lvasrgravc ggvlvhpqwv 61 ltaahcirnk svillgrhsl
fhpedtgqvf qvshsfphpl ydmsllknrf lrpgddsshd 121 lmllrlsepa
eltdavkvmd lptqepalgt tcyasgwgsi epeefltpkk lqcvdlhvis 181
ndvcaqvhpq kvtkfmlcag rwtggkstcs gdsggplvcn gvlqgitswg sepcalperp
241 slytkvvhyr kwikdtivan p Plasma kallikrein isoform 3 preprotein
NP_001025218.1 (SEQ ID NO: 279) 1 mwvpvvfltl svtwigaapl ilsrivggwe
cekhsqpwqv lvasrgravc ggvlvhpqwv 61 ltaahcirnk svillgrhsl
fhpedtgqvf qvshsfphpl ydmsllknrf lrpgddsshd 121 lmllrlsepa
eltdavkvmd lptqepalgt tcyasgwgsi epeefltpkk lqcvdlhvis 181
ndvcaqvhpq kvtkfmlcag rwtggkstcs wviliteltm palpmvlhgs lvpwrggv
Plasma kallikrein isoform 4 preprotein NP_001025219.1 (SEQ ID NO:
280) 1 mwvpvvfltl svtwigaapl ilsrivggwe cekhsqpwqv lvasrgravc
ggvlvhpqwv 61 ltaahcirkp gddsshdlml lrlsepaelt davkvmdlpt
qepalgttcy asgwgsiepe 121 efltpkklqc vdlhvisndv caqvhpqkvt
kfmlcagrwt ggkstcsgds ggplvcngvl 181 qgitswgsep calperpsly
tkvvhyrkwi kdtivanp Tyrosine-protein kinase LCK, isoform a
NP_001036236.1, NP_005347.3 (SEQ ID NO: 281) 1 mgcgcsshpe
ddwmenidvc enchypivpl dgkgtllirn gsevrdplvt yegsnppasp 61
lqdnlvialh syepshdgdl gfekgeqlri leqsgewwka qslttgqegf ipfnfvakan
121 slepepwffk nlsrkdaerq llapgnthgs fliresesta gsfslsvrdf
dqnqgevvkh 181 ykirnldngg fyispritfp glhelvrhyt nasdglctrl
srpcqtqkpq kpwwedewev 241 pretlklver lgagqfgevw mgyynghtkv
avkslkqgsm spdaflaean lmkqlqhqrl 301 vrlyavvtqe piyiiteyme
ngslvdflkt psgikltink lldmaaqiae gmafieerny 361 ihrdlraani
lvsdtlscki adfglarlie dneytarega kfpikwtape ainygtftik 421
sdvwsfgill teivthgrip ypgmtnpevi qnlergyrmv rpdncpeely qlmrlcwker
481 pedrptfdyl rsvledffta tegqyqpqp Tyrosine-protein kinase LCK,
isoform b NP_001317397.1 (SEQ ID NO: 282) 1 mgcgcsshpe ddwmenidvc
enchypivpl dgkgtllirn gsevrdplvt yegsnppasp 61 lqdnlvialh
syepshdgdl gfekgeqlri leqsgewwka qslttgqegf ipfnfvakan 121
slepepwffk nlsrkdaerq llapgnthgs fliresesta gsfslsvrdf dqnqgevvkh
181 ykirnldngg fyispritfp glhelvrhyt ryynghtkva vkslkqgsms
pdaflaeanl 241 mkqlqhqrlv rlyavvtqep iyiiteymen gslvdflktp
sgikltinkl ldmaaqiaeg 301 mafieernyi hrdlraanil vsdtlsckia
dfglarlied neytaregak fpikwtapea 361 inygtftiks dvwsfgillt
eivthgripy pgmtnpeviq nlergyrmvr pdncpeelyq 421 lmrlcwkerp
edrptfdylr svledfftat egqyqpqp Legumain preprotein NP_001008530.1,
NP_005597.3 (SEQ ID NO: 283) 1 mvwkvavfls valgigavpi ddpedggkhw
vvivagsngw ynyrhqadac hayqiihrng 61 ipdeqivvmm yddiaysedn
ptpgivinrp ngtdvyqgvp kdytgedvtp qnflavlrgd 121 aeavkgigsg
kvlksgpqdh vfiyftdhgs tgilvfpned lhvkdlneti hymykhkmyr 181
kmvfyieace sgsmmnhlpd ninvyattaa npressyacy ydekrstylg dwysvnwmed
241 sdvedltket lhkqyhlvks htntshvmqy gnktistmkv mqfqgmkrka
sspvplppvt 301 hldltpspdv pltimkrklm ntndleesrq lteeiqrhld
arhlieksvr kivsllaase 361 aeveqllser apltghscyp eallhfrthc
fnwhsptyey alrhlyvlvn lcekpyplhr
421 iklsmdhvol ghy Macrophage migration inhibitory factor
NP_002406.1 (SEQ ID NO: 284) 1 mpmfivntnv prasvpdgfl seltqqlaqa
tgkppqyiav hvvpdqlmaf ggssepcalc 61 slhsigkigg aqnrsyskll
cgllaerlri spdrvyinyy dmnaanvgwn nstfa MAGE family member A1
NP_004979.3 (SEQ ID NO: 285) 1 msleqrslhc kpeealeaqq ealglvcvqa
atssssplvl gtleevptag stdppqspqg 61 asafpttinf trqrqpsegs
ssreeegpst scileslfra vitkkvadlv gflllkyrar 121 epvtkaemle
sviknykhcf peifgkases lqlvfgidvk eadptghsyv lvtclglsyd 181
gllgdnqimp ktgfliivlv miamegghap eeeiweelsv mevydgrehs aygeprkllt
241 qdlvqekyle yrqvpdsdpa ryeflwgpra laetsyvkvl eyvikvsarv
rfffpslrea 301 alreeeegv Melanoma-associated antigen 10
NP_001011543.2, NP_001238757.1, NP_066386.2 (SEQ ID NO: 286) 1
mprapkrqrc mpeedlqsqs etqglegaqa plaveedass ststsssfps sfpsssssss
61 sscyplipst peevsaddet pnppqsaqia csspsvvasl pldqsdegss
sqkeespstl 121 qvlpdseslp rseidekvtd lvqfllfkyq mkepitkaei
lesvirnyed hfpllfseas 181 ecmllvfgid vkevdptghs fvlvtslglt
ydgmlsdvqs mpktgilili lsiifiegyc 241 tpeeviweal nmmglydgme
hliygeprkl ltqdwvqeny leyrqvpgsd paryeflwgp 301 rahaeirkms
llkflakvng sdprsfplwy eealkdeeer aqdriattdd ttamasasss 361
atgsfsype Melanoma-associated antigen 12 NP_001159858.1,
NP_001159859.1, NP_005358.2 (SEQ ID NO: 287) 1 mpleqrsqhc
kpeegleaqg ealglvgaqa pateeqetas ssstivevtl revpaaesps 61
pphspqgast lpttinytlw sqsdegssne eqegpstfpd letsfqvals rkmaelvhfl
121 llkyrarepf tkaemlgsvi rnfqdffpvi fskaseylql vfgievvevv
righlyilvt 181 clglsydgll gdnqivpktg lliivlaiia kegdcapeek
iweelsvlea sdgredsvfa 241 hprklltqdl vqenyleyrq vpgsdpacye
flwgpralve tsyvkvlhhl lkisggphis 301 ypplhewafr egee
Melanoma-associated antigen 2 NP_001269430.1, NP_001269431.1,
NP_001269433.1, NP_001269434.1, NP_005352.1, NP_786884.1,
NP_786885.1 (SEQ ID NO: 288) 1 mpleqrsqhc kpeeglearg ealglvgaqa
pateeqqtas ssstlvevtl gevpaadsps 61 pphspqgass fsttinytlw
rqsdegssnq eeegprmfpd lesefqaais rkmvelvhfl 121 llkyrarepv
tkaemlesvl rncqdffpvi fskaseylql vfgievvevv pishlyilvt 181
clglsydgll gdnqvmpktg lliivlaiia iegdcapeek iweelsmlev fegredsvfa
241 hprkllmqdl vqenyleyrq vpgsdpacye flwgpralie tsyvkvlhht
lkiggephis 301 ypplheralr egee MAGE family member A3 NP_005353.1
(SEQ ID NO: 289) 1 mpleqrsqhc kpeeglearg ealglvgaqa pateeqeaas
ssstlvevtl gevpaaespd 61 ppqspqgass lpttmnyplw sqsyedssnq
eeegpstfpd lesefqaals rkvaelvhfl 121 llkyrarepv tkaemlgsvv
gnwqyffpvi fskassslql vfgielmevd pighlyifat 181 clglsydgll
gdnqimpkag lliivlaiia regdcapeek iweelsvlev fegredsilg 241
dpkklltqhf vqenyleyrq vpgsdpacye flwgpralve tsyvkvlhhm vkisggphis
301 ypplhewvlr egee Melanoma-associated antigen 4 NP_001011548.1,
NP_001011549.1, NP_001011550.1, NP_002353.3 (SEQ ID NO: 290) 1
msseqksqhc kpeegveaqe ealglvgaqa ptteeqeaav ssssplvpgt leevpaaesa
61 gppqspqgas alpttisftc wrqpnegsss qeeegpstsp daeslfreal
snkvdelahf 121 llrkyrakel vtkaemlerv iknykrcfpv ifgkaseslk
mifgidvkev dpasntytlv 181 tclglsydgl lgnnqifpkt glliivlgti
amegdsasee eiweelgvmg vydgrehtvy 241 geprklltqd wvqenyleyr
qvpgsnpary eflwgprala etsyvkvleh vvrvnarvri 301 aypslreaal leeeegv
Melanoma-associated antigen 6 NP_005354.1, NP_787064.1 (SEQ ID NO:
291) 1 mpleqrsqhc kpeeglearg ealglvgaqa pateeqeaas ssstivevtl
gevpaaespd 61 ppgspqgass lpttmnyplw sqsyedssnq eeegpstfpd
lesefqaals rkvaklvhfl 121 llkyrarepv tkaemlgsvv gnwqyffpvi
fskasdslql vfgielmevd pighvyifat 181 clglsydgll gdnqimpktg
fliiilaiia kegdcapeek iweelsvlev fegredsifg 241 dpkklltqyf
vqenyleyrq vpgsdpacye flwgpralie tsyvkvlhhm vkisggpris 301
ypllhewalr egee Melanoma-associated antigen 9 NP_005356.1 (SEQ ID
NO: 292) 1 msleqrsphc kpdedleaqg edlglmgaqe ptgeeeetts ssdskeeevs
aagsssppqs 61 pqggasssis vyytlwsqfd egsssqeeee psssvdpaql
efmfqealkl kvaelvhfll 121 hkyrvkepvt kaemlesvik nykryfpvif
gkasefmqvi fgtdvkevdp aghsyilvta 181 lglscdsmlg dghsmpkaal
liivlgvilt kdncapeevi wealsvmgvy vgkehmfyge 241 prklltqdwv
qenyleyrqv pgsdpahyef lwgskahaet syekvinylv mlnarepicy 301
pslyeevlge eqegv Melanoma-associated antigen C2 NP_057333.1 (SEQ ID
NO: 293) 1 mppvpgvpfr nvdndsptsv eledwvdaqh ptdeeeeeas sasstlylvf
spssfstsss 61 lilggpeeee vpsgvipnit esipssppqg ppqgpsqspl
ssccssfsws sfseesssqk 121 gedtgtcqgl pdsessftyt ldekvaelve
flllkyeaee pvteaemlmi vikykdyfpv 181 ilkrarefme llfglaliev
gpdhfcvfan tvgltdegsd degmpensll iiilsvifik 241 gncaseeviw
evlnavgvya grehfvygep relltkvwvq ghyleyrevp hssppyyefl 301
wgprahsesi kkkvleflak lnntvpssfp swykdalkdv eervqatidt addatvmase
361 slsvmssnvs fse Melanoma-associated antigen D1, isoform a
NP_001005333.1 (SEQ ID NO: 294) 1 maqkmdcgag llgfqnpdac ravchplpqp
pastlplsaf ptlcdppysq lrdppavlsc 61 yctplgaspa paeasvedsa
llmqtlmeai qiseapptnq ataaaspqss qpptanemad 121 iqvsaaaarp
ksafkvqnat tkgpngvydf sqahnakdvp ntqpkaafks qnatpkgpna 181
aydfsqaatt gelaanksem afkaqnattk vgpnatynfs qslnandlan srpktpfkaw
241 ndttkaptad tqtqnvnqak matsqadiet dpgisepdga taqtsadgsq
aqnlesrtii 301 rgkrtrkinn lnveenssgd qrraplaagt wrsapvpvtt
qnppgappnv lwqtplawqn 361 psgwqnqtar qtpparqspp arqtppawqn
pvawqnpviw pnpviwqnpv iwpnpivwpg 421 pvvwpnplaw qnppgwqtpp
gwqtppgwqg ppdwqgppdw plppdwplpp dwplptdwpl 481 ppdwipadwp
ippdwqnlrp spnlrpspns rasqnpgaaq prdvallqer anklvkylml 541
kdytkvpikr semlrdiire ytdvypeiie racfvlekkf giqlkeidke ehlyilistp
601 eslagilgtt kdtpklglll vilgvifmng nraseavlwe alrkmglrpg
vrhpllgdlr 661 klltyefvkq kyldyrrvpn snppeyeflw glrsyhetsk
mkvlrfiaev qkrdprdwta 721 qfmeaadeal daldaaaaea earaeartrm
gigdeaysgp wswddiefel ltwdeegdfg 781 dpwsripftf waryhqnars
rfpqtfagpi igpggtasan faanfgaigf fwve Melanoma-associated antigen
D1, isoform b NP_001005332.1, NP_008917.3 (SEQ ID NO: 295) 1
maqkmdcgag llgfqaeasv edsallmqtl meaiqiseap ptnqataaas pqssqpptan
61 emadiqvsaa aarpksafkv qnattkgpng vydfsqahna kdvpntqpka
afksqnatpk 121 gpnaaydfsq aattgelaan ksemafkaqn attkvgpnat
ynfsqslnan dlansrpktp 181 fkawndttka ptadtqtqnv nqakmatsqa
dietdpgise pdgataqtsa dgsqaqnles 241 rtiirgkrtr kinnlnveen
ssgdqrrapl aagtwrsapv pvttqnppga ppnvlwqtpl 301 awqnpsgwqn
qtarqtppar qspparqtpp awqnpvawqn pviwpnpviw qnpviwpnpi 361
vwpgpvvwpn plawqnppgw qtppgwqtpp gwqgppdwqg ppdwplppdw plppdwplpt
421 dwplppdwip adwpippdwq nlrpspnlrp spnsrasqnp gaaqprdval
lqeranklvk 481 ylmlkdytkv pikrsemlrd iireytdvyp eiieracfvl
ekkfgiqlke idkeehlyil 541 istpeslagi lgttkdtpkl glllvilgvi
fmngnrasea vlwealrkmg lrpgvrhpll 601 gdlrklltye fvkqkyldyr
rvpnsnppey eflwglrsyh etskmkvlrf iaevqkrdpr 661 dwtaqfmeaa
dealdaldaa aaeaearaea rtrmgigdea vsgpwswddi efelltwdee 721
gdfgdpwsri pftfwaryhq narsrfpqtf agpiigpggt asanfaanfg aigffwve
Mitogen-activated protein kinase kinase kinase 5 NP_005914.1 (SEQ
ID NO: 296) 1 msteadegit fsvppfapsg fctipeggic rrggaaavge
geehqlpppp pgsfwnvesa 61 aapgigcpaa tssssatrgr gssvgggsrr
ttvayvinea sqgqlvvaes ealqslreac 121 etvgatletl hfgkldfget
tvldrfynad iavvemsdaf rqpslfyhlg vresfsmann 181 iilycdtnsd
slqslkeiic qkntmctgny tfvpymitph nkvyccdssf mkgltelmqp 241
nfelllgpic lplvdrfiql lkvaqasssq yfresilndi rkarnlytgk elaaelarir
301 qrvdnievlt adivinllls yrdiqdydsi vklvetlekl ptfdlashhh
vkfhyafaln 361 rrnlpgdrak aldimipmvq segqvasdmy clvgriykdm
fldsnftdte srdhgaswfk 421 kafeseptlq sginyavlll aaghqfessf
elrkvgvkls sllgkkgnle klqsywevgf 481 flgasvland hmrviqasek
lfklktpawy lksivetili ykhfvkltte qpvakqelvd 541 fwmdflveat
ktdvtvvrfp vlileptkiy gpsylsinne veektisiwh vlpddkkgih 601
ewnfsassvr gvsiskfeer ccflyvlhns ddfqiyfcte lhckkffemv ntiteekgrs
661 teegdcesdl leydyeyden gdrvvlgkgt ygivyagrdl snqvriaike
iperdsrysq 721 plheeialhk hlkhknivqy lgsfsengfi kifmeqvpgg
slsallrskw gplkdneqti 781 gfytkqileg lkylhdnqiv hrdikgdnvl
intysgvlki sdfgtskrla ginpctetft 841 gtlqymapei idkgprgygk
aadiwslgct iiematgkpp fyelgepqaa mfkvgmfkvh 901 peipesmsae
akafilkcfe pdpdkracan dllvdeflkv sskkkktqpk lsalsagsne 961
ylrsislpvp vlvedtssss eygsyspdte lkvdpfsfkt rakscgerdv kgirtlflgi
1021 pdenfedhsa ppspeekdsg ffmlrkdser ratlhrilte dqdkivrnlm
eslaqgaeep 1081 klkwehittl iaslrefvrs tdrkiiattl sklkleldfd
shgisqvqvv lfgfqdavnk 1141 vlrnhnikph wmfaldsiir kavqtaitil
vpelrphfsl asesdtadqe dldveddhee 1201 qpsnqtvrrp qaviedavat
sgvstlsstv shdsqsahrs lnvqlgrmki etnrlleelv 1261 rkekelqall
hraieekdqe ikhlklksqp ieipelpvfh lnssgtnted seltdwlrvn 1321
gadedtisrf laedytlldv lyyvtrddlk clrlrggmlc tlwkaiidfr nkqt
Mitogen-activated protein kinase kinase kinase 9, isoform 1
NP_149132.2 (SEQ ID NO: 297) 1 mepsrallgc lasaaaaapp gedgagagae
eeeeeeeeaa aavgpgelgc daplpywtav 61 feyeaagede ltlrlgdvve
vlskdsqvsg degwwtgqln qrvgifpsny vtprsafssr 121 cqpggedpsc
yppiqlleid faeltleeii giggfgkvyr afwigdevav kaarhdpded 181
isqtienvrq eaklfamlkh pniialrgvc lkepnlclvm efarggpinr vlsgkrippd
241 ilvnwavqia rgmnylhdea ivpiihrdlk ssnililqkv engdlsnkil
kitdfglare 301 whrttkmsaa gtyawmapev irasmfskgs dvwsygvllw
elltgevpfr gidglavayg 361 vamnklalpi pstcpepfak lmedcwnpdp
hsrpsftnil dqlttieesg ffempkdsfh 421 clqdnwkhei qemfdqlrak
ekelrtweee ltraalqqkn qeellrrreq elaereidil 481 erelniiihq
lcqekprvkk rkgkfrksrl klkdgnrisl psdfqhkftv qasptmdkrk 541
slinsrsspp asptiiprlr aiqltpgess ktwgrssvvp keegeeeekr apkkkgrtwg
601 pgtlgqkela sgdegspqrr ekanglstps esphfhlglk slvdgykqws
ssapnlvkgp 661 rsspalpgft slmemallaa swvvpidiee dedsegpgsg
esrlqhspsq sylcipfprg 721 edgdgpssdg iheeptpvns atstpqltpt
nslkrggahh rrcevallgc gavlaatglg 781 fdlleagkcq llpleepepp
areekkrreg lfqrssrprr stsppsrklf kkeepmlllg 841 dpsasltlls
lssisecnst rsllrsdsde ivvyempvsp veapplspct hnplvnvrve 901
rfkrdpnqsl tpthvtlttp sqpsshrrtp sdgalkpetl lasrspssng lspspgagml
961 ktpspsrdpg efprlpdpnv vfpptprrwn tqqdstlerp ktleflprpr
psanrqrldp 1021 wwfvspshar stspanssst etpsnldscf asssstveer
pglpallpfq agplpptert 1081 lldldaegqs qdstvplcra elnthrpapy
eiqqefws Mitogen-activated protein kinase kinase kinase 9, isoform
2 NP_001271159.1 (SEQ ID NO: 298) 1 mepsrallgc lasaaaaapp
gedgagagae eeeeeeeeaa aavgpgelgc daplpywtav 61 feyeaagede
ltlrlgdvve vlskdsqvsg degwwtgqln qrvgifpsny vtprsafssr 121
cqpggedpsc yppiqlleid faeltleeii giggfgkvyr afwigdevav kaarhdpded
181 isqtienvrq eaklfamlkh pniialrgvc lkepnlclvm efarggplnr
vlsgkrippd 241 ilvnwavqia rgmnylhdea ivpiihrdlk ssnililqkv
engdlsnkil kitdfglare 301 whrttkmsaa gtyawmapev irasmfskgs
dvwsygvllw elltgevpfr gidglavayg 361 vamnklalpi pstcpepfak
lmedcwnpdp hsrpsftnil dqlttieesg ffempkdsfh 421 clqdnwkhei
qemfdqlrak ekelrtweee ltraalqqkn geellrrreq elaereidil 481
erelniiihq lcqekprvkk rkgkfrksrl klkdgnrisl psdfqhkftv qasptmdkrk
541 slinsrsspp asptiiprlr aiqltpgess ktwgrssvvp keegeeeekr
apkkkgrtwg 601 pgtlgqkela sgdegspqrr ekanglstps esphfhlglk
slvdgykqws ssapnlvkgp 661 rsspalpgft slmemededs egpgsgesrl
qhspsqsylc ipfprgedgd gpssdgihee 721 ptpvnsatst pqltptnslk
rggahhrrce vallgcgavl aatglgfdll eagkcqllpl 781 eepepparee
kkrreglfqr ssrprrstsp psrklfkkee pmlllgdpsa sltllslssi 841
secnstrsll rsdsdeivvy empvspveap plspcthnpl vnvrverfkr dpnqsltpth
901 vtlttpsqps shrrtpsdga lkpetllasr spssnglsps pgagmlktps
psrdpgefpr 961 lpdpnvvfpp tprrwntqqd stlerpktle flprprpsan
rqrldpwwfv spsharstsp 1021 anssstetps nldscfasss stveerpglp
allpfqagpl pptertlldl daegqsqdst 1081 vplcraelnt hrpapyeiqq efws
Mitogen-activated protein kinase kinase kinase 9, isoform 3
NP_001271160.1 (SEQ ID NO: 299) 1 meltgleval vlilqkveng dlsnkilkit
dfglarewhr ttkmsaagty awmapevira 61 smfskgsdvw sygvllwell
tgevpfrgid glavaygvam nklalpipst cpepfaklme 121 dcwnpdphsr
psftnildql ttieesgffe mpkdsfhclq dnwkheiqem fdqlrakeke 181
lrtweeeltr aalqqknqee llrrreqela ereidilere lniiihqlcq ekprvkkrkg
241 kfrksrlklk dgnrislpsd fqhkftvqas ptmdkrksli nsrssppasp
tiiprlraiq 301 cetvsqiswg qntqghlspa lsshrlvqac sihnfchlss
tmciymhilt pgessktwgr 361 ssvvpkeege eeekrapkkk grtwgpgtlg
qkelasgdeg lkslvdgykq wsssapnlvk 421 gprsspalpg ftslmemall
aaswvvpidi eededsegpg sgesrlqhsp sqsylcipfp 481 rgedgdgpss
dgiheeptpv nsatstpqlt ptnslkrgga hhrrcevall gcgavlaatg 541
lgfdlleagk cqllpleepe ppareekkrr eglfqrssrp rrstsppsrk lfkkeepmll
601 lgdpsasltl lslssisecn strsllrsds deivvyempv spveapplsp
cthnplvnvr 661 verfkrdpnq sltpthvtlt tpsqpsshrr tpsdgalkpe
tllasrspss nglspspgag 721 mlktpspsrd pgefprlpdp nvvfpptprr
wntqqdstle rpktleflpr prpsanrqrl 781 dpwwfvspsh arstspanss
stetpsnlds cfasssstve erpglpallp fqagplppte 841 rtlldldaeg
qsqdstvplc raelnthrpa pyeiqqefws Mitogen-activated protein kinase
kinase kinase 9, isoform 4 NP_001271161.1 (SEQ ID NO: 300) 1
msaagtyawm apevirasmf skgsdvwsyg vllwelltge vpfrgidgla vaygvamnkl
61 alpipstcpe pfaklmedcw npdphsrpsf tnildqltti eesgffempk
dsfhclqdnw 121 kheiqemfdq lrakekelrt weeeltraal qqknqeellr
rreqelaere idilerelni 181 iihqlcqekp rvkkrkgkfr ksrlklkdgn
rislpsdfqh kftvqasptm dkrkslinsr 241 ssppasptii prlraiqcet
vsgiswgqnt qghlspalss hrlvqacsih nfchlsstmc 301 iymhiltpge
ssktwgrssv vpkeegeeee krapkkkgrt wgpgtlggke lasgdeglks 361
lvdgykqwss sapnlvkgpr sspalpgfts lmemallaas wvvpidieed edsegpgsge
421 srlqhspsqs ylcipfprge dgdgpssdgi heeptpvnsa tstpqltptn
slkrggahhr 481 rcevallgcg avlaatglgf dlleagkcql lpleepeppa
reekkrregl fqrssrprrs 541 tsppsrklfk keepmlllgd psasltllsl
ssisecnstr sllrsdsdei vvyempvspv 601 eapplspcth nplvnvrver
fkrdpnqslt pthvtlttps qpsshrrtps dgalkpetll 661 asrspssngl
spspgagmlk tpspsrdpge fprlpdpnvv fpptprrwnt qqdstlerpk 721
tleflprprp sanrqrldpw wfvspshars tspanssste tpsnldscfa sssstveerp
781 glpallpfqa gplpptertl ldldaeggsq dstvplcrae lnthrpapye iqqefws
Mitogen-activated protin kinase 1 NP_002736.3, NP_620407.1 (SEQ ID
NO: 301) 1 maaaaaagag pemvrgqvfd vgprytnlsy igegaygmvc saydnvnkvr
vaikkispfe 61 hqtycqrtlr eikillrfrh eniigindii raptieqmkd
vyivqdlmet dlykllktqh 121 lsndhicyfl yqilrglkyi hsanvlhrdl
kpsnlllntt cdlkicdfgl arvadpdhdh 181 tgflteyvat rwyrapeiml
nskgytksid iwsvgcilae mlsnrpifpg khyldqlnhi 241 lgilgspsqe
dlnciinlka rnyllslphk nkvpwnrlfp nadskaldll dkmltfnphk 301
rieveqalah pyleqyydps depiaeapfk fdmelddlpk eklkelifee tarfqpgyrs
Melan-A NP_005502.1 (SEQ ID NO: 302) 1 mpredahfiy gypkkghghs
yttaeeaagi giltvilgvl lligcwycrr rngyralmdk 61 slhvgtqcal
trrcpqegfd hrdskvslqe kncepvvpna ppayeklsae qspppysp
Melanotransferrin, isoform 1 preprotein NP_005920.2 (SEQ ID NO:
303) 1 mrgpsgalwl llalrtvlgg mevrwcatsd peqhkcgnms eafreagiqp
sllcvrgtsa 61 dhcvqliaaq eadaitldgg aiyeagkehg lkpvvgevyd
qevgtsyyav avvrrsshvt 121 idtlkgvksc htginrtvgw nvpvgylves
grlsvmgcdv lkaysdyfgg scvpgagets 181 yseslcrlcr gdssgegvcd
kspleryydy sgafrclaeg agdvafvkhs tvlentdgkt 241 lpswgqalls
qdfellcrdg sradvtewrq chlarvpaha vvvradtdgg lifrllnegq 301
rlfshegssf qmfsseaygq kdllfkdsts elvpiatqty eawlgheylh amkgllcdpn
361 rlppylrwcv lstpeiqkcg dmavafrrqr lkpeiqcvsa kspqhcmeri
qaeqvdavtl
421 sgediytagk tyglvpaage hyapedssns yyvvavvrrd sshaftldel
rgkrschagf 481 gspagwdvpv galiqrgfir pkdcdvltav seffnascvp
vnnpknypss lcalcvgdeq 541 grnkcvgnsq eryygyrgaf rclvenagdv
afvrhttvfd ntnghnsepw aaelrsedye 601 llcpngarae vsqfaacnla
qipphavmvr pdtniftvyg lldkaqdlfg ddhnkngfkm 661 fdssnyhgqd
llfkdatvra vpvgekttyr gwlgldyvaa legmssqqcs gaaapapgap 721
llplllpala arllppal Melanotransferrin, isoform 2 precursor
NP_201573.1 (SEQ ID NO: 304) 1 mrgpsgalwl llalrtvlgg mevrwcatsd
peqhkcgnms eafreagiqp sllcvrgtsa 61 dhcvqliaaq eadaitldgg
aiyeagkehg lkpvvgevyd qevgtsyyav avvrrsshvt 121 idtlkgvksc
htginrtvgw nvpvgylves grlsvmgcdv lkavsdyfgg scvpgagets 181
yseslcrlcr gdssgegvcd kspleryydy sgafrclaeg agdvafvkhs tvlentdesp
241 srrqtwtrse eeegecpahe earrtmrssa gqawkwapvh rpqdesdkge
fgkraksrdm 301 lg Baculoviral IAP repeat containing 7, isoform
alpha NP_647478.1 (SEQ ID NO: 305) 1 mgpkdsakcl hrgpqpshwa
agdgptqerc gprslgspvl gldtcrawdh vdgqilgqlr 61 plteeeeeeg
agatlsrgpa fpgmgseelr lasfydwplt aevppellaa agffhtghqd 121
kvrcffcygg lqswkrgddp wtehakwfps cqfllrskgr dfvhsvgeth sqllgswdpw
181 eepedaapva psvpasgype lptprrevqs esaqepggvs paeaqrawwv
leppgardve 241 aqlrrlqeer tckvcldrav sivfvpcghl vcaecapglq
lcpicrapvr srvrtfls Baculoviral IAP repeat containing 7, isoform
beta NP_071444.1 (SEQ ID NO: 306) 1 mgpkdsakcl hrgpqpshwa
agdgptqerc gprslgspvl gldtcrawdh vdgqilgqlr 61 plteeeeeeg
agatlsrgpa fpgmgseelr lasfydwplt aevppellaa agffhtghqd 121
kvrcffcygg lqswkrgddp wtehakwfps cqfllrskgr dfvhsvqeth sqllgswdpw
181 eepedaapva psvpasgype lptprrevqs esaqepgard veaqlrrlqe
ertckvcldr 241 avsivfvpcg hlvcaecapg lqlcpicrap vrsrvrtfls
Neutrophil collagenase, isoform 1 preprotein NP_002415.1 (SEQ ID
NO: 307) 1 mfslktlpfl lllhvqiska fpvsskeknt ktvqdylekf yqlpsnqyqs
trkngtnviv 61 eklkemqrff glnvtgkpne etldmmkkpr cgvpdsggfm
ltpgnpkwer tnityrirny 121 tpqlseaeve raikdafelw svaspliftr
isqgeadini afyqrdhgdn spfdgpngil 181 ahafqpgqgi ggdahfdaee
twtntsanyn lflvaahefg hslglahssd pgalmypnya 241 fretsnyslp
qddidgiqai yglssnpiqp tgpstpkpcd psltfdaitt lrgeilffkd 301
ryfwrrhpql qrvemnfisl fwpslptgiq aayedfdrdl iflfkgnqyw alsgydilqg
361 ypkdisnygf pssvqaidaa vfyrsktyff vndqfwrydn qrqfmepgyp
ksisgafpgi 421 eskvdavfqq ehffhvfsgp ryyafdliaq rvtrvargnk wlncryg
Neutrophil collagenase, isoform 2 NP_001291370.1, NP_001291371.1
(SEQ ID NO: 308) 1 mqqipqeksi ndylekfyql psnqyqstrk ngtnvivekl
kemqrffgln vtgkpneetl 61 dmmkkprcgv pdsggfmltp gnpkwertnl
tyrirnytpq lseaeverai kdafelwsva 121 spliftrisq geadiniafy
qrdhgdnspf dgpngilaha fqpgqgiggd ahfdaeetwt 181 ntsanynlfl
vaahefghsl glahssdpga lmypnyafre tsnyslpqdd idgiqaiygl 241
ssnpiqptgp stpkpcdpsl tfdaittlrg eilffkdryf wrrhpqlqrv emnfislfwp
301 slptgiqaay edfdrdlifl fkgnqywals gydilqgypk disnygfpss
vqaidaavfy 361 rsktyffvnd qfwrydnqrq fmepgypksi sgafpgiesk
vdavfqqehf fhvfsgpryy 421 afdliaqrvt rvargnkwln cryg Mesothelin,
isoform 1 preprotein NP_001170826.1, NP_005814.2 (SEQ ID NO: 309) 1
malptarpll gscgtpalgs llfllfslgw vqpsrtlage tgqeaapldg vlanppniss
61 lsprqllgfp caevsglste rvrelavala qknvklsteq lrclahrlse
ppedldalpl 121 dlllflnpda fsgpqactrf fsritkanvd llprgaperq
rllpaalacw gvrgsllsea 181 dvralgglac dlpgrfvaes aevllprlvs
cpgpldqdqq eaaraalqgg gppygppstw 241 systmdalrg llpvlgqpii
rsipqgivaa wrqrssrdps wrqpertilr prfrrevekt 301 acpsgkkare
ideslifykk weleacvdaa llatqmdrvn aipftyeqld vlkhkldely 361
pqgypesviq hlgylflkms pedirkwnvt sletlkalle vnkghemspq vatlidrfvk
421 grgqldkdtl dtltafypgy lcslspeels svppssiwav rpqdldtcdp
rqldvlypka 481 rlafqnmngs eyfvkiqsfl ggaptedlka lsqqnvsmdl
atfmklrtda vlpltvaevq 541 kllgphvegl kaeerhrpvr dwilrqrqdd
ldtlglglqg gipngylvld lsmqealsgt 601 pcllgpgpvl tvlalllast la
Mesothelin, isoform 2 preprotein NP_037536.2 (SEQ ID NO: 310) 1
malptarpll gscgtpalgs llfllfslgw vqpsrtlage tgqeaapldg vlanppniss
61 lsprqllgfp caevsglste rvrelavala qknvklsteq lrclahrlse
ppedldalpl 121 dlllflnpda fsgpqactrf fsritkanvd llprgaperq
rllpaalacw gvrgsllsea 181 dvralgglac dlpgrfvaes aevllprlvs
cpgpldqdqq eaaraalqgg gppygppstw 241 systmdalrg llpvlgqpii
rsipqgivaa wrqrssrdps wrqpertilr prfrrevekt 301 acpsgkkare
ideslifykk weleacvdaa llatqmdrvn aipftyeqld vlkhkldely 361
pqgypesviq hlgylflkms pedirkwnvt sletlkalle vnkghemspq aprrplpqva
421 tlidrfvkgr gqldkdtldt ltafypgylc slspeelssv ppssiwavrp
qdldtcdprq 481 ldvlypkarl afqnmngsey fvkiqsflgg aptedlkals
qqnvsmdlat fmklrtdavl 541 pltvaevqkl lgphveglka eerhrpvrdw
ilrqrqddld tlglglqggi pngylvldls 601 mqealsgtpc llgpgpvltv
lalllastla Mucin-1, isoform 1 precursor NP_002447.4 (SEQ ID NO:
311) 1 mtpgtqspff llllltvltv vtgsghasst pggeketsat qrssvpsste
knalstgvsf 61 fflsfhisnl qfnssledps tdyyqelqrd isemflqiyk
qggflglsni kfrpgsvvvq 121 ltlafregti nvhdvetqfn qykteaasry
nltisdvsvs dvpfpfsaqs gagvpgwgia 181 llvlvcvlva laivyliala
vcqcrrknyg qldifpardt yhpmseypty hthgryvpps 241 stdrspyekv
sagnggssls ytnpavaats anl Mucin-1, isoform 2 precursor
NP_001018016.1 (SEQ ID NO: 312) 1 mtpgtqspff llllltvlta ttapkpatvv
tgsghasstp ggeketsatq rssvpsstek 61 nafnssledp stdyyqelqr
disemflqiy kqggflglsn ikfrpgsvvv qltlafregt 121 invhdvetqf
nqykteaasr ynitisdvsv sdvpfpfsaq sgagvpgwgi allvlvcvlv 181
alaivylial avcqcrrkny gqldifpard tyhpmseypt yhthgryvpp sstdrspyek
241 vsagnggssl sytnpavaat sanl Mucin-1, isoform 3 precursor
NP_001018017.1 (SEQ ID NO: 313) 1 mtpgtqspff llllltvltv vtgsghasst
pggeketsat qrssvpsste knafnssled 61 pstdyyqelq rdisemflqi
ykqggflgls nikfrpgsvv vqltlafreg tinvhdvetq 121 fnqykteaas
rynltisdvs vsdvpfpfsa qsgagvpgwg iallvlvcvl valaivylia 181
lavcqcrrkn ygqldifpar dtyhpmseyp tyhthgryvp psstdrspye kvsagnggss
241 lsytnpavaa tsanl Mucin-1, isoform 5 precursor NP_001037855.1
(SEQ ID NO: 314) 1 mtpgtqspff llllltvltv vtgsghasst pggeketsat
qrssvpsste knaipapttt 61 kscretflkc fcrfinkgvf waspilssvs
dvpfpfsaqs gagvpgwgia llvlvcvlva 121 laivyliala vcgcrrknyg
qldifpardt yhpmseypty hthgryvpps stdrspyekv 181 sagnggssls
ytnpavaats anl Mucin-1, isoform 6 precursor NP_001037856.1 (SEQ ID
NO: 315) 1 mtpgtqspff llllltvltv vtgsghasst pggeketsat qrssvpsste
knafnssled 61 pstdyyqelq rdisemavcq crrknygqld ifpardtyhp
mseyptyhth gryvppsstd 121 rspyekvsag nggsslsytn pavaatsanl Mucin-1,
isoform 7 precursor NP_001037857.1 (SEQ ID NO: 316) 1 mtpgtqspff
llllltvlta ttapkpatvv tgsghasstp ggeketsatq rssvpsstek 61
nafnssledp stdyyqelqr disemavcqc rrknygqldi fpardtyhpm seyptyhthg
121 ryvppsstdr spyekvsagn ggsslsytnp avaatsanl Mucin-1, isoform 8
precursor NP_001037858.1 (SEQ ID NO: 317) 1 mtpgtqspff llllltvltv
vtgsghasst pggeketsat qrssvpsste knaipapttt 61 kscretflkc
fcrfinkgvf waspilssvw gwgarlghra agaglcsgca ghclshclgc 121
lsvppkelra aghlsspgyl psyervphlp hpwalcap Mucin-1, isoform 9
precursor NP_001191214.1 (SEQ ID NO: 318) 1 mtpgtqspff llllltvltv
vtgsghasst pggeketsat qrssvpsste knaysmtssv 61 lsshspgsgs
sttqgqdvtl apatepasgs aatwgqdvts vpvtrpalgs ttppandvts 121
apdnkpapgs tappahgvts apdtrpapgs tappahgvts apdnrpalgs tappvhnvts
181 asgsasgsas tlvhngtsar atttpaskst pfsipshhsd tpttlashst
ktdassthhs 241 tvppltssnh stspqlstgv sffflsfhis nlqfnssled
pstdyyqelq rdisemflqi 301 ykqggflgls nikfrpgsvv vqltlafreg
tinvhdvetq fnqykteaas rynitisdvs 361 vsdvpfpfsa qsgagvpgwg
iallvlvcvl valaivylia lavcqcrrkn ygqldifpar 421 dtyhpmseyp
tyhthgryvp psstdrspye kvsagnggss lsytnpavaa tsanl Mucin-1, isoform
10 precursor NP_001191215.1 (SEQ ID NO: 319) 1 mtpgtqspff
llllltvlta ttapkpatvv tgsghasstp ggeketsatq rssvpsstek 61
naysmtssvl sshspgsgss ttqgqdvtla patepasgsa atwgqdvtsv pvtrpalgst
121 tppandvtsa pdnkpapgst appahgvtsa pdtrpapgst appahgvtsa
pdnrpalgst 181 appvhnvtsa sgsasgsast lvhngtsara tttpaskstp
fsipshhsdt pttlashstk 241 tdassthhst vppltssnhs tspqlstgvs
ffflsfhisn lqfnssledp stdyyqelqr 301 disemflqiy kqggflglsn
ikfrpgsvvv qltlafregt invhdvetqf nqykteaasr 361 ynltisdvsv
sdvpfpfsaq sgagvpgwgi allvlvcvlv alaivylial avcqcrrkny 421
gqldifpard tyhpmseypt yhthgryvpp sstdrspyek vsagnggssl sytnpavaat
481 sanl Mucin-1, isoform 11 precursor NP_001191216.1 (SEQ ID NO:
320) 1 mtpgtqspff llllltvlta ttapkpatvv tgsghasstp ggeketsatq
rssvpsstek 61 nalstgvsff flsfhisnlq fnssledpst dyyqelqrdi
semflqiykq ggflglsnik 121 frpgsvvvql tlafregtin vhdvetqfnq
ykteaasryn ltisdvsysd vpfpfsaqsg 181 agvpgwgial lvlvcvlval
aivylialav cqcrrknygq ldifpardty hpmseyptyh 241 thgryvppss
tdrspyekvs agnggsslsy tnpavaatsa nl Mucin-1, isoform 12 precursor
NP_001191217.1 (SEQ ID NO: 321) 1 mtpgtqspff llllltvlta ttapkpatvv
tgsghasstp ggeketsatq rssvpsstek 61 nafnssledp stdyygelqr
disemflqiy kqggflglsn ikfrpgsvvv qltlafregt 121 invhdvetqf
nqykteaasr ynitisdvsv wgwgarlghr aagaglcsgc aghclshclg 181
clsvppkelr aaghlsspgy lpsyervphl phpwalcap Mucin-1, isoform 13
precursor NP_001191218.1 (SEQ ID NO: 322) 1 mtpgtqspff llllltvlta
ttapkpatvv tgsghasstp ggeketsatq rssvpsstek 61 naiykqggfl
glsnikfrpg svvvqltlaf regtinvhdv etqfnqykte aasrynltis 121
dvsysdvpfp fsaqsgagvp gwgiallvlv cvlvalaivy lialavcqcr rknygqldif
181 pardtyhpms eyptyhthgr yvppsstdrs pyekvsagng gsslsytnpa vaatsanl
Mucin-1, isoform 14 precursor NP_001191219.1 (SEQ ID NO: 323) 1
mtpgtqspff llllltvltg geketsatqr ssvpsstekn aiykqggflg lsnikfrpgs
61 vvvqltlafr egtinvhdve tqfnqyktea asrynltisd vsysdvpfpf
saqsgagvpg 121 wgiallvlvc vlvalaivyl ialavcqcrr knygqldifp
ardtyhpmse yptyhthgry 181 vppsstdrsp yekvsagngg sslsytnpav aatsanl
Mucin-1, isoform 15 precursor NP_001191220.1 (SEQ ID NO: 324) 1
mtpgtqspff llllltvlta ttapkpatvv tgsghasstp ggeketsatq rssvpsstek
61 naflqiykqg gflglsnikf rpgsvvvqlt lafregtinv hdvetqfnqy
kteaasrynl 121 tisdvsysdv pfpfsaqsga gvpgwgiall vlvcvlvala
ivylialavc qcrrknygql 181 difpardtyh pmseyptyht hgryvppsst
drspyekvsa gnggsslsyt npavaatsan 241 l Mucin-1, isoform 16
precursor NP_001191221.1 (SEQ ID NO: 325) 1 mtpgtqspff llllltvlta
ttapkpatvv tgsghasstp ggeketsatq rssvpsstek 61 naipaptttk
scretflkwp gsvvvqltla fregtinvhd vetqfnqykt eaasryniti 121
sdvsysdvpf pfsaqsgagv pgwgiallvl vcvlvalaiv ylialavcqc rrknygqldi
181 fpardtyhpm seyptyhthg ryvppsstdr spyekvsagn ggsslsytnp
avaatsanl Mucin-1, isoform 17 precursor NP_001191222.1 (SEQ ID NO:
326) 1 mtpgtqspff llllltvltv vtgsghasst pggeketsat qrssvpsste
knalstgvsf 61 fflsfhisnl qfnssledps tdyyqelqrd isemflqiyk
qggflglsni kfrpgsvvvq 121 ltlafregti nvhdvetqfn qykteaasry
nitisdvsgc lsvppkelra aghlsspgyl 181 psyervphlp hpwalcap Mucin-1,
isoform 18 precursor NP_001191223.1 (SEQ ID NO: 327) 1 mtpgtqspff
llllltvltv vtgsghasst pggeketsat qrssvpsste knaipapttt 61
kscretflkw pgsvvvqltl afregtinvh dvetqfnqyk teaasrynit isdvsysdvp
121 fpfsaqsgag vpgwgiallv lvcvlvalai vylialavcq crrknygqld
ifpardtyhp 181 mseyptyhth gryvppsstd rspyekvsag nggsslsytn
pavaatsanl Mucin-1, isoform 19 precursor NP_001191224.1 (SEQ ID NO:
328) 1 mtpgtqspff llllltvlta ttapkpatvv tgsghasstp ggeketsatq
rssvpsstek 61 nafnssledp stdyyqelqr disemsgagv pgwgiallvl
vcvlvalaiv ylialavcqc 121 rrknygqldi fpardtyhpm seyptyhthg
ryvppsstdr spyekvsagn ggsslsytnp 181 avaatsanl Mucin-1, isoform 20
precursor NP_001191225.1 (SEQ ID NO: 329) 1 mtpgtqspff llllltvlta
ttapkpatvv tgsghasstp ggeketsatq rssvpsstek 61 naipaptttk
scretflkcf crfinkgvfw aspilssysd vpfpfsaqsg agvpgwgial 121
lvlvcvlval aivylialav cqcrrknygq ldifpardty hpmseyptyh thgryvppss
181 tdrspyekvs agnggsslsy tnpavaatsa nl Mucin-1, isoform 21
precursor NP_001191226.1 (SEQ ID NO: 330) 1 mtpgtqspff llllltvlta
ttapkpatvv tgsghasstp ggeketsatq rssvpsstek 61 nalstgvsff
flsfhisnlq fnssledpst dyyqelqrdi semavcqcrr knygqldifp 121
ardtyhpmse yptyhthgry vppsstdrsp yekvsagngg sslsytnpav aatsanl
N-myc proto-oncogene protein, isoform 1 NP_001280157.1, NP_005369.2
(SEQ ID NO: 331) 1 mpscststmp gmicknpdle fdslqpcfyp deddfyfggp
dstppgediw kkfellptpp 61 lspsrgfaeh sseppswvte mllenelwgs
paeedafglg glggltpnpv ilqdcmwsgf 121 sareklerav seklqhgrgp
ptagstaqsp gagaaspagr ghggaagagr agaalpaela 181 hpaaecvdpa
vvfpfpvnkr epapvpaapa sapaagpava sgagiaapag apgvapprpg 241
grqtsggdhk alstsgedtl sdsddeddee edeeeeidvv tvekrrsssn tkavttftit
301 vrpknaalgp graqsselil krclpihqqh nyaapspyve sedappqkki
kseasprplk 361 svippkaksl sprnsdseds errrnhnile rqrrndlrss
fltlrdhvpe lvknekaakv 421 vilkkateyv hslqaeehql llekeklqar
qqqllkkieh artc N-myc proto-oncogene protein, isoform 2
NP_001280160.1 (SEQ ID NO: 332) 1 mrgapgncvg aeqalarrkr aqtvairghp
rppgppgdtr aesppdplqs agddeddeee 61 deeeeidvvt vekrrsssnt
kavttftitv rpknaalgpg raqsselilk rclpihqqhn 121 yaapspyves
edappqkkik seasprplks vippkaksls prnsdsedse rrrnhniler 181
qrrndlrssf ltlrdhvpel vknekaakvv ilkkateyvh slqaeehqll lekeklqarq
241 qqllkkieha rtc N-myc proto-oncogene protein, isoform 3
NP_001280162.1 (SEQ ID NO: 333) 1 mrgapgncvg aeqalarrkr aqtvairghp
rppgppgdtr aesppdplqs agvlevgagp 61 rlprppregs tpgiktngae
rspqspagrr adaellhvhh aghdlqeprp rv Cancer/testis antigen 1B
NP_001318.1 (SEQ ID NO: 334) 1 mqaegrgtgg stgdadgpgg pgipdgpggn
aggpgeagat ggrgprgaga arasgpggga 61 prgphggaas glngccrcga
rgpesrllef ylampfatpm eaelarrsla qdapplpvpg 121 vllkeftvsg
niltirltaa dhrqlqlsis sclqqlsllm witqcflpvf laqppsgqrr Opioid
growth factor receptor NP_031372.2 (SEQ ID NO: 335) 1 mddpdcdstw
eedeedaeda ededcedgea agardadagd edeeseepra arpssfqsrm 61
tgsrnwratr dmcryrhnyp dlverdcngd tpnlsfyrne irflpngcfi edilqnwtdn
121 ydllednhsy iqwlfplrep gvnwhakplt lrevevfkss qeiqerlvra
yelmlgfygi 181 rledrgtgtv graqnyqkrf qnlnwrshnn lritrilksl
gelglehfqa plvrffleet 241 lvrrelpgvr qsaldyfmfa vrcrhqrrql
vhfawehfrp rckfvwgpqd klrrfkpssl 301 phplegsrkv eeegspgdpd
heastqgrtc gpehskgggr vdegpqprsv epqdagpler 361 sqgdeagghg
edrpeplspk eskkrklels rreqpptepg pqsaseveki alnlegcals 421
qgslrtgtqe vggqdpgeav qpcrqplgar vadkvrkrrk vdegagdsaa vasggaqtla
481 lagspapsgh pkaghsengv eedtegrtgp kegtpgspse tpgpspagpa
gdepaespse 541 tpgprpagpa gdepaespse tpgprpagpa gdepaespse
tpgpspagpt rdepaespse 601 tpgprpagpa gdepaespse tpgprpagpa
gdepaespse tpgpspagpt rdepakagea
661 aelqdaeves saksgkp P antigen family member 4 NP_001305806.1,
NP_008934.1 (SEQ ID NO: 336) 1 msarvrsrsr grgdgqeapd vvafvapges
qqeepptdnq diepgqereg tppieerkve 61 gdcqemdlek trsergdgsd
vkektppnpk haktkeagdg qp Paired box protein Pax-3, isoform PAX3a
NP_000429.2 (SEQ ID NO: 337) 1 mttlagavpr mmrpgpgqny prsgfplevs
tplgqgrvnq lggvfingrp lpnhirhkiv 61 emahhgirpc visrqlrvsh
gcvskilcry qetgsirpga iggskpkqvt tpdvekkiee 121 ykrenpgmfs
weirdkllkd avcdrntvps vssisrilrs kfgkgeeeea dlerkeaees 181
ekkakhsidg ilsergkrwr lgrrtcwvtw rasas Paired box protein Pax-3,
isoform PAX3i NP_001120838.1 (SEQ ID NO: 338) 1 mttlagavpr
mmrpgpgqny prsgfplevs tplgqgrvnq lggvfingrp lpnhirhkiv 61
emahhgirpc visrqlrvsh gcvskilcry qetgsirpga iggskpkvtt pdvekkieey
121 krenpgmfsw eirdkllkda vcdrntvpsv ssisrilrsk fgkgeeeead
lerkeaeese 181 kkakhsidgi lserasapqs degsdidsep dlplkrkqrr
srttftaeql eelerafert 241 hypdiytree laqrakltea rvqvwfsnrr
arwrkqagan qlmafnhlip ggfpptampt 301 lptyqlsets yqptsipqav
sdpsstvhrp qplppstvhq stipsnpdss sayclpstrh 361 gfssytdsfv
ppsgpsnpmn ptignglspq vmglltnhgg vphqpqtdya lspltgglep 421
tttvsascsq rldhmkslds lptsqsycpp tysttgysmd pvtgyqygqy gqsafhylkp
481 dia Paired box protein Pax-3, isoform PAX3b NP_039230.1 (SEQ ID
NO: 339) 1 mttlagavpr mmrpgpgqny prsgfplevs tplgqgrvnq lggvfingrp
lpnhirhkiv 61 emahhgirpc visrqlrvsh gcvskilcry qetgsirpga
iggskpkqvt tpdvekkiee 121 ykrenpgmfs weirdkllkd avcdrntvps
vssisrilrs kfgkgeeeea dlerkeaees 181 ekkakhsidg ilsergkalv sgvssh
Paired box protein Pax-3, isoform PAX3 NP_852122.1 (SEQ ID NO: 340)
1 mttlagavpr mmrpgpgqny prsgfplevs tplgqgrvnq lggvfingrp lpnhirhkiv
61 emahhgirpc visrqlrvsh gcvskilcry qetgsirpga iggskpkqvt
tpdvekkiee 121 ykrenpgmfs weirdkllkd avcdrntvps vssisrilrs
kfgkgeeeea dlerkeaees 181 ekkakhsidg ilserasapq sdegsdidse
pdlplkrkqr rsrttftaeq leelerafer 241 thypdiytre elaqraklte
arvqvwfsnr rarwrkqaga nqlmafnhli pggfpptamp 301 tlptyqlset
syqptsipqa vsdpsstvhr pqplppstvh qstipsnpds ssayclpstr 361
hgfssytdsf vppsgpsnpm nptignglsp qvmglltnhg gvphqpqtdy alspltggle
421 ptttvsascs qrldhmksld slptsqsycp ptysttgysm dpvtgyqygq
ygqskpwtf Paired box protein Pax-3, isoform PAX3d NP_852123.1 (SEQ
ID NO: 341) 1 mttlagavpr mmrpgpgqny prsgfplevs tplgqgrvnq
lggvfingrp lpnhirhkiv 61 emahhgirpc visrqlrvsh gcvskilcry
qetgsirpga iggskpkqvt tpdvekkiee 121 ykrenpgmfs weirdkllkd
avcdrntvps vssisrilrs kfgkgeeeea dlerkeaees 181 ekkakhsidg
ilserasapq sdegsdidse pdlplkrkqr rsrttftaeq leelerafer 241
thypdiytre elaqraklte arvqvwfsnr rarwrkqaga nqlmafnhli pggfpptamp
301 tlptyqlset syqptsipqa vsdpsstvhr pqplppstvh qstipsnpds
ssayclpstr 361 hgfssytdsf vppsgpsnpm nptignglsp qvmglltnhg
gvphqpqtdy alspltggle 421 ptttvsascs qrldhmksld slptsqsycp
ptysttgysm dpvtgyqygq ygqsafhylk 481 pdia Paired box protein Pax-3,
isoform PAX3e NP_852124.1 (SEQ ID NO: 342) 1 mttlagavpr mmrpgpgqny
prsgfplevs tplgqgrvnq lggvfingrp lpnhirhkiv 61 emahhgirpc
visrqlrvsh gcvskilcry qetgsirpga iggskpkqvt tpdvekkiee 121
ykrenpgmfs weirdkllkd avcdrntvps vssisrilrs kfgkgeeeea dlerkeaees
181 ekkakhsidg ilserasapq sdegsdidse pdlplkrkqr rsrttftaeq
leelerafer 241 thypdiytre elaqraklte arvqvwfsnr rarwrkqaga
nqlmafnhli pggfpptamp 301 tlptyqlset syqptsipqa vsdpsstvhr
pqplppstvh qstipsnpds ssayclpstr 361 hgfssytdsf vppsgpsnpm
nptignglsp qvmglltnhg gvphqpqtdy alspltggle 421 ptttvsascs
qrldhmksld slptsqsycp ptysttgysm dpvtgyqygq ygqsafhylk 481
pdiawfqill ntfdkssgee edleq Paired box protein Pax-3, isoform PAX3h
NP_852125.1 (SEQ ID NO: 343) 1 mttlagavpr mmrpgpgqny prsgfplevs
tplgqgrvnq lggvfingrp lpnhirhkiv 61 emahhgirpc visrqlrvsh
gcvskilcry qetgsirpga iggskpkqvt tpdvekkiee 121 ykrenpgmfs
weirdkllkd avcdrntvps vssisrilrs kfgkgeeeea dlerkeaees 181
ekkakhsidg ilserasapq sdegsdidse pdlplkrkqr rsrttftaeq leelerafer
241 thypdiytre elaqraklte arvqvwfsnr rarwrkqaga nqlmafnhli
pggfpptamp 301 tlptyqlset syqptsipqa vsdpsstvhr pqplppstvh
qstipsnpds ssayclpstr 361 hgfssytdsf vppsgpsnpm nptignglsp
qvpfiissqi slgfksf Paired box protein Pax-3, isoform PAX3g
NP_852126.1 (SEQ ID NO: 344) 1 mttlagavpr mmrpgpgqny prsgfplevs
tplgqgrvnq lggvfingrp lpnhirhkiv 61 emahhgirpc visrqlrvsh
gcvskilcry qetgsirpga iggskpkqvt tpdvekkiee 121 ykrenpgmfs
weirdkllkd avcdrntvps vssisrilrs kfgkgeeeea dlerkeaees 181
ekkakhsidg ilserasapq sdegsdidse pdlplkrkqr rsrttftaeq leelerafer
241 thypdiytre elaqraklte arvqvwfsnr rarwrkqaga nqlmafnhli
pggfpptamp 301 tlptyqlset syqptsipqa vsdpsstvhr pqplppstvh
qstipsnpds ssayclpstr 361 hgfssytdsf vppsgpsnpm nptignglsp
qvpfiissqi srk Paired box protein Pax-5, isoform 1 NP_057953.1 (SEQ
ID NO: 345) 1 mdleknyptp rtsrtghggv nqlggvfvng rplpdvvrqr
ivelahqgvr pcdisrqlrv 61 shgcvskilg ryyetgsikp gviggskpkv
atpkvvekia eykrqnptmf aweirdrlla 121 ervcdndtvp svssinriir
tkvqqppnqp vpasshsivs tgsvtqvssv stdsagssys 181 isgilgitsp
sadtnkrkrd egiqespvpn ghslpgrdfl rkqmrgdlft qqqlevldrv 241
ferqhysdif tttepikpeq tteysamasl agglddmkan lasptpadig ssvpgpqsyp
301 ivtgrdlast tlpgypphvp pagqgsysap tltgmvpgse fsgspyshpq
yssyndswrf 361 pnpgllgspy yysaaargaa ppaaataydr h Paired box
protein Pax-5, isoform 2 NP_001267476.1 (SEQ ID NO: 346) 1
mdleknyptp rtsrtghggv nqlggvfvng rplpdvvrqr ivelahqgvr pcdisrqlrv
61 shgcvskilg ryyetgsikp gviggskpkv atpkvvekia eykrqnptmf
aweirdrlla 121 ervcdndtvp svssinriir tkvqqppnqp vpasshsivs
tgsvtqvssv stdsagssys 181 isgilgitsp sadtnkrkrd egiqespvpn
ghslpgrdfl rkqmrgdlft qqqlevldrv 241 ferqhysdif tttepikpeq
tteysamasl agglddmkan lasptpadig ssvpgpqsyp 301 ivtgsefsgs
pyshpqyssy ndswrfpnpg llgspyyysa aargaappaa ataydrh Paired box
protein Pax-5, isoform 3 NP_001267477.1 (SEQ ID NO: 347) 1
mdleknyptp rtsrtghggv nqlggvfvng rplpdvvrqr ivelahqgvr pcdisrqlrv
61 shgcvskilg ryyetgsikp gviggskpkv atpkvvekia eykrqnptmf
aweirdrlla 121 ervcdndtvp svssinriir tkvqqppnqp vpasshsivs
tgsvtqvssv stdsagssys 181 isgilgitsp sadtnkrkrd egiqespvpn
ghslpgrdfl rkqmrgdlft qqqlevldrv 241 ferqhysdif tttepikpeq
tteysamasl agglddmkan lasptpadig ssvpgpqsyp 301 ivtgrdlast
tlpgypphvp pagqgsysap tltgmvpgsp yyysaaarga appaaatayd 361 rh
Paired box protein Pax-5, isoform 4 NP_001267478.1 (SEQ ID NO: 348)
1 mdleknyptp rtsrtghggv nqlggvfvng rplpdvvrqr ivelahqgvr pcdisrqlrv
61 shgcvskilg ryyetgsikp gviggskpkv atpkvvekia eykrqnptmf
aweirdrlla 121 ervcdndtvp svssinriir tkvqqppnqp vpasshsivs
tgsvtqvssv stdsagssys 181 isgilgitsp sadtnkrkrd egiqespvpn
ghslpgrdfl rkqmrgdlft qqqlevldrv 241 ferqhysdif tttepikpeq
gvsfpgvpta tlsiprtttp ggsptrgcla pptiialppe 301 epphlqpplp
mtvtdpwsqa gtkh Paired box protein Pax-5, isoform 5 NP_001267479.1
(SEQ ID NO: 349) 1 mdleknyptp rtsrtghggv nqlggvfvng rplpdvvrqr
ivelahqgvr pcdisrqlrv 61 shgcvskilg ryyetgsikp gviggskpkv
atpkvvekia eykrqnptmf aweirdrlla 121 ervcdndtvp svssinriir
tkvqqppnqp vpasshsivs tgsvtqvssv stdsagssys 181 isgilgitsp
sadtnkrkrd egiqespvpn ghslpgrdfl rkqmrgdlft qqqlevldrv 241
ferqhysdif tttepikpeq apptiialpp eepphlqppl pmtvtdpwsq agtkh Paired
box protein Pax-5, isoform 6 NP_001267480.1 (SEQ ID NO: 350) 1
mfaweirdrl laervcdndt vpsyssinri irtkvqqppn qpvpasshsi vstgsvtqvs
61 systdsagss ysisgilgit spsadtnkrk rdegiqespv pnghslpgrd
flrkqmrgdl 121 ftqqqlevld rvferqhysd iftttepikp eqtteysama
slagglddmk anlasptpad 181 igssvpgpqs ypivtgspyy ysaaargaap
paaataydrh Paired box protein Pax-5, isoform 7 NP_001267481.1 (SEQ
ID NO: 351) 1 mdleknyptp rtsrtghggv nqlggvfvng rplpdvvrqr
ivelahqgvr pcdisrqlrv 61 shgcvskilg ryyetgsikp gviggskpkv
atpkvvekia eykrqnptmf aweirdrlla 121 ervcdndtvp svssinriir
tkvqqppnqp vpasshsivs tgsvtqvssv stdsagssys 181 isgilgitsp
sadtnkrkrd egiqespvpn ghslpgrdfl rkqmrgdlft qqqlevldrv 241
ferqhysdif tttepikpeq tteysamasl agglddmkan lasptpadig ssvpgpqsyp
301 ivtgspyyys aaargaappa aataydrh Paired box protein Pax-5,
isoform 8 NP_001267482.1 (SEQ ID NO: 352) 1 mdleknyptp rtsrtghggv
nqlggvfvng rplpdvvrqr ivelahqgvr pcdisrqlrv 61 shgcvskilg
ryyetgsikp gviggskpkv atpkvvekia eykrqnptmf aweirdrlla 121
ervcdndtvp svssinriir tkvqqppnqp vpasshsigi qespvpnghs lpgrdflrkg
181 mrgdlftqqq levldrvfer qhysdifttt epikpeqtte ysamaslagg
lddmkanlas 241 ptpadigssv pgpqsypivt grdlasttlp gypphvppag
qgsysaptlt gmvpgspyyy 301 saaargaapp aaataydrh Paired box protein
Pax-5, isoform 9 NP_001267483.1 (SEQ ID NO: 353) 1 mdleknyptp
rtsrtghggv nqlggvfvng rplpdvvrqr ivelahqgvr pcdisrqlrv 61
shgcvskilg ryyetgsikp gviggskpkv atpkvvekia eykrqnptmf aweirdrlla
121 ervcdndtvp svssinriir tkvqqppnqp vpasshsigi qespvpnghs
lpgrdflrkg 181 mrgdlftqqq levldrvfer qhysdifttt epikpeqtte
ysamaslagg lddmkanlas 241 ptpadigssv pgpqsypivt grdlasttlp
gypphvppag qgsysaptlt gmvpgsefsg 301 spyshpqyss yndswrfpnp
gllgspyyys aaargaappa aataydrh Paired box protein Pax-5, isoform 10
NP_001267484.1 (SEQ ID NO: 354) 1 mdleknyptp rtsrtghggv nqlggvfvng
rplpdvvrqr ivelahqgvr pcdisrqlrv 61 shgcvskilg riirtkvqqp
pnqpvpassh sivstgsvtq vssvstdsag ssysisgilg 121 itspsadtnk
rkrdegiqes pvpnghslpg rdflrkqmrg dlftqqqlev ldrvferqhy 181
sdiftttepi kpeqtteysa maslaggldd mkanlasptp adigssvpgp qsypivtgse
241 fsgspyshpq yssyndswrf pnpgllgspy yysaaargaa ppaaataydr h Paired
box protein Pax-5, isoform 11 NP_001267485.1 (SEQ ID NO: 355) 1
mfaweirdrl laervcdndt vpsvssinri irtkvqqppn qpvpasshsi vstgsvtqvs
61 systdsagss ysisgilgit spsadtnkrk rdegiqespv pnghslpgrd
flrkqmrgdl 121 ftqqqlevld rvferqhysd iftttepikp eqtteysama
slagglddmk anlasptpad 181 igssvpgpqs ypivtgrdla sttlpgypph
vppagqgsys aptltgmvpg sefsgspysh 241 pqyssyndsw rfpnpgllgs
pyyysaaarg aappaaatay drh Platelet-derived growth factor receptor
beta, isoform 1 NP_002600.1 (SEQ ID NO: 356) 1 mrlpgampal
alkgelllls lllllepqis qglvvtppgp elvlnvsstf vltcsgsapv 61
vwermsqepp qemakaqdgt fssvltltnl tgldtgeyfc thndsrglet derkrlyifv
121 pdptvgflpn daeelfiflt eiteitiper vtdpqlvvtl hekkgdvalp
vpydhqrgfs 181 gifedrsyic kttigdrevd sdayyvyrlq vssinvsvna
vqtvvrqgen itlmcivign 241 evvnfewtyp rkesgrlvep vtdflldmpy
hirsilhips aeledsgtyt cnvtesvndh 301 qdekainitv vesgyvrllg
evgtlqfael hrsrtlqvvf eayppptvlw fkdnrtlgds 361 sageialstr
nvsetryvse ltivrvkvae aghytmrafh edaevqlsfq lqinvpvrvl 421
elseshpdsg eqtvrcrgrg mpqpniiwsa crdlkrcpre lpptllgnss eeesqletnv
481 tyweeeqefe vvstlrlqhv drplsvrctl rnavgqdtqe vivvphslpf
kvvvisaila 541 lvvltiisli ilimlwqkkp ryeirwkvie svssdgheyi
yvdpmqlpyd stwelprdql 601 vlgrtlgsga fgqvveatah glshsqatmk
vavkmlksta rssekqalms elkimshlgp 661 hlnvvnllga ctkggpiyii
teycrygdlv dylhrnkhtf lqhhsdkrrp psaelysnal 721 pvglplpshv
sltgesdggy mdmskdesvd yvpmldmkgd vkyadiessn ymapydnyvp 781
sapertcrat linespvlsy mdlvgfsyqv angmeflask ncvhrdlaar nvlicegklv
841 kicdfglard imrdsnyisk gstflplkwm apesifnsly ttlsdvwsfg
illweiftlg 901 gtpypelpmn eqfynaikrg yrmaqpahas deiyeimqkc
weekfeirpp fsqlvlller 961 llgegykkky qqvdeeflrs dhpailrsqa
rlpgfhglrs pldtssvlyt avqpnegdnd 1021 yiiplpdpkp evadegpleg
spslasstln evntsstisc dsplepqdep epepqlelqv 1081 epepeleqlp
dsgcpaprae aedsfl Platelet-derived growth factor receptor beta,
isoform 2 NP_001341945.1 (SEQ ID NO: 357) 1 msqeppqema kaqdgtfssv
ltltnltgld tgeyfcthnd srgletderk rlyifvpdpt 61 vgflpndaee
lfiflteite itipervtdp qlvvtlhekk gdvalpvpyd hqrgfsgife 121
drsyicktti gdrevdsday yvyrlqvssi nvsvnavqtv vrqgenitlm civignevvn
181 fewtyprkes grlvepvtdf lldmpyhirs ilhipsaele dsgtytcnvt
esvndhqdek 241 ainitvvesg yvrllgevgt lqfaelhrsr tlqvvfeayp
pptvlwfkdn rtlgdssage 301 ialstrnvse tryvseltlv rvkvaeaghy
tmrafhedae vqlsfqlqin vpvrvlelse 361 shpdsgeqtv rcrgrgmpqp
niiwsacrdl krcprelppt llgnsseees qletnvtywe 421 eeqefevvst
lrlqhvdrpl svrctlrnav gqdtqevivv phslpfkvvv isailalvvl 481
tiisliilim lwqkkpryei rwkviesyss dgheyiyvdp mqlpydstwe lprdqlvlgr
541 tlgsgafgqv veatahglsh sqatmkvavk mlkstarsse kqalmselki
mshlgphlnv 601 vnllgactkg gpiyiiteyc rygdlvdylh rnkhtflqhh
sdkrrppsae lysnalpvgl 661 plpshvsltg esdggymdms kdesvdyvpm
ldmkgdvkya diessnymap ydnyvpsape 721 rtcratline spvlsymdlv
gfsyqvangm eflaskncvh rdlaarnvli cegklvkicd 781 fglardimrd
snyiskgstf lplkwmapes ifnslyttls dvwsfgillw eiftlggtpy 841
pelpmneqfy naikrgyrma qpahasdeiy eimqkcweek feirppfsql vlllerllge
901 gykkkyqqvd eeflrsdhpa ilrsqarlpg fhglrspldt ssvlytavqp
negdndyiip 961 lpdpkpevad egplegspsl asstlnevnt sstiscdspl
epqdepepep qlelqvepep 1021 eleqlpdsgc papraeaeds fl
Platelet-derived growth factor receptor beta, isoform 3
NP_001341946.1 (SEQ ID NO: 358) 1 mitnvaflvs lrteatsakp plgtgrwilm
ptmstdsrvs plsglmlsry ssinvsvnav 61 qtvvrqgeni tlmcivigne
vvnfewtypr kesgrlvepv tdflldmpyh irsilhipsa 121 eledsgtytc
nvtesvndhq dekainitvv esgyvrllge vgtlqfaelh rsrtlqvvfe 181
ayppptvlwf kdnrtlgdss ageialstrn vsetryvsel tivrvkvaea ghytmrafhe
241 daevqlsfql qinvpvrvle lseshpdsge qtvrcrgrgm pqpniiwsac
rdlkrcprel 301 pptllgnsse eesqletnvt yweeeqefev vstlrlqhvd
rplsvrctlr navgqdtgev 361 ivvphslpfk vvvisailal vvltiislii
limlwqkkpr yeirwkvies vssdgheyiy 421 vdpmqlpyds twelprdqlv
lgrtlgsgaf gqvveatahg lshsqatmkv avkmlkstar 481 ssekqalmse
lkimshlgph lnvvnllgac tkggpiyiit eycrygdlvd ylhrnkhtfl 541
qhhsdkrrpp saelysnalp vglplpshvs ltgesdggym dmskdesvdy vpmldmkgdv
601 kyadiessny mapydnyvps apertcratl inespvlsym dlvgfsyqva
ngmeflaskn 661 cvhrdlaarn vlicegklvk icdfglardi mrdsnyiskg
stflplkwma pesifnslyt 721 tlsdvwsfgi llweiftlgg tpypelpmne
qfynaikrgy rmaqpahasd eiyeimqkcw 781 eekfeirppf sqlvlllerl
lgegykkkyq qvdeeflrsd hpailrsqar lpgfhglrsp 841 ldtssvlyta
vqpnegdndy iiplpdpkpe vadegplegs pslasstlne vntsstiscd 901
splepqdepe pepqlelqve pepeleqlpd sgcpapraea edsfl Placenta-specific
protein 1 precursor NP_001303816.1, NP_001303817.1, NP_001303818.1,
NP_068568.1 (SEQ ID NO: 359) 1 mkvfkfiglm illtsafsag sgqspmtvlc
sidwfmvtvh pfmlnndvcv hfhelhlglg 61 cppnhvqpha yqftyrvtec
girakaysqd mviysteihy sskgtpskfv ipvscaapqk 121 spwltkpcsm
rvasksrata qkdekcyevf slsqssqrpn cdcppcvfse eehtqvpchq 181
agaqeaqplq pshfldised wslhtddmig sm Melanoma antigen preferentially
expressed in tumors, isoform a NP_001278644.1, NP_001278645.1,
NP_006106.1, NP_996836.1, NP_996837.1, NP_996838.1, NP_996839.1
(SEQ ID NO: 360) 1 merrrlwgsi qsryismsvw tsprrlvela gqsllkdeal
aiaalellpr elfpplfmaa 61 fdgrhsqtlk amvqawpftc lplgvlmkgq
hlhletfkav ldgldvllaq evrprrwklq 121 vldlrknshq dfwtvwsgnr
aslysfpepe aaqpmtkkrk vdglsteaeq pfipvevlvd 181 lflkegacde
lfsyliekvk rkknvlrlcc kklkifampm qdikmilkmv qldsiedlev 241
tctwklptla kfspylgqmi nlrrlllshi hassyispek eeqyiaqfts qflslqclqa
301 lyvdslfflr grldqllrhv mnpletlsit ncrlsegdvm hlsqspsysq
lsvlslsgvm 361 ltdvspeplq allerasatl qdlvfdecgi tddqllallp
slshcsqltt lsfygnsisi 421 salqsllqhl iglsnlthvl ypvplesyed
ihgtlhlerl aylharlrel lcelgrpsmv 481 wlsanpcphc gdrtfydpep
ilcpcfmpn Melanoma antigen preferentially expressed in tumors,
isoform b NP_001278646.1, NP_001278648.1, NP_001305055.1,
NP_001305056.1 (SEQ ID NO:
361) 1 msvwtsprrl velagqsllk dealaiaale llprelfppl fmaafdgrhs
qtlkamvqaw 61 pftclplgvl mkgqhlhlet fkavldgldv llaqevrprr
wklqvldlrk nshqdfwtvw 121 sgnraslysf pepeaaqpmt kkrkvdglst
eaeqpfipve vlvdlflkeg acdelfsyli 181 ekvkrkknvl rlcckklkif
ampmqdikmi lkmvqldsie dlevtctwkl ptlakfspyl 241 gqminlrrll
lshihassyi spekeeqyia qftsqflslq clqalyvdsl fflrgrldql 301
lrhvmnplet lsitncrlse gdvmhlsqsp sysqlsvlsl sgvmltdvsp eplqallera
361 satlqdlvfd ecgitddqll allpslshcs qlttlsfygn sisisalqsl
lqhliglsnl 421 thvlypvple syedihgtlh lerlaylhar lrellcelgr
psmvwlsanp cphcgdrtfy 481 dpepilcpcf mpn Phosphatidylinositol
3,4,5-triphosphate-dependent Rac exchanger 2 protein, isoform a
NP_079146.2 (SEQ ID NO: 362) 1 msedsrgdsr aesakdlekq lrlrvcvlse
lqkterdyvg tleflvsafl hrmnqcaask 61 vdknvteetv kmlfsniedi
lavhkeflkv veeclhpepn aqqevgtcfl hfkdkfriyd 121 eycsnhekaq
klllelnkir tirtfllncm llggrkntdv plegylvtpi qrickyplil 181
kellkrtprk hsdyaavmea lqamkavcsn ineakrqmek levleewqsh iegwegsnit
241 dtctemlmcg vllkissgni qervfflfdn llvyckrkhr rlknskastd
ghrylfrgri 301 ntevmevenv ddgtadfhss ghivvngwki hntaknkwfv
cmaktpeekh ewfeailker 361 errkglklgm eqdtwvmise qgeklykmmc
rqgnlikdrk rklttfpkcf lgsefvswll 421 eigeihrpee gvhlgqalle
ngiihhvtdk hqfkpeqmly rfryddgtfy prnemqdvis 481 kgvrlycrlh
slftpvirdk dyhlrtyksv vmanklidwl iaqgdcrtre eamifgvglc 541
dngfmhhvle ksefkdepll frffsdeeme gsnmkhrlmk hdlkvvenvi akslliksne
601 gsygfgledk nkvpiiklve kgsnaemagm evgkkifain gdlvfmrpfn
evdcflkscl 661 nsrkplrvlv stkpretvki pdsadglgfq irgfgpsvvh
avgrgtvaaa aglhpgqcii 721 kvnginvske thasviahvt acrkyrrptk
qdsiqwvyns iesaqedlqk shskppgdea 781 gdafdckvee vidkfntmai
idgkkehvsl tvdnvhleyg vvyeydstag ikcnvvekmi 841 epkgffslta
kilealaksd ehfvqnctsl nslneviptd lqskfsalcs eriehlcqri 901
ssykkfsrvl knrawptfkq akskisplhs sdfcptnchv nvmevsypkt stslgsafgv
961 qldsrkhnsh dkenksseqg klspmvyiqh tittmaapsg lslgqqdghg
lryllkeedl 1021 etqdiyqkll gklqtalkev emcvcqiddl lssityspkl
erktsegiip tdsdnekger 1081 nskrvcfnva gdeqedsghd tisnrdsysd
cnsnrnsias ftsicssqcs syfhsdemds 1141 gdelplsvri shdkqdkihs
clehlfsqvd sitnllkgqa vvrafdqtky ltpgrglqef 1201 qqemepklsc
pkrlrlhikq dpwnlpssvr tlaqnirkfv eevkcrllla lleysdsetq 1261
lrrdmvfcqt lvatvcafse qlmaalnqmf dnskenemet weasrrwldq ianagvlfhf
1321 qsllspnitd eqamledtiv alfdlekvsf yfkpseeepl vanvpltyqa
egsrqalkvy 1381 fyidsyhfeq lpqrlknggg fkihpvlfaq alesmegyyy
rdnvsveefq aqinaaslek 1441 vkqynqklra fyldksnspp nstskaayvd
klmrpinald elyrlvasfi rskrtaacan 1501 tacsasgvgl lsysselcnr
lgachiimcs sgvhrctlsv tleqaiilar shglppryim 1561 qatdvmrkqg
arvqntaknl gvrdrtpqsa prlyklcepp ppagee Phosphatidylinositol
3,4,5-triphosphate-dependent Rac exchanger 2 protein, isoform b
NP_079446.3 (SEQ ID NO: 363) 1 msedsrgdsr aesakdlekq lrlrvcvlse
lqkterdyvg tleflvsafl hrmnqcaask 61 vdknvteetv kmlfsniedi
lavhkeflkv veeclhpepn aqqevgtcfl hfkdkfriyd 121 eycsnhekaq
klllelnkir tirtfllncm llggrkntdv plegylvtpi qrickyplil 181
kellkrtprk hsdyaavmea lqamkavcsn ineakrqmek levleewqsh iegwegsnit
241 dtctemlmcg vllkissgni qervfflfdn llvyckrkhr rlknskastd
ghrylfrgri 301 ntevmevenv ddgtadfhss ghivvngwki hntaknkwfv
cmaktpeekh ewfeailker 361 errkglklgm eqdtwvmise qgeklykmmc
rqgnlikdrk rklttfpkcf lgsefvswll 421 eigeihrpee gvhlgqalle
ngiihhvtdk hqfkpeqmly rfryddgtfy prnemqdvis 481 kgvrlycrlh
slftpvirdk dyhlrtyksv vmanklidwl iaqgdcrtre eamifgvglc 541
dngfmhhvle ksefkdepll frffsdeeme gsnmkhrlmk hdlkvvenvi akslliksne
601 gsygfgledk nkvpiiklve kgsnaemagm evgkkifain gdlvfmrpfn
evdcflkscl 661 nsrkplrvlv stkpretvki pdsadglgfq irgfgpsvvh
avgrgtvaaa aglhpgqcii 721 kvnginvske thasviahvt acrkyrrptk
qdsiqwvyns iesaqedlqk shskppgdea 781 gdafdckvee vidkfntmai
idgkkehvsl tvdnvhleyg vvyeydstag ikcnvvekmi 841 epkgffslta
kilealaksd ehfvqnctsl nslneviptd lqskfsalcs eriehlcqri 901
ssykkvqase rfynftarha vwehsfdlhs vsstfpvpvt meflllpppl lgisqdgrqh
961 cipedlpsqe mllaerapv Protamine-2, isoform 1 NP_002753.2 (SEQ ID
NO: 364) 1 mvryrvrsls ershevyrqq lhgqeqghhg qeeqglspeh vevyerthgq
shyrrrhcsr 61 rrlhrihrrq hrscrrrkrr scrhrrrhrr gcrtrkrtcr rh
Protamine-2, isoform 2 NP_001273285.1 (SEQ ID NO: 365) 1 mvryrvrsls
ershevyrqq lhgqeqghhg qeeqglspeh vevyerthgq shyrrrhcsr 61
rrlhrihrrq hrscrrrkrr scrhrrrhrr eslgdplnqn flsqkaaepg rehaegtklp
121 gpltpswklr ksrpkhqvrp Protamine-2, isoform 3 NP_001273286.1
(SEQ ID NO: 366) 1 mvryrvrsls ershevyrqq lhgqeqghhg qeeqglspeh
vevyerthgq shyrrrhcsr 61 rrlhrihrrq hrscrrh Protamine-2, isoform 4
NP_001273287.1 (SEQ ID NO: 367) 1 mvryrvrsls ershevyrqq lhgqeqghhg
qeeqglspeh vevyerthgq shyrrrhcsr 61 rrlhrihrrq hrscrrrkrr
scrhrrrhrr epgrehaegt klpgpltpsw klrksrpkhq 121 vrp Protamine-2,
isoform 5 NP_001273288.1 (SEQ ID NO: 368) 1 mvryrvrsls ershevyrqq
lhgqeqghhg qeeqglspeh vevyerthgq shyrrrhcsr 61 rrlhrihrrq
hrscrrrkrr scrhrrrhrr glpapppcpa cp Progranulin NP_002078.1 (SEQ ID
NO: 369) 1 mwtlvswval taglvagtrc pdgqfcpvac cldpggasys ccrplldkwp
ttlsrhlggp 61 cqvdahcsag hsciftvsgt ssccpfpeav acgdghhccp
rgfhcsadgr scfqrsgnns 121 vgaiqcpdsq fecpdfstcc vmvdgswgcc
pmpqascced rvhccphgaf cdlvhtrcit 181 ptgthplakk lpaqrtnrav
alsssvmcpd arsrcpdgst ccelpsgkyg ccpmpnatcc 241 sdhlhccpqd
tvcdliqskc lskenattdl ltklpahtvg dvkcdmevsc pdgytccrlq 301
sgawgccpft qavccedhih ccpagftcdt qkgtceqgph qvpwmekapa hlslpdpqal
361 krdvpcdnvs scpssdtccq ltsgewgccp ipeavccsdh qhccpqgytc
vaegqcqrgs 421 eivaglekmp arraslshpr digcdqhtsc pvgqtccpsl
ggswaccqlp havccedrqh 481 ccpagytcnv karscekevv saqpatflar
sphvgvkdve cgeghfchdn qtccrdnrqg 541 waccpyrqgv ccadrrhccp
agfrcaargt kclrreaprw daplrdpalr qll Myeloblastin precursor
NP_002768.3 (SEQ ID NO: 370) 1 mahrppspal asvllallls gaaraaeivg
gheaqphsrp ymaslqmrgn pgshfcggtl 61 ihpsfvltaa hclrdipqrl
vnvvlgahnv rtqeptqqhf svaqvflnny daenklndvl 121 liqlsspanl
sasvatvqlp qqdqpvphgt qclamgwgrv gandppaqvl qelnvtvvtf 181
fcrphnictf vprrkagicf gdsggplicd giiqgidsfv iwgcatrlfp dfftrvalyv
241 dwirstlrrv eakgrp Prostate stem cell antigen preportein
NP_005663.2 (SEQ ID NO: 371) 1 maglalqpgt allcysckaq vsnedclqve
nctqlgeqcw tariravgll tviskgcsln 61 cvddsqdyyv gkknitccdt
dlcnasgaha lqpaaailal lpalglllwg pgql Ras-related C3 botulinum
toxin substrate 1 isoform Raclb NP_061485.1 (SEQ ID NO: 372) 1
mqaikcvvvg dgavgktcll isyttnafpg eyiptvfdny sanvmvdgkp vnlglwdtag
61 qedydrlrpl sypqtvgety gkditsrgkd kpiadvflic fslvspasfe
nvrakwypev 121 rhhcpntpii lvgtkldlrd dkdtieklke kkltpitypq
glamakeiga vkylecsalt 181 qrglktvfde airavlcppp vkkrkrkcll l
Regenerating islet-derived protein 3-alpha precursor NP_002571.1,
NP_620354.1, NP_620355.1 (SEQ ID NO: 373) 1 mlppmalpsv swmllsclml
lsqvqgeepq relpsarirc pkgskaygsh cyalflspks 61 wtdadlacqk
rpsgnlvsvl sgaegsfvss lvksignsys yvwiglhdpt qgtepngegw 121
ewsssdvmny fawernpsti sspghcasls rstaflrwkd yncnvrlpyv ckftd
Regulator of G-protein signaling 5, isoform 1 NP_003608.1 (SEQ ID
NO: 374) 1 mckglaalph sclerakeik iklgillqkp dsvgdlvipy nekpekpakt
qktsldealq 61 wrdsldkllq nnyglasfks flksefseen lefwiacedy
kkikspakma ekakqiyeef 121 iqteapkevn idhftkditm knlvepslss
fdmaqkriha lmekdslprf vrsefyqeli 181 k Regulator of G-protein
signaling 5, isoform 2 NP_001182232.1, NP_001241677.1 (SEQ ID NO:
375) 1 maekakqiye efiqteapke vnidhftkdi tmknlvepsl ssfdmaqkri
halmekdslp 61 rfvrsefyqe lik Regulator of G-protein signaling 5,
isoform 3 NP_001241678.1 (SEQ ID NO: 376) 1 mckglaalph sclerakeik
iklgillqkp dsvgdlvipy nekpekpakt qktsldealq 61 wrdsldkllq
nnyglasfks flksefseen lefwiacedy kkikspakma ekakqiyeef 121
iqteapkevg lwvnidhftk ditmknlvep slssfdmaqk rihalmekds lprfvrsefy
181 qelik Rho-related GTP-binding protein RhoC precursor
NP_001036143.1, NP_001036144.1, NP_786886.1 (SEQ ID NO: 377) 1
maairkklvi vgdgacgktc llivfskdqf pevyvptvfe nyiadievdg kqvelalwdt
61 agqedydrlr plsypdtdvi lmcfsidspd slenipekwt pevkhfcpnv
piilvgnkkd 121 lrqdehtrre lakmkqepvr seegrdmanr isafgylecs
aktkegvrev fematraglq 181 vrknkrrrgc pil Sarcoma antigen 1
NP_061136.2 (SEQ ID NO: 378) 1 mqasplqtsq ptppeelhaa ayvftndgqq
mrsdevnlva tghqskkkhs rkskrhsssk 61 rrksmsswld kqedaavths
iceerinngq pvadnvlsta ppwpdatiah nireermeng 121 qsrtdkvlst
appqlvhmaa agipsmstrd lhstvthnir eermengqpq pdnvlstgpt 181
glinmaatpi pamsardlya tvthnvceqk menvqpapdn vlltlrprri nmtdtgispm
241 strdpyatit ynvpeekmek gqpqpdnils tastglinva gagtpaistn
glystvphnv 301 ceekmendqp qpnnvlstvq pviiyltatg ipgmntrdqy
atithnvcee rvvnnqplps 361 nalstvlpgl aylatadmpa mstrdqhati
ihnlreekkd nsqptpdnvl savtpelinl 421 agagippmst rdqyatvnhh
vhearmengq rkqdnvlsnv lsglinmaga sipamssrdl 481 yatithsvre
ekmesgkpqt dkvisndapq lghmaaggip smstkdlyat vtqnvheerm 541
ennqpqpsyd lstvlpglty ltvagipams trdqyatvth nvheekikng qaasdnvfst
601 vppafinmaa tgvssmstrd qyaavthnir eekinnsqpa pgnilstapp
wlrhmaaagi 661 sstitrdlyv tathsvheek mtngqqapdn slstvppgci
nlsgagiscr strdlyatvi 721 hdiqeeemen dqtppdgfls nsdspelinm
tghcmppnal dsfshdftsl skdellykpd 781 snefavgtkn ysysagdppv
tvmslvetvp ntpqispama kkinddikyq lmkevrrfgq 841 nyerifille
evqgsmkvkr qfveftikea arfkkvvliq qlekalkeid shchlrkvkh 901 mrkr
Squamous cell carcinoma antigen recognized by T-cells 3 NP_055521.1
(SEQ ID NO: 379) 1 mataaetsas epeaeskagp kadgeedevk aartrrkvls
ravaaatykt mgpawdqqee 61 gvsesdgdey amassaessp geyeweydee
eeknqleier leeqlsinvy dynchvdlir 121 llrlegeltk vrmarqkmse
ifplteelwl ewlhdeisma qdgldrehvy dlfekavkdy 181 icpniwleyg
qysvggigqk gglekvrsvf eralssvglh mtkglalwea yrefesaive 241
aarlekvhsl frrqlaiply dmeatfaeye ewsedpipes viqnynkalq qlekykpyee
301 allqaeaprl aeyqayidfe mkigdpariq liferalven clvpdlwiry
sqyldrqlkv 361 kdlvlsvhnr airncpwtva lwsryllame rhgvdhqvis
vtfekalnag fiqatdyvei 421 wqayldylrr rvdfkqdssk eleelraaft
raleylkqev eerfnesgdp scvimqnwar 481 iearlcnnmq karelwdsim
trgnakyanm wleyynlera hgdtqhcrka lhravqctsd 541 ypehvcevll
tmertegsle dwdiavqkte trlarvneqr mkaaekeaal vqqeeekaeq 601
rkraraekka lkkkkkirgp ekrgadedde kewgddeeeq pskrrrvens ipaagetqnv
661 evaagpagkc aavdveppsk gkekaaslkr dmpkvlhdss kdsitvfvsn
lpysmqepdt 721 klrplfeacg evvqirpifs nrgdfrgycy vefkeeksal
qalemdrksv egrpmfvspc 781 vdksknpdfk vfrystslek hklfisglpf
sctkeeleei ckahgtvkdl rlvtnragkp 841 kglayveyen esqasqavmk
mdgmtikeni ikvaisnppq rkvpekpetr kapggpmllp 901 qtygargkgr
tqlsllpral qrpsaaapqa engpaaapav aapaateapk msnadfaklf 961 lrk
Secretory leukocyte protein inhibitor NP_003055.1 (SEQ ID NO: 380)
1 mkssglfpfl vllalgtlap wavegsgksf kagvcppkks aqclrykkpe cqsdwqcpgk
61 krccpdtcgi kcldpvdtpn ptrrkpgkcp vtyggclmln ppnfcemdgq
ckrdlkccmg 121 mcgkscvspv ka Transcription factor SOX-10
NP_008872.1 (SEQ ID NO: 381) 1 maeeqdlsev elspvgseep rclspgsaps
lgpdgggggs glraspgpge lgkvkkeqqd 61 geadddkfpv cireaysqvl
sgydwtivpm pvrvngasks kphvkrpmna fmvwaqaarr 121 kladqyphlh
naelsktlgk lwrllnesdk rpfieeaerl rmqhkkdhpd ykyqprrrkn 181
gkaaqgeaec pggeaeqggt aaiqahyksa hldhrhpgeg spmsdgnpeh psgqshgppt
241 ppttpktelq sgkadpkrdg rsmgeggkph idfgnvdige ishevmsnme
tfdvaeldqy 301 lppnghpghv ssysaagygl gsalavasgh sawiskppgv
alptvsppgv dakaqvktet 361 agpqgpphyt dqpstsqiay tslslphygs
afpsisrpqf dysdhqpsgp yyghsgqasg 421 lysafsymgp sqrplytais
dpspsgpqsh spthweqpvy ttlsrp Sperm surface protein Sp17 NP_059121.1
(SEQ ID NO: 382) 1 msipfsnthy ripqgfgnll egltreilre qpdnipafaa
ayfesllekr ektnfdpaew 61 gskvedrfyn nhafeeqepp eksdpkqees
qisgkeeets vtildsseed kekeevaavk 121 iqaafrghia reeakkmktn
slqneekeen k Protein SSX2, isoform a NP_003138.3 (SEQ ID NO: 383) 1
mngddafarr ptvgaqipek iqkafddiak yfskeewekm kasekifyvy mkrkyeamtk
61 lgfkatlppf mcnkraedfq gndldndpnr gnqverpqmt fgrlqgispk
impkkpaeeg 121 ndseevpeas gpqndgkelc ppgkpttsek ihersgnrea
qekeerrgta hrwssqnthn 181 igrfslstsm gavhgtpkti thnrdpkggn
mpgptdcvre nsw Protein SSX2, isoform b NP_783629.1 (SEQ ID NO: 384)
1 mngddafarr ptvgaqipek iqkafddiak yfskeewekm kasekifyvy mkrkyeamtk
61 lgfkatlppf mcnkraedfq gndldndpnr gnqverpqmt fgrlqgispk
impkkpaeeg 121 ndseevpeas gpqndgkelc ppgkpttsek ihersgpkrg
ehawthrlre rkqlviyeei 181 sdpeedde Protein SSX2, isoform c
NP_001265626.1 (SEQ ID NO: 385) 1 mngddafarr ptvgaqipek iqkafddiak
yfskeewekm kasekifyvy mkrkyeamtk 61 lgfkatlppf mcnkraedfq
gndldndpnr gnqverpqmt fgrlqgispk impkkpaeeg 121 ndseevpeas
gpqndgkelc ppgkpttsek ihersgnrea qekeerrgta hrwssqnthn 181
igpkrgehaw thrlrerkql viyeeisdpe edde Lactosylceramide
alpha-2,3-sialyltransferase, isoform 1 NP_003887.3 (SEQ ID NO: 386)
1 mrtkaagcae rrplqprtea aaapagramp seytyvklrs dcsrpslqwy traqskmrrp
61 slllkdilkc tllvfgvwil yilklnytte ecdmkkmhyv dpdhvkraqk
yaqqvlqkec 121 rpkfaktsma llfehrysvd llpfvqkapk dseaeskydp
pfgfrkfssk vqtllellpe 181 hdlpehlkak tcrrcvvigs ggilhglelg
htlnqfdvvi rlnsapvegy sehvgnktti 241 rmtypegapl sdleyysndl
fvavlfksvd fnwlqamvkk etlpfwvrlf fwkqvaekip 301 lqpkhfriln
pviiketafd ilqysepqsr fwgrdknvpt igviavvlat hlcdevslag 361
fgydlnqprt plhyfdsqcm aamnfqtmhn vttetkfllk lvkegvvkdl sggidref
Lactosylceramide alpha-2,3-sialyltransferase, isoform 2
NP_001035902.1 (SEQ ID NO: 387) 1 masvpmpsey tyvklrsdcs rpslqwytra
qskmrrpsll lkdilkctll vfgvwilyil 61 klnytteecd mkkmhyvdpd
hvkraqkyaq qvlqkecrpk faktsmallf ehrysvdllp 121 fvqkapkdse
aeskydppfg frkfsskvqt llellpehdl pehlkaktcr rcvvigsggi 181
lhglelghtl nqfdvvirin sapvegyseh vgnkttirmt ypegaplsdl eyysndlfva
241 vlfksvdfnw lqamvkketl pfwvrlffwk qvaekiplqp khfrilnpvi
iketafdilq 301 ysepqsrfwg rdknvptigv iavvlathlc devslagfgy
dlnqprtplh yfdsqcmaam 361 nfqtmhnvtt etkfllklvk egvvkdlsgg idref
Lactosylceramide alpha-2,3-sialyltransferase, isoform 3
NP_001341152.1, NP_001341153.1, NP_001341155.1, NP_001341162.1,
NP_001341163.1,
NP_001341177.1 (SEQ ID NO: 388) 1 mallfehrys vdllpfvqka pkdseaesky
dppfgfrkfs skvqtllell pehdlpehlk 61 aktcrrcvvi gsggilhgle
lghtlnqfdv virlnsapve gysehvgnkt tirmtypega 121 plsdleyysn
dlfvavlfks vdfnwlqamv kketlpfwvr lffwkqvaek iplqpkhfri 181
lnpviiketa fdilqysepq srfwgrdknv ptigviavvl athlcdevsl agfgydlnqp
241 rtplhyfdsq cmaamnfqtm hnvttetkfl lklvkegvvk dlsggidref
Lactosylceramide alpha-2,3-sialyltransferase, isoform 4
NP_001341156.1, NP_001341158.1, NP_001341167.1 (SEQ ID NO: 389) 1
mpseytyvkl rsdcsrpslq wytraqskmr rpslllkdil kctllvfgvw ilyilklnyt
61 teecdmkkmh yvdpdhvkra qkyaqqvlqk ecrpkfakts mallfehrys
vdllpfvqka 121 pkdseaesky dppfgfrkfs skvqtllell pehdlpehlk
aktcrrcvvi gsggilhgle 181 lghtlnqfdv virinsapve gysehvgnkt
tirmtypega plsdleyysn dlfvavlfks 241 vdfnwlqamv kketlpfwvr
lffwkqvaek iplqpkhfri lnpviiketa fdilqysepq 301 srfwgrdknv
ptigviavvl athlcdevsl agfgydlnqp rtplhyfdsq cmaamnfqtm 361
hnvttetkfl lklvkegvvk dlsggidref Lactosylceramide
alpha-2,3-sialyltransferase, isoform 5 NP_001341176.1 (SEQ ID NO:
390) 1 mtypegapls dleyysndlf vavlfksvdf nwlqamvkke tlpfwvrlff
wkqvaekipl 61 qpkhfrilnp viiketafdi lqysepqsrf wgrdknvpti
gviavvlath lcdevslagf 121 gydlnqprtp lhyfdsqcma amnfqtmhnv
ttetkfllkl vkegvvkdls ggidref Alpha-N-acetylneuraminide
alpha-2,8-sialyltransferase, isoform 1 NP_003025.1 (SEQ ID NO: 391)
1 mspcgrarrq tsrgamavla wkfprtrlpm gasalcvvvl cwlyifpvyr lpnekeivqg
61 vlqqgtawrr nqtaarafrk qmedccdpah lfamtkmnsp mgksmwydge
flysftidns 121 tyslfpqatp fqlplkkcav vgnggilkks gcgrqidean
fvmrcnlppl sseytkdvgs 181 ksqlvtanps iirqrfqnll wsrktfvdnm
kiynhsyiym pafsmktgte pslrvyytls 241 dvganqtvlf anpnflrsig
kfwksrgiha krlstglflv saalglceev aiygfwpfsv 301 nmheqpishh
yydnvlpfsg fhampeeflq lwylhkigal rmqldpcedt slqpts
Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase, isoform 2
NP_001291379.1 (SEQ ID NO: 392) 1 mtgsfythsp ltiqltlssh rcnlpplsse
ytkdvgsksq lvtanpsiir qrfqnllwsr 61 ktfvdnmkiy nhsyiympaf
smktgtepsl rvyytlsdvg anqtvlfanp nflrsigkfw 121 ksrgihakrl
stglflvsaa lglceevaiy gfwpfsvnmh eqpishhyyd nvlpfsgfha 181
mpeeflqlwy lhkigalrmq ldpcedtslq pts Survivin, isoform 1
NP_001159.2 (SEQ ID NO: 393) 1 mgaptlppaw qpflkdhris tfknwpfleg
cactpermae agfihcpten epdlaqcffc 61 fkelegwepd ddpieehkkh
ssgcaflsvk kqfeeltlge flkldrerak nkiaketnnk 121 kkefeetaek
vrraieqlaa md Survivin, isoform 2 NP_001012270.1 (SEQ ID NO: 394) 1
mgaptlppaw qpflkdhris tfknwpfleg cactpermae agfihcpten epdlaqcffc
61 fkelegwepd ddpmqrkpti rrknlrklrr kcavpssswl pwieasgrsc
lvpewlhhfq 121 glfpgatslp vgplams Survivin, isoform 3
NP_001012271.1 (SEQ ID NO: 395) 1 mgaptlppaw qpflkdhris tfknwpfleg
cactpermae agfihcpten epdlaqcffc 61 fkelegwepd ddpigpgtva
yacntstlgg rggritreeh kkhssgcafl svkkqfeelt 121 lgeflkldre
raknkiaket nnkkkefeet aekvrraieq laamd T-box 4, isoform 1
NP_001308049.1 (SEQ ID NO: 396) 1 mlqdkglses eeafrapgpa lgeasaanap
epalaapgls gaalgsppgp gadvvaaaaa 61 eqtienikvg lhekelwkkf
heagtemiit kagrrmfpsy kvkvtgmnpk tkyillidiv 121 paddhrykfc
dnkwmvagka epampgrlyv hpdspatgah wmrqlvsfqk lkltnnhldp 181
fghiilnsmh kyqprlhivk adennafgsk ntafcthvfp etsfisvtsy qnhkitqlki
241 ennpfakgfr gsddsdlrva rlqskeypvi sksimrqrli spqlsatpdv
gpllgthqal 301 qhyqhengah sqlaepqdlp lstfptqrds slfyhclkrr
adgtrhldlp ckrsyleaps 361 svgedhyfrs pppydqqmls psycsevtpr
eacmysgsgp eiagvsgvdd lpppplscnm 421 wtsyspytsy svqtmetvpy
qpfpthftat tmmprlptls aqssqppgna hfsvynqlsq 481 sqvrergpsa
sfprerglpq gcerkppsph lnaaneflys qtfslsress lqyhsgmgtv 541 enwtdg
T-box 4, isoform 2 NP_ 060958.2 (SEQ ID NO: 397) 1 mlqdkglses
eeafrapgpa lgeasaanap epalaapgls gaalgsppgp gadvvaaaaa 61
eqtienikvg lhekelwkkf heagtemiit kagrrmfpsy kvkvtgmnpk tkyillidiv
121 paddhrykfc dnkwmvagka epampgrlyv hpdspatgah wmrqlvsfqk
lkltnnhldp 181 fghiilnsmh kyqprlhivk adennafgsk ntafcthvfp
etsfisvtsy qnhkitqlki 241 ennpfakgfr gsddsdlrva rlqskeypvi
sksimrqrli spqlsatpdv gpllgthqal 301 qhyqhengah sqlaepqdlp
lstfptqrds slfyhclkrr dgtrhldlpc krsyleapss 361 vgedhyfrsp
ppydqqmlsp sycsevtpre acmysgsgpe iagvsgvddl pppplscnmw 421
tsyspytsys vqtmetvpyq pfpthftatt mmprlptlsa qssqppgnah fsvynqlsgs
481 qvrergpsas fprerglpqg cerkppsphl naaneflysq tfslsressl
qyhsgmgtve 541 nwtdg Angiopoietin-1 receptor, isoform 1 NP_000450.2
(SEQ ID NO: 398) 1 mdslaslvlc gvslllsgtv egamdlilin slplvsdaet
sltciasgwr phepitigrd 61 fealmnqhqd plevtqdvtr ewakkvvwkr
ekaskingay fcegrvrgea irirtmkmrq 121 qasflpatlt mtvdkgdnvn
isfkkvlike edaviykngs fihsvprhev pdilevhlph 181 aqpqdagvys
aryiggnlft saftrlivrr ceaqkwgpec nhlctacmnn gvchedtgec 241
icppgfmgrt cekacelhtf grtckercsg qegcksyvfc lpdpygcsca tgwkglqcne
301 achpgfygpd cklrcscnng emcdrfqgcl cspgwqglqc eregiprmtp
kivdlpdhie 361 vnsgkfnpic kasgwplptn eemtivkpdg tvlhpkdfnh
tdhfsvaift ihrilppdsg 421 vwvcsvntva gmvekpfnis vkvlpkpina
pnvidtghnf avinissepy fgdgpikskk 481 llykpvnhye awqhiqvtne
ivtlnylepr teyelcvqlv rrgeggeghp gpvrrfttas 541 iglppprgln
llpksqttln ltwqpifpss eddfyvever rsvqksdqqn ikvpgnitsv 601
llnnlhpreq yvvrarvntk aqgewsedlt awtlsdilpp qpenikisni thssaviswt
661 ildgysissi tirykvqgkn edqhvdvkik natitqyqlk glepetayqv
difaennigs 721 snpafshelv tlpesqapad lgggkmllia ilgsagmtcl
tvllafliil qlkranvqrr 781 maqafqnvre epavqfnsgt lalnrkvknn
pdptiypvld wndikfqdvi gegnfgqvlk 841 arikkdglrm daaikrmkey
askddhrdfa gelevlcklg hhpniinllg acehrgylyl 901 aieyaphgnl
ldflrksrvl etdpafaian stastlssqq llhfaadvar gmdylsqkqf 961
ihrdlaarni lvgenyvaki adfglsrgqe vyvkktmgrl pvrwmaiesl nysvyttnsd
1021 vwsygvllwe ivslggtpyc gmtcaelyek lpqgyrlekp lncddevydl
mrqcwrekpy 1081 erpsfaqilv slnrmleerk tyvnttlyek ftyagidcsa eeaa
Angiopoietin-1 receptor, isoform 2 NP_001277006.1 (SEQ ID NO: 399)
1 mdslaslvlc gvslllsgtv egamdlilin slplvsdaet sltciasgwr phepitigrd
61 fealmnqhqd plevtqdvtr ewakkvvwkr ekaskingay fcegrvrgea
irirtmkmrq 121 qasflpatlt mtvdkgdnvn isfkkvlike edaviykngs
fihsvprhev pdilevhlph 181 aqpqdagvys aryiggnlft saftrlivrr
ceaqkwgpec nhlctacmnn gvchedtgec 241 icppgfmgrt cekacelhtf
grtckercsg qegcksyvfc lpdpygcsca tgwkglqcne 301 giprmtpkiv
dlpdhievns gkfnpickas gwplptneem tivkpdgtvl hpkdfnhtdh 361
fsvaiftihr ilppdsgvwv csvntvagmv ekpfnisvkv lpkpinapnv idtghnfavi
421 nissepyfgd gpikskklly kpvnhyeawq hiqvtneivt lnyleprtey
elcvqlvrrg 481 eggeghpgpv rrfttasigl ppprglnllp ksqttlnitw
qpifpssedd fyveverrsv 541 qksdqqnikv pgnltsvlln nlhpreqyvv
rarvntkaqg ewsedltawt lsdilppqpe 601 nikisniths saviswtild
gysissitir ykvqgknedq hvdvkiknat itqyqlkgle 661 petayqvdif
aennigssnp afshelvtlp esqapadlgg gkmlliailg sagmtcltvl 721
lafliilqlk ranvqrrmaq afqnvreepa vqfnsgtlal nrkvknnpdp tiypvldwnd
781 ikfqdvigeg nfgqvlkari kkdglrmdaa ikrmkeyask ddhrdfagel
evlcklghhp 841 niinllgace hrgylylaie yaphgnlldf lrksrvletd
pafaiansta stlssqqllh 901 faadvargmd ylsqkqfihr dlaarnilvg
enyvakiadf glsrgqevyv kktmgrlpvr 961 wmaieslnys vyttnsdvws
ygvllweivs lggtpycgmt caelyeklpq gyrlekpinc 1021 ddevydlmrq
cwrekpyerp sfaqilvsln rmleerktyv nttlyekfty agidcsaeea 1081 a
Angiopoietin-1 receptor, isoform 3 NP_001277007.1 (SEQ ID NO: 400)
1 mdslaslvlc gvslllsasf lpatltmtvd kgdnvnisfk kvlikeedav iykngsfihs
61 vprhevpdil evhlphaqpq dagvysaryi ggnlftsaft rlivrrceaq
kwgpecnhlc 121 tacmnngvch edtgecicpp gfmgrtceka celhtfgrtc
kercsgqegc ksyvfclpdp 181 ygcscatgwk glqcnegipr mtpkivdlpd
hievnsgkfn pickasgwpl ptneemtivk 241 pdgtvlhpkd fnhtdhfsva
iftihrilpp dsgvwvcsvn tvagmvekpf nisvkvlpkp 301 lnapnvidtg
hnfaviniss epyfgdgpik skkllykpvn hyeawqhiqv tneivtlnyl 361
eprteyelcv qlvrrgegge ghpgpvrrft tasiglpppr glnllpksqt tlnitwqpif
421 psseddfyve verrsvqksd qqnikvpgnl tsvllnnlhp reqyvvrary
ntkaqgewse 481 dltawtlsdi lppqpeniki snithssavi swtildgysi
ssitirykvq gknedqhvdv 541 kiknatitqy qlkglepeta yqvdifaenn
igssnpafsh elvtlpesqa padlgggkml 601 liailgsagm tcltvllafl
iilqlkranv qrrmaqafqn reepavqfns gtlalnrkvk 661 nnpdptiypv
ldwndikfqd vigegnfgqv lkarikkdgl rmdaaikrmk eyaskddhrd 721
fagelevlck lghhpniinl lgacehrgyl ylaieyaphg nlldflrksr vletdpafai
781 anstastlss qqllhfaadv argmdylsqk qfihrdlaar nilvgenyva
kiadfglsrg 841 qevyvkktmg rlpvrwmaie slnysvyttn sdvwsygvll
weivslggtp ycgmtcaely 901 eklpqgyrle kpincddevy dlmrqcwrek
pyerpsfaqi lvslnrmlee rktyvnttly 961 ekftyagidc saeeaa Telomerase
reverse transcriptase, isoform 1 NP_937983.2 (SEQ ID NO: 401) 1
mpraprcrav rsllrshyre vlplatfvrr lgpqgwrlvq rgdpaafral vaqclvcvpw
61 darpppaaps frqvsclkel varvlqrlce rgaknvlafg falldgargg
ppeafttsvr 121 sylpntvtda lrgsgawgll lrrvgddvlv hllarcalfv
lvapscayqv cgpplyqlga 181 atqarpppha sgprrrlgce rawnhsvrea
gvplglpapg arrrggsasr slplpkrprr 241 gaapepertp vgqgswahpg
rtrgpsdrgf cvvsparpae eatslegals gtrhshpsvg 301 rqhhagppst
srpprpwdtp cppvyaetkh flyssgdkeq lrpsfllssl rpsltgarrl 361
vetiflgsrp wmpgtprrlp rlpqrywqmr plflellgnh aqcpygvllk thcplraavt
421 paagvcarek pqgsvaapee edtdprrlvq llrghsspwq vygfvraclr
rlvppglwgs 481 rhnerrflrn tkkfislgkh aklslqeltw kmsvrdcawl
rrspgvgcvp aaehrlreei 541 lakflhwlms vyvvellrsf fyvtettfqk
nrlffyrksv wsklqsigir qhlkrvqlre 601 lseaevrqhr earpalltsr
lrfipkpdgl rpivnmdyvv gartfrrekr aerltsrvka 661 lfsvinyera
rrpgllgasv lglddihraw rtfvlrvraq dpppelyfvk vdvtgaydti 721
pqdrltevia siikpqntyc vrryavvqka ahghvrkafk shvstltdlq pymrqfvahl
781 qetsplrdav vieqssslne assglfdvfl rfmchhavri rgksyvqcqg
ipqgsilstl 841 lcslcygdme nklfagirrd glllrlvddf llvtphltha
ktflrtivrg vpeygcvvnl 901 rktvvnfpve dealggtafv qmpahglfpw
cgllldtrtl evqsdyssya rtsirasltf 961 nrgfkagrnm rrklfgvlrl
kchslfldlq vnslqtvctn iykilllqay rfhacvlqlp 1021 fhqqvwknpt
fflrvisdta slcysilkak nagmslgakg aagplpseav qwlchqafll 1081
kltrhrvtyv pllgslrtaq tqlsrklpgt tltaleaaan palpsdfkti ld
Telomerase reverse transcriptase, isoform 2 NP_001180305.1 (SEQ ID
NO: 402) 1 mpraprcrav rsllrshyre vlplatfvrr lgpqgwrlvq rgdpaafral
vaqclvcvpw 61 darpppaaps frqvsclkel varvlqrlce rgaknvlafg
falldgargg ppeafttsvr 121 sylpntvtda lrgsgawgll lrrvgddvlv
hllarcalfv lvapscayqv cgpplyqlga 181 atqarpppha sgprrrlgce
rawnhsvrea gvplglpapg arrrggsasr slplpkrprr 241 gaapepertp
vgqgswahpg rtrgpsdrgf cvvsparpae eatslegals gtrhshpsvg 301
rqhhagppst srpprpwdtp cppvyaetkh flyssgdkeq lrpsfllssl rpsltgarrl
361 vetiflgsrp wmpgtprrlp rlpqrywqmr plflellgnh aqcpygvllk
thcplraavt 421 paagvcarek pqgsvaapee edtdprrlvq llrqhsspwq
vygfvraclr rlvppglwgs 481 rhnerrflrn tkkfislgkh aklslqeltw
kmsvrdcawl rrspgvgcvp aaehrlreei 541 lakflhwlms vyvvellrsf
fyvtettfqk nrlffyrksv wsklqsigir qhlkrvqlre 601 lseaevrqhr
earpalltsr lrfipkpdgl rpivnmdyvv gartfrrekr aerltsrvka 661
lfsvinyera rrpgllgasv lglddihraw rtfvlrvraq dpppelyfvk vdvtgaydti
721 pqdrltevia siikpqntyc vrryavvqka ahghvrkafk shvstltdlq
pymrqfvahl 781 qetsplrdav vieqssslne assglfdvfl rfmchhavri
rgksyvqcqg ipqgsilstl 841 lcslcygdme nklfagirrd glllrlvddf
llvtphltha ktflsyarts irasltfnrg 901 fkagrnmrrk lfgvlrlkch
slfldlqvns lqtvctniyk illlqayrfh acvlqlpfhq 961 qvwknptffl
rvisdtaslc ysilkaknag mslgakgaag plpseavqwl chqafllklt 1021
rhrvtyvpll gslrtaqtql srklpgttlt aleaaanpal psdfktild Cellular
tumor antigen p53, isoform a NP_000537.3, NP_00lll9584.1 (SEQ ID
NO: 403) 1 meepqsdpsv epplsqetfs dlwkllpenn vlsplpsqam ddlmlspddi
eqwftedpgp 61 deaprmpeaa ppvapapaap tpaapapaps wplsssvpsq
ktyqgsygfr lgflhsgtak 121 svtctyspal nkmfcqlakt cpvqlwvdst
pppgtrvram aiykqsqhmt evvrrcphhe 181 rcsdsdglap pqhlirvegn
lrveylddrn tfrhsvvvpy eppevgsdct tihynymcns 241 scmggmnrrp
iltiitleds sgnllgrnsf evrvcacpgr drrteeenlr kkgephhelp 301
pgstkralpn ntssspqpkk kpldgeyftl qirgrerfem frelnealel kdaqagkepg
361 gsrahsshlk skkgqstsrh kklmfktegp dsd Cellular tumor antigen
p53, isoform b NP_00lll9586.1 (SEQ ID NO: 404) 1 meepqsdpsv
epplsqetfs dlwkllpenn vlsplpsqam ddlmlspddi eqwftedpgp 61
deaprmpeaa ppvapapaap tpaapapaps wplsssvpsq ktyqgsygfr lgflhsgtak
121 svtctyspal nkmfcqlakt cpvqlwvdst pppgtrvram aiykqsqhmt
evvrrcphhe 181 rcsdsdglap pqhlirvegn lrveylddrn tfrhsvvvpy
eppevgsdct tihynymcns 241 scmggmnrrp iltiitleds sgnllgrnsf
evrvcacpgr drrteeenlr kkgephhelp 301 pgstkralpn ntssspqpkk
kpldgeyftl qdqtsfqken c Cellular tumor antigen p53, isoform c
NP_00lll9585.1 (SEQ ID NO: 405) 1 meepqsdpsv epplsqetfs dlwkllpenn
vlsplpsqam ddlmlspddi eqwftedpgp 61 deaprmpeaa ppvapapaap
tpaapapaps wplsssvpsq ktyqgsygfr lgflhsgtak 121 svtctyspal
nkmfcqlakt cpvqlwvdst pppgtrvram aiykqsqhmt evvrrcphhe 181
rcsdsdglap pqhlirvegn lrveylddrn tfrhsvvvpy eppevgsdct tihynymcns
241 scmggmnrrp iltiitleds sgnllgrnsf evrvcacpgr drrteeenlr
kkgephhelp 301 pgstkralpn ntssspqpkk kpldgeyftl qmlldlrwcy flinss
Cellular tumor antigen p53, isoform d NP_00lll9587.1 (SEQ ID NO:
406) 1 mfcqlaktcp vqlwvdstpp pgtrvramai ykqsqhmtev vrrcphherc
sdsdglappq 61 hlirvegnlr veylddrntf rhsvvvpyep pevgsdctti
hynymcnssc mggmnrrpil 121 tiitledssg nllgrnsfev rvcacpgrdr
rteeenlrkk gephhelppg stkralpnnt 181 ssspqpkkkp ldgeyftlqi
rgrerfemfr elnealelkd aqagkepggs rahsshlksk 241 kgqstsrhkk
lmfktegpds d Cellular tumor antigen p53, isoform e NP_00lll9588.1
(SEQ ID NO: 407) 1 mfcqlaktcp vqlwvdstpp pgtrvramai ykqsqhmtev
vrrcphherc sdsdglappq 61 hlirvegnlr veylddrntf rhsvvvpyep
pevgsdctti hynymcnssc mggmnrrpil 121 tiitledssg nllgrnsfev
rvcacpgrdr rteeenlrkk gephhelppg stkralpnnt 181 ssspqpkkkp
ldgeyftlqd qtsfqkenc Cellular tumor antigen p53, isoform f
NP_00lll9589.1 (SEQ ID NO: 408) 1 mfcqlaktcp vqlwvdstpp pgtrvramai
ykqsqhmtev vrrcphherc sdsdglappq 61 hlirvegnlr veylddrntf
rhsvvvpyep pevgsdctti hynymcnssc mggmnrrpil 121 tiitledssg
nllgrnsfev rvcacpgrdr rteeenlrkk gephhelppg stkralpnnt 181
ssspqpkkkp ldgeyftlqm lldlrwcyfl inss Cellular tumor antigen p53,
isoform g NP_00lll9590.1, NP_001263689.1, NP_001263690.1 (SEQ ID
NO: 409) 1 mddlmlspdd ieqwftedpg pdeaprmpea appvapapaa ptpaapapap
swplsssvps 61 qktyqgsygf rlgflhsgta ksvtctyspa lnkmfcqlak
tcpvqlwvds tpppgtrvra 121 maiykqsqhm tevvrrcphh ercsdsdgla
ppqhlirveg nlrveylddr ntfrhsvvvp 181 yeppevgsdc ttihynymcn
sscmggmnrr piltiitled ssgnllgrns fevrvcacpg 241 rdrrteeenl
rkkgephhel ppgstkralp nntssspqpk kkpldgeyft lqirgrerfe 301
mfrelneale lkdaqagkep ggsrahsshl kskkgqstsr hkklmfkteg pdsd
Cellular tumor antigen p53, isoform h NP_001263624.1 (SEQ ID NO:
410) 1 mddlmlspdd ieqwftedpg pdeaprmpea appvapapaa ptpaapapap
swplsssvps 61 qktyqgsygf rlgflhsgta ksvtctyspa lnkmfcqlak
tcpvqlwvds tpppgtrvra 121 maiykqsqhm tevvrrcphh ercsdsdgla
ppqhlirveg nlrveylddr ntfrhsvvvp 181 yeppevgsdc ttihynymcn
sscmggmnrr piltiitled ssgnllgrns fevrvcacpg 241 rdrrteeenl
rkkgephhel ppgstkralp nntssspqpk kkpldgeyft lqmlldlrwc 301 yflinss
Cellular tumor antigen p53, isoform i NP_001263625.1 (SEQ ID NO:
411) 1 mddlmlspdd ieqwftedpg pdeaprmpea appvapapaa ptpaapapap
swplsssvps 61 qktyqgsygf rlgflhsgta ksvtctyspa lnkmfcqlak
tcpvqlwvds tpppgtrvra 121 maiykqsqhm tevvrrcphh ercsdsdgla
ppqhlirveg nlrveylddr ntfrhsvvvp 181 yeppevgsdc ttihynymcn
sscmggmnrr piltiitled ssgnllgrns fevrvcacpg
241 rdrrteeenl rkkgephhel ppgstkralp nntssspqpk kkpldgeyft
lqdqtsfqke 301 nc Cellular tumor antigen p53, isoform j
NP_001263626.1 (SEQ ID NO: 412) 1 maiykqsqhm tevvrrcphh ercsdsdgla
ppqhlirveg nlrveylddr ntfrhsvvvp 61 yeppevgsdc ttihynymcn
sscmggmnrr piltiitled ssgnllgrns fevrvcacpg 121 rdrrteeenl
rkkgephhel ppgstkralp nntssspqpk kkpldgeyft lqirgrerfe 181
mfrelneale lkdaqagkep ggsrahsshl kskkgqstsr hkklmfkteg pdsd
Cellular tumor antigen p53, isoform k NP_001263627.1 (SEQ ID NO:
413) 1 maiykqsqhm tevvrrcphh ercsdsdgla ppqhlirveg nlrveylddr
ntfrhsvvvp 61 yeppevgsdc ttihynymcn sscmggmnrr piltiitled
ssgnllgrns fevrvcacpg 121 rdrrteeenl rkkgephhel ppgstkralp
nntssspqpk kkpldgeyft lqdqtsfqke 181 nc Cellular tumor antigen p53,
isoform 1 NP_001263628.1 (SEQ ID NO: 414) 1 maiykqsqhm tevvrrcphh
ercsdsdgla ppqhlirveg nlrveylddr ntfrhsvvvp 61 yeppevgsdc
ttihynymcn sscmggmnrr piltiitled ssgnllgrns fevrvcacpg 121
rdrrteeenl rkkgephhel ppgstkralp nntssspqpk kkpldgeyft lqmlldlrwc
181 yflinss Dopachrome tautomerase, isoform 1 NP_001913.2 (SEQ ID
NO: 415) 1 msplwwgfll sclgckilpg aqgqfprvcm tvdslvnkec cprlgaesan
vcgsqqgrgq 61 ctevradtrp wsgpyilrnq ddrelwprkf fhrtckctgn
fagyncgdck fgwtgpncer 121 kkppvirqni hslspqereq flgaldlakk
rvhpdyvitt qhwlgllgpn gtqpqfancs 181 vydffvwlhy ysvrdtllgp
grpyraidfs hqgpafvtwh ryhllclerd lqrlignesf 241 alpywnfatg
rnecdvctdq lfgaarpddp tlisrnsrfs swetvcdsld dynhlvtlcn 301
gtyegllrrn qmgrnsmklp tlkdirdcls lqkfdnppff qnstfsfrna legfdkadgt
361 ldsqvmslhn lvhsflngtn alphsaandp ifvvlhsftd aifdewmkrf
nppadawpqe 421 lapighnrmy nmvpffppvt neelfltsdq lgysyaidlp
vsveetpgwp ttllvvmgtl 481 valvglfvll aflqyrrlrk gytplmethl
sskryteea Dopachrome tautomerase, isoform 2 NP_001123361.1 (SEQ ID
NO: 416) 1 msplwwgfll sclgckilpg aqgqfprvcm tvdslvnkec cprlgaesan
vcgsqqgrgq 61 ctevradtrp wsgpyilrnq ddrelwprkf fhrtckctgn
fagyncgdck fgwtgpncer 121 kkppvirgni hslspqereq flgaldlakk
rvhpdyvitt qhwlgllgpn gtqpqfancs 181 vydffvwlhy ysvrdtllgp
grpyraidfs hqgpafvtwh ryhllclerd lqrlignesf 241 alpywnfatg
rnecdvctdq lfgaarpddp tlisrnsrfs swetvcdsld dynhlvtlcn 301
gtyegllrrn qmgrnsmklp tlkdirdcls lqkfdnppff qnstfsfrna legfdkadgt
361 ldsqvmslhn lvhsflngtn alphsaandp ifvvisnrll ynattnileh
vrkekatkel 421 pslhvlvlhs ftdaifdewm krfnppadaw pqelapighn
rmynmvpffp pvtneelflt 481 sdqlgysyai dlpvsveetp gwpttllvvm
gtlvalvglf vllaflqyrr lrkgytplme 541 thlsskryte ea Dopachrome
tautomerase, isoform 3 NP_001309lll.1, NP_001309112.1,
NP_001309113.1, NP_ 001309114.1 (SEQ ID NO: 417) 1 mgrnsmklpt
lkdirdclsl qkfdnppffq nstfsfrnal egfdkadgtl dsqvmslhnl 61
vhsflngtna lphsaandpi fvvlhsftda ifdewmkrfn ppadawpqel apighnrmyn
121 mvpffppvtn eelfltsdql gysyaidlpv sveetpgwpt tllvvmgtiv
alvglfvlla 181 flqyrrlrkg ytplmethls skryteea Dopachrome
tautomerase, isoform 4, NP_001309115.1 (SEQ ID NO: 418) 1
mllgiqrqmk crlrsdvtkr leedehvnth spmrrgnfag yncgdckfgw tgpncerkkp
61 pvirqnihsl spqereqflg aldlakkrvh pdyvittqhw lgllgpngtq
pqfancsvyd 121 ffvwlhyysv rdtllgpgrp yraidfshqg pafvtwhryh
llclerdlqr lignesfalp 181 ywnfatgrne cdvctdqlfg aarpddptli
srnsrfsswe tvcdslddyn hlvtlcngty 241 egllrrnqmg rnsmklptlk
dirdclslqk fdnppffqns tfsfrnaleg fdkadgtlds 301 qvmslhnlvh
sflngtnalp hsaandpifv vlhsftdaif dewmkrfnpp adawpgelap 361
ighnrmynmv pffppvtnee lfltsdqlgy syaidlpvsv eetpgwpttl lvvmgtlval
421 vglfvllafl qyrrlrkgyt plmethlssk ryteea
Transformation/transcription domain associated protein, isoform 1
NP_001231509.1 (SEQ ID NO: 419) 1 mafvatqgat vvdqttlmkk ylqfvaaltd
vntpdetklk mmqevsenfe nvtsspqyst 61 flehiiprfl tflqdgevqf
lqekpaqqlr klvleiihri ptnehlrpht knvlsvmfrf 121 leteneenvl
iclriiielh kqfrppitqe ihhfldfvkq iykelpkvvn ryfenpqvip 181
entvpppemv gmittiavkv nperedsetr thsiiprgsl slkvlaelpi ivvlmyglyk
241 lnihnvvaef vplimntiai qvsaqarghk lynkelyadf iaaqiktlsf
layiiriyqe 301 lvtkysqqmv kgmlqllsnc paetahlrke lliaakhilt
telrnqfipc mdklfdesil 361 igsgytaret lrplaystla dlvhhvrqhl
plsdlslavq lfakniddes lpssiqtmsc 421 klllnlvdci rskseqesgn
grdvlmrmle vfvlkfhtia ryqlsaifkk ckpqselgav 481 eaalpgvpta
paapgpapsp apvpappppp pppppatpvt papvppfekq gekdkedkqt 541
fqvtdcrslv ktivcgvkti twgitsckap geaqfipnkq lqpketqiyi klvkyamqal
601 diyqvqiagn gqtyirvanc qtvrmkeeke vlehfagvft mmnpltfkei
fqttvpymve 661 risknyalqi vansflanpt tsalfatilv eylldrlpem
gsnvelsnly lklfklvfgs 721 vslfaaeneq mlkphlhkiv nssmelaqta
kepynyflll ralfrsiggg shdllyqefl 781 pllpnllqgl nmlqsglhkq
hmkdlfvelc ltvpvrlssl lpylpmlmdp lvsalngsqt 841 lvsqglrtle
lcvdnlqpdf lydhiqpvra elmqalwrtl rnpadsishv ayrvlgkfgg 901
snrkmlkesq klhyvvtevq gpsitvefsd ckaslqlpme kaietaldcl ksantepyyr
961 rqawevikcf lvammsledn khalyqllah pnftektipn viishrykaq
dtparktfeq 1021 altgafmsav ikdlrpsalp fvaslirhyt mvavaqqcgp
fllpcyqvgs qpstamfhse 1081 engskgmdpl vlidaiaicm ayeekelcki
gevalavifd vasiilgske racqlplfsy 1141 iverlcaccy eqawyaklgg
vvsikflmer lpltwvlqnq qtflkallfv mmdltgevsn 1201 gavamakttl
eqllmrcatp lkdeeraeei vaaqeksfhh vthdlvrevt spnstvrkqa 1261
mhslqvlaqv tgksvtvime phkevlqdmv ppkkhllrhq panaqiglme gntfcttlqp
1321 rlftmdlnvv ehkvfytell nlceaedsal tklpcykslp slvplriaal
nalaacnylp 1381 qsrekiiaal fkalnstnse lqeageacmr kflegatiev
dqihthmrpl lmmlgdyrsl 1441 tlnvvnrlts vtrlfpnsfn dkfcdqmmqh
lrkwmevvvi thkggqrsdg nesisecgrc 1501 plspfcqfee mkicsaiinl
fhlipaapqt lvkpllevvm kteramliea gspfreplik 1561 fltrhpsqtv
elfmmeatln dpqwsrmfms flkhkdarpl rdvlaanpnr fitlllpgga 1621
qtavrpgsps tstmrldlqf qaikiisiiv knddswlasq hslvsqlrrv wvsenfqerh
1681 rkenmaatnw kepkllaycl lnyckrnygd iellfqllra ftgrflcnmt
flkeymeeei 1741 pknysiaqkr alffrfvdfn dpnfgdelka kvlqhilnpa
flysfekgeg eqllgppnpe 1801 gdnpesitsv fitkvldpek qadmldslri
yllqyatllv ehaphhihdn nknrnsklrr 1861 lmtfawpcll skacvdpack
ysghlllahi iakfaihkki vlqvfhsllk ahamearaiv 1921 rqamailtpa
vparmedghq mlthwtrkii veeghtvpql vhilhlivqh fkvyypvrhh 1981
lvqhmvsamq rlgftpsvti eqrrlavdls evvikwelqr ikdqqpdsdm dpnssgegvn
2041 sysssikrgl svdsaqevkr frtatgaisa vfgrsqslpg adsllakpid
kqhtdtvvnf 2101 lirvacqvnd ntntagspge vlsrrcvnll ktalrpdmwp
kselklqwfd kllmtveqpn 2161 qvnygnictg levlsflltv lqspailssf
kplqrgiaac mtcgntkvlr avhsllsrlm 2221 sifptepsts svaskyeele
clyaavgkvi yegltnyeka tnanpsqlfg tlmilksacs 2281 nnpsyidrli
svfmrslqkm vrehlnpqaa sgsteatsgt selvmlslel vktrlavmsm 2341
emrknfiqai ltsliekspd akilravvki veewvknnsp maanqtptlr eksillvkmm
2401 tyiekrfped lelnaqfldl vnyvyrdetl sgseltakle paflsglrca
qplirakffe 2461 vfdnsmkrrv yerllyvtcs qnweamgnhf wikqcielll
avcekstpig tscqgamlps 2521 itnvinlads hdraafamvt hvkqeprere
nseskeedve idielapgdq tstpktkels 2581 ekdignqlhm ltnrhdkfld
tlrevktgal lsafvqlchi sttlaektwv qlfprlwkil 2641 sdrqqhalag
eispflcsgs hqvgrdcqps alncfveams qcvppipirp cvlkylgkth 2701
nlwfrstlml ehqafekgls lqikpkqtte fyeqesitpp qqeildslae lysllqeedm
2761 waglwqkrck ysetataiay eqhgffeqaq esyekamdka kkehersnas
paifpeyqlw 2821 edhwircske lnqwealtey gqskghinpy lvlecawrvs
nwtamkealv qvevscpkem 2881 awkvnmyrgy laichpeeqq lsfierlvem
asslairewr rlphvvshvh tpllqaaqqi 2941 ielqeaaqin aglqptnlgr
nnslhdmktv vktwrnrlpi vsddlshwss ifmwrqhhyq 3001 gkptwsgmhs
ssivtayens sqhdpssnna mlgvhasasa iiqygkiark qglvnvaldi 3061
lsrihtiptv pivdcfqkir qqvkcylqla gvmgknecmq gleviestnl kyftkemtae
3121 fyalkgmfla qinkseeank afsaavqmhd vlvkawamwg dylenifvke
rqlhlgvsai 3181 tcylhacrhq nesksrkyla kvlwllsfdd dkntladavd
kycigvppiq wlawipqllt 3241 clvgsegkll lnlisqvgrv ypqavyfpir
tlyltlkieq reryksdpgp iratapmwrc 3301 srimhmqrel hptllssleg
ivdqmvwfre nwheevlrql qqglakcysv afeksgavsd 3361 akitphtlnf
vkklvstfgv glenvsnvst mfssaasesl arraqataqd pvfqklkgqf 3421
ttdfdfsvpg smklhnlisk lkkwikilea ktkqlpkffl ieekcrflsn fsaqtaevei
3481 pgeflmpkpt hyyikiarfm prveivqkhn taarrlyirg hngkiypylv
mndacltesr 3541 reervlqllr llnpclekrk ettkrhlfft vprvvayspq
mrlvednpss lslveiykqr 3601 cakkgiehdn pisryydrla tvqargtqas
hqvlrdilke vqsnmvprsm lkewalhtfp 3661 natdywtfrk mftiqlalig
faefvlhlnr lnpemlqiaq dtgklnvayf rfdindatgd 3721 ldanrpvpfr
ltpniseflt tigvsgplta smiavarcfa qpnfkvdgil ktvlrdeiia 3781
whkktqedts splsaagqpe nmdsqqlvsl vqkavtaimt rlhnlaqfeg geskvntlva
3841 aansldnlcr mdpawhpwl Transformation/transcription domain
associated protein, isoform 2 NP_003487.1 (SEQ ID NO: 420) 1
mafvatqgat vvdqttlmkk ylqfvaaltd vntpdetklk mmqevsenfe nvtsspqyst
61 flehiiprfl tflqdgevqf lqekpaqqlr klvleiihri ptnehlrpht
knvlsvmfrf 121 leteneenvl iclriiielh kqfrppitqe ihhfldfvkq
iykelpkvvn ryfenpqvip 181 entvpppemv gmittiavkv nperedsetr
thsiiprgsl slkvlaelpi ivvlmyqlyk 241 lnihnvvaef vplimntiai
qvsaqarqhk lynkelyadf iaaqiktlsf layiiriyqe 301 lvtkysqqmv
kgmlqllsnc paetahlrke lliaakhilt telrnqfipc mdklfdesil 361
igsgytaret lrplaystla dlvhhvrqhl plsdlslavq lfakniddes lpssiqtmsc
421 klllnlvdci rskseqesgn grdvlmrmle vfvlkfhtia ryqlsaifkk
ckpqselgav 481 eaalpgvpta paapgpapsp apvpappppp pppppatpvt
papvppfekq gekdkedkqt 541 fqvtdcrslv ktivcgvkti twgitsckap
geaqfipnkq lqpketqiyi klvkyamqal 601 diyqvqiagn gqtyirvanc
qtvrmkeeke vlehfagvft mmnpltfkei fqttvpymve 661 risknyalqi
vansflanpt tsalfatilv eylldrlpem gsnvelsnly lklfklvfgs 721
vslfaaeneq mlkphlhkiv nssmelaqta kepynyflll ralfrsiggg shdllyqefl
781 pllpnllqgl nmlqsglhkq hmkdlfvelc ltvpvrlssl lpylpmlmdp
lvsalngsqt 841 lvsqglrtle lcvdnlqpdf lydhiqpvra elmgalwrtl
rnpadsishv ayrvlgkfgg 901 snrkmlkesq klhyvvtevq gpsitvefsd
ckaslqlpme kaietaldcl ksantepyyr 961 rqawevikcf lvammsledn
khalyqllah pnftektipn viishrykaq dtparktfeq 1021 altgafmsav
ikdlrpsalp fvaslirhyt mvavaqqcgp fllpcyqvgs qpstamfhse 1081
engskgmdpl vlidaiaicm ayeekelcki gevalavifd vasiilgske racqlplfsy
1141 iverlcaccy eqawyaklgg vvsikflmer lpltwvlqnq qtflkallfv
mmdltgevsn 1201 gavamakttl eqllmrcatp lkdeeraeei vaaqeksfhh
vthdlvrevt spnstvrkqa 1261 mhslqvlaqv tgksvtvime phkevlqdmv
ppkkhllrhq panaqiglme gntfcttlqp 1321 rlftmdlnvv ehkvfytell
nlceaedsal tklpcykslp slvplriaal nalaacnylp 1381 qsrekiiaal
fkalnstnse lqeageacmr kflegatiev dqihthmrpl lmmlgdyrsl 1441
tlnvvnrlts vtrlfpnsfn dkfcdqmmqh lrkwmevvvi thkggqrsdg nemkicsaii
1501 nlfhlipaap qtlvkpllev vmkteramli eagspfrepl ikfltrhpsq
tvelfmmeat 1561 lndpqwsrmf msflkhkdar plrdvlaanp nrfitlllpg
gaqtavrpgs pststmrldl 1621 qfqaikiisi ivknddswla sqhslvsqlr
rvwvsenfqe rhrkenmaat nwkepkllay 1681 cllnyckrny gdiellfqll
raftgrflcn mtflkeymee eipknysiaq kralffrfvd 1741 fndpnfgdel
kakvlqhiln paflysfekg egeqllgppn pegdnpesit svfitkvldp 1801
ekqadmldsl riyllqyatl lvehaphhih dnnknrnskl rrlmtfawpc llskacvdpa
1861 ckysghllla hiiakfaihk kivlqvfhsl lkahameara ivrqamailt
pavparmedg 1921 hqmlthwtrk iiveeghtvp qlvhilhliv qhfkvyypvr
hhlvqhmvsa mqrlgftpsv 1981 tieqrrlavd lsevvikwel qrikdqqpds
dmdpnssgeg vnsysssikr glsvdsaqev 2041 krfrtatgai savfgrsqsl
pgadsllakp idkqhtdtvv nflirvacqv ndntntagsp 2101 gevlsrrcvn
llktalrpdm wpkselklqw fdkllmtveq pnqvnygnic tglevlsfll 2161
tvlqspails sfkplqrgia acmtcgntkv lravhsllsr lmsifpteps tssvaskyee
2221 leclyaavgk viyegltnye katnanpsql fgtlmilksa csnnpsyidr
lisvfmrslq 2281 kmvrehlnpq aasgsteats gtselvmlsl elvktrlavm
smemrknfiq ailtslieks 2341 pdakilravv kiveewvknn spmaanqtpt
lreksillvk mmtyiekrfp edlelnaqfl 2401 dlvnyvyrde tlsgseltak
lepaflsglr caqplirakf fevfdnsmkr rvyerllyvt 2461 csqnweamgn
hfwikqciel llavcekstp igtscqgaml psitnvinla dshdraafam 2521
vthvkqepre renseskeed veidielapg dqtstpktke lsekdignql hmltnrhdkf
2581 ldtlrevktg allsafvqlc histtlaekt wvqlfprlwk ilsdrqqhal
ageispflcs 2641 gshqvqrdcq psalncfvea msqcvppipi rpcvlkylgk
thnlwfrstl mlehqafekg 2701 lslqikpkqt tefyeqesit ppqqeildsl
aelysllqee dmwaglwqkr ckysetatai 2761 ayeqhgffeq aqesyekamd
kakkehersn aspaifpeyq lwedhwircs kelnqwealt 2821 eygqskghin
pylvlecawr vsnwtamkea lvqvevscpk emawkvnmyr gylaichpee 2881
qqlsfierlv emasslaire wrrlphvvsh vhtpllqaaq qiielqeaaq inaglqptnl
2941 grnnslhdmk tvvktwrnrl pivsddlshw ssifmwrqhh yqaivtayen
ssqhdpssnn 3001 amlgvhasas aiiqygkiar kqglvnvald ilsrihtipt
vpivdcfqki rqqvkcylql 3061 agvmgknecm qgleviestn lkyftkemta
efyalkgmfl aqinkseean kafsaavqmh 3121 dvlvkawamw gdylenifvk
erqlhlgvsa itcylhacrh qnesksrkyl akvlwllsfd 3181 ddkntladav
dkycigvppi qwlawipqll tclvgsegkl llnlisqvgr vypqavyfpi 3241
rtlyltlkie qreryksdpg piratapmwr csrimhmqre lhptllssle givdqmvwfr
3301 enwheevlrq lqgglakcys vafeksgavs dakitphtln fvkklvstfg
vglenvsnvs 3361 tmfssaases larraqataq dpvfqklkgq fttdfdfsvp
gsmklhnlis klkkwikile 3421 aktkqlpkff lieekcrfls nfsaqtaeve
ipgeflmpkp thyyikiarf mprveivqkh 3481 ntaarrlyir ghngkiypyl
vmndacltes rreervlqll rllnpclekr kettkrhlff 3541 tvprvvaysp
qmrlvednps slslveiykg rcakkgiehd npisryydrl atvqargtqa 3601
shgvlrdilk evqsnmvprs mlkewalhtf pnatdywtfr kmftiqlali gfaefvlhln
3661 rlnpemlqia qdtgklnvay frfdindatg dldanrpvpf rltpnisefl
ttigvsgplt 3721 asmiavarcf aqpnfkvdgi lktvlrdeii awhkktqedt
ssplsaagqp enmdsqqlvs 3781 lvqkavtaim trlhnlaqfe ggeskvntiv
aaansldnlc rmdpawhpwl Tyrosinase precursor NP_000363.1 (SEQ ID NO:
421) 1 mllavlycll wsfqtsaghf pracvssknl mekeccppws gdrspcgqls
grgscqnill 61 snaplgpqfp ftgvddresw psvfynrtcq csgnfmgfnc
gnckfgfwgp ncterrllvr 121 rnifdlsape kdkffayltl akhtissdyv
ipigtygqmk ngstpmfndi niydlfvwmh 181 yyvsmdallg gseiwrdidf
aheapaflpw hrlfllrweq eiqkltgden ftipywdwrd 241 aekcdictde
ymggqhptnp nllspasffs swqivcsrle eynshqslcn gtpegplrrn 301
pgnhdksrtp rlpssadvef clsltqyesg smdkaanfsf rntlegfasp ltgiadasqs
361 smhnalhiym ngtmsqvqgs andpifllhh afvdsifeqw lrrhrplqev
ypeanapigh 421 nresymvpfi plyrngdffi sskdlgydys ylqdsdpdsf
qdyiksyleq asriwswllg 481 aamvgavlta llaglvsllc rhkrkqlpee
kqpllmeked yhslyqshl Vascular endothelial growth factor A, isoform
a NP_001020537.2 (SEQ ID NO: 422) 1 mtdrqtdtap spsyhllpgr
rrtvdaaasr gqgpepapgg gvegvgargv alklfvqllg 61 csrfggavvr
ageaepsgaa rsassgreep gpeegeeeee keeergpqwr lgarkpgswt 121
geaavcadsa paarapqala rasgrggrva rrgaeesgpp hspsrrgsas ragpgraset
181 mnfllswvhw slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs
ychpietivd 241 ifqeypdeie yifkpscvpl mrcggccnde glecvptees
nitmqimrik phqgqhigem 301 sflqhnkcec rpkkdrarqe kksvrgkgkg
qkrkrkksry kswsvyvgar cclmpwslpg 361 phpcgpcser rkhlfvqdpq
tckcsckntd srckarqlel nertcrcdkp rr Vascular endothelial growth
factor A, isoform b NP_003367.4 (SEQ ID NO: 423) 1 mtdrqtdtap
spsyhllpgr rrtvdaaasr gqgpepapgg gvegvgargv alklfvqllg 61
csrfggavvr ageaepsgaa rsassgreep qpeegeeeee keeergpqwr lgarkpgswt
121 geaavcadsa paarapqala rasgrggrva rrgaeesgpp hspsrrgsas
ragpgraset 181 mnfllswvhw slalllylhh akwsqaapma egggqnhhev
vkfmdvyqrs ychpietivd 241 ifqeypdeie yifkpscvpl mrcggccnde
glecvptees nitmqimrik phqgqhigem 301 sflqhnkcec rpkkdrarqe
kksvrgkgkg qkrkrkksry kswsvpcgpc serrkhlfvq 361 dpqtckcsck
ntdsrckarq lelnertcrc dkprr Vascular endothelial growth factor A,
isoform c NP_001020538.2 (SEQ ID NO: 424) 1 mtdrqtdtap spsyhllpgr
rrtvdaaasr gqgpepapgg gvegvgargv alklfvqllg 61 csrfggavvr
ageaepsgaa rsassgreep qpeegeeeee keeergpqwr lgarkpgswt 121
geaavcadsa paarapqala rasgrggrva rrgaeesgpp hspsrrgsas ragpgraset
181 mnfllswvhw slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs
ychpietivd 241 ifqeypdeie yifkpscvpl mrcggccnde glecvptees
nitmqimrik phqgqhigem 301 sflqhnkcec rpkkdrarqe kksvrgkgkg
qkrkrkksrp cgpcserrkh lfvqdpqtck 361 csckntdsrc karqlelner
tcrcdkprr Vascular endothelial growth factor A, isoform d
NP_001020539.2 (SEQ ID NO: 425) 1 mtdrqtdtap spsyhllpgr rrtvdaaasr
gqgpepapgg gvegvgargv alklfvqllg 61 csrfggavvr ageaepsgaa
rsassgreep qpeegeeeee keeergpqwr lgarkpgswt 121 geaavcadsa
paarapqala rasgrggrva rrgaeesgpp hspsrrgsas ragpgraset 181
mnfllswvhw slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs ychpietivd
241 ifqeypdeie yifkpscvpl mrcggccnde glecvptees nitmqimrik
phqgqhigem 301 sflqhnkcec rpkkdrarqe npcgpcserr khlfvqdpqt
ckcsckntds rckarqleln 361 ertcrcdkpr r
Vascular endothelial growth factor A, isoform e NP_001020540.2 (SEQ
ID NO: 426) 1 mtdrqtdtap spsyhllpgr rrtvdaaasr gqgpepapgg
gvegvgargv alklfvqllg 61 csrfggavvr ageaepsgaa rsassgreep
qpeegeeeee keeergpqwr lgarkpgswt 121 geaavcadsa paarapqala
rasgrggrva rrgaeesgpp hspsrrgsas ragpgraset 181 mnfllswvhw
slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs ychpietivd 241
ifqeypdeie yifkpscvpl mrcggccnde glecvptees nitmqimrik phqgqhigem
301 sflqhnkcec rpkkdrarqe npcgpcserr khlfvqdpqt ckcsckntds rckm
Vascular endothelial growth factor A, isoform f NP_001020541.2 (SEQ
ID NO: 427) 1 mtdrqtdtap spsyhllpgr rrtvdaaasr gqgpepapgg
gvegvgargv alklfvqllg 61 csrfggavvr ageaepsgaa rsassgreep
qpeegeeeee keeergpqwr lgarkpgswt 121 geaavcadsa paarapqala
rasgrggrva rrgaeesgpp hspsrrgsas ragpgraset 181 mnfllswvhw
slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs ychpietivd 241
ifqeypdeie yifkpscvpl mrcggccnde glecvptees nitmqimrik phqgqhigem
301 sflqhnkcec rpkkdrarqe kcdkprr Vascular endothelial growth
factor A, isoform g NP_001028928.1 (SEQ ID NO: 428) 1 mtdrqtdtap
spsyhllpgr rrtvdaaasr gqgpepapgg gvegvgargv alklfvqllg 61
csrfggavvr ageaepsgaa rsassgreep qpeegeeeee keeergpqwr lgarkpgswt
121 geaavcadsa paarapqala rasgrggrva rrgaeesgpp hspsrrgsas
ragpgraset 181 mnfllswvhw slalllylhh akwsqaapma egggqnhhev
vkfmdvyqrs ychpietivd 241 ifqeypdeie yifkpscvpl mrcggccnde
glecvptees nitmqimrik phqgqhigem 301 sflqhnkcec rpkkdrarqe
npcgpcserr khlfvqdpqt ckcsckntds rckarqleln 361 ertcrsltrk d
Vascular endothelial growth factor A, isoform h NP_001165093.1 (SEQ
ID NO: 429) 1 mtdrqtdtap spsyhllpgr rrtvdaaasr gqgpepapgg
gvegvgargv alklfvqllg 61 csrfggavvr ageaepsgaa rsassgreep
qpeegeeeee keeergpqwr lgarkpgswt 121 geaavcadsa paarapqala
rasgrggrva rrgaeesgpp hspsrrgsas ragpgraset 181 mnfllswvhw
slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs ychpietivd 241
ifqeypdeie yifkpscvpl mrcggccnde glecvptees nitmqimrik phqgqhigem
301 sflqhnkcec rcdkprr Vascular endothelial growth factor A,
isoform i NP_001165094.1 (SEQ ID NO: 430) 1 mnfllswvhw slalllylhh
akwsqaapma egggqnhhev vkfmdvyqrs ychpietivd 61 ifqeypdeie
yifkpscvpl mrcggccnde glecvptees nitmqimrik phqgqhigem 121
sflqhnkcec rpkkdrarqe kksvrgkgkg qkrkrkksry kswsvyvgar cclmpwslpg
181 phpcgpcser rkhlfvqdpq tckcsckntd srckarqlel nertcrcdkp rr
Vascular endothelial growth factor A, isoform j NP_001165095.1 (SEQ
ID NO: 431) 1 mnfllswvhw slalllylhh akwsqaapma egggqnhhev
vkfmdvyqrs ychpietlvd 61 ifqeypdeie yifkpscvpl mrcggccnde
glecvptees nitmqimrik phqgqhigem 121 sflqhnkcec rpkkdrarqe
kksvrgkgkg qkrkrkksry kswsvpcgpc serrkhlfvq 181 dpqtckcsck
ntdsrckarq lelnertcrc dkprr Vascular endothelial growth factor A,
isoform k NP_001165096.1 (SEQ ID NO: 432) 1 mnfllswvhw slalllylhh
akwsqaapma egggqnhhev vkfmdvyqrs ychpietivd 61 ifqeypdeie
yifkpscvpl mrcggccnde glecvptees nitmqimrik phqgqhigem 121
sflqhnkcec rpkkdrarqe kksvrgkgkg qkrkrkksrp cgpcserrkh lfvqdpqtck
181 csckntdsrc karqlelner tcrcdkprr Vascular endothelial growth
factor A, isoform 1 NP_001165097.1 (SEQ ID NO: 433) 1 mnfllswvhw
slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs ychpietivd 61
ifqeypdeie yifkpscvpl mrcggccnde glecvptees nitmqimrik phqgqhigem
121 sflqhnkcec rpkkdrarqe npcgpcserr khlfvgdpqt ckcsckntds
rckarqleln 181 ertcrcdkpr r Vascular endothelial growth factor A,
isoform m NP_001165098.1 (SEQ ID NO: 434) 1 mnfllswvhw slalllylhh
akwsqaapma egggqnhhev vkfmdvyqrs ychpietivd 61 ifqeypdeie
yifkpscvpl mrcggccnde glecvptees nitmqimrik phqgqhigem 121
sflqhnkcec rpkkdrarqe npcgpcserr khlfvqdpqt ckcsckntds rckm
Vascular endothelial growth factor A, isoform n NP_001165099.1 (SEQ
ID NO: 435) 1 mnfllswvhw slalllylhh akwsqaapma egggqnhhev
vkfmdvyqrs ychpietivd 61 ifqeypdeie yifkpscvpl mrcggccnde
glecvptees nitmqimrik phqgqhigem 121 sflqhnkcec rpkkdrarqe kcdkprr
Vascular endothelial growth factor A, isoform o NP_001165100.1 (SEQ
ID NO: 436) 1 mnfllswvhw slalllylhh akwsqaapma egggqnhhev
vkfmdvyqrs ychpietivd 61 ifqeypdeie yifkpscvpl mrcggccnde
glecvptees nitmqimrik phqgqhigem 121 sflqhnkcec rpkkdrarqe
npcgpcserr khlfvqdpqt ckcsckntds rckarqleln 181 ertcrsltrk d
Vascular endothelial growth factor A, isoform p NP_001165101.1 (SEQ
ID NO: 437) 1 mnfllswvhw slalllylhh akwsqaapma egggqnhhev
vkfmdvyqrs ychpietivd 61 ifqeypdeie yifkpscvpl mrcggccnde
glecvptees nitmqimrik phqgqhigem 121 sflqhnkcec rcdkprr Vascular
endothelial growth factor A, isoform q NP_001191313.1 (SEQ ID NO:
438) 1 mnfllswvhw slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs
ychpietivd 61 ifqeypdeie yifkpscvpl mrcggccnde glecvptees
nitmqimrik phqgqhigem 121 sflqhnkcec rpkkdrarqe kksvrgkgkg
qkrkrkksry kswsvcdkpr r Vascular endothelial growth factor A,
isoform r NP_001191314.1 (SEQ ID NO: 439) 1 mtdrqtdtap spsyhllpgr
rrtvdaaasr gqgpepapgg gvegvgargv alklfvqllg 61 csrfggavvr
ageaepsgaa rsassgreep qpeegeeeee keeergpqwr lgarkpgswt 121
geaavcadsa paarapqala rasgrggrva rrgaeesgpp hspsrrgsas ragpgraset
181 mnfllswvhw slalllylhh akwsqaapma egggqnhhev vkfmdvyqrs
ychpietivd 241 ifqeypdeie yifkpscvpl mrcggccnde glecvptees
nitmqimrik phqgqhigem 301 sflqhnkcec rpkkdrarqe kksvrgkgkg
qkrkrkksry kswsvcdkpr r Vascular endothelial growth factor A,
isoform s NP_001273973.1 (SEQ ID NO: 440) 1 maegggqnhh evvkfmdvyq
rsychpietl vdifqeypde ieyifkpscv plmrcggccn 61 deglecvpte
esnitmqimr ikphqgqhig emsflqhnkc ecrpkkdrar genpcgpcse 121
rrkhlfvqdp qtckcscknt dsrckarqle lnertcrcdk prr Vascular
endothelial growth factor A, isoform VEGF-Ax precursor
NP_001303939.1 (SEQ ID NO: 441) 1 mnfllswvhw slalllylhh akwsqaapma
egggqnhhev vkfmdvyqrs ychpietivd 61 ifqeypdeie yifkpscvpl
mrcggccnde glecvptees nitmqimrik phqgqhigem 121 sflqhnkcec
rpkkdrarqe npcgpcserr khlfvqdpqt ckcsckntds rckarqleln 181
ertcrcdkpr rsagqeegas lrvsgtrslt rkd WD repeat-containing protein
46, isoform 1 NP_005443.3 (SEQ ID NO: 442) 1 metapkpgkd vppkkdklqt
krkkprrywe eetvpttaga spgpprnkkn relrpqrpkn 61 ayilkksris
kkpqvpkkpr ewknpesqrg lsgtqdpfpg papvpvevvq kfcridksrk 121
lphskaktrs rlevaeaeee etsikaarse lllaeepgfl egedgedtak icqadiveav
181 diasaakhfd lnlrqfgpyr lnysrtgrhl afggrrghva aldwvtkklm
ceinvmeavr 241 dirflhseal lavaqnrwlh iydnqgielh cirrcdrvtr
leflpfhfll atasetgflt 301 yldvsvgkiv aalnaragrl dvmsqnpyna
vihlghsngt vslwspamke plakilchrg 361 gvravavdst gtymatsgld
hqlkifdlrg tyqplstrtl phgaghlafs qrgllvagmg 421 dvvniwagqg
kasppsleqp ylthrlsgpv hglqfcpfed vlgvghtggi tsmlvpgage 481
pnfdglesnp yrsrkgrqew evkallekvp aelicldpra laevdvisle qgkkeqierl
541 gydpqakapf qpkpkqkgrs staslvkrkr kvmdeehrdk vrqslqqqhh
keakakptga 601 rpsaldrfvr WD repeat-containing protein 46, isoform
2 NP_001157739.1 (SEQ ID NO: 443) 1 metapkpgkd vppkkdklqt
krkkprewkn pesqrglsgt qdpfpgpapv pvevvqkfcr 61 idksrklphs
kaktrsrlev aeaeeeetsi kaarsellla eepgfleged gedtakicqa 121
diveavdias aakhfdlnlr qfgpyrlnys rtgrhlafgg rrghvaaldw vtkklmcein
181 vmeavrdirf lhseallava qnrwlhiydn qgielhcirr cdrvtrlefl
pfhfllatas 241 etgfltyldv svgkivaaln aragrldvms qnpynavihl
ghsngtvslw spamkeplak 301 ilchrggvra vavdstgtym atsgldhqlk
ifdlrgtyqp lstrtlphga ghlafsqrgl 361 lvagmgdvvn iwagqgkasp
psleqpylth rlsgpvhglq fcpfedvlgv ghtggitsml 421 vpgagepnfd
glesnpyrsr kqrqewevka llekvpaeli cldpralaev dvisleqgkk 481
eqierlgydp qakapfqpkp kqkgrsstas lvkrkrkvmd eehrdkvrqs lqqqhhkeak
541 akptgarpsa ldrfvr Wilms tumor protein, isoform A NP_000369.4
(SEQ ID NO: 444) 1 mdflllqdpa stcvpepasq htlrsgpgcl qqpeqqgvrd
pggiwaklga aeasaerlqg 61 rrsrgasgse pqqmgsdvrd lnallpavps
lgggggcalp vsgaaqwapv ldfappgasa 121 ygslggpapp papppppppp
phsfikqeps wggaepheeq clsaftvhfs gqftgtagac 181 rygpfgpppp
sqassgqarm fpnapylpsc lesqpairnq gystvtfdgt psyghtpshh 241
aaqfpnhsfk hedpmgqqgs lgeqqysvpp pvygchtptd sctgsqalll rtpyssdnly
301 qmtsqlecmt wnqmnlgatl kghstgyesd nhttpilcga qyrihthgvf
rgiqdvrrvp 361 gvaptlvrsa setsekrpfm caypgcnkry fklshlqmhs
rkhtgekpyq cdfkdcerrf 421 srsdqlkrhq rrhtgvkpfq cktcqrkfsr
sdhlkthtrt htgekpfscr wpscqkkfar 481 sdelvrhhnm hqrnmtklql al Wilms
tumor protein, isoform B NP_077742.3 (SEQ ID NO: 445) 1 mdflllqdpa
stcvpepasq htlrsgpgcl qqpeqqgvrd pggiwaklga aeasaerlqg 61
rrsrgasgse pqqmgsdvrd lnallpavps lgggggcalp vsgaaqwapv ldfappgasa
121 ygslggpapp papppppppp phsfikqeps wggaepheeq clsaftvhfs
gqftgtagac 181 rygpfgpppp sqassgqarm fpnapylpsc lesqpairnq
gystvtfdgt psyghtpshh 241 aaqfpnhsfk hedpmgqqgs lgeqqysvpp
pvygchtptd sctgsgalll rtpyssdnly 301 qmtsqlecmt wnqmnlgatl
kgvaagssss vkwtegqsnh stgyesdnht tpilcgaqyr 361 ihthgvfrgi
qdvrrvpgva ptivrsaset sekrpfmcay pgcnkryfkl shlqmhsrkh 421
tgekpyqcdf kdcerrfsrs dqlkrhgrrh tgvkpfqckt cqrkfsrsdh lkthtrthtg
481 ekpfscrwps cqkkfarsde lvrhhnmhqr nmtklqlal Wilms tumor protein,
isoform D NP_077744.4 (SEQ ID NO: 446) 1 mdflllqdpa stcvpepasq
htlrsgpgcl qqpeqqgvrd pggiwaklga aeasaerlqg 61 rrsrgasgse
pqqmgsdvrd lnallpavps lgggggcalp vsgaaqwapv ldfappgasa 121
ygslggpapp papppppppp phsfikqeps wggaepheeq clsaftvhfs gqftgtagac
181 rygpfgpppp sqassgqarm fpnapylpsc lesqpairnq gystvtfdgt
psyghtpshh 241 aaqfpnhsfk hedpmgqqgs lgeqqysvpp pvygchtptd
sctgsqalll rtpyssdnly 301 qmtsqlecmt wnqmnlgatl kgvaagssss
vkwtegqsnh stgyesdnht tpilcgaqyr 361 ihthgvfrgi qdvrrvpgva
ptivrsaset sekrpfmcay pgcnkryfkl shlqmhsrkh 421 tgekpyqcdf
kdcerrfsrs dqlkrhqrrh tgvkpfqckt cqrkfsrsdh lkthtrthtg 481
ktsekpfscr wpscqkkfar sdelvrhhnm hqrnmtklql al Wilms tumor protein,
isoform E NP_001185480.1 (SEQ ID NO: 447) 1 mekgystvtf dgtpsyghtp
shhaaqfpnh sfkhedpmgq qgslgeqqys vpppvygcht 61 ptdsctgsqa
lllrtpyssd nlyqmtsqle cmtwnqmnlg atlkgvaags sssvkwtegq 121
snhstgyesd nhttpilcga qyrihthgvf rgiqdvrrvp gvaptlvrsa setsekrpfm
181 caypgcnkry fklshlqmhs rkhtgekpyq cdfkdcerrf srsdqlkrhq
rrhtgvkpfq 241 cktcqrkfsr sdhlkthtrt htgekpfscr wpscqkkfar
sdelvrhhnm hqrnmtklql 301 al Wilms tumor protein, isoform F
NP_001185481.1 (SEQ ID NO: 448) 1 mekgystvtf dgtpsyghtp shhaaqfpnh
sfkhedpmgq qgslgeqqys vpppvygcht 61 ptdsctgsqa lllrtpyssd
nlyqmtsqle cmtwnqmnlg atlkghstgy esdnhttpil 121 cgaqyrihth
gvfrgiqdvr rvpgvaptiv rsasetsekr pfmcaypgcn kryfklshlq 181
mhsrkhtgek pyqcdfkdce rrfsrsdqlk rhqrrhtgvk pfqcktcqrk fsrsdhlkth
241 trthtgktse kpfscrwpsc qkkfarsdel vrhhnmhqrn mtklqlal X antigen
family member 1, isoform a NP_001091063.2 (SEQ ID NO: 449) 1
mespkkknqq lkvgilhlgs rqkkiriqlr sqcatwkvic kscisqtpgi nldlgsgvkv
61 kiipkeehck mpeageeqpq v X antigen family member 1, isoform d
NP_001091065.1 (SEQ ID NO: 450) 1 mespkkknqq lkvgilhlgs rqkkiriqlr
sqvlgremrd megdlqelhq sntgdksgfg 61 frrqgednt X-linked inhibitor of
apoptosis NP_001158.2, NP_001191330.1 (SEQ ID NO: 451) 1 mtfnsfegsk
tcvpadinke eefveefnrl ktfanfpsgs pvsastlara gflytgegdt 61
vrcfschaav drwqygdsav grhrkvspnc rfingfylen satqstnsgi qngqykveny
121 lgsrdhfald rpsethadyl lrtgqvvdis dtiyprnpam yseearlksf
qnwpdyahlt 181 prelasagly ytgigdqvqc fccggklknw epcdrawseh
rrhfpncffv lgrnlnirse 241 sdavssdrnf pnstnlprnp smadyearif
tfgtwiysvn keqlaragfy algegdkvkc 301 fhcgggltdw kpsedpweqh
akwypgckyl leqkgqeyin nihlthslee clvrttektp 361 sltrriddti
fqnpmvqeai rmgfsfkdik kimeekiqis gsnykslevl vadlvnaqkd 421
smgdessqts lqkeisteeq lrrlqeeklc kicmdrniai vfvpcghlvt ckqcaeavdk
481 cpmcytvitf kqkifms
EQUIVALENTS
[0408] It is to be understood that while the disclosure has been
described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the scope of the following claims:
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
web site
(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20210199644A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20210199644A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References