U.S. patent application number 16/126751 was filed with the patent office on 2019-01-03 for novel immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemia (cll).
The applicant listed for this patent is immatics biotechnologies GmbH. Invention is credited to Daniel Johannes KOWALEWSKI, Hans-Georg RAMMENSEE, Stefan STEVANOVIC, Juliane STICKEL.
Application Number | 20190002497 16/126751 |
Document ID | / |
Family ID | 54869046 |
Filed Date | 2019-01-03 |
United States Patent
Application |
20190002497 |
Kind Code |
A1 |
STICKEL; Juliane ; et
al. |
January 3, 2019 |
NOVEL IMMUNOTHERAPY AGAINST SEVERAL TUMORS OF THE BLOOD, IN
PARTICULAR CHRONIC LYMPHOID LEUKEMIA (CLL)
Abstract
The present invention relates to peptides, nucleic acids and
cells for use in immunotherapeutic methods. In particular, the
present invention relates to the immunotherapy of cancer. The
present invention furthermore relates to tumor-associated cytotoxic
T cell (CTL) peptide epitopes, alone or in combination with other
tumor-associated peptides that serve as active pharmaceutical
ingredients of vaccine compositions that stimulate anti-tumor
immune responses. The present invention relates to several novel
peptide sequences and their variants derived from HLA class I and
HLA class II molecules of human tumor cells that can be used in
vaccine compositions for eliciting anti-tumor immune responses.
Inventors: |
STICKEL; Juliane; (Tubingen,
DE) ; KOWALEWSKI; Daniel Johannes; (Tubingen, DE)
; RAMMENSEE; Hans-Georg; (Unterjesingen, DE) ;
STEVANOVIC; Stefan; (Tubingen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
immatics biotechnologies GmbH |
Tubingen |
|
DE |
|
|
Family ID: |
54869046 |
Appl. No.: |
16/126751 |
Filed: |
September 10, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15965212 |
Apr 27, 2018 |
|
|
|
16126751 |
|
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|
|
14743335 |
Jun 18, 2015 |
10000533 |
|
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15965212 |
|
|
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|
62014849 |
Jun 20, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G16B 15/30 20190201;
A61K 39/001163 20180801; G16B 35/00 20190201; C12Q 2600/136
20130101; C12Q 2600/106 20130101; G01N 2333/70539 20130101; G16C
20/60 20190201; A61K 39/00 20130101; C12N 5/0638 20130101; A61K
39/001164 20180801; A61K 39/001166 20180801; A61K 2039/804
20180801; C12Q 1/6886 20130101; C12Q 2600/158 20130101; G16B 20/00
20190201; C12Q 2600/156 20130101; C07K 14/70539 20130101; C12N
2501/998 20130101; A61K 39/001154 20180801; C07K 14/4748 20130101;
A61K 39/001117 20180801; A61K 39/001162 20180801; A61K 39/001149
20180801; A61K 39/0011 20130101; A61K 2039/585 20130101; A61K
2039/5158 20130101; C07K 7/06 20130101; A61K 39/001152 20180801;
C12Q 2600/118 20130101; A61P 35/00 20180101; G16B 40/10 20190201;
G01N 33/574 20130101; A61K 39/001148 20180801 |
International
Class: |
C07K 7/06 20060101
C07K007/06; A61K 39/00 20060101 A61K039/00; G01N 33/574 20060101
G01N033/574; C12Q 1/6886 20060101 C12Q001/6886; C12N 5/0783
20060101 C12N005/0783; C40B 30/02 20060101 C40B030/02; C07K 14/74
20060101 C07K014/74; C07K 14/47 20060101 C07K014/47 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2014 |
GB |
1411037.3 |
Jun 17, 2015 |
EP |
PCT/EP2015/063566 |
Claims
1. A method of eliciting an immune response in a patient who has
cancer, comprising administering to said patient a population of
activated T cells that selectively recognize cells, which present a
peptide consisting of the amino acid sequence selected from the
group consisting of from SEQ ID NO: 2 to SEQ ID NO: 76 and from SEQ
ID NO: 78 to SEQ ID NO: 1016, wherein said cancer is selected from
the group consisting of chronic lymphoid leukemia (CLL), acute
myelogenous leukemia (AML), adrenal gland adrenal cortical adenoma,
bone giant cell tumor of bone, bone non-ossifying fibroma, breast
carcinoma, colon adenocarcinoma, non-Hodgkin's lymphoma,
endometrium adenocarcinoma endometrioid, kidney angiomyolipoma,
kidney carcinoma, kidney oncocytoma, liver focal nodular
hyperplasia, liver hepatocellular carcinoma, lymph node Hodgkin's
disease, lymph node papillary carcinoma of thyroid, medullary
carcinoma of thyroid origin, metastatic adenocarcinoma of stomach,
neurofibroma, ovary thecoma fibroma, pancreas adenocarcinoma,
pancreas microcystic adenoma, parathyroid gland adenoma, rectum
adenocarcinoma, skin squamous cell carcinoma, spleen chronic
myeloid leukemia, stomach gastrointestinal stromal tumor (GIST),
thyroid gland nodular hyperplasia, thyroid gland papillary
carcinoma, and uterine cervix squamous cell carcinoma.
2. The method of claim 1, wherein the T cells are autologous to the
patient.
3. The method of claim 1, wherein the T cells are obtained from a
healthy donor.
4. The method of claim 1, wherein the T cells are obtained from
tumor infiltrating lymphocytes or peripheral blood mononuclear
cells.
5. The method of claim 1, wherein the activated T cells are
expanded in vitro.
6. The method of claim 1, wherein the peptide is in a complex with
an MHC molecule,
7. The method of claim 6, wherein the MHC molecule is a class I MHC
molecule.
8. The method of claim 1, wherein the activated T cells are
cytotoxic T cells produced by contacting T cells with an antigen
presenting cell that expresses the peptide in a complex with an MHC
class I molecule on the surface of the antigen presenting cell, for
a period of time sufficient to activate said T cell.
9. The method of claim 8, wherein the antigen presenting cell is
infected with recombinant virus expressing the peptide.
10. The method of claim 9, wherein the antigen presenting cell is a
dendritic cell or a macrophage.
11. The method of claim 8, wherein the contacting is in vitro.
12. The method of claim 1, wherein the population of activated T
cells are administered in the form of a composition.
13. The method of claim 12, wherein the composition further
comprises an adjuvant.
14. The method of claim 13, wherein the adjuvant is selected from
the group consisting of anti-CD40 antibody, imiquimod, resiguimod,
GM-CSF, cyclophosphamide, Sunitinib, bevacizumab, interferon-alpha,
interferon-beta, CpG oligonucleotides and derivatives, poly-(I:C)
and derivatives, RNA, sildenafil, and particulate formations with
poly(lactid co-glycolid) (PLG), virosomes, interleukin (IL)-1,
IL-2, IL-4, IL-7, IL-12, IL-13, IL-15, IL-21, and IL-23.
15. The method of claim 1, wherein the immune response is capable
of killing cancer cells that present a peptide consisting of the
amino acid sequence selected from the group consisting of from SEQ
ID NO: 2 to SEQ ID NO: 76 and from SEQ ID NO: 78 to SEQ ID NO:
1016.
16. The method of claim 15, wherein the immune response comprises a
cytotoxic T cell response.
17. The method of claim 1, wherein the cancer is chronic lymphoid
leukemia (CLL).
18. The method of claim 1, wherein the cancer is acute myelogenous
leukemia (AML).
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/965,212, filed Apr. 27, 2018, which is a
continuation of U.S. patent application Ser. No. 14/743,335, filed
Jun. 18, 2015 (now U.S. Pat. No. 10,000,533), which claims priority
to U.S. Provisional Application 62/014,849, filed Jun. 20, 2014, GB
1411037.3, filed Jun. 20, 2014, and PCT/EP2015/063566, filed Jun.
17, 2015. Each of these applications is incorporated by reference
in its entirety.
REFERENCE TO SEQUENCE LISTING SUBMITTED AS A COMPLIANT ASCII TEXT
FILE (.txt)
[0002] A Sequence Listing is submitted herewith as an ASCII
compliant text file named
"2912919-036003_Sequence_Listing_ST25.txt", created on Sep. 10,
2018, and having a size of 178,108 bytes as permitted under 37
C.F.R. .sctn. 1.821(c). The material in the aforementioned text
file is hereby incorporated by reference in its entirety.
BACKGROUND
Field of the Invention
[0003] The present invention relates to peptides, nucleic acids and
cells for use in immunotherapeutic methods. In particular, the
present invention relates to the immunotherapy of cancer. The
present invention furthermore relates to tumor-associated cytotoxic
T cell (CTL) peptide epitopes, alone or in combination with other
tumor-associated peptides that serve as active pharmaceutical
ingredients of vaccine compositions that stimulate anti-tumor
immune responses. The present invention relates to several novel
peptide sequences and their variants derived from HLA class I and
HLA class II molecules of human tumor cells that can be used in
vaccine compositions for eliciting anti-tumor immune responses.
Description of Related Art
[0004] B-cell chronic lymphocytic leukemia (B-CLL), also known as
chronic lymphoid leukemia (CLL), is the most common type of
leukemia.
[0005] Leukemias are cancers of the white blood cells (leukocytes).
CLL affects B cell lymphocytes. B cells originate in the bone
marrow, develop in the lymph nodes, and normally fight infection by
producing antibodies. In CLL, B cells grow out of control and
accumulate in the bone marrow and blood, where they crowd out
healthy blood cells. CLL is a stage of small lymphocytic lymphoma
(SLL), a type of B-cell lymphoma, which presents primarily in the
lymph nodes. CLL and SLL are considered the same underlying
disease, just with different appearances.
[0006] CLL is a disease of adults, but, in rare cases, it can occur
in teenagers and occasionally in children (inherited). Most
(>75%) people newly diagnosed with CLL are over the age of 50,
and the majority are men, with a median age of 70 years at the time
of diagnosis. Though less common, CLL sometimes affects people
between 30 and 39 years of age. The incidence of CLL increases very
quickly with increasing age.
[0007] In the United States, during 2012 about 16,060 new cases are
expected to be diagnosed, and 4,580 patients are expected to die
from CLL.
[0008] CLL is very rare in Asian countries, such as Japan and
China, and may account for as few as 10 percent of all leukemias in
those regions.
[0009] In view of the above, there remains a need for new
efficacious and safe treatment option for cancers, in particular
chronic lymphoid leukemia (CLL) and other cancers of the blood of
different phenotypes which improve the well-being of the patients
by not using excessive chemotherapeutic agents or other agents that
may lead to severe side effects.
SUMMARY
[0010] The present invention employs peptides that stimulate the
immune system of the patient and act as anti-tumor-agents in a
non-invasive fashion.
[0011] In a first aspect of the present invention, the present
invention relates to a peptide comprising an amino acid sequence
selected from the group of SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID
NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016 or a
variant sequence thereof which is at least 80%, preferably at least
90%, homologous (preferably at least 80% or at least 90% identical)
to SEQ ID NO: 1 to SEQ ID NO: 225 or SEQ ID NO: 543 to SEQ ID NO:
1016, wherein said variant induces T cells cross-reacting with said
peptide, or a pharmaceutical acceptable salt thereof, wherein said
peptide is not the underlying full-length polypeptide.
[0012] The present invention further relates to a peptide of the
present invention comprising a sequence that is selected from the
group SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO:
542 or SEQ ID NO: 543 to SEQ ID NO: 1016 or a variant thereof,
which is at least 80%, preferably at least 90%, homologous
(preferably at least 80% or at least 90% identical) to SEQ ID NO: 1
to SEQ ID NO: 225 or SEQ ID NO: 543 to SEQ ID NO: 1016, wherein
said peptide or variant thereof has an overall length for SEQ ID
NO: 1 to SEQ ID NO: 225 of between 8 and 100, preferably between 8
and 30, and most preferred of between 8 and 14 amino acids, and for
SEQ ID NO: SEQ ID NO: 543 to SEQ ID NO: 1016 of between 12 and 100,
preferably between 12 and 30, and most preferred of between 12 to
18 amino acids.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0014] FIGS. 1a-11 depict embodiments as described herein.
[0015] FIG. 3a shows the peptides YGYDNVKEY (SEQ ID NO: 21),
AVFDGAQVTSK (SEQ ID NO: 82), SSSGLHPPK (SEQ ID NO: 77), ILDEKPVII
(SEQ ID NO: 63), YLNKEIEEA (SEQ ID NO: 44), SILEDPPSI (SEQ ID NO:
213), DLDVKKMPL (SEQ ID NO: 78), QLLDQVEQI (SEQ ID NO: 199),
AAANIIRTL (SEQ ID NO: 13), SPRPPLGSSL (SEQ ID NO: 93), APLQRSQSL
(SEQ ID NO: 96), SPTSSRTSSL (SEQ ID NO: 26), KPRQSSPQL (SEQ ID NO:
49), and SASVQRADTSL (SEQ ID NO: 113).
[0016] FIG. 4c shows the peptides LPSQAFEYILYNKG (SEQ ID NO: 561),
RVEYHFLSPYVSPK (SEQ ID NO: 554), NSVIIVDKNGRLV (SEQ ID NO: 552),
DIMRVNVDKVLERDQKL (SEQ ID NO: 831), YKAFSSLLASSAVSPE (SEQ ID NO:
651), and VDKVLERDQKLSELDDR (SEQ ID NO: 821).
[0017] FIG. 5a shows the peptides KITVPASQK (SEQ ID NO: 145),
SPRASGSGL (SEQ ID NO: 100), SPTSSRTSSL (SEQ ID NO: 26), SPAPRTAL
(SEQ ID NO: 202), TPSSRPASL (SEQ ID NO: 205), and RPKNLMQTL (SEQ ID
NO: 36).
[0018] FIG. 5b shows the peptides VPVPHTTAL (SEQ ID NO: 84),
GPRPITQSEL (SEQ ID NO: 203), and KLYELHVFTF (SEQ ID NO: 42).
[0019] FIG. 5c shows the peptides TFGERVVAF (SEQ ID NO: 143) and
KFAEEFYSF (SEQ ID NO: 20).
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
[0020] The following tables show the peptides according to the
present invention, their respective SEQ ID NO:, and the prospective
source (underlying) proteins for these peptides. All peptides in
Table 1 a and 1 b bind to HLA A HLA B or HLA C alleles, peptides in
Table 2 bind to HLA-DR alleles (MHC class II). The peptides in
table 3 are further useful in the diagnosis and/or treatment of
CLL, Acute myelogenous leukemia (AML), and other hematological
malignancies, which involve an over-expression or over-presentaion
of the respective underlying polypeptide.
[0021] Thus, the present invention relates in particular to a
peptide of the present invention comprising a sequence according to
SEQ ID NO: 543 to SEQ ID NO: 1016 or a variant thereof, which is at
least 80%, preferably at least 90%, homologous (preferably at least
80% or at least 90% identical) to SEQ ID NO: 543 to SEQ ID NO:
1016, wherein said peptide or variant thereof has an overall length
of between 12 and 100, preferably between 12 and 30, and most
preferred of between 12 to 18 amino acids. The present invention
relates in particular to a peptide of the present invention
consisting of the sequence according to SEQ ID NO: 543 to SEQ ID
NO: 1016.
TABLE-US-00001 TABLE 1a Preferred 49 HLA class I ligandome derived
tumor associated antigens (LiTAAs) according to the invention found
represented in .gtoreq.20%, of CLL patient ligandomes (n = 30) and
the 225 representing HLA ligands (LiTAPs) annotated with respective
HLA restriction. Number of SEQ positive CLLs ID NO: Underlying
source protein/HLA ligands (frequency [%]) HLA APOBEC3D
apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3D
13 (43.3) 1 AEHPNVTLTI 1 B*40 2 FLAEHPNVTL 8 A*02 3 ILYGRSYTW 1
A*32 4 EVAEFLARH 2 A*26 5 RHSNVNLTI 1 C*07 CDK14 cyclin-dependent
kinase 14 12 (40.0) 6 HPDNVKLFL 1 B*35 7 ISDTGELKL 1 C*05 8
KVNGKLVALK 1 A*03 9 NRLSAQAAL 1 B*39 10 TPFTAIREA 1 B*55 11
FGLARAKSV 6 B*08 12 KIADFGLAR 1 A*03 RASGRF1 Ras protein-specific
guanine nucleotide-releasing factor 1 12 (40.0) B*35 13 AAANIIRTL 8
A*02, B*13, B*51 14 GRFKNLREAL 1 B*27 15 MSPFSKATL 2 C*14 16
QEDPGDNQITL 1 B*40 17 SPFSKATL 2 B*08, B*07 CDCA7L cell division
cycle associated 7-like 11 (36.7) 18 DALLKRTM 1 B*08 19 GEDVRSALL 3
B*40 20 KFAEEFYSF 2 A*24 21 YGYDNVKEY 7 C*03, C*12 CELSR1 cadherin,
EGF LAG seven-pass G- type receptor 1 11 (36.7) 22 LEVEERTKPV 1
B*44 23 RDSPINANLRY 1 B*40 24 RPFVIVTA 1 B*55 25 RPIINTPMV 1 B*55
26 SPTSSRTSSL 7 B*07 27 ATSAPLVSR 1 A*11 AKAP2 A kinase (PRKA)
anchor protein 2 11 (36.7) 28 AELRSTASLL 1 B*40 29 APASSHERASM 2
B*07 30 ASRQAPPHI 1 A*30 31 AVKKNPGIAA 2 A*02 32 EEHLESHKKY 2 B*44
33 GEFTSARAV 1 B*49 34 GQSTPRLFSI 1 B*13 35 LVDDPLEY 1 A*01 36
RPKNLMQTL 3 B*07 37 RQAPPHIEL 2 B*13 38 SEAAELRSTA 1 B*50 CTDP1 CTD
phosphatase, subunit 1 11 (36.7) 39 AAVRIGSVL 2 A*02, B*13 40
ERAGVVREL 1 C*07 41 GAAVRIGSVL 1 A*02 42 KLYELHVFTF 1 A*32 43
LYELHVFTF 2 A*24, A*23 44 YLNKEIEEA 6 A*02 DNMBP dynamin binding
protein 10 [33.3] 45 DELPKFHQY 2 B*18 46 DVTGQFPSSF 1 A*26 47
EHSRVLQQL 2 B*39:01 48 IKVSKQLL 1 B*08 49 KPRQSSPQL 3 B*07 50
KQLLAALEI 1 B*13 51 RRKDLVLKY 2 B*27 52 RTRDYASLPPK 1 A*03 TAGAP
T-cell activation RhoGTPase activating protein 10 (33.3) 53
APGSVLPRAL 3 B*07 54 DIKEHPLL 1 B*08 55 DSAGPQDAR 1 A*68 56
FQYAKESYI 1 B*13 57 KVLSWPFLM 1 A*32 58 LENDQSLSF 1 B*44 59
SPSRQPQV 1 B*07 60 SRHQSFTTK 3 B*27 61 SSHNASKTL 2 C*12 ABCA6
ATP-binding cassette, sub-family A (ABC1), member 6 10 (33.3) 62
EEIDTTMRW 1 B*44 63 ILDEKPVII 5 A*02 64 LPQEPRTSL 2 B*07 65
LTYKLPVA 1 B*57 66 NEMELAHSSF 2 B*18 67 REFPEANFEL 1 B*40 68
THHIPDAKL 1 B*38 69 TVKENLSLF 1 A*26 70 VLLKKAVL 1 B*08 DMXL1
Dmx-like 1 10 (33.3) 71 HLKSIPVSL 2 B*08, B*07 72 KVWYNVENW 1 A*32
73 LPAYRAQLL 1 B*07 74 LSEQTSVPL 1 A*02 75 SLNQWLVSF 1 A*32 76
SMTSLAQKI 1 A*02 77 SSSGLHPPK 2 A*03, A*11, A*68 PARP3 poly
(ADP-ribose) polymerase family, member 3 10 (33.3) 78 DLDVKKMPL 4
B*08 79 FYTVIPHNF 3 A*24 80 HHINTDNPSL 2 B*39 81 RVGEVGQSK 2 A*03
TP53I11 tumor protein p53 inducible protein 11 8 (26.7) 82
AVFDGAQVTSK 7 A*03, A*11 83 SQTDLVSRL 1 B*15 B4GALT1
UDP-Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 1 8
(26.7) 84 VPVPHTTAL 7 B*07 85 YQVLDVQRY 1 B*15 IRF9 interferon
regulatory factor 9 8 (26.7) 86 APFQGDQRSL 2 B*07 87 DVAEPYKVY 1
A*26 88 IVSGQPGTQK 3 A*03 89 TPEQQAAIL 1 B*35 90 VELFRTAYF 1 B*37
KDM2B lysine (K)-specific demethylase 2B 8 (26.7) 91 EHADDDPSL 1
B*38 92 SEESVKSTTL 2 B*40 93 SPRPPLGSSL 4 B*07 94 SPWWRSSL 1 B*07
95 VYTPVDSLVF 1 A*24 TBC1D22A TBC1 domain family, member 22A 8
(26.7) 96 APLQRSQSL 6 B*07, B*08 97 DEVHQDTY 1 B*18 98 LPHSATVTL 1
B*07 ZNF296 zinc finger protein 296 8 (26.7) 99 SEAPEAPLL 1 B*40
100 SPRASGSGL 6 B*07 101 VVGPAAEAK 2 A*03 BACH2 BTB and CNC
homology 1, basic leucine zipper transcription factor 2 8 (26.7)
102 FSITKSVEL 4 A*02 103 GQTKNDLVV 1 B*13 104 LSQEVCRD 2 n.a. 105
RDIQSPEQI 1 B*40 106 REDNSSNSL 1 B*40 107 TEHQEPGL 2 B*40 108
TKNDLVVSL 1 B*39 PRR12 proline rich 12 8 (26.7) 109 AEEAGGTRL 1
B*40 110 ENVNKKDY 1 A*26 111 GLDPNKPPEL 4 A*02 112 RPAGEPYNRKTL 2
B*07 ZFAND5 zinc finger, AN1-type domain 5 7 (23.3) 113 SASVQRADTSL
5 C*03 114 YGNPRTNGM 2 B*08 ATP5G1 ATP synthase, H+ transporting,
mitochondrial Fo complex, subunit Cl 7 (23.3) 115 LIRPVSASF 3 B*07
116 SPVNSSKQPSY 3 B*35 117 QLFSYAILGF 1 A*32 DMD dystrophin 7
(23.3) 118 DEHLLIQHY 2 B*18 119 KQVASSTGF 1 B*15 120 RDFGPASQHFL 1
B*40 121 RQLGEVASF 2 A*32 122 TEAETTANVL 1 B*40 123 GYLPVQTVL 1
A*24 ARID5B AT rich interactive domain 5B (MRF1- like) 7(23.3) 124
GQKEALLKY 1 B*15 125 KPSEERKTI 1 B*07 126 KQTPKVLVV 1 B*13 127
SVIQHVQSF 1 A*26 128 TPIERIPYL 3 B*51 ZNF638 zinc finger protein
638 7 (23.3) 129 AEVEKNETV 1 B*40 130 EVKEEIPLV 1 B*08 131
KPTSARSGL 2 B*07 132 KYIETTPLTI 1 A*24 133 SEIKTSIEV 1 B*40 134
SVKPTSATK 4 A*03 135 YPNKGVGQA 1 B*55 DDX46 DEAD (Asp-Glu-Ala-Asp)
box polypeptide 46 7 (23.3) 136 ISMKILNSL 2 A*02 137 KTIAFLLPMF 1
A*32 138 RDSIINDF 2 B*37 139 SVKGGGGNEK 1 A*03 140 GIAKTGSGK 1 A*03
RRM2B ribonucleotide reductase M2 B (TP53 inducible) 7 (23.3) 141
AETTDNVFTL 1 B*40 142 SEYQRFAVM 3 B*37, B*40, B*49 143 TFGERVVAF 1
A*24 144 NENLVERF 2 B*18 BLNK B-cell linker 7 (23.3) 145 KITVPASQK
1 A*03 146 KITVPASQKL 7 A*02 147 VPASQKLRQL 2 B*07 HSH2D
hematopoietic 5H2 domain containing 7 (23.3) 148 HVGYTLSYK 1 A*03
149 KLPLPLPPRL 3 C*14 150 KPIEPRREL 1 B*07 151 SHSHVGYTL 3 B*38,
B*39 ERP44 endoplasmic reticulum protein 44 7 (23.3) 152 APSEYRYTL
1 B*07 153 APSEYRYTLL 3 B*07 154 EIFQNEVAR 1 A*68 155 KDVLIPGKL 1
B*40 156 VPLVREITF 2 B*08 METTL7A methyltransferase like 7A 7
(23.3) 157 DPNPNFEKF 1 B*35 158 IQAPLSWEL 1 B*13 159 VIYNEQMASK 3
A*03 160 VLRPGGAFY 2 B*15
ELP3 elongator acetyltransferase complex subunit 3 7 (23.3) 161
EDPDQDILI 1 B*18 162 HGNLRELAL 3 B*08 163 KLYPTLVIR 4 A*03 164
SEETFRFEL 1 B*40 NLRP2 NLR family, pyrin domain containing 2 6
(20.0) 165 ELNKLLEEI 3 A*02 166 IPFSNPRVL 2 B*07 167 LLDEGAKLLY 2
A*01 168 SPADAHRNL 1 B*07 ZC3H12D zinc finger CCCH-type containing
12D 6 (20.0) 169 AELERQAVL 1 B*37 170 GRVPGPLSL 1 B*27 171
SDLARLILL 1 B*27 172 TPIREQHVL 3 B*35 NELFE negative elongation
factor complex member E 6 (20.0) 173 APRKGNTL 1 B*07 174 EEEEALQKKF
1 B*44 175 KENLVDGF 2 B*37 176 VYKENLVDGF 2 A*23, A*24 ATP6V1C1
ATPase, H+ transporting, lysosomal 42kDa, V1 subunit C1 6 (20.0)
177 TLLVVVPKL 6 A*02 HLA-DMA major histocompatibility complex,
class II, DM alpha 6(20.0) 178 HEIDRYTAI 1 B*40 179 VFTLKPLEF 3
A*23, A*24 180 YWVPRNAL 2 B*08 TUFM Tu translation elongation
factor, mitochondria! 6 (20.0) 181 IGVEHVVVY 5 C*12 182 RDKPHVNV 1
B*37 E1F6 eukaryotic translation initiation 6 (20.0) factor 6 183
ADVLKVEVF 2 B*37 184 IPVVHASI 1 B*51 185 RDSLIDSLT 1 B*40 186
TVADQVLVGSY 2 A*26 CKAP4 cytoskeleton-associated protein 4 6 (20.0)
187 AADTERLAL 1 A*02 188 DMKAKVASL 2 B*08 189 HVLEEVQQV 2 B*13 190
KEAADTERL 1 B*40 191 RISEVLQKL 1 A*02 192 TEVRELVSL 2 B*40 COBLL1
cordon-bleu WH2 repeat protein-like 1 6 (20.0) 193 AIRSGEAAAK 2
A*03 194 APNPAPKEL 4 B*07 195 RQSLLTAI 1 B*13 196 SPEQTLSPL 1 B*35
197 TEHQVPSSV 1 B*40 198 TTYKIVPPK 1 A*03 TMED4 transmembrane emp24
protein transport domain containing 4 6 (20.0) 199 QLLDQVEQI 4 A*02
200 DETMVIGNY 1 B*18 201 RQYGSEGRFTF 1 B*37 TNFRSF13C tumor
necrosis factor receptor superfamily, member 13C 6 (20.0) 202
SPAPRTAL 6 B*07 UBL7 ubiquitin-like 7 6 (20.0) 203 GPRPITQSEL 6
B*07 204 KPEPVDKVA 1 B*07 205 TPSSRPASL 4 B*07 CXorf21 chromosome X
open reading frame 21 6 (20.0) 206 DETQVRSLY 2 B*18 207 KEEETNSVATL
1 B*40 208 LEQKVVELY 2 B*18 209 NPISNAVLNEY 1 B*35 210 SIKEKSSL 1
B*08 211 TEITEISTPSL 1 B*40 ASUN asunder spermatogenesis regulator
6 (20.0) 212 GRLNSVNNR 1 B*27 213 SILEDPPSI 3 A*02 214 TPRTNNIEL 2
B*07 RSL24D1 ribosomal L24 domain containing 1 6 (20.0) 215
DAMKRVEEI 3 B*08 216 DIKEVKQNI 3 B*08 217 GPIYPGHGM 1 B*07 Q9U115,
ZNF107 zinc finger protein 107 6 (20.0) 218 GDYGRAFNL 2 B*37 219
TRHKIVHTK 2 B*27 220 RIHTGEKPYK 1 A*03 221 KAFNWFSTL 1 A*32
TRAF3IP3 TRAF3 interacting protein 3 6 (20.0) 222 QSTQRSLAL 2 B*08
223 RDLQMNQALRF 1 B*40 224 RELESQLHVL 2 B*40 225 SEAEKLTLV 1
B*40
TABLE-US-00002 TABLE 1b Additional peptides according to the
invention for CLL - MHC class I SEQ ID NO: Amino acid sequence HLA
226 AAAKPVATK A*03, A*11 227 ATYHGSFSTK A*03, A*11 228 FMYDRPLRL
A*02 229 FRVGNVQEL 230 GVAPFTIAR A*03, A*11, A*68 231 KMKPLDGSALY
A*30 232 KPAPAKPVA B*55 233 KPVAAKPAA n.a. 234 KQFGVAPFTI B*13 235
QEELVKISL B*40: 01 236 RQLGTVQQVI B*13 237 RQLINALQI B*13, A*32 238
RVIGGLLAGQTY B*15: 01 239 SENAFYLSP n.a. 240 SQAPVLDAI B*13 241
STRYPPPAV A*30 242 TEDTLKVYL B*40: 01, B*52 243 VAAKPVATK A*03 244
VQRVVESL B*08 245 VRNPSVVVK B*27 246 GESEVAIKI B*49, B*52 247
LIYSVGLLLA A*02 248 SAYPHQLSF A*32 249 SVIGVFITK A*03, A*11, A*68
250 AELGNSVQLI B*49 251 ANMTVTRI n.a 252 ARISNVEFY C*07 253
AVFIGNQQF B*15: 01 254 DIELQAENI A*02 255 DSYTVRVSV B*51 256
DVKIFVNTI B*51 257 ElIPKYGSI A*25 258 EQSKIFIHR n.a 259 FVDVGLYQY
A*03 260 GHTSTISTL B*39 261 GRIEYVEVF C*07 262 GTSIIPFQK A*11 263
HPFLRGIGY B*35 264 IPVEIHTA B*55 265 KIFVNTIAY B*15: 01 266
LPEDKVRIAY B*35 267 LPFSEGLTV B*51 268 LPWANKVTI B*51 269 PWANKVTI
n.a. 270 QAYNRAVTI B*51 271 RSFPQKMAY B*15: 01 272 RYPIHWHLL C*07
273 SPQNLRLML B*07 274 SYFSSPTQR B*27 275 VQIKSSLI B*13 276
VYIGHTSTI C*07 277 YHVPGTGESY C*07 278 ATNGDLASR A*31 279
GLHAEVTGVGY B*15: 01 280 HVSSTSSSF A*32 281 LQADLQNGL B*13 282
SELPVSEVA B*45 283 SQTKSVFEI B*13 284 THIFTSDGL B*39 285 VIYFPPLQK
A*11 286 YPFSSEQKW B*35 287 GQYFGELAL B*13 288 RIIVKNNAK n.a. 289
RRIIVKNNAK B*27 290 SFGELALMY n.a. 291 AFNAPVINR B*27 292 IMKRNIATY
B*15: 01 293 KVVDVIGTK A*11 294 LPFLKSLEF B*07, B*35 295
RLKVVDVIGTK A*03 296 TPRAATITA B*07, B*51, B*55 297 KPSEKIQVL B*07
298 VPYPVTTTV B*35 299 ASFPPFVEK B*15 300 AFIHISTAY A*29 301
ATFEKIPFER A*11 302 KLFEKVKEV A*02 303 SQMPKLEAF B*15: 01 304
AVLGQHHNY A*03 305 GPPAHKPR n.a. 306 RVYDVLVLK A*03, A*11 307
LPRPQGITV B*07 308 VLYVGSKTK A*03 309 KTKEQVTNV A*11 310 MPVDPDNEAY
B*35 311 AEKTKQGVA B*40 312 DIADFFTTR A*68 313 HSYLQRQSV C*12 314
KEVTLIEEL B*40: 01 315 REDGPGVAL B*40: 01 316 REDPLPPGL B*40: 01
317 SLFGGSQGLRK A*03 318 AEFQRLKQA B*50 319 EVIDGVPGKW A*25 320
IPKAPGKII B*07, B*08, B*55 321 SHNGSAIRY A*32 322 TEVTVVGDKL B*40:
01 323 YASVVVKRY A*28 324 ATDLALYIK A*11 325 AYHNWRHAF C*07 326
EPLNIKDAY B*35 327 KIAATIISF B*15: 01 328 KIFLHIHGL B*71 329
LEVILKKI n.a. 330 SEHPLAQLY B*44 331 VPSAQTLKI B*51 332 AEYRSYVA
B*45 333 ALAPGRGTLY A*24 334 GPRGTQAAL B*07 335 IEDPGTLHI B*49 336
IEDPGTLHIW B*44 337 RPIPIAVKY B*35 338 VEKLLTNW n.a. 339
FLDPDIGGVAV A*02 340 HTAPPENKTW A*30
341 LLDTPVKTQY A*01 342 NAVKDFTSF A*03, A*11 343 SGLLQIKKL n.a. 344
YHDKNIVLL B*39 345 SVDPKNYPK A*11, A*03 346 AVGLVLPAK A*11 347
AVGLVLPAKL n.a. 348 ALLEVLSQK A*03 349 HEKQDTLVA B*45 350 KELELQIGM
B*40: 01, B*52 351 MYSDVWKQL A*24 352 RELQDEKAEL B*40: 01 353
RITDVLDQK A*11 354 EVIKITGLK A*68 355 HHVDITKKL B*39 356 LPFNVKVSV
B*51 357 TLPRVLEI B*51 358 TVDLPKSPK A*11 359 AEHGLLLTA B*45 360
AQAGALLQV B*13 361 DGGFVLKV B*51 362 IVYPSGKVY B*15: 01 363
KLDNQVSKV A*02 364 SENVKLFSA B*45 365 VQKLQNII 366 FSTPHGLEV B*51
367 KRFHQKSDM B*27 368 KTFGHAVSL A*32 369 SSNLITHSR A*31 370
GVIDGHIYAV A*02 371 IEPAKETTTNV B*40: 01, B*44 372 NAPPSEVLL n.a.
373 SIEPAKETTTNV A*02 374 AQSQHNQSL B*13 375 AQSRTNPQV B*13 376
KMHDKVFAY A*03 377 TAKAPLSTV B*51 378 IPTRTVAI B*51 379 NHDRKHAV
B*39 380 NNHDRKHAV B*08 381 TPGGTRIIY B*35 382 EHWPSPETF A*68 383
EIITNTLSF A*25 384 EVRGALMSAF A*25 385 IPRPILVLL B*07 386 LPNKNRDEL
B*07 387 QRIPAGAVL B*27 388 AEGPAGGFMVV B*49 389 AYYRDAEAY C*07 390
QVNRPLTMR A*03 391 RHSPVFQVY A*32 392 SLPVPNSAY B*15: 01 393
TLGPPGTAHLY B*15: 01 394 IEPAKETTTNV B*40: 01, B*44 395 NAPPSEVLL
n.a. 396 SIEPAKETTTNV A*02 397 DLYSGLNQR A*68 398 KAKAKPVTR A*31
399 AVLDKAMKAK A*03 400 LELSTPLKI B*49 401 LPLNLDTKY B*35 402
TVIYRIQAL A*02 403 DAHIYLNHI B*51 404 NHIEPLKIQL B*39 405 AYRPAVHPR
B*27 406 LRAPLEHEL n.a. 407 RLFMVLLLK A*03 408 RSPDVLKDF B*15: 01
409 ETAPGVHKR A*68 410 LYHGYIYTY A*24 411 GQHVATQHF B*15: 01 412
LNGQLPNL n.a. 413 LPFPDETHERY B*35 414 LPHNTHRVV B*51 415 VVFDSPRNR
A*03 416 YPLGRILI B*51 417 KEFAEFVTS B*50 418 VMLDVPIRL A*02 419
VPMTPLRTV B*51 420 QIDYKTLVL B*13 421 VEDPTIVRI B*40: 01, B*44,
B*52 422 IPYQDLPHL B*07 423 DTPFLTGHGR A*68 424 EFYRALYI 425
RYYPQILTNK 426 KAYERHVL B*08 427 LPSPEFHDY B*35 428 SLYAHPIEH A*03
429 LVREPGSQA B*08 430 RLAGPGSEKY B*15: 01 431 SPGAGRNSVL B*07 432
SVQSDQGYISR A*11 433 GVRPPAPSL B*13 434 IFSEKPVFV n.a. 435
KASNLLLGF B*58 436 KRYIFADAY n.a. 437 RNLQLSLPR A*31 438 EASEPVALR
A*68 439 RPKVPDQSV B*7, B*8, B*35 440 VLYENALKL A*02 441 EVLDKSQTNY
A*25 442 MPSPIPAKY B*35 443 YGIENFTSV B*51 444 ARAAQVFFL B*27 445
EHIVPNAEL B*39 446 EAFEFVKQR A*68 447 NHFEGHYQY n.a. 448 DAYPKNPHL
B*51 449 DVNIKSTER A*68 450 HINSIKSVF A*31 451 YESEKVGVA B*50 452
ENAPTTVSR A*68 453 RFPHLLAHTY C*14 454 TLDGSLHAV A*02 455
RTVLKNLSLLK A*03 456 FEAKVQAI B*49 457 FFEAKVQAI C*12 458 KELQSTFK
n.a. 459 NVSSRFEEEI A*02 460 EVWNNLGTTK A*68 461 MIFRSGSLI n.a.
462 NHALPLPGF B*39 463 ASVFGTMPLK A*11 464 REFPDRLVGY B*44 465
SVFGTMPLK A*11 466 DEMRFVTQI n.a. 467 ETVHFATTQW A*25 468 LPPPATQI
B*51 469 LARDLYAF C*03, C*12 470 LPGIGLSTSL B*53 471 MEVILPML n.a.
472 AILDYILAK A*03 473 KIASQLSKL A*02 474 KVTSTTTVK A*03, A*11 475
YNTLLPYTF n.a. 476 FLDPRPLTV A*02 477 SAFADRPAF C*03 478 AAVPVIISR
A*68 479 EEIGKVAAA B*45 480 FLKDLVASV A*02 481 VIISRALEL C*03 482
APRTTGTPRTSL B*07 483 ESVGGSPQTK A*68 484 IPKDKAIL B*08 485
LPAYGRTTL B*07 486 HQAAIVSKI B*13 487 QAAIVSKI B*51 488 RQKMPEDGL
B*13 489 SVQKSSGVK A*11 490 DSIGSTVSSER A*68 491 LPYNNKDRDAL B*07
492 IYDEIQQEM C*14 493 AQAKGLIQV B*13 494 EVSSEIYQW A*25 495
KWNPVPLSY A*29 496 NRLLAQQSL B*27 497 APRPVAVAV B*07 498 FYRETVQVGR
A*33 499 LLAPRPVAV A*02 500 GLAALVILK A*03 501 KIQEVFSSY B*15: 01
502 ASLDKFLSH A*11 503 ALYATKTLR A*03 504 MEYVISRI n.a. 505
VPVGRQPII B*51 506 KLLIGVIAAV A*02 507 LPSLIKLD n.a. (B*51!!) 508
PSLIKLDL n.a. 509 ARNKELIGK B*27 510 AVKSNAAAY B*15: 01 511
EVIIPHSGW A*25 512 SVKEQEAQF B*15: 01 513 APRGLEPIAI B*07 514
GRFGGVITI B*27 515 PVAGFFINR A*68 516 TPKTPSRDA B*08, B*55 517
VLFGGKVSGA A*02 518 AEHIESRTL B*40, B*44 519 DQYPYLKSV C*12 520
IARNLTQQL B*07 521 IESRTLAIA B*50 522 MTSALPIIQK A*11 523
SLLTSSKGQLQK A*03 524 TSALPIIQK A*11, A*03 525 VRLGSLSTK B*27 526
RINEFSISSF B*15 527 DEKQQHIVY B*18 528 DEVYQVTVY B*18 529 GEISEKAKL
B*40 530 YTMKEVLFY A*03 531 SQLTTLSFY B*15 532 LEKQLIEL B*44 533
ELTLGEFLK A*68, A*33 534 LTLGEFLK A*68 535 LTLGEFLKL A*02 536
TLGEFLKL A*02 537 ITARPVLW B*58 538 KLMSPKLYVW A*32 539 KVSAVTLAY
A*03 540 VEGSGELFRW B*44 541 RPKSNIVL B*07 542 RPKSNIVLL B*07
TABLE-US-00003 TABLE 1c Additional peptides according to the
invention for CLL - MHC class II SEQ ID NO: Amino acid sequence MHC
543 GEPLSYTRFSLARQ class II 544 GEPLSYTRFSLARQVD class II 545
GEPLSYTRFSLARQVDG class II 546 GGEPLSYTRFSLARQVD class II 547
GGEPLSYTRFSLARQVDG class II 548 NPGGYVAYSKAATVTG class II 549
NPGGYVAYSKAATVTGK class II 550 NPGGYVAYSKAATVTGKL class II 551
NSVIIVDKNGRL class II 552 NSVIIVDKNGRLV class II 553 NSVIIVDKNGRLVY
class II 554 RVEYHFLSPYVSPK class II 555 RVEYHFLSPYVSPKE class II
556 RVEYHFLSPYVSPKESPF class II 557 SPFRHVFWGSGSHTL class II 558
SVIIVDKNGRLV class II 559 VEYHFLSPYVSPK class II 560 VEYHFLSPYVSPKE
class II 561 LPSQAFEYILYNKG class II 562 LPSQAFEYILYNKGI class II
563 LPSQAFEYILYNKGIM class II 564 LPSQAFEYILYNKGIMG class II 565
MNGYFLIERGKNM class II 566 NGYFLIERGKNM class II 567 PSQAFEYILYNKG
class II 568 PSQAFEYILYNKGI class II 569 PSQAFEYILYNKGIM class II
570 EGVQYSYSLFHLM class II 571 EGVQYSYSLFHLML class II 572
GVQYSYSLFHLM class II 573 GVQYSYSLFHLML class II 574
SIISIHPKIQEHQPR class II 575 SSIRTSTNSQVDK class II 576
VLVGYKAVYRIS class II 577 YSSIRTSTNSQVDK class II 578
GGGYGSGGGSGGYGSRRF class II 579 GGSFGGRSSGSP class II 580
KGGSFGGRSSGSP class II 581 SGQQQSNYGPMKGGSFGGRSSGSPY class II 582
SGSPYGGGYGSGGGSGGYGSRRF class II 583 SPYGGGYGSGGGSGGYGSRRF class II
584 YGGGYGSGGGSGGYGSRRF class II 585 GNRINEFSISSF class II 586
HGNQITSDKVGRKV class II 587 IPPVNTNLENLYLQ class II 588
LQVLRLDGNEIKR class II 589 LQVLRLDGNEIKRS class II 590
LQVLRLDGNEIKRSA class II 591 LRELHLDHNQISRVPN class II 592
LYVRLSHNSLTNNG class II 593 VPSRMKYVYFQNNQ class II 594
VPSRMKYVYFQNNQIT class II 595 VPSRMKYVYFQNNQITS class II 596
WIALHGNQITSD class II 597 WIALHGNQITSDK class II 598
ADDNVSFRWEALGNT class II 599 ADDNVSFRWEALGNTL class II 600
DADDNVSFRWEALGNTL class II 601 DDNVSFRWEALGNT class II 602
DDNVSFRWEALGNTL class II 603 DNVSFRWEALGNT class II 604
DNVSFRWEALGNTL class II 605 DNVSFRWEALGNTLS class II 606
DTGSYRAQISTKTSAK class II 607 DTGSYRAQISTKTSAKL class II 608
DTITIYSTINHSK class II 609 EDTGSYRAQISTKTSAK class II 610
ENDTITIYSTINHSK class II 611 ENDTITIYSTINHSKESKPT class II 612
GSYRAQISTKTSAK class II 613 NDTITIYSTINH class II 614 NDTITIYSTINHS
class II 615 NDTITIYSTINHSK class II 616 NVSFRWEALGNTL class II 617
SPTNNTVYASVTHSNRET class II 618 TGSYRAQISTKTSAK class II 619
TPRENDTITIYSTINHSK class II 620 TPRENDTITIYSTINHSKESKPT class II
621 VSFRWEALGNTL class II 622 APIHFTIEKLELNEK class II 623
DAQFEVIKGQTIE class II 624 DAQFEVIKGQTIEVR class II 625
ESYFIPEVRIYDSGT class II 626 IPEVRIYDSGTY class II 627
KDKAIVAHNRHGNK class II 628 KDKAIVAHNRHGNKA class II 629
NFVILEFPVEEQDR class II 630 SQPRISYDAQFEVIK class II 631
SQPRISYDAQFEVIKG class II 632 YDAQFEVIKGQTIE class II 633
GNPAYRSFSNSLSQ class II 634 GPPGEAGYKAFSSLLA class II 635
GPPGEAGYKAFSSLLASS class II 636 GPPGEAGYKAFSSLLASSA class II 637
GPPGEAGYKAFSSLLASSAVSPE class II 638 GPPGEAGYKAFSSLLASSAVSPEK class
II 639 GYKAFSSLLASSAVSP class II 640 GYKAFSSLLASSAVSPE class II 641
KAFSSLLASSAVSPE class II 642 NPAYRSFSNSLSQ class II 643
SRDDFQEGREGIVAR class II 644 SSSSFHPAPGNAQ class II 645
VARLTESLFLDL class II 646 VARLTESLFLDLLG class II 647 VIAGNPAYRSFSN
class II 648 VPQPEPETWEQILRRNVLQ class II 649 YKAFSSLLASSAVS class
II 650 YKAFSSLLASSAVSP class II 651 YKAFSSLLASSAVSPE class II 652
GNQVFSYTANKEIRTDD class II 653 IEEIVLVDDASERD class II 654
IEEIVLVDDASERDF class II 655 LENIYPDSQIPRH class II 656
LENIYPDSQIPRHY class II 657 NQVFSYTANKEIR class II 658
NQVFSYTANKEIRT class II 659 NQVFSYTANKEIRTDD class II 660
VHSVINRSPRHMIEE class II 661 EYVSLYHQPAAM class II 662
IKAEYKGRVTLKQYPR class II 663 LNVHSEYEPSWEEQP class II 664
LPYLFQMPAYASSS class II
665 LPYLFQMPAYASSSK class II 666 NFIKAEYKGRVT class II 667
TNFIKAEYKGRVT class II 668 TTNFIKAEYKGRVT class II 669
VTLNVHSEYEPSWEEQP class II 670 YPRKNLFLVEVTQLTESDS class II 671
YPRKNLFLVEVTQLTESDSG class II 672 ADLSSFKSQELN class II 673
ADLSSFKSQELNER class II 674 ADLSSFKSQELNERN class II 675
ADLSSFKSQELNERNE class II 676 ADLSSFKSQELNERNEA class II 677
AEQQRLKSQDLELSWNLNG class II 678 EQQRLKSQDLELSWN class II 679
ISQELEELRAEQQR class II 680 ISQELEELRAEQQRLK class II 681
KGTKQWVHARYA class II 682 QADLSSFKSQELNER class II 683
SWNLNGLQADLSSFK class II 684 TGSWIGLRNLDLKG class II 685
FGNYNNQSSNFGPMKGGNFGGRS class II 686 FGPMKGGNFGGRSSGPYGGGGQY class
II 687 GPMKGGNFGGRSSGP class II 688 GPYGGGGQYFAKP class II 689
KGGNFGGRSSGP class II 690 NDFGNYNNQSSNFGP class II 691
SGPYGGGGQYFAKP class II 692 DAGSYKAQINQRNFE class II 693
DAGSYKAQINQRNFEVT class II 694 DGELIRTQPQRLPQ class II 695
GELIRTQPQRLPQ class II 696 NPSDGELIRTQPQRLP class II 697
NPSDGELIRTQPQRLPQ class II 698 NPSDGELIRTQPQRLPQL class II 699
ASNDMYHSRALQVVR class II 700 ASNDMYHSRALQVVRA class II 701
EGVRRALDFAVGEYN class II 702 EGVRRALDFAVGEYNK class II 703
SNDMYHSRALQVVR class II 704 VGEYNKASNDMYH class II 705
VRARKQIVAGVNY class II 706 VRRALDFAVGEYNKASND class II 707
VVRARKQIVAGVN class II 708 VVRARKQIVAGVNY class II 709
APLEGARFALVRED class II 710 APVELILSDETLPAPE class II 711
ELILSDETLPAPE class II 712 LAPLEGARFALVRE class II 713
LAPLEGARFALVRED class II 714 RGEKELLVPRSSTSPD class II 715
ASKTFTTQETITNAET class II 716 DQHFRTTPLEKNAPV class II 717
NTPILVDGKDVMPE class II 718 NTPILVDGKDVMPEV class II 719
NTPILVDGKDVMPEVN class II 720 SNTPILVDGKDVMPE class II 721
SNTPILVDGKDVMPEVN class II 722 TPILVDGKDVMP class II 723
TPILVDGKDVMPE class II 724 TPILVDGKDVMPEV class II 725
TPILVDGKDVMPEVN class II 726 GPLKFLHQDIDSGQG class II 727
GPLKFLHQDIDSGQGIR class II 728 LGDIYFKLFRASG class II 729
TGHLFDLSSLSGRAG class II 730 VPSPVDCQVTDLAGNE class II 731
DGLNSLTYQVLDVQRYPL class II 732 HPVLQRQQLDYGIY class II 733
LNSLTYQVLDVQR class II 734 LNSLTYQVLDVQRYP class II 735
LNSLTYQVLDVQRYPL class II 736 LPQLVGVSTPLQG class II 737
LPQLVGVSTPLQGG class II 738 LPQLVGVSTPLQGGS class II 739
RLPQLVGVSTPLQGGS class II 740 SPHKVAIIIPFRNR class II 741
SPHKVAIIIPFRNRQE class II 742 SPHKVAIIIPFRNRQEH class II 743
AIVQAVSAHRHR class II 744 ARNFERNKAIKVI class II 745
ARNFERNKAIKVIIA class II 746 NFERNKAIKVII class II 747
NFERNKAIKVIIA class II 748 VAIVQAVSAHRH class II 749 VAIVQAVSAHRHR
class II 750 VAIVQAVSAHRHRA class II 751 VAIVQAVSAHRHRAR class II
752 EEVITLIRSNQQLE class II 753 EEVITLIRSNQQLEN class II 754
IPADTFAALKNPNAML class II 755 LKQLLSDKQQKRQSG class II 756
LKQLLSDKQQKRQSGQ class II 757 TPSYVAFTDTER class II 758
TPSYVAFTDTERL class II 759 EGLYSRTLAGSIT class II 760
EGLYSRTLAGSITTPP class II 761 EKWYIPDPTGKFN class II 762
GAIAAINSIQHNTR class II 763 LPILVPSAKKAI class II 764 LPILVPSAKKAIY
class II 765 LPILVPSAKKAIYM class II 766 LPILVPSAKKAIYMD class II
767 LPILVPSAKKAIYMDD class II 768 VEEGLYSRTLAGSIT class II 769
WEKWYIPDPTGKFN class II 770 YKIVNFDPKLLE class II 771 YKIVNFDPKLLEG
class II 772 YKIVNFDPKLLEGKV class II 773 LPEFYKTVSPAL class II 774
VGQFIQDVKNSRST class II 775 VGQFIQDVKNSRSTD class II 776
VVGQFIQDVKNSRS class II 777 VVGQFIQDVKNSRST class II 778
VVGQFIQDVKNSRSTD class II 779 VVGQFIQDVKNSRSTDS class II 780
DNGHLYREDQTSPAPG class II 781 DNGHLYREDQTSPAPGLR class II 782
EVQVFAPANALPARSE class II 783 GHLYREDQTSPAPG class II 784
LPARSEAAAVQPVIG class II 785 NGHLYREDQTSPAPG class II 786
NGHLYREDQTSPAPGL class II 787 NGHLYREDQTSPAPGLR class II 788
VFAPANALPARSEAA class II 789 VQVFAPANALPARSE class II 790
AIVVSDRDGVPVIK class II
791 GLHAIVVSDRDGVPV class II 792 GLHAIVVSDRDGVPVIK class II 793
HAIVVSDRDGVPV class II 794 KLPSVEGLHAIVVSDRDG class II 795
LHAIVVSDRDGVPV class II 796 LHAIVVSDRDGVPVI class II 797
LHAIVVSDRDGVPVIK class II 798 LPSVEGLHAIVVSDR class II 799
VPVIKVANDNAPE class II 800 YNTYQVVQFNRLP class II 801
YNTYQVVQFNRLPL class II 802 YNTYQVVQFNRLPLV class II 803
YNTYQVVQFNRLPLVV class II 804 YYNTYQVVQFNRLP class II 805
YYNTYQVVQFNRLPL class II 806 YYNTYQVVQFNRLPLV class II 807
DKIYFMAGSSRKE class II 808 DVGTDEEEETAKESTAEKDE class II 809
EVTFKSILFVPTSAP class II 810 KSEKFAFQAEVNR class II 811
LPEFDGKRFQNVAK class II 812 DGSYRIFSKGASE class II 813 GSYRIFSKGASE
class II 814 SDGSYRIFSKGASE class II 815 SVKKMMKDNNLVRH class II
816 VKKMMKDNNLVRH class II 817 NNMRIFGEAAEKN class II 818
VDKVLERDQKLSE class II 819 VDKVLERDQKLSELD class II 820
VDKVLERDQKLSELDD class II 821 VDKVLERDQKLSELDDR class II 822
VLERDQKLSELDDR class II 823 ATRSIQVDGKTIKAQ class II 824
ATRSIQVDGKTIKAQI class II 825 IGVEFATRSIQVDGK class II 826
RSIQVDGKTIKA class II 827 RSIQVDGKTIKAQ class II 828 RSIQVDGKTIKAQI
class II 829 TRSIQVDGKTIKAQ class II 830 DIMRVNVDKVLERDQK class II
831 DIMRVNVDKVLERDQKL class II 832 IMRVNVDKVLERDQK class II 833
VDKVLERDQKLSE class II 834 VDKVLERDQKLSELD class II 835
VDKVLERDQKLSELDD class II 836 VDKVLERDQKLSELDDR class II 837
VLERDQKLSELDDR class II 838 ATRSIQVDGKTIKAQ class II 839
ATRSIQVDGKTIKAQI class II 840 IGVEFATRSIQVDGK class II 841
RSIQVDGKTIKA class II 842 RSIQVDGKTIKAQ class II 843 RSIQVDGKTIKAQI
class II 844 TRSIQVDGKTIKAQ class II 845 GIRVAPVPLYNS class II 846
GIRVAPVPLYNSFH class II 847 NPNGIRVAPVPLYNSFH class II 848
DDPAIDVCKKLLGKYPN class II 849 DKQPYSKLPGVSLLKP class II 850
DKQPYSKLPGVSLLKPL class II 851 HPRYYISANVTGFK class II 852
SHPRYYISANVTG class II 853 SHPRYYISANVTGFK class II 854
TSHPRYYISANVTG class II 855 TSHPRYYISANVTGFK class II 856
ADIFVDPVLHTA class II 857 ADIFVDPVLHTACA class II 858
DPGADYRIDRALNEA class II 859 IAQDYKVSYSLA class II 860
IAQDYKVSYSLAK class II 861 ISRDWKLDPVLYRK class II 862
LIAQDYKVSYSLA class II 863 RQKLIAQDYKVSYS class II 864
RQKLIAQDYKVSYSL class II 865 RQKLIAQDYKVSYSLA class II 866
RQKLIAQDYKVSYSLAK class II 867 SALDYRLDPQLQLH class II 868
SKADIFVDPVLHTA class II 869 SPSKNYILSVISGSI class II 870
ETTQLTADSHPSYHTDG class II 871 SGESLYHVLGLDKNATSDD class II 872
TTQLTADSHPSYHT class II 873 TTQLTADSHPSYHTD class II 874
TTQLTADSHPSYHTDG class II 875 SVEEFLSEKLERI class II 876
VEEFLSEKLERI class II 877 DLSSSILAQSRERVA class II 878
EKGVRTLTAAAVSGAQ class II 879 EKGVRTLTAAAVSGAQP class II 880
EKGVRTLTAAAVSGAQPI class II 881 KGVRTLTAAAVSGA class II 882
KGVRTLTAAAVSGAQ class II 883 VGPFAPGITEKAPEEKK class II 884
DPPLIALDKDAPLR class II 885 EIITPDVPFTVDKDG class II 886
IITPDVPFTVDKDG class II 887 PPLIALDKDAPLR class II 888
TNVKKSHKATVHIQ class II 889 DDNIKTYSDHPE class II 890 DDNIKTYSDHPEK
class II 891 DSAVFFEQGTTRIG class II 892 GDKVYVHLKNLASRPY class II
893 GDKVYVHLKNLASRPYT class II 894 VHLKNLASRPYT class II 895
VYVHLKNLASRPY class II 896 VYVHLKNLASRPYT class II 897
VYVHLKNLASRPYTFH class II 898 YVHLKNLASRPY class II 899
YVHLKNLASRPYT class II 900 YVHLKNLASRPYTFH class II 901
SNLIKLAQKVPTAD class II 902 YDTRTSALSAKS class II 903
ALMTDPKLITWSPV class II 904 NDVAWNFEKFLVGPDG class II 905
QSVYAFSARPLAG class II 906 QSVYAFSARPLAGGEPV class II 907
WNFEKFLVGPDG class II 908 DVGMFVALTKLGQPD class II 909
VGMFVALTKLGQPD class II 910 AGVFHVEKNGRY class II 911
FAGVFHVEKNGRYS class II 912 GPITITIVNRDGTR class II 913
NGRYSISRTEAADL class II 914 RKSRQGSLAMEELK class II 915
RRKSRQGSLAMEELK class II
916 EEFKKLTSIKIQNDK class II 917 INRRMADDNKLFR class II 918
TATIVMVTNLKERKE class II 919 ELFYKGIRPAINVG class II 920
GQKRSTVAQLVKR class II 921 SDLDAATQQLLSRGV class II 922
FDFSQNTRVPRLPE class II 923 GDAPAILFDKEF class II 924 VTHEIDRYTAIAY
class II 925 GQGYLIKDGKLIKNNA class II 926 IDTTSKFGHGRFQTM class II
927 IDVIGVTKGKGYKGVTSRW class II 928 MGPLKKDRIAKEEGA class II 929
AAKYQLDPTASISA class II 930 IAAKYQLDPTASISA class II 931
IAAKYQLDPTASISAK class II 932 AGLGRAYALAFAERG class II 933
DAFGRIDVVVNNAG class II 934 GLGRAYALAFAER class II 935
GLGRAYALAFAERG class II 936 AKFALNGEEFMNFDL class II 937
AKFALNGEEFMNFDLK class II 938 ALNGEEFMNFDLK class II 939
KFALNGEEFMNFDL class II 940 SDGSFHASSSLTVK class II 941
EERNLLSVAYKNVVGAR class II 942 ERNLLSVAYKNVVGAR class II 943
IAELDTLSEESYKD class II 944 IAELDTLSEESYKDS class II 945
ADSYLDEGFLLDKKIG class II 946 DSYLDEGFLLDKK class II 947
DSYLDEGFLLDKKIG class II 948 VDNIIKAAPRKRVPD class II 949
SPPQFRVNGAISN class II 950 SPPQFRVNGAISNFE class II 951
SPPQFRVNGAISNFEE class II 952 SPPQFRVNGAISNFEEF class II 953
VGKMFVDVYFQEDKK class II 954 VGKMFVDVYFQEDKKE class II 955
DPKRTIAQDYGVLKADE class II 956 DPKRTIAQDYGVLKADEG class II 957
PKRTIAQDYGVLKADEG class II 958 GLFIIDDKGILRQ class II 959
GLFIIDDKGILRQIT class II 960 RGLFIIDDKGILR class II 961
RGLFIIDDKGILRQ class II 962 RGLFIIDDKGILRQIT class II 963
GNTVIHLDQALARMR class II 964 NTVIHLDQALARMR class II 965
NTVIHLDQALARMRE class II 966 ENNEIISNIRDSVIN class II 967
NNEIISNIRDSVIN class II 968 SPTVQVFSASGKPV class II 969
SSPTVQVFSASGKPVE class II 970 AEPNYHSLPSARTDEQ class II 971
SSILAKTASNIIDVS class II 972 LEARATAPPAPSAPN class II 973
ADDLEGEAFLPL class II 974 ADDLEGEAFLPLR class II 975 ADDLEGEAFLPLRE
class II 976 GADDLEGEAFLPLR class II 977 AGREINLVDAHLKSE class II
978 AGREINLVDAHLKSEQT class II 979 GREINLVDAHLKSE class II 980
KPGIVYASLNHSVIG class II 981 NKPGIVYASLNHSVIG class II 982
TTLYVTDVKSASERPS class II 983 APSTYAHLSPAKTPPP class II 984
APSTYAHLSPAKTPPPP class II 985 APSTYAHLSPAKTPPPPA class II 986
RDDLYDQDDSRDFPR class II 987 TRPYHSLPSEAVFA class II 988
TRPYHSLPSEAVFAN class II 989 VAVFTFHNHGRT class II 990
VAVFTFHNHGRTA class II 991 VAVFTFHNHGRTANL class II 992
EDDYIKSWEDNQQGDE class II 993 ELERIQIQEAAKKKPG class II 994
ERIQIQEAAKKKP class II 995 ERIQIQEAAKKKPG class II 996
ERIQIQEAAKKKPGI class II 997 LERIQIQEAAKKKPG class II 998
LSSISQYSGKIK class II 999 SPAKDSLSFEDF class II 1000
SPAKDSLSFEDFLDL class II 1001 INSRFPIPSATDPD class II 1002
VQHYELLNGQSVFG class II 1003 DNQYAVLENQKSSH class II 1004
GPPEIYSDTQFPS class II 1005 GPPEIYSDTQFPSLQ class II 1006
TPQGPPEIYSDTQFPS class II 1007 TPQGPPEIYSDTQFPSLQ class II 1008
TPQGPPEIYSDTQFPSLQST class II 1009 ANLQRAYSLAKEQR class II 1010
NLQRAYSLAKEQR class II 1011 TPSGITYDRKDIEEH class II 1012
VSTLNSEDFVLVSR class II 1013 VSTLNSEDFVLVSRQ class II 1014
VSTLNSEDFVLVSRQG class II 1015 GSSFFGELFNQNPE class II 1016
SGSSFFGELFNQNPE class II
TABLE-US-00004 TABLE 2 Peptides according to the invention suitable
for the (combined) treatment of CLL and/or AML SEQ ID NO: Amino
acid sequence 710 APVELILSDETLPAPE 878 EKGVRTLTAAAVSGAQ 879
EKGVRTLTAAAVSGAQP 533 ELTLGEFLK 476 FLDPRPLTV 892 GDKVYVHLKNLASRPY
111 GLDPNKPPEL 178 HEIDRYTAI 181 IGVEHVVVY 184 IPVVHASI 882
KGVRTLTAAAVSGAQ 363 KLDNQVSKV 42 KLYELHVFTF 163 KLYPTLVIR 137
KTIAFLLPMF 713 LAPLEGARFALVRED 532 LEKQLIEL 734 LNSLTYQVLDVQRYP 736
LPQLVGVSTPLQG 737 LPQLVGVSTPLQGG 738 LPQLVGVSTPLQGGS 534 LTLGEFLK
535 LTLGEFLKL 914 RKSRQGSLAMEELK 739 RLPQLVGVSTPLQGGS 477 SAFADRPAF
164 SEETFRFEL 364 SENVKLFSA 531 SQLTTLSFY 536 TLGEFLKL 186
TVADQVLVGSY 179 VFTLKPLEF 159 VIYNEQMASK 365 VQKLQNII 895
VYVHLKNLASRPY 44 YLNKEIEEA 180 YWVPRNAL
[0022] Thus, particularly preferred is at least one peptide
according to the present invention selected from the group
consisting of SEQ ID NO: 710, 878, 879, 533, 476, 892, 111, 178,
181, 184, 882, 363, 42, 163, 137, 713, 532, 734, 736, 737, 738,
534, 535, 914, 739, 477, 164, 364, 531, 536, 186, 179, 159, 365,
895, 44, and 180, and the use thereof in the treatment of AML
and/or CML as described herein.
[0023] The present invention furthermore relates to the peptides
according to the present invention for use in the treatment of
CLLAML As shown in the following table 3, many of the peptides
according to the present invention can also be used in other
cancerous and proliferative indications.
TABLE-US-00005 TABLE 3 Peptides according to the present invention
and their specific uses in other proliferative diseases, optionally
in other organs. Seq ID Sequence Tissue and disease 1 AEHPNVTLTI
colon or rectum, spleen, non-Hodgkin's lymphoma 2 FLAEHPNVTL colon
or rectum, spleen, non-Hodgkin's lymphoma 3 ILYGRSYTW stomach,
adenocarcinoma, skin, squamous cell carcinoma 4 EVAEFLARH colon or
rectum, spleen, non-Hodgkin's lymphoma 5 RHSNVNLTI colon or rectum,
spleen, non-Hodgkin's lymphoma 6 HPDNVKLFL pancreas,
adenocarcinoma, non- Hodgkin's lymphoma, small lymphocytic type 7
ISDTGELKL pancreas, adenocarcinoma, non- Hodgkin's lymphoma, small
lymphocytic type 8 KVNGKLVALK pancreas, adenocarcinoma, non-
Hodgkin's lymphoma, small lymphocytic type 9 NRLSAQAAL pancreas,
adenocarcinoma, non- Hodgkin's lymphoma, small lymphocytic type 10
TPFTAIREA pancreas, adenocarcinoma, non- Hodgkin's lymphoma, small
lymphocytic type 11 FGLARAKSV kidney, clear cell renal cell
carcinoma, brain, glioblastoma, liver, hepatocellular carcinoma 12
KIADFGLAR liver, hepatocellular carcinoma, adrenal gland, adrenal
cortical carcinoma 13 AAANIIRTL liver, hepatocellular carcinoma,
adrenal gland, adrenal cortical carcinoma 14 GRFKNLREAL liver,
hepatocellular carcinoma, adrenal gland, adrenal cortical carcinoma
15 MSPFSKATL liver, hepatocellular carcinoma, adrenal gland,
adrenal cortical carcinoma 16 QEDPGDNQITL liver, hepatocellular
carcinoma, adrenal gland, adrenal cortical carcinoma 17 SPFSKATL
stomach, metastatic, skin, basal cell carcinoma 18 DALLKRTM
stomach, metastatic, skin, basal cell carcinoma 19 GEDVRSALL
stomach, metastatic, skin, basal cell carcinoma 20 KFAEEFYSF
stomach, metastatic, skin, basal cell carcinoma 21 YGYDNVKEY lung,
non-small cell lung carcinoma, breast, carcinoma 22 LEVEERTKPV
lung, non-small cell lung carcinoma, breast, carcinoma 23
RDSPINANLRY lung, non-small cell lung carcinoma, breast, carcinoma
24 RPFVIVTA lung, non-small cell lung carcinoma, breast, carcinoma
25 RPIINTPMV lung, non-small cell lung carcinoma, breast, carcinoma
26 SPTSSRTSSL stomach, metastatic, lung, neuroendocrine 27
ATSAPLVSR carcinoma (non-small cell type) 28 AELRSTASLL lipoma 29
APASSHERASM lipoma 30 ASRQAPPHI lipoma 31 AVKKNPGIAA lipoma 32
EEHLESHKKY lipoma 33 GEFTSARAV lipoma 34 GQSTPRLFSI lipoma 35
LVDDPLEY lipoma 36 RPKNLMQTL lipoma 37 RQAPPHIEL lipoma 38
SEAAELRSTA lipoma 39 AAVRIGSVL colon, adenoma 40 ERAGVVREL colon,
adenoma 41 GAAVRIGSVL colon, adenoma 42 KLYELHVFTF colon, adenoma
43 LYELHVFTF colon, adenoma 44 YLNKEIEEA colon, adenoma 45
DELPKFHQY stomach, adenocarcinoma, white blood cell s, chronic
lymphocytic leukemia 46 DVTGQFPSSF stomach, adenocarcinoma, white
blood cell s, chronic lymphocytic leukemia 47 EHSRVLQQL stomach,
adenocarcinoma, white blood cell s, chronic lymphocytic leukemia 48
IKVSKQLL stomach, adenocarcinoma, white blood cell s, chronic
lymphocytic leukemia 49 KPRQSSPQL stomach, adenocarcinoma, white
blood cell s, chronic lymphocytic leukemia 50 KQLLAALEI stomach,
adenocarcinoma, white blood cell s, chronic lymphocytic leukemia 51
RRKDLVLKY stomach, adenocarcinoma, liver, focal nodular hyperplasia
52 RTRDYASLPPK stomach, adenocarcinoma, white blood cell s, chronic
lymphocytic leukemia 53 APGSVLPRAL stomach, adenocarcinoma, lymph
node, Hodgkin's disease 54 DIKEHPLL stomach, adenocarcinoma, lymph
node, Hodgkin's disease 55 DSAGPQDAR stomach, adenocarcinoma, lymph
node, Hodgkin's disease 56 FQYAKESYI stomach, adenocarcinoma, lymph
node, Hodgkin's disease 57 KVLSWPFLM stomach, adenocarcinoma, lymph
node, Hodgkin's disease 58 LENDQSLSF stomach, adenocarcinoma, lymph
node, Hodgkin's disease 59 SPSRQPQV stomach, adenocarcinoma, lymph
node, Hodgkin's disease 60 SRHQSFTTK stomach, adenocarcinoma, lymph
node, Hodgkin's disease 61 SSHNASKTL stomach, adenocarcinoma, lymph
node, Hodgkin's disease 62 EEIDTTMRW liver, hepatocellular
carcinoma, lipoma 63 ILDEKPVII liver, hepatocellular carcinoma,
lipoma 64 LPQEPRTSL liver, hepatocellular carcinoma, lipoma 65
LTYKLPVA liver, hepatocellular carcinoma, lipoma 66 NEMELAHSSF
liver, hepatocellular carcinoma, lipoma 67 REFPEANFEL liver,
hepatocellular carcinoma, lipoma 68 THHIPDAKL liver, hepatocellular
carcinoma, lipoma 69 TVKENLSLF liver, hepatocellular carcinoma,
lipoma 70 VLLKKAVL liver, hepatocellular carcinoma, lipoma 71
HLKSIPVSL kidney, clear cell renal cell carcinoma 72 KVWYNVENW
kidney, clear cell renal cell carcinoma, prostate, adenocarcinoma
73 LPAYRAQLL kidney, clear cell renal cell carcinoma, prostate,
adenocarcinoma 74 LSEQTSVPL kidney, clear cell renal cell
carcinoma, prostate, adenocarcinoma 75 SLNQWLVSF kidney, clear cell
renal cell carcinoma, prostate, adenocarcinoma 76 SMTSLAQKI kidney,
clear cell renal cell carcinoma, prostate, adenocarcinoma 77
SSSGLHPPK kidney, clear cell renal cell carcinoma, prostate,
adenocarcinoma 78 DLDVKKMPL stomach, metastatic, kidney, carcinoma
79 FYTVIPHNF stomach, metastatic, kidney, carcinoma 80 HHINTDNPSL
stomach, metastatic, kidney, carcinoma 81 RVGEVGQSK stomach,
metastatic, kidney, carcinoma 82 AVFDGAQVTSK lung, non-small cell
lung carcinoma, kidney, oncocytoma 83 SQTDLVSRL lung, non-small
cell lung carcinoma, kidney, oncocytoma 84 VPVPHTTAL kidney, clear
cell renal cell carcinoma, endometrium, adenocarcinoma,
endometrioid type 85 YQVLDVQRY kidney, clear cell renal cell
carcinoma, endometrium, adenocarcinoma, endometrioid type 86
APFQGDQRSL colon or rectum, breast, mucinous carcinoma 87 DVAEPYKVY
colon or rectum, breast, mucinous carcinoma 88 IVSGQPGTQK colon or
rectum, breast, mucinous carcinoma 89 TPEQQAAIL colon or rectum,
breast, mucinous carcinoma
90 VELFRTAYF colon or rectum, breast, mucinous carcinoma 91
EHADDDPSL brain, cancer, kidney, Wilm's tumor 92 SEESVKSTTL brain,
cancer, kidney, Wilm's tumor 93 SPRPPLGSSL brain, cancer, kidney,
Wilm's tumor 94 SPWWRSSL brain, cancer, kidney, Wilm's tumor 95
VYTPVDSLVF brain, cancer, kidney, Wilm's tumor 96 APLQRSQSL
pancreas, adenocarcinoma, kidney, renal cell carcinoma 97 DEVHQDTY
pancreas, adenocarcinoma, kidney, renal cell carcinoma 98 LPHSATVTL
pancreas, adenocarcinoma, kidney, renal cell carcinoma 99 SEAPEAPLL
testis, seminoma 100 SPRASGSGL testis, seminoma 101 VVGPAAEAK
testis, seminoma 102 FSITKSVEL non-Hodgkin's lymphoma, small
lymphocytic type 103 GQTKNDLVV non-Hodgkin's lymphoma, small
lymphocytic type 104 LSQEVCRD non-Hodgkin's lymphoma, small
lymphocytic type 105 RDIQSPEQI non-Hodgkin's lymphoma, small
lymphocytic type 106 REDNSSNSL non-Hodgkin's lymphoma, small
lymphocytic type 107 TEHQEPGL non-Hodgkin's lymphoma, small
lymphocytic type 108 TKNDLVVSL non-Hodgkin's lymphoma, small
lymphocytic type 109 AEEAGGTRL breast, carcinoma 110 ENVNKKDY
breast, carcinoma 111 GLDPNKPPEL breast, carcinoma 112 RPAGEPYNRKTL
breast, carcinoma 113 SASVQRADTSL liver, hepatocellular carcinoma,
adrenal gland, adrenal cortical adenoma 114 YGNPRTNGM stomach,
metastatic, breast, carcinoma 115 LIRPVSASF esophagus,
adenocarcinoma 116 SPVNSSKQPSY esophagus, adenocarcinoma 117
QLFSYAILGF liver, hepatocellular carcinoma, colon, non-Hodgkin's
lymphoma 118 DEHLLIQHY liver, hepatocellular carcinoma, parotid
gland, pleomorphic adenoma 119 KQVASSTGF liver, hepatocellular
carcinoma, parotid gland, pleomorphic adenoma 120 RDFGPASQHFL
liver, hepatocellular carcinoma, parotid gland, pleomorphic adenoma
121 RQLGEVASF liver, hepatocellular carcinoma, parotid gland,
pleomorphic adenoma 122 TEAETTANVL liver, hepatocellular carcinoma,
parotid gland, pleomorphic adenoma 123 GYLPVQTVL kidney, clear cell
renal cell carcinoma, parotid gland, pleomorphic adenoma 124
GQKEALLKY liver, hepatocellular carcinoma, synovial sarcoma 125
KPSEERKTI liver, hepatocellular carcinoma, synovial sarcoma 126
KQTPKVLVV liver, hepatocellular carcinoma, synovial sarcoma 127
SVIQHVQSF liver, hepatocellular carcinoma, synovial sarcoma 128
TPIERIPYL liver, hepatocellular carcinoma, synovial sarcoma 129
AEVEKNETV kidney, clear cell renal cell carcinoma, spleen,
non-Hodgkin's lymphoma 130 EVKEEIPLV kidney, clear cell renal cell
carcinoma, spleen, non-Hodgkin's lymphoma 131 KPTSARSGL kidney,
clear cell renal cell carcinoma, spleen, non-Hodgkin's lymphoma 132
KYIETTPLTI kidney, clear cell renal cell carcinoma, spleen,
non-Hodgkin's lymphoma 133 SEIKTSIEV kidney, clear cell renal cell
carcinoma, spleen, non-Hodgkin's lymphoma 134 SVKPTSATK kidney,
clear cell renal cell carcinoma, spleen, non-Hodgkin's lymphoma 135
YPNKGVGQA kidney, clear cell renal cell carcinoma, spleen,
non-Hodgkin's lymphoma 136 ISMKILNSL lung, non-small cell lung
carcinoma, thymus, thymoma, benign 137 KTIAFLLPMF lung, non-small
cell lung carcinoma, thymus, thymoma, benign 138 RDSIINDF lung,
non-small cell lung carcinoma, thymus, thymoma, benign 139
SVKGGGGNEK lung, non-small cell lung carcinoma, thymus, thymoma,
benign 140 GIAKTGSGK lung, non-small cell lung carcinoma, thymus,
thymoma, benign 141 AETTDNVFTL kidney, clear cell renal cell
carcinoma, thyroid gland, follicular adenoma 142 SEYQRFAVM kidney,
clear cell renal cell carcinoma, thyroid gland, follicular adenoma
143 TFGERVVAF kidney, clear cell renal cell carcinoma, thyroid
gland, follicular adenoma 144 NENLVERF stomach, adenocarcinoma,
colon, adenocarcinoma 145 KITVPASQK stomach, adenocarcinoma, colon,
non- Hodgkin's lymphoma 146 KITVPASQKL stomach, adenocarcinoma,
colon, non- Hodgkin's lymphoma 147 VPASQKLRQL stomach,
adenocarcinoma, colon, non- Hodgkin's lymphoma 148 HVGYTLSYK
stomach, adenocarcinoma 149 KLPLPLPPRL stomach, adenocarcinoma 150
KPIEPRREL stomach, adenocarcinoma 151 SHSHVGYTL stomach,
adenocarcinoma 152 APSEYRYTL colon or rectum, stomach, mucinous
adenocarcinoma 153 APSEYRYTLL colon or rectum, stomach, mucinous
adenocarcinoma 154 EIFQNEVAR colon or rectum, stomach, mucinous
adenocarcinoma 155 KDVLIPGKL colon or rectum, stomach, mucinous
adenocarcinoma 156 VPLVREITF colon or rectum, stomach, mucinous
adenocarcinoma 157 DPNPNFEKF liver, hepatocellular carcinoma,
cancer, liver, focal nodular hyperplasia 158 IQAPLSWEL liver,
hepatocellular carcinoma, cancer, liver, focal nodular hyperplasia
159 VIYNEQMASK liver, hepatocellular carcinoma, cancer, liver,
focal nodular hyperplasia 160 VLRPGGAFY liver, hepatocellular
carcinoma, cancer, liver, focal nodular hyperplasia 161 EDPDQDILI
stomach, adenocarcinoma, endometrium, adenocarcinoma, endometrioid
162 HGNLRELAL stomach, adenocarcinoma, endometrium, adenocarcinoma,
endometrioid 163 KLYPTLVIR stomach, adenocarcinoma, endometrium,
adenocarcinoma, endometrioid 164 SEETFRFEL stomach, adenocarcinoma,
endometrium, adenocarcinoma, endometrioid 165 ELNKLLEEI stomach,
adenocarcinoma, ovary, adenocarcinoma, endometrioid 166 IPFSNPRVL
stomach, adenocarcinoma, ovary, adenocarcinoma, endometrioid 167
LLDEGAKLLY stomach, adenocarcinoma, ovary, adenocarcinoma,
endometrioid 168 SPADAHRNL stomach, adenocarcinoma, ovary,
adenocarcinoma, endometrioid 173 APRKGNTL stomach, metastatic,
endometrium, Mullerian mixed tumor 174 EEEEALQKKF stomach,
metastatic, endometrium, Mullerian mixed tumor 175 KENLVDGF
stomach, metastatic, endometrium, Mullerian mixed tumor 176
VYKENLVDGF stomach, metastatic, endometrium, Mullerian mixed tumor
177 TLLVVVPKL stomach, adenocarcinoma, bone, giant cell tumor of
bone 178 HEIDRYTAI kidney, clear cell renal cell carcinoma,
non-Hodgkin's lymphoma 179 VFTLKPLEF kidney, clear cell renal cell
carcinoma, non-Hodgkin's lymphoma 180 YWVPRNAL kidney, clear cell
renal cell carcinoma, non-Hodgkin's lymphoma 181 IGVEHVVVY brain,
cancer, kidney, oncocytoma 182 RDKPHVNV brain, cancer, omentum,
leiomyosarcoma 183 ADVLKVEVF stomach, adenocarcinoma, colon,
adenocarcinoma 184 IPVVHASI stomach, adenocarcinoma, colon,
adenocarcinoma
185 RDSLIDSLT stomach, adenocarcinoma, colon, adenocarcinoma 186
TVADQVLVGSY stomach, adenocarcinoma, colon, adenocarcinoma 187
AADTERLAL lung, non-small cell lung carcinoma, chondrosarcoma 188
DMKAKVASL lung, non-small cell lung carcinoma, chondrosarcoma 189
HVLEEVQQV lung, non-small cell lung carcinoma, chondrosarcoma 190
KEAADTERL lung, non-small cell lung carcinoma, chondrosarcoma 191
RISEVLQKL lung, non-small cell lung carcinoma, chondrosarcoma 192
TEVRELVSL lung, non-small cell lung carcinoma, chondrosarcoma 193
AIRSGEAAAK liver, hepatocellular carcinoma, pleura, malignant
mesothelioma 194 APNPAPKEL liver, hepatocellular carcinoma, pleura,
malignant mesothelioma 195 RQSLLTAI liver, hepatocellular
carcinoma, liver, hepatocellular carcinoma, cancer, pleura,
malignant mesothelioma 196 SPEQTLSPL liver, hepatocellular
carcinoma, pleura, malignant mesothelioma 197 TEHQVPSSV liver,
hepatocellular carcinoma, liver, hepatocellular carcinoma, cancer,
pleura, malignant mesothelioma 198 TTYKIVPPK liver, hepatocellular
carcinoma, liver, hepatocellular carcinoma, cancer, pleura,
malignant mesothelioma 199 QLLDQVEQI stomach, metastatic thyroid
gland, papillary carcinoma 200 DETMVIGNY stomach, metastatic,
rectum, adenocarcinoma 201 RQYGSEGRFTF kidney, clear cell renal
cell carcinoma, rectum, adenocarcinoma 203 GPRPITQSEL stomach,
metastatic, lymph node, non- Hodgkin's lymphoma 204 KPEPVDKVA
stomach, metastatic, lymph node, non- Hodgkin's lymphoma 205
TPSSRPASL stomach, metastatic, lymph node, non- Hodgkin's lymphoma
212 GRLNSVNNR kidney, clear cell renal cell carcinoma,
leiomyosarcoma 213 SILEDPPSI kidney, clear cell renal cell
carcinoma, leiomyosarcoma 214 TPRTNNIEL kidney, clear cell renal
cell carcinoma, leiomyosarcoma 215 DAMKRVEEI stomach,
adenocarcinoma, ovary, thecoma-fibroma 216 DIKEVKQNI stomach,
adenocarcinoma, ovary, thecoma-fibroma 217 GPIYPGHGM stomach,
adenocarcinoma, ovary, thecoma-fibroma 218 GDYGRAFNL stomach,
metastatic, lymph node, non- Hodgkin's lymphoma 219 TRHKIVHTK
stomach, metastatic, lymph node, non- Hodgkin's lymphoma 220
RIHTGEKPYK colon or rectum, thyroid gland, nodular hyperplasia 221
KAFNWFSTL stomach, metastatic, lymph node, non- Hodgkin's lymphoma
222 QSTQRSLAL liver, hepatocellular carcinoma, uterin cervix,
squamous cell carcinoma 223 RDLQMNQALRF liver, hepatocellular
carcinoma, uterin cervix, squamous cell carcinoma 224 RELESQLHVL
liver, hepatocellular carcinoma, uterin cervix, squamous cell
carcinoma 225 SEAEKLTLV liver, hepatocellular carcinoma, uterin
cervix, squamous cell carcinoma 226 AAAKPVATK pancreas,
adenocarcinoma, fibromatosis 227 ATYHGSFSTK pancreas,
adenocarcinoma, fibromatosis 228 FMYDRPLRL pancreas,
adenocarcinoma, fibromatosis 229 FRVGNVQEL pancreas,
adenocarcinoma, fibromatosis 230 GVAPFTIAR pancreas,
adenocarcinoma, fibromatosis 231 KMKPLDGSALY pancreas,
adenocarcinoma, fibromatosis 232 KPAPAKPVA pancreas,
adenocarcinoma, fibromatosis 233 KPVAAKPAA pancreas,
adenocarcinoma, fibromatosis 234 KQFGVAPFTI pancreas,
adenocarcinoma, fibromatosis 235 QEELVKISL pancreas,
adenocarcinoma, fibromatosis 236 RQLGTVQQVI pancreas,
adenocarcinoma, fibromatosis 237 RQLINALQI pancreas,
adenocarcinoma, fibromatosis 238 RVIGGLLAGQTY pancreas,
adenocarcinoma, fibromatosis 239 SENAFYLSP pancreas,
adenocarcinoma, fibromatosis 240 SQAPVLDAI pancreas,
adenocarcinoma, fibromatosis 241 STRYPPPAV pancreas,
adenocarcinoma, fibromatosis 242 TEDTLKVYL pancreas,
adenocarcinoma, fibromatosis 243 VAAKPVATK pancreas,
adenocarcinoma, fibromatosis 244 VQRVVESL pancreas, adenocarcinoma,
fibromatosis 245 VRNPSVVVK pancreas, adenocarcinoma, fibromatosis
246 GESEVAIKI myometrium, leiomyoma 247 LIYSVGLLLA myometrium,
leiomyoma 248 SAYPHQLSF myometrium, leiomyoma 249 SVIGVFITK
myometrium, leiomyoma 250 AELGNSVQLI liver, hepatocellular
carcinoma, thyroid gland, nodular hyperplasia 251 ANMTVTRI liver,
hepatocellular carcinoma, thyroid gland, nodular hyperplasia 252
ARISNVEFY liver, hepatocellular carcinoma, thyroid gland, nodular
hyperplasia 253 AVFIGNQQF liver, hepatocellular carcinoma, thyroid
gland, nodular hyperplasia 254 DIELQAENI liver, hepatocellular
carcinoma, thyroid gland, nodular hyperplasia 255 DSYTVRVSV liver,
hepatocellular carcinoma, thyroid gland, nodular hyperplasia 256
DVKIFVNTI liver, hepatocellular carcinoma, thyroid gland, nodular
hyperplasia 257 EIIPKYGSI liver, hepatocellular carcinoma, thyroid
gland, nodular hyperplasia 258 EQSKIFIHR liver, hepatocellular
carcinoma, thyroid gland, nodular hyperplasia 259 FVDVGLYQY liver,
hepatocellular carcinoma, thyroid gland, nodular hyperplasia 260
GHTSTISTL liver, hepatocellular carcinoma, thyroid gland, nodular
hyperplasia 261 GRIEYVEVF liver, hepatocellular carcinoma, thyroid
gland, nodular hyperplasia 262 GTSIIPFQK liver, hepatocellular
carcinoma, thyroid gland, nodular hyperplasia 263 HPFLRGIGY liver,
hepatocellular carcinoma, thyroid gland, nodular hyperplasia 264
IPVEIHTA liver, hepatocellular carcinoma, thyroid gland, nodular
hyperplasia 265 KIFVNTIAY liver, hepatocellular carcinoma, thyroid
gland, nodular hyperplasia 266 LPEDKVRIAY liver, hepatocellular
carcinoma, thyroid gland, nodular hyperplasia 267 LPFSEGLTV liver,
hepatocellular carcinoma, thyroid gland, nodular hyperplasia 268
LPWANKVTI liver, hepatocellular carcinoma, thyroid gland, nodular
hyperplasia 269 PWANKVTI liver, hepatocellular carcinoma, thyroid
gland, nodular hyperplasia 270 QAYNRAVTI liver, hepatocellular
carcinoma, thyroid gland, nodular hyperplasia 271 RSFPQKMAY liver,
hepatocellular carcinoma, thyroid gland, nodular hyperplasia 272
RYPIHWHLL liver, hepatocellular carcinoma, thyroid gland, nodular
hyperplasia 273 SPQNLRLML liver, hepatocellular carcinoma, thyroid
gland, nodular hyperplasia 274 SYFSSPTQR liver, hepatocellular
carcinoma, thyroid gland, nodular hyperplasia 275 VQIKSSLI liver,
hepatocellular carcinoma, thyroid gland, nodular hyperplasia 276
VYIGHTSTI liver, hepatocellular carcinoma, thyroid gland, nodular
hyperplasia 277 YHVPGTGESY liver, hepatocellular carcinoma, thyroid
gland, nodular hyperplasia 278 ATNGDLASR pancreas, adenocarcinoma,
prostate, benign nodular hyperplasia 279 GLHAEVTGVGY pancreas,
adenocarcinoma, prostate, benign nodular hyperplasia 280 HVSSTSSSF
pancreas, adenocarcinoma, prostate, benign nodular hyperplasia 281
LQADLQNGL pancreas, adenocarcinoma, prostate, benign nodular
hyperplasia 282 SELPVSEVA pancreas, adenocarcinoma, prostate,
benign nodular hyperplasia 283 SQTKSVFEI pancreas, adenocarcinoma,
prostate, benign nodular hyperplasia 284 THIFTSDGL pancreas,
adenocarcinoma, prostate, benign nodular hyperplasia 285 VIYFPPLQK
pancreas, adenocarcinoma, prostate, benign nodular hyperplasia 286
YPFSSEQKW pancreas, adenocarcinoma, prostate, benign nodular
hyperplasia 287 GQYFGELAL stomach, gastrointestinal stromal tumor
(GIST) 288 RIIVKNNAK stomach, gastrointestinal stromal tumor (GIST)
289 RRIIVKNNAK stomach, gastrointestinal stromal tumor (GIST) 290
SFGELALMY stomach, gastrointestinal stromal tumor (GIST) 291
AFNAPVINR stomach, gastrointestinal stromal tumor (GIST) 292
IMKRNIATY stomach, gastrointestinal stromal tumor (GIST) 293
KVVDVIGTK stomach, gastrointestinal stromal tumor (GIST) 294
LPFLKSLEF stomach, gastrointestinal stromal tumor (GIST) 295
RLKVVDVIGTK stomach, gastrointestinal stromal tumor (GIST) 296
TPRAATITA stomach, gastrointestinal stromal tumor (GIST) 297
KPSEKIQVL lipoma 298 VPYPVTTTV lipoma 299 ASFPPFVEK lipoma 300
AFIHISTAY colon or rectum, colon, adenocarcinoma 301 ATFEKIPFER
colon or rectum, colon, adenocarcinoma 302 KLFEKVKEV colon or
rectum, colon, adenocarcinoma 303 SQMPKLEAF colon or rectum, colon,
adenocarcinoma 304 AVLGQHHNY colon or rectum, colon, adenocarcinoma
305 GPPAHKPR spleen, chronic myeloid leukemia 306 RVYDVLVLK colon
or rectum, colon, adenocarcinoma 307 LPRPQGITV liver,
hepatocellular carcinoma, liver, focal nodular hyperplasia 308
VLYVGSKTK brain, glioblastoma, schwannoma 309 KTKEQVTNV brain,
glioblastoma, schwannoma 310 MPVDPDNEAY brain, glioblastoma,
schwannoma 311 AEKTKQGVA brain, glioblastoma, schwannoma 312
DIADFFTTR kidney, clear cell renal cell carcinoma, adrenal gland,
adrenal cortical adenoma 313 HSYLQRQSV kidney, clear cell renal
cell carcinoma, adrenal gland, adrenal cortical adenoma 314
KEVTLIEEL kidney, clear cell renal cell carcinoma, adrenal gland,
adrenal cortical adenoma 315 REDGPGVAL kidney, clear cell renal
cell carcinoma, adrenal gland, adrenal cortical adenoma 316
REDPLPPGL kidney, clear cell renal cell carcinoma, adrenal gland,
adrenal cortical adenoma 317 SLFGGSQGLRK kidney, clear cell renal
cell carcinoma, adrenal gland, adrenal cortical adenoma 318
AEFQRLKQA intramuscular lipoma 319 EVIDGVPGKW intramuscular lipoma
320 IPKAPGKII intramuscular lipoma 321 SHNGSAIRY intramuscular
lipoma 322 TEVTVVGDKL intramuscular lipoma 323 YASVVVKRY
intramuscular lipoma 324 ATDLALYIK stomach, adenocarcinoma, thyroid
gland, papillary carcinoma 325 AYHNWRHAF stomach, adenocarcinoma,
thyroid gland, papillary carcinoma 326 EPLNIKDAY stomach,
adenocarcinoma, thyroid gland, papillary carcinoma 327 KIAATIISF
stomach, adenocarcinoma, thyroid gland, papillary carcinoma 328
KIFLHIHGL stomach, adenocarcinoma, thyroid gland, papillary
carcinoma 329 LEVILKKI stomach, adenocarcinoma, thyroid gland,
papillary carcinoma 330 SEHPLAQLY stomach, adenocarcinoma, thyroid
gland, papillary carcinoma 331 VPSAQTLKI stomach, adenocarcinoma,
thyroid gland, papillary carcinoma 332 AEYRSYVA stomach, metastatic
adrenal gland, adrenal cortical carcinoma 333 ALAPGRGTLY stomach,
metastatic adrenal gland, adrenal cortical carcinoma 334 GPRGTQAAL
stomach, metastatic adrenal gland, adrenal cortical carcinoma 335
IEDPGTLHI stomach, metastatic adrenal gland, adrenal cortical
carcinoma 336 IEDPGTLHIW stomach, metastatic adrenal gland, adrenal
cortical carcinoma 337 RPIPIAVKY stomach, metastatic adrenal gland,
adrenal cortical carcinoma 338 VEKLLTNW stomach, metastatic,
pancreas, adenocarcinoma 339 FLDPDIGGVAV kidney, clear cell renal
cell carcinoma, pancreas, adenocarcinoma 340 HTAPPENKTW kidney,
clear cell renal cell carcinoma, pancreas, adenocarcinoma 341
LLDTPVKTQY kidney, clear cell renal cell carcinoma, pancreas,
adenocarcinoma 342 NAVKDFTSF kidney, clear cell renal cell
carcinoma, pancreas, adenocarcinoma 343 SGLLQIKKL kidney, clear
cell renal cell carcinoma, pancreas, adenocarcinoma 344 YHDKNIVLL
kidney, clear cell renal cell carcinoma, pancreas, adenocarcinoma
345 SVDPKNYPK pancreas, adenocarcinoma, colon, adenocarcinoma 346
AVGLVLPAK liver, hepatocellular carcinoma, cancer, thyroid gland,
papillary carcinoma 347 AVGLVLPAKL liver, hepatocellular carcinoma,
cancer, thyroid gland, papillary carcinoma 348 ALLEVLSQK stomach,
adenocarcinoma, breast, carcinoma 349 HEKQDTLVA kidney, clear cell
renal cell carcinoma, spleen, chronic myeloid leukemia 350
KELELQIGM kidney, clear cell renal cell carcinoma, spleen, chronic
myeloid leukemia 351 MYSDVWKQL kidney, clear cell renal cell
carcinoma, spleen, chronic myeloid leukemia 352 RELQDEKAEL kidney,
clear cell renal cell carcinoma, spleen, chronic myeloid leukemia
353 RITDVLDQK kidney, clear cell renal cell carcinoma, spleen,
chronic myeloid leukemia 354 EVIKITGLK stomach, adenocarcinoma 355
HHVDITKKL stomach, adenocarcinoma, kidney, carcinoma 356 LPFNVKVSV
stomach, adenocarcinoma, stomach, gastrointestinal stromal tumor
(GIST) 357 TLPRVLEI stomach, adenocarcinoma, bone, giant cell tumor
of bone 358 TVDLPKSPK stomach, adenocarcinoma, thyroid gland,
nodular hyperplasia 359 AEHGLLLTA stomach, metastatic, uterin
cervix, adenocarcinoma 360 AQAGALLQV stomach, metastatic, uterin
cervix, adenocarcinoma 361 DGGFVLKV stomach, metastatic, uterin
cervix, adenocarcinoma 362 IVYPSGKVY stomach, metastatic, uterin
cervix, adenocarcinoma 363 KLDNQVSKV colon or rectum, prostate,
benign nodular hyperplasia 364 SENVKLFSA colon or rectum, prostate,
benign nodular hyperplasia 365 VQKLQNII colon or rectum, prostate,
benign nodular hyperplasia 366 FSTPHGLEV pancreas, adenocarcinoma,
spleen, chronic myeloid leukemia 367 KRFHQKSDM pancreas,
adenocarcinoma, spleen, chronic myeloid leukemia 368 KTFGHAVSL
pancreas, adenocarcinoma, spleen, chronic myeloid leukemia 369
SSNLITHSR pancreas, adenocarcinoma, spleen, chronic myeloid
leukemia 370 GVIDGHIYAV stomach, metastatic, leiomyosarcoma 371
IEPAKETTTNV pancreas, adenocarcinoma, lung, adenocarcinoma 372
NAPPSEVLL pancreas, adenocarcinoma, lung, adenocarcinoma 373
SIEPAKETTTNV pancreas, adenocarcinoma, lung,
adenocarcinoma 374 AQSQHNQSL spleen, extramedullary hematopoiesis
375 AQSRTNPQV spleen, extramedullary hematopoiesis 376 KMHDKVFAY
spleen, extramedullary hematopoiesis 377 TAKAPLSTV spleen,
extramedullary hematopoiesis 378 IPTRTVAI liver, hepatocellular
carcinoma, lipoma 379 NHDRKHAV liver, hepatocellular carcinoma,
lipoma 380 NNHDRKHAV liver, hepatocellular carcinoma, lipoma 381
TPGGTRIIY liver, hepatocellular carcinoma, breast, carcinoma 382
EHWPSPETF bone, non-ossifying fibroma 383 EIITNTLSF bone,
non-ossifying fibroma 384 EVRGALMSAF bone, non-ossifying fibroma
385 IPRPILVLL bone, non-ossifying fibroma 386 LPNKNRDEL bone,
non-ossifying fibroma 387 QRIPAGAVL bone, non-ossifying fibroma 388
AEGPAGGFMVV pancreas, adenocarcinoma, spleen, chronic myeloid
leukemia 389 AYYRDAEAY pancreas, adenocarcinoma, spleen, chronic
myeloid leukemia 390 QVNRPLTMR pancreas, adenocarcinoma, spleen,
chronic myeloid leukemia 391 RHSPVFQVY pancreas, adenocarcinoma,
spleen, chronic myeloid leukemia 392 SLPVPNSAY pancreas,
adenocarcinoma, spleen, chronic myeloid leukemia 393 TLGPPGTAHLY
pancreas, adenocarcinoma, spleen, chronic myeloid leukemia 394
IEPAKETTTNV pancreas, adenocarcinoma, lung, adenocarcinoma 395
NAPPSEVLL pancreas, adenocarcinoma, lung, adenocarcinoma 396
SIEPAKETTTNV pancreas, adenocarcinoma, lung, adenocarcinoma 397
DLYSGLNQR lymph node, Hodgkin's disease 398 KAKAKPVTR lymph node,
Hodgkin's disease 399 AVLDKAMKAK liver, hepatocellular carcinoma,
liver, hepatic adenoma 400 LELSTPLKI liver, hepatocellular
carcinoma, liver, hepatic adenoma 401 LPLNLDTKY liver,
hepatocellular carcinoma, liver, hepatic adenoma 402 TVIYRIQAL
liver, hepatocellular carcinoma, liver, hepatic adenoma 403
DAHIYLNHI stomach, adenocarcinoma, pancreas, microcystic adenoma
404 NHIEPLKIQL stomach, adenocarcinoma, pancreas, microcystic
adenoma 405 AYRPAVHPR thyroid gland, nodular hyperplasia 406
LRAPLEHEL thyroid gland, nodular hyperplasia 407 RLFMVLLLK thyroid
gland, nodular hyperplasia 408 RSPDVLKDF thyroid gland, nodular
hyperplasia 409 ETAPGVHKR stomach, metastatic, non-Hodgkin's
lymphoma 410 LYHGYIYTY stomach, metastatic, non-Hodgkin's lymphoma
415 VVFDSPRNR liver, hepatocellular carcinoma, pancreas,
adenocarcinoma 416 YPLGRILI lung, non-small cell lung carcinoma,
pancreas, adenocarcinoma 417 KEFAEFVTS pancreas, adenocarcinoma,
pancreas, adenocarcinoma 418 VMLDVPIRL pancreas, adenocarcinoma,
pancreas, adenocarcinoma 419 VPMTPLRTV liver, hepatocellular
carcinoma, cancer, rectum, adenocarcinoma 420 QIDYKTLVL stomach,
metastatic, leiomyosarcoma 421 VEDPTIVRI stomach, metastatic,
leiomyosarcoma 422 IPYQDLPHL kidney, clear cell renal cell
carcinoma, lipoma 423 DTPFLTGHGR stomach, adenocarcinoma, bone,
non- ossifying fibroma 424 EFYRALYI stomach, adenocarcinoma, bone,
non- ossifying fibroma 425 RYYPQILTNK stomach, adenocarcinoma,
bone, non- ossifying fibroma 426 KAYERHVL intestines, malignant
carcinoid tumor 427 LPSPEFHDY intestines, malignant carcinoid tumor
428 SLYAHPIEH intestines, malignant carcinoid tumor 429 LVREPGSQA
kidney, clear cell renal cell carcinoma, lymph node, Hodgkin's
disease 430 RLAGPGSEKY kidney, clear cell renal cell carcinoma,
lymph node, Hodgkin's disease 431 SPGAGRNSVL kidney, clear cell
renal cell carcinoma, lymph node, Hodgkin's disease 432 SVQSDQGYISR
kidney, clear cell renal cell carcinoma, lymph node, Hodgkin's
disease 433 GVRPPAPSL liver, hepatocellular carcinoma, kidney,
carcinoma 434 IFSEKPVFV liver, hepatocellular carcinoma, kidney,
carcinoma 435 KASNLLLGF liver, hepatocellular carcinoma, kidney,
carcinoma 436 KRYIFADAY liver, hepatocellular carcinoma, kidney,
carcinoma 437 RNLQLSLPR liver, hepatocellular carcinoma, kidney,
carcinoma 438 EASEPVALR brain, glioblastoma, liver, hepatic adenoma
439 RPKVPDQSV brain, glioblastoma, liver, hepatic adenoma 440
VLYENALKL spleen, extramedullary hematopoiesis 441 EVLDKSQTNY
liver, hepatocellular carcinoma, endometrium, hyperplasia 442
MPSPIPAKY liver, hepatocellular carcinoma, endometrium, hyperplasia
443 YGIENFTSV liver, hepatocellular carcinoma, endometrium,
hyperplasia 444 ARAAQVFFL colon or rectum, kidney, renal cell
carcinoma 445 EHIVPNAEL colon or rectum, kidney, renal cell
carcinoma 446 EAFEFVKQR stomach, adenocarcinoma, breast, carcinoma
447 NHFEGHYQY stomach, adenocarcinoma, breast, carcinoma 448
DAYPKNPHL stomach, adenocarcinoma, liver, hepatocellular carcinoma
449 DVNIKSTER stomach, adenocarcinoma, liver, hepatocellular
carcinoma 450 HINSIKSVF stomach, adenocarcinoma, liver,
hepatocellular carcinoma 451 YESEKVGVA stomach, adenocarcinoma,
liver, hepatocellular carcinoma 452 ENAPTTVSR stomach,
adenocarcinoma, adrenal gland, adrenal cortical adenoma 453
RFPHLLAHTY stomach, adenocarcinoma, adrenal gland, adrenal cortical
adenoma 454 TLDGSLHAV stomach, adenocarcinoma, adrenal gland,
adrenal cortical adenoma 455 RTVLKNLSLLK liver, hepatocellular
carcinoma, pancreas, microcystic adenoma 456 FEAKVQAI stomach,
adenocarcinoma, metastatic adenocarcinoma of stomach 457 FFEAKVQAI
stomach, adenocarcinoma, metastatic adenocarcinoma of stomach 458
KELQSTFK stomach, adenocarcinoma, metastatic adenocarcinoma of
stomach 459 NVSSRFEEEI stomach, adenocarcinoma, metastatic
adenocarcinoma of stomach 460 EVWNNLGTTK brain, cancer, lymph node,
malignant melanoma 461 MIFRSGSLI brain, cancer, lymph node,
malignant melanoma 462 NHALPLPGF brain, cancer, lymph node,
malignant melanoma 463 ASVFGTMPLK kidney, polycystic kidney disease
464 REFPDRLVGY kidney, polycystic kidney disease 465 SVFGTMPLK
kidney, polycystic kidney disease 466 DEMRFVTQI lung, non-small
cell lung carcinoma, testis, mixed germ cell tumor 467 ETVHFATTQW
lung, non-small cell lung carcinoma, testis, mixed germ cell tumor
468 LPPPATQI lung, non-small cell lung carcinoma, testis, mixed
germ cell tumor 469 LARDLYAF liver, hepatocellular carcinoma,
neuroblastoma 470 LPGIGLSTSL liver, hepatocellular carcinoma,
neuroblastoma 471 MEVILPML liver, hepatocellular carcinoma,
neuroblastoma 472 AILDYILAK stomach, metastatic, lung,
neuroendocrine carcinoma (non-small cell type) 473 KIASQLSKL
stomach, metastatic, lung, neuroendocrine carcinoma (non-small cell
type) 474 KVTSTTTVK stomach, metastatic, lung, neuroendocrine
carcinoma (non-small cell type) 475 YNTLLPYTF stomach, metastatic,
lung, neuroendocrine carcinoma (non-small cell type) 476 FLDPRPLTV
pancreas, adenocarcinoma, myometrium, leiomyoma 477 SAFADRPAF
pancreas, adenocarcinoma, myometrium, leiomyoma 478 AAVPVIISR lymph
node, papillary carcinoma of thyroid 479 EEIGKVAAA lymph node,
papillary carcinoma of thyroid 480 FLKDLVASV lymph node, papillary
carcinoma of thyroid 481 VIISRALEL lymph node, papillary carcinoma
of thyroid 482 APRTTGTPRTSL kidney, oncocytoma 483 ESVGGSPQTK
kidney, oncocytoma 484 IPKDKAIL kidney, oncocytoma 485 LPAYGRTTL
kidney, oncocytoma 486 HQAAIVSKI stomach, adenocarcinoma, kidney,
angiomyolipoma 487 QAAIVSKI stomach, adenocarcinoma, kidney,
angiomyolipoma 488 RQKMPEDGL stomach, adenocarcinoma, kidney,
angiomyolipoma 489 SVQKSSGVK stomach, adenocarcinoma, kidney,
angiomyolipoma 490 DSIGSTVSSER stomach, adenocarcinoma 491
LPYNNKDRDAL stomach, adenocarcinoma 492 IYDEIQQEM colon or rectum,
colon, adenoma 493 AQAKGLIQV thymus, thymoma, benign 494 EVSSEIYQW
thymus, thymoma, benign 495 KWNPVPLSY thymus, thymoma, benign 496
NRLLAQQSL thymus, thymoma, benign 497 APRPVAVAV stomach,
adenocarcinoma 498 FYRETVQVGR stomach, adenocarcinoma 499 LLAPRPVAV
stomach, adenocarcinoma 500 GLAALVILK stomach, adenocarcinoma,
neurofibroma 501 KIQEVFSSY stomach, adenocarcinoma, neurofibroma
502 ASLDKFLSH spleen, chronic myeloid leukemia 503 ALYATKTLR colon
or rectum, pancreas, microcystic adenoma 504 MEYVISRI colon or
rectum, pancreas, microcystic adenoma 505 VPVGRQPII colon or
rectum, pancreas, microcystic adenoma 506 KLLIGVIAAV stomach,
metastatic, colon, adenocarcinoma 507 LPSLIKLD stomach, metastatic,
colon, adenocarcinoma 508 PSLIKLDL stomach, metastatic, colon,
adenocarcinoma 509 ARNKELIGK stomach, adenocarcinoma 510 AVKSNAAAY
stomach, adenocarcinoma 511 EVIIPHSGW stomach, adenocarcinoma 512
SVKEQEAQF stomach, adenocarcinoma 513 APRGLEPIAI liver,
hepatocellular carcinoma, liver, focal nodular hyperplasia 514
GRFGGVITI liver, hepatocellular carcinoma, liver, focal nodular
hyperplasia 518 AEHIESRTL kidney, clear cell renal cell carcinoma,
liver, focal nodular hyperplasia 519 DQYPYLKSV kidney, clear cell
renal cell carcinoma, liver, focal nodular hyperplasia 520
IARNLTQQL kidney, clear cell renal cell carcinoma, liver, focal
nodular hyperplasia 521 IESRTLAIA kidney, clear cell renal cell
carcinoma, liver, focal nodular hyperplasia 522 MTSALPIIQK kidney,
clear cell renal cell carcinoma, liver, focal nodular hyperplasia
523 SLLTSSKGQLQK kidney, clear cell renal cell carcinoma, liver,
focal nodular hyperplasia 524 TSALPIIQK kidney, clear cell renal
cell carcinoma, liver, focal nodular hyperplasia 525 VRLGSLSTK
kidney, clear cell renal cell carcinoma, liver, focal nodular
hyperplasia 526 RINEFSISSF chondrosarcoma 527 DEKQQHIVY liver,
hepatocellular carcinoma, synovial sarcoma 528 DEVYQVTVY liver,
hepatocellular carcinoma, synovial sarcoma 529 GEISEKAKL liver,
hepatocellular carcinoma, synovial sarcoma 530 YTMKEVLFY liver,
hepatocellular carcinoma, synovial sarcoma 531 SQLTTLSFY lung,
non-small cell lung carcinoma, omentum, adenocarcinoma 532 LEKQLIEL
stomach, adenocarcinoma, rectum, adenocarcinoma 533 ELTLGEFLK
stomach, metastatic, ovary, Mullerian mixed tumor 534 LTLGEFLK
stomach, metastatic, ovary, Mullerian mixed tumor 535 LTLGEFLKL
stomach, metastatic, ovary, Mullerian mixed tumor 536 TLGEFLKL
stomach, metastatic, ovary, Mullerian mixed tumor 537 ITARPVLW
non-Hodgkin's lymphoma 538 KLMSPKLYVW non-Hodgkin's lymphoma 539
KVSAVTLAY non-Hodgkin's lymphoma 540 VEGSGELFRW non-Hodgkin's
lymphoma 541 RPKSNIVL non-Hodgkin's lymphoma 542 RPKSNIVLL
non-Hodgkin's lymphoma 543 GEPLSYTRFSLARQ lung, non-small cell lung
carcinoma, lung, adenocarcinoma 544 GEPLSYTRFSLARQVD lung,
non-small cell lung carcinoma, lung, adenocarcinoma 545
GEPLSYTRFSLARQVDG lung, non-small cell lung carcinoma, lung,
adenocarcinoma 546 GGEPLSYTRFSLARQVD lung, non-small cell lung
carcinoma, lung, adenocarcinoma 547 GGEPLSYTRFSLARQVDG lung,
non-small cell lung carcinoma, lung, adenocarcinoma 548
NPGGYVAYSKAATVTG lung, non-small cell lung carcinoma, lung,
adenocarcinoma 549 NPGGYVAYSKAATVTGK lung, non-small cell lung
carcinoma, lung, adenocarcinoma 550 NPGGYVAYSKAATVTGKL lung,
non-small cell lung carcinoma, lung, adenocarcinoma 551
NSVIIVDKNGRL lung, non-small cell lung carcinoma, lung,
adenocarcinoma 552 NSVIIVDKNGRLV lung, non-small cell lung
carcinoma, lung, adenocarcinoma 553 NSVIIVDKNGRLVY lung, non-small
cell lung carcinoma, lung, adenocarcinoma 554 RVEYHFLSPYVSPK lung,
non-small cell lung carcinoma, lung, adenocarcinoma 555
RVEYHFLSPYVSPKE lung, non-small cell lung carcinoma, lung,
adenocarcinoma 556 RVEYHFLSPYVSPKESPF lung, non-small cell lung
carcinoma, lung, adenocarcinoma 557 SPFRHVFWGSGSHTL lung, non-small
cell lung carcinoma, lung, adenocarcinoma 558 SVIIVDKNGRLV lung,
non-small cell lung carcinoma, lung, adenocarcinoma 559
VEYHFLSPYVSPK lung, non-small cell lung carcinoma, lung,
adenocarcinoma 560 VEYHFLSPYVSPKE lung, non-small cell lung
carcinoma, lung, adenocarcinoma 561 LPSQAFEYILYNKG lung, non-small
cell lung carcinoma, lung, adenocarcinoma 562 LPSQAFEYILYNKGI lung,
non-small cell lung carcinoma, lung, adenocarcinoma 563
LPSQAFEYILYNKGIM lung, non-small cell lung carcinoma, lung,
adenocarcinoma 564 LPSQAFEYILYNKGIMG lung, non-small cell lung
carcinoma, lung, adenocarcinoma 565 MNGYFLIERGKNM lung, non-small
cell lung carcinoma, lung, adenocarcinoma 566 NGYFLIERGKNm lung,
non-small cell lung carcinoma, lung, adenocarcinoma 567
PSQAFEYILYNKG lung, non-small cell lung carcinoma, lung,
adenocarcinoma
568 PSQAFEYILYNKGI lung, non-small cell lung carcinoma, lung,
adenocarcinoma 569 PSQAFEYILYNKGIM lung, non-small cell lung
carcinoma, lung, adenocarcinoma 570 EGVQYSYSLFHLM stomach,
metastatic, stomach, gastrointestinal stromal tumor (GIST) 571
EGVQYSYSLFHLML stomach, metastatic, stomach, gastrointestinal
stromal tumor (GIST) 572 GVQYSYSLFHLM stomach, metastatic, stomach,
gastrointestinal stromal tumor (GIST) 573 GVQYSYSLFHLML stomach,
metastatic, stomach, gastrointestinal stromal tumor (GIST) 574
SIISIHPKIQEHQPR stomach, metastatic, stomach, gastrointestinal
stromal tumor (GIST) 575 SSIRTSTNSQVDK stomach, metastatic,
stomach, gastrointestinal stromal tumor (GIST) 576 VLVGYKAVYRIS
stomach, metastatic, stomach, gastrointestinal stromal tumor (GIST)
577 YSSIRTSTNSQVDK stomach, metastatic, stomach, gastrointestinal
stromal tumor (GIST) 578 GGGYGSGGGSGGYGSRR colon or rectum, thymus,
thymoma, F malignant 579 GGSFGGRSSGSP colon or rectum, thymus,
thymoma, malignant 580 KGGSFGGRSSGSP colon or rectum, thymus,
thymoma, malignant 581 SGQQQSNYGPMKGGSFG colon or rectum, thymus,
thymoma, GRSSGSPY malignant 582 SGSPYGGGYGSGGGSGG colon or rectum,
thymus, thymoma, YGSRRF malignant 583 SPYGGGYGSGGGSGGYG colon or
rectum, thymus, thymoma, SRRF malignant 584 YGGGYGSGGGSGGYGSR colon
or rectum, thymus, thymoma, RF malignant 585 GNRINEFSISSF
chondrosarcoma 586 HGNQITSDKVGRKV chondrosarcoma 587 IPPVNTNLENLYLQ
chondrosarcoma 588 LQVLRLDGNEIKR chondrosarcoma 589 LQVLRLDGNEIKRS
chondrosarcoma 590 LQVLRLDGNEIKRSA chondrosarcoma 591
LRELHLDHNQISRVPN chondrosarcoma 592 LYVRLSHNSLTNNG chondrosarcoma
593 VPSRMKYVYFQNNQ chondrosarcoma 594 VPSRMKYVYFQNNQIT
chondrosarcoma 595 VPSRMKYVYFQNNQITS chondrosarcoma 596
WIALHGNQITSD chondrosarcoma 597 WIALHGNQITSDK chondrosarcoma 598
ADDNVSFRWEALGNT chondrosarcoma 599 ADDNVSFRWEALGNTL colon or rectum
600 DADDNVSFRWEALGNTL colon or rectum 601 DDNVSFRWEALGNT colon or
rectum 602 DDNVSFRWEALGNTL colon or rectum 603 DNVSFRWEALGNT colon
or rectum 604 DNVSFRWEALGNTL colon or rectum 605 DNVSFRWEALGNTLS
colon or rectum 606 DTGSYRAQISTKTSAK colon or rectum 607
DTGSYRAQISTKTSAKL colon or rectum 608 DTITIYSTINHSK colon or rectum
609 EDTGSYRAQISTKTSAK colon or rectum 610 ENDTITIYSTINHSK colon or
rectum 611 ENDTITIYSTINHSKESKPT colon or rectum 612 GSYRAQISTKTSAK
colon or rectum 613 NDTITIYSTINH colon or rectum 614 NDTITIYSTINHS
colon or rectum 615 NDTITIYSTINHSK colon or rectum 616
NVSFRWEALGNTL colon or rectum 617 SPTNNTVYASVTHSNRET colon or
rectum 618 TGSYRAQISTKTSAK colon or rectum 619 TPRENDTITIYSTINHSK
colon or rectum 620 TPRENDTITIYSTINHSKESK colon or rectum PT 621
VSFRWEALGNTL colon or rectum 622 APIHFTIEKLELNEK lipoma 623
DAQFEVIKGQTIE lipoma 624 DAQFEVIKGQTIEVR lipoma 625 ESYFIPEVRIYDSGT
lipoma 626 IPEVRIYDSGTY lipoma 627 KDKAIVAHNRHGNK lipoma 628
KDKAIVAHNRHGNKA lipoma 629 NFVILEFPVEEQDR lipoma 630
SQPRISYDAQFEVIK lipoma 631 SQPRISYDAQFEVIKG lipoma 632
YDAQFEVIKGQTIE lipoma 633 GNPAYRSFSNSLSQ colon or rectum, kidney,
angiomyolipoma 634 GPPGEAGYKAFSSLLA colon or rectum, kidney,
angiomyolipoma 635 GPPGEAGYKAFSSLLASS colon or rectum, kidney,
angiomyolipoma 636 GPPGEAGYKAFSSLLASSA colon or rectum, kidney,
angiomyolipoma 637 GPPGEAGYKAFSSLLASSA colon or rectum, kidney,
angiomyolipoma VSPE 638 GPPGEAGYKAFSSLLASSA colon or rectum,
kidney, angiomyolipoma VSPEK 639 GYKAFSSLLASSAVSP colon or rectum,
kidney, angiomyolipoma 640 GYKAFSSLLASSAVSPE colon or rectum,
kidney, angiomyolipoma 641 KAFSSLLASSAVSPE colon or rectum, kidney,
angiomyolipoma 642 NPAYRSFSNSLSQ colon or rectum, kidney,
angiomyolipoma 643 SRDDFQEGREGIVAR colon or rectum, kidney,
angiomyolipoma 644 SSSSFHPAPGNAQ colon or rectum, kidney,
angiomyolipoma 645 VARLTESLFLDL colon or rectum, kidney,
angiomyolipoma 646 VARLTESLFLDLLG colon or rectum, kidney,
angiomyolipoma 647 VIAGNPAYRSFSN colon or rectum, kidney,
angiomyolipoma 648 VPQPEPETWEQILRRNVLQ colon or rectum, kidney,
angiomyolipoma 649 YKAFSSLLASSAVS colon or rectum, kidney,
angiomyolipoma 650 YKAFSSLLASSAVSP colon or rectum, kidney,
angiomyolipoma 651 YKAFSSLLASSAVSPE colon or rectum, kidney,
angiomyolipoma, 652 GNQVFSYTANKEIRTDD colon or rectum, urinary
bladder, transitional cell carcinoma 653 IEEIVLVDDASERD colon or
rectum, urinary bladder, transitional cell carcinoma 654
IEEIVLVDDASERDF colon or rectum, urinary bladder, transitional cell
carcinoma 655 LENIYPDSQIPRH colon or rectum, urinary bladder,
transitional cell carcinoma 656 LENIYPDSQIPRHY colon or rectum,
urinary bladder, transitional cell carcinoma 657 NQVFSYTANKEIR
colon or rectum, urinary bladder, transitional cell carcinoma 658
NQVFSYTANKEIRT colon or rectum, urinary bladder, transitional cell
carcinoma 659 NQVFSYTANKEIRTDD colon or rectum, urinary bladder,
transitional cell carcinoma 660 VHSVINRSPRHMIEE colon or rectum,
urinary bladder, transitional cell carcinoma 661 EYVSLYHQPAAM
non-Hodgkin's lymphoma 662 IKAEYKGRVTLKQYPR non-Hodgkin's lymphoma
663 LNVHSEYEPSWEEQP non-Hodgkin's lymphoma 664 LPYLFQmPAYASSS
non-Hodgkin's lymphoma 665 LPYLFQmPAYASSSK non-Hodgkin's lymphoma
666 NFIKAEYKGRVT non-Hodgkin's lymphoma 667 TNFIKAEYKGRVT
non-Hodgkin's lymphoma 668 TTNFIKAEYKGRVT non-Hodgkin's lymphoma
669 VTLNVHSEYEPSWEEQP non-Hodgkin's lymphoma 670
YPRKNLFLVEVTQLTESDS non-Hodgkin's lymphoma 671 YPRKNLFLVEVTQLTESDS
non-Hodgkin's lymphoma G 672 ADLSSFKSQELN lymph node, papillary
carcinoma of thyroid 673 ADLSSFKSQELNER lymph node, papillary
carcinoma of thyroid 674 ADLSSFKSQELNERN lymph node, papillary
carcinoma of thyroid 675 ADLSSFKSQELNERNE lymph node, papillary
carcinoma of thyroid 676 ADLSSFKSQELNERNEA lymph node, papillary
carcinoma of thyroid 677 AEQQRLKSQDLELSWNLN lymph node, papillary
carcinoma of G thyroid, metastatic
678 EQQRLKSQDLELSWN lymph node, papillary carcinoma of thyroid 679
ISQELEELRAEQQR lymph node, papillary carcinoma of thyroid 680
ISQELEELRAEQQRLK lymph node, papillary carcinoma of thyroid 681
KGTKQWVHARYA lymph node, papillary carcinoma of thyroid 682
QADLSSFKSQELNER lymph node, papillary carcinoma of thyroid,
metastatic 683 SWNLNGLQADLSSFK lymph node, papillary carcinoma of
thyroid 684 TGSWIGLRNLDLKG lymph node, papillary carcinoma of
thyroid 685 FGNYNNQSSNFGPMKGGN pancreas, adenocarcinoma, thymus,
FGGRS thymoma, malignant 686 FGPMKGGNFGGRSSGPYG pancreas,
adenocarcinoma, thymus, GGGQY thymoma, malignant 687
GPMKGGNFGGRSSGP pancreas, adenocarcinoma, thymus, thymoma,
malignant 688 GPYGGGGQYFAKP pancreas, adenocarcinoma, thymus,
thymoma, malignant 689 KGGNFGGRSSGP pancreas, adenocarcinoma,
thymus, thymoma, malignant 690 NDFGNYNNQSSNFGP pancreas,
adenocarcinoma, thymus, thymoma, malignant 691 SGPYGGGGQYFAKP
pancreas, adenocarcinoma, thymus, thymoma, malignant 692
DAGSYKAQINQRNFE lung, non-small cell lung carcinoma, lymph node,
non-Hodgkin's lymphoma 693 DAGSYKAQINQRNFEVT lung, non-small cell
lung carcinoma, lymph node, non-Hodgkin's lymphoma 694
DGELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma 695
GELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma 696
NPSDGELIRTQPQRLP pancreas, adenocarcinoma, intramuscular lipoma 697
NPSDGELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma
698 NPSDGELIRTQPQRLPQL pancreas, adenocarcinoma, intramuscular
lipoma 699 ASNDMYHSRALQVVR colon or rectum, bone, giant cell tumor
of bone 700 ASNDMYHSRALQVVRA colon or rectum, bone, giant cell
tumor of bone 701 EGVRRALDFAVGEYN colon or rectum, bone, giant cell
tumor of bone 702 EGVRRALDFAVGEYNK colon or rectum, bone, giant
cell tumor of bone 703 SNDMYHSRALQVVR colon or rectum, bone, giant
cell tumor of bone 704 VGEYNKASNDMYH colon or rectum, bone, giant
cell tumor of bone 705 VRARKQIVAGVNY colon or rectum, bone, giant
cell tumor of bone 706 VRRALDFAVGEYNKASND colon or rectum, bone,
giant cell tumor of bone 707 VVRARKQIVAGVN colon or rectum, bone,
giant cell tumor of bone 708 VVRARKQIVAGVNY colon or rectum, bone,
giant cell tumor of bone 709 APLEGARFALVRED liver, hepatocellular
carcinoma 710 APVELILSDETLPAPE liver, hepatocellular carcinoma 711
ELILSDETLPAPE liver, hepatocellular carcinoma 712 LAPLEGARFALVRE
liver, hepatocellular carcinoma 713 LAPLEGARFALVRED liver,
hepatocellular carcinoma 714 RGEKELLVPRSSTSPD liver, hepatocellular
carcinoma 715 ASKTFTTQETITNAET kidney, clear cell renal cell
carcinoma, kidney, angiomyolipoma 716 DQHFRTTPLEKNAPV kidney, clear
cell renal cell carcinoma, kidney, angiomyolipoma 717
NTPILVDGKDVMPE kidney, clear cell renal cell carcinoma, kidney,
angiomyolipoma 718 NTPILVDGKDVMPEV kidney, clear cell renal cell
carcinoma, kidney, angiomyolipoma 719 NTPILVDGKDVMPEVN kidney,
clear cell renal cell carcinoma, kidney, angiomyolipoma 720
SNTPILVDGKDVMPE kidney, clear cell renal cell carcinoma, kidney,
angiomyolipoma 721 SNTPILVDGKDVMPEVN kidney, clear cell renal cell
carcinoma, kidney, angiomyolipoma 722 TPILVDGKDVMP kidney, clear
cell renal cell carcinoma, kidney, angiomyolipoma 723 TPILVDGKDVMPE
kidney, clear cell renal cell carcinoma, kidney, angiomyolipoma 724
TPILVDGKDVMPEV kidney, clear cell renal cell carcinoma, kidney,
angiomyolipoma 725 TPILVDGKDVMPEVN kidney, clear cell renal cell
carcinoma, kidney, angiomyolipoma 726 GPLKFLHQDIDSGQG kidney, renal
cell carcinoma 727 GPLKFLHQDIDSGQGIR kidney, renal cell carcinoma
728 LGDIYFKLFRASG kidney, renal cell carcinoma 729 TGHLFDLSSLSGRAG
kidney, renal cell carcinoma 730 VPSPVDCQVTDLAGNE kidney, renal
cell carcinoma 731 DGLNSLTYQVLDVQRYPL kidney, clear cell renal cell
carcinoma, endometrium, adenocarcinoma, endometrioid type 732
HPVLQRQQLDYGIY kidney, clear cell renal cell carcinoma,
endometrium, adenocarcinoma, endometrioid type 733 LNSLTYQVLDVQR
kidney, clear cell renal cell carcinoma, endometrium,
adenocarcinoma, endometrioid type 734 LNSLTYQVLDVQRYP kidney, clear
cell renal cell carcinoma, endometrium, adenocarcinoma,
endometrioid type 735 LNSLTYQVLDVQRYPL kidney, clear cell renal
cell carcinoma, endometrium, adenocarcinoma, endometrioid type 736
LPQLVGVSTPLQG kidney, clear cell renal cell carcinoma, endometrium,
adenocarcinoma, endometrioid type 737 LPQLVGVSTPLQGG kidney, clear
cell renal cell carcinoma, endometrium, adenocarcinoma,
endometrioid type 738 LPQLVGVSTPLQGGS kidney, clear cell renal cell
carcinoma, endometrium, adenocarcinoma, endometrioid type 739
RLPQLVGVSTPLQGGS kidney, clear cell renal cell carcinoma,
endometrium, adenocarcinoma, endometrioid type 740 SPHKVAIIIPFRNR
kidney, clear cell renal cell carcinoma, endometrium,
adenocarcinoma, endometrioid type 741 SPHKVAIIIPFRNRQE kidney,
clear cell renal cell carcinoma, endometrium, adenocarcinoma,
endometrioid type 742 SPHKVAIIIPFRNRQEH kidney, clear cell renal
cell carcinoma, endometrium, adenocarcinoma, endometrioid type 743
AIVQAVSAHRHR non-Hodgkin's lymphoma, peripheral T cell type 744
ARNFERNKAIKVI non-Hodgkin's lymphoma, peripheral T cell type 745
ARNFERNKAIKVIIA non-Hodgkin's lymphoma, peripheral T cell type 746
NFERNKAIKVII non-Hodgkin's lymphoma, peripheral T cell type 747
NFERNKAIKVIIA non-Hodgkin's lymphoma, peripheral T cell type 748
VAIVQAVSAHRH non-Hodgkin's lymphoma, peripheral T cell type 749
VAIVQAVSAHRHR non-Hodgkin's lymphoma, peripheral T cell type 750
VAIVQAVSAHRHRA non-Hodgkin's lymphoma, peripheral T cell type 751
VAIVQAVSAHRHRAR non-Hodgkin's lymphoma, peripheral T cell type 752
EEVITLIRSNQQLE lung, non-small cell lung carcinoma, pancreas,
adenocarcinoma 753 EEVITLIRSNQQLEN lung, non-small cell lung
carcinoma, pancreas, adenocarcinoma 754 IPADTFAALKNPNAML lung,
non-small cell lung carcinoma, pancreas, adenocarcinoma 755
LKQLLSDKQQKRQSG lung, non-small cell lung carcinoma, pancreas,
adenocarcinoma 756 LKQLLSDKQQKRQSGQ lung, non-small cell lung
carcinoma, pancreas, adenocarcinoma 757 TPSYVAFTDTER pancreas,
adenocarcinoma, rectum, adenocarcinoma 758 TPSYVAFTDTERL pancreas,
adenocarcinoma, rectum, adenocarcinoma 759 EGLYSRTLAGSIT liver,
hepatocellular carcinoma, cancer, thyroid gland, nodular
hyperplasia 760 EGLYSRTLAGSITTPP liver, hepatocellular carcinoma,
cancer, thyroid gland, nodular hyperplasia 761 EKWYIPDPTGKFN liver,
hepatocellular carcinoma, cancer, thyroid gland, nodular
hyperplasia 762 GAIAAINSIQHNTR liver, hepatocellular carcinoma,
cancer, thyroid gland, nodular hyperplasia 763 LPILVPSAKKAI liver,
hepatocellular carcinoma, cancer,
thyroid gland, nodular hyperplasia 764 LPILVPSAKKAIY liver,
hepatocellular carcinoma, cancer, thyroid gland, nodular
hyperplasia 765 LPILVPSAKKAIYM liver, hepatocellular carcinoma,
cancer, thyroid gland, nodular hyperplasia 766 LPILVPSAKKAIYMD
liver, hepatocellular carcinoma, cancer, thyroid gland, nodular
hyperplasia 767 LPILVPSAKKAIYMDD liver, hepatocellular carcinoma,
cancer, thyroid gland, nodular hyperplasia 768 VEEGLYSRTLAGSIT
liver, hepatocellular carcinoma, cancer, thyroid gland, nodular
hyperplasia 769 WEKWYIPDPTGKFN liver, hepatocellular carcinoma,
cancer, thyroid gland, nodular hyperplasia 770 YKIVNFDPKLLE liver,
hepatocellular carcinoma, cancer, thyroid gland, nodular
hyperplasia 771 YKIVNFDPKLLEG liver, hepatocellular carcinoma,
cancer, thyroid gland, nodular hyperplasia 772 YKIVNFDPKLLEGKV
liver, hepatocellular carcinoma, cancer, thyroid gland, nodular
hyperplasia 773 LPEFYKTVSPAL colon or rectum, endometrium,
adenocarcinoma, endometrioid type 774 VGQFIQDVKNSRST colon or
rectum, endometrium, adenocarcinoma, endometrioid type 775
VGQFIQDVKNSRSTD colon or rectum, endometrium, adenocarcinoma,
endometrioid type 776 VVGQFIQDVKNSRS colon or rectum, endometrium,
adenocarcinoma, endometrioid type 777 VVGQFIQDVKNSRST colon or
rectum, endometrium, adenocarcinoma, endometrioid type 778
VVGQFIQDVKNSRSTD colon or rectum, endometrium, adenocarcinoma,
endometrioid type 779 VVGQFIQDVKNSRSTDS colon or rectum,
endometrium, adenocarcinoma, endometrioid type 780 DNGHLYREDQTSPAPG
pancreas, adenocarcinoma, kidney, angiomyolipoma 781
DNGHLYREDQTSPAPGLR pancreas, adenocarcinoma, kidney, angiomyolipoma
782 EVQVFAPANALPARSE pancreas, adenocarcinoma, kidney,
angiomyolipoma 783 GHLYREDQTSPAPG pancreas, adenocarcinoma, kidney,
angiomyolipoma 784 LPARSEAAAVQPVIG pancreas, adenocarcinoma,
kidney, angiomyolipoma 785 NGHLYREDQTSPAPG pancreas,
adenocarcinoma, kidney, angiomyolipoma 786 NGHLYREDQTSPAPGL
pancreas, adenocarcinoma, kidney, angiomyolipoma 787
NGHLYREDQTSPAPGLR pancreas, adenocarcinoma, kidney, angiomyolipoma
788 VFAPANALPARSEAA pancreas, adenocarcinoma, kidney,
angiomyolipoma 789 VQVFAPANALPARSE pancreas, adenocarcinoma,
kidney, angiomyolipoma 790 AIVVSDRDGVPVIK stomach, adenocarcinoma,
parathyroid gland, adenoma 791 GLHAIVVSDRDGVPV stomach,
adenocarcinoma, parathyroid gland, adenoma 792 GLHAIVVSDRDGVPVIK
stomach, adenocarcinoma, parathyroid gland, adenoma 793
HAIVVSDRDGVPV stomach, adenocarcinoma, parathyroid gland, adenoma
794 KLPSVEGLHAIVVSDRDG stomach, adenocarcinoma, parathyroid gland,
adenoma 795 LHAIVVSDRDGVPV stomach, adenocarcinoma, parathyroid
gland, adenoma 796 LHAIVVSDRDGVPVI stomach, adenocarcinoma,
parathyroid gland, adenoma 797 LHAIVVSDRDGVPVIK stomach,
adenocarcinoma, parathyroid gland, adenoma 798 LPSVEGLHAIVVSDR
stomach, adenocarcinoma, parathyroid gland, adenoma 799
VPVIKVANDNAPE stomach, adenocarcinoma, parathyroid gland, adenoma
800 YNTYQVVQFNRLP stomach, adenocarcinoma, parathyroid gland,
adenoma 801 YNTYQVVQFNRLPL stomach, adenocarcinoma, parathyroid
gland, adenoma 802 YNTYQVVQFNRLPLV stomach, adenocarcinoma,
parathyroid gland, adenoma 803 YNTYQVVQFNRLPLVV stomach,
adenocarcinoma, parathyroid gland, adenoma 804 YYNTYQVVQFNRLP
stomach, adenocarcinoma, parathyroid gland, adenoma 805
YYNTYQVVQFNRLPL stomach, adenocarcinoma, parathyroid gland, adenoma
806 YYNTYQVVQFNRLPLV stomach, adenocarcinoma, parathyroid gland,
adenoma 807 DKIYFmAGSSRKE liver, hepatocellular carcinoma, thyroid
gland, nodular hyperplasia 808 DVGTDEEEETAKESTAEKD liver,
hepatocellular carcinoma, thyroid E gland, nodular hyperplasia 809
EVTFKSILFVPTSAP liver, hepatocellular carcinoma, thyroid gland,
nodular hyperplasia 810 KSEKFAFQAEVNR liver, hepatocellular
carcinoma, thyroid gland, nodular hyperplasia 811 LPEFDGKRFQNVAK
liver, hepatocellular carcinoma, thyroid gland, nodular hyperplasia
812 DGSYRIFSKGASE colon or rectum, liposarcoma 813 GSYRIFSKGASE
colon or rectum, liposarcoma 814 SDGSYRIFSKGASE colon or rectum,
liposarcoma 815 SVKKMMKDNNLVRH colon or rectum, liver,
hepatocellular carcinoma 816 VKKMMKDNNLVRH colon or rectum, liver,
hepatocellular carcinoma 817 NNmRIFGEAAEKN stomach, adenocarcinoma,
thyroid gland, papillary carcinoma 818 VDKVLERDQKLSE lung,
non-small cell lung carcinoma, lymph node, papillary carcinoma of
thyroid 819 VDKVLERDQKLSELD lung, non-small cell lung carcinoma,
lymph node, papillary carcinoma of thyroid 820 VDKVLERDQKLSELDD
lung, non-small cell lung carcinoma, lymph node, papillary
carcinoma of thyroid 821 VDKVLERDQKLSELDDR stomach, adenocarcinoma,
lymph node, papillary carcinoma of thyroid 822 VLERDQKLSELDDR lung,
non-small cell lung carcinoma, lymph node, papillary carcinoma of
thyroid 823 ATRSIQVDGKTIKAQ stomach, adenocarcinoma, kidney,
angiomyolipoma 824 ATRSIQVDGKTIKAQI stomach, adenocarcinoma,
kidney, angiomyolipoma 825 IGVEFATRSIQVDGK stomach, adenocarcinoma,
kidney, angiomyolipoma 826 RSIQVDGKTIKA stomach, adenocarcinoma,
kidney, angiomyolipoma 827 RSIQVDGKTIKAQ stomach, adenocarcinoma,
kidney, angiomyolipoma 828 RSIQVDGKTIKAQI stomach, adenocarcinoma,
kidney, angiomyolipoma 829 TRSIQVDGKTIKAQ stomach, adenocarcinoma,
kidney, angiomyolipoma 830 DIMRVNVDKVLERDQK stomach,
adenocarcinoma, medullary carcinoma of thyroid origin 831
DIMRVNVDKVLERDQKL stomach, adenocarcinoma, medullary carcinoma of
thyroid origin 832 IMRVNVDKVLERDQK lung, non-small cell lung
carcinoma, lymph node, Hodgkin's disease 833 VDKVLERDQKLSE lung,
non-small cell lung carcinoma, lymph node, papillary carcinoma of
thyroid 834 VDKVLERDQKLSELD lung, non-small cell lung carcinoma,
lymph node, papillary carcinoma of thyroid 835 VDKVLERDQKLSELDD
lung, non-small cell lung carcinoma, lymph node, papillary
carcinoma of thyroid 836 VDKVLERDQKLSELDDR stomach, adenocarcinoma,
lymph node, papillary carcinoma of thyroid 837 VLERDQKLSELDDR lung,
non-small cell lung carcinoma, lymph node, papillary carcinoma of
thyroid 838 ATRSIQVDGKTIKAQ stomach, adenocarcinoma 839
ATRSIQVDGKTIKAQI stomach, adenocarcinoma, kidney, angiomyolipoma
840 IGVEFATRSIQVDGK stomach, adenocarcinoma, kidney, angiomyolipoma
841 RSIQVDGKTIKA stomach, adenocarcinoma, kidney, angiomyolipoma
842 RSIQVDGKTIKAQ stomach, adenocarcinoma, kidney, angiomyolipoma
843 RSIQVDGKTIKAQI stomach, adenocarcinoma, kidney, angiomyolipoma
844 TRSIQVDGKTIKAQ stomach, adenocarcinoma, kidney, angiomyolipoma
845 GIRVAPVPLYNS lung, non-small cell lung carcinoma, liver,
hepatocellular carcinoma 846 GIRVAPVPLYNSFH lung, non-small cell
lung carcinoma, liver, hepatocellular carcinoma 847
NPNGIRVAPVPLYNSFH lung, non-small cell lung carcinoma, liver,
hepatocellular carcinoma 848 DDPAIDVCKKLLGKYPN kidney, clear cell
renal cell carcinoma,
pancreas, adenocarcinoma 849 DKQPYSKLPGVSLLKP kidney, clear cell
renal cell carcinoma, pancreas, adenocarcinoma 850
DKQPYSKLPGVSLLKPL kidney, clear cell renal cell carcinoma,
pancreas, adenocarcinoma 851 HPRYYISANVTGFK kidney, clear cell
renal cell carcinoma, pancreas, adenocarcinoma 852 SHPRYYISANVTG
kidney, clear cell renal cell carcinoma, pancreas, adenocarcinoma
853 SHPRYYISANVTGFK kidney, clear cell renal cell carcinoma,
pancreas, adenocarcinoma 854 TSHPRYYISANVTG kidney, clear cell
renal cell carcinoma, pancreas, adenocarcinoma 855 TSHPRYYISANVTGFK
kidney, clear cell renal cell carcinoma, pancreas, adenocarcinoma
856 ADIFVDPVLHTA kidney, renal cell carcinoma 857 ADIFVDPVLHTACA
kidney, renal cell carcinoma 858 DPGADYRIDRALNEA kidney, renal cell
carcinoma 859 IAQDYKVSYSLA kidney, renal cell carcinoma 860
IAQDYKVSYSLAK kidney, renal cell carcinoma 861 ISRDWKLDPVLYRK
kidney, renal cell carcinoma 862 LIAQDYKVSYSLA kidney, renal cell
carcinoma 863 RQKLIAQDYKVSYS kidney, renal cell carcinoma 864
RQKLIAQDYKVSYSL kidney, renal cell carcinoma 865 RQKLIAQDYKVSYSLA
kidney, renal cell carcinoma 866 RQKLIAQDYKVSYSLAK kidney, renal
cell carcinoma 867 SALDYRLDPQLQLH kidney, renal cell carcinoma 868
SKADIFVDPVLHTA kidney, renal cell carcinoma 869 SPSKNYILSVISGSI
kidney, renal cell carcinoma 870 ETTQLTADSHPSYHTDG stomach,
metastatic, skin, squamous cell carcinoma 871 SGESLYHVLGLDKNATSDD
stomach, metastatic, skin, squamous cell carcinoma 872
TTQLTADSHPSYHT stomach, metastatic, skin, squamous cell carcinoma
873 TTQLTADSHPSYHTD stomach, metastatic, skin, squamous cell
carcinoma 874 TTQLTADSHPSYHTDG stomach, metastatic, skin, squamous
cell carcinoma 875 SVEEFLSEKLERI pancreas, adenocarcinoma, liver,
hepatic adenoma 876 VEEFLSEKLERI pancreas, adenocarcinoma, liver,
hepatic adenoma 877 DLSSSILAQSRERVA pancreas, adenocarcinoma, bone,
giant cell tumor of bone 878 EKGVRTLTAAAVSGAQ pancreas,
adenocarcinoma, bone, giant cell tumor of bone 879
EKGVRTLTAAAVSGAQP pancreas, adenocarcinoma, bone, giant cell tumor
of bone 880 EKGVRTLTAAAVSGAQPI pancreas, adenocarcinoma, bone,
giant cell tumor of bone 881 KGVRTLTAAAVSGA pancreas,
adenocarcinoma, bone, giant cell tumor of bone 882 KGVRTLTAAAVSGAQ
pancreas, adenocarcinoma, bone, giant cell tumor of bone 883
VGPFAPGITEKAPEEKK pancreas, adenocarcinoma, bone, giant cell tumor
of bone 884 DPPLIALDKDAPLR brain, glioblastoma, parotid gland,
pleomorphic adenoma 885 EIITPDVPFTVDKDG brain, glioblastoma,
parotid gland, pleomorphic adenoma 886 IITPDVPFTVDKDG brain,
glioblastoma, parotid gland, pleomorphic adenoma 887 PPLIALDKDAPLR
brain, glioblastoma, parotid gland, pleomorphic adenoma 888
TNVKKSHKATVHIQ brain, glioblastoma, parotid gland, pleomorphic
adenoma 889 DDNIKTYSDHPE kidney, clear cell renal cell carcinoma,
liver, hepatocellular carcinoma 890 DDNIKTYSDHPEK kidney, clear
cell renal cell carcinoma, liver, hepatocellular carcinoma 891
DSAVFFEQGTTRIG kidney, clear cell renal cell carcinoma, liver,
hepatocellular carcinoma 892 GDKVYVHLKNLASRPY kidney, clear cell
renal cell carcinoma, liver, hepatocellular carcinoma 893
GDKVYVHLKNLASRPYT kidney, clear cell renal cell carcinoma, liver,
hepatocellular carcinoma 894 VHLKNLASRPYT kidney, clear cell renal
cell carcinoma, liver, hepatocellular carcinoma 895 VYVHLKNLASRPY
kidney, clear cell renal cell carcinoma, liver, hepatocellular
carcinoma 896 VYVHLKNLASRPYT kidney, clear cell renal cell
carcinoma, liver, hepatocellular carcinoma 897 VYVHLKNLASRPYTFH
kidney, clear cell renal cell carcinoma, liver, hepatocellular
carcinoma 898 YVHLKNLASRPY kidney, clear cell renal cell carcinoma,
liver, hepatocellular carcinoma 899 YVHLKNLASRPYT kidney, clear
cell renal cell carcinoma, liver, hepatocellular carcinoma 900
YVHLKNLASRPYTFH kidney, clear cell renal cell carcinoma, liver,
hepatocellular carcinoma 901 SNLIKLAQKVPTAD liver, hepatocellular
carcinom 902 YDTRTSALSAKS liver, hepatocellular carcinoma 903
ALMTDPKLITWSPV bone, non-ossifying fibroma 904 NDVAWNFEKFLVGPDG
bone, non-ossifying fibroma 905 QSVYAFSARPLAG bone, non-ossifying
fibroma 906 QSVYAFSARPLAGGEPV bone, non-ossifying fibroma 907
WNFEKFLVGPDG colon or rectum, bone, non-ossifying fibroma 908
DVGMFVALTKLGQPD stomach, adenocarcinoma, uterin cervix, squamous
cell carcinoma 909 VGMFVALTKLGQPD stomach, adenocarcinoma, uterin
cervix, squamous cell carcinoma 910 AGVFHVEKNGRY stomach,
adenocarcinoma, colon, adenocarcinoma 911 FAGVFHVEKNGRYS stomach,
adenocarcinoma, colon, adenocarcinoma 912 GPITITIVNRDGTR stomach,
adenocarcinoma, colon, adenocarcinoma 913 NGRYSISRTEAADL stomach,
adenocarcinoma, colon, adenocarcinoma 914 RKSRQGSLAMEELK rectum,
adenocarcinoma 915 RRKSRQGSLAMEELK rectum, adenocarcinoma 916
EEFKKLTSIKIQNDK brain, glioblastoma, small Intestine,
gastrointestinal stromal tumor (GIST) 917 INRRMADDNKLFR brain,
glioblastoma, small Intestine, gastrointestinal stromal tumor
(GIST) 918 TATIVMVTNLKERKE brain, glioblastoma, small Intestine,
gastrointestinal stromal tumor (GIST) 919 ELFYKGIRPAINVG liver,
hepatocellular carcinoma, kidney, oncocytoma 920 GQKRSTVAQLVKR
liver, hepatocellular carcinoma, kidney, oncocytoma 921
SDLDAATQQLLSRGV liver, hepatocellular carcinoma, kidney, oncocytoma
922 FDFSQNTRVPRLPE kidney, clear cell renal cell carcinoma,
non-Hodgkin's lymphoma 923 GDAPAILFDKEF kidney, clear cell renal
cell carcinoma, non-Hodgkin's lymphoma 924 VTHEIDRYTAIAY kidney,
clear cell renal cell carcinoma, non-Hodgkin's lymphoma 929
AAKYQLDPTASISA kidney, oncocytoma 930 IAAKYQLDPTASISA kidney,
oncocytoma 931 IAAKYQLDPTASISAK kidney, oncocytoma 932
AGLGRAYALAFAERG liver, hepatocellular carcinoma, hepatic adenoma
933 DAFGRIDVVVNNAG liver, hepatocellular carcinoma, hepatic adenoma
934 GLGRAYALAFAER liver, hepatocellular carcinoma, hepatic adenoma
935 GLGRAYALAFAERG liver, hepatocellular carcinoma, hepatic adenoma
936 AKFALNGEEFMNFDL liver, hepatocellular carcinoma, liposarcoma
937 AKFALNGEEFMNFDLK liver, hepatocellular carcinoma, liposarcoma
938 ALNGEEFMNFDLK liver, hepatocellular carcinoma, liposarcoma 939
KFALNGEEFMNFDL liver, hepatocellular carcinoma, liposarcoma 940
SDGSFHASSSLTVK liver, hepatocellular carcinoma, liposarcoma 941
EERNLLSVAYKNVVGAR colon or rectum, esophagus, adenocarcinoma 942
ERNLLSVAYKNVVGAR colon or rectum, esophagus, adenocarcinoma 943
IAELDTLSEESYKD colon or rectum, Vulva, squamous cell carcinoma 944
IAELDTLSEESYKDS colon or rectum, Vulva, squamous cell
carcinoma 945 ADSYLDEGFLLDKKIG lung, non-small cell lung carcinoma,
ovary, Mullerian mixed tumor 946 DSYLDEGFLLDKK lung, non-small cell
lung carcinoma, ovary, Mullerian mixed tumor 947 DSYLDEGFLLDKKIG
lung, non-small cell lung carcinoma, ovary, Mullerian mixed tumor
948 VDNIIKAAPRKRVPD lung, non-small cell lung carcinoma, ovary,
Mullerian mixed tumor 949 SPPQFRVNGAISN colon or rectum, ovary,
granulosa cell tumor 950 SPPQFRVNGAISNFE colon or rectum, ovary,
granulosa cell tumor 951 SPPQFRVNGAISNFEE colon or rectum, ovary,
granulosa cell tumor 952 SPPQFRVNGAISNFEEF colon or rectum, ovary,
granulosa cell tumor 953 VGKMFVDVYFQEDKK colon or rectum, ovary,
granulosa cell tumor 954 VGKMFVDVYFQEDKKE colon or rectum, ovary,
granulosa cell tumor 955 DPKRTIAQDYGVLKADE lung, non-small cell
lung carcinoma, thyroid gland, nodular hyperplasia 956
DPKRTIAQDYGVLKADEG lung, non-small cell lung carcinoma, thyroid
gland, nodular hyperplasia 957 PKRTIAQDYGVLKADEG lung, non-small
cell lung carcinoma, thyroid gland, nodular hyperplasia 958
GLFIIDDKGILRQ lung, non-small cell lung carcinoma, thyroid gland,
nodular hyperplasia 959 GLFIIDDKGILRQIT lung, non-small cell lung
carcinoma, thyroid gland, nodular hyperplasia 960 RGLFIIDDKGILR
lung, non-small cell lung carcinoma, thyroid gland, nodular
hyperplasia 961 RGLFIIDDKGILRQ lung, non-small cell lung carcinoma,
thyroid gland, nodular hyperplasia 962 RGLFIIDDKGILRQIT lung,
non-small cell lung carcinoma, thyroid gland, nodular hyperplasia
963 GNTVIHLDQALARMR brain, glioblastoma, lung, small cell carcinoma
964 NTVIHLDQALARMR brain, glioblastoma, lung, small cell carcinoma
965 NTVIHLDQALARMRE brain, glioblastoma, lung, small cell carcinoma
966 ENNEIISNIRDSVIN stomach, adenocarcinoma, kidney, oncocytoma 967
NNEIISNIRDSVIN stomach, adenocarcinoma, kidney, oncocytoma 968
SPTVQVFSASGKPV stomach, adenocarcinoma, kidney, oncocytoma 969
SSPTVQVFSASGKPVE stomach, adenocarcinoma, kidney, oncocytoma 970
AEPNYHSLPSARTDEQ thyroid gland, follicular adenoma 971
SSILAKTASNIIDVS thyroid gland, follicular adenoma 973 ADDLEGEAFLPL
stomach, adenocarcinoma, spleen, chronic myeloid leukemia 974
ADDLEGEAFLPLR stomach, adenocarcinoma, spleen, chronic myeloid
leukemia 975 ADDLEGEAFLPLRE stomach, adenocarcinoma, spleen,
chronic myeloid leukemia 976 GADDLEGEAFLPLR stomach,
adenocarcinoma, spleen, chronic myeloid leukemia 977
AGREINLVDAHLKSE lymph node, Hodgkin's disease 978 AGREINLVDAHLKSEQT
lymph node, Hodgkin's disease 979 GREINLVDAHLKSE lymph node,
Hodgkin's disease 980 KPGIVYASLNHSVIG lymph node, Hodgkin's disease
981 NKPGIVYASLNHSVIG lymph node, Hodgkin's disease 982
TTLYVTDVKSASERPS lymph node, Hodgkin's disease 983 APSTYAHLSPAKTPPP
stomach, adenocarcinoma, pancreas, adenocarcinoma 984
APSTYAHLSPAKTPPPP stomach, adenocarcinoma, pancreas, adenocarcinoma
985 APSTYAHLSPAKTPPPPA stomach, adenocarcinoma, pancreas,
adenocarcinoma 986 RDDLYDQDDSRDFPR stomach, adenocarcinoma,
pancreas, adenocarcinoma 987 TRPYHSLPSEAVFA adrenal gland, adrenal
cortical adenoma 988 TRPYHSLPSEAVFAN adrenal gland, adrenal
cortical adenoma 989 VAVFTFHNHGRT adrenal gland, adrenal cortical
adenoma 990 VAVFTFHNHGRTA adrenal gland, adrenal cortical adenoma
991 VAVFTFHNHGRTANL adrenal gland, adrenal cortical adenoma 992
EDDYIKSWEDNQQGDE brain, glioblastoma, pleura, malignant
mesothelioma 993 ELERIQIQEAAKKKPG brain, glioblastoma, pleura,
malignant mesothelioma 994 ERIQIQEAAKKKP brain, glioblastoma,
pleura, malignant mesothelioma 995 ERIQIQEAAKKKPG brain,
glioblastoma, pleura, malignant mesothelioma 996 ERIQIQEAAKKKPGI
brain, glioblastoma, pleura, malignant mesothelioma 997
LERIQIQEAAKKKPG brain, glioblastoma, pleura, malignant mesothelioma
998 LSSISQYSGKIK brain, glioblastoma, pleura, malignant
mesothelioma 999 SPAKDSLSFEDF rectum, adenocarcinoma 1000
SPAKDSLSFEDFLDL rectum, adenocarcinoma 1001 INSRFPIPSATDPD brain,
glioblastoma, brain, oligodendroglioma 1002 VQHYELLNGQSVFG brain,
glioblastoma, brain, oligodendroglioma 1003 DNQYAVLENQKSSH colon or
rectum, pleura, malignant mesothelioma 1004 GPPEIYSDTQFPS colon or
rectum, pleura, malignant mesothelioma 1005 GPPEIYSDTQFPSLQ colon
or rectum, pleura, malignant mesothelioma 1006 TPQGPPEIYSDTQFPS
colon or rectum, pleura, malignant mesothelioma 1007
TPQGPPEIYSDTQFPSLQ colon or rectum, pleura, malignant mesothelioma
1008 TPQGPPEIYSDTQFPSLQS colon or rectum, pleura, malignant T
mesothelioma 1009 ANLQRAYSLAKEQR kidney, clear cell renal cell
carcinoma, adrenal gland, adrenal cortical carcinoma 1010
NLQRAYSLAKEQR kidney, clear cell renal cell carcinoma, adrenal
gland, adrenal cortical carcinoma 1011 TPSGITYDRKDIEEH kidney,
clear cell renal cell carcinoma, adrenal gland, adrenal cortical
carcinoma 1012 VSTLNSEDFVLVSR brain, glioblastoma, kidney,
angiomyolipoma 1013 VSTLNSEDFVLVSRQ brain, glioblastoma, kidney,
angiomyolipoma 1014 VSTLNSEDFVLVSRQG brain, glioblastoma, kidney,
angiomyolipoma 1015 GSSFFGELFNQNPE brain, glioblastoma, thyroid
gland, papillary carcinoma 1016 SGSSFFGELFNQNPE brain,
glioblastoma, thyroid gland, papillary carcinoma
[0024] Thus, another aspect of the present invention relates to the
use of the peptides according to the present invention for
the--preferably combined--treatment of a proliferative disease
selected from the group of adrenal cortical adenoma; non-ossifying
fibroma; brain cancer and a proliferative disease selected from
kidney oncocytoma, kidney Wilm's tumor, lymph node malignant
melanoma, and omentum leiomyosarcoma; glioblastoma and a
proliferative disease selected from oligodendroglioma, kidney
angiomyolipoma, liver hepatic adenoma, liver hepatocellular
carcinoma, lung small cell carcinoma, parotid gland pleomorphic
adenoma, pleura malignant mesothelioma, schwannoma, small intestine
gastrointestinal stromal tumor (GIST), and thyroid gland papillary
carcinoma; breast carcinoma; chondrosarcoma; colonal or rectal
cancer and a proliferative disease selected from bone giant cell
tumor of bone, bone, non-ossifying fibroma, breast mucinous
carcinoma, colon adenocarcinoma, colon adenoma, endometrium
adenocarcinoma endometrioid type, esophagus adenocarcinoma, kidney
angiomyolipoma, kidney renal cell carcinoma, liposarcoma, liver
hepatocellular carcinoma, ovary granulosa cell tumor, pancreas
microcystic adenoma, pleura malignant mesothelioma, prostate benign
nodular hyperplasia, spleen non-Hodgkin's lymphoma, stomach
mucinous adenocarcinoma, thymus thymoma, malignant, thyroid gland
nodular hyperplasia, urinary bladder, transitional cell carcinoma,
and vulva squamous cell carcinoma; colon adenoma; esophagus
adenocarcinoma; intestines malignant carcinoid tumor; intramuscular
lipoma; kidney clear cell renal cell carcinoma and a proliferative
disease selected from adrenal gland, adrenal cortical carcinoma,
endometrium adenocarcinoma endometrioid type, endometrium
adenocarcinoma endometrioid type, kidney angiomyolipoma
leiomyosarcoma, lipoma liver hepatocellular carcinoma, lymph node
Hodgkin's disease, non-Hodgkin's lymphoma, pancreas adenocarcinoma,
parotid gland pleomorphic adenoma, prostate adenocarcinoma, rectum
adenocarcinoma, spleen chronic myeloid leukemia, spleen
non-Hodgkin's lymphoma, and thyroid gland follicular adenoma;
kidney oncocytoma; kidney polycystic kidney disease; kidney renal
cell carcinoma; lipoma; liver hepatocellular carcinoma and a
proliferative disease selected from, adrenal gland adrenal cortical
adenoma, breast carcinoma, liver focal nodular hyperplasia, cancer
rectum adenocarcinoma, cancer thyroid gland, nodular hyperplasia,
cancer thyroid gland, papillary carcinoma, colon non-Hodgkin's
lymphoma, endometrium hyperplasia, hepatic adenoma, kidney
carcinoma, kidney oncocytoma, lipoma, liposarcoma, liver focal
nodular hyperplasia, liver hepatic adenoma, pleura malignant
mesothelioma, neuroblastoma, pancreas adenocarcinoma, pancreas
microcystic adenoma, parotid gland pleomorphic adenoma, pleura
malignant mesothelioma, synovial sarcoma, thyroid gland nodular
hyperplasia, and uterine cervix squamous cell carcinoma; lung,
non-small cell lung carcinoma, and a proliferative disease selected
from breast carcinoma, chondrosarcoma, kidney oncocytoma, liver
hepatocellular carcinoma, lung adenocarcinoma, lymph node Hodgkin's
disease, lymph node non-Hodgkin's lymphoma, lymph node papillary
carcinoma of thyroid, omentum adenocarcinoma, ovary Mullerian mixed
tumor, pancreas adenocarcinoma, testis mixed germ cell tumor,
thymus thymoma benign, and thyroid gland, nodular hyperplasia;
lymph node Hodgkin's disease; lymph node papillary carcinoma of
thyroid; lymph node papillary carcinoma of thyroid metastatic;
myometrium leiomyoma; non-Hodgkin's lymphoma; non-Hodgkin's
lymphoma, peripheral T cell type or small lymphocytic type;
pancreas adenocarcinoma and a proliferative disease selected from
bone giant cell tumor of bone, colon adenocarcinoma, fibromatosis,
intramuscular lipoma, kidney angiomyolipoma, kidney renal cell
carcinoma, liver hepatic adenoma, lung adenocarcinoma, myometrium
leiomyoma, non-Hodgkin's lymphoma small lymphocytic type, pancreas
adenocarcinoma, prostate benign nodular hyperplasia, rectum
adenocarcinoma, spleen chronic myeloid leukemia, and thymus,
thymoma, malignant; rectum adenocarcinoma; spleen chronic myeloid
leukemia; spleen extramedullary hematopoiesis; stomach,
adenocarcinoma and a proliferative disease selected from , adrenal
gland adrenal cortical adenoma, bone giant cell tumor of bone, bone
non-ossifying fibroma, breast carcinoma, colon adenocarcinoma,
colon non-Hodgkin's lymphoma, endometrium adenocarcinoma
endometrioid, kidney angiomyolipoma, kidney carcinoma, kidney
oncocytoma, liver, focal nodular hyperplasia, liver hepatocellular
carcinoma, lymph node Hodgkin's disease, lymph node papillary
carcinoma of thyroid, medullary carcinoma of thyroid origin,
metastatic adenocarcinoma of stomach, neurofibroma, ovary
thecoma-fibroma, pancreas adenocarcinoma, pancreas microcystic
adenoma, parathyroid gland adenoma, rectum adenocarcinoma, skin
squamous cell carcinoma, spleen chronic myeloid leukemia, stomach
gastrointestinal stromal tumor (GIST), thyroid gland nodular
hyperplasia, thyroid gland papillary carcinoma, uterin cervix
squamous cell carcinoma, and white blood cells chronic lymphocytic
leukemia; stomach gastrointestinal stromal tumor (GIST); stomach
cancer metastatic and a proliferative disease selected from adrenal
gland adrenal cortical carcinoma, thyroid gland papillary
carcinoma, skin, squamous cell carcinoma, breast carcinoma, colon
adenocarcinoma , endometrium Mullerian mixed tumor, kidney
carcinoma, leiomyosarcoma, lung neuroendocrine carcinoma (non-small
cell type), lymph node non-Hodgkin's lymphoma, non-Hodgkin's
lymphoma, ovary Mullerian mixed tumor, pancreas adenocarcinoma,
rectum adenocarcinoma, skin basal cell carcinoma, stomach
gastrointestinal stromal tumor (GIST), and uterine cervix
adenocarcinoma; testis seminoma; thymus benign thymoma; thyroid
gland follicular adenoma; and thyroid gland nodular
hyperplasia.
[0025] Another preferred aspect of the present invention relates to
the use of the peptides according to the present invention for
the--preferably combined--preferred immunotherapy of diseases
according to the following table 4.
TABLE-US-00006 TABLE 4 Preferred peptides according to the present
invention and diseases to be treated Seq ID Sequence Tissue and
disease 22 LEVEERTKPV lung, non-small cell lung carcinoma, breast,
carcinoma 23 RDSPINANLRY lung, non-small cell lung carcinoma,
breast, carcinoma 24 RPFVIVTA lung, non-small cell lung carcinoma,
breast, carcinoma 25 RPIINTPMV lung, non-small cell lung carcinoma,
breast, carcinoma 26 SPTSSRTSSL lung, non-small cell lung
carcinoma, breast, carcinoma 27 ATSAPLVSR stomach, metastatic,
lung, neuroendocrine carcinoma 114 YGNPRTNGM stomach, metastatic,
breast, carcinoma 102 FSITKSVEL non-Hodgkin's lymphoma, small
lymphocytic type 103 GQTKNDLVV non-Hodgkin's lymphoma, small
lymphocytic type 104 LSQEVCRD non-Hodgkin's lymphoma, small
lymphocytic type 105 RDIQSPEQI non-Hodgkin's lymphoma, small
lymphocytic type 106 REDNSSNSL non-Hodgkin's lymphoma, small
lymphocytic type 107 TEHQEPGL non-Hodgkin's lymphoma, small
lymphocytic type 108 TKNDLVVSL non-Hodgkin's lymphoma, small
lymphocytic type 977 AGREINLVDAHLKSE lymph node, Hodgkin's disease
979 GREINLVDAHLKSE lymph node, Hodgkin's disease 980
KPGIVYASLNHSVIG lymph node, Hodgkin's disease 220 RIHTGEKPYK colon
or rectum, thyroid gland, nodular hyperplasia 53 APGSVLPRAL lymph
node, Hodgkin's disease 54 DIKEHPLL lymph node, Hodgkin's disease
55 DSAGPQDAR lymph node, Hodgkin's disease 56 FQYAKESYI lymph node,
Hodgkin's disease 57 KVLSWPFLM lymph node, Hodgkin's disease 58
LENDQSLSF lymph node, Hodgkin's disease 59 SPSRQPQV lymph node,
Hodgkin's disease 60 SRHQSFTTK lymph node, Hodgkin's disease 61
SSHNASKTL lymph node, Hodgkin's disease 1003 DNQYAVLENQKSSH colon
or rectum, pleura, malignant mesothelioma, 1004 GPPEIYSDTQFPS colon
or rectum, pleura, malignant mesothelioma, 1005 GPPEIYSDTQFPSLQ
colon or rectum, pleura, malignant mesothelioma, 1006
TPQGPPEIYSDTQFPS colon or rectum, pleura, malignant mesothelioma,
1007 TPQGPPEIYSDTQFPSLQ colon or rectum, pleura, malignant
mesothelioma, 1008 TPQGPPEIYSDTQFPSLQST colon or rectum, pleura,
malignant mesothelioma, 91 EHADDDPSL kidney, Wilm's tumor 92
SEESVKSTTL kidney, Wilm's tumor 93 SPRPPLGSSL kidney, Wilm's tumor
94 SPWWRSSL kidney, Wilm's tumor 95 VYTPVDSLVF kidney, Wilm's tumor
18 DALLKRTM stomach, metastatic, skin, basal cell carcinoma 19
GEDVRSALL stomach, metastatic, skin, basal cell carcinoma 20
KFAEEFYSF stomach, metastatic, skin, basal cell carcinoma 21
YGYDNVKEY stomach, metastatic, skin, basal cell carcinoma 661
EYVSLYHQPAAM non-Hodgkin's lymphoma, peripheral T cell type 664
LPYLFQMPAYASSS non-Hodgkin's lymphoma, peripheral T cell type 665
LPYLFQMPAYASSSK non-Hodgkin's lymphoma, peripheral T cell type 666
NFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 667
TNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 668
TTNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 780
DNGHLYREDQTSPAPG kidney, angiomyolipoma 781 DNGHLYREDQTSPAPGLR
kidney, angiomyolipoma 782 EVQVFAPANALPARSE kidney, angiomyolipoma
783 GHLYREDQTSPAPG kidney, angiomyolipoma 784 LPARSEAAAVQPVIG
kidney, angiomyolipoma 785 NGHLYREDQTSPAPG kidney, angiomyolipoma
786 NGHLYREDQTSPAPGL kidney, angiomyolipoma 787 NGHLYREDQTSPAPGLR
kidney, angiomyolipoma 788 VFAPANALPARSEAA kidney, angiomyolipoma
789 VQVFAPANALPARSE kidney, angiomyolipoma 178 HEIDRYTAI
non-Hodgkin's lymphoma, follicular type, 179 VFTLKPLEF
non-Hodgkin's lymphoma, follicular type, 180 YWVPRNAL non-Hodgkin's
lymphoma, follicular type, 694 DGELIRTQPQRLPQ pancreas,
adenocarcinoma, intramuscular lipoma 695 GELIRTQPQRLPQ pancreas,
adenocarcinoma, intramuscular lipoma 696 NPSDGELIRTQPQRLP pancreas,
adenocarcinoma, intramuscular lipoma 697 NPSDGELIRTQPQRLPQ
pancreas, adenocarcinoma, intramuscular lipoma 698
NPSDGELIRTQPQRLPQL pancreas, adenocarcinoma, intramuscular lipoma
922 FDFSQNTRVPRLPE non-Hodgkin's lymphoma, follicular type 923
GDAPAILFDKEF non-Hodgkin's lymphoma, follicular type 924
VTHEIDRYTAIAY non-Hodgkin's lymphoma, follicular type 692
DAGSYKAQINQRNFE lymph node, non-Hodgkin's lymphoma 693
DAGSYKAQINQRNFEVT lymph node, non-Hodgkin's lymphoma 1 AEHPNVTLTI
spleen, non-Hodgkin's lymphoma 2 FLAEHPNVTL spleen, non-Hodgkin's
lymphoma 4 EVAEFLARH spleen, non-Hodgkin's lymphoma 5 RHSNVNLTI
spleen, non-Hodgkin's lymphoma 222 QSTQRSLAL uterine cervix,
squamous cell carcinoma 223 RDLQMNQALRF uterine cervix, squamous
cell carcinoma 224 RELESQLHVL uterine cervix, squamous cell
carcinoma 225 SEAEKLTLV uterine cervix, squamous cell carcinoma 6
HPDNVKLFL pancreas, adenocarcinoma, non-Hodgkin's lymphoma, small
lymphocytic type 7 ISDTGELKL pancreas, adenocarcinoma,
non-Hodgkin's lymphoma, small lymphocytic type 8 KVNGKLVALK
pancreas, adenocarcinoma, non-Hodgkin's lymphoma, small lymphocytic
type 9 NRLSAQAAL pancreas, pancreas, adenocarcinoma, non- Hodgkin's
lymphoma, small lymphocytic type 10 TPFTAIREA pancreas, pancreas,
adenocarcinoma, non- Hodgkin's lymphoma, small lymphocytic type 11
FGLARAKSV kidney, clear cell renal cell carcinoma, kidney, renal
cell carcinoma, clear cell type 12 KIADFGLAR brain, glioblastoma,
liver, hepatocellular carcinoma 812 DGSYRIFSKGASE colon or rectum,
liposarcoma 813 GSYRIFSKGASE colon or rectum, liposarcoma 814
SDGSYRIFSKGASE colon or rectum, liposarcoma 815 SVKKMMKDNNLVRH
colon or rectum, liver, hepatocellular carcinoma 816 VKKMMKDNNLVRH
colon or rectum, liver, hepatocellular carcinoma 145 KITVPASQK
colon, non-Hodgkin's lymphoma 146 KITVPASQKL colon, non-Hodgkin's
lymphoma 147 VPASQKLRQL colon, non-Hodgkin's lymphoma 537 ITARPVLW
non-Hodgkin's lymphoma, diffuse large B-cell type 538 KLMSPKLYVW
non-Hodgkin's lymphoma, diffuse large B-cell type 539 KVSAVTLAY
non-Hodgkin's lymphoma, diffuse large B-cell type 540 VEGSGELFRW
non-Hodgkin's lymphoma, diffuse large B-cell type 672 ADLSSFKSQELN
lymph node, papillary carcinoma of thyroid, metastatic 673
ADLSSFKSQELNER lymph node, papillary carcinoma of thyroid,
metastatic 674 ADLSSFKSQELNERN lymph node, papillary carcinoma of
thyroid, metastatic 679 ISQELEELRAEQQR lymph node, papillary
carcinoma of thyroid, metastatic
680 ISQELEELRAEQQRLK lymph node, papillary carcinoma of thyroid,
metastatic 681 KGTKQWVHARYA lymph node, papillary carcinoma of
thyroid, metastatic 682 QADLSSFKSQELNER lymph node, papillary
carcinoma of thyroid, metastatic 684 TGSWIGLRNLDLKG lymph node,
papillary carcinoma of thyroid, metastatic 743 AIVQAVSAHRHR
non-Hodgkin's lymphoma, peripheral T cell type 744 ARNFERNKAIKVI
non-Hodgkin's lymphoma, peripheral T cell type 745 ARNFERNKAIKVIIA
non-Hodgkin's lymphoma, peripheral T cell type 746 NFERNKAIKVII
non-Hodgkin's lymphoma, peripheral T cell type 747 NFERNKAIKVIIA
non-Hodgkin's lymphoma, peripheral T cell type 748 VAIVQAVSAHRH
non-Hodgkin's lymphoma, peripheral T cell type 749 VAIVQAVSAHRHR
non-Hodgkin's lymphoma, peripheral T cell type 750 VAIVQAVSAHRHRA
non-Hodgkin's lymphoma, peripheral T cell type 818 VDKVLERDQKLSE
lung, non-small cell lung carcinoma, lymph node, papillary
carcinoma of thyroid, metastatic 819 VDKVLERDQKLSELD lung,
non-small cell lung carcinoma, lymph node, papillary carcinoma of
thyroid, metastatic 820 VDKVLERDQKLSELDD lung, non-small cell lung
carcinoma, lymph node, papillary carcinoma of thyroid, metastatic
821 VDKVLERDQKLSELDDR stomach, diffuse subtype adenocarcinoma,
lymph node, papillary carcinoma of thyroid, metastatic 822
VLERDQKLSELDDR lung, non-small cell lung carcinoma, lymph node,
papillary carcinoma of thyroid, metastatic 833 VDKVLERDQKLSE lung,
non-small cell lung carcinoma, lymph node, papillary carcinoma of
thyroid, metastatic 834 VDKVLERDQKLSELD lung, non-small cell lung
carcinoma, lymph node, papillary carcinoma of thyroid, etastatic
835 VDKVLERDQKLSELDD lung, non-small cell lung carcinoma, lymph
node, papillary carcinoma of thyroid, metastatic 836
VDKVLERDQKLSELDDR stomach, diffuse subtype adenocarcinoma, lymph
node, papillary carcinoma of thyroid, metastatic 837 VLERDQKLSELDDR
lung, non-small cell lung carcinoma, lymph node, papillary
carcinoma of thyroid, metastatic 848 DDPAIDVCKKLLGKYPN kidney,
clear cell renal cell carcinoma, pancreas, adenocarcinoma 849
DKQPYSKLPGVSLLKP kidney, clear cell renal cell carcinoma, pancreas,
adenocarcinoma 850 DKQPYSKLPGVSLLKPL kidney, clear cell renal cell
carcinoma, pancreas, adenocarcinoma 851 HPRYYISANVTGFK kidney,
clear cell renal cell carcinoma, pancreas, adenocarcinoma 852
SHPRYYISANVTG kidney, clear cell renal cell carcinoma, pancreas,
adenocarcinoma 853 SHPRYYISANVTGFK kidney, clear cell renal cell
carcinoma, pancreas, adenocarcinoma 854 TSHPRYYISANVTG kidney,
clear cell renal cell carcinoma, pancreas, adenocarcinoma 855
TSHPRYYISANVTGFK kidney, clear cell renal cell carcinoma, pancreas,
adenocarcinoma 908 DVGMFVALTKLGQPD stomach, differentiated subtype
adenocarcinoma, 909 VGMFVALTKLGQPD uterine cervix, squamous cell
carcinoma, stomach, differentiated subtype adenocarcinoma, uterine
cervix, squamous cell carcinoma 1015 GSSFFGELFNQNPE brain,
glioblastoma, thyroid gland, papillary carcinoma 1016
SGSSFFGELFNQNPE brain, glioblastoma, thyroid gland, papillary
carcinoma 466 DEMRFVTQI testis, mixed germ cell tumor 467
ETVHFATTQW testis, mixed germ cell tumor 468 LPPPATQI testis, mixed
germ cell tumor 633 GNPAYRSFSNSLSQ kidney, angiomyolipoma 634
GPPGEAGYKAFSSLLA kidney, angiomyolipoma 635 GPPGEAGYKAFSSLLASS
kidney, angiomyolipoma 636 GPPGEAGYKAFSSLLASSA kidney,
angiomyolipoma 637 GPPGEAGYKAFSSLLASSA kidney, angiomyolipoma VSPE
638 GPPGEAGYKAFSSLLASSA kidney, angiomyolipoma VSPEK 639
GYKAFSSLLASSAVSP kidney, angiomyolipoma 640 GYKAFSSLLASSAVSPE
kidney, angiomyolipoma 641 KAFSSLLASSAVSPE kidney, angiomyolipoma
642 NPAYRSFSNSLSQ kidney, angiomyolipoma 643 SRDDFQEGREGIVAR
kidney, angiomyolipoma 644 SSSSFHPAPGNAQ kidney, angiomyolipoma 645
VARLTESLFLDL kidney, angiomyolipoma 646 VARLTESLFLDLLG kidney,
angiomyolipoma 647 VIAGNPAYRSFSN kidney, angiomyolipoma 648
VPQPEPETWEQILRRNVLQ kidney, angiomyolipoma 649 YKAFSSLLASSAVS
kidney, angiomyolipoma 650 YKAFSSLLASSAVSP kidney, angiomyolipoma
651 YKAFSSLLASSAVSPE kidney, angiomyolipoma 992 EDDYIKSWEDNQQGDE
pleura, malignant mesothelioma 993 ELERIQIQEAAKKKPG pleura,
malignant mesothelioma 994 ERIQIQEAAKKKP pleura, malignant
mesothelioma 995 ERIQIQEAAKKKPG pleura, malignant mesothelioma 996
ERIQIQEAAKKKPGI pleura, malignant mesothelioma 997 LERIQIQEAAKKKPG
pleura, malignant mesothelioma 998 LSSISQYSGKIK pleura, malignant
mesothelioma 941 EERNLLSVAYKNVVGAR colon or rectum, esophagus,
adenocarcinoma, 942 ERNLLSVAYKNVVGAR colon or rectum, esophagus,
adenocarcinoma, 943 IAELDTLSEESYKD colon or rectum, vulva, squamous
cell carcinoma, 944 IAELDTLSEESYKDS colon or rectum, vulva,
squamous cell carcinoma, 218 GDYGRAFNL stomach, metastatic, lymph
node, non-Hodgkin's lymphoma, small lymphocytic type 219 TRHKIVHTK
stomach, metastatic, lymph node, non-Hodgkin's lymphoma, small
lymphocytic type 221 KAFNWFSTL stomach, metastatic, lymph node,
non-Hodgkin's lymphoma, small lymphocytic type 541 RPKSNIVL
non-Hodgkin's lymphoma, diffuse large B-cell type 542 RPKSNIVLL
non-Hodgkin's lymphoma, diffuse large B-cell type 1001
INSRFPIPSATDPD brain, glioblastoma, brain, oligodendroglioma, 1002
VQHYELLNGQSVFG brain, glioblastoma, brain, oligodendroglioma, 910
AGVFHVEKNGRY stomach, diffuse subtype adenocarcinoma, colon,
adenocarcinoma 911 FAGVFHVEKNGRYS stomach, diffuse subtype
adenocarcinoma, colon, adenocarcinoma 912 GPITITIVNRDGTR stomach,
diffuse subtype adenocarcinoma, colon, adenocarcinoma 913
NGRYSISRTEAADL stomach, diffuse subtype adenocarcinoma, colon,
adenocarcinoma 45 DELPKFHQY stomach, adenocarcinoma, white blood
cells, chronic lymphocytic leukemia 46 DVTGQFPSSF white blood
cells, chronic lymphocytic leukemia 47 EHSRVLQQL white blood cells,
chronic lymphocytic leukemia 48 IKVSKQLL white blood cells, chronic
lymphocytic leukemia 49 KPRQSSPQL white blood cells, chronic
lymphocytic leukemia 50 KQLLAALEI white blood cells, chronic
lymphocytic leukemia 51 RRKDLVLKY liver, focalnodular hyperplasia
52 RTRDYASLPPK white blood cells, chronic lymphocytic leukemia 124
GQKEALLKY liver, hepatocellular carcinoma, synovial sarcoma 125
KPSEERKTI liver, hepatocellular carcinoma, synovial sarcoma 126
KQTPKVLVV liver, hepatocellular carcinoma, synovial sarcoma 127
SVIQHVQSF liver, hepatocellular carcinoma, synovial sarcoma 128
TPIERIPYL liver, hepatocellular carcinoma, synovial sarcoma 773
LPEFYKTVSPAL colon or rectum, endometrium, adenocarcinoma,
endometrioid type 774 VGQFIQDVKNSRST colon or rectum, endometrium,
adenocarcinoma, endometrioid type 775 VGQFIQDVKNSRSTD colon or
rectum, endometrium, adenocarcinoma, endometrioid type 776
VVGQFIQDVKNSRS colon or rectum, endometrium, adenocarcinoma,
endometrioid type 777 VVGQFIQDVKNSRST colon or rectum, endometrium,
adenocarcinoma, endometrioid type 778 VVGQFIQDVKNSRSTD colon or
rectum, endometrium, adenocarcinoma,
endometrioid type 779 VVGQFIQDVKNSRSTDS colon or rectum,
endometrium, adenocarcinoma, endometrioid type 685
FGNYNNQSSNFGPMKGGN pancreas, adenocarcinoma, thymus, thymoma, FGGRS
malignant 686 FGPMKGGNFGGRSSGPYG pancreas, adenocarcinoma, thymus,
thymoma, GGGQY malignant 687 GPMKGGNFGGRSSGP pancreas,
adenocarcinoma, thymus, thymoma, malignant 688 GPYGGGGQYFAKP
pancreas, adenocarcinoma, thymus, thymoma, malignant 689
KGGNFGGRSSGP pancreas, adenocarcinoma, thymus, thymoma, malignant
690 NDFGNYNNQSSNFGP pancreas, adenocarcinoma, thymus, thymoma,
malignant 691 SGPYGGGGQYFAKP pancreas, adenocarcinoma, thymus,
thymoma, malignant 13 AAANIIRTL liver, hepatocellular carcinoma,
adrenal gland, adrenal cortical carcinoma 14 GRFKNLREAL liver,
hepatocellular carcinoma, adrenal gland, adrenal cortical
carcinoma, 15 MSPFSKATL liver, hepatocellular carcinoma, adrenal
gland, adrenal cortical carcinoma, 16 QEDPGDNQITL liver,
hepatocellular carcinoma, adrenal gland, adrenal cortical
carcinoma, 17 SPFSKATL liver, hepatocellular carcinoma, adrenal
gland, adrenal cortical carcinoma, 129 AEVEKNETV kidney, clear cell
renal cell carcinoma, spleen, non-Hodgkin's lymphoma, follicular
type 130 EVKEEIPLV kidney, clear cell renal cell carcinoma, spleen,
non-Hodgkin's lymphoma, follicular type 131 KPTSARSGL kidney, clear
cell renal cell carcinoma, spleen, non-Hodgkin's lymphoma,
follicular type 132 KYIETTPLTI kidney, clear cell renal cell
carcinoma, spleen, non-Hodgkin's lymphoma, follicular type 133
SEIKTSIEV kidney, clear cell renal cell carcinoma, spleen,
non-Hodgkin's lymphoma, follicular type 134 SVKPTSATK kidney, clear
cell renal cell carcinoma, spleen, non-Hodgkin's lymphoma,
follicular type 135 YPNKGVGQA kidney, clear cell renal cell
carcinoma, spleen, non-Hodgkin's lymphoma, follicular type 966
ENNEIISNIRDSVIN stomach, adenocarcinoma, kidney, oncocytoma 967
NNEIISNIRDSVIN stomach, adenocarcinoma, kidney, oncocytoma 968
SPTVQVFSASGKPV stomach, adenocarcinoma, kidney, oncocytoma 969
SSPTVQVFSASGKPVE stomach, adenocarcinoma, kidney, oncocytoma 830
DIMRVNVDKVLERDQK stomach, diffuse subtype adenocarcinoma, 831
DIMRVNVDKVLERDQKL Medullary carcinoma of thyroid Origin stomach,
diffuse subtype adenocarcinoma, medullary carcinoma 832
IMRVNVDKVLERDQK lung, non-small cell lung carcinoma, lymph node,
Hodgkin's disease 752 EEVITLIRSNQQLE pancreas, adenocarcinoma 753
EEVITLIRSNQQLEN pancreas, adenocarcinoma 754 IPADTFAALKNPNAML
pancreas, adenocarcinoma 755 LKQLLSDKQQKRQSG pancreas,
adenocarcinoma 756 LKQLLSDKQQKRQSGQ pancreas, adenocarcinoma 118
DEHLLIQHY parotid gland, pleomorphic adenoma 119 KQVASSTGF parotid
gland, pleomorphic adenoma 120 RDFGPASQHFL parotid gland,
pleomorphic adenoma 121 RQLGEVASF parotid gland, pleomorphic
adenoma 122 TEAETTANVL parotid gland, pleomorphic adenoma 123
GYLPVQTVL kidney, clear cell renal cell carcinoma, parotid gland,
pleomorphic adenoma 987 TRPYHSLPSEAVFA adrenal gland, adrenal
cortical adenoma 988 TRPYHSLPSEAVFAN adrenal gland, adrenal
cortical adenoma 989 VAVFTFHNHGRT adrenal gland, adrenal cortical
adenoma 990 VAVFTFHNHGRTA adrenal gland, adrenal cortical adenoma
991 VAVFTFHNHGRTANL adrenal gland, adrenal cortical adenoma 339
FLDPDIGGVAV kidney, clear cell renal cell carcinoma, pancreas,
adenocarcinoma 340 HTAPPENKTW kidney, clear cell renal cell
carcinoma, pancreas, adenocarcinoma 341 LLDTPVKTQY kidney, clear
cell renal cell carcinoma, pancreas, adenocarcinoma 342 NAVKDFTSF
kidney, clear cell renal cell carcinoma, pancreas, adenocarcinoma
343 SGLLQIKKL kidney, clear cell renal cell carcinoma, pancreas,
adenocarcinoma 344 YHDKNIVLL kidney, clear cell renal cell
carcinoma, pancreas, adenocarcinoma 71 HLKSIPVSL kidney, clear cell
renal cell carcinoma, prostate, adenocarcinoma 72 KVWYNVENW kidney,
clear cell renal cell carcinoma, prostate, adenocarcinoma 73
LPAYRAQLL kidney, clear cell renal cell carcinoma, prostate,
adenocarcinoma 74 LSEQTSVPL kidney, clear cell renal cell
carcinoma, prostate, adenocarcinoma 75 SLNQWLVSF kidney, clear cell
renal cell carcinoma, prostate, adenocarcinoma 76 SMTSLAQKI kidney,
clear cell renal cell carcinoma, prostate, adenocarcinoma 77
SSSGLHPPK kidney, clear cell renal cell carcinoma, prostate,
adenocarcinoma 578 GGGYGSGGGSGGYGSRRF colon or rectum, thymus,
thymoma, malignant, 579 GGSFGGRSSGSP colon or rectum, thymus,
thymoma, malignant 580 KGGSFGGRSSGSP colon or rectum, thymus,
thymoma, malignant 581 SGQQQSNYGPMKGGSFGG colon or rectum, thymus,
thymoma, malignant RSSGSPY 582 SGSPYGGGYGSGGGSGGY colon or rectum,
thymus, thymoma, malignant GSRRF 583 SPYGGGYGSGGGSGGYGS colon or
rectum, thymus, thymoma, malignant RRF 584 YGGGYGSGGGSGGYGSRR colon
or rectum, thymus, thymoma, malignant F 84 VPVPHTTAL kidney, clear
cell renal cell carcinoma, endometrium, adenocarcinoma,
endometrioid type 85 YQVLDVQRY kidney, clear cell renal cell
carcinoma, endometrium, adenocarcinoma, endometrioid type 731
DGLNSLTYQVLDVQRYPL kidney, clear cell renal cell carcinoma,
endometrium, adenocarcinoma, endometrioid type 732 HPVLQRQQLDYGIY
kidney, clear cell renal cell carcinoma, endometrium,
adenocarcinoma, endometrioid type 733 LNSLTYQVLDVQR kidney, clear
cell renal cell carcinoma, endometrium, adenocarcinoma,
endometrioid type 734 LNSLTYQVLDVQRYP kidney, clear cell renal cell
carcinoma, endometrium, adenocarcinoma, endometrioid type 735
LNSLTYQVLDVQRYPL kidney, clear cell renal cell carcinoma,
endometrium, adenocarcinoma, endometrioid type 736 LPQLVGVSTPLQG
kidney, clear cell renal cell carcinoma, endometrium,
adenocarcinoma, endometrioid type 737 LPQLVGVSTPLQGG kidney, clear
cell renal cell carcinoma, endometrium, adenocarcinoma,
endometrioid type 738 LPQLVGVSTPLQGGS kidney, clear cell renal cell
carcinoma, endometrium, adenocarcinoma, endometrioid type 739
RLPQLVGVSTPLQGGS kidney, clear cell renal cell carcinoma,
endometrium, adenocarcinoma, endometrioid type 740 SPHKVAIIIPFRNR
kidney, clear cell renal cell carcinoma, endometrium,
adenocarcinoma, endometrioid type 741 SPHKVAIIIPFRNRQE kidney,
clear cell renal cell carcinoma, endometrium, adenocarcinoma,
endometrioid type 742 SPHKVAIIIPFRNRQEH kidney, clear cell renal
cell carcinoma, endometrium, adenocarcinoma, endometrioid type 527
DEKQQHIVY liver, hepatocellular carcinoma, synovial sarcoma 528
DEVYQVTVY liver, hepatocellular carcinoma, synovial sarcoma 529
GEISEKAKL liver, hepatocellular carcinoma, synovial sarcoma 530
YTMKEVLFY liver, hepatocellular carcinoma, synovial sarcoma 203
GPRPITQSEL lymph node, non-Hodgkin's lymphoma, marginal zone B-cell
type 204 KPEPVDKVA lymph node, non-Hodgkin's lymphoma 205 TPSSRPASL
lymph node, non-Hodgkin's lymphoma 949 SPPQFRVNGAISN ovary,
granulosa cell tumor 950 SPPQFRVNGAISNFE ovary, granulosa cell
tumor 951 SPPQFRVNGAISNFEE ovary, granulosa cell tumor 952
SPPQFRVNGAISNFEEF ovary, granulosa cell tumor
953 VGKMFVDVYFQEDKK ovary, granulosa cell tumor 954
VGKmFVDVYFQEDKKE ovary, granulosa cell tumor 916 EEFKKLTSIKIQNDK
brain, glioblastoma, small intestine, gastrointestinal stromal
tumor (GIST) 917 INRRMADDNKLFR brain, glioblastoma, small
intestine, gastrointestinal stromal tumor (GIST) 918
TATIVMVTNLKERKE brain, glioblastoma, small intestine,
gastrointestinal stromal tumor (GIST) 526 RINEFSISSF chondrosarcoma
585 GNRINEFSISSF chondrosarcoma 586 HGNQITSDKVGRKV chondrosarcoma
587 IPPVNTNLENLYLQ chondrosarcoma 588 LQVLRLDGNEIKR chondrosarcoma
589 LQVLRLDGNEIKRS chondrosarcoma 590 LQVLRLDGNEIKRSA
chondrosarcoma 592 LYVRLSHNSLTNNG chondrosarcoma 596 WIALHGNQITSD
chondrosarcoma 597 WIALHGNQITSDK chondrosarcoma 165 ELNKLLEEI
ovary, adenocarcinoma 166 IPFSNPRVL ovary, adenocarcinoma 167
LLDEGAKLLY ovary, adenocarcinoma 168 SPADAHRNL ovary,
adenocarcinoma 96 APLQRSQSL kidney, renal cell carcinoma, clear
cell type 97 DEVHQDTY kidney, renal cell carcinoma, clear cell type
98 LPHSATVTL kidney, renal cell carcinoma, clear cell type 152
APSEYRYTL stomach, mucinous adenocarcinoma 153 APSEYRYTLL stomach,
mucinous adenocarcinoma 154 EIFQNEVAR stomach, mucinous
adenocarcinoma 155 KDVLIPGKL stomach, mucinous adenocarcinoma 156
VPLVREITF stomach, mucinous adenocarcinoma 62 EEIDTTMRW liver,
hepatocellular carcinoma, lipoma 63 ILDEKPVII liver, hepatocellular
carcinoma, lipoma 64 LPQEPRTSL liver, hepatocellular carcinoma,
lipoma 65 LTYKLPVA liver, hepatocellular carcinoma, lipoma 66
NEMELAHSSF liver, hepatocellular carcinoma, lipoma 67 REFPEANFEL
liver, hepatocellular carcinoma, lipoma 68 THHIPDAKL liver,
hepatocellular carcinoma, lipoma 69 TVKENLSLF liver, hepatocellular
carcinoma, lipoma 70 VLLKKAVL liver, hepatocellular carcinoma,
lipoma 136 ISMKILNSL lung, non-small cell lung carcinoma, thymus,
thymoma 137 KTIAFLLPMF lung, non-small cell lung carcinoma, thymus,
thymoma 138 RDSIINDF lung, non-small cell lung carcinoma, thymus,
thymoma 139 SVKGGGGNEK lung, non-small cell lung carcinoma, thymus,
thymoma 140 GIAKTGSGK lung, non-small cell lung carcinoma, thymus,
thymoma 503 ALYATKTLR pancreas, microcystic adenoma 504 MEYVISRI
pancreas, microcystic adenoma 505 VPVGRQPII pancreas, microcystic
adenoma 278 ATNGDLASR pancreas, adenocarcinoma, prostate, benign
nodular hyperplasia 279 GLHAEVTGVGY pancreas, adenocarcinoma,
prostate, benign nodular hyperplasia 280 HVSSTSSSF pancreas,
adenocarcinoma, prostate, benign nodular hyperplasia 281 LQADLQNGL
pancreas, adenocarcinoma, prostate, benign nodular hyperplasia 282
SELPVSEVA pancreas, adenocarcinoma, prostate, benign nodular
hyperplasia 283 SQTKSVFEI pancreas, adenocarcinoma, prostate,
benign nodular hyperplasia 284 THIFTSDGL pancreas, adenocarcinoma,
prostate, benign nodular hyperplasia 285 VIYFPPLQK pancreas,
adenocarcinoma, prostate, benign nodular hyperplasia 286 YPFSSEQKW
pancreas, adenocarcinoma, prostate, benign nodular hyperplasia 78
DLDVKKMPL kidney, carcinoma 79 FYTVIPHNF kidney, carcinoma 80
HHINTDNPSL kidney, carcinoma 81 RVGEVGQSK kidney, carcinoma 28
AELRSTASLL lipoma 29 APASSHERASM lipoma 30 ASRQAPPHI lipoma 31
AVKKNPGIAA lipoma 32 EEHLESHKKY lipoma 33 GEFTSARAV lipoma 34
GQSTPRLFSI lipoma 35 LVDDPLEY lipoma 36 RPKNLMQTL lipoma 37
RQAPPHIEL lipoma 38 SEAAELRSTA lipoma 490 DSIGSTVSSER stomach,
adenocarcinoma, signet ring cell type, 491 LPYNNKDRDAL stomach,
adenocarcinoma, signet ring cell type, 215 DAMKRVEEI ovary,
thecoma-fibroma 216 DIKEVKQNI ovary, thecoma-fibroma 217 GPIYPGHGM
ovary, thecoma-fibroma 963 GNTVIHLDQALARMR lung, small cell
carcinoma 964 NTVIHLDQALARMR lung, small cell carcinoma 965
NTVIHLDQALARMRE lung, small cell carcinoma 187 AADTERLAL
chondrosarcoma 188 DMKAKVASL chondrosarcoma 189 HVLEEVQQV
chondrosarcoma 190 KEAADTERL chondrosarcoma 191 RISEVLQKL
chondrosarcoma 192 TEVRELVSL chondrosarcoma 875 SVEEFLSEKLERI
liver, hepatic adenoma 876 VEEFLSEKLERI liver, hepatic adenoma 973
ADDLEGEAFLPL spleen, chronic myeloid leukemia 974 ADDLEGEAFLPLR
spleen, chronic myeloid leukemia 975 ADDLEGEAFLPLRE spleen, chronic
myeloid leukemia 976 GADDLEGEAFLPLR spleen, chronic myeloid
leukemia 141 AETTDNVFTL kidney, clear cell renal cell carcinoma,
thyroid gland, follicular adenoma 142 SEYQRFAVM kidney, clear cell
renal cell carcinoma, thyroid gland, follicular adenoma 143
TFGERVVAF kidney, clear cell renal cell carcinoma, thyroid gland,
follicular adenoma 144 NENLVERF stomach, colon, adenocarcinoma,
mucinous type 117 QLFSYAILGF liver, hepatocellular carcinoma,
colon, non- Hodgkin's lymphoma 845 GIRVAPVPLYNS lung, non-small
cell lung carcinoma, liver, hepatocellular carcinoma 846
GIRVAPVPLYNSFH lung, non-small cell lung carcinoma, liver,
hepatocellular carcinoma 847 NPNGIRVAPVPLYNSFH lung, non-small cell
lung carcinoma, liver, hepatocellular carcinoma 478 AAVPVIISR lymph
node, papillary carcinoma of thyroid, metastatic 479 EEIGKVAAA
lymph node, papillary carcinoma of thyroid, metastatic 480
FLKDLVASV lymph node, papillary carcinoma of thyroid, metastatic
481 VIISRALEL lymph node, papillary carcinoma of thyroid,
metastatic 420 QIDYKTLVL stomach, metastatic, leiomyosarcoma 421
VEDPTIVRI stomach, metastatic, leiomyosarcoma 543 GEPLSYTRFSLARQ
lung, non-small cell lung carcinoma, lung, adenocarcinoma 544
GEPLSYTRFSLARQVD lung, non-small cell lung carcinoma, lung,
adenocarcinoma 545 GEPLSYTRFSLARQVDG lung, non-small cell lung
carcinoma, lung, adenocarcinoma 546 GGEPLSYTRFSLARQVD lung,
non-small cell lung carcinoma, lung, adenocarcinoma 547
GGEPLSYTRFSLARQVDG lung, non-small cell lung carcinoma, lung,
adenocarcinoma 548 NPGGYVAYSKAATVTG lung, non-small cell lung
carcinoma, lung, adenocarcinoma
549 NPGGYVAYSKAATVTGK lung, non-small cell lung carcinoma, lung,
adenocarcinoma 550 NPGGYVAYSKAATVTGKL lung, non-small cell lung
carcinoma, lung, adenocarcinoma 551 NSVIIVDKNGRL lung, non-small
cell lung carcinoma, lung, adenocarcinoma 552 NSVIIVDKNGRLV lung,
non-small cell lung carcinoma, lung, adenocarcinoma 553
NSVIIVDKNGRLVY lung, non-small cell lung carcinoma, lung,
adenocarcinoma 554 RVEYHFLSPYVSPK lung, non-small cell lung
carcinoma, lung, adenocarcinoma 555 RVEYHFLSPYVSPKE lung, non-small
cell lung carcinoma, lung, adenocarcinoma 556 RVEYHFLSPYVSPKESPF
lung, non-small cell lung carcinoma, lung, adenocarcinoma 557
SPFRHVFWGSGSHTL lung, non-small cell lung carcinoma, lung,
adenocarcinoma 558 SVIIVDKNGRLV lung, non-small cell lung
carcinoma, lung, adenocarcinoma 559 VEYHFLSPYVSPK lung, non-small
cell lung carcinoma, lung, adenocarcinoma 560 VEYHFLSPYVSPKE lung,
non-small cell lung carcinoma, lung, adenocarcinoma 388 AEGPAGGFMVV
spleen, chronic myeloid leukemia 389 AYYRDAEAY spleen, chronic
myeloid leukemia 390 QVNRPLTMR spleen, chronic myeloid leukemia 391
RHSPVFQVY spleen, chronic myeloid leukemia 392 SLPVPNSAY spleen,
chronic myeloid leukemia 393 TLGPPGTAHLY spleen, chronic myeloid
leukemia 308 VLYVGSKTK schwannoma 309 KTKEQVTNV schwannoma 310
MPVDPDNEAY schwannoma 311 AEKTKQGVA schwannoma 446 EAFEFVKQR
stomach, adenocarcinoma, breast, carcinoma 447 NHFEGHYQY stomach,
adenocarcinoma, breast, carcinoma
[0026] Another more preferred aspect of the present invention
relates to the use of the peptides according to the present
invention for the--preferably combined--more preferred
immunotherapy of diseases according to the following table 5.
TABLE-US-00007 TABLE 5 More preferred peptides according to the
present invention and diseases to be treated Seq ID Sequence Tissue
and disease 22 LEVEERTKPV breast, carcinoma 23 RDSPINANLRY breast,
carcinoma 24 RPFVIVTA breast, carcinoma 25 RPIINTPMV breast,
carcinoma 26 SPTSSRTSSL breast, carcinoma 27 ATSAPLVSR lung,
neuroendocrine carcinoma 114 YGNPRTNGM breast, carcinoma 102
FSITKSVEL non-Hodgkin's lymphoma, small lymphocytic type 103
GQTKNDLVV non-Hodgkin's lymphoma, small lymphocytic type 104
LSQEVCRD non-Hodgkin's lymphoma, small lymphocytic type 105
RDIQSPEQI non-Hodgkin's lymphoma, small lymphocytic type 106
REDNSSNSL non-Hodgkin's lymphoma, small lymphocytic type 107
TEHQEPGL non-Hodgkin's lymphoma, small lymphocytic type 108
TKNDLVVSL non-Hodgkin's lymphoma, small lymphocytic type 977
AGREINLVDAHLKSE lymph node, Hodgkin's disease 978 AGREINLVDAHLKSEQT
lymph node, Hodgkin's disease 979 GREINLVDAHLKSE lymph node,
Hodgkin's disease 980 KPGIVYASLNHSVIG lymph node, Hodgkin's disease
981 NKPGIVYASLNHSVIG lymph node, Hodgkin's disease 982
TTLYVTDVKSASERPS lymph node, Hodgkin's disease 220 RIHTGEKPYK
thyroid gland, nodular hyperplasia 53 APGSVLPRAL lymph node,
Hodgkin's disease 54 DIKEHPLL lymph node, Hodgkin's disease 55
DSAGPQDAR lymph node, Hodgkin's disease 56 FQYAKESYI lymph node,
Hodgkin's disease 57 KVLSWPFLM lymph node, Hodgkin's disease 58
LENDQSLSF lymph node, Hodgkin's disease 59 SPSRQPQV lymph node,
Hodgkin's disease 60 SRHQSFTTK lymph node, Hodgkin's disease 61
SSHNASKTL lymph node, Hodgkin's disease 1003 DNQYAVLENQKSSH pleura,
malignant mesothelioma 1004 GPPEIYSDTQFPS pleura, malignant
mesothelioma 1005 GPPEIYSDTQFPSLQ pleura, malignant mesothelioma
1006 TPQGPPEIYSDTQFPS pleura, malignant mesothelioma 1007
TPQGPPEIYSDTQFPSLQ pleura, malignant mesothelioma 1008
TPQGPPEIYSDTQFPSLQS pleura, malignant mesothelioma T 91 EHADDDPSL
kidney, Wilm's tumor 92 SEESVKSTTL kidney, Wilm's tumor 93
SPRPPLGSSL kidney, Wilm's tumor 94 SPWWRSSL kidney, Wilm's tumor 95
VYTPVDSLVF kidney, Wilm's tumor 18 DALLKRTM skin, basal cell
carcinoma 19 GEDVRSALL skin, basal cell carcinoma 20 KFAEEFYSF
skin, basal cell carcinoma 21 YGYDNVKEY skin, basal cell carcinoma
661 EYVSLYHQPAAM non-Hodgkin's lymphoma, peripheral T cell type,
662 IKAEYKGRVTLKQYPR non-Hodgkin's lymphoma, peripheral T cell type
663 LNVHSEYEPSWEEQP non-Hodgkin's lymphoma, peripheral T cell type
664 LPYLFQmPAYASSS non-Hodgkin's lymphoma, peripheral T cell type
665 LPYLFQmPAYASSSK non-Hodgkin's lymphoma, peripheral T cell type
666 NFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 667
TNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 668
TTNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 669
VTLNVHSEYEPSWEEQP non-Hodgkin's lymphoma, peripheral T cell type
670 YPRKNLFLVEVTQLTESDS non-Hodgkin's lymphoma, peripheral T cell
type 671 YPRKNLFLVEVTQLTESDS non-Hodgkin's lymphoma, peripheral T
cell type G 780 DNGHLYREDQTSPAPG kidney, angiomyolipoma 781
DNGHLYREDQTSPAPGLR kidney, angiomyolipoma 782 EVQVFAPANALPARSE
kidney, angiomyolipoma 783 GHLYREDQTSPAPG kidney, angiomyolipoma
784 LPARSEAAAVQPVIG kidney, angiomyolipoma 785 NGHLYREDQTSPAPG
kidney, angiomyolipoma 786 NGHLYREDQTSPAPGL kidney, angiomyolipoma
787 NGHLYREDQTSPAPGLR kidney, angiomyolipoma 788 VFAPANALPARSEAA
kidney, angiomyolipoma 789 VQVFAPANALPARSE kidney, angiomyolipoma
178 HEIDRYTAI non-Hodgkin's lymphoma 179 VFTLKPLEF non-Hodgkin's
lymphoma 180 YWVPRNAL non-Hodgkin's lymphoma 694 DGELIRTQPQRLPQ
intramuscular lipoma 695 GELIRTQPQRLPQ intramuscular lipoma 696
NPSDGELIRTQPQRLP intramuscular lipoma 697 NPSDGELIRTQPQRLPQ
intramuscular lipoma 698 NPSDGELIRTQPQRLPQL intramuscular lipoma
922 FDFSQNTRVPRLPE non-Hodgkin's lymphoma 923 GDAPAILFDKEF
non-Hodgkin's lymphoma 924 VTHEIDRYTAIAY non-Hodgkin's lymphoma 692
DAGSYKAQINQRNFE lymph node, non-Hodgkin's lymphoma 693
DAGSYKAQINQRNFEVT lymph node, non-Hodgkin's lymphoma 1 AEHPNVTLTI
spleen, non-Hodgkin's lymphoma 2 FLAEHPNVTL spleen, non-Hodgkin's
lymphoma 4 EVAEFLARH spleen, non-Hodgkin's lymphoma 5 RHSNVNLTI
spleen, non-Hodgkin's lymphoma 222 QSTQRSLAL uterine cervix,
squamous cell carcinoma 223 RDLQMNQALRF uterine cervix, squamous
cell carcinoma 224 RELESQLHVL uterine cervix, squamous cell
carcinoma 225 SEAEKLTLV uterine cervix, squamous cell carcinoma 6
HPDNVKLFL non-Hodgkin's lymphoma, small lymphocytic type 7
ISDTGELKL non-Hodgkin's lymphoma, small lymphocytic type 8
KVNGKLVALK non-Hodgkin's lymphoma, small lymphocytic type 9
NRLSAQAAL non-Hodgkin's lymphoma, small lymphocytic type 10
TPFTAIREA non-Hodgkin's lymphoma, small lymphocytic type 11
FGLARAKSV kidney, renal cell carcinoma, clear cell type 12
KIADFGLAR liver, hepatocellular carcinoma 812 DGSYRIFSKGASE
liposarcoma 813 GSYRIFSKGASE liposarcoma 814 SDGSYRIFSKGASE
liposarcoma 815 SVKKMMKDNNLVRH liver, hepatocellular carcinoma 816
VKKMMKDNNLVRH liver, hepatocellular carcinoma 145 KITVPASQK colon,
non-Hodgkin's lymphoma 146 KITVPASQKL colon, non-Hodgkin's lymphoma
147 VPASQKLRQL colon, non-Hodgkin's lymphoma 537 ITARPVLW
non-Hodgkin's lymphoma, diffuse large B-cell type 538 KLMSPKLYVW
non-Hodgkin's lymphoma, diffuse large B-cell type 539 KVSAVTLAY
non-Hodgkin's lymphoma, diffuse large B-cell type 540 VEGSGELFRW
non-Hodgkin's lymphoma, diffuse large B-cell type 672 ADLSSFKSQELN
lymph node, papillary carcinoma of thyroid, metastatic 673
ADLSSFKSQELNER lymph node, papillary carcinoma of thyroid,
metastatic 674 ADLSSFKSQELNERN lymph node, papillary carcinoma of
thyroid, metastatic 675 ADLSSFKSQELNERNE lymph node, papillary
carcinoma of thyroid, metastatic 676 ADLSSFKSQELNERNEA lymph node,
papillary carcinoma of thyroid, metastatic 677 AEQQRLKSQDLELSWNLN
lymph node, papillary carcinoma of thyroid, G metastatic 678
EQQRLKSQDLELSWN lymph node, papillary carcinoma of thyroid,
metastatic 679 ISQELEELRAEQQR lymph node, papillary carcinoma of
thyroid, metastatic 680 ISQELEELRAEQQRLK lymph node, papillary
carcinoma of thyroid, metastatic 681 KGTKQWVHARYA lymph node,
papillary carcinoma of thyroid,
metastatic 682 QADLSSFKSQELNER lymph node, papillary carcinoma of
thyroid, metastatic 683 SWNLNGLQADLSSFK lymph node, papillary
carcinoma of thyroid, metastatic 684 TGSWIGLRNLDLKG lymph node,
papillary carcinoma of thyroid, metastatic 743 AIVQAVSAHRHR
non-Hodgkin's lymphoma, peripheral T cell type 744 ARNFERNKAIKVI
non-Hodgkin's lymphoma, peripheral T cell type 745 ARNFERNKAIKVIIA
non-Hodgkin's lymphoma, peripheral T cell type 746 NFERNKAIKVII
non-Hodgkin's lymphoma, peripheral T cell type 747 NFERNKAIKVIIA
non-Hodgkin's lymphoma, peripheral T cell type 748 VAIVQAVSAHRH
non-Hodgkin's lymphoma, peripheral T cell type 749 VAIVQAVSAHRHR
non-Hodgkin's lymphoma, peripheral T cell type 750 VAIVQAVSAHRHRA
non-Hodgkin's lymphoma, peripheral T cell type 751 VAIVQAVSAHRHRAR
non-Hodgkin's lymphoma, peripheral T cell type 818 VDKVLERDQKLSE
lymph node, papillary carcinoma of thyroid, metastatic 819
VDKVLERDQKLSELD lymph node, papillary carcinoma of thyroid,
metastatic 820 VDKVLERDQKLSELDD lymph node, papillary carcinoma of
thyroid, metastatic 821 VDKVLERDQKLSELDDR lymph node, papillary
carcinoma of thyroid, metastatic 822 VLERDQKLSELDDR lymph node,
papillary carcinoma of thyroid, metastatic 833 VDKVLERDQKLSE lymph
node, papillary carcinoma of thyroid, metastatic 834
VDKVLERDQKLSELD lymph node, papillary carcinoma of thyroid,
metastatic 835 VDKVLERDQKLSELDD lymph node, papillary carcinoma of
thyroid, metastatic 836 VDKVLERDQKLSELDDR lymph node, papillary
carcinoma of thyroid, metastatic 837 VLERDQKLSELDDR lymph node,
papillary carcinoma of thyroid, metastatic 848 DDPAIDVCKKLLGKYPN
pancreas, adenocarcinoma 849 DKQPYSKLPGVSLLKP pancreas,
adenocarcinoma 850 DKQPYSKLPGVSLLKPL pancreas, adenocarcinoma 851
HPRYYISANVTGFK pancreas, adenocarcinoma 852 SHPRYYISANVTG pancreas,
adenocarcinoma 853 SHPRYYISANVTGFK pancreas, adenocarcinoma 854
TSHPRYYISANVTG pancreas, adenocarcinoma 855 TSHPRYYISANVTGFK
pancreas, adenocarcinoma 908 DVGMFVALTKLGQPD uterine cervix,
squamous cell carcinoma 909 VGmFVALTKLGQPD uterine cervix, squamous
cell carcinoma 1015 GSSFFGELFNQNPE thyroid gland, papillary
carcinoma 1016 SGSSFFGELFNQNPE thyroid gland, papillary carcinoma
466 DEMRFVTQI testis, mixed germ cell tumor 467 ETVHFATTQW testis,
mixed germ cell tumor 468 LPPPATQI testis, mixed germ cell tumor
633 GNPAYRSFSNSLSQ kidney, angiomyolipoma 634 GPPGEAGYKAFSSLLA
kidney, angiomyolipoma 635 GPPGEAGYKAFSSLLASS kidney,
angiomyolipoma 636 GPPGEAGYKAFSSLLASS kidney, angiomyolipoma A 637
GPPGEAGYKAFSSLLASS kidney, angiomyolipoma AVSPE 639
GYKAFSSLLASSAVSP kidney, angiomyolipoma 640 GYKAFSSLLASSAVSPE
kidney, angiomyolipoma 641 KAFSSLLASSAVSPE kidney, angiomyolipoma
642 NPAYRSFSNSLSQ kidney, angiomyolipoma 643 SRDDFQEGREGIVAR
kidney, angiomyolipoma 644 SSSSFHPAPGNAQ kidney, angiomyolipoma 645
VARLTESLFLDL kidney, angiomyolipoma 646 VARLTESLFLDLLG kidney,
angiomyolipoma 647 VIAGNPAYRSFSN kidney, angiomyolipoma 648
VPQPEPETWEQILRRNVL kidney, angiomyolipoma Q 649 YKAFSSLLASSAVS
kidney, angiomyolipoma 650 YKAFSSLLASSAVSP kidney, angiomyolipoma
651 YKAFSSLLASSAVSPE kidney, angiomyolipoma 992 EDDYIKSWEDNQQGDE
pleura, malignant mesothelioma 993 ELERIQIQEAAKKKPG pleura,
malignant mesothelioma 994 ERIQIQEAAKKKP pleura, malignant
mesothelioma 995 ERIQIQEAAKKKPG pleura, malignant mesothelioma 996
ERIQIQEAAKKKPGI pleura, malignant mesothelioma 997 LERIQIQEAAKKKPG
pleura, malignant mesothelioma 998 LSSISQYSGKIK pleura, malignant
mesothelioma, 941 EERNLLSVAYKNVVGAR esophagus, adenocarcinoma 942
ERNLLSVAYKNVVGAR esophagus, adenocarcinoma 943 IAELDTLSEESYKD
vulva, squamous cell carcinoma 944 IAELDTLSEESYKDS vulva, squamous
cell carcinoma 218 GDYGRAFNL stomach, metastatic, lymph node,
non-Hodgkin's lymphoma, small lymphocytic type 219 TRHKIVHTK
stomach, metastatic, lymph node, non-Hodgkin's lymphoma, small
lymphocytic type 221 KAFNWFSTL stomach, metastatic, lymph node,
non-Hodgkin's lymphoma, small lymphocytic type 541 RPKSNIVL
non-Hodgkin's lymphoma, diffuse large B-cell type 542 RPKSNIVLL
non-Hodgkin's lymphoma, diffuse large B-cell type 1001
INSRFPIPSATDPD brain, glioblastoma, brain, oligodendroglioma, 1002
VQHYELLNGQSVFG brain, glioblastoma, brain, oligodendroglioma, 910
AGVFHVEKNGRY colon, adenocarcinoma, mucinous type 911
FAGVFHVEKNGRYS colon, adenocarcinoma, mucinous type 912
GPITITIVNRDGTR colon, adenocarcinoma, mucinous type 913
NGRYSISRTEAADL colon, adenocarcinoma, mucinous type 45 DELPKFHQY
white blood cells, chronic lymphocytic leukemia 46 DVTGQFPSSF white
blood cells, chronic lymphocytic leukemia 47 EHSRVLQQL white blood
cells, chronic lymphocytic leukemia 48 IKVSKQLL white blood cells,
chronic lymphocytic leukemia 49 KPRQSSPQL white blood cells,
chronic lymphocytic leukemia 50 KQLLAALEI white blood cells,
chronic lymphocytic leukemia 51 RRKDLVLKY liver, focalnodular
hyperplasia 52 RTRDYASLPPK white blood cells, chronic lymphocytic
leukemia 124 GQKEALLKY synovial sarcoma 125 KPSEERKTI synovial
sarcoma 126 KQTPKVLVV synovial sarcoma 127 SVIQHVQSF synovial
sarcoma 128 TPIERIPYL synovial sarcoma 773 LPEFYKTVSPAL
endometrium, adenocarcinoma, endometrioid type 774 VGQFIQDVKNSRST
endometrium, adenocarcinoma, endometrioid type 775 VGQFIQDVKNSRSTD
endometrium, adenocarcinoma, endometrioid type 776 VVGQFIQDVKNSRS
endometrium, adenocarcinoma, endometrioid type 777 VVGQFIQDVKNSRST
endometrium, adenocarcinoma, endometrioid type 778 VVGQFIQDVKNSRSTD
endometrium, adenocarcinoma, endometrioid type 779
VVGQFIQDVKNSRSTDS endometrium, adenocarcinoma, endometrioid type
687 GPMKGGNFGGRSSGP thymus, thymoma, malignant 688 GPYGGGGQYFAKP
thymus, thymoma, malignant 689 KGGNFGGRSSGP thymus, thymoma,
malignant 690 NDFGNYNNQSSNFGP thymus, thymoma, malignant 691
SGPYGGGGQYFAKP thymus, thymoma, malignant 13 AAANIIRTL adrenal
gland, adrenal cortical carcinoma 14 GRFKNLREAL adrenal gland,
adrenal cortical carcinoma 15 MSPFSKATL adrenal gland, adrenal
cortical carcinoma 16 QEDPGDNQITL adrenal gland, adrenal cortical
carcinoma 17 SPFSKATL adrenal gland, adrenal cortical carcinoma 129
AEVEKNETV spleen, non-Hodgkin's lymphoma 130 EVKEEIPLV spleen,
non-Hodgkin's lymphoma 131 KPTSARSGL spleen, non-Hodgkin's lymphoma
132 KYIETTPLTI spleen, non-Hodgkin's lymphoma 133 SEIKTSIEV spleen,
non-Hodgkin's lymphoma 134 SVKPTSATK spleen, non-Hodgkin's lymphoma
135 YPNKGVGQA spleen, non-Hodgkin's lymphoma 966 ENNEIISNIRDSVIN
kidney, oncocytoma
967 NNEIISNIRDSVIN kidney, oncocytoma 968 SPTVQVFSASGKPV kidney,
oncocytoma 969 SSPTVQVFSASGKPVE kidney, oncocytoma 830
DIMRVNVDKVLERDQK Medullary carcinoma of thyroid origin 831
DIMRVNVDKVLERDQKL Medullary carcinoma of thyroid origin 832
IMRVNVDKVLERDQK lymph node, Hodgkin's disease 752 EEVITLIRSNQQLE
pancreas, adenocarcinoma, 753 EEVITLIRSNQQLEN pancreas,
adenocarcinoma, 754 IPADTFAALKNPNAML pancreas, adenocarcinoma 755
LKQLLSDKQQKRQSG pancreas, adenocarcinoma 756 LKQLLSDKQQKRQSGQ
pancreas, adenocarcinoma 339 FLDPDIGGVAV pancreas, adenocarcinoma
340 HTAPPENKTW pancreas, adenocarcinoma 341 LLDTPVKTQY pancreas,
adenocarcinoma 342 NAVKDFTSF pancreas, adenocarcinoma 343 SGLLQIKKL
pancreas, adenocarcinoma 344 YHDKNIVLL pancreas, adenocarcinoma 71
HLKSIPVSL prostate, adenocarcinoma 72 KVWYNVENW prostate,
adenocarcinoma 73 LPAYRAQLL prostate, adenocarcinoma 74 LSEQTSVPL
prostate, adenocarcinoma 75 SLNQWLVSF prostate, adenocarcinoma 76
SMTSLAQKI prostate, adenocarcinoma 77 SSSGLHPPK prostate,
adenocarcinoma 578 GGGYGSGGGSGGYGSRR thymus, thymoma, malignant F
579 GGSFGGRSSGSP thymus, thymoma, malignant 580 KGGSFGGRSSGSP
thymus, thymoma, malignant 583 SPYGGGYGSGGGSGGYG thymus, thymoma,
malignant SRRF 584 YGGGYGSGGGSGGYGSR thymus, thymoma, malignant RF
84 VPVPHTTAL endometrium, adenocarcinoma 85 YQVLDVQRY endometrium,
adenocarcinoma 731 DGLNSLTYQVLDVQRYPL endometrium, adenocarcinoma
732 HPVLQRQQLDYGIY endometrium, adenocarcinoma 733 LNSLTYQVLDVQR
endometrium, adenocarcinoma 734 LNSLTYQVLDVQRYP endometrium,
adenocarcinoma 735 LNSLTYQVLDVQRYPL endometrium, adenocarcinoma 736
LPQLVGVSTPLQG endometrium, adenocarcinoma 737 LPQLVGVSTPLQGG
endometrium, adenocarcinoma 738 LPQLVGVSTPLQGGS endometrium,
adenocarcinoma 739 RLPQLVGVSTPLQGGS endometrium, adenocarcinoma 740
SPHKVAIIIPFRNR endometrium, adenocarcinoma 741 SPHKVAIIIPFRNRQE
endometrium, adenocarcinoma 742 SPHKVAIIIPFRNRQEH endometrium,
adenocarcinoma 527 DEKQQHIVY synovial sarcoma 528 DEVYQVTVY
synovial sarcoma 529 GEISEKAKL synovial sarcoma 530 YTMKEVLFY
synovial sarcoma 203 GPRPITQSEL lymph node, non-Hodgkin's lymphoma,
marginal Zone B-cell type 204 KPEPVDKVA lymph node, non-Hodgkin's
lymphoma, marginal Zone B-cell type 205 TPSSRPASL lymph node,
non-Hodgkin's lymphoma, marginal Zone B-cell type 949 SPPQFRVNGAISN
ovary, granulosa cell tumor 950 SPPQFRVNGAISNFE ovary, granulosa
cell tumor 951 SPPQFRVNGAISNFEE ovary, granulosa cell tumor 952
SPPQFRVNGAISNFEEF ovary, granulosa cell tumor 953 VGKMFVDVYFQEDKK
ovary, granulosa cell tumor 954 VGKmFVDVYFQEDKKE ovary, granulosa
cell tumor 916 EEFKKLTSIKIQNDK small intestine, gastrointestinal
stromal tumor (GIST) 917 INRRMADDNKLFR small intestine,
gastrointestinal stromal tumor (GIST) 918 TATIVMVTNLKERKE small
intestine, gastrointestinal stromal tumor (GIST) 526 RINEFSISSF
connective tissues, chondrosarcoma 585 GNRINEFSISSF connective
tissues, chondrosarcoma 586 HGNQITSDKVGRKV connective tissues,
chondrosarcoma 587 IPPVNTNLENLYLQ connective tissues,
chondrosarcoma 588 LQVLRLDGNEIKR connective tissues, chondrosarcoma
589 LQVLRLDGNEIKRS connective tissues, chondrosarcoma 590
LQVLRLDGNEIKRSA connective tissues, chondrosarcoma 591
LRELHLDHNQISRVPN connective tissues, chondrosarcoma 592
LYVRLSHNSLTNNG connective tissues, chondrosarcoma, 593
VPSRMKYVYFQNNQ connective tissues, chondrosarcoma 594
VPSRMKYVYFQNNQIT connective tissues, chondrosarcoma 595
VPSRMKYVYFQNNQITS connective tissues, chondrosarcoma 596
WIALHGNQITSD connective tissues, chondrosarcoma 597 WIALHGNQITSDK
connective tissues, chondrosarcoma 165 ELNKLLEEI ovary,
adenocarcinoma, endometrioid type 166 IPFSNPRVL ovary,
adenocarcinoma, endometrioid type 167 LLDEGAKLLY ovary,
adenocarcinoma, endometrioid type 168 SPADAHRNL ovary,
adenocarcinoma, endometrioid type 96 APLQRSQSL kidney, renal cell
carcinoma, clear cell type 97 DEVHQDTY kidney, renal cell
carcinoma, clear cell type 98 LPHSATVTL kidney, renal cell
carcinoma, clear cell type 152 APSEYRYTL stomach, mucinous
adenocarcinoma 153 APSEYRYTLL stomach, mucinous adenocarcinoma 154
EIFQNEVAR stomach, mucinous adenocarcinoma 155 KDVLIPGKL stomach,
mucinous adenocarcinoma 156 VPLVREITF stomach, mucinous
adenocarcinoma 136 ISMKILNSL thymus, thymoma, benign 137 KTIAFLLPMF
thymus, thymoma, benign 138 RDSIINDF thymus, thymoma, benign 139
SVKGGGGNEK thymus, thymoma, benign 140 GIAKTGSGK thymus, thymoma,
benign 503 ALYATKTLR pancreas, microcystic adenoma 504 MEYVISRI
pancreas, microcystic adenoma 505 VPVGRQPII pancreas, microcystic
adenoma 278 ATNGDLASR prostate, benign nodular hyperplasia 279
GLHAEYTGVGY prostate, benign nodular hyperplasia 280 HVSSTSSSF
prostate, benign nodular hyperplasia 281 LQADLQNGL prostate, benign
nodular hyperplasia 282 SELPVSEVA prostate, benign nodular
hyperplasia 283 SQTKSVFEI prostate, benign nodular hyperplasia 284
THIFTSDGL prostate, benign nodular hyperplasia 285 VIYFPPLQK
prostate, benign nodular hyperplasia 286 YPFSSEQKW prostate, benign
nodular hyperplasia 963 GNTVIHLDQALARMR lung, small cell carcinoma
964 NTVIHLDQALARMR lung, small cell carcinoma 965 NTVIHLDQALARMRE
lung, small cell carcinoma 187 AADTERLAL connective tissues,
chondrosarcoma 188 DMKAKVASL connective tissues, chondrosarcoma 189
HVLEEVQQV connective tissues, chondrosarcoma 190 KEAADTERL
connective tissues, chondrosarcoma 191 RISEVLQKL connective
tissues, chondrosarcoma 192 TEVRELVSL 973 ADDLEGEAFLPL spleen,
chronic myeloid leukemia 974 ADDLEGEAFLPLR spleen, chronic myeloid
leukemia 975 ADDLEGEAFLPLRE spleen, chronic myeloid leukemia 976
GADDLEGEAFLPLR spleen, chronic myeloid leukemia 141 AETTDNVFTL
thyroid gland, follicular adenoma 142 SEYQRFAVM thyroid gland,
follicular adenoma 143 TFGERVVAF thyroid gland, follicular adenoma
144 NENLVERF stomach, colon, adenocarcinoma, mucinous type 117
QLFSYAILGF colon, non-Hodgkin's lymphoma 845 GIRVAPVPLYNS lung,
non-small cell lung carcinoma, liver,
hepatocellular carcinoma 846 GIRVAPVPLYNSFH lung, non-small cell
lung carcinoma, liver, hepatocellular carcinoma 847
NPNGIRVAPVPLYNSFH lung, non-small cell lung carcinoma, liver,
hepatocellular carcinoma 478 AAVPVIISR lymph node, papillary
carcinoma of thyroid, metastatic 479 EEIGKVAAA lymph node,
papillary carcinoma of thyroid, metastatic 480 FLKDLVASV lymph
node, papillary carcinoma of thyroid, metastatic 481 VIISRALEL
lymph node, papillary carcinoma of thyroid, metastatic 420
QIDYKTLVL leiomyosarcoma 421 VEDPTIVRI leiomyosarcoma 543
GEPLSYTRFSLARQ lung, non-small cell lung carcinoma, lung,
adenocarcinoma 544 GEPLSYTRFSLARQVD lung, non-small cell lung
carcinoma, lung, adenocarcinoma 545 GEPLSYTRFSLARQVDG lung,
non-small cell lung carcinoma, lung, adenocarcinoma 546
GGEPLSYTRFSLARQVD lung, non-small cell lung carcinoma, lung,
adenocarcinoma 547 GGEPLSYTRFSLARQVDG lung, non-small cell lung
carcinoma, lung, adenocarcinoma 548 NPGGYVAYSKAATVTG lung,
non-small cell lung carcinoma, lung, adenocarcinoma 549
NPGGYVAYSKAATVTGK lung, non-small cell lung carcinoma, lung,
adenocarcinoma 550 NPGGYVAYSKAATVTGKL lung, non-small cell lung
carcinoma, lung, adenocarcinoma 551 NSVIIVDKNGRL lung, non-small
cell lung carcinoma, lung, adenocarcinoma 552 NSVIIVDKNGRLV lung,
non-small cell lung carcinoma, lung, adenocarcinoma 553
NSVIIVDKNGRLVY lung, non-small cell lung carcinoma, lung,
adenocarcinoma 554 RVEYHFLSPYVSPK lung, non-small cell lung
carcinoma, lung, adenocarcinoma 555 RVEYHFLSPYVSPKE lung, non-small
cell lung carcinoma, lung, adenocarcinoma 556 RVEYHFLSPYVSPKESPF
lung, non-small cell lung carcinoma, lung, adenocarcinoma 557
SPFRHVFWGSGSHTL lung, non-small cell lung carcinoma, lung,
adenocarcinoma 558 SVIIVDKNGRLV lung, non-small cell lung
carcinoma, lung, adenocarcinoma 559 VEYHFLSPYVSPK lung, non-small
cell lung carcinoma, lung, adenocarcinoma 560 VEYHFLSPYVSPKE lung,
non-small cell lung carcinoma, lung, adenocarcinoma 388 AEGPAGGFmVV
spleen, chronic myeloid leukemia 389 AYYRDAEAY spleen, chronic
myeloid leukemia 390 QVNRPLTMR spleen, chronic myeloid leukemia 391
RHSPVFQVY spleen, chronic myeloid leukemia 392 SLPVPNSAY spleen,
chronic myeloid leukemia 393 TLGPPGTAHLY spleen, chronic myeloid
leukemia 308 VLYVGSKTK schwannoma 309 KTKEQVTNV schwannoma 310
MPVDPDNEAY schwannoma 311 AEKTKQGVA schwannoma 446 EAFEFVKQR
stomach, diffuse subtype adenocarcinoma, breast, carcinoma 447
NHFEGHYQY stomach, diffuse subtype adenocarcinoma, breast,
carcinoma
[0027] Finally a most preferred aspect of the present invention
relates to the use of the peptides according to the present
invention for the--preferably combined--most preferred
immunotherapy of diseases according to the following table 6.
TABLE-US-00008 TABLE 6 Most preferred peptides according to the
present invention and diseases to be treated Seq ID Sequence Tissue
and disease 22 LEVEERTKPV breast, carcinoma 23 RDSPINANLRY breast,
carcinoma 24 RPFVIVTA breast, carcinoma 25 RPIINTPMV breast,
carcinoma 26 SPTSSRTSSL breast, carcinoma 27 ATSAPLVSR lung,
neuroendocrine carcinoma (non-small cell type) 114 YGNPRTNGM
breast, carcinoma 102 FSITKSVEL non-Hodgkin's lymphoma, small
lymphocytic type 103 GQTKNDLVV non-Hodgkin's lymphoma, small
lymphocytic type 104 LSQEVCRD non-Hodgkin's lymphoma, small
lymphocytic type 105 RDIQSPEQI non-Hodgkin's lymphoma, small
lymphocytic type 106 REDNSSNSL non-Hodgkin's lymphoma, small
lymphocytic type 107 TEHQEPGL non-Hodgkin's lymphoma, small
lymphocytic type 108 TKNDLVVSL non-Hodgkin's lymphoma, small
lymphocytic type 977 AGREINLVDAHLKSE lymph node, Hodgkin's disease
978 AGREINLVDAHLKSEQT lymph node, Hodgkin's disease 979
GREINLVDAHLKSE lymph node, Hodgkin's disease 980 KPGIVYASLNHSVIG
lymph node, Hodgkin's disease 981 NKPGIVYASLNHSVIG lymph node,
Hodgkin's disease 982 TTLYVTDVKSASERPS lymph node, Hodgkin's
disease 220 RIHTGEKPYK colon or rectum, thyroid gland, nodular
hyperplasia 53 APGSVLPRAL lymph node, Hodgkin's disease 54 DIKEHPLL
lymph node, Hodgkin's disease 55 DSAGPQDAR lymph node, Hodgkin's
disease 56 FQYAKESYI lymph node, Hodgkin's disease 57 KVLSWPFLM
lymph node, Hodgkin's disease 58 LENDQSLSF lymph node, Hodgkin's
disease 59 SPSRQPQV lymph node, Hodgkin's disease 60 SRHQSFTTK
lymph node, Hodgkin's disease 61 SSHNASKTL lymph node, Hodgkin's
disease 1003 DNQYAVLENQKSSH pleura, malignant mesothelioma 1004
GPPEIYSDTQFPS pleura, malignant mesothelioma 1005 GPPEIYSDTQFPSLQ
pleura, malignant mesothelioma 1006 TPQGPPEIYSDTQFPS pleura,
malignant mesothelioma 1007 TPQGPPEIYSDTQFPSLQ pleura, malignant
mesothelioma 1008 TPQGPPEIYSDTQFPSLQS pleura, malignant
mesothelioma T 661 EYVSLYHQPAAM non-Hodgkin's lymphoma, peripheral
T cell type 662 IKAEYKGRVTLKQYPR non-Hodgkin's lymphoma, peripheral
T cell type 663 LNVHSEYEPSWEEQP non-Hodgkin's lymphoma, peripheral
T cell type 664 LPYLFQMPAYASSS non-Hodgkin's lymphoma, peripheral T
cell type 665 LPYLFQMPAYASSSK non-Hodgkin's lymphoma, peripheral T
cell type 666 NFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T
cell type 667 TNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T
cell type 668 TTNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T
cell type 669 VTLNVHSEYEPSWEEQP non-Hodgkin's lymphoma, peripheral
T cell type 670 YPRKNLFLVEVTQLTESDS non-Hodgkin's lymphoma,
peripheral T cell type 671 YPRKNLFLVEVTQLTESDS non-Hodgkin's
lymphoma, peripheral T cell G type 780 DNGHLYREDQTSPAPG kidney,
angiomyolipoma 781 DNGHLYREDQTSPAPGLR kidney, angiomyolipoma 782
EVQVFAPANALPARSE kidney, angiomyolipoma 783 GHLYREDQTSPAPG kidney,
angiomyolipoma 784 LPARSEAAAVQPVIG kidney, angiomyolipoma 785
NGHLYREDQTSPAPG kidney, angiomyolipoma 786 NGHLYREDQTSPAPGL kidney,
angiomyolipoma 787 NGHLYREDQTSPAPGLR kidney, angiomyolipoma 788
VFAPANALPARSEAA kidney, angiomyolipoma 789 VQVFAPANALPARSE kidney,
angiomyolipoma 222 QSTQRSLAL uterine cervix, squamous cell
carcinoma 223 RDLQMNQALRF uterine cervix, squamous cell carcinoma
224 RELESQLHVL uterine cervix, squamous cell carcinoma 225
SEAEKLTLV uterine cervix, squamous cell carcinoma 12 KIADFGLAR
liver, hepatocellular carcinoma 812 DGSYRIFSKGASE colon or rectum
813 GSYRIFSKGASE colon or rectum 814 SDGSYRIFSKGASE colon or rectum
815 SVKKMMKDNNLVRH colon or rectum, liver, hepatocellular carcinoma
816 VKKMMKDNNLVRH colon or rectum, liver, hepatocellular carcinoma
743 AIVQAVSAHRHR non-Hodgkin's lymphoma, peripheral T cell type 744
ARNFERNKAIKVI non-Hodgkin's lymphoma, peripheral T cell type 745
ARNFERNKAIKVIIA non-Hodgkin's lymphoma, peripheral T cell type 746
NFERNKAIKVII non-Hodgkin's lymphoma, peripheral T cell type 747
NFERNKAIKVIIA non-Hodgkin's lymphoma, peripheral T cell type 748
VAIVQAVSAHRH non-Hodgkin's lymphoma, peripheral T cell type 749
VAIVQAVSAHRHR non-Hodgkin's lymphoma, peripheral T cell type 750
VAIVQAVSAHRHRA non-Hodgkin's lymphoma, peripheral T cell type 751
VAIVQAVSAHRHRAR non-Hodgkin's lymphoma, peripheral T cell type 818
VDKVLERDQKLSE lymph node, papillary carcinoma of thyroid,
metastatic 819 VDKVLERDQKLSELD lymph node, papillary carcinoma of
thyroid, metastatic 820 VDKVLERDQKLSELDD lymph node, papillary
carcinoma of thyroid, metastatic 821 VDKVLERDQKLSELDDR lymph node,
papillary carcinoma of thyroid, metastatic 822 VLERDQKLSELDDR lymph
node, papillary carcinoma of thyroid, metastatic 833 VDKVLERDQKLSE
lymph node, papillary carcinoma of thyroid, metastatic 834
VDKVLERDQKLSELD lymph node, papillary carcinoma of thyroid,
metastatic 835 VDKVLERDQKLSELDD lymph node, papillary carcinoma of
thyroid, metastatic 836 VDKVLERDQKLSELDDR lymph node, papillary
carcinoma of thyroid, metastatic 837 VLERDQKLSELDDR lymph node,
papillary carcinoma of thyroid, metastatic 908 DVGMFVALTKLGQPD
uterine cervix, squamous cell carcinoma 909 VGmFVALTKLGQPD uterine
cervix, squamous cell carcinoma 218 GDYGRAFNL lymph node,
non-Hodgkin's lymphoma, small lymphocytic type 219 TRHKIVHTK lymph
node, non-Hodgkin's lymphoma, small lymphocytic type 221 KAFNWFSTL
lymph node, non-Hodgkin's lymphoma, small lymphocytic type 541
RPKSNIVL non-Hodgkin's lymphoma, diffuse large B-cell type 542
RPKSNIVLL non-Hodgkin's lymphoma, diffuse large B-cell type 752
EEVITLIRSNQQLE pancreas, adenocarcinoma 753 EEVITLIRSNQQLEN
pancreas, adenocarcinoma 754 IPADTFAALKNPNAML pancreas,
adenocarcinoma 755 LKQLLSDKQQKRQSG pancreas, adenocarcinoma 756
LKQLLSDKQQKRQSGQ pancreas, adenocarcinoma
71 HLKSIPVSL prostate, adenocarcinoma 72 KVWYNVENW prostate,
adenocarcinoma 73 LPAYRAQLL prostate, adenocarcinoma 74 LSEQTSVPL
prostate, adenocarcinoma 75 SLNQWLVSF prostate, adenocarcinoma 76
SMTSLAQKI prostate, adenocarcinoma 77 SSSGLHPPK prostate,
adenocarcinoma 527 DEKQQHIVY synovial sarcoma 528 DEVYQVTVY
synovial sarcoma 529 GEISEKAKL synovial sarcoma 530 YTMKEVLFY
synovial sarcoma 165 ELNKLLEEI ovary, adenocarcinoma, endometrioid
type 166 IPFSNPRVL ovary, adenocarcinoma, endometrioid type 167
LLDEGAKLLY ovary, adenocarcinoma, endometrioid type 168 SPADAHRNL
ovary, adenocarcinoma, endometrioid type 96 APLQRSQSL kidney, renal
cell carcinoma, clear cell type 97 DEVHQDTY kidney, renal cell
carcinoma, clear cell type 98 LPHSATVTL kidney, renal cell
carcinoma, clear cell type 278 ATNGDLASR prostate, benign nodular
hyperplasia 279 GLHAEVTGVGY prostate, benign nodular hyperplasia
280 HVSSTSSSF prostate, benign nodular hyperplasia 281 LQADLQNGL
prostate, benign nodular hyperplasia 282 SELPVSEVA prostate, benign
nodular hyperplasia 283 SQTKSVFEI prostate, benign nodular
hyperplasia 284 THIFTSDGL prostate, benign nodular hyperplasia 285
VIYFPPLQK prostate, benign nodular hyperplasia 286 YPFSSEQKW
prostate, benign nodular hyperplasia 973 ADDLEGEAFLPL spleen,
chronic myeloid leukemia 974 ADDLEGEAFLPLR spleen, chronic myeloid
leukemia 975 ADDLEGEAFLPLRE spleen, chronic myeloid leukemia 976
GADDLEGEAFLPLR spleen, chronic myeloid leukemia 141 AETTDNVFTL
thyroid gland, follicular adenoma 142 SEYQRFAVM thyroid gland,
follicular adenoma 143 TFGERVVAF thyroid gland, follicular adenoma
144 NENLVERF colon, adenocarcinoma, mucinous type 845 GIRVAPVPLYNS
liver, hepatocellular carcinoma 846 GIRVAPVPLYNSFH liver,
hepatocellular carcinoma 847 NPNGIRVAPVPLYNSFH liver,
hepatocellular carcinoma 478 AAVPVIISR lymph node, papillary
carcinoma of thyroid, metastatic 479 EEIGKVAAA lymph node,
papillary carcinoma of thyroid, metastatic 480 FLKDLVASV lymph
node, papillary carcinoma of thyroid, metastatic 481 VIISRALEL
lymph node, papillary carcinoma of thyroid, metastatic 420
QIDYKTLVL leiomyosarcoma 421 VEDPTIVRI leiomyosarcoma 543
GEPLSYTRFSLARQ lung, non-small cell lung carcinoma, lung,
adenocarcinoma 544 GEPLSYTRFSLARQVD lung, non-small cell lung
carcinoma, lung, adenocarcinoma 545 GEPLSYTRFSLARQVDG lung,
non-small cell lung carcinoma, lung, adenocarcinoma 546
GGEPLSYTRFSLARQVD lung, non-small cell lung carcinoma, lung,
adenocarcinoma 547 GGEPLSYTRFSLARQVDG lung, non-small cell lung
carcinoma, lung, adenocarcinoma 548 NPGGYVAYSKAATVTG lung,
non-small cell lung carcinoma, lung, adenocarcinoma 549
NPGGYVAYSKAATVTGK lung, non-small cell lung carcinoma, lung,
adenocarcinoma 550 NPGGYVAYSKAATVTGKL lung, non-small cell lung
carcinoma, lung, adenocarcinoma 551 NSVIIVDKNGRL lung, non-small
cell lung carcinoma, lung, adenocarcinoma 552 NSVIIVDKNGRLV lung,
non-small cell lung carcinoma, lung, adenocarcinoma 553
NSVIIVDKNGRLVY lung, non-small cell lung carcinoma, lung,
adenocarcinoma 554 RVEYHFLSPYVSPK lung, non-small cell lung
carcinoma, lung, adenocarcinoma 555 RVEYHFLSPYVSPKE lung, non-small
cell lung carcinoma, lung, adenocarcinoma 556 RVEYHFLSPYVSPKESPF
lung, non-small cell lung carcinoma, lung, adenocarcinoma 557
SPFRHVFWGSGSHTL lung, non-small cell lung carcinoma, lung,
adenocarcinoma 558 SVIIVDKNGRLV lung, non-small cell lung
carcinoma, lung, adenocarcinoma 559 VEYHFLSPYVSPK lung, non-small
cell lung carcinoma, lung, adenocarcinoma 560 VEYHFLSPYVSPKE lung,
non-small cell lung carcinoma, lung, adenocarcinoma
[0028] B4GALT1 encodes a type II membrane-bound glycoprotein that
appears to have exclusive specificity for the donor substrate
UDP-galactose (RefSeq). B4GALT1 was shown to be up-regulated in a
variety of highly metastatic cell lines such as human lung cancer
and ovarian cancer cell lines and was described as a valuable
candidate biomarker of invasive phenotype of colorectal cancer
(Poeta et al., 2012; Zhou et al., 2012).
[0029] CP encodes a metalloprotein that binds most of the copper in
plasma and is involved in the peroxidation of Fe(II)transferrin to
Fe(III) transferrin (RefSeq).
[0030] CST3 encodes a member of the cystatin superfamily, which
encompasses proteins that contain multiple cystatin-like sequences
(RefSeq).
[0031] CTSH encodes a lysosomal cysteine proteinase, which is
important in the overall degradation of lysosomal proteins
(RefSeq). CTSH expression is increased in pathologic conditions
including breast carcinoma, melanoma, gliomas, colorectal carcinoma
and prostate carcinoma. CTSH-mediated processing of talin is
thought to promote cancer cell progression by affecting integrin
activation and adhesion strength (Jevnikar et al., 2013).
[0032] DNAJC5 encodes a member of the J protein family. J proteins
function in many cellular processes by regulating the ATPase
activity of 70 kDa heat shock proteins (RefSeq).
[0033] FAIM3 also known as TOSO encodes an Fc receptor for IgM
(RefSeq). FAIM3 was identified as being over-expressed and
associated with anti-apoptotic characteristics in chronic
lymphocytic leukemia and it is regulated by B-cell receptor
activation. These studies show that FAIM3 could be used as a
prognostic marker for high-risk chronic lymphocytic leukemia
(Pallasch et al., 2008; Yi et al., 2011; Yu et al., 2011).
[0034] FCER2 encodes a B-cell specific antigen and a low-affinity
receptor for IgE. It has essential roles in B cell growth and
differentiation, and the regulation of IgE production (RefSeq).
[0035] FMOD encodes a member of the family of small interstitial
proteoglycans. The encoded protein possesses a central region
containing leucine-rich repeats with 4 keratan sulfate chains,
flanked by terminal domains containing disulphide bonds (RefSeq).
FMOD was shown to be highly over-expressed in chronic lymphocytic
leukemia cells. Hence, FMOD might serve as potential
tumor-associated antigen in chronic lymphocytic leukemia (Mayr et
al., 2005).
[0036] GALNT1 encodes a member of the
UDP-N-acetyl-alpha-D-galactosamine:polypeptide
N-acetylgalactosaminyltransferase (GalNAc-T) family of enzymes
(RefSeq). Studies have revealed that GALNT1 expression correlates
with the degree of proliferation and recurrence in human breast
cancer, ovarian cancer and bladder carcinoma. The latter suggests
the use of GALNT1 as a clinical prognostic marker in human bladder
carcinoma (Ding et al., 2012).
[0037] GLT8D1 encodes a member of the glycosyltransferase family
(RefSeq). Studies revealed that GLT8D1 was ubiquitously
up-regulated in the majority of human cancers, such as brain,
liver, breast, lung, stomach, pancreas, colon, kidney, bladder,
prostate and testis. GLT8D1-induced differentially methylated genes
have strong potential as epigenetic biomarkers for early cancer
screening, diagnostic, prognostic and therapeutic interventions
(Teh et al., 2012).
[0038] GPI encodes a member of the glucose phosphate isomerase
protein family (RefSeq). The GPI gene has been identified to be
hypoxia inducible in human pancreatic cancer. The use of GPI
inhibitors such as erythrose-4-phosphate diminishes the migratory
and invasive capacities in bi-dimensional cultures of several
breast cancer cell lines, suggesting that GPI inhibition could be a
selective strategy to block tumor metastasis (Yoon et al., 2001;
Gallardo-Perez et al., 2014).
[0039] GPX1 encodes a member of the glutathione peroxidase family
(RefSeq). The GPX1 rs1050450 C>T polymorphism was associated
with an increased risk of bladder cancer, but not prostate cancer.
High expression of GPX1 in breast cancer cells of patients
correlated with a worse clinical outcome and reduced overall
survival of patients who underwent chemotherapy, implying that GPX1
could be used as a prognostic marker for these patients (Jardim et
al., 2013; Men et al., 2014).
[0040] TFRC encodes the transferrin receptor and it is located on
chromosome 3q29 (RefSeq). The expression rate of TFRC in oral
squamous cell carcinoma was significantly higher than that in
dysplasia, suggesting that oral squamous cell carcinoma disease
progression might be related to TFRC expression. Anti-TFRC antibody
blocked the interaction between transferrin and TFRC and,
consequently, iron uptake. The resulting iron deprivation inhibited
cell growth and induced apoptosis (Nagai et al., 2014).
[0041] UGCG encodes an enzyme that catalyzes the first
glycosylation step in the biosynthesis of glycosphingolipids, which
are membrane components containing lipid and sugar moieties
(RefSeq). Studies have shown that UGCG is over-expressed in
leukemia, breast cancer, renal cell cancer and papillary thyroid
carcinomas. UGCG up-regulates MDR1 expression through activation of
cSrc and beta-catenin signaling (Zhang et al., 2013; Liu et al.,
2010).
[0042] The present invention furthermore relates to the peptides
according to the present invention that have the ability to bind to
a molecule of the human major histocompatibility complex (MHC)
class-I or -II.
[0043] The present invention further relates to the peptides
according to the present invention wherein said peptides (each)
consist or consist essentially of an amino acid sequence according
to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542
or SEQ ID NO: 543 to SEQ ID NO: 1016.
[0044] A peptide consisting essentially of the amino acid sequence
as indicated can have one or two non-anchor amino acids (see below
regarding the anchor motif) exchanged without that the ability to
bind to a molecule of the human major histocompatibility complex
(MHC) class-I or -II is substantially changed or is negatively
affected, compared to the non-modified peptide. In another peptide
consisting essentially of the amino acid sequence, one or two amino
acids are exchanged with their conservative exchange partners (see
herein below as well) without that the ability to bind to a
molecule of the human major histocompatibility complex (MHC)
class-I or -II is substantially changed or is negatively affected,
compared to the non-modified peptide.
[0045] The present invention further relates to the peptides
according to the present invention, wherein said peptide is
modified and/or includes non-peptide bonds.
[0046] The present invention further relates to the peptides
according to the present invention, wherein said peptide is part of
a fusion protein, in particular fused to the N-terminal amino acids
of the HLA-DR antigen-associated invariant chain (Ii), or fused to
(or into the sequence of) an antibody, such as, for example, an
antibody that is specific for dendritic cells.
[0047] The present invention further relates to a nucleic acid,
encoding the peptides according to the present invention.
[0048] The present invention further relates to the nucleic acid
according to the present invention that is DNA, cDNA, PNA, RNA or
combinations thereof.
[0049] The present invention further relates to an expression
vector capable of expressing and/or presenting a nucleic acid
according to the present invention.
[0050] The present invention further relates to a peptide according
to the present invention according to SEQ ID NO: 1 to SEQ ID NO:
225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID
NO: 1016, a nucleic acid according to the present invention or an
expression vector according to the present invention for use in
medicine.
[0051] The present invention further relates to antibodies
according to the present invention that are specific for a peptide
according to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ
ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016, and methods of
making them.
[0052] The present invention further relates to T-cell receptors
(TCR), in particular soluble TCR (sTCRs) targeting the peptides
according to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ
ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016 and/or complexes of
said peptides according to the present invention with MHC, and
methods of making them.
[0053] The present invention further relates to a host cell
comprising a nucleic acid according to the present invention or an
expression vector as described before.
[0054] The present invention further relates to the host cell
according to the present invention that is an antigen presenting
cell.
[0055] The present invention further relates to the host cell
according to the present invention wherein the antigen presenting
cell is a dendritic cell.
[0056] The present invention further relates to a method of
producing a peptide according to the present invention, the method
comprising culturing the host cell according to the present
invention, and isolating the peptide from the host cell or its
culture medium.
[0057] The present invention further relates to an in vitro method
for producing activated cytotoxic T lymphocytes (CTL), the method
comprising contacting in vitro CTL with antigen loaded human class
I or II MHC molecules expressed on the surface of a suitable
antigen-presenting cell for a period of time sufficient to activate
said CTL in an antigen specific manner, wherein said antigen is any
peptide according to the present invention.
[0058] The present invention further relates to the method
according to the present invention, wherein the antigen is loaded
onto class I or II MHC molecules expressed on the surface of a
suitable antigen-presenting cell by contacting a sufficient amount
of the antigen with an antigen-presenting cell.
[0059] The present invention further relates to the method
according to the present invention, wherein the antigen-presenting
cell comprises an expression vector capable of expressing said
peptide containing SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 527
to SEQ ID NO: 551 or SEQ ID NO: 552 to SEQ ID NO: 1016, or said
variant amino acid sequence.
[0060] The present invention further relates to activated cytotoxic
T lymphocytes (CTL), produced by the method according to the
present invention, which selectively recognize a cell which
aberrantly expresses a polypeptide comprising an amino acid
sequence according to the present invention.
[0061] The present invention further relates to a method of killing
target cells in a patient which target cells aberrantly express a
polypeptide comprising any amino acid sequence according to the
present invention, the method comprising administering to the
patient an effective number of cytotoxic T lymphocytes (CTL) as
according to the present invention.
[0062] The present invention further relates to the use of any
peptide described, a nucleic acid according to the present
invention, an expression vector according to the present invention,
a cell according to the present invention, or an activated
cytotoxic T lymphocyte according to the present invention as a
medicament or in the manufacture of a medicament.
[0063] The present invention further relates to a use according to
the present invention, wherein said medicament is a vaccine.
[0064] The present invention further relates to a use according to
the present invention, wherein the medicament is active against
cancer.
[0065] The present invention further relates to a use according to
the present invention, wherein said cancer cells are cells of
haematological malignancies, such as, CLL or AML cells.
[0066] The present invention further relates to particular marker
proteins and biomarkers based on the peptides according to the
present invention that can be used in the diagnosis and/or
prognosis of haematological malignancies, in particular chronic
lymphoid leukemia (CLL) cells.
[0067] Further, the present invention relates to the use of these
novel targets for cancer treatment.
[0068] Further, the present invention relates to a method for
producing a personalized anti-cancer vaccine for an individual
patient using a database ("warehouse") of prescreened tumour
associated peptides.
[0069] Stimulation of an immune response is dependent upon the
presence of antigens recognised as foreign by the host immune
system. The discovery of the existence of tumor associated antigens
has raised the possibility of using a host's immune system to
intervene in tumor growth. Various mechanisms of harnessing both
the humoral and cellular arms of the immune system are currently
being explored for cancer immunotherapy.
[0070] Specific elements of the cellular immune response are
capable of specifically recognising and destroying tumor cells. The
isolation of cytotoxic T-cells (CTL) from tumor-infiltrating cell
populations or from peripheral blood suggests that such cells play
an important role in natural immune defences against cancer.
CD8-positive T-cells in particular, which recognise Class I
molecules of the major histocompatibility complex (MHC)-bearing
peptides of usually 8 to 10 amino acid residues derived from
proteins or defect ribosomal products (DRIPS) located in the
cytosol, play an important role in this response. The MHC-molecules
of the human are also designated as human leukocyte-antigens
(HLA).
[0071] There are two classes of MHC-molecules: MHC class I
molecules that can be found on most cells having a nucleus. MHC
molecules are composed of an alpha heavy chain and
beta-2-microglobulin (MHC class I receptors) or an alpha and a beta
chain (MHC class II receptors), respectively. Their
three-dimensional conformation results in a binding groove, which
is used for non-covalent interaction with peptides. MHC class I
present peptides that result from proteolytic cleavage of
predominantly endogenous proteins, DRIPs and larger peptides. MHC
class II molecules can be found predominantly on professional
antigen presenting cells (APCs), and primarily present peptides of
exogenous or transmembrane proteins that are taken up by APCs
during the course of endocytosis, and are subsequently processed.
Complexes of peptide and MHC class I molecules are recognized by
CD8-positive cytotoxic T-lymphocytes bearing the appropriate TCR
(T-cell receptor), whereas complexes of peptide and MHC class II
molecules are recognized by CD4-positive-helper-T cells bearing the
appropriate TCR. It is well known that the TCR, the peptide and the
MHC are thereby present in a stoichiometric amount of 1:1:1.
[0072] CD4-positive helper T cells play an important role in
inducing and sustaining effective responses by CD8-positive
cytotoxic T cells. The identification of CD4-positive T-cell
epitopes derived from tumor associated antigens (TAA) is of great
importance for the development of pharmaceutical products for
triggering anti-tumor immune responses (Gnjatic S, et al. Survey of
naturally occurring CD4+ T cell responses against NY-ESO-1 in
cancer patients: correlation with antibody responses. Proc Natl
Acad Sci USA. 2003 Jul. 22; 100(15):8862-7). At the tumor site, T
helper cells, support a CTL friendly cytokine milieu Mortara L, et
al. CIITA-induced MHC class II expression in mammary adenocarcinoma
leads to a Th1 polarization of the tumor microenvironment, tumor
rejection, and specific antitumor memory. Clin Cancer Res. 2006
Jun. 1; 12(11 Pt 1):3435-43) and attract effector cells, e.g. CTLs,
NK cells, macrophages, granulocytes (Hwang M L, et al. Cognate
memory CD4+ T cells generated with dendritic cell priming influence
the expansion, trafficking, and differentiation of secondary CD8+ T
cells and enhance tumor control. J Immunol. 2007 Nov. 1;
179(9):5829-38).
[0073] In the absence of inflammation, expression of MHC class II
molecules is mainly restricted to cells of the immune system,
especially professional antigen-presenting cells (APC), e.g.,
monocytes, monocyte-derived cells, macrophages, dendritic cells. In
cancer patients, cells of the tumor have surprisingly been found to
express MHC class II molecules (Dengjel J, et al. Unexpected
abundance of HLA class II presented peptides in primary renal cell
carcinomas. Clin Cancer Res. 2006 Jul. 15; 12(14 Pt
1):4163-70).
[0074] It was shown in mammalian animal models, e.g., mice, that
even in the absence of CTL effector cells (i.e., CD8-positive T
lymphocytes), CD4-positive T cells are sufficient for inhibiting
manifestation of tumors via inhibition of angiogenesis by secretion
of interferon-gamma (IFN.gamma.).
[0075] Additionally, it was shown that CD4-positive T cells
recognizing peptides from tumor-associated antigens presented by
HLA class II molecules can counteract tumor progression via the
induction of antibody (Ab) responses.
[0076] In contrast to tumor-associated peptides binding to HLA
class I molecules, only a small number of class II ligands of tumor
associated antigens (TAA) have been described to date.
[0077] Since the constitutive expression of HLA class II molecules
is usually limited to cells of the immune system, the possibility
of isolating class II peptides directly from primary tumors was not
considered possible. However, Dengjel et al. were successful in
identifying a number of MHC Class II epitopes directly from tumors
(WO 2007/028574, EP 1 760 088 B1; (Dengjel et al., 2006).
[0078] The antigens that are recognized by the tumor specific
cytotoxic T lymphocytes, that is, their epitopes, can be molecules
derived from all protein classes, such as enzymes, receptors,
transcription factors, etc. which are expressed and, as compared to
unaltered cells of the same origin, up-regulated in cells of the
respective tumor.
[0079] Since both types of response, CD8 and CD4 dependent,
contribute jointly and synergistically to the anti-tumor effect,
the identification and characterization of tumor-associated
antigens recognized by either CD8+ CTLs (ligand: MHC class I
molecule+peptide epitope) or by CD4-positive T-helper cells
(ligand: MHC class II molecule+peptide epitope) is important in the
development of tumor vaccines.
[0080] The present invention also relates to two new and very
useful MHC class II peptides (according to SEQ ID NO: 543 to SEQ ID
NO: 1016). These peptides are particularly useful in the diagnosis
and/or treatment of CLL and other cancers over-expressing and/or
over--presenting the antigens the peptides are derived from
respectively, such as AML.
[0081] The present invention also relates to so-called length
variants of the inventive MHC class II peptides according to SEQ ID
NO: 543 to SEQ ID NO: 1016.
[0082] The length variants are generally N- and/or C-terminally
extended (between 1 and 5, preferably 1 to 10 amino acids) or N-
and/or C-terminally shortened (between 1 and 5 amino acids)
peptides, which still can bind to MHC, and elicit a cellular immune
response as described herein. As is known in the state of the art,
peptides binding to class II proteins are not constrained in size
and can vary from 11 to 30 amino acids in length. The peptide
binding groove in the MHC class II molecules is open at both ends,
which enables binding of peptides with relatively longer length.
Though the "core" nine residues long segment contributes the most
to the recognition of the peptide, the flanking regions are also
important for the specificity of the peptide to the class II allele
(see, for example, Meydan C, et al., Prediction of peptides binding
to MHC class I and II alleles by temporal motif mining. BMC
Bioinformatics. 2013; 14 Suppl 2: S13). Using the many software
tools as available (e.g. as described above), the person of skill
in the art will be able to identify the binding motif, and thus
identify the possibilities for extensions and/or deletions of the
MHC class II peptides according to Table 1c, in order to create
length variants.
[0083] For a peptide to trigger (elicit) a cellular immune
response, it must bind to an MHC-molecule. This process is
dependent on the allele of the MHC-molecule and specific
polymorphisms of the amino acid sequence of the peptide.
MHC-class-1-binding peptides are usually 8-12 amino acid residues
in length and usually contain two conserved residues ("anchors") in
their sequence that interact with the corresponding binding groove
of the MHC-molecule. In this way each MHC allele has a "binding
motif" determining which peptides can bind specifically to the
binding groove.
[0084] In the MHC class I dependent immune reaction, peptides not
only have to be able to bind to certain MHC class I molecules being
expressed by tumor cells, they also have to be recognized by T
cells bearing specific T cell receptors (TCR).
[0085] The antigens that are recognized by the tumor specific
cytotoxic T lymphocytes, that is, their epitopes, can be molecules
derived from all protein classes, such as enzymes, receptors,
transcription factors, etc. which are expressed and, as compared to
unaltered cells of the same origin, up-regulated in cells of the
respective tumor.
[0086] The current classification of tumor associated antigens
comprises the following major groups:
[0087] a) Cancer-testis antigens: The first TAAs ever identified
that can be recognized by T cells belong to this class, which was
originally called cancer-testis (CT) antigens because of the
expression of its members in histologically different human tumors
and, among normal tissues, only in spermatocytes/spermatogonia of
testis and, occasionally, in placenta. Since the cells of testis do
not express class I and II HLA molecules, these antigens cannot be
recognized by T cells in normal tissues and can therefore be
considered as immunologically tumor-specific. Well-known examples
for CT antigens are the MAGE family members or NY-ESO-1.
[0088] b) Differentiation antigens: These TAAs are shared between
tumors and the normal tissue from which the tumor arose; most are
found in melanomas and normal melanocytes. Many of these melanocyte
lineage-related proteins are involved in the biosynthesis of
melanin and are therefore not tumor specific but nevertheless are
widely used for cancer immunotherapy. Examples include, but are not
limited to, tyrosinase and Melan-A/MART-1 for melanoma or PSA for
prostate cancer.
[0089] c) Overexpressed TAAs: Genes encoding widely expressed TAAs
have been detected in histologically different types of tumors as
well as in many normal tissues, generally with lower expression
levels. It is possible that many of the epitopes processed and
potentially presented by normal tissues are below the threshold
level for T-cell recognition, while their overexpression in tumor
cells can trigger an anticancer response by breaking previously
established tolerance. Prominent examples for this class of TAAs
are Her-2/neu, Survivin, Telomerase or WT1.
[0090] d) Tumor specific antigens: These unique TAAs arise from
mutations of normal genes (such as .beta.-catenin, CDK4, etc.).
Some of these molecular changes are associated with neoplastic
transformation and/or progression. Tumor specific antigens are
generally able to induce strong immune responses without bearing
the risk for autoimmune reactions against normal tissues. On the
other hand, these TAAs are in most cases only relevant to the exact
tumor on which they were identified and are usually not shared
between many individual tumors.
[0091] e) TAAs arising from abnormal post-translational
modifications: Such TAAs may arise from proteins which are neither
specific nor overexpressed in tumors but nevertheless become tumor
associated by posttranslational processes primarily active in
tumors. Examples for this class arise from altered glycosylation
patterns leading to novel epitopes in tumors as for MUC1 or events
like protein splicing during degradation which may or may not be
tumor specific.
[0092] f) Oncoviral proteins: These TAAs are viral proteins that
may play a critical role in the oncogenic process and, because they
are foreign (not of human origin), they can evoke a T-cell
response. Examples of such proteins are the human papilloma type 16
virus proteins, E6 and E7, which are expressed in cervical
carcinoma.
[0093] For proteins to be recognized by cytotoxic T-lymphocytes as
tumor-specific or -associated antigens, and to be used in a
therapy, particular prerequisites must be fulfilled. The antigen
should be expressed mainly by tumor cells and not or in comparably
small amounts by normal healthy tissues or in another preferred
embodiment the peptide should be over-presented by tumor cells as
compared to normal healthy tissues. It is furthermore desirable,
that the respective antigen is not only present in a type of tumor,
but also in high concentrations (i.e. copy numbers of the
respective peptide per cell). Tumor-specific and tumor-associated
antigens are often derived from proteins directly involved in
transformation of a normal cell to a tumor cell due to a function
e.g. in cell cycle control or suppression of apoptosis.
Additionally, downstream targets of the proteins directly causative
for a transformation may be upregulated and thus may be indirectly
tumor-associated. Such indirect tumor-associated antigens may also
be targets of a vaccination approach (Singh-Jasuja et al., 2004).
In both cases it is essential that epitopes are present in the
amino acid sequence of the antigen, since such a peptide
("immunogenic peptide") that is derived from a tumor associated
antigen should lead to an in vitro or in vivo T-cell-response.
[0094] Basically, any peptide able to bind a MHC molecule may
function as a T-cell epitope. A prerequisite for the induction of
an in vitro or in vivo T-cell-response is the presence of a T cell
with a corresponding TCR and the absence of immunological tolerance
for this particular epitope.
[0095] Therefore, TAAs are a starting point for the development of
a tumor vaccine. The methods for identifying and characterizing the
TAAs are based on the use of CTL that can be isolated from patients
or healthy subjects, or they are based on the generation of
differential transcription profiles or differential peptide
expression patterns between tumors and normal tissues.
[0096] However, the identification of genes over-expressed in tumor
tissues or human tumor cell lines, or selectively expressed in such
tissues or cell lines, does not provide precise information as to
the use of the antigens being transcribed from these genes in an
immune therapy. This is because only an individual subpopulation of
epitopes of these antigens are suitable for such an application
since a T cell with a corresponding TCR has to be present and
immunological tolerance for this particular epitope needs to be
absent or minimal. In a very preferred embodiment of the invention
it is therefore important to select only those over- or selectively
presented peptides against which a functional and/or a
proliferating T cell can be found. Such a functional T cell is
defined as a T cell, which upon stimulation with a specific antigen
can be clonally expanded and is able to execute effector functions
("effector T cell").
[0097] In case of TCRs and antibodies according to the invention
the immunogenicity of the underlying peptides is secondary. For
TCRs and antibodies according to the invention the presentation is
the determining factor.
[0098] T-helper cells play an important role in orchestrating the
effector function of CTLs in anti-tumor immunity. T-helper cell
epitopes that trigger a T-helper cell response of the T.sub.H1 type
support effector functions of CD8-positive killer T cells, which
include cytotoxic functions directed against tumor cells displaying
tumor-associated peptide/MHC complexes on their cell surfaces. In
this way tumor-associated T-helper cell peptide epitopes, alone or
in combination with other tumor-associated peptides, can serve as
active pharmaceutical ingredients of vaccine compositions that
stimulate anti-tumor immune responses.
[0099] The inventors identified a novel category of
ligandome-derived tumor-associated antigens (LiTAAs), which were
frequently and exclusively detected in CLL patients. Specific
immune recognition of the corresponding HLA ligands (LiTAPs) was
observed exclusively in CLL patients, remarkably showing a direct
correlation with the frequency of HLA restricted presentation.
Furthermore, retrospective survival analysis of 33 CLL patients
indicated a potential association of LiTAP-specific immune
responses with improved overall survival in CLL patients.
[0100] Uses against further cancers are disclosed in the following
description of the proteins of the peptides according to the
invention.
[0101] As used herein and except as noted otherwise all terms are
defined as given below.
[0102] The term "peptide" is used herein to designate a series of
amino acid residues, connected one to the other typically by
peptide bonds between the alpha-amino and carbonyl groups of the
adjacent amino acids. The peptides are preferably 9 amino acids in
length, but can be as short as 8 amino acids in length, and as long
as 10, 11, 12, 13 or 14 and in case of MHC class II peptides they
can be as long as 15, 16, 17, 18, 19 or 20 amino acids in
length.
[0103] Furthermore, the term "peptide" shall include salts of a
series of amino acid residues, connected one to the other typically
by peptide bonds between the alpha-amino and carbonyl groups of the
adjacent amino acids. Preferably, the salts are pharmaceutical
acceptable salts of the peptides, such as, for example, the
chloride or acetate (trifluoroacetate) salts.
[0104] The term "peptide" shall include "oligopeptide". The term
"oligopeptide" is used herein to designate a series of amino acid
residues, connected one to the other typically by peptide bonds
between the alpha-amino and carbonyl groups of the adjacent amino
acids. The length of the oligopeptide is not critical to the
invention, as long as the correct epitope or epitopes are
maintained therein. The oligopeptides are typically less than about
30 amino acid residues in length, and greater than about 15 amino
acids in length.
[0105] The term "the peptides of the present invention" shall
include the peptides consisting of or comprising a peptide as
defined above according to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID
NO: 527 to SEQ ID NO: 551 or SEQ ID NO: 552 to SEQ ID NO: 1016.
[0106] The term "polypeptide" designates a series of amino acid
residues, connected one to the other typically by peptide bonds
between the alpha-amino and carbonyl groups of the adjacent amino
acids. The length of the polypeptide is not critical to the
invention as long as the correct epitopes are maintained. In
contrast to the terms peptide or oligopeptide, the term polypeptide
is meant to refer to molecules containing more than about 30 amino
acid residues.
[0107] A peptide, oligopeptide, protein or polynucleotide coding
for such a molecule is "immunogenic" (and thus is an "immunogen"
within the present invention), if it is capable of inducing an
immune response. In the case of the present invention,
immunogenicity is more specifically defined as the ability to
induce a T-cell response. Thus, an "immunogen" would be a molecule
that is capable of inducing an immune response, and in the case of
the present invention, a molecule capable of inducing a T-cell
response. In another aspect, the immunogen can be the peptide, the
complex of the peptide with MHC, oligopeptide, and/or protein that
is used to raise specific antibodies or TCRs against it.
[0108] A class I T cell "epitope" requires a short peptide that is
bound to a class I MHC receptor, forming a ternary complex (MHC
class I alpha chain, beta-2-microglobulin, and peptide) that can be
recognized by a T cell bearing a matching T-cell receptor binding
to the MHC/peptide complex with appropriate affinity. Peptides
binding to MHC class I molecules are typically 8-14 amino acids in
length, and most typically 9 amino acids in length.
[0109] In humans there are three different genetic loci that encode
MHC class I molecules (the MHC-molecules of the human are also
designated human leukocyte antigens (HLA)): HLA-A, HLA-B, and
HLA-C. HLA-A*01, HLA-A*02, and HLA-B*07 are examples of different
MHC class I alleles that can be expressed from these loci.
TABLE-US-00009 TABLE 7 Expression frequencies F of HLA*A02 and the
most frequent HLA-DR serotypes. Frequencies are deduced from
haplotype frequencies G.sub.f within the American population
adapted from Mori et al. (Mori M, et al. HLA gene and haplotype
frequencies in the North American population: the National Marrow
Donor Program Donor Registry. Transplantation. 1997 Oct. 15; 64(7):
1017-27) employing the Hardy-Weinberg formula F =
1-(1-G.sub.f).sup.2. Combinations of A*02 with certain HLA-DR
alleles might be enriched or less frequent than expected from their
single frequencies due to linkage disequilibrium. For details refer
to Chanock et al. (S.J. Chanock, et al (2004) HLA-A, -B, -Cw, -DQA1
and DRB1 in an African American population from Bethesda, USA Human
Immunology, 65: 1223-1235). Expression frequencies of HLA*02 and
HLA-DR serotypes within North American subpopulations Caucasian
African Asian Latin HLA Allele American American American American
A*02 49.1% 34.1% 43.2% 48.3% DR1 19.4% 13.2% 6.8% 15.3% DR2 28.2%
29.8% 33.8% 21.2% DR3 20.6% 24.8% 9.2% 15.2% DR4 30.7% 11.1% 28.6%
36.8% DR5 23.3% 31.1% 30.0% 20.0% DR6 26.7% 33.7% 25.1% 31.1% DR7
24.8% 19.2% 13.4% 20.2% DR8 5.7% 12.1% 12.7% 18.6% DR9 2.1% 5.8%
18.6% 2.1%
[0110] Therefore, for therapeutic and diagnostic purposes a peptide
that binds with appropriate affinity to several different HLA class
II receptors is highly desirable. A peptide binding to several
different HLA class II molecules is called a promiscuous
binder.
[0111] As used herein, reference to a DNA sequence includes both
single stranded and double stranded DNA. Thus, the specific
sequence, unless the context indicates otherwise, refers to the
single strand DNA of such sequence, the duplex of such sequence
with its complement (double stranded DNA) and the complement of
such sequence. The term "coding region" refers to that portion of a
gene which either naturally or normally codes for the expression
product of that gene in its natural genomic environment, i.e., the
region coding in vivo for the native expression product of the
gene.
[0112] The coding region can be from a non-mutated ("normal"),
mutated or altered gene, or can even be from a DNA sequence, or
gene, wholly synthesized in the laboratory using methods well known
to those of skill in the art of DNA synthesis.
[0113] The term "nucleotide sequence" refers to a heteropolymer of
deoxyribonucleotides.
[0114] The nucleotide sequence coding for a particular peptide,
oligopeptide, or polypeptide may be naturally occurring or they may
be synthetically constructed. Generally, DNA segments encoding the
peptides, polypeptides, and proteins of this invention are
assembled from cDNA fragments and short oligonucleotide linkers, or
from a series of oligonucleotides, to provide a synthetic gene that
is capable of being expressed in a recombinant transcriptional unit
comprising regulatory elements derived from a microbial or viral
operon.
[0115] As used herein the term "a nucleotide coding (or encoding)
for a peptide" refers to a nucleotide sequence coding for the
peptide including artificial (man-made) start and stop codons
compatible for the biological system the sequence is going to be
expressed by.
[0116] The term "expression product" means the polypeptide or
protein that is the natural translation product of the gene and any
nucleic acid sequence coding equivalents resulting from genetic
code degeneracy and thus coding for the same amino acid(s).
[0117] The term "fragment", when referring to a coding sequence,
means a portion of DNA comprising less than the complete coding
region, whose expression product retains essentially the same
biological function or activity as the expression product of the
complete coding region.
[0118] The term "DNA segment" refers to a DNA polymer, in the form
of a separate fragment or as a component of a larger DNA construct,
which has been derived from DNA isolated at least once in
substantially pure form, i.e., free of contaminating endogenous
materials and in a quantity or concentration enabling
identification, manipulation, and recovery of the segment and its
component nucleotide sequences by standard biochemical methods, for
example, by using a cloning vector. Such segments are provided in
the form of an open reading frame uninterrupted by internal
non-translated sequences, or introns, which are typically present
in eukaryotic genes. Sequences of non-translated DNA may be present
downstream from the open reading frame, where the same do not
interfere with manipulation or expression of the coding
regions.
[0119] The term "primer" means a short nucleic acid sequence that
can be paired with one strand of DNA and provides a free 3'-OH end
at which a DNA polymerase starts synthesis of a deoxyribonucleotide
chain.
[0120] The term "promoter" means a region of DNA involved in
binding of RNA polymerase to initiate transcription.
[0121] The term "isolated" means that the material is removed from
its original environment (e.g., the natural environment if it is
naturally occurring). For example, a naturally-occurring
polynucleotide or polypeptide present in a living animal is not
isolated, but the same polynucleotide or polypeptide, separated
from some or all of the coexisting materials in the natural system,
is isolated. Such polynucleotides could be part of a vector and/or
such polynucleotides or polypeptides could be part of a
composition, and still be isolated in that such vector or
composition is not part of its natural environment.
[0122] The polynucleotides, and recombinant or immunogenic
polypeptides, disclosed in accordance with the present invention
may also be in "purified" form. The term "purified" does not
require absolute purity; rather, it is intended as a relative
definition, and can include preparations that are highly purified
or preparations that are only partially purified, as those terms
are understood by those of skill in the relevant art. For example,
individual clones isolated from a cDNA library have been
conventionally purified to electrophoretic homogeneity.
Purification of starting material or natural material to at least
one order of magnitude, preferably two or three orders, and more
preferably four or five orders of magnitude is expressly
contemplated. Furthermore, a claimed polypeptide which has a purity
of preferably 99.999%, or at least 99.99% or 99.9%; and even
desirably 99% by weight or greater is expressly contemplated.
[0123] The nucleic acids and polypeptide expression products
disclosed according to the present invention, as well as expression
vectors containing such nucleic acids and/or such polypeptides, may
be in "enriched form". As used herein, the term "enriched" means
that the concentration of the material is at least about 2, 5, 10,
100, or 1000 times its natural concentration (for example),
advantageously 0.01%, by weight, preferably at least about 0.1% by
weight. Enriched preparations of about 0.5%, 1%, 5%, 10%, and 20%
by weight are also contemplated. The sequences, constructs,
vectors, clones, and other materials comprising the present
invention can advantageously be in enriched or isolated form.
[0124] The term "active fragment" means a fragment that generates
an immune response (i.e., has immunogenic activity) when
administered, alone or optionally with a suitable adjuvant, to an
animal, such as a mammal, for example, a rabbit or a mouse, and
also including a human, such immune response taking the form of
stimulating a T-cell response within the recipient animal, such as
a human. Alternatively, the "active fragment" may also be used to
induce a T-cell response in vitro.
[0125] As used herein, the terms "portion", "segment" and
"fragment," when used in relation to polypeptides, refer to a
continuous sequence of residues, such as amino acid residues, which
sequence forms a subset of a larger sequence. For example, if a
polypeptide were subjected to treatment with any of the common
endopeptidases, such as trypsin or chymotrypsin, the oligopeptides
resulting from such treatment would represent portions, segments or
fragments of the starting polypeptide. When used in relation to
polynucleotides, these terms refer to the products produced by
treatment of said polynucleotides with any of the
endonucleases.
[0126] In accordance with the present invention, the term "percent
identity" or "percent identical", when referring to a sequence,
means that a sequence is compared to a claimed or described
sequence after alignment of the sequence to be compared (the
"Compared Sequence") with the described or claimed sequence (the
"Reference Sequence"). The Percent Identity is then determined
according to the following formula:
Percent Identity=100 [1-(C/R)]
wherein C is the number of differences between the Reference
Sequence and the Compared Sequence over the length of alignment
between the Reference Sequence and the Compared Sequence,
wherein
[0127] (i) each base or amino acid in the Reference Sequence that
does not have a corresponding aligned base or amino acid in the
Compared Sequence and
[0128] (ii) each gap in the Reference Sequence and
[0129] (iii) each aligned base or amino acid in the Reference
Sequence that is different from an aligned base or amino acid in
the Compared Sequence, constitutes a difference and
[0130] (iiii) the alignment has to start at position 1 of the
aligned sequences;
and R is the number of bases or amino acids in the Reference
Sequence over the length of the alignment with the Compared
Sequence with any gap created in the Reference Sequence also being
counted as a base or amino acid.
[0131] If an alignment exists between the Compared Sequence and the
Reference Sequence for which the Percent Identity as calculated
above is about equal to or greater than a specified minimum Percent
Identity then the Compared Sequence has the specified minimum
Percent Identity to the Reference Sequence even though alignments
may exist in which the herein above calculated Percent Identity is
less than the specified Percent Identity.
[0132] The original (unmodified) peptides as disclosed herein can
be modified by the substitution of one or more residues at
different, possibly selective, sites within the peptide chain, if
not otherwise stated. Preferably those substitutions are located at
the end of the amino acid chain. Such substitutions may be of a
conservative nature, for example, where one amino acid is replaced
by an amino acid of similar structure and characteristics, such as
where a hydrophobic amino acid is replaced by another hydrophobic
amino acid. Even more conservative would be replacement of amino
acids of the same or similar size and chemical nature, such as
where leucine is replaced by isoleucine. In studies of sequence
variations in families of naturally occurring homologous proteins,
certain amino acid substitutions are more often tolerated than
others, and these are often show correlation with similarities in
size, charge, polarity, and hydrophobicity between the original
amino acid and its replacement, and such is the basis for defining
"conservative substitutions."
[0133] Conservative substitutions are herein defined as exchanges
within one of the following five groups: Group 1-small aliphatic,
nonpolar or slightly polar residues (Ala, Ser, Thr, Pro, Gly);
Group 2-polar, negatively charged residues and their amides (Asp,
Asn, Glu, Gln); Group 3-polar, positively charged residues (His,
Arg, Lys); Group 4-large, aliphatic, nonpolar residues (Met, Leu,
Ile, Val, Cys); and Group 5-large, aromatic residues (Phe, Tyr,
Trp).
[0134] Less conservative substitutions might involve the
replacement of one amino acid by another that has similar
characteristics but is somewhat different in size, such as
replacement of an alanine by an isoleucine residue. Highly
non-conservative replacements might involve substituting an acidic
amino acid for one that is polar, or even for one that is basic in
character. Such "radical" substitutions cannot, however, be
dismissed as potentially ineffective since chemical effects are not
totally predictable and radical substitutions might well give rise
to serendipitous effects not otherwise predictable from simple
chemical principles.
[0135] Of course, such substitutions may involve structures other
than the common L-amino acids. Thus, D-amino acids might be
substituted for the L-amino acids commonly found in the antigenic
peptides of the invention and yet still be encompassed by the
disclosure herein. In addition, amino acids possessing non-standard
R groups (i.e., R groups other than those found in the common 20
amino acids of natural proteins) may also be used for substitution
purposes to produce immunogens and immunogenic polypeptides
according to the present invention.
[0136] If substitutions at more than one position are found to
result in a peptide with substantially equivalent or greater
antigenic activity as defined below, then combinations of those
substitutions will be tested to determine if the combined
substitutions result in additive or synergistic effects on the
antigenicity of the peptide. At most, no more than 4 positions
within the peptide would simultaneously be substituted.
[0137] The peptides of the invention can be elongated by up to four
amino acids, that is 1, 2, 3 or 4 amino acids can be added to
either end in any combination between 4:0 and 0:4.
[0138] Combinations of the elongations according to the invention
can be depicted from table 8:
TABLE-US-00010 C-terminus N-terminus 4 0 3 0 or 1 2 0 or 1 or 2 1 0
or 1 or 2 or 3 0 0 or 1 or 2 or 3 or 4 N-terminus C-terminus 4 0 3
0 or 1 2 0 or 1 or 2 1 0 or 1 or 2 or 3 0 0 or 1 or 2 or 3 or 4
[0139] The amino acids for the elongation can be the peptides of
the original sequence of the protein or any other amino acid. The
elongation can be used to enhance the stability or solubility of
the peptides.
[0140] The term "T-cell response" means the specific proliferation
and activation of effector functions induced by a peptide in vitro
or in vivo. For MHC class I restricted CTLs, effector functions may
be lysis of peptide-pulsed, peptide-precursor pulsed or naturally
peptide-presenting target cells, secretion of cytokines, preferably
Interferon-gamma, TNF-alpha, or IL-2 induced by peptide, secretion
of effector molecules, preferably granzymes or perforins induced by
peptide, or degranulation.
[0141] Preferably, when the CTLs specific for a peptide according
to the present invention are tested against the substituted
peptides, the peptide concentration at which the substituted
peptides achieve half the maximal increase in lysis relative to
background is no more than about 1 mM, preferably no more than
about 1 .mu.M, more preferably no more than about 1 nM, and still
more preferably no more than about 100 pM, and most preferably no
more than about 10 pM. It is also preferred that the substituted
peptide be recognized by CTLs from more than one individual, at
least two, and more preferably three individuals.
[0142] Thus, the epitopes of the present invention may be identical
to naturally occurring tumor-associated or tumor-specific epitopes
or may include epitopes that differ by no more than 4 residues from
the reference peptide, as long as they have substantially identical
antigenic activity.
[0143] Stimulation of an immune response is dependent upon the
presence of antigens recognized as foreign by the host immune
system. The discovery of the existence of tumor associated antigens
has now raised the possibility of using a host's immune system to
intervene in tumor growth. Various mechanisms of harnessing both
the humoral and cellular arms of the immune system are currently
explored for cancer immunotherapy.
[0144] Specific elements of the cellular immune response are
capable of specifically recognizing and destroying tumor cells. The
isolation of cytotoxic T-cells (CTL) from tumor-infiltrating cell
populations or from peripheral blood suggests that such cells play
an important role in natural immune defences against cancer.
CD8-positive T-cells in particular, which recognize class I
molecules of the major histocompatibility complex (MHC)-bearing
peptides of usually 8 to 12 residues derived from proteins or
defect ribosomal products (DRIPS) located in the cytosols, play an
important role in this response. The MHC-molecules of the human are
also designated as human leukocyte-antigens (HLA).
[0145] MHC class I molecules can be found on most cells having a
nucleus which present peptides that result from proteolytic
cleavage of mainly endogenous, cytosolic or nuclear proteins,
DRIPS, and larger peptides. However, peptides derived from
endosomal compartments or exogenous sources are also frequently
found on MHC class I molecules. This non-classical way of class I
presentation is referred to as cross-presentation in
literature.
[0146] Since both types of response, CD8 and CD4 dependent,
contribute jointly and synergistically to the anti-tumor effect,
the identification and characterization of tumor-associated
antigens recognized by either CD8-positive CTLs (MHC class I
molecule) or by CD4-positive CTLs (MHC class II molecule) is
important in the development of tumor vaccines. It is therefore an
object of the present invention, to provide compositions of
peptides that contain peptides binding to MHC complexes of either
class.
[0147] Considering the severe side-effects and expense associated
with treating cancer better prognosis and diagnostic methods are
desperately needed. Therefore, there is a need to identify other
factors representing biomarkers for cancer in general and CLL in
particular. Furthermore, there is a need to identify factors that
can be used in the treatment of cancer in general and CLL in
particular.
[0148] The present invention provides peptides that are useful in
treating cancers/tumors, preferably CLL that over- or exclusively
present the peptides of the invention. These peptides were shown by
mass spectrometry to be naturally presented by HLA molecules on
primary human CLL samples.
[0149] The source gene/protein (also designated "full-length
protein" or "underlying protein") from which the peptides are
derived were shown to be highly overexpressed in diseased (e.g.
cancerous) compared with normal tissues. "Normal tissues" in
relation to this invention shall particularly mean a blood sample
from a healthy donor and sub-populations of blood cells,especially
white blood cells, (see example 2, and FIGS. 2a-2f) demonstrating a
high degree of tumor association of the source genes. Moreover, the
peptides themselves are strongly over-presented on tumor
tissue--"tumor tissue" in relation to this invention shall mean a
blood sample from a patient suffering from CLL and sub-populations
of blood cells,especially white blood cells, but not on normal
tissues (see example 3 and FIGS. 3a-3e).
[0150] HLA-bound peptides can be recognized by the immune system,
specifically T lymphocytes/T cells. T cells can destroy the cells
presenting the recognized HLA/peptide complex, e.g. cells
presenting the peptides of the present invention that are derived
from their underlying proteins.
[0151] The peptides of the present invention have been shown to be
capable of stimulating T cell responses and/or are over-presented
and thus can be used for the production of antibodies and/or TCRs,
in particular sTCRs, according to the present invention (see
example 4 and FIG. 4a-4g). Furthermore, the peptides when complexed
with the respective MHC can be used for the production of
antibodies and/or TCRs, in particular sTCRs, according to the
present invention, as well. Respective methods are well known to
the person of skill, and can be found in the respective literature
as well. Thus, the peptides of the present invention are useful for
generating an immune response in a patient by which tumor cells can
be destroyed. An immune response in a patient can be induced by
direct administration of the described peptides or suitable
precursor substances (e.g. elongated peptides, proteins, or nucleic
acids encoding these peptides) to the patient, ideally in
combination with an agent enhancing the immunogenicity (i.e. an
adjuvant). The immune response originating from such a therapeutic
vaccination can be expected to be highly specific against tumor
cells because the target peptides of the present invention are not
presented on normal tissues in comparable copy numbers, preventing
the risk of undesired autoimmune reactions against normal cells in
the patient.
[0152] A "pharmaceutical composition" is a composition suitable for
administration to a human being in a medical setting. Preferably,
said pharmaceutical composition is sterile and produced according
to the GMP guidelines.
[0153] The pharmaceutical compositions comprise the peptides either
in the free form or in the form of a pharmaceutically acceptable
salt (see also above). As used herein, "a pharmaceutically
acceptable salt" refers to a derivative of the disclosed peptides
wherein the peptide is modified by making acid or base salts of the
agent. For example, acid salts are prepared from the free base
(typically wherein the neutral form of the drug has a neutral
--NH.sub.2 group) involving reaction with a suitable acid. Suitable
acids for preparing acid salts include both organic acids, e.g.,
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, methane sulfonic acid, ethane sulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like, as well as
inorganic acids, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid phosphoric acid and the like.
Conversely, preparation of basic salts of acid moieties which may
be present on a peptide are prepared using a pharmaceutically
acceptable base such as sodium hydroxide, potassium hydroxide,
ammonium hydroxide, calcium hydroxide, trimethylamine or the
like.
[0154] In an especially preferred embodiment, the pharmaceutical
compositions comprise the peptides as salts of acetic acid
(acetates), trifluoro acetates or hydrochloric acid
(chlorides).
[0155] In addition to being useful for treating cancer, the
peptides of the present invention are also useful as diagnostics.
Since the peptides were generated from CLL (leukimea) cells and
since it was determined that these peptides are not or at lower
levels present in normal tissues (such as white blood cells), these
peptides can be used to diagnose the presence of a cancer.
[0156] The presence of claimed peptides in blood samples can assist
a pathologist in diagnosis of cancer. Detection of certain peptides
by means of antibodies, mass spectrometry or other methods known in
the art can tell the pathologist that the sample is malignant or
generally diseased, or can be usesd as a biomarker for CLL.
Presence of groups of peptides can enable classification or
sub-classification of diseased tissues.
[0157] The detection of peptides on diseased tissue specimen can
enable the decision about the benefit of therapies involving the
immune system, especially if T-lymphocytes are known or expected to
be involved in the mechanism of action. Loss of MHC expression is a
well described mechanism by which infected of malignant cells
escape immuno-surveillance. Thus, presence of peptides shows that
this mechanism is not exploited by the analyzed cells.
[0158] The peptides of the present invention might be used to
analyze lymphocyte responses against those peptides such as T cell
responses or antibody responses against the peptide or the peptide
complexed to MHC molecules. These lymphocyte responses can be used
as prognostic markers for decision on further therapy steps. These
responses can also be used as surrogate markers in immunotherapy
approaches aiming to induce lymphocyte responses by different
means, e.g. vaccination of protein, nucleic acids, autologous
materials, adoptive transfer of lymphocytes. In gene therapy
settings, lymphocyte responses against peptides can be considered
in the assessment of side effects. Monitoring of lymphocyte
responses might also be a valuable tool for follow-up examinations
of transplantation therapies, e.g. for the detection of graft
versus host and host versus graft diseases.
[0159] The peptides of the present invention can be used to
generate and develop specific antibodies against MHC/peptide
complexes. These can be used for therapy, targeting toxins or
radioactive substances to the diseased tissue. Another use of these
antibodies can be targeting radionuclides to the diseased tissue
for imaging purposes such as PET. This use can help to detect small
metastases or to determine the size and precise localization of
diseased tissues.
[0160] Therefore, it is a further aspect of the invention to
provide a method for producing a recombinant antibody specifically
binding to a human major histocompatibility complex (MHC) class I
or II being complexed with a HLA-restricted antigen, the method
comprising: immunizing a genetically engineered non-human mammal
comprising cells expressing said human major histocompatibility
complex (MHC) class I or II with a soluble form of a MHC class I or
II molecule being complexed with said HLA-restricted antigen;
isolating mRNA molecules from antibody producing cells of said
non-human mammal; producing a phage display library displaying
protein molecules encoded by said mRNA molecules; and isolating at
least one phage from said phage display library, said at least one
phage displaying said antibody specifically binding to said human
major histocompatibility complex (MHC) class I or II being
complexed with said HLA-restricted antigen.
[0161] It is a further aspect of the invention to provide an
antibody that specifically binds to a human major
histocompatibility complex (MHC) class I or II being complexed with
a HLA-restricted antigen, wherein the antibody preferably is a
polyclonal antibody, monoclonal antibody, bi-specific antibody
and/or a chimeric antibody.
[0162] Yet another aspect of the present invention then relates to
a method of producing said antibody specifically binding to a human
major histocompatibility complex (MHC) class I or II being
complexed with a HLA-restricted antigen, the method comprising:
immunizing a genetically engineered non-human mammal comprising
cells expressing said human major histocompatibility complex (MHC)
class I or II with a soluble form of a MHC class I or II molecule
being complexed with said HLA-restricted antigen; isolating mRNA
molecules from antibody producing cells of said non-human mammal;
producing a phage display library displaying protein molecules
encoded by said mRNA molecules; and isolating at least one phage
from said phage display library, said at least one phage displaying
said antibody specifically bindable to said human major
histocompatibility complex (MHC) class I or II being complexed with
said HLA-restricted antigen. Respective methods for producing such
antibodies and single chain class I major histocompatibility
complexes, as well as other tools for the production of these
antibodies are disclosed in WO 03/068201, WO 2004/084798, WO
01/72768, WO 03/070752, and Cohen C J, et al. Recombinant
antibodies with MHC-restricted, peptide-specific, T-cell
receptor-like specificity: new tools to study antigen presentation
and TCR-peptide-MHC interactions. J Mol Recognit. 2003 Sep-October;
16(5):324-32.; Denkberg G, et al. Selective targeting of melanoma
and APCs using a recombinant antibody with TCR-like specificity
directed toward a melanoma differentiation antigen. J Immunol. 2003
Sep .1; 171(5):2197-207; and Cohen C J, et al. Direct phenotypic
analysis of human MHC class I antigen presentation: visualization,
quantitation, and in situ detection of human viral epitopes using
peptide-specific, MHC-restricted human recombinant antibodies. J
Immunol. 2003 Apr. 15; 170(8):4349-61, which for the purposes of
the present invention are all explicitly incorporated by reference
in their entireties.
[0163] Preferably, the antibody is binding with a binding affinity
of below 20 nanomolar, preferably of below 10 nanomolar, to the
complex, which is regarded as "specific" in the context of the
present invention.
[0164] It is a further aspect of the invention to provide a method
for producing a soluble T-cell receptor recognizing a specific
peptide-MHC complex. Such soluble T-cell receptors can be generated
from specific T-cell clones, and their affinity can be increased by
mutagenesis targeting the complementarity-determining regions. For
the purpose of T-cell receptor selection, phage display can be used
(US 2010/0113300, Liddy N, et al. Monoclonal TCR-redirected tumor
cell killing. Nat Med 2012 June;18(6):980-987). For the purpose of
stabilization of T-cell receptors during phage display and in case
of practical use as drug, alpha and beta chain can be linked e.g.
by non-native disulfide bonds, other covalent bonds (single-chain
T-cell receptor), or by dimerization domains (see Boulter J M, et
al. Stable, soluble T-cell receptor molecules for crystallization
and therapeutics. Protein Eng 2003 September; 16(9):707-711.; Card
K F, et al. A soluble single-chain T-cell receptor IL-2 fusion
protein retains MHC-restricted peptide specificity and IL-2
bioactivity. Cancer Immunol Immunother 2004 April; 53(4):345-357;
and Willcox BE, et al. Production of soluble alphabeta T-cell
receptor heterodimers suitable for biophysical analysis of ligand
binding. Protein Sci 1999 November; 8 (11):2418-2423). The T-cell
receptor can be linked to toxins, drugs, cytokines (see US
2013/0115191), domains recruiting effector cells such as an
anti-CD3 domain, etc., in order to execute particular functions on
target cells. Moreover, it could be expressed in T cells used for
adoptive transfer.
[0165] Further information can be found in WO 2004/033685A1 and WO
2004/074322A1. A combination of sTCRs is described in WO
2012/056407A1. Further methods for the production are disclosed in
WO 2013/057586A1.
[0166] In addition, they can be used to verify a pathologist's
diagnosis of a cancer based on a biopsied sample.
[0167] In order to select over-presented peptides, a presentation
profile is calculated showing the median sample presentation as
well as replicate variation. The profile juxtaposes samples of the
tumor entity of interest to a baseline of normal tissue samples.
Each of these profiles can then be consolidated into an
over-presentation score by calculating the p-value of a Linear
Mixed-Effects Model (J. Pinheiro, et al. The nlme Package: Linear
and Nonlinear Mixed Effects Models. 2007) adjusting for multiple
testing by False Discovery Rate (Y. Benjamini and Y. Hochberg.
Controlling the False Discovery Rate: A Practical and Powerful
Approach to Multiple Testing. Journal of the Royal Statistical
Society. Series B (Methodological), Vol.57 (No.1):289-300,
1995).
[0168] For the identification and relative quantitation of HLA
ligands by mass spectrometry, HLA molecules from shock-frozen
tissue samples were purified and HLA-associated peptides were
isolated. The isolated peptides were separated and sequences were
identified by online nano-electrospray-ionization (nanoESl) liquid
chromatography-mass spectrometry (LC-MS) experiments. The resulting
peptide sequences were verified by comparison of the fragmentation
pattern of natural TUMAPs recorded from CLL samples with the
fragmentation patterns of corresponding synthetic reference
peptides of identical sequences. Since the peptides were directly
identified as ligands of HLA molecules of primary tumors, these
results provide direct evidence for the natural processing and
presentation of the identified peptides on primary cancer tissue
obtained from CLL patients.
[0169] The discovery pipeline XPRESIDENT.RTM. v2.1 (see, for
example, US 2013-0096016, which is hereby incorporated by reference
in its entirety) allows the identification and selection of
relevant over-presented peptide vaccine candidates based on direct
relative quantitation of HLA-restricted peptide levels on cancer
tissues in comparison to several different non-cancerous tissues
and organs. This was achieved by the development of label-free
differential quantitation using the acquired LC-MS data processed
by a proprietary data analysis pipeline, combining algorithms for
sequence identification, spectral clustering, ion counting,
retention time alignment, charge state deconvolution and
normalization.
[0170] Presentation levels including error estimates for each
peptide and sample were established. Peptides exclusively presented
on tumor tissue and peptides over-presented in tumor versus
non-cancerous tissues and organs have been identified.
[0171] HLA-peptide complexes from CLL tissue samples were purified
and HLA-associated peptides were isolated and analysed by LC-MS
(see examples). All TUMAPs contained in the present application
were identified with this approach on primary CLL samples
confirming their presentation on primary CLL.
[0172] All TUMAPs contained in the application at hand were
identified with this approach on primary CLL samples confirming
their presentation on primary CLL.
[0173] TUMAPs identified on multiple CLL tumor and normal tissues
were quantified using ion-counting of label-free LC-MS data. The
method assumes that LC-MS signal areas of a peptide correlate with
its abundance in the sample. All quantitative signals of a peptide
in various LC-MS experiments were normalized based on central
tendency, averaged per sample and merged into a bar plot, called
presentation profile. The presentation profile consolidates
different analysis methods like protein database search, spectral
clustering, charge state deconvolution (decharging) and retention
time alignment and normalization.
[0174] The present invention therefore relates to a peptide
comprising a sequence that is selected from the group consisting of
SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 527 to SEQ ID NO: 551 or
SEQ ID NO: 552 to SEQ ID NO: 1016 or a variant thereof which is at
least 90% homologous (preferably identical) to SEQ ID NO: 1 to SEQ
ID NO: 225, SEQ ID NO: 527 to SEQ ID NO: 551 or SEQ ID NO: 552 to
SEQ ID NO: 1016 or a variant thereof that induces T cells
cross-reacting with said peptide, wherein said peptide is not the
underlying full-length polypeptide.
[0175] The present invention further relates to a peptide
comprising a sequence that is selected from the group consisting of
SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 527 to SEQ ID NO: 551 or
SEQ ID NO: 552 to SEQ ID NO: 1024 or a variant thereof which is at
least 90% homologous (preferably identical) to SEQ ID NO: 1 to SEQ
ID NO: 225, SEQ ID NO: 527 to SEQ ID NO: 551 or SEQ ID NO: 552 to
SEQ ID NO: 1016, wherein said peptide or variant has an overall
length of between 8 and 100, preferably between 8 and 30, and most
preferred between 8 and 14 amino acids.
[0176] The present invention further relates to the peptides
according to the invention that have the ability to bind to a
molecule of the human major histocompatibility complex (MHC)
class-I or -II.
[0177] The present invention further relates to the peptides
according to the invention wherein the peptide consists or consists
essentially of an amino acid sequence according to SEQ ID NO: 1 to
SEQ ID NO: 225, SEQ ID NO: 527 to SEQ ID NO: 551 or SEQ ID NO: 552
to SEQ ID NO: 1016.
[0178] The present invention further relates to the peptides
according to the invention, wherein the peptide is (chemically)
modified and/or includes non-peptide bonds.
[0179] The present invention further relates to the peptides
according to the invention, wherein the peptide is part of a fusion
protein, in particular comprising N-terminal amino acids of the
HLA-DR antigen-associated invariant chain (Ii), or wherein the
peptide is fused to (or into) an antibody, such as, for example, an
antibody that is specific for dendritic cells.
[0180] The present invention further relates to a nucleic acid,
encoding the peptides according to the invention, provided that the
peptide is not the full human protein.
[0181] The present invention further relates to the nucleic acid
according to the invention that is DNA, cDNA, PNA, RNA or
combinations thereof.
[0182] The present invention further relates to an expression
vector capable of expressing a nucleic acid according to the
invention.
[0183] The present invention further relates to a peptide according
to the invention, a nucleic acid according to the invention or an
expression vector according to the invention for use in
medicine.
[0184] The present invention further relates to a host cell
comprising a nucleic acid according to the invention or an
expression vector according to the invention.
[0185] The present invention further relates to the host cell
according to the invention that is an antigen presenting cell.
[0186] The present invention further relates to the host cell
according to the invention wherein the antigen presenting cell is a
dendritic cell.
[0187] The present invention further relates to a method for
producing a peptide according to the invention, the method
comprising culturing the host cell described, and isolating the
peptide from the host cell or its culture medium.
[0188] The present invention further relates to an in vitro method
for producing activated cytotoxic T lymphocytes (CTL), the method
comprising contacting in vitro CTL with antigen loaded human class
I or II MHC molecules expressed on the surface of a suitable
antigen-presenting cell for a period of time sufficient to activate
said CTL in an antigen specific manner, wherein said antigen is any
peptide according to the invention.
[0189] The present invention further relates to the method as
described, wherein said antigen is loaded onto class I or II MHC
molecules expressed on the surface of a suitable antigen-presenting
cell by contacting a sufficient amount of the antigen with an
antigen-presenting cell.
[0190] The present invention further relates to the method
according to the invention, wherein the antigen-presenting cell
comprises an expression vector capable of expressing said peptide
containing SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 527 to SEQ ID
NO: 551 or SEQ ID NO: 552 to SEQ ID NO: 1016 or said variant amino
acid sequence.
[0191] The present invention further relates to activated cytotoxic
T lymphocytes (CTL), produced by the method according to the
invention, which selectively recognise a cell which aberrantly
expresses a polypeptide comprising an amino acid sequence
described.
[0192] The present invention further relates to a method of killing
target cells in a patient which target cells aberrantly express a
polypeptide comprising any amino acid sequence according to the
invention, the method comprising administering to the patient an
effective number of cytotoxic T lymphocytes (CTL) according to the
invention.
[0193] The present invention further relates to the use of any
peptide according to the invention, a nucleic acid according to the
invention, an expression vector according to the invention, a cell
according to the invention, or an activated cytotoxic T lymphocyte
according to the invention as a medicament or in the manufacture of
a medicament.
[0194] The present invention further relates to a use according to
the invention, wherein the medicament is a vaccine.
[0195] The present invention further relates to a use according to
the invention, wherein the medicament is active against cancer.
[0196] The present invention further relates to a use according to
the invention, wherein said cancer cells are CLL cells or other non
solid tumor cells.
[0197] The present invention further relates to particular marker
proteins and biomarkers that can be used in the prognosis of
CLL.
[0198] Further, the present invention relates to the use of the
novel targets as described in accordance with the present invention
for cancer treatment.
[0199] The term "antibody" or "antibodies" is used herein in a
broad sense and includes both polyclonal and monoclonal antibodies.
In addition to intact or "full" immunoglobulin molecules, also
included in the term "antibodies" are fragments or polymers of
those immunoglobulin molecules and humanized versions of
immunoglobulin molecules, so long as they exhibit any of the
desired properties (e.g., specific binding of an CLL marker
polypeptide, delivery of a toxin to an CLL (leukimea) cells
expressing a CLL marker gene at an increased level, and/or
inhibiting the activity of a CLL marker polypeptide) according to
the invention.
[0200] Whenever possible, the antibodies of the invention may be
purchased from commercial sources. The antibodies of the invention
may also be generated using well-known methods. The skilled artisan
will understand that either full length CLL marker polypeptides or
fragments thereof may be used to generate the antibodies of the
invention. A polypeptide to be used for generating an antibody of
the invention may be partially or fully purified from a natural
source, or may be produced using recombinant DNA techniques.
[0201] For example, a cDNA encoding a peptide according to the
present invention, such as a peptide according to SEQ ID NO: 1 to
SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543
to SEQ ID NO: 1016 polypeptide, or a variant or fragment thereof,
can be expressed in prokaryotic cells (e.g., bacteria) or
eukaryotic cells (e.g., yeast, insect, or mammalian cells), after
which the recombinant protein can be purified and used to generate
a monoclonal or polyclonal antibody preparation that specifically
bind the CLL marker polypeptide used to generate the antibody
according to the invention.
[0202] One of skill in the art will realize that the generation of
two or more different sets of monoclonal or polyclonal antibodies
maximizes the likelihood of obtaining an antibody with the
specificity and affinity required for its intended use (e.g.,
ELISA, immunohistochemistry, in vivo imaging, immunotoxin therapy).
The antibodies are tested for their desired activity by known
methods, in accordance with the purpose for which the antibodies
are to be used (e.g., ELISA, immunohistochemistry, immunotherapy,
etc.; for further guidance on the generation and testing of
antibodies, see, e.g., Harlow and Lane, Antibodies: A Laboratory
Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor,
N.Y., 1988, new 2.sup.nd edition 2013). For example, the antibodies
may be tested in ELISA assays or Western blots. After their initial
in vitro characterization, antibodies intended for therapeutic or
in vivo diagnostic use are tested according to known clinical
testing methods.
[0203] The term "monoclonal antibody" as used herein refers to an
antibody obtained from a substantially homogeneous population of
antibodies, i.e.; the individual antibodies comprising the
population are identical except for possible naturally occurring
mutations that may be present in minor amounts. The monoclonal
antibodies herein specifically include "chimeric" antibodies in
which a portion of the heavy and/or light chain is identical with
or homologous to corresponding sequences in antibodies derived from
a particular species or belonging to a particular antibody class or
subclass, while the remainder of the chain(s) is identical with or
homologous to corresponding sequences in antibodies derived from
another species or belonging to another antibody class or subclass,
as well as fragments of such antibodies, so long as they exhibit
the desired antagonistic activity (U.S. Pat. No. 4,816,567, which
is hereby incorporated in its entirety).
[0204] Monoclonal antibodies of the invention may be prepared using
hybridoma methods. In a hybridoma method, a mouse or other
appropriate host animal is typically immunized with an immunizing
agent to elicit lymphocytes that produce or are capable of
producing antibodies that will specifically bind to the immunizing
agent. Alternatively, the lymphocytes may be immunized in
vitro.
[0205] The monoclonal antibodies may also be made by recombinant
DNA methods, such as those described in U.S. Pat. No. 4,816,567.
DNA encoding the monoclonal antibodies of the invention can be
readily isolated and sequenced using conventional procedures (e.g.,
by using oligonucleotide probes that are capable of binding
specifically to genes encoding the heavy and light chains of murine
antibodies).
[0206] In vitro methods are also suitable for preparing monovalent
antibodies. Digestion of antibodies to produce fragments thereof,
particularly, Fab fragments, can be accomplished using routine
techniques known in the art. For instance, digestion can be
performed using papain. Examples of papain digestion are described
in WO 94/29348 and U.S. Pat. No. 4,342,566. Papain digestion of
antibodies typically produces two identical antigen binding
fragments, called Fab fragments, each with a single antigen binding
site, and a residual Fc fragment. Pepsin treatment yields a a
F(ab').sub.2 fragment and a pFc' fragment.
[0207] The antibody fragments, whether attached to other sequences
or not, can also include insertions, deletions, substitutions, or
other selected modifications of particular regions or specific
amino acids residues, provided the activity of the fragment is not
significantly altered or impaired compared to the non-modified
antibody or antibody fragment. These modifications can provide for
some additional property, such as to remove/add amino acids capable
of disulfide bonding, to increase its bio-longevity, to alter its
secretory characteristics, etc. In any case, the antibody fragment
must possess a bioactive property, such as binding activity,
regulation of binding at the binding domain, etc. Functional or
active regions of the antibody may be identified by mutagenesis of
a specific region of the protein, followed by expression and
testing of the expressed polypeptide. Such methods are readily
apparent to a skilled practitioner in the art and can include
site-specific mutagenesis of the nucleic acid encoding the antibody
fragment.
[0208] The antibodies of the invention may further comprise
humanized antibodies or human antibodies. Humanized forms of
non-human (e.g., murine) antibodies are chimeric immunoglobulins,
immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab'
or other antigen-binding subsequences of antibodies) which contain
minimal sequence derived from non-human immunoglobulin. Humanized
antibodies include human immunoglobulins (recipient antibody) in
which residues from a complementary determining region (CDR) of the
recipient are replaced by residues from a CDR of a non-human
species (donor antibody) such as mouse, rat or rabbit having the
desired specificity, affinity and capacity. In some instances, Fv
framework (FR) residues of the human immunoglobulin are replaced by
corresponding non-human residues. Humanized antibodies may also
comprise residues which are found neither in the recipient antibody
nor in the imported CDR or framework sequences. In general, the
humanized antibody will comprise substantially all of at least one,
and typically two, variable domains, in which all or substantially
all of the CDR regions correspond to those of a non-human
immunoglobulin and all or substantially all of the FR regions are
those of a human immunoglobulin consensus sequence. The humanized
antibody optimally also will comprise at least a portion of an
immunoglobulin constant region (Fc), typically that of a human
immunoglobulin.
[0209] Methods for humanizing non-human antibodies are well known
in the art. Generally, a humanized antibody has one or more amino
acid residues introduced into it from a source which is non-human.
These non-human amino acid residues are often referred to as
"import" residues, which are typically taken from an "import"
variable domain. Humanization can be essentially performed by
substituting rodent CDRs or CDR sequences for the corresponding
sequences of a human antibody. Accordingly, such "humanized"
antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567),
wherein substantially less than an intact human variable domain has
been substituted by the corresponding sequence from a non-human
species. In practice, humanized antibodies are typically human
antibodies in which some CDR residues and possibly some FR residues
are substituted by residues from analogous sites in rodent
antibodies.
[0210] Transgenic animals (e.g., mice) that are capable, upon
immunization, of producing a full repertoire of human antibodies in
the absence of endogenous immunoglobulin production can be
employed. For example, it has been described that the homozygous
deletion of the antibody heavy chain joining region gene in
chimeric and germ-line mutant mice results in complete inhibition
of endogenous antibody production. Transfer of the human germ-line
immunoglobulin gene array in such germ-line mutant mice will result
in the production of human antibodies upon antigen challenge. Human
antibodies can also be produced in phage display libraries.
[0211] Antibodies of the invention are preferably administered to a
subject in a pharmaceutically acceptable carrier. Typically, an
appropriate amount of a pharmaceutically-acceptable salt is used in
the formulation to render the formulation isotonic. Examples of the
pharmaceutically-acceptable carrier include saline, Ringer's
solution and dextrose solution. The pH of the solution is
preferably from about 5 to about 8, and more preferably from about
7 to about 7.5. Further carriers include sustained release
preparations such as semipermeable matrices of solid hydrophobic
polymers containing the antibody, which matrices are in the form of
shaped articles, e.g., films, liposomes or microparticles. It will
be apparent to those persons skilled in the art that certain
carriers may be more preferable depending upon, for instance, the
route of administration and concentration of antibody being
administered.
[0212] The antibodies can be administered to the subject, patient,
or cell by injection (e.g., intravenous, intraperitoneal,
subcutaneous, intramuscular), or by other methods such as infusion
that ensure its delivery to the bloodstream in an effective form.
The antibodies may also be administered by intratumoral or
peritumoral routes, to exert local as well as systemic therapeutic
effects. Local or intravenous injection is preferred.
[0213] Effective dosages and schedules for administering the
antibodies may be determined empirically, and making such
determinations is within the skill in the art. Those skilled in the
art will understand that the dosage of antibodies that must be
administered will vary depending on, for example, the subject that
will receive the antibody, the route of administration, the
particular type of antibody used and other drugs being
administered. A typical daily dosage of the antibody used alone
might range from about 1 (.mu.g/kg to up to 100 mg/kg of body
weight or more per day, depending on the factors mentioned above.
Following administration of an antibody for treating CLL, the
efficacy of the therapeutic antibody can be assessed in various
ways well known to the skilled practitioner. s secondary to CLL
[0214] Because the peptides as mentioned in the Tables above
(specifically the ones associated with CLL) of the invention and
thus their underlying polypeptides are highly expressed in CLL, and
are expressed at rather to extremely low levels in normal cells,
the inhibition of a protein selected from the group consisting of
APOBEC3D, CDK14, RASGRF1, CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP,
TAGAP, ABCA6, DMXL1, PARP3, TP53I11, B4GALT1, IRF9, KDM2B,
TBC1D22A, ZNF296, BACH2, PRR12, ZFAND5, ATP5G1, DMD, ARID5B,
ZNF638, DDX46, RRM2B, BLNK, HSH2D, ERP44, METTL7A, ELP3, NLRP2,
ZC3H12D, NELFE, ATP6V1C1, HLA-DMA, TUFM, EIF6, CKAP4, COBLL1,
TMED4, TNFRSF13C, UBL7, CXorf21, ASUN, SL24D1, and TRAF3IP3
expression or of the activity thereof may be preferably integrated
into a therapeutic strategy for treating or preventing CLL.
[0215] The principle of antisense therapy is based on the
hypothesis that sequence-specific suppression of gene expression
(via transcription or translation) may be achieved by
intra-cellular hybridization between genomic DNA or mRNA and a
complementary antisense species. The formation of such a hybrid
nucleic acid duplex interferes with transcription of the target
tumor antigen-encoding genomic DNA, or
processing/transport/translation and/or stability of the target
tumor antigen mRNA.
[0216] Antisense nucleic acids can be delivered by a variety of
approaches. For example, antisense oligonucleotides or anti-sense
RNA can be directly administered (e.g., by intravenous injection)
to a subject in a form that allows uptake into tumor cells.
Alternatively, viral or plasmid vectors that encode antisense RNA
(or RNA fragments) can be introduced into cells in vivo. Antisense
effects can also be induced by sense sequences; however, the extent
of phenotypic changes is highly variable. Phenotypic changes
induced by effective antisense therapy are assessed according to
changes in, e.g., target mRNA levels, target protein levels, and/or
target protein activity levels.
[0217] In a specific example, inhibition of CLL marker function by
antisense gene therapy may be accomplished by direct administration
of antisense lung tumor marker RNA to a subject. The antisense
tumor marker RNA may be produced and isolated by any standard
technique, but is most readily produced by in vitro transcription
using an antisense tumor marker cDNA under the control of a high
efficiency promoter (e.g., the
[0218] T7 promoter). Administration of anti-sense tumor marker RNA
to cells can be carried out by any of the methods for direct
nucleic acid administration described below.
[0219] An alternative strategy for inhibiting the function of a
protein selected from the group consisting of APOBEC3D, CDK14,
RASGRF1, CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6, DMXL1,
PARP3, TP53I11, B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296, BACH2,
PRR12, ZFAND5, ATP5G1, DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK,
HSH2D, ERP44, METTL7A, ELP3, NLRP2, ZC3H12D, NELFE, ATP6V1C1,
HLA-DMA, TUFM, EIF6, CKAP4, COBLL1, TMED4, TNFRSF13C, UBL7,
CXorf21, ASUN, SL24D1, and TRAF3IP3 using gene therapy involves
intracellular expression of an anti-protein antibody or a portion
of an anti-protein antibody. For example, the gene (or gene
fragment) encoding a monoclonal antibody that specifically binds to
a protein selected from the group consisting of APOBEC3D, CDK14,
RASGRF1, CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6, DMXL1,
PARP3, TP53I11, B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296, BACH2,
PRR12, ZFAND5, ATP5G1, DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK,
HSH2D, ERP44, METTL7A, ELP3, NLRP2, ZC3H12D, NELFE, ATP6V1C1,
HLA-DMA, TUFM, EIF6, CKAP4, COBLL1, TMED4, TNFRSF13C, UBL7,
CXorf21, ASUN, SL24D1, and TRAF3IP3 and inhibits its biological
activity is placed under the transcriptional control of a specific
(e.g., tissue- or tumor-specific) gene regulatory sequence, within
a nucleic acid expression vector. The vector is then administered
to the subject such that it is taken up by CLL cells or other
cells, which then secrete the anti-protein antibody, and thereby
block biological activity of the respective polypeptide.
Preferably, proteins are present on the cellular surface of CLL
cancer cells.
[0220] In the methods described above, which include the
administration and uptake of exogenous DNA into the cells of a
subject (i.e., gene transduction or transfection), the nucleic
acids of the present invention can be in the form of naked DNA or
the nucleic acids can be in a vector for delivering the nucleic
acids to the cells for inhibition of CLL tumor marker protein
expression. The vector can be a commercially available preparation,
such as an adenovirus vector (Quantum Biotechnologies, Inc. (Laval,
Quebec, Canada). Delivery of the nucleic acid or vector to cells
can be via a variety of mechanisms. As one example, delivery can be
via a liposome, using commercially available liposome preparations
such as LIPOFECTIN, LIPOFECTAMINE (GIBCO-25 BRL, Inc.,
Gaithersburg, Md.), SUPERFECT (Qiagen, Inc. Hilden, Germany) and
TRANSFECTAM (Promega Biotec, Inc., Madison, Wis., US), as well as
other liposomes developed according to procedures standard in the
art. In addition, the nucleic acid or vector of this invention can
be delivered in vivo by electroporation, the technology for which
is available from Genetronics, Inc. (San Diego, US) as well as by
means of a SONOPORATION machine (ImaRx Pharmaceutical Corp.,
Tucson, Arizona, US).
[0221] As one example, vector delivery can be via a viral system,
such as a retroviral vector system that can package a recombinant
retroviral genome. The recombinant retrovirus can then be used to
infect and thereby deliver to the infected cells antisense nucleic
acid that inhibits expression of a protein selected from the group
consisting of APOBEC3D, CDK14, RASGRF1, CDCA7L, CELSR1, AKAP2,
CTDP1, DNMBP, TAGAP, ABCA6, DMXL1, PARP3, TP53I11, B4GALT1, IRF9,
KDM2B, TBC1D22A, ZNF296, BACH2, PRR12, ZFAND5, ATP5G1, DMD, ARID5B,
ZNF638, DDX46, RRM2B, BLNK, HSH2D, ERP44, METTL7A, ELP3, NLRP2,
ZC3H12D, NELFE, ATP6V1C1, HLA-DMA, TUFM, EIF6, CKAP4, COBLL1,
TMED4, TNFRSF13C, UBL7, CXorf21, ASUN, SL24D1, and TRAF3IP3. The
exact method of introducing the altered nucleic acid into mammalian
cells is, of course, not limited to the use of retroviral vectors.
Other techniques are widely available for this procedure including
the use of adenoviral vectors, adeno-associated viral (AAV)
vectors, lentiviral vectors, pseudotyped retroviral vectors.
Physical transduction techniques can also be used, such as liposome
delivery and receptor-mediated and other endocytosis mechanisms.
This invention can be used in conjunction with any of these or
other commonly used gene transfer methods.
[0222] The antibodies may also be used for in vivo diagnostic
assays. Generally, the antibody is labeled with a radionucleotide
(such as .sup.111In, .sup.99Tc, .sup.14C, .sup.131I, .sup.3H,
.sup.32P or .sup.35S) so that the tumor can be localized using
immunoscintiography. In one embodiment, antibodies or fragments
thereof bind to the extracellular domains of two or more targets of
a protein selected from the group consisting of APOBEC3D, CDK14,
RASGRF1, CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6, DMXL1,
PARP3, TP53I11, B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296, BACH2,
PRR12, ZFAND5, ATP5G1, DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK,
HSH2D, ERP44, METTL7A, ELP3, NLRP2, ZC3H12D, NELFE, ATP6V1C1,
HLA-DMA, TUFM, EIF6, CKAP4, COBLL1, TMED4, TNFRSF13C, UBL7,
CXorf21, ASUN, SL24D1, and TRAF3IP3, and the affinity value (Kd) is
less than 1.times.10 .mu.M.
[0223] Antibodies for diagnostic use may be labeled with probes
suitable for detection by various imaging methods. Methods for
detection of probes include, but are not limited to, fluorescence,
light, confocal and electron microscopy; magnetic resonance imaging
and spectroscopy; fluoroscopy, computed tomography and positron
emission tomography. Suitable probes include, but are not limited
to, fluorescein, rhodamine, eosin and other fluorophores,
radioisotopes, gold, gadolinium and other lanthanides, paramagnetic
iron, fluorine-18 and other positron-emitting radionuclides.
Additionally, probes may be bi- or multi-functional and be
detectable by more than one of the methods listed. These antibodies
may be directly or indirectly labeled with said probes. Attachment
of probes to the antibodies includes covalent attachment of the
probe, incorporation of the probe into the antibody, and the
covalent attachment of a chelating compound for binding of probe,
amongst others well recognized in the art. For
immunohistochemistry, the disease tissue sample may be fresh or
frozen or may be embedded in paraffin and fixed with a preservative
such as formalin. The fixed or embedded section contains the sample
are contacted with a labeled primary antibody and secondary
antibody, wherein the antibody is used to detect the expression of
the proteins in situ.
[0224] The present invention thus provides a peptide comprising a
sequence that is selected from the group of consisting of SEQ ID
NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID
NO: 543 to SEQ ID NO: 1016 or a variant thereof which is 90%
homologous to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ
ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016, or a variant
thereof that will induce T cells cross-reacting with said
peptide.
[0225] The peptides of the invention have the ability to bind to a
molecule of the human major histocompatibility complex (MHC)
class-I and/or class II.
[0226] In the present invention, the term "homologous" refers to
the degree of identity (see Percent Identity above) between
sequences of two amino acid sequences, i.e. peptide or polypeptide
sequences. The aforementioned "homology" is determined by comparing
two sequences aligned under optimal conditions over the sequences
to be compared. Such a sequence homology can be calculated by
creating an alignment using, for example, the ClustalW algorithm.
Commonly available sequence analysis software, more specifically,
Vector NTI, GENETYX or other analysis tools are provided by public
databases.
[0227] A person skilled in the art will be able to assess, whether
T cells induced by a variant of a specific peptide will be able to
cross-react with the peptide itself (Fong L, et al. Altered peptide
ligand vaccination with Flt3 ligand expanded dendritic cells for
tumor immunotherapy. Proc Natl Acad Sci USA. 2001 Jul. 17;
98(15):8809-14; Zaremba S, et al. Identification of an enhancer
agonist cytotoxic T lymphocyte peptide from human carcinoembryonic
antigen. Cancer Res. 1997 Oct. 15; 57(20):4570-7; Colombetti S, et
al. Impact of orthologous melan-A peptide immunizations on the
anti-self melan-A/HLA-A2 T cell cross-reactivity. J Immunol. 2006
Jun. 1; 176(11):6560-7; Appay V, et al. Decreased specific CD8+ T
cell cross-reactivity of antigen recognition following vaccination
with Melan-A peptide. Eur J Immunol. 2006 July; 36(7):1805-14).
[0228] By a "variant" of the given amino acid sequence the
inventors mean that the side chains of, for example, one or two of
the amino acid residues are altered (for example by replacing them
with the side chain of another naturally occurring amino acid
residue or some other side chain) such that the peptide is still
able to bind to an HLA molecule in substantially the same way as a
peptide consisting of the given amino acid sequence in consisting
of SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542
or SEQ ID NO: 543 to SEQ ID NO: 1016. For example, a peptide may be
modified so that it at least maintains, if not improves, the
ability to interact with and bind to the binding groove of a
suitable MHC molecule, such as HLA-A*02 or -DR, and in that way it
at least maintains, if not improves, the ability to bind to the TCR
of activated CTL.
[0229] These CTL can subsequently cross-react with cells and kill
cells that express a polypeptide that contains the natural amino
acid sequence of the cognate peptide as defined in the aspects of
the invention. As can be derived from the scientific literature
(Godkin A, et al. Use of eluted peptide sequence data to identify
the binding characteristics of peptides to the insulin-dependent
diabetes susceptibility allele HLA-DQ8 (DQ 3.2). Int Immunol. 1997
Jun;9(6):905-11) and databases (Rammensee H. et al. SYFPEITHI:
database for MHC ligands and peptide motifs. Immunogenetics. 1999
November; 50(3-4):213-9), certain positions of HLA binding peptides
are typically anchor residues forming a core sequence fitting to
the binding motif of the HLA receptor, which is defined by polar,
electrophysical, hydrophobic and spatial properties of the
polypeptide chains constituting the binding groove. Thus, one
skilled in the art would be able to modify the amino acid sequences
set forth in SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ
ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016, by maintaining the
known anchor residues, and would be able to determine whether such
variants maintain the ability to bind MHC class I or II molecules.
The variants of the present invention retain the ability to bind to
the TCR of activated CTL, which can subsequently cross-react
with--and kill cells that express a polypeptide containing the
natural amino acid sequence of the cognate peptide as defined in
the aspects of the invention.
[0230] The amino acid residues that do not substantially contribute
to interactions with the T-cell receptor can be modified by
replacement with another amino acid whose incorporation does not
substantially affect T-cell reactivity and does not eliminate
binding to the relevant MHC. Thus, apart from the proviso given,
the peptide of the invention may be any peptide (by which term the
inventors include oligopeptide or polypeptide), which includes the
amino acid sequences or a portion or variant thereof as given.
[0231] Longer peptides may also be suitable. It is also possible,
that MHC class I epitopes, although usually between 8 and 11 amino
acids long, are generated by peptide processing from longer
peptides or proteins that include the actual epitope. It is
preferred that the residues that flank the actual epitope are
residues that do not substantially affect proteolytic cleavage
necessary to expose the actual epitope during processing.
[0232] Accordingly, the present invention also provides peptides
and variants of MHC class I epitopes wherein the peptide or variant
has an overall length of between 8 and 100, preferably between 8
and 30, and most preferred between 8 and 14, namely 8, 9, 10, 11,
12, 13, 14 amino acids, in case of the class II binding peptides
the length can also be 15, 16, 17, 18, 19, 20, 21 or 22 amino
acids.
[0233] Of course, the peptide or variant according to the present
invention will have the ability to bind to a molecule of the human
major histocompatibility complex (MHC) class I. Binding of a
peptide or a variant to a MHC complex may be tested by methods
known in the art.
[0234] In a particularly preferred embodiment of the invention the
peptide consists or consists essentially of an amino acid sequence
according to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ
ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016.
[0235] "Consisting essentially of" shall mean that a peptide
according to the present invention, in addition to the sequence
according to any of SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226:
to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016 or a variant
thereof contains additional N- and/or C-terminally located
stretches of amino acids that are not necessarily forming part of
the peptide that functions as an epitope for MHC molecules
epitope.
[0236] Nevertheless, these stretches can be important to provide an
efficient introduction of the peptide according to the present
invention into the cells. In one embodiment of the present
invention, the peptide is a fusion protein which comprises, for
example, the 80 N-terminal amino acids of the HLA-DR
antigen-associated invariant chain (p33, in the following "li") as
derived from the NCBI, GenBank Accession number X00497. In other
fusions, the peptides of the present invention can be fused to an
antibody as described herein, or a functional part thereof, in
particular into a sequence of an antibody, so as to be specifically
targeted by said antibody, or, for example, to or into an antibody
that is specific for dendritic cells.
[0237] In addition, the peptide or variant may be modified further
to improve stability and/or binding to MHC molecules in order to
elicit a stronger immune response. Methods for such an optimization
of a peptide sequence are well known in the art and include, for
example, the introduction of reverse peptide bonds or non-peptide
bonds.
[0238] In a reverse peptide bond amino acid residues are not joined
by peptide (--CO--NH--) linkages but the peptide bond is reversed.
Such retro-inverso peptidomimetics may be made using methods known
in the art, for example such as those described in Meziere et al
(1997) J. Immunol. 159, 3230-3237, incorporated herein by
reference. This approach involves making pseudopeptides containing
changes involving the backbone, and not the orientation of side
chains. Meziere et al (1997) show that for MHC binding and T helper
cell responses, these pseudopeptides are useful. Retro-inverse
peptides, which contain NH--CO bonds instead of CO--NH peptide
bonds, are much more resistant to proteolysis.
[0239] A non--peptide bond is, for example, --CH.sub.2--NH,
--CH.sub.2S--, --CH.sub.2CH.sub.2--, --CH.dbd.CH--, --COCH.sub.2--,
--CH(OH)CH.sub.2--, and --CH.sub.2SO--. U.S. Pat. No. 4,897,445
provides a method for the solid phase synthesis of non-peptide
bonds (--CH.sub.2--NH) in polypeptide chains which involves
polypeptides synthesized by standard procedures and the non-peptide
bond synthesized by reacting an amino aldehyde and an amino acid in
the presence of NaCNBH.sub.3.
[0240] Peptides comprising the sequences described above may be
synthesized with additional chemical groups present at their amino
and/or carboxy termini, to enhance the stability, bioavailability,
and/or affinity of the peptides. For example, hydrophobic groups
such as carbobenzoxyl, dansyl, or t-butyloxycarbonyl groups may be
added to the peptides' amino termini. Likewise, an acetyl group or
a 9-fluorenylmethoxy-carbonyl group may be placed at the peptides'
amino termini. Additionally, the hydrophobic group,
t-butyloxycarbonyl, or an amido group may be added to the peptides'
carboxy termini.
[0241] Further, the peptides of the invention may be synthesized to
alter their steric configuration. For example, the D-isomer of one
or more of the amino acid residues of the peptide may be used,
rather than the usual L-isomer. Still further, at least one of the
amino acid residues of the peptides of the invention may be
substituted by one of the well-known non-naturally occurring amino
acid residues. Alterations such as these may serve to increase the
stability, bioavailability and/or binding action of the peptides of
the invention.
[0242] Similarly, a peptide or variant of the invention may be
modified chemically by reacting specific amino acids either before
or after synthesis of the peptide. Examples for such modifications
are well known in the art and are summarized e.g. in R. Lundblad,
Chemical Reagents for Protein Modification, 3rd ed. CRC Press,
2005, which is incorporated herein by reference. Chemical
modification of amino acids includes but is not limited to,
modification by acylation, amidination, pyridoxylation of lysine,
reductive alkylation, trinitrobenzylation of amino groups with
2,4,6-trinitrobenzene sulphonic acid (TNBS), amide modification of
carboxyl groups and sulphydryl modification by performic acid
oxidation of cysteine to cysteic acid, formation of mercurial
derivatives, formation of mixed disulphides with other thiol
compounds, reaction with maleimide, carboxymethylation with
iodoacetic acid or iodoacetamide and carbamoylation with cyanate at
alkaline pH, although without limitation thereto. In this regard,
the skilled person is referred to Chapter 15 of Current Protocols
In Protein Science, Eds. Coligan et al. (John Wiley and Sons NY
1995-2000) for more extensive methodology relating to chemical
modification of proteins.
[0243] Briefly, modification of e.g. arginyl residues in proteins
is often based on the reaction of vicinal dicarbonyl compounds such
as phenylglyoxal, 2,3-butanedione, and 1,2-cyclohexanedione to form
an adduct. Another example is the reaction of methylglyoxal with
arginine residues. Cysteine can be modified without concomitant
modification of other nucleophilic sites such as lysine and
histidine. As a result, a large number of reagents are available
for the modification of cysteine. The websites of companies such as
Sigma-Aldrich provide information on specific reagents.
[0244] Selective reduction of disulfide bonds in proteins is also
common. Disulfide bonds can be formed and oxidized during the heat
treatment of biopharmaceuticals.
[0245] Woodward's Reagent K may be used to modify specific glutamic
acid residues. N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide can
be used to form intra-molecular crosslinks between a lysine residue
and a glutamic acid residue.
[0246] For example, diethylpyrocarbonate is a reagent for the
modification of histidyl residues in proteins. Histidine can also
be modified using 4-hydroxy-2-nonenal.
[0247] The reaction of lysine residues and other a-amino groups is,
for example, useful in binding of peptides to surfaces or the
cross-linking of proteins/peptides. Lysine is the site of
attachment of poly(ethylene)glycol and the major site of
modification in the glycosylation of proteins.
[0248] Methionine residues in proteins can be modified with e.g.
iodoacetamide, bromoethylamine, and chloramine T.
[0249] Tetranitromethane and N-acetylimidazole can be used for the
modification of tyrosyl residues. Cross-linking via the formation
of dityrosine can be accomplished with hydrogen peroxide/copper
ions.
[0250] Recent studies on the modification of tryptophan have used
N-bromosuccinimide, 2-hydroxy-5-nitrobenzyl bromide or
3-bromo-3-methyl-2-(2-nitrophenylmercapto)-3H-indole
(BPNS-skatole).
[0251] Successful modification of therapeutic proteins and peptides
with PEG is often associated with an extension of circulatory
half-life while cross-linking of proteins with glutaraldehyde,
polyethyleneglycol diacrylate and formaldehyde is used for the
preparation of hydrogels. Chemical modification of allergens for
immunotherapy is often achieved by carbamylation with potassium
cyanate.
[0252] A peptide or variant, wherein the peptide is modified or
includes non-peptide bonds is a preferred embodiment of the
invention. Generally, peptides and variants (at least those
containing peptide linkages between amino acid residues) may be
synthesized by the Fmoc-polyamide mode of solid-phase peptide
synthesis as disclosed by Lukas et al. (Solid-phase peptide
synthesis under continuous-flow conditions. Proc Natl Acad Sci USA.
May 1981; 78(5): 2791-2795) and references therein. Temporary
N-amino group protection is afforded by the
9-fluorenylmethyloxycarbonyl (Fmoc) group. Repetitive cleavage of
this highly base-labile protecting group is done using 20%
piperidine in N, N-dimethylformamide. Side-chain functionalities
may be protected as their butyl ethers (in the case of serine
threonine and tyrosine), butyl esters (in the case of glutamic acid
and aspartic acid), butyloxycarbonyl derivative (in the case of
lysine and histidine), trityl derivative (in the case of cysteine)
and 4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative (in the
case of arginine). Where glutamine or asparagine are C-terminal
residues, use is made of the 4,4'-dimethoxybenzhydryl group for
protection of the side chain amido functionalities. The solid-phase
support is based on a polydimethyl-acrylamide polymer constituted
from the three monomers dimethylacrylamide (backbone-monomer),
bisacryloylethylene diamine (cross linker) and acryloylsarcosine
methyl ester (functionalizing agent). The peptide-to-resin
cleavable linked agent used is the acid-labile
4-hydroxymethyl-phenoxyacetic acid derivative. All amino acid
derivatives are added as their preformed symmetrical anhydride
derivatives with the exception of asparagine and glutamine, which
are added using a reversed N, N-dicyclohexyl-carbodiimide/1
hydroxybenzotriazole mediated coupling procedure. All coupling and
deprotection reactions are monitored using ninhydrin,
trinitrobenzene sulphonic acid or isotin test procedures. Upon
completion of synthesis, peptides are cleaved from the resin
support with concomitant removal of side-chain protecting groups by
treatment with 95% trifluoroacetic acid containing a 50% scavenger
mix. Scavengers commonly used include ethandithiol, phenol, anisole
and water, the exact choice depending on the constituent amino
acids of the peptide being synthesized. Also a combination of solid
phase and solution phase methodologies for the synthesis of
peptides is possible (see, for example, Bruckdorfer et al., 2004,
and the references as cited therein).
[0253] Trifluoroacetic acid is removed by evaporation in vacuo,
with subsequent trituration with diethyl ether affording the crude
peptide. Any scavengers present are removed by a simple extraction
procedure which on lyophilisation of the aqueous phase affords the
crude peptide free of scavengers. Reagents for peptide synthesis
are generally available from e.g. Calbiochem-Novabiochem (UK) Ltd,
Nottingham NG7 2QJ, UK.
[0254] Purification may be performed by any one, or a combination
of, techniques such as re-crystallization, size exclusion
chromatography, ion-exchange chromatography, hydrophobic
interaction chromatography and (usually) reverse-phase high
performance liquid chromatography using e.g. acetonitril/water
gradient separation.
[0255] Analysis of peptides may be carried out using thin layer
chromatography, electrophoresis, in particular capillary
electrophoresis, solid phase extraction (CSPE), reverse-phase high
performance liquid chromatography, amino-acid analysis after acid
hydrolysis and by fast atom bombardment (FAB) mass spectrometric
analysis, as well as MALDI and ESI-Q-TOF mass spectrometric
analysis.
[0256] A further aspect of the invention provides a nucleic acid
(for example a polynucleotide) encoding a peptide or peptide
variant of the invention. The polynucleotide may be, for example,
DNA, cDNA, PNA, RNA or combinations thereof, either single- and/or
double-stranded, or native or stabilized forms of polynucleotides,
such as, for example, polynucleotides with a phosphorothioate
backbone and it may or may not contain introns so long as it codes
for the peptide. Of course, only peptides that contain naturally
occurring amino acid residues joined by naturally occurring peptide
bonds are encodable by a polynucleotide. A still further aspect of
the invention provides an expression vector capable of expressing a
polypeptide according to the invention.
[0257] A variety of methods have been developed to link
polynucleotides, especially DNA, to vectors for example via
complementary cohesive termini. For instance, complementary
homopolymer tracts can be added to the DNA segment to be inserted
to the vector DNA. The vector and DNA segment are then joined by
hydrogen bonding between the complementary homopolymeric tails to
form recombinant DNA molecules.
[0258] Synthetic linkers containing one or more restriction sites
provide an alternative method of joining the DNA segment to
vectors. Synthetic linkers containing a variety of restriction
endonuclease sites are commercially available from a number of
sources including International Biotechnologies Inc. New Haven,
Conn., USA.
[0259] A desirable method of modifying the DNA encoding the
polypeptide of the invention employs the polymerase chain reaction
as disclosed by Saiki R K, et al. (Diagnosis of sickle cell anemia
and beta-thalassemia with enzymatically amplified DNA and
nonradioactive allele-specific oligonucleotide probes. N Engl J
Med. 1988 Sep. 1; 319(9):537-41). This method may be used for
introducing the DNA into a suitable vector, for example by
engineering in suitable restriction sites, or it may be used to
modify the DNA in other useful ways as is known in the art. If
viral vectors are used, pox- or adenovirus vectors are
preferred.
[0260] The DNA (or in the case of retroviral vectors, RNA) may then
be expressed in a suitable host to produce a polypeptide comprising
the peptide or variant of the invention. Thus, the DNA encoding the
peptide or variant of the invention may be used in accordance with
known techniques, appropriately modified in view of the teachings
contained herein, to construct an expression vector, which is then
used to transform an appropriate host cell for the expression and
production of the polypeptide of the invention. Such techniques
include those disclosed in U.S. Pat. Nos. 4,440,859, 4,530,901,
4,582,800, 4,677,063, 4,678,751, 4,704,362, 4,710,463, 4,757,006,
4,766,075, and 4,810,648.
[0261] The DNA (or in the case of retroviral vectors, RNA) encoding
the polypeptide constituting the compound of the invention may be
joined to a wide variety of other DNA sequences for introduction
into an appropriate host. The companion DNA will depend upon the
nature of the host, the manner of the introduction of the DNA into
the host, and whether episomal maintenance or integration is
desired.
[0262] Generally, the DNA is inserted into an expression vector,
such as a plasmid, in proper orientation and correct reading frame
for expression. If necessary, the DNA may be linked to the
appropriate transcriptional and translational regulatory control
nucleotide sequences recognized by the desired host, although such
controls are generally available in the expression vector. The
vector is then introduced into the host through standard
techniques. Generally, not all of the hosts will be transformed by
the vector. Therefore, it will be necessary to select for
transformed host cells. One selection technique involves
incorporating into the expression vector a DNA sequence, with any
necessary control elements, that codes for a selectable trait in
the transformed cell, such as antibiotic resistance.
[0263] Alternatively, the gene for such selectable trait can be on
another vector, which is used to co-transform the desired host
cell.
[0264] Host cells that have been transformed by the recombinant DNA
of the invention are then cultured for a sufficient time and under
appropriate conditions known to those skilled in the art in view of
the teachings disclosed herein to permit the expression of the
polypeptide, which can then be recovered.
[0265] Many expression systems are known, including bacteria (for
example E. coli and Bacillus subtilis), yeasts (for example
Saccharomyces cerevisiae), filamentous fungi (for example
Aspergillus spec.), plant cells, animal cells and insect cells.
Preferably, the system can be mammalian cells such as CHO cells
available from the ATCC Cell Biology Collection.
[0266] A typical mammalian cell vector plasmid for constitutive
expression comprises the CMV or SV40 promoter with a suitable poly
A tail and a resistance marker, such as neomycin. One example is
pSVL available from Pharmacia, Piscataway, N.J., USA. An example of
an inducible mammalian expression vector is pMSG, also available
from Pharmacia. Useful yeast plasmid vectors are pRS403-406 and
pRS413-416 and are generally available from Stratagene Cloning
Systems, La Jolla, Calif. 92037, USA. Plasmids pRS403, pRS404,
pRS405 and pRS406 are Yeast Integrating plasmids (Ylps) and
incorporate the yeast selectable markers HIS3, TRP1, LEU2 and URA3.
Plasmids pRS413-416 are Yeast Centromere plasmids (Ycps). CMV
promoter-based vectors (for example from Sigma-Aldrich) provide
transient or stable expression, cytoplasmic expression or
secretion, and N-terminal or C-terminal tagging in various
combinations of FLAG, 3.times.FLAG, c-myc or MAT. These fusion
proteins allow for detection, purification and analysis of
recombinant protein. Dual-tagged fusions provide flexibility in
detection.
[0267] The strong human cytomegalovirus (CMV) promoter regulatory
region drives constitutive protein expression levels as high as 1
mg/L in COS cells. For less potent cell lines, protein levels are
typically .about.0.1 mg/L. The presence of the SV40 replication
origin will result in high levels of DNA replication in SV40
replication permissive COS cells. CMV vectors, for example, can
contain the pMB1 (derivative of pBR322) origin for replication in
bacterial cells, the b-lactamase gene for ampicillin resistance
selection in bacteria, hGH polyA, and the f1 origin. Vectors
containing the preprotrypsin leader (PPT) sequence can direct the
secretion of FLAG fusion proteins into the culture medium for
purification using ANTI-FLAG antibodies, resins, and plates. Other
vectors and expression systems are well known in the art for use
with a variety of host cells.
[0268] In another embodiment two or more peptides or peptide
variants of the invention are encoded and thus expressed in a
successive order (similar to "beads on a string" constructs). In
doing so, the peptides or peptide variants may be linked or fused
together by stretches of linker amino acids, such as for example
LLLLLL, or may be linked without any additional peptide(s) between
them.
[0269] The present invention also relates to a host cell
transformed with a polynucleotide vector construct of the present
invention. The host cell can be either prokaryotic or eukaryotic.
Bacterial cells may be preferred prokaryotic host cells in some
circumstances and typically are a strain of E. coli such as, for
example, the E. coli strains DH5 available from Bethesda Research
Laboratories Inc., Bethesda, Md., USA, and RR1 available from the
American Type Culture Collection (ATCC) of Rockville, Md., USA (No
ATCC 31343). Preferred eukaryotic host cells include yeast, insect
and mammalian cells, preferably vertebrate cells such as those from
a mouse, rat, monkey or human fibroblastic and colon cell lines.
Yeast host cells include YPH499, YPH500 and YPH501, which are
generally available from Stratagene Cloning Systems, La Jolla,
Calif. 92037, USA. Preferred mammalian host cells include Chinese
hamster ovary (CHO) cells available from the ATCC as CCL61, NIH
Swiss mouse embryo cells NIH/3T3 available from the ATCC as CRL
1658, monkey kidney-derived COS-1 cells available from the ATCC as
CRL 1650 and 293 cells which are human embryonic kidney cells.
Preferred insect cells are Sf9 cells which can be transfected with
baculovirus expression vectors. An overview regarding the choice of
suitable host cells for expression can be found in, for example,
the textbook of Paulina Balba s and Argelia Lorence "Methods in
Molecular Biology Recombinant Gene Expression, Reviews and
Protocols," Part One, Second Edition, ISBN 978-1-58829-262-9, and
other literature known to the person of skill.
[0270] Transformation of appropriate cell hosts with a DNA
construct of the present invention is accomplished by well-known
methods that typically depend on the type of vector used. With
regard to transformation of prokaryotic host cells, see, for
example, Cohen et al (1972) Proc. Natl. Acad. Sci. USA 69, 2110,
and Sambrook et al (1989) Molecular Cloning, A Laboratory Manual,
Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.
Transformation of yeast cells is described in Sherman et al (1986)
Methods In Yeast Genetics, A Laboratory Manual, Cold Spring Harbor,
N.Y. The method of Beggs (1978) Nature 275,104-109 is also useful.
With regard to vertebrate cells, reagents useful in transfecting
such cells, for example calcium phosphate and DEAE-dextran or
liposome formulations, are available from Stratagene Cloning
Systems, or Life Technologies Inc., Gaithersburg, Md. 20877, USA.
Electroporation is also useful for transforming and/or transfecting
cells and is well known in the art for transforming yeast cell,
bacterial cells, insect cells and vertebrate cells.
[0271] Successfully transformed cells, i.e. cells that contain a
DNA construct of the present invention, can be identified by
well-known techniques such as PCR. Alternatively, the presence of
the protein in the supernatant can be detected using
antibodies.
[0272] It will be appreciated that certain host cells of the
invention are useful in the preparation of the peptides of the
invention, for example bacterial, yeast and insect cells. However,
other host cells may be useful in certain therapeutic methods. For
example, antigen-presenting cells, such as dendritic cells, may
usefully be used to express the peptides of the invention such that
they may be loaded into appropriate MHC molecules. Thus, the
current invention provides a host cell comprising a nucleic acid or
an expression vector according to the invention.
[0273] In a preferred embodiment the host cell is an antigen
presenting cell, in particular a dendritic cell or antigen
presenting cell. APCs loaded with a recombinant fusion protein
containing prostatic acid phosphatase (PAP) were approved by the
U.S. Food and Drug Administration (FDA) on Apr. 29, 2010, to treat
asymptomatic or minimally symptomatic metastatic HRPC
(Sipuleucel-T) (Small E J, et al. Placebo-controlled phase III
trial of immunologic therapy with sipuleucel-T (APC8015) in
patients with metastatic, asymptomatic hormone refractory prostate
cancer. J Clin Oncol. 2006 Jul. 1; 24(19):3089-94. Rini et al.
Combination immunotherapy with prostatic acid phosphatase pulsed
antigen-presenting cells (provenge) plus bevacizumab in patients
with serologic progression of prostate cancer after definitive
local therapy. Cancer. 2006 Jul. 1; 107(1):67-74).
[0274] A further aspect of the invention provides a method of
producing a peptide or its variant, the method comprising culturing
a host cell and isolating the peptide from the host cell or its
culture medium.
[0275] In another embodiment the peptide, the nucleic acid or the
expression vector of the invention are used in medicine. For
example, the peptide or its variant may be prepared for intravenous
(i.v.) injection, sub-cutaneous (s.c.) injection, intradermal
(i.d.) injection, intraperitoneal (i.p.) injection, intramuscular
(i.m.) injection. Preferred methods of peptide injection include
s.c., i.d., i.p., i.m., and i.v. Preferred methods of DNA injection
include i.d., i.m., s.c., i.p. and i.v. Doses of e.g. between 50
.mu.g and 1.5 mg, preferably 125 .mu.g to 500 .mu.g, of peptide or
DNA may be given and will depend on the respective peptide or DNA.
Dosages of this range were successfully used in previous trials
(Walter et al Nature Medicine 18, 1254-1261 (2012)).
[0276] Another aspect of the present invention includes an in vitro
method for producing activated T cells, the method comprising
contacting in vitro T cells with antigen loaded human MHC molecules
expressed on the surface of a suitable antigen-presenting cell for
a period of time sufficient to activate the T cell in an antigen
specific manner, wherein the antigen is a peptide according to the
invention. Preferably a sufficient amount of the antigen is used
with an antigen-presenting cell.
[0277] Preferably the mammalian cell lacks or has a reduced level
or function of the TAP peptide transporter. Suitable cells that
lack the TAP peptide transporter include T2, RMA-S and Drosophila
cells. TAP is the transporter associated with antigen
processing.
[0278] The human peptide loading deficient cell line T2 is
available from the American Type Culture Collection, 12301 Parklawn
Drive, Rockville, Md. 20852, USA under Catalogue No CRL 1992; the
Drosophila cell line Schneider line 2 is available from the ATCC
under Catalogue No CRL 19863; the mouse RMA-S cell line is
described in Karre et al 1985 (Ljunggren, H.-G., and K. Karre.
1985. J. Exp. Med. 162:1745).
[0279] Preferably, the host cell before transfection expresses
substantially no MHC class I molecules. It is also preferred that
the stimulator cell expresses a molecule important for providing a
co-stimulatory signal for T-cells such as any of B7.1, B7.2, ICAM-1
and LFA 3. The nucleic acid sequences of numerous MHC class I
molecules and of the co-stimulator molecules are publicly available
from the GenBank and EMBL databases.
[0280] In case of a MHC class I epitope being used as an antigen,
the T cells are CD8-positive CTLs.
[0281] If an antigen-presenting cell is transfected to express such
an epitope, preferably the cell comprises an expression vector
capable of expressing a peptide containing SEQ ID NO: 1 to SEQ ID
NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ
ID NO: 1016, or a variant amino acid sequence thereof.
[0282] A number of other methods may be used for generating CTL in
vitro. For example, autologous tumor-infiltrating lymphocytes can
be used in the generation of CTL. Plebanski et al (1995) (Induction
of peptide-specific primary cytotoxic T lymphocyte responses from
human peripheral blood.Eur J Immunol. 1995 Jun.; 25(6):1783-7) make
use of autologous peripheral blood lymphocytes (PLBs) in the
preparation of CTL. Furthermore, the production of autologous CTL
by pulsing dendritic cells with peptide or polypeptide, or via
infection with recombinant virus is possible. Also, B cells can be
used in the production of autologous CTL. In addition, macrophages
pulsed with peptide or polypeptide, or infected with recombinant
virus, may be used in the preparation of autologous CTL. S. Walter
et al. 2003 (Cutting edge: predetermined avidity of human CD8 T
cells expanded on calibrated MHC/anti-CD28-coated microspheres.J
Immunol. 2003 Nov. 15; 171(10):4974-8) describe the in vitro
priming of T cells by using artificial antigen presenting cells
(aAPCs), which is also a suitable way for generating T cells
against the peptide of choice. In the present invention, aAPCs were
generated by the coupling of preformed MHC:peptide complexes to the
surface of polystyrene particles (microbeads) by
biotin:streptavidin biochemistry. This system permits the exact
control of the MHC density on aAPCs, which allows to selectively
elicit high- or low-avidity antigen-specific T cell responses with
high efficiency from blood samples. Apart from MHC:peptide
complexes, aAPCs should carry other proteins with co-stimulatory
activity like anti-CD28 antibodies coupled to their surface.
Furthermore such aAPC-based systems often require the addition of
appropriate soluble factors, e. g. cytokines, like
interleukin-12.
[0283] Allogeneic cells may also be used in the preparation of T
cells and a method is described in detail in WO 97/26328,
incorporated herein by reference. For example, in addition to
Drosophila cells and T2 cells, other cells may be used to present
antigens such as CHO cells, baculovirus-infected insect cells,
bacteria, yeast, vaccinia-infected target cells. In addition plant
viruses may be used (see, for example, Porta et al. (1994)
Development of cowpea mosaic virus as a high-yielding system for
the presentation of foreign peptides.Virology. 1994 Aug. 1;
202(2):949-55) which describes the development of cowpea mosaic
virus as a high-yielding system for the presentation of foreign
peptides.
[0284] The activated T cells that are directed against the peptides
of the invention are useful in therapy. Thus, a further aspect of
the invention provides activated T cells obtainable by the
foregoing methods of the invention.
[0285] Activated T cells, which are produced by the above method,
will selectively recognize a cell that aberrantly expresses a
polypeptide that comprises an amino acid sequence of SEQ ID NO: 1
to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO:
543 to SEQ ID NO: 1016.
[0286] Preferably, the T cell recognizes the cell by interacting
through its TCR with the HLA/peptide-complex (for example,
binding). The T cells are useful in a method of killing target
cells in a patient whose target cells aberrantly express a
polypeptide comprising an amino acid sequence of the invention
wherein the patient is administered an effective number of the
activated T cells. The T cells that are administered to the patient
may be derived from the patient and activated as described above
(i.e. they are autologous T cells). Alternatively, the T cells are
not from the patient but are from another individual. Of course, it
is preferred if the individual is a healthy individual. By "healthy
individual" the inventors mean that the individual is generally in
good health, preferably has a competent immune system and, more
preferably, is not suffering from any disease that can be readily
tested for, and detected.
[0287] In vivo, the target cells for the CD8-positive T cells
according to the present invention can be cells of the tumor (which
sometimes express MHC class II) and/or stromal cells surrounding
the tumor (tumor cells) (which sometimes also express MHC class II;
(Dengjel et al., 2006)).
[0288] The T cells of the present invention may be used as active
ingredients of a therapeutic composition. Thus, the invention also
provides a method of killing target cells in a patient whose target
cells aberrantly express a polypeptide comprising an amino acid
sequence of the invention, the method comprising administering to
the patient an effective number of T cells as defined above.
[0289] By "aberrantly expressed" the inventors also mean that the
polypeptide is over-expressed compared to normal levels of
expression or that the gene is silent in the tissue from which the
tumor is derived but in the tumor it is expressed. By
"over-expressed" the inventors mean that the polypeptide is present
at a level at least 1.2-fold of that present in normal tissue;
preferably at least 2-fold, and more preferably at least 5-fold or
10-fold the level present in normal tissue.
[0290] T cells may be obtained by methods known in the art, e.g.
those described above.
[0291] Protocols for this so-called adoptive transfer of T cells
are well known in the art. Reviews can be found in: Gattinoni L, et
al. Adoptive immunotherapy for cancer: building on success. Nat Rev
Immunol. 2006 May; 6(5):383-93. Review. and Morgan RA, et al.
Cancer regression in patients after transfer of genetically
engineered lymphocytes. Science. 2006 Oct. 6; 314(5796):126-9).
[0292] Any molecule of the invention, i.e. the peptide, nucleic
acid, antibody, expression vector, cell, activated CTL, T-cell
receptor or the nucleic acid encoding it is useful for the
treatment of disorders, characterized by cells escaping an immune
response. Therefore any molecule of the present invention may be
used as medicament or in the manufacture of a medicament. The
molecule may be used by itself or combined with other molecule(s)
of the invention or (a) known molecule(s).
[0293] Preferably, the medicament of the present invention is a
vaccine. It may be administered directly into the patient, into the
affected organ or systemically i.d., i.m., s.c., i.p. and i.v., or
applied ex vivo to cells derived from the patient or a human cell
line which are subsequently administered to the patient, or used in
vitro to select a subpopulation of immune cells derived from the
patient, which are then re-administered to the patient. If the
nucleic acid is administered to cells in vitro, it may be useful
for the cells to be transfected so as to co-express
immune-stimulating cytokines, such as interleukin-2. The peptide
may be substantially pure, or combined with an immune-stimulating
adjuvant (see below) or used in combination with immune-stimulatory
cytokines, or be administered with a suitable delivery system, for
example liposomes. The peptide may also be conjugated to a suitable
carrier such as keyhole limpet haemocyanin (KLH) or mannan (see WO
95/18145 and Longenecker, 1993). The peptide may also be tagged,
may be a fusion protein, or may be a hybrid molecule. The peptides
whose sequence is given in the present invention are expected to
stimulate CD4 or CD8 T cells. However, stimulation of CD8 CTLs is
more efficient in the presence of help provided by CD4 T-helper
cells. Thus, for MHC Class I epitopes that stimulate CD8 CTL the
fusion partner or sections of a hybrid molecule suitably provide
epitopes which stimulate CD4-positive T cells. CD4- and
CD8-stimulating epitopes are well known in the art and include
those identified in the present invention.
[0294] In one aspect, the vaccine comprises at least one peptide
having the amino acid sequence set forth SEQ ID No. 1 to SEQ ID No.
1016, and at least one additional peptide, preferably two to 50,
more preferably two to 25, even more preferably two to 20 and most
preferably two, three, four, five, six, seven, eight, nine, ten,
eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen or
eighteen peptides. The peptide(s) may be derived from one or more
specific TAAs and may bind to MHC class I molecules.
[0295] In another aspect, the vaccine comprises at least one
peptide having the amino acid sequence set forth in SEQ ID NO: 1 to
SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543
to SEQ ID NO: 1016, and at least one additional peptide, preferably
two to 50, more preferably two to 25, even more preferably two to
20 and most preferably two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,
seventeen or eighteen peptides. The peptide(s) may be derived from
one or more specific TAAs and may bind to MHC class I
molecules.
[0296] The polynucleotide may be substantially pure, or contained
in a suitable vector or delivery system. The nucleic acid may be
DNA, cDNA, PNA, RNA or a combination thereof. Methods for designing
and introducing such a nucleic acid are well known in the art. An
overview is provided by e.g. (Pascolo et al., Human peripheral
blood mononuclear cells transfected with messenger RNA stimulate
antigen-specific cytotoxic T-lymphocytes in vitro.Cell Mol Life
Sci. 2005 August; 62(15):1755-62). Polynucleotide vaccines are easy
to prepare, but the mode of action of these vectors in inducing an
immune response is not fully understood. Suitable vectors and
delivery systems include viral DNA and/or RNA, such as systems
based on adenovirus, vaccinia virus, retroviruses, herpes virus,
adeno-associated virus or hybrids containing elements of more than
one virus. Non-viral delivery systems include cationic lipids and
cationic polymers and are well known in the art of DNA delivery.
Physical delivery, such as via a "gene-gun" may also be used. The
peptide or peptides encoded by the nucleic acid may be a fusion
protein, for example with an epitope that stimulates T cells for
the respective opposite CDR as noted above.
[0297] The medicament of the invention may also include one or more
adjuvants. Adjuvants are substances that non-specifically enhance
or potentiate the immune response (e.g., immune responses mediated
by CTLs and helper-T (TH) cells to an antigen, and would thus be
considered useful in the medicament of the present invention.
Suitable adjuvants include, but are not limited to, 1018 ISS,
aluminium salts, AMPLIVAX.RTM., AS15, BCG, CP-870,893, CpG7909,
CyaA, dSLIM, flagellin or TLRS ligands derived from flagellin, FLT3
ligand, GM-CSF, IC30, IC31, Imiquimod (ALDARA.RTM.), resiquimod,
ImuFact IMP321, Interleukins as IL-2, IL-13, IL-21,
Interferon-alpha or -beta, or pegylated derivatives thereof, IS
Patch, ISS, ISCOMATRIX, ISCOMs, JuvImmune.RTM., LipoVac, MALP2,
MF59, monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA
206, Montanide ISA 50V, Montanide ISA-51, water-in-oil and
oil-in-water emulsions, OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA,
PepTel.RTM. vector system, poly(lactid co-glycolid) [PLG]-based and
dextran microparticles, talactoferrin SRL172, Virosomes and other
Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan,
Pam3Cys, Aquila's QS21 stimulon, which is derived from saponin,
mycobacterial extracts and synthetic bacterial cell wall mimics,
and other proprietary adjuvants such as Ribi's Detox, Quil, or
Superfos. Adjuvants such as Freund's or GM-CSF are preferred.
Several immunological adjuvants (e.g., MF59) specific for dendritic
cells and their preparation have been described previously (Allison
and Krummel, 1995 The Yin and Yang of T cell costimulation.Science.
1995 Nov. 10; 270(5238):932-3. Review). Also cytokines may be used.
Several cytokines have been directly linked to influencing
dendritic cell migration to lymphoid tissues (e.g., TNF-),
accelerating the maturation of dendritic cells into efficient
antigen-presenting cells for T-lymphocytes (e.g., GM-CSF, IL-1 and
IL-4) (U.S. Pat. No. 5,849,589, specifically incorporated herein by
reference in its entirety) and acting as immunoadjuvants (e.g.,
IL-12, IL-15, IL-23, IL-7, IFN-alpha. IFN-beta) (Gabrilovich, 1996
Production of vascular endothelial growth factor by human tumors
inhibits the functional maturation of dendritic cells Nat Med. 1996
October; 2(10):1096-103).
[0298] CpG immunostimulatory oligonucleotides have also been
reported to enhance the effects of adjuvants in a vaccine setting.
Without being bound by theory, CpG oligonucleotides act by
activating the innate (non-adaptive) immune system via Toll-like
receptors (TLR), mainly TLR9. CpG triggered TLR9 activation
enhances antigen-specific humoral and cellular responses to a wide
variety of antigens, including peptide or protein antigens, live or
killed viruses, dendritic cell vaccines, autologous cellular
vaccines and polysaccharide conjugates in both prophylactic and
therapeutic vaccines. More importantly it enhances dendritic cell
maturation and differentiation, resulting in enhanced activation of
T.sub.H1 cells and strong cytotoxic T-lymphocyte (CTL) generation,
even in the absence of CD4 T cell help. The T.sub.H1 bias induced
by TLR9 stimulation is maintained even in the presence of vaccine
adjuvants such as alum or incomplete Freund's adjuvant (IFA) that
normally promote a T.sub.H2 bias. CpG oligonucleotides show even
greater adjuvant activity when formulated or co-administered with
other adjuvants or in formulations such as microparticles,
nanoparticles, lipid emulsions or similar formulations, which are
especially necessary for inducing a strong response when the
antigen is relatively weak. They also accelerate the immune
response and enable the antigen doses to be reduced by
approximately two orders of magnitude, with comparable antibody
responses to the full-dose vaccine without CpG in some experiments
(Krieg, 2006). U.S. Pat. No. 6,406,705 B1 describes the combined
use of CpG oligonucleotides, non-nucleic acid adjuvants and an
antigen to induce an antigen-specific immune response. A CpG TLR9
antagonist is dSLIM (double Stem Loop Immunomodulator) by Mologen
(Berlin, Germany) which is a preferred component of the
pharmaceutical composition of the present invention. Other TLR
binding molecules such as RNA binding TLR 7, TLR 8 and/or TLR 9 may
also be used.
[0299] Other examples for useful adjuvants include, but are not
limited to chemically modified CpGs (e.g. CpR, Idera), dsRNA
analogues such as Poly(I:C) and derivates thereof (e.g.
AmpliGen.RTM., Hiltonal.RTM., poly-(ICLC), poly(IC-R),
poly(I:C12U), non-CpG bacterial DNA or RNA as well as immunoactive
small molecules and antibodies such as cyclophosphamide, sunitinib,
Bevacizumab.RTM., celebrex, NCX-4016, sildenafil, tadalafil,
vardenafil, sorafenib, temozolomide, temsirolimus, XL-999,
CP-547632, pazopanib, VEGF Trap, ZD2171, AZD2171, anti-CTLA4, other
antibodies targeting key structures of the immune system (e.g.
anti-CD40, anti-TGFbeta, anti-TNFalpha receptor) and SC58175, which
may act therapeutically and/or as an adjuvant. The amounts and
concentrations of adjuvants and additives useful in the context of
the present invention can readily be determined by the skilled
artisan without undue experimentation.
[0300] Preferred adjuvants are imiquimod, resiquimod, GM-CSF,
cyclophosphamide, sunitinib, bevacizumab, interferon-alpha, CpG
oligonucleotides and derivates, poly-(I:C) and derivates, RNA,
sildenafil, and particulate formulations with PLG or virosomes.
[0301] In a preferred embodiment, the pharmaceutical composition
according to the invention the adjuvant is selected from the group
consisting of colony-stimulating factors, such as Granulocyte
Macrophage Colony Stimulating Factor (GM-CSF, sargramostim),
cyclophosphamide, imiquimod, resiquimod, and interferon-alpha.
[0302] In a preferred embodiment, the pharmaceutical composition
according to the invention the adjuvant is selected from the group
consisting of colony-stimulating factors, such as Granulocyte
Macrophage Colony Stimulating Factor (GM-CSF, sargramostim),
cyclophosphamide, immiquimod and resiquimod.
[0303] In a preferred embodiment of the pharmaceutical composition
according to the invention, the adjuvant is cyclophosphamide,
imiquimod or resiquimod.
[0304] Even more preferred adjuvants are Montanide IMS 1312,
Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, poly-ICLC
(Hiltonal.RTM.) and anti-CD40 mAB or combinations thereof.
[0305] This composition is used for parenteral administration, such
as subcutaneous, intradermal, intramuscular or oral administration.
For this, the peptides and optionally other molecules are dissolved
or suspended in a pharmaceutically acceptable, preferably aqueous
carrier. In addition, the composition can contain excipients, such
as buffers, binding agents, blasting agents, diluents, flavours,
lubricants, etc. The peptides can also be administered together
with immune stimulating substances, such as cytokines. An extensive
listing of excipients that can be used in such a composition, can
be, for example, taken from A. Kibbe, Handbook of Pharmaceutical
Excipients, 3.sup.rd Ed., 2000, American Pharmaceutical Association
and pharmaceutical press. The composition can be used for a
prevention, prophylaxis and/or therapy of adenomateous or cancerous
diseases. Exemplary formulations can be found in, for example,
EP2112253.
[0306] Nevertheless depending on the number and the
physico-chemical characteristics of the peptides of the invention
further research is needed to provide formulations for specific
combinations of peptides, especially combinations with more than 20
peptides that are stable for more than 12 to 18 months.
[0307] The present invention provides a medicament that useful in
treating cancer, in particular AML, Chronic lymphoid leukemia (CLL)
and other hematological malignancies.
[0308] The present invention is further directed at a kit
comprising:
[0309] (a) a container containing a pharmaceutical composition as
described above, in solution or in lyophilized form;
[0310] (b) optionally a second container containing a diluent or
reconstituting solution for the lyophilized formulation; and
[0311] (c) optionally, instructions for (i) use of the solution or
(ii) reconstitution and/or use of the lyophilized formulation.
[0312] The kit may further comprise one or more of (iii) a buffer,
(iv) a diluent, (v) a filter, (vi) a needle, or (v) a syringe. The
container is preferably a bottle, a vial, a syringe or test tube;
and it may be a multi-use container. The pharmaceutical composition
is preferably lyophilized.
[0313] Kits of the present invention preferably comprise a
lyophilized formulation of the present invention in a suitable
container and instructions for its reconstitution and/or use.
Suitable containers include, for example, bottles, vials (e.g. dual
chamber vials), syringes (such as dual chamber syringes) and test
tubes. The container may be formed from a variety of materials such
as glass or plastic. Preferably the kit and/or container contain/s
instructions on or associated with the container that indicates
directions for reconstitution and/or use. For example, the label
may indicate that the lyophilized formulation is to be
reconstituted to peptide concentrations as described above. The
label may further indicate that the formulation is useful or
intended for subcutaneous administration.
[0314] The container holding the formulation may be a multi-use
vial, which allows for repeat administrations (e.g., from 2-6
administrations) of the reconstituted formulation. The kit may
further comprise a second container comprising a suitable diluent
(e.g., sodium bicarbonate solution).
[0315] Upon mixing of the diluent and the lyophilized formulation,
the final peptide concentration in the reconstituted formulation is
preferably at least 0.15 mg/mL/peptide (=75 .mu.g) and preferably
not more than 3 mg/mL/peptide (=1500 .mu.g). The kit may further
include other materials desirable from a commercial and user
standpoint, including other buffers, diluents, filters, needles,
syringes, and package inserts with instructions for use.
[0316] Kits of the present invention may have a single container
that contains the formulation of the pharmaceutical compositions
according to the present invention with or without other components
(e.g., other compounds or pharmaceutical compositions of these
other compounds) or may have distinct container for each
component.
[0317] Preferably, kits of the invention include a formulation of
the invention packaged for use in combination with the
co-administration of a second compound (such as adjuvants (e.g.
GM-CSF), a chemotherapeutic agent, a natural product, a hormone or
antagonist, an anti-angiogenesis agent or inhibitor, a
apoptosis-inducing agent or a chelator) or a pharmaceutical
composition thereof. The components of the kit may be pre-complexed
or each component may be in a separate distinct container prior to
administration to a patient. The components of the kit may be
provided in one or more liquid solutions, preferably, an aqueous
solution, more preferably, a sterile aqueous solution. The
components of the kit may also be provided as solids, which may be
converted into liquids by addition of suitable solvents, which are
preferably provided in another distinct container.
[0318] The container of a therapeutic kit may be a vial, test tube,
flask, bottle, syringe, or any other means of enclosing a solid or
liquid. Usually, when there is more than one component, the kit
will contain a second vial or other container, which allows for
separate dosing. The kit may also contain another container for a
pharmaceutically acceptable liquid. Preferably, a therapeutic kit
will contain an apparatus (e.g., one or more needles, syringes, eye
droppers, pipette, etc.), which enables administration of the
agents of the invention that are components of the present kit.
[0319] The present formulation is one that is suitable for
administration of the peptides by any acceptable route such as oral
(enteral), nasal, ophthal, subcutaneous, intradermal,
intramuscular, intravenous or transdermal. Preferably the
administration is s.c., and most preferably i.d. Administration may
be by infusion pump.
[0320] Since the peptides of the invention were isolated from CLL,
the medicament of the invention is preferably used to treat CLL. In
a preferred embodiment, since the peptides of the invention derived
from a protein selected from the group consisting of APOBEC3D,
CDK14, RASGRF1, CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6,
DMXL1, PARP3, TP53I11, B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296,
BACH2, PRR12, ZFAND5, ATP5G1, DMD, ARID5B, ZNF638, DDX46, RRM2B,
BLNK, HSH2D, ERP44, METTL7A, ELP3, NLRP2, ZC3H12D, NELFE, ATP6V1C1,
HLA-DMA, TUFM, EIF6, CKAP4, COBLL1, TMED4, TNFRSF13C, UBL7,
CXorf21, ASUN, SL24D1, and TRAF3IP3 were isolated from CLL, and
thus the medicament of the invention is preferably used to treat
CLL.
[0321] The present invention further includes a method for
producing a personalized pharmaceutical for an individual patient
comprising manufacturing a pharmaceutical composition comprising at
least one peptide selected from a warehouse of pre-screened TUMAPs,
wherein the at least one peptide used in the pharmaceutical
composition is selected for suitability in the individual patient.
Preferably, the pharmaceutical composition is a vaccine.The method
could also be adapted to produce T cell clones for down-stream
applications such as TCR isolations.
[0322] A "personalized pharmaceutical" shall mean specifically
tailored therapies for one individual patient that will only be
used for therapy in such individual patient, including actively
personalized cancer vaccines and adoptive cellular therapies using
autologous patient tissue.
[0323] As used herein, the term "warehouse" shall refer to a group
of peptides that have been pre-screened for immunogenicity and
over-presentation in a particular tumour type. The term "warehouse"
is not intended to imply that the particular peptides included in
the vaccine have been pre-manufactured and stored in a physical
facility, although that possibility is contemplated. It is
expressly contemplated that the peptides may be manufactured de
novo for each individualized vaccine produced, or may be
pre-manufactured and stored.
[0324] The warehouse (e.g. in the form of a database) is composed
of tumour-associated peptides which were highly overexpressed in
the tumour tissue of several HLA-A, HLA-B and HLA-C positive CLL
patients analyzed (see tables above). It contains MHC class I and
MHC class II peptides. In addition to the tumor associated peptides
collected from several GBM tissues, the warehouse may contain an
HLA-A*02 and an HLA-A*24 marker peptide. These peptides allow
comparison of the magnitude of T-cell immunity induced by TUMAPS in
a quantitative manner and hence allow important conclusion to be
drawn on the capacity of the vaccine to elicit anti-tumor
responses. Secondly, it functions as an important positive control
peptide derived from a "non-self" antigen in the case that any
vaccine-induced T-cell responses to TUMAPs derived from "self"
antigens in a patient are not observed. And thirdly, it may allow
conclusions to be drawn, regarding the status of immunocompetence
of the patient population.
[0325] HLA class I and II TUMAPs for the warehouse are identified
by using an integrated functional genomics approach combining gene
expression analysis, mass spectrometry, and T-cell immunology. The
approach assures that only TUMAPs truly present on a high
percentage of tumours but not or only minimally expressed on normal
tissue, are chosen for further analysis. For peptide selection, CLL
samples from patients and blood from healthy donors were analyzed
in a stepwise approach:
[0326] 1. HLA ligands from the malignant material were identified
by mass spectrometry
[0327] 2. Genome-wide messenger ribonucleic acid (mRNA) expression
analysis by microarrays was used to identify genes over-expressed
in the malignant tissue (CLL) compared with a range of normal
organs and tissues
[0328] 3. Identified HLA ligands were compared to gene expression
data. Peptides encoded by selectively expressed or over-expressed
genes as detected in step 2 were considered suitable TUMAP
candidates for a multi-peptide vaccine.
[0329] 4. Literature research was performed in order to identify
additional evidence supporting the relevance of the identified
peptides as TUMAPs
[0330] 5. The relevance of over-expression at the mRNA level was
confirmed by redetection of selected TUMAPs from step 3 on tumor
tissue and lack of (or infrequent) detection on healthy tissues
[0331] 6. To assess whether an induction of in vivo T-cell
responses by the selected peptides may be feasible, in vitro
immunogenicity assays were performed using human T cells from
healthy donors as well as from CLL patients.
[0332] In an aspect, the peptides are pre-screened for
immunogenicity before being included in the warehouse. By way of
example, and not limitation, the immunogenicity of the peptides
included in the warehouse is determined by a method comprising in
vitro T-cell priming through repeated stimulations of CD8+ T cells
from healthy donors with artificial antigen presenting cells loaded
with peptide/MHC complexes and anti-CD28 antibody.
[0333] This method is preferred for rare cancers and patients with
a rare expression profile. In contrast to multi-peptide cocktails
with a fixed composition as currently developed the warehouse
allows a significantly higher matching of the actual expression of
antigens in the tumour with the vaccine. Selected single or
combinations of several "off-the-shelf" peptides will be used for
each patient in a multitarget approach. In theory an approach based
on selection of e.g. 5 different antigenic peptides from a library
of 50 would already lead to approximately 17 million possible drug
product (DP) compositions.
[0334] In an aspect, the peptides are selected for inclusion in the
vaccine based on their suitability for the individual patient based
on the method according to the present invention as described
herein, and as follows.
[0335] The HLA phenotype, transcriptomic and peptidomic data will
be gathered from the patient's tumour material and blood samples to
identify the most suitable peptides for each patient containing
warehouse and patient-unique (ie. mutated) TUMAPs. Those peptides
will be chosen, which are selectively or over-expressed in the
patients tumor and, where possible, showed strong in vitro
immunogenicity if tested with the patients individual PBMCs.
[0336] Preferably, the peptides included in the vaccine are
identified by a method comprising: (a) identifying
tumour-associated peptides (TUMAPs) presented by a tumor sample
from the individual patient; (b) comparing the peptides identified
in (a) with a warehouse (database) of peptides as described above;
and (c) selecting at least one peptide from the warehouse
(database) that correlates with a tumour-associated peptide
identified in the patient. For example, the TUMAPs presented by the
tumor sample are identified by: (al) comparing expression data from
the tumor sample to expression data from a sample of normal tissue
corresponding to the tissue type of the tumor sample to identify
proteins that are over-expressed or aberrantly expressed in the
tumor sample; and (a2) correlating the expression data with
sequences of MHC ligands bound to MHC class I and/or class II
molecules in the tumor sample to identify MHC ligands derived from
proteins over-expressed or aberrantly expressed by the tumor.
Preferably, the sequences of MHC ligands are identified by eluting
bound peptides from MHC molecules isolated from the tumor sample,
and sequencing the eluted ligands. Preferably, the tumor sample and
the normal tissue are obtained from the same patient.
[0337] In addition to, or as an alternative to, selecting peptides
using a warehousing (database) model, TUMAPs may be identified in
the patient de novo and then included in the vaccine. As one
example, candidate TUMAPs may be identified in the patient by (a1)
comparing expression data from the tumor sample to expression data
from a sample of normal tissue corresponding to the tissue type of
the tumor sample to identify proteins that are over-expressed or
aberrantly expressed in the tumor sample; and (a2) correlating the
expression data with sequences of MHC ligands bound to MHC class I
and/or class II molecules in the tumor sample to identify MHC
ligands derived from proteins over-expressed or aberrantly
expressed by the tumor. As another example, proteins may be
identified containing mutations that are unique to the tumor sample
relative to normal corresponding tissue from the individual
patient, and TUMAPs can be identified that specifically target the
mutation. For example, the genome of the tumour and of
corresponding normal tissue can be sequenced by whole genome
sequencing: For discovery of non-synonymous mutations in the
protein-coding regions of genes, genomic DNA and RNA are extracted
from tumour tissues and normal non-mutated genomic germline DNA is
extracted from peripheral blood mononuclear cells (PBMCs). The
applied NGS approach is confined to the re-sequencing of protein
coding regions (exome re-sequencing). For this purpose, exonic DNA
from human samples is captured using vendor-supplied target
enrichment kits, followed by sequencing with e.g. a HiSeq2000
(Illumina). Additionally, tumour mRNA is sequenced for direct
quantification of gene expression and validation that mutated genes
are expressed in the patients' tumours. The resultant millions of
sequence reads are processed through software algorithms. The
output list contains mutations and gene expression. Tumour-specific
somatic mutations are determined by comparison with the
PBMC-derived germline variations and prioritized.. The de novo
identified peptides may then be tested for immunogenicity as
described above for the warehouse, and candidate TUMAPs possessing
suitable immunogenicity are selected for inclusion in the
vaccine.
[0338] In one exemplary embodiment, the peptides included in the
vaccine are identified by: (a) identifying tumour-associated
peptides (TUMAPs) presented by a tumor sample from the individual
patient by the methdos described above; (b) comparing the peptides
identified in a) with a warehouse of peptides that have been
prescreened for immunogenicity and overpresentation in tumors as
compared to corresponding normal tissue; (c) selecting at least one
peptide from the warehouse that correlates with a tumour-associated
peptide identified in the patient; and (d) optionally, selecting at
least one peptide identified de novo in (a) confirming its
immunogenicity.
[0339] In one exemplary embodiment, the peptides included in the
vaccine are identified by: (a) identifying tumour-associated
peptides (TUMAPs) presented by a tumor sample from the individual
patient; and (b) selecting at least one peptide identified de novo
in (a) and confirming its immunogenicity.
[0340] Once the peptides are selected, the vaccine is
manufactured.
[0341] The vaccine preferably is a liquid formulation consisting of
the individual peptides dissolved in 33% DMSO.
[0342] Each peptide to be included into a product is dissolved in
DMSO. The concentration of the single peptide solutions has to be
chosen depending on the number of peptides to be included into the
product. The single peptide-DMSO solutions are mixed in equal parts
to achieve a solution containing all peptides to be included in the
product with a concentration of -2.5 mg/ml per peptide. The mixed
solution is then diluted 1:3 with water for injection to achieve a
concentration of 0.826 mg/ml per peptide in 33% DMSO. The diluted
solution is filtered through a 0.22 pm sterile filter. The final
bulk solution is obtained.
[0343] Final bulk solution is filled into vials and stored at
-20.degree. C. until use. One vial contains 700 .mu.L solution
containing 0.578 mg of each peptide. Of this, 500 .mu.L (approx.
400 .mu.g per peptide) will be applied for intradermal
injection.
[0344] The present invention will now be described in the following
examples that describe preferred embodiments thereof, nevertheless,
without being limited thereto. For the purposes of the present
invention, all references as cited herein are incorporated by
reference in their entireties.
[0345] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0346] FIGS. 1a-1d show the HLA surface expression of primary CLL
samples. (FIG. 1a) HLA class I and (FIG. 1b) HLA class II
expression of CD5+CD19+CLL cells compared to autologous
CD5.sup.-CD19+B cells in 7 primary CLL samples. Data are expressed
as mean.+-.s.d. of triplicate experiments. (FIG. 1c) Mean HLA class
I and (FIG. 1d) HLA class II expression CD5+CD19+CLL cells compared
to autologous CD5.sup.-CD19+B cells (n=7).* P<0.01
Abbreviations: UPN, uniform patient number
[0347] FIGS. 2a-2f show the identification of a novel category of
tumor-associated antigens by HLA ligandome profiling. (FIG. 2a)
Overlap of HLA class I ligand source proteins of primary CLL
samples (n=30) and HV PBMC (n=30). (FIG. 2b) Comparative profiling
of HLA class I ligand source proteins based on the frequency of HLA
restricted representation in CLL and HV PBMC ligandomes.
Frequencies [%] of CLL patients/HVs positive for HLA restricted
presentation of the respective source protein (x-axis) are
indicated on the y-axis. The box on the left-hand side highlights
the subset of source proteins showing CLL-exclusive representation
in >20% of patients (LiTAAs: ligandome-derived tumor-associated
antigens). (FIG. 2c) Representation of published CLL-associated
antigens in HLA class I ligandomes. Bars indicate relative
representation [%] of respective antigens by HLA class I ligands in
CLL and HV PBMC. Dashed lines separate the antigens into three
groups according to their degree of CLL-association. (FIG. 2d)
Source protein overlaps of CLL samples from different stages of
disease (Binet A (n=9), Binet B (n=7), Binet C (n=14)). (FIG. 2e)
Heatmap analysis of the representation frequencies [%] of LiTAAs
across different disease stages (Binet A-C, as in (FIG. 2d)) (FIG.
2f) Heatmap analysis of LiTAA representation [%] on primary CLL
samples with dell7p (n=5) and without dell7p (n=25). Abbreviations:
CLL, chronic lymphocytic leukemia; HV, healthy volunteer
[0348] FIGS. 3a-3e show that LiTAAs are specifically recognized by
CLL patient immune responses. (FIG. 3a) HLA class I LiTAAs and
corresponding LiTAPs (3 HLA-A*03, 5 HLA-A*02, 5 HLA-B*07)
functionally evaluated in IFNy ELISPOT assays. Absolute numbers and
frequencies of peptide-specific immune recognition by CLL patient
PBMC are summarized in the right hand column. (FIG. 3b) Example of
A*03 LiTAPs evaluated in ELISPOT using HV PBMC as a control. An EBV
epitope mix containing 4 frequently recognized peptides ( . . . )
was used as positive control, HIV GAG1826A*03 peptide served as
negative control. (FIG. 3c) Example of ELISPOT assays using
HLA-A*03 LiTAPs (n=3) on PBMC of 3 different CLL patients. Results
are shown for immunoreactive LiTAPs. EBV epitope mix served as
positive control, HIV GAG18-26 A*03 peptide as negative control.
(FIG. 3d) Example of HLA-A*03 benign tissue-derived LiBAPs (n=3)
tested on CLL patient PBMC as internal control for the target
selection strategy. EBV epitope mix served as positive control, HIV
GAG 18-26 A*03 peptide as negative control. (FIG. 3e) Scatterplot
of the allele-adjusted frequencies of LiTAP presentation in CLL
ligandomes (as detected by MS) and the corresponding
allele-adjusted frequencies of immune recognition by CLL patient
PBMC in IFNy ELISPOT. Data points are shown for the 14/15 LiTAPs
showing immune recognition. Abbreviations: LiTAP, ligandome-derived
tumor-associated peptide; HV, healthy volunteer; neg., negative;
pos., positive; UPN, uniform patient number; LiBAP,
ligandome-derived benign tissue-associated peptide; MS, mass
spectrometry .
[0349] FIGS. 4a-4g show the identification of
additional/synergistic HLA class II LiTAAs and LiTAPs. (FIG. 4a)
Overlap of HLA class II ligand source proteins of primary CLL
samples (n=20) and HV PBMC (n=13). (FIG. 4b) Comparative profiling
of HLA class II ligand source proteins based on the frequency of
HLA restricted representation in CLL and HV PBMC ligandomes.
Frequencies [%] of CLL patients/HVs positive for HLA restricted
presentation of the respective source protein (x-axis) are
indicated on the y-axis. The box on the left-hand side highlights
the subset of source proteins showing CLL-exclusive representation
in >20% of patients (LiTAAs: ligandome-derived tumor-associated
antigens). (FIG. 4c) HLA class II LiTAAs and corresponding LiTAPs
(n=6) functionally evaluated in IFNy ELISPOT assays. Absolute
numbers and frequencies of peptide-specific immune recognition by
CLL patient PBMC are summarized in the right hand column. (FIG. 4d)
Example of HLA class II LiTAPs evaluated in ELISPOT using HV PBMC
as a control. PHA was used as positive control. FLNA1669-1683
HLA-DR peptide served as negative control. (FIG. 4e) Example of
ELISPOT assays using HLA class II LiTAPs (n=6) on PBMC of 3
different CLL patients. Results are shown for immunoreactive
LiTAPs. PHA was used as positive control, FLNA1669-1683 HLA-DR
peptide served as negative control. (FIG. 4f) Overlap analysis of
CLL-exclusive HLA class I and HLA class II ligand source proteins
for shared/synergistic vaccine targets. (FIG. 4g) Heatmap analysis
of the 132 shared HLA class I/II LiTAAs (identified in (FIG. 4d)).
The two source proteins showing representation in .gtoreq.20% of
both, HLA class I and II CLL patient ligandomes are specified.
[0350] FIGS. 5a-5c show the longitudinal HLA class I ligandome
analysis of CLL patients undergoing chemo-/immunotherapy.
Volcano-Plots of the relative abundances of ligands in the HLA
class I ligandomes of patients after treatment compared to their
respective abundance prior to therapy (ratio post therapy/pre
therapy). Dashed lines indicate the thresholds for significant
changes in abundance (.gtoreq.2-fold ratio, p<0.05), with
significantly up-regulated ligands in the upper-right and
significantly down-regulated ligands in the upper-left. Frequencies
of significantly regulated ligands are specified in the respective
quadrants. LiTAPs showing significant regulation over the course of
therapy are marked in red and their sequences are specified. (FIG.
5a) Analysis of a CLL patient ligandome prior to therapy and
48h/24h after treatment with rituximab/bendamustin (375
mg/m.sup.2/90 mg/m.sup.2). 1/28 (3.6%) of detectable LiTAPs showed
significant changes in abundance. (FIG. 5b) Analysis of a CLL
patient ligandome prior to therapy and after the first 7 days of
treatment with alemtuzumab (3 doses of alemtuzumab, 10 mg, 20 mg
and 30mg on day 1, 3 and 5; ligandome analysis on day 7). 3/24
(12.5%) of detectable LiTAPs showed significant changes in
abundance. (FIG. 5c) Analysis of a CLL patient ligandome prior to
therapy and 24 h after treatment with 300 mg ofatumumab. 2/10
(20.0%) of detectable LiTAPs showed significant changes in
abundance.
[0351] FIGS. 6a and 6b show the retrospective survival analysis of
CLL patients with respect to their immune recognition of LiTAPs.
(FIG. 6a) Kaplan Meier plot of the overall survival of 44 CLL
patients. (FIG. 6b) Overall survival of subjects evaluated for
LiTAP-specific immune responses grouped as follows: black, CLL
patients showing immune responses to >1 LiTAPs (n=10). Red, CLL
patients showing immune reactions to 0-1 LiTAPs (n=34).
[0352] FIG. 7 shows the saturation analysis of HLA class I ligand
source protein identifications in CLL patients. Number of unique
HLA ligand source protein identifications as a function of total
HLA ligand source protein identifications in 30 CLL patients.
Exponential regression allowed for the robust calculation
(R.sup.2=0.9912) of the maximum attainable number of different
source protein identifications (dashed line). The dotted line
depicts the source proteome coverage achieved in our CLL patient
cohort.
[0353] FIGS. 8a-8f show that HLA-A*02 and B*07 LiTAPs are
specifically recognized by CLL patient immune responses. (FIG. 8a)
Example of HLA-A*02 (n=3) and (FIG. 8d) HLA-B*07 (n=3) benign
tissue-derived LiBAPs tested on CLL patient PBMC as internal
control for the target selection strategy. EBV epitope mix served
as positive control, HIV XX.sub.xx-xx A*02 and HIV XX.sub.xx-xx
HLA-B*07 peptide served as negative control, respectively. (FIG.
8b) Example of HLA-A*02 (n=6) and (FIG. 8e) HLA-B*07 (n=5) LiTAPs
evaluated in ELISPOT assays using HV PBMC as a control. Positive
and negative controls as described in (FIG. 8a). (FIG. 8c) Example
of ELISPOT assays using HLA-A*02 (n=6) and (FIG. 8f) HLA-B*07 (n=5)
LiTAPs on PBMC of 3 different HLA-matched CLL patients, each.
Results are shown for immunoreactive LiTAPs. Positive and negative
controls as described in (FIG. 8a). Abbreviations: LiBAP,
ligandome-derived benign tissue-associated peptide; LiTAP,
ligandome-derived tumor-associated peptide; HV, healthy volunteer;
neg., negative; pos., positive; UPN, uniform patient number.
[0354] FIGS. 9a and 9b show the intracellular cytokine and tetramer
staining of HLA-A*03 LiTAP specific CLL patient T cells. (FIG. 9a)
Intracellular staining for IFNy and TNF.alpha. of PA*03.sup.3
(DMXL11271-1279 SSSGLHPPK (SEQ ID NO: 77) stimulated CLL patient
PBMC. PMA/ionomycin served as positive control, HIV GAG.sub.18-26
A*03 peptide as negative control. (FIG. 9b) Tetramer staining of
CLL patient CD8+ T cells with P.sub.A*033 (DMXL1.sub.1271-1279
SSSGLHPPK (SEQ ID NO: 77)) tetramers. As control, tetramer staining
with the non-recognized P.sub.A*02.sup.1 (ABCA6.sub.1270-1278
ILDEKPVII (SEQ ID NO: 63) in the same patient is shown.
[0355] FIGS. 10a-10d show the quantification of HLA surface
expression on primary CLL cells from patients undergoing
chemo-/immunotherapy. HLA surface expression on CD5+CD19+CLL cells
was quantified by flow cytometry, before and after therapy. Data
are expressed as mean.+-.s.d. of triplicate experiments. (FIG. 10a)
HLA class I and (FIG. 10b) HLA class II surface expression on
primary CLL cells of 4 patients prior to therapy and 24h after
treatment with rituximab. (FIG. 10c) HLA class I and (FIG. 10d) HLA
class II surface expression on primary CLL cells of a patient prior
to therapy, 72 h (10 mg) and 7d (60 mg) after treatment with
alemtuzumab. *P<0.01 Abbreviations: UPN, uniform patient number;
h, hour; d, day.
[0356] FIG. 11 shows the over-presentation of peptide ILDEKPVII
(SEQ ID NO: 63) in normal tissues as compared to CLL samples. Shown
are only samples on which the peptide was detected. The test panel
included 12 CLL samples and the following normal samples:
1.times.adipose tissue, 3.times.adrenal gland, 6.times.artery,
5.times.bone marrow, 7.times.brain, 3.times.breast, 5.times.nerve,
13.times.colon, 7.times.esophagus, 2.times.gallbladder,
5.times.heart, 12.times.kidney, 20.times.liver, 44.times.lung,
3.times.lymph node, 4.times.peripheral blood mononuclear cells,
2.times.ovary, 6.times.pancreas, 1.times.peritoneum,
3.times.pituitary, 2.times.placenta, 3.times.pleura,
3.times.prostate, 6.times.rectum, 7.times.salivary gland,
4.times.skeletal muscle, 5.times.skin, 3.times.small intestine,
4.times.spleen, 5.times.stomach, 4.times.testis, 3.times.thymus,
3.times.thyroid gland, 3.times.trachea, 2.times.ureter,
5.times.urinary bladder, 2.times.uterus, 2.times.vein.
EXAMPLES
Example 1
[0357] Identification and Quantitation of Tumor Associated Peptides
Presented on the Cell Surface
[0358] Tissue Samples
[0359] Patients' tumor samples were provided by University of
Tubingen, Tubingen, Germany. Written informed consents of all
patients had been given. For ligandome analysis, PBMC from CLL
patients (>80% CLL cell frequency) as well as PBMC from healthy
volunteers (HVs) were isolated by density gradient centrifugation.
Informed consent was obtained in accordance with the Helsinki
protocol. This study was performed according to the guidelines of
the local ethics committee. HLA typing was carried out by the
Department of Hematology and Oncology, Tubingen. Samples were
stored at -80.degree. C. until further use.
[0360] Quantification of HLA Surface Expression
[0361] For comparison with healthy autologous B lymphocytes,
quantification of HLA surface expression was performed in patient
samples containing at least 0.5% CD5.sup.-CD19+ normal B cells. HLA
surface expression was analyzed using the QIFIKIT.RTM. quantitative
flow cytometric assay (Dako) according to the manufacturer's
instructions. In brief, triplicates of each sample were stained
with the pan-HLA class I specific monoclonal antibody (mAb) W6/32,
HLA-DR specific mAb L243 (both produced in house) or IgG isotype
control (BioLegend), respectively. Surface marker staining was
carried out with directly labeled CD3 (BD), CD5 (BD) and CD19 (BD)
antibodies. 7-AAD (BioLegend) was added as viability marker
immediately prior to flow cytometric analysis on a FACSCanto
Analyzer (BD).
[0362] Isolation of HLA Peptides from Tissue Samples
[0363] HLA class I and II molecules were isolated employing
standard immunoaffinity purification as described previously. In
brief, snap-frozen cell pellets were lysed in 10 mM CHAPS/PBS
(AppliChem, St. Louis, Mo., USA/Gibco, Carlsbad, Calif., USA)
containing 1.times. protease inhibitor (Complete, Roche, Basel,
Switzerland). HLA molecules were single-step purified using the
pan-HLA class I specific mAb W6/32 and the pan-HLA class II
specific mAb TU39 respectively, covalently linked to CNBr-activated
sepharose (GE Healthcare, Chalfont St Giles, UK). HLA:peptide
complexes were eluted by repeated addition of 0.2% trifluoroacetic
acid (TFA, Merck, Whitehouse Station, N.J., USA). Elution fractions
E1-E8 were pooled and free HLA ligands were isolated by
ultrafiltration using centrifugal filter units (Amicon, Millipore,
Billerica, Mass., USA). HLA ligands were extracted and desalted
from the filtrate using ZipTip C18 pipette tips (Millipore).
Extracted peptides were eluted in 35 .mu.l of 80% acetonitrile
(ACN, Merck)/0.2% TFA, centrifuged to complete dryness and
resuspended in 25 .mu.l of 1% ACN/0.05% TFA. Samples were stored at
-20.degree. C. until analysis by LC-MS/MS.
[0364] Analysis of HLA Ligands by LC-MS/MS
[0365] Peptide samples were separated by reversed-phase liquid
chromatography (nanoUHPLC, UltiMate 3000 RSLCnano,ThermoFisher,
Waltham, Mass., USA) and subsequently analyzed in an on-line
coupled LTQ Orbitrap XL hybrid mass spectrometer (ThermoFisher).
Samples were analyzed in 5 technical replicates. Sample volumes of
5 .mu.l (sample shares of 20%) were injected onto a 75
.mu.m.times.2 cm trapping column (Acclaim PepMap RSLC,
ThermoFisher) at 4 .mu.l/min for 5.75 min. Peptide separation was
subsequently performed at 50.degree. C. and a flow rate of 175
nl/min on a 50 .mu.m.times.50 cm separation column (Acclaim PepMap
RSLC, ThermoFisher) applying a gradient ranging from 2.4-32.0% of
ACN over the course of 140 min. Eluting peptides were ionized by
nanospray ionization and analyzed in the mass spectrometer
implementing a top 5 CID (collision induced dissociation) method
generating fragment spectra for the 5 most abundant precursor ions
in the survey scans. Resolution was set to 60,000. For HLA class I
ligands, the mass range was limited to 400-650 m/z with charge
states 2 and 3 permitted for fragmentation. For HLA class II, a
mass range of 300-1,500 m/z was analyzed with charge states allowed
for fragmentation.
[0366] Database Search and Spectral Annotation
[0367] For data processing, the software Proteome Discoverer (v1.3,
ThermoFisher) was used to integrate the search results of the
Mascot search engine (Mascot 2.2.04, Matrix Science) against the
human proteome as comprised in the Swiss-Prot database (release:
Sep. 27, 2013; 20,279 reviewed protein sequences contained). The
search combined data of technical replicates and was not restricted
by enzymatic specificity. Precursor mass tolerance was set to 5
ppm, fragment mass tolerance to 0.5 Da. Oxidized methionine was
allowed as a dynamic modification. False discovery rates (FDR) were
determined by the Percolator algorithm based on processing against
a decoy database consisting of the shuffled target database. FDR
was set at a target value of q.ltoreq.0.05 (5% FDR).
Peptide-spectrum matches (PSMs) with q.ltoreq.0.05 were filtered
according to additional, orthogonal parameters, to ensure spectral
quality and validity. Mascot scores were filtered to .gtoreq.20.
For HLA class I, peptide lengths were limited to 8-12 amino acids
(aa) of length. For HLA class II, peptides were limited to 12-25 aa
length. Protein grouping was disabled, allowing for multiple
annotations of peptides (e.g. conserved sequences mapping into
multiple proteins). For quality control, yield thresholds of
.gtoreq.300 unique HLA class I ligands and .gtoreq.100 unique HLA
class II ligands per sample were applied. HLA annotation was
performed using SYFPEITHI or an extended in-house database.
[0368] Longitudinal Analysis of CLL Patient Ligandomes Over the
Course of Therapy
[0369] For label-free quantification (LFQ) of the relative HLA
ligand abundances over the course of therapy, the injected peptide
amounts of paired samples were normalized and LC-MS/MS analysis was
performed in 5 technical replicates for each sample.
[0370] In brief, relative amounts of substance of paired samples
were calculated from average precursor ion intensities determined
in dose-finding mass spectrometry runs and adjusted accordingly by
dilution. Relative quantification of HLA ligands was performed by
calculating the area under the curve of the corresponding precursor
extracted ion chromatograms (XIC) using Proteome Discoverer 1.3.
The ratios of the mean areas of the individual peptides in the 5
LFQ-MS runs of each sample were calculated and two-tailed t-tests
were performed using an in-house Matlab script (v8.2,
Mathworks).
[0371] Peptide Synthesis
[0372] The automated peptide synthesizer EPS221 (Abimed) was used
to synthesize peptides using the
9-fluorenylmethyl-oxycarbonyl/tert-butyl (Fmoc/tBu) strategy as
described. Synthetic peptides were used for validation of LC-MS/MS
identifications as well as for functional experiments.
[0373] Amplification of Peptide-Specific T Cells
[0374] PBMC from CLL patients and healthy volunteers were cultured
in RPMI1640 medium (Gibco) supplemented with 10% pooled human serum
(PHS, produced in-house), 100 mM .beta.-mercaptoethanol (Roth,
Karlsruhe, Germany) and 1% penicillin/streptomycin (GE). For CD8+ T
cell stimulation, PBMC were thawed and pulsed with 1 .mu.g/ml per
peptide. Peptide-pulsed PBMC (5-6.times.10.sup.6 cells/ml) were
cultured at 37.degree. C. and 5% CO.sub.2 for 12 days. On day 0 and
day 1.5 ng/ml IL-4 (R&D Systems, Minneapolis, Minn., USA) and 5
ng/ml IL-7 (Promokine, Heidelberg, Germany) were added to the
culture medium. On days 3, 5, 7 and 9, 2 ng/ml IL-2 (R&D
Systems) were added to the culture medium. Peptide-stimulated PBMC
were functionally characterized by ELISPOT assays on day 12 and by
intracellular cytokine staining on day 13 respectively. For CD4+
T-cell stimulation, culture was performed as described for CD8+ T
cells with 2 modifications: pulsing was carried out with 10
.mu.g/ml of HLA class II peptide and no IL-4 and IL-7 was
added.
[0375] IFN-.gamma. ELISPOT Assay
[0376] IFN-.gamma. ELISPOT assays were carried out as described
previously (33). In brief, 96-well nitrocellulose plates
(Millipore) were coated with 1 mg/ml IFN-.gamma. mAb (Mabtech,
Cincinnati, Ohio, USA) and incubated over night at 4 .degree. C.
Plates were blocked with 10% PHS for 2 h at 37.degree. C.
5.times.10.sup.5 cells/well of pre-stimulated PBMC were pulsed with
1 .mu.g/ml (HLA class I) or 2.5 .mu.g/ml (HLA class II) peptide and
incubated for 24-26 h. Readout was performed according to
manufacturer's instructions. Spots were counted using an ImmunoSpot
S5 analyzer (CTL, Shaker Heights, Ohio, USA). T cell responses were
considered to be positive when >15 spots/well were counted and
the mean spot count per well was at least 3-fold higher than the
mean number of spots in the negative control wells (according to
the cancer immunoguiding program (CIP) guidelines).
[0377] Intracellular IFN-.gamma. and TNF-.alpha. Staining
[0378] The frequency and functionality of peptide-specific CD8+ T
cells was analyzed by intracellular IFN-.gamma. and TNF-.alpha.
staining. PBMC were pulsed with 1 .mu.g/ml of individual peptide
and incubated in the presence of 10 .mu.g/ml Brefeldin A (Sigma,
St. Louis, Mo., USA) and 10 .mu.g/ml GolgiStop (BD) for 6-8 h.
Cells were labeled using Cytofix/Cytoperm (BD), CD8-PECy7 (Beckman
Coulter, Fullerton, Calif., USA), CD4-APC (BD Bioscience),
TNF-.alpha.-PE (Beckman Coulter) and IFN-.gamma.-FITC (BD). Samples
were analyzed on a FACS Canto II.
[0379] The frequency of peptide-specific CD8+ T cells was
determined by staining with anti-CD8 and
HLA:peptide-tetramer-PE
[0380] Results
[0381] Primary CLL Cells Display No Loss or Down-regulation of HLA
Expression Compared to Autologous Normal B Cells
[0382] HLA loss or down-regulation in malignancies may pose a major
limitation for T cell based immunotherapy. Therefore, as a first
step, the inventors determined the HLA expression levels on
CD19.sup.+CD5.sup.+CLL cells compared to autologous
CD19.sup.+CD5.sup.-B lymphocytes. HLA surface levels were
quantified by flow cytometry in a panel of 7 CLL patients. HLA
surface expression levels revealed patient-individual heterogeneity
with total HLA class I molecule counts ranging from
.about.42,500-288,500 molecules/cell on CLL cells and
.about.32,000-256,500 molecules/cell on normal B cells. Patient
individual analysis of HLA surface expression in triplicates
revealed small, albeit significant differences in expression levels
(P<0.01) for 4/7 patients (FIG. 1a). HLA-DR expression ranged
from .about.29,000-100,500 on CLL cells and .about.19,500-79,500 on
B cells. Minor differences in HLA-DR levels (P<0.01) were
detected for 5/7 patients. Statistical analysis of mean HLA surface
expression on CLL cells compared to normal B cells showed no
significant differences in HLA class I and II expression (FIGS. 1c,
1d). Taken together, these data demonstrate high levels of HLA
class I and II expression on CLL cells without evidence of HLA loss
or down-regulation compared to normal B cells.
[0383] LC-MS/MS identifies a vast array of naturally presented HLA
class I & II ligands Mapping the HLA class I ligandomes of 30
CLL patients, the inventors were able to identify a total of 18,844
different peptides representing 7,377 source proteins, attaining
>95% of maximum attainable coverage (FIG. 7). The numbers of
different peptides identified per patient ranged from 345-2,497
(mean 1,131). Overall, peptides restricted by more than 30
different HLA-A and -B alleles (covering >99% of the Caucasian
population_ENREF_27) were identified in this study. In the HV
cohort of 30 PBMC donors, a total of 17,322 unique peptides
representing 7,180 different source proteins were identified
(>90% coverage). The HLA allele distribution in the HV cohort
covered 100% of HLA-A and >80% of HLA-B alleles in the CLL
patient cohort.
[0384] Analysis of the HLA class II ligandomes was performed for 20
CLL patients. A total of 5,059 unique peptides representing 1,486
source proteins was identified. The HLA class II HV cohort of 13
PBMC donors yielded 2,046 different peptides representing 756
source proteins.
[0385] Comparative Profiling of HLA Class I Ligandomes Reveals a
Multitude of CLL-Associated Antigens
[0386] In order to identify novel CLL-associated antigens, the
inventors compared the HLA ligand source proteomes of the CLL and
HV cohorts. Overlap analysis of HLA source proteins revealed 2,148
proteins (29.1% of the mapped CLL source proteome) to be
exclusively represented in the HLA ligandome of CLL (FIG. 2a). With
the aim of designing a broadly applicable off-the-shelf peptide
vaccine, the inventors subsequently prioritized the selection of
potential targets according to the following criteria:
[0387] CLL-exclusivity was defined as paramount criterion, followed
by ranking of antigens according to frequency of representation in
CLL ligandomes (FIG. 2b). Our platform highlighted 49 source
proteins (0.7% of the CLL source proteome) represented by 225
different HLA ligands showing CLL-exclusive representation in
.gtoreq.20% of CLL patients. Applying the same antigen ranking
strategy to HV PBMC exclusive antigens, a set of 71
ligandome-derived benign tissue-associated antigens (LiBAAs) and
the 298 corresponding ligands (LiBAPs) were identified for use as
internal control in immunological assays.
[0388] Apart from broadly represented CLL-LiTAAs suited for the
design of off-the-shelf vaccines, a second panel of 2,099
CLL-exclusive antigens with representation frequencies <20% was
identified by our platform. These targets lend themselves as
repositories for more individualized therapeutic approaches.
[0389] Detection of Naturally Presented HLA Class I Ligands Derived
from Established CLL-Associated Antigens by LC-MS/MS
[0390] Alongside the identification of novel CLL-associated
antigens, a secondary approach focused on the ranking of the few
established CLL-antigens within the present dataset of naturally
presented HLA ligands. The inventors were able to identify 28
different HLA ligands representing 8 described CLL-associated
antigens. Of note, only Fibromodulin (FMOD.sub.324-333, RINEFSISSF,
HLA-A*23 (SEQ ID NO: 526) showed CLL-exclusive representation,
ranking at #437 of CLL-antigens in the present dataset, due to low
frequency of representation in the CLL patient cohort. The
remaining seven antigens showed representation, both on CLL and HV
PBMC, thus failing to fulfill the paramount criterion of
CLL-exclusivity. However, for CD19, CD20, RHAMM and PRAME,
CLL-associated overrepresentation of varying degrees was detected
(FIG. 2c).
[0391] Comparative Ligandome Profiling Identifies LiTAAs Shared
Among Different Disease Stages and Risk Strata
[0392] In order to assess the applicability of the novel targets
across different stages of disease, the inventors performed
subset-specific ligandome profiling comparing patients in disease
stages Binet A (n=9), B (n=7) and C (n=14). Overlap analysis of the
2,148 CLL-exclusive source proteins found 550 (25.6%) of them
shared among at least two stages, with a core group of 137 proteins
(6.1%) represented in patients of all three stages of disease (FIG.
2d). Of note, 45/49 (91.8%) of LiTAAs belong to the core group of
shared source proteins represented in all three subsets. Heatmap
analysis of the representation frequencies of all 49 LiTAAs across
Binet stages A, B and C is shown in FIG. 2e.
[0393] Another focus was placed on determining the representation
of LiTAAs in the subsets of high-risk patients carrying the 17p13
deletion (deli 7p, n=5) as compared to patients without this
genetic aberration (no del17p, n=25). The inventors found 77.7% of
the identified LiTAAs to be represented in both subsets (FIG. 2f).
Together, these data support the devised strategy of
cohort-comprising analysis of HLA ligandomes for selection of
broadly applicable targets.
[0394] Functional Characterization of HLA Class I LiTAPs Reveals
CLL-Associated Immunoreactivity
[0395] In order to evaluate the immunogenicity and specificity of
our HLA class I LiTAPs, the inventors next performed 12-day recall
IFNy ELISPOT assays. A panel of 15 LiTAPs (6 A*02, 4 A*03 and 5
B*07 LiTAPs) was implemented for stimulation of HLA-matched PBMC
obtained from CLL patients and healthy volunteers (FIG. 3a). The
inventors observed IFNy secretion for 14/15 (93.3%) of tested
LiTAPs in CLL patients (3/4 A*03 (FIGS. 3c), 6/6 A*02 and 5/5 B*07
LiTAPs (FIGS. 8c, 8f)), but not in healthy controls (0/10, FIG. 3b,
FIGS. 8b, 8e). These findings were confirmed exemplarily for
PA*03.sup.3 (DMXL11271-1279 SSSGLHPPK (SEQ ID NO:77)) by tetramer
staining of CD8+ T cells and intracellular cytokine staining for
IFN.gamma. and TNF.alpha. (FIGS. 9a, 9b). ELISPOT assays using
HLA-matched benign tissue-derived LiBAPs were performed to control
for the CLL-specificity of the observed LiTAP-directed immune
recognition in CLL patients. The inventors tested a panel of 9
LiBAPs (3 A*02, 3 A*03, 3*B*07) and observed no significant
IFN.gamma. secretion in any of the tested CLL patients (0/7 A*03
(FIG. 3d), 0/10 A*02+ and 0/5 B*07 (FIGS. 8a, 8d)).
[0396] For the 14/15 LiTAPs showing immune recognition in 1 or more
patients, the inventors calculated the allele-adjusted frequencies
of HLA restricted presentation (as detected by LC-MS/MS) and the
frequencies of immunoreactivity (as detected by ELISPOT) in CLL
patients. Strikingly, a linear correlation of these two parameters
was observed (Pearson's r=0.77, R.sup.2=0.59, FIG. 3e). These
findings suggest two main points: First, tumor-exclusive
representation is prerequisite for immune recognition. Secondly,
frequency of immune recognition can be directly deduced from the
frequency of HLA restricted presentation for immunoreactive LiTAPs.
Together, these data demonstrate the efficacy of our approach
identifying immunologically relevant targets for CLL-specific
peptide vaccines.
[0397] HLA Class II Ligandome Analysis Identifies Additional CD4+ T
Cell Epitopes for Synergistic Vaccine Design
[0398] Because of the important indirect and direct roles CD4+ T
cells play in anti-cancer immune responses, optimal vaccine design
calls for the inclusion of additional HLA class II epitopes. The
inventors performed overlap analysis of CLL and HV PBMC ligandomes
and identified 937 proteins (63.0% of the identified CLL source
proteins) to be exclusively represented in the ligandomes of CLL
patients (FIG. 4a). Applying the same antigen-ranking strategy as
described for HLA class I, the inventors identified 73 HLA class II
LiTAAs represented by 460 corresponding LiTAPs (FIG. 4b).
Functional characterization of a panel of 7 HLA class II LiTAPs
(FIG. 4c) in IFNy ELISPOT assays revealed significant IFNy
secretion for 6/7 (85.7%) LiTAPs in CLL patients (FIG. 4e), but not
in healthy controls (0/10, FIG. 4d). Next, the inventors performed
combined analysis of HLA class I and II ligandomes in order to
identify shared, synergistic targets. Overlap analysis of
CLL-exclusive source proteins revealed 132 proteins to be
represented both in HLA class I and II ligandomes (FIG. 4f).
Heatmap analysis identified 2 proteins displaying representation
frequencies .gtoreq.20% in both ligandomes (B4GALT1 (26.7% class
I/30.0% class II), HLA-DMA (20.0% class I/20% class II), FIG. 4g).
Strikingly, one of the class I LiTAPs (HLA-DMA.sub.206-214,
HEIDRYTAI, B*18 (SEQ ID NO: 178)) was revealed to be completely
embedded in the corresponding HLA class II LiTAP (VTHEIDRYTAIAY
(SEQ ID No. 924)). Together, the inventors identified a panel of
class II LiTAPs, which could be verified as T cell epitopes, as
well as an array of potentially synergistic HLA class II ligands
covering class I LiTAAs.
[0399] Longitudinal Analysis of CLL Patient Ligandomes Under
Different Therapeutic Regimens
[0400] The scope of peptide based immunotherapy is maintenance
therapy and eradication of MRD. As a consequence, peptide
vaccination in CLL would take place after standard
chemo-/immunotherapy. Therefore, the inventors analyzed HLA
expression and performed ligandome profiling across different time
points of CLL patients undergoing different therapeutic
regimens.
[0401] The inventors quantified HLA class I and II surface
expression in 4 patients undergoing rituximab treatment (Rt.sub.0
h, Rt.sub.24 h) and 1 patient receiving alemtuzumab (At.sub.0 h,
At.sub.72 h, At.sub.7 d, FIGS. 10a-10d). HLA surface expression
showed patient-individual heterogeneity with no significant changes
in mean HLA class I (Rt.sub.0 h=50,500, Rt.sub.24 h=48,000;
At.sub.0 h=42,500, At.sub.7 d=61,500) and HLA class II (Rt.sub.0
h=36,500, Rt.sub.24 h=27,500; At.sub.0 h=47,000, At.sub.7 d=55,500)
expression over the course of either therapeutic regimen.
[0402] Longitudinal HLA class I ligandome profiling was performed
in single patients undergoing rituximab-bendamustin, alemtuzumab or
ofatumumab treatment, respectively (FIGS. 5a-5c). Differential
presentation (.gtoreq.2-fold change, p.ltoreq.05) was observed for
11.1% of HLA class I ligands under rituximab-bendamustin treatment,
for 21.6% of ligands under ofatumumab treatment and for 33.6% of
ligands under alemtuzumab treatment. Overall, LiTAPs representing
8/49 (16.3%) LiTAAs were revealed to be differentially presented
over the course of therapy. Taken together, these data demonstrate
stable expression of surface HLA and robust presentation of LiTAPs
over the course of different therapies.
[0403] Immune Responses Against LiTAPs Might be Associated with
Improved Overall Survival of CLL Patients
[0404] As a last step, the inventors performed retrospective
survival analysis of 33 CLL patients (FIG. 6a) analyzed by ELISPOT
assays comparing cases with 0-1 LiTAP-specific (n=23) versus >1
LiTAP-specific (n=10) T cell responses (FIG. 6b). In the
low-responding cohort 6/23 (26.1%) of patients, in the
high-responding cohort 0/11 of patients died. Overall survival
seems to be prolonged in the cohort showing >1 immune
reactions.
Example 2
[0405] Synthesis of Peptides
[0406] All peptides were synthesized using standard and
well-established solid phase peptide synthesis using the
Fmoc-strategy. After purification by preparative RP-HPLC,
ion-exchange procedure was performed to incorporate physiological
compatible counter ions (for example trifluoro-acetate, acetate,
ammonium or chloride).
[0407] Identity and purity of each individual peptide have been
determined by mass spectrometry and analytical RP-HPLC. After
ion-exchange procedure the peptides were obtained as white to
off-white lyophilizates in purities of 90% to 99.7%.
[0408] All TUMAPs are preferably administered as trifluoro-acetate
salts or acetate salts, other salt-forms are also possible. For the
measurements of example 4, trifluoro-acetate salts of the peptides
were used.
Example 3
[0409] MHC Binding Assays
[0410] Candidate peptides for T cell based therapies according to
the present invention were further tested for their MHC binding
capacity (affinity). The individual peptide-MHC complexes were
produced by peptide-ligand exchange, where a cleavage-sensitive
peptide is cleaved, and exchanged with the peptide of interest as
analyzed. Only peptide candidates that can effectively bind and
stabilize the peptide-receptive MHC molecules prevent dissociation
of the MHC complexes. To determine the yield of the exchange
reaction, an ELISA was performed based on the detection of the
light chain (.beta.2m) of stabilized MHC complexes. The assay was
performed as generally described in Rodenko et al. (Rodenko et al.,
Nat Protoc. 1 (2006): 1120-1132).
[0411] 96 well MAXISorp plates (NUNC) were coated over night with 2
ug/ml streptavidin in PBS at room temperature, washed 4x and
blocked for 1 h at 37.degree. C. in 2% BSA containing blocking
buffer. Refolded HLA-A*0201/MLA-001 monomers served as standards,
covering the range of 15-500 ng/ml. Peptide-MHC monomers of the
UV-exchange reaction were diluted 100 fold in blocking buffer.
Samples were incubated for 1 h at 37.degree. C., washed four times,
incubated with 2 ug/ml HRP conjugated anti-.beta.2m for 1 h at
37.degree. C., washed again and detected with TMB solution that is
stopped with NH.sub.2SO.sub.4. Absorption was measured at 450 nm.
Candidate peptides that show a high exchange yield (preferably
higher than 50%, most preferred higher than 75%) are generally
preferred for a generation and production of antibodies or
fragments thereof, and/or T cell receptors or fragments thereof, as
they show sufficient avidity to the MHC molecules and prevent
dissociation of the MHC complexes.
TABLE-US-00011 MHC class I binding scores for the peptides as
tested were; <20% = +; 20%-49% = ++; 50%-75%. = +++; >=75% =
++++ Seq ID Peptide NO. sequence exchange 229 FRVGNVQEL ++++ 239
SENAFYLSP ++++
Example 4
[0412] In Vitro Immunogenicity for MHC Class I Presented
Peptides
[0413] In order to obtain information regarding the immunogenicity
of the TUMAPs of the present invention, the inventors performed
investigations using an in vitro T-cell priming assay based on
repeated stimulations of CD8+ T cells with artificial antigen
presenting cells (aAPCs) loaded with peptide/MHC complexes and
anti-CD28 antibody. This way the inventors could show
immunogenicity for HLA-A*0201 restricted TUMAPs of the invention,
demonstrating that these peptides are T-cell epitopes against which
CD8+ precursor T cells exist in humans.
[0414] In Vitro Priming of CD8+ T Cells
[0415] In order to perform in vitro stimulations by artificial
antigen presenting cells loaded with peptide-MHC complex (pMHC) and
anti-CD28 antibody, the inventors first isolated CD8+ T cells from
fresh HLA-A*02 leukapheresis products via positive selection using
CD8 microbeads (Miltenyi Biotec, Bergisch-Gladbach, Germany) of
healthy donors obtained from the University clinics Mannheim,
Germany, after informed consent.
[0416] PBMCs and isolated CD8+ lymphocytes were incubated in T-cell
medium (TCM) until use consisting of RPMI-Glutamax (Invitrogen,
Karlsruhe, Germany) supplemented with 10% heat inactivated human AB
serum (PAN-Biotech, Aidenbach, Germany), 100 U/ml Penicillin/100
.mu.g/ml Streptomycin (Cambrex, Cologne, Germany), 1 mM sodium
pyruvate (CC Pro, Oberdorla, Germany), 20 .mu.g/ml Gentamycin
(Cambrex). 2.5 ng/ml IL-7 (PromoCell, Heidelberg, Germany) and 10
U/ml IL-2 (Novartis Pharma, Nurnberg, Germany) were also added to
the TCM at this step.
[0417] Generation of pMHC/anti-CD28 coated beads, T-cell
stimulations and readout was performed in a highly defined in vitro
system using four different pMHC molecules per stimulation
condition and 8 different pMHC molecules per readout condition.
[0418] The purified co-stimulatory mouse IgG2a anti human CD28 Ab
9.3 (Jung et al., Proc Natl Acad Sci USA 84 (1987): 4611-4615) was
chemically biotinylated using Sulfo-N-hydroxysuccinimidobiotin as
recommended by the manufacturer (Perbio, Bonn, Germany). Beads used
were 5.6 .mu.m diameter streptavidin coated polystyrene particles
(Bangs Laboratories, Illinois, USA).
[0419] pMHC used for positive and negative control stimulations
were A*0201/MLA-001 (peptide ELAGIGILTV (SEQ ID NO. 1017) from
modified Melan-A/MART-1) and A*0201/DDX5-001 (YLLPAIVHI from DDX5,
SEQ ID NO. 1018), respectively.
[0420] 800.000 beads/200 .mu.I were coated in 96-well plates in the
presence of 4.times.12.5 ng different biotin-pMHC, washed and 600
ng biotin anti-CD28 were added subsequently in a volume of 200
.mu.l. Stimulations were initiated in 96-well plates by
co-incubating 1.times.10.sup.6 CD8+ T cells with 2.times.10.sup.5
washed coated beads in 200 .mu.l TCM supplemented with 5 ng/ml
IL-12 (PromoCell) for 3 days at 37.degree. C. Half of the medium
was then exchanged by fresh TCM supplemented with 80 U/ml IL-2 and
incubating was continued for 4 days at 37.degree. C. This
stimulation cycle was performed for a total of three times. For the
pMHC multimer readout using 8 different pMHC molecules per
condition, a two-dimensional combinatorial coding approach was used
as previously described (Andersen et al., Nat. Protoc. 7 (2012):
891-902) with minor modifications encompassing coupling to 5
different fluorochromes. Finally, multimeric analyses were
performed by staining the cells with Live/dead near IR dye
(Invitrogen, Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD,
Heidelberg, Germany) and fluorescent pMHC multimers. For analysis,
a BD LSRII SORP cytometer equipped with appropriate lasers and
filters was used. Peptide specific cells were calculated as
percentage of total CD8+cells. Evaluation of multimeric analysis
was done using the FlowJo software (Tree Star, Oreg., USA). In
vitro priming of specific multimer+CD8+ lymphocytes was detected by
by comparing to negative control stimulations. Immunogenicity for a
given antigen was detected if at least one evaluable in vitro
stimulated well of one healthy donor was found to contain a
specific CD8+ T-cell line after in vitro stimulation (i.e. this
well contained at least 1% of specific multimer+among CD8+ T-cells
and the percentage of specific multimer+cells was at least
10.times. the median of the negative control stimulations).
[0421] In Vitro Immunogenicity for CLL Peptides
[0422] For tested HLA class I peptides, in vitro immunogenicity
could be demonstrated by generation of peptide specific T-cell
lines. As an exemplary result, peptide KFAEEFYSF (SEQ ID NO. 20)
led to in vitro T-cell responses in 2 of 5 tested donors.
Example 5
[0423] Identification and Quantitation of Tumor Associated Peptides
Presented on the Cell Surface
[0424] Tissue Samples:
[0425] In addition to the samples used for identification of
peptides, an independent sample set comprising both normal and
tumor (CLL) tissues was used for analysis/confirmation of
HLA-A*02-associated peptides of the invention. Written informed
consents of all patients had been given before surgery or autopsy.
Tissues were shock-frozen immediately after excision and stored
until isolation of TUMAPs at -70.degree. C. or below.
[0426] Isolation of HLA Peptides from Tissue Samples
[0427] HLA peptide pools from shock-frozen tissue samples were
obtained by immune precipitation from solid tissues according to a
slightly modified protocol (Falk et al., Nature 351 (1991):
290-296; Seeger et al., Immunogenetics 49 (1999): 571-576) using
the HLA-A*02-specific antibody BB7.2, the HLA-A, -B, C-specific
antibody W6/32, CNBr-activated sepharose, acid treatment, and
ultrafiltration.
[0428] Mass Spectrometry Analyses
[0429] The HLA peptide pools as obtained were separated according
to their hydrophobicity by reversed-phase chromatography
(nanoAcquity UPLC system, Waters) and the eluting peptides were
analyzed in LTQ-velos and fusion hybrid mass spectrometers
(ThermoElectron) equipped with an ESI source. Peptide pools were
loaded directly onto the analytical fused-silica micro-capillary
column (75 .mu.m i.d..times.250 mm) packed with 1.7 .mu.m C18
reversed-phase material (Waters) applying a flow rate of 400 nL per
minute. Subsequently, the peptides were separated using a two-step
180 minute-binary gradient from 10% to 33% B at a flow rate of 300
nL per minute. The gradient was composed of Solvent A (0.1% formic
acid in water) and solvent B (0.1% formic acid in acetonitrile). A
gold coated glass capillary (PicoTip, New Objective) was used for
introduction into the nanoESl source. The LTQ-Orbitrap mass
spectrometers were operated in the data-dependent mode using a TOP5
strategy. In brief, a scan cycle was initiated with a full scan of
high mass accuracy in the orbitrap (R=30 000), which was followed
by MS/MS scans also in the orbitrap (R=7500) on the 5 most abundant
precursor ions with dynamic exclusion of previously selected ions.
Tandem mass spectra were interpreted by SEQUEST and additional
manual control. The identified peptide sequence was assured by
comparison of the generated natural peptide fragmentation pattern
with the fragmentation pattern of a synthetic sequence-identical
reference peptide.
[0430] Label-free relative LC-MS quantitation was performed by ion
counting i.e. by extraction and analysis of LC-MS features (Mueller
et al., Proteomics. 7 (2007): 3470-3480). The method assumes that
the peptide's LC-MS signal area correlates with its abundance in
the sample. Extracted features were further processed by charge
state deconvolution and retention time alignment (Mueller et al., J
Proteome.Res 7 (2008): 51-61; Sturm et al., BMC. Bioinformatics. 9
(2008): 163). Finally, all LC-MS features were cross-referenced
with the sequence identification results to combine quantitative
data of different samples and tissues to peptide presentation
profiles. The quantitative data were normalized in a two-tier
fashion according to central tendency to account for variation
within technical and biological replicates. Thus each identified
peptide can be associated with quantitative data allowing relative
quantification between samples and tissues. In addition, all
quantitative data acquired for peptide candidates was inspected
manually to assure data consistency and to verify the accuracy of
the automated analysis. For each peptide a presentation profile was
calculated showing the mean sample presentation as well as
replicate variations. The profiles juxtapose CLL samples to a
baseline of normal tissue samples. The presentation profile of an
exemplary over-presented peptide is shown in FIG. 11.
CITED REFERENCES
[0431] Ding, M. X. et al., Asian Pac.J Cancer Prey. 13 (2012):
5653-5657
[0432] Gallardo-Perez, J. C. et al., Biochim. Biophys. Acta 1843
(2014): 1043-1053
[0433] Jardim, B. V. et al., Oncol Rep. 30 (2013): 1119-1128
[0434] Jevnikar, Z. et al., J Biol.Chem 288 (2013): 2201-2209
[0435] Liu, Y. Y. et al., Mol.Cancer 9 (2010): 145
[0436] Mayr, C. et al., Blood 105 (2005): 1566-1573
[0437] Men, T. et al., Tumour. Biol. 35 (2014): 269-275
[0438] Nagai, K. et al., Cancer Med. 3 (2014): 1085-1099
[0439] Pallasch, C. P. et al., Blood 112 (2008): 4213-4219
[0440] Poeta, M. L. et al., Genes Chromosomes. Cancer 51 (2012):
1133-1143
[0441] Teh, M. T. et al., PLoS. One. 7 (2012): e34329
[0442] Yi, S. et al., Leuk. Lymphoma 52 (2011): 72-78
[0443] Yoon, D. Y. et al., Biochem. Biophys. Res. Commun. 288
(2001): 882-886
[0444] Yu, Z. et al., Zhonghua Yi.Xue.Za Zhi. 91 (2011):
1371-1374
[0445] Zhang, K. et al., Chin Med. J (Engl.) 126 (2013):
4660-4664
[0446] Zhou, H. et al., IUBMB. Life 64 (2012): 889-900
Sequence CWU 1
1
1018110PRTHomo sapiens 1Ala Glu His Pro Asn Val Thr Leu Thr Ile 1 5
10 210PRTHomo sapiens 2Phe Leu Ala Glu His Pro Asn Val Thr Leu 1 5
10 39PRTHomo sapiens 3Ile Leu Tyr Gly Arg Ser Tyr Thr Trp 1 5
49PRTHomo sapiens 4Glu Val Ala Glu Phe Leu Ala Arg His 1 5
59PRTHomo sapiens 5Arg His Ser Asn Val Asn Leu Thr Ile 1 5
69PRTHomo sapiens 6His Pro Asp Asn Val Lys Leu Phe Leu 1 5
79PRTHomo sapiens 7Ile Ser Asp Thr Gly Glu Leu Lys Leu 1 5
810PRTHomo sapiens 8Lys Val Asn Gly Lys Leu Val Ala Leu Lys 1 5 10
99PRTHomo sapiens 9Asn Arg Leu Ser Ala Gln Ala Ala Leu 1 5
109PRTHomo sapiens 10Thr Pro Phe Thr Ala Ile Arg Glu Ala 1 5
119PRTHomo sapiens 11Phe Gly Leu Ala Arg Ala Lys Ser Val 1 5
129PRTHomo sapiens 12Lys Ile Ala Asp Phe Gly Leu Ala Arg 1 5
139PRTHomo sapiens 13Ala Ala Ala Asn Ile Ile Arg Thr Leu 1 5
1410PRTHomo sapiens 14Gly Arg Phe Lys Asn Leu Arg Glu Ala Leu 1 5
10 159PRTHomo sapiens 15Met Ser Pro Phe Ser Lys Ala Thr Leu 1 5
1611PRTHomo sapiens 16Gln Glu Asp Pro Gly Asp Asn Gln Ile Thr Leu 1
5 10 178PRTHomo sapiens 17Ser Pro Phe Ser Lys Ala Thr Leu 1 5
188PRTHomo sapiens 18Asp Ala Leu Leu Lys Arg Thr Met 1 5 199PRTHomo
sapiens 19Gly Glu Asp Val Arg Ser Ala Leu Leu 1 5 209PRTHomo
sapiens 20Lys Phe Ala Glu Glu Phe Tyr Ser Phe 1 5 219PRTHomo
sapiens 21Tyr Gly Tyr Asp Asn Val Lys Glu Tyr 1 5 2210PRTHomo
sapiens 22Leu Glu Val Glu Glu Arg Thr Lys Pro Val 1 5 10
2311PRTHomo sapiens 23Arg Asp Ser Pro Ile Asn Ala Asn Leu Arg Tyr 1
5 10 248PRTHomo sapiens 24Arg Pro Phe Val Ile Val Thr Ala 1 5
259PRTHomo sapiens 25Arg Pro Ile Ile Asn Thr Pro Met Val 1 5
2610PRTHomo sapiens 26Ser Pro Thr Ser Ser Arg Thr Ser Ser Leu 1 5
10 279PRTHomo sapiens 27Ala Thr Ser Ala Pro Leu Val Ser Arg 1 5
2810PRTHomo sapiens 28Ala Glu Leu Arg Ser Thr Ala Ser Leu Leu 1 5
10 2911PRTHomo sapiens 29Ala Pro Ala Ser Ser His Glu Arg Ala Ser
Met 1 5 10 309PRTHomo sapiens 30Ala Ser Arg Gln Ala Pro Pro His Ile
1 5 3110PRTHomo sapiens 31Ala Val Lys Lys Asn Pro Gly Ile Ala Ala 1
5 10 3210PRTHomo sapiens 32Glu Glu His Leu Glu Ser His Lys Lys Tyr
1 5 10 339PRTHomo sapiens 33Gly Glu Phe Thr Ser Ala Arg Ala Val 1 5
3410PRTHomo sapiens 34Gly Gln Ser Thr Pro Arg Leu Phe Ser Ile 1 5
10 358PRTHomo sapiens 35Leu Val Asp Asp Pro Leu Glu Tyr 1 5
369PRTHomo sapiens 36Arg Pro Lys Asn Leu Met Gln Thr Leu 1 5
379PRTHomo sapiens 37Arg Gln Ala Pro Pro His Ile Glu Leu 1 5
3810PRTHomo sapiens 38Ser Glu Ala Ala Glu Leu Arg Ser Thr Ala 1 5
10 399PRTHomo sapiens 39Ala Ala Val Arg Ile Gly Ser Val Leu 1 5
409PRTHomo sapiens 40Glu Arg Ala Gly Val Val Arg Glu Leu 1 5
4110PRTHomo sapiens 41Gly Ala Ala Val Arg Ile Gly Ser Val Leu 1 5
10 4210PRTHomo sapiens 42Lys Leu Tyr Glu Leu His Val Phe Thr Phe 1
5 10 439PRTHomo sapiens 43Leu Tyr Glu Leu His Val Phe Thr Phe 1 5
449PRTHomo sapiens 44Tyr Leu Asn Lys Glu Ile Glu Glu Ala 1 5
459PRTHomo sapiens 45Asp Glu Leu Pro Lys Phe His Gln Tyr 1 5
4610PRTHomo sapiens 46Asp Val Thr Gly Gln Phe Pro Ser Ser Phe 1 5
10 479PRTHomo sapiens 47Glu His Ser Arg Val Leu Gln Gln Leu 1 5
488PRTHomo sapiens 48Ile Lys Val Ser Lys Gln Leu Leu 1 5 499PRTHomo
sapiens 49Lys Pro Arg Gln Ser Ser Pro Gln Leu 1 5 509PRTHomo
sapiens 50Lys Gln Leu Leu Ala Ala Leu Glu Ile 1 5 519PRTHomo
sapiens 51Arg Arg Lys Asp Leu Val Leu Lys Tyr 1 5 5211PRTHomo
sapiens 52Arg Thr Arg Asp Tyr Ala Ser Leu Pro Pro Lys 1 5 10
5310PRTHomo sapiens 53Ala Pro Gly Ser Val Leu Pro Arg Ala Leu 1 5
10 548PRTHomo sapiens 54Asp Ile Lys Glu His Pro Leu Leu 1 5
559PRTHomo sapiens 55Asp Ser Ala Gly Pro Gln Asp Ala Arg 1 5
569PRTHomo sapiens 56Phe Gln Tyr Ala Lys Glu Ser Tyr Ile 1 5
579PRTHomo sapiens 57Lys Val Leu Ser Trp Pro Phe Leu Met 1 5
589PRTHomo sapiens 58Leu Glu Asn Asp Gln Ser Leu Ser Phe 1 5
598PRTHomo sapiens 59Ser Pro Ser Arg Gln Pro Gln Val 1 5 609PRTHomo
sapiens 60Ser Arg His Gln Ser Phe Thr Thr Lys 1 5 619PRTHomo
sapiens 61Ser Ser His Asn Ala Ser Lys Thr Leu 1 5 629PRTHomo
sapiens 62Glu Glu Ile Asp Thr Thr Met Arg Trp 1 5 639PRTHomo
sapiens 63Ile Leu Asp Glu Lys Pro Val Ile Ile 1 5 649PRTHomo
sapiens 64Leu Pro Gln Glu Pro Arg Thr Ser Leu 1 5 658PRTHomo
sapiens 65Leu Thr Tyr Lys Leu Pro Val Ala 1 5 6610PRTHomo sapiens
66Asn Glu Met Glu Leu Ala His Ser Ser Phe 1 5 10 6710PRTHomo
sapiens 67Arg Glu Phe Pro Glu Ala Asn Phe Glu Leu 1 5 10 689PRTHomo
sapiens 68Thr His His Ile Pro Asp Ala Lys Leu 1 5 699PRTHomo
sapiens 69Thr Val Lys Glu Asn Leu Ser Leu Phe 1 5 708PRTHomo
sapiens 70Val Leu Leu Lys Lys Ala Val Leu 1 5 719PRTHomo sapiens
71His Leu Lys Ser Ile Pro Val Ser Leu 1 5 729PRTHomo sapiens 72Lys
Val Trp Tyr Asn Val Glu Asn Trp 1 5 739PRTHomo sapiens 73Leu Pro
Ala Tyr Arg Ala Gln Leu Leu 1 5 749PRTHomo sapiens 74Leu Ser Glu
Gln Thr Ser Val Pro Leu 1 5 759PRTHomo sapiens 75Ser Leu Asn Gln
Trp Leu Val Ser Phe 1 5 769PRTHomo sapiens 76Ser Met Thr Ser Leu
Ala Gln Lys Ile 1 5 779PRTHomo sapiens 77Ser Ser Ser Gly Leu His
Pro Pro Lys 1 5 789PRTHomo sapiens 78Asp Leu Asp Val Lys Lys Met
Pro Leu 1 5 799PRTHomo sapiens 79Phe Tyr Thr Val Ile Pro His Asn
Phe 1 5 8010PRTHomo sapiens 80His His Ile Asn Thr Asp Asn Pro Ser
Leu 1 5 10 819PRTHomo sapiens 81Arg Val Gly Glu Val Gly Gln Ser Lys
1 5 8211PRTHomo sapiens 82Ala Val Phe Asp Gly Ala Gln Val Thr Ser
Lys 1 5 10 839PRTHomo sapiens 83Ser Gln Thr Asp Leu Val Ser Arg Leu
1 5 849PRTHomo sapiens 84Val Pro Val Pro His Thr Thr Ala Leu 1 5
859PRTHomo sapiens 85Tyr Gln Val Leu Asp Val Gln Arg Tyr 1 5
8610PRTHomo sapiens 86Ala Pro Phe Gln Gly Asp Gln Arg Ser Leu 1 5
10 879PRTHomo sapiens 87Asp Val Ala Glu Pro Tyr Lys Val Tyr 1 5
8810PRTHomo sapiens 88Ile Val Ser Gly Gln Pro Gly Thr Gln Lys 1 5
10 899PRTHomo sapiens 89Thr Pro Glu Gln Gln Ala Ala Ile Leu 1 5
909PRTHomo sapiens 90Val Glu Leu Phe Arg Thr Ala Tyr Phe 1 5
919PRTHomo sapiens 91Glu His Ala Asp Asp Asp Pro Ser Leu 1 5
9210PRTHomo sapiens 92Ser Glu Glu Ser Val Lys Ser Thr Thr Leu 1 5
10 9310PRTHomo sapiens 93Ser Pro Arg Pro Pro Leu Gly Ser Ser Leu 1
5 10 948PRTHomo sapiens 94Ser Pro Trp Trp Arg Ser Ser Leu 1 5
9510PRTHomo sapiens 95Val Tyr Thr Pro Val Asp Ser Leu Val Phe 1 5
10 969PRTHomo sapiens 96Ala Pro Leu Gln Arg Ser Gln Ser Leu 1 5
978PRTHomo sapiens 97Asp Glu Val His Gln Asp Thr Tyr 1 5 989PRTHomo
sapiens 98Leu Pro His Ser Ala Thr Val Thr Leu 1 5 999PRTHomo
sapiens 99Ser Glu Ala Pro Glu Ala Pro Leu Leu 1 5 1009PRTHomo
sapiens 100Ser Pro Arg Ala Ser Gly Ser Gly Leu 1 5 1019PRTHomo
sapiens 101Val Val Gly Pro Ala Ala Glu Ala Lys 1 5 1029PRTHomo
sapiens 102Phe Ser Ile Thr Lys Ser Val Glu Leu 1 5 1039PRTHomo
sapiens 103Gly Gln Thr Lys Asn Asp Leu Val Val 1 5 1048PRTHomo
sapiens 104Leu Ser Gln Glu Val Cys Arg Asp 1 5 1059PRTHomo sapiens
105Arg Asp Ile Gln Ser Pro Glu Gln Ile 1 5 1069PRTHomo sapiens
106Arg Glu Asp Asn Ser Ser Asn Ser Leu 1 5 1078PRTHomo sapiens
107Thr Glu His Gln Glu Pro Gly Leu 1 5 1089PRTHomo sapiens 108Thr
Lys Asn Asp Leu Val Val Ser Leu 1 5 1099PRTHomo sapiens 109Ala Glu
Glu Ala Gly Gly Thr Arg Leu 1 5 1108PRTHomo sapiens 110Glu Asn Val
Asn Lys Lys Asp Tyr 1 5 11110PRTHomo sapiens 111Gly Leu Asp Pro Asn
Lys Pro Pro Glu Leu 1 5 10 11212PRTHomo sapiens 112Arg Pro Ala Gly
Glu Pro Tyr Asn Arg Lys Thr Leu 1 5 10 11311PRTHomo sapiens 113Ser
Ala Ser Val Gln Arg Ala Asp Thr Ser Leu 1 5 10 1149PRTHomo sapiens
114Tyr Gly Asn Pro Arg Thr Asn Gly Met 1 5 1159PRTHomo sapiens
115Leu Ile Arg Pro Val Ser Ala Ser Phe 1 5 11611PRTHomo sapiens
116Ser Pro Val Asn Ser Ser Lys Gln Pro Ser Tyr 1 5 10 11710PRTHomo
sapiens 117Gln Leu Phe Ser Tyr Ala Ile Leu Gly Phe 1 5 10
1189PRTHomo sapiens 118Asp Glu His Leu Leu Ile Gln His Tyr 1 5
1199PRTHomo sapiens 119Lys Gln Val Ala Ser Ser Thr Gly Phe 1 5
12011PRTHomo sapiens 120Arg Asp Phe Gly Pro Ala Ser Gln His Phe Leu
1 5 10 1219PRTHomo sapiens 121Arg Gln Leu Gly Glu Val Ala Ser Phe 1
5 12210PRTHomo sapiens 122Thr Glu Ala Glu Thr Thr Ala Asn Val Leu 1
5 10 1239PRTHomo sapiens 123Gly Tyr Leu Pro Val Gln Thr Val Leu 1 5
1249PRTHomo sapiens 124Gly Gln Lys Glu Ala Leu Leu Lys Tyr 1 5
1259PRTHomo sapiens 125Lys Pro Ser Glu Glu Arg Lys Thr Ile 1 5
1269PRTHomo sapiens 126Lys Gln Thr Pro Lys Val Leu Val Val 1 5
1279PRTHomo sapiens 127Ser Val Ile Gln His Val Gln Ser Phe 1 5
1289PRTHomo sapiens 128Thr Pro Ile Glu Arg Ile Pro Tyr Leu 1 5
1299PRTHomo sapiens 129Ala Glu Val Glu Lys Asn Glu Thr Val 1 5
1309PRTHomo sapiens 130Glu Val Lys Glu Glu Ile Pro Leu Val 1 5
1319PRTHomo sapiens 131Lys Pro Thr Ser Ala Arg Ser Gly Leu 1 5
13210PRTHomo sapiens 132Lys Tyr Ile Glu Thr Thr Pro Leu Thr Ile 1 5
10 1339PRTHomo sapiens 133Ser Glu Ile Lys Thr Ser Ile Glu Val 1 5
1349PRTHomo sapiens 134Ser Val Lys Pro Thr Ser Ala Thr Lys 1 5
1359PRTHomo sapiens 135Tyr Pro Asn Lys Gly Val Gly Gln Ala 1 5
1369PRTHomo sapiens 136Ile Ser Met Lys Ile Leu Asn Ser Leu 1 5
13710PRTHomo sapiens 137Lys Thr Ile Ala Phe Leu Leu Pro Met Phe 1 5
10 1388PRTHomo sapiens 138Arg Asp Ser Ile Ile Asn Asp Phe 1 5
13910PRTHomo sapiens 139Ser Val Lys Gly Gly Gly Gly Asn Glu Lys 1 5
10 1409PRTHomo sapiens 140Gly Ile Ala Lys Thr Gly Ser Gly Lys 1 5
14110PRTHomo sapiens 141Ala Glu Thr Thr Asp Asn Val Phe Thr Leu 1 5
10 1429PRTHomo sapiens 142Ser Glu Tyr Gln Arg Phe Ala Val Met 1 5
1439PRTHomo sapiens 143Thr Phe Gly Glu Arg Val Val Ala Phe 1 5
1448PRTHomo sapiens 144Asn Glu Asn Leu Val Glu Arg Phe 1 5
1459PRTHomo sapiens 145Lys Ile Thr Val Pro Ala Ser Gln Lys 1 5
14610PRTHomo sapiens 146Lys Ile Thr Val Pro Ala Ser Gln Lys Leu 1 5
10 14710PRTHomo sapiens 147Val Pro Ala Ser Gln Lys Leu Arg Gln Leu
1 5 10 1489PRTHomo sapiens 148His Val Gly Tyr Thr Leu Ser Tyr Lys 1
5 14910PRTHomo sapiens 149Lys Leu Pro Leu Pro Leu Pro Pro Arg Leu 1
5 10 1509PRTHomo sapiens 150Lys Pro Ile Glu Pro Arg Arg Glu Leu 1 5
1519PRTHomo sapiens 151Ser His Ser His Val Gly Tyr Thr Leu 1 5
1529PRTHomo sapiens 152Ala Pro Ser Glu Tyr Arg Tyr Thr Leu 1 5
15310PRTHomo sapiens 153Ala Pro Ser Glu Tyr Arg Tyr Thr Leu Leu 1 5
10 1549PRTHomo sapiens 154Glu Ile Phe Gln Asn Glu Val Ala Arg 1 5
1559PRTHomo sapiens 155Lys Asp Val Leu Ile Pro Gly Lys Leu 1 5
1569PRTHomo sapiens 156Val Pro Leu Val Arg Glu Ile Thr Phe 1 5
1579PRTHomo sapiens 157Asp Pro Asn Pro Asn Phe Glu Lys Phe 1 5
1589PRTHomo sapiens 158Ile Gln Ala Pro Leu Ser Trp Glu Leu 1 5
15910PRTHomo sapiens 159Val Ile Tyr Asn Glu Gln Met Ala Ser Lys 1 5
10 1609PRTHomo sapiens 160Val Leu Arg Pro Gly Gly Ala Phe Tyr 1 5
1619PRTHomo sapiens 161Glu Asp Pro Asp Gln Asp Ile Leu Ile 1 5
1629PRTHomo sapiens 162His Gly Asn Leu Arg Glu Leu Ala Leu 1 5
1639PRTHomo sapiens 163Lys Leu Tyr Pro Thr Leu Val Ile Arg 1 5
1649PRTHomo sapiens 164Ser Glu Glu Thr Phe Arg Phe Glu Leu 1 5
1659PRTHomo sapiens 165Glu Leu Asn Lys Leu Leu Glu Glu Ile 1 5
1669PRTHomo sapiens 166Ile Pro Phe Ser Asn Pro Arg Val Leu 1 5
16710PRTHomo sapiens 167Leu Leu Asp Glu Gly Ala Lys Leu Leu Tyr 1 5
10 1689PRTHomo sapiens 168Ser Pro Ala Asp Ala His Arg Asn Leu 1 5
1699PRTHomo sapiens 169Ala Glu Leu Glu Arg Gln Ala Val Leu 1 5
1709PRTHomo sapiens 170Gly Arg Val Pro Gly Pro Leu Ser Leu 1 5
1719PRTHomo sapiens 171Ser Asp Leu Ala Arg Leu Ile Leu Leu 1 5
1729PRTHomo sapiens 172Thr Pro Ile Arg Glu Gln His Val Leu 1 5
1738PRTHomo sapiens 173Ala Pro Arg Lys Gly Asn Thr Leu 1 5
17410PRTHomo sapiens 174Glu Glu Glu Glu Ala Leu Gln Lys Lys Phe 1 5
10 1758PRTHomo sapiens 175Lys Glu Asn Leu Val Asp Gly Phe 1 5
17610PRTHomo sapiens 176Val Tyr Lys Glu Asn Leu Val Asp Gly Phe 1 5
10 1779PRTHomo sapiens 177Thr Leu Leu Val Val Val Pro Lys Leu 1 5
1789PRTHomo sapiens 178His Glu Ile Asp Arg Tyr Thr Ala Ile 1 5
1799PRTHomo sapiens 179Val Phe Thr Leu Lys Pro Leu Glu Phe 1 5
1808PRTHomo sapiens 180Tyr Trp Val Pro Arg Asn Ala Leu 1 5
1819PRTHomo sapiens 181Ile Gly Val Glu His Val Val Val Tyr 1 5
1828PRTHomo sapiens 182Arg Asp Lys Pro His Val Asn Val 1 5
1839PRTHomo sapiens 183Ala Asp Val Leu Lys Val Glu Val Phe 1 5
1848PRTHomo sapiens 184Ile Pro Val Val His Ala Ser Ile 1 5
1859PRTHomo sapiens 185Arg Asp Ser Leu Ile Asp Ser Leu Thr 1 5
18611PRTHomo sapiens 186Thr Val Ala Asp Gln Val Leu Val Gly Ser Tyr
1 5 10 1879PRTHomo sapiens 187Ala Ala Asp Thr Glu Arg Leu Ala Leu 1
5 1889PRTHomo sapiens 188Asp Met Lys Ala Lys Val Ala Ser Leu 1 5
1899PRTHomo sapiens 189His Val Leu Glu Glu Val Gln Gln Val 1 5
1909PRTHomo sapiens 190Lys Glu Ala Ala Asp Thr Glu Arg Leu 1 5
1919PRTHomo sapiens 191Arg Ile Ser Glu Val Leu Gln Lys Leu 1 5
1929PRTHomo sapiens 192Thr Glu Val Arg Glu Leu Val Ser Leu 1 5
19310PRTHomo sapiens 193Ala Ile Arg Ser Gly Glu Ala Ala Ala Lys 1 5
10 1949PRTHomo sapiens 194Ala Pro Asn Pro Ala Pro Lys Glu Leu 1 5
1958PRTHomo sapiens 195Arg Gln Ser Leu Leu Thr Ala Ile 1 5
1969PRTHomo sapiens 196Ser Pro Glu Gln Thr Leu Ser Pro Leu 1 5
1979PRTHomo sapiens 197Thr Glu His Gln Val Pro Ser Ser Val 1 5
1989PRTHomo sapiens 198Thr Thr Tyr Lys Ile Val Pro Pro Lys 1 5
1999PRTHomo sapiens 199Gln Leu Leu Asp Gln Val Glu Gln Ile 1 5
2009PRTHomo sapiens 200Asp Glu Thr Met Val Ile Gly Asn Tyr 1 5
20111PRTHomo sapiens 201Arg Gln Tyr Gly Ser Glu Gly Arg Phe Thr Phe
1 5 10 2028PRTHomo sapiens 202Ser Pro Ala Pro Arg Thr Ala Leu 1 5
20310PRTHomo sapiens 203Gly Pro Arg Pro Ile Thr Gln Ser Glu Leu 1 5
10 2049PRTHomo sapiens 204Lys Pro Glu Pro Val Asp Lys Val Ala 1 5
2059PRTHomo sapiens 205Thr Pro Ser Ser Arg Pro Ala Ser Leu 1 5
2069PRTHomo sapiens 206Asp Glu Thr Gln Val Arg Ser Leu Tyr 1 5
20711PRTHomo sapiens 207Lys Glu Glu Glu Thr Asn Ser Val Ala Thr Leu
1 5 10 2089PRTHomo sapiens 208Leu Glu Gln Lys Val Val Glu Leu Tyr 1
5 20911PRTHomo sapiens 209Asn Pro Ile Ser Asn Ala Val Leu Asn Glu
Tyr 1 5 10 2108PRTHomo sapiens 210Ser Ile Lys Glu Lys Ser Ser Leu 1
5 21111PRTHomo sapiens 211Thr Glu Ile Thr Glu Ile Ser Thr Pro Ser
Leu 1 5 10 2129PRTHomo sapiens 212Gly Arg Leu Asn Ser Val Asn Asn
Arg 1 5 2139PRTHomo sapiens 213Ser Ile Leu Glu Asp Pro Pro Ser Ile
1 5 2149PRTHomo sapiens 214Thr Pro Arg Thr Asn Asn Ile Glu Leu 1 5
2159PRTHomo sapiens 215Asp Ala Met Lys Arg Val Glu Glu Ile 1 5
2169PRTHomo sapiens 216Asp Ile Lys Glu Val Lys Gln Asn Ile 1 5
2179PRTHomo sapiens 217Gly Pro Ile Tyr Pro Gly His Gly Met 1 5
2189PRTHomo sapiens 218Gly Asp Tyr Gly Arg Ala Phe Asn Leu 1 5
2199PRTHomo sapiens 219Thr Arg His Lys Ile Val His Thr Lys 1 5
22010PRTHomo sapiens 220Arg Ile His Thr Gly Glu Lys Pro Tyr Lys 1 5
10 2219PRTHomo sapiens 221Lys Ala Phe Asn Trp Phe Ser Thr Leu 1 5
2229PRTHomo sapiens 222Gln Ser Thr Gln Arg Ser Leu Ala Leu 1 5
22311PRTHomo sapiens 223Arg Asp Leu Gln Met Asn Gln Ala Leu Arg Phe
1 5 10 22410PRTHomo sapiens 224Arg Glu Leu Glu Ser Gln Leu His Val
Leu 1 5 10 2259PRTHomo sapiens 225Ser Glu Ala Glu Lys Leu Thr Leu
Val 1 5 2269PRTHomo sapiens 226Ala Ala Ala Lys Pro Val Ala Thr Lys
1 5 22710PRTHomo sapiens 227Ala Thr Tyr His Gly Ser Phe Ser Thr Lys
1 5 10 2289PRTHomo sapiens 228Phe Met Tyr Asp Arg Pro Leu Arg Leu 1
5 2299PRTHomo sapiens 229Phe Arg Val Gly Asn Val Gln Glu Leu 1 5
2309PRTHomo sapiens 230Gly Val Ala Pro Phe Thr Ile Ala Arg 1 5
23111PRTHomo sapiens 231Lys Met Lys Pro Leu Asp Gly Ser Ala Leu Tyr
1 5 10 2329PRTHomo sapiens 232Lys Pro Ala Pro Ala Lys Pro Val Ala 1
5 2339PRTHomo sapiens 233Lys Pro Val Ala Ala Lys Pro Ala Ala 1 5
23410PRTHomo sapiens 234Lys Gln Phe Gly Val Ala Pro Phe Thr Ile 1 5
10 2359PRTHomo sapiens 235Gln Glu Glu Leu Val Lys Ile Ser Leu 1 5
23610PRTHomo sapiens 236Arg Gln Leu Gly Thr Val Gln Gln Val Ile 1 5
10 2379PRTHomo sapiens 237Arg Gln Leu Ile Asn Ala Leu Gln Ile 1 5
23812PRTHomo sapiens 238Arg Val Ile Gly Gly Leu Leu Ala Gly Gln Thr
Tyr 1 5 10 2399PRTHomo sapiens 239Ser Glu Asn Ala Phe Tyr Leu Ser
Pro 1 5 2409PRTHomo sapiens 240Ser Gln Ala Pro Val Leu Asp Ala Ile
1 5 2419PRTHomo sapiens 241Ser Thr Arg Tyr Pro Pro Pro Ala Val 1 5
2429PRTHomo sapiens 242Thr Glu Asp Thr Leu Lys Val Tyr Leu 1 5
2439PRTHomo sapiens 243Val Ala Ala Lys Pro Val Ala Thr Lys 1 5
2448PRTHomo sapiens 244Val Gln Arg Val Val Glu Ser Leu 1 5
2459PRTHomo sapiens 245Val Arg Asn Pro Ser Val Val Val Lys 1 5
2469PRTHomo sapiens 246Gly Glu Ser Glu Val Ala Ile Lys Ile 1 5
24710PRTHomo sapiens 247Leu Ile Tyr Ser Val Gly Leu Leu Leu Ala 1 5
10 2489PRTHomo sapiens 248Ser Ala Tyr Pro His Gln Leu Ser Phe 1 5
2499PRTHomo sapiens 249Ser Val Ile Gly Val Phe Ile Thr Lys 1 5
25010PRTHomo sapiens 250Ala Glu Leu Gly Asn Ser Val Gln Leu Ile 1 5
10 2518PRTHomo sapiens 251Ala Asn Met Thr Val Thr Arg Ile 1 5
2529PRTHomo sapiens 252Ala Arg Ile Ser Asn Val Glu Phe Tyr 1 5
2539PRTHomo sapiens 253Ala Val Phe Ile Gly Asn Gln Gln Phe 1 5
2549PRTHomo sapiens 254Asp Ile Glu Leu Gln Ala Glu Asn Ile 1 5
2559PRTHomo sapiens 255Asp Ser Tyr Thr Val Arg Val Ser Val 1 5
2569PRTHomo sapiens 256Asp Val Lys Ile Phe Val Asn Thr Ile 1 5
2579PRTHomo sapiens 257Glu Ile Ile Pro Lys Tyr Gly Ser Ile 1 5
2589PRTHomo sapiens 258Glu Gln Ser Lys Ile Phe Ile His Arg 1 5
2599PRTHomo sapiens 259Phe Val Asp Val Gly Leu Tyr Gln Tyr 1 5
2609PRTHomo sapiens 260Gly His Thr Ser Thr Ile Ser Thr Leu 1 5
2619PRTHomo sapiens 261Gly Arg Ile Glu Tyr Val Glu Val Phe 1 5
2629PRTHomo sapiens 262Gly Thr Ser Ile Ile Pro Phe Gln Lys 1 5
2639PRTHomo sapiens 263His Pro Phe Leu Arg Gly Ile Gly Tyr 1 5
2648PRTHomo sapiens 264Ile Pro Val Glu Ile His Thr Ala 1 5
2659PRTHomo sapiens 265Lys Ile Phe Val Asn Thr Ile Ala Tyr 1 5
26610PRTHomo sapiens 266Leu Pro Glu Asp Lys Val Arg Ile Ala Tyr 1 5
10 2679PRTHomo sapiens 267Leu Pro Phe Ser Glu Gly Leu Thr Val 1 5
2689PRTHomo sapiens 268Leu Pro Trp Ala Asn Lys Val Thr Ile 1 5
2698PRTHomo sapiens 269Pro Trp Ala Asn Lys Val Thr Ile 1 5
2709PRTHomo sapiens 270Gln Ala Tyr Asn Arg Ala Val Thr Ile 1 5
2719PRTHomo sapiens 271Arg Ser Phe Pro Gln Lys Met Ala Tyr 1 5
2729PRTHomo sapiens 272Arg Tyr Pro Ile His Trp His Leu Leu 1 5
2739PRTHomo sapiens 273Ser Pro Gln Asn Leu Arg Leu Met Leu 1 5
2749PRTHomo sapiens 274Ser Tyr Phe Ser Ser Pro Thr Gln Arg 1 5
2758PRTHomo sapiens 275Val Gln Ile Lys Ser Ser Leu Ile 1 5
2769PRTHomo sapiens 276Val Tyr Ile Gly His Thr Ser Thr Ile 1 5
27710PRTHomo sapiens 277Tyr His Val Pro Gly Thr Gly Glu Ser Tyr 1 5
10 2789PRTHomo sapiens 278Ala Thr Asn Gly Asp Leu Ala Ser Arg 1 5
27911PRTHomo sapiens 279Gly Leu His Ala Glu Val Thr Gly Val Gly Tyr
1 5 10 2809PRTHomo sapiens 280His Val Ser Ser Thr Ser Ser Ser Phe 1
5 2819PRTHomo sapiens 281Leu Gln Ala Asp Leu Gln Asn Gly Leu 1 5
2829PRTHomo sapiens 282Ser Glu Leu Pro Val Ser Glu Val Ala 1 5
2839PRTHomo sapiens 283Ser Gln Thr Lys Ser Val Phe Glu Ile 1 5
2849PRTHomo sapiens 284Thr His Ile Phe Thr Ser Asp Gly Leu 1 5
2859PRTHomo sapiens 285Val Ile Tyr Phe Pro Pro Leu Gln Lys 1 5
2869PRTHomo sapiens 286Tyr Pro Phe Ser Ser Glu Gln Lys Trp 1 5
2879PRTHomo sapiens 287Gly Gln Tyr Phe Gly Glu Leu Ala Leu 1 5
2889PRTHomo sapiens 288Arg Ile Ile Val Lys Asn Asn Ala Lys 1 5
28910PRTHomo sapiens 289Arg Arg Ile Ile Val Lys Asn Asn Ala Lys 1 5
10 2909PRTHomo sapiens 290Ser Phe Gly Glu Leu Ala Leu Met Tyr 1 5
2919PRTHomo sapiens 291Ala Phe Asn Ala Pro Val Ile Asn Arg 1 5
2929PRTHomo sapiens 292Ile Met Lys Arg Asn Ile Ala Thr Tyr 1 5
2939PRTHomo sapiens 293Lys Val Val Asp Val Ile Gly Thr Lys 1 5
2949PRTHomo sapiens 294Leu Pro Phe Leu Lys Ser Leu Glu Phe 1 5
29511PRTHomo sapiens 295Arg Leu Lys Val Val Asp Val Ile Gly Thr Lys
1 5 10 2969PRTHomo sapiens 296Thr Pro Arg Ala Ala Thr Ile Thr Ala 1
5 2979PRTHomo sapiens 297Lys Pro Ser Glu Lys Ile Gln Val Leu 1 5
2989PRTHomo sapiens 298Val Pro Tyr Pro Val Thr Thr Thr Val 1 5
2999PRTHomo sapiens 299Ala Ser Phe Pro Pro Phe Val Glu Lys 1 5
3009PRTHomo sapiens 300Ala Phe Ile His Ile Ser Thr Ala Tyr 1 5
30110PRTHomo sapiens 301Ala Thr Phe Glu Lys Ile Pro Phe Glu Arg 1 5
10 3029PRTHomo sapiens 302Lys Leu Phe Glu Lys Val Lys Glu Val 1 5
3039PRTHomo sapiens 303Ser Gln Met Pro Lys Leu Glu Ala Phe 1 5
3049PRTHomo sapiens 304Ala Val Leu Gly Gln His His Asn Tyr 1 5
3058PRTHomo sapiens 305Gly Pro Pro Ala His Lys Pro Arg 1 5
3069PRTHomo sapiens 306Arg Val Tyr Asp Val Leu Val Leu Lys 1 5
3079PRTHomo sapiens 307Leu Pro Arg Pro Gln Gly Ile Thr Val 1 5
3089PRTHomo sapiens 308Val Leu Tyr Val Gly Ser Lys Thr Lys 1 5
3099PRTHomo sapiens 309Lys Thr Lys Glu Gln Val Thr Asn Val 1 5
31010PRTHomo sapiens 310Met Pro Val Asp Pro Asp Asn Glu Ala Tyr 1 5
10 3119PRTHomo sapiens 311Ala Glu Lys Thr Lys Gln Gly Val Ala 1 5
3129PRTHomo sapiens 312Asp Ile Ala Asp Phe Phe Thr Thr Arg 1 5
3139PRTHomo sapiens 313His Ser Tyr Leu Gln Arg Gln Ser Val 1 5
3149PRTHomo sapiens 314Lys Glu Val Thr Leu Ile Glu Glu Leu 1 5
3159PRTHomo sapiens 315Arg Glu Asp Gly Pro Gly Val Ala Leu 1 5
3169PRTHomo sapiens 316Arg Glu Asp Pro Leu Pro Pro Gly Leu 1 5
31711PRTHomo sapiens 317Ser Leu Phe Gly Gly Ser Gln Gly Leu Arg Lys
1 5 10 3189PRTHomo sapiens 318Ala Glu Phe Gln Arg Leu Lys Gln Ala 1
5 31910PRTHomo sapiens 319Glu Val Ile Asp Gly Val Pro Gly Lys Trp 1
5 10 3209PRTHomo sapiens 320Ile Pro Lys Ala Pro Gly Lys Ile Ile 1 5
3219PRTHomo sapiens 321Ser His Asn Gly Ser Ala Ile Arg Tyr 1 5
32210PRTHomo sapiens 322Thr Glu Val Thr Val Val Gly Asp Lys Leu 1 5
10 3239PRTHomo sapiens 323Tyr Ala Ser Val Val Val Lys Arg Tyr 1 5
3249PRTHomo sapiens 324Ala Thr Asp Leu Ala Leu Tyr Ile Lys 1 5
3259PRTHomo sapiens 325Ala Tyr His Asn Trp Arg His Ala Phe 1 5
3269PRTHomo sapiens 326Glu Pro Leu Asn Ile Lys Asp Ala Tyr 1 5
3279PRTHomo sapiens 327Lys Ile Ala Ala Thr Ile Ile Ser Phe 1 5
3289PRTHomo sapiens 328Lys Ile Phe Leu His Ile His Gly Leu 1 5
3298PRTHomo sapiens 329Leu Glu Val Ile Leu Lys Lys Ile 1 5
3309PRTHomo sapiens 330Ser Glu His Pro Leu Ala Gln Leu Tyr 1 5
3319PRTHomo sapiens 331Val Pro Ser Ala Gln Thr Leu Lys Ile 1 5
3328PRTHomo sapiens 332Ala Glu Tyr Arg Ser Tyr Val Ala 1 5
33310PRTHomo sapiens 333Ala Leu Ala Pro Gly Arg Gly Thr Leu Tyr 1 5
10 3349PRTHomo sapiens 334Gly Pro Arg Gly Thr Gln Ala Ala Leu 1 5
3359PRTHomo sapiens 335Ile Glu Asp Pro Gly Thr Leu His Ile 1 5
33610PRTHomo sapiens 336Ile Glu Asp Pro Gly Thr Leu His Ile Trp 1 5
10 3379PRTHomo sapiens 337Arg Pro Ile Pro Ile Ala Val Lys Tyr 1 5
3388PRTHomo sapiens 338Val Glu Lys Leu Leu Thr Asn Trp 1 5
33911PRTHomo sapiens 339Phe Leu Asp Pro Asp Ile Gly Gly Val Ala Val
1 5 10 34010PRTHomo sapiens 340His Thr Ala Pro Pro Glu Asn Lys Thr
Trp 1 5 10 34110PRTHomo sapiens 341Leu Leu Asp Thr Pro Val Lys Thr
Gln Tyr 1 5 10 3429PRTHomo sapiens 342Asn Ala Val Lys Asp Phe Thr
Ser Phe 1 5 3439PRTHomo sapiens 343Ser Gly Leu Leu Gln Ile Lys Lys
Leu 1 5 3449PRTHomo sapiens 344Tyr His Asp Lys Asn Ile Val Leu Leu
1 5 3459PRTHomo sapiens 345Ser Val Asp Pro Lys Asn Tyr Pro Lys 1 5
3469PRTHomo sapiens 346Ala Val Gly Leu Val Leu Pro Ala Lys 1 5
34710PRTHomo sapiens 347Ala Val Gly Leu Val Leu Pro Ala Lys Leu 1 5
10 3489PRTHomo sapiens 348Ala Leu Leu Glu Val Leu Ser Gln Lys 1 5
3499PRTHomo sapiens 349His Glu Lys Gln Asp Thr Leu Val Ala 1 5
3509PRTHomo sapiens 350Lys Glu Leu Glu Leu Gln Ile Gly Met 1 5
3519PRTHomo sapiens 351Met Tyr Ser Asp Val Trp Lys Gln Leu 1 5
35210PRTHomo sapiens 352Arg Glu Leu Gln Asp Glu Lys Ala Glu Leu 1 5
10 3539PRTHomo sapiens 353Arg Ile Thr Asp Val Leu Asp Gln Lys 1 5
3549PRTHomo sapiens 354Glu Val Ile Lys Ile Thr Gly Leu Lys 1 5
3559PRTHomo sapiens 355His His Val Asp Ile Thr Lys Lys Leu 1 5
3569PRTHomo sapiens 356Leu Pro Phe Asn Val Lys Val Ser Val 1 5
3578PRTHomo sapiens 357Thr Leu Pro Arg Val Leu Glu Ile 1 5
3589PRTHomo sapiens 358Thr Val Asp Leu Pro Lys Ser Pro Lys 1 5
3599PRTHomo sapiens 359Ala Glu His Gly Leu Leu Leu Thr Ala 1 5
3609PRTHomo sapiens 360Ala Gln Ala Gly Ala Leu Leu Gln Val 1 5
3618PRTHomo sapiens 361Asp Gly Gly Phe Val Leu Lys Val 1 5
3629PRTHomo sapiens 362Ile Val Tyr Pro Ser Gly Lys Val Tyr 1 5
3639PRTHomo sapiens 363Lys Leu Asp Asn Gln Val Ser Lys Val 1 5
3649PRTHomo sapiens 364Ser Glu Asn Val Lys Leu Phe Ser Ala 1 5
3658PRTHomo sapiens 365Val Gln Lys Leu Gln Asn Ile Ile 1 5
3669PRTHomo sapiens 366Phe Ser Thr Pro His Gly Leu Glu Val 1 5
3679PRTHomo sapiens 367Lys Arg Phe His Gln Lys Ser Asp Met 1 5
3689PRTHomo sapiens 368Lys Thr Phe Gly His Ala Val Ser Leu 1 5
3699PRTHomo sapiens 369Ser Ser Asn Leu Ile Thr His Ser Arg 1 5
37010PRTHomo sapiens 370Gly Val Ile Asp Gly His Ile Tyr Ala Val 1 5
10 37111PRTHomo sapiens 371Ile Glu Pro Ala Lys Glu Thr Thr Thr Asn
Val 1 5 10 3729PRTHomo sapiens 372Asn Ala Pro Pro Ser Glu Val Leu
Leu 1 5 37312PRTHomo sapiens 373Ser Ile Glu Pro Ala Lys Glu Thr Thr
Thr Asn Val 1 5 10 3749PRTHomo sapiens 374Ala Gln Ser Gln His Asn
Gln Ser Leu 1 5 3759PRTHomo sapiens 375Ala Gln Ser Arg Thr Asn Pro
Gln Val 1 5 3769PRTHomo sapiens 376Lys Met His Asp Lys Val Phe Ala
Tyr 1 5 3779PRTHomo sapiens 377Thr Ala Lys Ala Pro Leu Ser Thr Val
1 5 3788PRTHomo sapiens 378Ile Pro Thr Arg Thr Val Ala
Ile 1 5 3798PRTHomo sapiens 379Asn His Asp Arg Lys His Ala Val 1 5
3809PRTHomo sapiens 380Asn Asn His Asp Arg Lys His Ala Val 1 5
3819PRTHomo sapiens 381Thr Pro Gly Gly Thr Arg Ile Ile Tyr 1 5
3829PRTHomo sapiens 382Glu His Trp Pro Ser Pro Glu Thr Phe 1 5
3839PRTHomo sapiens 383Glu Ile Ile Thr Asn Thr Leu Ser Phe 1 5
38410PRTHomo sapiens 384Glu Val Arg Gly Ala Leu Met Ser Ala Phe 1 5
10 3859PRTHomo sapiens 385Ile Pro Arg Pro Ile Leu Val Leu Leu 1 5
3869PRTHomo sapiens 386Leu Pro Asn Lys Asn Arg Asp Glu Leu 1 5
3879PRTHomo sapiens 387Gln Arg Ile Pro Ala Gly Ala Val Leu 1 5
38811PRTHomo sapiens 388Ala Glu Gly Pro Ala Gly Gly Phe Met Val Val
1 5 10 3899PRTHomo sapiens 389Ala Tyr Tyr Arg Asp Ala Glu Ala Tyr 1
5 3909PRTHomo sapiens 390Gln Val Asn Arg Pro Leu Thr Met Arg 1 5
3919PRTHomo sapiens 391Arg His Ser Pro Val Phe Gln Val Tyr 1 5
3929PRTHomo sapiens 392Ser Leu Pro Val Pro Asn Ser Ala Tyr 1 5
39311PRTHomo sapiens 393Thr Leu Gly Pro Pro Gly Thr Ala His Leu Tyr
1 5 10 39411PRTHomo sapiens 394Ile Glu Pro Ala Lys Glu Thr Thr Thr
Asn Val 1 5 10 3959PRTHomo sapiens 395Asn Ala Pro Pro Ser Glu Val
Leu Leu 1 5 39612PRTHomo sapiens 396Ser Ile Glu Pro Ala Lys Glu Thr
Thr Thr Asn Val 1 5 10 3979PRTHomo sapiens 397Asp Leu Tyr Ser Gly
Leu Asn Gln Arg 1 5 3989PRTHomo sapiens 398Lys Ala Lys Ala Lys Pro
Val Thr Arg 1 5 39910PRTHomo sapiens 399Ala Val Leu Asp Lys Ala Met
Lys Ala Lys 1 5 10 4009PRTHomo sapiens 400Leu Glu Leu Ser Thr Pro
Leu Lys Ile 1 5 4019PRTHomo sapiens 401Leu Pro Leu Asn Leu Asp Thr
Lys Tyr 1 5 4029PRTHomo sapiens 402Thr Val Ile Tyr Arg Ile Gln Ala
Leu 1 5 4039PRTHomo sapiens 403Asp Ala His Ile Tyr Leu Asn His Ile
1 5 40410PRTHomo sapiens 404Asn His Ile Glu Pro Leu Lys Ile Gln Leu
1 5 10 4059PRTHomo sapiens 405Ala Tyr Arg Pro Ala Val His Pro Arg 1
5 4069PRTHomo sapiens 406Leu Arg Ala Pro Leu Glu His Glu Leu 1 5
4079PRTHomo sapiens 407Arg Leu Phe Met Val Leu Leu Leu Lys 1 5
4089PRTHomo sapiens 408Arg Ser Pro Asp Val Leu Lys Asp Phe 1 5
4099PRTHomo sapiens 409Glu Thr Ala Pro Gly Val His Lys Arg 1 5
4109PRTHomo sapiens 410Leu Tyr His Gly Tyr Ile Tyr Thr Tyr 1 5
4119PRTHomo sapiens 411Gly Gln His Val Ala Thr Gln His Phe 1 5
4128PRTHomo sapiens 412Leu Asn Gly Gln Leu Pro Asn Leu 1 5
41311PRTHomo sapiens 413Leu Pro Phe Pro Asp Glu Thr His Glu Arg Tyr
1 5 10 4149PRTHomo sapiens 414Leu Pro His Asn Thr His Arg Val Val 1
5 4159PRTHomo sapiens 415Val Val Phe Asp Ser Pro Arg Asn Arg 1 5
4168PRTHomo sapiens 416Tyr Pro Leu Gly Arg Ile Leu Ile 1 5
4179PRTHomo sapiens 417Lys Glu Phe Ala Glu Phe Val Thr Ser 1 5
4189PRTHomo sapiens 418Val Met Leu Asp Val Pro Ile Arg Leu 1 5
4199PRTHomo sapiens 419Val Pro Met Thr Pro Leu Arg Thr Val 1 5
4209PRTHomo sapiens 420Gln Ile Asp Tyr Lys Thr Leu Val Leu 1 5
4219PRTHomo sapiens 421Val Glu Asp Pro Thr Ile Val Arg Ile 1 5
4229PRTHomo sapiens 422Ile Pro Tyr Gln Asp Leu Pro His Leu 1 5
42310PRTHomo sapiens 423Asp Thr Pro Phe Leu Thr Gly His Gly Arg 1 5
10 4248PRTHomo sapiens 424Glu Phe Tyr Arg Ala Leu Tyr Ile 1 5
42510PRTHomo sapiens 425Arg Tyr Tyr Pro Gln Ile Leu Thr Asn Lys 1 5
10 4268PRTHomo sapiens 426Lys Ala Tyr Glu Arg His Val Leu 1 5
4279PRTHomo sapiens 427Leu Pro Ser Pro Glu Phe His Asp Tyr 1 5
4289PRTHomo sapiens 428Ser Leu Tyr Ala His Pro Ile Glu His 1 5
4299PRTHomo sapiens 429Leu Val Arg Glu Pro Gly Ser Gln Ala 1 5
43010PRTHomo sapiens 430Arg Leu Ala Gly Pro Gly Ser Glu Lys Tyr 1 5
10 43110PRTHomo sapiens 431Ser Pro Gly Ala Gly Arg Asn Ser Val Leu
1 5 10 43211PRTHomo sapiens 432Ser Val Gln Ser Asp Gln Gly Tyr Ile
Ser Arg 1 5 10 4339PRTHomo sapiens 433Gly Val Arg Pro Pro Ala Pro
Ser Leu 1 5 4349PRTHomo sapiens 434Ile Phe Ser Glu Lys Pro Val Phe
Val 1 5 4359PRTHomo sapiens 435Lys Ala Ser Asn Leu Leu Leu Gly Phe
1 5 4369PRTHomo sapiens 436Lys Arg Tyr Ile Phe Ala Asp Ala Tyr 1 5
4379PRTHomo sapiens 437Arg Asn Leu Gln Leu Ser Leu Pro Arg 1 5
4389PRTHomo sapiens 438Glu Ala Ser Glu Pro Val Ala Leu Arg 1 5
4399PRTHomo sapiens 439Arg Pro Lys Val Pro Asp Gln Ser Val 1 5
4409PRTHomo sapiens 440Val Leu Tyr Glu Asn Ala Leu Lys Leu 1 5
44110PRTHomo sapiens 441Glu Val Leu Asp Lys Ser Gln Thr Asn Tyr 1 5
10 4429PRTHomo sapiens 442Met Pro Ser Pro Ile Pro Ala Lys Tyr 1 5
4439PRTHomo sapiens 443Tyr Gly Ile Glu Asn Phe Thr Ser Val 1 5
4449PRTHomo sapiens 444Ala Arg Ala Ala Gln Val Phe Phe Leu 1 5
4459PRTHomo sapiens 445Glu His Ile Val Pro Asn Ala Glu Leu 1 5
4469PRTHomo sapiens 446Glu Ala Phe Glu Phe Val Lys Gln Arg 1 5
4479PRTHomo sapiens 447Asn His Phe Glu Gly His Tyr Gln Tyr 1 5
4489PRTHomo sapiens 448Asp Ala Tyr Pro Lys Asn Pro His Leu 1 5
4499PRTHomo sapiens 449Asp Val Asn Ile Lys Ser Thr Glu Arg 1 5
4509PRTHomo sapiens 450His Ile Asn Ser Ile Lys Ser Val Phe 1 5
4519PRTHomo sapiens 451Tyr Glu Ser Glu Lys Val Gly Val Ala 1 5
4529PRTHomo sapiens 452Glu Asn Ala Pro Thr Thr Val Ser Arg 1 5
45310PRTHomo sapiens 453Arg Phe Pro His Leu Leu Ala His Thr Tyr 1 5
10 4549PRTHomo sapiens 454Thr Leu Asp Gly Ser Leu His Ala Val 1 5
45511PRTHomo sapiens 455Arg Thr Val Leu Lys Asn Leu Ser Leu Leu Lys
1 5 10 4568PRTHomo sapiens 456Phe Glu Ala Lys Val Gln Ala Ile 1 5
4579PRTHomo sapiens 457Phe Phe Glu Ala Lys Val Gln Ala Ile 1 5
4588PRTHomo sapiens 458Lys Glu Leu Gln Ser Thr Phe Lys 1 5
45910PRTHomo sapiens 459Asn Val Ser Ser Arg Phe Glu Glu Glu Ile 1 5
10 46010PRTHomo sapiens 460Glu Val Trp Asn Asn Leu Gly Thr Thr Lys
1 5 10 4619PRTHomo sapiens 461Met Ile Phe Arg Ser Gly Ser Leu Ile 1
5 4629PRTHomo sapiens 462Asn His Ala Leu Pro Leu Pro Gly Phe 1 5
46310PRTHomo sapiens 463Ala Ser Val Phe Gly Thr Met Pro Leu Lys 1 5
10 46410PRTHomo sapiens 464Arg Glu Phe Pro Asp Arg Leu Val Gly Tyr
1 5 10 4659PRTHomo sapiens 465Ser Val Phe Gly Thr Met Pro Leu Lys 1
5 4669PRTHomo sapiens 466Asp Glu Met Arg Phe Val Thr Gln Ile 1 5
46710PRTHomo sapiens 467Glu Thr Val His Phe Ala Thr Thr Gln Trp 1 5
10 4688PRTHomo sapiens 468Leu Pro Pro Pro Ala Thr Gln Ile 1 5
4698PRTHomo sapiens 469Leu Ala Arg Asp Leu Tyr Ala Phe 1 5
47010PRTHomo sapiens 470Leu Pro Gly Ile Gly Leu Ser Thr Ser Leu 1 5
10 4718PRTHomo sapiens 471Met Glu Val Ile Leu Pro Met Leu 1 5
4729PRTHomo sapiens 472Ala Ile Leu Asp Tyr Ile Leu Ala Lys 1 5
4739PRTHomo sapiens 473Lys Ile Ala Ser Gln Leu Ser Lys Leu 1 5
4749PRTHomo sapiens 474Lys Val Thr Ser Thr Thr Thr Val Lys 1 5
4759PRTHomo sapiens 475Tyr Asn Thr Leu Leu Pro Tyr Thr Phe 1 5
4769PRTHomo sapiens 476Phe Leu Asp Pro Arg Pro Leu Thr Val 1 5
4779PRTHomo sapiens 477Ser Ala Phe Ala Asp Arg Pro Ala Phe 1 5
4789PRTHomo sapiens 478Ala Ala Val Pro Val Ile Ile Ser Arg 1 5
4799PRTHomo sapiens 479Glu Glu Ile Gly Lys Val Ala Ala Ala 1 5
4809PRTHomo sapiens 480Phe Leu Lys Asp Leu Val Ala Ser Val 1 5
4819PRTHomo sapiens 481Val Ile Ile Ser Arg Ala Leu Glu Leu 1 5
48212PRTHomo sapiens 482Ala Pro Arg Thr Thr Gly Thr Pro Arg Thr Ser
Leu 1 5 10 48310PRTHomo sapiens 483Glu Ser Val Gly Gly Ser Pro Gln
Thr Lys 1 5 10 4848PRTHomo sapiens 484Ile Pro Lys Asp Lys Ala Ile
Leu 1 5 4859PRTHomo sapiens 485Leu Pro Ala Tyr Gly Arg Thr Thr Leu
1 5 4869PRTHomo sapiens 486His Gln Ala Ala Ile Val Ser Lys Ile 1 5
4878PRTHomo sapiens 487Gln Ala Ala Ile Val Ser Lys Ile 1 5
4889PRTHomo sapiens 488Arg Gln Lys Met Pro Glu Asp Gly Leu 1 5
4899PRTHomo sapiens 489Ser Val Gln Lys Ser Ser Gly Val Lys 1 5
49011PRTHomo sapiens 490Asp Ser Ile Gly Ser Thr Val Ser Ser Glu Arg
1 5 10 49111PRTHomo sapiens 491Leu Pro Tyr Asn Asn Lys Asp Arg Asp
Ala Leu 1 5 10 4929PRTHomo sapiens 492Ile Tyr Asp Glu Ile Gln Gln
Glu Met 1 5 4939PRTHomo sapiens 493Ala Gln Ala Lys Gly Leu Ile Gln
Val 1 5 4949PRTHomo sapiens 494Glu Val Ser Ser Glu Ile Tyr Gln Trp
1 5 4959PRTHomo sapiens 495Lys Trp Asn Pro Val Pro Leu Ser Tyr 1 5
4969PRTHomo sapiens 496Asn Arg Leu Leu Ala Gln Gln Ser Leu 1 5
4979PRTHomo sapiens 497Ala Pro Arg Pro Val Ala Val Ala Val 1 5
49810PRTHomo sapiens 498Phe Tyr Arg Glu Thr Val Gln Val Gly Arg 1 5
10 4999PRTHomo sapiens 499Leu Leu Ala Pro Arg Pro Val Ala Val 1 5
5009PRTHomo sapiens 500Gly Leu Ala Ala Leu Val Ile Leu Lys 1 5
5019PRTHomo sapiens 501Lys Ile Gln Glu Val Phe Ser Ser Tyr 1 5
5029PRTHomo sapiens 502Ala Ser Leu Asp Lys Phe Leu Ser His 1 5
5039PRTHomo sapiens 503Ala Leu Tyr Ala Thr Lys Thr Leu Arg 1 5
5048PRTHomo sapiens 504Met Glu Tyr Val Ile Ser Arg Ile 1 5
5059PRTHomo sapiens 505Val Pro Val Gly Arg Gln Pro Ile Ile 1 5
50610PRTHomo sapiens 506Lys Leu Leu Ile Gly Val Ile Ala Ala Val 1 5
10 5078PRTHomo sapiens 507Leu Pro Ser Leu Ile Lys Leu Asp 1 5
5088PRTHomo sapiens 508Pro Ser Leu Ile Lys Leu Asp Leu 1 5
5099PRTHomo sapiens 509Ala Arg Asn Lys Glu Leu Ile Gly Lys 1 5
5109PRTHomo sapiens 510Ala Val Lys Ser Asn Ala Ala Ala Tyr 1 5
5119PRTHomo sapiens 511Glu Val Ile Ile Pro His Ser Gly Trp 1 5
5129PRTHomo sapiens 512Ser Val Lys Glu Gln Glu Ala Gln Phe 1 5
51310PRTHomo sapiens 513Ala Pro Arg Gly Leu Glu Pro Ile Ala Ile 1 5
10 5149PRTHomo sapiens 514Gly Arg Phe Gly Gly Val Ile Thr Ile 1 5
5159PRTHomo sapiens 515Pro Val Ala Gly Phe Phe Ile Asn Arg 1 5
5169PRTHomo sapiens 516Thr Pro Lys Thr Pro Ser Arg Asp Ala 1 5
51710PRTHomo sapiens 517Val Leu Phe Gly Gly Lys Val Ser Gly Ala 1 5
10 5189PRTHomo sapiens 518Ala Glu His Ile Glu Ser Arg Thr Leu 1 5
5199PRTHomo sapiens 519Asp Gln Tyr Pro Tyr Leu Lys Ser Val 1 5
5209PRTHomo sapiens 520Ile Ala Arg Asn Leu Thr Gln Gln Leu 1 5
5219PRTHomo sapiens 521Ile Glu Ser Arg Thr Leu Ala Ile Ala 1 5
52210PRTHomo sapiens 522Met Thr Ser Ala Leu Pro Ile Ile Gln Lys 1 5
10 52312PRTHomo sapiens 523Ser Leu Leu Thr Ser Ser Lys Gly Gln Leu
Gln Lys 1 5 10 5249PRTHomo sapiens 524Thr Ser Ala Leu Pro Ile Ile
Gln Lys 1 5 5259PRTHomo sapiens 525Val Arg Leu Gly Ser Leu Ser Thr
Lys 1 5 52610PRTHomo sapiens 526Arg Ile Asn Glu Phe Ser Ile Ser Ser
Phe 1 5 10 5279PRTHomo sapiens 527Asp Glu Lys Gln Gln His Ile Val
Tyr 1 5 5289PRTHomo sapiens 528Asp Glu Val Tyr Gln Val Thr Val Tyr
1 5 5299PRTHomo sapiens 529Gly Glu Ile Ser Glu Lys Ala Lys Leu 1 5
5309PRTHomo sapiens 530Tyr Thr Met Lys Glu Val Leu Phe Tyr 1 5
5319PRTHomo sapiens 531Ser Gln Leu Thr Thr Leu Ser Phe Tyr 1 5
5328PRTHomo sapiens 532Leu Glu Lys Gln Leu Ile Glu Leu 1 5
5339PRTHomo sapiens 533Glu Leu Thr Leu Gly Glu Phe Leu Lys 1 5
5348PRTHomo sapiens 534Leu Thr Leu Gly Glu Phe Leu Lys 1 5
5359PRTHomo sapiens 535Leu Thr Leu Gly Glu Phe Leu Lys Leu 1 5
5368PRTHomo sapiens 536Thr Leu Gly Glu Phe Leu Lys Leu 1 5
5378PRTHomo sapiens 537Ile Thr Ala Arg Pro Val Leu Trp 1 5
53810PRTHomo sapiens 538Lys Leu Met Ser Pro Lys Leu Tyr Val Trp 1 5
10 5399PRTHomo sapiens 539Lys Val Ser Ala Val Thr Leu Ala Tyr 1 5
54010PRTHomo sapiens 540Val Glu Gly Ser Gly Glu Leu Phe Arg Trp 1 5
10 5418PRTHomo sapiens 541Arg Pro Lys Ser Asn Ile Val Leu 1 5
5429PRTHomo sapiens 542Arg Pro Lys Ser Asn Ile Val Leu Leu 1 5
54314PRTHomo sapiens 543Gly Glu Pro Leu Ser Tyr Thr Arg Phe Ser Leu
Ala Arg Gln 1 5 10 54416PRTHomo sapiens 544Gly Glu Pro Leu Ser Tyr
Thr Arg Phe Ser Leu Ala Arg Gln Val Asp 1 5 10 15 54517PRTHomo
sapiens 545Gly Glu Pro Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln
Val Asp 1 5 10 15 Gly 54617PRTHomo sapiens 546Gly Gly Glu Pro Leu
Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val 1 5 10 15 Asp
54718PRTHomo sapiens 547Gly Gly Glu Pro Leu Ser Tyr Thr Arg Phe Ser
Leu Ala Arg Gln Val 1 5 10 15 Asp Gly 54816PRTHomo sapiens 548Asn
Pro Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly 1 5 10
15 54917PRTHomo sapiens 549Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys
Ala Ala Thr Val Thr Gly 1 5 10 15 Lys 55018PRTHomo sapiens 550Asn
Pro Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly 1 5 10
15 Lys Leu 55112PRTHomo sapiens 551Asn Ser Val Ile Ile Val Asp Lys
Asn Gly Arg Leu 1 5 10 55213PRTHomo sapiens 552Asn Ser Val Ile Ile
Val Asp Lys Asn Gly Arg Leu Val 1 5 10 55314PRTHomo sapiens 553Asn
Ser Val Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr 1 5 10
55414PRTHomo sapiens 554Arg Val Glu Tyr His Phe Leu Ser Pro Tyr Val
Ser Pro Lys 1 5 10 55515PRTHomo sapiens 555Arg Val Glu Tyr His Phe
Leu Ser Pro Tyr Val Ser Pro Lys Glu 1 5 10 15 55618PRTHomo sapiens
556Arg Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser
1 5 10 15 Pro Phe 55715PRTHomo sapiens 557Ser Pro Phe Arg His Val
Phe Trp Gly Ser Gly Ser His Thr Leu 1 5 10 15 55812PRTHomo sapiens
558Ser Val Ile Ile Val Asp Lys Asn Gly Arg Leu Val 1 5
10 55913PRTHomo sapiens 559Val Glu Tyr His Phe Leu Ser Pro Tyr Val
Ser Pro Lys 1 5 10 56014PRTHomo sapiens 560Val Glu Tyr His Phe Leu
Ser Pro Tyr Val Ser Pro Lys Glu 1 5 10 56114PRTHomo sapiens 561Leu
Pro Ser Gln Ala Phe Glu Tyr Ile Leu Tyr Asn Lys Gly 1 5 10
56215PRTHomo sapiens 562Leu Pro Ser Gln Ala Phe Glu Tyr Ile Leu Tyr
Asn Lys Gly Ile 1 5 10 15 56316PRTHomo sapiens 563Leu Pro Ser Gln
Ala Phe Glu Tyr Ile Leu Tyr Asn Lys Gly Ile Met 1 5 10 15
56417PRTHomo sapiens 564Leu Pro Ser Gln Ala Phe Glu Tyr Ile Leu Tyr
Asn Lys Gly Ile Met 1 5 10 15 Gly 56513PRTHomo sapiens 565Met Asn
Gly Tyr Phe Leu Ile Glu Arg Gly Lys Asn Met 1 5 10 56612PRTHomo
sapiens 566Asn Gly Tyr Phe Leu Ile Glu Arg Gly Lys Asn Met 1 5 10
56713PRTHomo sapiens 567Pro Ser Gln Ala Phe Glu Tyr Ile Leu Tyr Asn
Lys Gly 1 5 10 56814PRTHomo sapiens 568Pro Ser Gln Ala Phe Glu Tyr
Ile Leu Tyr Asn Lys Gly Ile 1 5 10 56915PRTHomo sapiens 569Pro Ser
Gln Ala Phe Glu Tyr Ile Leu Tyr Asn Lys Gly Ile Met 1 5 10 15
57013PRTHomo sapiens 570Glu Gly Val Gln Tyr Ser Tyr Ser Leu Phe His
Leu Met 1 5 10 57114PRTHomo sapiens 571Glu Gly Val Gln Tyr Ser Tyr
Ser Leu Phe His Leu Met Leu 1 5 10 57212PRTHomo sapiens 572Gly Val
Gln Tyr Ser Tyr Ser Leu Phe His Leu Met 1 5 10 57313PRTHomo sapiens
573Gly Val Gln Tyr Ser Tyr Ser Leu Phe His Leu Met Leu 1 5 10
57415PRTHomo sapiens 574Ser Ile Ile Ser Ile His Pro Lys Ile Gln Glu
His Gln Pro Arg 1 5 10 15 57513PRTHomo sapiens 575Ser Ser Ile Arg
Thr Ser Thr Asn Ser Gln Val Asp Lys 1 5 10 57612PRTHomo sapiens
576Val Leu Val Gly Tyr Lys Ala Val Tyr Arg Ile Ser 1 5 10
57714PRTHomo sapiens 577Tyr Ser Ser Ile Arg Thr Ser Thr Asn Ser Gln
Val Asp Lys 1 5 10 57818PRTHomo sapiens 578Gly Gly Gly Tyr Gly Ser
Gly Gly Gly Ser Gly Gly Tyr Gly Ser Arg 1 5 10 15 Arg Phe
57912PRTHomo sapiens 579Gly Gly Ser Phe Gly Gly Arg Ser Ser Gly Ser
Pro 1 5 10 58013PRTHomo sapiens 580Lys Gly Gly Ser Phe Gly Gly Arg
Ser Ser Gly Ser Pro 1 5 10 58125PRTHomo sapiens 581Ser Gly Gln Gln
Gln Ser Asn Tyr Gly Pro Met Lys Gly Gly Ser Phe 1 5 10 15 Gly Gly
Arg Ser Ser Gly Ser Pro Tyr 20 25 58223PRTHomo sapiens 582Ser Gly
Ser Pro Tyr Gly Gly Gly Tyr Gly Ser Gly Gly Gly Ser Gly 1 5 10 15
Gly Tyr Gly Ser Arg Arg Phe 20 58321PRTHomo sapiens 583Ser Pro Tyr
Gly Gly Gly Tyr Gly Ser Gly Gly Gly Ser Gly Gly Tyr 1 5 10 15 Gly
Ser Arg Arg Phe 20 58419PRTHomo sapiens 584Tyr Gly Gly Gly Tyr Gly
Ser Gly Gly Gly Ser Gly Gly Tyr Gly Ser 1 5 10 15 Arg Arg Phe
58512PRTHomo sapiens 585Gly Asn Arg Ile Asn Glu Phe Ser Ile Ser Ser
Phe 1 5 10 58614PRTHomo sapiens 586His Gly Asn Gln Ile Thr Ser Asp
Lys Val Gly Arg Lys Val 1 5 10 58714PRTHomo sapiens 587Ile Pro Pro
Val Asn Thr Asn Leu Glu Asn Leu Tyr Leu Gln 1 5 10 58813PRTHomo
sapiens 588Leu Gln Val Leu Arg Leu Asp Gly Asn Glu Ile Lys Arg 1 5
10 58914PRTHomo sapiens 589Leu Gln Val Leu Arg Leu Asp Gly Asn Glu
Ile Lys Arg Ser 1 5 10 59015PRTHomo sapiens 590Leu Gln Val Leu Arg
Leu Asp Gly Asn Glu Ile Lys Arg Ser Ala 1 5 10 15 59116PRTHomo
sapiens 591Leu Arg Glu Leu His Leu Asp His Asn Gln Ile Ser Arg Val
Pro Asn 1 5 10 15 59214PRTHomo sapiens 592Leu Tyr Val Arg Leu Ser
His Asn Ser Leu Thr Asn Asn Gly 1 5 10 59314PRTHomo sapiens 593Val
Pro Ser Arg Met Lys Tyr Val Tyr Phe Gln Asn Asn Gln 1 5 10
59416PRTHomo sapiens 594Val Pro Ser Arg Met Lys Tyr Val Tyr Phe Gln
Asn Asn Gln Ile Thr 1 5 10 15 59517PRTHomo sapiens 595Val Pro Ser
Arg Met Lys Tyr Val Tyr Phe Gln Asn Asn Gln Ile Thr 1 5 10 15 Ser
59612PRTHomo sapiens 596Trp Ile Ala Leu His Gly Asn Gln Ile Thr Ser
Asp 1 5 10 59713PRTHomo sapiens 597Trp Ile Ala Leu His Gly Asn Gln
Ile Thr Ser Asp Lys 1 5 10 59815PRTHomo sapiens 598Ala Asp Asp Asn
Val Ser Phe Arg Trp Glu Ala Leu Gly Asn Thr 1 5 10 15 59916PRTHomo
sapiens 599Ala Asp Asp Asn Val Ser Phe Arg Trp Glu Ala Leu Gly Asn
Thr Leu 1 5 10 15 60017PRTHomo sapiens 600Asp Ala Asp Asp Asn Val
Ser Phe Arg Trp Glu Ala Leu Gly Asn Thr 1 5 10 15 Leu 60114PRTHomo
sapiens 601Asp Asp Asn Val Ser Phe Arg Trp Glu Ala Leu Gly Asn Thr
1 5 10 60215PRTHomo sapiens 602Asp Asp Asn Val Ser Phe Arg Trp Glu
Ala Leu Gly Asn Thr Leu 1 5 10 15 60313PRTHomo sapiens 603Asp Asn
Val Ser Phe Arg Trp Glu Ala Leu Gly Asn Thr 1 5 10 60414PRTHomo
sapiens 604Asp Asn Val Ser Phe Arg Trp Glu Ala Leu Gly Asn Thr Leu
1 5 10 60515PRTHomo sapiens 605Asp Asn Val Ser Phe Arg Trp Glu Ala
Leu Gly Asn Thr Leu Ser 1 5 10 15 60616PRTHomo sapiens 606Asp Thr
Gly Ser Tyr Arg Ala Gln Ile Ser Thr Lys Thr Ser Ala Lys 1 5 10 15
60717PRTHomo sapiens 607Asp Thr Gly Ser Tyr Arg Ala Gln Ile Ser Thr
Lys Thr Ser Ala Lys 1 5 10 15 Leu 60813PRTHomo sapiens 608Asp Thr
Ile Thr Ile Tyr Ser Thr Ile Asn His Ser Lys 1 5 10 60917PRTHomo
sapiens 609Glu Asp Thr Gly Ser Tyr Arg Ala Gln Ile Ser Thr Lys Thr
Ser Ala 1 5 10 15 Lys 61015PRTHomo sapiens 610Glu Asn Asp Thr Ile
Thr Ile Tyr Ser Thr Ile Asn His Ser Lys 1 5 10 15 61120PRTHomo
sapiens 611Glu Asn Asp Thr Ile Thr Ile Tyr Ser Thr Ile Asn His Ser
Lys Glu 1 5 10 15 Ser Lys Pro Thr 20 61214PRTHomo sapiens 612Gly
Ser Tyr Arg Ala Gln Ile Ser Thr Lys Thr Ser Ala Lys 1 5 10
61312PRTHomo sapiens 613Asn Asp Thr Ile Thr Ile Tyr Ser Thr Ile Asn
His 1 5 10 61413PRTHomo sapiens 614Asn Asp Thr Ile Thr Ile Tyr Ser
Thr Ile Asn His Ser 1 5 10 61514PRTHomo sapiens 615Asn Asp Thr Ile
Thr Ile Tyr Ser Thr Ile Asn His Ser Lys 1 5 10 61613PRTHomo sapiens
616Asn Val Ser Phe Arg Trp Glu Ala Leu Gly Asn Thr Leu 1 5 10
61718PRTHomo sapiens 617Ser Pro Thr Asn Asn Thr Val Tyr Ala Ser Val
Thr His Ser Asn Arg 1 5 10 15 Glu Thr 61815PRTHomo sapiens 618Thr
Gly Ser Tyr Arg Ala Gln Ile Ser Thr Lys Thr Ser Ala Lys 1 5 10 15
61918PRTHomo sapiens 619Thr Pro Arg Glu Asn Asp Thr Ile Thr Ile Tyr
Ser Thr Ile Asn His 1 5 10 15 Ser Lys 62023PRTHomo sapiens 620Thr
Pro Arg Glu Asn Asp Thr Ile Thr Ile Tyr Ser Thr Ile Asn His 1 5 10
15 Ser Lys Glu Ser Lys Pro Thr 20 62112PRTHomo sapiens 621Val Ser
Phe Arg Trp Glu Ala Leu Gly Asn Thr Leu 1 5 10 62215PRTHomo sapiens
622Ala Pro Ile His Phe Thr Ile Glu Lys Leu Glu Leu Asn Glu Lys 1 5
10 15 62313PRTHomo sapiens 623Asp Ala Gln Phe Glu Val Ile Lys Gly
Gln Thr Ile Glu 1 5 10 62415PRTHomo sapiens 624Asp Ala Gln Phe Glu
Val Ile Lys Gly Gln Thr Ile Glu Val Arg 1 5 10 15 62515PRTHomo
sapiens 625Glu Ser Tyr Phe Ile Pro Glu Val Arg Ile Tyr Asp Ser Gly
Thr 1 5 10 15 62612PRTHomo sapiens 626Ile Pro Glu Val Arg Ile Tyr
Asp Ser Gly Thr Tyr 1 5 10 62714PRTHomo sapiens 627Lys Asp Lys Ala
Ile Val Ala His Asn Arg His Gly Asn Lys 1 5 10 62815PRTHomo sapiens
628Lys Asp Lys Ala Ile Val Ala His Asn Arg His Gly Asn Lys Ala 1 5
10 15 62914PRTHomo sapiens 629Asn Phe Val Ile Leu Glu Phe Pro Val
Glu Glu Gln Asp Arg 1 5 10 63015PRTHomo sapiens 630Ser Gln Pro Arg
Ile Ser Tyr Asp Ala Gln Phe Glu Val Ile Lys 1 5 10 15 63116PRTHomo
sapiens 631Ser Gln Pro Arg Ile Ser Tyr Asp Ala Gln Phe Glu Val Ile
Lys Gly 1 5 10 15 63214PRTHomo sapiens 632Tyr Asp Ala Gln Phe Glu
Val Ile Lys Gly Gln Thr Ile Glu 1 5 10 63314PRTHomo sapiens 633Gly
Asn Pro Ala Tyr Arg Ser Phe Ser Asn Ser Leu Ser Gln 1 5 10
63416PRTHomo sapiens 634Gly Pro Pro Gly Glu Ala Gly Tyr Lys Ala Phe
Ser Ser Leu Leu Ala 1 5 10 15 63518PRTHomo sapiens 635Gly Pro Pro
Gly Glu Ala Gly Tyr Lys Ala Phe Ser Ser Leu Leu Ala 1 5 10 15 Ser
Ser 63619PRTHomo sapiens 636Gly Pro Pro Gly Glu Ala Gly Tyr Lys Ala
Phe Ser Ser Leu Leu Ala 1 5 10 15 Ser Ser Ala 63723PRTHomo sapiens
637Gly Pro Pro Gly Glu Ala Gly Tyr Lys Ala Phe Ser Ser Leu Leu Ala
1 5 10 15 Ser Ser Ala Val Ser Pro Glu 20 63824PRTHomo sapiens
638Gly Pro Pro Gly Glu Ala Gly Tyr Lys Ala Phe Ser Ser Leu Leu Ala
1 5 10 15 Ser Ser Ala Val Ser Pro Glu Lys 20 63916PRTHomo sapiens
639Gly Tyr Lys Ala Phe Ser Ser Leu Leu Ala Ser Ser Ala Val Ser Pro
1 5 10 15 64017PRTHomo sapiens 640Gly Tyr Lys Ala Phe Ser Ser Leu
Leu Ala Ser Ser Ala Val Ser Pro 1 5 10 15 Glu 64115PRTHomo sapiens
641Lys Ala Phe Ser Ser Leu Leu Ala Ser Ser Ala Val Ser Pro Glu 1 5
10 15 64213PRTHomo sapiens 642Asn Pro Ala Tyr Arg Ser Phe Ser Asn
Ser Leu Ser Gln 1 5 10 64315PRTHomo sapiens 643Ser Arg Asp Asp Phe
Gln Glu Gly Arg Glu Gly Ile Val Ala Arg 1 5 10 15 64413PRTHomo
sapiens 644Ser Ser Ser Ser Phe His Pro Ala Pro Gly Asn Ala Gln 1 5
10 64512PRTHomo sapiens 645Val Ala Arg Leu Thr Glu Ser Leu Phe Leu
Asp Leu 1 5 10 64614PRTHomo sapiens 646Val Ala Arg Leu Thr Glu Ser
Leu Phe Leu Asp Leu Leu Gly 1 5 10 64713PRTHomo sapiens 647Val Ile
Ala Gly Asn Pro Ala Tyr Arg Ser Phe Ser Asn 1 5 10 64819PRTHomo
sapiens 648Val Pro Gln Pro Glu Pro Glu Thr Trp Glu Gln Ile Leu Arg
Arg Asn 1 5 10 15 Val Leu Gln 64914PRTHomo sapiens 649Tyr Lys Ala
Phe Ser Ser Leu Leu Ala Ser Ser Ala Val Ser 1 5 10 65015PRTHomo
sapiens 650Tyr Lys Ala Phe Ser Ser Leu Leu Ala Ser Ser Ala Val Ser
Pro 1 5 10 15 65116PRTHomo sapiens 651Tyr Lys Ala Phe Ser Ser Leu
Leu Ala Ser Ser Ala Val Ser Pro Glu 1 5 10 15 65217PRTHomo sapiens
652Gly Asn Gln Val Phe Ser Tyr Thr Ala Asn Lys Glu Ile Arg Thr Asp
1 5 10 15 Asp 65314PRTHomo sapiens 653Ile Glu Glu Ile Val Leu Val
Asp Asp Ala Ser Glu Arg Asp 1 5 10 65415PRTHomo sapiens 654Ile Glu
Glu Ile Val Leu Val Asp Asp Ala Ser Glu Arg Asp Phe 1 5 10 15
65513PRTHomo sapiens 655Leu Glu Asn Ile Tyr Pro Asp Ser Gln Ile Pro
Arg His 1 5 10 65614PRTHomo sapiens 656Leu Glu Asn Ile Tyr Pro Asp
Ser Gln Ile Pro Arg His Tyr 1 5 10 65713PRTHomo sapiens 657Asn Gln
Val Phe Ser Tyr Thr Ala Asn Lys Glu Ile Arg 1 5 10 65814PRTHomo
sapiens 658Asn Gln Val Phe Ser Tyr Thr Ala Asn Lys Glu Ile Arg Thr
1 5 10 65916PRTHomo sapiens 659Asn Gln Val Phe Ser Tyr Thr Ala Asn
Lys Glu Ile Arg Thr Asp Asp 1 5 10 15 66015PRTHomo sapiens 660Val
His Ser Val Ile Asn Arg Ser Pro Arg His Met Ile Glu Glu 1 5 10 15
66112PRTHomo sapiens 661Glu Tyr Val Ser Leu Tyr His Gln Pro Ala Ala
Met 1 5 10 66216PRTHomo sapiens 662Ile Lys Ala Glu Tyr Lys Gly Arg
Val Thr Leu Lys Gln Tyr Pro Arg 1 5 10 15 66315PRTHomo sapiens
663Leu Asn Val His Ser Glu Tyr Glu Pro Ser Trp Glu Glu Gln Pro 1 5
10 15 66414PRTHomo sapiens 664Leu Pro Tyr Leu Phe Gln Met Pro Ala
Tyr Ala Ser Ser Ser 1 5 10 66515PRTHomo sapiens 665Leu Pro Tyr Leu
Phe Gln Met Pro Ala Tyr Ala Ser Ser Ser Lys 1 5 10 15 66612PRTHomo
sapiens 666Asn Phe Ile Lys Ala Glu Tyr Lys Gly Arg Val Thr 1 5 10
66713PRTHomo sapiens 667Thr Asn Phe Ile Lys Ala Glu Tyr Lys Gly Arg
Val Thr 1 5 10 66814PRTHomo sapiens 668Thr Thr Asn Phe Ile Lys Ala
Glu Tyr Lys Gly Arg Val Thr 1 5 10 66917PRTHomo sapiens 669Val Thr
Leu Asn Val His Ser Glu Tyr Glu Pro Ser Trp Glu Glu Gln 1 5 10 15
Pro 67019PRTHomo sapiens 670Tyr Pro Arg Lys Asn Leu Phe Leu Val Glu
Val Thr Gln Leu Thr Glu 1 5 10 15 Ser Asp Ser 67120PRTHomo sapiens
671Tyr Pro Arg Lys Asn Leu Phe Leu Val Glu Val Thr Gln Leu Thr Glu
1 5 10 15 Ser Asp Ser Gly 20 67212PRTHomo sapiens 672Ala Asp Leu
Ser Ser Phe Lys Ser Gln Glu Leu Asn 1 5 10 67314PRTHomo sapiens
673Ala Asp Leu Ser Ser Phe Lys Ser Gln Glu Leu Asn Glu Arg 1 5 10
67415PRTHomo sapiens 674Ala Asp Leu Ser Ser Phe Lys Ser Gln Glu Leu
Asn Glu Arg Asn 1 5 10 15 67516PRTHomo sapiens 675Ala Asp Leu Ser
Ser Phe Lys Ser Gln Glu Leu Asn Glu Arg Asn Glu 1 5 10 15
67617PRTHomo sapiens 676Ala Asp Leu Ser Ser Phe Lys Ser Gln Glu Leu
Asn Glu Arg Asn Glu 1 5 10 15 Ala 67719PRTHomo sapiens 677Ala Glu
Gln Gln Arg Leu Lys Ser Gln Asp Leu Glu Leu Ser Trp Asn 1 5 10 15
Leu Asn Gly 67815PRTHomo sapiens 678Glu Gln Gln Arg Leu Lys Ser Gln
Asp Leu Glu Leu Ser Trp Asn 1 5 10 15 67914PRTHomo sapiens 679Ile
Ser Gln Glu Leu Glu Glu Leu Arg Ala Glu Gln Gln Arg 1 5 10
68016PRTHomo sapiens 680Ile Ser Gln Glu Leu Glu Glu Leu Arg Ala Glu
Gln Gln Arg Leu Lys 1 5 10 15 68112PRTHomo sapiens 681Lys Gly Thr
Lys Gln Trp Val His Ala Arg Tyr Ala 1 5 10 68215PRTHomo sapiens
682Gln Ala Asp Leu Ser Ser Phe Lys Ser Gln Glu Leu Asn Glu Arg 1 5
10 15 68315PRTHomo sapiens 683Ser Trp Asn Leu Asn Gly Leu Gln Ala
Asp Leu Ser Ser Phe Lys 1 5 10 15 68414PRTHomo sapiens 684Thr Gly
Ser Trp Ile Gly Leu Arg Asn Leu Asp Leu Lys Gly 1 5 10 68523PRTHomo
sapiens 685Phe Gly Asn Tyr Asn Asn Gln Ser Ser Asn Phe Gly
Pro Met Lys Gly 1 5 10 15 Gly Asn Phe Gly Gly Arg Ser 20
68623PRTHomo sapiens 686Phe Gly Pro Met Lys Gly Gly Asn Phe Gly Gly
Arg Ser Ser Gly Pro 1 5 10 15 Tyr Gly Gly Gly Gly Gln Tyr 20
68715PRTHomo sapiens 687Gly Pro Met Lys Gly Gly Asn Phe Gly Gly Arg
Ser Ser Gly Pro 1 5 10 15 68813PRTHomo sapiens 688Gly Pro Tyr Gly
Gly Gly Gly Gln Tyr Phe Ala Lys Pro 1 5 10 68912PRTHomo sapiens
689Lys Gly Gly Asn Phe Gly Gly Arg Ser Ser Gly Pro 1 5 10
69015PRTHomo sapiens 690Asn Asp Phe Gly Asn Tyr Asn Asn Gln Ser Ser
Asn Phe Gly Pro 1 5 10 15 69114PRTHomo sapiens 691Ser Gly Pro Tyr
Gly Gly Gly Gly Gln Tyr Phe Ala Lys Pro 1 5 10 69215PRTHomo sapiens
692Asp Ala Gly Ser Tyr Lys Ala Gln Ile Asn Gln Arg Asn Phe Glu 1 5
10 15 69317PRTHomo sapiens 693Asp Ala Gly Ser Tyr Lys Ala Gln Ile
Asn Gln Arg Asn Phe Glu Val 1 5 10 15 Thr 69414PRTHomo sapiens
694Asp Gly Glu Leu Ile Arg Thr Gln Pro Gln Arg Leu Pro Gln 1 5 10
69513PRTHomo sapiens 695Gly Glu Leu Ile Arg Thr Gln Pro Gln Arg Leu
Pro Gln 1 5 10 69616PRTHomo sapiens 696Asn Pro Ser Asp Gly Glu Leu
Ile Arg Thr Gln Pro Gln Arg Leu Pro 1 5 10 15 69717PRTHomo sapiens
697Asn Pro Ser Asp Gly Glu Leu Ile Arg Thr Gln Pro Gln Arg Leu Pro
1 5 10 15 Gln 69818PRTHomo sapiens 698Asn Pro Ser Asp Gly Glu Leu
Ile Arg Thr Gln Pro Gln Arg Leu Pro 1 5 10 15 Gln Leu 69915PRTHomo
sapiens 699Ala Ser Asn Asp Met Tyr His Ser Arg Ala Leu Gln Val Val
Arg 1 5 10 15 70016PRTHomo sapiens 700Ala Ser Asn Asp Met Tyr His
Ser Arg Ala Leu Gln Val Val Arg Ala 1 5 10 15 70115PRTHomo sapiens
701Glu Gly Val Arg Arg Ala Leu Asp Phe Ala Val Gly Glu Tyr Asn 1 5
10 15 70216PRTHomo sapiens 702Glu Gly Val Arg Arg Ala Leu Asp Phe
Ala Val Gly Glu Tyr Asn Lys 1 5 10 15 70314PRTHomo sapiens 703Ser
Asn Asp Met Tyr His Ser Arg Ala Leu Gln Val Val Arg 1 5 10
70413PRTHomo sapiens 704Val Gly Glu Tyr Asn Lys Ala Ser Asn Asp Met
Tyr His 1 5 10 70513PRTHomo sapiens 705Val Arg Ala Arg Lys Gln Ile
Val Ala Gly Val Asn Tyr 1 5 10 70618PRTHomo sapiens 706Val Arg Arg
Ala Leu Asp Phe Ala Val Gly Glu Tyr Asn Lys Ala Ser 1 5 10 15 Asn
Asp 70713PRTHomo sapiens 707Val Val Arg Ala Arg Lys Gln Ile Val Ala
Gly Val Asn 1 5 10 70814PRTHomo sapiens 708Val Val Arg Ala Arg Lys
Gln Ile Val Ala Gly Val Asn Tyr 1 5 10 70914PRTHomo sapiens 709Ala
Pro Leu Glu Gly Ala Arg Phe Ala Leu Val Arg Glu Asp 1 5 10
71016PRTHomo sapiens 710Ala Pro Val Glu Leu Ile Leu Ser Asp Glu Thr
Leu Pro Ala Pro Glu 1 5 10 15 71113PRTHomo sapiens 711Glu Leu Ile
Leu Ser Asp Glu Thr Leu Pro Ala Pro Glu 1 5 10 71214PRTHomo sapiens
712Leu Ala Pro Leu Glu Gly Ala Arg Phe Ala Leu Val Arg Glu 1 5 10
71315PRTHomo sapiens 713Leu Ala Pro Leu Glu Gly Ala Arg Phe Ala Leu
Val Arg Glu Asp 1 5 10 15 71416PRTHomo sapiens 714Arg Gly Glu Lys
Glu Leu Leu Val Pro Arg Ser Ser Thr Ser Pro Asp 1 5 10 15
71516PRTHomo sapiens 715Ala Ser Lys Thr Phe Thr Thr Gln Glu Thr Ile
Thr Asn Ala Glu Thr 1 5 10 15 71615PRTHomo sapiens 716Asp Gln His
Phe Arg Thr Thr Pro Leu Glu Lys Asn Ala Pro Val 1 5 10 15
71714PRTHomo sapiens 717Asn Thr Pro Ile Leu Val Asp Gly Lys Asp Val
Met Pro Glu 1 5 10 71815PRTHomo sapiens 718Asn Thr Pro Ile Leu Val
Asp Gly Lys Asp Val Met Pro Glu Val 1 5 10 15 71916PRTHomo sapiens
719Asn Thr Pro Ile Leu Val Asp Gly Lys Asp Val Met Pro Glu Val Asn
1 5 10 15 72015PRTHomo sapiens 720Ser Asn Thr Pro Ile Leu Val Asp
Gly Lys Asp Val Met Pro Glu 1 5 10 15 72117PRTHomo sapiens 721Ser
Asn Thr Pro Ile Leu Val Asp Gly Lys Asp Val Met Pro Glu Val 1 5 10
15 Asn 72212PRTHomo sapiens 722Thr Pro Ile Leu Val Asp Gly Lys Asp
Val Met Pro 1 5 10 72313PRTHomo sapiens 723Thr Pro Ile Leu Val Asp
Gly Lys Asp Val Met Pro Glu 1 5 10 72414PRTHomo sapiens 724Thr Pro
Ile Leu Val Asp Gly Lys Asp Val Met Pro Glu Val 1 5 10 72515PRTHomo
sapiens 725Thr Pro Ile Leu Val Asp Gly Lys Asp Val Met Pro Glu Val
Asn 1 5 10 15 72615PRTHomo sapiens 726Gly Pro Leu Lys Phe Leu His
Gln Asp Ile Asp Ser Gly Gln Gly 1 5 10 15 72717PRTHomo sapiens
727Gly Pro Leu Lys Phe Leu His Gln Asp Ile Asp Ser Gly Gln Gly Ile
1 5 10 15 Arg 72813PRTHomo sapiens 728Leu Gly Asp Ile Tyr Phe Lys
Leu Phe Arg Ala Ser Gly 1 5 10 72915PRTHomo sapiens 729Thr Gly His
Leu Phe Asp Leu Ser Ser Leu Ser Gly Arg Ala Gly 1 5 10 15
73016PRTHomo sapiens 730Val Pro Ser Pro Val Asp Cys Gln Val Thr Asp
Leu Ala Gly Asn Glu 1 5 10 15 73118PRTHomo sapiens 731Asp Gly Leu
Asn Ser Leu Thr Tyr Gln Val Leu Asp Val Gln Arg Tyr 1 5 10 15 Pro
Leu 73214PRTHomo sapiens 732His Pro Val Leu Gln Arg Gln Gln Leu Asp
Tyr Gly Ile Tyr 1 5 10 73313PRTHomo sapiens 733Leu Asn Ser Leu Thr
Tyr Gln Val Leu Asp Val Gln Arg 1 5 10 73415PRTHomo sapiens 734Leu
Asn Ser Leu Thr Tyr Gln Val Leu Asp Val Gln Arg Tyr Pro 1 5 10 15
73516PRTHomo sapiens 735Leu Asn Ser Leu Thr Tyr Gln Val Leu Asp Val
Gln Arg Tyr Pro Leu 1 5 10 15 73613PRTHomo sapiens 736Leu Pro Gln
Leu Val Gly Val Ser Thr Pro Leu Gln Gly 1 5 10 73714PRTHomo sapiens
737Leu Pro Gln Leu Val Gly Val Ser Thr Pro Leu Gln Gly Gly 1 5 10
73815PRTHomo sapiens 738Leu Pro Gln Leu Val Gly Val Ser Thr Pro Leu
Gln Gly Gly Ser 1 5 10 15 73916PRTHomo sapiens 739Arg Leu Pro Gln
Leu Val Gly Val Ser Thr Pro Leu Gln Gly Gly Ser 1 5 10 15
74014PRTHomo sapiens 740Ser Pro His Lys Val Ala Ile Ile Ile Pro Phe
Arg Asn Arg 1 5 10 74116PRTHomo sapiens 741Ser Pro His Lys Val Ala
Ile Ile Ile Pro Phe Arg Asn Arg Gln Glu 1 5 10 15 74217PRTHomo
sapiens 742Ser Pro His Lys Val Ala Ile Ile Ile Pro Phe Arg Asn Arg
Gln Glu 1 5 10 15 His 74312PRTHomo sapiens 743Ala Ile Val Gln Ala
Val Ser Ala His Arg His Arg 1 5 10 74413PRTHomo sapiens 744Ala Arg
Asn Phe Glu Arg Asn Lys Ala Ile Lys Val Ile 1 5 10 74515PRTHomo
sapiens 745Ala Arg Asn Phe Glu Arg Asn Lys Ala Ile Lys Val Ile Ile
Ala 1 5 10 15 74612PRTHomo sapiens 746Asn Phe Glu Arg Asn Lys Ala
Ile Lys Val Ile Ile 1 5 10 74713PRTHomo sapiens 747Asn Phe Glu Arg
Asn Lys Ala Ile Lys Val Ile Ile Ala 1 5 10 74812PRTHomo sapiens
748Val Ala Ile Val Gln Ala Val Ser Ala His Arg His 1 5 10
74913PRTHomo sapiens 749Val Ala Ile Val Gln Ala Val Ser Ala His Arg
His Arg 1 5 10 75014PRTHomo sapiens 750Val Ala Ile Val Gln Ala Val
Ser Ala His Arg His Arg Ala 1 5 10 75115PRTHomo sapiens 751Val Ala
Ile Val Gln Ala Val Ser Ala His Arg His Arg Ala Arg 1 5 10 15
75214PRTHomo sapiens 752Glu Glu Val Ile Thr Leu Ile Arg Ser Asn Gln
Gln Leu Glu 1 5 10 75315PRTHomo sapiens 753Glu Glu Val Ile Thr Leu
Ile Arg Ser Asn Gln Gln Leu Glu Asn 1 5 10 15 75416PRTHomo sapiens
754Ile Pro Ala Asp Thr Phe Ala Ala Leu Lys Asn Pro Asn Ala Met Leu
1 5 10 15 75515PRTHomo sapiens 755Leu Lys Gln Leu Leu Ser Asp Lys
Gln Gln Lys Arg Gln Ser Gly 1 5 10 15 75616PRTHomo sapiens 756Leu
Lys Gln Leu Leu Ser Asp Lys Gln Gln Lys Arg Gln Ser Gly Gln 1 5 10
15 75712PRTHomo sapiens 757Thr Pro Ser Tyr Val Ala Phe Thr Asp Thr
Glu Arg 1 5 10 75813PRTHomo sapiens 758Thr Pro Ser Tyr Val Ala Phe
Thr Asp Thr Glu Arg Leu 1 5 10 75913PRTHomo sapiens 759Glu Gly Leu
Tyr Ser Arg Thr Leu Ala Gly Ser Ile Thr 1 5 10 76016PRTHomo sapiens
760Glu Gly Leu Tyr Ser Arg Thr Leu Ala Gly Ser Ile Thr Thr Pro Pro
1 5 10 15 76113PRTHomo sapiens 761Glu Lys Trp Tyr Ile Pro Asp Pro
Thr Gly Lys Phe Asn 1 5 10 76214PRTHomo sapiens 762Gly Ala Ile Ala
Ala Ile Asn Ser Ile Gln His Asn Thr Arg 1 5 10 76312PRTHomo sapiens
763Leu Pro Ile Leu Val Pro Ser Ala Lys Lys Ala Ile 1 5 10
76413PRTHomo sapiens 764Leu Pro Ile Leu Val Pro Ser Ala Lys Lys Ala
Ile Tyr 1 5 10 76514PRTHomo sapiens 765Leu Pro Ile Leu Val Pro Ser
Ala Lys Lys Ala Ile Tyr Met 1 5 10 76615PRTHomo sapiens 766Leu Pro
Ile Leu Val Pro Ser Ala Lys Lys Ala Ile Tyr Met Asp 1 5 10 15
76716PRTHomo sapiens 767Leu Pro Ile Leu Val Pro Ser Ala Lys Lys Ala
Ile Tyr Met Asp Asp 1 5 10 15 76815PRTHomo sapiens 768Val Glu Glu
Gly Leu Tyr Ser Arg Thr Leu Ala Gly Ser Ile Thr 1 5 10 15
76914PRTHomo sapiens 769Trp Glu Lys Trp Tyr Ile Pro Asp Pro Thr Gly
Lys Phe Asn 1 5 10 77012PRTHomo sapiens 770Tyr Lys Ile Val Asn Phe
Asp Pro Lys Leu Leu Glu 1 5 10 77113PRTHomo sapiens 771Tyr Lys Ile
Val Asn Phe Asp Pro Lys Leu Leu Glu Gly 1 5 10 77215PRTHomo sapiens
772Tyr Lys Ile Val Asn Phe Asp Pro Lys Leu Leu Glu Gly Lys Val 1 5
10 15 77312PRTHomo sapiens 773Leu Pro Glu Phe Tyr Lys Thr Val Ser
Pro Ala Leu 1 5 10 77414PRTHomo sapiens 774Val Gly Gln Phe Ile Gln
Asp Val Lys Asn Ser Arg Ser Thr 1 5 10 77515PRTHomo sapiens 775Val
Gly Gln Phe Ile Gln Asp Val Lys Asn Ser Arg Ser Thr Asp 1 5 10 15
77614PRTHomo sapiens 776Val Val Gly Gln Phe Ile Gln Asp Val Lys Asn
Ser Arg Ser 1 5 10 77715PRTHomo sapiens 777Val Val Gly Gln Phe Ile
Gln Asp Val Lys Asn Ser Arg Ser Thr 1 5 10 15 77816PRTHomo sapiens
778Val Val Gly Gln Phe Ile Gln Asp Val Lys Asn Ser Arg Ser Thr Asp
1 5 10 15 77917PRTHomo sapiens 779Val Val Gly Gln Phe Ile Gln Asp
Val Lys Asn Ser Arg Ser Thr Asp 1 5 10 15 Ser 78016PRTHomo sapiens
780Asp Asn Gly His Leu Tyr Arg Glu Asp Gln Thr Ser Pro Ala Pro Gly
1 5 10 15 78118PRTHomo sapiens 781Asp Asn Gly His Leu Tyr Arg Glu
Asp Gln Thr Ser Pro Ala Pro Gly 1 5 10 15 Leu Arg 78216PRTHomo
sapiens 782Glu Val Gln Val Phe Ala Pro Ala Asn Ala Leu Pro Ala Arg
Ser Glu 1 5 10 15 78314PRTHomo sapiens 783Gly His Leu Tyr Arg Glu
Asp Gln Thr Ser Pro Ala Pro Gly 1 5 10 78415PRTHomo sapiens 784Leu
Pro Ala Arg Ser Glu Ala Ala Ala Val Gln Pro Val Ile Gly 1 5 10 15
78515PRTHomo sapiens 785Asn Gly His Leu Tyr Arg Glu Asp Gln Thr Ser
Pro Ala Pro Gly 1 5 10 15 78616PRTHomo sapiens 786Asn Gly His Leu
Tyr Arg Glu Asp Gln Thr Ser Pro Ala Pro Gly Leu 1 5 10 15
78717PRTHomo sapiens 787Asn Gly His Leu Tyr Arg Glu Asp Gln Thr Ser
Pro Ala Pro Gly Leu 1 5 10 15 Arg 78815PRTHomo sapiens 788Val Phe
Ala Pro Ala Asn Ala Leu Pro Ala Arg Ser Glu Ala Ala 1 5 10 15
78915PRTHomo sapiens 789Val Gln Val Phe Ala Pro Ala Asn Ala Leu Pro
Ala Arg Ser Glu 1 5 10 15 79014PRTHomo sapiens 790Ala Ile Val Val
Ser Asp Arg Asp Gly Val Pro Val Ile Lys 1 5 10 79115PRTHomo sapiens
791Gly Leu His Ala Ile Val Val Ser Asp Arg Asp Gly Val Pro Val 1 5
10 15 79217PRTHomo sapiens 792Gly Leu His Ala Ile Val Val Ser Asp
Arg Asp Gly Val Pro Val Ile 1 5 10 15 Lys 79313PRTHomo sapiens
793His Ala Ile Val Val Ser Asp Arg Asp Gly Val Pro Val 1 5 10
79418PRTHomo sapiens 794Lys Leu Pro Ser Val Glu Gly Leu His Ala Ile
Val Val Ser Asp Arg 1 5 10 15 Asp Gly 79514PRTHomo sapiens 795Leu
His Ala Ile Val Val Ser Asp Arg Asp Gly Val Pro Val 1 5 10
79615PRTHomo sapiens 796Leu His Ala Ile Val Val Ser Asp Arg Asp Gly
Val Pro Val Ile 1 5 10 15 79716PRTHomo sapiens 797Leu His Ala Ile
Val Val Ser Asp Arg Asp Gly Val Pro Val Ile Lys 1 5 10 15
79815PRTHomo sapiens 798Leu Pro Ser Val Glu Gly Leu His Ala Ile Val
Val Ser Asp Arg 1 5 10 15 79913PRTHomo sapiens 799Val Pro Val Ile
Lys Val Ala Asn Asp Asn Ala Pro Glu 1 5 10 80013PRTHomo sapiens
800Tyr Asn Thr Tyr Gln Val Val Gln Phe Asn Arg Leu Pro 1 5 10
80114PRTHomo sapiens 801Tyr Asn Thr Tyr Gln Val Val Gln Phe Asn Arg
Leu Pro Leu 1 5 10 80215PRTHomo sapiens 802Tyr Asn Thr Tyr Gln Val
Val Gln Phe Asn Arg Leu Pro Leu Val 1 5 10 15 80316PRTHomo sapiens
803Tyr Asn Thr Tyr Gln Val Val Gln Phe Asn Arg Leu Pro Leu Val Val
1 5 10 15 80414PRTHomo sapiens 804Tyr Tyr Asn Thr Tyr Gln Val Val
Gln Phe Asn Arg Leu Pro 1 5 10 80515PRTHomo sapiens 805Tyr Tyr Asn
Thr Tyr Gln Val Val Gln Phe Asn Arg Leu Pro Leu 1 5 10 15
80616PRTHomo sapiens 806Tyr Tyr Asn Thr Tyr Gln Val Val Gln Phe Asn
Arg Leu Pro Leu Val 1 5 10 15 80713PRTHomo sapiens 807Asp Lys Ile
Tyr Phe Met Ala Gly Ser Ser Arg Lys Glu 1 5 10 80820PRTHomo sapiens
808Asp Val Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala
1 5 10 15 Glu Lys Asp Glu 20 80915PRTHomo sapiens 809Glu Val Thr
Phe Lys Ser Ile Leu Phe Val Pro Thr Ser Ala Pro 1 5 10 15
81013PRTHomo sapiens 810Lys Ser Glu Lys Phe Ala Phe Gln Ala Glu Val
Asn Arg 1 5 10 81114PRTHomo sapiens 811Leu Pro Glu Phe Asp Gly Lys
Arg Phe Gln Asn Val Ala Lys 1 5 10 81213PRTHomo sapiens 812Asp Gly
Ser Tyr Arg Ile Phe Ser Lys Gly Ala Ser Glu 1 5 10 81312PRTHomo
sapiens 813Gly Ser Tyr Arg Ile Phe Ser Lys Gly Ala Ser Glu 1 5 10
81414PRTHomo sapiens 814Ser Asp Gly Ser
Tyr Arg Ile Phe Ser Lys Gly Ala Ser Glu 1 5 10 81514PRTHomo sapiens
815Ser Val Lys Lys Met Met Lys Asp Asn Asn Leu Val Arg His 1 5 10
81613PRTHomo sapiens 816Val Lys Lys Met Met Lys Asp Asn Asn Leu Val
Arg His 1 5 10 81713PRTHomo sapiens 817Asn Asn Met Arg Ile Phe Gly
Glu Ala Ala Glu Lys Asn 1 5 10 81813PRTHomo sapiens 818Val Asp Lys
Val Leu Glu Arg Asp Gln Lys Leu Ser Glu 1 5 10 81915PRTHomo sapiens
819Val Asp Lys Val Leu Glu Arg Asp Gln Lys Leu Ser Glu Leu Asp 1 5
10 15 82016PRTHomo sapiens 820Val Asp Lys Val Leu Glu Arg Asp Gln
Lys Leu Ser Glu Leu Asp Asp 1 5 10 15 82117PRTHomo sapiens 821Val
Asp Lys Val Leu Glu Arg Asp Gln Lys Leu Ser Glu Leu Asp Asp 1 5 10
15 Arg 82214PRTHomo sapiens 822Val Leu Glu Arg Asp Gln Lys Leu Ser
Glu Leu Asp Asp Arg 1 5 10 82315PRTHomo sapiens 823Ala Thr Arg Ser
Ile Gln Val Asp Gly Lys Thr Ile Lys Ala Gln 1 5 10 15 82416PRTHomo
sapiens 824Ala Thr Arg Ser Ile Gln Val Asp Gly Lys Thr Ile Lys Ala
Gln Ile 1 5 10 15 82515PRTHomo sapiens 825Ile Gly Val Glu Phe Ala
Thr Arg Ser Ile Gln Val Asp Gly Lys 1 5 10 15 82612PRTHomo sapiens
826Arg Ser Ile Gln Val Asp Gly Lys Thr Ile Lys Ala 1 5 10
82713PRTHomo sapiens 827Arg Ser Ile Gln Val Asp Gly Lys Thr Ile Lys
Ala Gln 1 5 10 82814PRTHomo sapiens 828Arg Ser Ile Gln Val Asp Gly
Lys Thr Ile Lys Ala Gln Ile 1 5 10 82914PRTHomo sapiens 829Thr Arg
Ser Ile Gln Val Asp Gly Lys Thr Ile Lys Ala Gln 1 5 10 83016PRTHomo
sapiens 830Asp Ile Met Arg Val Asn Val Asp Lys Val Leu Glu Arg Asp
Gln Lys 1 5 10 15 83117PRTHomo sapiens 831Asp Ile Met Arg Val Asn
Val Asp Lys Val Leu Glu Arg Asp Gln Lys 1 5 10 15 Leu 83215PRTHomo
sapiens 832Ile Met Arg Val Asn Val Asp Lys Val Leu Glu Arg Asp Gln
Lys 1 5 10 15 83313PRTHomo sapiens 833Val Asp Lys Val Leu Glu Arg
Asp Gln Lys Leu Ser Glu 1 5 10 83415PRTHomo sapiens 834Val Asp Lys
Val Leu Glu Arg Asp Gln Lys Leu Ser Glu Leu Asp 1 5 10 15
83516PRTHomo sapiens 835Val Asp Lys Val Leu Glu Arg Asp Gln Lys Leu
Ser Glu Leu Asp Asp 1 5 10 15 83617PRTHomo sapiens 836Val Asp Lys
Val Leu Glu Arg Asp Gln Lys Leu Ser Glu Leu Asp Asp 1 5 10 15 Arg
83714PRTHomo sapiens 837Val Leu Glu Arg Asp Gln Lys Leu Ser Glu Leu
Asp Asp Arg 1 5 10 83815PRTHomo sapiens 838Ala Thr Arg Ser Ile Gln
Val Asp Gly Lys Thr Ile Lys Ala Gln 1 5 10 15 83916PRTHomo sapiens
839Ala Thr Arg Ser Ile Gln Val Asp Gly Lys Thr Ile Lys Ala Gln Ile
1 5 10 15 84015PRTHomo sapiens 840Ile Gly Val Glu Phe Ala Thr Arg
Ser Ile Gln Val Asp Gly Lys 1 5 10 15 84112PRTHomo sapiens 841Arg
Ser Ile Gln Val Asp Gly Lys Thr Ile Lys Ala 1 5 10 84213PRTHomo
sapiens 842Arg Ser Ile Gln Val Asp Gly Lys Thr Ile Lys Ala Gln 1 5
10 84314PRTHomo sapiens 843Arg Ser Ile Gln Val Asp Gly Lys Thr Ile
Lys Ala Gln Ile 1 5 10 84414PRTHomo sapiens 844Thr Arg Ser Ile Gln
Val Asp Gly Lys Thr Ile Lys Ala Gln 1 5 10 84512PRTHomo sapiens
845Gly Ile Arg Val Ala Pro Val Pro Leu Tyr Asn Ser 1 5 10
84614PRTHomo sapiens 846Gly Ile Arg Val Ala Pro Val Pro Leu Tyr Asn
Ser Phe His 1 5 10 84717PRTHomo sapiens 847Asn Pro Asn Gly Ile Arg
Val Ala Pro Val Pro Leu Tyr Asn Ser Phe 1 5 10 15 His 84817PRTHomo
sapiens 848Asp Asp Pro Ala Ile Asp Val Cys Lys Lys Leu Leu Gly Lys
Tyr Pro 1 5 10 15 Asn 84916PRTHomo sapiens 849Asp Lys Gln Pro Tyr
Ser Lys Leu Pro Gly Val Ser Leu Leu Lys Pro 1 5 10 15 85017PRTHomo
sapiens 850Asp Lys Gln Pro Tyr Ser Lys Leu Pro Gly Val Ser Leu Leu
Lys Pro 1 5 10 15 Leu 85114PRTHomo sapiens 851His Pro Arg Tyr Tyr
Ile Ser Ala Asn Val Thr Gly Phe Lys 1 5 10 85213PRTHomo sapiens
852Ser His Pro Arg Tyr Tyr Ile Ser Ala Asn Val Thr Gly 1 5 10
85315PRTHomo sapiens 853Ser His Pro Arg Tyr Tyr Ile Ser Ala Asn Val
Thr Gly Phe Lys 1 5 10 15 85414PRTHomo sapiens 854Thr Ser His Pro
Arg Tyr Tyr Ile Ser Ala Asn Val Thr Gly 1 5 10 85516PRTHomo sapiens
855Thr Ser His Pro Arg Tyr Tyr Ile Ser Ala Asn Val Thr Gly Phe Lys
1 5 10 15 85612PRTHomo sapiens 856Ala Asp Ile Phe Val Asp Pro Val
Leu His Thr Ala 1 5 10 85714PRTHomo sapiens 857Ala Asp Ile Phe Val
Asp Pro Val Leu His Thr Ala Cys Ala 1 5 10 85815PRTHomo sapiens
858Asp Pro Gly Ala Asp Tyr Arg Ile Asp Arg Ala Leu Asn Glu Ala 1 5
10 15 85912PRTHomo sapiens 859Ile Ala Gln Asp Tyr Lys Val Ser Tyr
Ser Leu Ala 1 5 10 86013PRTHomo sapiens 860Ile Ala Gln Asp Tyr Lys
Val Ser Tyr Ser Leu Ala Lys 1 5 10 86114PRTHomo sapiens 861Ile Ser
Arg Asp Trp Lys Leu Asp Pro Val Leu Tyr Arg Lys 1 5 10 86213PRTHomo
sapiens 862Leu Ile Ala Gln Asp Tyr Lys Val Ser Tyr Ser Leu Ala 1 5
10 86314PRTHomo sapiens 863Arg Gln Lys Leu Ile Ala Gln Asp Tyr Lys
Val Ser Tyr Ser 1 5 10 86415PRTHomo sapiens 864Arg Gln Lys Leu Ile
Ala Gln Asp Tyr Lys Val Ser Tyr Ser Leu 1 5 10 15 86516PRTHomo
sapiens 865Arg Gln Lys Leu Ile Ala Gln Asp Tyr Lys Val Ser Tyr Ser
Leu Ala 1 5 10 15 86617PRTHomo sapiens 866Arg Gln Lys Leu Ile Ala
Gln Asp Tyr Lys Val Ser Tyr Ser Leu Ala 1 5 10 15 Lys 86714PRTHomo
sapiens 867Ser Ala Leu Asp Tyr Arg Leu Asp Pro Gln Leu Gln Leu His
1 5 10 86814PRTHomo sapiens 868Ser Lys Ala Asp Ile Phe Val Asp Pro
Val Leu His Thr Ala 1 5 10 86915PRTHomo sapiens 869Ser Pro Ser Lys
Asn Tyr Ile Leu Ser Val Ile Ser Gly Ser Ile 1 5 10 15 87017PRTHomo
sapiens 870Glu Thr Thr Gln Leu Thr Ala Asp Ser His Pro Ser Tyr His
Thr Asp 1 5 10 15 Gly 87119PRTHomo sapiens 871Ser Gly Glu Ser Leu
Tyr His Val Leu Gly Leu Asp Lys Asn Ala Thr 1 5 10 15 Ser Asp Asp
87214PRTHomo sapiens 872Thr Thr Gln Leu Thr Ala Asp Ser His Pro Ser
Tyr His Thr 1 5 10 87315PRTHomo sapiens 873Thr Thr Gln Leu Thr Ala
Asp Ser His Pro Ser Tyr His Thr Asp 1 5 10 15 87416PRTHomo sapiens
874Thr Thr Gln Leu Thr Ala Asp Ser His Pro Ser Tyr His Thr Asp Gly
1 5 10 15 87513PRTHomo sapiens 875Ser Val Glu Glu Phe Leu Ser Glu
Lys Leu Glu Arg Ile 1 5 10 87612PRTHomo sapiens 876Val Glu Glu Phe
Leu Ser Glu Lys Leu Glu Arg Ile 1 5 10 87715PRTHomo sapiens 877Asp
Leu Ser Ser Ser Ile Leu Ala Gln Ser Arg Glu Arg Val Ala 1 5 10 15
87816PRTHomo sapiens 878Glu Lys Gly Val Arg Thr Leu Thr Ala Ala Ala
Val Ser Gly Ala Gln 1 5 10 15 87917PRTHomo sapiens 879Glu Lys Gly
Val Arg Thr Leu Thr Ala Ala Ala Val Ser Gly Ala Gln 1 5 10 15 Pro
88018PRTHomo sapiens 880Glu Lys Gly Val Arg Thr Leu Thr Ala Ala Ala
Val Ser Gly Ala Gln 1 5 10 15 Pro Ile 88114PRTHomo sapiens 881Lys
Gly Val Arg Thr Leu Thr Ala Ala Ala Val Ser Gly Ala 1 5 10
88215PRTHomo sapiens 882Lys Gly Val Arg Thr Leu Thr Ala Ala Ala Val
Ser Gly Ala Gln 1 5 10 15 88317PRTHomo sapiens 883Val Gly Pro Phe
Ala Pro Gly Ile Thr Glu Lys Ala Pro Glu Glu Lys 1 5 10 15 Lys
88414PRTHomo sapiens 884Asp Pro Pro Leu Ile Ala Leu Asp Lys Asp Ala
Pro Leu Arg 1 5 10 88515PRTHomo sapiens 885Glu Ile Ile Thr Pro Asp
Val Pro Phe Thr Val Asp Lys Asp Gly 1 5 10 15 88614PRTHomo sapiens
886Ile Ile Thr Pro Asp Val Pro Phe Thr Val Asp Lys Asp Gly 1 5 10
88713PRTHomo sapiens 887Pro Pro Leu Ile Ala Leu Asp Lys Asp Ala Pro
Leu Arg 1 5 10 88814PRTHomo sapiens 888Thr Asn Val Lys Lys Ser His
Lys Ala Thr Val His Ile Gln 1 5 10 88912PRTHomo sapiens 889Asp Asp
Asn Ile Lys Thr Tyr Ser Asp His Pro Glu 1 5 10 89013PRTHomo sapiens
890Asp Asp Asn Ile Lys Thr Tyr Ser Asp His Pro Glu Lys 1 5 10
89114PRTHomo sapiens 891Asp Ser Ala Val Phe Phe Glu Gln Gly Thr Thr
Arg Ile Gly 1 5 10 89216PRTHomo sapiens 892Gly Asp Lys Val Tyr Val
His Leu Lys Asn Leu Ala Ser Arg Pro Tyr 1 5 10 15 89317PRTHomo
sapiens 893Gly Asp Lys Val Tyr Val His Leu Lys Asn Leu Ala Ser Arg
Pro Tyr 1 5 10 15 Thr 89412PRTHomo sapiens 894Val His Leu Lys Asn
Leu Ala Ser Arg Pro Tyr Thr 1 5 10 89513PRTHomo sapiens 895Val Tyr
Val His Leu Lys Asn Leu Ala Ser Arg Pro Tyr 1 5 10 89614PRTHomo
sapiens 896Val Tyr Val His Leu Lys Asn Leu Ala Ser Arg Pro Tyr Thr
1 5 10 89716PRTHomo sapiens 897Val Tyr Val His Leu Lys Asn Leu Ala
Ser Arg Pro Tyr Thr Phe His 1 5 10 15 89812PRTHomo sapiens 898Tyr
Val His Leu Lys Asn Leu Ala Ser Arg Pro Tyr 1 5 10 89913PRTHomo
sapiens 899Tyr Val His Leu Lys Asn Leu Ala Ser Arg Pro Tyr Thr 1 5
10 90015PRTHomo sapiens 900Tyr Val His Leu Lys Asn Leu Ala Ser Arg
Pro Tyr Thr Phe His 1 5 10 15 90114PRTHomo sapiens 901Ser Asn Leu
Ile Lys Leu Ala Gln Lys Val Pro Thr Ala Asp 1 5 10 90212PRTHomo
sapiens 902Tyr Asp Thr Arg Thr Ser Ala Leu Ser Ala Lys Ser 1 5 10
90314PRTHomo sapiens 903Ala Leu Met Thr Asp Pro Lys Leu Ile Thr Trp
Ser Pro Val 1 5 10 90416PRTHomo sapiens 904Asn Asp Val Ala Trp Asn
Phe Glu Lys Phe Leu Val Gly Pro Asp Gly 1 5 10 15 90513PRTHomo
sapiens 905Gln Ser Val Tyr Ala Phe Ser Ala Arg Pro Leu Ala Gly 1 5
10 90617PRTHomo sapiens 906Gln Ser Val Tyr Ala Phe Ser Ala Arg Pro
Leu Ala Gly Gly Glu Pro 1 5 10 15 Val 90712PRTHomo sapiens 907Trp
Asn Phe Glu Lys Phe Leu Val Gly Pro Asp Gly 1 5 10 90815PRTHomo
sapiens 908Asp Val Gly Met Phe Val Ala Leu Thr Lys Leu Gly Gln Pro
Asp 1 5 10 15 90914PRTHomo sapiens 909Val Gly Met Phe Val Ala Leu
Thr Lys Leu Gly Gln Pro Asp 1 5 10 91012PRTHomo sapiens 910Ala Gly
Val Phe His Val Glu Lys Asn Gly Arg Tyr 1 5 10 91114PRTHomo sapiens
911Phe Ala Gly Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser 1 5 10
91214PRTHomo sapiens 912Gly Pro Ile Thr Ile Thr Ile Val Asn Arg Asp
Gly Thr Arg 1 5 10 91314PRTHomo sapiens 913Asn Gly Arg Tyr Ser Ile
Ser Arg Thr Glu Ala Ala Asp Leu 1 5 10 91414PRTHomo sapiens 914Arg
Lys Ser Arg Gln Gly Ser Leu Ala Met Glu Glu Leu Lys 1 5 10
91515PRTHomo sapiens 915Arg Arg Lys Ser Arg Gln Gly Ser Leu Ala Met
Glu Glu Leu Lys 1 5 10 15 91615PRTHomo sapiens 916Glu Glu Phe Lys
Lys Leu Thr Ser Ile Lys Ile Gln Asn Asp Lys 1 5 10 15 91713PRTHomo
sapiens 917Ile Asn Arg Arg Met Ala Asp Asp Asn Lys Leu Phe Arg 1 5
10 91815PRTHomo sapiens 918Thr Ala Thr Ile Val Met Val Thr Asn Leu
Lys Glu Arg Lys Glu 1 5 10 15 91914PRTHomo sapiens 919Glu Leu Phe
Tyr Lys Gly Ile Arg Pro Ala Ile Asn Val Gly 1 5 10 92013PRTHomo
sapiens 920Gly Gln Lys Arg Ser Thr Val Ala Gln Leu Val Lys Arg 1 5
10 92115PRTHomo sapiens 921Ser Asp Leu Asp Ala Ala Thr Gln Gln Leu
Leu Ser Arg Gly Val 1 5 10 15 92214PRTHomo sapiens 922Phe Asp Phe
Ser Gln Asn Thr Arg Val Pro Arg Leu Pro Glu 1 5 10 92312PRTHomo
sapiens 923Gly Asp Ala Pro Ala Ile Leu Phe Asp Lys Glu Phe 1 5 10
92413PRTHomo sapiens 924Val Thr His Glu Ile Asp Arg Tyr Thr Ala Ile
Ala Tyr 1 5 10 92516PRTHomo sapiens 925Gly Gln Gly Tyr Leu Ile Lys
Asp Gly Lys Leu Ile Lys Asn Asn Ala 1 5 10 15 92615PRTHomo sapiens
926Ile Asp Thr Thr Ser Lys Phe Gly His Gly Arg Phe Gln Thr Met 1 5
10 15 92719PRTHomo sapiens 927Ile Asp Val Ile Gly Val Thr Lys Gly
Lys Gly Tyr Lys Gly Val Thr 1 5 10 15 Ser Arg Trp 92815PRTHomo
sapiens 928Met Gly Pro Leu Lys Lys Asp Arg Ile Ala Lys Glu Glu Gly
Ala 1 5 10 15 92914PRTHomo sapiens 929Ala Ala Lys Tyr Gln Leu Asp
Pro Thr Ala Ser Ile Ser Ala 1 5 10 93015PRTHomo sapiens 930Ile Ala
Ala Lys Tyr Gln Leu Asp Pro Thr Ala Ser Ile Ser Ala 1 5 10 15
93116PRTHomo sapiens 931Ile Ala Ala Lys Tyr Gln Leu Asp Pro Thr Ala
Ser Ile Ser Ala Lys 1 5 10 15 93215PRTHomo sapiens 932Ala Gly Leu
Gly Arg Ala Tyr Ala Leu Ala Phe Ala Glu Arg Gly 1 5 10 15
93314PRTHomo sapiens 933Asp Ala Phe Gly Arg Ile Asp Val Val Val Asn
Asn Ala Gly 1 5 10 93413PRTHomo sapiens 934Gly Leu Gly Arg Ala Tyr
Ala Leu Ala Phe Ala Glu Arg 1 5 10 93514PRTHomo sapiens 935Gly Leu
Gly Arg Ala Tyr Ala Leu Ala Phe Ala Glu Arg Gly 1 5 10 93615PRTHomo
sapiens 936Ala Lys Phe Ala Leu Asn Gly Glu Glu Phe Met Asn Phe Asp
Leu 1 5 10 15 93716PRTHomo sapiens 937Ala Lys Phe Ala Leu Asn Gly
Glu Glu Phe Met Asn Phe Asp Leu Lys 1 5 10 15 93813PRTHomo sapiens
938Ala Leu Asn Gly Glu Glu Phe Met Asn Phe Asp Leu Lys 1 5 10
93914PRTHomo sapiens 939Lys Phe Ala Leu Asn Gly Glu Glu Phe Met Asn
Phe Asp Leu 1 5 10 94014PRTHomo sapiens 940Ser Asp Gly Ser Phe His
Ala Ser Ser Ser Leu Thr Val Lys 1 5 10 94117PRTHomo sapiens 941Glu
Glu Arg Asn Leu Leu Ser Val Ala Tyr Lys Asn Val Val Gly Ala 1 5 10
15 Arg 94216PRTHomo sapiens 942Glu Arg Asn Leu Leu Ser Val Ala Tyr
Lys Asn Val Val Gly Ala Arg 1 5 10 15 94314PRTHomo sapiens 943Ile
Ala Glu Leu Asp Thr Leu Ser Glu Glu Ser Tyr Lys Asp 1 5 10
94415PRTHomo sapiens 944Ile Ala Glu Leu Asp Thr Leu Ser Glu Glu Ser
Tyr Lys Asp Ser 1 5
10 15 94516PRTHomo sapiens 945Ala Asp Ser Tyr Leu Asp Glu Gly Phe
Leu Leu Asp Lys Lys Ile Gly 1 5 10 15 94613PRTHomo sapiens 946Asp
Ser Tyr Leu Asp Glu Gly Phe Leu Leu Asp Lys Lys 1 5 10 94715PRTHomo
sapiens 947Asp Ser Tyr Leu Asp Glu Gly Phe Leu Leu Asp Lys Lys Ile
Gly 1 5 10 15 94815PRTHomo sapiens 948Val Asp Asn Ile Ile Lys Ala
Ala Pro Arg Lys Arg Val Pro Asp 1 5 10 15 94913PRTHomo sapiens
949Ser Pro Pro Gln Phe Arg Val Asn Gly Ala Ile Ser Asn 1 5 10
95015PRTHomo sapiens 950Ser Pro Pro Gln Phe Arg Val Asn Gly Ala Ile
Ser Asn Phe Glu 1 5 10 15 95116PRTHomo sapiens 951Ser Pro Pro Gln
Phe Arg Val Asn Gly Ala Ile Ser Asn Phe Glu Glu 1 5 10 15
95217PRTHomo sapiens 952Ser Pro Pro Gln Phe Arg Val Asn Gly Ala Ile
Ser Asn Phe Glu Glu 1 5 10 15 Phe 95315PRTHomo sapiens 953Val Gly
Lys Met Phe Val Asp Val Tyr Phe Gln Glu Asp Lys Lys 1 5 10 15
95416PRTHomo sapiens 954Val Gly Lys Met Phe Val Asp Val Tyr Phe Gln
Glu Asp Lys Lys Glu 1 5 10 15 95517PRTHomo sapiens 955Asp Pro Lys
Arg Thr Ile Ala Gln Asp Tyr Gly Val Leu Lys Ala Asp 1 5 10 15 Glu
95618PRTHomo sapiens 956Asp Pro Lys Arg Thr Ile Ala Gln Asp Tyr Gly
Val Leu Lys Ala Asp 1 5 10 15 Glu Gly 95717PRTHomo sapiens 957Pro
Lys Arg Thr Ile Ala Gln Asp Tyr Gly Val Leu Lys Ala Asp Glu 1 5 10
15 Gly 95813PRTHomo sapiens 958Gly Leu Phe Ile Ile Asp Asp Lys Gly
Ile Leu Arg Gln 1 5 10 95915PRTHomo sapiens 959Gly Leu Phe Ile Ile
Asp Asp Lys Gly Ile Leu Arg Gln Ile Thr 1 5 10 15 96013PRTHomo
sapiens 960Arg Gly Leu Phe Ile Ile Asp Asp Lys Gly Ile Leu Arg 1 5
10 96114PRTHomo sapiens 961Arg Gly Leu Phe Ile Ile Asp Asp Lys Gly
Ile Leu Arg Gln 1 5 10 96216PRTHomo sapiens 962Arg Gly Leu Phe Ile
Ile Asp Asp Lys Gly Ile Leu Arg Gln Ile Thr 1 5 10 15 96315PRTHomo
sapiens 963Gly Asn Thr Val Ile His Leu Asp Gln Ala Leu Ala Arg Met
Arg 1 5 10 15 96414PRTHomo sapiens 964Asn Thr Val Ile His Leu Asp
Gln Ala Leu Ala Arg Met Arg 1 5 10 96515PRTHomo sapiens 965Asn Thr
Val Ile His Leu Asp Gln Ala Leu Ala Arg Met Arg Glu 1 5 10 15
96615PRTHomo sapiens 966Glu Asn Asn Glu Ile Ile Ser Asn Ile Arg Asp
Ser Val Ile Asn 1 5 10 15 96714PRTHomo sapiens 967Asn Asn Glu Ile
Ile Ser Asn Ile Arg Asp Ser Val Ile Asn 1 5 10 96814PRTHomo sapiens
968Ser Pro Thr Val Gln Val Phe Ser Ala Ser Gly Lys Pro Val 1 5 10
96916PRTHomo sapiens 969Ser Ser Pro Thr Val Gln Val Phe Ser Ala Ser
Gly Lys Pro Val Glu 1 5 10 15 97016PRTHomo sapiens 970Ala Glu Pro
Asn Tyr His Ser Leu Pro Ser Ala Arg Thr Asp Glu Gln 1 5 10 15
97115PRTHomo sapiens 971Ser Ser Ile Leu Ala Lys Thr Ala Ser Asn Ile
Ile Asp Val Ser 1 5 10 15 97215PRTHomo sapiens 972Leu Glu Ala Arg
Ala Thr Ala Pro Pro Ala Pro Ser Ala Pro Asn 1 5 10 15 97312PRTHomo
sapiens 973Ala Asp Asp Leu Glu Gly Glu Ala Phe Leu Pro Leu 1 5 10
97413PRTHomo sapiens 974Ala Asp Asp Leu Glu Gly Glu Ala Phe Leu Pro
Leu Arg 1 5 10 97514PRTHomo sapiens 975Ala Asp Asp Leu Glu Gly Glu
Ala Phe Leu Pro Leu Arg Glu 1 5 10 97614PRTHomo sapiens 976Gly Ala
Asp Asp Leu Glu Gly Glu Ala Phe Leu Pro Leu Arg 1 5 10 97715PRTHomo
sapiens 977Ala Gly Arg Glu Ile Asn Leu Val Asp Ala His Leu Lys Ser
Glu 1 5 10 15 97817PRTHomo sapiens 978Ala Gly Arg Glu Ile Asn Leu
Val Asp Ala His Leu Lys Ser Glu Gln 1 5 10 15 Thr 97914PRTHomo
sapiens 979Gly Arg Glu Ile Asn Leu Val Asp Ala His Leu Lys Ser Glu
1 5 10 98015PRTHomo sapiens 980Lys Pro Gly Ile Val Tyr Ala Ser Leu
Asn His Ser Val Ile Gly 1 5 10 15 98116PRTHomo sapiens 981Asn Lys
Pro Gly Ile Val Tyr Ala Ser Leu Asn His Ser Val Ile Gly 1 5 10 15
98216PRTHomo sapiens 982Thr Thr Leu Tyr Val Thr Asp Val Lys Ser Ala
Ser Glu Arg Pro Ser 1 5 10 15 98316PRTHomo sapiens 983Ala Pro Ser
Thr Tyr Ala His Leu Ser Pro Ala Lys Thr Pro Pro Pro 1 5 10 15
98417PRTHomo sapiens 984Ala Pro Ser Thr Tyr Ala His Leu Ser Pro Ala
Lys Thr Pro Pro Pro 1 5 10 15 Pro 98518PRTHomo sapiens 985Ala Pro
Ser Thr Tyr Ala His Leu Ser Pro Ala Lys Thr Pro Pro Pro 1 5 10 15
Pro Ala 98615PRTHomo sapiens 986Arg Asp Asp Leu Tyr Asp Gln Asp Asp
Ser Arg Asp Phe Pro Arg 1 5 10 15 98714PRTHomo sapiens 987Thr Arg
Pro Tyr His Ser Leu Pro Ser Glu Ala Val Phe Ala 1 5 10 98815PRTHomo
sapiens 988Thr Arg Pro Tyr His Ser Leu Pro Ser Glu Ala Val Phe Ala
Asn 1 5 10 15 98912PRTHomo sapiens 989Val Ala Val Phe Thr Phe His
Asn His Gly Arg Thr 1 5 10 99013PRTHomo sapiens 990Val Ala Val Phe
Thr Phe His Asn His Gly Arg Thr Ala 1 5 10 99115PRTHomo sapiens
991Val Ala Val Phe Thr Phe His Asn His Gly Arg Thr Ala Asn Leu 1 5
10 15 99216PRTHomo sapiens 992Glu Asp Asp Tyr Ile Lys Ser Trp Glu
Asp Asn Gln Gln Gly Asp Glu 1 5 10 15 99316PRTHomo sapiens 993Glu
Leu Glu Arg Ile Gln Ile Gln Glu Ala Ala Lys Lys Lys Pro Gly 1 5 10
15 99413PRTHomo sapiens 994Glu Arg Ile Gln Ile Gln Glu Ala Ala Lys
Lys Lys Pro 1 5 10 99514PRTHomo sapiens 995Glu Arg Ile Gln Ile Gln
Glu Ala Ala Lys Lys Lys Pro Gly 1 5 10 99615PRTHomo sapiens 996Glu
Arg Ile Gln Ile Gln Glu Ala Ala Lys Lys Lys Pro Gly Ile 1 5 10 15
99715PRTHomo sapiens 997Leu Glu Arg Ile Gln Ile Gln Glu Ala Ala Lys
Lys Lys Pro Gly 1 5 10 15 99812PRTHomo sapiens 998Leu Ser Ser Ile
Ser Gln Tyr Ser Gly Lys Ile Lys 1 5 10 99912PRTHomo sapiens 999Ser
Pro Ala Lys Asp Ser Leu Ser Phe Glu Asp Phe 1 5 10 100015PRTHomo
sapiens 1000Ser Pro Ala Lys Asp Ser Leu Ser Phe Glu Asp Phe Leu Asp
Leu 1 5 10 15 100114PRTHomo sapiens 1001Ile Asn Ser Arg Phe Pro Ile
Pro Ser Ala Thr Asp Pro Asp 1 5 10 100214PRTHomo sapiens 1002Val
Gln His Tyr Glu Leu Leu Asn Gly Gln Ser Val Phe Gly 1 5 10
100314PRTHomo sapiens 1003Asp Asn Gln Tyr Ala Val Leu Glu Asn Gln
Lys Ser Ser His 1 5 10 100413PRTHomo sapiens 1004Gly Pro Pro Glu
Ile Tyr Ser Asp Thr Gln Phe Pro Ser 1 5 10 100515PRTHomo sapiens
1005Gly Pro Pro Glu Ile Tyr Ser Asp Thr Gln Phe Pro Ser Leu Gln 1 5
10 15 100616PRTHomo sapiens 1006Thr Pro Gln Gly Pro Pro Glu Ile Tyr
Ser Asp Thr Gln Phe Pro Ser 1 5 10 15 100718PRTHomo sapiens 1007Thr
Pro Gln Gly Pro Pro Glu Ile Tyr Ser Asp Thr Gln Phe Pro Ser 1 5 10
15 Leu Gln 100820PRTHomo sapiens 1008Thr Pro Gln Gly Pro Pro Glu
Ile Tyr Ser Asp Thr Gln Phe Pro Ser 1 5 10 15 Leu Gln Ser Thr 20
100914PRTHomo sapiens 1009Ala Asn Leu Gln Arg Ala Tyr Ser Leu Ala
Lys Glu Gln Arg 1 5 10 101013PRTHomo sapiens 1010Asn Leu Gln Arg
Ala Tyr Ser Leu Ala Lys Glu Gln Arg 1 5 10 101115PRTHomo sapiens
1011Thr Pro Ser Gly Ile Thr Tyr Asp Arg Lys Asp Ile Glu Glu His 1 5
10 15 101214PRTHomo sapiens 1012Val Ser Thr Leu Asn Ser Glu Asp Phe
Val Leu Val Ser Arg 1 5 10 101315PRTHomo sapiens 1013Val Ser Thr
Leu Asn Ser Glu Asp Phe Val Leu Val Ser Arg Gln 1 5 10 15
101416PRTHomo sapiens 1014Val Ser Thr Leu Asn Ser Glu Asp Phe Val
Leu Val Ser Arg Gln Gly 1 5 10 15 101514PRTHomo sapiens 1015Gly Ser
Ser Phe Phe Gly Glu Leu Phe Asn Gln Asn Pro Glu 1 5 10
101615PRTHomo sapiens 1016Ser Gly Ser Ser Phe Phe Gly Glu Leu Phe
Asn Gln Asn Pro Glu 1 5 10 15 101710PRTHomo sapiens 1017Glu Leu Ala
Gly Ile Gly Ile Leu Thr Val 1 5 10 10189PRTHomo sapiens 1018Tyr Leu
Leu Pro Ala Ile Val His Ile 1 5
* * * * *