Peptides

SUMMARY OF THE INVENTION

This invention relates to peptides which are fragments of protein products arising from frameshift mutations in genes, which peptides elicit T cellular immunity, and to cancer vaccines and compositions for anticancer treatment comprising said peptides.

The invention further relates to a method for identifying such peptides which are fragments of protein products arising from frameshift mutations in genes, which may elicit T cellular immunity which is useful for combating cancer associated with said mutated genes.

The invention also relates to DNA sequences encoding at least one frameshift mutant peptide, and vectors comprising at least one insertion site containing a DNA sequence encoding at least one frameshift mutant peptide.

Further the invention relates to methods for the treatment or prophylaxis of cancers associated with frameshift mutations in genes by administration of at least one frameshift mutant peptide or a recombinant virus vector comprising at least one insertion site containing a DNA sequence encoding at least one frameshift mutant peptide, or an isolated DNA sequence comprising a DNA sequence encoding at least one frameshift mutant peptide.

The present invention represents a further development of anticancer treatment or prophylaxis based on the use of peptides to generate activation and strengthening of the anti cancer activity of the T cellular arm of the body's own immune system.

TECHNICAL BACKGROUND

Tumour Antigens, Status:

T cell defined antigens have now been characterised in a broad spectrum of cancer types. These antigens can be divided into several main groups, depending on their expression. The two main groups are constituted by developmental differentiation related antigens (tumour-testis antigens, oncofoetal antigens etc., such as MAGE antigens and CEA) and tissue specific differentiation antigens (Tyrosinase, gp100 etc.). The group containing the truly tumour specific antigens contains proteins that are altered due to mutations in the genes encoding them. In the majority of these, the mutations are unique and have been detected in a single or in a small number of tumours. Several of these antigens seem to play a role in oncogenesis.

Cancer Vaccines, Status:

The focus in cancer vaccine development has been on antigens expressed in a high degree within one form of cancer (such as melanoma) or in many kinds of cancers. One reason for this is the increased recruitment of patients into clinical protocols. The field is in rapid growth, illustrated by the accompanying table listing the cancer vaccine protocols currently registered in the PDQ database of NCI.

Inheritable Cancer/Cancer Gene Testing:

Inherited forms of cancer occur at a certain frequency in the population. For several of these cancer forms, the underlying genetic defects have been mapped. This is also the case in Lynch syndrome cancers which constitute an important group of inheritable cancer. In families inflicted with this syndrome, family members inherit defect genes encoding DNA Mismatch Repair (MMR) Enzymes. Carriers of such MMR defects frequently develop colorectal cancer (HNPCC) and other forms of cancer (list?). Mutations in MMR enzymes can be detected using gene testing in the same way as other cancer related genes can be detected.

Gene testing of risk groups in this case represents an ethical dilemma, since no acceptable forms for prophylactic treatment exist. At present surgery to remove the organ in danger to develop cancer has been the only treatment option. In these patients, cancer vaccines will be a very (interesting) form of prophylaxis, provided efficient vaccines can be developed.

The lack of efficient repair of mismatched DNA results in deletions and insertions in one strand of DNA, and this happens preferentially in stretches of DNA containing repeated units (repeat sequences). Until now, focus has been on repeat sequences in the form of non-coding microsattelite loci. Indeed microsattelite instability is the hallmark of cancers resulting from MMR defects. We have taken another approach, and have concentrated on frameshift mutations occurring in DNA sequences coding for proteins related to the oncogenic process. Such frameshift mutations result in completely new amino acid sequences in the C-terminal part of the proteins, prematurely terminating where a novel stop codon appears. This results in two important consequences:

1) The truncated protein resulting from the frameshift is generally nonfunctional, in most cases resulting in “knocking out” of an important cellular function. Aberrant proteins may also gain new functions such as the capacity to aggragate and form plaques. In both cases the frameshift results in disease.

2) The short new C-terminal amino acid sequence resulting from the shift in the reading frame (the “frameshift sequence”) is foreign to the body. It does not exist prior to the mutation, and it only exists in cells having the mutation, i.e. in tumour cells and their pre malignant progenitors. Since they are completely novel and therefore foreign to the immune system of the carrier, they may be recognised by T-cells in the repertoire of the carrier. So far, nobody has focused on this aspect of frameshift mutations, and no reports exist on the characterisation of frameshift peptides from coding regions of proteins as tumour antigens. This concept is therefore novel and forms the basis for developing vaccines based on these sequences. It follows that such vaccines may also be used prophyllactively in persons who inherit defective enzymes belonging to the MMR machinery. Such vaccines will therefore fill an empty space in the therapeutic armament against inherited forms of cancer.

It has been shown that single amino acid substitutions in intracellular “self”-proteins may give rise to tumour rejection antigens, consisting of peptides differing in their amino acid sequence from the normal peptide. The T cells which recognise these peptides in the context of the major histocompatibility (MHC) molecules on the surface of the tumour cells, are capable of killing the tumour cells and thus rejecting the tumour from the host.

In contrast to antibodies produced by the B cells, which typically recognise a free antigen in its native conformation and further potentially recognise almost any site exposed on the antigen surface, T cells recognise an antigen only if the antigen is bound and presented by a MHC molecule. Usually this binding will take place only after appropriate antigen processing, which comprises a proteolytic fragmentation of the protein, so that the resulting peptide fragment fits into the groove of the MHC molecule. Thereby T cells are enabled to also recognise peptides derived from intracellular proteins. T cells can thus recognise aberrant peptides derived from anywhere in the tumour cell, in the context of MHC molecules on the surface of the tumour cell, and can subsequently be activated to eliminate the tumour cell harbouring the aberrant peptide.

M. Barinaga, Science, 257, 880-881, 1992 offers a short review of how MHC binds peptides. A more comprehensive explanation of the Technical Background for this Invention may be found in D. Male et al, Advanced Immunology, 1987, J.B.lippincott Company, Philadelphia. Both references are hereby included in their entirety.

The MHC molecules in humans are normally referred to as HLA (human leukocyte antigen) molecules. They are encoded by the HLA region on the human chromosome No 6.

The HLA molecules appear as two distinct classes depending on which region of the chromosome they are encoded by and which T cell subpopulations they interact with and thereby activate primarily. The class I molecules are encoded by the HLA A, B and C subloci and they primarily activate CD8+ cytotoxic T cells. The HLA class II molecules are encoded by the DR, DP and DQ subloci and primarily activate CD4+ T cells, both helper cells and cytotoxic cells.

Normally every individual has six HLA Class I molecules, usually two from each of the three groups A, B and C. Correspondingly, all individuals have their own selection of HLA Class II molecules, again two from each of the three groups DP, DQ and DR. Each of the groups A, B, C and DP, DQ and DR are again divided into several subgroups. In some cases the number of different HLA Class I or II molecules is reduced due to the overlap of two HLA subgroups.

All the gene products are highly polymorphic. Different individuals thus express distinct HLA molecules that differ from those of other individuals. This is the basis for the difficulties in finding HLA matched organ donors in transplantations. The significance of the genetic variation of the HLA molecules in immunobiology is reflected by their role as immune-response genes. Through their peptide binding capacity, the presence or absence of certain HLA molecules governs the capacity of an individual to respond to peptide epitopes. As a consequence, HLA molecules determine resistance or susceptibility to disease.

T cells may control the development and growth of cancer by a variety of mechanisms. Cytotoxic T cells, both HLA class I restricted CD8+ and HLA Class II restricted CD4+, may directly kill tumour cells carrying the appropriate tumour antigens. CD4+ helper T cells are needed for cytotoxic CD8+ T cell responses as well as for antibody responses, and for inducing macrophage and LAK cell killing.

A requirement for both HLA class I and II binding is that the peptides must contain a binding motif, which usually is different for different HLA groups and subgroups. A binding motif is characterised by the requirement for amino acids of a certain type, for instance the ones carrying large and hydrophobic or positively charged side groups, in definite positions of the peptide so that a narrow fit with the pockets of the HLA binding groove is achieved. The result of this, taken together with the peptide length restriction of 8-10 amino acids within the binding groove, is that it is quite unlikely that a peptide binding to one type of HLA class I molecules will also bind to another type. Thus, for example, it may very well be that the peptide binding motif for the HLA-A1 and HLA-A2 subgroups, which both belong to the class I gender, are as different as the motifs for the HLA-A1 and HLA-B1 molecules.

For the same reasons it is not likely that exactly the same sequence of amino acids will be located in the binding groove of the different class II molecules. In the case of HLA class II molecules the binding sequences of peptides may be longer, and it has been found that they usually contain from 10 to 16 amino acids, some of which, at one or both terminals, are not a part of the binding motif for the HLA groove.

However, an overlap of the different peptide binding motifs of several HLA class I and class II molecules may occur. Peptides that have an overlap in the binding sequences for at least two different HLA molecules are said to contain “nested T cell epitopes”. The various epitopes contained in a “nested epitope peptide” may be formed by processing of the peptide by antigen presenting cells and thereafter be presented to T cells bound to different HLA molecules. The individual variety of HLA molecules in humans makes peptides containing nested epitopes more useful as general vaccines than peptides that are only capable of binding to one type of HLA molecule.

Effective vaccination of an individual can only be achieved if at least one type of HLA class I and/or II molecule in the patient can bind a vaccine peptide either in it's full length or as processed and trimmed by the patient's own antigen presenting cells.

The usefulness of a peptide as a general vaccine for the majority of the population increases with the number of different HLA molecules it can bind to, either in its full length or after processing by antigen presenting cells.

In order to use peptides derived from a protein encoded by a mutated gene as vaccines or anticancer agents to generate anti tumour CD4+ and/or CD8+ T cells, it is necessary to investigate the mutant protein in question and identify peptides that are capable, eventually after processing to shorter peptides by the antigene presenting cells, to stimulate T cells.

PRIOR ART

In our International Application PCT/NO92/00032 (published as WO92/14756), the content of which is herein incorporated by reference we described synthetic peptides and fragments of oncogene protein products which have a point of mutation or translocations as compared to their proto-oncogene or tumour suppressor gene protein. These peptides correspond to, completely cover or are fragments of the processed oncogene protein fragment or tumour suppressor gene fragment as presented by cancer cells or other antigen presenting cells, and are presented as a HLA-peptide complex by at least one allele in every individual. These peptides were also shown to induce specific T cell responses to the actual oncogene protein fragment produced by the cell by processing and presented in the HLA molecule. In particular, we described peptides derived from the p21 ras protein which had point mutations at particular amino acid positions, namely position 12, 13 and 61. These peptides have been shown to be effective in regulating the growth of cancer cells in vitro. Furthermore, the peptides were shown to elicit CD4+ T cell immunity against cancer cells harbouring the mutated p21 ras oncogene protein through the administration of such peptides in vaccination or cancer therapy schemes. Later we have shown that these peptides also elicit CD8+ T cell immunity against cancer cells harbouring the mutated p21 ras oncogene protein through the administration mentioned above.

However, the peptides described above will be useful only in certain number of cancers, namely those which involve oncogenes with point mutations or translocation in a proto-oncogene or tumour suppressor gene. There is therefore a strong need for an anticancer treatment or vaccine which will be effective against a more general range of cancers.

In general, tumors are very heterogenous with respect to genetic alterations found in the tumour cells. This implies that both the potential therapeutic effect and prophylactic strength of a cancer vaccine will increase with the number of targets that the vaccine is able to elicit T cell immunity against. A multiple target vaccine will also reduce the risk of new tumour formation by treatment escape variants from the primary tumour.

DEFINITION OF PROBLEM SOLVED BY THE INVENTION

There is a continuing need for new anticancer agents based on antigenic peptides giving rise to specific T cellular responses and toxicity against tumours and cancer cells carrying genes with mutations related to cancer. The present invention will contribute largely to supply new peptides that can have a use in the combat and prevention of cancer as ingredients in a multiple target anti-cancer vaccine.

Another problem solved by the present invention is that a protection or treatment can be offered to the individuals belonging to family's or groups with high risk for hereditary cancers. Hereditary cancers are in many cases associated with genes susceptible to frameshift mutations as described in this invention (i.e. mutations in mismatch repair genes). Today it is possible to diagnose risk of getting hereditary cancer but no pharmaceutical method for protection against the onset of the cancer is available.

DEFINITION OF THE INVENTION

A main object of the invention is to obtain peptides corresponding to peptide fragments of mutant proteins produced by cancer cells which can be used to stimulate T cells.

Another main object of the invention is to develop a cancer therapy for cancers based on the T cell immunity which may be induced in patients by stimulating their T cells either in vivo or in vitro with the peptides according to the invention.

A third main object of the invention is to develop a vaccine to prevent the establishment of or to eradicate cancers based solely or partly on peptides corresponding to peptides of the present invention which can be used to generate and activate T cells which produce cytotoxic T cell immunity against cells harbouring the mutated genes.

A fourth main object of the invention is to design an anticancer treatment or prophylaxis specifically adapted to a human individual in need of such treatment or prophylaxis, which comprises administering at least one peptide according to this invention.

These and other objects of the invention are achieved by the attached claims.

Since frameshift mutations result in premature stop codons and therefore deletion in large parts of the proteins, proteins with frameshift mutations have generally not been considered to be immunogenetic and have therefore not been considered as targets for immunotherapy. Thus it has now surprisingly been found that a whole group of new peptides resulting from frameshift mutations in tumour relevant genes are useful for eliciting T cell responses against cancer cells harbouring genes with such frameshift mutations.

Genes containing a mono nucleoside base repeat sequence of at least five residues, for example of eighth deoxyadenosine bases (AAAAAAAA), or a di-nucleoside base repeat sequence of at least four di-nucleoside base units, for example of two deoxyadenosine-deoxycytosine units (ACAC), are susceptible to frameshift mutations. The frameshift mutations occur, respectively, either by insertion of one or two of the mono-nucleoside base residue or of one or two of the di-nucleoside base unit in the repeat sequence, or by deletion of one or two of the mono-nucleoside base residue or of one or two of the di-nucleoside base unit from the repeat sequence. A gene with a frameshift mutation will from the point of mutation code for a protein with a new and totally different amino acid sequence as compared to the normal gene product. This mutant protein with the new amino acid sequence at the carboxy end will be specific for all cells carrying the modified gene.

In the remainder of this specification and claims the denomination frameshift mutant peptides will comprise such proteins and peptide fragments thereof.

It has now according to the present invention been found that such new protein sequences arising from frameshift mutations in genes in cancer cells give rise to tumour rejection antigens that are recognised by T cells in the context of HLA molecules.

It has further according to the present invention been found a group of peptides corresponding to fragments of mutant proteins arising from frameshift mutations in genes in cancer cells which can be used to generate T cells. The said peptides can therefore also be used to rise a T cell activation against cancer cells harbouring a gene with a frameshift mutation as described above.

These peptides are at least 8 amino acids long and correspond, either in their full length or after processing by antigen presenting cells, to the mutant gene products or fragments thereof produced by cancer cells in a human patient afflicted with cancer.

A peptide according to this invention is characterised in that it

a) is at least 8 amino acids long and is a fragment of a mutant protein arising from a frameshift mutation in a gene of a cancer cell; and

b) consists of at least one amino acid of the mutant part of a protein sequence encoded by said gene; and

c) comprises 0-10 amino acids from the carboxyl terminus of the normal part of the protein sequence preceding the amino terminus of the mutant sequence and may further extend to the carboxyl terminus of the mutant part of the protein as determined by a new stop codon generated by the frameshift mutation in the gene; and

d) induces, either in its full length or after processing by antigen presenting cell, T cell responses.

The peptides of this invention contain preferably 8-25, 9-20, 9-16, 8-12 or 20-25 amino acids. They may for instance contain 9, 12, 13, 16 or 21 amino acids.

It is most preferred that the peptides of the present invention are at least 9 amino acids long, for instance 9-18 amino acids long, but due to the processing possibility of the antigen presenting cells also longer peptides are very suitable for the present invention. Thus the whole mutant amino acid sequence may be used as a frameshift mutant peptide according to the present invention, if it comprises 8 amino acids or more.

The invention further relates to a method for vaccination of a person disposed for cancer, associated with a frameshift mutation in a gene, consisting of administering at least one peptide of the invention one or more times in an amount sufficient for induction of T-cell immunity to the mutant proteins encoded by the frameshift mutated gene.

The invention also relates to a method for treatment of a patient afflicted with cancer associated with frameshift mutation in genes, consisting of administering at least one peptide of the invention one or more times in an amount sufficient for induction of T-cell immunity to mutant proteins arising from frameshift mutations in the genes of cancer cells.

Furthermore, it has according to the present invention been found a method for identifying new peptides which correspond to fragments of proteins arising from frameshift mutations in genes. This method is characterised by the following steps:

1) identifying a gene in a cancer cell susceptible to frameshift mutation by having a mono nucleoside base repeat sequence of at least five residues, or a di-nucleoside base repeat sequence of at least four di-nucleoside base units; and

2) removing, respectively, one nucleoside base residue or one di-nucleoside base unit from the repeat sequence and identifying the amino acid sequence of the protein encoded by the altered gene sequence as far as to include a new stop codon; and/or

3) removing, respectively, two nucleoside base residues or two di-nucleoside base units from the repeat sequence and identifying the amino acid sequence of the protein encoded by the altered gene sequence as far as to include a new stop codon; and/or

4) inserting, respectively, one nucleoside base residue or one di-nucleoside base unit in the repeat sequence and identifying the amino acid sequence of the protein encoded by the altered gene sequence as far as to include a new stop codon; and/or

5) inserting, respectively, two nucleoside base residues or two di-nucleoside base units in the repeat sequence and identifying the amino acid sequence of the protein encoded by the altered gene sequence as far as to include a new stop codon.

In order to determine whether the peptides thus identified are useable in the compositions and methods according to the present invention for the treatment or prophylaxis of cancer, the following further step should be performed:

6) determining whether the new peptide, either in their full length or as shorter fragments of the peptides, are able to stimulate T cells.

Optionally a further step may be added as follows:

7) determining peptides containing nested epitopes for different major HLA class I and/or HLA class II molecules.

DETAILED DESCRIPTION OF THE INVENTION

In the present description and claims, the amino acids are represented by their one letter abbreviation as known in the art.

The peptides of the present invention shall be explicitly exemplified through two different embodiments, wherein cancer develops based on frameshift mutations in specific genes, namely the BAX gene and TGFβRII gene:

I) BAX Gene

It has been established that the BAX gene is involved in regulation of survival or death of cells by promoting apoptosis. The human BAX gene contains a repeat sequence of eight deoxyguanosine bases (G8) in the third exon, spanning codons 38 to 41 (AT

G GGG GGG G

AG).

Frameshift mutations in this G8 repeat have been observed, both as G7 (AT

G GGG GGG

AGG) and G9 (AT

G GGG GGG GG

A) repeats, both in colon cancer cells and prostate cancer cells. The occurency is more than 50% of the examined cases (Rampino, N. et al., “Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype.”, Science (Washington D.C.), 275: 967-969, 1997). The modified BAX gene products are unable to promote apoptosis and thus makes further tumour progress possible. Furthermore the modified gene products are only found in cancer cells and are therefore targets for specific immunotherapy.

According to the present invention, peptides corresponding to the transformed BAX protein products arising from frameshift mutations in the BAX gene can be used as anticancer therapeutical agents or vaccines with the function to trigger the cellular arm of the immune system (T-cells) against cancer cells in patients afflicted with cancers associated with a modified BAX gene.

Frameshift mutations in the BAX gene result in mutant peptide sequences with the first amino acid of the altered sequence in position 41 as compared to the normal BAX protein (Table 1, seq.id. no. 1 to 4).

TABLE 1

amino acid pos

41 51 61 71

normal bax

EAPELALDPV PQDASTKKLS ECLKRIGDEL

peptide;

DS . . .

seq.id.no. 1

RHPSWPWTRC LRMRPPRS

(bax−1G);

seq.id.no. 4

GRHPSWPWTR CLRMRPPRS

(bax+2G);

seq.id.no. 2

GTRAGPGPGA SGCVHQEAER VSQAHRGRTG Q

(bax−2G);

seq.id.no. 3

GGTRAGPGPG ASGCVHQEAE RVSQAHRGRT GQ

(bax+1G);

Table 2 shows one group of peptides according to the present invention:

TABLE 2

seq.id.

IQDRAGRMGGRHPSWPWTRCLRMRPPRS

no. 5:

seq.id.

IQDRAGRMGGGRHPSWPWT

no. 6:

seq.id.

IQDRAGRMGGGGTRAGPGPGASGCVHQEAERVSQAHRGRTGQ

no. 7:

seq.id.

IQDRAGRMGGGTRAGPGPG

no. 8:

The peptides listed in Table 3 were used for in vitro generation of T cells that recognise mutant BAX peptides.

TABLE 3

seq id no 1:

RHPSWPWTRCLRMRPPRS

seq id no 9:

IQDRAGRMGGRHPSWPWTRCLR

seq id no 6:

IQDRAGRMGGGRHPSWPWT

seq id no 10:

ASGCVRQEAERVSQAHRGRTGQ

seq id no 11:

GGTRAGPGPGASGCVHQEAERV

seq id no 12:

IQDRAGRMGGGGTRAGPGPGAS

seq id no 8:

IQDRAGRMGGGTRAGPGPG

The most preferred peptides according to this embodiment of the present invention are listed in Table 4:

TABLE 4

seq id

RHPSWPWTRCLRMRPPRS

no 1:

seq id

GTRAGPGPGASGCVHQEAERVSQAHRGRTGQ

no 2:

seq id

GGTRAGPGPGASGCVHQEAERVSQAHRGRTGQ

no 3:

seq id

GRHPSWPWTRCLRMRPPRS

no 4:

seq.id.

IQDRAGRMGGRHPSWPWTRCLRMRPPRS

no. 5:

seq.id.

IQDRAGRMGGGRHPSWPWT

no. 6:

seq.id.

IQDRAGRMGGGGTRAGPGPGASGCVHQEAERVSQAHRGRTGQ

no. 7:

seq id

IQDRAGRMGGGTRAGPGPG

no 8:

seq id

IQDRAGRMGGRHPSWPWTRCLR

no 9:

seq id

ASGCVHQEAERVSQAHRGRTGQ

no 10:

seq id

GGTRAGPGPGASGCVHQEAERV

no 11:

seq id

IQDRAGRMGGGGTRAGPGPGAS

no 12:

2) TGFβRII

It has been established that the TGFβRII gene is involved in regulation of cell growth. TGFβRII is a receptor for TGFβ which down regulates cell growth. The human gene coding for TGFβRII contains a repeat sequence of ten deoxyadenosine bases (A10) from base no. 709 to base no. 718 (G

AA AAA AAA AA

G CCT). In colon cancers and pancreatic cancers frameshift mutations in this A10 repeat have been observed, both as A9 (G

AA AAA AAA A

GC CT) and A11 (G

AA AAA AAA AAA

GCC) repeats, in approximately 80% of the examined cases (Yamamoto, H., “Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer.”, Cancer Research 58, 997-1003, Mar. 1, 1998). The modified TGFβRII gene products are unable to bind TGFβ and the signal for down regulation of cell growth is eliminated and thus makes further tumour progress possible. Furthermore the modified gene products are only found in cancer cells and are therefore targets for immunotherapy.

Consequently peptides corresponding to the transformed TGFβRII protein products arising from frameshift mutations in the TGFβRII gene can be used as anticancer therapeutical agents or vaccines with the function to trigger the cellular arm of the immune system (T-cells) against cancer cells in patients afflicted with cancers associated with a modified TGFβRII gene.

Frameshift mutations in the TGFβRII gene result in mutant peptide sequences with the first amino acid of the altered sequence in either position 133 (one and two base deletions) or 134 (one and two base insertions) as compared to the normal TGFβRII protein (Table 5, seq.id.nos. 13 and 21).

TABLE 5

amino acid

133

pos.

normal

K PGETFFMCSC SSDECNDNII FSEEYNTSNP

TGFβRII;

DLLL

seq id no

S LVRLSSCVPV ALMSAMTTSS SQKNITPAIL TCC

13(−1A);

seq id no

SLVRLSSCVP VALMSAMTTS SSQKNITPAI

13(+2A);

LTCC

TGFbRII +

AW

1A);

TGFbRII −

A W

2A);

Table 6 shows one groups of peptides of this invention:

TABLE 6

seq id

SPKCIMKEKKSLVRLSSCVPVALMSAMTTSSSQKNITPAILTCC

no 14:

seq id

PKCIMKEKKKSLVRLSSCV

no 15:

seq id

SPKCIMKEKKAW

no 19:

seq id

PKCIMKEKKKAW

no 20:

Table 7 presents peptides that were used for in vitro generation of T cells that recognise mutant TGFβRII peptides.

TABLE 7

seq id no 15:

PKCIMKEKKKSLVRLSSCV

seq id no 16:

ALMSAMTTSSSQKNITPAILTCC

seq id no 17:

SLVRLSSCVPVALMSAMTTSSSQ

seq id no 18:

SPKCIMKEKKSLVRLSSCVPVA

seq id no 19:

SPKCIMKEKKAW

seq id no 20:

PKCIMKEKKKAW

seg id no 21:

AMTTSSSQKNITPAILTCC

seq id no 428:

SLVRLSSCV

The most preferred peptides of this embodiment of the present invention are:

TABLE 8

seq id no 13:

SLVRLSSCVPVALMSAMTTSSSQKNITPAILTCC

seq id no 14:

SPKCIMKEKKSLVRLSSCVPVALMSAMTTSSSQKNITPAILTCC

seq id no 15:

PKCIMKEKKKSLVRLSSCV

seq id no 16:

ALMSAMTTSSSQKNITPAILTCC

seg id no 17:

SLVRLSSCVPVALMSAMTTSSSQ

seq id no 18:

SPKCIMKEKKSLVRLSSCVPVA

seq id no 19:

SPKCIMKEKKAW

seg id no 20:

PKCIMKEKKKAW

seq id no 21:

AMTTSSSQKNITPAILTCC

seq id no 428:

SLVRLSSCV

Other peptides of the invention can be fragments of the peptides listed in the Tables 1-8 above. Such fragments are most preferred from 9-16 amino acids long and include at least one amino acid from the mutant part of the protein.

As used in this description and claims the term fragment is intended to specify a shorter part of a longer peptide or of a protein.

Other cancer associated genes containing repeat sequences of a nucleoside base and which therefore are susceptible to frameshift mutations and consequently are potential candidates for peptides according to the present invention (seq id nos according to table 9 are given in parentheses in each case) are the following:

Human TGF-β-2 (hTGFβ2) gene (seq id nos 22-29)

Deleted in colorectal cancer (DCC) gene (seq.id.nos. 30-34)

Human breast and ovarian cancer susceptibility (BRCA1) gene (seq.id.nos. 378-387)

Human breast cancer susceptibility (BRCA2) gene (seq.id.nos. 35-94)

Human protein tyrosine phosphatase (hPTP) gene (seq.id.nos. 95-102)

Human DNA topoisomerase II (top2) gene (seq.id.nos. 103-108)

Human kinase (TTK) gene (seq.id.nos. 109-120)

Human transcriptional repressor (CTCF) gene (seq.id.nos. 121-127)

Human FADD-homologous ICE/CED-3-like protease gene (seq.id.nos. 128-133)

Human putative mismatch repair/binding protein (hMSH3) gene (seq.id.nos. 134-147)

Human retinoblastoma binding protein 1 isoform I (hRBP1) gene (seq.id.nos. 148-156)

Human FMR1 (hFMR1) gene (seq.id.nos. 157-161)

Human TINUR gene (seq.id.nos. 162-169) b-raf oncogene (seq.id.nos. 170-175)

Human neurofibromin (NF1) gene (seq.id.nos. 176-181)

Human germline n-myc gene (seq.id.nos. 182-188)

Human n-myc gene (seq.id.nos. 189-194)

Human ras inhibitor gene (seq.id.nos. 195-199)

Human hMSH6 gene (seq.id.nos. 200-203 and 293-297)

Human nasopharynx carcinoma EBV BNLF-1 gene (seq.id.nos. 204-210)

Human cell cycle regulatory protein (E1A-binding protein) p300 gene (seq.id.nos. 211-218)

Human B-cell lymphoma 3-encoded protein (bcl-3) gene (seq.id.nos. 219-226)

Human transforming growth factor-beta induced gene product (BIGH3) (seq.id.nos. 227-232)

Human transcription factor ETV1 gene (seq.id.nos. 233-239)

Human insulin-like growth factor binding protein (IGFBP4) gene (seq.id.nos. 240-246)

Human MUC1 gene (seq.id.nos. 247-266)

Human protein-tyrosine kinase (JAK1) gene (seq.id.nos. 267-271)

Human protein-tyrosine kinase (JAK3) gene (seq.id.nos. 272-279)

Human Flt4 gene (for transmembrane tyrosinase kinase) (seq.id.nos. 280-284)

Human p53 associated gene (seq.id.nos. 285-292)

Human can (hCAN) gene (seq.id.nos. 298-300)

Human DBL (hDBL) proto-oncogene/Human MCF2PO (hMCF2PO) gene (seq.id.nos. 301-306)

Human dek (hDEK) gene (seq.id.nos. 307-309)

Human retinoblastoma related protein (p107) gene (seq.id.nos. 310-313)

Human G protein-coupled receptor (hGPR1) gene (seq.id.nos. 314-319)

Human putative RNA binding protein (hRBP56) gene (seq.id.nos. 320-325)

Human transcription factor (hITF-2) gene (seq.id.nos. 326-327)

Human malignant melanoma metastasis-supressor (hKiSS-1) gene (seq.id.nos. 328-334)

Human telomerase-associated protein TP-1 (hTP-1) gene (seq.id.nos. 335-348)

Human FDF-5 (hFDF-5) gene (seq.id.nos. 349-356)

Human metastasis-associated mta1 (hMTA1) gene (seq.id.nos. 357-362)

Human transcription factor TFIIB 90 kDa subunit (hTFIIB90) gene (seq id nos 363-369)

Human tumour suppressor (hLUCA-1) gene (seq id nos 370-377)

Human Wilm's tumour (WIT-1) associated protein (seq id nos 388-393)

Human cysteine protease (ICErel-III) gene (seq id nos 394-398 and 459)

Human Fas ligand (FasL) gene (seq id nos 399-403)

Human BRCA1-associated RING domain protein (BARD1) gene (seq id nos 404-417)

Human mcf.2 (hMCF.2) gene (seq id nos 418-422)

Human Fas antigen (fas) gene (seq id nos 423-427)

Human DPC4 gene (seq id nos 429-437).

The mutant peptides that are the results of frameshift mutation in these genes, in accordance with the present invention, are listed in table 9.

TABLE 9

seq id no 22;

TVGRPHISC

seq id no 23;

KTVGRPHISC

seq id no 24;

KQWEDPTSPANVIALLQT

seq id no 25;

QWEDPTSPANVIALLQT

seq id no 26;

QKTIKSTRKKTVGRPHISC

seq id no 27;

QKTIKSTRKKKTVGRPHISC

seq id no 28;

QKTIRSTRKKKQWEDPTSPANVIALLQT

seq id no 29;

QKTIKSTRKKQWEDPTSPANVIALLQT

seq id no 30;

AADLQQQFVHFLDCWDVSSIPFTLHLPQAQDITT

seq id no 31;

GKDAKEKSS

seq id no 32;

GKDAKEKKSS

seq id no 33;

GKDAKEKKAADLQQQFVHFLDCWDVSSIPFTLHLPQAQDITT

seq id no 34;

GKDAKEKAADLQQQFVHFLDCWDVSSIPFTLHLPQAQDITT

seq id no 35;

FSMKQTLMKVKNLKTK

seq id no 36;

KFSMKQTLMNVKNLKTK

seq id no 37;

VRTSKTRKKFSMKQTLMNVKNLKTK

seq id no 38;

VRTSKTRKKKFSMKQTLMVKNLKTK

seq id no 39;

VRTSKTRKKNFP

seq id no 40;

VRTSKTRKNFP

seq id no 41;

IKKKLLQFQK

seq id no 42;

KIKKKLLQFQK

seq id no 43;

KSRRNYFNFKNNCQSRL

seq id no 44;

SRRNYFNFKNNCQSRL

seq id no 45;

TNLRVIQKIKKKLLQFQK

seq id no 46;

TNLRVIQKKIKKKLLQFQK

seq id no 47;

TNLRVIQKKSRRNYFNFKNNCQSRL

seq id no 48;

TNLRVIQKSRRNYFNFKNNCQSRL

seq id no 49;

KIMIT

seq id no 50;

NIDKIPEKIMIT

seq id no 51;

NIDKIPEKKIMIT

seq id no 52;

IINAN

seq id no 53;

KIINAN

seq id no 54;

NDKTVSEKIINAN

seq id no 55;

NDKTVSEKKIINAN

seq id no 56;

NGLEKEYLMVNQKE

seq id no 57;

SQTSLLEAKNGLEKEYLMVNQKE

seq id no 58;

SQTSLLEAKKNCLEKEYLMVNQKE

seq id no 59;

SQTSLLEAKKMA

seq id no 60;

SQTSLLEAXMA

seq id no 61;

TLVFPK

seq id no 62;

KTLVFPK

seq id no 63;

LKNVEDQKTLVFPK

seq id no 64;

LKNVEDQKKTLVFPK

seq id no 65;

LKNVEDQKKH

seq id no 66;

LKNVEDQKH

seq id no 67;

KKIQLY

seq id no 68;

KKKIQLY

seq id no 69;

RKRFSYTEYLASIIRFIFSVNRRKEIQNLSSCNFKI

seq id no 70;

LRIVSYSKKKKIQLY

seq id no 71;

LRIVSYSKKKKKIQLY

seq id no 72;

LRIVSYSKKRKRFSYTEYLASIIRFIFSVNRRKEIQNLS-

SCNFKI

seq id no 73;

LRIVSYSKRKRFSYTEYLASIIRFIFSVNRRKEIQNLS-

SCNFKI

seq id no 74;

QDLPLSSICQTIVTIYWQ

seq id no 75;

KQDLPLSSICQTIVTIYWQ

seq id no 76;

NRTCPFRLFVPRILQFTCNKVLDRP

seq id no 77;

GFWSVVKKQDLPLSSICQTIVTIYWQ

seq id no 78;

GFVVSWKKKQDLPLSSICQTIVTIYWQ

seq id no 79;

GFVVSWKKNRTCPFRLFVRRMLQFTGNKVLDRP

seq id no 80;

GFVVSVVKNRTCPFRLFVRRMLQFTGNKVLDRP

seq id no 81;

YRKTKNQN

seq id no 82;

KYRKTKNQN

seq id no 83;

NTERPKIRTN

seq id no 84;

DETFYKGKKYRKTKNQN

seq id no 85;

DETFYKGKKKYRKTKNQN

seq id no 86;

DETFYKGKKNTERPKIRTN

seq id no 87;

DETFYKGKNTERPKIRTN

seq id no 88;

LSINNYRFQMKFYFRFTSHGSPFTSANF

seq id no 89;

KLSINNYRFQMKFYFRFTSHGSPFTSANF

seq id no 90;

NSVSTTTGFR

seq id no 91;

NIQLAATKKLSINNYRFQMKFYFRFTSHGSPFTSANF

seq id no 92;

NIQLAATKKKLSINNYRFQMKFYFRFTSHGSPFTSANF

seq id no 93;

NIQLAATKKNSVSTTTGFR

seq id no 94;

NIQLAATKNSVSTTTGFR

seq id no 95;

MEHVAPGRMSASPQSPTQ

seq id no 96;

KMEHVAPGRMSASPQSPTQ

seq id no 97;

KWSTWLQAECQHLHSPQRSDKPQQAGLDQQHHCFALDS-

SPGPRPVFLQLLGLMGQGRHD

seq id no 98;

WSTWLQAECQRLHSPQRSDKPQQAGLDQQHHCFALDSS-

PGPRPVFLQLLGLMGQGRHD

seq id no 99;

TFSVWAEKMEHVAPGRMSASPQSPTQ

seq id no 100;

TFSVWAEKKMEHVAPGRMSASPQSPTQ

seq id no 101;

TFSVWAEKKWSTWLQAECQHLHSPQRSDKPQQAGLDQ-

QHHCFALDSSPGPRPVFLQLLGLMGQGRHD

seq id no 102;

TFSVWAEKWSTWLQAECQHLHSPQRSDKPQQAGLDQ-

QHHCFALDSSPGPRPVFLQLLGLMGQGRHD

seq id no 103;

HKWLKFCLLRLVKESFHE

seq id no 104;

KHKWLKFCLLRLVKESFHE

seq id no 105;

KGGKAKGKKHKWLKFCLLRLVKESFHE

seq id no 106;

KGGKAKGKKKHKWLKFCLLRLVKESFHE

seq id no 107;

KGGKAKGKKNTNG

seq id no 108;

KGGKAKGKNTNG

seq id no 109;

VNNFFKKL

seq id no 110;

KVNNFFKKL

seq id no 111;

LSQGNVKKVNNFFKKL

seq id no 112;

LSQGNVKKKVNNFFKKL

seq id no 113;

GEKNDLQLFVMSDRRYKIYWTVILLNPCGNLHLKTTSL

seq id no 114;

KGEKNDLQLFVMSDRRYKIYWTVILLNPCGNLHLKTTSL

seq id no 115;

KGKKMICSYS

seq id no 116;

GKKMICSYS

seq id no 117;

SSKTFEKKGEKNDLQLFVMSDRRYKIYWTVILLNPCGN-

LHLKTTSL

seq id no 118;

SSKTFEKKKGEKNDLQLFVMSDRRYKIYWTVILLNPCGN-

LHLKTTSL

seq id no 119;

SSKTFEKKKGKKMICSYS

seq id no 120;

SSKTFEKKCKKMICSYS

seq id no 121;

QRKPKRANCVIQRRAKM

seq id no 122;

KQRKPKRANCVIQRRAKM

seq id no 123;

NKENQKEQTALLYRGGQRCRCVCLRF

seq id no 123;

NKENQKEQTALLYRGGQRCRCVCLRF

seq id no 124;

PDYQPPAKKQRXPKRANCVIQRRAKM

seq id no 125;

PDYQPPAKKKQRKPKRANCVIQRRAKM

seq id no 126;

PDYQPPAKKNKENQKEQTALLYRCGQRCRCVCLRF

seq id no 127;

PDYQPPAKNKENQKEQTALLYRGGQRCRCVCLRF

seq id no 128;

NLSSLLI

seq id no 129;

TCLPF

seq id no 130;

QPTFTLRKNLSSLLI

seq id no 131;

QPTFTLRKKNLSSLLI

seq id no 132;

QPTFTLRKKTCLPF

seq id no 133;

QPTFTLRKTCLPF

seq id no 134;

RATFLLSLWECSLPQARLCLIVSRTGLLVQS

seq id no 135;

GQHFYWHCGSAACHRRGCV

seq id no 136;

KENVRDKKRATFLLSLWECSLPQARLCLIVSRTGLLVQS

seq id no 137;

KENVRDKKKRATFLLSLWECSLPQARLCLIVSRTGLLVQS

seq id no 138;

KENVRDKKKGQHFYWHCGSAACHRRGCV

seq id no 139;

KENVRDKKGQHFYWHCGSAACHRRGCV

seq id no 140;

ITHTRWGITTWDSWSVRMKANWIQAQQNKSLILSPSFTK

seq id no 141;

KITHTRWGITTWDSWSVRRKANWIQAQQNKSLILSPSFTK

seq id no 142;

KLLTPGGELPHGILGQ

seq id no 143;

LLTPGGELPHGILCQ

seq id no 144;

PPVCELEKITHTRWGITTWDSWSVRMKANWIQAQQNKS-

LILSPSFTK

seq id no 145;

PPVCELEKKITHTRWGITTWDSWSVRMKANWIQAQQNKS-

LILSPSFTK

seq id no 146;

PPVCELEKKLLTPGGELPHGILGQ

seq id no 147;

PPVCELEKLLTPGGELPHGILGQ

seq id no 148;

SLKDELEKMKI

seq id no 149;

SLKDELEKKMKI

seq id no 150;

LGQSSPEKKNKN

seq id no 151;

LGQSSPEKNKN

seq id no 152;

RLRRINGRGSQIRSRNAFNRSEE

seq id no 153;

EPKVKEEKKT

seq id no 154;

EPKVKEEKKKT

seq id no 155;

EPKVKEEKKRLRRINGRGSQIRSRNAFNRSEE

seq id no 156;

EPKVKEEKRLRRINGRGSQIRSRNAFNRSEE

seq id no 157;

TFRYKGKQHPFFST

seq id no 158;

GPNAPEEKNH

seq id no 159;

GPNAPEEKKNH

seq id no 160;

GPNAPEEKKTFRYKGKQHPFFST

seq id no 161;

GPNAPEEKTFRYKGKQHPFFST

seq id no 162;

MQNTCV

seq id no 163;

KMQNTCV

seq id no 164;

KCKIRVFSK

seq id no 165;

CKIRVFSK

seq id no 166;

FFKRTVQKMQNTCV

seq id no 167;

FFKRTVQKKMQNTCV

seq id no 168;

FFKRTVQKKCKIRVFSK

seq id no 169;

FFKRTVQKCKIRVFSK

seq id no 170;

LPHYLAH

seq id no 171;

CLITWLTN

seq id no 172;

GSTTGLSATPLPHYLAH

seq id no 173;

GSTTGLSATPPLPHYLAH

seq id no 174;

GSTTGLSATPPCLITWLTN

seq id no 175;

GSTTGLSATPCLITWLTN

seq id no 176;

RFADKPRPN

seq id no 177;

DLPTSPDQTRSGPVHVSVEP

seq id no 178;

DSAAGCSGTPRFADKPRPN

seq id no 179;

DSAAGCSGTPPRFADKPRPN

seq id no 180;

DSAAGCSGTPPDLPTSPDQTRSGPVHVSVEP

seq id no 181;

DSAAGCSGTPDLPTSPDQTRSGPVHVSVEP

seq id no 182;

AHPETPAQNRLRIPCSRREVRSRACKPPGAQGSDER-

RGKASPGRDCDVRTGRP

seq id no 183;

PAHPETPAQNRLRIPCSRREVRSRACKPPGAQGSDER-

RGKASPGRDCDVRTGRP

seq id no 184;

RPTRRHPRRIASGSPAVGGR

seq id no 185;

VAIRGHPRPPAHPETPAQNRLRIPCSRREVRSRACKP-

PGAQGSDERRGKASPGRDCDVRTGRP

seq id no 186;

VAIRGHPRPPPAHPETPAQNRLRIPCSRREVRSRACKP-

PGAQGSDERRGKASPGRDCDVRTGRP

seq id no 187;

VAIRGHPRPPRPTRRHPRRIASGSPAVGGR

seq id no 188;

VAIRGHPRPRPTRRHPRRIASGSPAVGGR

seq id no 189;

RGRTSGRSLSCCRRPRCRPAVASRSTAPSPRAGSR-

RCCLRTSCGAARPRRTRSACGDWVASPPTRSS-

SRTACGAASPPARSWSAP

seq id no 190;

GGGHLEEV

seq id no 191;

YFGGPDSTPRGRTSGRSLSCCRRPRCRPAVASR-

STAPSPRAGSRRCCLRTSCGAARPRRTRSACGD-

WVASPPTRSSSRTACGAASPPARSWSAP

seq id no 192;

YFGGPDSTPPRGRTSGRSLSCCRRPRCRPAVASR-

STAPSPRAGSRRCCLRTSCGAARPRRTRSACGDW-

VASPPTRSSSRTACGAASPPARSWSAP

seq id no 193;

YFGGPDSTPPGGGHLEEV

seq id no 194;

YFGGPDSTPGGGHLEEV

seq id no 195;

HRVADP

seq id no 196;

LSQSSELDPPSSR

seq id no 197;

LSQSSELDPPPSSR

seq id no 198;

LSQSSELDPPHRVADP

seq id no 199;

LSQSSELDPHRVADP

seq id no 200;

VILLPEDTPPS

seq id no 201;

VILLPEDTPPPS

seq id no 202;

VILLPEDTPPLLRA

seq id no 203;

VILLPELDPLLRA

seq id no 204;

PSPLP

seq id no 205;

PLLFHRPCSPSPALGATVLAVYRYE

seq id no 206;

LLFHRPCSPSPALGATVLAVYRYE

seq id no 207;

APRPPLGPPSPLP

seq id no 208;

APRPPLGPPPSPLP

seq id no 209;

APRPPLGPPPLLFHRPCSPSPALGATVLAVYRYE

seq id no 210;

APRPPLGPPLLFHRPCSPSPALGATVLAVYRYE

seq id no 211;

TQVLPQGCSLSLLHTTFPHRQVPHILDW

seq id no 212;

PTQVLPQGCSLSLLHTTFPHRQVPHILDW

seq id no 213;

PLQSFPKDAASAFSTPRFPTDKFPTSWTGSCPGQPHGT-

RAFCQPGPEFNAFSAC

seq id no 214;

LQSFPKDAASAFSTPRFPTDKFPTSWTGSCPGQPHGT-

RAFCQPGPEFNAFSAC

seq id no 215;

PSPRPQSQPPTQVLPQGCSLSLLHTTFPHRQVPHILDW

seq id no 216;

PSPRPQSQPPPTQVLPQGCSLSLLHTTFPHRQVPHILDW

seq id no 217;

PSPRPQSQPPPLQSFPKDAASAFSTPRFPTDKFPTS-

WTGSCPGQPHGTRAFCQPGPEFNAFSAC

seq id no 218;

PSPRPQSQPPLQSFPKDAASAFSTPRFPTDKFPTS-

WTGSCPGQPHGTRAFCQPGPEFNAFSAC

seq id no 219;

TAWPGRRRFTTPEPYCLCTPLGPWAPRFLW

seq id no 220;

PTAWPGRRRFTTPEPYCLCTPLGPWAPRFLW

seq id no 221;

PRPGPAGGALLPRSLTAFVPHSGHGLPVSSGEPAYTPIP-

HDVPHGTPPFC

seq id no 222;

RPGPAGGALLPRSLTAFVPHSGHGLPVSSGEPAYTPIPH-

DVPHGTPPFC

seq id no 223;

DLPAVPGPPTAWPGRRRFTTPEPYCLCTPLGPWAPRFLW

seq id no 224;

DLPAVPGPPPTAWPGRRRFTTPEPYCLCTPLGPWAPRFLW

seq id no 225;

DLPAVPGPPPRPGPAGGALLPRSLTAFVPHSGHGLPVSSG-

EPAYTPIPHDVPHGTPPFC

seq id no 226;

DLPAVPGPPRPGPAGGALLPRSLTAFVPHSGMGLPVSSG-

EPAYTPIPHDVPHGTPPFC

seq id no 227;

QWCLSWMS

seq id no 228;

NGDCHGCPEGRQSL

seq id no 229;

FTMDRVLTPQWGLSWMS

seq id no 230;

FTMDRVLTPPQWGLSWMS

seq id no 231;

FTMDRVLTPPNGDCHGCPEGRQSL

seq id no 232;

FTMDRVLTPNGDCHGCPEGRQSL

seq id no 233;

HHPARQCPHCIMHLQTQLIHRNLTGPSQLTSLHRS-

PYQIAATPWTTDFAASFFLNPVTPFLLCRRCQGKDV-

LCTNARCLSQTSPSHHKALSRTTTQCMNT-

TPWLAVRPAKAFPLL

seq id no 234;

PHHPARQCPHCIMHLQTQLIHRNLTGPSQLTSLHRS-

PYQIAATPWTTDFAASFFLNPVTPFLLCRRCQGK-

DVLCTNARCLSQTSPSHHKALSRTTTQCMNTTP-

WLAVRPAKAFPLL

seq id no 235;

HTIQHASVPTASCISKLNSYTEN

seq id no 236;

PQVGMRPSNPPHHPARQCPHCIMHLQTQLIHRNLT-

GPSQLTSLHRSPYQIAATPWTTDFAASFFLNPVTPFL-

LCRRCQGKDVLCTNARCLSQTSPSHHKALSRTTTQC-

MNTTPWLAVRPAKAFPLL

seq id no 237;

PQVGMRPSNPPPHHPARQCPHCIMHLQTQLIHRNLTGPS-

QLTSLHRSPYQIAATPWTTDFAASFFLNPVTPFLLCRRC-

QGKDVLCTNARCLSQTSPSHHKALSRTTTQCMNTTPWLA-

VRPAKAFPLL

seq id no 238;

PQVGMRPSNPPHTIQHASVPTASCISKLNSYTEN

seq id no 239;

PQVGMRPSNPHTIQHASVPTASCISKLNSYTEN

seq id no 240;

WAARSWCERAAAAVAPLAPWAWGCPAGCTPPVAARAC-

AATRPEGWRSPCTH

seq id no 241;

PWAARSWCERRAAAVAPLAPWAWGCPAGCTPPVAA-

RACAATRPEGWRSPCTH

seq id no 242;

RGLRGAGARGGLRLLRHLRPGLGDALRGVHPPLR-

LGPALLPAPRGGEAPAHTDARARRVHGAGGDRGHPGPAAL

seq id no 243;

EEKLARCRPPWAARSWCERRAAAVAPLAPWAWGCPAGC-

TPPVAARACAATRPEGWRSPCTH

seq id no 244;

EEKLARCRPPPWAARSWCERRAAAVAPLAPWAWGCPA-

GCTPPVAARACAATRPEGWRSPCTH

seq id no 245;

EEKLARCRPPRGLRGAGARGGLRLLRHLRPGLGDA-

LRGVHPPLRLGPALLPAPRGGEAPAHTDARARRVHGAGG-

DRGHPGPAAL

seq id no 246;

EEKLARCRPRGLRGAGARGGLRLLRHLRPGLGDALRG-

VHPPLRLGPALLPAPRGGEAPAHTDARARRVHGAGG-

DRGHPGPAAL

seq id no 247;

QPPVSPRPRRPGRPRAPPPPQPMVSPRRRTTGPPW-

RPPPLQSTMSPPPQALHQAQLLLWCTTAPLPGLPQPQ-

PARALHSQFPATTLILLPPLPAIAPRLMPVALTIARYL-

LSPPPITALLPSCLLGSLSFSCLFTFQTSSLIPLW-

KIPAPTTTKSCRETFLKW

seq id no 248;

SPGCHLGPGDQAAPGLHRPPSPWCHLGAGQQARLGVHR-

PSSPQCHLGLRLCIRLSFYSGAQRHLCQGYHNPSQQEHS

ILNSQPPL

seq id no 249;

KPAPGSTAPQPPVSPRPRRPGRPRAPPPPQPMVSPRR-

RTTGPPWRPPPLQSTMSPPPQALHQAQLLLWCTTAP-

LPGLPQPQPARALHSQFPATTLILLPPLPAIAPRLMPVA-

LTIARYLLSPPPITALLPSCLLGSLSFSCLFTFQTS-

SLIPLWKIPAPTTTKSCRETFLKW

seq id no 250;

KPAPGSTAPPQPPVSPRPRRPGRPRAPPPPQPMVSPR-

RRTTGPPWRPPPLQSTMSPPPQALHQAQLLLWCT-

TAPLPGLPQPQPARALHSQFPATTLILLPPLPAIAP-

RLMPVALTIARYLLSPPPITALLPSCLLGSLSFSCLF-

TFQTSSLIPLWKIPAPTTTKSCRETFLKW

seq id no 251;

KPAPGSTAPPSPGCHLGPGDQAAPGLHRPPSPWCHL-

GAGQQARLGVHRPSSPQCHLGLRLCIRLSFYSGA-

QRHLCQGYHNPSQQEHSILNSQPPL

seq id no 252;

KPAPGSTAPSPGCHLGPGDQAAPGLHRPPSPWCHL-

GAGQQARLGVHRPSSPQCHLGLRLCIRLSFYSGAQ-

RHLCQGYHNPSQQEHSILNSQPPL

seq id no 253;

QPMVSPRRRTTGPPWRPPPLQSTMSPPPQALHQAQL-

LLWCTTAPLPGLPQPQPARALHSQFPATTLILLPPLP-

AIAPRLMPVALTIARYLLSPPPITALLPSCLLGSL-

SFSCLFTFQTSSLIPLWKIPAPTTTKSCRETFLKW

seq id no 254;

SPWCHLGAGQQARLGVHRPSSPQCHLGLRLCIRLSF-

YSGAQRHLCQGYHNPSQQEHSILNSQPPL

seq id no 255;

RPPPGSTAPQPMVSPRRR

seq id no 256;

RPPPGSTAPPQPMVSPRRR

seq id no 257;

RPPPGSTAPPSPWCHLGA

seq id no 258;

RPPPGSTAPSPWCHLGA

seq id no 259;

RPRAPPPPSPWCHL

seq id no 260;

RPRAPPPPPSPWC

seq id no 261;

RPRAPPPPAHGVTSAP

seq id no 262;

RPRAPPPPPAHGV

seq id no 263;

APGLHRPPQPMVSP

seq id no 264;

AAPGLHRPQPMVSPR

seq id no 265;

PGLHRPPPAHGVT

seq id no 266;

APGLHRPPAHGVTS

seq id no 267;

VDRPQHTEWLSWSNLYRIRHQ

seq id no 268;

HYLCTDVAPR

seq id no 269;

HYLCTDVAPPR

seq id no 270;

HYLCTDVAPPVDRPQHTEWLSWSNLYRIRHQ

seq id no 271;

HYLCTDVAPVDRPQHTEWLSWSNLYRIRHQ

seq id no 272;

SAYLSPLCTTWLRTCACRLPRPAASCLCTTPSLLW-

PRRTCPAGSPRATSSPWRMPAPKSCCTTCLAFTS-

PIGLGWRSATASGYARIWPVLSLTCQSWSTSLPSTAVTW

seq id no 273;

PSAYLSPLGTTWLRTCACRLPRPAASCLCTTPSLLWP-

RRTCPACSPRATSSPWRMPAPKSCCTTCLAFTSP-

IGLGWRSATASGYARIWPVLSLTCQSWSTSLPSTAVTW

seq id no 274;

PAPIFLLWGPLG

seq id no 275;

APIFLLWGPLC

seq id no 276;

LPARAPGPPSAYLSPLGTTWLRTCACRLPRPAASCL-

CTTPSLLWPRRTCPACSPRATSSPWRMPAPKSCC-

TTGLAFTSPIGLGWRSATASGYARIWPVLSLT-

CQSWSTSLPSTAVTW

seq id no 277;

LPARAPGPPPSAYLSPLGTTWLRTCACRLPRPAAS-

CLCTTPSLLWPRRTCPAGSPRATSSPWRMPAPKSCC-

TTGLAFTSPIGLGWRSATASGYARIWPVLSLTC-

QSWSTSLPSTAVTW

seq id no 278;

LPARAPGPPPAPIFLLWGPLG

seq id no 279;

LPARAPGPPAPIFLLWGPLG

seq id no 280;

DLEHHCGVTRHRHR

seq id no 281;

LVSDYSMTPRP

seq id no 282;

LVSDYSMTPPRP

seq id no 283;

LVSDYSMTPPDLEHHCGVTRHRHR

seq id no 284;

LVSDYSMTPDLEHHGGVTRHRHR

seq id no 285;

FHHIATDVGPFVRIGFLKIKGKIKGKSLRKPNW-

KTQHKLKRALMFLIVKKL

seq id no 286;

PFHHIATDVGPFVRIGFLKIKGKIKGKSLRKPNWK-

TQHKLKRALMFLIVKKL

seq id no 287;

PSITLQQMLAPS

seq id no 288;

SITLQQMLAPS

seq id no 289;

TSCNEMNPPFHHIATDVGPFVRIGFLKIKGKIKGKSL-

RKPNWKTQHKLKRALMFLIVKKL

seq id no 290;

TSCNEMNPPPFHHIATDVGPFVRIGFLKIKGKIKG-

KSLRKPNWKTQHKLKRALMFLIVKKL

seq id no 291;

TSCNEMNPPSITLQQMLAPS

seq id no 292;

TSCNEMNPPPSITLQQMLAPS

seq id no 293;

LEMILFLMTF

seq id no 294;

HPCITKTFLEMILFLMTF

seq id no 295;

HPCITKTFFLEMILFLMTF

seq id no 296;

HPCITKTFFWR

seq id no 297;

HPCITKTFWR

seq id no 298;

LMFEHSQMRLNSKNAHLPIISF

seq id no 299;

EYGSIIAFLMFERSQMRLNSKNAHLPIISF

seq id no 300:

EYGSIIAFFLMFEHSQMRLNSKNAHLPIISF

seq id no 301:

HLNKGRRLGDKIRAT

seq id no 302;

FHLNKGRRLGDKIRAT

seq id no 303;

VTSGTPFFHLNKGRRLGDKIRAT

seq id no 304;

VTSGTPFFFHLNKGRRLGDKIRAT

seq id no 305;

VTSGTPFFFI

seq id no 306;

VTSGTPFFI

seq id no 307;

CEIERIHFFF

seq id no 308;

CEIERIHFFSK

seq id no 309;

CEIERIHFSK

seq id no 310;

FRYISKSI

seq id no 311;

RYISKSI

seq id no 312;

FKKYEPIFFRYISKSI

seq id no 313;

FKKYEPIFRYISKSI

seq id no 314;

FPDSDQPGPLYPLDPSCLISSASNPQELSDCHYIH-

LAFGFSNWRSCPVLPGHCGVQ

seq id no 315;

PDSDQPGPLYPLDPSCLISSASNPQELSDCHYIHL-

AFGFSNWRSCPVLPGHCGVQ

seq id no 316;

LNMFASVFS

seq id no 317;

LNMFASVFFS

seq id no 318;

LNMFASVFFPDSDQPGPLYPLDPSCLISSASNPQE-

LSDCHYIHLAFGFSNWRSCPVLPGHCGVQ

seq id no 319;

LNMFASVFPDSDQPGPLYPLDPSCLISSASNPQELS-

DCHYIHLAFGFSNWRSCPVLPGHCGVQ

seq id no 320;

AMEETVVVAVATVETEVEAMEETGVVAAMEETEVGAT-

EETEVAMEAKWEEETTTEMISATDHT

seq id no 321;

LWVRPWLWEWLRWRPKWRLWRRQEWWRLWRRPRWGL-

RRRPRWLWRENGRKKRLQK

seq id no 322;

YGGDRSRGAMEETVVVAVATVETEVEAMEETGVVAAM-

EETEVGATEETEVAMEAKWEEETTTEMISATDHT

seq id no 323;

YGGDRSRGGAMEETVVVAVATVETEVEAMEETGVVA-

AMEETEVGATEETEVAMEAKWEEETTTEMISATDHT

seq id no 324;

YGGDRSRGGLWVRPWLWEWLRWEPKWRLWRRQEWW-

RLWRRPRWGLRRRPRWLWRENGRKKRLQK

seq id no 325;

YGGDRSRGLWVRPWLWEWLRWEPKWRLWRRQEWWR-

LWRRPRWGLRRRPRWLWRENGRKKRLQK

seq id no 326;

EFGGGRRQK

seq id no 327;

EFGGRRQK

seq id no 328;

RRAKGGGAGASNPRQ

seq id no 329;

GRRAKGGGAGASNPRQ

seq id no 330;

DVGLREGALELPTRGNKRNVA

seq id no 331;

MRGGGGVGGRRAKGGGAGASNPRQ

seq id no 332;

MRGGGGVGGGRRAKGGGAGASNPRQ

seq id no 333;

MRGGGGVGGDVGLREGALELPTRGNKRNVA

seq id no 334;

MRGGGGVGDVGLREGALELPTRGNKRNVA

seq id no 335;

VWQLAGPMLAGWRSLGSWFCRMYGI

seq id no 336;

CGSWPALCWRAGGVWAVGSAGCMEYDPEALPAAWGP-

AAAATVHPRR

seq id no 337;

RRYPCEWGVWQLAGPMLAGWRSLGSWFCRMYGI

seq id no 338;

RRYPCEWGGVWQLAGPMLAGWRSLGSWFCRMYGI

seq id no 339;

RRYPCEWGGCGSWPALCWRAGGVWAVGSAGCMEYD-

EALPAAWGPAAAATVHPRR

seq id no 340;

RRYPCEWGCGSWPALCWRAGGVWAVGSAGCMEYDPE-

ALPAAWGPAAAAIVHPRR

seq id no 341;

LWLWAGWTVWWSCGPGEKGHGWPSLPTMALLLLRFSCM-

RVASY

seq id no 342;

GLWLWAGWTVWWSCGPGEKGHGWPSLPTMALLLL-

RFSCMRVASY

seq id no 343;

GCGCGPAGQYGGAVGLARRGTAGCLPCPPWLCCCCAF-

PACGLPGTDGWRGWQGSGCVRVSGSAPWAPGFPFSP-

PCPLCGTQPRW

seq id no 344;

CGCGPAGQYGGAVGLARRGTAGCLPCPPWLCCCCAFPACG-

LPGTDGWRGWQGSGCVRVSGSAPWAPGFPFSPPC-

PLCGTQPRW

seq id no 345;

LAFNVPGGLWLWAGWTVWWSCGPGEKGHGWPSLPTMA-

LLLLRFSCMRVASY

seq id no 346;

LAFNVPGGGLWLWAGWTVWWSCGPGEKGHGWPSLPTM-

ALLLLRFSCMRVASY

seq id no 347;

LAFNVPGGCCGCGPAGQYCGAVGLARRGTACCLPCPP-

WLCCCCAFPACGLPGTDGWRGWQGSGCVRVSGSAPW-

APGFPFSPPCFLCGTQPRW

seq id no 348;

LAFNVPGGCGCGPAGQYGGAVGLARRGTAGCLPCPPW-

LCCCCAFPACGLPGTDGWRGWQGSGCVRVSGSAPWA-

PGFPFSPPCPLCGTQPRW

seq id no 349;

PPMPMPGQREAPGRQEA

seq id no 350;

GPFMPMPGQREAPGRQEA

seq id no 351;

GHQCQCQGKGRHRADRRPDTAQEE

seq id no 352;

HQCQCQGKGRHRADRRPDTAQEE

seq id no 353;

GGHSYGGGPPMPMPGQREAPGRQEA

seq id no 354;

GGHSYGGGGPPMPMPGQREAPGRQEA

seq id no 355;

GGHSYGGGGHQCQCQGKGRHRADRRPDTAQEE

seq id no 356;

GGHSYGGGHQCQCQGKGRHRADRRPDTAQEE

seq id no 357;

APCPQSSGGG

seq id no 358;

LPAPSQAAADELDRRPG

seq id no 359;

TKVRLIRGAPCPQSSGGG

seq id no 360;

TKVRLIRGGAPCPQSSGGG

seq id no 36l;

TKVRLIRGGLPAPSQAAADELDRRPG

seq id no 362;

TKVRLIRGLPAPSQAAADELDRRPG

seq id no 363;

CSLAKDGSTEDTVSSLCGEEDTEDEELEAAASHLNK-

DLYRELLGG

seq id no 364;

GCSLAKDGSTEDTVSSLCGEEDTEDEELEAAASHLNK-

DLYRELLGG

seq id no 365;

AAAWQKMAPPRTPRPACVARR

seq id no 366;

ENSRPKRGGCSLAKDGSTEDTVSSLCGEEDTEDEELE-

AAASHLNKDLYRELLGG

seq id no 367;

ENSRPKRGGGCSLAKDGSTEDTVSSLCGEEDTEDE-

ELEAAASHLNKDLYRELLGG

seq id no 368;

ENSRPKRGGAAAWQKMAPPRTPRPACVARR

seq id no 369;

ENSRPKRGAAAWQKMAPPRTPRPACVARR

seq id no 370;

HCVLAASGAS

seq id no 371;

GHCVLAASGAS

seq id no 372;

GTASSRPLGLPKPHLHRPVPIRHPSCPK

seq id no 373;

TASSRPLGLPKPHLHRPVPIRHPSCPK

seq id no 374;

AGTLQLGGHCVLAASGAS

seq id no 375;

AGTLQLGGGHCVLAASGAS

seq id no 376;

AGTLQLGGGTASSRPLGLPKPHLHRPVPIRHPSCPK

seq id no 377;

AGTLQLGGTASSRPLGLPKPHLHRPVPIRHPSCPK

seq id no 378;

RRTPSTEKR

seq id no 379;

RRTPSTEKKR

seq id no 380;

RRTPSTEKKGRSEC

seq id.no 381;

RRTPSTEKGRSEC

seq id no 382;

STTKCQSGTAETYNSWKVKNLQLEPRRVTSQMNRQVK-

DMTAILSQS

seq id no 384;

SSEEIKKKSTTKCQSGTAETYNSWKVKNLQLEPRRV-

TSQMNRQVKDMTAILSQS

seq id no 385;

SSEEIKKKKSTTKCQSGTAETYNSWKVKNLQLEPRR-

VTSQMNRQVKDMTAILSQS

seq id no 386;

SSEEIKKKKVQPNASQAQQKPTTHGR

seq id no 387;

SSEEIKKKVQPNASQAQQKPTTHGR

seq.id no 388;

NRGWVGAGE

seq id no 389;

IEAG

seq id no 390;

VHNYCNMKNRGWVGAGE

seq id no 391;

VHNYCNMKKNRGWVGAGE

seq id no 392;

VHNYCNMKKIEAG

seq id no 393;

VHNYCNMKIEAG

seq id no 394;

QLRCWNTWAKMFFMVFLIIWQNTMF

seq id no 395;

VKKDWHKKQLRCWNTWAKMFFMVFLIIWQNTMF

seq id no 396;

VKKDNHKKKQLRCWNTWAKMFFMVFLIIWQNTMF

seq id no 397;

VKKDNHKKKNS

seq id no 398;

VKKDNHKKNS

seq id no 399;

GAEESGPFNRQVQLKVHASGMGRHLWNCPAFWSEV

seq id no 400;

IIPSPPPEKRS

seq id no 401;

HPSPPPEKKRS

seq id no 402;

HPSPPPEKKGAEESGPFNRQVQLKVHASGMGRHLW-

NCPAFWSEV

seq id no 403;

HPSPPPEKGAEESGPFNRQVQLKVHASGMGRHLWN-

CPAFWSEV

seq id no 404;

MQVLSKTHMNLFPQVLLQMFLRGLKRLLQDLEKSKKRKL

seq id no 405;

RCKSARLI

seq id no 406;

VQTQPAIKKMQVLSKTHMNLFPQVLLQMFLRGLKRLLQ-

DLEKSKKRKL

seq id no 407;

VQTQPAIKKKMQVLSKTHMNLFPQVLLQMFLRGLKRL-

LQDLEKSKKRKL

seq id no 408;

VQTQPAIKKRCKSARLI

seq id no 409;

VQTQPAIKRCKSARLI

seq id no 410;

ARSGKKQKRKL

seq id no 411;

ARSGKKQKKRKL

seq id no 412;

ARSGKKQKKENFS

seq id no 413;

ARSGKKQKENFS

seq id no 414;

KASARSGKSKKRKL

seq id no 415;

KASARSGKKSKKRKL

seq id no 416;

KASARSGKKAKKENSF

seq id no 417;

KASARSGKAKKENSF

seq id no 418;

HLNKGRRLGDKIRAT

seq id no 419;

VTSGTPFFHLNKGRRLGDKIRAT

seq id no 420;

VTSGTPFFFHLNKGRRLGDKIRAT

seq id no 421;

VTSGTPFFFI

seq id no 422;

VTSGTPFFI

seq id no 423;

VTLLYVNTVTLAPNVNMESSRNAHSPATPSAKRK-

DPDLTWGGFVFFFCQFH

seq id no 424;

KCRCKPNFFVTLLYVNTVTLAPNVNMESSRNAHSP-

ATPSAKRKDPDLTWGGFVFFFCQFH

seq id no 425;

KCRCKPNFFFVTLLYVNTVTLAPNVNMESSRNAH-

SPATPSAKRKDPDLTWGGFVFFFCQFH

seq id no 426;

KCRCKPNFFL

seq id no 427;

KCRCKPNFL

seq id no 429;

LVKKLKEKKMNWIL

seq id no 430;

LVKKLKEKKKNNWIL

seq id no 431;

LVKKLKEKKR

seq id no 432;

LVKKLKEKR

seq id no 433;

AAIVKDCCR

seq id no 434;

SQPASILGRKL

seq id no 435;

SQPASILGKRKL

SQPASILGKAAIVKDCCR

seq id no 436;

SQPASILGKAAIVKDCCR

seq id no 437;

SQPASILGAAIVKDCCR

seq id no 459;

NTWAKMFFMVFLIIWQNTMF

Examples of cancers particularly suitable for treatment with one or a combination of several of this compounds are: colorectal cancer, breast cancer, small-cell lung cancer, non small-cell lung cancer, liver cancer (primary and secondary), renal cancer, melanoma, ovarian cancer, cancer of the brain, head and neck cancer, pancreatic cancer, gastric cancer, eosophageal cancer, prostate cancer and leukemias and lymphomas.

Below are listed some examples of where these mutations may result in gene products that result in development of tumours:

Development of colorectal cancers are believed to result from a series of genetic alterations. Deleted in colorectal cancer (DCC) gene (seq id nos 30-34), Human cysteine protease (ICErel-III) gene (seq id nos 394-398 and 459), Human putative mismatch repair/binding protein (hMSH3) gene (Seq id nos 134-147), Human hMSH6 gene (seq id nos 200-203 and 293-297), Human n-myc gene (seq id nos 189-194), Human TGFβ2 (hTGFβ2) gene (seq id nos 22-29), Human p53 associated gene (seq id nos 285-292) may be involved in colorectal cancer.

Human breast cancer susceptibility (BRCA2) (seq id nos 35-94) and Human BRCA1-associated RING domain protein (BARD1) gene (seq id nos 404-417) are involved in breast cancer and ovarian cancer Human hMSH6 gene (seq id nos 200-203 and 293-297) may be involved in brain tumours.

Gene alteration are frequent in many types of adenocarcinomas, below are listed some genes that are mutated in many cancers:

Human breast cancer susceptibility (BRCA2) gene (seq id nos 35-94), Deleted in colorectal cancer (DCC) gene (seq id nos 30-34), Human putatative mismatch repair/binding protein (hMSH3) gene (seq id nos 134-147), Human hMSH6 gene (seq id nos 200-203 and 293-297), human N-MYC gene (seq id no 189-194), Human TGFb2 (hTGFb2) gene (seq id nos 22-29), Human p53 associated gene (seq id nos 285-292), Human MUC1 gene (seq id nos 247-266), Human germline n-myc gene (seq id nos 182-188), Human Wilm's tumour (WIT-1) associated protein (seq id nos 388-393), Human nasopharynx carcinoma EBV BNLF-1 gene (seq id nos 204-210), Human transforming growth factor-beta induced gene product (BIGH3) seq id nos 227-232).

Many of the mutated genes may result in development of leukemias and lymphomas: Human neurofibromin (NF1) gene (seq id nos 176-181), b-raf oncogene (seq id nos 170-175), Human protein-tyrosine kinase (JAK1) gene (seq id nos 267-271), Human protein-tyrosine kinase (JAK3) gene (seq id nos 272-279) are examples.

Genes involved in malignant melanoma: Human malignant melanoma (metastasis-supressor (hKiSS-1) gene (seq id nos 328-334), Genes involved in metastasis: Human metastasis-associated mta1 (hMTA1) gene (seq id nos 357-362).

Cell cycle control and signal transduction is strikcly regulated. Frameshift mutations in these genes may result in uncontrolled cell growth. Examples of genes which may be suseptable are: Human protein tyrosine phosphatase (hPTP) gene (seq id nos 95-102), Human kinase (TTK) gene (seq id nos 109-120), Human transcriptional repressor (CTCF) gene (seq id nos 121-127), Human cell cycle regulatory protein (E1A-binding protein) p300 gene (seq id nos 211-218), Human transforming growth factor-beta induced gene product (BIGH3) (seq id nos 227-232), Human FLt4 gene (for transmembrane tyrosinase kinase (seq id nos 280-284), Human G protein-coupled receptor (hGPR1) gene (seq id nos 314-319), Human transcription factor (hITF-2) gene (seq id nos 326-327), Human telomerase-associated protein TP-1 (hTP-1) gene (seq id nos 335-348), Human transcription TFIIB 90 kDa subunit (hTFBIIB90) gene (seq id nos 363-369), Human FADD-homologous ICE/CED-3like protease gene (seq id nos

128-133)

Mutations in DNA synthesis or -repair enzymes may also lead to uncontrolled cell growth. Human DNA topoisomerase II (top2) gene (seq id nos 103-108) and Human putative mismatch repair/binding protein (hMSH3) gene (seq id nos 134-1471 and (hMSH6) gene (seq id nos 200-203 and 293-297).

The following are tumour suppressor genes, Human retinoblastoma binding protein 1 isoform I (hRBP1) gene (seq id nos 148-156), Human neurofibromin (NF1) gene (seq id nos 176-181), Human p53 associated gene (seq id nos 285-292), Human retinoblastoma related protein (p107) gene (seq id nos 310-313), Human tumour suppressor (hLUCA-1) gene (seq id nos 370-377), Mutations in these genes may result in development of cancer.

The following are oncogenes, proto-oncogenes or putative oncogenes; Human germline n-myc gene (seq id nos 182-188), Human n-myc gene (seq id nos 189-194), Human can (hCAN) gene (seq id nos 298-300), Human dek (hDEK) gene (seq id nos 307-309), b-raf oncogene (seq id nos 170-175), Human DBL (hDBL) proto-cogene/Human MCF2PO (hMCF2PO) gene (seq id nos 301-306). Frameshift mutations in these genes may lead to development of cancer.

BIOLOGICAL EXPERIMENTS

DESCRIPTION OF THE FIGURES

FIG.

1

:

It has been demonstrated that T cells from normal donors can be stimulated with a mixture of peptides containing both mutant BAX and mutant TGFβRII peptides. Peptide mixture dependent T cell proliferation in blood samples from six different donors are shown in FIG.

1

. The results were obtained by stimulating peripheral blood mononuclear cells (PBMCs) from each donor with a mixture of mutant BAX peptides (seq id nos 1,9-12) and mutant TGFβRII peptides (seq id nos 15-21). The concentration of each individual peptide in the mixture was 20 μM. After two weeks, and weekly thereafter, the bulk cultures were restimulated with autologous PBMCs pulsed with 10-25 μM of the peptide mixture. After 4-5 restimulations the bulk cultures were tested in a standard proliferation assay with PBMCs alone or as a control or PBMCs pulsed with 25 μM of the peptides as antigen presenting cells (APCs)

FIG.

2

:

It has further been found that T cell clones can be generated against separate peptides of the mixture used in the bulk stimulation experiments.

FIG. 2

shows the proliferation of T cell clone 521-2 which was obtained by cloning the bulk culture from donor 1 (

FIG. 1

) by seeding 5 cells per well in U-bottomed, 96-well microtiter plates and using autologous PBMCs pulsed with 25 μM of the mutant BAX peptide with seq id no 12 as feeder cells. Autologous B-lymphoblastoid cells were used as APCs in the proliferation assay.

FIG.

3

:

In figure three it is shown that mutant BAX peptides and mutant TGFβRII peptides can be used to stimulate T cells (PBMCs) from a patient with breast cancer. Dendritic cells (DCs) from the same cancer patient were used as APCs. The T cell stimulation (

FIG. 3

) was obtained by pulsing DCs separately with a mixture of mutant BAX peptides (seq id nos 1,9-12) and a mixture of mutant TGFβRII peptides (seq id nos 15-21) followed by addition of autologous PBMCs and 10 ng/ml tumour necrosis factor. The concentration of each peptide in the mixtures used for pulsing was 25 μM. The PBMCs and the DCs were obtained by leukapheresis from a patient with breast cancer who had been on a granulocyte colony stimulating factor (G-CSF) treatment. The CD34+ cells were isolated from the cell product before DCs were derived using standard methods.

FIG.

4

:

FIG. 4

shows the capability of T cells obtained from ascites fluid of a pancreatic cancer patient to recognise and proliferate to different synthetic peptides derived from mutant BAX (seq id nos 1,9-12) and mutant TGFβRII (seq id nos 15,17-21). The T cell line was obtained after expansion of T cells present in the ascites fluid of a patient with pancreatic adenocarcinoma. The T cell line was expanded in vitro by culturing with 100 U/ml recombinant interleukin-2 (rIL-2) (Amersham, Aylesbury, UK) for one week before being tested in a proliferation assay.

Autologous, irradiated (30 Gy) PBMCs were seeded 5×104 in u-bottomed 96-well plates (Costar, Cambridge, Mass.) and pulsed with single synthetic peptides at 20 μM for 2 h. The T cells were added 5×104 per well and the plates were incubated for four days at 37° C. with addition of 18.5×104 Bq/mL 3H-thymidine for the last 12 hours before harvesting. The plates were counted in a liquid scintillation counter (Packard Topcount). Data represent specific proliferation to the different synthetic peptides and values are expressed as the mean of triplicate cultures. These results show that T cells isolated from a pancreatic cancer patient are capable of responding to a panel of peptides carrying amino acid sequences derived from mutant BAX and TGFβRII.

FIG.

5

:

FIG. 5

further demonstrates the capability T cells from another pancreatic cancer patient to recognise and proliferate to different synthetic peptides derived from mutant BAX and mutant TGFβRII. The T cell line was obtained after expansion of T cells present in the ascites fluid of a patient with pancreatic adencarcinoma. The experiment was set up in the same way as described above. Data represent specific proliferation to the different synthetic peptides and values are expressed as the mean of triplicate cultures.

In order to investigate the T cell response from the latter pancreatic cancer patient, responding T cells were cloned. Peritoneal macrophages were irradiated (30 Gy) and plated 1×104 into U-bottomed 96-well plates (Costar) together with 25 μM of each peptide. T cell blasts were counted in a microscope and added 5 blasts per well together with 100 U/ml human recombinant interleukin-2 (rIL-2) (Amersham, Aylesbury, UK) in a total volume of 200 mL. After 14 days T cell clones were transferred onto 24-well plates (Costar) with 1 mg/mL phytohemagglutinin (PHA, Wellcome, Dartford, UK), 100 U/ml rIL-2 and allogeneic, irradiated PBMCs as feeder cells and screened for peptide specificity after 7 and 14 days.

FIG.

6

:

T cell clone 520.5, 520.7 and 520.8 were selected for further characterisation and express the cell surface phenotype CD3+, CD8+ and TcR+.

FIG. 6

shows the recognition and cytotoxicity of T cell clone 520.5, 520.7 and 520.8 against peptide-pulsed autologous target cells pulsed with the seq id no 10 peptide. Autologous Epstein-barr virus transformed B-cells (EBV) were labelled with 3H-thymidine (9.25×104 Bq/ml) over night, washed once and plated 2500 cells per well in 96-well plates with or without 25 mM of synthetic peptide (seq id no 10) and 1% DMSO in medium. After 30 minutes incubation at 37° C. the plates were washed before addition of T cells. The plates were further incubated at 37° C. for 4 hours and then harvested before counting in a liquid scintillation counter (Packard Topcount). Data represent percent specific lysis of 3H-thymidine labelled peptide pulsed target cells at an effector/target ratio of 10/1. Values are expressed as the mean of triplicate cultures. These results demonstrate that the three different T cell clones obtained from ascites fluid of a pancreatic carcinoma patient, exhibit specific cytotoxicity of autologous EBV targets pulsed with the relevant peptide (seq id no 10) derived from mutant BAX.

FIG.

7

:

FIG. 7

shows the cytolytic properties of three different T cell clones obtained from the same patient. These T cell clones were cultured and expanded as described above, but they were generated against a synthetic peptide the seq id no 17 peptide carrying amino acid sequences derived from mutant TGFβRII. T cell clone 538.1, 538.3 and 538.4 all show the cell-surface phenotype CD3+, CD8+ and TcR+. The experimental conditions were as described above (FIG.

6

). Data represent percent specific lysis of 3H-thymidine labelled peptide pulsed target cells pulsed with the seq id no 428 peptide at an effector/target ratio of 10/1. Values are expressed as the mean of triplicate cultures. These results demonstrate that the three different T cell clones obtained from ascites fluid of a pancreatic carcinoma patient, exhibit specific cytotoxicity of autologous EBV targets pulsed with the relevant peptide (seq id no 428) derived from mutant TGFβRII.

FIG.

8

:

FIG. 8

shows the specificity of two CD4+ T cell clones, IMT8 and IMT9, obtained from a tumour biopsy taken from a patient with an adenocarcinoma localised to the proximal colon. Immunohistochemistry revealed that the patient had an abundant infiltrate of predominantly CD4+ T cells, many of which carried activation markers. In areas of CD4 T cell infiltration islands of HLA DR positive tumour cells were observed. The T cell clones were obtained from the component of tumour infiltrating lymphocytes which grew out of the biopsy following culture in medium containing 15 U/ml of recombinant human IL-2 for 16 days. The T cells from this culture were cloned by limiting dilution (1 cells/well) in Terasaki plates with irradiated peptide pulsed APC and 100 U/ml of IL-2. Pulsing of autologous APC was performed with a mixture of the TGFβRII frameshift peptides with sequence identity no. 15, 17 and 18 at 1 μg/ml of each peptide in the presence of 3 μg/ml of purified human β2 microglobulin and 10 ng/ml of recombinant human TNFα for 3 hrs at 37° C. Of the 14 clones that could be expanded preliminary tests showed that two of the clones were reactive with the peptide mixture used for cloning. After expansion the clones were screened for reactivity with the single peptides in a standard proliferative assay. The results show that IMT8 and IMT9 both react specifically with the TGFβRII frameshift peptide with seq. id. no. 17, no reactivity was observed with the two other frameshift peptides tested.

The figure (

FIG. 8

) depicts the results of conventional T cell proliferative assays, where cloned T cells (5×10

4

) and irradiated APC (5×10

4

) were cocultured for 3 days in triplicates before harvesting. To measure the proliferative capacity of the cultures,

3

H-thymidine (3, 7×10

4

Bq/well) was added to the culture overnight before harvesting) Values are given as mean counts per minute (cpm) of the triplicates.

FIG.

9

:

FIG. 9

demonstrates that the specific reactivity of the two T cell clones IMT8 and IMT9 against the peptide with seq. id.no. 17 is completely blocked by treatment of the cells with an antibody that specifically binds to HLA-DR molecules, since the reactivity after blocking is the same as the background reactivity of the clones with APC in the absence of the peptide. On the other hand antibodies to the HLA class II isotypes HLA-DQ and -DP failed to block the reactivity of the clones with peptide pulsed APC. This experiment unequivocally identifies HLA-DR as the molecule responsible to present the peptide to these two T cell clones. Antibody blocking experiments were performed using the homozygous EBV transformed cell line 9061 (IHWS9 nomenclature) as APC. The APC were pulsed with peptide at a concentration of 15 μg/ml for 1 hr at 37° C. before addition of blocking antibodies L243 (pan-DR antibody), SPVL3 (pan-DQ antibody) and B7.21 (pan-DP antibody) at 10 μg/ml. Unpulsed APC and APC pulsed with peptide in the absence of blocking antibody served as negative and positive controls respectively. Results are expressed as in FIG.

8

.

FIG.

10

:

The patient IMT was HLA typed and turned out to be HLA: A1,2; B7,8; DR3,14; DQ1,2. To determine which of the HLA-DR molecules that were responsible for presentation of the peptide with seq. id. no. 17, a panel of HLA workshop derived homozygous BCL cell lines were obtained and pulsed with the peptide with seq. id. no. 17.

FIG. 10

describes the identification of HLA-DR14 (DRA*0102, DRB*1401) as the HLA-DR molecule responsible for presentation of the peptide with seq. id. no. 17 to the T cell clones IMT8 and IMT9. A specific proliferative response was observed when peptide was presented by the autologous EBV transformed cell line (Auto APC) and by cell lines 9054 (EK) and 9061 (31227ABO), both of which expressed DR14 as the only DR molecule on their surface. The homozygous cell line gave higher responses, reflecting a higher level of expression of the relevant class II/peptide complexes due to the effect of a double dose of the genes encoding this DR molecule. No response was obtained when the peptide was presented by cell lines expressing HLA-DR3 (9018, LOO81785), which represents the other DR molecule expressed by the patients APC, nor by irrelevant HLA-DR molecules. The experiment was performed as described in

FIG. 9

, with the exception that no antibody blocking was performed. Results are expressed as in FIG.

8

.

FIG.

11

:

FIG. 11

describes the dose response curves obtained by pulsing the cell line 9054 with increasing concentrations of the peptide with seq. id. no. 17. Both IMT 8 and IMT9 demonstrate a dose dependent increase in the proliferative response to the peptide. Results were performed as described in

FIG. 9 and 10

with the peptide concentrations indicated on the Figure (FIG.

11

). Results are expressed as in FIG.

8

.

FIG.

12

:

FIG. 12

describes the reactivity of a cell line generated by in vitro stimulation of T cells isolated from peripheral blood from a healthy blood donor (Donor 2892) by weekly stimulation with irradiated autologous dendritic cells pulsed with the peptides with sequence identity numbers 16, 17 and 21. A specific response above background values was obtained when the T cells were co-incubated with autologous dendritic cells pulsed with the peptide with seq. id. no. 21. No activity could be detected in the culture after the first and second in vitro stimulation. These data demonstrate that the T cell repertoire of normal individuals contain a few precursor cells that have the capacity to recognise this frameshift peptide derived from a mutation in TGFβRII that does not occur in normal people. In two other blood donors (#2706 and #2896), the level of precursor cells with the relevant specificity was too low to be detected. The results are expressed as spots per 10

4

T cells tested in a conventional IFNg ELISPOT assay. This assay enumerates the number of cells present in a mixture of cells that are capable of specifically reacting with a defined antigen. Briefly 10

7

T cells (non adherent cells) were stimulated weekly with 2-5×10

6

irradiated peptide pulsed autologous dendritic cells (DC) as APC. The DC were generated from the adherent cell population by culture for one week in recombinant human GM-CSF and IL-4 according to standard protocols as described in the literature. After peptide pulsing overnight at 15 μg/ml of peptide, full maturation of the DC was obtained by culture with recombinant TNFα. ELISPOT was performed according to standard published protocols using 10

4

cultured T cells per well in duplicate and 10

4

peptide pulsed or unpulsed DC as APC. The results are expressed as mean number of spots per 10

4

T cells.

FIG.

13

:

FIG. 13

shows the results of in vitro stimulation of T cells from a healthy blood donor (Donor 322) with peptides with sequence identity number 15-21. In vitro culture was performed as described in

FIG. 12. A

proliferative response above background values was seen when the T cell culture primed with a mixture of the peptides with seq. id. no. 16 and 21 was stimulated with peptide 21 and the culture primed with the peptide with seq. id. no. 17 was stimulated with the same peptide. These results demonstrate that normal blood donors have small numbers of circulating T cells specific for these frameshift peptides, and that it is possible to expand these cells in culture by stimulation with frameshift peptides. These results also confirmed the results shown in FIGS. 8-11, demonstrating that the peptide with seq. id. no. 17 is immunogenic in humans, and indicate that the peptide with seq. id. no. 21 may also be used as a cancer vaccine in humans. The results are expressed as described in FIG.

8

.

FIG.

14

:

The results shown in

FIG. 14

demonstrate that CD8+ T cells specific for HLA class I epitopes can be generated from T cells present in the T cell repertoire of a healthy blood donor (donor 905). No reactivity above background was seen with any of the peptides after the second round of in vitro restimulation. After the fourth restimulation, the frequency of T cells specific for the peptide with seq. id. no. 428 had increased from undetectable levels to approximately 2,5% of the cells. These results demonstrate that CTL precursors of the CD8+ phenotype are present in the unprimed T cell repertoire of healthy blood donors. Such T cells may be expanded in vitro by specific stimulation with the peptide with seq. id. no. 428. This forms the basis for using this peptide as a cancer vaccine to elicit cytotoxic T cells specific for frameshift peptides in cancer patient having such mutations. T cells were generated by weekly restimulation of T cells isolated from peripheral blood and stimulated with peptide pulsed autologous DC as described in

FIG. 12

, with the exception that Il-7 and Il-2 was added during culture according to standard procedures for generating cytotoxic T cells (CTL) of the CD8 phenotype. The peptides used were peptides with sequence identity number 428, 439, 446 and 451. Cells were tested in ELISPOT assay as described in FIG.

12

. The results are expressed as described in FIG.

12

.

The peptide with seq. id. no. 17 was selected and designed to contain binding motifs for both several HLA class I and HLA class II molecules. These peptides thus contains epitopes both for CD4+ and CD8+ T cells, and was predicted to elicit both CD4 and CD8 T cell responses in cancer patient provided processing of the aberrant TGFβRII protein naturally occurring in cancer cells would take place and result in an overlapping peptide. This has now been proven for CD4 T cells by the results in

FIGS. 8-11

. These results have the following implication:

1) The results in

FIG. 8

prove that the mutated form of TGFβRII Receptor which occurs in a high proportion of cancer patients with defects in their mismatch repair machinery is a tumour specific antigen.

2) The antigen specificity of the infiltrating T cells commonly observed in colorectal cancer are generally not known. The results in

FIG. 8

demonstrate that one component of the T cells constituting the population of tumour infiltrating lymphocytes in this patients tumour is specific for a frameshift mutation, demonstrating that TGFβRII frameshift peptides are immunogenic in vivo, occasionally giving rise to spontaneous T cell activation.

3) It follows from this observation that processing of the non-functional form of the TGFβRII Receptor that is formed by the common frameshift mutation is processed. This processing may take place either in the tumour cell as part of natural breakdown of the aberrant protein, or after the tumour cell itself or a released form of the receptor has been taken up by a professional APC or both.

4) The results in

FIG. 8

also indicate that the peptide with seq. id. no. 17 is capable of binding to an HLA class II molecule, since pulsing of APC with this peptide results in a specific proliferative response against the peptide, and since CD4 T cell responses always are class II restricted. That this is the case is demonstrated by the results of the experiment shown in FIG.

9

. Here it is shown that the specific response against the peptide with seq. id. no. 17 is completely blocked by an antibody to HLA-DR, but not with antibodies to the two other HLA class II molecules, HLA-DQ and -DP. Furthermore, by using a panel of standard homozygous Epstein Barr Virus (EBV) transformed B Cell Lines (BCL) covering the relevant HLA class II molecules present on the patients own APC, we were able to identify the class II molecule responsible for presentation of the peptide with seq. id. no. 17 to TLC IMT8 and IMT9 as being HLA-DR 14. Together these findings fit extremely well with the immunohistological observations made in parallel sections taken from the same tumour biopsy, where we could show that activated CD4+ T cells were abundant in the proximity of tumour cells that had been induced to express HLA-DR. molecules. The results in

FIG. 11

demonstrate that these T cell clones are capable of mounting a proliferative response over a range of peptide doses and that the responses are dose dependent.

5) Since these T cell clones were obtained by cloning T cells isolated from a tumour biopsy, another implication of our finding is that activated T cells specific for the peptide with seq. id. no. 17 are capable of homing to the tumour tissue after activation.

6) Since the peptide with seq. id. no. 17 is a tumour specific antigen, and since frameshift mutations giving rise to this peptide or peptides with overlapping sequences are commonly found in cancers with defects in enzymes that are part of the mismatch repair machinery, this peptide may be used as a vaccine to elicit T cell response in cancer patients or patients at high risk for developing cancer. Such T cell responses may potentially influence the growth of an existing tumour or prohibit regrowth of tumour after surgery and other forms of treatment or be given to patients with an inheritable form of cancer where a defect mismatch enzyme is detected or suspected and that have a high chance of developing a cancer where this precise mismatch repair mutation will occur.

SYNTHESIS

The peptides were synthesised by using continuous flow solid phase peptide synthesis. N-a-Fmoc-amino acids with appropriate side chain protection were used. The Fmoc-amino acids were activated for coupling as pentafluorophenyl esters or by using either TBTU or diisopropyl carbodiimide activation prior to coupling. 20% piperidine in DMF was used for selective removal of Fmoc after each coupling. Cleavage from the resin and final removal of side chain protection was performed by 95% TFA containing appropriate scavengers. The peptides were purified and analysed by reversed phase (C18) HPLC. The identity of the peptides was confirmed by using electro-spray mass spectroscopy (Finnigan mat SSQ710).

The peptides used for in vitro studies of T cell stimulation were synthesised by this method.

Several other well known methods can be applied by a person skilled in the art to synthesise the peptides.

Examples of the Method for Determining New Frameshift Mutation Peptides

In this Example, the BAX gene is used to illustrate the principle.

In each of the steps listed below, the 1st line is the gene sequence and 2nd line is amino acid sequence.

In the steps 2-5, the outlined sequences represent the mutant part of the protein.

In the next Example, the TGFβRII gene is used to illustrate the principle.

In each of the steps listed below, the 1st line is the gene sequence and 2nd line is amino acid sequence. In the steps 2-5, the outlined sequences represent the mutant part of the protein.

Thus the peptides of the invention may be used in a method for the treatment of cancers with cancer cells harbouring genes with frameshift mutations, which treatment comprises administering at least one peptide of the present invention in vivo or ex vivo to a human patient in need of such treatment.

In another embodiment the peptides of the invention may be used to vaccinate a human being disposed for cancers with cancer cells harbouring genes with frameshift mutations, by administering at least one peptide of the present invention to said human being.

It is further considered to be an advantage to administer to a human individual a mixture of the peptides of this invention, whereby each of the peptides of the invention can bind to different types of HLA class I and/or class II molecules of the individual.

It is further anticipated that the power of an anticancer vaccine or peptide drug as disclosed in the above mentioned PCT/NO92/00032 application, can be greatly enhanced if the peptides of the present invention were included. Thus in another embodiment of the present invention peptides of the present invention are administered together with, either simultaneously or in optional sequence, with the peptides disclosed in PCT/NO92/00032.

It is considered that the peptides may be administered together, either simultaneously or separately, with compounds such as cytokines and/or growth factors, i.e. interleukin-2 (IL-2), interleukin-12 (IL-12), granulocyte macrophage colony stimulating factor (GM-CSF), Flt-3 ligand or the like in order to strengthen the immune response as known in the art.

The peptides according to the present invention can be used in a vaccine or a therapeutical composition either alone or in combination with other materials, such as for instance standard adjuvants or in the form of a lipopeptide conjugate which as known in the art can induce high-affinity cytotoxic T lymphocytes, (K. Deres, Nature, Vol.342, (November 1989)).

The peptides according to the present invention may be useful to include in either a peptide or recombinant fragment based vaccine.

The peptides according to the present invention can be included in pharmaceutical compositions or in vaccines together with usual additives, diluents, stabilisers or the like as known in the art.

According to this invention, a pharmaceutical composition or vaccine may include the peptides alone or in combination with at least one pharmaceutically acceptable carrier or diluent.

Further a vaccine or therapeutical composition can comprise a selection of peptides which are fragments of the mutant proteins arising from insertion or deletion of bases in a repeat sequence of the gene.

Further a vaccine composition can comprise at least one peptide selected for one cancer, which vaccine would be administered to a person carrying a genetic disposition for this particular cancer.

Further a vaccine composition can comprise at least one peptide selected for one cancer, which vaccine would be administered to a person belonging to a high risk group for this particular cancer.

The cancer vaccine according to this invention may further be administered to the population in general for example as a mixture of peptides giving rise to T cell immunity against various common cancers connected with frameshift mutation genes.

The peptides according to this invention may be administered as single peptides or as a mixture of peptides. Alternatively the peptides may be covalently linked with each other to form larger polypeptides or even cyclic polypeptides.

A cancer therapy according to the present invention may be administered both in vivo or ex vivo having as the main goal the raising of specific T cell lines or clones against the mutant gene product associated with the cancer type with which the patient is afflicted.

Further, the frameshift mutant peptides of this invention may be administered to a patient by various routes including but not limited to subcutaneous, intramuscular, intradermal, intraperitoneal, intravenous or the like. In one embodiment the peptides of this invention are administered intradermally. The peptides may be administered at single or multiple injection sites to a patient in a therapeutically or prophylactically effective amount.

The peptides of this invention may be administered only once or alternatively several times, for instance once a week over a period of 1-2 months with a repeated sequence later all according to the need of the patient being treated.

The peptides of this invention can be administered in an amount in the range of 1 microgram (1 μg) to 1 gram (1 g) to an average human patient or individual to be vaccinated. It is preferred to use a smaller dose in the rage of 1 microgram (1 μg) to 1 milligram (1 mg) for each administration.

The invention further encompasses DNA sequences which encodes a frameshift mutation peptide.

The invention additionally encompasses isolated DNA sequences comprising a DNA sequence encoding at least one frameshift mutant peptide, and administration of such isolated DNA sequences as a vaccine for treatment or prophylaxis of cancers associated with frameshift mutations in the genes.

The peptides according to this invention may be administered to an individual in the form of DNA vaccines. The DNA encoding these peptides may be in the form of cloned plasmid DNA or synthetic oligonucleotide. The DNA may be delivered together with cytokines, such as IL-2, and/or other co-stimulatory molecules. The cytokines and/or co-stimulatory molecules may themselves be delivered in the form of plasmid or oligonucleotide DNA. The response to a DNA vaccine has been shown to be increased by the presence of immunostimulatory DNA sequences (ISS). These can take the form of hexameric motifs containing methylated CpG, according to the formula:

5′-purine-purine-CG-pyrimidine-pyrimidine-3′. Our DNA vaccines may therefore incorporate these or other ISS, in the DNA encoding the peptides, in the DNA encoding the cytokine or other co-stimulatory molecules, or in both. A review of the advantages of DNA vaccination is provided by Tighe et al (1998

, Immunology Today

, 19(2), 89-97).

In one embodiment, the DNA sequence encoding the mutant BAX peptides comprises:

Normal BAX.

AT

G GGG GGG G

AG GCA CCC GAG CTG GCC CTG GAC CCG GTG . . . .

1G deleted from BAX gene sequence.

ATG GGG GGG

AGG

CAC CCG AGC TGG CCC TGG ACC CGG TGC CTC AGG ATG CGT CCA CCA AGA AGC

TGA

2G deleted from BAX gene sequence.

ATG GGG

GGA

GGC ACC CGA GCT GGC CCT GGA CCC GGT GCC TCA GGA TGC GTC CAC CAA GAA GCT GAG CGA GTG TCT CAA GCG CAT CGG GGA CGA ACT GGA CAG

TAA

1G inserted in BAX gene sequence.

ATG GGG GGG

GGA

GGC ACC CGA GCT GGC CCT GGA CCC GGT GCC TCA GGA TGC GTC CAC CAA GAA GCT GAG CGA GTG TCT CAA GCG CAT CGG GAA CGA ACT GGA CAG

TAA

2G inserted in BAX gene sequence.

ATG GGG GGG GGG

AGG

CAC CCG AGC TGG CCC TGG ACC CGG TGC CTC AGG ATG CGT CCA CCA AGA AGC

TGA

In a second embodiment, the DNA sequence encoding the mutant TGFβRII peptides comprises:

Normal TGFβRII gene.

G

AA AAA AAA AA

G CCT GGT GAG ACT TTC TTC ATG TGT TCC . . . .

1A deleted from TGFβRII gene sequence.

G

AA AAA AAA A

GC CTG GTG AGA CTT TCT TCA TGT GTT CCT GTA GCT CTG ATG AGT GCA ATG ACA ACA TCA TCT TCT CAG AAG AAT ATA ACA CCA GCA ATC CTG ACT TGT TGC

TAG

2A deleted from TGFβRII gene sequence.

G

AA AAA AAA

GCC TGG

TGA

1A inserted in TGFβRII gene sequence.

G

AA AAA AAA AAA

GCC TGG

TGA

2A inserted in TGFβRII gene sequence.

G

AA AAA AAA AAA A

GC CTG GTG AGA CTT TCT TCA TGT GTT CCT GTA GCT CTG ATG AGT GCA ATG ACA ACA TCA TCT TCT CAG AAG AAT ATA ACA CCA GCA ATC CTG ACT TGT TGC

TAG

The invention further encompasses vectors and plasmids comprising a DNA sequence encoding a frameshift mutant peptide. The vectors include, but are not limited to

E. Coli

plasmid, a Listeria vector and recombinant viral vectors. Recombinant viral vectors include, but are not limited to orthopox virus, canary virus, capripox virus, suipox virus, vaccinia, baculovirus, human adenovirus, SV40, bovine papilloma virus and the like comprising the DNA sequence encoding a frameshift mutant peptide.

It is considered that an anticancer treatment or prophylaxis may be achieved also through the administration of an effective amount of a recombinant virus vector or plasmid comprising at least one insertion site containing a DNA sequence encoding a frameshift mutant peptide to a patient, whereby the patient's antigen presenting cells are turned into host cells for the vector/plasmid and presentation of HLA/frameshift mutation peptide complex is achieved.

A person skilled in the art will find other possible use combinations with the peptides of this invention, and these are meant to be encompassed by the present claim.

The peptides according to this invention may be produced by conventional processes as known in the art, such as chemical peptide synthesis, recombinant DNA technology or protease cleavage of a protein or peptide encoded by a frameshift mutated gene. One method for chemical synthesis is elucidated in the description below.

In order for a cancer vaccine and methods for specific cancer therapy based on specific T cell immunity to be effective, three conditions must be met:

1. The peptides used must correspond, either in their full length or after processing by antigen presenting cells, to the processed mutant protein fragment as presented by a HLA Class I and/or class II molecule on the cancer cell or other antigen presenting cells,

2. The peptides used must be bound to a HLA Class I and/or Class II molecule in an immunogenic form, and

3. T-cells capable of recognising and responding to the HLA/peptide complex must be present in the circulation of the human being.

It has been established that all these conditions are met for some representative peptides according to the present invention. The peptides according to the present invention give rise to specific T cell immune responses in vitro. It has been established that the peptides according to this invention correspond to processed mutant protein fragments. This is exemplified with peptides corresponding to fragments of transformed mutant BAX and TGFβRII peptides.

Through the present invention the following advantages are achieved:

It offers a possibility to treat patients suffering from cancers arising from frame-shift mutations in their genes, most of which cancers known at present do not have any good treatment alternatives.

It offers a possibility to vaccinate prophylaxtically humans carrying genetic dispositions or belonging to other high risk groups.

It offers a possibility to prepare a combination treatment for a specific cancer, such as for instance colorectal or pancreatic cancers, wherein the cancer commonly is associated with either a frameshift mutation or a point mutation in the genes.

Since described frameshift mutations occurs in a large variety of cancers it will be possible to use this peptides in combination with established vaccines and future vaccines to obtain a multiple targetting treatment.

Likewise patients suffering from cancers associated with multiple frameshift mutations in genes can be treated more efficiently through a combination treatment.

459

1

18

PRT

Homo sapiens

1
Arg His Pro Ser Trp Pro Trp Thr Arg Cys Leu Arg Met Arg Pro Pro
1 5 10 15
Arg Ser

2

31

PRT

Homo sapiens

2
Gly Thr Arg Ala Gly Pro Gly Pro Gly Ala Ser Gly Cys Val His Gln
1 5 10 15
Glu Ala Glu Arg Val Ser Gln Ala His Arg Gly Arg Thr Gly Gln
20 25 30

3

32

PRT

Homo sapiens

3
Gly Gly Thr Arg Ala Gly Pro Gly Pro Gly Ala Ser Gly Cys Val His
1 5 10 15
Gln Glu Ala Glu Arg Val Ser Gln Ala His Arg Gly Arg Thr Gly Gln
20 25 30

4

19

PRT

Homo sapiens

4
Gly Arg His Pro Ser Trp Pro Trp Thr Arg Cys Leu Arg Met Arg Pro
1 5 10 15
Pro Arg Ser

5

28

PRT

Homo sapiens

5
Ile Gln Asp Arg Ala Gly Arg Met Gly Gly Arg His Pro Ser Trp Pro
1 5 10 15
Trp Thr Arg Cys Leu Arg Met Arg Pro Pro Arg Ser
20 25

6

19

PRT

Homo sapiens

6
Ile Gln Asp Arg Ala Gly Arg Met Gly Gly Gly Arg His Pro Ser Trp
1 5 10 15
Pro Trp Thr

7

42

PRT

Homo sapiens

7
Ile Gln Asp Arg Ala Gly Arg Met Gly Gly Gly Gly Thr Arg Ala Gly
1 5 10 15
Pro Gly Pro Gly Ala Ser Gly Cys Val His Gln Glu Ala Glu Arg Val
20 25 30
Ser Gln Ala His Arg Gly Arg Thr Gly Gln
35 40

8

19

PRT

Homo sapiens

8
Ile Gln Asp Arg Ala Gly Arg Met Gly Gly Gly Thr Arg Ala Gly Pro
1 5 10 15
Gly Pro Gly

9

22

PRT

Homo sapiens

9
Ile Gln Asp Arg Ala Gly Arg Met Gly Gly Arg His Pro Ser Trp Pro
1 5 10 15
Trp Thr Arg Cys Leu Arg
20

10

22

PRT

Homo sapiens

10
Ala Ser Gly Cys Val His Gln Glu Ala Glu Arg Val Ser Gln Ala His
1 5 10 15
Arg Gly Arg Thr Gly Gln
20

11

22

PRT

Homo sapiens

11
Gly Gly Thr Arg Ala Gly Pro Gly Pro Gly Ala Ser Gly Cys Val His
1 5 10 15
Gln Glu Ala Glu Arg Val
20

12

22

PRT

Homo sapiens

12
Ile Gln Asp Arg Ala Gly Arg Met Gly Gly Gly Gly Thr Arg Ala Gly
1 5 10 15
Pro Gly Pro Gly Ala Ser
20

13

34

PRT

Homo sapiens

13
Ser Leu Val Arg Leu Ser Ser Cys Val Pro Val Ala Leu Met Ser Ala
1 5 10 15
Met Thr Thr Ser Ser Ser Gln Lys Asn Ile Thr Pro Ala Ile Leu Thr
20 25 30
Cys Cys

14

44

PRT

Homo sapiens

14
Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Ser Leu Val Arg Leu Ser
1 5 10 15
Ser Cys Val Pro Val Ala Leu Met Ser Ala Met Thr Thr Ser Ser Ser
20 25 30
Gln Lys Asn Ile Thr Pro Ala Ile Leu Thr Cys Cys
35 40

15

19

PRT

Homo sapiens

15
Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Ser Leu Val Arg Leu Ser
1 5 10 15
Ser Cys Val

16

23

PRT

Homo sapiens

16
Ala Leu Met Ser Ala Met Thr Thr Ser Ser Ser Gln Lys Asn Ile Thr
1 5 10 15
Pro Ala Ile Leu Thr Cys Cys
20

17

23

PRT

Homo sapiens

17
Ser Leu Val Arg Leu Ser Ser Cys Val Pro Val Ala Leu Met Ser Ala
1 5 10 15
Met Thr Thr Ser Ser Ser Gln
20

18

22

PRT

Homo sapiens

18
Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Ser Leu Val Arg Leu Ser
1 5 10 15
Ser Cys Val Pro Val Ala
20

19

12

PRT

Homo sapiens

19
Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Ala Trp
1 5 10

20

12

PRT

Homo sapiens

20
Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Ala Trp
1 5 10

21

19

PRT

Homo sapiens

21
Ala Met Thr Thr Ser Ser Ser Gln Lys Asn Ile Thr Pro Ala Ile Leu
1 5 10 15
Thr Cys Cys

22

9

PRT

Homo sapiens

22
Thr Val Gly Arg Pro His Ile Ser Cys
1 5

23

10

PRT

Homo sapiens

23
Lys Thr Val Gly Arg Pro His Ile Ser Cys
1 5 10

24

18

PRT

Homo sapiens

24
Lys Gln Trp Glu Asp Pro Thr Ser Pro Ala Asn Val Ile Ala Leu Leu
1 5 10 15
Gln Thr

25

17

PRT

Homo sapiens

25
Gln Trp Glu Asp Pro Thr Ser Pro Ala Asn Val Ile Ala Leu Leu Gln
1 5 10 15
Thr

26

19

PRT

Homo sapiens

26
Gln Lys Thr Ile Lys Ser Thr Arg Lys Lys Thr Val Gly Arg Pro His
1 5 10 15
Ile Ser Cys

27

20

PRT

Homo sapiens

27
Gln Lys Thr Ile Lys Ser Thr Arg Lys Lys Lys Thr Val Gly Arg Pro
1 5 10 15
His Ile Ser Cys
20

28

28

PRT

Homo sapiens

28
Gln Lys Thr Ile Lys Ser Thr Arg Lys Lys Lys Gln Trp Glu Asp Pro
1 5 10 15
Thr Ser Pro Ala Asn Val Ile Ala Leu Leu Gln Thr
20 25

29

27

PRT

Homo sapiens

29
Gln Lys Thr Ile Lys Ser Thr Arg Lys Lys Gln Trp Glu Asp Pro Thr
1 5 10 15
Ser Pro Ala Asn Val Ile Ala Leu Leu Gln Thr
20 25

30

34

PRT

Homo sapiens

30
Ala Ala Asp Leu Gln Gln Gln Phe Val His Phe Leu Asp Cys Trp Asp
1 5 10 15
Val Ser Ser Ile Pro Phe Thr Leu His Leu Pro Gln Ala Gln Asp Ile
20 25 30
Thr Thr

31

9

PRT

Homo sapiens

31
Gly Lys Asp Ala Lys Glu Lys Ser Ser
1 5

32

10

PRT

Homo sapiens

32
Gly Lys Asp Ala Lys Glu Lys Lys Ser Ser
1 5 10

33

42

PRT

Homo sapiens

33
Gly Lys Asp Ala Lys Glu Lys Lys Ala Ala Asp Leu Gln Gln Gln Phe
1 5 10 15
Val His Phe Leu Asp Cys Trp Asp Val Ser Ser Ile Pro Phe Thr Leu
20 25 30
His Leu Pro Gln Ala Gln Asp Ile Thr Thr
35 40

34

41

PRT

Homo sapiens

34
Gly Lys Asp Ala Lys Glu Lys Ala Ala Asp Leu Gln Gln Gln Phe Val
1 5 10 15
His Phe Leu Asp Cys Trp Asp Val Ser Ser Ile Pro Phe Thr Leu His
20 25 30
Leu Pro Gln Ala Gln Asp Ile Thr Thr
35 40

35

16

PRT

Homo sapiens

35
Phe Ser Met Lys Gln Thr Leu Met Asn Val Lys Asn Leu Lys Thr Lys
1 5 10 15

36

17

PRT

Homo sapiens

36
Lys Phe Ser Met Lys Gln Thr Leu Met Asn Val Lys Asn Leu Lys Thr
1 5 10 15
Lys

37

25

PRT

Homo sapiens

37
Val Arg Thr Ser Lys Thr Arg Lys Lys Phe Ser Met Lys Gln Thr Leu
1 5 10 15
Met Asn Val Lys Asn Leu Lys Thr Lys
20 25

38

26

PRT

Homo sapiens

38
Val Arg Thr Ser Lys Thr Arg Lys Lys Lys Phe Ser Met Lys Gln Thr
1 5 10 15
Leu Met Asn Val Lys Asn Leu Lys Thr Lys
20 25

39

12

PRT

Homo sapiens

39
Val Arg Thr Ser Lys Thr Arg Lys Lys Asn Phe Pro
1 5 10

40

11

PRT

Homo sapiens

40
Val Arg Thr Ser Lys Thr Arg Lys Asn Phe Pro
1 5 10

41

10

PRT

Homo sapiens

41
Ile Lys Lys Lys Leu Leu Gln Phe Gln Lys
1 5 10

42

11

PRT

Homo sapiens

42
Lys Ile Lys Lys Lys Leu Leu Gln Phe Gln Lys
1 5 10

43

17

PRT

Homo sapiens

43
Lys Ser Arg Arg Asn Tyr Phe Asn Phe Lys Asn Asn Cys Gln Ser Arg
1 5 10 15
Leu

44

16

PRT

Homo sapiens

44
Ser Arg Arg Asn Tyr Phe Asn Phe Lys Asn Asn Cys Gln Ser Arg Leu
1 5 10 15

45

18

PRT

Homo sapiens

45
Thr Asn Leu Arg Val Ile Gln Lys Ile Lys Lys Lys Leu Leu Gln Phe
1 5 10 15
Gln Lys

46

19

PRT

Homo sapiens

46
Thr Asn Leu Arg Val Ile Gln Lys Lys Ile Lys Lys Lys Leu Leu Gln
1 5 10 15
Phe Gln Lys

47

25

PRT

Homo sapiens

47
Thr Asn Leu Arg Val Ile Gln Lys Lys Ser Arg Arg Asn Tyr Phe Asn
1 5 10 15
Phe Lys Asn Asn Cys Gln Ser Arg Leu
20 25

48

24

PRT

Homo sapiens

48
Thr Asn Leu Arg Val Ile Gln Lys Ser Arg Arg Asn Tyr Phe Asn Phe
1 5 10 15
Lys Asn Asn Cys Gln Ser Arg Leu
20

49

5

PRT

Homo sapiens

49
Lys Ile Met Ile Thr
1 5

50

12

PRT

Homo sapiens

50
Asn Ile Asp Lys Ile Pro Glu Lys Ile Met Ile Thr
1 5 10

51

13

PRT

Homo sapiens

51
Asn Ile Asp Lys Ile Pro Glu Lys Lys Ile Met Ile Thr
1 5 10

52

5

PRT

Homo sapiens

52
Ile Ile Asn Ala Asn
1 5

53

6

PRT

Homo sapiens

53
Lys Ile Ile Asn Ala Asn
1 5

54

13

PRT

Homo sapiens

54
Asn Asp Lys Thr Val Ser Glu Lys Ile Ile Asn Ala Asn
1 5 10

55

14

PRT

Homo sapiens

55
Asn Asp Lys Thr Val Ser Glu Lys Lys Ile Ile Asn Ala Asn
1 5 10

56

14

PRT

Homo sapiens

56
Asn Gly Leu Glu Lys Glu Tyr Leu Met Val Asn Gln Lys Glu
1 5 10

57

23

PRT

Homo sapiens

57
Ser Gln Thr Ser Leu Leu Glu Ala Lys Asn Gly Leu Glu Lys Glu Tyr
1 5 10 15
Leu Met Val Asn Gln Lys Glu
20

58

24

PRT

Homo sapiens

58
Ser Gln Thr Ser Leu Leu Glu Ala Lys Lys Asn Gly Leu Glu Lys Glu
1 5 10 15
Tyr Leu Met Val Asn Gln Lys Glu
20

59

12

PRT

Homo sapiens

59
Ser Gln Thr Ser Leu Leu Glu Ala Lys Lys Met Ala
1 5 10

60

11

PRT

Homo sapiens

60
Ser Gln Thr Ser Leu Leu Glu Ala Lys Met Ala
1 5 10

61

6

PRT

Homo sapiens

61
Thr Leu Val Phe Pro Lys
1 5

62

7

PRT

Homo sapiens

62
Lys Thr Leu Val Phe Pro Lys
1 5

63

14

PRT

Homo sapiens

63
Leu Lys Asn Val Glu Asp Gln Lys Thr Leu Val Phe Pro Lys
1 5 10

64

15

PRT

Homo sapiens

64
Leu Lys Asn Val Glu Asp Gln Lys Lys Thr Leu Val Phe Pro Lys
1 5 10 15

65

10

PRT

Homo sapiens

65
Leu Lys Asn Val Glu Asp Gln Lys Lys His
1 5 10

66

9

PRT

Homo sapiens

66
Leu Lys Asn Val Glu Asp Gln Lys His
1 5

67

6

PRT

Homo sapiens

67
Lys Lys Ile Gln Leu Tyr
1 5

68

7

PRT

Homo sapiens

68
Lys Lys Lys Ile Gln Leu Tyr
1 5

69

36

PRT

Homo sapiens

69
Arg Lys Arg Phe Ser Tyr Thr Glu Tyr Leu Ala Ser Ile Ile Arg Phe
1 5 10 15
Ile Phe Ser Val Asn Arg Arg Lys Glu Ile Gln Asn Leu Ser Ser Cys
20 25 30
Asn Phe Lys Ile
35

70

15

PRT

Homo sapiens

70
Leu Arg Ile Val Ser Tyr Ser Lys Lys Lys Lys Ile Gln Leu Tyr
1 5 10 15

71

16

PRT

Homo sapiens

71
Leu Arg Ile Val Ser Tyr Ser Lys Lys Lys Lys Lys Ile Gln Leu Tyr
1 5 10 15

72

45

PRT

Homo sapiens

72
Leu Arg Ile Val Ser Tyr Ser Lys Lys Arg Lys Arg Phe Ser Tyr Thr
1 5 10 15
Glu Tyr Leu Ala Ser Ile Ile Arg Phe Ile Phe Ser Val Asn Arg Arg
20 25 30
Lys Glu Ile Gln Asn Leu Ser Ser Cys Asn Phe Lys Ile
35 40 45

73

44

PRT

Homo sapiens

73
Leu Arg Ile Val Ser Tyr Ser Lys Arg Lys Arg Phe Ser Tyr Thr Glu
1 5 10 15
Tyr Leu Ala Ser Ile Ile Arg Phe Ile Phe Ser Val Asn Arg Arg Lys
20 25 30
Glu Ile Gln Asn Leu Ser Ser Cys Asn Phe Lys Ile
35 40

74

18

PRT

Homo sapiens

74
Gln Asp Leu Pro Leu Ser Ser Ile Cys Gln Thr Ile Val Thr Ile Tyr
1 5 10 15
Trp Gln

75

19

PRT

Homo sapiens

75
Lys Gln Asp Leu Pro Leu Ser Ser Ile Cys Gln Thr Ile Val Thr Ile
1 5 10 15
Tyr Trp Gln

76

25

PRT

Homo sapiens

76
Asn Arg Thr Cys Pro Phe Arg Leu Phe Val Arg Arg Met Leu Gln Phe
1 5 10 15
Thr Gly Asn Lys Val Leu Asp Arg Pro
20 25

77

27

PRT

Homo sapiens

77
Gly Phe Val Val Ser Val Val Lys Lys Gln Asp Leu Pro Leu Ser Ser
1 5 10 15
Ile Cys Gln Thr Ile Val Thr Ile Tyr Trp Gln
20 25

78

28

PRT

Homo sapiens

78
Gly Phe Val Val Ser Val Val Lys Lys Lys Gln Asp Leu Pro Leu Ser
1 5 10 15
Ser Ile Cys Gln Thr Ile Val Thr Ile Tyr Trp Gln
20 25

79

34

PRT

Homo sapiens

79
Gly Phe Val Val Ser Val Val Lys Lys Asn Arg Thr Cys Pro Phe Arg
1 5 10 15
Leu Phe Val Arg Arg Met Leu Gln Phe Thr Gly Asn Lys Val Leu Asp
20 25 30
Arg Pro

80

33

PRT

Homo sapiens

80
Gly Phe Val Val Ser Val Val Lys Asn Arg Thr Cys Pro Phe Arg Leu
1 5 10 15
Phe Val Arg Arg Met Leu Gln Phe Thr Gly Asn Lys Val Leu Asp Arg
20 25 30
Pro

81

8

PRT

Homo sapiens

81
Tyr Arg Lys Thr Lys Asn Gln Asn
1 5

82

9

PRT

Homo sapiens

82
Lys Tyr Arg Lys Thr Lys Asn Gln Asn
1 5

83

10

PRT

Homo sapiens

83
Asn Thr Glu Arg Pro Lys Ile Arg Thr Asn
1 5 10

84

17

PRT

Homo sapiens

84
Asp Glu Thr Phe Tyr Lys Gly Lys Lys Tyr Arg Lys Thr Lys Asn Gln
1 5 10 15
Asn

85

18

PRT

Homo sapiens

85
Asp Glu Thr Phe Tyr Lys Gly Lys Lys Lys Tyr Arg Lys Thr Lys Asn
1 5 10 15
Gln Asn

86

19

PRT

Homo sapiens

86
Asp Glu Thr Phe Tyr Lys Gly Lys Lys Asn Thr Glu Arg Pro Lys Ile
1 5 10 15
Arg Thr Asn

87

18

PRT

Homo sapiens

87
Asp Glu Thr Phe Tyr Lys Gly Lys Asn Thr Glu Arg Pro Lys Ile Arg
1 5 10 15
Thr Asn

88

28

PRT

Homo sapiens

88
Leu Ser Ile Asn Asn Tyr Arg Phe Gln Met Lys Phe Tyr Phe Arg Phe
1 5 10 15
Thr Ser His Gly Ser Pro Phe Thr Ser Ala Asn Phe
20 25

89

29

PRT

Homo sapiens

89
Lys Leu Ser Ile Asn Asn Tyr Arg Phe Gln Met Lys Phe Tyr Phe Arg
1 5 10 15
Phe Thr Ser His Gly Ser Pro Phe Thr Ser Ala Asn Phe
20 25

90

10

PRT

Homo sapiens

90
Asn Ser Val Ser Thr Thr Thr Gly Phe Arg
1 5 10

91

37

PRT

Homo sapiens

91
Asn Ile Gln Leu Ala Ala Thr Lys Lys Leu Ser Ile Asn Asn Tyr Arg
1 5 10 15
Phe Gln Met Lys Phe Tyr Phe Arg Phe Thr Ser His Gly Ser Pro Phe
20 25 30
Thr Ser Ala Asn Phe
35

92

38

PRT

Homo sapiens

92
Asn Ile Gln Leu Ala Ala Thr Lys Lys Lys Leu Ser Ile Asn Asn Tyr
1 5 10 15
Arg Phe Gln Met Lys Phe Tyr Phe Arg Phe Thr Ser His Gly Ser Pro
20 25 30
Phe Thr Ser Ala Asn Phe
35

93

19

PRT

Homo sapiens

93
Asn Ile Gln Leu Ala Ala Thr Lys Lys Asn Ser Val Ser Thr Thr Thr
1 5 10 15
Gly Phe Arg

94

18

PRT

Homo sapiens

94
Asn Ile Gln Leu Ala Ala Thr Lys Asn Ser Val Ser Thr Thr Thr Gly
1 5 10 15
Phe Arg

95

18

PRT

Homo sapiens

95
Met Glu His Val Ala Pro Gly Arg Met Ser Ala Ser Pro Gln Ser Pro
1 5 10 15
Thr Gln

96

19

PRT

Homo sapiens

96
Lys Met Glu His Val Ala Pro Gly Arg Met Ser Ala Ser Pro Gln Ser
1 5 10 15
Pro Thr Gln

97

59

PRT

Homo sapiens

97
Lys Trp Ser Thr Trp Leu Gln Ala Glu Cys Gln His Leu His Ser Pro
1 5 10 15
Gln Arg Ser Asp Lys Pro Gln Gln Ala Gly Leu Asp Gln Gln His His
20 25 30
Cys Phe Ala Leu Asp Ser Ser Pro Gly Pro Arg Pro Val Phe Leu Gln
35 40 45
Leu Leu Gly Leu Met Gly Gln Gly Arg His Asp
50 55

98

58

PRT

Homo sapiens

98
Trp Ser Thr Trp Leu Gln Ala Glu Cys Gln His Leu His Ser Pro Gln
1 5 10 15
Arg Ser Asp Lys Pro Gln Gln Ala Gly Leu Asp Gln Gln His His Cys
20 25 30
Phe Ala Leu Asp Ser Ser Pro Gly Pro Arg Pro Val Phe Leu Gln Leu
35 40 45
Leu Gly Leu Met Gly Gln Gly Arg His Asp
50 55

99

26

PRT

Homo sapiens

99
Thr Phe Ser Val Trp Ala Glu Lys Met Glu His Val Ala Pro Gly Arg
1 5 10 15
Met Ser Ala Ser Pro Gln Ser Pro Thr Gln
20 25

100

27

PRT

Homo sapiens

100
Thr Phe Ser Val Trp Ala Glu Lys Lys Met Glu His Val Ala Pro Gly
1 5 10 15
Arg Met Ser Ala Ser Pro Gln Ser Pro Thr Gln
20 25

101

67

PRT

Homo sapiens

101
Thr Phe Ser Val Trp Ala Glu Lys Lys Trp Ser Thr Trp Leu Gln Ala
1 5 10 15
Glu Cys Gln His Leu His Ser Pro Gln Arg Ser Asp Lys Pro Gln Gln
20 25 30
Ala Gly Leu Asp Gln Gln His His Cys Phe Ala Leu Asp Ser Ser Pro
35 40 45
Gly Pro Arg Pro Val Phe Leu Gln Leu Leu Gly Leu Met Gly Gln Gly
50 55 60
Arg His Asp
65

102

66

PRT

Homo sapiens

102
Thr Phe Ser Val Trp Ala Glu Lys Trp Ser Thr Trp Leu Gln Ala Glu
1 5 10 15
Cys Gln His Leu His Ser Pro Gln Arg Ser Asp Lys Pro Gln Gln Ala
20 25 30
Gly Leu Asp Gln Gln His His Cys Phe Ala Leu Asp Ser Ser Pro Gly
35 40 45
Pro Arg Pro Val Phe Leu Gln Leu Leu Gly Leu Met Gly Gln Gly Arg
50 55 60
His Asp
65

103

18

PRT

Homo sapiens

103
His Lys Trp Leu Lys Phe Cys Leu Leu Arg Leu Val Lys Glu Ser Phe
1 5 10 15
His Glu

104

19

PRT

Homo sapiens

104
Lys His Lys Trp Leu Lys Phe Cys Leu Leu Arg Leu Val Lys Glu Ser
1 5 10 15
Phe His Glu

105

27

PRT

Homo sapiens

105
Lys Gly Gly Lys Ala Lys Gly Lys Lys His Lys Trp Leu Lys Phe Cys
1 5 10 15
Leu Leu Arg Leu Val Lys Glu Ser Phe His Glu
20 25

106

28

PRT

Homo sapiens

106
Lys Gly Gly Lys Ala Lys Gly Lys Lys Lys His Lys Trp Leu Lys Phe
1 5 10 15
Cys Leu Leu Arg Leu Val Lys Glu Ser Phe His Glu
20 25

107

13

PRT

Homo sapiens

107
Lys Gly Gly Lys Ala Lys Gly Lys Lys Asn Thr Asn Gly
1 5 10

108

12

PRT

Homo sapiens

108
Lys Gly Gly Lys Ala Lys Gly Lys Asn Thr Asn Gly
1 5 10

109

8

PRT

Homo sapiens

109
Val Asn Asn Phe Phe Lys Lys Leu
1 5

110

9

PRT

Homo sapiens

110
Lys Val Asn Asn Phe Phe Lys Lys Leu
1 5

111

16

PRT

Homo sapiens

111
Leu Ser Gln Gly Asn Val Lys Lys Val Asn Asn Phe Phe Lys Lys Leu
1 5 10 15

112

17

PRT

Homo sapiens

112
Leu Ser Gln Gly Asn Val Lys Lys Lys Val Asn Asn Phe Phe Lys Lys
1 5 10 15
Leu

113

38

PRT

Homo sapiens

113
Gly Glu Lys Asn Asp Leu Gln Leu Phe Val Met Ser Asp Arg Arg Tyr
1 5 10 15
Lys Ile Tyr Trp Thr Val Ile Leu Leu Asn Pro Cys Gly Asn Leu His
20 25 30
Leu Lys Thr Thr Ser Leu
35

114

39

PRT

Homo sapiens

114
Lys Gly Glu Lys Asn Asp Leu Gln Leu Phe Val Met Ser Asp Arg Arg
1 5 10 15
Tyr Lys Ile Tyr Trp Thr Val Ile Leu Leu Asn Pro Cys Gly Asn Leu
20 25 30
His Leu Lys Thr Thr Ser Leu
35

115

10

PRT

Homo sapiens

115
Lys Gly Lys Lys Met Ile Cys Ser Tyr Ser
1 5 10

116

9

PRT

Homo sapiens

116
Gly Lys Lys Met Ile Cys Ser Tyr Ser
1 5

117

46

PRT

Homo sapiens

117
Ser Ser Lys Thr Phe Glu Lys Lys Gly Glu Lys Asn Asp Leu Gln Leu
1 5 10 15
Phe Val Met Ser Asp Arg Arg Tyr Lys Ile Tyr Trp Thr Val Ile Leu
20 25 30
Leu Asn Pro Cys Gly Asn Leu His Leu Lys Thr Thr Ser Leu
35 40 45

118

47

PRT

Homo sapiens

118
Ser Ser Lys Thr Phe Glu Lys Lys Lys Gly Glu Lys Asn Asp Leu Gln
1 5 10 15
Leu Phe Val Met Ser Asp Arg Arg Tyr Lys Ile Tyr Trp Thr Val Ile
20 25 30
Leu Leu Asn Pro Cys Gly Asn Leu His Leu Lys Thr Thr Ser Leu
35 40 45

119

18

PRT

Homo sapiens

119
Ser Ser Lys Thr Phe Glu Lys Lys Lys Gly Lys Lys Met Ile Cys Ser
1 5 10 15
Tyr Ser

120

17

PRT

Homo sapiens

120
Ser Ser Lys Thr Phe Glu Lys Lys Gly Lys Lys Met Ile Cys Ser Tyr
1 5 10 15
Ser

121

17

PRT

Homo sapiens

121
Gln Arg Lys Pro Lys Arg Ala Asn Cys Val Ile Gln Arg Arg Ala Lys
1 5 10 15
Met

122

18

PRT

Homo sapiens

122
Lys Gln Arg Lys Pro Lys Arg Ala Asn Cys Val Ile Gln Arg Arg Ala
1 5 10 15
Lys Met

123

26

PRT

Homo sapiens

123
Asn Lys Glu Asn Gln Lys Glu Gln Thr Ala Leu Leu Tyr Arg Gly Gly
1 5 10 15
Gln Arg Cys Arg Cys Val Cys Leu Arg Phe
20 25

124

26

PRT

Homo sapiens

124
Pro Asp Tyr Gln Pro Pro Ala Lys Lys Gln Arg Lys Pro Lys Arg Ala
1 5 10 15
Asn Cys Val Ile Gln Arg Arg Ala Lys Met
20 25

125

27

PRT

Homo sapiens

125
Pro Asp Tyr Gln Pro Pro Ala Lys Lys Lys Gln Arg Lys Pro Lys Arg
1 5 10 15
Ala Asn Cys Val Ile Gln Arg Arg Ala Lys Met
20 25

126

35

PRT

Homo sapiens

126
Pro Asp Tyr Gln Pro Pro Ala Lys Lys Asn Lys Glu Asn Gln Lys Glu
1 5 10 15
Gln Thr Ala Leu Leu Tyr Arg Gly Gly Gln Arg Cys Arg Cys Val Cys
20 25 30
Leu Arg Phe
35

127

34

PRT

Homo sapiens

127
Pro Asp Tyr Gln Pro Pro Ala Lys Asn Lys Glu Asn Gln Lys Glu Gln
1 5 10 15
Thr Ala Leu Leu Tyr Arg Gly Gly Gln Arg Cys Arg Cys Val Cys Leu
20 25 30
Arg Phe

128

7

PRT

Homo sapiens

128
Asn Leu Ser Ser Leu Leu Ile
1 5

129

5

PRT

Homo sapiens

129
Thr Cys Leu Pro Phe
1 5

130

15

PRT

Homo sapiens

130
Gln Pro Thr Phe Thr Leu Arg Lys Asn Leu Ser Ser Leu Leu Ile
1 5 10 15

131

16

PRT

Homo sapiens

131
Gln Pro Thr Phe Thr Leu Arg Lys Lys Asn Leu Ser Ser Leu Leu Ile
1 5 10 15

132

14

PRT

Homo sapiens

132
Gln Pro Thr Phe Thr Leu Arg Lys Lys Thr Cys Leu Pro Phe
1 5 10

133

13

PRT

Homo sapiens

133
Gln Pro Thr Phe Thr Leu Arg Lys Thr Cys Leu Pro Phe
1 5 10

134

31

PRT

Homo sapiens

134
Arg Ala Thr Phe Leu Leu Ser Leu Trp Glu Cys Ser Leu Pro Gln Ala
1 5 10 15
Arg Leu Cys Leu Ile Val Ser Arg Thr Gly Leu Leu Val Gln Ser
20 25 30

135

19

PRT

Homo sapiens

135
Gly Gln His Phe Tyr Trp His Cys Gly Ser Ala Ala Cys His Arg Arg
1 5 10 15
Gly Cys Val

136

39

PRT

Homo sapiens

136
Lys Glu Asn Val Arg Asp Lys Lys Arg Ala Thr Phe Leu Leu Ser Leu
1 5 10 15
Trp Glu Cys Ser Leu Pro Gln Ala Arg Leu Cys Leu Ile Val Ser Arg
20 25 30
Thr Gly Leu Leu Val Gln Ser
35

137

40

PRT

Homo sapiens

137
Lys Glu Asn Val Arg Asp Lys Lys Lys Arg Ala Thr Phe Leu Leu Ser
1 5 10 15
Leu Trp Glu Cys Ser Leu Pro Gln Ala Arg Leu Cys Leu Ile Val Ser
20 25 30
Arg Thr Gly Leu Leu Val Gln Ser
35 40

138

28

PRT

Homo sapiens

138
Lys Glu Asn Val Arg Asp Lys Lys Lys Gly Gln His Phe Tyr Trp His
1 5 10 15
Cys Gly Ser Ala Ala Cys His Arg Arg Gly Cys Val
20 25

139

27

PRT

Homo sapiens

139
Lys Glu Asn Val Arg Asp Lys Lys Gly Gln His Phe Tyr Trp His Cys
1 5 10 15
Gly Ser Ala Ala Cys His Arg Arg Gly Cys Val
20 25

140

39

PRT

Homo sapiens

140
Ile Thr His Thr Arg Trp Gly Ile Thr Thr Trp Asp Ser Trp Ser Val
1 5 10 15
Arg Met Lys Ala Asn Trp Ile Gln Ala Gln Gln Asn Lys Ser Leu Ile
20 25 30
Leu Ser Pro Ser Phe Thr Lys
35

141

40

PRT

Homo sapiens

141
Lys Ile Thr His Thr Arg Trp Gly Ile Thr Thr Trp Asp Ser Trp Ser
1 5 10 15
Val Arg Met Lys Ala Asn Trp Ile Gln Ala Gln Gln Asn Lys Ser Leu
20 25 30
Ile Leu Ser Pro Ser Phe Thr Lys
35 40

142

16

PRT

Homo sapiens

142
Lys Leu Leu Thr Pro Gly Gly Glu Leu Pro His Gly Ile Leu Gly Gln
1 5 10 15

143

15

PRT

Homo sapiens

143
Leu Leu Thr Pro Gly Gly Glu Leu Pro His Gly Ile Leu Gly Gln
1 5 10 15

144

47

PRT

Homo sapiens

144
Pro Pro Val Cys Glu Leu Glu Lys Ile Thr His Thr Arg Trp Gly Ile
1 5 10 15
Thr Thr Trp Asp Ser Trp Ser Val Arg Met Lys Ala Asn Trp Ile Gln
20 25 30
Ala Gln Gln Asn Lys Ser Leu Ile Leu Ser Pro Ser Phe Thr Lys
35 40 45

145

48

PRT

Homo sapiens

145
Pro Pro Val Cys Glu Leu Glu Lys Lys Ile Thr His Thr Arg Trp Gly
1 5 10 15
Ile Thr Thr Trp Asp Ser Trp Ser Val Arg Met Lys Ala Asn Trp Ile
20 25 30
Gln Ala Gln Gln Asn Lys Ser Leu Ile Leu Ser Pro Ser Phe Thr Lys
35 40 45

146

24

PRT

Homo sapiens

146
Pro Pro Val Cys Glu Leu Glu Lys Lys Leu Leu Thr Pro Gly Gly Glu
1 5 10 15
Leu Pro His Gly Ile Leu Gly Gln
20

147

23

PRT

Homo sapiens

147
Pro Pro Val Cys Glu Leu Glu Lys Leu Leu Thr Pro Gly Gly Glu Leu
1 5 10 15
Pro His Gly Ile Leu Gly Gln
20

148

11

PRT

Homo sapiens

148
Ser Leu Lys Asp Glu Leu Glu Lys Met Lys Ile
1 5 10

149

12

PRT

Homo sapiens

149
Ser Leu Lys Asp Glu Leu Glu Lys Lys Met Lys Ile
1 5 10

150

12

PRT

Homo sapiens

150
Leu Gly Gln Ser Ser Pro Glu Lys Lys Asn Lys Asn
1 5 10

151

11

PRT

Homo sapiens

151
Leu Gly Gln Ser Ser Pro Glu Lys Asn Lys Asn
1 5 10

152

23

PRT

Homo sapiens

152
Arg Leu Arg Arg Ile Asn Gly Arg Gly Ser Gln Ile Arg Ser Arg Asn
1 5 10 15
Ala Phe Asn Arg Ser Glu Glu
20

153

10

PRT

Homo sapiens

153
Glu Pro Lys Val Lys Glu Glu Lys Lys Thr
1 5 10

154

11

PRT

Homo sapiens

154
Glu Pro Lys Val Lys Glu Glu Lys Lys Lys Thr
1 5 10

155

32

PRT

Homo sapiens

155
Glu Pro Lys Val Lys Glu Glu Lys Lys Arg Leu Arg Arg Ile Asn Gly
1 5 10 15
Arg Gly Ser Gln Ile Arg Ser Arg Asn Ala Phe Asn Arg Ser Glu Glu
20 25 30

156

31

PRT

Homo sapiens

156
Glu Pro Lys Val Lys Glu Glu Lys Arg Leu Arg Arg Ile Asn Gly Arg
1 5 10 15
Gly Ser Gln Ile Arg Ser Arg Asn Ala Phe Asn Arg Ser Glu Glu
20 25 30

157

14

PRT

Homo sapiens

157
Thr Phe Arg Tyr Lys Gly Lys Gln His Pro Phe Phe Ser Thr
1 5 10

158

10

PRT

Homo sapiens

158
Gly Pro Asn Ala Pro Glu Glu Lys Asn His
1 5 10

159

11

PRT

Homo sapiens

159
Gly Pro Asn Ala Pro Glu Glu Lys Lys Asn His
1 5 10

160

23

PRT

Homo sapiens

160
Gly Pro Asn Ala Pro Glu Glu Lys Lys Thr Phe Arg Tyr Lys Gly Lys
1 5 10 15
Gln His Pro Phe Phe Ser Thr
20

161

22

PRT

Homo sapiens

161
Gly Pro Asn Ala Pro Glu Glu Lys Thr Phe Arg Tyr Lys Gly Lys Gln
1 5 10 15
His Pro Phe Phe Ser Thr
20

162

6

PRT

Homo sapiens

162
Met Gln Asn Thr Cys Val
1 5

163

7

PRT

Homo sapiens

163
Lys Met Gln Asn Thr Cys Val
1 5

164

9

PRT

Homo sapiens

164
Lys Cys Lys Ile Arg Val Phe Ser Lys
1 5

165

8

PRT

Homo sapiens

165
Cys Lys Ile Arg Val Phe Ser Lys
1 5

166

14

PRT

Homo sapiens

166
Phe Phe Lys Arg Thr Val Gln Lys Met Gln Asn Thr Cys Val
1 5 10

167

15

PRT

Homo sapiens

167
Phe Phe Lys Arg Thr Val Gln Lys Lys Met Gln Asn Thr Cys Val
1 5 10 15

168

17

PRT

Homo sapiens

168
Phe Phe Lys Arg Thr Val Gln Lys Lys Cys Lys Ile Arg Val Phe Ser
1 5 10 15
Lys

169

16

PRT

Homo sapiens

169
Phe Phe Lys Arg Thr Val Gln Lys Cys Lys Ile Arg Val Phe Ser Lys
1 5 10 15

170

7

PRT

Homo sapiens

170
Leu Pro His Tyr Leu Ala His
1 5

171

8

PRT

Homo sapiens

171
Cys Leu Ile Thr Trp Leu Thr Asn
1 5

172

17

PRT

Homo sapiens

172
Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Leu Pro His Tyr Leu Ala
1 5 10 15
His

173

18

PRT

Homo sapiens

173
Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Leu Pro His Tyr Leu
1 5 10 15
Ala His

174

19

PRT

Homo sapiens

174
Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Pro Cys Leu Ile Thr Trp
1 5 10 15
Leu Thr Asn

175

18

PRT

Homo sapiens

175
Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Cys Leu Ile Thr Trp Leu
1 5 10 15
Thr Asn

176

9

PRT

Homo sapiens

176
Arg Phe Ala Asp Lys Pro Arg Pro Asn
1 5

177

20

PRT

Homo sapiens

177
Asp Leu Pro Thr Ser Pro Asp Gln Thr Arg Ser Gly Pro Val His Val
1 5 10 15
Ser Val Glu Pro
20

178

19

PRT

Homo sapiens

178
Asp Ser Ala Ala Gly Cys Ser Gly Thr Pro Arg Phe Ala Asp Lys Pro
1 5 10 15
Arg Pro Asn

179

20

PRT

Homo sapiens

179
Asp Ser Ala Ala Gly Cys Ser Gly Thr Pro Pro Arg Phe Ala Asp Lys
1 5 10 15
Pro Arg Pro Asn
20

180

31

PRT

Homo sapiens

180
Asp Ser Ala Ala Gly Cys Ser Gly Thr Pro Pro Asp Leu Pro Thr Ser
1 5 10 15
Pro Asp Gln Thr Arg Ser Gly Pro Val His Val Ser Val Glu Pro
20 25 30

181

30

PRT

Homo sapiens

181
Asp Ser Ala Ala Gly Cys Ser Gly Thr Pro Asp Leu Pro Thr Ser Pro
1 5 10 15
Asp Gln Thr Arg Ser Gly Pro Val His Val Ser Val Glu Pro
20 25 30

182

53

PRT

Homo sapiens

182
Ala His Pro Glu Thr Pro Ala Gln Asn Arg Leu Arg Ile Pro Cys Ser
1 5 10 15
Arg Arg Glu Val Arg Ser Arg Ala Cys Lys Pro Pro Gly Ala Gln Gly
20 25 30
Ser Asp Glu Arg Arg Gly Lys Ala Ser Pro Gly Arg Asp Cys Asp Val
35 40 45
Arg Thr Gly Arg Pro
50

183

54

PRT

Homo sapiens

183
Pro Ala His Pro Glu Thr Pro Ala Gln Asn Arg Leu Arg Ile Pro Cys
1 5 10 15
Ser Arg Arg Glu Val Arg Ser Arg Ala Cys Lys Pro Pro Gly Ala Gln
20 25 30
Gly Ser Asp Glu Arg Arg Gly Lys Ala Ser Pro Gly Arg Asp Cys Asp
35 40 45
Val Arg Thr Gly Arg Pro
50

184

20

PRT

Homo sapiens

184
Arg Pro Thr Arg Arg His Pro Arg Arg Ile Ala Ser Gly Ser Pro Ala
1 5 10 15
Val Gly Gly Arg
20

185

63

PRT

Homo sapiens

185
Val Ala Ile Arg Gly His Pro Arg Pro Pro Ala His Pro Glu Thr Pro
1 5 10 15
Ala Gln Asn Arg Leu Arg Ile Pro Cys Ser Arg Arg Glu Val Arg Ser
20 25 30
Arg Ala Cys Lys Pro Pro Gly Ala Gln Gly Ser Asp Glu Arg Arg Gly
35 40 45
Lys Ala Ser Pro Gly Arg Asp Cys Asp Val Arg Thr Gly Arg Pro
50 55 60

186

64

PRT

Homo sapiens

186
Val Ala Ile Arg Gly His Pro Arg Pro Pro Pro Ala His Pro Glu Thr
1 5 10 15
Pro Ala Gln Asn Arg Leu Arg Ile Pro Cys Ser Arg Arg Glu Val Arg
20 25 30
Ser Arg Ala Cys Lys Pro Pro Gly Ala Gln Gly Ser Asp Glu Arg Arg
35 40 45
Gly Lys Ala Ser Pro Gly Arg Asp Cys Asp Val Arg Thr Gly Arg Pro
50 55 60

187

30

PRT

Homo sapiens

187
Val Ala Ile Arg Gly His Pro Arg Pro Pro Arg Pro Thr Arg Arg His
1 5 10 15
Pro Arg Arg Ile Ala Ser Gly Ser Pro Ala Val Gly Gly Arg
20 25 30

188

29

PRT

Homo sapiens

188
Val Ala Ile Arg Gly His Pro Arg Pro Arg Pro Thr Arg Arg His Pro
1 5 10 15
Arg Arg Ile Ala Ser Gly Ser Pro Ala Val Gly Gly Arg
20 25

189

85

PRT

Homo sapiens

189
Arg Gly Arg Thr Ser Gly Arg Ser Leu Ser Cys Cys Arg Arg Pro Arg
1 5 10 15
Cys Arg Pro Ala Val Ala Ser Arg Ser Thr Ala Pro Ser Pro Arg Ala
20 25 30
Gly Ser Arg Arg Cys Cys Leu Arg Thr Ser Cys Gly Ala Ala Arg Pro
35 40 45
Arg Arg Thr Arg Ser Ala Cys Gly Asp Trp Val Ala Ser Pro Pro Thr
50 55 60
Arg Ser Ser Ser Arg Thr Ala Cys Gly Ala Ala Ser Pro Pro Ala Arg
65 70 75 80
Ser Trp Ser Ala Pro
85

190

8

PRT

Homo sapiens

190
Gly Gly Gly His Leu Glu Glu Val
1 5

191

94

PRT

Homo sapiens

191
Tyr Phe Gly Gly Pro Asp Ser Thr Pro Arg Gly Arg Thr Ser Gly Arg
1 5 10 15
Ser Leu Ser Cys Cys Arg Arg Pro Arg Cys Arg Pro Ala Val Ala Ser
20 25 30
Arg Ser Thr Ala Pro Ser Pro Arg Ala Gly Ser Arg Arg Cys Cys Leu
35 40 45
Arg Thr Ser Cys Gly Ala Ala Arg Pro Arg Arg Thr Arg Ser Ala Cys
50 55 60
Gly Asp Trp Val Ala Ser Pro Pro Thr Arg Ser Ser Ser Arg Thr Ala
65 70 75 80
Cys Gly Ala Ala Ser Pro Pro Ala Arg Ser Trp Ser Ala Pro
85 90

192

95

PRT

Homo sapiens

192
Tyr Phe Gly Gly Pro Asp Ser Thr Pro Pro Arg Gly Arg Thr Ser Gly
1 5 10 15
Arg Ser Leu Ser Cys Cys Arg Arg Pro Arg Cys Arg Pro Ala Val Ala
20 25 30
Ser Arg Ser Thr Ala Pro Ser Pro Arg Ala Gly Ser Arg Arg Cys Cys
35 40 45
Leu Arg Thr Ser Cys Gly Ala Ala Arg Pro Arg Arg Thr Arg Ser Ala
50 55 60
Cys Gly Asp Trp Val Ala Ser Pro Pro Thr Arg Ser Ser Ser Arg Thr
65 70 75 80
Ala Cys Gly Ala Ala Ser Pro Pro Ala Arg Ser Trp Ser Ala Pro
85 90 95

193

18

PRT

Homo sapiens

193
Tyr Phe Gly Gly Pro Asp Ser Thr Pro Pro Gly Gly Gly His Leu Glu
1 5 10 15
Glu Val

194

17

PRT

Homo sapiens

194
Tyr Phe Gly Gly Pro Asp Ser Thr Pro Gly Gly Gly His Leu Glu Glu
1 5 10 15
Val

195

6

PRT

Homo sapiens

195
His Arg Val Ala Asp Pro
1 5

196

13

PRT

Homo sapiens

196
Leu Ser Gln Ser Ser Glu Leu Asp Pro Pro Ser Ser Arg
1 5 10

197

14

PRT

Homo sapiens

197
Leu Ser Gln Ser Ser Glu Leu Asp Pro Pro Pro Ser Ser Arg
1 5 10

198

16

PRT

Homo sapiens

198
Leu Ser Gln Ser Ser Glu Leu Asp Pro Pro His Arg Val Ala Asp Pro
1 5 10 15

199

15

PRT

Homo sapiens

199
Leu Ser Gln Ser Ser Glu Leu Asp Pro His Arg Val Ala Asp Pro
1 5 10 15

200

11

PRT

Homo sapiens

200
Val Ile Leu Leu Pro Glu Asp Thr Pro Pro Ser
1 5 10

201

12

PRT

Homo sapiens

201
Val Ile Leu Leu Pro Glu Asp Thr Pro Pro Pro Ser
1 5 10

202

14

PRT

Homo sapiens

202
Val Ile Leu Leu Pro Glu Asp Thr Pro Pro Leu Leu Arg Ala
1 5 10

203

13

PRT

Homo sapiens

203
Val Ile Leu Leu Pro Glu Leu Asp Pro Leu Leu Arg Ala
1 5 10

204

5

PRT

Homo sapiens

204
Pro Ser Pro Leu Pro
1 5

205

25

PRT

Homo sapiens

205
Pro Leu Leu Phe His Arg Pro Cys Ser Pro Ser Pro Ala Leu Gly Ala
1 5 10 15
Thr Val Leu Ala Val Tyr Arg Tyr Glu
20 25

206

24

PRT

Homo sapiens

206
Leu Leu Phe His Arg Pro Cys Ser Pro Ser Pro Ala Leu Gly Ala Thr
1 5 10 15
Val Leu Ala Val Tyr Arg Tyr Glu
20

207

13

PRT

Homo sapiens

207
Ala Pro Arg Pro Pro Leu Gly Pro Pro Ser Pro Leu Pro
1 5 10

208

14

PRT

Homo sapiens

208
Ala Pro Arg Pro Pro Leu Gly Pro Pro Pro Ser Pro Leu Pro
1 5 10

209

34

PRT

Homo sapiens

209
Ala Pro Arg Pro Pro Leu Gly Pro Pro Pro Leu Leu Phe His Arg Pro
1 5 10 15
Cys Ser Pro Ser Pro Ala Leu Gly Ala Thr Val Leu Ala Val Tyr Arg
20 25 30
Tyr Glu

210

33

PRT

Homo sapiens

210
Ala Pro Arg Pro Pro Leu Gly Pro Pro Leu Leu Phe His Arg Pro Cys
1 5 10 15
Ser Pro Ser Pro Ala Leu Gly Ala Thr Val Leu Ala Val Tyr Arg Tyr
20 25 30
Glu

211

28

PRT

Homo sapiens

211
Thr Gln Val Leu Pro Gln Gly Cys Ser Leu Ser Leu Leu His Thr Thr
1 5 10 15
Phe Pro His Arg Gln Val Pro His Ile Leu Asp Trp
20 25

212

29

PRT

Homo sapiens

212
Pro Thr Gln Val Leu Pro Gln Gly Cys Ser Leu Ser Leu Leu His Thr
1 5 10 15
Thr Phe Pro His Arg Gln Val Pro His Ile Leu Asp Trp
20 25

213

54

PRT

Homo sapiens

213
Pro Leu Gln Ser Phe Pro Lys Asp Ala Ala Ser Ala Phe Ser Thr Pro
1 5 10 15
Arg Phe Pro Thr Asp Lys Phe Pro Thr Ser Trp Thr Gly Ser Cys Pro
20 25 30
Gly Gln Pro His Gly Thr Arg Ala Phe Cys Gln Pro Gly Pro Glu Phe
35 40 45
Asn Ala Phe Ser Ala Cys
50

214

53

PRT

Homo sapiens

214
Leu Gln Ser Phe Pro Lys Asp Ala Ala Ser Ala Phe Ser Thr Pro Arg
1 5 10 15
Phe Pro Thr Asp Lys Phe Pro Thr Ser Trp Thr Gly Ser Cys Pro Gly
20 25 30
Gln Pro His Gly Thr Arg Ala Phe Cys Gln Pro Gly Pro Glu Phe Asn
35 40 45
Ala Phe Ser Ala Cys
50

215

38

PRT

Homo sapiens

215
Pro Ser Pro Arg Pro Gln Ser Gln Pro Pro Thr Gln Val Leu Pro Gln
1 5 10 15
Gly Cys Ser Leu Ser Leu Leu His Thr Thr Phe Pro His Arg Gln Val
20 25 30
Pro His Ile Leu Asp Trp
35

216

39

PRT

Homo sapiens

216
Pro Ser Pro Arg Pro Gln Ser Gln Pro Pro Pro Thr Gln Val Leu Pro
1 5 10 15
Gln Gly Cys Ser Leu Ser Leu Leu His Thr Thr Phe Pro His Arg Gln
20 25 30
Val Pro His Ile Leu Asp Trp
35

217

64

PRT

Homo sapiens

217
Pro Ser Pro Arg Pro Gln Ser Gln Pro Pro Pro Leu Gln Ser Phe Pro
1 5 10 15
Lys Asp Ala Ala Ser Ala Phe Ser Thr Pro Arg Phe Pro Thr Asp Lys
20 25 30
Phe Pro Thr Ser Trp Thr Gly Ser Cys Pro Gly Gln Pro His Gly Thr
35 40 45
Arg Ala Phe Cys Gln Pro Gly Pro Glu Phe Asn Ala Phe Ser Ala Cys
50 55 60

218

63

PRT

Homo sapiens

218
Pro Ser Pro Arg Pro Gln Ser Gln Pro Pro Leu Gln Ser Phe Pro Lys
1 5 10 15
Asp Ala Ala Ser Ala Phe Ser Thr Pro Arg Phe Pro Thr Asp Lys Phe
20 25 30
Pro Thr Ser Trp Thr Gly Ser Cys Pro Gly Gln Pro His Gly Thr Arg
35 40 45
Ala Phe Cys Gln Pro Gly Pro Glu Phe Asn Ala Phe Ser Ala Cys
50 55 60

219

30

PRT

Homo sapiens

219
Thr Ala Trp Pro Gly Arg Arg Arg Phe Thr Thr Pro Glu Pro Tyr Cys
1 5 10 15
Leu Cys Thr Pro Leu Gly Pro Trp Ala Pro Arg Phe Leu Trp
20 25 30

220

31

PRT

Homo sapiens

220
Pro Thr Ala Trp Pro Gly Arg Arg Arg Phe Thr Thr Pro Glu Pro Tyr
1 5 10 15
Cys Leu Cys Thr Pro Leu Gly Pro Trp Ala Pro Arg Phe Leu Trp
20 25 30

221

50

PRT

Homo sapiens

221
Pro Arg Pro Gly Pro Ala Gly Gly Ala Leu Leu Pro Arg Ser Leu Thr
1 5 10 15
Ala Phe Val Pro His Ser Gly His Gly Leu Pro Val Ser Ser Gly Glu
20 25 30
Pro Ala Tyr Thr Pro Ile Pro His Asp Val Pro His Gly Thr Pro Pro
35 40 45
Phe Cys
50

222

49

PRT

Homo sapiens

222
Arg Pro Gly Pro Ala Gly Gly Ala Leu Leu Pro Arg Ser Leu Thr Ala
1 5 10 15
Phe Val Pro His Ser Gly His Gly Leu Pro Val Ser Ser Gly Glu Pro
20 25 30
Ala Tyr Thr Pro Ile Pro His Asp Val Pro His Gly Thr Pro Pro Phe
35 40 45
Cys

223

39

PRT

Homo sapiens

223
Asp Leu Pro Ala Val Pro Gly Pro Pro Thr Ala Trp Pro Gly Arg Arg
1 5 10 15
Arg Phe Thr Thr Pro Glu Pro Tyr Cys Leu Cys Thr Pro Leu Gly Pro
20 25 30
Trp Ala Pro Arg Phe Leu Trp
35

224

40

PRT

Homo sapiens

224
Asp Leu Pro Ala Val Pro Gly Pro Pro Pro Thr Ala Trp Pro Gly Arg
1 5 10 15
Arg Arg Phe Thr Thr Pro Glu Pro Tyr Cys Leu Cys Thr Pro Leu Gly
20 25 30
Pro Trp Ala Pro Arg Phe Leu Trp
35 40

225

59

PRT

Homo sapiens

225
Asp Leu Pro Ala Val Pro Gly Pro Pro Pro Arg Pro Gly Pro Ala Gly
1 5 10 15
Gly Ala Leu Leu Pro Arg Ser Leu Thr Ala Phe Val Pro His Ser Gly
20 25 30
His Gly Leu Pro Val Ser Ser Gly Glu Pro Ala Tyr Thr Pro Ile Pro
35 40 45
His Asp Val Pro His Gly Thr Pro Pro Phe Cys
50 55

226

58

PRT

Homo sapiens

226
Asp Leu Pro Ala Val Pro Gly Pro Pro Arg Pro Gly Pro Ala Gly Gly
1 5 10 15
Ala Leu Leu Pro Arg Ser Leu Thr Ala Phe Val Pro His Ser Gly His
20 25 30
Gly Leu Pro Val Ser Ser Gly Glu Pro Ala Tyr Thr Pro Ile Pro His
35 40 45
Asp Val Pro His Gly Thr Pro Pro Phe Cys
50 55

227

8

PRT

Homo sapiens

227
Gln Trp Gly Leu Ser Trp Met Ser
1 5

228

14

PRT

Homo sapiens

228
Asn Gly Asp Cys His Gly Cys Pro Glu Gly Arg Gln Ser Leu
1 5 10

229

17

PRT

Homo sapiens

229
Phe Thr Met Asp Arg Val Leu Thr Pro Gln Trp Gly Leu Ser Trp Met
1 5 10 15
Ser

230

18

PRT

Homo sapiens

230
Phe Thr Met Asp Arg Val Leu Thr Pro Pro Gln Trp Gly Leu Ser Trp
1 5 10 15
Met Ser

231

24

PRT

Homo sapiens

231
Phe Thr Met Asp Arg Val Leu Thr Pro Pro Asn Gly Asp Cys His Gly
1 5 10 15
Cys Pro Glu Gly Arg Gln Ser Leu
20

232

23

PRT

Homo sapiens

232
Phe Thr Met Asp Arg Val Leu Thr Pro Asn Gly Asp Cys His Gly Cys
1 5 10 15
Pro Glu Gly Arg Gln Ser Leu
20

233

115

PRT

Homo sapiens

233
His His Pro Ala Arg Gln Cys Pro His Cys Ile Met His Leu Gln Thr
1 5 10 15
Gln Leu Ile His Arg Asn Leu Thr Gly Pro Ser Gln Leu Thr Ser Leu
20 25 30
His Arg Ser Pro Tyr Gln Ile Ala Ala Thr Pro Trp Thr Thr Asp Phe
35 40 45
Ala Ala Ser Phe Phe Leu Asn Pro Val Thr Pro Phe Leu Leu Cys Arg
50 55 60
Arg Cys Gln Gly Lys Asp Val Leu Cys Thr Asn Ala Arg Cys Leu Ser
65 70 75 80
Gln Thr Ser Pro Ser His His Lys Ala Leu Ser Arg Thr Thr Thr Gln
85 90 95
Cys Met Asn Thr Thr Pro Trp Leu Ala Val Arg Pro Ala Lys Ala Phe
100 105 110
Pro Leu Leu
115

234

116

PRT

Homo sapiens

234
Pro His His Pro Ala Arg Gln Cys Pro His Cys Ile Met His Leu Gln
1 5 10 15
Thr Gln Leu Ile His Arg Asn Leu Thr Gly Pro Ser Gln Leu Thr Ser
20 25 30
Leu His Arg Ser Pro Tyr Gln Ile Ala Ala Thr Pro Trp Thr Thr Asp
35 40 45
Phe Ala Ala Ser Phe Phe Leu Asn Pro Val Thr Pro Phe Leu Leu Cys
50 55 60
Arg Arg Cys Gln Gly Lys Asp Val Leu Cys Thr Asn Ala Arg Cys Leu
65 70 75 80
Ser Gln Thr Ser Pro Ser His His Lys Ala Leu Ser Arg Thr Thr Thr
85 90 95
Gln Cys Met Asn Thr Thr Pro Trp Leu Ala Val Arg Pro Ala Lys Ala
100 105 110
Phe Pro Leu Leu
115

235

23

PRT

Homo sapiens

235
His Thr Ile Gln His Ala Ser Val Pro Thr Ala Ser Cys Ile Ser Lys
1 5 10 15
Leu Asn Ser Tyr Thr Glu Asn
20

236

126

PRT

Homo sapiens

236
Pro Gln Val Gly Met Arg Pro Ser Asn Pro Pro His His Pro Ala Arg
1 5 10 15
Gln Cys Pro His Cys Ile Met His Leu Gln Thr Gln Leu Ile His Arg
20 25 30
Asn Leu Thr Gly Pro Ser Gln Leu Thr Ser Leu His Arg Ser Pro Tyr
35 40 45
Gln Ile Ala Ala Thr Pro Trp Thr Thr Asp Phe Ala Ala Ser Phe Phe
50 55 60
Leu Asn Pro Val Thr Pro Phe Leu Leu Cys Arg Arg Cys Gln Gly Lys
65 70 75 80
Asp Val Leu Cys Thr Asn Ala Arg Cys Leu Ser Gln Thr Ser Pro Ser
85 90 95
His His Lys Ala Leu Ser Arg Thr Thr Thr Gln Cys Met Asn Thr Thr
100 105 110
Pro Trp Leu Ala Val Arg Pro Ala Lys Ala Phe Pro Leu Leu
115 120 125

237

127

PRT

Homo sapiens

237
Pro Gln Val Gly Met Arg Pro Ser Asn Pro Pro Pro His His Pro Ala
1 5 10 15
Arg Gln Cys Pro His Cys Ile Met His Leu Gln Thr Gln Leu Ile His
20 25 30
Arg Asn Leu Thr Gly Pro Ser Gln Leu Thr Ser Leu His Arg Ser Pro
35 40 45
Tyr Gln Ile Ala Ala Thr Pro Trp Thr Thr Asp Phe Ala Ala Ser Phe
50 55 60
Phe Leu Asn Pro Val Thr Pro Phe Leu Leu Cys Arg Arg Cys Gln Gly
65 70 75 80
Lys Asp Val Leu Cys Thr Asn Ala Arg Cys Leu Ser Gln Thr Ser Pro
85 90 95
Ser His His Lys Ala Leu Ser Arg Thr Thr Thr Gln Cys Met Asn Thr
100 105 110
Thr Pro Trp Leu Ala Val Arg Pro Ala Lys Ala Phe Pro Leu Leu
115 120 125

238

34

PRT

Homo sapiens

238
Pro Gln Val Gly Met Arg Pro Ser Asn Pro Pro His Thr Ile Gln His
1 5 10 15
Ala Ser Val Pro Thr Ala Ser Cys Ile Ser Lys Leu Asn Ser Tyr Thr
20 25 30
Glu Asn

239

33

PRT

Homo sapiens

239
Pro Gln Val Gly Met Arg Pro Ser Asn Pro His Thr Ile Gln His Ala
1 5 10 15
Ser Val Pro Thr Ala Ser Cys Ile Ser Lys Leu Asn Ser Tyr Thr Glu
20 25 30
Asn

240

51

PRT

Homo sapiens

240
Trp Ala Ala Arg Ser Trp Cys Glu Arg Arg Ala Ala Ala Val Ala Pro
1 5 10 15
Leu Ala Pro Trp Ala Trp Gly Cys Pro Ala Gly Cys Thr Pro Pro Val
20 25 30
Ala Ala Arg Ala Cys Ala Ala Thr Arg Pro Glu Gly Trp Arg Ser Pro
35 40 45
Cys Thr His
50

241

52

PRT

Homo sapiens

241
Pro Trp Ala Ala Arg Ser Trp Cys Glu Arg Arg Ala Ala Ala Val Ala
1 5 10 15
Pro Leu Ala Pro Trp Ala Trp Gly Cys Pro Ala Gly Cys Thr Pro Pro
20 25 30
Val Ala Ala Arg Ala Cys Ala Ala Thr Arg Pro Glu Gly Trp Arg Ser
35 40 45
Pro Cys Thr His
50

242

74

PRT

Homo sapiens

242
Arg Gly Leu Arg Gly Ala Gly Ala Arg Gly Gly Leu Arg Leu Leu Arg
1 5 10 15
His Leu Arg Pro Gly Leu Gly Asp Ala Leu Arg Gly Val His Pro Pro
20 25 30
Leu Arg Leu Gly Pro Ala Leu Leu Pro Ala Pro Arg Gly Gly Glu Ala
35 40 45
Pro Ala His Thr Asp Ala Arg Ala Arg Arg Val His Gly Ala Gly Gly
50 55 60
Asp Arg Gly His Pro Gly Pro Ala Ala Leu
65 70

243

61

PRT

Homo sapiens

243
Glu Glu Lys Leu Ala Arg Cys Arg Pro Pro Trp Ala Ala Arg Ser Trp
1 5 10 15
Cys Glu Arg Arg Ala Ala Ala Val Ala Pro Leu Ala Pro Trp Ala Trp
20 25 30
Gly Cys Pro Ala Gly Cys Thr Pro Pro Val Ala Ala Arg Ala Cys Ala
35 40 45
Ala Thr Arg Pro Glu Gly Trp Arg Ser Pro Cys Thr His
50 55 60

244

62

PRT

Homo sapiens

244
Glu Glu Lys Leu Ala Arg Cys Arg Pro Pro Pro Trp Ala Ala Arg Ser
1 5 10 15
Trp Cys Glu Arg Arg Ala Ala Ala Val Ala Pro Leu Ala Pro Trp Ala
20 25 30
Trp Gly Cys Pro Ala Gly Cys Thr Pro Pro Val Ala Ala Arg Ala Cys
35 40 45
Ala Ala Thr Arg Pro Glu Gly Trp Arg Ser Pro Cys Thr His
50 55 60

245

84

PRT

Homo sapiens

245
Glu Glu Lys Leu Ala Arg Cys Arg Pro Pro Arg Gly Leu Arg Gly Ala
1 5 10 15
Gly Ala Arg Gly Gly Leu Arg Leu Leu Arg His Leu Arg Pro Gly Leu
20 25 30
Gly Asp Ala Leu Arg Gly Val His Pro Pro Leu Arg Leu Gly Pro Ala
35 40 45
Leu Leu Pro Ala Pro Arg Gly Gly Glu Ala Pro Ala His Thr Asp Ala
50 55 60
Arg Ala Arg Arg Val His Gly Ala Gly Gly Asp Arg Gly His Pro Gly
65 70 75 80
Pro Ala Ala Leu

246

83

PRT

Homo sapiens

246
Glu Glu Lys Leu Ala Arg Cys Arg Pro Arg Gly Leu Arg Gly Ala Gly
1 5 10 15
Ala Arg Gly Gly Leu Arg Leu Leu Arg His Leu Arg Pro Gly Leu Gly
20 25 30
Asp Ala Leu Arg Gly Val His Pro Pro Leu Arg Leu Gly Pro Ala Leu
35 40 45
Leu Pro Ala Pro Arg Gly Gly Glu Ala Pro Ala His Thr Asp Ala Arg
50 55 60
Ala Arg Arg Val His Gly Ala Gly Gly Asp Arg Gly His Pro Gly Pro
65 70 75 80
Ala Ala Leu

247

163

PRT

Homo sapiens

247
Gln Pro Pro Val Ser Pro Arg Pro Arg Arg Pro Gly Arg Pro Arg Ala
1 5 10 15
Pro Pro Pro Pro Gln Pro Met Val Ser Pro Arg Arg Arg Thr Thr Gly
20 25 30
Pro Pro Trp Arg Pro Pro Pro Leu Gln Ser Thr Met Ser Pro Pro Pro
35 40 45
Gln Ala Leu His Gln Ala Gln Leu Leu Leu Trp Cys Thr Thr Ala Pro
50 55 60
Leu Pro Gly Leu Pro Gln Pro Gln Pro Ala Arg Ala Leu His Ser Gln
65 70 75 80
Phe Pro Ala Thr Thr Leu Ile Leu Leu Pro Pro Leu Pro Ala Ile Ala
85 90 95
Pro Arg Leu Met Pro Val Ala Leu Thr Ile Ala Arg Tyr Leu Leu Ser
100 105 110
Pro Pro Pro Ile Thr Ala Leu Leu Pro Ser Cys Leu Leu Gly Ser Leu
115 120 125
Ser Phe Ser Cys Leu Phe Thr Phe Gln Thr Ser Ser Leu Ile Pro Leu
130 135 140
Trp Lys Ile Pro Ala Pro Thr Thr Thr Lys Ser Cys Arg Glu Thr Phe
145 150 155 160
Leu Lys Trp

248

85

PRT

Homo sapiens

248
Ser Pro Gly Cys His Leu Gly Pro Gly Asp Gln Ala Ala Pro Gly Leu
1 5 10 15
His Arg Pro Pro Ser Pro Trp Cys His Leu Gly Ala Gly Gln Gln Ala
20 25 30
Arg Leu Gly Val His Arg Pro Ser Ser Pro Gln Cys His Leu Gly Leu
35 40 45
Arg Leu Cys Ile Arg Leu Ser Phe Tyr Ser Gly Ala Gln Arg His Leu
50 55 60
Cys Gln Gly Tyr His Asn Pro Ser Gln Gln Glu His Ser Ile Leu Asn
65 70 75 80
Ser Gln Pro Pro Leu
85

249

172

PRT

Homo sapiens

249
Lys Pro Ala Pro Gly Ser Thr Ala Pro Gln Pro Pro Val Ser Pro Arg
1 5 10 15
Pro Arg Arg Pro Gly Arg Pro Arg Ala Pro Pro Pro Pro Gln Pro Met
20 25 30
Val Ser Pro Arg Arg Arg Thr Thr Gly Pro Pro Trp Arg Pro Pro Pro
35 40 45
Leu Gln Ser Thr Met Ser Pro Pro Pro Gln Ala Leu His Gln Ala Gln
50 55 60
Leu Leu Leu Trp Cys Thr Thr Ala Pro Leu Pro Gly Leu Pro Gln Pro
65 70 75 80
Gln Pro Ala Arg Ala Leu His Ser Gln Phe Pro Ala Thr Thr Leu Ile
85 90 95
Leu Leu Pro Pro Leu Pro Ala Ile Ala Pro Arg Leu Met Pro Val Ala
100 105 110
Leu Thr Ile Ala Arg Tyr Leu Leu Ser Pro Pro Pro Ile Thr Ala Leu
115 120 125
Leu Pro Ser Cys Leu Leu Gly Ser Leu Ser Phe Ser Cys Leu Phe Thr
130 135 140
Phe Gln Thr Ser Ser Leu Ile Pro Leu Trp Lys Ile Pro Ala Pro Thr
145 150 155 160
Thr Thr Lys Ser Cys Arg Glu Thr Phe Leu Lys Trp
165 170

250

173

PRT

Homo sapiens

250
Lys Pro Ala Pro Gly Ser Thr Ala Pro Pro Gln Pro Pro Val Ser Pro
1 5 10 15
Arg Pro Arg Arg Pro Gly Arg Pro Arg Ala Pro Pro Pro Pro Gln Pro
20 25 30
Met Val Ser Pro Arg Arg Arg Thr Thr Gly Pro Pro Trp Arg Pro Pro
35 40 45
Pro Leu Gln Ser Thr Met Ser Pro Pro Pro Gln Ala Leu His Gln Ala
50 55 60
Gln Leu Leu Leu Trp Cys Thr Thr Ala Pro Leu Pro Gly Leu Pro Gln
65 70 75 80
Pro Gln Pro Ala Arg Ala Leu His Ser Gln Phe Pro Ala Thr Thr Leu
85 90 95
Ile Leu Leu Pro Pro Leu Pro Ala Ile Ala Pro Arg Leu Met Pro Val
100 105 110
Ala Leu Thr Ile Ala Arg Tyr Leu Leu Ser Pro Pro Pro Ile Thr Ala
115 120 125
Leu Leu Pro Ser Cys Leu Leu Gly Ser Leu Ser Phe Ser Cys Leu Phe
130 135 140
Thr Phe Gln Thr Ser Ser Leu Ile Pro Leu Trp Lys Ile Pro Ala Pro
145 150 155 160
Thr Thr Thr Lys Ser Cys Arg Glu Thr Phe Leu Lys Trp
165 170

251

95

PRT

Homo sapiens

251
Lys Pro Ala Pro Gly Ser Thr Ala Pro Pro Ser Pro Gly Cys His Leu
1 5 10 15
Gly Pro Gly Asp Gln Ala Ala Pro Gly Leu His Arg Pro Pro Ser Pro
20 25 30
Trp Cys His Leu Gly Ala Gly Gln Gln Ala Arg Leu Gly Val His Arg
35 40 45
Pro Ser Ser Pro Gln Cys His Leu Gly Leu Arg Leu Cys Ile Arg Leu
50 55 60
Ser Phe Tyr Ser Gly Ala Gln Arg His Leu Cys Gln Gly Tyr His Asn
65 70 75 80
Pro Ser Gln Gln Glu His Ser Ile Leu Asn Ser Gln Pro Pro Leu
85 90 95

252

94

PRT

Homo sapiens

252
Lys Pro Ala Pro Gly Ser Thr Ala Pro Ser Pro Gly Cys His Leu Gly
1 5 10 15
Pro Gly Asp Gln Ala Ala Pro Gly Leu His Arg Pro Pro Ser Pro Trp
20 25 30
Cys His Leu Gly Ala Gly Gln Gln Ala Arg Leu Gly Val His Arg Pro
35 40 45
Ser Ser Pro Gln Cys His Leu Gly Leu Arg Leu Cys Ile Arg Leu Ser
50 55 60
Phe Tyr Ser Gly Ala Gln Arg His Leu Cys Gln Gly Tyr His Asn Pro
65 70 75 80
Ser Gln Gln Glu His Ser Ile Leu Asn Ser Gln Pro Pro Leu
85 90

253

143

PRT

Homo sapiens

253
Gln Pro Met Val Ser Pro Arg Arg Arg Thr Thr Gly Pro Pro Trp Arg
1 5 10 15
Pro Pro Pro Leu Gln Ser Thr Met Ser Pro Pro Pro Gln Ala Leu His
20 25 30
Gln Ala Gln Leu Leu Leu Trp Cys Thr Thr Ala Pro Leu Pro Gly Leu
35 40 45
Pro Gln Pro Gln Pro Ala Arg Ala Leu His Ser Gln Phe Pro Ala Thr
50 55 60
Thr Leu Ile Leu Leu Pro Pro Leu Pro Ala Ile Ala Pro Arg Leu Met
65 70 75 80
Pro Val Ala Leu Thr Ile Ala Arg Tyr Leu Leu Ser Pro Pro Pro Ile
85 90 95
Thr Ala Leu Leu Pro Ser Cys Leu Leu Gly Ser Leu Ser Phe Ser Cys
100 105 110
Leu Phe Thr Phe Gln Thr Ser Ser Leu Ile Pro Leu Trp Lys Ile Pro
115 120 125
Ala Pro Thr Thr Thr Lys Ser Cys Arg Glu Thr Phe Leu Lys Trp
130 135 140

254

65

PRT

Homo sapiens

254
Ser Pro Trp Cys His Leu Gly Ala Gly Gln Gln Ala Arg Leu Gly Val
1 5 10 15
His Arg Pro Ser Ser Pro Gln Cys His Leu Gly Leu Arg Leu Cys Ile
20 25 30
Arg Leu Ser Phe Tyr Ser Gly Ala Gln Arg His Leu Cys Gln Gly Tyr
35 40 45
His Asn Pro Ser Gln Gln Glu His Ser Ile Leu Asn Ser Gln Pro Pro
50 55 60
Leu
65

255

18

PRT

Homo sapiens

255
Arg Pro Pro Pro Gly Ser Thr Ala Pro Gln Pro Met Val Ser Pro Arg
1 5 10 15
Arg Arg

256

19

PRT

Homo sapiens

256
Arg Pro Pro Pro Gly Ser Thr Ala Pro Pro Gln Pro Met Val Ser Pro
1 5 10 15
Arg Arg Arg

257

18

PRT

Homo sapiens

257
Arg Pro Pro Pro Gly Ser Thr Ala Pro Pro Ser Pro Trp Cys His Leu
1 5 10 15
Gly Ala

258

17

PRT

Homo sapiens

258
Arg Pro Pro Pro Gly Ser Thr Ala Pro Ser Pro Trp Cys His Leu Gly
1 5 10 15
Ala

259

14

PRT

Homo sapiens

259
Arg Pro Arg Ala Pro Pro Pro Pro Ser Pro Trp Cys His Leu
1 5 10

260

13

PRT

Homo sapiens

260
Arg Pro Arg Ala Pro Pro Pro Pro Pro Ser Pro Trp Cys
1 5 10

261

16

PRT

Homo sapiens

261
Arg Pro Arg Ala Pro Pro Pro Pro Ala His Gly Val Thr Ser Ala Pro
1 5 10 15

262

13

PRT

Homo sapiens

262
Arg Pro Arg Ala Pro Pro Pro Pro Pro Ala His Gly Val
1 5 10

263

14

PRT

Homo sapiens

263
Ala Pro Gly Leu His Arg Pro Pro Gln Pro Met Val Ser Pro
1 5 10

264

15

PRT

Homo sapiens

264
Ala Ala Pro Gly Leu His Arg Pro Gln Pro Met Val Ser Pro Arg
1 5 10 15

265

13

PRT

Homo sapiens

265
Pro Gly Leu His Arg Pro Pro Pro Ala His Gly Val Thr
1 5 10

266

14

PRT

Homo sapiens

266
Ala Pro Gly Leu His Arg Pro Pro Ala His Gly Val Thr Ser
1 5 10

267

21

PRT

Homo sapiens

267
Val Asp Arg Pro Gln His Thr Glu Trp Leu Ser Trp Ser Asn Leu Tyr
1 5 10 15
Arg Ile Arg His Gln
20

268

10

PRT

Homo sapiens

268
His Tyr Leu Cys Thr Asp Val Ala Pro Arg
1 5 10

269

11

PRT

Homo sapiens

269
His Tyr Leu Cys Thr Asp Val Ala Pro Pro Arg
1 5 10

270

31

PRT

Homo sapiens

270
His Tyr Leu Cys Thr Asp Val Ala Pro Pro Val Asp Arg Pro Gln His
1 5 10 15
Thr Glu Trp Leu Ser Trp Ser Asn Leu Tyr Arg Ile Arg His Gln
20 25 30

271

30

PRT

Homo sapiens

271
His Tyr Leu Cys Thr Asp Val Ala Pro Val Asp Arg Pro Gln His Thr
1 5 10 15
Glu Trp Leu Ser Trp Ser Asn Leu Tyr Arg Ile Arg His Gln
20 25 30

272

108

PRT

Homo sapiens

272
Ser Ala Tyr Leu Ser Pro Leu Gly Thr Thr Trp Leu Arg Thr Cys Ala
1 5 10 15
Cys Arg Leu Pro Arg Pro Ala Ala Ser Cys Leu Cys Thr Thr Pro Ser
20 25 30
Leu Leu Trp Pro Arg Arg Thr Cys Pro Ala Gly Ser Pro Arg Ala Thr
35 40 45
Ser Ser Pro Trp Arg Met Pro Ala Pro Lys Ser Cys Cys Thr Thr Gly
50 55 60
Leu Ala Phe Thr Ser Pro Ile Gly Leu Gly Trp Arg Ser Ala Thr Ala
65 70 75 80
Ser Gly Tyr Ala Arg Ile Trp Pro Val Leu Ser Leu Thr Cys Gln Ser
85 90 95
Trp Ser Thr Ser Leu Pro Ser Thr Ala Val Thr Trp
100 105

273

109

PRT

Homo sapiens

273
Pro Ser Ala Tyr Leu Ser Pro Leu Gly Thr Thr Trp Leu Arg Thr Cys
1 5 10 15
Ala Cys Arg Leu Pro Arg Pro Ala Ala Ser Cys Leu Cys Thr Thr Pro
20 25 30
Ser Leu Leu Trp Pro Arg Arg Thr Cys Pro Ala Gly Ser Pro Arg Ala
35 40 45
Thr Ser Ser Pro Trp Arg Met Pro Ala Pro Lys Ser Cys Cys Thr Thr
50 55 60
Gly Leu Ala Phe Thr Ser Pro Ile Gly Leu Gly Trp Arg Ser Ala Thr
65 70 75 80
Ala Ser Gly Tyr Ala Arg Ile Trp Pro Val Leu Ser Leu Thr Cys Gln
85 90 95
Ser Trp Ser Thr Ser Leu Pro Ser Thr Ala Val Thr Trp
100 105

274

12

PRT

Homo sapiens

274
Pro Ala Pro Ile Phe Leu Leu Trp Gly Pro Leu Gly
1 5 10

275

11

PRT

Homo sapiens

275
Ala Pro Ile Phe Leu Leu Trp Gly Pro Leu Gly
1 5 10

276

117

PRT

Homo sapiens

276
Leu Pro Ala Arg Ala Pro Gly Pro Pro Ser Ala Tyr Leu Ser Pro Leu
1 5 10 15
Gly Thr Thr Trp Leu Arg Thr Cys Ala Cys Arg Leu Pro Arg Pro Ala
20 25 30
Ala Ser Cys Leu Cys Thr Thr Pro Ser Leu Leu Trp Pro Arg Arg Thr
35 40 45
Cys Pro Ala Gly Ser Pro Arg Ala Thr Ser Ser Pro Trp Arg Met Pro
50 55 60
Ala Pro Lys Ser Cys Cys Thr Thr Gly Leu Ala Phe Thr Ser Pro Ile
65 70 75 80
Gly Leu Gly Trp Arg Ser Ala Thr Ala Ser Gly Tyr Ala Arg Ile Trp
85 90 95
Pro Val Leu Ser Leu Thr Cys Gln Ser Trp Ser Thr Ser Leu Pro Ser
100 105 110
Thr Ala Val Thr Trp
115

277

118

PRT

Homo sapiens

277
Leu Pro Ala Arg Ala Pro Gly Pro Pro Pro Ser Ala Tyr Leu Ser Pro
1 5 10 15
Leu Gly Thr Thr Trp Leu Arg Thr Cys Ala Cys Arg Leu Pro Arg Pro
20 25 30
Ala Ala Ser Cys Leu Cys Thr Thr Pro Ser Leu Leu Trp Pro Arg Arg
35 40 45
Thr Cys Pro Ala Gly Ser Pro Arg Ala Thr Ser Ser Pro Trp Arg Met
50 55 60
Pro Ala Pro Lys Ser Cys Cys Thr Thr Gly Leu Ala Phe Thr Ser Pro
65 70 75 80
Ile Gly Leu Gly Trp Arg Ser Ala Thr Ala Ser Gly Tyr Ala Arg Ile
85 90 95
Trp Pro Val Leu Ser Leu Thr Cys Gln Ser Trp Ser Thr Ser Leu Pro
100 105 110
Ser Thr Ala Val Thr Trp
115

278

21

PRT

Homo sapiens

278
Leu Pro Ala Arg Ala Pro Gly Pro Pro Pro Ala Pro Ile Phe Leu Leu
1 5 10 15
Trp Gly Pro Leu Gly
20

279

20

PRT

Homo sapiens

279
Leu Pro Ala Arg Ala Pro Gly Pro Pro Ala Pro Ile Phe Leu Leu Trp
1 5 10 15
Gly Pro Leu Gly
20

280

14

PRT

Homo sapiens

280
Asp Leu Glu His His Gly Gly Val Thr Arg His Arg His Arg
1 5 10

281

11

PRT

Homo sapiens

281
Leu Val Ser Asp Tyr Ser Met Thr Pro Arg Pro
1 5 10

282

12

PRT

Homo sapiens

282
Leu Val Ser Asp Tyr Ser Met Thr Pro Pro Arg Pro
1 5 10

283

24

PRT

Homo sapiens

283
Leu Val Ser Asp Tyr Ser Met Thr Pro Pro Asp Leu Glu His His Gly
1 5 10 15
Gly Val Thr Arg His Arg His Arg
20

284

23

PRT

Homo sapiens

284
Leu Val Ser Asp Tyr Ser Met Thr Pro Asp Leu Glu His His Gly Gly
1 5 10 15
Val Thr Arg His Arg His Arg
20

285

51

PRT

Homo sapiens

285
Phe His His Ile Ala Thr Asp Val Gly Pro Phe Val Arg Ile Gly Phe
1 5 10 15
Leu Lys Ile Lys Gly Lys Ile Lys Gly Lys Ser Leu Arg Lys Pro Asn
20 25 30
Trp Lys Thr Gln His Lys Leu Lys Arg Ala Leu Met Phe Leu Ile Val
35 40 45
Lys Lys Leu
50

286

52

PRT

Homo sapiens

286
Pro Phe His His Ile Ala Thr Asp Val Gly Pro Phe Val Arg Ile Gly
1 5 10 15
Phe Leu Lys Ile Lys Gly Lys Ile Lys Gly Lys Ser Leu Arg Lys Pro
20 25 30
Asn Trp Lys Thr Gln His Lys Leu Lys Arg Ala Leu Met Phe Leu Ile
35 40 45
Val Lys Lys Leu
50

287

12

PRT

Homo sapiens

287
Pro Ser Ile Thr Leu Gln Gln Met Leu Ala Pro Ser
1 5 10

288

11

PRT

Homo sapiens

288
Ser Ile Thr Leu Gln Gln Met Leu Ala Pro Ser
1 5 10

289

60

PRT

Homo sapiens

289
Thr Ser Cys Asn Glu Met Asn Pro Pro Phe His His Ile Ala Thr Asp
1 5 10 15
Val Gly Pro Phe Val Arg Ile Gly Phe Leu Lys Ile Lys Gly Lys Ile
20 25 30
Lys Gly Lys Ser Leu Arg Lys Pro Asn Trp Lys Thr Gln His Lys Leu
35 40 45
Lys Arg Ala Leu Met Phe Leu Ile Val Lys Lys Leu
50 55 60

290

61

PRT

Homo sapiens

290
Thr Ser Cys Asn Glu Met Asn Pro Pro Pro Phe His His Ile Ala Thr
1 5 10 15
Asp Val Gly Pro Phe Val Arg Ile Gly Phe Leu Lys Ile Lys Gly Lys
20 25 30
Ile Lys Gly Lys Ser Leu Arg Lys Pro Asn Trp Lys Thr Gln His Lys
35 40 45
Leu Lys Arg Ala Leu Met Phe Leu Ile Val Lys Lys Leu
50 55 60

291

20

PRT

Homo sapiens

291
Thr Ser Cys Asn Glu Met Asn Pro Pro Ser Ile Thr Leu Gln Gln Met
1 5 10 15
Leu Ala Pro Ser
20

292

21

PRT

Homo sapiens

292
Thr Ser Cys Asn Glu Met Asn Pro Pro Pro Ser Ile Thr Leu Gln Gln
1 5 10 15
Met Leu Ala Pro Ser
20

293

10

PRT

Homo sapiens

293
Leu Glu Met Ile Leu Phe Leu Met Thr Phe
1 5 10

294

18

PRT

Homo sapiens

294
His Pro Cys Ile Thr Lys Thr Phe Leu Glu Met Ile Leu Phe Leu Met
1 5 10 15
Thr Phe

295

19

PRT

Homo sapiens

295
His Pro Cys Ile Thr Lys Thr Phe Phe Leu Glu Met Ile Leu Phe Leu
1 5 10 15
Met Thr Phe

296

11

PRT

Homo sapiens

296
His Pro Cys Ile Thr Lys Thr Phe Phe Trp Arg
1 5 10

297

10

PRT

Homo sapiens

297
His Pro Cys Ile Thr Lys Thr Phe Trp Arg
1 5 10

298

22

PRT

Homo sapiens

298
Leu Met Phe Glu His Ser Gln Met Arg Leu Asn Ser Lys Asn Ala His
1 5 10 15
Leu Pro Ile Ile Ser Phe
20

299

30

PRT

Homo sapiens

299
Glu Tyr Gly Ser Ile Ile Ala Phe Leu Met Phe Glu His Ser Gln Met
1 5 10 15
Arg Leu Asn Ser Lys Asn Ala His Leu Pro Ile Ile Ser Phe
20 25 30

300

31

PRT

Homo sapiens

300
Glu Tyr Gly Ser Ile Ile Ala Phe Phe Leu Met Phe Glu His Ser Gln
1 5 10 15
Met Arg Leu Asn Ser Lys Asn Ala His Leu Pro Ile Ile Ser Phe
20 25 30

301

15

PRT

Homo sapiens

301
His Leu Asn Lys Gly Arg Arg Leu Gly Asp Lys Ile Arg Ala Thr
1 5 10 15

302

16

PRT

Homo sapiens

302
Phe His Leu Asn Lys Gly Arg Arg Leu Gly Asp Lys Ile Arg Ala Thr
1 5 10 15

303

23

PRT

Homo sapiens

303
Val Thr Ser Gly Thr Pro Phe Phe His Leu Asn Lys Gly Arg Arg Leu
1 5 10 15
Gly Asp Lys Ile Arg Ala Thr
20

304

24

PRT

Homo sapiens

304
Val Thr Ser Gly Thr Pro Phe Phe Phe His Leu Asn Lys Gly Arg Arg
1 5 10 15
Leu Gly Asp Lys Ile Arg Ala Thr
20

305

10

PRT

Homo sapiens

305
Val Thr Ser Gly Thr Pro Phe Phe Phe Ile
1 5 10

306

9

PRT

Homo sapiens

306
Val Thr Ser Gly Thr Pro Phe Phe Ile
1 5

307

10

PRT

Homo sapiens

307
Cys Glu Ile Glu Arg Ile His Phe Phe Phe
1 5 10

308

11

PRT

Homo sapiens

308
Cys Glu Ile Glu Arg Ile His Phe Phe Ser Lys
1 5 10

309

10

PRT

Homo sapiens

309
Cys Glu Ile Glu Arg Ile His Phe Ser Lys
1 5 10

310

8

PRT

Homo sapiens

310
Phe Arg Tyr Ile Ser Lys Ser Ile
1 5

311

7

PRT

Homo sapiens

311
Arg Tyr Ile Ser Lys Ser Ile
1 5

312

16

PRT

Homo sapiens

312
Phe Lys Lys Tyr Glu Pro Ile Phe Phe Arg Tyr Ile Ser Lys Ser Ile
1 5 10 15

313

15

PRT

Homo sapiens

313
Phe Lys Lys Tyr Glu Pro Ile Phe Arg Tyr Ile Ser Lys Ser Ile
1 5 10 15

314

56

PRT

Homo sapiens

314
Phe Pro Asp Ser Asp Gln Pro Gly Pro Leu Tyr Pro Leu Asp Pro Ser
1 5 10 15
Cys Leu Ile Ser Ser Ala Ser Asn Pro Gln Glu Leu Ser Asp Cys His
20 25 30
Tyr Ile His Leu Ala Phe Gly Phe Ser Asn Trp Arg Ser Cys Pro Val
35 40 45
Leu Pro Gly His Cys Gly Val Gln
50 55

315

55

PRT

Homo sapiens

315
Pro Asp Ser Asp Gln Pro Gly Pro Leu Tyr Pro Leu Asp Pro Ser Cys
1 5 10 15
Leu Ile Ser Ser Ala Ser Asn Pro Gln Glu Leu Ser Asp Cys His Tyr
20 25 30
Ile His Leu Ala Phe Gly Phe Ser Asn Trp Arg Ser Cys Pro Val Leu
35 40 45
Pro Gly His Cys Gly Val Gln
50 55

316

9

PRT

Homo sapiens

316
Leu Asn Met Phe Ala Ser Val Phe Ser
1 5

317

10

PRT

Homo sapiens

317
Leu Asn Met Phe Ala Ser Val Phe Phe Ser
1 5 10

318

64

PRT

Homo sapiens

318
Leu Asn Met Phe Ala Ser Val Phe Phe Pro Asp Ser Asp Gln Pro Gly
1 5 10 15
Pro Leu Tyr Pro Leu Asp Pro Ser Cys Leu Ile Ser Ser Ala Ser Asn
20 25 30
Pro Gln Glu Leu Ser Asp Cys His Tyr Ile His Leu Ala Phe Gly Phe
35 40 45
Ser Asn Trp Arg Ser Cys Pro Val Leu Pro Gly His Cys Gly Val Gln
50 55 60

319

63

PRT

Homo sapiens

319
Leu Asn Met Phe Ala Ser Val Phe Pro Asp Ser Asp Gln Pro Gly Pro
1 5 10 15
Leu Tyr Pro Leu Asp Pro Ser Cys Leu Ile Ser Ser Ala Ser Asn Pro
20 25 30
Gln Glu Leu Ser Asp Cys His Tyr Ile His Leu Ala Phe Gly Phe Ser
35 40 45
Asn Trp Arg Ser Cys Pro Val Leu Pro Gly His Cys Gly Val Gln
50 55 60

320

63

PRT

Homo sapiens

320
Ala Met Glu Glu Thr Val Val Val Ala Val Ala Thr Val Glu Thr Glu
1 5 10 15
Val Glu Ala Met Glu Glu Thr Gly Val Val Ala Ala Met Glu Glu Thr
20 25 30
Glu Val Gly Ala Thr Glu Glu Thr Glu Val Ala Met Glu Ala Lys Trp
35 40 45
Glu Glu Glu Thr Thr Thr Glu Met Ile Ser Ala Thr Asp His Thr
50 55 60

321

55

PRT

Homo sapiens

321
Leu Trp Val Arg Pro Trp Leu Trp Glu Trp Leu Arg Trp Arg Pro Lys
1 5 10 15
Trp Arg Leu Trp Arg Arg Gln Glu Trp Trp Arg Leu Trp Arg Arg Pro
20 25 30
Arg Trp Gly Leu Arg Arg Arg Pro Arg Trp Leu Trp Arg Glu Asn Gly
35 40 45
Arg Lys Lys Arg Leu Gln Lys
50 55

322

71

PRT

Homo sapiens

322
Tyr Gly Gly Asp Arg Ser Arg Gly Ala Met Glu Glu Thr Val Val Val
1 5 10 15
Ala Val Ala Thr Val Glu Thr Glu Val Glu Ala Met Glu Glu Thr Gly
20 25 30
Val Val Ala Ala Met Glu Glu Thr Glu Val Gly Ala Thr Glu Glu Thr
35 40 45
Glu Val Ala Met Glu Ala Lys Trp Glu Glu Glu Thr Thr Thr Glu Met
50 55 60
Ile Ser Ala Thr Asp His Thr
65 70

323

72

PRT

Homo sapiens

323
Tyr Gly Gly Asp Arg Ser Arg Gly Gly Ala Met Glu Glu Thr Val Val
1 5 10 15
Val Ala Val Ala Thr Val Glu Thr Glu Val Glu Ala Met Glu Glu Thr
20 25 30
Gly Val Val Ala Ala Met Glu Glu Thr Glu Val Gly Ala Thr Glu Glu
35 40 45
Thr Glu Val Ala Met Glu Ala Lys Trp Glu Glu Glu Thr Thr Thr Glu
50 55 60
Met Ile Ser Ala Thr Asp His Thr
65 70

324

64

PRT

Homo sapiens

324
Tyr Gly Gly Asp Arg Ser Arg Gly Gly Leu Trp Val Arg Pro Trp Leu
1 5 10 15
Trp Glu Trp Leu Arg Trp Glu Pro Lys Trp Arg Leu Trp Arg Arg Gln
20 25 30
Glu Trp Trp Arg Leu Trp Arg Arg Pro Arg Trp Gly Leu Arg Arg Arg
35 40 45
Pro Arg Trp Leu Trp Arg Glu Asn Gly Arg Lys Lys Arg Leu Gln Lys
50 55 60

325

63

PRT

Homo sapiens

325
Tyr Gly Gly Asp Arg Ser Arg Gly Leu Trp Val Arg Pro Trp Leu Trp
1 5 10 15
Glu Trp Leu Arg Trp Glu Pro Lys Trp Arg Leu Trp Arg Arg Gln Glu
20 25 30
Trp Trp Arg Leu Trp Arg Arg Pro Arg Trp Gly Leu Arg Arg Arg Pro
35 40 45
Arg Trp Leu Trp Arg Glu Asn Gly Arg Lys Lys Arg Leu Gln Lys
50 55 60

326

9

PRT

Homo sapiens

326
Glu Phe Gly Gly Gly Arg Arg Gln Lys
1 5

327

8

PRT

Homo sapiens

327
Glu Phe Gly Gly Arg Arg Gln Lys
1 5

328

15

PRT

Homo sapiens

328
Arg Arg Ala Lys Gly Gly Gly Ala Gly Ala Ser Asn Pro Arg Gln
1 5 10 15

329

16

PRT

Homo sapiens

329
Gly Arg Arg Ala Lys Gly Gly Gly Ala Gly Ala Ser Asn Pro Arg Gln
1 5 10 15

330

21

PRT

Homo sapiens

330
Asp Val Gly Leu Arg Glu Gly Ala Leu Glu Leu Pro Thr Arg Gly Asn
1 5 10 15
Lys Arg Asn Val Ala
20

331

24

PRT

Homo sapiens

331
Met Arg Gly Gly Gly Gly Val Gly Gly Arg Arg Ala Lys Gly Gly Gly
1 5 10 15
Ala Gly Ala Ser Asn Pro Arg Gln
20

332

25

PRT

Homo sapiens

332
Met Arg Gly Gly Gly Gly Val Gly Gly Gly Arg Arg Ala Lys Gly Gly
1 5 10 15
Gly Ala Gly Ala Ser Asn Pro Arg Gln
20 25

333

30

PRT

Homo sapiens

333
Met Arg Gly Gly Gly Gly Val Gly Gly Asp Val Gly Leu Arg Glu Gly
1 5 10 15
Ala Leu Glu Leu Pro Thr Arg Gly Asn Lys Arg Asn Val Ala
20 25 30

334

29

PRT

Homo sapiens

334
Met Arg Gly Gly Gly Gly Val Gly Asp Val Gly Leu Arg Glu Gly Ala
1 5 10 15
Leu Glu Leu Pro Thr Arg Gly Asn Lys Arg Asn Val Ala
20 25

335

25

PRT

Homo sapiens

335
Val Trp Gln Leu Ala Gly Pro Met Leu Ala Gly Trp Arg Ser Leu Gly
1 5 10 15
Ser Trp Phe Cys Arg Met Tyr Gly Ile
20 25

336

46

PRT

Homo sapiens

336
Cys Gly Ser Trp Pro Ala Leu Cys Trp Arg Ala Gly Gly Val Trp Ala
1 5 10 15
Val Gly Ser Ala Gly Cys Met Glu Tyr Asp Pro Glu Ala Leu Pro Ala
20 25 30
Ala Trp Gly Pro Ala Ala Ala Ala Thr Val His Pro Arg Arg
35 40 45

337

33

PRT

Homo sapiens

337
Arg Arg Tyr Pro Cys Glu Trp Gly Val Trp Gln Leu Ala Gly Pro Met
1 5 10 15
Leu Ala Gly Trp Arg Ser Leu Gly Ser Trp Phe Cys Arg Met Tyr Gly
20 25 30
Ile

338

34

PRT

Homo sapiens

338
Arg Arg Tyr Pro Cys Glu Trp Gly Gly Val Trp Gln Leu Ala Gly Pro
1 5 10 15
Met Leu Ala Gly Trp Arg Ser Leu Gly Ser Trp Phe Cys Arg Met Tyr
20 25 30
Gly Ile

339

55

PRT

Homo sapiens

339
Arg Arg Tyr Pro Cys Glu Trp Gly Gly Cys Gly Ser Trp Pro Ala Leu
1 5 10 15
Cys Trp Arg Ala Gly Gly Val Trp Ala Val Gly Ser Ala Gly Cys Met
20 25 30
Glu Tyr Asp Pro Glu Ala Leu Pro Ala Ala Trp Gly Pro Ala Ala Ala
35 40 45
Ala Thr Val His Pro Arg Arg
50 55

340

54

PRT

Homo sapiens

340
Arg Arg Tyr Pro Cys Glu Trp Gly Cys Gly Ser Trp Pro Ala Leu Cys
1 5 10 15
Trp Arg Ala Gly Gly Val Trp Ala Val Gly Ser Ala Gly Cys Met Glu
20 25 30
Tyr Asp Pro Glu Ala Leu Pro Ala Ala Trp Gly Pro Ala Ala Ala Ala
35 40 45
Thr Val His Pro Arg Arg
50

341

43

PRT

Homo sapiens

341
Leu Trp Leu Trp Ala Gly Trp Thr Val Trp Trp Ser Cys Gly Pro Gly
1 5 10 15
Glu Lys Gly His Gly Trp Pro Ser Leu Pro Thr Met Ala Leu Leu Leu
20 25 30
Leu Arg Phe Ser Cys Met Arg Val Ala Ser Tyr
35 40

342

44

PRT

Homo sapiens

342
Gly Leu Trp Leu Trp Ala Gly Trp Thr Val Trp Trp Ser Cys Gly Pro
1 5 10 15
Gly Glu Lys Gly His Gly Trp Pro Ser Leu Pro Thr Met Ala Leu Leu
20 25 30
Leu Leu Arg Phe Ser Cys Met Arg Val Ala Ser Tyr
35 40

343

84

PRT

Homo sapiens

343
Gly Cys Gly Cys Gly Pro Ala Gly Gln Tyr Gly Gly Ala Val Gly Leu
1 5 10 15
Ala Arg Arg Gly Thr Ala Gly Cys Leu Pro Cys Pro Pro Trp Leu Cys
20 25 30
Cys Cys Cys Ala Phe Pro Ala Cys Gly Leu Pro Gly Thr Asp Gly Trp
35 40 45
Arg Gly Trp Gln Gly Ser Gly Cys Val Arg Val Ser Gly Ser Ala Pro
50 55 60
Trp Ala Pro Gly Phe Pro Phe Ser Pro Pro Cys Pro Leu Cys Gly Thr
65 70 75 80
Gln Pro Arg Trp

344

83

PRT

Homo sapiens

344
Cys Gly Cys Gly Pro Ala Gly Gln Tyr Gly Gly Ala Val Gly Leu Ala
1 5 10 15
Arg Arg Gly Thr Ala Gly Cys Leu Pro Cys Pro Pro Trp Leu Cys Cys
20 25 30
Cys Cys Ala Phe Pro Ala Cys Gly Leu Pro Gly Thr Asp Gly Trp Arg
35 40 45
Gly Trp Gln Gly Ser Gly Cys Val Arg Val Ser Gly Ser Ala Pro Trp
50 55 60
Ala Pro Gly Phe Pro Phe Ser Pro Pro Cys Pro Leu Cys Gly Thr Gln
65 70 75 80
Pro Arg Trp

345

51

PRT

Homo sapiens

345
Leu Ala Phe Asn Val Pro Gly Gly Leu Trp Leu Trp Ala Gly Trp Thr
1 5 10 15
Val Trp Trp Ser Cys Gly Pro Gly Glu Lys Gly His Gly Trp Pro Ser
20 25 30
Leu Pro Thr Met Ala Leu Leu Leu Leu Arg Phe Ser Cys Met Arg Val
35 40 45
Ala Ser Tyr
50

346

52

PRT

Homo sapiens

346
Leu Ala Phe Asn Val Pro Gly Gly Gly Leu Trp Leu Trp Ala Gly Trp
1 5 10 15
Thr Val Trp Trp Ser Cys Gly Pro Gly Glu Lys Gly His Gly Trp Pro
20 25 30
Ser Leu Pro Thr Met Ala Leu Leu Leu Leu Arg Phe Ser Cys Met Arg
35 40 45
Val Ala Ser Tyr
50

347

92

PRT

Homo sapiens

347
Leu Ala Phe Asn Val Pro Gly Gly Gly Cys Gly Cys Gly Pro Ala Gly
1 5 10 15
Gln Tyr Gly Gly Ala Val Gly Leu Ala Arg Arg Gly Thr Ala Gly Cys
20 25 30
Leu Pro Cys Pro Pro Trp Leu Cys Cys Cys Cys Ala Phe Pro Ala Cys
35 40 45
Gly Leu Pro Gly Thr Asp Gly Trp Arg Gly Trp Gln Gly Ser Gly Cys
50 55 60
Val Arg Val Ser Gly Ser Ala Pro Trp Ala Pro Gly Phe Pro Phe Ser
65 70 75 80
Pro Pro Cys Pro Leu Cys Gly Thr Gln Pro Arg Trp
85 90

348

91

PRT

Homo sapiens

348
Leu Ala Phe Asn Val Pro Gly Gly Cys Gly Cys Gly Pro Ala Gly Gln
1 5 10 15
Tyr Gly Gly Ala Val Gly Leu Ala Arg Arg Gly Thr Ala Gly Cys Leu
20 25 30
Pro Cys Pro Pro Trp Leu Cys Cys Cys Cys Ala Phe Pro Ala Cys Gly
35 40 45
Leu Pro Gly Thr Asp Gly Trp Arg Gly Trp Gln Gly Ser Gly Cys Val
50 55 60
Arg Val Ser Gly Ser Ala Pro Trp Ala Pro Gly Phe Pro Phe Ser Pro
65 70 75 80
Pro Cys Pro Leu Cys Gly Thr Gln Pro Arg Trp
85 90

349

17

PRT

Homo sapiens

349
Pro Pro Met Pro Met Pro Gly Gln Arg Glu Ala Pro Gly Arg Gln Glu
1 5 10 15
Ala

350

18

PRT

Homo sapiens

350
Gly Pro Pro Met Pro Met Pro Gly Gln Arg Glu Ala Pro Gly Arg Gln
1 5 10 15
Glu Ala

351

24

PRT

Homo sapiens

351
Gly His Gln Cys Gln Cys Gln Gly Lys Gly Arg His Arg Ala Asp Arg
1 5 10 15
Arg Pro Asp Thr Ala Gln Glu Glu
20

352

23

PRT

Homo sapiens

352
His Gln Cys Gln Cys Gln Gly Lys Gly Arg His Arg Ala Asp Arg Arg
1 5 10 15
Pro Asp Thr Ala Gln Glu Glu
20

353

25

PRT

Homo sapiens

353
Gly Gly His Ser Tyr Gly Gly Gly Pro Pro Met Pro Met Pro Gly Gln
1 5 10 15
Arg Glu Ala Pro Gly Arg Gln Glu Ala
20 25

354

26

PRT

Homo sapiens

354
Gly Gly His Ser Tyr Gly Gly Gly Gly Pro Pro Met Pro Met Pro Gly
1 5 10 15
Gln Arg Glu Ala Pro Gly Arg Gln Glu Ala
20 25

355

32

PRT

Homo sapiens

355
Gly Gly His Ser Tyr Gly Gly Gly Gly His Gln Cys Gln Cys Gln Gly
1 5 10 15
Lys Gly Arg His Arg Ala Asp Arg Arg Pro Asp Thr Ala Gln Glu Glu
20 25 30

356

31

PRT

Homo sapiens

356
Gly Gly His Ser Tyr Gly Gly Gly His Gln Cys Gln Cys Gln Gly Lys
1 5 10 15
Gly Arg His Arg Ala Asp Arg Arg Pro Asp Thr Ala Gln Glu Glu
20 25 30

357

10

PRT

Homo sapiens

357
Ala Pro Cys Pro Gln Ser Ser Gly Gly Gly
1 5 10

358

17

PRT

Homo sapiens

358
Leu Pro Ala Pro Ser Gln Ala Ala Ala Asp Glu Leu Asp Arg Arg Pro
1 5 10 15
Gly

359

18

PRT

Homo sapiens

359
Thr Lys Val Arg Leu Ile Arg Gly Ala Pro Cys Pro Gln Ser Ser Gly
1 5 10 15
Gly Gly

360

19

PRT

Homo sapiens

360
Thr Lys Val Arg Leu Ile Arg Gly Gly Ala Pro Cys Pro Gln Ser Ser
1 5 10 15
Gly Gly Gly

361

26

PRT

Homo sapiens

361
Thr Lys Val Arg Leu Ile Arg Gly Gly Leu Pro Ala Pro Ser Gln Ala
1 5 10 15
Ala Ala Asp Glu Leu Asp Arg Arg Pro Gly
20 25

362

25

PRT

Homo sapiens

362
Thr Lys Val Arg Leu Ile Arg Gly Leu Pro Ala Pro Ser Gln Ala Ala
1 5 10 15
Ala Asp Glu Leu Asp Arg Arg Pro Gly
20 25

363

45

PRT

Homo sapiens

363
Cys Ser Leu Ala Lys Asp Gly Ser Thr Glu Asp Thr Val Ser Ser Leu
1 5 10 15
Cys Gly Glu Glu Asp Thr Glu Asp Glu Glu Leu Glu Ala Ala Ala Ser
20 25 30
His Leu Asn Lys Asp Leu Tyr Arg Glu Leu Leu Gly Gly
35 40 45

364

46

PRT

Homo sapiens

364
Gly Cys Ser Leu Ala Lys Asp Gly Ser Thr Glu Asp Thr Val Ser Ser
1 5 10 15
Leu Cys Gly Glu Glu Asp Thr Glu Asp Glu Glu Leu Glu Ala Ala Ala
20 25 30
Ser His Leu Asn Lys Asp Leu Tyr Arg Glu Leu Leu Gly Gly
35 40 45

365

21

PRT

Homo sapiens

365
Ala Ala Ala Trp Gln Lys Met Ala Pro Pro Arg Thr Pro Arg Pro Ala
1 5 10 15
Cys Val Ala Arg Arg
20

366

54

PRT

Homo sapiens

366
Glu Asn Ser Arg Pro Lys Arg Gly Gly Cys Ser Leu Ala Lys Asp Gly
1 5 10 15
Ser Thr Glu Asp Thr Val Ser Ser Leu Cys Gly Glu Glu Asp Thr Glu
20 25 30
Asp Glu Glu Leu Glu Ala Ala Ala Ser His Leu Asn Lys Asp Leu Tyr
35 40 45
Arg Glu Leu Leu Gly Gly
50

367

55

PRT

Homo sapiens

367
Glu Asn Ser Arg Pro Lys Arg Gly Gly Gly Cys Ser Leu Ala Lys Asp
1 5 10 15
Gly Ser Thr Glu Asp Thr Val Ser Ser Leu Cys Gly Glu Glu Asp Thr
20 25 30
Glu Asp Glu Glu Leu Glu Ala Ala Ala Ser His Leu Asn Lys Asp Leu
35 40 45
Tyr Arg Glu Leu Leu Gly Gly
50 55

368

30

PRT

Homo sapiens

368
Glu Asn Ser Arg Pro Lys Arg Gly Gly Ala Ala Ala Trp Gln Lys Met
1 5 10 15
Ala Pro Pro Arg Thr Pro Arg Pro Ala Cys Val Ala Arg Arg
20 25 30

369

29

PRT

Homo sapiens

369
Glu Asn Ser Arg Pro Lys Arg Gly Ala Ala Ala Trp Gln Lys Met Ala
1 5 10 15
Pro Pro Arg Thr Pro Arg Pro Ala Cys Val Ala Arg Arg
20 25

370

10

PRT

Homo sapiens

370
His Cys Val Leu Ala Ala Ser Gly Ala Ser
1 5 10

371

11

PRT

Homo sapiens

371
Gly His Cys Val Leu Ala Ala Ser Gly Ala Ser
1 5 10

372

28

PRT

Homo sapiens

372
Gly Thr Ala Ser Ser Arg Pro Leu Gly Leu Pro Lys Pro His Leu His
1 5 10 15
Arg Pro Val Pro Ile Arg His Pro Ser Cys Pro Lys
20 25

373

27

PRT

Homo sapiens

373
Thr Ala Ser Ser Arg Pro Leu Gly Leu Pro Lys Pro His Leu His Arg
1 5 10 15
Pro Val Pro Ile Arg His Pro Ser Cys Pro Lys
20 25

374

18

PRT

Homo sapiens

374
Ala Gly Thr Leu Gln Leu Gly Gly His Cys Val Leu Ala Ala Ser Gly
1 5 10 15
Ala Ser

375

19

PRT

Homo sapiens

375
Ala Gly Thr Leu Gln Leu Gly Gly Gly His Cys Val Leu Ala Ala Ser
1 5 10 15
Gly Ala Ser

376

35

PRT

Homo sapiens

376
Ala Gly Thr Leu Gln Leu Gly Gly Thr Ala Ser Ser Arg Pro Leu Gly
1 5 10 15
Leu Pro Lys Pro His Leu His Arg Pro Val Pro Ile Arg His Pro Ser
20 25 30
Cys Pro Lys
35

377

36

PRT

Homo sapiens

377
Ala Gly Thr Leu Gln Leu Gly Gly Gly Thr Ala Ser Ser Arg Pro Leu
1 5 10 15
Gly Leu Pro Lys Pro His Leu His Arg Pro Val Pro Ile Arg His Pro
20 25 30
Ser Cys Pro Lys
35

378

9

PRT

Homo sapiens

378
Arg Arg Thr Pro Ser Thr Glu Lys Arg
1 5

379

10

PRT

Homo sapiens

379
Arg Arg Thr Pro Ser Thr Glu Lys Lys Arg
1 5 10

380

14

PRT

Homo sapiens

380
Arg Arg Thr Pro Ser Thr Glu Lys Lys Gly Arg Ser Glu Cys
1 5 10

381

13

PRT

Homo sapiens

381
Arg Arg Thr Pro Ser Thr Glu Lys Gly Arg Ser Glu Cys
1 5 10

382

46

PRT

Homo sapiens

382
Ser Thr Thr Lys Cys Gln Ser Gly Thr Ala Glu Thr Tyr Asn Ser Trp
1 5 10 15
Lys Val Lys Asn Leu Gln Leu Glu Pro Arg Arg Val Thr Ser Gln Met
20 25 30
Asn Arg Gln Val Lys Asp Met Thr Ala Ile Leu Ser Gln Ser
35 40 45

383

17

PRT

Homo sapiens

383
Val Gln Pro Asn Ala Ser Gln Ala Gln Gln Lys Pro Thr Thr His Gly
1 5 10 15
Arg

384

54

PRT

Homo sapiens

384
Ser Ser Glu Glu Ile Lys Lys Lys Ser Thr Thr Lys Cys Gln Ser Gly
1 5 10 15
Thr Ala Glu Thr Tyr Asn Ser Trp Lys Val Lys Asn Leu Gln Leu Glu
20 25 30
Pro Arg Arg Val Thr Ser Gln Met Asn Arg Gln Val Lys Asp Met Thr
35 40 45
Ala Ile Leu Ser Gln Ser
50

385

55

PRT

Homo sapiens

385
Ser Ser Glu Glu Ile Lys Lys Lys Lys Ser Thr Thr Lys Cys Gln Ser
1 5 10 15
Gly Thr Ala Glu Thr Tyr Asn Ser Trp Lys Val Lys Asn Leu Gln Leu
20 25 30
Glu Pro Arg Arg Val Thr Ser Gln Met Asn Arg Gln Val Lys Asp Met
35 40 45
Thr Ala Ile Leu Ser Gln Ser
50 55

386

26

PRT

Homo sapiens

386
Ser Ser Glu Glu Ile Lys Lys Lys Lys Val Gln Pro Asn Ala Ser Gln
1 5 10 15
Ala Gln Gln Lys Pro Thr Thr His Gly Arg
20 25

387

25

PRT

Homo sapiens

387
Ser Ser Glu Glu Ile Lys Lys Lys Val Gln Pro Asn Ala Ser Gln Ala
1 5 10 15
Gln Gln Lys Pro Thr Thr His Gly Arg
20 25

388

9

PRT

Homo sapiens

388
Asn Arg Gly Trp Val Gly Ala Gly Glu
1 5

389

4

PRT

Homo sapiens

389
Ile Glu Ala Gly
1

390

17

PRT

Homo sapiens

390
Val His Asn Tyr Cys Asn Met Lys Asn Arg Gly Trp Val Gly Ala Gly
1 5 10 15
Glu

391

18

PRT

Homo sapiens

391
Val His Asn Tyr Cys Asn Met Lys Lys Asn Arg Gly Trp Val Gly Ala
1 5 10 15
Gly Glu

392

13

PRT

Homo sapiens

392
Val His Asn Tyr Cys Asn Met Lys Lys Ile Glu Ala Gly
1 5 10

393

12

PRT

Homo sapiens

393
Val His Asn Tyr Cys Asn Met Lys Ile Glu Ala Gly
1 5 10

394

25

PRT

Homo sapiens

394
Gln Leu Arg Cys Trp Asn Thr Trp Ala Lys Met Phe Phe Met Val Phe
1 5 10 15
Leu Ile Ile Trp Gln Asn Thr Met Phe
20 25

395

33

PRT

Homo sapiens

395
Val Lys Lys Asp Asn His Lys Lys Gln Leu Arg Cys Trp Asn Thr Trp
1 5 10 15
Ala Lys Met Phe Phe Met Val Phe Leu Ile Ile Trp Gln Asn Thr Met
20 25 30
Phe

396

34

PRT

Homo sapiens

396
Val Lys Lys Asp Asn His Lys Lys Lys Gln Leu Arg Cys Trp Asn Thr
1 5 10 15
Trp Ala Lys Met Phe Phe Met Val Phe Leu Ile Ile Trp Gln Asn Thr
20 25 30
Met Phe

397

11

PRT

Homo sapiens

397
Val Lys Lys Asp Asn His Lys Lys Lys Asn Ser
1 5 10

398

10

PRT

Homo sapiens

398
Val Lys Lys Asp Asn His Lys Lys Asn Ser
1 5 10

399

35

PRT

Homo sapiens

399
Gly Ala Glu Glu Ser Gly Pro Phe Asn Arg Gln Val Gln Leu Lys Val
1 5 10 15
His Ala Ser Gly Met Gly Arg His Leu Trp Asn Cys Pro Ala Phe Trp
20 25 30
Ser Glu Val
35

400

10

PRT

Homo sapiens

400
His Pro Ser Pro Pro Pro Glu Lys Arg Ser
1 5 10

401

11

PRT

Homo sapiens

401
His Pro Ser Pro Pro Pro Glu Lys Lys Arg Ser
1 5 10

402

44

PRT

Homo sapiens

402
His Pro Ser Pro Pro Pro Glu Lys Lys Gly Ala Glu Glu Ser Gly Pro
1 5 10 15
Phe Asn Arg Gln Val Gln Leu Lys Val His Ala Ser Gly Met Gly Arg
20 25 30
His Leu Trp Asn Cys Pro Ala Phe Trp Ser Glu Val
35 40

403

43

PRT

Homo sapiens

403
His Pro Ser Pro Pro Pro Glu Lys Gly Ala Glu Glu Ser Gly Pro Phe
1 5 10 15
Asn Arg Gln Val Gln Leu Lys Val His Ala Ser Gly Met Gly Arg His
20 25 30
Leu Trp Asn Cys Pro Ala Phe Trp Ser Glu Val
35 40

404

39

PRT

Homo sapiens

404
Met Gln Val Leu Ser Lys Thr His Met Asn Leu Phe Pro Gln Val Leu
1 5 10 15
Leu Gln Met Phe Leu Arg Gly Leu Lys Arg Leu Leu Gln Asp Leu Glu
20 25 30
Lys Ser Lys Lys Arg Lys Leu
35

405

8

PRT

Homo sapiens

405
Arg Cys Lys Ser Ala Arg Leu Ile
1 5

406

48

PRT

Homo sapiens

406
Val Gln Thr Gln Pro Ala Ile Lys Lys Met Gln Val Leu Ser Lys Thr
1 5 10 15
His Met Asn Leu Phe Pro Gln Val Leu Leu Gln Met Phe Leu Arg Gly
20 25 30
Leu Lys Arg Leu Leu Gln Asp Leu Glu Lys Ser Lys Lys Arg Lys Leu
35 40 45

407

49

PRT

Homo sapiens

407
Val Gln Thr Gln Pro Ala Ile Lys Lys Lys Met Gln Val Leu Ser Lys
1 5 10 15
Thr His Met Asn Leu Phe Pro Gln Val Leu Leu Gln Met Phe Leu Arg
20 25 30
Gly Leu Lys Arg Leu Leu Gln Asp Leu Glu Lys Ser Lys Lys Arg Lys
35 40 45
Leu

408

17

PRT

Homo sapiens

408
Val Gln Thr Gln Pro Ala Ile Lys Lys Arg Cys Lys Ser Ala Arg Leu
1 5 10 15
Ile

409

16

PRT

Homo sapiens

409
Val Gln Thr Gln Pro Ala Ile Lys Arg Cys Lys Ser Ala Arg Leu Ile
1 5 10 15

410

11

PRT

Homo sapiens

410
Ala Arg Ser Gly Lys Lys Gln Lys Arg Lys Leu
1 5 10

411

12

PRT

Homo sapiens

411
Ala Arg Ser Gly Lys Lys Gln Lys Lys Arg Lys Leu
1 5 10

412

13

PRT

Homo sapiens

412
Ala Arg Ser Gly Lys Lys Gln Lys Lys Glu Asn Ser Phe
1 5 10

413

12

PRT

Homo sapiens

413
Ala Arg Ser Gly Lys Lys Gln Lys Glu Asn Ser Phe
1 5 10

414

14

PRT

Homo sapiens

414
Lys Ala Ser Ala Arg Ser Gly Lys Ser Lys Lys Arg Lys Leu
1 5 10

415

15

PRT

Homo sapiens

415
Lys Ala Ser Ala Arg Ser Gly Lys Lys Ser Lys Lys Arg Lys Leu
1 5 10 15

416

16

PRT

Homo sapiens

416
Lys Ala Ser Ala Arg Ser Gly Lys Lys Ala Lys Lys Glu Asn Ser Phe
1 5 10 15

417

15

PRT

Homo sapiens

417
Lys Ala Ser Ala Arg Ser Gly Lys Ala Lys Lys Glu Asn Ser Phe
1 5 10 15

418

15

PRT

Homo sapiens

418
His Leu Asn Lys Gly Arg Arg Leu Gly Asp Lys Ile Arg Ala Thr
1 5 10 15

419

23

PRT

Homo sapiens

419
Val Thr Ser Gly Thr Pro Phe Phe His Leu Asn Lys Gly Arg Arg Leu
1 5 10 15
Gly Asp Lys Ile Arg Ala Thr
20

420

24

PRT

Homo sapiens

420
Val Thr Ser Gly Thr Pro Phe Phe Phe His Leu Asn Lys Gly Arg Arg
1 5 10 15
Leu Gly Asp Lys Ile Arg Ala Thr
20

421

10

PRT

Homo sapiens

421
Val Thr Ser Gly Thr Pro Phe Phe Phe Ile
1 5 10

422

9

PRT

Homo sapiens

422
Val Thr Ser Gly Thr Pro Phe Phe Ile
1 5

423

51

PRT

Homo sapiens

423
Val Thr Leu Leu Tyr Val Asn Thr Val Thr Leu Ala Pro Asn Val Asn
1 5 10 15
Met Glu Ser Ser Arg Asn Ala His Ser Pro Ala Thr Pro Ser Ala Lys
20 25 30
Arg Lys Asp Pro Asp Leu Thr Trp Gly Gly Phe Val Phe Phe Phe Cys
35 40 45
Gln Phe His
50

424

60

PRT

Homo sapiens

424
Lys Cys Arg Cys Lys Pro Asn Phe Phe Val Thr Leu Leu Tyr Val Asn
1 5 10 15
Thr Val Thr Leu Ala Pro Asn Val Asn Met Glu Ser Ser Arg Asn Ala
20 25 30
His Ser Pro Ala Thr Pro Ser Ala Lys Arg Lys Asp Pro Asp Leu Thr
35 40 45
Trp Gly Gly Phe Val Phe Phe Phe Cys Gln Phe His
50 55 60

425

61

PRT

Homo sapiens

425
Lys Cys Arg Cys Lys Pro Asn Phe Phe Phe Val Thr Leu Leu Tyr Val
1 5 10 15
Asn Thr Val Thr Leu Ala Pro Asn Val Asn Met Glu Ser Ser Arg Asn
20 25 30
Ala His Ser Pro Ala Thr Pro Ser Ala Lys Arg Lys Asp Pro Asp Leu
35 40 45
Thr Trp Gly Gly Phe Val Phe Phe Phe Cys Gln Phe His
50 55 60

426

10

PRT

Homo sapiens

426
Lys Cys Arg Cys Lys Pro Asn Phe Phe Leu
1 5 10

427

9

PRT

Homo sapiens

427
Lys Cys Arg Cys Lys Pro Asn Phe Leu
1 5

428

9

PRT

Homo sapiens

428
Ser Leu Val Arg Leu Ser Ser Cys Val
1 5

429

14

PRT

Homo sapiens

429
Leu Val Lys Lys Leu Lys Glu Lys Lys Met Asn Trp Ile Leu
1 5 10

430

15

PRT

Homo sapiens

430
Leu Val Lys Lys Leu Lys Glu Lys Lys Lys Met Asn Trp Ile Leu
1 5 10 15

431

10

PRT

Homo sapiens

431
Leu Val Lys Lys Leu Lys Glu Lys Lys Arg
1 5 10

432

9

PRT

Homo sapiens

432
Leu Val Lys Lys Leu Lys Glu Lys Arg
1 5

433

9

PRT

Homo sapiens

433
Ala Ala Ile Val Lys Asp Cys Cys Arg
1 5

434

11

PRT

Homo sapiens

434
Ser Gln Pro Ala Ser Ile Leu Gly Arg Lys Leu
1 5 10

435

12

PRT

Homo sapiens

435
Ser Gln Pro Ala Ser Ile Leu Gly Lys Arg Lys Leu
1 5 10

436

18

PRT

Homo sapiens

436
Ser Gln Pro Ala Ser Ile Leu Gly Lys Ala Ala Ile Val Lys Asp Cys
1 5 10 15
Cys Arg

437

17

PRT

Homo sapiens

437
Ser Gln Pro Ala Ser Ile Leu Gly Ala Ala Ile Val Lys Asp Cys Cys
1 5 10 15
Arg

438

18

PRT

Homo sapiens

438
Lys Ser Leu Val Arg Leu Ser Ser Cys Val Pro Val Ala Leu Met Ser
1 5 10 15
Ala Met

439

9

PRT

Homo sapiens

439
Arg Leu Ser Ser Cys Val Pro Val Ala
1 5

440

9

PRT

Homo sapiens

440
Val Arg Leu Ser Ser Cys Val Pro Val
1 5

441

9

PRT

Homo sapiens

441
Leu Val Arg Leu Ser Ser Cys Val Pro
1 5

442

9

PRT

Homo sapiens

442
Ser Cys Val Pro Val Ala Leu Met Ser
1 5

443

9

PRT

Homo sapiens

443
Ser Ser Cys Val Pro Val Ala Leu Met
1 5

444

9

PRT

Homo sapiens

444
Leu Ser Ser Cys Val Pro Val Ala Leu
1 5

445

9

PRT

Homo sapiens

445
Val Pro Val Ala Leu Met Ser Ala Met
1 5

446

9

PRT

Homo sapiens

446
Cys Val Pro Val Ala Leu Met Ser Ala
1 5

447

9

PRT

Homo sapiens

447
Lys Lys Lys Ser Leu Val Arg Leu Ser
1 5

448

9

PRT

Homo sapiens

448
Glu Lys Lys Lys Ser Leu Val Arg Leu
1 5

449

9

PRT

Homo sapiens

449
Lys Glu Lys Lys Lys Ser Leu Val Arg
1 5

450

9

PRT

Homo sapiens

450
Met Lys Glu Lys Lys Lys Ser Leu Val
1 5

451

9

PRT

Homo sapiens

451
Ile Met Lys Glu Lys Lys Lys Ser Leu
1 5

452

9

PRT

Homo sapiens

452
Lys Cys Ile Met Lys Glu Lys Lys Ala
1 5

453

9

PRT

Homo sapiens

453
Cys Ile Met Lys Glu Lys Lys Ala Trp
1 5

454

9

PRT

Homo sapiens

454
Cys Ile Met Lys Glu Lys Lys Lys Ala
1 5

455

9

PRT

Homo sapiens

455
Ile Met Lys Glu Lys Lys Lys Ala Trp
1 5

456

13

PRT

Homo sapiens

456
His Pro Ser Trp Pro Trp Thr Arg Cys Leu Arg Met Arg
1 5 10

457

14

PRT

Homo sapiens

457
Arg His Pro Ser Trp Pro Trp Thr Arg Cys Leu Arg Met Arg
1 5 10

458

16

PRT

Homo sapiens

458
Gly Ala Ser Gly Cys Val His Gln Glu Ala Glu Arg Val Ser Gln Ala
1 5 10 15

459

20

PRT

Homo sapiens

459
Asn Thr Trp Ala Lys Met Phe Phe Met Val Phe Leu Ile Ile Trp Gln
1 5 10 15
Asn Thr Met Phe
20

Number	Date	Country
WO 9214756	Sep 1992	WO
WO 9532731	Dec 1995	WO
WO 9618409	Jun 1996	WO
9631605	Oct 1996	WO
WO 9712992	Apr 1997	WO
WO 9910382	Mar 1999	WO
WO 9958564	Nov 1999	WO

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Priority Claims (1)

PCT Information

Foreign Referenced Citations (7)

Non-Patent Literature Citations (11)

Entry
Rampino et al. (1997), Science 275:967-969, “Somatic Frameshift Mutations in the BAX Gene in Colon Cancers of the Microsatellite Mutator Pheotype”.
Yamamoto et al. (Mar., 1988), Cancer Research 58:997-1003, “Somatic Frameshift Mutations in DNA Mismatch Repair and Proapoptosis Genes in Hereditary Nonpolyposis Colorectal Cancer”.
Markowitz et al. (1995), Science 268:1336-1338, “Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite Instability”.
Gaudernack (1996), Immunotechnology 2:3-9, “T cell responses against mutant ras: a basis for novel cancer vaccines”.
Gjertsen et al. (1996), Int. Journal of Cancer 65:450-453, “Ex Vivo ras Peptide Vaccination in Patients with Advanced Pancreatic Cancer: Results of a Phase I/II Study”.
Gjertsen et al. (1996), British Journal of Cancer 74:1828-1833, “Characterisation of immun responses in pancreatic carcinoma patients after mutant p21 ras peptide vaccination”.
Gjertsen et al. (1997), Int. J. Cancer 72:784-790, “Cytotoxic CD4 +and CD8+T-Lymphocytes, Generated by Mutant p21-ras (12Val) Peptide Vaccination of a Patient, Recognize . . . Tumour Cells Carrying This Mutation”.
Gjertsen et al. (1998) Vox Sanguinis 74(suppl. 2): 489-495, “Mutated Ras Peptides as Vaccines in Immunotherapy of Cancer”.
Barinaga, (1992) Science, vol. 257, pp. 880-881, “Getting Some Backbone”: How MHC Binds Peptides.
Deres et al., (1989) Nature, vol. 342, pp. 561-564, “In vivo priming of virus-specific cytotoxic T lymphocytes with synthetic lipopeptide vaccine”.
Tighe et al., (1998) Immun. Today, vol. 19(2), pp. 89-97, “Gene vaccination: plasmid DNA is more than just a blueprint”.