NZ789493A - Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers - Google Patents
Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancersInfo
- Publication number
- NZ789493A NZ789493A NZ789493A NZ78949318A NZ789493A NZ 789493 A NZ789493 A NZ 789493A NZ 789493 A NZ789493 A NZ 789493A NZ 78949318 A NZ78949318 A NZ 78949318A NZ 789493 A NZ789493 A NZ 789493A
- Authority
- NZ
- New Zealand
- Prior art keywords
- seq
- peptide
- cell
- cancer
- cells
- Prior art date
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Abstract
The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes comprising SEQ ID No 35, SEQ ID Nos. 1 to 34, SEQ ID Nos. 37 to 128, SEQ ID Nos. 130 to 417, and SEQ ID No. 419 to 772,alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 5, SEQ ID Nos. 1 to 34, SEQ ID Nos. 37 to 128, SEQ ID Nos. 130 to 417, and SEQ ID No. 419 to 772,alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.
Description
Novel peptides and ation of peptides for use in therapy against ovarian cancer and other cancers The present application is a divisional application from New Zealand patent application number 754139, the entire disclosure of which is incorporated herein by way of this reference.
The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore s to tumorassociated T-cell peptide es, alone or in combination with other tumorassociated es that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.
The present invention s to several novel peptide sequences and their ts derived from HLA class I and HLA class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses, or as s for the development of ceutically / immunologically active compounds and cells.
BACKGROUND OF THE INVENTION Ovarian cancer With an estimated 239 000 new cases in 2012, ovarian cancer is the seventh most common cancer in women, representing 4% of all cancers in women. The fatality rate of ovarian cancer tends to be rather high relative to other cancers of the female reproductive organs, and case fatality is higher in lower-resource settings. Therefore, ovarian cancer is the eighth most frequent cause of cancer death among women, with 152 000 deaths. In 2012, almost 55% of all new cases ed in countries with high or very high levels of human development; 37% of the new cases and 39% of the deaths occurred in Europe and North America. Incidence rates are highest in northern and eastern , North America, and Oceania, and tend to be relatively low in Africa and much of Asia. Incidence rates have been declining in certain countries with very high levels of human development, notably in Europe and North America.
The most common ovarian cancers are ovarian carcinomas, which are also the most lethal gynecological ancies. Based on histopathology and molecular genetics, ovarian carcinomas are divided into five main types: high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (< 5%), which er account for more than 95% of cases. Much less common are ant germ cell tumors (dysgerminomas, yolk sac tumors, and immature teratomas) (3% of n cancers) and potentially malignant sex cord stromal tumors (1—2%), the most common of which are granulosa cell tumors.
Ovarian carcinomas most commonly affect nulliparous women and occur least frequently in women with suppressed ion, typically by pregnancy or oral contraceptives. These tumors are generally considered to originate from the cells covering the ovarian surface or the pelvic peritoneum. ant transformation of this mesothelium has been explained by the "incessant ovulation" theory (La, 2001).
Family history of ovarian cancer accounts for 10% of cases; the risk is increased 3-fold when two or more first-degree relatives have been affected. Women with germline mutations in BRCA1 or BRCA2 have a 30—70% risk of developing ovarian , mainly rade serous carcinomas, by age 70 (Risch et al., 2006).
Surgical ion is the primary therapy in early as well as advanced stage ovarian carcinoma. The ultimate goal is the complete removal of the tumor mass in healthy surrounding tissue. Surgical removal is followed by systemic chemotherapy with platinum analogs, except for very low grade ovarian cancers (stage IA, grade 1), where post-operative herapy is not indicated. In advanced stage, ovarian cancer, the first line chemotherapy comprises a combination of carboplatin with axel, which can be supplemented with bevacizumab. The standard ent for platinum-resistant ovarian cancers consists of a monotherapy with one of the following chemotherapeutics: _ 3 _ ted mal doxorubicin, topotecane, gemcitabine or paclitaxel (S3-Leitlinie maligne Ovarialtumore, 2013). therapy appears to be a promising strategy to ameliorate the treatment of n cancer patients, as the presence of pro-inflammatory tumor rating lymphocytes, especially CD8—positive T cells, ates with good prognosis and T cells specific for tumor-associated antigens can be isolated from cancer tissue.
Therefore, a lot of scientific effort is put into the investigation of different immunotherapies in ovarian cancer. A considerable number of pre-clinical and clinical studies has already been performed and further studies are currently ongoing. Clinical data are available for cytokine therapy, vaccination, monoclonal antibody ent, adoptive cell transfer and immunomodulation.
Cytokine therapy with interleukin-2, interferon-alpha, eron-gamma or granulocytemacrophage colony stimulating factor aims at boosting the patient’s own anti-tumor immune se and these ents have already shown ing results in small study cohorts.
Phase I and II vaccination studies, using single or multiple peptides, derived from several tumor-associated proteins (Her2/neu, NY-ESO-l, p53, Wilms tumor-1) or whole tumor antigens, derived from autologous tumor cells revealed good safety and tolerability profiles, but only low to moderate clinical effects.
Monoclonal antibodies that specifically recognize tumor-associated proteins are t to enhance immune cell-mediated killing of tumor cells. The anti-CA-125 antibodies oregovomab and abagovomab as well as the anti-EpCAM antibody catumaxomab achieved promising results in phase II and III studies. In contrast, the anti-MUC1 antibody HMFG1 failed to clearly enhance survival in a phase III study.
An alternative approach uses monoclonal dies to target and block growth factor and survival receptors on tumor cells. While administration of trastuzumab (anti- HER2/neu antibody) and MOv18 and MORAb-OO3 (anti-folate or alpha antibodies) only conferred limited clinical benefit to ovarian cancer patients, addition of zumab (anti-VEGF antibody) to the standard chemotherapy in advanced ovarian cancer appears to be advantageous.
Adoptive er of immune cells achieved heterogeneous s in clinical trials.
Adoptive transfer of autologous, in vitro expanded tumor infiltrating T cells was shown to be a promising approach in a pilot trial. In st, transfer of T cells harboring a chimeric antigen receptor specific for folate receptor alpha did not induce a significant clinical response in a phase I trial. Dendritic cells pulsed with tumor cell lysate or tumor- associated proteins in vitro were shown to enhance the anti-tumor T cell response upon transfer, but the extent of T cell activation did not ate with clinical effects. Transfer of natural killer cells caused significant toxicities in a phase II study. lntrinsic anti-tumor ty as well as therapy are hampered by an immunosuppressive tumor microenvironment. To overcome this obstacle immunomodulatory drugs, like cyclophosphamide, anti-CD25 antibodies and pegylated liposomal doxorubicin are tested in combination with immunotherapy. Most reliable data are tly available for ipilimumab, an anti-CTLA4 antibody, which enhances T cell activity. lpilimumab was shown to exert significant anti-tumor effects in ovarian cancer ts (Mantia-Smaldone et al., 2012).
Considering the severe side-effects and expense associated with ng cancer, there is a need to identify factors that can be used in the treatment of cancer in general and ovarian cancer in particular. There is also a need to identify factors representing biomarkers for cancer in general and ovarian cancer in particular, leading to better diagnosis of cancer, ment of prognosis, and prediction of treatment success. _ 5 _ Immunotherapy of cancer represents an option of specific ing of cancer cells while minimizing side effects. Cancer immunotherapy makes use of the existence of tumor associated antigens.
The current classification of tumor associated antigens (TAAs) comprises the following major groups: a) Cancer-testis antigens: The first TAAs ever identified that can be recognized by T cells belong to this class, which was originally called cancer-testis (CT) antigens because of the expression of its members in histologically different human tumors and, among normal tissues, only in spermatocytes/spermatogonia of testis and, occasionally, in placenta. Since the cells of testis do not s class I and II HLA molecules, these antigens cannot be ized by T cells in normal tissues and can therefore be ered as immunologically tumor-specific. nown es for CT antigens are the MAGE family members and NY-ESO-1. b) Differentiation antigens: These TAAs are shared between tumors and the normal tissue from which the tumor arose. Most of the known differentiation ns are found in melanomas and normal melanocytes. Many of these melanocyte lineage-related proteins are involved in biosynthesis of melanin and are therefore not tumor specific but nevertheless are widely used for cancer immunotherapy. Examples include, but are not limited to, tyrosinase and Melan-A/MART-1 for melanoma or PSA for prostate cancer. c) Over-expressed TAAs: Genes encoding widely expressed TAAs have been detected in histologically ent types of tumors as well as in many normal tissues, generally with lower expression levels. It is possible that many of the epitopes processed and potentially ted by normal tissues are below the old level for T-cell recognition, while their over-expression in tumor cells can trigger an anticancer response by breaking previously ished tolerance. Prominent examples for this class of TAAs are Her-2/neu, survivin, telomerase, or WT1. d) Tumor-specific antigens: These unique TAAs arise from mutations of normal genes (such as B-catenin, CDK4, etc.). Some of these molecular changes are associated with neoplastic transformation and/or progression. Tumor-specific antigens are generally able to induce strong immune responses t bearing the risk for autoimmune _ 6 _ reactions against normal tissues. On the other hand, these TAAs are in most cases only relevant to the exact tumor on which they were identified and are usually not shared between many dual . Tumor-specificity (or -association) of a peptide may also arise if the peptide originates from a tumor- ciated) exon in case of proteins with tumor-specific (-associated) isoforms. e) TAAs arising from abnormal post-translational modifications: Such TAAs may arise from proteins which are neither specific nor overexpressed in tumors but nevertheless become tumor associated by posttranslational processes ily active in .
Examples for this class arise from altered glycosylation patterns leading to novel es in tumors as for MUC1 or events like protein splicing during degradation which may or may not be tumor specific. f) Oncoviral proteins: These TAAs are viral proteins that may play a al role in the oncogenic process and, because they are foreign (not of human origin), they can evoke a T-cell response. Examples of such proteins are the human papilloma type 16 virus proteins, E6 and E7, which are expressed in cervical carcinoma.
T-cell based immunotherapy targets peptide epitopes derived from tumor-associated or tumor-specific proteins, which are presented by molecules of the major histocompatibility complex (MHC). The antigens that are recognized by the tumor specific T lymphocytes, that is, the epitopes f, can be molecules derived from all protein classes, such as enzymes, receptors, transcription factors, etc. which are sed and, as compared to unaltered cells of the same origin, y up-regulated in cells of the respective tumor.
There are two classes of MHC-molecules, MHC class I and MHC class II. MHC class I molecules are composed of an alpha heavy chain and betamicroglobulin, MHC class II molecules of an alpha and a beta chain. Their dimensional conformation results in a binding groove, which is used for non-covalent interaction with peptides.
MHC class I molecules can be found on most nucleated cells. They present peptides that result from proteolytic cleavage of predominantly endogenous proteins, defective WO 38257 ribosomal products (DRlPs) and larger peptides. However, peptides derived from endosomal compartments or exogenous sources are also frequently found on MHC class I les. This non-classical way of class I presentation is referred to as cross- presentation in the literature (Brossart and Bevan, 1997; Rock et al., 1990). MHC class II molecules can be found inantly on professional antigen presenting cells (APCs), and primarily present peptides of exogenous or transmembrane proteins that are taken up by APCs e.g. during endocytosis, and are uently processed.
Complexes of peptide and MHC class I are recognized by CD8—positive T cells bearing the riate T-cell receptor (TCR), whereas complexes of peptide and MHC class II molecules are recognized by CD4-positive-helper—T cells bearing the appropriate TCR.
It is well known that the TCR, the peptide and the MHC are thereby present in a iometric amount of 1:1 :1.
CD4-positive helper T cells play an important role in inducing and sustaining effective responses by CD8—positive cytotoxic T cells. The identification of CD4-positive T-cell epitopes derived from tumor associated antigens (TAA) is of great importance for the development of pharmaceutical products for triggering anti-tumor immune responses (anatic et al., 2003). At the tumor site, T helper cells, t a cytotoxic T cell- (CTL-) friendly cytokine milieu (Mortara et al., 2006) and attract or cells, e.g. CTLs, natural killer (NK) cells, macrophages, and granulocytes (Hwang et al., 2007).
In the absence of inflammation, expression of MHC class II molecules is mainly restricted to cells of the immune system, especially professional antigen-presenting cells (APC), e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells. In cancer patients, cells of the tumor have been found to express MHC class II molecules (Dengjel et al., 2006).
Elongated (longer) peptides of the ion can act as MHC class II active epitopes. _ 8 _ T-helper cells, activated by MHC class II epitopes, play an important role in orchestrating the effector function of CTLs in anti-tumor immunity. T-helper cell epitopes that trigger a er cell response of the TH1 type support effector functions of CD8- positive killer T cells, which e cytotoxic functions directed against tumor cells displaying tumor-associated peptide/MHC complexes on their cell surfaces. In this way tumor-associated T-helper cell peptide epitopes, alone or in combination with other tumor-associated peptides, can serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses.
It was shown in mammalian animal models, e.g., mice, that even in the absence of CD8-positive T lymphocytes, CD4-positive T cells are sufficient for inhibiting manifestation of tumors via inhibition of angiogenesis by secretion of interferon-gamma (lFNv) y and Paterson, 2001; Mumberg et al., 1999). There is evidence for CD4 T cells as direct umor effectors uller et al., 2013; Tran et al., 2014).
Since the constitutive expression of HLA class II molecules is usually limited to immune cells, the ility of isolating class II peptides directly from primary tumors was previously not considered possible. However, Dengjel et al. were sful in identifying a number of MHC Class II epitopes directly from tumors ( EP 1 760 088 Bl).
Since both types of response, CD8 and CD4 dependent, contribute jointly and synergistically to the anti-tumor effect, the identification and characterization of tumor- associated antigens recognized by either CD8+ T cells (ligand: MHC class I molecule + peptide epitope) or by CD4-positive T-helper cells (ligand: MHC class II molecule + peptide epitope) is important in the development of tumor vaccines.
For an MHC class I peptide to trigger (elicit) a ar immune response, it also must bind to an MHC-molecule. This s is dependent on the allele of the MHC-molecule and specific polymorphisms of the amino acid sequence of the peptide. MHC-class-l- binding peptides are usually 8-12 amino acid es in length and y contain two _ g _ conserved residues ("anchors") in their sequence that interact with the corresponding binding groove of the MHC-molecule. In this way, each MHC allele has a "binding motif" determining which peptides can bind specifically to the binding groove.
In the MHC class I dependent immune reaction, es not only have to be able to bind to certain MHC class I molecules expressed by tumor cells, they subsequently also have to be recognized by T cells bearing specific T cell receptors (TCR).
For proteins to be recognized by T-Iymphocytes as tumor-specific or -associated antigens, and to be used in a therapy, particular prerequisites must be fulfilled. The n should be expressed mainly by tumor cells and not, or in comparably small amounts, by normal healthy tissues. In a preferred embodiment, the peptide should be resented by tumor cells as compared to normal healthy s. It is furthermore desirable that the respective antigen is not only present in a type of tumor, but also in high concentrations (i.e. copy numbers of the respective peptide per cell). Tumor- specific and tumor-associated antigens are often derived from proteins directly involved in transformation of a normal cell to a tumor cell due to their function, e.g. in cell cycle control or suppression of apoptosis. Additionally, downstream targets of the proteins directly causative for a transformation may be up-regulated und thus may be indirectly tumor-associated. Such indirect tumor-associated antigens may also be targets of a ation approach (Singh-Jasuja et a|., 2004). It is essential that epitopes are present in the amino acid sequence of the antigen, in order to ensure that such a e ("immunogenic peptide"), being derived from a tumor ated n, leads to an in vitro or in vivo T-ce||-response.
Basically, any peptide able to bind an MHC molecule may function as a T-cell epitope. A uisite for the induction of an in vitro or in vivo T-ceII-response is the presence of a T cell having a ponding TCR and the absence of immunological tolerance for this particular epitope. _ 10 _ Therefore, TAAs are a starting point for the development of a T cell based therapy including but not limited to tumor vaccines. The methods for identifying and characterizing the TAAs are y based on the use of T-cells that can be isolated from patients or healthy subjects, or they are based on the generation of differential transcription profiles or differential peptide expression patterns n tumors and normal tissues. However, the identification of genes over-expressed in tumor tissues or human tumor cell lines, or selectively expressed in such s or cell lines, does not provide precise information as to the use of the antigens being ribed from these genes in an immune therapy. This is because only an individual subpopulation of epitopes of these ns are suitable for such an application since a T cell with a corresponding TCR has to be present and the immunological tolerance for this particular e needs to be absent or minimal. In a very preferred embodiment of the invention it is therefore important to select only those over— or selectively presented peptides against which a functional and/or a proliferating T cell can be found. Such a functional T cell is defined as a T cell, which upon stimulation with a specific antigen can be clonally expanded and is able to execute effector ons ("effector T cell").
In case of targeting peptide-MHC by ic TCRs (e.g. soluble TCRs) and antibodies or other binding molecules (scaffolds) ing to the invention, the immunogenicity of the underlying peptides is secondary. In these cases, the presentation is the determining factor.
SUMMARY OF THE INVENTION In a first aspect of the present invention, the present ion relates to a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 772 or a variant sequence thereof which is at least 77%, preferably at least 88%, homologous (preferably at least 77% or at least 88% cal) to SEQ ID NO: 1 to SEQ ID NO: 772, wherein said variant binds to MHC and/or induces T cells cross-reacting with said peptide, or a pharmaceutical acceptable salt thereof, wherein said peptide is not the underlying full-length polypeptide.
The present ion further relates to a peptide of the present invention comprising a sequence that is selected from the group ting of SEQ ID NO: 1 to SEQ ID NO: 772 or a variant f, which is at least 77%, preferably at least 88%, homologous (preferably at least 77% or at least 88% identical) to SEQ ID NO: 1 to SEQ ID NO: 772, wherein said peptide or variant f has an overall length of between 8 and 100, preferably between 8 and 30, and most preferred of between 8 and 14 amino acids.
The following tables show the peptides according to the present invention, their respective SEQ ID NOs, and the prospective source (underlying) genes for these es. In Table 1, peptides with SEQ ID NO: 1 to SEQ ID NO: 9 bind to HLA-A*O2, peptides with SEQ ID NO: 10 to SEQ ID NO: 19 bind to HLA-A*24, peptides with SEQ ID NO: 20 to SEQ ID NO: 30 bind to HLA-A*03, peptide with SEQ ID NO: 31 binds to HLA-A*O1, peptides with SEQ ID NO: 32 to SEQ ID NO: 41 bind to HLA-B*07, peptides with SEQ ID NO: 42 to SEQ ID NO: 51 bind to HLA-B*08, peptides with SEQ ID NO: 52 to SEQ ID NO: 59 bind to HLA-B*44. In Table 2, peptides with SEQ ID NO: 60 to SEQ ID NO: 75 bind to HLA-A*02, peptides with SEQ ID NO: 76 to SEQ ID NO: 82 bind to HLA-A*24, peptides with SEQ ID NO: 83 to SEQ ID NO: 111 bind to HLA-A*O3, peptides with SEQ ID NO: 112 to SEQ ID NO: 116 bind to HLA-A*O1, es with SEQ ID NO: 117 to SEQ ID NO: 149 bind to HLA-B*O7, peptides with SEQ ID NO: 150 to SEQ ID NO: 172 bind to HLA-B*O8, peptides with SEQ ID NO: 173 to SEQ ID NO: 215 bind to 44. In Table 3, peptides with SEQ ID NO: 216 to SEQ ID NO: 245 bind to HLA-A*02, peptides with SEQ ID NO: 246 to SEQ ID NO: 255 bind to HLA-A*24, peptides with SEQ ID NO: 256 to SEQ ID NO: 287 bind to HLA-A*O3, peptides with SEQ ID NO: 288 to SEQ ID NO: 292 bind to HLA-A*O1, peptides with SEQ ID NO: 293 to SEQ ID NO: 392 bind to HLA-B*O7, peptides with SEQ ID NO: 393 to SEQ ID NO: 395 bind to HLA-B*08, peptides with SEQ ID NO: 396 to SEQ ID NO: 438 bind to HLA- B*44. In Table 4, peptides with SEQ ID NO: 439 to SEQ ID NO: 551 bind to several HLA class I alleles, peptide with SEQ ID NO: 773 binds to HLA-A*O2, peptide with SEQ ID NO: 774 binds to HLA-A*24. In Table 5, peptides with SEQ ID NO: 552 to SEQ ID NO: 772 bind to several HLA class II alleles.
Table 1: Peptides according to the present invention.
Seq ID HLA No Sequence Gene Uniprot Accession allotype 1 MIPTFTALL L|LRB4 08NHJ6 A*02 2 TLLKALLEI |DO1 P14902 A*02 ATP7A, ATP7B, 3 ALIYNLVGI CTAGE1 P35670 A*02 4 ALFKAWAL |RF4 015306 A*02 RLLDFINVL OVGP1 012889 A*02 6 SLGKHTVAL OVGP1 012889 A*02 PCDHB5, PCDHB15, PCDHB11, 0, PCDHB9, PCDHB8, PCDHB7, PCDHB4, ALOAFEFR PCDHB3,PCDHB2, 7 V 6 09Y5E7 A*02 PCDHGA12, PCDHB5, , PCDHB18, , 096TAO, PCDHGB7, 6, 09NRJ7, 09UN66, PCDHGB5, PCDHGB3, 09UN67, 09UN71, 2, PCDHGB1, , 09Y5E2, PCDHGA11, 09Y5E3, 09Y5E4, PCDHGA10, PCDHGA9, 09Y5E5, , PCDHGA7, PCDHGA6, 09Y5E7, 09Y5E8, PCDHGA5, PCDHGA4, 09Y5E9, 09Y5F0, PCDHGA3, PCDHGA2, 09Y5F1, 09Y5F2, PCDHGA1, PCDHGB8P, 09Y5F3, 09Y5F8, PCDHB15, PCDHB14, 09Y5F9, 09Y5G0, PCDHB13, PCDHB12, 09Y5G1, 09Y5G2, PCDHB11, PCDHB10, 09Y5G3, 09Y5G4, PCDHB9, PCDHB8, 09Y5G5, 09Y5G6, PCDHB7, , 09Y5G7, 09Y5G8, PCDHB4, PCDHB3, 09Y5G9, 09Y5H0, PCDHB2, PCDHB16, , 09Y5H2, 8 YLVTKVVAV PCDHGB4, 8 09Y5H3, 09Y5H4 A*02 VLLAGFKPP 9 L RNF17 09BXT8 A*02 RYSDSVGR VSF CAPN13 06MZZ7 A*24 SYSDLHYG 11 F CAPN13 06MZZ7 A*24 CT45A3, CT45A4, CT45A5, CT45A6, 12 KYEKIFEML CT45A1, CT45A2 05DJT8 A*24 13 VYTFLSSTL ESR1 P03372 A*24 WO 38257 Seq ID HLA No Sequence Gene Uniprot Accession allotype 14 FYFPTPTVL FOLR1 P15328 A*24 VYHDDKQP TF GXYLT2 AOPJZ3 A*24 16 IYSPQFSRL MYO3B Q8WXR4 A*24 17 RFTTMLSTF OVGP1 Q12889 A*24 18 KYPVHIYRL RAD54B QQY62O A*24 KYVKVFHQ 19 F ZNF90, ZNF93, ZNF486 096H40 A*24 RMASPVNV K C2orf88 QQBSFO A*03 21 AVRKPIVLK CDCA5 QQ6FF9 A*03 22 SLKERNPLK CDH3 P22223 A*03 GMMKGGIR 23 K ESR1 P03372 A*03 SMYYPLQL 24 K GXYLT2 AOPJZ3 A*03 GTSPPSVE K MUC16 Q8WXI7 A*03 26 RISEYLLEK MYO3B Q8WXR4 A*03 VLYGPAGL 27 GK NLRP2 QQNXO2 A*03 KTYETNLEI 28 KK NLRP7 Q8WX94 A*03 29 QQFLTALFY NLRP7, NLRP2 Q8WX94 A*03 3O ALEVAHRLK ZBTB12 QQY33O A*03 LLDEGAMLL 31 Y NLRP7 Q8WX94 A*O1 SPNKGTLS 32 V BCAM P50895 B*07 33 SPTFHLTL BCAM P50895 B*07 34 L CDH3 P22223 B*07 FPDNQRPA L ETV4 P43268 B*07 APAAWLRS 36 A MMP11 P24347 B*O7/B*55 RPLFQKSS 37 M MUC16 Q8WXI7 B*07 SPHPVTALL 38 TL MUC16 Q8WXI7 B*07 RPAPFEVV 39 F NXNL2 QSVZO3 B*07 _ 14 _ Seq ID HLA No Sequence Gene Uniprot Accession allotype KPGTSYRV 40 TL SPON1 09HCB6 B*07 TCEA1 P2, TCEA1, 41 RVRSRISNL TCEA2, TCEA3 015560 B*07 42 TLKVTSAL BCAM P50895 B*08 43 ALKARTVTF CCR2, CCR5 P51681 B*08 44 LNKQKVTF , CTAGE5 015320 B*08 VGREKKLA 45 L , CTAGE5 015320 B*08 DMKKAKEQ FUNDC2P2, 46 L FUNDC2P3, FUNDC2 QQBWH2 B*08 47 L LRRTM1 Q86UE6 B*08 48 DVKKKIKEV MFN1 Q8IWA4 B*08 49 LPRLKAFMI ST6GALNAC5 QQBVH7 B*08 TCEA1 P2, TCEA1, 50 DMKYKNRV TCEA2 015560 B*08 51 SLRLKNVQL VTCN1 Q7Z7D3 B*08 52 AEFLLRIFL CAPN13 Q6MZZ7 B*44 MEHPGKLL 53 F ESR1 P03372 B*44 AEITITTQTG 54 Y MUC16 Q8WXI7 B*44 HETETRTT 55 W MUC16 Q8WXI7 B*44 SEPDTTAS 56 W MUC16 Q8WXI7 B*44 57 QESDLRLFL NLRP7, NLRP2 09NX02 B*44 58 GEMEQKQL PNOC 013519 B*44 SENVTMKV 59 V VTCN1 Q7Z7D3 B*44 Table 2: Additional peptides according to the present invention.
Seq ID HLA No Sequence Gene t Accession allotype GLLSLTSTL 60 YL BCAM P50895 A*02 61 YMVHIQVTL CD70 P32970 A*02 KVLGVNVM 62 L CRABP2 P29373 A*02 MMEEMIFN 63 L EYA2 000167 A*02 _ 15 _ Seq ID HLA No Sequence Gene Uniprot Accession allotype 64 FLDPDRHFL FAM83H Q6ZRV2 A*02 65 TMFLRETSL GUCY1A2 P33402 A*02 66 GLLQELSSI HTR3A P46098 A*02 67 SLLLPSIFL HTR3A P46098 A*02 68 KLFDTQQFL |RF4 Q15306 A*02 69 TTYEGSITV MUC16 Q8WXI7 A*02 70 RSL MUC16 Q8WXI7 A*02 YLEDTDRN 71 L NFE2L3 Q9Y4A8 A*02 72 YLTDLQVSL NFE2L3 Q9Y4A8 A*02 73 FLIEELLFA OVGP1 Q12889 A*02 SQSPSVSQ 74 L PRAME P78395 A*02 KWSVLYN 75 V VTCN1 Q7Z7D3 A*02 76 KYVAELSLL CCNA1 P78396 A*24 77 RYGPVFTV CYP2W1 Q8TAV3 A*24 SFAPRSAV 78 F HOXD9 P28356 A*24 SYNEHWNY 79 L LTBR P36941 A*24 TAYMVSVA 80 AF SDK2 QS8EX2 A*24 WNHTTRP 81 L SPINT1 043278 A*24 82 TLI SPON1 Q9HCB6 A*24 GTYAHTVN 83 R ALPI, ALPP, ALPPL2 P05187, PO9923 A*03/A*31 KLQPAQTA 84 AK ALPP, ALPPL2 P05187 A*03 VLLGSLFSR 85 K BCL2L1 QO7817 A*03 VVLLGSLFS A*03/A*31/ 86 RK BCL2L1 QO7817 A*66 AVAPPTPA 87 SK CBX2 Q14781 A*03/A*11 88 VVHAVFALK CCR5 P51681 A*03 89 RVAELLLLH CDKN2A, CDKN2B P42771, P42772 A*03 YV , P43268, 9O YK ETV1, ETV4, ETV5 P50549 A*03 RSLRYYYE 91 K ETV1, ETV4, ETV5 P43268 A*03 _ 16 _ Seq ID HLA No Sequence Gene t Accession allotype 92 SVFPIEN |Y EYA2 000167 A*03 93 KILEEHTNK FSBP, RAD54B 095073 A*03 94 ATFERVLLR GUCY1A2 P33402 A*03/A*11 QSMYYPLQ 95 LK GXYLT2 AOPJ23 A*03 TAFGGFLK 96 Y LAMA1 P25391 A*03 TMLDVEGL 97 FY LAMA1 P25391 A*03 LLQPPPLLA 98 R MMP1 1 P24347 A*03 KWDRWNE 99 K MRPL51 Q4U2R6 A*03 RLFTSPIMT 100 K MUC16 Q8WXI7 A*03 RVFTSSIKT 101 K MUC16 Q8WXI7 A*03 102 SVLTSSLVK MUC16 Q8WXI7 A*03 TSRSVDEA 103 Y MUC16 Q8WXI7 A*03 104 VLADSVTTK MUC16 Q8WXI7 A*03 RLFSWLVN 105 R MYO1 B Q8WXR4 A*03 106 AAFVPLLLK NCAPD2 Q15021 A*03/A*11 RLQEWKAL 107 K PDCL2 Q8N4E4 A*03 VLYPVPLES 108 Y PRAME P78395 A*03 KTFTIKRFL 109 AK RPL39L Q96EH5 A*03 SAAPPSYF A*03/A*11/ 110 R SPON1 Q9HCB6 A*66 1 1 1 GY WNT7A 000755 A*03 TVTGAEQIQ 112 Y CAPN13 QBMZZ7 A*01 QLDSNRLT 113 Y LRRTM1 Q86UE6 A*01 VMEQSAGI 114 MY LYPD1 Q8N2G4 A*01 115 Y MMP12 P39900 A*01 116 VLLDEGAM NLRP7 Q8WX94 A*01 _ 17 _ Seq ID HLA No Sequence Gene Uniprot Accession allotype APRLLLLAV 117 L BCAM P50895 B*07 118 SPASRSISL CD70 P32970 B*07 APLPRPGA 1 19 VL CTAG2 075638 B*07 RPAMNYDK ETV1, ETV4, ETV5, 120 L SPDEF P43268 B*07 VPNQSSES 121 L EYA2 000167 *35 YPGFPQSQ 122 Y EYA2 000167 B*07/B*35 123 L FAM111B Q6SJ93 B*07 LPSDSHFKI 124 TF FAM111B Q6SJ93 B*07 VPVYILLDE 125 M FAM83H Q6ZRV2 B*07/B*35 126 KL FOLR1, FOLR2 P15328 B*07 APRAGSQV 127 V FUNDC2 QQBWH2 B*07 128 YPRTITPGM KLK14 QQPOG3 B*07 129 APRPASSL MMP11 P24347 B*07 FPRLVGPD 130 F MMP11 P24347 B*07 131 APTEDLKAL MSLN Q13421 B*07 132 IPGPAQSTI MUC16 Q8WXI7 B*07 MPNLPSTT 133 SL MUC16 Q8WXI7 B*07 134 RPIVPGPLL MUC16 Q8WXI7 B*07 135 RVRSTISSL MUC16 Q8WXI7 B*07 SPFSAEEA 136 NSL MUC16 Q8WXI7 B*07 SPGATSRG 137 TL MUC16 Q8WXI7 B*07 138 SPMATTSTL MUC16 Q8WXI7 B*07 SPQSMSNT 139 L MUC16 Q8WXI7 B*07 SPRTEASS 140 AVL MUC16 Q8WXI7 B*07 SPMTSLLTS 141 GL MUC16 Q8WXI7 B*07 _ 18 _ Seq ID HLA No Sequence Gene Uniprot Accession allotype 142 TSI MUC16 08WXI7 B*07 SPAMTSTS 143 F MUC16 08WXI7 B*07/B*35 144 SPSPVSSTL MUC16 08WXI7 B*07/B*35 SPSSPMST 145 F MUC16 08WXI7 B*07/B*35 146 IPRPEVQAL PLEKHG4 058EX7 B*07 APRWFPQP 147 TVV VTCN1 07Z7D3 B*07 KPYGGSGP 148 L ZNF217 075362 B*07 ZSCAN30, ZNF263, 014978, 043309, ZNF500, ZKSCAN4, 060304, P17029, ZNF323, ZKSCAN1, P49910, 016670, ZNF165, ZNF187, 086W11, 08NF99, GPREALSR 3, ZNF397, 0969J2, 096LW9, 149 L ZSCAN12 09BRRO B*07 150 MAAVKQAL BCL2L1 007817 B*08 151 HLLLKVLAF CCNA1 P78396 B*08 MGSARVAE 152 L CDKN2A, CDKN2B P42771 B*08 NAMLRKVA 153 V CRABP1 P29762 B*08 154 MLRKIAVAA CRABP2 P29373 B*08 NKKMMKRL 155 M DPPA2 07Z7J5 B*08 156 HVKEKFLL FAM83H 06ZRV2 B*08 157 SYI LAMC2 013753 B*08 158 LPKLAGLL L|NC00176 06ZNR8 B*08/B*07 159 VLKHKLDEL MSLN 013421 B*08 160 YPKARLAF MSLN 013421 B*08 161 ALKTTTTAL DNAJC22, MUC16 08WXI7 B*08 162 TL MUC16 08WXI7 B*08 163 QGLLRPVF MUC16 08WXI7 B*08 164 SIKTKSAEM MUC16 08WXI7 B*08 165 SPRFKTGL MUC16 08WXI7 B*08 166 TSI MUC16 08WXI7 B*08 167 TSHERLTTL MUC16 08WXI7 B*08 168 TSHERLTTY MUC16 08WXI7 B*08 TSMPRSSA 169 M MUC16 08WXI7 B*08 170 YLLEKSRVI MY03B, MYH15, MYH6, , B0|1T2, B*08 Seq ID HLA No Sequence Gene Uniprot Accession allotype MYH7, MYO1D, MYO3A, 094832, P12883, MYH7B P13533, Q8NEV4, , Q9Y2K3 171 FAFRKEAL OVGP1 Q12889 B*08 KLKERNRE 172 L OVGP1 Q12889 B*08 AEAQVGDE 173 RDY BCAM P50895 B*44 174 VF BCAM P50895 B*44 175 AEIEPKADG BCAM P50895 B*44 AEIEPKADG 176 SW BCAM P50895 B*44 TEVGTMNL 177 F BCAT1 P54687 B*44 NELFRDGV 178 NW BCL2L1 QO7817 B*44 REAGDEFE 179 L BCL2L1 QO7817 B*44 REAGDEFE 180 LRY BCL2L1 QO7817 B*44 181 GEGPKTSW CRABP2 P29373 B*44 , CTAGE1OP, QS CTAGE16P, CTAGE5, 182 L CTAGE1 Q96RT6 B*44/B*40 YEKGIMQK 183 V ETV1, ETV4, ETV5 P43268 B*44/B*49 AELEALTDL 184 W EYA2 000167 B*44 AERQPGAA 185 SL FAM83H Q6ZRV2 B*44 REGPEEPG 186 L FAM83H Q6ZRV2 B*44 GEAQTRIA 187 W FOLR1 P15328 B*44 AEFAKKQP 188 WW FUNDC2 Q9BWH2 B*44 HOXA9, HOXA10, HOXB9, HOXC9, HOXC10, HOXD9, 189 KEFLFNMY HOXD1O P28356 B*44 190 YEVARILNL HOXD9 P28356 B*44 191 EEDAALFKA |RF4 Q15306 B*44 Seq ID HLA No ce Gene Uniprot Accession allotype B*44/B*18/ 192 YEFKFPNRL LGALS1 P09382 B*40 193 LEAQQEAL MAGEA1, MRPL40 P43355 B*44 KEVDPTSH 194 SY MAGEA1 1 P43364 B*44 AEDKRHYS 195 V MFN1 Q8IWA4 B*44 REMPGGPV 196 W MMP12 P39900 B*44 197 RLV MSLN Q13421 B*44 198 QEAARAAL MSLN Q13421 B*44 199 REIDESLIFY MSLN Q13421 B*44 200 AESIPTVSF MUC16 Q8WXI7 B*44 201 F MUC16 Q8WXI7 B*44 HESEATAS 202 W MUC16 Q8WXI7 B*44 IEHSTQAQD 203 TL MUC16 Q8WXI7 B*44 RETSTSEET 204 SL MUC16 Q8WXI7 B*44 205 SEITRIEM MUC16 Q8WXI7 B*44 SESVTSRT 206 SY MUC16 Q8WXI7 B*44 TEARATSD 207 SW MUC16 Q8WXI7 B*44 208 TEVSRTEAI MUC16 Q8WXI7 B*44 209 TEVSRTEL MUC16 Q8WXI7 B*44 VEAADIFQN 210 F NXNL2 Q5VZ03 B*44 EEKVFPSPL 211 W PNOC Q13519 B*44 MEQKQLQK 212 RF PNOC Q13519 B*44 KESIPRWY 213 Y SPI NT1 043278 B*44 VEQTRAGS 214 LL TDRD5 Q8NAT2 B*44 SEDGLPEGI 215 HL ZN F21 7 075362 B*44 Table 3: Additional peptides according to the present invention.
Seq ID HLA No Sequence Gene Uniprot Accession allotype 216 A ALPP, ALPPL2 P05187 A*02 217 VSSSLTLKV BCAM P50895 A*02 TIASQRLTP 218 L CD70 P32970 A*02 PLPRPGAV 219 L CTAG2 075638 A*02 220 RMTTQLLLL FOLR1 P15328 A*02/B*13 221 SLLDLYQL FTHL17 Q9BXU8 A*02/B*35 222 L GPC2 Q8N158 A*02 223 FAHHGRSL |RF4 Q15306 A*02 224 SLPRFQVTL |RF4 Q15306 A*02 SVFAHPRK MAGEA2B, MAGEA2, 225 L MAGEA6, MAGEA12 P43365 A*02 QVDPKKRIS 226 M MELK Q14680 A*02 227 LSL MMP11 P24347 A*02 RLWDWVPL 228 A MRPL51 Q4U2R6 A*02 229 ISVPAKTSL MUC16 Q8WXI7 A*02 SAFREGTS 230 L MUC16 Q8WXI7 A*02 231 HHL MUC16 Q8WXI7 A*02 232 TISSLTHEL MUC16 Q8WXI7 A*02 GSDTSSKS 233 L MUC16 Q8WXI7 A*02/B*14 234 GVATRVDAI MUC16 Q8WXI7 A*02/B*14 235 SAIETSAVL MUC16 Q8WXI7 A*02/B*35 236 SAIPFSMTL MUC16 Q8WXI7 A*02/B*35 237 SAMGTISIM MUC16 Q8WXI7 A*02/B*35 238 PLLVLFTI MUC16 Q8WXI7 A*02/B*51 239 FAVPTGISM MUC16 Q8WXI7 A*02/C*03 240 FSTDTSIVL MUC16 Q8WXI7 A*02/C*03 241 RQPNILVHL MUC16 Q8WXI7 A*02:05 242 STIPALHEI MUC16 Q8WXI7 A*02:05 243 V SPON1 Q9HCB6 A*02/B*51 DTDSSVHV 244 QV TENM4 Q6N022 A*02 Seq ID HLA No Sequence Gene Uniprot Accession allotype LAVEGGQS 245 L UBXN8 000124 A*02 RYLAWHA 246 VF CCR5 P51681 A*24/A*23 ARPPWMW 247 VL KLK5 Q9Y337 A*24/B*27 248 SVIQHLGY MSLN Q13421 A*24 249 VYTPTLGTL DNAJC22, MUC16 Q8WXI7 A*24 HFPEKTTH 250 SF MUC16 Q8WXI7 A*24/C*14 251 KQRQVLIFF PCDHB2 Q9Y5E7 A*24/B*15 LYQPRASE 252 M PNOC Q13519 A*24/A*25 253 KF PTTG2, PTTG1 095997 *O4 254 IIQHLTEQF STAG3 Q9UJ98 A*24/C*O3 255 VFVSFSSLF ZNF56O Q96MR9 *27 RTEEVLLTF 256 K GPR64 Q8IZP9 A*03 VTADHSHV ALPI, ALPL, ALPP, 257 F ALPPL2 PO5187 A*03 GAYAHTVN 258 R ALPPL2 P10696 A*03 259 KTLELRVAY BCAM P50895 A*03/A*32 260 GTNTVILEY C2orf88 Q9BSFO A*03 HTFGLFYQ 261 R FAM111B Q6SJ93 A*03 RSRLNPLV 262 QR FAM83H Q6ZRV2 A*03 263 SSSSATISK HOXD3 P31249 A*O3/A*11 264 AIKVIPTVFK |DO1 P14902 A*03 QIHDHVNP 265 K |DO1 P14902 A*03/A*1 1 266 K |GF2BP1 Q9NZI8 A*03 267 VTDLISPRK LAMA1 P25391 A*03 A*03/A*11/ 268 GLLGLSLRY LRRTM1 Q86UE6 A*29 RLKGDAWV 269 YK MELK Q14680 A*03 270 RTY MMP12 P399OO A*03/A*1 1 271 RMFADDLH MRPL51 Q4U2R6 A*03 _ 23 _ Seq ID HLA No Sequence Gene Uniprot Accession pe RQPERTILR 272 PR MSLN 013421 A*03 273 RVNAIPFTY MSLN 013421 A*03/A*26 274 KTFPASTVF MUC16 08WX|7 A*03 275 STTFPTLTK MUC16 08WX|7 A*03 VSKTTGME 276 F MUC16 08WX|7 A*03 277 TTALKTTSR DNAJC22, MUC16 08WXI7 A*03/A*66 278 NLSSITHER MUC16 08WXI7 *68 279 KR MUC16 08WXI7 A*03/A*68 SVSGVKTT 280 F MUC16 08WXI7 A*03/B*15 281 RAKELEATF NLRP7, NLRP2 09NX02 A*03 CLTRTGLFL 282 RF NLRP7, NLRP2 09NX02 A*03 283 EEK PAGE2, PAGE2B 07Z2X7 A*03/A*11 TCEA1 P2, TCEA1, 284 KSLIKSWKK TCEA2 P23193, 015560 A*03/A*11 GTVNPTVG 285 K TENM4 06N022 A*03/A*11 TVAPPOGV 286 VK ZBTB12 09Y330 A*03/A*68 ZNF271, KLF8, ZNF816, ZFP28, ZSCAN29, , ZNF480, ZNF714, ZNF836, ZNF600, ZNF320, ZNF100, ZNF721, ZNF841, ZNF678, ZNF860, ZNF429, ZNF888, ZNF761, ZNF701, ZNF83, ZNF695, ZNF471, ZNF22, ZNF28, ZNF137P, ZNF665, ZNF606, ZNF430, ZNF34, ZNF616, EKP ZNF468, ZNF160, 287 YK ZN F765, ZN F845 Q8IW36 A*O3/A*11 SPVTSVHG 288 GTY L|LRB4 Q8NHJ6 A*O1/B*35 Seq ID HLA No Sequence Gene t Accession allotype RWEKTDLT 289 Y MMP11 P2434? A*01 DMDEEIEAE 290 Y MYO3B Q8WXR4 A*01/A*25 291 ETIRSVGYY TENM4 Q6N022 A*01/A*25 NVTMKWS 292 VLY VTCN1 Q?Z?D3 A*01 VPDSGATA 293 TAY ALPP, ALPPL2 P0518? B*0?/B*35 294 YPLRGSSIF ALPP,ALPPL2 P0518? B*0?/B*35 295 GL ALPP, ALPPL2 P0518? B*0?/B*35 296 YPLRGSSI ALPP,ALPPL2 P0518? B*51/B*0? 29? TVREASGLL BCAM P50895 B*0? 298 YPTEHVQF BCAM P50895 B*0?/B*35 HPGSSALH 299 Y BCAT1 P5468? B*0?/B*35 IPMAAVKQA 300 L BCL2L1 QO?81? B*0? 301 F CDCA5 Q96FF9 B*0? 302 RVEEVRALL CDKN2A P42??1 B*0? LPMWKVTA 303 F CLDN6 P56?4? B*0? 304 LPRPGAVL CTAG2 075638 B*0? TPWAESST 305 KF DPEP3 Q9H4B8 B*0?/B*35 B*55/B*56/ 306 APVIFSHSA DPEP2, DPEP3 Q9H4B8 B*0? LPYGPGSE ? AAAF ESR1 P033?2 B*0?/B*35 308 F ESR1 P033?2 B*0?/B*35 FPQSQYPQ 309 Y EYA2 00016? B*0?/B*35 310 RPNPITIIL FBN2 P35556 B*0? 311 RPLFYVVSL HTR3A P46098 B*0? 312 M HTR3A P46098 B*0?/B*35 KVKSDRSV 313 F HTR3A P46098 B*15/B*0? 314 VPDQPHPEI |RF4 Q15306 B*0?/B*35 WO 38257 Seq ID HLA No Sequence Gene Uniprot Accession allotype SPRENFPD 315 TL KLK8 060259 B*07 316 EPKTATVL LAMA1 P25391 B*42/B*O7 317 FPFQPGSV LGALS1 P09382 B*51/B*O7 B*54/B*55/ 318 LEA LGALS1 PO9382 B*07 SPAEPSVY 319 ATL L|LRB4 Q8NHJ6 B*07 FPMSPVTS 320 V L|LRB4 Q8NHJ6 B*O7/B*51 321 LLI L|LRB4 Q8NHJ6 B*51/B*O7 322 SPDPSKHLL LRRK1 Q38SD2 B*O7/B*35 RPMPNLRS 323 V LRRTM1 Q86UE6 B*55/B*07 MEX3D, MEX3C, 324 VPYRWGL MEX3B,MEX3A A1LO2O B*51/B*O7 GPRNAQRV 325 L MFN1 Q8IWA4 B*07 326 VPSEIDAAF MMP11 P24347 B*O7/B*35 327 SPLPVTSLI MUC16 Q8WXI7 B*07 EPVTSSLPN 328 F MUC16 Q8WXI7 B*O7/B*35 FPAMTESG 329 GMIL MUC16 Q8WXI7 B*O7/B*35 FPFVTGSTE 330 M MUC16 Q8WXI7 B*O7/B*35 FPHPEMTT 331 SM MUC16 Q8WXI7 B*O7/B*35 FPHSEMTT 332 L MUC16 Q8WXI7 *35 333 VM MUC16 Q8WXI7 B*O7/B*35 334 FPYSEVTTL MUC16 Q8WXI7 B*O7/B*35 HPDPVGPG 335 L MUC16 Q8WXI7 B*O7/B*35 HPKTESAT 336 PAAY MUC16 Q8WXI7 B*O7/B*35 337 HPVETSSAL MUC16 Q8WXI7 B*O7/B*35 HVTKTQAT 338 F MUC16 Q8WXI7 B*O7/B*35 LPAGTTGSL 339 VF MUC16 Q8WXI7 B*O7/B*35 340 LPEISTRTM MUC16 Q8WXI7 B*O7/B*35 Seq ID HLA No Sequence Gene Uniprot ion allotype 341 TTL MUC16 Q8WXI7 B*O7/B*35 342 LPLGTSMTF MUC16 Q8WXI7 B*O7/B*35 LPSVSGVK 343 TTF MUC16 Q8WXI7 B*O7/B*35 344 LPTQTTSSL MUC16 Q8WXI7 B*O7/B*35 LPTSESLVS 345 F MUC16 Q8WXI7 B*O7/B*35 LPWDTSTT 346 LF MUC16 Q8WXI7 B*O7/B*35 347 GM MUC16 Q8WXI7 B*O7/B*35 348 M MUC16 Q8WXI7 B*O7/B*35 MPSLSEAM 349 TSF MUC16 Q8WXI7 B*O7/B*35 350 NPSSTTTEF MUC16 Q8WXI7 B*O7/B*35 351 NVLTSTPAF MUC16 Q8WXI7 B*O7/B*35 SPAETSTN 352 M MUC16 Q8WXI7 B*O7/B*35 SPAMTTPS 353 L MUC16 Q8WXI7 B*O7/B*35 354 SPLPVTSLL MUC16 Q8WXI7 B*O7/B*35 355 SPLVTSHIM MUC16 Q8WXI7 B*O7/B*35 356 SPNEFYFTV MUC16 Q8WXI7 B*O7/B*35 357 SPSPVPTTL MUC16 Q8WXI7 B*O7/B*35 358 SPSPVTSTL MUC16 Q8WXI7 B*O7/B*35 359 SPSTIKLTM MUC16 Q8WXI7 B*O7/B*35 SPSVSSNT 360 Y MUC16 Q8WXI7 B*O7/B*35 SPTHVTQS 361 L MUC16 Q8WXI7 B*O7/B*35 362 SPVPVTSLF MUC16 Q8WXI7 B*O7/B*35 363 TAKTPDATF MUC16 Q8WXI7 B*O7/B*35 364 TPLATTQRF MUC16 Q8WXI7 *35 TPLATTQRF 365 TY MUC16 Q8WXI7 *35 TPLTTTGSA 366 EM MUC16 Q8WXI7 B*O7/B*35 TPSVVTEG 367 F MUC16 Q8WXI7 B*O7/B*35 VPTPVFPT 368 M MUC16 Q8WXI7 B*O7/B*35 _ 27 _ Seq ID HLA No Sequence Gene Uniprot Accession pe FPHSEMTT B*O7/B*35/ 369 V MUC16 Q8WXI7 B*51 B*14:O2/B* 370 PGGTRQSL MUC16 Q8WXI7 O7 LYVDGFTH B*35/B*55/ 371 W MUC16 Q8WXI7 B*07 IPRNPPPTL 372 L MYO3B Q8WXR4 B*07 RPRALRDL 373 RIL NLRP7, NLRP2 Q9NXO2 B*07 NPIGDTGVK 374 F NLRP7 Q8WX94 B*O7/B*35 375 AAASPLLLL NMU P48645 B*07 RPRSPAGQ 376 VA NMU P48645 B*O7/B*55 377 VAAA NMU P48645 B*O7/B*55 RPRSPAGQ 378 VAA NMU P48645 B*O7/B*56 379 GPFPLVYVL OVGP1 Q12889 B*O7/B*35 380 IPTYGRTF OVGP1 Q12889 B*O7/B*35 381 LPEQTPLAF OVGP1 Q12889 B*O7/B*35 SPMHDRWT 382 F OVGP1 Q12889 B*O7/B*35 383 TPTKETVSL OVGP1 Q12889 B*O7/B*35 YPGLRGSP 384 M OVGP1 Q12889 B*O7/B*35 PCDHB5, PCDHB18, Q96TAO, , PCDHB17, 5, , Q9UN67, PCDHB14, PCDHB11, Q9Y5E1, Q9Y5E3, PCDHB10, PCDHB9, Q9Y5E4, Q9Y5E5, PCDHB8, PCDHB6, Q9Y5E6, Q9Y5E7, PCDHB4, , Q9Y5E8, Q9Y5E9, 385 SPALHIGSV PCDHB2, PCDHB16 Q9Y5F2 B*07 386 FPFNPLDF PTTG1 O95997 B*O7/B*35 APLKLSRTP 387 A SPON1 Q9HCB6 B*O7/B*55 SPAPLKLSR B*O7/B*55/ 388 TPA SPON1 Q9HCB6 B*56 SPGAQRTF STAG3, STAG3L3, 389 FQL STAG3L2, STAG3L1 POCL83, Q9UJ98 B*07 NPDLRRNV 390 L TCEA2 Q15560 B*07 WO 38257 Seq ID HLA No Sequence Gene Uniprot Accession allotype APSTPRITT 391 F TCEA2 Q15560 B*07 392 KPIESTLVA TMEM158 Q8WZ71 *55 393 ASKPHVEI CRABP1 P29762 B*08 394 MYKMKKPI MAGEB3 O15480 B*08 395 VLLPRLVSC MSLN Q13421 B*08/A*02 396 LSL BCAM P50895 B*44 REGDTVQL 397 L BCAM P50895 B*44 SFEQWNE 398 LF BCL2L1 QO7817 B*44 399 RELLHLVTL CAPN13 Q6MZZ7 B*44/B*37 400 GEIEIHLL CCDC146 Q8IYEO B*44/B*40 401 EDLKEELLL CPXCR1 Q8N123 B*44/B*18 402 L CRABP1 P29762 B*44 EEAQWVRK 403 Y FAM111B Q6SJ93 B*44 404 NEAIMHQY FAM111B Q6SJ93 B*44/B*18 405 NEIWTHSY FOLR1 P15328 *18 406 EDGRLVIEF FRAS1 Q86XX4 B*44/B*18 AEHEGVSV 407 L GXYLT2 AOPJZ3 B*44 408 LEKALQVF |DO1 P14902 B*44 REFVLSKG 409 DAGL |DO1 P14902 B*44 SEDPSKLE 410 A |DO1 P14902 B*44 411 LELPPILVY |DO1 P14902 B*44/B*18 412 QEILTQVKQ |GF2BP3 000425 B*44/B*40 413 IEALSGKIEL |GF2BP3 000425 B*44/B*45 EDAALFKA 414 W |RF4 Q15306 B*44 REEDAALF 415 KAW |RF4 Q15306 B*44 SEEETRVV 416 F MELK Q14680 B*44 MEX3C, MEX3B, A1L020, Q5U5Q3, 417 AEHFSMIRA MEX3A Q6ZN04 B*44/B*50 FEDAQGHI 418 W MMP11 P24347 B*44 419 HEFGHVLG MMP11 P24347 B*44/B*40 _ 29 _ Seq ID HLA No Sequence Gene Uniprot Accession allotype FESHSTVS 420 A MUC16 Q8WXI7 B*44 421 GEPATTVSL MUC16 Q8WXI7 B*44 422 SETTFSLIF MUC16 Q8WXI7 B*44 423 A MUC16 Q8WXI7 B*44 424 SAA MUC16 Q8WXI7 B*44 425 SEVPLPMAI MUC16 Q8WXI7 B*44/B*18 426 PEKTTHSF MUC16 Q8WXI7 O1 HESSSHHD 427 L NFE2L3 Q9Y4A8 B*44 428 LDLGLNHI NLRP2 Q9NXO2 B*44/B*47 429 REKFIASVI OVGP1 Q12889 B*44 430 DEKILYPEF OVGP1 Q12889 B*44/B*18 AEQDPDEL 431 NKA POMZP3, ZP3 P21754, Q6PJE2 B*44/B*41 432 QF PRAME P78395 B*44/B*18 , Q8WVM7, 433 SDSQVRAF STAG1, STAG3, STAG2 Q9UJ98 B*44/B*37 KEAIREHQ TCEA1 P2, TCEA1, 434 M TCEA2 P23193, Q15560 B*44/B*41 REEFVSIDH 435 L TMPRSS3 P57727 B*44 REPGDIFSE 436 L WISP3 095389 B*44 437 TEAVVTNEL XPR1 Q9UBH6 B*44 SEVDSPNV 438 L ZNF217 O75362 B*44 Table 4: HLA Class | peptides according to the present invention.
Seq ID HLA No Sequence Gene Uniprot Accession allotype 439 EALAKLMSL ATP7B P3567O B*51 440 ELFEGLKAF BCAT1 P54687 A*25 HQITEVGT 441 M BCAT1 P54687 B*15 442 |LSKLTD|QY BCAT1 P54687 B*15 GTFNPVSL 443 W BCAT1 P54687 B*58 WO 38257 _ 30 _ Seq ID HLA No Sequence Gene t Accession allotype KLSQKGYS 444 W BCL2L1 QO7817 A*32 445 LHITPGTAY BCL2L1 QO7817 B*13 446 GRIVAFFSF BCL2L1 QO7817 B*27 447 MQVLVSRI BCL2L1 QO7817 B*52/B*13 448 LSQKGYSW BCL2L1 QO7817 B*57 RAFSDLTS 449 QL BCL2L1 QO7817 C*15 450 KQTFPFPTI C2orf88 Q9BSFO B*13 DYLNEWGS 451 RF CDH3 P22223 A*23 LKVLGVNV 452 M CRABP2 P29373 C*07 453 DVKLEKPK DPPA2 Q7Z7J5 A*68 AQTDPTTG 454 Y LOXL2, ENTPD4 Q9Y4KO B*15 AAAANAQV 455 Y ESR1 P03372 B*35 IPLERPLGE 456 VY ESR1 P03372 B*35 NAAAAANA 457 QVY ESR1 P03372 B*35 458 TDTLIHLM ESR1 P03372 B*37 KVAGERYV P41161, P43268, 459 Y ETV1, ETV4, ETV5 P50549 A*32/A*31 RLSSATAN 460 ALY FAM83H Q6ZRV2 A*26 AQRMTTQL 461 L FOLR1 P15328 B*15 QRMTTQLL 462 L FOLR1 P15328 B*27/C*07 463 VNQSLLDLY FTHL17 Q9BXU8 A*26 464 LL GPC2 Q8N158 C*15 465 DLIESGQLR |DO1 P14902 A*66 DLIESGQLR 466 ER |DO1 P14902 A*66 MQMQERD 467 TL |DO1 P14902 B*15 468 ALAKLLPL KLK1O 043240 B*35 QEQSSWR 469 A KLK6 Q92876 B*45 470 QGERLLGA LAG3 P18627 C*03 Seq ID HLA No Sequence Gene Uniprot Accession allotype 471 F LAMC2 Q13753 B*15 472 MRLLVAPL LRRN2 O75325 B*14 473 AL LRRN2 O75325 B*35 AADGGLRA 474 SVTL LY6E Q16553 C*05 GRDPTSYP 475 SL MAGEA11 P43364 B*39 476 ISYPPLHEW MAGEA3, MAGEA12 P43357 B*57 RIQQQTNT 477 Y MEX3A A1 L020 B*15 MEX3D, MEX3C, A1L020, Q5U5Q3, 478 VVGPKGATI MEX3B, MEX3A Q6ZN04, Q86XN8 C*14 TEGSHFVE 479 A MFN1 Q8IWA4 B*45 480 GRADIMIDF MMP11 P24347 B*27 GRWEKTDL 481 TY MMP11 P24347 B*27 GRWEKTDL 482 TYR MMP1 1 P24347 B*27 VRFPVHAA 483 LVW MMP1 1 P24347 B*27 484 AWLRSAAA MMP1 1 P24347 B*56 VRFPVHAA 485 L MMP11 P24347 C*O7 486 DRFFWLKV MMP12 P39900 B*14 487 GMADILVVF MMP12 P39900 B*15 RSFSLGVP 488 R MRPL51 Q4U2R6 A*31 EVSGLSTE 489 R MSLN Q13421 A*68 AEVQKLLG 490 P MSLN Q13421 B*5O 491 W MUC16 Q8WXI7 A*25 EVTPWISLT 492 L MUC16 Q8WXI7 A*25 DTNLEPVT 493 R MUC16 Q8WXI7 A*68 494 ETTASLVSR MUC16 Q8WXI7 A*68 495 EVPSGATT MUC16 Q8WXI7 A*68 Seq ID HLA No ce Gene Uniprot Accession allotype EVPTGTTA 496 EVSR MUC16 Q8WXI7 A*68 EVSRTEVIS 497 SR MUC16 Q8WXI7 A*68 EVYPELGT 498 QGR MUC16 Q8WXI7 A*68 499 SSETTKIKR MUC16 Q8WXI7 A*68 500 AHVLHSTL MUC16 Q8WXI7 B*14 501 IQIEPTSSL MUC16 Q8WXI7 B*14 502 SGDQGITSL MUC16 Q8WXI7 B*14 TVFDKAFTA 503 A MUC16 Q8WXI7 B*14 504 L MUC16 Q8WXI7 B*14 YVPTGAITQ 505 A MUC16 Q8WXI7 B*14 HQFITSTNT 506 F MUC16 Q8WXI7 B*15 507 TSIFSGQSL MUC16 Q8WXI7 B*15 508 TVAKTTTTF MUC16 Q8WXI7 B*15 GRGPGGVS 509 W MUC16 Q8WXI7 B*27 510 RRIPTEPTF MUC16 Q8WXI7 B*27 SRIPQDVS 511 W MUC16 Q8WXI7 B*27 SRSPENPS 512 W MUC16 Q8WXI7 B*27 513 SRTEISSSR MUC16 Q8WXI7 B*27 SRTEVASS 514 R MUC16 Q8WXI7 B*27 515 TRIEMESTF MUC16 Q8WXI7 B*27 516 TASTPISTF MUC16 Q8WXI7 B*35 TAETILTFH 517 AF MUC16 Q8WXI7 B*35 518 TSDFPTITV MUC16 Q8WXI7 B*35 VTSLLTPG 519 MV MUC16 Q8WXI7 B*35 THSAMTHG 520 F MUC16 Q8WXI7 B*38 THSTASQG 521 F MUC16 Q8WXI7 B*38 SquD HLA No Sequence Gene t Accession allotype 522 THSTISQGF MUC16 Q8WXI7 B*38 523 TSA MUC16 Q8WXI7 B*55 AVSPTVQG 524 L MUC16 Q8WXI7 C*07 525 QRFPHSEM MUC16 Q8WXI7 C*07 526 SVPDILST MUC16 Q8WXI7 C*07 QSTPYVNS 527 V MUC16 Q8WXI7 C*16 528 TRTGLFLRF NLRP7,NLRP2 Q9NXO2 B*27 529 PFSNPRVL NLRP2 Q9NXO2 C*04 530 MLPRAALL NLRP7 Q8WX94 B*51 QGAQLRGA 531 L NLRP7, NLRP2 Q8WX94 B*52 532 AISFSYKAW OVGP1 Q12889 A*25 GQHLHLET 533 F PRAME P78395 B*15 CRPGALQIE 534 L RAD54B Q9Y620 C*02 535 IK RNF17 Q9BXT8 B*13 VQDQACVA 536 KF RNF17 Q9BXT8 B*15 537 Q RPL37A, RPL37AP8 A6NKH3, P61513 n/a 538 QLEKALKEI SAGE1 Q9NXZ1 C*05 IPIPSTGSV 539 EM SPINT1 O43278 B*35/B*42 540 AGIPAVALW SPINT1 O43278 B*58 541 RLSPAPLKL SPON1 Q9HCB6 B*13 QIIDEEETQ 542 F SPON1 Q9HCB6 B*15 MRLSPAPL 543 K SPON1 Q9HCB6 B*27 544 LRNPSIQKL SPON1 Q9HCB6 C*07 545 RVGPPLLI TMEM158 Q8WZ71 B*15 GRAFFAAA 546 F TMEM158 Q8WZ71 B*27 EVNKPGVY 547 TR TMPRSS3 P57727 A*68 VSEASLVSS 548 | ZBTB12 Q9Y330 C*05 549 ARSKLQQG ZNF217 O75362 B*27 Seq ID HLA No Sequence Gene Uniprot Accession allotype RRFKEPWF ZNF217, ZNF516, 015090, 075362, 550 L ZNF536 092618 B*27 A2RRD8, A6NHJ4, A6NK21, A6NK53, A6NK75, A6NN14, A6NNF4, A6NP11, , A8MUV8, B4DU55, B4DX44, B4DXR9, 014628, 014709, 015090, 043309, 043345, 043361, 075346, , 075437, 075820, 095600, 095780, POCB33, POCJ79, PODKXO, P10073, P17019, P17026, P17035, P17038, P17040, P17097, P35789, P51522, P51815, P52742, 002386, 003923, 003924, 003936, 003938, 005481, , 009FC8, 00VGE8, 014584, 014586, 014590, 014591, 014593, 015928, , 015937, ZNF816, ZNF813, 016587, 02M3W8, ZNF578, , 02M3X9, 02VY69, ZNF600, , 03KP31, 03MIS6, ZNF525, ZNF485, , 04V348, ZNF860, ZNF429, 053GI3, 05HY98, ZNF808, ZNF888, , 05SXM1, ZNF761, ZNF701, 05V|Y5, 05VV52, ZNF83, ZNF167, ZFP62, 068DY1, 06AZW8, ZNF28, 1, 06P280, 06P9G9, ZNF91, ZNF229, 06PDB4, 06ZMV8, ZNF702P, , 06ZMW2, 06ZN06, RLHTGEKP ZNF468, , 06ZN08, 06ZN19, 551 YK ZNF845 06ZN57, 06ZNA1, A*30 Seq ID HLA No Sequence Gene Uniprot ion allotype QBZNG’I, QBZR52, Q76KX8, Q7L2R6, Q7L945, Q7Z3V5, Q7Z7L9, Q86TJ5, Q86UE3, Q86V71, Q86XN6, Q86XUO, Q86Y25, Q8IW36, Q8IWY8, Q8IYNO, Q8|226, , Q8N782, , Q8N823, Q8N859, Q8N8CO, Q8N8J6, Q8N972, Q8N988, Q8N9F8, Q8NB50, Q8NCK3, Q8NDQB, Q8NEM1, Q8NF99, , Q8TAQS, Q8TBZS, Q8TD23, Q8TF20, Q8TF32, , Q8WV37, Q8WXB4, QQBCX3, QQ6|R2, QQBJC4, 096LX8, QQBMRQ, 096N22, QQ6N38, QQ6N58, , 096NL3, QQ6PE6, QQBREQ, QQ6SE7, 099676, QQBX82, QQH5H4, QQH7R5, QQH8G’I, QQH963, QQHBT7, QQHCG’I, QQHCL3, QQNQXES, QQNV72, QQPOL’I, QQP255, QQP2F9, QQP2J8, QQUEG4, QQUII5, QQUJW7, QQUL36, QQYZQ’I, QQY473, QQY5A6 773 ALYGKLLKL VPS13B A*02 774 YVI CASCS A*24 Table 5: HLA Class II peptides according to the t invention.
Seq ID No Sequence Additional Sequence variants Gene CRABP 552 GVNAMLRKVAVAAASKPHVE 1 CRABP 553 VNAMLRKVAVAAASKPHVE 1 CRABP 554 GVNAMLRKVAVAAASKPH 1 CRABP 555 VNAMLRKVAVAAASKPH 1 CRABP 556 NAMLRKVAVAAASKPH 1 CRABP 557 AVAAASKPH 1 CRABP 558 LRKVAVAAASKPH 1 CRABP 559 RKVAVAAASKPH 1 CRABP 560 PNFSGNWKIIRSENFEELLK 2 CRABP 561 PNFSGNWKIIRSENFEELL 2 CRABP 562 GNWKIIRSENFEELLKVL 2 CRABP 563 PNFSGNWKIIRSENFEEL 2 CRABP 564 GNWKIIRSENFEELLKV 2 CRABP 565 NWKIIRSENFEELLKV 2 CRABP 566 SENFEELLK 2 CRABP 567 NWKIIRSENFEELL 2 CRABP 568 WKIIRSENFEELLK 2 CRABP 569 WKIIRSENFEELL 2 CRABP 570 GNWKIIRSENF 2 CRABP 571 PNFSGNWKIIR 2 CRABP 572 INFKVGEEFEEQTV 2 573 RLLSADTKGWVRLQ DPPA2 Seq ID No Sequence Additional ce variants Gene 574 LPDFYNDWMFIAKHLPDL |DO1 575 VGDDHLLLLQGEQLRRT KLK10 576 VGDDHLLLLQGEQLRR KLK10 577 GDDHLLLLQGEQLRR KLK10 578 DDHLLLLQGEQLRR KLK10 579 SGGPLVCDETLQGILS KLK10 580 GGPLVCDETLQGILS KLK10 581 GGPLVCDETLQGIL KLK10 582 GSQPWQVSLFNGLSFH KLK10 583 LTVKLPDGYEFKFPNRLNLEAINY LGALS1 GYEFKFPNRLNLEAIN 584 Y LGALS1 585 LTVKLPDGYEFKFPNRLNL LGALS1 586 TVKLPDGYEFKFPNRLNL LGALS1 587 DQANLTVKLPDGYEFKFPNRLNL LGALS1 588 VAPDAKSFVLNLGKDSNNL LGALS1 589 APDAKSFVLNLGKDSNNL LGALS1 590 RVRGEVAPDAKSFVLNLG LGALS1 591 VRGEVAPDAKSFVLNL LGALS1 592 VRGEVAPDAKSFVLNLG LGALS1 593 GEVAPDAKSFVLNLG LGALS1 594 VRGEVAPDAKSFVLN LGALS1 595 VRGEVAPDAKSFVL LGALS1 596 MAADGDFKIKCVAFD LGALS1 MAGEA 597 SPDAESLFREALSNKVDEL 4 MAGEA 598 EALSNKVDEL 4 MAGEA 599 AESLFREALSNKVDE 4 MAGEA 600 FREALSNKVDE 4 MAGEA 601 LSNKVDELAHFLLRK 4 MAGEB 602 KDPVAWEAGMLMH 1 MAGEB 603 KARDETRGLNVPQ 2 MAGEB 604 KLITQDLVKLKYLEYRQ 3 605 LTVAEVQKLLGPHVEGLKAEERH MSLN Seq ID No Sequence Additional Sequence variants Gene LTVAEVQKLLGPHVEGLKAEE 606 R MSLN 607 LTVAEVQKLLGPHVEGLKAEE MSLN 608 LTVAEVQKLLGPHVEGLKAE MSLN 609 LTVAEVQKLLGPHVEGLKA MSLN 610 LTVAEVQKLLGPHVEGLK MSLN 611 LTVAEVQKLLGPHVEGL MSLN 612 TVAEVQKLLGPHVEGLK MSLN 613 LTVAEVQKLLGPHVEG MSLN 614 TVAEVQKLLGPHVEGL MSLN 615 VAEVQKLLGPHVEGLK MSLN 616 TVAEVQKLLGPHVEG MSLN 617 VAEVQKLLGPHVEGL MSLN 618 LLGPHVEG MSLN 619 VAEVQKLLGPHVE MSLN 620 GPHVEG MSLN 621 LTVAEVQKLLG MSLN 622 MDALRGLLPVLGQPIIRSIPQGIVA MSLN 623 ALRGLLPVLGQPIIRSIPQGIVA MSLN 624 LRGLLPVLGQPIIRSIPQGIVA MSLN 625 DALRGLLPVLGQPIIRSIPQG MSLN 626 LGQPIIRSIPQGIVA MSLN 627 ALRGLLPVLGQPIIRSIPQG MSLN 628 DALRGLLPVLGQPIIRSIPQ MSLN 629 GLLPVLGQPIIRSIPQGIVA MSLN 630 ALRGLLPVLGQPIIRSIPQ MSLN 631 DALRGLLPVLGQPIIRSIP MSLN 632 LLPVLGQPIIRSIPQGIVA MSLN 633 LRGLLPVLGQPIIRSIPQ MSLN 634 DALRGLLPVLGQPIIRS MSLN 635 ALRGLLPVLGQPIIRS MSLN 636 DALRGLLPVLGQPIIR MSLN 637 PVLGQPIIR MSLN 638 LRGLLPVLGQPIIRS MSLN 639 ALRGLLPVLGQPII MSLN 640 ALRGLLPVLGQPI MSLN 641 RGLLPVLGQPIIR MSLN 642 GLLPVLGQPIIR MSLN 643 LRGLLPVLGQPI MSLN Seq ID No Sequence onal Sequence variants Gene 644 RGLLPVLGQPI MSLN RGLLPVLGQPIIRSIPQGIVAAWR 645 Q MSLN GLLPVLGQPIIRSIPQGIVAAW 646 R0 MSLN 647 LPVLGQPIIRSIPQGIVAAWRQ MSLN 648 GLLPVLGQPIIRSIPQGIVAA MSLN 649 LLPVLGQPIIRSIPQGIVAA MSLN 650 LPVLGQPIIRSIPQGIVAAW MSLN 651 LPVLGQPIIRSIPQGIVAA MSLN 652 PVLGQPIIRSIPQGIVAAW MSLN 653 LPVLGQPIIRSIPQGIVA MSLN 654 PVLGQPIIRSIPQGIVA MSLN 655 LGQPIIRSIPQGIVAA MSLN 656 VLGQPIIRSIPQGIVA MSLN 657 IPQGIVA MSLN VSTMDALRGLLPVLGQPIIRSIPQ 658 G MSLN VSTMDALRGLLPVLGQPIIRSI 659 PO MSLN 660 VSTMDALRGLLPVLGQPIIR MSLN 661 LRGLLPVLGQPIIRSIPQG MSLN LRTDAVLPLTVAEVQKLLGPHVE 662 G MSLN RTDAVLPLTVAEVQKLLGPHV 663 EG MSLN 664 AVLPLTVAEVQKLLGPHVEG MSLN 665 VLPLTVAEVQKLLGPHVEG MSLN 666 LPLTVAEVQKLLGPHVEG MSLN 667 TDAVLPLTVAEVQ MSLN 668 AVLPLTVAEVQK MSLN VLPLTVAEVQKLLGPHVEGLKAE 669 E MSLN 670 AEVQKLLGPHVEGLK MSLN 671 LPLTVAEVQKLLGPHVEGLK MSLN 672 LRGLLPVLGQPIIRSIPQGIVAA MSLN 673 IPFTYEQLDVLKHKLDELYPQ MSLN 674 IPFTYEQLDVLKHKLDE MSLN 675 IPFTYEQLDVLKHKLD MSLN 676 VPPSSIWAVRPQDLDTCDPR MSLN 677 IWAVRPQDLDTCDPR MSLN Seq ID No Sequence Additional Sequence variants Gene 678 LDTCDPR MSLN 679 WGVRGSLLSEADVRALGGLA MSLN 680 LSEADVRALGGLA MSLN 681 WGVRGSLLSEADVRALGGL MSLN 682 GVRGSLLSEADVRALGGL MSLN 683 VRGSLLSEADVRALGGLA MSLN 684 WGVRGSLLSEADVRALGG MSLN 685 GVRGSLLSEADVRALGG MSLN 686 VRGSLLSEADVRALGGL MSLN 687 LLSEADVRALG MSLN 688 GVRGSLLSEADVRALG MSLN 689 WGVRGSLLSEADVRAL MSLN 690 GSLLSEADVRALGGL MSLN 691 GVRGSLLSEADVRAL MSLN 692 RGSLLSEADVRALGG MSLN 693 WGVRGSLLSEADVRA MSLN 694 GSLLSEADVRALGG MSLN 695 RGSLLSEADVRALG MSLN 696 WGVRGSLLSEADVR MSLN 697 GSLLSEADVRALG MSLN 698 VRGSLLSEADVRA MSLN 699 LLSEADVRALGG MSLN 700 SLLSEADVRALG MSLN 701 GSLLSEADVRA MSLN 702 LLSEADVRALG MSLN 703 LSEADVRALGG MSLN 704 SEADVRALGG MSLN 705 EADVRALGG MSLN 706 LSTERVRELAVALAQKNVK MSLN 707 LSTERVRELAVALAQKN MSLN 708 ERVRELAVALAQKNVK MSLN 709 LSTERVRELAVALAQK MSLN 710 LSTERVRELAVALAQ MSLN 711 STERVRELAVALAQK MSLN 712 TERVRELAVALAQKN MSLN 713 VRELAVALAQKNVK MSLN 714 AIPFTYEQLDVLKHKLDE MSLN 715 GLSTERVRELAVALAQKN MSLN 716 GLSTERVRELAVALAQ MSLN Seq ID No Sequence Additional Sequence variants Gene 717 IPQGIVAAWRQRSSRDPS MSLN 718 GIVAAWRQRSSRDPS MSLN 719 AAWRQRSSR MSLN 720 ALGGLACDLPGRFVAES MSLN 721 RELAVALAQKNVKLSTE MSLN 722 LKALLEVNKGHEMSPQ MSLN 723 TFMKLRTDAVLPLTVA MSLN 724 FMKLRTDAVLPLTVA MSLN 725 FMKLRTDAVLPLT MSLN 726 FMKLRTDAVLPL MSLN 727 TLGLGLQGGIPNGYLV MSLN 728 DLPGRFVAESAEVLL MSLN 729 DLPGRFVAESAEVL MSLN 730 LPGRFVAESAEVL MSLN 731 DLPGRFVAESA MSLN 732 ERHRPVRDWILRQRQ MSLN 733 SPRQLLGFPCAEVSG MSLN 734 SRTLAGETGQEAAPL MSLN 735 VTSLETLKALLEVNK MSLN 736 LGLQGGIPNGYLVL MSLN 737 LQGGIPNGYLVL MSLN 738 GGIPNGYLVL MSLN 739 LQGGIPNGYLVLDL MSLN 740 APERQRLLPAALA MSLN 741 FVKIQSFLGGAPT MSLN 742 FLGG MSLN 743 FVKIQSFLG MSLN 744 EDIRK MSLN 745 TNSVTELGPYTLDRD MUC16 746 EITITTQTGYSLATSQVTLP MUC16 747 ATTPSWVETHSIVIQGFPH MUC16 748 GIKELGPYTLDRNSLYVNG MUC16 749 GIKELGPYTLDRNSL MUC16 750 GPYTLDRNSLYVNG MUC16 751 GIKELGPYTLDRN MUC16 752 LGPYTLDRNSLYV MUC16 753 LGPYTLDRNSLY MUC16 754 LGPYTLDRNSL MUC16 755 IELGPYLLDRGSLYVNG MUC16 _ 42 _ Seq ID No ce Additional Sequence variants Gene 756 LGPYLLDRGSLYVNG MUC16 757 LGPYLLDRGSLYVN MUC16 758 DRGSLYV MUC16 759 EELGPYTLDRNSLYVNG MUC16 760 LKPLFKSTSVGPLYSG MUC16 761 LKPLFKSTSVGPLYS MUC16 762 LKPLFKSTSVGPLY MUC16 763 LKPLFKSTSVGPL MUC16 764 FDKAFTAATTEVSRTE MUC16 765 ELGPYTLDRDSLYVN MUC16 766 GLLKPLFKSTSVGPL MUC16 767 LLKPLFKSTSVGPL MUC16 768 SDPYKATSAVVITST MUC16 769 SDPYKATSAWITS MUC16 770 SRKFNTMESVLQGLL MUC16 771 SRKFNTMESVLQG MUC16 772 LGFYVLDRDSLFIN MUC16 The present invention furthermore generally relates to the peptides according to the present invention for use in the treatment of proliferative diseases, such as, for example, hepatocellular carcinoma, colorectal carcinoma, glioblastoma, gastric cancer, esophageal cancer, non-small cell lung cancer, small cell lung , pancreatic cancer, renal cell carcinoma, te cancer, melanoma, breast , chronic lymphocytic leukemia, Non-Hodgkin ma, acute myeloid leukemia, gallbladder cancer and cholangiocarcinoma, urinary bladder cancer, e cancer, head and neck squamous cell carcinoma, mesothelioma.
Particularly preferred are the peptides — alone or in combination - according to the present invention selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 772. More preferred are the peptides — alone or in combination - selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 215 (see Tables 1 and 2), and their uses in the immunotherapy of ovarian cancer, hepatocellular carcinoma, colorectal carcinoma, astoma, gastric cancer, esophageal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, renal cell carcinoma, prostate cancer, melanoma, breast cancer, chronic lymphocytic leukemia, Non-Hodgkin lymphoma, acute myeloid leukemia, gallbladder cancer and cholangiocarcinoma, y bladder , uterine cancer, head and neck us cell carcinoma, mesothelioma, and preferably ovarian cancer.
Thus, another aspect of the t invention relates to the use of the peptides ing to the present invention for the - preferably combined - treatment of a proliferative disease selected from the group of ovarian cancer, hepatocellular carcinoma, colorectal carcinoma, glioblastoma, gastric cancer, esophageal cancer, non- small cell lung cancer, small cell lung cancer, pancreatic cancer, renal cell carcinoma, prostate cancer, melanoma, breast cancer, chronic lymphocytic ia, Non-Hodgkin lymphoma, acute myeloid leukemia, gallbladder cancer and cholangiocarcinoma, urinary bladder cancer, uterine , head and neck squamous cell carcinoma, mesothelioma.
The present ion furthermore relates to peptides according to the present invention that have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-l or - in an elongated form, such as a length-variant - MHC class -II.
The present invention further relates to the peptides according to the present invention wherein said peptides (each) consist or consist essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 772.
The present invention further relates to the es ing to the t invention, wherein said peptide is modified and/or includes non-peptide bonds.
The present invention further relates to the peptides according to the present invention, wherein said peptide is part of a fusion protein, in particular fused to the N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii), or fused to (or into the sequence of) an antibody, such as, for example, an antibody that is specific for dendritic cells.
The present invention further relates to a nucleic acid, encoding the peptides according to the present invention. The present invention r relates to the nucleic acid according to the present invention that is DNA, cDNA, PNA, RNA or combinations thereof.
The present invention further relates to an sion vector capable of expressing and/or expressing a nucleic acid according to the present ion.
The present invention further relates to a peptide according to the present invention, a nucleic acid ing to the present invention or an expression vector according to the present invention for use in the treatment of diseases and in medicine, in particular in the treatment of cancer.
The present invention further relates to antibodies that are specific against the peptides according to the present invention or xes of said peptides according to the present invention with MHC, and methods of making these.
The present invention further s to T-cell receptors (TCRs), in particular soluble TCR (sTCRs) and cloned TCRs engineered into autologous or allogeneic T cells, and functional fragments thereof, and methods of making these, as well as NK cells or other cells bearing said TCR or cross-reacting with said TCRs.
The antibodies and TCRs are additional embodiments of the immunotherapeutic use of the es according to the t invention.
The present invention further relates to a host cell comprising a nucleic acid ing to the t invention or an expression vector as described . The present _ 45 _ invention further relates to the host cell according to the present invention that is an antigen presenting cell, and preferably is a dendritic cell.
The present invention further relates to a method for producing a peptide according to the present invention, said method comprising culturing the host cell according to the present invention, and isolating the peptide from said host cell or its culture medium.
The present invention further relates to said method ing to the present invention, wherein the antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or artificial antigen-presenting cell by contacting a ient amount of the antigen with an antigen-presenting cell.
The present invention further relates to the method according to the present invention, wherein the antigen-presenting cell comprises an expression vector capable of expressing or expressing said peptide containing SEQ ID No. 1 to SEQ ID No.: 772, preferably containing SEQ ID No. 1 to SEQ ID No. 215, or a variant amino acid The t invention further relates to activated T cells, produced by the method according to the present invention, wherein said T cell selectively recognizes a cell which expresses a polypeptide comprising an amino acid ce according to the present invention.
The present invention further relates to a method of killing target cells in a patient which target cells aberrantly express a polypeptide comprising any amino acid sequence according to the present ion, the method comprising stering to the t an effective number of T cells as produced according to the t invention.
The t ion further relates to the use of any peptide as described, the nucleic acid according to the present ion, the expression vector according to the present invention, the cell ing to the present invention, the activated T lymphocyte, the T _ 46 _ cell receptor or the antibody or other peptide- and/or peptide-MHC-binding les according to the present invention as a medicament or in the manufacture of a medicament. Preferably, said medicament is active against . ably, said medicament is a cellular therapy, a vaccine or a protein based on a soluble TCR or antibody.
The present invention further relates to a use according to the t invention, wherein said cancer cells are ovarian cancer, hepatocellular carcinoma, colorectal carcinoma, glioblastoma, gastric cancer, esophageal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, renal cell carcinoma, prostate cancer, melanoma, breast cancer, c lymphocytic leukemia, Non-Hodgkin lymphoma, acute myeloid leukemia, adder cancer and cholangiocarcinoma, urinary bladder cancer, uterine cancer, head and neck squamous cell carcinoma, mesothelioma, and preferably ovarian cancer cells.
The present invention further relates to kers based on the peptides according to the present invention, herein called "targets" that can be used in the diagnosis of , preferably ovarian cancer. The marker can be over-presentation of the peptide(s) themselves, or over-expression of the corresponding gene(s). The s may also be used to predict the probability of success of a treatment, preferably an immunotherapy, and most red an immunotherapy targeting the same target that is identified by the ker. For example, an antibody or soluble TCR can be used to stain sections of the tumor to detect the ce of a peptide of interest in complex with MHC.
Optionally the antibody carries a further effector function such as an immune stimulating domain or toxin.
The present invention also relates to the use of these novel targets in the context of cancer treatment.
Both therapeutic and diagnostic uses against additional cancerous es are disclosed in the following more detailed description of the underlying expression products (polypeptides) of the peptides according to the invention.
ALPP, also known as ALP, PLAP or PALP, encodes an alkaline atase, a metallo-enzyme that catalyzes the hydrolysis of phosphoric acid monoesters q, 2002). ALPP was described to be hyper-expressed in various human tumors and their cell lines, particularly in cancers of the testis and ovary (Millan and Fishman, 1995).
ALPP was identified as an independent prognostic factor for the survival of osteosarcoma patients which also correlates with lung metastasis. Furthermore, ALPP was described as an immunohistochemical marker of gastrointestinal smooth muscle neoplasms, germ cell tumor precursors, such as carcinoma in situ and gonadoblastoma, and as a promising ovarian cancer biomarker (Ravenni et al., 2014; Wong et al., 2014b; Faure et al., 2016; Han et al., 2012).
ALPPL2, also known as GCAP, encodes a membrane bound glycosylated enzyme, localized to testis, thymus and certain germ cell tumors, which is closely d to both the tal and intestinal forms of alkaline phosphatase q, 2002). ALPPL2 was shown to be ectopically expressed in seminoma as well as in many atic cancer cell lines at both mRNA and protein levels and to be involved in cancer cell growth and invasion. Additionally, ALPPL2 was described as a potential diagnostic marker of atic ductal adenocarcinoma (Hofmann and Millan, 1993; Dua et al., 2013; Fishman, 1995). RT-PCR for ALPPL2 was described to be suitable for the sensitive detection of residual germ cell tumor cells in peripheral blood and progenitor cell harvests (Hildebrandt et al., 1998).
BCAM encodes the basal cell adhesion molecule ran blood group), a member of the globulin superfamily and a receptor for the extracellular matrix protein, laminin (RefSeq, 2002). BCAM is a specific receptor for laminin alpha5 (LAMA5), a subunit of laminin-511 1) that is a major component of basement membranes in _ 48 _ s tissues; the BCAM/LAMA5 system plays a functional role in the atic spreading of KRAS-mutant colorectal cancer as well as in the migration of hepatocellular oma (Kikkawa et al., 2013; Kikkawa et al., 2014; Bartolini et al., 2016). Serum levels of BCAM were found to be significantly increased in breast cancer patients and its over-expression was found to be associated with skin, ovarian and pancreatic s as well as with endometrioid endometrial carcinoma, ovarian trioid carcinoma and cutaneous us cell carcinoma (Kikkawa et al., 2008; Planaguma et al., 2011; Latini et al., 2013; Kim et al., 2015a; Li et al., 2017). Being able to form a fusion protein with AKT2, BCAM was identified as AKT2 kinase tor in high-grade serous ovarian cancer (Kannan et al., 2015).
CBX2 encodes chromobox 2 which is a component of the polycomb multiprotein complex, which is required to in the riptionally repressive state of many genes throughout development via chromatin remodeling and cation of histones (RefSeq, 2002). CBX2 is involved in cell proliferation and metastasis (Clermont et al., 2016). CBX2 is regulated by SMARCE1 leading to suppressed EGFR transcription.
CBX2 is involved in the regulation of three tumor suppressor genes encoded in the lNK4A/ARF locus (Papadakis et al., 2015; Agherbi et al., 2009; Miyazaki et al., 2008).
CBX2 is over-expressed in cancer including breast cancer, ovarian cancer, lung cancer, metastatic castration-resistant and neuroendocrine prostate cancer and basal-like endometrioid endometrial carcinoma (Parris et al., 2010; Clermont et al., 2016; Clermont et al., 2014; Clermont et al., 2015; Jiang et al., 2015; Xu et al., 2016). CBX2 is associated with lower patient survival and metastatic progression. CBX2 is linked to peritumoral inflammatory ration, metastatic spread to the cervical lymph nodes, and tumor size (Parris et al., 2014; Clermont et al., 2014; Xu et al., 2016). CBX2 over- expression results in hematopoietic stem cell differentiation and exhaustion (Klauke et aL,2013) CCNA1 encodes cyclin A1, which belongs to the highly conserved cyclin family involved in the regulation of CDK kinases (RefSeq, 2002). Elevated levels of CCNA1 were detected in epithelial ovarian , lymphoblastic leukemic cell lines as well as in childhood acute lymphoblastic leukemia patients. Others have observed over- expression of CCNA1 protein and mRNA in prostate cancer and in tumor tissues of anap|astic d carcinoma patients (Holm et al., 2006; Wegiel et al., 2008; Marlow et al., 2012; Arsenic et al., 2015). Recent s have shown that silencing of CCNA1 in highly cyclin A1 expressing ML1 leukemic cells slowed S phase entry, decreased eration and ted colony formation (Ji et al., 2005).
CD70 encodes CD70 molecule which is a ne that belongs to the tumor necrosis factor (TNF) ligand family. It induces proliferation of co-stimulated T cells, enhances the generation of cytolytic T cells, and contributes to T cell activation. This cytokine is also ed to play a role in regulating B-cell activation, cytotoxic function of natural killer cells, and immunoglobulin synthesis (RefSeq, 2002). Targeting of CD70 may be used to specifically target and kill cancer cells. It may be a potential target in oral cancer (Bundela et al., 2014; Jacobs et al., 2015b; Wang et al., 2016a). CD70 is expressed in head-and-neck squamous cell carcinoma. It is ectopically sed in lymphomas, renal cell carcinomas, and glioblastomas. CD70 expression levels decrease during melanoma progression. CD70 is highly expressed on CD4+ CD25+ T-cells from patients with acute-type adult T-cell ia/lymphoma (Jacobs et al., 2015b; Curran et al., 2015; De et al., 2016; Jacobs et al., 2015a; Masamoto et al., 2016; Pich et al., 2016b; Ruf et al., 2015a). CD70 is involved in immune response, cancer development, and cancer progression (Petrau et al., 2014; Pich et al., 2016a). CD70 up-regulation in clear cell renal cell carcinoma is associated with worse survival (Ruf et al., 2015b).
Cisplatin mediates cytotoxicity through APCs expressing relatively higher levels of CD70 nvand et al., 2016). CD70 expression is almost not affected by ionizing radiation. It is associated with radio sensitivity in lung cancer. Single-dose external beam ion up-regulates CD70 in PC3 cells (Bernstein et al., 2014; Kumari and Garnett-Benson, 2016; Pu et al., 2014).
CDH3 (also known as P-cadherin) encodes cadherin 3 which is a classical cadherin of the cadherin superfamily. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. This gene is d in a gene cluster in a region on the long arm of chromosome 16 that is ed in loss of heterozygosity events in breast and prostate cancer. In addition, aberrant sion of this protein is observed in cervical adenocarcinomas (RefSeq, 2002). CDH3 is involved in oncogenic signaling and activates integrins, receptor tyrosine s, small molecule GTPases, EMT transcription factors, and other cadherin family members. CDH3 signaling induces invasion and metastasis (Albergaria et al., 2011; Paredes et al., 2012; Bryan, 2015; Vieira and Paredes, 2015). nic activation of CDH3 is ed in gastric carcinogenesis (Resende et al., 2011). CDH3 over-expression promotes breast cancer, bladder cancer, ovarian cancer, prostate cancer, endometrial cancer, skin cancer, gastric cancer, pancreas , and colon cancer (Albergaria et al., 2011; Paredes et al., 2007; Bryan and Tselepis, 2010; Reyes et al., 2013; Vieira and Paredes, 2015).
CDH3 is a basal lial marker expressed in basal-like breast cancer. BRCA1 carcinomas are characterized by the expression of basal markers like CDH3 and show a high-grade, highly proliferating, ER-negative, and HER3-negative ype do et al., 2006; Palacios et al., 2008; Rastelli et al., 2010; Dewar et al., 2011).
CDH3 is a tumor suppressor in melanoma and oral squamous cell carcinoma (Haass et al., 2005; Vieira and Paredes, 2015). CDH3 may be used as EMT marker. There is a shift from E-cadherin to N-cadherin and CDH3 expression during tumor formation and progression (Piura et al., 2005; Bonitsis et al., 2006; Bryan and Tselepis, 2010; Ribeiro and Paredes, 2014). Competitive interaction n CDH3 and beta-catenin causes impaired intercellular interactions and metastases in c cancer (Moskvina and Mal'kov, 2010). CDH3 may be an early marker of cancer formation in colon cancer (Alrawi et al., 2006). Dys-regulation of CDH3 is a marker for poor prognosis and increased malignancy en and Wheelock, 2005).
CDKN2A (also known as p16 and p16|NK4a) encodes cyclin dependent kinase inhibitor 2A which generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode urally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally ted to the products of the other _ 51 _ variants. This ARF t ons as a izer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53 (RefSeq, 2002). CDKN2A is mutated in pancreatic ductal adenocarcinoma, cutaneous malignant melanoma, vulvar squamous cell carcinoma, and biliary tract cancer. Mutations may be inherited and increase the risk for developing pancreatic cancer. CDKN2A is deleted in malignant pleural mesothelioma. CDKN2A is down-regulated in bladder cancer (Clancy et al., 2016; Fabbri et al., 2017; Gan et al., 2016; Kleeff et al., 2016; Nabeshima et al., 2016; Pacholczyk et al., 2016; Petersen, 2016; Sohal et al., 2016; Tatarian and Winter, 2016).
CDKN2A is involved in cancer cell proliferation, tumorigenesis, metastasis, Wnt signaling, senescence, apoptosis, and DNA repair mechanism (Gupta et al., 2016; K0 et al., 2016; Low et al., 2016; Sedgwick and D'Souza-Schorey, 2016; Zhao et al., 2016).
CDKN2A is a tumor suppressor gene which is down-regulated upon over-expression of the oncogenic protein UHRF1. CDKN2A interacts with p53 to suppress breast cancer (Alhosin et al., 2016; Fry et al., 2017). CDKN2A promotor hyper-methylation is associated with increased risk for low-grade us intra-epithelial lesion, high- grade squamous intra-epithelial lesion, and al cancer and with smoking habit.
CDKN2A is epigenetically dysregulated during the development of hepatocellular carcinoma and esophageal squamous cell carcinoma (Han et al., 2017; Khan et al., 2017; Ma et al., 2016a). CDKN2A may be used in the diagnosis of cervical cancer and oropharyngeal us cell carcinoma (Mahajan, 2016; Savone et al., 2016; Tjalma, 2017). CDKN2A expression is caused by HPV infection, a virus which is known to have oncogenic potential (Hoff et al., 2017; z, 2016).
CDKN2B (also known as p15) s cyclin dependent kinase inhibitor 28 which lies adjacent to the tumor suppressor gene CDKN2A in a region that is ntly mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, which forms a x with CDK4 or CDK6, and prevents the activation of the CDK kinases, thus the encoded protein functions as a cell growth regulator that controls cell cycle G1 ssion. The expression of this gene was found to be ically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition (RefSeq, 2002). CDKN2B is involved in the regulation of the cell cycle progression and the inhibition of cell proliferation (Hu and man, 2014; Roy and Banerjee, 2015). CDKN2B deletion is associated with schistosomal-associated bladder cancer. Mutations in CDKN2B may be involved in inherited susceptibility to glial tumors.
CDKN2B is altered in meningiomas and mutated in non-muscle-invasive urothelial carcinoma (Mawrin and Perry, 2010; Melin, 2011; Pollard et al., 2010; Alentorn et al., 2013; ldbaih, 2011; Koonrungsesomboon et al., 2015). CDKN2B is hyper-methylated in acute myeloid leukemia and pituitary adenomas. CDKN2B is aberrantly ted in cutaneous malignant melanoma (Bailey et al., 2010; Jiang et al., 2014; Popov and Gil, 2010; van den Hurk et al., 2012; Wolff and Bies, 2013; Zhou et al., 2014). CDKN2B interacts with the tumor suppressor RB and is regulated by Miz-1 and TGF-beta (Zhou et al., 2014; Geyer, 2010; Moroy et al., 2011). CDKN2B is a tumor suppressor gene which is ed by long non-coding RNAs. CDKN2B itself in ation with A81 is part of a long non-coding RNA (ANRIL) which may be involved in cancer development (Popov and Gil, 2010; Aguilo et al., 2016; Shi et al., 2013; Wanli and Al, 2015).
CLDN6, also known as claudin 6, encodes a member of the claudin family which is a ent of tight junction s and an integral ne n (RefSeq, 2002).
CLDN6 expression was shown to be associated with lymph node metastasis and TNM stage in non-small cell lung cancer (Wang et al., 2015b). Furthermore, low expression of CLDN6 was shown to be associated with significantly lower survival rates in patients with non-small cell lung cancer (Wang et al., 2015b). Thus, low CLDN6 expression is an independent prognostic biomarker that indicates worse prognosis in patients with non- small cell lung cancer (Wang et al., 2015b). CLDN6 was shown to be down-regulated in cervical carcinoma and gastric cancer (Zhang et al., 2015e; Lin et al., 2013b). CLDN6 was shown to be up-regulated in BRCA1-related breast cancer and ovarian papillary serous carcinoma (Wang et al., 2013; Heerma van Voss et al., 2014). CLDN6 was described as a tumor suppressor for breast cancer (Zhang et al., 2015e). Gain of CLDN6 expression in the cervical carcinoma cell lines HeLa and C33A was shown to suppress cell proliferation, colony formation in vitro, and tumor growth in vivo, suggesting that CLDN6 may on as a tumor suppressor in cervical carcinoma cells (Zhang et al., . CLDN6 may play a positive role in the invasion and metastasis of ovarian cancer (Wang et al., 2013). CLDN6 was shown to be consistently expressed in germ cell tumors and thus is a novel diagnostic marker for primitive germ cell tumors (Ushiku et al., 2012). CLDN6 sion was shown to be positive in most tumors of an assessed set of atypical teratoid/rhabdoid tumors of the central nervous system, with strong CLDN6 positivity being a ial independent prognostic factor for outcome of the disease (Dufour et al., 2012).
CT45A1, also known as CT45, encodes the cancer/testis antigen family 45 member A1 protein and is located on chromosome Xq26.3 (RefSeq, 2002). CT45 genes were shown to be ial prognostic biomarkers and therapeutic targets in epithelial n cancer (Zhang et al., 2015d). The CT45A1protein which is usually only sed in testicular germ cells was shown to be also expressed in lung cancer, breast cancer and ovarian cancer (Chen et al., 2009). CT45A1 was also shown to be associated with poor prognosis and poor outcomes in multiple myeloma (Andrade et al., 2009). CT45A1 was described as gene ulating epithelial-mesenchymal transition (EMT) and atic genes, promoting EMT and tumor dissemination. Furthermore, CT45A1 was described as being implicated in the initiation or maintenance of cancer stem-like cells, promoting tumorigenesis and malignant progression (Yang et al., 2015b). CT45A1 over- expression in a breast cancer model was shown to result in the ulation of s oncogenic and metastatic genes, constitutively activated ERK and CREB signaling pathways and increased tumorigenesis, invasion and metastasis. Silencing of CT45A1 was shown to reduce cancer cell migration and invasion. Thus, CT45A1 may function as a novel proto-oncogene and may be a target for anticancer drug discovery and therapy (Shang et al., 2014).
CT45A2 encodes one of a cluster of several r genes, which is a member of the cancer/testis family of antigens and is located on chromosome Xq26.3 (RefSeq, 2002).
CT45A2 was shown to be a novel spliced MLL fusion partner in a pediatric patient with de novo bi-phenotypic acute leukemia and thus might be relevant for leukemogenesis (Cerveira et al., 2010). The cancer/testis antigen family 45 was shown to be frequently expressed in both cancer cell lines and lung cancer specimens (Chen et al., 2005).
CT45 genes were shown to be potential prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., 2015d).
CT45A3 encodes the cancer/testis antigen family 45 member A3 protein and is located on some Xq26.3 (RefSeq, 2002). The cancer/testis antigen family 45 was shown to be frequently expressed in both cancer cell lines and lung cancer specimens (Chen et al., 2005). CT45 genes were shown to be potential prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., 2015d).
CT45A4 encodes the cancer/testis antigen family 45 member A4 protein and is located on chromosome Xq26.3 (RefSeq, 2002). The cancer/testis antigen family 45 was shown to be frequently sed in both cancer cell lines and lung cancer specimens (Chen et al., 2005). CT45 genes were shown to be potential prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., 2015d).
CT45A5 encodes the cancer/testis antigen family 45 member A5 and is located on some Xq26.3 (RefSeq, 2002). The cancer/testis antigen family 45 was shown to be frequently expressed in both cancer cell lines and lung cancer specimens (Chen et al., 2005). CT45 genes were shown to be ial prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., 2015d).
CT45A6 encodes the cancer/testis antigen family 45 member A6 protein and is located on chromosome Xq26.3 (RefSeq, 2002). The cancer/testis antigen family 45 was shown to be frequently expressed in both cancer cell lines and lung cancer specimens (Chen et al., 2005). CT45 genes were shown to be potential prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., .
CTAG2 encodes /testis antigen 2 which is an auto immunogenic tumor antigen that belongs to the ESO/LAGE family of cancer-testis ns. This protein is sed in a wide array of cancers including melanoma, breast cancer, bladder cancer and prostate cancer. This protein is also expressed in normal testis tissue (RefSeq, 2002). CTAG2 is involved in cancer cell ion and invasiveness (Maine et al., 2016). CTAG2 expression is ulated by LSAMP resulting in reduced cell proliferation (Baroy et al., 2014). CTAG2 is expressed in liposarcoma, lung , urothelial cancer, and colorectal cancer. CTAG2 is over-expressed in several entities including esophageal squamous cell carcinoma (Kim et al., 2012; Dyrskjot et al., 2012; _ 55 _ Hemminger et al., 2014; Forghanifard et al., 2011; McCormack et al., 2013; Shantha Kumara et al., 2012). Engineered T cells against CTAG2 may be used in multiple myeloma treatment. Autoantibodies against CTAG2 may be used in cancer diagnosis.
CTAG2 may be a target in immunotherapy. CTAG2 expression is associated with shorter progression-free survival (van et al., 2011; Dyrskjot et al., 2012; n et al., 2013; Pollack et al., 2012; Rapoport et al., 2015; Wang et al., 2015a).
CYP2W1 encodes a member of the cytochrome P450 superfamily of enzymes which are ygenases catalyzing many reactions ed in drug metabolism and in the synthesis of cholesterol, steroids and other lipids (RefSeq, 2002). CYP2W1 is over- expressed in a variety of human cancers including hepatocellular, colorectal and gastric cancer. CYP2W1 over-expression is associated with tumor ssion and poor sun/ival (Aung et al., 2006; Gomez et al., 2010; Zhang et al., 2014a). Due to tumor- specific expression, CYP2W1 is an interesting drug target or enzymatic activator of prodrugs during cancer therapy (Karlgren and lngelman-Sundberg, 2007; Nishida et al., 2010).
DPPA2 encodes developmental pluripotency ated 2 and is d on chromosome 3q13.13 (RefSeq, 2002). DPPA2 is over-expressed in gastric cancer, non- small cell lung cancer, epithelial n cancer, and colorectal cancer. DPPA2 is an oncogene up-regulated in several entities. DPPA2 is reciprocally repressed in teratoma (Tung et al., 2013; Ghodsi et al., 2015; John et al., 2008; Raeisossadati et al., 2014; Shabestarian et al., 2015; Tchabo et al., 2009; n et al., 2011). DPPA2 expression correlates with tumor invasion depth, stage, lymph node metastasis, and aggressiveness (Ghodsi et al., 2015; ssadati et al., 2014; Shabestarian et al., 2015). DPPA2 is involved in the pathogenesis of non-small cell lung cancer (Watabe, 2012). DPPA2 is differentially methylated in thyroid cancer guez-Rodero et al., 2013).
ENTPD4 (UDPase) encodes ectonucleoside triphosphate diphosphohydrolase 4, a member of the e protein family and may play a role in salvaging nucleotides from lysosomes (RefSeq, 2002). UDPase activity is increased in patients with ovarian cancer _ 56 _ or testicular cancer and decreased after chemotherapy (Papadopoulou-Boutis et a|., 1985).
ESR1 encodes an estrogen receptor, a ligand-activated transcription factor important for hormone binding, DNA binding and activation of transcription, that is essential for sexual development and reproductive function (RefSeq, 2002). Mutations and single nucleotide rphisms of ESR1 are associated with risk for different cancer types including liver, prostate, gallbladder and breast cancer. The up-regulation of ESR1 expression is ted with cell proliferation and tumor growth but the overall survival of patients with ESR1 positive tumors is better due to the successfully therapy with selective estrogen receptor modulators (Sun et a|., 2015; Hayashi et a|., 2003; Bogush et al., 2009; Miyoshi et a|., 2010; Xu et a|., 2011; Yakimchuk et a|., 2013; Fuqua et a|., 2014).
ESR1 ing interferes with different ys responsible for cell transformation, growth and survival like the EGFR/IGFR, Pl3K/Akt/mTOR, p53, HER2, NFkappaB and TGF-beta pathways (Frasor et a|., 2015; Band and Laiho, 2011; Berger et a|., 2013; Skandalis et a|., 2014; Mehta and Tripathy, 2014; Ciruelos Gil, 2014).
ETV1 encodes ETS variant 1 which is a member of the ETS (E twenty-six) family of transcription s. The ETS proteins regulate many target genes that modulate ical processes like cell growth, angiogenesis, migration, proliferation and entiation q, 2002). ETV1 is involved in epithelial-to-mesenchymal transition, DNA damage response, AR and PTEN signaling, cancer cell invasion, and asis.
ETV1 interacts with JMJD2A to promote prostate carcinoma formation and to increase YAP1 sion affecting the Hippo signaling pathway (Mesquita et a|., 2015; Baty et a|., 2015; Heeg et a|., 2016; Higgins et a|., 2015; Kim et a|., 2016; Lunardi et a|., 2015).
ETV1 expression is decreased in prostate cancer. ETV1 is over-expressed in pancreatic , gastrointestinal stromal tumors, oligodendroglial tumors, and renal cell carcinoma. ETV1 may be an oncogene in non-small cell lung cancer (Heeg et a|., 2016; Gleize et a|., 2015; Ta et a|., 2016; Al et a|., 2015; Hashimoto et a|., 2017; Jang et a|., 2015). Increased mRNA levels of ETV1 in microvesicles of prostate cancer cell lines are correlated with prostate cancer progression (Lazaro-lbanez et al., 2017). ETV1 is an oncogene which interacts with the Ewing’s sarcoma breakpoint protein EWS. ETV1 _ 57 _ interacts with Sparc and Has2 which e in part cancer cell metastasis and desmoplastic l expansion (Heeg et al., 2016; Kedage et al., 2016). ETV1 gene fusion products as well as ETV1 promotor methylation status are diagnostically useful (Angulo et al., 2016; 2015; Kumar—Sinha et al., 2015; Linn et al., 2015).
ETV4 (also called E1AF or PEA3) encodes a member of the Ets oncogene family of transcription factors and is involved in the regulation of metastasis gene expression and in the induction of differentiation-associated genes in embryonic stem cell (Akagi et al., 2015; Coutte et al., 1999; lshida et al., 2006). ETV4 is over-expressed in different cancer entities including breast, lung, colorectal and c cancer and is ated with migration, invasion, metastasis and poor prognosis (Benz et al., 1997; Horiuchi et al., 2003; to et al., 2004; Keld et al., 2011; Hiroumi et al., 2001). ETV4 is up- regulated by different pathways like ERK/MAPK, HER2, PI3K and Ras following an induction of several targets including MMPs and lL-8 (Maruta et al., 2009; Keld et al., 2010; Chen et al., 2011b; Aytes et al., 2013).
ETV5 encodes the ETS variant 5 protein and is located on chromosome 3q28 (RefSeq, 2002). ys including ETV5 were described as being deeply related to the epithelial to mesenchymal process in trial cancer (Colas et al., 2012). ETV5 was shown to interact with l signaling ys such as cell-cycle progression and the TGF-beta signaling pathway in the OV90 ovarian cancer cell line, and ETV5 expression was shown to be associated with the sion of the oncogenic transcription factor FOXM1 in ovarian cancer (Llaurado et al., 2012b). Furthermore, ETV5 was shown to be up-regulated in ovarian cancer. In the spheroid model, the inhibition and up-regulation of ETV5 effected cell eration, cell migration, cell adhesion to extracellular matrix components, cell-cell adhesion and cell survival. Thus, ETV5 may play a role in ovarian cancer progression, cell dissemination and metastasis (Llaurado et al., 2012a). Chromosomal rearrangements of ETV5 among other members of the oncogenic PEA3 subfamily, were described to occur in prostate tumors and are thought to be one of the major driving forces in the genesis of prostate cancer.
Furthermore, ETV5 was also described as an oncoprotein which is implicated in melanomas, breast and some other types of cancer (Oh et al., 2012). ETV5 was suggested to have a significant role in regulating matrix oproteinase 2 expression and therefore resorption in human osarcoma, and thus may be a targetable up- stream effector of the metastatic cascade in this cancer (Power et al., 2013).
EYA2 encodes EYA riptional coactivator and phosphatase 2, a member of the eyes absent (EYA) family of ns involved in eye development (RefSeq, 2002).
EYA2 over-expression has been observed in several tumor types such as epithelial ovarian tumor, prostate, breast cancer, urinary tract cancers, glioblastoma, lung adenocarcinoma, al cancer, colon and hematopoietic cancers (Bierkens et al., 2013; Zhang et al., 2005; Guo et al., 2009; Patrick et al., 2013; Kohrt et al., 2014).
Studies have revealed that EYA2 influences transcription of TGF beta pathway members as well as orylation of , implying a dual role of EYA2 in the pancreas (Vincent et al., 2014).
FAM111B encodes the family with sequence similarity 111 member B, a protein with a trypsin-like cysteine/serine peptidase domain in the C-terminus which leads, in case of a mutation, to mottled pigmentation, telangiectasia, epidermal atrophy, tendon contractures, and ssive pulmonary fibrosis (RefSeq, 2002). FAM111B was found to be egulated during metformin and aspirin induced inhibition of pancreatic cancer development (Yue et al., 2015).
FAM83H encodes family with sequence similarity 83 member H which plays an important role in the structural development and calcification of tooth enamel. Defects in this gene are a cause of amelogenesis imperfecta type 3 (Al3) (RefSeq, 2002). The long non-coding RNA FAM83H-A81 is involved in cell proliferation, migration, and invasion and regulates MET/EGFR signaling (Zhang et al., 2017). The long non-coding RNA FAM83H-A81 is over-expressed in lung cancer and colorectal cancer. FAM83H is an oncogene over-expressed in several entities including breast cancer and colorectal cancer (Zhang et al., 2017; Kuga et al., 2013; Snijders et al., 2017; Yang et al., 2016c; Yang et al., 2016b). Increased expression of long non-coding RNA -A81 is associated with shorter overall al. FAM83H-A81 is ated with poor prognosis (Yang et al., 2016c; Yang et al., 2016b). FAM83H may be involved in androgen independent prostate cancer (Nalla et al., 2016). FAM83H cts with CK1alpha to form keratin filaments and desmosomes (Kuga et al., 2016).
FBN2, also known as fibrillin 2, encodes a protein which is a component of the tive tissue and may be involved in elastic fiber assembly (RefSeq, 2002). FBN2 was described as an extracellular matrix regulatory protein of ta signaling activity (Lilja-Maula et al., 2014). Hyper-methylation of FBN2 was bed as an epigenetic biomarker for clear cell renal cell oma and early detection of colorectal cancer and as being associated with poor prognosis by colorectal cancer patients (Ricketts et al., 2014; Rasmussen et al., 2016; Yi et al., 2012). FBN2 was shown to be a candidate cell surface target enriched in medulloblastoma which could be used for the development of tumor-specific probes for guided resection in medulloblastoma (Haeberle et al., 2012).
FOLR1 encodes the folate receptor 1, which binds folic acid and its d derivatives, and transports 5-methyltetrahydrofolate into cells; FOLR1 is a ed protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form (RefSeq, 2002). Being a major part of the FOLR1/cSrc/ERK1/2/NFKB/p53 pathway, which is required for the up-take of folic acid, FOLR1 is able to regulate the proliferation of cancer cells such as breast, lung and colon cancer (Kuo and Lee, 2016; Cheung et al., 2016). FOLR1 was found to be widely expressed in epithelial ovarian cancer, where its expression increases with tumor stage and might represent a potential therapeutic target (Leung et al., 2016; Ponte et al., 2016; Moore et al., 2016; Hou et al., 2017; Notaro et al., 2016; Bergamini et al., 2016). Reducing FOLR1 expression during ctal cancer y was shown to increase the effectiveness of 5-fluorouracil treatment (Tsukihara et al., 2016). FOLR1 represents an ideal tumor-associated marker for immunotherapy for triple-negative breast cancer as well as colon cancer (Liang et al., 2016; Song et al., 2016).
GPR64 encodes adhesion G protein-coupled receptor G2, a member of the G protein- d receptor family described as an epididymis-specific transmembrane protein _ 60 _ (RefSeq, 2002). In breast cancer cell lines, own of GPR64 resulted in a strong ion in cell adhesion as well as in cell migration (Peeters et al., 2015).
HOXA10 encodes homebox A10. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor that may regulate gene expression, morphogenesis, and differentiation. More specifically, it may on in fertility, embryo viability, and regulation of hematopoietic lineage commitment. Read-through transcription exists n this gene and the downstream homeobox A9 (HOXA9) gene (RefSeq, 2002). HOXA10 is a stem cell factor whose expression correlates with CD133 expression in glioma and may be involved in cancer progression. HOXA10 is involved in cancer cell proliferation, migration, invasion, and metastasis. HOXA10 is involved in multidrug ance by inducing P-gp and MRP1 expression. HOXA10 promotes epithelial-to-mesenchymal transition. HOXA10 may be a downstream target of miR-218/PTEN/AKT/PI3K signaling. HOXA10 promotes expression of the AML- associated transcription factor Prdm16. HOXA10 may e G1 cell cycle arrest in a p21-dependent manner. HOXA10 is involved in ta2/p38 MAPK signaling promoting cancer cell invasion in a MMPdependent manner (Carrera et al., 2015; Cui et al., 2014; Emmrich et al., 2014; Han et al., 2015; Li et al., 2014a; Li et al., 2016a; Sun et al., 2016; Xiao et al., 2014; Yang et al., 2016a; Yi et al., 2016; Yu et al., 2014; Zhang et al., 2014b; Zhang et al., 2015b). HOXA10 is up-regulated in gastric cancer and acute myeloid leukemia. HOXA10 is differentially expressed in oral squamous cell carcinoma.
HOXA10 is differentially methylated in non-serous n carcinoma and glioblastoma (Carrera et al., 2015; Han et al., 2015; Kurscheid et al., 2015; Niskakoski et al., 2014; Due et al., 2015; Shima et al., 2014). HOXA10 methylation status may be used in breast cancer diagnosis. HOXA10 and CD44 co-expression is correlated with tumor size and patient survival in gastric . HOXA10 and miR-196b co-expression is correlated with poor prognosis in gastric cancer (Han et al., 2015; Lim et al., 2013; Uehiro et al., 2016). SGl-110 treatment hypo-methylate HOXA10 which sensitizes ovarian cancer cells for chemotherapy (Fang et al., .
HOXA9 s homebox protein A9. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. A specific translocation event which causes a fusion between this gene and the NUP98 gene has been associated with myeloid leukemogenesis q, 2002). HOXA9 is expressed in acute myeloid leukemia and high expression is associated with adverse prognosis. HOXA9 and MEIS1 co-expression induces AML. HOXA9 is down-regulated in cervical cancer. HOXA9 is frequently methylated in endometrial cancer (Alvarado-Ruiz et al., 2016; Chen et al., 2015; Li et al., 2016b; Li et al., 2016e; Sykes et al., 2016). The gene fusion product NUP98—HOXA9 acts as ne (Abe et al., 2016; Sontakke et al., 2016). Response to cisplatin-based chemotherapy is linked to HOXA9 promotor methylation status.
HOXA9, MEIS1, and MN1 co-expression in leukemia make the cells sensitive to pharmacologic inhibition of DOT1L (Li et al., 2016c; Riedel et al., 2016; Xylinas et al., 2016). HOXA9 is a tumor suppressor whose expression may be used to diagnose cancer (Ma et al., 2016b). HOXA9 mediates leukemic stem cell self-renewal and HlF- 2alpha deletion rates this process (Vukovic et al., 2015; Zhu et al., 2016).
HOXBQ s homebox BQ which is a member of the Abd-B homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded nuclear protein functions as a sequence-specific ription factor that is ed in cell proliferation and differentiation. Increased expression of this gene is ated with some cases of leukemia, prostate cancer and lung cancer (RefSeq, 2002). HOXBQ is involved in angiogenic pathways which are regulated by miR-192. HOXBQ is a downstream target of ta-catenin signaling induced by N-acetylgalactosaminyltransferase resulting in metastasis. HOXBQ may te mesenchymal-to-epithelial transition in gastric carcinoma and colon adenocarcinoma and epithelial-to-mesenchymal tion in breast cancer and hepatocellular carcinoma in a TGF-beta1-dependent manner.
HOXBQ is involved in cell proliferation, migration, and invasion. TGF-beta1 down- regulates HOXBQ in a Kindlin-2/PDAC-dependent manner (Chang et al., 2015b; Darda et al., 2015; Hoshino et al., 2014; Huang et al., 2014; Kwon et al., 2015; Seki et al., 2012; Sha et al., 2015; Wu et al., 2016; Zhan et al., 2014; Zhan et al., 2015; pova et al., 2014). HOXBQ is differentially expressed in PBRM1 mutated clear cell renal cell carcinoma. HOXBQ is over-expressed in platinum-resistant high-grade serous ovarian cancer, breast , glioma, colon adenocarcinoma, hepatocellular carcinoma, and head and neck squamous cell carcinoma. HOXBQ expression is decreased in gastric carcinoma. HOXBQ is mutated in leukemia (Menezes et al., 2014; Chang et a|., 2015b; Darda et a|., 2015; Zhan et a|., 2014; pova et a|., 2014; Fang et a|., 2014b; Hayashida et a|., 2010; Kelly et a|., 2016; Sha et a|., 2013; Shrestha et al., 2012; Wang et al., 2016b; Yuan et al., 2014). HOXBQ expression is regulated by E2F1 and FAT10 (Zhussupova et a|., 2014; Yuan et a|., 2014). HOXBQ expression is correlated with tumor size in oral cancer. HOXBQ expression is associated with advanced clinical stage in glioma. HOXBQ down-regulation is associated with decreased patient survival in gastric carcinoma (Fang et al., 2014b; Sha et al., 2013; ra-Costa et al., 2015; Tomioka et a|., 2010). HOXBQ tes bladder cancer progression (Zhang et a|., 2016b). Long non-coding RNA nc-HOXBQ-205 is down- regulated in urothelial carcinoma of the bladder (Luo et a|., 2014). BCAS3-HOXBQ gene fusion product is expressed in breast cancer (Schulte et al., 2012).
HOXC10 encodes homeobox C10 which belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in genesis in all multicellular sms. This gene is one of several homeobox HOXC genes located in a cluster on chromosome 12. The protein level is controlled during cell differentiation and proliferation, which may indicate this protein has a role in origin activation (RefSeq, 2002). HOXC10 is involved in chemo resistance by suppressing apoptosis and up-regulating NF-kappaB and DNA damage repair. HOXC10 induces apoptosis and inhibits cell growth. HOXC10 may be ed in cen/ical cancer progression and invasion (Pathiraja et al., 2014; Sadik et al., 2016; Zhai et al., 2007). HOXC10 is up-regulated in thyroid cancer, cervical squamous cell carcinoma, and breast cancer (Abba et al., 2007; Zhai et al., 2007; Ansari et al., 2012; Feng et al., 2015). HOXC10 expression correlates with shorter recurrence-free and overall survival in ative breast cancer. HOXC10 expression is associated with advanced stage, poor pathologic stage, poor prognosis, cytokine-cytokine receptor interaction, and chemokine signaling pathways in thyroid cancer (Sadik et a|., 2016; Feng et al., 2015). HOXC10 is differentially methylated in oral squamous cell carcinoma _ 63 _ and small B cell lymophoma (Marcinkiewicz and Gudas, 2014a; Marcinkiewicz and Gudas, 2014b; Rahmatpanah et al., 2006).
HOXC9 encodes homebox C9 which belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organismsThis gene is one of several ox HOXC genes located in a cluster on chromosome 12 (RefSeq, 2002). HOXC9 is involved in cancer cell invasion and proliferation. HOXC9 knock-down results in reduced cell viability, migration, invasion, tumorigenicity, and sed autophagy. HOXC9 is involved in chemo resistance in r cancer in a miR-193a- 3p-dependent manner. HOXC9 is involved in retinoic acid signaling and is involved in cell growth and differentiation (Hur et al., 2016; Kocak et al., 2013; Lv et al., 2015a; Mao et al., 2011; Simeone et al., 1991; iuolo et al., 1990; Xuan et al., 2016; Zha et al., 2012). HOXC9 is differentially expressed in breast , lung cancer, and lastoma. HOXC9 is methylated in stage I non-small cell lung cancer. HOXC9 is up-regulated in ytoma. HOXC9 is expressed in esophageal cancer and cervical cancer (Hur et al., 2016; Xuan et al., 2016; Gu et al., 2007; Lin et al., 2009; Lopez et al., 2006; Okamoto et al., 2007). HOXC9 may be transcriptionally repressed by Smad4 (Zhou et al., 2008). HOXC9 expression is inversely associated with disease-free survival and distant metastasis-free survival in breast cancer. HOXC9 expression is associated with poor prognosis in glioblastoma (Hur et al., 2016; Xuan et al., 2016).
HOXC9 inhibits DAPK1 resulting in disturbed autophagy induced by Beclin-1 (Xuan et aL,2016) HOXD10 encodes homeobox D10 protein, which functions as a sequence-specific ription factor that is expressed in the developing limb buds and is involved in differentiation and limb development (RefSeq, 2002). HOXD10 was identified as target gene of miR-10b, which is ulated in gastric cancer (GC) and may have a key role in GO pathogenesis and development (Ma et al., 2015; Wang et al., 2015c). HOXD10 was found to be ulated in neck squamous cell carcinoma and urothelial cancer promoting cell proliferation and invasion and may represent a new biomarker for ductal invasive breast carcinoma (Sharpe et al., 2014; Vardhini et al., 2014; Heubach et al., 2015). However, HOXD10 also showed tumor-suppressive functions in cholangiocellular carcinoma by inactivating the RHOC/AKT/MAPK pathway and ng G1 phase cell cycle arrest (Yang et al., 2015a). As part of the miR- 224/HOXD10/p-PAK4/MMP-9 signaling pathway, HOXD10 is contributed to the regulation of cell migration and invasion and provides a new bio target for hepatocellular carcinoma treatment (Li et al., 2014b).
HOXD9 encodes homeobox D9 which belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. This gene is one of several ox HOXD genes d at 2q31-2q37 chromosome regions. ons that removed the entire HOXD gene cluster or 5' end of this cluster have been associated with severe limb and genital abnormalities. The exact role of this gene has not been determined (RefSeq, 2002). HOXD9 is involved in lial-to-mesenchymal transition, cancer cell migration, invasion, and metastasis in a ZEB1-dependent manner.
Over-expressed HOXD9 increases anchorage-independent growth and reduces contact inhibition. HOXD9 is involved in growth arrest and neuronal differentiation. Depletion of HOXD9 results in sed cell proliferation, cell cycle arrest, and induction of apoptosis (Zha et al., 2012; Lawrenson et al., 2015b; Lv et al., 2015b; Tabuse et al., 2011). HOXD9 is up-regulated in lung squamous carcinoma and invasive hepatocellular carcinoma. HOXD9 is expressed in esophageal carcinoma, astrocytomas and astomas. HOXD9 is differentially sed in cervical cancer (Bao et al., 2016; Gu et al., 2007; Lv et al., 2015b; Tabuse et al., 2011; Li et al., 2002; Liu et al., 2005).
HOXD9 expression is induced by retinoic acid and Wnt signaling (lshikawa and lto, 2009). HOXD9 may be involved in cervical ogenesis (Lopez-Romero et al., 2015).
HOXD9 methylation is associated with poorer disease-free and overall al in lymph node metastasis (Marzese et al., 2014). HOXD9 is hyper-methylated in cholangiocarcinoma and melanoma brain metastasis (Marzese et al., 2014; Sriraksa et al., 2013). HOXD9 may be involved in mucinous ovarian carcinoma susceptibility (Kelemen et al., 2015). HOXD9 may be an oncogene (Wu et al., 2013). _ 65 _ HTR3A encodes a 5-hydroxytryptamine (serotonin) receptor belonging to the ligand- gated ion channel receptor superfamily that causes fast, rizing responses in neurons after activation (RefSeq, 2002). HTR3A (also called 5-HT3) is de-regulated in several cancer types for example a down-regulation in mantle cell lymphomas, a differential sion in diverse B cell tumors and a decreased expression in breast cancer cell lines (Pai et al., 2009; Rinaldi et al., 2010; Ek et al., 2002).
|GF2BP1, also known as , s a member of the insulin-like growth factor 2 mRNA-binding protein family which functions by binding to the mRNAs of certain genes and regulating their translation (RefSeq, 2002). Two members of the |GF2 mRNA binding protein , including |GF2BP1 were described as bona fide oncofetal proteins which are de novo synthesized in various human cancers and which may be powerful post-transcriptional oncogenes ing tumor growth, drug-resistance and metastasis er et al., 2014). Expression of |GF2BP1 was reported to correlate with an overall poor sis and metastasis in various human cancers (Lederer et al., 2014). Thus, |GF2BP1 was suggested to be a powerful biomarker and candidate target for cancer therapy (Lederer et al., 2014). |GF2BP family members were described to be highly associated with cancer metastasis and expression of oncogenic factors such as KRAS, MYC and MDR1 (Bell et al., 2013). |GF2BP1 was shown to interact with C-MYC and was found to be expressed in the vast majority of colon and breast tumors and sarcomas as well as in benign tumors such as breast fibroadenomas and meningiomas (loannidis et al., 2003). |GF2BP1 was shown to be ulated in hepatocellular carcinoma and basal cell carcinoma (Noubissi et al., 2014; Zhang et al., 2015c). Up- tion of |GF2BP1 and other genes was shown to be significantly associated with poor post-surgery prognosis in hepatocellular carcinoma (Zhang et al., .
|GF2BP1 was shown to be a target of the tumor suppressor miR-9 and miR-372 in hepatocellular carcinoma and in renal cell carcinoma, respectively (Huang et al., 2015; Zhang et al., 2015c). Loss of stromal |GF2BP1 was shown to promote a tumorigenic microenvironment in the colon, indicating that |GF2BP1 plays a tumor-suppressive role in colon stromal cells (Hamilton et al., 2015). |GF2BP1 was shown to be associated with stage 4 tumors, decreased patient survival and MYCN gene amplification in lastoma and may therefore be a potential oncogene and an independent negative prognostic factor in neuroblastoma (Bell et al., 2015). |GF2BP1 was described as a direct target of WNT/B-catenin signaling which tes GL|1 expression and activities in the development of basal cell carcinoma (Noubissi et al., 2014).
IGF2BP3 encodes insulin-like growth factor II mRNA binding n 3, an oncofetal protein, which represses translation of n-like growth factor II (RefSeq, 2002).
Several studies have shown that IGF2BP3 acts in various ant aspects of cell function, such as cell polarization, migration, morphology, metabolism, proliferation and differentiation. In vitro studies have shown that |GF2BP3 promotes tumor cell proliferation, adhesion, and invasion. Furthermore, IGF2BP3 has been shown to be associated with aggressive and advanced cancers (Bell et al., 2013; Gong et al., 2014).
IGF2BP3 over-expression has been described in numerous tumor types and ated with poor prognosis, advanced tumor stage and metastasis, as for e in neuroblastoma, ctal carcinoma, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, prostate cancer, and renal cell carcinoma (Bell et al., 2013; s-Hosey and Xu, 2012; Hu et al., 2014; Szarvas et al., 2014; Jeng et al., 2009; Chen et al., 2011a; Chen et al., 2013; Hoffmann et al., 2008; Lin et al., 2013a; Yuan et al., 2009).
IRF4 encodes the interferon regulatory factor 4, a transcription factor that negatively regulates Toll-like-receptor (TLR) signaling in lymphocytes, what is central to the activation of innate and adaptive immune system (RefSeq, 2002). IRFA is considered to be a key regulator of several steps in lymphoid, myeloid, and dendritic cell differentiation and maturation and is characterized by g within the hematopoietic system in a lineage and stage-specific way (Shaffer et al., 2009; Gualco et al., 2010). IRF4 plays a pivotal role in adaptive immunity, cell growth, differentiation and genesis of chronic myeloid leukemia, primary central nervous system lymphoma, T-cell ma, -induced adult T cell leukemia and intravascular large B-cell ma (Mamane et al., 2002; Orwat and Batalis, 2012; Bisig et al., 2012; Ponzoni et al., 2014; Manzella et al., 2016). IRF4 is a well-known oncogene that is regulated by enhancer of zeste homolog 2 (EZH2) in multiple myeloma (Alzrigat et al., 2016).
KLK14 encodes kallikrein related peptidase 14 which is a member of the kallikrein subfamily of serine proteases that have diverse physiological ons such as regulation of blood pressure and desquamation. The altered expression of this gene is implicated in the progression of different cancers including breast and prostate tumors.
The encoded protein is a precursor that is proteolytically sed to generate the functional enzyme. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19 (RefSeq, 2002). KLK14 is involved in cell proliferation via phosphorylation of ERK1/2/MAP kinase and tumorigenesis. KLK14 induces PAR-2 signaling. KLK14 may be involved in tumor progression, growth, invasion, and angiogenesis r et al., 2014; Borgono et al., 2007; Chung et al., 2012a; Devetzi et al., 2013; Gratio et al., 2011; Sanchez et al., 2012; Zhang et al., 2012a). KLK14 is down-regulated by miR-378/422a and androgen receptor signaling. Androgen receptor signaling up-regulates KLK14 expression in breast cancer (Paliouras and Diamandis, 2008b; Lose et al., 2012; Paliouras and Diamandis, 2007; Paliouras and Diamandis, 2008a; Samaan et al., 2014). KLK14 is over-expressed in chronic lymphocytic leukemia, non-small cell lung cancer, salivary gland , and n cancer. KLK14 is differentially expressed in breast cancer (Planque et al., 2008b; Fritzsche et al., 2006; Hashem et al., 2010; Kontos et al., 2016; Papachristopoulou et al., 2013; Planque et al., 2008a). KLK14 expression is inversely ated with overall al. KLK14 expression may be used as biomarker and to predict risk of disease ence. KLK14 expression correlates with clinical tumor stage and positive nodal status zi et al., 2013; Lose et al., 2012; Fritzsche et al., 2006; Kontos et al., 2016; Borgono et al., 2003; Obiezu and Diamandis, 2005; Rabien et al., 2008; Rajapakse and shi, 2007; Talieri et al., 2009).
KLK8 encodes the kallikrein related peptidase 8, a serine protease that may be ed in proteolytic cascade in the skin and may serve as a biomarker for ovarian cancer q, 2002). KLK8 expression was shown to correlate with the progression of breast cancer colorectal cancer (CRC), endometrial carcinoma and ovarian cancer and might ent a potential independent prognostic indicator for colorectal, breast and ovarian cancer (Liu et al., 2017; Jin et al., 2006; urakis et al., 2009; Darling et al., 2008; Michaelidou et al., 2015; Borgono et al., 2006). KLK8 is able to undergo alternative _ 68 _ splicing that generates an mRNA transcript missing exon 4; this alternative variant is, in contrast to KLK8, significantly egulated in cancer cells (Angelopoulou and Karagiannis, 2010). Nevertheless, the KLK8-T4 alternative splice variant, alone or in combination, may be a new independent marker of unfavorable prognosis in lung cancer (Planque et al., 2010). KLK8 expression confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness (Sher et al., 2006).
LAMA1 encodes an alpha 1 subunit of laminin an extracellular matrix glycoprotein with heterotrimeric structure, which tute a major component of the basement membrane (RefSeq, 2002). LAMA1 is de-regulated in different cancer types ing up-regulation in glioblastomas, hyper-methylation in colorectal cancer, abnormal methylation in breast cancer and frameshift mutations in gastric cancer (Scrideli et al., 2008; Choi et al., 2015; Simonova et al., 2015; Kim et al., 2011). a can induce the expression of LAMA1. LAMA1 in turn promotes collagenase lV production, which leads to an ve phenotype in benign tumor cells, but is not ient to confer metastatic potential (Chakrabarty et al., 2001; Royce et al., 1992).
LAMC2 belongs to the family of laminins, a family of extracellular matrix glycoproteins.
Laminins are the major non-collagenous constituent of basement membranes. They have been implicated in a wide y of biological processes including cell adhesion, entiation, migration, signaling, neurite wth and metastasis. LAMC2 encodes a protein which is expressed in several fetal tissues and is specifically localized to epithelial cells in skin, lung and kidney q, 2002). LAMC2 is highly expressed in anaplastic thyroid carcinoma and is associated with tumor progression, migration, and invasion by modulating signaling of EGFR (Garg et al., 2014). LAMC2 expression predicted poorer sis in stage II colorectal cancer patients (Kevans et al., 2011).
LAMC2 expression together with three other biomarkers was found to be icantly associated with the presence of LN metastasis in oral squamous cell carcinoma patients (Zanaruddin et al., 2013).
LILRB4 (also known as lLT-3) encodes leukocyte immunoglobulin like receptor B4 which is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene cluster at chromosomal region 19q13.4. The receptor is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. The or can also function in n capture and presentation. It is thought to control inflammatory responses and cytotoxicity to help focus the immune se and limit autoreactivity (RefSeq, 2002). Over-expression of LILRB4 may be involved in tolerance of dendritic cells during cancer. LILRB4 may be involved in immune suppression.
LILRB4 is involved in cancer immune escape (Zhang et al., 2012b; dt et al., 2016; Cortesini, 2007; de Goeje et al., 2015; Suciu-Foca et al., 2007). LILRB4 expression is induced by TNF-alpha. Over-expression of LILRB4 inhibits paB activation, transcription of inflammatory cytokines, and co-stimulatory molecules. LILRB4 is overexpressed by cyclosporine resulting in decreased tumor cytotoxicity by natural killer cells (Si et al., 2012; Thorne et al., 2015; Vlad and Foca, 2012). LILRB4 is over- expressed on dendritic cells in cancer. LILRB4 is expressed in monocytic acute myeloid leukemia. LILRB4 is over-expressed in n cancer (Dobrowolska et al., 2013; Khan et al., 2012; Orsini et al., 2014). LILRB4 expression is associated with shorter survival in non-small cell lung cancer. LILRB4 expression may be used in chronic lymphocytic leukemia prognosis ai et al., 2007; de Goeje et al., 2015).
LOXL2 encodes an extracellular copper-dependent amine oxidase, known as lysyl oxidase like 2. The enzyme is essential to the biogenesis of connective tissue and catalyses the first step in the ion of crosslinks between collagens and elastin (RefSeq, 2002). LOXL2 was shown to be involved in regulation of extracellular and intracellular cell signaling pathways. Extracellularly, LOXL2 remodels the extracellular matrix of the tumor microenvironment. Intracellularly, it regulates the epithelial-tomesenchymal transition (Cano et al., 2012; Moon et al., 2014). In general, LOXL2 has been associated with tumor progression including the promotion of cancer cell invasion, metastasis, enesis, and the malignant transformation of solid tumors in s tumors. A high expression of LOXL2 is associated with a poor prognosis (Wu and Zhu, 2015). LOXL2 was shown to be overexpressed in colon, esophageal squamous cell, breast ceel, clear cell renal cell, hepatocellular, cholangio-, lung us cell and head and neck squamous cell carcinomas. In various cancer types, the high expression _ 70 _ of LOXL2 was associated with higher recurrence, progression, or metastasis. In various cancer cell lines, the high expression of LOXL2 was associated with increased cell mobility and invasion and its silencing showed the opposite effects (Xu et a|., 2014a; Kim et a|., 2014; Wong et a|., 2014a; Hase et a|., 2014; Lv et a|., 2014; Torres et a|., 2015). In gastric , fibroblast-derived LOXL2 was shown potentially to stimulate the motility of gastric cancer cells. The expression of LOXL2 in stromal cells could serve as a prognostic marker (Kasashima et al., 2014). A number of micro RNAs family is icantly reduced in cancer tissues. LOXL2 was shown to be a direct regulator of those tumor-suppressive micro-RNAs (Fukumoto et al., 2016; Mizuno et al., 2016).
EGF induces LRRK1 translocation as it is an EGF receptor specific interaction partner (lshikawa et a|., 2012; Hanafusa and Matsumoto, 2011; Reyniers et a|., 2014). LRRK1 is a component of the Grb2/Gab2/Shc1 complex and interacts with Arap1. It may be a component of the MAPK signaling in response to cellular stress (Titz et a|., 2010).
Arsenic trioxide which is used for acute promyelocytic leukemia treatment up-regulates LRRK1 in breast cancer cells (Wang et a|., 2011). LRRK1 shows e allele-specific expression in familial pancreatic cancer (Tan et a|., 2008). LRRK1 encodes leucine rich repeat kinase 1 and is d on some 15q26.3. It belongs to the ROCO proteins, a novel subgroup of Ras-like GTPases (RefSeq, 2002; Korr et a|., 2006).
LYPD1 encodes LY6/PLAUR domain containing 1 and is d on chromosome 2q21.2 (RefSeq, 2002). LYPD1 is over-expressed in brain metastases d from breast cancer. LYPD1 is over-expressed in metastasis. LYPD1 is differentially expressed in ovarian cancer. LYPD1 is a tumor suppressor which is egulated in CD133+ cancer stem ike cells d from uterine carcinosarcoma (Burnett et al., 2015; mts et a|., 2011; Dat et a|., 2012; Ge et a|., 2015b; Lawrenson et a|., 2015a). LYPD1 is a negative regulator of cell proliferation (Salazar et a|., 2011).
MAGEA11 encodes MAGE family member A11 which is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under ent transcriptional controls. The MAGEA genes are red at chromosomal location Xq28 (RefSeq, 2002). MAGEA11 is a cancer germline antigen which is involved in tumor progression and correlates with poor prognosis and sun/ival in silico. MAGEA11 is involved in PR-B signaling and acts as co- regulator for the androgen or. MAGEA11 ly cts with TIF2. MAGEA11 is involved in c ing and knock-down leads to decreased HlF-1alpha expression (Aprelikova et al., 2009; Askew et al., 2009; James et al., 2013; Liu et al., 2011; Su et al., 2012; Wilson, 2010; Wilson, 2011). MAGEA11 is up-regulated in oral squamous cell carcinoma, paclitaxel-resistant ovarian cancer, and during prostate cancer progression (Duan et al., 2003; , 2010; Ge et al., 2015a; Karpf et al., 2009). MAGEA11 expression is associated with hypo-methylation in prostate and epithelial n cancer (James et al., 2013).
MAGEA12 encodes MAGE family member A12 and is closely d to several other genes clustered on chromosome X (RefSeq, 2002). MAGEA12 is expressed in 20.5% of multiple myeloma patients (Andrade et al., 2008). The surfacing of systemic immune reactivity toward a cryptic epitope from the MAGEA12, after temporary regression of a single melanoma metastasis, in response to specific vaccination was reported (Lally et al., 2001). MAGEA12 was expressed at the highest frequencies, relative to the other MAGE antigens, in early stage lesions of malignant melanoma (Gibbs et al., 2000).
MAGEA3 encodes melanoma-associated antigen family member A3. MAGEA3 is widely known as cancer-testis antigen (RefSeq, 2002; Pineda et al., 2015; De et al., 1994).
MAGEA3 has been known long time for being used in therapeutic vaccination trials of metastatic melanoma cancer. The currently performed percutaneous peptide immunization with MAGEA3 and 4 other antigens of ts with advanced malignant melanoma was shown to contribute significantly to longer overall survival by complete ders compared to incomplete responders (Coulie et al., 2002; ma et al., 2014). In NSCLC, MAGEA3 was shown to be frequently expressed. The expression of MAGEA3 correlated with higher number of tumor necrosis in NSCLC tissue samples and was shown to inhibit the proliferation and invasion and promote the apoptosis in lung cancer cell line. By the patients with adenocarcinomas, the expression of MAGEA3 was associated with better survival. The whole cell anti MAGEA3 vaccine is currently under the investigation in the promising phase III clinical trial for treatment of NSCLC (Perez et al., 2011; Reck, 2012; Hall et al., 2013; Grah et al., 2014; Liu et al., 2015b).
MAGEA3 together with 4 other genes was shown to be frequently expressed in HCC.
The expression of those genes was correlated with the number of circulating tumor cells, high tumor grade and ed stage in HCC patients. The ncy of liver asis was shown to be significantly higher in cases with tumor samples that expressed MAGE3 than in those that did not express this gene (Bahnassy et al., 2014; Hasegawa et al., 1998). Cancer stem cell-like side populations isolated from a r cancer cell line as well as from lung, colon, or breast cancer cell lines showed expression of MAGEA3 among other cancer-testis ns. In general, cancer stem cells are known for being resistant to current cancer therapy and cause post-therapeutic cancer recurrence and progression. Thus, MAGEA3 may serve as a novel target for immunotherapeutic treatment in particular of bladder cancer (Yamada et al., 2013; Yin et al., 2014). In head and neck squamous cell oma, the expression of MAGEA3 was shown to be associated with better disease-free survival (Zamuner et al., 2015).
Furthermore, MAGEA3 can be used as a prognostic marker for ovarian cancer (Szajnik et al., 2013).
MAGEA4, also known as MAGE4, encodes a member of the MAGEA gene family and is located on chromosome Xq28 (RefSeq, 2002). MAGEA4 was described as a cancer testis antigen which was found to be expressed in a small on of classic seminomas but not in non-seminomatous testicular germ cell tumors, in breast carcinoma, Epstein- Barr Virus-negative cases of Hodgkin’s lymphoma, esophageal carcinoma, lung carcinoma, bladder carcinoma, head and neck oma, and colorectal cancer, oral us cell carcinoma, and hepatocellular carcinoma (Ries et al., 2005; Bode et al., 2014; Li et al., 2005; Ottaviani et al., 2006; Hennard et al., 2006; Chen et al., 2003).
MAGEA4 was shown to be frequently expressed in primary mucosal melanomas of the head and neck and thus may be a potential target for cancer testis antigen-based immunotherapy (Prasad et al., 2004). MAGEA4 was shown to be preferentially expressed in cancer stem-like cells derived from LHK2 lung adenocarcinoma cells, SW480 colon adenocarcinoma cells and MCF7 breast adenocarcinoma cells (Yamada et al., 2013). Over-expression of MAGEA4 in spontaneously transformed normal oral keratinocytes was shown to promote growth by preventing cell cycle arrest and by inhibiting apoptosis ed by the p53 transcriptional targets BAX and CDKN1A (Bhan et al., 2012). MAGEA4 was shown to be more frequently expressed in hepatitis C virus-infected patients with cirrhosis and tage hepatocellular carcinoma ed to ts with early stage hepatocellular carcinoma, thus making the detection of MAGEA4 transcripts potentially helpful to t prognosis (Hussein et al., 2012).
MAGEA4 was shown to be one of several cancer/testis antigens that are expressed in lung cancer and which may function as potential candidates in lung cancer patients for polyvalent immunotherapy (Kim et al., 2012). MAGEA4 was described as being up- regulated in esophageal carcinoma and hepatocellular carcinoma (Zhao et al., 2002; Wu et al., 2011). A MAGEA4-derived native peptide analogue called p286-1Y2L9L was described as a novel candidate epitope suitable to develop peptide vaccines against esophageal cancer (Wu et al., 2011).
MAGEA6 encodes melanoma-associated antigen family member A6. MAGEA3 is widely known as cancer-testis antigen (RefSeq, 2002; Pineda et al., 2015; De et al., 1994).
MAGEA6 was shown to be frequently expressed in melanoma, advanced a, pediatric rhabdomyosarcoma, sarcoma, lung, bladder, prostate, breast, and colorectal cancers, head and neck squamous cell, esophageal us cell, and oral squamous cell carcinomas (Ries et al., 2005; Hasegawa et al., 1998; Gibbs et al., 2000; Dalerba et al., 2001; Otte et al., 2001; van der Bruggen et al., 2002; Lin et al., 2004; Tanaka et al., 1997). MAGEA6 expression has been associated with r progression-free survival in multiple a patients. In contrast in head and neck squamous cell carcinoma, the expression of MAGEA6 was shown to be associated with better disease-free survival (van et al., 2011; Zamuner et al., 2015). MAGEA6 was among a set of genes overexpressed in a paclitaxel-resistant ovarian cancer cell line. Moreover, transfection of MAGEA6 also conferred sed drug resistance to paclitaxel-sensitive cells (Duan et al., 2003). MAGEA6 can be used as a prognostic marker for ovarian cancer (Szajnik et al., 2013). Cancer stem cell-like side populations ed from lung, colon, or breast cancer cell lines showed expression of MAGEA6 among other -testis antigens (Yamada et al., 2013).
MAGEB2 is classified as cancer testis antigen, since it is expressed in testis and placenta, and in a significant fraction of tumors of s histological types, amongst others multiple myeloma and head and neck squamous cell carcinoma (Pattani et al., 2012; van et al., 2011).
MELK s maternal embryonic e zipper kinase and is located on chromosome 9p13.2 (RefSeq, 2002). MELK is a member of the SNF1/AMPK family of serine-threonine kinases and is a cell cycle dependent protein kinase. It plays a key role in multiple cellular processes such as the proliferation, cell cycle ssion, mitosis and spliceosome assembly and has recently emerged as an oncogene and a biomarker over-expressed in multiple cancer stem cells (Du et al., 2014). MELK is over-expressed in various cancers, including colon, gastric, breast, ovaries, pancreas, prostate and brain cancer and over-expression correlates with poor prognosis (Pickard et al., 2009; Kuner et al., 2013; Gu et al., 2013; Liu et al., 2015a). Inhibition of MELK is under investigation as a therapeutic strategy for a variety of cancers, including breast cancer, lung cancer and prostate cancer. MELK-T1 inhibits catalytic activity and MELK protein stability and might sensitize tumors to DNA-damaging agents or radiation therapy by ng the DNA-damage threshold. MELK inhibitor OTSSP167 is undergoing phase I clinical trials (Chung et al., 2012b; Ganguly et al., 2014; Beke et al., 2015).
MEX3A encodes a member of the mex-3 RNA g family which consists of ionarily conserved RNA-binding proteins recruited to P bodies and potentially involved in post-transcriptional regulatory mechanisms (Buchet-Poyau et al., 2007).
MEX3A is over-expressed and the gene is amplified in Wilms tumors associated with a late relapse (Krepischi et al., 2016). MEX3A regulates CDX2 via a post-transcriptional mechanism with impact in intestinal differentiation, polarity and stemness, contributing to inal homeostasis and ogeneses (Pereira et al., 2013).
MMP-11, also named stromelysin-3, is a member of the stromelysin subgroup belonging to MMPs superfamily, which has been detected in cancer cells, stromal cells and adjacent microenvironment. Differently, MMP-11 exerts a dual effect on . On the one hand MMP-11 promotes cancer development by inhibiting apoptosis as well as _ 75 _ enhancing migration and invasion of cancer cells, on the other hand MMP-11 plays a negative role t cancer development via suppressing metastasis in animal models.
Overexpression of MMP-11 was discovered in sera of cancer patients ed with normal control group as well as in multiple tumor tissue specimens, such as gastric cancer, breast cancer, and pancreatic cancer (Zhang et al., 2016c). MMP-11 was trated to be over-expressed at mRNA level and protein level in CRC tissue than paired normal mucosa. r MMP-11 expression was correlated with CRC lymph node metastasis, distant metastasis and TNM stage (Tian et al., 2015). MMP-11 overexpression is associated with aggressive tumor phenotype and rable clinical outcome in upper urinary tract lial carcinomas (UTUC) and urinary bladder urothelial carcinomas (UBUC), suggesting it may serve as a novel prognostic and therapeutic target (Li et al., 2016d).
MMP12 (also called MME) encodes a member of the matrix metalloproteinase family which is involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction and tissue remodeling as well as in disease processes, such as arthritis and metastasis (RefSeq, 2002). De-regulation of MMP12 is shown for different cancer entities. MMP12 is ulated in lung, skin, pancreatic and gastric cancer and related to tumor invasion and metastasis. In contrast, over-expression of MMP12 mRNA was found in gastric and colorectal cancer and correlated with a better prognosis (Zhang et al., 2007; Yang et al., 2001; Balaz et al., 2002; Zheng et al., 2013; Wen and Cai, 2014; Zhang et al., 2015f). MMP12 is up- regulated by TNF-alpha or EGF via the NF-kappaB/MAPK and JNK/AP-1 pathways (Yu et al., 2010; Yang et al., 2012).
MYO3B encodes the myosin lllB, a member of a myosin-class that is characterized by an amino-terminal kinase domain and shown to be present in photoreceptors (RefSeq, 2002). MYO3B was identified as an antagonist to zumab treatment among HER2+ cell lines (Lapin et al., 2014). tide polymorphisms in the MYOB3 gene were found to be associated with changes in the AUA Symptom Score after radiotherapy for prostate cancer (Kerns et al., 2013). _ 76 _ NFE2L3 encodes nuclear factor, erythroid 2 like 3, a member of the cap 'n' collar basic- region leucine zipper family of transcription factors (RefSeq, 2002). Recent work has revealed that loss of NFE2L3 predisposes mice to lymphoma development. Others have observed high levels of NFE2L3 in colorectal cancer cells, s aberrant expression of NFE2L3 was found in Hodgkin lymphoma. Furthermore, NFE2L3 exhibited hyper- methylation in ER positive tumors rs et al., 2003; Chevillard et al., 2011; Palma et al., 2012; er et al., 2015).
NLRP2 (also known as NALP2) encodes the NLR family, pyrin domain containing 2 protein and is involved in the activation of caspase-1 and may also form protein complexes activating proinflammatory caspases. NLRP7 is a paralog of NLRP2 (RefSeq, 2002; Wu et al., 2010; Slim et al., 2012). The PYRIN domain of NLRP2 inhibits cell proliferation and tumor growth of glioblastoma (Wu et al., 2010). An ATM/NLRP2/MDC1-dependent pathway may shut down ribosomal gene transcription in response to chromosome breaks (Kruhlak et al., 2007). Mutations in NLRP2 can cause rare human imprinting disorders such as familial diform mole, Beckwith- Wiedemann me and familial transient al diabetes mellitus (Aghajanova et al., 2015; Dias and Maher, 2013; Ulker et al., 2013). NLRP2 ts NF-kappaB activation (Kinoshita et al., 2005; Kinoshita et al., 2006; Fontalba et al., 2007; Bruey et aL,2004) NLRP7 encodes the NLR family pyrin domain containing 7, a member of the NACHT, leucine rich repeat, and PYD containing (NLRP) protein family that may act as a feedback regulator of caspasedependent interleukin 1-beta ion (RefSeq, 2002).
NLRP7 expression correlates significantly with the depth of tumor invasion and poor prognosis in endometrial cancer and was identified as one of the genes highly expressed in embryonal carcinomas (Ohno et al., 2008; Skotheim et al., 2005). NLRP7 might play a l role in cell proliferation in testicular tumorigenesis and represents a promising eutic target for testicular germ cell tumors (Okada et al., 2004).
OVGP1 or oviduct-specific glycoprotein, encodes a large, carbohydrate-rich, epithelial glycoprotein which is ed from non-ciliated oviductal epithelial cells and associates with ovulated oocytes, blastomeres and spermatozoan mal regions (RefSeq, 2002). Gain of OVGP1 was shown to be associated with the development of endometrial hyperplasia and endometrial cancer (Woo et al., 2004). OVGP1 was described as a molecular marker for invasion in endometrial tumorigenesis and a entiation-based marker of different ovarian s (Maines-Bandiera et al., 2010; Wang et al., 2009).
PAGE2 encodes a member of the PAGE protein family, which is predominantly expressed in testis (Brinkmann et al., 1998). The -testis gene PAGE2 is up- regulated by de-methylation during spontaneous differentiation of colorectal cancer cells resulting in mesenchymal-to-epithelial tion (MET). Accordingly, down-regulation of PAGE2 has been shown in EMT (Yilmaz-Ozcan et al., 2014). A genome-wide screening identifies PAGE2 as a possible regulator of telomere signaling in human cells (Lee et aL,2011) PNOC encodes prepronociceptin which is a preproprotein that is proteolytically processed to generate multiple protein products. These products include nociceptin, nocistatin, and orphanin FQ2 . Nociceptin, also known as orphanin F0, is a 17- amino acid neuropeptide that binds to the nociceptin receptor to induce increased pain sensitivity, and may additionally regulate body temperature, learning and memory, and hunger. Another product of the d preproprotein, nocistatin, may inhibit the effects of nociception (RefSeq, 2002). Inhibition of cancer pain also inhibits tumor growth and lung asis. PNOC is involved in morphine tolerance development. PNOC is ed in neuronal growth. PNOC is involved in cell damage, viability, inflammation and impaired immune on (Caputi et al., 2013; Chan et al., 2012; Kirkova et al., 2009; Kuraishi, 2014; Stamer et al., 2011). PNOC is up-regulated in ganglioglioma.
PNOC expression is down-regulated in end-stage cancer. PNOC is highly expressed in the plasma of hepatocellular carcinoma patients (Chan et al., 2012; Stamer et al., 2011; Horvath et al., 2004; Spadaro et al., 2006; Szalay et al., 2004). Cebranopadol is an analgesic PNOC e may be used in bone cancer treatment and buprenorphine in lung cancer treatment (Davis, 2012; Linz et al., 2014). PNOC is involved in c-Fos expression (Gottlieb et al., 2007; Kazi et al., 2007). _ 78 _ PRAME encodes an antigen that is preferentially expressed in human mas and acts as a repressor of retinoic acid receptor, likely conferring a growth advantage to cancer cell via this function (RefSeq, 2002). PRAME was shown to be up-regulated in multiple myeloma, clear cell renal cell carcinoma, breast cancer, acute myeloid ia, melanoma, chronic myeloid leukemia, head and neck squamous cell carcinoma and arcoma cell lines (Dannenmann et al., 2013; Yao et al., 2014; Zou et al., 2012; Szczepanski and Whiteside, 2013; Zhang et al., 2013; Beard et al., 2013; Abdelmalak et al., 2014; Qin et al., 2014). PRAME is associated with myxoid and round- cell liposarcoma nger et al., 2014). PRAME is associated with shorter ssion-free survival and chemotherapeutic response in diffuse large B-cell lymphoma treated with R-CHOP, markers of poor prognosis in head and neck squamous cell carcinoma, poor response to chemotherapy in urothelial carcinoma and poor prognosis and lung metastasis in osteosarcoma (Tan et al., 2012; Dyrskjot et al., 2012; Szczepanski et al., 2013; Mitsuhashi et al., 2014). PRAME is associated with lower e, lower mortality and overall sun/ival in acute lymphoblastic leukemia (Abdelmalak et al., 2014). PRAME may be a prognostic marker for diffuse large B-cell lymphoma treated with R-CHOP therapy hashi et al., 2014).
RAD54 encodes a protein belonging to the DEAD-like se superfamily. |t shares similarity with Saccharomyces cerevisiae RAD54 and RDH54, both of which are involved in homologous recombination and repair of DNA. This protein binds to double- stranded DNA, and displays ATPase ty in the presence of DNA. This gene is highly expressed in testis and spleen, which suggests active roles in meiotic and mitotic recombination (RefSeq, 2002). Homozygous mutations of RAD54B were observed in primary lymphoma and colon cancer (Hiramoto et al., 1999). RAD54B counteracts -destabilizing effects of direct g of RAD51 to dsDNA in human tumor cells (Mason et al., 2015).
RNF17 encodes ring finger protein 17 which is similar to a mouse gene that encodes a testis-specific protein containing a RING finger domain. Alternatively spliced ript variants encoding different isoforms have been found (RefSeq, 2002). RNF17 is involved in cytokine production and apoptosis. RNF17 enhances c-Myc function _ 7g _ (Jnawali et al., 2014; Lee et al., 2013; Yin et al., 1999; Yin et al., 2001). RNF17 is up- regulated upon RHOXF1 knock-down (Seifi-Alan et al., 2014). RNF17 is expressed in liver cancer (Yoon et al., 2011). RNF17 is a cancer-associated marker (de Matos et al., 2015).
SDK2 encodes the ck cell adhesion molecule 2, a member of the immunoglobulin superfamily that contains two immunoglobulin domains and thirteen fibronectin type III domains which represent binding sites for DNA, heparin and the cell surface (RefSeq, 2002). It was shown that SDK2 guides axonal terminals to specific synapses in developing neurons and promotes lamina-specific targeting of retinal dendrites in the inner plexiform layer (Kaufman et al., 2004; ta and Sanes, 2012).
SPDEF (also called PDEF) encodes SAM d domain ning ETS transcription factor, a member of the E26 transformation-specific (ETS) family of transcription factors.
It is highly expressed in prostate lial cells where it functions as an androgen- independent transactivator of prostate specific antigen (PSA) promoter (RefSeq, 2002).
SPDEF expression is often lost or egulated in late-stage of tumor progression which means that it plays a role in tumor cell invasion and metastasis. In earlier stages of tumor progression SPDEF is sometimes up-regulated. De-regulation of SPDEF is described for several cancer entities including breast, prostate and colorectal cancer (Moussa et al., 2009; Schaefer et al., 2010; Steffan and Koul, 2011). SPDEF induces the transcription of erin and suppresses thereby cell invasion and migration (Pal et al., 2013). SPDEF interacts with beta-catenin and blocks the transcriptional activity resulting in lower protein levels of the oncogenes cyclin D1 and c-Myc (Noah et al., 2013).
SPON1 encodes spondin 1 and is located on chromosome 11p15.2 (RefSeq, 2002).
SPON1 is involved in cancer cell eration, migration, on, and metastasis.
SPON1 is involved in Fak and Src signaling. SPON1 is involved in lL-6 nance via MEKK/p38 MAPK/NF-kappaB signaling and this may support murine neuroblastoma survival (Chang et al., 2015a; Cheng et al., 2009; Dai et al., 2015). SPON1 is down- regulated by miR-506 (Dai et al., 2015). SPON1 is over-expressed in ovarian cancer _ 80 _ (Davidson et al., 2011; Jiao et al., 2013; henault et al., 2005). SPON1 may have diagnostic potential in cancer prognosis tta et al., 2013).
STAG3 encodes stromal antigen 3, which is expressed in the nucleus and is a subunit of the cohesin complex which regulates the cohesion of sister tids during cell division q, 2002). Researchers have reported the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer. Another group has identified STAG3 to be capable of effectively discriminating lung , c obstructive lung disease and fibrotic interstitial lung diseases. Others have detected expression of the STAG3 gene in p53 mutated lymphoma cells (Notaridou et al., 2011; Wielscher et al., 2015; Kalejs et al., 2006).
TDRD5 encodes tudor domain containing 5 and is located on chromosome 1q25.2 (RefSeq, 2002). TDRD5 may be over-expressed in breast cancer (Jiang et al., 2016).
TDRD5 methylation is altered upon resveratrol ent in triple negative breast cancer (Medina-Aguilar et al., 2017). TDRD5 is part of a run of homozygosity associated with thyroid cancer (Thomsen et al., 2016).
TENM4 encodes teneurin transmembrane protein 4 which is expressed in the nervous systems and mesenchymal tissues and is a regulator of chondrogenesis (Suzuki et al., 2014). Among the four most frequently mutated genes was TENM4 showing proteinchanging mutations in primary CNS lymphomas (Vater et al., 2015). MDA-MB-175 cell line contains a chromosomal translocation that leads to the fusion of TENM4 and receptors of the ErbB family. Chimeric genes were also found in neuroblastomas (Wang et al., 1999; Boeva et al., 2013).
TMPRSS3 encodes transmembrane protease, serine 3 which is a protein that belongs to the serine protease . The encoded protein ns a serine protease domain, a transmembrane domain, an LDL or-like , and a scavenger receptor cysteine-rich domain. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders.
This gene was identified by its association with both congenital and childhood onset mal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and nance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors (RefSeq, 2002).
TMPRSS3 is involved in cell proliferation, invasion, and migration. TMPRSS3 induces ERK1/2 ing (Zhang et al., 2016a). TMPRSS3 affects E-cadherin, vimentin, and Twist expression. TMPRSS3 is down-regulated by thylene bisacetamide (Zhang et al., 2016a; Zhang et al., 2004). TMPRSS3 is up-regulated in breast cancer, pancreatic cancer, and ovarian cancer. 3 is de-regulated in gastric cancer and pancreatic ductal adenocarcinoma (Rui et al., 2015; Zhang et al., 2016a; Zhang et al., 2004; Amsterdam et al., 2014; lacobuzio-Donahue et al., 2003; Luo et al., 2017; ood et al., 2000; Wallrapp et al., 2000). TMPRSS3 is associated with TNM stage, lymph node metastasis, distant organ metastasis, shorter survival, r disease-free survival, and poor prognosis. TMPRSS3 may be used as biomarker in cancer. TMPRSS3 mutations are associated with cancer risk. TMPRSS3 may be used for early pancreatic ductal adenocarcinoma ion (Rui et al., 2015; Amsterdam et al., 2014; Luo et al., 2017; Dorn et al., 2014; Luostari et al., 2014; Pelkonen et al., 2015; Sawasaki et al., 2004). TMPRSS3 is ethylated in cancer (Guerrero et al., 2012).
VTCN1, also known as B7-H4, encodes a member of the B7 costimulatory protein family which is present on the surface of antigen-presenting cells and interacts with ligands bound to ors on the surface of T cells (RefSeq, 2002). VTCN1 was shown to be up-regulated in lung cancer, colorectal cancer, hepatocellular carcinoma, osteosarcoma, breast cancer, cervical cancer, urothelial cell carcinoma, gastric cancer, endometrial cancer, thyroid cancer and eal carcinoma (Klatka et al., 2013; Zhu et al., 2013; Vanderstraeten et al., 2014; Shi et al., 2014; Fan et al., 2014; Wang et al., 2014; Leong et al., 2015; Dong and Ma, 2015; Zhang et al., 2015a; Peng et al., 2015; Xu et al., 2015a). VTCN1 is associated with poor l survival and higher ence probability in hepatocellular carcinoma and poor overall survival in osteosarcoma, urothelial cell carcinoma, pancreatic cancer, gastric cancer, cervical , melanoma and thyroid cancer (Zhu et al., 2013; Seliger, 2014; Liu et al., 2014b; Chen et al., 2014; Fan et al., 2014; Dong and Ma, 2015; Zhang et al., 2015a). VTCN1 is associated with clear cell renal cell carcinoma (Xu et al., 2014b). VTCN1 expression levels were shown _ 82 _ to be inversely correlated with patient survival in ovarian cancer (Smith et al., 2014).
VTCN1 may be a ial prognostic indicator of urothelial cell carcinoma and gastric cancer (Shi et al., 2014; Fan et al., 2014).
WNT7A encodes Wnt family member 7A which is a member of the WNT gene .
These proteins have been implicated in oncogenesis and in several pmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is involved in the development of the anterior-posterior axis in the female reproductive tract, and also plays a critical role in uterine smooth muscle pattering and maintenance of adult e function. ons in this gene are associated with Fuhrmann and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndromes (RefSeq, 2002). WNT7A is d by STAT4 resulting in the activation of cancer-associated fibroblasts. WNT7A potentiates TGF-beta receptor signaling. WNT7A is involved in cell proliferation and migration. WNT7A is an upstream inducer of senescence. PG545 cts with WNT7A resulting in inhibited cell proliferation. WNT7A suppresses tumor growth. WNT7A is involved in Wnt/beta-catenin signaling and regulates hsa-miR29b (Avasarala et al., 2013; Avgustinova et al., 2016; Bikkavilli et al., 2015; Borowicz et al., 2014; Jung et al., 2015; King et al., 2015; Ramos-Solano et al., 2015; Zhao et al., 2017). WNT7A is regulated by miR-15b and down-regulated by DNMT1. Endosulfan disrupts WNT7A. WNT7A is a target gene of miR-199a-5p and miR-195/497. WNT7A is down-regulated by chronic ethanol exposure and rescued by PPAR-delta agonist treatment. Dkk-1 affects WNT7A. Bilobalide enhances WNT7A expression (Kim et al., 2015a; Chandra et al., 2014; lngaramo et al., 2016; ltesako et al., 2014; Liu et al., 2014a; n et al., 2016; Mercer et al., 2014; Mercer et al., 2015; Xu et al., .
WNT7A is down-regulated and methylated in cervical cancer. WNT7A is lost in lung cancer. WNT7A is over-expressed in endometrial cancer (Ramos-Solano et al., 2015; Kim et al., 2015b; Liu et al., 2013). WNT7A expression ates with poor prognosis and poor patient outcome. WNT7A promotor methylation correlates with ed tumor stage, distant metastasis, and loss of E-cadherin. Decreased WNT7A expression correlates with decreased overall survival in malignant pleural mesothelioma and may be used for chemosensitivity prediction (Avgustinova et al., 2016; King et al., _ 83 _ 2015; Kim et al., 2015b; Hirata et al., 2015). WNT7A may be a tumor ssor gene in nasopharyngeal cancer (Nawaz et al., 2015).
DETAILED DESCRIPTION OF THE INVENTION Stimulation of an immune response is dependent upon the presence of ns recognized as foreign by the host immune system. The discovery of the existence of tumor associated antigens has raised the possibility of using a host's immune system to intervene in tumor growth. Various isms of harnessing both the l and cellular arms of the immune system are currently being explored for cancer immunotherapy.
Specific elements of the cellular immune response are capable of specifically recognizing and ying tumor cells. The isolation of T-cells from tumor-infiltrating cell populations or from peripheral blood suggests that such cells play an important role in natural immune defense against cancer. CD8—positive T-cells in particular, which recognize class I molecules of the major histocompatibility complex (MHC)—bearing peptides of usually 8 to 10 amino acid residues derived from proteins or defect ribosomal products ) located in the cytosol, play an important role in this response. The MHC-molecules of the human are also designated as human leukocyte- antigens (HLA).
The term "T-cell response" means the specific proliferation and activation of effector functions induced by a peptide in vitro or in vivo. For MHC class I restricted cytotoxic T cells, effector functions may be lysis of peptide-pulsed, peptide-precursor pulsed or lly peptide-presenting target cells, secretion of cytokines, preferably eron- gamma, TNF-alpha, or lL-2 induced by peptide, ion of effector molecules, preferably granzymes or perforins induced by peptide, or degranulation.
The term "peptide" is used herein to ate a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and yl groups of the adjacent amino acids. The peptides are preferably 9 amino acids _ 84 _ in length, but can be as short as 8 amino acids in length, and as long as 10, 11, or 12 or longer, and in case of MHC class II peptides (elongated ts of the peptides of the invention) they can be as long as 13, 14, 15, 16, 17, 18, 19 or 20 or more amino acids in Furthermore, the term "peptide" shall include salts of a series of amino acid residues, connected one to the other typically by e bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. ably, the salts are pharmaceutical acceptable salts of the es, such as, for example, the chloride or acetate (trifluoroacetate) salts. It has to be noted that the salts of the peptides according to the present invention differ substantially from the peptides in their state(s) in vivo, as the peptides are not salts in vivo.
The term "peptide" shall also include "oligopeptide". The term "oligopeptide" is used herein to designate a series of amino acid residues, connected one to the other typically by peptide bonds between the amino and carbonyl groups of the adjacent amino acids. The length of the oligopeptide is not critical to the invention, as long as the correct e or epitopes are maintained therein. The oligopeptides are typically less than about 30 amino acid residues in length, and greater than about 15 amino acids in length.
The term "polypeptide" designates a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. The length of the polypeptide is not critical to the invention as long as the correct epitopes are maintained. In contrast to the terms peptide or oligopeptide, the term polypeptide is meant to refer to molecules containing more than about 30 amino acid residues.
A peptide, oligopeptide, protein or polynucleotide coding for such a molecule is "immunogenic" (and thus is an "immunogen" within the present ion), if it is e of inducing an immune response. In the case of the present invention, immunogenicity is more ically defined as the y to induce a T-cell response. Thus, an "immunogen" would be a molecule that is capable of inducing an immune response, and in the case of the present invention, a molecule capable of ng a T-cell response.
In another aspect, the immunogen can be the peptide, the complex of the peptide with MHC, oligopeptide, and/or protein that is used to raise specific antibodies or TCRs against it.
A class I T cell "epitope" requires a short peptide that is bound to a class I MHC receptor, g a ternary complex (MHC class I alpha chain, betamicroglobulin, and peptide) that can be recognized by a T cell bearing a matching T-cell or binding to the MHC/peptide complex with appropriate affinity. Peptides binding to MHC class I molecules are typically 8-14 amino acids in length, and most typically 9 amino acids in length.
In , there are three different genetic loci that encode MHC class I les (the MHC-molecules of the human are also designated human leukocyte antigens (HLA)): HLA-A, HLA-B, and HLA-C. HLA-A*01, HLA-A*02, and HLA-B*O7 are examples of different MHC class I alleles that can be expressed from these loci.
Table 6: Expression frequencies F of HLA-A*02, HLA-A*O1, O3, HLA-A*24, HLA-B*O7, O8 and HLA-B*44 serotypes. Haplotype frequencies Gf are derived from a study which used HLA-typing data from a registry of more than 6.5 million volunteer donors in the U.S. (Gragert et al., 2013). The haplotype frequency is the frequency of a distinct allele on an individual chromosome. Due to the d set of chromosomes within mammalian cells, the frequency of genotypic occurrence of this allele is higher and can be calculated employing the Weinberg principle (F = 1 — (1-Gf)2).
Calculated phenotype from Allele Population allele frequency (F) African (N=28557) 32.3% European Caucasian 49.3% _ 86 _ Calculated phenotype from Allele tion allele frequency (F) (N=1242890) Japanese 82) 42.7% Hispanic, S + Cent Amer.
(N=146714) 46.1% Southeast Asian (N=27978) 30.4% African 57) 10.2% European Caucasian (N=1242890) 30.2% A*01 se (N=24582) 1.8% Hispanic, S + Cent Amer.
(N=146714) 14.0% Southeast Asian (N=27978) 21.0% African (N=28557) 14.8% European Caucasian (N=1242890) 26.4% A*03 Japanese (N=24582) 1.8% ic, S + Cent Amer.
(N=146714) 14.4% Southeast Asian (N=27978) 10.6% African (N=28557) 2.0% European Caucasian (N=1242890) 8.6% A*24 Japanese (N=24582) 35.5% Hispanic, S + Cent Amer.
(N=146714) 13.6% Southeast Asian (N=27978) 16.9% African (N=28557) 14.7% European Caucasian (N=1242890) 25.0% B*07 Japanese (N=24582) 11.4% Hispanic, S + Cent Amer.
(N=146714) 12.2% Southeast Asian (N=27978) 10.4% African (N=28557) 6.0% European Caucasian (N=1242890) 21.6% B*08 se (N=24582) 1.0% Hispanic, S + Cent Amer.
(N=146714) 7.6% Southeast Asian (N=27978) 6.2% W0 38257 2018/051952 _ 87 _ Calculated phenotype from Allele Population allele frequency (F) African (N=28557) 10.6% European Caucasian (N=1242890) 26.9% B*44 Japanese (N=24582) 13.0% Hispanic, S + Cent Amer.
(N=146714) 18.2% Southeast Asian (N=27978) 13.1% The peptides of the ion, preferably when ed into a vaccine of the invention as described herein bind to A*02, A*01, A*03, A*24, B*07, B*08 or B*44. A vaccine may also include pan-binding MHC class II peptides. Therefore, the vaccine of the invention can be used to treat cancer in patients that are A*02-, A*01-, A*03-, A*24-, B*07-, B*08- or B*44-positive, whereas no selection for MHC class II allotypes is necessary due to the pan-binding nature of these peptides. |f A*02 peptides of the invention are combined with peptides g to another allele, for example A*24, a higher percentage of any patient population can be treated compared with addressing either MHC class I allele alone. While in most populations less than 50% of patients could be addressed by either allele alone, a vaccine comprising HLA-A*24 and HLA-A*02 epitopes can treat at least 60% of ts in any relevant population. Specifically, the following percentages of patients will be positive for at least one of these s in various regions: USA 61%, Western Europe 62%, China 75%, South Korea 77%, Japan 86% lated from www.allelefrequencies.net).
Table 7: HLA alleles coverage in European Caucasian population (calculated from (Gragert et al., 2013)). coverage (at least combined one A- combined combined with B*07 allele) with B*07 with B*44 and B*44 A*02 / A*O1 70% 78% 78% 84% A*02 / A*03 68% 76% 76% 83% A*02 / A*24 61% 71% 71% 80% _ 88 _ A*‘01 /A*03 52% 64% 65% 75% A*01 /A*24 44% 58% 59% 71% A*O3 / A*24 40% 55% 56% 69% A*02 / A*01 /A*03 84% 88% 88% 91% A*02 / A*01 / A*24 79% 84% 84% 89% A*02 / A*O3 / A*24 77% 82% 83% 88% A*01 / A*03 / A*24 63% 72% 73% 81% A*02 / A*01 /A*03 / A*24 90% 92% 93% 95% In a preferred ment, the term "nucleotide sequence" refers to a heteropolymer of deoxyribonucleotides.
The nucleotide sequence coding for a particular peptide, eptide, or polypeptide may be naturally occurring or they may be synthetically constructed. Generally, DNA segments encoding the peptides, polypeptides, and proteins of this invention are assembled from cDNA fragments and short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic gene that is capable of being expressed in a recombinant transcriptional unit comprising regulatory ts derived from a microbial or viral operon.
As used herein the term "a nucleotide coding for (or encoding) a peptide" refers to a nucleotide sequence coding for the peptide ing artificial (man-made) start and stop codons compatible for the biological system the ce is to be expressed by, for e, a dendritic cell or another cell system useful for the production of TCRs.
As used herein, nce to a nucleic acid sequence includes both single stranded and double stranded nucleic acid. Thus, for example for DNA, the specific sequence, unless the context indicates otherwise, refers to the single strand DNA of such sequence, the duplex of such sequence with its complement (double stranded DNA) and the complement of such sequence.
The term "coding " refers to that portion of a gene which either naturally or normally codes for the expression product of that gene in its natural genomic environment, i.e., the region coding in vivo for the native expression product of the gene.
The coding region can be derived from a tated ("normal"), mutated or altered gene, or can even be d from a DNA sequence, or gene, wholly synthesized in the laboratory using methods well known to those of skill in the art of DNA synthesis.
The term "expression product" means the polypeptide or protein that is the natural translation product of the gene and any nucleic acid sequence coding equivalents resulting from genetic code degeneracy and thus coding for the same amino acid(s).
The term "fragment", when referring to a coding sequence, means a portion of DNA comprising less than the complete coding , whose sion product retains ially the same biological function or activity as the expression product of the complete coding region.
The term "DNA segment" refers to a DNA polymer, in the form of a separate fragment or as a component of a larger DNA construct, which has been derived from DNA isolated at least once in substantially pure form, i.e., free of inating endogenous materials and in a quantity or concentration enabling identification, lation, and recovery of the segment and its ent nucleotide sequences by standard biochemical methods, for example, by using a cloning vector. Such segments are provided in the form of an open reading frame rrupted by internal non-translated sequences, or introns, which are typically present in eukaryotic genes. Sequences of non-translated DNA may be present downstream from the open reading frame, where the same do not interfere with manipulation or expression of the coding regions.
The term "primer" means a short nucleic acid sequence that can be paired with one strand of DNA and provides a free 3'-OH end at which a DNA polymerase starts synthesis of a deoxyribonucleotide chain.
The term "promoter" means a region of DNA involved in binding of RNA polymerase to initiate transcription.
The term "isolated" means that the material is removed from its original nment (e.g., the natural environment, if it is naturally occurring). For example, a naturally- occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, ted from some or all of the coexisting materials in the natural system, is ed. Such polynucleotides could be part of a vector and/or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of its natural environment.
The polynucleotides, and recombinant or immunogenic polypeptides, disclosed in ance with the present invention may also be in "purified" form. The term "purified" does not require absolute purity; rather, it is intended as a relative definition, and can include preparations that are highly purified or preparations that are only partially purified, as those terms are understood by those of skill in the relevant art. For example, individual clones isolated from a cDNA y have been conventionally purified to electrophoretic homogeneity. Purification of starting material or natural material to at least one order of ude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. Furthermore, a claimed polypeptide which has a purity of preferably 99.999%, or at least 99.99% or 99.9%; and even desirably 99% by weight or greater is sly encompassed.
The nucleic acids and polypeptide expression ts disclosed according to the present ion, as well as expression s containing such nucleic acids and/or such polypeptides, may be in "enriched form". As used herein, the term "enriched" means that the concentration of the material is at least about 2, 5, 10, 100, or 1000 times its natural concentration (for e), ageously 0.01%, by weight, ably at least about 0.1% by weight. Enriched preparations of about 0.5%, 1%, 5%, %, and 20% by weight are also contemplated. The sequences, constructs, vectors, clones, and other materials comprising the present invention can advantageously be in enriched or isolated form. The term "active fragment" means a fragment, usually of a peptide, polypeptide or nucleic acid sequence, that generates an immune response (i.e., has immunogenic activity) when administered, alone or optionally with a le adjuvant or in a vector, to an animal, such as a , for example, a rabbit or a mouse, and also including a human, such immune response taking the form of stimulating a T-cell se within the ent animal, such as a human. Alternatively, the e fragment" may also be used to induce a T-cell response in vitro.
As used herein, the terms "portion", "segment" and ent", when used in on to polypeptides, refer to a continuous ce of residues, such as amino acid residues, which sequence forms a subset of a larger sequence. For example, if a polypeptide were subjected to treatment with any of the common endopeptidases, such as trypsin or chymotrypsin, the oligopeptides resulting from such treatment would represent portions, segments or fragments of the starting polypeptide. When used in relation to polynucleotides, these terms refer to the products produced by treatment of said polynucleotides with any of the endonucleases.
In accordance with the present invention, the term "percent identity" or "percent identical", when referring to a sequence, means that a sequence is compared to a claimed or described sequence after alignment of the sequence to be compared (the "Compared Sequence") with the described or claimed sequence (the "Reference Sequence"). The percent identity is then determined according to the following formula: percent ty = 100 [1 -(C/R)] wherein C is the number of differences between the Reference Sequence and the Compared Sequence over the length of alignment between the Reference Sequence and the Compared Sequence, wherein (i) each base or amino acid in the Reference Sequence that does not have a ponding aligned base or amino acid in the Compared Sequence and (ii) each gap in the Reference ce and (iii) each aligned base or amino acid in the Reference Sequence that is different from an aligned base or amino acid in the ed ce, constitutes a difference and (iiii) the alignment has to start at position 1 of the aligned ces; and R is the number of bases or amino acids in the Reference Sequence over the length of the alignment with the Compared Sequence with any gap created in the Reference Sequence also being counted as a base or amino acid.
If an alignment exists between the Compared ce and the Reference ce for which the percent identity as calculated above is about equal to or greater than a specified minimum Percent ty then the Compared Sequence has the specified minimum percent identity to the Reference Sequence even though alignments may exist in which the herein above calculated percent identity is less than the specified percent identity.
As mentioned above, the present invention thus es a peptide comprising a ce that is selected from the group of ting of SEQ ID NO: 1 to SEQ ID NO: 772 or a variant thereof which is 88% homologous to SEQ ID NO: 1 to SEQ ID NO: 772, or a variant thereof that will induce T cells cross-reacting with said peptide. The es of the ion have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or elongated versions of said peptides to class In the present invention, the term "homologous" refers to the degree of identity (see percent identity above) between sequences of two amino acid sequences, i.e. peptide or polypeptide sequences. The aforementioned "homology" is determined by comparing two sequences aligned under optimal conditions over the sequences to be compared.
Such a sequence gy can be calculated by creating an alignment using, for example, the ClustalW algorithm. Commonly available sequence analysis software, more specifically, Vector NTI, GENETYX or other tools are provided by public databases. _ 93 _ A person skilled in the art will be able to assess, whether T cells induced by a variant of a specific peptide will be able to cross-react with the peptide itself (Appay et al., 2006; Colombetti et al., 2006; Fong et al., 2001; Zaremba et al., 1997).
By a "variant" of the given amino acid sequence the inventors mean that the side chains of, for example, one or two of the amino acid es are altered (for example by replacing them with the side chain of another naturally occurring amino acid residue or some other side chain) such that the peptide is still able to bind to an HLA molecule in substantially the same way as a peptide consisting of the given amino acid sequence in consisting of SEQ ID NO: 1 to SEQ ID NO: 772. For example, a peptide may be modified so that it at least maintains, if not improves, the ability to interact with and bind to the binding groove of a le MHC molecule, such as HLA-A*02 or -DR, and in that way it at least maintains, if not improves, the ability to bind to the TCR of activated T cells.
These T cells can uently cross-react with cells and kill cells that express a ptide that contains the natural amino acid sequence of the e peptide as defined in the aspects of the invention. As can be derived from the scientific literature and databases (Rammensee et al., 1999; Godkin et al., 1997), certain positions of HLA binding peptides are typically anchor residues forming a core sequence fitting to the binding motif of the HLA receptor, which is defined by polar, electrophysical, hydrophobic and spatial properties of the ptide chains constituting the binding groove. Thus, one skilled in the art would be able to modify the amino acid ces set forth in SEQ ID NO: 1 to SEQ ID NO 772, by maintaining the known anchor residues, and would be able to determine whether such variants maintain the ability to bind MHC class I or II les. The variants of the present invention retain the ability to bind to the TCR of activated T cells, which can uently cross-react with and kill cells that express a ptide containing the natural amino acid sequence of the cognate peptide as defined in the aspects of the invention. _ g4 _ The original ified) es as disclosed herein can be modified by the substitution of one or more residues at different, possibly ive, sites within the peptide chain, if not otherwise stated. ably those substitutions are located at the end of the amino acid chain. Such substitutions may be of a conservative nature, for example, where one amino acid is replaced by an amino acid of r structure and characteristics, such as where a hydrophobic amino acid is replaced by another hydrophobic amino acid. Even more conservative would be replacement of amino acids of the same or similar size and chemical , such as where leucine is replaced by isoleucine. In studies of sequence variations in families of naturally occurring homologous proteins, certain amino acid substitutions are more often tolerated than others, and these are often show correlation with similarities in size, charge, polarity, and hydrophobicity between the original amino acid and its ement, and such is the basis for defining "conservative substitutions." Conservative substitutions are herein defined as exchanges within one of the following five groups: Group 1-small aliphatic, ar or slightly polar residues (Ala, Ser, Thr, Pro, Gly); Group 2-polar, negatively charged residues and their amides (Asp, Asn, Glu, Gln); Group 3-polar, positively charged residues (His, Arg, Lys); Group 4-large, aliphatic, nonpolar residues (Met, Leu, lle, Val, Cys); and Group 5-large, aromatic residues (Phe, Tyr, Trp).
Less conservative substitutions might involve the replacement of one amino acid by r that has similar characteristics but is somewhat different in size, such as replacement of an alanine by an cine residue. Highly non-conservative replacements might e substituting an acidic amino acid for one that is polar, or even for one that is basic in character. Such al" substitutions cannot, however, be dismissed as potentially ineffective since chemical effects are not totally predictable and radical substitutions might well give rise to serendipitous effects not otherwise predictable from simple chemical principles.
Of course, such substitutions may involve structures other than the common L-amino acids. Thus, D-amino acids might be substituted for the L-amino acids commonly found in the nic peptides of the invention and yet still be encompassed by the disclosure herein. In addition, non-standard amino acids (i.e., other than the common naturally ing proteinogenic amino acids) may also be used for substitution es to produce immunogens and immunogenic polypeptides according to the present invenfion. |f substitutions at more than one position are found to result in a peptide with substantially equivalent or r nic ty as defined below, then combinations of those substitutions will be tested to determine if the combined substitutions result in additive or synergistic effects on the antigenicity of the peptide. At most, no more than 4 positions within the peptide would be simultaneously substituted.
A peptide consisting essentially of the amino acid sequence as indicated herein can have one or two non-anchor amino acids (see below regarding the anchor motif) exchanged without that the ability to bind to a le of the human major ompatibility x (MHC) class-l or —II is substantially changed or is negatively affected, when compared to the non-modified peptide. In another embodiment, in a peptide consisting essentially of the amino acid sequence as indicated herein, one or two amino acids can be exchanged with their conservative exchange partners (see herein below) without that the ability to bind to a molecule of the human major ompatibility complex (MHC) class-l or —II is substantially changed, or is negatively affected, when compared to the non-modified peptide.
The amino acid residues that do not substantially contribute to interactions with the T- cell receptor can be modified by replacement with other amino acid whose incorporation does not substantially affect T-cell reactivity and does not eliminate binding to the relevant MHC. Thus, apart from the proviso given, the peptide of the invention may be any e (by which term the inventors include oligopeptide or polypeptide), which includes the amino acid sequences or a n or variant thereof as given.
Table 8: Variants and motif of the peptides according to SEQ ID NO: 3, 225, 13, 17, 84, 108, 113, 114, 147, 36, 51, 172, 54, and 57 Position 1 2 3 4 5 6 7 8 SEQ ID No 3 A L I Y N L V G Variant |_<_tO >>§§§§rrrr>>>§§§§ |_ on 1 3 4 5 6 7 8 9 SEQ ID No 225 S F A H P R K L Variant V _ 97 _ A A T V T I T A Q V Q I Q A Position 1 2 3 4 5 6 7 8 9 SEQ ID No 13 V Y T F L S S T L Variant I F I F F Position 1 2 3 4 5 6 7 8 9 SEQ ID No 17 R F T T M L S T F t Y I Y L Position 1 2 3 4 5 6 7 8 9 10 SEQ ID No 84 K L Q P A Q T A A K Variant Y I Y I R I F M Y M R M F _ 98 _ V Y V R V F T Y T R T F Position 1 2 3 4 5 6 7 8 9 10 SEQ ID No 108 V L Y P V P L E S Y Variant K | K | R | F M K M R M F V K V R V F T K T R T F Position 1 2 3 4 5 6 7 8 9 SEQ ID No 113 Q L D S N R L T Y t S S A S E S E A T A T E T E A Position 1 2 3 4 5 6 7 8 9 10 SEQ ID No 114 V M E Q S A G | M Y Variant S D _ 99 _ S D A S A T D T D A T A on 1 2 3 4 5 6 7 8 9 1O 11 SEQID No147 A P R W F P Q P T V V Variant L Position 1 2 3 4 5 6 7 8 9 SEQ ID No 36 A P A A W L R S A Variant L Position 1 2 3 4 5 6 7 8 9 SEQ ID No 51 S L R L K N V Q L Variant K K V K | K M K F K R K R V K R | K R M K R F K H K H V K H | K H M K H F WO 38257 PosMon SEQ ID N0172 K L Vafiant WO 38257 PosMon 1O 11 SEQ ID No 54 A E Vafiant PosMon SEQ ID No 57 Q E S D L R L F UUUU -
The es of the invention can be elongated by up to four amino acids, that is 1, 2, 3 or 4 amino acids can be added to either end in any combination between 4:0 and 0:4.
Combinations of the elongations according to the invention can be found in Table 9.
Table 9: Combinations of the tions of peptides of the invention C-terminus N-terminus o-xNoo-hzo—xmoois O Oor1or2 Oor1or20r3 Oor1or20r3or4 -terminus C-terminus Oor1or2 Oor1or20r3 Oor1or20r3or4 The amino acids for the elongation/extension can be the peptides of the original sequence of the protein or any other amino ). The elongation can be used to enhance the stability or solubility of the peptides.
Thus, the epitopes of the present invention may be cal to naturally occurring tumor-associated or tumor-specific epitopes or may include es that differ by no more than four residues from the reference peptide, as long as they have substantially identical antigenic activity.
In an alternative embodiment, the peptide is elongated on either or both sides by more than 4 amino acids, preferably to a total length of up to 30 amino acids. This may lead to MHC class II binding peptides. Binding to MHC class II can be tested by methods known in the art.
Accordingly, the present invention es peptides and variants of MHC class I es, wherein the peptide or variant has an overall length of between 8 and 100, preferably n 8 and 30, and most red between 8 and 14, namely 8, 9, 10, 11, 12, 13, 14 amino acids, in case of the elongated class II binding peptides the length can also be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 amino acids.
Of course, the peptide or variant according to the present invention will have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class I or II.
Binding of a peptide or a variant to a MHC complex may be tested by methods known in the art. ably, when the T cells specific for a peptide according to the t invention are tested against the substituted peptides, the peptide concentration at which the substituted peptides achieve half the maximal increase in lysis relative to background is no more than about 1 mM, preferably no more than about 1 pM, more preferably no more than about 1 nM, and still more preferably no more than about 100 pM, and most preferably no more than about 10 pM. It is also preferred that the substituted peptide be -1o4- recognized by T cells from more than one individual, at least two, and more preferably three individuals.
In a particularly preferred embodiment of the invention the peptide consists or consists essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 772.
"Consisting essentially of" shall mean that a e according to the present invention, in addition to the sequence according to any of SEQ ID NO: 1 to SEQ ID NO 772 or a variant thereof contains additional N- and/or C-terminally located stretches of amino acids that are not necessarily forming part of the peptide that functions as an epitope for MHC molecules e.
Nevertheless, these stretches can be important to provide an efficient introduction of the peptide according to the present invention into the cells. In one ment of the present invention, the e is part of a fusion protein which comprises, for example, the 80 N-terminal amino acids of the HLA-DR antigen-associated invariant chain (p33, in the following "Ii") as derived from the NCBI, GenBank Accession number X00497. In other s, the peptides of the t invention can be fused to an antibody as described , or a functional part thereof, in particular into a sequence of an antibody, so as to be specifically targeted by said antibody, or, for example, to or into an antibody that is specific for dendritic cells as bed herein.
In addition, the peptide or variant may be modified r to improve stability and/or binding to MHC molecules in order to elicit a stronger immune response. Methods for such an optimization of a peptide ce are well known in the art and include, for example, the introduction of reverse peptide bonds or non-peptide bonds.
In a reverse peptide bond amino acid residues are not joined by e (-CO-NH-) linkages but the peptide bond is reversed. Such retro-inverso peptidomimetics may be made using methods known in the art, for e such as those described in Meziere et al (1997) (Meziere et al., 1997), incorporated herein by reference. This approach involves making pseudopeptides containing changes involving the backbone, and not the orientation of side chains. Meziere et al. (Meziere et al., 1997) show that for MHC binding and T helper cell responses, these pseudopeptides are . Retro-inverse peptides, which n NH-CO bonds instead of CO-NH peptide bonds, are much more resistant to proteolysis.
A non-peptide bond is, for example, -CH2-NH, -CH28-, -CH20H2-, -CH=CH-, -COCH2-, - CH(OH)CH2-, and -CH280-. US 445 provides a method for the solid phase synthesis of non-peptide bonds (-CHz-NH) in polypeptide chains which involves ptides synthesized by standard procedures and the non-peptide bond synthesized by reacting an amino aldehyde and an amino acid in the presence of NaCNBHg.
Peptides comprising the sequences bed above may be synthesized with additional chemical groups present at their amino and/or y termini, to enhance the stability, bioavailability, and/or affinity of the peptides. For example, hydrophobic groups such as carbobenzoxyl, dansyl, or t-butyloxycarbonyl groups may be added to the peptides' amino termini. Likewise, an acetyl group or a renylmethoxy-carbonyl group may be placed at the peptides' amino i. Additionally, the hydrophobic group, t-butyloxycarbonyl, or an amido group may be added to the peptides' carboxy termini.
Further, the peptides of the ion may be synthesized to alter their steric configuration. For example, the D-isomer of one or more of the amino acid residues of the peptide may be used, rather than the usual L-isomer. Still further, at least one of the amino acid residues of the peptides of the invention may be substituted by one of the well-known non-naturally occurring amino acid residues. Alterations such as these may serve to increase the stability, bioavailability and/or binding action of the peptides of the invenfion.
Similarly, a peptide or variant of the invention may be modified chemically by reacting specific amino acids either before or after synthesis of the peptide. Examples for such cations are well known in the art and are summarized e.g. in R. Lundblad, Chemical Reagents for n Modification, 3rd ed. CRC Press, 2004 (Lundblad, 2004), which is incorporated herein by reference. Chemical modification of amino acids includes but is not limited to, cation by acylation, amidination, pyridoxylation of lysine, reductive alkylation, trinitrobenzylation of amino groups with 2,4,6-trinitrobenzene sulphonic acid (TNBS), amide modification of carboxyl groups and sulphydryl modification by mic acid oxidation of cysteine to cysteic acid, formation of mercurial derivatives, formation of mixed disulphides with other thiol compounds, reaction with maleimide, ymethylation with iodoacetic acid or iodoacetamide and carbamoylation with cyanate at alkaline pH, gh without limitation thereto. In this regard, the skilled person is referred to Chapter 15 of Current Protocols In Protein Science, Eds. Coligan et al. (John Wiley and Sons NY 000) (Coligan et al., 1995) for more extensive ology relating to chemical modification of ns.
Briefly, modification of e.g. arginyl residues in proteins is often based on the reaction of vicinal dicarbonyl compounds such as phenylglyoxal, 2,3-butanedione, and 1,2- cyclohexanedione to form an adduct. Another example is the reaction of methylglyoxal with arginine residues. Cysteine can be modified without concomitant modification of other nucleophilic sites such as lysine and histidine. As a result, a large number of reagents are available for the modification of cysteine. The websites of companies such as Sigma-Aldrich (http://www.sigma-aldrich.com) provide information on specific reagents. ive reduction of disulfide bonds in proteins is also common. Disulfide bonds can be formed and oxidized during the heat treatment of biopharmaceuticals. Woodward’s Reagent K may be used to modify specific glutamic acid es. N-(3- hylamino)propyl)-N’-ethylcarbodiimide can be used to form intra-molecular inks between a lysine residue and a glutamic acid residue. For example, diethylpyrocarbonate is a reagent for the modification of histidyl residues in proteins. ine can also be modified using 4-hydroxynonenal. The reaction of lysine residues and other d-amino groups is, for example, useful in binding of peptides to surfaces or the cross-linking of proteins/peptides. Lysine is the site of attachment of thylene)glycol and the major site of modification in the glycosylation of proteins.
Methionine residues in ns can be modified with e.g. iodoacetamide, bromoethylamine, and chloramine T.
Tetranitromethane and N-acetylimidazole can be used for the modification of tyrosyl residues. Cross-linking via the formation of dityrosine can be accomplished with hydrogen peroxide/copper ions.
Recent studies on the modification of tryptophan have used N-bromosuccinimide, 2- hydroxynitrobenzyl bromide or 3-bromomethyl(2-nitrophenylmercapto)-3H- indole (BPNS-skatole).
Successful modification of eutic proteins and peptides with PEG is often associated with an extension of circulatory half-life while cross-linking of proteins with glutaraldehyde, polyethylene glycol diacrylate and formaldehyde is used for the preparation of hydrogels. Chemical modification of allergens for immunotherapy is often achieved by carbamylation with potassium cyanate.
A peptide or t, n the e is modified or includes non-peptide bonds is a preferred embodiment of the invention.
Another embodiment of the present invention relates to a non-naturally occurring peptide wherein said peptide consists or consists essentially of an amino acid sequence according to SEQ ID No: 1 to SEQ ID No: 772 and has been synthetically ed (e.g. synthesized) as a pharmaceutically able salt. Methods to synthetically produce peptides are well known in the art. The salts of the peptides according to the present ion differ substantially from the peptides in their state(s) in vivo, as the peptides as ted in vivo are no salts. The non-natural salt form of the peptide mediates the solubility of the peptide, in particular in the context of pharmaceutical compositions comprising the peptides, e.g. the peptide vaccines as disclosed herein. A sufficient and at least substantial solubility of the peptide(s) is required in order to efficiently provide the peptides to the subject to be treated. Preferably, the salts are ceutically acceptable salts of the peptides. These salts according to the invention include alkaline and earth ne salts such as salts of the Hofmeister series comprising as anions P043', 3042', ', cr, Br', Nog', Cl04', l', 8CN' and as cations NH4+, Rb", k*, Na+, Cs*, Li*, Zn", Mg", Ca", Mn", Cu" and Ba". ularly salts are selected from (NH4)3P04, (NH4)2HP04, (NH4)H2P04, (NH4)2804, NH4CH3C00, NH4CI, NH4Br, NH4N03, NH4Cl04, NH4l, NH48CN, Rb3P04, Rb2HP04, RbH2P04, Rb2804, Rb4CH3C00, Rb4Cl, Rb4Br, Rb4N03, Rb4Cl04, Rb4l, Rb48CN, K3P04, K2HP04, KH2P04, K2804, KCH3C00, KCI, KBr, KN03, KCI04, Kl, K8CN, Na3P04, Na2HP04, NaH2P04, Na2804, NaCH3C00, NaCl, NaBr, NaN03, , Nal, Na8CN, ZnCl2 , Cs2HP04, CsH2P04, Cs2804, CsCH3C00, CsCl, CsBr, CsN03, CsCl04, Csl, Cs8CN, Li3P04, Li2HP04, LiH2P04, Li2804, LiCH3C00, LiCl, LiBr, LiN03, LiCl04, Lil, Li8CN, Cu2804, Mg3(P04)2, Mg2HP04, Mg(H2P04)2, Mg2804, Mg(CH3C00)2, MgCl2, MgBr2, Mg(N03)2, Mg(Cl04)2, Mgl2, Mg(8CN)2, MnCl2, Ca3(P04),, Ca2HP04, 04)2, Ca804, Ca(CH3C00)2, CaCl2, CaBr2, )2, Ca(Cl04)2, Cal2, Ca(8CN)2, Ba3(P04)2, Ba2HP04, Ba(H2P04)2, Ba804, Ba(CH3C00)2, BaCl2, BaBr2, Ba(N03)2, Ba(ClO4)2, Bal2, and Ba(SCN)2. Particularly preferred are NH acetate, MgCl2, KH2P04, Na2804, KCI, NaCl, and CaCl2, such as, for example, the chloride or acetate (trifluoroacetate) salts.
Generally, peptides and variants (at least those ning peptide linkages between amino acid residues) may be synthesized by the Fmoc-polyamide mode of solid-phase peptide synthesis as disclosed by Lukas et al. (Lukas et al., 1981) and by nces as cited therein. Temporary N-amino group protection is afforded by the 9- fluorenylmethyloxycarbonyl (Fmoc) group. tive cleavage of this highly base-labile protecting group is done using 20% piperidine in N, N-dimethylformamide. 8ide-chain functionalities may be protected as their butyl ethers (in the case of serine threonine and ne), butyl esters (in the case of glutamic acid and aspartic acid), xycarbonyl derivative (in the case of lysine and histidine), trityl derivative (in the case of cysteine) and 4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative (in the case of arginine). Where glutamine or asparagine are C-terminal residues, use is made of the 4,4'-dimethoxybenzhydryl group for protection of the side chain amido functionalities. The solid-phase support is based on a polydimethyl-acrylamide polymer constituted from the three monomers dimethylacrylamide (backbone-monomer), bisacryloylethylene diamine (cross linker) and acryloylsarcosine methyl ester ionalizing agent). The e-to-resin ble linked agent used is the acidlabile 4-hydroxymethyl-phenoxyacetic acid derivative. All amino acid derivatives are added as their preformed symmetrical anhydride derivatives with the exception of asparagine and glutamine, which are added using a reversed N, N-dicyclohexylcarbodiimide /1hydroxybenzotriazole mediated coupling procedure. All coupling and deprotection reactions are monitored using ninhydrin, trinitrobenzene sulphonic acid or isotin test procedures. Upon completion of synthesis, peptides are cleaved from the resin support with concomitant removal of side-chain protecting groups by treatment with 95% trifluoroacetic acid containing a 50 % scavenger mix. gers commonly used include ethanedithiol, phenol, anisole and water, the exact choice depending on the constituent amino acids of the peptide being synthesized. Also a combination of solid phase and solution phase methodologies for the synthesis of peptides is possible (see, for example, dorfer et al., 2004), and the nces as cited therein).
Trifluoroacetic acid is removed by evaporation in vacuo, with subsequent trituration with diethyl ether affording the crude peptide. Any scavengers present are removed by a simple extraction procedure which on lyophilization of the s phase affords the crude peptide free of gers. ts for peptide synthesis are generally available from e.g. Calbiochem-Novabiochem (Nottingham, UK).
Purification may be performed by any one, or a combination of, techniques such as re- crystallization, size exclusion chromatography, ion-exchange tography, hydrophobic interaction tography and (usually) reverse-phase high performance liquid chromatography using e.g. acetonitrile/water nt separation.
Analysis of peptides may be carried out using thin layer chromatography, electrophoresis, in particular capillary electrophoresis, solid phase extraction (CSPE), e-phase high performance liquid chromatography, amino-acid analysis after acid hydrolysis and by fast atom dment (FAB) mass spectrometric analysis, as well as MALDI and ESl-Q-TOF mass spectrometric analysis.
For the identification of HLA ligands by mass spectrometry, HLA molecules from shock- frozen tissue s were purified and HLA-associated peptides were isolated. The isolated peptides were separated and sequences were identified by online nano- electrospray-ionization (nanoESl) liquid chromatography-mass ometry (LC-MS) experiments. The resulting peptide sequences were verified by comparison of the ntation pattern of natural tumor-associated peptides (TUMAPs) recorded from ovarian cancer samples (N 2 80 samples) with the fragmentation patterns of corresponding tic reference peptides of identical sequences. Since the peptides were directly identified as ligands of HLA molecules of y tumors, these results e direct evidence for the natural processing and presentation of the identified peptides on primary cancer tissue obtained from 2 80 ovarian cancer patients (cf.
Example 1).
The discovery pipeline XPRESIDENT® v2.1 (see, for example, US 2013-0096016, which is hereby incorporated by reference in its entirety) allows the identification and ion of relevant over-presented peptide vaccine candidates based on direct ve quantitation of HLA-restricted peptide levels on cancer tissues in comparison to l different non-cancerous tissues and organs. This was achieved by the development of label-free differential quantitation using the acquired LC-MS data processed by a etary data is pipeline, combining algorithms for sequence identification, spectral clustering, ion counting, retention time alignment, charge state deconvolution and normalization.
HLA-peptide complexes from ovarian cancer tissue samples were purified and HLA- associated es were isolated and analyzed by LC-MS (see example 1). All TUMAPs ned in the t application were identified with this approach on primary ovarian cancer samples ming their presentation on primary ovarian cancer.
Besides presentation of the peptide, mRNA expression of the underlying gene was tested. mRNA data were obtained via RNASeq analyses of normal tissues and cancer tissues (cf. Example 2, Figure 1). Peptides which are derived from ns whose coding mRNA is highly expressed in cancer tissue, but very low or absent in vital normal tissues, were preferably included in the present invention.
The present invention provides peptides that are useful in treating cancers/tumors, preferably ovarian cancer that over- or ively present the peptides of the invention.
These peptides were shown by mass spectrometry to be naturally ted by HLA molecules on primary human ovarian cancer samples.
Many of the source gene/proteins (also designated "full-length proteins" or "underlying proteins") from which the peptides are derived were shown to be highly over-expressed in cancer compared with normal tissues — "normal tissues" in relation to this invention shall mean either healthy ovarian cells or other normal tissue cells, demonstrating a high degree of tumor association of the source genes (see Example 2). Moreover, the peptides themselves are presented on tumor tissue — "tumor tissue" in relation to this invention shall mean a sample from a patient suffering from ovarian cancer.
HLA-bound peptides can be ized by the immune system, specifically T cytes. T cells can destroy the cells presenting the recognized HLA/peptide complex, e.g. n cancer cells presenting the derived peptides.
The peptides of the t invention have been shown to be capable of stimulating T cell responses and/or are over-presented and thus can be used for the production of antibodies and/or TCRs, such as soluble TCRs, according to the present invention (see Example 3, Example 4). Furthermore, the peptides when complexed with the respective MHC can be used for the tion of antibodies and/or TCRs, in particular sTCRs, according to the present invention, as well. Respective methods are well known to the person of skill, and can be found in the respective literature as well (see also below).
Thus, the peptides of the present ion are useful for generating an immune response in a patient by which tumor cells can be destroyed. An immune response in a patient can be induced by direct administration of the described peptides or suitable precursor substances (e.g. elongated peptides, proteins, or nucleic acids encoding these peptides) to the patient, ideally in combination with an agent enhancing the immunogenicity (i.e. an adjuvant). The immune response originating from such a therapeutic vaccination can be expected to be highly specific against tumor cells because the target es of the t invention are not presented on normal tissues in comparable copy numbers, preventing the risk of red autoimmune reactions against normal cells in the patient.
The present description further relates to T-cell receptors (TCRs) sing an alpha chain and a beta chain ("alpha/beta TCRs"). Also provided are peptides according to the ion capable of binding to TCRs and antibodies when presented by an MHC molecule.
The t description also relates to fragments of the TCRs according to the invention that are capable of binding to a peptide antigen according to the present invention when presented by an HLA molecule. The term particularly relates to soluble TCR fragments, for example TCRs missing the embrane parts and/or constant regions, single chain TCRs, and fusions thereof to, for e, with lg.
The present description also relates to nucleic acids, s and host cells for expressing TCRs and peptides of the present description; and methods of using the same.
The term "T-cell receptor" viated TCR) refers to a heterodimeric molecule comprising an alpha ptide chain (alpha chain) and a beta polypeptide chain (beta chain), wherein the heterodimeric receptor is capable of binding to a peptide antigen presented by an HLA molecule. The term also includes so-called gamma/delta TCRs.
In one embodiment the description provides a method of producing a TCR as described herein, the method comprising culturing a host cell capable of expressing the TCR under conditions suitable to promote expression of the TCR.
The description in another aspect relates to methods according to the description, wherein the antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or artificial antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell or the antigen is loaded onto class I or II MHC tetramers by tetramerizing the antigen/class | or II MHC complex monomers.
The alpha and beta chains of beta TCR's, and the gamma and delta chains of gamma/delta TCRs, are generally regarded as each having two "domains", namely variable and nt domains. The variable domain consists of a concatenation of le region (V), and joining region (J). The variable domain may also include a leader region (L). Beta and delta chains may also include a diversity region (D). The alpha and beta nt domains may also include C-terminal transmembrane (TM) domains that anchor the alpha and beta chains to the cell membrane.
With respect to gamma/delta TCRs, the term "TCR gamma le domain" as used herein refers to the concatenation of the TCR gamma V (TRGV) region without leader region (L), and the TCR gamma J (TRGJ) region, and the term TCR gamma constant domain refers to the ellular TRGC region, or to a C-terminal truncated TRGC sequence. se the term "TCR delta variable domain" refers to the concatenation of the TCR delta V (TRDV) region without leader region (L) and the TCR delta D/J (TRDD/TRDJ) region, and the term "TCR delta constant domain" refers to the extracellular TRDC region, or to a C-terminal truncated TRDC sequence.
TCRs of the present ption preferably bind to an peptide-HLA molecule complex with a g affinity (KD) of about 100 uM or less, about 50 uM or less, about 25 uM or less, or about 10 uM or less. More preferred are high affinity TCRs having binding affinities of about 1 uM or less, about 100 nM or less, about 50 nM or less, about 25 nM or less. Non-limiting examples of preferred binding affinity ranges for TCRs of the t invention include about 1 nM to about 10 nM; about 10 nM to about 20 nM; about 20 nM to about 30 nM; about 30 nM to about 40 nM; about 40 nM to about 50 nM; about 50 nM to about 60 nM; about 60 nM to about 70 nM; about 70 nM to about 80 nM; about 80 nM to about 90 nM; and about 90 nM to about 100 nM.
As used herein in connect with TCRs of the present description, "specific binding" and grammatical variants thereof are used to mean a TCR having a binding affinity (KD) for a peptide-HLA molecule complex of 100 uM or less.
Alpha/beta heterodimeric TCRs of the present description may have an introduced disulfide bond between their nt s. Preferred TCRs of this type include those which have a TRAC constant domain ce and a TRBC1 or TRBCZ constant domain sequence except that Thr 48 of TRAC and Ser 57 of TRBCl or TRBCZ are replaced by cysteine residues, the said cysteines forming a disulfide bond between the TRAC constant domain sequence and the TRBC1 or TRBCZ constant domain sequence of the TCR.
With or without the introduced inter-chain bond mentioned above, alpha/beta hetero- dimeric TCRs of the present description may have a TRAC nt domain sequence and a TRBCl or TRBCZ constant domain sequence, and the TRAC nt domain sequence and the TRBCl or TRBCZ constant domain sequence of the TCR may be linked by the native disulfide bond between Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBCl or TRBCZ.
TCRs of the present description may comprise a detectable label selected from the group consisting of a radionuclide, a fluorophore and biotin. TCRs of the present description may be ated to a therapeutically active agent, such as a radionuclide, a chemotherapeutic agent, or a toxin.
In an embodiment, a TCR of the present description having at least one mutation in the alpha chain and/or having at least one mutation in the beta chain has ed glycosylation compared to the unmutated TCR.
In an embodiment, a TCR comprising at least one mutation in the TCR alpha chain and/or TCR beta chain has a g affinity for, and/or a binding half-life for, a peptide- HLA molecule complex, which is at least double that of a TCR comprising the unmutated TCR alpha chain and/or unmutated TCR beta chain. Affinity-enhancement of tumor-specific TCRs, and its exploitation, relies on the existence of a window for optimal TCR affinities. The nce of such a window is based on observations that TCRs ic for HLA-A2-restricted pathogens have KD values that are generally about 10- fold lower when compared to TCRs specific for —restricted tumor-associated self-antigens. It is now known, although tumor antigens have the potential to be immunogenic, because tumors arise from the individual’s own cells only mutated proteins or proteins with altered ational processing will be seen as foreign by the immune system. Antigens that are upregulated or overexpressed (so called self- antigens) will not arily induce a functional immune response against the tumor: T-cells expressing TCRs that are highly ve to these antigens will have been negatively selected within the thymus in a process known as central tolerance, meaning that only T-cells with low-affinity TCRs for self-antigens remain. Therefore, affinity of TCRs or variants of the present description to pepides can be enhanced by s well known in the art.
The present description further relates to a method of identifying and ing a TCR according to the present description, said method comprising incubating PBMCs from HLA-A*02-negative healthy donors with, for example, A2/peptide monomers, incubating the PBMCs with tetramer-phycoerythrin (PE) and isolating the high avidity T-cells by fluo-rescence activated cell sorting (FACS)—Calibur analysis.
The present description further relates to a method of identifying and isolating a TCR according to the present description, said method comprising obtaining a transgenic mouse with the entire human TCRdB gene loci (1.1 and 0.7 Mb), whose T-cells express a diverse human TCR repertoire that sates for mouse TCR deficiency, immunizing the mouse with a peptide, incubating PBMCs obtained from the transgenic mice with tetramer—phycoerythrin (PE), and isolating the high avidity T-cells by fluorescence activated cell sorting (FACS)—Calibur analysis.
In one aspect, to obtain T-cells expressing TCRs of the present description, nucleic acids encoding TCR-alpha and/or TCR-beta chains of the present description are cloned into expression vectors, such as gamma retrovirus or lentivirus. The inant viruses are generated and then tested for functionality, such as antigen specificity and functional avidity. An t of the final product is then used to transduce the target T- cell population (generally purified from patient PBMCs), which is expanded before infusion into the patient.
In another aspect, to obtain T-cells expressing TCRs of the present ption, TCR RNAs are synthesized by techniques known in the art, e.g., in vitro transcription sys- tems. The in vitro-synthesized TCR RNAs are then introduced into primary CD8+ T-cells obtained from y donors by electroporation to re-express tumor specific TCR-alpha and/or TCR-beta chains.
To increase the expression, nucleic acids ng TCRs of the present description may be operably linked to strong promoters, such as retroviral long terminal s (LTRs), cytomegalovirus (CMV), murine stem cell virus (MSCV) U3, oglycerate kinase (PGK), n, ubiquitin, and a simian virus 40 (SV40)/CD43 ite promoter, elongation factor (EF)—1a and the spleen focus-forming virus (SFFV) WO 38257 promoter. In a preferred embodiment, the promoter is heterologous to the nucleic acid being expressed.
In addition to strong promoters, TCR expression cassettes of the present description may contain additional elements that can enhance transgene expression, including a l polypurine tract (cPPT), which promotes the nuclear translocation of lentiviral constructs (Follenzi et al., 2000), and the woodchuck hepatitis virus posttranscriptional regulatory element (wPRE), which ses the level of transgene expression by increasing RNA stability (Zufferey et al., 1999).
The alpha and beta chains of a TCR of the present invention may be d by nucleic acids located in separate s, or may be encoded by polynucleotides located in the same vector.
Achieving high-level TCR surface sion requires that both the TCR-alpha and TCR-beta chains of the introduced TCR be transcribed at high levels. To do so, the TCR-alpha and TCR-beta chains of the present description may be cloned into ronic constructs in a single vector, which has been shown to be capable of over- coming this obstacle. The use of a viral intraribosomal entry site (IRES) between the TCR-alpha and TCR-beta chains results in the nated expression of both chains, because the TCR-alpha and TCR-beta chains are ted from a single transcript that is broken into two proteins during translation, ensuring that an equal molar ratio of TCR-alpha and TCR-beta chains are produced tt et al., 2009).
Nucleic acids encoding TCRs of the t description may be codon optimized to increase expression from a host cell. Redundancy in the genetic code allows some amino acids to be encoded by more than one codon, but certain codons are less "op- timal" than others because of the relative availability of matching tRNAs as well as other factors (Gustafsson et al., 2004). Modifying the TCR-alpha and TCR-beta gene sequences such that each amino acid is encoded by the optimal codon for mammalian gene expression, as well as ating mRNA instability motifs or cryptic splice sites, has been shown to significantly enhance TCR-alpha and TCR-beta gene expression ten et al., 2006).
Furthermore, mispairing between the introduced and endogenous TCR chains may result in the acquisition of specificities that pose a significant risk for autoimmunity. For example, the formation of mixed TCR dimers may reduce the number of CD3 molecules available to form properly paired TCR complexes, and therefore can significantly decrease the functional y of the cells expressing the introduced TCR l et al., 2007).
To reduce mispairing, the C-terminus domain of the introduced TCR chains of the present description may be modified in order to promote interchain ty, while de- creasing the ability of the introduced chains to pair with the endogenous TCR. These strategies may include replacing the human TCR-alpha and TCR-beta C-terminus domains with their murine rparts ized C-terminus domain); generating a second hain disulfide bond in the C-terminus domain by introducing a second cysteine residue into both the TCR-alpha and TCR-beta chains of the introduced TCR (cysteine modification); swapping interacting residues in the TCR-alpha and TCR-beta chain C-terminus domains -in-hole"); and fusing the variable domains of the TCR-alpha and TCR-beta chains directly to CD3C (CD3C fusion) (Schmitt et al., 2009).
In an embodiment, a host cell is engineered to express a TCR of the present description. In preferred embodiments, the host cell is a human T-cell or T-cell progenitor. In some embodiments the T-cell or T-cell progenitor is obtained from a cancer t. In other embodiments the T-cell or T-cell progenitor is obtained from a healthy donor. Host cells of the present description can be allogeneic or autologous with respect to a patient to be treated. In one ment, the host is a gamma/delta T-cell transformed to express an alpha/beta TCR.
A "pharmaceutical composition" is a composition suitable for administration to a human being in a medical setting. Preferably, a pharmaceutical composition is sterile and produced according to GMP guidelines.
The pharmaceutical compositions comprise the peptides either in the free form or in the form of a pharmaceutically acceptable salt (see also above). As used herein, a pharmaceutically acceptable salt" refers to a derivative of the disclosed peptides wherein the peptide is modified by making acid or base salts of the agent. For example, acid salts are prepared from the free base (typically wherein the neutral form of the drug has a neutral —NH2 group) involving reaction with a suitable acid. Suitable acids for preparing acid salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as nic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid phosphoric acid and the like. Conversely, preparation of basic salts of acid moieties which may be present on a peptide are prepared using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, m hydroxide, trimethylamine or the like.
In an especially preferred embodiment, the pharmaceutical compositions comprise the es as salts of acetic acid (acetates), trifluoro acetates or hydrochloric acid (chlorides).
Preferably, the ment of the present ion is an immunotherapeutic such as a e. It may be administered directly into the patient, into the affected organ or systemically i.d., i.m., s.c., i.p. and iv, or applied ex vivo to cells derived from the t or a human cell line which are uently administered to the patient, or used in vitro to select a ulation of immune cells derived from the t, which are then re-administered to the patient. If the nucleic acid is administered to cells in vitro, it may be useful for the cells to be transfected so as to co-express immune-stimulating WO 38257 cytokines, such as interleukin-2. The peptide may be substantially pure, or combined with an immune-stimulating adjuvant (see below) or used in ation with immune- stimulatory cytokines, or be administered with a suitable delivery system, for example liposomes. The peptide may also be conjugated to a suitable carrier such as keyhole limpet haemocyanin (KLH) or mannan (see WO 95/18145 and (Longenecker et al., 1993)). The e may also be , may be a fusion protein, or may be a hybrid molecule. The peptides whose sequence is given in the present invention are expected to ate CD4 or CD8 T cells. r, stimulation of CD8 T cells is more efficient in the presence of help provided by CD4 T-helper cells. Thus, for MHC Class | es that stimulate CD8 T cells the fusion partner or sections of a hybrid molecule suitably provide epitopes which ate CD4-positive T cells. CD4- and CD8-stimulating epitopes are well known in the art and include those identified in the present invention.
In one aspect, the vaccine comprises at least one peptide having the amino acid sequence set forth SEQ ID No. 1 to SEQ ID No. 772, and at least one additional peptide, preferably two to 50, more preferably two to 25, even more preferably two to 20 and most preferably two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen or eighteen peptides. The peptide(s) may be d from one or more specific TAAs and may bind to MHC class I molecules.
A further aspect of the invention provides a c acid (for example a cleotide) encoding a peptide or peptide variant of the invention. The polynucleotide may be, for example, DNA, cDNA, PNA, RNA or combinations thereof, either single- and/or double- stranded, or native or stabilized forms of polynucleotides, such as, for example, cleotides with a orothioate backbone and it may or may not contain introns so long as it codes for the peptide. Of course, only peptides that contain naturally occurring amino acid residues joined by naturally occurring peptide bonds are encodable by a polynucleotide. A still further aspect of the invention provides an expression vector capable of expressing a polypeptide according to the invention.
A variety of methods have been developed to link polynucleotides, especially DNA, to vectors for example via complementary cohesive termini. For instance, complementary homopolymer tracts can be added to the DNA segment to be inserted to the vector DNA. The vector and DNA segment are then joined by hydrogen bonding between the complementary homopolymeric tails to form recombinant DNA molecules.
Synthetic linkers containing one or more restriction sites provide an alternative method of joining the DNA segment to vectors. tic linkers containing a variety of ction endonuclease sites are commercially available from a number of sources including ational Biotechnologies Inc. New Haven, CN, USA.
A desirable method of modifying the DNA encoding the polypeptide of the invention employs the polymerase chain reaction as disclosed by Saiki RK, et al. (Saiki et al., 1988). This method may be used for introducing the DNA into a suitable vector, for example by engineering in suitable restriction sites, or it may be used to modify the DNA in other useful ways as is known in the art. If viral vectors are used, pox- or adenovirus vectors are preferred.
The DNA (or in the case of retroviral vectors, RNA) may then be expressed in a le host to produce a polypeptide comprising the e or variant of the invention. Thus, the DNA encoding the peptide or variant of the invention may be used in accordance with known techniques, appropriately modified in view of the teachings ned herein, to construct an expression , which is then used to transform an appropriate host cell for the sion and production of the polypeptide of the invention. Such techniques include those disclosed, for e, in US 4,440,859, 4,530,901, 4,582,800, 4,677,063, 4,678,751, 4,704,362, 4,710,463, 006, 075, and 4,810,648.
The DNA (or in the case of retroviral vectors, RNA) encoding the polypeptide constituting the compound of the invention may be joined to a wide variety of other DNA sequences for introduction into an riate host. The companion DNA will depend upon the nature of the host, the manner of the introduction of the DNA into the host, and whether episomal maintenance or integration is desired.
Generally, the DNA is inserted into an expression vector, such as a plasmid, in proper orientation and correct reading frame for sion. If necessary, the DNA may be linked to the appropriate transcriptional and translational regulatory control nucleotide sequences recognized by the desired host, although such controls are lly available in the expression vector. The vector is then introduced into the host through standard techniques. Generally, not all of the hosts will be transformed by the vector.
Therefore, it will be necessary to select for transformed host cells. One ion technique involves orating into the expression vector a DNA sequence, with any necessary control ts, that codes for a selectable trait in the transformed cell, such as antibiotic ance.
Alternatively, the gene for such selectable trait can be on another vector, which is used to co-transform the desired host cell.
Host cells that have been transformed by the recombinant DNA of the invention are then cultured for a sufficient time and under appropriate conditions known to those skilled in the art in view of the teachings sed herein to permit the expression of the ptide, which can then be recovered.
Many expression systems are known, including bacteria (for example E. coli and Bacillus subtilis), yeasts (for example Saccharomyces cerevisiae), filamentous fungi (for example Aspergillus spec.), plant cells, animal cells and insect cells. Preferably, the system can be mammalian cells such as CHO cells available from the ATCC Cell Biology tion.
A l mammalian cell vector plasmid for constitutive expression comprises the CMV or SV4O promoter with a suitable poly A tail and a resistance marker, such as neomycin.
One example is pSVL available from Pharmacia, away, NJ, USA. An example of WO 38257 an inducible mammalian expression vector is pMSG, also available from Pharmacia.
Useful yeast plasmid vectors are pRS403-406 and pRS413-416 and are generally available from Stratagene Cloning s, La Jolla, CA 92037, USA. Plasmids pRS403, , pRS405 and pRS406 are Yeast ating plasmids (Ylps) and incorporate the yeast selectable markers HIS3, TRP1, LEU2 and URA3. ds pRS413-416 are Yeast Centromere ds (chs). CMV promoter-based vectors (for example from Sigma-Aldrich) provide transient or stable expression, asmic expression or secretion, and N-terminal or C-terminal tagging in various combinations of FLAG, 3xFLAG, c-myc or MAT. These fusion proteins allow for detection, purification and analysis of inant protein. Dual-tagged fusions provide flexibility in detection.
The strong human cytomegalovirus (CMV) promoter regulatory region drives constitutive protein expression levels as high as 1 mg/L in COS cells. For less potent cell lines, protein levels are typically ~0.1 mg/L. The presence of the SV4O replication origin will result in high levels of DNA replication in SV4O replication permissive COS cells. CMV vectors, for example, can contain the pMB1 (derivative of ) origin for replication in bacterial cells, the b-lactamase gene for ampicillin resistance selection in bacteria, hGH polyA, and the f1 . Vectors containing the pre-pro-trypsin leader (PPT) sequence can direct the secretion of FLAG fusion proteins into the culture medium for purification using ANTI-FLAG dies, resins, and plates. Other vectors and expression systems are well known in the art for use with a variety of host cells.
In another embodiment two or more peptides or peptide variants of the invention are encoded and thus expressed in a successive order (similar to "beads on a string" constructs). In doing so, the peptides or peptide variants may be linked or fused together by stretches of linker amino acids, such as for example LLLLLL, or may be linked without any additional peptide(s) between them. These ucts can also be used for cancer therapy, and may induce immune responses both involving MHC l and MHC II.
The present invention also relates to a host cell transformed with a polynucleotide vector construct of the present invention. The host cell can be either prokaryotic or eukaryotic. Bacterial cells may be preferred prokaryotic host cells in some circumstances and typically are a strain of E. coli such as, for example, the E. coli strains DH5 available from Bethesda Research Laboratories Inc., Bethesda, MD, USA, and RR1 available from the American Type Culture tion (ATCC) of Rockville, MD, USA (No ATCC 31343). Preferred eukaryotic host cells include yeast, insect and mammalian cells, preferably vertebrate cells such as those from a mouse, rat, monkey or human fibroblastic and colon cell lines. Yeast host cells e YPH499, YPH500 and YPH501, which are generally available from Stratagene Cloning Systems, La Jolla, CA 92037, USA. Preferred mammalian host cells include Chinese hamster ovary (CHO) cells available from the ATCC as CCL61, NIH Swiss mouse embryo cells NIH/3T3 available from the ATCC as CRL 1658, monkey kidney-derived COS-1 cells available from the ATCC as CRL 1650 and 293 cells which are human embryonic kidney cells. red insect cells are Sf9 cells which can be transfected with baculovirus expression vectors. An overview regarding the choice of suitable host cells for sion can be found in, for example, the textbook of Paulina Balbas and a Lorence ds in Molecular Biology Recombinant Gene Expression, s and Protocols," Part One, Second Edition, ISBN 978588299, and other literature known to the person of skill.
Transformation of appropriate ce|| hosts with a DNA construct of the present invention is accomplished by well-known methods that lly depend on the type of vector used.
With regard to transformation of prokaryotic host cells, see, for example, Cohen et aI.
(Cohen et al., 1972) and (Green and Sambrook, 2012) . Transformation of yeast cells is described in n et aI. (Sherman et al., 1986) . The method of Beggs (Beggs, 1978) is also useful. With regard to vertebrate cells, reagents useful in transfecting such cells, for example calcium phosphate and DEAE-dextran or liposome formulations, are available from gene Cloning Systems, or Life logies Inc, Gaithersburg, MD 20877, USA. Electroporation is also useful for transforming and/or transfecting ce||s WO 38257 and is well known in the art for transforming yeast cell, bacterial cells, insect cells and vertebrate cells.
Successfully transformed cells, i.e. cells that contain a DNA construct of the present invention, can be identified by well-known techniques such as PCR. Alternatively, the presence of the protein in the supernatant can be detected using antibodies.
It will be appreciated that certain host cells of the invention are useful in the preparation of the es of the invention, for example bacterial, yeast and insect cells. r, other host cells may be useful in certain therapeutic s. For example, antigen- presenting cells, such as tic cells, may usefully be used to express the peptides of the invention such that they may be loaded into riate MHC molecules. Thus, the current invention provides a host cell sing a nucleic acid or an expression vector according to the invention.
In a preferred embodiment the host cell is an antigen presenting cell, in particular a dendritic cell or antigen presenting cell. APCs loaded with a recombinant fusion protein containing prostatic acid phosphatase (PAP) were approved by the U.S. Food and Drug Administration (FDA) on April 29, 2010, to treat asymptomatic or minimally symptomatic metastatic HRPC (Sipuleucel-T) (Rini et al., 2006; Small et al., 2006).
A r aspect of the invention provides a method of producing a peptide or its variant, the method comprising culturing a host cell and isolating the peptide from the host cell or its culture medium.
In another embodiment, the peptide, the nucleic acid or the expression vector of the invention are used in medicine. For example, the peptide or its variant may be prepared for intravenous (iv) injection, sub-cutaneous (s.c.) ion, ermal (i.d.) injection, intraperitoneal (i.p.) injection, intramuscular (i.m.) injection. Preferred methods of peptide injection e s.c., i.d., i.p., i.m., and iv Preferred methods of DNA injection include i.d., i.m., s.c., i.p. and iv Doses of e.g. between 50 pg and 1.5 mg, preferably 125 pg to 500 pg, of peptide or DNA may be given and will depend on the respective peptide or DNA. Dosages of this range were successfully used in previous trials (Walter et al., 2012).
The polynucleotide used for active vaccination may be ntially pure, or contained in a suitable vector or delivery system. The nucleic acid may be DNA, cDNA, PNA, RNA or a combination thereof. Methods for designing and introducing such a nucleic acid are well known in the art. An oven/iew is provided by e.g. Teufel et al. (Teufel et al., 2005).
Polynucleotide vaccines are easy to e, but the mode of action of these vectors in inducing an immune response is not fully understood. Suitable vectors and delivery systems include viral DNA and/or RNA, such as systems based on irus, vaccinia virus, retroviruses, herpes virus, adeno-associated virus or s containing elements of more than one virus. Non-viral delivery s include ic lipids and cationic polymers and are well known in the art of DNA delivery. Physical delivery, such as via a "gene-gun" may also be used. The peptide or peptides encoded by the nucleic acid may be a fusion protein, for example with an epitope that stimulates T cells for the respective opposite CDR as noted above.
The ment of the invention may also include one or more adjuvants. Adjuvants are nces that non-specifically enhance or potentiate the immune response (e.g., immune responses mediated by CD8—positive T cells and helper-T (TH) cells to an antigen, and would thus be considered useful in the medicament of the present invention. Suitable adjuvants include, but are not limited to, 1018 ISS, aluminum salts, AMPLIVAX®, A815, BCG, CP-870,893, CpG7909, CyaA, dSLlM, flagellin or TLR5 ligands derived from flagellin, FLT3 , GM-CSF, |C30, |C31, lmiquimod (ALDARA®), resiquimod, lmuFact |MP321, Interleukins as |L-2, |L-13, |L-21, eron- alpha or -beta, or pegylated derivatives thereof, IS Patch, ISS, ISCOMATRIX, lSCOMs, Juvlmmune®, LipoVac, MALP2, MF59, monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, water-in-oil and oil-in-water emulsions, OK-432, OM-174, OMMP-EC, ONTAK, OspA, PepTel® vector , actid co-glycolid) [PLG]—based and dextran microparticles, talactoferrin SRL172, Virosomes and other Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, Aquila's 0821 stimulon, which is derived from saponin, mycobacterial extracts and synthetic bacterial cell wall mimics, and other proprietary adjuvants such as Ribi's Detox, Quil, or Superfos. Adjuvants such as Freund's or GM-CSF are red. Several immunological adjuvants (e.g., MF59) specific for tic cells and their preparation have been described previously (Allison and Krummel, 1995). Also cytokines may be used. l cytokines have been directly linked to influencing dendritic cell migration to lymphoid s (e.g., TNF-), accelerating the maturation of tic cells into efficient antigen-presenting cells for T-lymphocytes (e.g., GM-CSF, lL-1 and lL-4) (U.S. Pat. No. 5,849,589, specifically incorporated herein by reference in its entirety) and acting as immunoadjuvants (e.g., lL-12, lL-15, lL-23, lL-7, lFN-alpha. lFN-beta) (Gabrilovich et al., 1996).
CpG immunostimulatory oligonucleotides have also been reported to enhance the effects of adjuvants in a vaccine setting. t being bound by , CpG ucleotides act by activating the innate daptive) immune system via Toll-like receptors (TLR), mainly TLR9. CpG triggered TLR9 activation enhances antigenspecific l and cellular responses to a wide variety of antigens, including peptide or n antigens, live or killed s, dendritic cell vaccines, autologous cellular vaccines and ccharide conjugates in both prophylactic and therapeutic vaccines.
More importantly it enhances tic cell maturation and differentiation, resulting in enhanced activation of TH1 cells and strong cytotoxic T-lymphocyte (CTL) generation, even in the e of CD4 T cell help. The TH1 bias induced by TLR9 stimulation is maintained even in the presence of vaccine adjuvants such as alum or incomplete Freund’s adjuvant (IFA) that normally promote a TH2 bias. CpG oligonucleotides show even greater adjuvant activity when formulated or co-administered with other adjuvants or in formulations such as microparticles, nanoparticles, lipid emulsions or similar formulations, which are especially necessary for inducing a strong response when the antigen is relatively weak. They also accelerate the immune response and enable the antigen doses to be reduced by approximately two orders of magnitude, with comparable antibody responses to the full-dose vaccine without CpG in some experiments (Krieg, 2006). US 6,406,705 Bi describes the combined use of CpG oligonucleotides, non-nucleic acid adjuvants and an antigen to induce an antigen- specific immune response. A CpG TLR9 antagonist is dSLlM (double Stem Loop |mmunomodu|ator) by Mologen (Berlin, Germany) which is a preferred component of the pharmaceutical composition of the present invention. Other TLR binding molecules such as RNA binding TLR 7, TLR 8 and/or TLR 9 may also be used.
Other examples for useful adjuvants include, but are not limited to chemically modified Cst (e.g. CpR, ldera), dsRNA analogues such as Poly(l:C) and derivates thereof (e.g.
AmpliGen®, Hiltonol®, poly-(ICLC), poly(lC-R), poly(l:C12U), non-CpG bacterial DNA or RNA as well as active small molecules and antibodies such as cyclophosphamide, nib, Bevacizumab®, ex, NCX-4016, sildenafil, tadalafil, vardenafil, sorafenib, lomide, temsirolimus, XL-999, CP-547632, pazopanib, VEGF Trap, ZD2171, AZD2171, anti-CTLA4, other antibodies targeting key structures of the immune system (e.g. anti-CD40, anti-TGFbeta, anti-TNFalpha receptor) and 8058175, which may act therapeutically and/or as an adjuvant. The s and concentrations of adjuvants and additives useful in the context of the present invention can readily be ined by the skilled artisan without undue experimentation.
Preferred adjuvants are anti-CD40, imiquimod, resiquimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab, interferon-alpha, CpG oligonucleotides and derivates, poly-(|:C) and derivates, RNA, sildenafil, and particulate formulations with PLG or virosomes.
In a red embodiment, the pharmaceutical ition according to the ion the nt is selected from the group consisting of colony-stimulating factors, such as Granulocyte Macrophage Colony Stimulating Factor F, sargramostim), cyclophosphamide, imiquimod, resiquimod, and interferon-alpha.
In a preferred embodiment, the ceutical ition according to the invention the adjuvant is selected from the group consisting of colony-stimulating factors, such as Granulocyte Macrophage Colony Stimulating Factor F, mostim), cyclophosphamide, imiquimod and resiquimod. In a preferred embodiment of the pharmaceutical composition according to the invention, the adjuvant is cyclophosphamide, imiquimod or resiquimod. Even more preferred adjuvants are Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, poly- ICLC (Hiltonol®) and anti-CD40 mAB, or combinations thereof.
This composition is used for parenteral administration, such as subcutaneous, intradermal, intramuscular or oral administration. For this, the peptides and optionally other molecules are dissolved or ded in a pharmaceutically able, preferably aqueous carrier. In addition, the composition can contain excipients, such as buffers, g agents, blasting agents, diluents, flavors, lubricants, etc. The peptides can also be stered together with immune stimulating substances, such as nes. An extensive listing of excipients that can be used in such a composition, can be, for example, taken from A. Kibbe, Handbook of Pharmaceutical Excipients (Kibbe, 2000). The composition can be used for a prevention, prophylaxis and/or therapy of adenomatous or ous diseases. Exemplary formulations can be found in, for e, EP2112253.
It is important to realize that the immune response triggered by the e according to the invention attacks the cancer in different cell-stages and different stages of development. Furthermore different cancer associated ing pathways are attacked.
This is an advantage over vaccines that address only one or few targets, which may cause the tumor to easily adapt to the attack (tumor escape). Furthermore, not all individual tumors express the same pattern of antigens. Therefore, a combination of several tumor-associated peptides ensures that every single tumor bears at least some of the targets. The composition is designed in such a way that each tumor is expected to express l of the antigens and cover several independent pathways necessary for tumor growth and maintenance. Thus, the vaccine can easily be used "off-the—shelf" for a larger patient population. This means that a pre-selection of patients to be treated with the vaccine can be restricted to HLA , does not require any additional biomarker ments for n expression, but it is still d that several targets are simultaneously attacked by the induced immune response, which is important for efficacy (Banchereau et al., 2001; Walter et al., 2012).
As used herein, the term "scaffold" refers to a le that specifically binds to an (e.g. antigenic) determinant. In one embodiment, a scaffold is able to direct the entity to which it is attached (e.g. a (second) antigen binding moiety) to a target site, for example to a specific type of tumor cell or tumor stroma bearing the antigenic determinant (e.g. the complex of a peptide with MHC, according to the application at hand). In another embodiment a scaffold is able to activate signaling through its target antigen, for example a T cell receptor complex antigen. Scaffolds include but are not limited to antibodies and fragments thereof, antigen binding s of an antibody, sing an antibody heavy chain variable region and an antibody light chain variable region, g proteins sing at least one ankyrin repeat motif and single domain antigen binding (SDAB) molecules, aptamers, (soluble) TCRs and (modified) cells such as allogenic or autologous T cells. To assess whether a le is a scaffold binding to a target, g assays can be performed.
"Specific" g means that the scaffold binds the peptide-MHC-complex of interest better than other naturally occurring peptide-MHC-complexes, to an extent that a ld armed with an active molecule that is able to kill a cell bearing the specific target is not able to kill another cell without the specific target but presenting other peptide-MHC complex(es). Binding to other peptide-MHC complexes is irrelevant if the peptide of the cross-reactive peptide-MHC is not naturally occurring, i.e. not derived from the human HLA-peptidome. Tests to assess target cell killing are well known in the art. They should be performed using target cells (primary cells or cell lines) with unaltered peptide-MHC presentation, or cells loaded with peptides such that naturally occurring e-MHC levels are reached.
Each scaffold can comprise a labelling which provides that the bound scaffold can be detected by determining the presence or absence of a signal provided by the label. For example, the scaffold can be labelled with a fluorescent dye or any other applicable cellular marker molecule. Such marker molecules are well known in the art. For example a fluorescence-labelling, for example provided by a scence dye, can provide a visualization of the bound aptamer by fluorescence or laser scanning microscopy or flow cytometry.
Each scaffold can be conjugated with a second active molecule such as for example IL- 21, anti-CD3, and anti-CD28. For further ation on polypeptide scaffolds see for e the background section of WO 71978A1 and the references cited therein.
The present invention further relates to aptamers. Aptamers (see for example WO 2014/191359 and the literature as cited therein) are short single-stranded nucleic acid molecules, which can fold into defined three-dimensional structures and ize specific target structures. They have appeared to be suitable alternatives for developing ed therapies. Aptamers have been shown to selectively bind to a variety of complex targets with high ty and icity.
Aptamers recognizing cell surface located molecules have been identified within the past decade and provide means for developing diagnostic and therapeutic approaches.
Since aptamers have been shown to s almost no toxicity and immunogenicity they are promising candidates for biomedical applications. lndeed aptamers, for example prostate-specific membrane-antigen recognizing aptamers, have been successfully employed for targeted ies and shown to be functional in xenograft in vivo models. Furthermore, rs recognizing ic tumor cell lines have been idenfified.
DNA aptamers can be selected to reveal broad-spectrum recognition properties for various cancer cells, and particularly those derived from solid tumors, while non- tumorigenic and primary healthy cells are not recognized. If the identified aptamers recognize not only a specific tumor sub-type but rather interact with a series of tumors, this renders the aptamers applicable as so-called spectrum diagnostics and therapeutics.
Further, investigation of cell-binding behavior with flow cytometry showed that the aptamers revealed very good apparent affinities that are within the nanomolar range.
Aptamers are useful for diagnostic and therapeutic purposes. Further, it could be shown that some of the aptamers are taken up by tumor cells and thus can function as molecular vehicles for the targeted delivery of anti-cancer agents such as siRNA into tumor cells.
Aptamers can be selected against complex targets such as cells and tissues and complexes of the peptides comprising, ably consisting of, a sequence according to any of SEQ ID NO 1 to SEQ ID NO 772, according to the ion at hand with the MHC molecule, using the cell-SELEX (Systematic ion of Ligands by Exponential enrichment) que.
The peptides of the present invention can be used to generate and develop specific antibodies against MHC/peptide complexes. These can be used for therapy, ing toxins or ctive substances to the diseased . Another use of these antibodies can be targeting radionuclides to the diseased tissue for imaging purposes such as PET. This use can help to detect small metastases or to determine the size and precise localization of diseased tissues.
Therefore, it is a further aspect of the invention to provide a method for producing a recombinant dy specifically binding to a human major histocompatibility x (MHC) class I or II being complexed with a HLA-restricted antigen (preferably a e according to the present invention), the method comprising: immunizing a genetically engineered non-human mammal comprising cells expressing said human major histocompatibility complex (MHC) class I or II with a soluble form of a MHC class I or II molecule being complexed with said HLA-restricted antigen; isolating mRNA molecules from antibody producing cells of said non-human mammal; producing a phage display library displaying protein les encoded by said mRNA molecules; and isolating at least one phage from said phage display y, said at least one phage displaying said antibody ically binding to said human major histocompatibility complex (MHC) class I or II being complexed with said HLA-restricted antigen.
It is thus a further aspect of the invention to provide an antibody that specifically binds to a human major histocompatibility complex (MHC) class I or II being complexed with a HLA-restricted antigen, wherein the antibody preferably is a polyclonal antibody, monoclonal antibody, cific antibody and/or a chimeric antibody.
Respective methods for producing such dies and single chain class I major histocompatibility complexes, as well as other tools for the production of these antibodies are disclosed in 03/070752, and in ations (Cohen et al., 2003a; Cohen et al., 2003b; Denkberg et al., 2003), which for the purposes of the present invention are all explicitly incorporated by reference in their entireties.
Preferably, the dy is binding with a binding affinity of below 20 nanomolar, ably of below 10 lar, to the complex, which is also regarded as "specific" in the t of the present invention.
The present ion relates to a peptide comprising a sequence that is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 772, or a variant thereof which is at least 88% gous (preferably identical) to SEQ ID NO: 1 to SEQ ID NO: 772 or a variant thereof that induces T cells cross-reacting with said peptide, wherein said peptide is not the underlying full-length polypeptide.
The present invention further relates to a peptide comprising a sequence that is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 772 or a variant thereof which is at least 88% homologous (preferably identical) to SEQ ID NO: 1 to SEQ ID NO: 772, wherein said peptide or variant has an overall length of between 8 and 100, preferably between 8 and 30, and most preferred between 8 and 14 amino acids.
The present invention further relates to the peptides according to the invention that have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II.
The present invention r relates to the peptides according to the invention wherein the e consists or consists essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 772.
The present invention further relates to the peptides according to the invention, wherein the peptide is (chemically) ed and/or includes non-peptide bonds.
The present invention further relates to the es according to the ion, wherein the peptide is part of a fusion protein, in particular comprising N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii), or wherein the e is fused to (or into) an antibody, such as, for example, an antibody that is specific for dendritic cells.
The present ion further relates to a nucleic acid, ng the peptides ing to the invention, provided that the peptide is not the complete (full) human protein.
The present invention further relates to the nucleic acid according to the invention that is DNA, cDNA, PNA, RNA or combinations thereof.
The present invention further relates to an expression vector capable of sing a nucleic acid according to the present invention.
The present invention further relates to a peptide according to the present invention, a nucleic acid according to the present invention or an expression vector according to the present invention for use in medicine, in particular in the treatment of ovarian cancer.
The present invention further relates to a host cell comprising a nucleic acid according to the invention or an expression vector according to the invention.
The t invention further relates to the host cell according to the present ion that is an n presenting cell, and preferably a dendritic cell.
The present invention r relates to a method of producing a peptide according to the present invention, said method comprising culturing the host cell according to the present invention, and isolating the peptide from said host cell or its culture medium.
The present invention further relates to the method according to the present invention, where-in the antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell.
The present invention r relates to the method according to the invention, wherein the antigen-presenting cell comprises an expression vector capable of expressing said peptide containing SEQ ID NO: 1 to SEQ ID NO: 772 or said t amino acid sequence.
The present invention further relates to activated T cells, produced by the method according to the present invention, n said T cells selectively recognizes a cell which aberrantly expresses a ptide comprising an amino acid ce according to the present invention.
The present invention further relates to a method of killing target cells in a t which target cells aberrantly express a ptide comprising any amino acid sequence according to the present invention, the method comprising administering to the patient an effective number of T cells as according to the t invention.
The present invention further relates to the use of any peptide described, a nucleic acid according to the present invention, an expression vector ing to the present invention, a cell according to the present invention, or an activated cytotoxic T lymphocyte according to the t invention as a medicament or in the manufacture of a medicament. The present invention further relates to a use according to the present invention, wherein the medicament is active against .
The present invention r relates to a use according to the ion, wherein the medicament is a vaccine. The t invention r relates to a use according to the invention, wherein the medicament is active against cancer.
The present invention further relates to a use according to the invention, wherein said cancer cells are ovarian cancer cells or other solid or logical tumor cells such as hepatocellular carcinoma, colorectal carcinoma, glioblastoma, gastric cancer, esophageal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic , renal cell carcinoma, prostate cancer, melanoma, breast cancer, c lymphocytic leukemia, Non-Hodgkin lymphoma, acute myeloid leukemia, gallbladder cancer and cholangiocarcinoma, urinary bladder cancer, e cancer, head and neck squamous cell carcinoma, mesothelioma.
The present ion r relates to particular marker proteins and biomarkers based on the peptides according to the present invention, herein called "targets" that can be used in the diagnosis and/or prognosis of ovarian cancer. The present invention also relates to the use of these novel targets for cancer treatment.
The term "antibody" or "antibodies" is used herein in a broad sense and includes both polyclonal and monoclonal antibodies. In addition to intact or "full" immunoglobulin molecules, also included in the term "antibodies" are fragments (e.g. CDRs, Fv, Fab and Fc fragments) or polymers of those immunoglobulin molecules and humanized versions of immunoglobulin molecules, as long as they exhibit any of the desired properties (e.g., specific binding of a ovarian cancer marker (poly)peptide, delivery of a toxin to a ovarian cancer cell expressing a cancer marker gene at an increased level, and/or inhibiting the activity of a n cancer marker polypeptide) according to the invention. er possible, the antibodies of the invention may be purchased from commercial sources. The antibodies of the invention may also be generated using well-known methods. The skilled artisan will understand that either full length ovarian cancer marker polypeptides or fragments thereof may be used to generate the antibodies of the invention. A polypeptide to be used for generating an dy of the invention may be partially or fully purified from a natural source, or may be produced using recombinant DNA techniques.
For example, a cDNA encoding a peptide according to the present invention, such as a peptide according to SEQ ID NO: 1 to SEQ ID NO: 772 polypeptide, or a variant or fragment thereof, can be expressed in prokaryotic cells (e.g., bacteria) or eukaryotic cells (e.g., yeast, , or mammalian cells), after which the inant protein can be purified and used to generate a onal or polyclonal dy preparation that specifically bind the ovarian cancer marker polypeptide used to generate the antibody according to the invention.
One of skill in the art will realize that the generation of two or more different sets of onal or polyclonal antibodies maximizes the likelihood of obtaining an antibody with the specificity and affinity required for its intended use (e.g., ELISA, histochemistry, in vivo imaging, immunotoxin y). The antibodies are tested for their desired activity by known methods, in accordance with the e for which the antibodies are to be used (e.g., ELISA, immunohistochemistry, immunotherapy, etc.; for further guidance on the generation and testing of antibodies, see, e.g., ield, 2014 field, 2014)). For example, the antibodies may be tested in ELISA assays or, Western blots, immunohistochemical staining of formalin- fixed cancers or frozen tissue sections. After their initial in vitro characterization, antibodies ed for eutic or in vivo diagnostic use are tested according to known clinical testing methods.
The term "monoclonal antibody" as used herein refers to an dy obtained from a substantially homogeneous population of antibodies, i.e.; the individual dies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. The monoclonal antibodies herein specifically include "chimeric" antibodies in which a n of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired antagonistic activity (US 4,816,567, which is hereby incorporated in its entirety).
Monoclonal antibodies of the invention may be prepared using oma methods. In a hybridoma method, a mouse or other appropriate host animal is lly immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the zing agent. Alternatively, the lymphocytes may be immunized in vitro.
The monoclonal dies may also be made by recombinant DNA methods, such as those described in US 567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional ures (e.g., by using oligonucleotide probes that are capable of g specifically to genes encoding the heavy and light chains of murine antibodies).
In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly Fab fragments, can be accomplished using routine techniques known in the art. For instance, digestion can be performed using . Examples of papain digestion are described in WO 94/29348 and US 4,342,566. Papain digestion of antibodies typically produces two identical antigen binding fragments, called Fab nts, each with a single antigen binding site, and a residual Fc fragment. Pepsin treatment yields a F(ab')2 fragment and a ch' fragment.
The antibody fragments, whether attached to other sequences or not, can also include insertions, deletions, substitutions, or other selected modifications of particular regions or ic amino acids residues, provided the activity of the fragment is not significantly altered or impaired compared to the non-modified antibody or antibody fragment. These modifications can provide for some additional property, such as to /add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its ory characteristics, etc. In any case, the antibody fragment must possess a bioactive property, such as binding activity, regulation of binding at the binding domain, etc.
Functional or active regions of the antibody may be identified by mutagenesis of a specific region of the protein, followed by expression and testing of the expressed polypeptide. Such methods are readily apparent to a d practitioner in the art and can include site-specific mutagenesis of the nucleic acid ng the antibody fragment.
The antibodies of the invention may further comprise humanized antibodies or human antibodies. zed forms of non-human (e.g., ) dies are chimeric immunoglobulins, globulin chains or fragments thereof (such as Fv, Fab, Fab' or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a mentary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework (FR) residues of the human immunoglobulin are replaced by ponding non-human residues.
Humanized antibodies may also comprise residues which are found neither in the ent antibody nor in the imported CDR or ork sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human globulin consensus ce. The humanized antibody optimally also will comprise at least a portion of an globulin constant region (Fc), typically that of a human immunoglobulin.
Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These man amino acid es are often referred to as t" residues, which are typically taken from an "import" variable domain.
Humanization can be ially med by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human dy. Accordingly, such "humanized" antibodies are chimeric antibodies (US 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, zed antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
Transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production can be employed. For example, it has been described that the homozygous deletion of the antibody heavy chain joining region gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody tion. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. Human antibodies can also be produced in phage display libraries.
Antibodies of the invention are preferably administered to a subject in a pharmaceutically acceptable carrier. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. r carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of stration and concentration of antibody being administered.
The dies can be administered to the subject, patient, or cell by injection (e.g., intravenous, eritoneal, subcutaneous, intramuscular), or by other methods such as infusion that ensure its delivery to the bloodstream in an effective form. The antibodies may also be administered by intratumoral or peritumoral routes, to exert local as well as systemic therapeutic s. Local or intravenous injection is red.
Effective dosages and schedules for stering the antibodies may be determined empirically, and making such determinations is within the skill in the art. Those skilled in the art will understand that the dosage of antibodies that must be administered will vary depending on, for example, the t that will receive the antibody, the route of administration, the particular type of antibody used and other drugs being administered.
A typical daily dosage of the antibody used alone might range from about 1 (pg/kg to up to 100 mg/kg of body weight or more per day, depending on the s mentioned above. Following administration of an antibody, preferably for treating ovarian , the efficacy of the therapeutic dy can be assessed in various ways well known to the skilled practitioner. For instance, the size, number, and/or distribution of cancer in a subject receiving treatment may be monitored using standard tumor imaging ques. A therapeutically-administered antibody that arrests tumor growth, results in tumor shrinkage, and/or prevents the development of new tumors, compared to the disease course that would occurs in the absence of antibody administration, is an efficacious antibody for treatment of cancer.
WO 38257 It is a further aspect of the invention to provide a method for ing a soluble T-cell receptor (sTCR) recognizing a specific peptide-MHC complex. Such e T-cell receptors can be generated from specific T-cell clones, and their affinity can be increased by mutagenesis targeting the complementarity-determining regions. For the purpose of T-cell receptor ion, phage display can be used (US 2010/0113300, (Liddy et al., 2012)). For the purpose of stabilization of T-cell receptors during phage display and in case of practical use as drug, alpha and beta chain can be linked e.g. by non-native disulfide bonds, other covalent bonds (single-chain T-cell or), or by dimerization domains (Boulter et al., 2003; Card et al., 2004; Willcox et al., 1999). The T-cell or can be linked to toxins, drugs, cytokines (see, for example, US 2013/0115191), and domains recruiting effector cells such as an anti-CD3 domain, etc., in order to e particular functions on target cells. Moreover, it could be expressed in T cells used for adoptive transfer. Further information can be found in WC 2004/033685A1 and 2012/056407A1. Further methods for the production are disclosed in WC 2013/057586A1.
In addition, the peptides and/or the TCRs or antibodies or other g molecules of the present ion can be used to verify a pathologist’s diagnosis of a cancer based on a ed sample.
The antibodies or TCRs may also be used for in vivo diagnostic assays. Generally, the antibody is labeled with a radionucleotide (such as 111in, 99To, 14c, 131i, 3H, 32p or 353) so that the tumor can be localized using immunoscintiography. In one embodiment, antibodies or fragments thereof bind to the extracellular domains of two or more targets of a protein selected from the group consisting of the above-mentioned proteins, and the affinity value (Kd) is less than 1 x 10uM.
Antibodies for diagnostic use may be labeled with probes suitable for detection by various imaging methods. Methods for detection of probes include, but are not limited to, fluorescence, light, confocal and electron microscopy; magnetic resonance imaging and oscopy; fluoroscopy, computed aphy and on emission tomography. Suitable probes include, but are not limited to, fluorescein, rhodamine, eosin and other fluorophores, radioisotopes, gold, gadolinium and other nides, paramagnetic iron, fluorine-18 and other positron-emitting radionuclides. Additionally, probes may be bi- or multi-functional and be detectable by more than one of the methods listed. These antibodies may be directly or indirectly labeled with said .
Attachment of probes to the antibodies includes covalent ment of the probe, incorporation of the probe into the antibody, and the covalent attachment of a chelating compound for binding of probe, amongst others well recognized in the art. For immunohistochemistry, the disease tissue sample may be fresh or frozen or may be embedded in paraffin and fixed with a preservative such as formalin. The fixed or embedded section contains the sample are contacted with a labeled primary antibody and secondary antibody, wherein the antibody is used to detect the expression of the proteins in situ. r aspect of the t invention includes an in vitro method for producing activated T cells, the method comprising contacting in vitro T cells with antigen loaded human MHC molecules expressed on the surface of a le n-presenting cell for a period of time sufficient to activate the T cell in an antigen specific manner, wherein the antigen is a peptide according to the invention. Preferably a sufficient amount of the antigen is used with an antigen-presenting cell.
Preferably the mammalian cell lacks or has a reduced level or function of the TAP peptide transporter. Suitable cells that lack the TAP peptide transporter include T2, RMA-S and hila cells. TAP is the transporter associated with antigen processing.
The human peptide loading deficient cell line T2 is available from the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, USA under Catalogue No CRL 1992; the Drosophila cell line Schneider line 2 is available from the WO 38257 ATCC under Catalogue No CRL 19863; the mouse RMA-S cell line is described in Ljunggren et al. (Ljunggren and Karre, 1985).
Preferably, before transfection the host cell expresses substantially no MHC class I molecules. It is also preferred that the stimulator cell expresses a molecule important for providing a co-stimulatory signal for T-cells such as any of 87.1, 87.2, lCAM-1 and LFA 3. The nucleic acid sequences of numerous MHC class I les and of the co- stimulator molecules are publicly available from the GenBank and EMBL databases.
In case of a MHC class I e being used as an antigen, the T cells are sitive T cells.
If an antigen-presenting cell is transfected to express such an epitope, preferably the cell comprises an expression vector capable of expressing a peptide containing SEQ ID NO: 1 to SEQ ID NO: 772, or a variant amino acid sequence thereof.
A number of other methods may be used for generating T cells in vitro. For example, autologous tumor-infiltrating lymphocytes can be used in the generation of CTL.
Plebanski et al. (Plebanski et al., 1995) made use of autologous peripheral blood lymphocytes (PLBs) in the preparation of T cells. Furthermore, the production of autologous T cells by pulsing dendritic cells with peptide or polypeptide, or via infection with recombinant virus is le. Also, B cells can be used in the production of gous T cells. In addition, macrophages pulsed with peptide or polypeptide, or infected with recombinant virus, may be used in the preparation of autologous T cells. 8. Walter et al. (Walter et al., 2003) describe the in vitro priming of T cells by using artificial n presenting cells (aAPCs), which is also a suitable way for generating T cells t the e of choice. In the present invention, aAPCs were generated by the coupling of preformed MHC:peptide complexes to the surface of polystyrene les (microbeads) by biotin:streptavidin biochemistry. This system permits the exact control of the MHC density on aAPCs, which allows to selectively eliciting high- or low- avidity n-specific T cell responses with high efficiency from blood samples. Apart from MHC:peptide complexes, aAPCs should carry other proteins with co-stimulatory activity like anti-CD28 antibodies coupled to their surface. rmore such aAPC- based systems often e the on of appropriate soluble factors, e. g. cytokines, like eukin-12.
Allogeneic cells may also be used in the preparation of T cells and a method is described in detail in WO 97/26328, incorporated herein by reference. For example, in addition to Drosophila cells and T2 cells, other cells may be used to present antigens such as CHO cells, baculovirus-infected insect cells, bacteria, yeast, and vaccinia- infected target cells. In addition plant viruses may be used (see, for e, Porta et al. (Porta et al., 1994) which describes the development of cowpea mosaic virus as a high-yielding system for the presentation of foreign peptides.
The activated T cells that are ed against the peptides of the invention are useful in therapy. Thus, a further aspect of the invention provides activated T cells obtainable by the foregoing methods of the invention.
Activated T cells, which are produced by the above method, will selectively recognize a cell that aberrantly expresses a polypeptide that comprises an amino acid sequence of SEQ ID NO: 1 to SEQ ID NO 772.
Preferably, the T cell recognizes the cell by interacting h its TCR with the HLA/peptide-complex (for example, binding). The T cells are useful in a method of killing target cells in a patient whose target cells aberrantly express a polypeptide comprising an amino acid sequence of the invention wherein the patient is administered an effective number of the activated T cells. The T cells that are administered to the patient may be derived from the patient and activated as described above (i.e. they are gous T cells). atively, the T cells are not from the patient but are from another individual. Of course, it is red if the individual is a healthy individual. By "healthy individual" the inventors mean that the individual is generally in good health, preferably has a competent immune system and, more preferably, is not suffering from any disease that can be readily tested for, and detected.
In vivo, the target cells for the CD8—positive T cells according to the present invention can be cells of the tumor (which mes express MHC class II) and/or stromal cells surrounding the tumor (tumor cells) (which sometimes also express MHC class II; (Dengjel et al., .
The T cells of the present invention may be used as active ingredients of a therapeutic composition. Thus, the invention also es a method of killing target cells in a patient whose target cells aberrantly express a polypeptide comprising an amino acid ce of the invention, the method comprising administering to the patient an effective number of T cells as defined above.
By "aberrantly expressed" the inventors also mean that the ptide is over- expressed compared to levels of expression in normal tissues or that the gene is silent in the tissue from which the tumor is derived but in the tumor it is sed. By "over- expressed" the inventors mean that the polypeptide is t at a level at least 1.2-fold of that present in normal tissue; preferably at least 2—fold, and more preferably at least -fold or 10-fold the level present in normal tissue.
T cells may be obtained by methods known in the art, e.g. those described above.
Protocols for this so-called ve transfer of T cells are well known in the art.
Reviews can be found in: Gattioni et al. and Morgan et al. (Gattinoni et al., 2006; Morgan et al., 2006).
Another aspect of the present invention includes the use of the peptides xed with MHC to generate a T-cell receptor whose nucleic acid is cloned and is introduced into a host cell, preferably a T cell. This engineered T cell can then be transferred to a patient for therapy of cancer.
Any molecule of the invention, i.e. the peptide, nucleic acid, antibody, expression vector, cell, activated T cell, T-cell receptor or the nucleic acid encoding it, is useful for the treatment of disorders, characterized by cells ng an immune response. Therefore any molecule of the present invention may be used as ment or in the cture of a ment. The molecule may be used by itself or combined with other molecule(s) of the invention or (a) known molecule(s).
The present invention is further directed at a kit comprising: (a) a container ning a pharmaceutical composition as described above, in solution or in lyophilized form; (b) optionally a second container containing a diluent or reconstituting solution for the lyophilized formulation; and (c) ally, instructions for (i) use of the solution or (ii) reconstitution and/or use of the lyophilized formulation.
The kit may further comprise one or more of (iii) a buffer, (iv) a diluent, (v) a filter, (vi) a needle, or (v) a syringe. The container is preferably a bottle, a vial, a syringe or test tube; and it may be a multi-use container. The pharmaceutical composition is preferably lyophmzed.
Kits of the present invention preferably comprise a lyophilized formulation of the present invention in a suitable container and instructions for its reconstitution and/or use.
Suitable containers include, for example, bottles, vials (e.g. dual chamber , syringes (such as dual chamber syringes) and test tubes. The container may be formed from a variety of materials such as glass or plastic. Preferably the kit and/or container contain/s instructions on or associated with the container that indicates directions for titution and/or use. For e, the label may indicate that the lyophilized formulation is to be reconstituted to peptide concentrations as described above. The label may further indicate that the formulation is useful or intended for subcutaneous administration.
The container holding the formulation may be a multi-use vial, which allows for repeat administrations (e.g., from 2-6 administrations) of the reconstituted formulation. The kit may r comprise a second container comprising a suitable diluent (e.g., sodium bicarbonate solution).
Upon mixing of the diluent and the lyophilized formulation, the final peptide concentration in the reconstituted formulation is ably at least 0.15 mg/mL/peptide (=75 pg) and preferably not more than 3 mg/mL/peptide (=1500 pg). The kit may further include other materials desirable from a commercial and user oint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
Kits of the present invention may have a single container that contains the formulation of the pharmaceutical compositions according to the present invention with or t other components (e.g., other compounds or pharmaceutical compositions of these other compounds) or may have distinct container for each component.
Preferably, kits of the invention include a formulation of the ion ed for use in combination with the co-administration of a second compound (such as adjuvants (e.g. ), a chemotherapeutic agent, a natural product, a hormone or antagonist, an anti-angiogenesis agent or inhibitor, an apoptosis-inducing agent or a chelator) or a pharmaceutical composition thereof. The components of the kit may be pre-complexed or each component may be in a separate distinct container prior to administration to a patient. The components of the kit may be provided in one or more liquid solutions, preferably, an s solution, more preferably, a sterile aqueous solution. The components of the kit may also be provided as solids, which may be converted into s by addition of suitable solvents, which are preferably provided in another distinct container.
The container of a therapeutic kit may be a vial, test tube, flask, bottle, syringe, or any other means of enclosing a solid or liquid. Usually, when there is more than one component, the kit will contain a second vial or other container, which allows for separate dosing. The kit may also contain another container for a pharmaceutically acceptable liquid. Preferably, a therapeutic kit will n an apparatus (e.g., one or more needles, syringes, eye droppers, pipette, etc.), which enables stration of the agents of the invention that are components of the present kit.
The t formulation is one that is suitable for administration of the peptides by any acceptable route such as oral (enteral), nasal, l, subcutaneous, intradermal, intramuscular, intravenous or transdermal. Preferably, the administration is so, and most preferably i.d. administration may be by infusion pump.
Since the peptides of the invention were isolated from ovarian , the medicament of the invention is preferably used to treat ovarian cancer.
The present invention further relates to a method for producing a personalized pharmaceutical for an individual t comprising manufacturing a ceutical composition comprising at least one peptide selected from a warehouse of eened TUMAPs, wherein the at least one peptide used in the pharmaceutical composition is selected for suitability in the individual patient. In one embodiment, the pharmaceutical composition is a vaccine. The method could also be d to produce T cell clones for down-stream ations, such as TCR ions, or soluble antibodies, and other treatment options.
A "personalized pharmaceutical" shall mean specifically tailored ies for one individual patient that will only be used for therapy in such individual patient, including actively personalized cancer vaccines and adoptive cellular therapies using autologous paflentfissue.
As used herein, the term "warehouse" shall refer to a group or set of peptides that have been pre-screened for immunogenicity and/or over-presentation in a particular tumor type. The term ouse" is not intended to imply that the particular peptides included in the vaccine have been pre-manufactured and stored in a physical facility, although that possibility is contemplated. It is expressly contemplated that the peptides may be manufactured de novo for each individualized vaccine ed, or may be pre- manufactured and stored. The warehouse (e.g. in the form of a database) is composed of tumor-associated peptides which were highly overexpressed in the tumor tissue of ovarian cancer ts with various HLA-A HLA-B and HLA-C alleles. It may contain MHC class I and MHC class II peptides or elongated MHC class I peptides. In addition to the tumor associated peptides collected from several ovarian cancer tissues, the warehouse may contain HLA-A*02, HLA-A*01, O3, 24, HLA-B*O7, HLA- B*O8 and 44 marker peptides. These peptides allow comparison of the magnitude of T-cell immunity d by TUMAPS in a quantitative manner and hence allow important conclusion to be drawn on the capacity of the e to elicit anti-tumor responses. Secondly, they function as important positive control peptides derived from a elf" antigen in the case that any vaccine-induced T-cell responses to TUMAPs derived from "self" ns in a patient are not observed. And thirdly, it may allow conclusions to be drawn, regarding the status of immunocompetence of the t.
TUMAPs for the warehouse are identified by using an integrated functional genomics approach combining gene expression analysis, mass spectrometry, and T-cell immunology (XPresident ®). The approach assures that only TUMAPs truly present on a high percentage of tumors but not or only minimally expressed on normal tissue, are chosen for further analysis. For initial peptide selection, ovarian cancer s from ts and blood from healthy donors were analyzed in a stepwise approach: 1. HLA ligands from the malignant material were identified by mass spectrometry 2. Genome-wide messenger cleic acid (mRNA) expression analysis was used to identify genes over-expressed in the malignant tissue (ovarian cancer) compared with a range of normal organs and tissues 3. Identified HLA ligands were compared to gene sion data. Peptides ted on tumor tissue, preferably encoded by selectively expressed or over-expressed genes as detected in step 2 were considered suitable TUMAP candidates for a multi-peptide vaccine. 4. Literature research was performed in order to identify additional evidence supporting the relevance of the identified peptides as TUMAPs . The relevance of over-expression at the mRNA level was confirmed by redetection of ed TUMAPs from step 3 on tumor tissue and lack of (or infrequent) detection on healthy tissues. 6. In order to assess, whether an induction of in vivo T-cell responses by the selected peptides may be feasible, in vitro immunogenicity assays were performed using human T cells from healthy donors as well as from ovarian cancer ts.
In an aspect, the peptides are pre-screened for immunogenicity before being included in the warehouse. By way of example, and not limitation, the immunogenicity of the es included in the warehouse is determined by a method sing in vitro T-cell priming h repeated stimulations of CD8+ T cells from healthy donors with artificial antigen presenting cells loaded with peptide/MHC complexes and anti-CD28 antibody.
This method is preferred for rare cancers and patients with a rare expression profile. In contrast to multi-peptide cocktails with a fixed composition as tly developed, the warehouse allows a significantly higher matching of the actual expression of antigens in the tumor with the vaccine. Selected single or combinations of l "off-the-shelf" peptides will be used for each patient in a multitarget approach. In theory, an approach based on selection of e.g. 5 different antigenic peptides from a library of 50 would already lead to approximately 17 million possible drug t (DP) compositions.
In an aspect, the peptides are selected for inclusion in the vaccine based on their suitability for the dual patient based on the method according to the t invention as described herein, or as below.
The HLA phenotype, transcriptomic and peptidomic data is gathered from the patient’s tumor material, and blood samples to identify the most suitable peptides for each patient containing ouse" and patient-unique (i.e. mutated) TUMAPs. Those peptides will be chosen, which are ively or over-expressed in the patients’ tumor and, where possible, show strong in vitro genicity if tested with the patients’ individual PBMCs.
Preferably, the peptides included in the vaccine are identified by a method comprising: (a) identifying tumor-associated peptides (TUMAPs) ted by a tumor sample from the individual patient; (b) comparing the peptides identified in (a) with a warehouse (database) of peptides as described above; and (c) selecting at least one peptide from the warehouse ase) that correlates with a tumor-associated peptide identified in the patient. For example, the TUMAPs presented by the tumor sample are identified by: (a1) comparing sion data from the tumor sample to expression data from a sample of normal tissue corresponding to the tissue type of the tumor sample to identify proteins that are over-expressed or aberrantly expressed in the tumor sample; and (a2) correlating the expression data with sequences of MHC ligands bound to MHC class I and/or class II les in the tumor sample to identify MHC ligands derived from proteins over-expressed or aberrantly expressed by the tumor. Preferably, the ces of MHC ligands are identified by eluting bound peptides from MHC molecules isolated from the tumor sample, and sequencing the eluted ligands.
Preferably, the tumor sample and the normal tissue are obtained from the same patient.
In addition to, or as an ative to, selecting peptides using a warehousing (database) model, TUMAPs may be identified in the patient de novo, and then included in the vaccine. As one e, candidate TUMAPs may be identified in the patient by (a1) comparing expression data from the tumor sample to expression data from a sample of normal tissue corresponding to the tissue type of the tumor sample to identify proteins that are over-expressed or aberrantly expressed in the tumor ; and (a2) correlating the expression data with sequences of MHC ligands bound to MHC class I and/or class II molecules in the tumor sample to identify MHC ligands derived from proteins over-expressed or aberrantly expressed by the tumor. As another example, proteins may be identified containing mutations that are unique to the tumor sample relative to normal corresponding tissue from the individual patient, and TUMAPs can be identified that specifically target the mutation. For example, the genome of the tumor and of ponding normal tissue can be sequenced by whole genome sequencing: For discovery of non-synonymous mutations in the protein-coding regions of genes, genomic DNA and RNA are extracted from tumor tissues and normal non-mutated genomic germline DNA is extracted from peripheral blood mononuclear cells (PBMCs).
The applied NGS approach is confined to the uencing of protein coding regions (exome re-sequencing). For this purpose, exonic DNA from human samples is captured using vendor-supplied target enrichment kits, followed by sequencing with e.g. a HiSeq2000 (lllumina). onally, tumor mRNA is sequenced for direct quantification of gene expression and validation that mutated genes are expressed in the patients’ tumors. The resultant ns of sequence reads are processed through software algorithms. The output list contains mutations and gene expression. Tumor-specific somatic mutations are determined by comparison with the PBMC-derived germline variations and prioritized. The de novo identified es can then be tested for immunogenicity as described above for the warehouse, and candidate TUMAPs possessing suitable immunogenicity are selected for inclusion in the e.
In one exemplary embodiment, the peptides included in the vaccine are identified by: (a) fying tumor-associated peptides (TUMAPs) presented by a tumor sample from the individual patient by the method as described above; (b) ing the peptides identified in a) with a warehouse of peptides that have been prescreened for immunogenicity and overpresentation in tumors as compared to corresponding normal tissue; (c) selecting at least one e from the use that correlates with a tumor-associated peptide identified in the patient; and (d) ally, ing at least one e identified de novo in (a) confirming its immunogenicity.
In one exemplary embodiment, the peptides included in the vaccine are identified by: (a) identifying tumor-associated peptides (TUMAPs) presented by a tumor sample from the individual patient; and (b) selecting at least one peptide fied de novo in (a) and confirming its immunogenicity.
Once the peptides for a personalized peptide based vaccine are selected, the e is produced. The vaccine preferably is a liquid formulation consisting of the individual peptides dissolved in between 20-40% DMSO, preferably about 30-35% DMSO, such as about 33% DMSO.
Each peptide to be included into a product is dissolved in DMSO. The concentration of the single e solutions has to be chosen depending on the number of es to be included into the product. The single peptide-DMSO solutions are mixed in equal parts to achieve a solution containing all peptides to be included in the product with a tration of ~2.5 mg/ml per peptide. The mixed solution is then diluted 1:3 with water for injection to achieve a concentration of 0.826 mg/ml per peptide in 33% DMSO.
The diluted solution is filtered through a 0.22 pm sterile filter. The final bulk solution is obtained.
Final bulk solution is filled into vials and stored at -20°C until use. One vial contains 700 uL solution, containing 0.578 mg of each peptide. Of this, 500 uL (approx. 400 pg per peptide) will be applied for intradermal ion.
In addition to being useful for treating cancer, the peptides of the present invention are also useful as diagnostics. Since the peptides were ted from ovarian cancer cells and since it was determined that these peptides are not or at lower levels present in normal tissues, these es can be used to diagnose the presence of a cancer.
The presence of claimed peptides on tissue biopsies in blood s can assist a pathologist in diagnosis of cancer. Detection of certain peptides by means of antibodies, mass spectrometry or other methods known in the art can tell the pathologist that the tissue sample is malignant or inflamed or lly diseased, or can be used as a biomarker for ovarian cancer. ce of groups of peptides can enable classification or sub-classification of diseased tissues.
The detection of peptides on diseased tissue specimen can enable the decision about the benefit of therapies involving the immune system, especially if T-lymphocytes are known or expected to be involved in the mechanism of action. Loss of MHC expression is a well described mechanism by which infected of malignant cells escape immuno- sun/eillance. Thus, presence of peptides shows that this mechanism is not ted by the analyzed cells.
The peptides of the present invention might be used to analyze lymphocyte responses against those peptides such as T cell responses or antibody responses against the peptide or the peptide xed to MHC molecules. These cyte responses can be used as prognostic markers for decision on further therapy steps. These responses can also be used as surrogate response markers in immunotherapy approaches aiming to induce lymphocyte responses by different means, e.g. vaccination of protein, nucleic acids, autologous als, adoptive transfer of lymphocytes. In gene therapy settings, lymphocyte responses against peptides can be considered in the ment of side effects. Monitoring of lymphocyte responses might also be a valuable tool for follow-up examinations of transplantation therapies, e.g. for the detection of graft versus host and host versus graft es.
The t invention will now be described in the following examples which describe red embodiments thereof, and with nce to the anying s, nevertheless, without being limited thereto. For the purposes of the present invention, all references as cited herein are incorporated by reference in their entireties.
FIGURES Figure 1A through Figure 18 show exemplary expression profile of source genes of the present invention that are over-expressed in different cancer samples. Tumor (black dots) and normal (grey dots) samples are grouped according to organ of origin, and WO 38257 d-whisker plots represent median, 25th and 75th percentile (box), and minimum and m (whiskers) RPKM values. Normal organs are ordered according to risk categories. RPKM = reads per se per million mapped reads. Normal samples: blood cells; blood vessel; brain; heart; liver; lung; adipose: adipose tissue; adren.gl.: adrenal gland; bile duct; bladder; BM: bone marrow; cartilage; esoph: esophagus; eye; gallb: gallbladder; head and neck; kidney; large_int: large intestine; LN: lymph node; nerve; pancreas; parathyr: parathyroid; pituit: pituitary; skel.mus: skeletal ; skin; small_int: small intestine; spleen; h; thyroid; trachea; bladder; breast; ovary; placenta; prostate; testis; thymus; uterus. Tumor s: AML: acute myeloid leukemia; BRCA: breast cancer; CLL: chronic lymphocytic leukemia; CRC: colorectal cancer; GALB: gallbladder cancer; GB: glioblastoma; GC: c cancer; HCC: hepatocellular carcinoma; HNSCC: head-and-neck cancer; MEL: melanoma; NHL: non- hodgkin lymphoma; NSCLC: non-small cell lung cancer; 00: ovarian cancer; OSC_GC: geal / gastric cancer; OSCAR: esophageal cancer; PC: pancreatic cancer; PCA: prostate cancer; RCC: renal cell carcinoma; SCLC: small cell lung ; UBC: urinary bladder carcinoma; UEC: uterine and endometrial cancer. Figure 1A) Gene symbol: CT45A2, Peptide: KYEKIFEML (SEQ ID No.: 12), Figure 18) Gene : NLRP2, Peptide: VLYGPAGLGK (SEQ ID No.: 27), Figure 10) Gene symbol: NLRP7, Peptide: LLDEGAMLLY (SEQ ID No.: 31), Figure 1D) Gene symbol: HTR3A, Peptide: GLLQELSSI (SEQ ID No.: 66), Figure 1E) Gene symbol: VTCN1, Peptide: KVVSVLYNV (SEQ ID No.: 75), Figure 1F) Gene symbol: CYP2W1, Peptide: RYGPVFTV (SEQ ID No.: 98), Figure 1G) Gene symbol: MMP11, Peptide: LLQPPPLLAR (SEQ ID No.: 98), Figure 1H) Gene symbol: MMP12, Peptide: FVDNQYWRY (SEQ ID No.: 115), Figure 1|) Gene symbol: CTAG2, Peptide: APLPRPGAVL (SEQ ID No.: 119), Figure 1J) Gene symbol: FAM111B, Peptide: KPSESIYSAL (SEQ ID No.: 123), Figure 1K) Gene : CCNA1, Peptide: LAF (SEQ ID No.: 151), Figure 1L) Gene symbol: FAM83H, Peptide: HVKEKFLL (SEQ ID No.: 156), Figure 1M) Gene symbol: MAGEA11, Peptide: KEVDPTSHSY (SEQ ID No.: 194), Figure 1N) Gene symbol: MMP11, Peptide: YTFRYPLSL (SEQ ID No.: 227), Figure 10) Gene symbol: ZNF560, Peptide: VFVSFSSLF (SEQ ID No.: 255), Figure 1P) Gene symbol: IGF2BP1, Peptide: ISYSGQFLVK (SEQ ID No.: 266), Figure 1Q) Gene symbol: CLDN6, Peptide: LPMWKVTAF (SEQ ID No.: 303), Figure 1R) Gene symbol: IGFZBP3, Peptide: IEALSGKIEL (SEQ ID No.: 413), Figure 18) Gene symbol: PRAME, Peptide: EEQYIAQF (SEQ ID No.: 432).
Figures 1T through 1V show exemplary expression profiles of source genes of the present invention, that are over-expressed in different cancer samples. Tumor (black dots) and normal (grey dots) samples are grouped according to organ of origin. Box- and-whisker plots represent median FPKM value, 25th and 75th percentile (box) plus whiskers that extend to the lowest data point still within 1.5 interquartile range (IQR) of the lower quartile and the highest data point still within 1.5 IQR of the upper le.
Normal organs are ordered according to risk categories. FPKM: fragments per kilobase per million mapped reads. Normal samples: blood cells; ess (blood vessels); brain; heart; liver, lung; adipose (adipose tissue); adrenal gl (adrenal ; bile duct; bladder, bone ; cartilage; esoph (esophagus); eye; gall bl ladder); head&neck; intest. la (large intestine); intest. sm (small intestine); kidney; lymph node; nerve perith (peripheral nerve); pancreas; yr (parathyroid gland); perit (peritoneum); pituit (pituitary); pleura; skel. mus (skeletal muscle); skin; spleen; h; thyroid; trachea; , breast; ovary; placenta; prostate; testis; thymus; uterus. Tumor samples: AML (acute myeloid leukemia); BRCA (breast cancer); CCC (cholangiocellular carcinoma); CLL ic cytic leukemia); CRC (colorectal cancer); GBC (gallbladder cancer); GBM (glioblastoma); GC (gastric cancer); HCC (hepatocellular carcinoma); HNSCC (head and neck squamous cell carcinoma); MEL (melanoma); NHL (non-hodgkin lymphoma); NSCLCadeno (non-small cell lung cancer adenocarcinoma); NSCLCother (NSCLC samples that could not unambiguously be assigned to NSCLCadeno or NSCLquuam); NSCLquuam (squamous cell all cell lung cancer); 00 (ovarian ); OSCAR (esophageal cancer); PACA (pancreatic ); PRCA (prostate cancer); RCC (renal cell carcinoma); SCLC (small cell lung cancer); UBC (urinary bladder carcinoma); UEC (uterine and endometrial cancer).
Figure 1T) Gene symbol: , Peptide: SPDAESLFREALSNKVDEL (SEQ ID No.: 597), Figure 1U) Gene symbol: MAGEA4, Peptide: LSNKVDELAHFLLRK (SEQ ID No.: 601), Figure 1V) Gene symbol: MAGEB3, Peptide: KLITQDLVKLKYLEYRQ (SEQ ID No.: 604).
Figure 2 shows exemplary results of peptide-specific in vitro CD8+ T cell responses of a y HLA-A*02+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*02 in complex with SquD No 773 peptide (ALYGKLLKL, Seq ID NO: 773) (A, left panel. After three cycles of stimulation, the detection of peptide-reactive cells was performed by 2D multimer staining with A*02/SeqlD No 773 (A). Right panel (A) show control staining of cells stimulated with irrelevant eptide complexes. Viable singlet cells were gated for CD8+ lymphocytes. n gates helped excluding false-positive events detected with multimers specific for different peptides. Frequencies of specific er+ cells among CD8+ lymphocytes are indicated.
Figure 3 shows exemplary s of peptide-specific in vitro CD8+ T cell responses of a healthy HLA-A*24+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*24 in complex with SquD No 774 peptide (A, left panel).
After three cycles of ation, the detection of peptide-reactive cells was performed by 2D multimer staining with A*24/SeqlD No 774 (VYVDDIYVI, Seq ID NO: 774) (A).
Right panel (A) shows control staining of cells stimulated with irrelevant A*24/peptide complexes. Viable t cells were gated for CD8+ lymphocytes. Boolean gates helped excluding false-positive events detected with multimers specific for different peptides. Frequencies of ic multimer+ cells among CD8+ lymphocytes are indicated.
Figure 4 shows exemplary results of e-specific in vitro CD8+ T cell responses of a healthy HLA-A*02+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*02 in complex with SquD No 67 peptide SLLLPSIFL (A, left panel) and SquD No 75 e KVVSVLYNV (B, left panel), respectively. After three cycles of stimulation, the detection of peptide-reactive cells was performed by 2D multimer staining with A*02/SeqlD No 67 (A) or A*02/SeqlD No 75 (B). Right panels (A and B) show control staining of cells stimulated with irrelevant A*02/peptide xes.
Viable singlet cells were gated for CD8+ lymphocytes. Boolean gates helped excluding positive events detected with multimers specific for different peptides. Frequencies of specific multimer+ cells among CD8+ lymphocytes are indicated.
Figure 5 shows exemplary results of peptide-specific in vitro CD8+ T cell responses of a healthy HLA-A*24+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*24 in x with SquD No 11 peptide SYSDLHYGF (A, left panel) and SquD No 79 peptide SYNEHWNYL (B, left panel), respectively. After three cycles of stimulation, the detection of peptide-reactive cells was performed by 2D multimer ng with eqlD No 11 (A) or A*24/SeqlD No 79 (B). Right panels (A and B) show control staining of cells stimulated with irrelevant A*24/peptide complexes.
Viable singlet cells were gated for CD8+ cytes. Boolean gates helped ing false-positive events detected with multimers specific for different peptides. Frequencies of specific multimer+ cells among CD8+ cytes are indicated.
Figure 6 shows exemplary results of peptide-specific in vitro CD8+ T cell responses of a healthy HLA-B*07+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-B*07 in complex with SquD No 33 peptide SPTFHLTL (A, left panel) and SquD No 40 peptide KPGTSYRVTL (B, left panel), respectively. After three cycles of stimulation, the detection of peptide-reactive cells was performed by 2D er staining with B*07/SeqlD No 33 (A) or B*07/SeqlD No 40 (B). Right panels (A and B) show control staining of cells stimulated with irrelevant eptide complexes.
Viable singlet cells were gated for CD8+ lymphocytes. Boolean gates helped excluding false-positive events detected with multimers ic for different peptides. Frequencies of specific er+ cells among CD8+ lymphocytes are indicated.
Figure 7 shows exemplary results of peptide-specific in vitro CD8+ T cell responses of a healthy HLA-A*01+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*O1 in complex with SquD No 113 peptide QLDSNRLTY (A, left panel) and SquD No 115 peptide FVDNQYWRY (B, left panel), respectively. After three cycles of stimulation, the detection of peptide-reactive cells was performed by 2D multimer staining with A*O1/SeqlD No 113 (A) or A*O1/SeqlD No 115 (B). Right panels (A and B) show control staining of cells stimulated with irrelevant A*O1/peptide complexes. Viable singlet cells were gated for CD8+ lymphocytes. n gates helped excluding false-positive events detected with multimers specific for different peptides. Frequencies of ic er+ cells among CD8+ lymphocytes are indicated.
Figure 8 shows exemplary results of peptide-specific in vitro CD8+ T cell ses of a y HLA-A*03+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*03 in complex with SquD No 23 peptide GMMKGGIRK (A, left panel) and SquD No 90 peptide KVAGERYWK (B, left panel), respectively. After three cycles of stimulation, the ion of peptide-reactive cells was performed by 2D multimer staining with A*03/SeqlD No 23 (A) or A*03/SeqlD No 90 (B). Right panels (A and B) show control staining of cells stimulated with irrelevant A*O3/peptide complexes.
Viable singlet cells were gated for CD8+ lymphocytes. Boolean gates helped excluding false-positive events detected with multimers specific for different peptides. Frequencies of specific multimer+ cells among CD8+ lymphocytes are indicated.
Figure 9 shows exemplary results of peptide-specific in vitro CD8+ T cell responses of a healthy HLA-B*44+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and 44 in complex with SquD No 200 peptide AESIPTVSF (A, left panel) and SquD No 211 peptide EEKVFPSPLW (B, left panel), respectively. After three cycles of stimulation, the ion of peptide-reactive cells was performed by 2D multimer staining with B*44/SeqlD No 200 (A) or B*44/SeqlD No 211 (B). Right panels (A and B) show control staining of cells stimulated with irrelevant eptide complexes. Viable singlet cells were gated for CD8+ lymphocytes. Boolean gates helped excluding false-positive events detected with multimers specific for different peptides. Frequencies of specific multimer+ cells among CD8+ lymphocytes are indicated.
WO 38257 EXAMPLE 1 Identification of tumor associated peptides presented on the cell e Tissue samples Patients’ tumor tissues and normal tissues were obtained from the University Hospital Tiibingen (Tiibingen, Germany). Written ed consents of all patients had been given before surgery or autopsy. Tissues were shock-frozen immediately after excision and stored until isolation of TUMAPs at -70°C or below.
Isolation of HLA peptides from tissue samples HLA peptide pools from shock-frozen tissue samples were obtained by immune precipitation from solid tissues according to a slightly modified protocol (Falk et al., 1991; Seeger et al., 1999) using the HLA-A*02-specific antibody BB7.2, the HLA-A, -B, - C-specific antibody W6/32, the HLA-DR specific antibody L243 and the A class II specific dy T039, CNBr—activated sepharose, acid treatment, and ultrafiltration.
Mass spectrometm analyses The HLA peptide pools as obtained were separated according to their hydrophobicity by reversed-phase chromatography (Ultimate 3000 RSLC Nano UHPLC System, Dionex) ) and the eluting peptides were analyzed in LTQ-Orbitrap and Fusion Lumos hybrid mass spectrometers (ThermoElectron) equipped with an ESI source. Peptide samples were loaded with 3% of t B (20% H20, 80% acetonitrile and 0.04% formic acid) on a 2 cm PepMap 100 C18 ap column (Dionex) at a flowrate of 4 ul/min for 10 min.
Separation was med on either 25 cm or 50 cm PepMap C18 columns with a particle size of 2 pm (Dionex) mounted in a column oven running at 50°C. The applied gradient ranged from 3 to 32% solvent B within 90 min at a flow rate of 300 nl/min (for cm columns) or 140 min at a flow rate of 175 nl/min (for 50 cm columns). (Solvent A: 99% H20, 1% ACN and 0.1% formic acid; Solvent B: 20% H20, 80% ACN and 0.1% formic acid).
WO 38257 Mass spectrometry analysis was performed in data dependent acquisition mode employing a top five method (i.e. during each survey scan the five most abundant precursor ions were selected for fragmentation). Alternatively, a TopSpeed method was employed for analysis on Fusion Lumos instruments, Survey scans were recorded in the Orbitrap at a resolution of 60,000 (for Orbitrap XL) or 120,000 (for Orbitrap Fusion Lumos). MS/MS is was performed by collision induced iation (CID, normalized ion energy 35%, activation time 30 ms, ion width 1.3 m/z) with subsequent analysis in the linear trap quadrupole (LTQ).
Mass range for HLA class I ligands was limited to 400-650 m/z with possible charge states 2+ and 3+ selected for fragmentation. For HLA class II mass range was set to 300-1500 m/z allowing for fragmentation with all positive charge states 2 2.
Tandem mass spectra were interpreted by MASCOT or T at a fixed false discovery rate (qS0.05)and onal manual control. In cases where the identified peptide sequence was uncertain it was onally validated by comparison of the generated natural peptide fragmentation pattern with the fragmentation pattern of a synthetic sequence-identical reference peptide.
Table 19 shows the presentation on various cancer entities for selected peptides, and thus the particular relevance of the peptides as mentioned for the diagnosis and/or ent of the cancers as indicated (e.g. peptide SEQ ID No. 1 for colorectal cancer, gallbladder cancer, non-hodgkin lymphoma, non-small cell lung cancer, and uterine and endometrial cancer, peptide SEQ ID No. 2 for breast cancer, cholangiocellular carcinoma, ctal cancer, gallbladder , gastric cancer, head and neck squamous cell carcinoma, melanoma, non-hodgkin lymphoma, non-small cell lung cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer,and uterine and trial cancer).
Table 19: Overview of presentation of selected tumor-associated peptides of the t invention across tumor types.
AML: acute myeloid leukemia; BRCA: breast cancer; CCC: giocellular carcinoma; CLL: chronic lymphocytic leukemia; CRC: colorectal cancer; GBC: gallbladder cancer; GBM: glioblastoma; GC: gastric cancer; GEJC: gastro-esophageal junction cancer; HCC: hepatocellular carcinoma; HNSCC: head and neck squamous cell carcinoma; MEL: melanoma; NHL: non-hodgkin lymphoma; NSCLC: non-small cell lung cancer; OC: ovarian cancer; OSCAR: esophageal cancer; PACA: pancreatic cancer; PRCA: prostate cancer; RCC: renal cell carcinoma; SCLC: small cell lung cancer; UBC: urinary bladder carcinoma; UEC: uterine and endometrial cancer Seq ID No ce e Presentation on tumor types 1 MIPTFTALL CRC, GBC, NHL, NSCLC, UEC BRCA, CCC, CRC, GBC, GC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, 2 TLLKALLEI PRCA, RCC, SCLC, UEC 3 ALIYNLVGI HCC AML, BRCA, CLL, CRC, GBC, GC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, 4 ALFKAWAL RCC, SCLC, UBC, UEC RLLDFINVL UEC GC, GEJC, HNSCC, NSCLC, PACA, 7 ALQAFEFRV SCLC, UBC AML, BRCA, CCC, CLL, CRC, GBC, GBM, GC, GEJC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, 8 YLVTKVVAV RCC, SCLC, UBC, UEC BRCA, CRC, GBC, GC, NSCLC, SCLC, GRVSF UBC, UEC 11 SYSDLHYGF GC, NSCLC, UEC 12 KYEKIFEML AML, NSCLC 13 VYTFLSSTL NSCLC 14 FYFPTPTVL GBC, NSCLC VYHDDKQPTF GBM, GC, NSCLC, OSCAR, UEC BRCA, NHL, NSCLC, OSCAR, UBC, 16 SRL UEC AML, BRCA, GBC, GC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, RCC, 18 KYPVHIYRL UBC, UEC Seq ID No Sequence Peptide Presentation on tumor types AML, BRCA, CLL, CRC, GBC, GBM, GC, HCC, MEL, NHL, NSCLC, OSCAR, 19 KYVKVFHQF PACA, PRCA, RCC, SCLC, UBC, UEC 2O RMASPVNVK CLL AML, BRCA, CCC, CRC, GBC, GBM, GC, HCC, HNSCC, MEL, NHL, NSCLC, 21 AVRKPIVLK OSCAR, PACA, RCC, SCLC, UBC, UEC 22 SLKERNPLK NSCLC 24 SMYYPLQLK BRCA, CRC, GBM, HCC, NHL, RCC GTSPPSVEK UEC HCC, HNSCC, NSCLC, OSCAR, PACA, 27 VLYGPAGLGK SCLC, UBC, UEC 28 KTYETNLEIKK NSCLC, UBC 29 QQFLTALFY PACA, PRCA 31 LLDEGAMLLY GBC, HNSCC, NSCLC, SCLC, UBC 32 LSV NSCLC 33 SPTFHLTL NSCLC, PRCA, SCLC, UBC, UEC 34 LPRGPLASLL HNSCC, NSCLC, OSCAR, PACA, SCLC BRCA, CRC, GBC, MEL, NSCLC, PACA, PAL UBC, UEC BRCA, CCC, CRC, GBC, GC, HCC, HNSCC, NSCLC, OSCAR, PACA, SCLC, 36 APAAWLRSA UBC, UEC 38 SPHPVTALLTL PACA, UEC 4O RVTL GBM BRCA, CCC, GBM, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PRCA, SCLC, 43 ALKARTVTF UBC, UEC 48 DVKKKIKEV NSCLC, RCC, SCLC 53 MEHPGKLLF UEC 56 SEPDTTASW NSCLC, UEC BRCA, CLL, CRC, GC, GEJC, HNSCC, 57 QESDLRLFL NHL, NSCLC, PACA, UBC, UEC 59 SENVTMKW UEC 60 GLLSLTSTLYL BRCA 62 KVLGVNVML BRCA, HNSCC, MEL, NSCLC, SCLC 63 MMEEMIFNL UBC BRCA, CCC, CRC, GBC, GC, GEJC, HCC, HNSCC, MEL, NSCLC, OSCAR, 64 FLDPDRHFL PACA, PRCA, RCC, SCLC, UBC, UEC 65 TMFLRETSL MEL, NHL, NSCLC, PRCA, SCLC 68 KLFDTQQFL AML, BRCA, CRC, HCC, HNSCC, MEL, Seq ID No Sequence Peptide Presentation on tumor types NHL, NSCLC, OSCAR, RCC 69 TTYEGSITV NSCLC, UEC AML, BRCA, CCC, CRC, GBC, GC, GEJC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, RCC, 71 YLEDTDRNL SCLC, UBC, UEC AML, BRCA, CCC, CLL, CRC, GBC, GBM, GC, GEJC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, 72 YLTDLQVSL RCC, SCLC, UBC, UEC 74 SQSPSVSQL UEC 75 KVVSVLYNV BRCA, UEC 77 RYGPVFTV CCC, GC 78 SFAPRSAVF SCLC BRCA, CCC, CRC, GBC, GC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, 79 SYNEHWNYL PACA, PRCA, RCC, SCLC, UBC, UEC 81 VYNHTTRPL OSCAR AML, CRC, HCC, MEL, NHL, NSCLC, 85 VLLGSLFSRK RCC, UEC 86 WLLGSLFSRK AML, CRC, GC, HCC, PACA, RCC AML, CRC, GBC, MEL, NSCLC, OSCAR, 87 AVAPPTPASK RCC, SCLC, UEC 90 KVAGERYVYK CCC, UEC 92 SVFPIENIY UEC 94 ATFERVLLR BRCA, NSCLC 96 TAFGGFLKY OSCAR, RCC 97 GLFY GC 99 NEK CRC, NHL, RCC 101 RVFTSSIKTK NSCLC, PACA, UEC 106 AAFVPLLLK AML, BRCA, NHL, NSCLC, SCLC AML, MEL, NHL, NSCLC, RCC, SCLC, 108 VLYPVPLESY UEC BRCA, CCC, MEL, NHL, NSCLC, 109 KTFTIKRFLAK OSCAR, SCLC, UEC 110 SAAPPSYFR RCC, UEC 113 QLDSNRLTY HCC BRCA, GBC, GC, GEJC, 115 FVDNQYWRY NSCLC,OSCAR, PACA, SCLC 116 AMLLY NSCLC, PACA BRCA, CRC, HNSCC, MEL, NSCLC, 117 APRLLLLAVL OSCAR, PRCA, RCC, SCLC, UBC, UEC Seq ID No Sequence Peptide tation on tumor types 118 SPASRSISL NHL, OSCAR, RCC 119 APLPRPGAVL MEL, OSCAR 120 RPAMNYDKL CRC BRCA, CRC, HNSCC, MEL, NHL, 123 KPSESIYSAL NSCLC, OSCAR, SCLC, UBC 124 LPSDSHFKITF CRC, HNSCC, NHL, OSCAR, SCLC 125 VPVYILLDEM CCC, GC, HNSCC, UEC AML, BRCA, CRC, GBM, HCC, HNSCC, MEL, NSCLC, OSCAR, PACA, PRCA, 127 APRAGSQW RCC, SCLC, UBC, UEC BRCA, CRC, NSCLC, OSCAR, SCLC, 129 APRPASSL UEC 133 MPNLPSTTSL UEC 141 SPMTSLLTSGL UEC 146 IPRPEVQAL AML, CRC, GC, HNSCC, MEL 147 APRWFPQPTW BRCA 148 GPL AML, BRCA, NHL, RCC AML, BRCA, CCC, CRC, HCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, 149 GPREALSRL RCC, SCLC, UEC 150 MAAVKQAL CCC, NSCLC, PACA 151 HLLLKVLAF HNSCC 152 MGSARVAEL HNSCC 156 HVKEKFLL CCC, HNSCC 157 EAMKRLSYI CCC, HNSCC, PACA 174 LNVF NSCLC 176 AEIEPKADGSW CCC, NSCLC, PRCA AML, BRCA, CCC, CLL, CRC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, 178 NELFRDGVNW PACA, PRCA, SCLC, UBC, UEC 179 REAGDEFEL CCC, NSCLC, SCLC CRC, HCC, MEL, NSCLC, OSCAR, 180 REAGDEFELRY PACA, RCC, UEC 181 GEGPKTSW NSCLC 182 KEATEAQSL NSCLC 184 AELEALTDLW NHL, NSCLC, NSCLC 186 REGPEEPGL CC 188 AEFAKKQPWW CCC, CLL, CRC, MEL, NHL, NSCLC AML, BRCA, CCC, CLL, CRC, GC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, 191 EEDAALFKAW PACA, PRCA, RCC, SCLC, UBC, UEC Seq ID No Sequence e Presentation on tumor types 192 NRL BRCA, HCC, NSCLC, OSCAR, UEC BRCA, CCC, CRC, GC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, 196 REMPGGPVW SCLC, UBC, UEC 197 AEVLLPRLV NSCLC, PACA, UEC 199 REIDESLIFY NSCLC 200 AESIPTVSF NSCLC 208 TEVSRTEAI NSCLC, UEC 211 SPLW NHL CLL, GC, GEJC, HNSCC, NHL, NSCLC, 215 SEDGLPEGIHL PACA 216 IMFDDAIERA UEC 217 VSSSLTLKV BRCA, RCC BRCA, HCC, NHL, NSCLC, OSCAR, 224 SLPRFQVTL UBC, UEC 225 SVFAHPRKL BRCA, OSCAR 226 QVDPKKRISM BRCA, NHL, NSCLC, SCLC CCC, CRC, GBC, GC, HCC, HNSCC, NSCLC, OSCAR, PACA, SCLC, UBC, 227 YTFRYPLSL UEC 228 RLWDWVPLA AML, NHL 235 SAIETSAVL NSCLC, UEC 237 SAMGTISIM UEC 240 FSTDTSIVL PACA 241 RQPNILVHL UEC 243 YASEGVKQV UEC AML, BRCA, CCC, CRC, GBC, GBM, GC, GEJC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, RCC, 245 LAVEGGQSL SCLC, UBC, UEC 246 RYLAWHAVF HCC, NHL, NSCLC, PACA, SCLC 247 ARPPWMWVL BRCA, GBC, HNSCC, OSCAR 251 KQRQVLIFF GBM, NSCLC, OSCAR, PACA, RCC 252 LYQPRASEM NHL 256 RTEEVLLTFK RCC, SCLC, UEC 257 VTADHSHVF UEC 259 KTLELRVAY GBC, HNSCC 260 GTNTVILEY MEL, PACA, UEC 262 RSRLNPLVQR HNSCC, NSCLC 264 AIKVIPTVFK HNSCC, MEL, NSCLC, RCC, UEC 268 GLLGLSLRY PRCA Seq ID No Sequence Peptide Presentation on tumor types 269 RLKGDAWVYK MEL, NHL, OSCAR, UEC 271 RMFADDLHNLNK NSCLC 273 RVNAIPFTY GBC 275 STTFPTLTK UEC 277 TTALKTTSR NSCLC 279 SVSSETTKIKR UEC 280 SVSGVKTTF HCC, UEC 281 RAKELEATF CLL, GC, NSCLC 283 IVQEPTEEK HCC, NHL, NSCLC 286 TVAPPQGVVK HCC 288 SPVTSVHGGTY NHL 289 RWEKTDLTY CRC, UEC 291 ETIRSVGYY GBM, NSCLC, UBC 295 YPLRGSSIFGL UEC 296 YPLRGSSI UEC AML, CCC, CRC, GC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, 299 LHY RCC, UEC AML, BRCA, CLL, CRC, GC, HCC, HNSCC, MEL, NSCLC, OSCAR, PACA, 300 IPMAAVKQAL RCC, UEC 302 ALL BRCA, CRC, GBM, UBC 306 HSA AML, CCC, HCC, MEL, NSCLC, UBC 307 LPYGPGSEAAAF BRCA, UEC 308 YPEGAAYEF PRCA, UEC 314 VPDQPHPEI PACA 315 SPRENFPDTL HNSCC AML, BRCA, CLL, CRC, GBC, GBM, GC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, RCC, SCLC, 317 FPFQPGSV UBC, UEC CCC, CLL, GC, HNSCC, MEL, NSCLC, 318 FPNRLNLEA PRCA, RCC, SCLC, UBC 319 SPAEPSWATL BRCA, GC, NSCLC, OSCAR AML, BRCA, CCC, CRC, GBC, GBM, GC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, RCC, SCLC, 320 FPMSPVTSV UBC, UEC AML, BRCA, CLL, CRC, GBC, GBM, GC, HCC, HNSCC, MEL, NHL, NSCLC, 321 SPMDTFLLI OSCAR, PACA, PRCA, RCC, SCLC, Seq ID No Sequence e Presentation on tumor types UBC, UEC 322 SPDPSKHLL NHL, NSCLC, PRCA, RCC CLL, CRC, GC, MEL, NHL, NSCLC, 324 VPYRVVGL PRCA, SCLC 325 GPRNAQRVL CRC, GBC, NHL, NSCLC BRCA, CCC, CRC, GBC, GC, NSCLC, 326 AAF OSCAR, PACA, RCC, SCLC, UEC 330 FPFVTGSTEM UEC 331 FPHPEMTTSM UEC 332 FPHSEMTTL NSCLC, PACA 333 FPHSEMTTVM NSCLC, SCLC, UEC 334 FPYSEVTTL NSCLC, SCLC, UEC 335 HPDPVGPGL NSCLC, UEC 337 HPVETSSAL UEC 355 SPLVTSHIM UEC 363 TAKTPDATF CCC 369 FPHSEMTTV PACA, UEC 371 LYVDGFTHW NSCLC, UEC 376 RPRSPAGQVA PACA 378 RPRSPAGQVAA NHL, PACA, SCLC BRCA, GBM, HCC, NSCLC, PRCA, 385 SPALHIGSV SCLC, UBC, UEC 386 FPFNPLDF GC, NHL 388 SPAPLKLSRTPA MEL 389 SPGAQRTFFQL AML, MEL 391 APSTPRITTF HCC, NHL 392 KPIESTLVA GBM, MEL, NSCLC, UEC 393 EI CRC 395 VLLPRLVSC NSCLC 399 RELLHLVTL NSCLC, SCLC, UEC 403 EEAQWVRKY BRCA, CLL, NHL BRCA, CCC, CLL, CRC, GBC, GC, HCC, MEL, NHL, NSCLC, OSCAR, SCLC, 404 NEAIMHQY UBC, UEC 405 NEIWTHSY NSCLC, UEC 407 AEHEGVSVL NSCLC, UEC 408 LEKALQVF CRC, GC, HNSCC, OSCAR, UEC 409 REFVLSKGDAGL GBC, GC, GEJC, HNSCC, NSCLC BRCA, HNSCC, NSCLC, OSCAR, SCLC, 410 SEDPSKLEA UEC Seq ID No Sequence Peptide Presentation on tumor types BRCA, CRC, GBC, GBM, GC, NHL, NSCLC, OSCAR, PRCA, SCLC, UBC, 411 LVY UEC 414 KAW CLL, CRC, MEL, NHL BRCA, CLL, CRC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PRCA, UBC, 415 REEDAALFKAW UEC 416 SEEETRVVF AML, CRC, HNSCC, NSCLC, UEC AML, BRCA, CRC, GBM, GC, HNSCC, NHL, NSCLC, OSCAR, PACA, PRCA, 417 AEHFSMIRA RCC, UEC BRCA, CCC, CRC, HCC, NSCLC, 418 FEDAQGHIW OSCAR, PACA, UBC, UEC BRCA, CCC, CRC, GC, HNSCC, MEL, 419 HEFGHVLGL NSCLC, OSCAR, PACA, UEC 420 FESHSTVSA UEC 423 SEVPTGTTA GBC, GBM 425 SEVPLPMAI NSCLC, UEC 429 REKFIASVI UEC 430 DEKILYPEF UEC 431 ELNKA CRC, OSCAR, SCLC, UEC 432 EEQYIAQF OSCAR, SCLC GBM, GC, HCC, HNSCC, NSCLC, 433 SDSQVRAF OSCAR, RCC, SCLC, UEC 436 REPGDIFSEL CRC 437 TEAVVTNEL CRC, GC, NSCLC, SCLC, UEC CCC, CLL, CRC, GC, HNSCC, MEL, 438 SEVDSPNVL NHL, NSCLC, SCLC, UBC 442 |LSKLTD|QY BRCA, GBM, NHL, NSCLC BRCA, GBC, GBM, HNSCC, MEL, NHL, 443 GTFNPVSLW NSCLC, OSCAR, PACA, SCLC BRCA, CCC, CRC, GBM, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, 444 KLSQKGYSW PRCA, SCLC, UBC 445 LHITPGTAY HCC, PRCA AML, BRCA, CRC, HCC, HNSCC, MEL, NHL, NSCLC, OSCAR, PACA, PRCA, 446 GRIVAFFSF SCLC, UBC, UEC 447 MQVLVSRI GC, NSCLC, PACA, PRCA, RCC, SCLC 448 LSQKGYSW NHL, NSCLC, UBC 451 DYLNEWGSRF NSCLC, OSCAR, UEC 454 AQTDPTTGY GBM, GC, NSCLC Seq ID No Sequence Peptide Presentation on tumor types 455 AAAANAQW BRCA, UEC 456 LGEW BRCA, UEC 457 NAAAAANAQVY BRCA, NSCLC, UEC 458 TDTLIHLM UEC BRCA, CCC, CRC, GBM, HNSCC, MEL, NSCLC, OSCAR, PACA, PRCA, SCLC, 459 KVAGERYW UBC 460 RLSSATANALY GBC 461 AQRMTTQLL CRC, MEL, NSCLC, RCC 462 QRMTTQLLL NSCLC, RCC, UEC 466 DLIESGQLRER UEC 467 MQMQERDTL GEJC, HNSCC, NHL, NSCLC, OSCAR CCC, CRC, GBC, GEJC, NSCLC, 471 AQRLDPWF OSCAR, PACA, SCLC, UBC 472 PL SCLC, UEC 474 AADGGLRASVTL BRCA, NSCLC, OSCAR 477 RIQQQTNTY GBM, SCLC 479 TEGSHFVEA BRCA, SCLC, UEC BRCA, CRC, HNSCC, MEL, NSCLC, 480 GRADIMIDF OSCAR, SCLC, UEC BRCA, GBC, HNSCC, MEL, NSCLC, 481 GRWEKTDLTY OSCAR, PACA, SCLC, UBC, UEC HNSCC, NSCLC, OSCAR, PACA, SCLC, 482 DLTYR UEC 484 AWLRSAAA CCC 485 VRFPVHAAL MEL, NSCLC, OSCAR 486 DRFFWLKV NSCLC, SCLC 487 GMADILVVF NSCLC AML, CLL, GC, HCC, HNSCC, NHL, 488 RSFSLGVPR NSCLC, PRCA, SCLC, UEC 490 AEVQKLLGP HNSCC, NSCLC, OSCAR, UEC 491 EAYSSTSSW GBC, UEC 493 DTNLEPVTR UEC 495 EVPSGATTEVSR UEC 496 EVPTGTTAEVSR UEC 498 EWPELGTQGR UEC 503 TVFDKAFTAA NSCLC 507 TSIFSGQSL UEC 508 TVAKTTTTF UEC 509 GRGPGGVSW NSCLC 518 TSDFPTITV PACA Seq ID No Sequence Peptide Presentation on tumor types 520 THSAMTHGF NHL 527 QSTPYVNSV UEC 528 TRTGLFLRF HNSCC, NSCLC, UEC AML, CCC, GBC, GC, HCC, MEL, NHL, NSCLC, OSCAR, RCC, SCLC, UBC, 533 ETF UEC 537 IRRLKELKDQ NSCLC CCC, GC, HNSCC, NSCLC, OSCAR, 539 IPIPSTGSVEM PRCA, SCLC, UBC, UEC 540 AGIPAVALW HCC, NSCLC, OSCAR 541 RLSPAPLKL GBM, NSCLC 544 LRNPSIQKL GBM 545 RVGPPLLI BRCA, CRC, NSCLC, OSCAR, UEC CRC, GBM, HNSCC, MEL, NSCLC, 546 GRAFFAAAF OSCAR, PACA, SCLC, UBC, UEC 547 EVNKPGVYTR HCC, UEC 549 ARSKLQQGL MEL BRCA, HCC, MEL, NSCLC, PRCA, 550 RRFKEPWFL SCLC, UBC, UEC 563 PNFSGNWKIIRSENFEEL NSCLC 589 APDAKSFVLNLGKDSNNL NSCLC 590 RVRGEVAPDAKSFVLNLG NSCLC 591 VRGEVAPDAKSFVLNL NSCLC, RCC 592 VRGEVAPDAKSFVLNLG NSCLC, RCC 593 GEVAPDAKSFVLNLG NSCLC, RCC 594 VRGEVAPDAKSFVLN NSCLC, RCC 598 EALSNKVDEL NSCLC 599 AESLFREALSNKVDE NSCLC 607 LTVAEVQKLLGPHVEGLKAEE NSCLC 608 LTVAEVQKLLGPHVEGLKAE NSCLC 609 LTVAEVQKLLGPHVEGLKA NSCLC 610 LTVAEVQKLLGPHVEGLK NSCLC 611 LTVAEVQKLLGPHVEGL NSCLC 612 TVAEVQKLLGPHVEGLK NSCLC 613 LTVAEVQKLLGPHVEG NSCLC 614 TVAEVQKLLGPHVEGL NSCLC 615 VAEVQKLLGPHVEGLK NSCLC 616 TVAEVQKLLGPHVEG NSCLC 617 LLGPHVEGL NSCLC 618 VAEVQKLLGPHVEG NSCLC Seq ID No Sequence Peptide Presentation on tumor types 619 VAEVQKLLGPHVE NSCLC 620 EVQKLLGPHVEG NSCLC 625 LPVLGQPIIRSIPQG NSCLC 628 DALRGLLPVLGQPIIRSIPQ NSCLC 629 GLLPVLGQPIIRSIPQGIVA NSCLC 630 ALRGLLPVLGQPIIRSIPQ NSCLC 633 LRGLLPVLGQPIIRSIPQ NSCLC 634 DALRGLLPVLGQPIIRS NSCLC 635 ALRGLLPVLGQPIIRS NSCLC 637 ALRGLLPVLGQPIIR NSCLC 638 LRGLLPVLGQPIIRS NSCLC 639 ALRGLLPVLGQPII NSCLC 646 GLLPVLGQPIIRSIPQGIVAAWRQ NSCLC 648 GLLPVLGQPIIRSIPQGIVAA NSCLC 651 LPVLGQPIIRSIPQGIVAA NSCLC 653 LPVLGQPIIRSIPQGIVA NSCLC 654 PVLGQPIIRSIPQGIVA GC, NSCLC 656 VLGQPIIRSIPQGIVA NSCLC 661 VLGQPIIRSIPQG NSCLC 666 LPLTVAEVQKLLGPHVEG NSCLC BRCA, CRC, GBC, GC, NSCLC, PACA, 668 AVLPLTVAEVQK UEC 677 IWAVRPQDLDTCDPR NSCLC 680 GVRGSLLSEADVRALGGLA NSCLC 682 GVRGSLLSEADVRALGGL NSCLC 686 VRGSLLSEADVRALGGL NSCLC 694 GSLLSEADVRALGG NSCLC 695 RGSLLSEADVRALG NSCLC 697 GSLLSEADVRALG NSCLC 717 IPQGIVAAWRQRSSRDPS GO 730 LPGRFVAESAEVL NSCLC Exgression ing of genes encoding the gegtides of the invention Over-presentation or specific tation of a peptide on tumor cells ed to normal cells is sufficient for its usefulness in therapy, and some peptides are tumor-specific despite their source n occurring also in normal tissues. Still, mRNA expression profiling adds an additional level of safety in selection of peptide targets for immunotherapies. Especially for eutic options with high safety risks, such as affinity-matured TCRs, the ideal target peptide will be derived from a protein that is unique to the tumor and not found on normal tissues.
RNA sources and preparation Surgically removed tissue specimens were provided as indicated above (see Example 1) after written informed consent had been obtained from each t. Tumor tissue specimens were snap-frozen ately after surgery and later homogenized with mortar and pestle under liquid nitrogen. Total RNA was prepared from these samples using TRl Reagent (Ambion, Darmstadt, Germany) followed by a cleanup with RNeasy (QIAGEN, Hilden, Germany); both methods were performed according to the manufacturer's protocol.
Total RNA from healthy human tissues for RNASeq experiments was ed from: Asterand (Detroit, MI, USA & Royston, Herts, UK); Bio-Options lnc. (Brea, CA, USA); Geneticist lnc. (Glendale, CA, USA); ProteoGenex lnc. (Culver City, CA, USA); Tissue Solutions Ltd (Glasgow, UK).
Total RNA from tumor tissues for RNASeq experiments was obtained from: Asterand (Detroit, MI, USA & Royston, Herts, UK); BioCat GmbH (Heidelberg, Germany); BioServe (Beltsville, MD, USA); Geneticist lnc. (Glendale, CA, USA); lstituto Nazionale Tumori "Pascale" (Naples, Italy); ProteoGenex lnc. (Culver City, CA, USA); University Hospital Heidelberg lberg, Germany).
Quality and quantity of all RNA samples were assessed on an Agilent 2100 Bioanalyzer (Agilent, onn, Germany) using the RNA 6000 Pico LabChip Kit (Agilent).
RNAseg experiments Gene sion analysis of - tumor and normal tissue RNA samples was performed by next generation sequencing q) by CeGaT (Ttibingen, Germany). Briefly, sequencing ies are prepared using the lllumina HiSeq v4 reagent kit according to the er’s protocol (lllumina Inc, San Diego, CA, USA), which includes RNA fragmentation, cDNA conversion and addition of sequencing adaptors. Libraries derived from multiple s are mixed equimolar and ced on the lllumina HiSeq 2500 sequencer according to the manufacturer’s instructions, generating 50 bp single end reads. Processed reads are mapped to the human genome (GRCh38) using the STAR software. Expression data are provided on transcript level as RPKM (Reads Per Kilobase per Million mapped reads, generated by the software Cufflinks) and on exon level (total reads, ted by the software Bedtools), based on annotations of the ensembl sequence database (Ensembl77). Exon reads are normalized for exon length and alignment size to obtain RPKM values. ary expression profiles of source genes of the present invention that are highly over-expressed or exclusively expressed in ovarian cancer are shown in Figure 1.
Expression scores for further exemplary genes are shown in Table 10.
Table 10: Expression scores. The table lists peptides from genes that are very highly over-expressed in 00 tumors compared to a panel of normal s (+++), highly overexpressed in 00 tumors compared to a panel of normal tissues (++) or over-expressed in 00 tumors compared to a panel of normal tissues (+).The baseline for this score was calculated from measurements of the following relevant normal tissues: adipose tissue, adrenal gland, bile duct, blood cells, blood vessels, bone marrow, brain, cartilage, gus, eye, gallbladder, heart, head&neck, kidney, large intestine, liver, lung, lymph node, nerve, parathyroid, pancreas, pituitary, skeletal , skin, small intestine, spleen, stomach, thyroid gland, trachea, urinary bladder. In case expression data for several samples of the same tissue type were available, the arithmetic mean of all respective samples was used for the calculation.
Seq ID Sequence Gene Expression 1 MIPTFTALL ++ RLLDFINVL +++ 6 SLGKHTVAL +++ 1 0 RYSDSVGRVSF + 11 SYSDLHYGF ++ 12 EML +++ 13 VYTFLSSTL +++ 14 TVL ++ 16 SRL +++ 17 RFTTMLSTF +++ 18 KYPVHIYRL + RMASPVNVK ++ 21 AVRKPIVLK + 22 SLKERNPLK ++ 23 GMMKGGIRK +++ GTSPPSVEK ++ 26 RISEYLLEK +++ 27 VLYGPAGLGK +++ 28 KTYETNLEIKK +++ 29 QQFLTALFY +++ ALEVAHRLK + 31 MLLY +++ 32 SPNKGTLSV + 33 SPTFHLTL + 34 LPRGPLASLL ++ FPDNQRPAL ++ 36 APAAWLRSA +++ 37 RPLFQKSSM +++ 38 SPHPVTALLTL ++ 39 RPAPFEVVF ++ 40 KPGTSYRVTL +++ 42 TLKVTSAL + 43 ALKARTVTF + 47 MPNLRSVDL +++ 51 SLRLKNVQL +++ 52 AEFLLRIFL + 53 MEHPGKLLF +++ 54 AEITITTQTGY ++ 55 HETETRTTW ++ Seq ID Sequence Gene Expression 56 SEPDTTASW ++ 57 QESDLRLFL +++ 58 QL +++ 59 SENVTMKW +++ 60 GLLSLTSTLYL + 61 YMVHIQVTL ++ 62 KVLGVNVML ++ 63 MMEEMIFNL ++ 64 FLDPDRHFL ++ 66 GLLQELSSI +++ 67 SLLLPSIFL +++ 69 TTYEGSITV ++ 70 VLQGLLRSL +++ 71 YLEDTDRNL + 72 YLTDLQVSL + 73 FLIEELLFA +++ 74 SQSPSVSQL +++ 75 KVVSVLYNV +++ 76 KYVAELSLL +++ 77 RYGPVFTV +++ 78 SFAPRSAVF ++ 82 SYFRGFTLI +++ 83 GTYAHTVNR +++ 84 TAAK +++ 87 AVAPPTPASK ++ 88 VVHAVFALK + 89 RVAELLLLH +++ 90 KVAGERYVYK ++ 91 YEK ++ 92 SVFPIENIY ++ 96 TAFGGFLKY +++ 97 TMLDVEGLFY ++ 98 LLQPPPLLAR +++ 100 RLFTSPIMTK ++ 101 RVFTSSIKTK ++ 102 LVK ++ 103 TSRSVDEAY ++ 104 VLADSVTTK ++ 107 RLQEWKALK +++ Seq ID Sequence Gene Expression 108 VLYPVPLESY +++ 110 SAAPPSYFR +++ 111 ELGY ++ 112 TVTGAEQIQY ++ 113 QLDSNRLTY ++ 114 VMEQSAGIMY +++ 115 FVDNQYWRY +++ 116 AMLLY +++ 117 APRLLLLAVL ++ 118 SPASRSISL ++ 119 APLPRPGAVL +++ 120 RPAMNYDKL ++ 121 VPNQSSESL +++ 122 YPGFPQSQY +++ 123 KPSESIYSAL +++ 124 LPSDSHFKITF +++ 125 VPVYILLDEM ++ 126 KPGPEDKL ++ 128 YPRTITPGM + 129 APRPASSL ++ 130 FPRLVGPDF + 131 APTEDLKAL ++ 132 IPGPAQSTI ++ 133 MPNLPSTTSL ++ 135 RVRSTISSL ++ 136 SPFSAEEANSL ++ 137 SPGATSRGTL ++ 138 SPMATTSTL ++ 139 SPQSMSNTL ++ 140 SPRTEASSAVL ++ 141 LTSGL ++ 142 TPGLRETSI ++ 143 SPAMTSTSF ++ 144 SPSPVSSTL ++ 145 SPSSPMSTF ++ 147 APRWFPQPTW +++ 151 HLLLKVLAF +++ 152 AEL +++ 154 MLRKIAVAA ++ WO 38257 Seq ID Sequence Gene Expression 155 NKKMMKRLM +++ 156 HVKEKFLL ++ 157 EAMKRLSYI + 159 VLKHKLDEL ++ 160 AF ++ 1 61 ALKTTTTAL ++ 162 QAKTHSTL ++ 163 QGLLRPVF +++ 164 SIKTKSAEM ++ 165 SPRFKTGL ++ 166 TPKLRETSI ++ 167 TSH ERLTTL ++ 168 TSHERLTTY ++ 169 TSMPRSSAM ++ 170 YLLEKSRVI +++ 171 AL +++ 172 KLKERNREL +++ 173 AEAQVGDERDY + 174 AEATARLNVF + 175 AEIEPKADG + 176 AEIEPKADGSW + 177 TEVGTMNLF ++ 181 GEGPKTSW + 183 QKV ++ 184 AELEALTDLW ++ 185 AERQPGAASL ++ 186 REGPEEPGL ++ 187 GEAQTRIAW ++ 189 KEFLFNMY ++ 190 YEVARILNL ++ 193 LEAQQEAL ++ 194 KEVDPTSHSY +++ 195 AEDKRHYSV + 196 REMPGGPVW +++ 197 AEVLLPRLV ++ 198 QEAARAAL ++ 199 REIDESLIFY ++ 200 AESIPTVSF ++ 201 AETILTFHAF ++ Seq ID Sequence Gene Expression 202 HESEATASW ++ 203 AQDTL ++ 204 RETSTSEETSL ++ 205 SEITRIEM ++ 206 SESVTSRTSY +++ 207 TEARATSDSW ++ 208 TEVSRTEAI ++ 209 TEVSRTEL ++ 210 VEAADIFQNF ++ 211 EEKVFPSPLW +++ 212 MEQKQLQKRF +++ 214 VEQTRAGSLL ++ 216 IMFDDAIERA +++ 217 VSSSLTLKV + 218 TIASQRLTPL ++ 219 PLPRPGAVL +++ 220 RMTTQLLLL ++ 225 SVFAHPRKL ++ 226 QVDPKKRISM ++ 227 YTFRYPLSL ++ 229 ISVPAKTSL ++ 230 TSL ++ 231 HHL ++ 232 TISSLTHEL ++ 233 GSDTSSKSL ++ 234 GVATRVDAI +++ 235 SAIETSAVL ++ 236 SAIPFSMTL ++ 237 SAMGTISIM ++ 238 PLLVLFTI +++ 239 FAVPTGISM ++ 240 FSTDTSIVL ++ 241 RQPNILVHL ++ 242 STIPALHEI ++ 243 YASEGVKQV ++ 244 DTDSSVHVQV ++ 246 RYLAWHAVF + 247 WVL +++ 248 SVIQHLGY ++ Seq ID Sequence Gene Expression 249 VYTPTLGTL ++ 250 THSF ++ 252 LYQPRASEM +++ 254 IIQHLTEQF +++ 255 VFVSFSSLF +++ 256 RTEEVLLTFK ++ 257 VTADHSHVF +++ 258 GAYAHTVNR +++ 259 KTLELRVAY + 260 GTNTVILEY ++ 261 YQR ++ 262 RSRLNPLVQR ++ 263 SSSSATISK ++ 266 ISYSGQFLVK +++ 267 VTDLISPRK +++ 268 GLLGLSLRY +++ 269 RLKGDAWVYK ++ 270 AVFNPRFYRTY +++ 272 RQPERTILRPR ++ 273 RVNAIPFTY ++ 274 TVF ++ 275 STTFPTLTK ++ 276 MEF ++ 277 TTALKTTSR ++ 278 NLSSITH ER ++ 279 SVSSETTKIKR ++ 280 SVSGVKTTF ++ 281 RAKELEATF +++ 282 CLTRTGLFLRF +++ 285 GTVNPTVGK ++ 286 TVAPPQGVVK + 287 RRIHTGEKPYK ++ 288 SPVTSVHGGTY + 289 RWEKTDLTY ++ 290 DMDEEIEAEY +++ 291 ETIRSVGYY ++ 292 NVTMKWSVLY +++ 293 VPDSGATATAY +++ 294 YPLRGSSIF +++ Seq ID Sequence Gene Expression 295 YPLRGSSIFGL +++ 296 YPLRGSSI +++ 297 GLL + 298 YPTEHVQF + 299 HPGSSALHY ++ 301 SPRRSPRISF + 302 RVEEVRALL +++ 303 TAF +++ 304 LPRPGAVL +++ 305 TPWAESSTKF ++ 306 APVIFSHSA ++ 307 SEAAAF +++ 308 YPEGAAYEF +++ 309 FPQSQYPQY +++ 310 RPNPITIIL +++ 311 RPLFWVSL +++ 312 LPYFREFSM +++ 313 KVKSDRSVF +++ 315 SPRENFPDTL +++ 316 EPKTATVL ++ 320 FPMSPVTSV + 321 SPMDTFLLI + 322 SPDPSKHLL + 323 RPMPNLRSV +++ 324 VPYRVVGL +++ 326 VPSEIDAAF ++ 327 SPLPVTSLI ++ 328 EPVTSSLPNF ++ 329 FPAMTESGGMIL ++ 330 STEM ++ 331 FPHPEMTTSM ++ 332 FPHSEMTTL ++ 333 FPHSEMTTVM ++ 334 FPYSEVTTL ++ 335 HPDPVGPGL +++ 336 HPKTESATPAAY ++ 337 HPVETSSAL ++ 338 HVTKTQATF ++ 339 LPAGTTGSLVF ++ Seq ID Sequence Gene Expression 340 LPEISTRTM ++ 341 LPLDTSTTL ++ 342 MTF ++ 343 LPSVSGVKTTF ++ 344 LPTQTTSSL ++ 345 LPTSESLVSF ++ 346 LPWDTSTTLF ++ 347 MPLTTGSQGM ++ 348 MPNSAIPFSM ++ 349 MPSLSEAMTSF ++ 350 NPSSTTTEF ++ 351 NVLTSTPAF ++ 352 SPAETSTNM ++ 353 SPAMTTPSL ++ 354 SPLPVTSLL ++ 355 SPLVTSHIM ++ 356 SPNEFYFTV ++ 357 SPSPVPTTL ++ 358 STL ++ 359 SPSTIKLTM ++ 360 SPSVSSNTY ++ 361 SPTHVTQSL ++ 362 SPVPVTSLF ++ 363 TAKTPDATF ++ 364 QRF ++ 365 TPLATTQRFTY ++ 366 TPLTTTGSAEM ++ 367 TPSWTEGF ++ 368 VPTPVFPTM ++ 369 FPHSEMTTV ++ 370 PGGTRQSL ++ 372 PTLL +++ 373 RPRALRDLRIL +++ 374 NPIGDTGVKF +++ 375 AAASPLLLL +++ 376 RPRSPAGQVA +++ 377 RPRSPAGQVAAA +++ 378 RPRSPAGQVAA +++ 379 GPFPLVYVL +++ WO 38257 Seq ID Sequence Gene Expression 380 IPTYGRTF +++ 381 LPEQTPLAF +++ 382 WTF +++ 383 VSL +++ 384 YPGLRGSPM +++ 387 APLKLSRTPA +++ 388 SPAPLKLSRTPA +++ 389 SPGAQRTFFQL ++ 395 VSC ++ 396 REASGLLSL + 397 REGDTVQLL + 399 RELLHLVTL + 400 GEIEIHLL + 403 EEAQWVRKY ++ 404 NEAIMHQY ++ 405 NEIWTHSY ++ 411 LELPPILVY + 412 QEILTQVKQ +++ 413 IEALSGKIEL +++ 416 SEEETRVVF ++ 417 AEHFSMIRA +++ 418 FEDAQGHIW ++ 419 HEFGHVLGL ++ 420 FESHSTVSA ++ 421 GEPATTVSL ++ 422 SETTFSLIF ++ 423 SEVPTGTTA ++ 424 TEFPLFSAA ++ 425 SEVPLPMAI ++ 426 PEKTTHSF ++ 427 HESSSHHDL + 428 LDLGLNHI ++ 429 REKFIASVI +++ 430 DEKILYPEF +++ 432 EEQYIAQF +++ 433 SDSQVRAF +++ 435 REEFVSIDHL +++ 436 REPGDIFSEL +++ 437 TEAVVTNEL + EXAMPLE 3 In vitro immunogenicity for MHC class I presented peptides In order to obtain information regarding the immunogenicity of the TUMAPs of the present invention, the ors performed investigations using an in vitro T-cell priming assay based on repeated stimulations of CD8+ T cells with artificial antigen presenting cells (aAPCs) loaded with peptide/MHC complexes and anti-CD28 antibody. This way the inventors could show genicity for HLA-A*0201, HLA-A*24:02, HLA-A*01:O1, HLA-A*03:O1, HLA-B*O7:02 and HLA-B*44:02 restricted TUMAPs of the invention, demonstrating that these peptides are T-cell epitopes against which CD8+ precursor T cells exist in humans (Table 11).
In vitro priming of CD8+ T cells In order to perform in vitro stimulations by artificial antigen presenting cells loaded with peptide-MHC complex (pMHC) and anti-CD28 antibody, the inventors first isolated CD8+ T cells from fresh HLA-A*02, HLA-A*24, HLA-A*O1, HLA-A*O3, HLA-B*O7 or HLA- B*44 leukapheresis ts via positive ion using CD8 microbeads (Miltenyi Biotec, Bergisch-Gladbach, Germany) of healthy donors obtained from the sity clinics im, Germany, after informed t.
PBMCs and isolated CD8+ lymphocytes were incubated in T-cell medium (TCM) until use consisting of RPMl-Glutamax (lnvitrogen, Karlsruhe, Germany) supplemented with % heat inactivated human AB serum iotech, Aidenbach, Germany), 100 U/ml Penicillin/100 ug/ml Streptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro, Oberdorla, y), 20 pg/ml Gentamycin (Cambrex). 2.5 ng/ml IL- 7 (PromoCell, Heidelberg, Germany) and 10 U/ml lL-2 (Novartis Pharma, Ntirnberg, Germany) were also added to the TCM at this step.
Generation of pMHC/anti-CD28 coated beads, T-cell stimulations and readout was performed in a highly defined in vitro system using four different pMHC les per stimulation condition and 8 different pMHC molecules per readout condition.
The purified co-stimulatory mouse IgG2a anti human CD28 Ab 9.3 (Jung et al., 1987) was chemically biotinylated using sulfo-N-hydroxysuccinimidobiotin as recommended by the manufacturer (Perbio, Bonn, Germany). Beads used were 5.6 pm diameter streptavidin coated polystyrene particles (Bangs Laboratories, Illinois, USA). pMHC used for ve and negative control stimulations were /MLA-001 (peptide ELAGIGILTV (SEQ ID NO. 775) from modified Melan-A/MART-1) and A*0201/DDX5-001 (YLLPAIVHI from DDX5, SEQ ID NO. 776), respectively. 800.000 beads/200 pl were coated in 96-well plates in the presence of 4 x 12.5 ng different biotin-pMHC, washed and 600 ng biotin anti-CD28 were added subsequently in a volume of 200 pl. Stimulations were initiated in 96-well plates by co-incubating 1x106 CD8+ T cells with 2x105 washed coated beads in 200 pl TCM supplemented with 5 ng/ml IL-12 (PromoCell) for 3 days at 37°C. Half of the medium was then exchanged by fresh TCM supplemented with 80 U/ml IL-2 and incubating was continued for 4 days at 37°C. This stimulation cycle was performed for a total of three times. For the pMHC multimer readout using 8 different pMHC molecules per condition, a two-dimensional combinatorial coding approach was used as previously described (Andersen et al., 2012) with minor cations encompassing ng to 5 ent chromes.
Finally, multimeric analyses were performed by staining the cells with Live/dead near IR dye (lnvitrogen, Karlsruhe, Germany), CD8—FITC antibody clone 8K1 (BD, Heidelberg, Germany) and fluorescent pMHC multimers. For analysis, a BD LSRII SORP cytometer equipped with appropriate lasers and filters was used. Peptide ic cells were calculated as percentage of total CD8+ cells. Evaluation of eric analysis was done using the FlowJo re (Tree Star, Oregon, USA). In vitro g of specific multimer+ CD8+ lymphocytes was detected by ing to negative control stimulations. Immunogenicity for a given antigen was detected if at least one evaluable in vitro stimulated well of one healthy donor was found to contain a specific CD8+ T-cell line after in vitro stimulation (i.e. this well contained at least 1% of specific multimer+ among CD8+ T-cells and the percentage of specific er+ cells was at least 10x the median of the negative control stimulations).
In vitro immunogenicity for ovarian cancer peptides For tested HLA class I peptides, in vitro immunogenicity could be demonstrated by generation of peptide specific T-cell lines. Exemplary flow cytometry results after TUMAP-specific multimer ng for 14 peptides of the ion are shown in Figures 2 through 9 together with corresponding negative controls. Results for 118 peptides from the invention are summarized in Table 11a and Table 11b.
Table 11a: in vitro immunogenicity of HLA class I peptides of the invention. Exemplary results of in vitro immunogenicity experiments conducted by the applicant for the peptides of the invention. <20 % = +; 20 % - 49 % = ++; 50 % - 69 %= +++; >= 70 % = Seq ID Sequence Wells positive [%] 773 ALYGKLLKL +++ 774 VYVDDIYVI +++ Table 11b: in vitro immunogenicity of HLA class I peptides of the invention. Exemplary results of in vitro immunogenicity experiments conducted by the applicant for the peptides of the invention. <20 % = +; 20 % - 49 % = ++; 50 % - 69 %= +++; >= 70 % = Seq ID No Sequence gills ve HLA 2 TLLKALLEI ++ A*02 3 ALIYNLVGI ++ N02 4 ALFKAWAL ++++ N02 RLLDFINVL ++ A*02 7 ALQAFEFRV ++++ N02 60 GLLSLTSTLYL + A*02 62 KVLGVNVML ++ N02 64 FLDPDRHFL +++ A*02 66 GLLQELSSI + A*02 67 IFL +++ A*02 71 YLEDTDRNL + A*02 Seq ID No ce Eaglls Ve HLA 73 FLIEELLFA +++ N02 75 KVVSVLYNV +++ N02 11 SYSDLHYGF +++ N24 12 KYEKIFEML + N24 13 VYTFLSSTL + N24 16 IYSPQFSRL + N24 18 YRL + N24 79 SYNEHWNYL + N24 80 TAYMVSVAAF + N24 82 SYFRGFTLI + N24 113 QLDSNRLTY + N01 115 FVDNQYWRY + N01 RMASPVNVK + N03 21 AVRKPIVLK + N03 22 SLKERNPLK + N03 23 GMMKGGIRK ++ N03 24 SMYYPLQLK + A*03 GTSPPSVEK +++ N03 26 RISEYLLEK + A*03 27 VLYGPAGLGK + N03 28 KTYETNLEIKK + N03 ALEVAHRLK ++ N03 83 GTYAHTVNR + N03 84 KLQPAQTAAK + N03 85 VLLGSLFSRK + N03 86 WLLGSLFSRK + N03 87 AVAPPTPASK + N03 90 KVAGERYVYK +++ N03 91 RSLRYYYEK ++ N03 94 ATFERVLLR + N03 95 QSMYYPLQLK + A*03 99 KVVDRWNEK ++ N03 100 IMTK + N03 102 SVLTSSLVK + N03 106 AAFVPLLLK +++ N03 109 KTFTIKRFLAK + N03 110 SAAPPSYFR ++ N03 32 SPNKGTLSV + 907 33 SPTFHLTL ++++ 8*07 Seq ID No SeqUence EQZIIS pOS't'Ve HLA 34 LPRGPLASLL + B*O7 FPDNQRPAL + B*O7 36 APAAWLRSA +++ BW 37 RPLFQKSSM + B*O7 38 ALLTL + B*O7 39 RPAPFEVVF +++ B*O7 40 KPGTSYRVTL ++++ BW 41 RVRSRISNL + B*O7 118 SPASRSISL + B*O7 119 APLPRPGAVL ++ B*O7 120 RPAMNYDKL + B*O7 121 VPNQSSESL + B*O7 123 KPSESIYSAL ++ B*O7 124 LPSDSHFKITF ++ B*O7 128 YPRTITPGM + B*O7 129 APRPASSL + B*O7 130 FPRLVGPDF +++ B*O7 131 KAL ++ B*O7 133 MPNLPSTTSL ++++ B*O7 134 RPIVPGPLL ++ B*O7 139 NTL + B*O7 140 SPRTEASSAVL + B*O7 141 SPMTSLLTSGL ++ B*O7 146 IPRPEVQAL +++ B*O7 147 APRWFPQPTW ++ B*O7 148 KPYGGSGPL + B*O7 149 GPREALSRL ++ B*O7 52 AEFLLRIFL + B*44 53 MEHPGKLLF + B*44 55 HETETRTTW +++ B*44 57 QESDLRLFL + B*44 58 GEMEQKQL ++++ B*44 59 SENVTMKW ++ B*44 174 AEATARLNVF + B*44 175 ADG ++++ B*44 177 TEVGTMNLF ++ B*44 178 NELFRDGVNW + B*44 179 REAGDEFEL + B*44 180 REAGDEFELRY ++++ B*44 Seq ID No SeQuence EQZIIS pOS't'Ve HLA 181 GEGPKTSW + B*44 182 KEATEAQSL + B*44 183 YEKGIMQKV ++++ 13*44 184 AELEALTDLW + B*44 186 REGPEEPGL + B*44 187 GEAQTRIAW ++ B*44 188 AEFAKKQPWW ++ 9144 189 KEFLFNMY ++++ B*44 190 YEVARILNL ++++ B*44 191 EEDAALFKAW +++ 13*44 192 YEFKFPNRL + B*44 195 AEDKRHYSV +++ B*44 197 RLV ++ B*44 198 QEAARAAL ++ 8,144 199 REIDESLIFY + B*44 200 AESIPTVSF +++ B*44 201 FHAF +++ B*44 202 HESEATASW ++ B*44 203 IEHSTQAQDTL ++++ 3*44 205 SEITRIEM ++++ B*44 207 TEARATSDSW + B*44 208 EAI + B*44 209 TEVSRTEL ++++ B*44 210 VEAADIFQNF + B*44 211 EEKVFPSPLW +++ 13*44 212 MEQKQLQKRF ++ B*44 213 KESIPRWYY + B*44 EXAMPLE 4 Synthesis of peptides All peptides were synthesized using standard and stablished solid phase peptide synthesis using the Fmoc-strategy. Identity and purity of each individual peptide have been ined by mass spectrometry and analytical RP-HPLC. The peptides were obtained as white to off-white lyophilizes (trifluoro acetate salt) in es of >50%. All TUMAPs are preferably administered as trifluoro-acetate salts or acetate salts, other salt-forms are also possible.
EXAMPLE 5 MHC Binding Assays Candidate peptides for T cell based therapies according to the present invention were further tested for their MHC binding capacity (affinity). The individual peptide-MHC complexes were produced by UV-ligand exchange, where a UV-sensitive peptide is cleaved upon UV-irradiation, and exchanged with the peptide of interest as analyzed.
Only peptide candidates that can effectively bind and stabilize the peptide-receptive MHC molecules prevent dissociation of the MHC complexes. To determine the yield of the exchange reaction, an ELISA was performed based on the ion of the light chain (02m) of stabilized MHC xes. The assay was performed as generally described in Rodenko et al. (Rodenko et al., 2006). 96 well rp plates (NUNC) were coated over night with 2ug/ml streptavidin in PBS at room temperature, washed 4x and blocked for1h at 37°C in 2% BSA containing blocking buffer. ed HLA-A*02:01/MLA-001 monomers served as rds, covering the range of 15-500 ng/ml. Peptide-MHC monomers of the UV-exchange reaction were diluted 100-fold in blocking buffer. Samples were incubated for 1h at 37°C, washed four times, incubated with 2ug/ml HRP conjugated anti-02m for 1h at 37°C, washed again and ed with TMB solution that is d with NH2804.
Absorption was ed at 450nm. Candidate peptides that show a high exchange yield rably higher than 50%, most preferred higher than 75%) are generally preferred for a generation and production of antibodies or fragments thereof, and/or T cell ors or fragments f, as they show sufficient avidity to the MHC molecules and prevent dissociation of the MHC complexes.
Table 12: MHC class I binding scores. Binding of HLA-class l restricted peptides to HLA-A*02:01 was ranged by peptide exchange yield: >10% = +; >20% = ++; >50 = +++; > 75% = ++++ Peptide Seq ID NO sequence exchange 1 MIPTFTALL +++ Peptide Seq ID No Sequence exchange 2 TLLKALLEI ++++ 3 ALIYNLVGI ++++ 4 ALFKAWAL ++++ RLLDFINVL ++++ 6 SLGKHTVAL +++ 7 ALQAFEFRV ++++ 8 YLVTKVVAV ++++ 9 VLLAGFKPPL + 60 GLLSLTSTLYL ++++ 61 YMVHIQVTL ++++ 62 KVLGVNVML ++++ 63 MMEEMIFNL ++++ 64 FLDPDRHFL ++++ 66 SSI ++++ 67 SLLLPSIFL ++++ 68 KLFDTQQFL ++++ 69 TTYEGSITV ++++ 70 VLQGLLRSL ++++ 71 YLEDTDRNL ++++ 72 YLTDLQVSL ++++ 73 FLIEELLFA ++++ 75 KVVSVLYNV ++++ 216 IMFDDAIERA ++++ 217 VSSSLTLKV + 219 PLPRPGAVL + 220 RMTTQLLLL +++ 221 SLLDLYQL ++ 222 GCPL ++++ 223 SL + 224 SLPRFQVTL ++++ 225 SVFAHPRKL +++ 227 YTFRYPLSL +++ 228 RLWDWVPLA ++++ 229 TSL + 231 SVTESTHHL +++ 232 TISSLTHEL ++++ 234 GVATRVDAI ++ 236 SAIPFSMTL +++ 241 RQPNILVHL ++ Seq ID NO Sequence Efghgrfge 242 STIPALHEI +++ 243 YASEGVKQV +++ 244 DTDSSVHVQV + Table 13: MHC class I binding scores. Binding of HLA-class l restricted peptides to HLA-A*24:02 was ranged by peptide exchange yield: >10% = +; >20% = ++; >50 = +++; > 75% = ++++ Seq ID Peptide Sequence No exchange 1O RYSDSVGRVSF ++++ 11 SYSDLHYGF ++++ 12 KYEKIFEML ++++ 13 VYTFLSSTL ++++ 14 FYFPTPTVL ++++ VYHDDKQPTF ++++ 16 IYSPQFSRL ++++ 17 RFTTMLSTF ++++ 18 YRL ++++ 19 KWKVFHQF ++++ 76 KYVAELSLL ++++ 77 RYGPVFTV ++++ 78 AVF ++++ 79 NYL ++++ 80 TAYMVSVAAF +++ 81 VYNHTTRPL ++++ 82 SYFRGFTLI ++++ 246 RYLAWHAVF ++++ 249 GTL ++++ 252 LYQPRASEM +++ 255 VFVSFSSLF +++ Table 14: MHC class I binding scores. g of HLA-class l restricted peptides to HLA-A*O1 :01 was ranged by peptide exchange yield: >10% = +; >20% = ++; >50 = +++; > 75% = ++++ Seq ID Peptide Sequence No exchange 31 LLDEGAMLLY ++++ WO 38257 2018/051952 Seq ID Peptide Sequence No exchange 112 TVTGAEQIQY ++ 113 QLDSNRLTY +++ 114 VMEQSAGIMY ++ 115 FVDNQYWRY +++ 116 VLLDEGAMLLY ++ 288 SPVTSVHGGTY ++ 289 RWEKTDLTY ++ 290 DMDEEIEAEY ++ 291 ETI RSVGYY +++ 292 NVTMKWSVLY +++ Table 15: MHC class I binding scores. Binding of HLA-class | restricted peptides to HLA-A*O3:O1 was ranged by peptide exchange yield: >10% = +; >20% = ++; >50 = +++; > 75% = ++++ SeNoq ID Pe tide Sequence exthange RMASPVNVK ++++ 21 AVRKPIVLK +++ 22 SLKERNPLK ++ 23 GMMKGGIRK +++ 24 QLK +++ GTSPPSVEK ++ 26 RISEYLLEK ++ 27 VLYGPAGLGK +++ 28 KTYETNLEIKK +++ 3O ALEVAHRLK ++ 83 GTYAHTVNR +++ 84 KLQPAQTAAK ++ 85 VLLGSLFSRK ++ 86 WLLGSLFSRK ++ 87 AVAPPTPASK ++ 88 VVHAVFALK +++ 89 RVAELLLLH ++ 90 KVAGERYVYK +++ 91 RSLRYYYEK ++ 93 TNK ++ 94 ATFERVLLR +++ 95 QSMYYPLQLK ++ SeNoq ID Pe Sequence getide 98 LLQPPPLLAR ++ 99 NEK ++ 100 RLFTSPIMTK +++ 101 RVFTSSIKTK ++ 102 LVK ++ 104 VLADSVTTK ++ 105 RLFSWLVNR +++ 106 AAFVPLLLK ++ 107 RLQEWKALK +++ 109 KTFTIKRFLAK ++ 110 SAAPPSYFR ++ 256 RTEEVLLTFK ++ 257 VTADHSHVF + 258 GAYAHTVNR +++ 259 KTLELRVAY ++ 260 GTNTVILEY +++ 261 HTFGLFYQR ++ 262 RSRLNPLVQR ++ 263 SSSSATISK ++ 264 AIKVIPTVFK ++ 265 QIHDHVNPK ++ 266 FLVK +++ 267 VTDLISPRK ++ 269 RLKGDAWVYK +++ 270 AVFNPRFYRTY ++ 271 RMFADDLHNLNK +++ 272 RQPERTILRPR ++ 273 RVNAIPFTY +++ 274 KTFPASTVF + 275 STTFPTLTK ++ 276 VSKTTGMEF + 277 TTALKTTSR + 278 NLSSITHER ++ 279 SVSSETTKIKR ++ 280 SVSGVKTTF ++ 281 RAKELEATF + 283 IVQEPTEEK ++ 284 KSLIKSWKK ++ 285 GTVNPTVGK ++ Seq ID Peptide Sequence No exchange 286 TVAPPQGVVK ++ 287 RRIHTGEKPYK ++ Table 16: MHC class I binding scores. Binding of HLA-class | restricted peptides to HLA-B*07:O2 was ranged by peptide exchange yield: >10% = +; >20% = ++; >50 = +++; > 75% = ++++ Peptide Seq ID No Sequence exchange 32 SPNKGTLSV "+++" 33 SPTFHLTL "+++" 34 LPRGPLASLL "+++" FPDNQRPAL "+++" 36 APAAWLRSA "++" 37 RPLFQKSSM "+++" 38 ALLTL "+++" 39 RPAPFEVVF "+++" 4O KPGTSYRVTL "+++" 41 RVRSRISNL "+++" 118 SPASRSISL "+++" 119 APLPRPGAVL "+++" 120 DKL "++" 121 VPNQSSESL "+++" 122 YPGFPQSQY "++" 123 KPSESIYSAL "+++" 124 LPSDSHFKITF "+++" 125 VPVYILLDEM "++" 126 KPGPEDKL "++" 127 APRAGSQW "+++" 128 YPRTITPGM "+++" 129 APRPASSL "+++" 130 FPRLVGPDF "+++" 131 APTEDLKAL "+++" 132 IPGPAQSTI "++" 133 TTSL "+++" 134 PLL "+++" 135 RVRSTISSL "+++" 136 SPFSAEEANSL "+++" 137 SPGATSRGTL "+++" Peptide Seq ID No Sequence exchange 138 SPMATTSTL "++¥' 139 SPQSMSNTL '4+¥' 140 SPRTEASSAVL "++¥' 141 SPMTSLLTSGL "++¥' 142 TPGLRETSI "+¥' 143 TSF "+¥' 144 STL "++¥' 145 SPSSPMSTF "+¥' 146 IPRPEVQAL '4+¥' 147 APRWFPQPTW "+++" 148 KPYGGSGPL "+++" 149 GPREALSRL '4+¥' 293 VPDSGATATAY "+¥' 294 YPLRGSSIF "+++" 295 YPLRGSSIFGL "+++" 296 YPLRGSSI "+¥' 297 GLL "++¥' 298 YPTEHVQF "++" 299 HPGSSALHY "+¥' 300 IPMAAVKQAL '4++" 301 SPRRSPRBF "+¥ 302 RVEEVRALL "++¥' 303 LPNWVKVTAF "+++" 304 LPRPGAVL "+++" 305 TPWAESSTKF "++" 306 APVWSHSA '4+" 307 LPYGPGSEAAAF "++¥' 308 YPEGAAYEF "+¥' 309 FPQSQYPQY "++++" 311 RPLFYVVSL "++" 312 FSM "++¥' 313 KVKSDRSVF "¥' 314 VPDQPHPEI '4+¥' 315 SPRENFPDTL "++¥' 316 EPKTATVL "++" 317 FPFQPGSV "++¥' 318 FPNRLNLEA "++¥' 319 SPAEPSVYATL "+++¥' 320 FPMSPVTSV Peptide Seq ID No Sequence 321 SPMDTFLLI "++" 322 SPDPSKHLL "++" 323 RPMPNLRSV "+++" 324 VPYRVVGL "++" 325 GPRNAQRVL "+++" 326 VPSEIDAAF "++" 327 SPLPVTSLI "+++" 328 EPVTSSLPNF "++" 329 FPAMTESGGMIL "+++" 330 FPFVTGSTEM "++" 331 FPHPEMTTSM "+++" 332 FPHSEMTTL "+++" 333 FPHSEMTTVM "+++" 334 FPYSEVTTL "+++" 335 PGL "++" 336 HPKTESATPAAY "++" 337 HPVETSSAL "+++" 338 HVTKTQATF "++" 339 LPAGTTGSLVF "+++" 340 LPEISTRTM "++" 341 LPLDTSTTL "+++" 342 LPLGTSMTF "+++" 343 LPSVSGVKTTF "++" 344 LPTQTTSSL "+++" 345 LPTSESLVSF "++" 346 LPWDTSTTLF "+++" 347 MPLTTGSQGM "++" 348 MPNSAIPFSM "+++" 349 MPSLSEAMTSF "+++" 350 NPSSTTTEF "+++" 351 NVLTSTPAF "++" 352 SPAETSTNM "+++" 353 SPAMTTPSL "+++" 354 SPLPVTSLL "+++" 355 SPLVTSHIM "+++" 356 SPNEFYFTV "+++" 357 SPSPVPTTL "+++" 358 STL "+++" 359 SPSTIKLTM "+++" Peptide Seq ID No Sequence exchange 360 SPSVSSNTY "++" 361 SPTHVTQSL "+++" 362 SPVPVTSLF "+++" 363 TAKTPDATF "++" 364 TPLATTQRF "++" 365 TPLATTQRFTY "++" 367 TPSWTEGF "++" 368 VPTPVFPTM "++" 369 FPHSEMTTV "+++" 370 PGGTRQSL "+" 371 LYVDGFTHW "++" 372 IPRNPPPTLL "+++" 373 RPRALRDLRIL "+++" 374 NPIGDTGVKF "+++" 375 LLL "++" 376 RPRSPAGQVA "+++" 377 RPRSPAGQVAAA "+++" 378 RPRSPAGQVAA "+++" 379 GPFPLVYVL "+++" 380 TF "+++" 381 LPEQTPLAF "++" 382 SPMHDRWTF "+++" 383 TPTKETVSL "+++" 384 YPGLRGSPM "++++" 385 SPALHIGSV "+++" 386 FPFNPLDF "++" 387 APLKLSRTPA "+++" 388 SPAPLKLSRTPA "++" 389 SPGAQRTFFQL "+++" 390 NPDLRRNVL "+++" 391 APSTPRITTF "+++" 392 KPIESTLVA "+++" Table 17: MHC class I binding scores. Binding of HLA-class l restricted peptides to HLA-B*44:O2 was measured by peptide exchange yield: >10% = +; >20% = ++; >50 = +++, > 75A, _ ++++. 0 _ Pepfide Seq ID No Sequence exchange Peptide Seq ID No Sequence 52 AEFLLRIFL "++" 53 MEHPGKLLF "++++" 54 AEITITTQTGY "+++" 55 TTW "+++" 56 SEPDTTASW "+++" 57 QESDLRLFL "+++" 58 GEMEQKQL "++" 59 SENVTMKW "+++" 173 AEAQVGDERDY "+++" 174 AEATARLNVF "++++" 175 AEIEPKADG "++" 176 AEIEPKADGSW "+++" 177 TEVGTMNLF "+++" 178 NELFRDGVNW "+++" 179 REAGDEFEL "++" 180 REAGDEFELRY "++" 181 GEGPKTSW "++" 182 KEATEAQSL "+++" 183 YEKGIMQKV "++" 184 AELEALTDLW "+++" 185 AERQPGAASL "++" 186 REGPEEPGL "++" 187 GEAQTRIAW "+++" 188 AEFAKKQPWW "+++" 189 KEFLFNMY "++" 190 YEVARILNL "++" 191 FKAW "+++" 192 YEFKFPNRL "+++" 193 LEAQQEAL "++" 194 KEVDPTSHSY "++" 195 AEDKRHYSV "++" 196 REMPGGPVW "+++" 197 AEVLLPRLV "+++" 198 QEAARAAL "++" 199 REIDESLIFY "+++" 200 AESIPTVSF "+++" 201 AETILTFHAF "+++" 202 HESEATASW "+++" 203 IEHSTQAQDTL "++" Peptide Seq ID No Sequence exchange 204 RETSTSEETSL "++¥' 205 SEITRIEM "++" 206 SESVTSRTSY "++¥' 207 TEARATSDSM/ '4+¥' 208 EAI "++" 209 TEVSRTEL "++" 210 VEAADIFQNF "+++" 211 EEKVFPSPLM/ "++¥' 212 QKRF "++¥' 213 KESIPRWYY "++" 214 GSLL '4+" 215 SEDGLPEGHfl. '4+" 396 REASGLLSL "++¥' 397 REGDTVQLL '4+" 398 SFEQVVNELF "++" 399 RELLHLVTL '4++" 400 GEIEIHLL "+" 402 RELANDELm "+¥' 403 EEAQWVRKY "++" 404 NEAIMHQY "++" 405 NEMNTHSY "+" 406 EDGRLVIEF "+" 407 AEHEGVSVL '4+" 408 LEKALQVF '4+" 409 REFVLSKGDAGL '4+¥' 410 SEDPSKLEA '4" 411 LELPPmVY '4" 412 QEmTQVKQ "+¥' 413 IEALSGKIEL "++" 414 EDAALFKAM/ "++" 415 LFKAM/ "++¥' 416 SEEETRVVF '4+¥' 417 AEHFSMIRA "++" 418 FEDAQGHMN '4+¥' 419 HEFGHVLGL "+¥' 420 FESHSTVSA "+" 421 GEPATTVSL "++" 422 SETTFSUF "++¥' 423 SEVPTGTTA Peptide Seq ID No Sequence exchange 424 TEFPLFSAA "+" 425 SEVPLPMAI "+++" 426 PEKTTHSF "+" 427 HESSSHHDL "++" 429 REKFIASVI "++" 431 AEQDPDELNKA "++" 432 EEQYIAQF "+" 433 SDSQVRAF "+" 434 KEAIREHQM "++" 435 REEFVSIDHL "++" 436 REPGDIFSEL "++" 437 TEAVVTNEL "++" 438 NVL "+++" EXAMPLE 6 Stability of peptide-MHC class I complexes Peptide-MHC stability assays for HLA-B*08:01 peptides were performed. The data were obtained using a proximity based, homogenous, ime assay in order to measure the dissociation of peptides from HLA class I les. First, human recombinant HLA- B*08:01 and b2m were sed in E. coli and purified in a series of liquid chromatography based steps (Ferre et al., 2003; Ostergaard et al., 2001). Then, the stability of a peptide-MHC complex (pMHC) was determined by ing the amount of b2m associated with the MHC heavy chain over time at 37°C ahl et al., 2012).
The stability of each pMHC, expressed as the half life of b2m associated with the respective heavy chain, was calculated by fitting the data to a one-phase dissociation equafion.
The pMHC stabilities were measured in three independent experiments with the peptides in question, and for HLA-B*08:01 were found to span the range from weak- binders (+) to very stable binders (++++). The mean half-life (T1/2) is shown in Table Table 18: Mean half-life (T1/2) based on three individual measurements. T1/2 > 2 h = +; T1/2 > 4 h = ++; T1/2 > 6 h = +++; T1/2 >10 h = ++++ Seq ID Mean Half-life No Sequence (T1/2) 43 ALKARTVTF +++ 44 LNKQKVTF ++++ 45 VGREKKLAL ++ 46 DMKKAKEQL + 47 MPNLRSVDL ++ 48 DVKKKIKEV + 49 LPRLKAFMI ++ 50 RV + 51 SLRLKNVQL + 150 MAAVKQAL ++ 151 LAF ++ 152 MGSARVAEL ++ 153 NAMLRKVAV + 154 MLRKIAVAA + 156 HVKEKFLL ++ 157 EAMKRLSYI + 158 LL + 159 VLKHKLDEL + 160 YPKARLAF +++ 161 ALKTTTTAL + 162 QAKTHSTL + 163 VF ++ 164 SIKTKSAEM +++ 166 TPKLRETSI ++ 167 TSHERLTTL ++ 169 TSMPRSSAM +++ 170 YLLEKSRVI ++ 171 FAFRKEAL ++ 172 KLKERNREL +++ 394 MYKMKKPI + 395 VLLPRLVSC + EXAMPLE 7 Binding scores of selected peptides for HLA Class II allotypes -2o4- Major histocompatibility complex class II (MHC-ll) molecules are predominantly expressed on the surface of professional antigen presenting cells, where they display peptides to T helper cells, which orchestrate the onset and outcome of many host immune responses. tanding which peptides will be presented by the MHC-ll molecule is ore ant for understanding the activation of T helper cells and can be used to identify T-cell es. Peptides ted by the MHC class II molecule bind to a binding groove formed by residues of the MHC d- and B-chain. The peptide-MHC binding affinity is primarily determined by the amino acid sequence of the peptide-binding core. HLA class II binding prediction algorithms are only available for the most important class II alleles and have been tested using the SYFPEITHI algorithm (Rammensee et al., 1999). The algorithm has already been successfully used to identify class I and class II epitopes from a wide range of antigens, e.g. from the human tumor- associated antigens TRP2 (class |) (Sun et al., 2000) and SSX2 (class II) (Neumann et al., 2004). Table 20 shows the HLA class II allotypes which are likely to bind the selected es. The peptide was considered as binding to an HLA molecule if the SYFPEITHI score was equal to or higher than 18.
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Cell 163 (2015): 1011-1025 Abba, M. C. et aI., Mo|.Cancer Res 5 (2007): 881-890 Abdelmalak, C. A. et a|., Clin Lab 60 (2014): 55-61 Abe, A. et aI., Genes Chromosomes.Cancer 55 (2016): 242-250 Aghajanova, L. et al., Hum.Reprod. 30 : 232-238 Agherbi, H. et al., ne. 4 (2009): e5622 Aguilo, F. et al., Curr.Top.Microbiol.|mmunol. 394 (2016): 29-39 Akagi, T. et a|., J Biol Chem 290 : 22460-22473 Al, Zeyadi M. et al., Biotechnol.Biotechnol.Equip. 29 (2015): 111-118 Albergaria, A. et al., lnt.J Dev.Bio| 55 (2011): 811-822 A|entorn, A. et al., Presse Med 42 (2013): 806-813 Alhosin, M. et al., J Exp.C|in Cancer Res 35 (2016): 174 Allison, J. P. et al., Science 270 (1995): 932-933 A|rawi, S. J. et al., Anticancer Res 26 (2006): 107-119 Alvarado-Ruiz, L. et al., Asian Pac.J Cancer Prev. 17 : 1037-1047 Alzrigat, M. et al., Oncotarget. (2016) Amsterdam, A. et al., Acta hem. 116 (2014): 781-787 Andersen, R. S. et al., Nat.Protoc. 7 (2012): 891-902 Andrade, V. C. et al., Cancer lmmun. 8 (2008): 2 Andrade, V. C. et al., Exp.Hematol. 37 (2009): 446-449 Angelopoulou, K. et al., Mamm.Genome 21 (2010): 516-524 Angulo, J. C. et al., J Urol. 195 (2016): 619-626 Ansari, K. I. et al., J docrino|. 48 (2012): 61-75 Appay, V. et al., Eur.J Immunol. 36 (2006): 1805-1814 Aprelikova, O. et al., Cancer Res 69 (2009): 616-624 Arsenic, R. et al., BMC.Cancer 15 (2015): 784 Askew, E. B. et al., J Biol Chem 284 (2009): 34793-34808 Aung, P. P. et al., Oncogene 25 (2006): 557 Avasarala, S. et al., Biol Open. 2 (2013): 675-685 Avgustinova, A. et al., Nat Commun. 7 (2016): 10305 Aytes, A. et al., atl.Acad.Sci.U.S.A 110 (2013): E3506-E3515 Bahnassy, A. A. et al., World J Gastroenterol. 20 (2014): 18240-18248 Bailey, V. J. et al., Methods 52 (2010): 237-241 Balaz, P. et al., Ann.Surg. 235 (2002): 7 reau, J. et al., Cell 106 (2001): 271-274 Band, A. M. et al., J Mammary.Gland.Biol Neoplasia. 16 (2011): 109-115 Bao, L. et al., Cell Biol Toxicol. 32 (2016): 419-435 Baroy, T. et al., Mol.Cancer 13 (2014): 93 Bartolini, A. et al., Clin Cancer Res 22 (2016): 4923-4933 Baty, F. et al., J Biomed.lnform. 58 : 175-185 Beard, R. E. et al., Clin Cancer Res 19 (2013): 4941-4950 Beatty, G. et al., J Immunol 166 (2001): 2276-2282 Beggs, J. D., Nature 275 (1978): 104-109 Beke, L. et al., Biosci.Rep. 35 (2015) Bell, J. L. et al., J Clin Oncol 33 : 1285-1293 Bell, J. L. et al., Cell Mol Life Sci. 70 (2013): 2657-2675 Benz, C. C. et al., Oncogene 15 (1997): 525 Bergamini, A. et al., Expert.Opin.lnvestig.Drugs 25 (2016): 1405-1412 WO 38257 Berger, C. et al., Curr.Mol.Med. 13 (2013): 1229-1240 Bernstein, M. B. et al., Cancer Biother.Radiopharm. 29 (2014): 153-161 Beyranvand, Nejad E. et al., Cancer Res 76 (2016): 6017-6029 Bhan, S. et al., Oncol Rep. 28 (2012): 1498-1502 Bierkens, M. et al., Genes Chromosomes.Cancer 52 (2013): 56-68 Bikkavilli, R. K. et al., Oncogene 34 (2015): 5317-5328 Bisig, B. et al., ract.Res Clin Haematol. 25 (2012): 13-28 Bode, P. K. et al., Mod.Patho|. 27 (2014): 899-905 Boeva, V. et al., PLoS.One. 8 (2013): e72182 Bogush, T. A. et al., Antibiot.Khimioter. 54 (2009): 41-49 Bonitsis, N. et al., Exp.Oncol 28 : 187-193 o, C. A. et al., Cancer Res 63 (2003): 9032-9041 o, C. A. et al., Clin Cancer Res 12 (2006): 1487-1493 Borgono, C. A. et al., J Biol Chem 282 (2007): 2405-2422 Borowicz, S. et al., J Vis.Exp. (2014): e51998 Boulter, J. M. et al., n Eng 16 (2003): 707-711 Braumuller, H. et al., Nature (2013) Brinkmann, U. et al., Proc.Nat|.Acad.Sci.U.S.A 95 (1998): 10757-10762 Brossart, P. et al., Blood 90 (1997): 1594-1599 Bruckdorfer, T. et al., Curr.Pharm.Biotechnol. 5 : 29-43 Bruey, J. M. et al., J Biol Chem 279 (2004): 51897-51907 Bryan, R. T., Philos.Trans.R Soc.Lond B Biol Sci. 370 (2015): 20140042 Bryan, R. T. et al., J Urol. 184 (2010): 423-431 Buchet-Poyau, K. et a|., Nucleic Acids Res 35 (2007): 1289-1300 Bundela, S. et al., PLoS.One. 9 (2014): e102610 Burnett, R. M. et a|., Oncotarget. 6 (2015): 12682-12696 Cano, A. et a|., Future.Oncol 8 (2012): 1095-1108 , F. F. et a|., J Mol.Neurosci. 51 (2013): 532-538 Card, K. F. et a|., Cancer Immunol ther. 53 (2004): 7 Carrera, M. et a|., |nt.J Clin Exp.Pathol. 8 (2015): 3613-3623 Cerveira, N. et a|., BMC.Cancer 10 (2010): 518 Chakrabarty, S. et a|., J Cell Physiol 186 (2001): 47-52 Chan, M. H. et a|., Pediatr.Blood Cancer 59 (2012): 1173-1179 Chandra, V. et a|., Cell Death.Dis. 5 (2014): e1380 Chang, H. et a|., Biochem.Biophys.Res Commun. 464 (2015a): 45-50 Chang, Q. et a|., Oncotarget. 6 (2015b): 42838-42853 Chen, H. S. et a|., ua Gan Zang.Bing.Za Zhi. 11 (2003): 145-148 Chen, S. T. et a|., Cancer Sci. 102 ): 2191-2198 Chen, Y. et a|., Cancer Biol Ther. 11 (2011b): 497-511 Chen, Y. et a|., Onco.Targets.Ther. 7 (2014): 1465-1472 Chen, Y. C. et a|., Taiwan.J Obstet.Gynecol. 54 (2015): 9 Chen, Y. L. et a|., Int J Surg. 11 : 85-91 Chen, Y. T. et a|., |nt.J Cancer 124 (2009): 2893-2898 Chen, Y. T. et a|., Proc.Nat|.Acad.Sci.U.S.A 102 (2005): 7940-7945 Cheng, Y. C. et a|., J Neurochem. 110 (2009): 947-955 Cheung, A. et a|., Oncotarget. 7 (2016): 52553-52574 Chevillard, G. et a|., Blood 117 (2011): 2005-2008 Choi, M. R. et a|., APMIS 123 (2015): 65-71 Choijamts, B. et a|., Stem Cells 29 (2011): 1485-1495 Chung, H. et a|., Biol Chem 393 (2012a): 413-420 Chung, S. et a|., Oncotarget. 3 (2012b): 1629-1640 Ciruelos Gil, E. M., Cancer Treat.Rev 40 : 862-871 , A. A. et a|., Ann.Oncol 27 (2016): 1696-1705 Clermont, P. L. et a|., Clin Epigenetics. 8 (2016): 16 Clermont, P. L. et a|., Clin etics. 7 (2015): 40 Clermont, P. L. et a|., Br.J Cancer 111 (2014): 1663-1672 Cohen, C. J. et a|., J Mol Recognit. 16 (2003a): 324-332 Cohen, C. J. et a|., J Immunol 170 (2003b): 4349-4361 Cohen, S. N. et a|., atl.Acad.Sci.U.S.A 69 (1972): 2110-2114 Colas, E. et a|., Clin Transl.Oncol 14 (2012): 715-720 Coligan, J. E. et al., Current Protocols in Protein Science (1995) Colombetti, S. et a|., J Immunol. 176 (2006): 2730-2738 Co|ovai, A. I. et a|., Cytometry B Clin Cytom. 72 (2007): 354-362 Cortesini, R., JOP. 8 (2007): 697-703 Coulie, P. G. et a|., |mmuno|.Rev 188 (2002): 33-42 Coutte, L. et a|., Gene 240 (1999): 201-207 Cui, X. P. et a|., Dig.Dis.Sci. 59 (2014): 1442-1451 Curran, K. J. et a|., Mol.Ther. 23 (2015): 769-778 Dai, W. et a|., Am.J Cancer Res 5 (2015): 2697-2707 Dalerba, P. et a|., |nt.J Cancer 93 (2001): 85-90 mann, S. R. et a|., Cancer |mmuno|.Res. 1 (2013): 288-295 Darda, L. et a|., PLoS.One. 10 (2015): e0122285 Darling, M. R. et a|., Head Neck Pathol. 2 (2008): 169-174 Dat, le T. et a|., |nt.J Oncol 40 (2012): 469 Davidson, B. et a|., J Cell MOLMed. 15 (2011): 535-544 Davis, M. P., CIeve.C|in J Med 79 Electronic Suppl 1 (2012): eS51-eS55 de Goeje, P. L. et a|., Oncoimmunology 4 (2015): e1014242 de Matos, Simoes R. et a|., BMC.Syst.Bio| 9 (2015): 21 De, aere A. et a|., Pathobiology 83 (2016): 327-333 De, Plaen E. et a|., Immunogenetics 40 : 360-369 Dengjel, J. et a|., Clin Cancer Res 12 (2006): 4163-4170 Denkberg, G. et a|., J Immunol 171 (2003): 2197-2207 Devetzi, M. et a|., Thromb.Haemost. 109 (2013): 716-725 Dewar, R. et a|., Arch.Pathol.Lab Med 135 (2011): 9 Dias, R. P. et a|., Epigenomics. 5 (2013): 331-340 Dobrowolska, H. et a|., Cytometry B Clin Cytom. 84 (2013): 21-29 Dong, Q. et a|., Biomed.Res Int. 2015 (2015): 156432 Dorn, J. et a|., Crit Rev Clin Lab Sci. 51 (2014): 63-84 Du, T. et a|., MoI.Cancer 13 (2014): 100 Dua, P. et a|., Cancer Res 73 (2013): 1934-1945 Duan, Z. et a|., Clin Cancer Res 9 (2003): 2778-2785 Dufour, C. et a|., Cancer 118 (2012): 821 Dyrskjot, L. et a|., Br.J Cancer 107 (2012): 116-122 Ek, S. et a|., Cancer Res 62 (2002): 4398-4405 Emmrich, S. et a|., Genes Dev. 28 (2014): 858-874 Fabbri, C. et a|., dosc. (2017) Falk, K. et a|., Nature 351 (1991): 6 Fan, M. et a|., |nt.J Clin Exp.PathoI. 7 (2014): 775 Fang, F. et a|., Clin Cancer Res 20 (2014a): 6504-6516 Fang, L. et a|., Biochem.Biophys.Res Commun. 446 (2014b): 272-279 Faure, A. et a|., Nat Rev Urol. 13 (2016): 141-150 Feng, X. et a|., Mo|.Biosyst. 11 (2015): 2946-2954 Ferre, H. et a|., n Sci. 12 (2003): 551-559 Findeis-Hosey, J. J. et a|., Biotech.Histochem. 87 (2012): 24-29 Fishman, W. H., Tumour.BioI 16 (1995): 2 Follenzi, A. et a|., Nat Genet. 25 (2000): 217-222 Fong, L. et a|., Proc.Nat|.Acad.Sci.U.S.A 98 (2001): 8809-8814 Fontalba, A. et a|., J l. 179 (2007): 8519-8524 Forghanifard, M. M. et a|., Cancer Biol Ther. 12 : 7 Frasor, J. et a|., Mo|.Ce|| Endocrinol. 418 Pt 3 (2015): 235-239 Fritzsche, F. et a|., Br.J Cancer 94 (2006): 540-547 Fry, E. A. et a|., |nt.J Cancer 140 (2017): 495-503 Fujiyama, T. et a|., J DermatoI.Sci. 75 (2014): 43-48 Fukumoto, I. et a|., J Hum.Genet. 61 (2016): 109-118 Fuqua, S. A. et a|., Breast Cancer Res Treat. 144 (2014): 11-19 Gabrilovich, D. I. et a|., Nat Med. 2 (1996): 1096-1103 Gan, X. et a|., Dis.Markers 2016 (2016): 5259602 Ganguly, R. et a|., Mo|.Cancer Ther. 13 (2014): 1393-1398 Garg, M. et a|., J C|in Endocrino|.Metab 99 (2014): 2 Gattinoni, L. et a|., Nat Rev.|mmuno| 6 (2006): 3 Ge, L. et a|., J Biomed.Res 29 (2015a) Ge, L. et a|., Eur.Rev Med PharmacoI.Sci. 19 (2015b): 2703-2710 Geyer, C. R., Epigenetics. 5 (2010): 696-703 Ghodsi, M. et a|., |nt.J Surg. 13 (2015): 193-197 Gibbs, P. et a|., Melanoma Res 10 (2000): 259-264 G|eize, V. et a|., Ann.Neuro|. 78 (2015): 355-374 anatic, S. et a|., Proc Natl.Acad.SCi.U.S.A 100 (2003): 8862-8867 Godkin, A. et a|., lnt.lmmunol 9 (1997): 905-911 Gomez, A. et a|., Mo|.Pharmaco|. 78 (2010): 1004-1011 Gong, Y. et a|., Adv.Anat.Patho|. 21 (2014): 191-200 Gott|ieb, H. B. et a|., J Neuroendocrinol. 19 (2007): 531-542 Gragert, L. et a|., Hum.lmmunol. 74 (2013): 1313-1320 Grah, J. J. et a|., Tumori 100 (2014): 60-68 , V. et a|., Am.J Pathol. 179 (2011): 2625-2636 Green, M. R. et a|., Molecular Cloning, A Laboratory Manual 4th (2012) Greenfield, E. A., Antibodies: A Laboratory Manual 2nd (2014) Gu, C. et a|., Stem Cells 31 (2013): 870-881 Gu, Z. D. et a|., Zhonghua Wei Chang Wai Ke.Za Zhi. 10 (2007): 365-367 Gualco, G. et a|., Appl.lmmunohistochem.Mol.Morpho|. 18 (2010): 301-310 Guerrero, K. et a|., Gynecol.OncoI 125 (2012): 720-726 Guo, J. T. et a|., Zhonghua Liu Za Zhi. 31 (2009): 528-531 Gupta, A. K. et a|., Med J Armed.Forces.lndia 72 (2016): 837-842 Gustafsson, C. et a|., Trends hnol. 22 (2004): 346-353 Haass, N. K. et a|., Pigment Cell Res 18 (2005): 150-159 Haeberle, H. et a|., Neoplasia. 14 (2012): 666-669 Hall, R. D. et a|., Cancer l 20 (2013): 22-31 Hamilton, K. E. et a|., Mol.Cancer Res 13 : 486 Han, J. et a|., World J Surg.Oncol 10 : 37 Han, Y. et a|., Eur.J Cell Biol 94 (2015): 642-652 Han, Y. D. et a|., Oncotarget. 8 (2017): 1871-1883 Hanafusa, H. et al., aku 83 (2011): 1127-1131 Harndahl, M. et al., Eur.J Immunol. 42 (2012): 1405-1416 Hase, H. et al., Mol.Cancer Res 12 (2014): 1807-1817 Hasegawa, H. et al., Arch.Patho|.Lab Med. 122 (1998): 551-554 Hashem, N. N. et al., lnt.J Biol Markers 25 (2010): 32-37 Hashimoto, Y. et al., Oncotarget. (2017) Hayashi, S. I. et al., Endocr.Relat Cancer 10 (2003): 193-202 Hayashida, T. et al., atl.Acad.Sci.U.S.A 107 (2010): 1100-1105 Heeg, S. et al., enterology 151 (2016): 540-553 Heerma van Voss, M. R. et al., Histopathology 65 (2014): 814-827 Hemminger, J. A. et al., Mod.Patho|. 27 (2014): 1238-1245 Hennard, C. et al., J Pathol. 209 (2006): 430-435 Heubach, J. et al., Mo|.Cancer 14 (2015): 108 s, J. et al., Horm.Cancer 6 (2015): 67-86 Hildebrandt, M. O. et al., Bone Marrow Transplant. 22 (1998): 771-775 Hiramoto, T. et al., ne 18 (1999): 3422-3426 Hirata, T. et al., Oncol Rep. 33 (2015): 2052-2060 Hiroumi, H. et al., lnt.J Cancer 93 (2001): 786-791 Hoff, P. M. et al., Surg.Oncol Clin N.Am. 26 (2017): 57-71 nn, N. E. et al., Cancer 112 (2008): 479 Hofmann, M. C. et al., Eur.Urol. 23 (1993): 38-44 Holm, C. et al., Leuk.Res 30 (2006): 254-261 Honrado, E. et al., Crit Rev Oncol Hematol. 59 (2006): 27-39 Horiuchi, S. et al., J Pathol. 200 : 568-576 Horvath, A. et al., World J Gastroenterol. 10 (2004): 152-154 o, Y. et a|., Mo|.Cancer 13 (2014): 102 Hou, Z. et a|., Mo|.Cancer Ther. (2017) Hu, 8. et a|., J Cancer Res C|in Oncol 140 (2014): 883-893 Hu, X. T. et a|., Cell Prolif. 47 (2014): 200-210 Huang, K. et a|., Chin J Cancer Res 26 (2014): 72-80 Huang, X. et a|., Cell Prolif. 48 (2015): 593-599 Hudolin, T. et a|., J .Med 11 (2013): 123 Hur, H. et a|., J Cancer 7 : 768-773 Hussein, Y. M. et a|., Med.Onco| 29 : 3055-3062 Hwang, M. L. et a|., J Immunol. 179 (2007): 5829-5838 |acobuzio-Donahue, C. A. et a|., Cancer Res 63 (2003): 622 Idbaih, A., Rev Neuro|.(Paris) 167 (2011): 691-698 Ingaramo, P. I. et a|., Mo|.Ce|| Endocrinol. 425 (2016): 37-47 |oannidis, P. et a|., Anticancer Res 23 (2003): 2179-2183 Ishida, S. et a|., Biochem.Biophys.Res Commun. 339 (2006): 325-330 Ishikawa, K. et a|., MoI.Bio| Cell 23 (2012): 1294-1306 Ishikawa, S. et a|., Cell Tissue Res 337 (2009): 381-391 Itesako, T. et a|., PLoS.One. 9 (2014): e84311 Jacobs, J. et a|., PharmacoI.Ther. 155 (2015a): 1-10 Jacobs, J. et a|., Oncotarget. 6 (2015b): 13462-13475 James, S. R. et a|., Epigenetics. 8 : 849-863 Jang, B. G. et a|., Virchows Arch. 467 (2015): 393-403 Jeng, Y. M. et a|., Br.J Surg. 96 (2009): 66-73 Ji, P. et a|., Oncogene 24 (2005): 2739-2744 Jiang, D. et a|., PLoS.One. 9 (2014): e96822 WO 38257 Jiang, Y. et al., Mol.Oncol 10 (2016): 292-302 Jiang, Y. et al., Oncotarget. 6 (2015): 39865-39876 Jiao, T. T. et al., |nt.J Clin thol. 6 (2013): 3036-3041 Jin, H. et al., Tumour.Biol 27 (2006): 274-282 Jnawali, H. N. et al., J Nat Prod. 77 (2014): 258-263 John, T. et al., Clin Cancer Res 14 (2008): 3291-3298 Jung, D. B. et al., Oncotarget. 6 : 4992-5004 Jung, G. et al., Proc Natl Acad Sci U S A 84 (1987): 4611-4615 Kalejs, M. et al., BMC.Cancer 6 (2006): 6 Kannan, K. et al., Proc.Natl.Acad.Sci.U.S.A 112 (2015): E1272-E1277 Karlgren, M. et al., Expert.Opin.Ther.Targets. 11 (2007): 61-67 Karpf, A. R. et al., Mol.Cancer Res 7 (2009): 523-535 Kasashima, H. et al., Cancer Lett. 354 (2014): 438-446 Kaufman, L. et al., J Am.Soc.Nephrol. 15 (2004): 1721-1730 Kazi, J. A. et al., Neuropeptides 41 (2007): 227-231 Kedage, V. et al., Cell Rep. 17 : 1289-1301 Keld, R. et al., Br.J Cancer 105 (2011): 124-130 Keld, R. et al., Mol.Cancer 9 (2010): 313 n, L. E. et al., Nat Genet. 47 (2015): 888-897 Kelly, Z. et al., |nt.J Cancer 139 : 1608-1617 Kerns, S. L. et al., J Urol. 190 (2013): 102-108 Kevans, D. et al., Int J Surg.Pathol. 19 (2011): 751-760 Khan, F. S. et al., Hepatol.lnt. 11 (2017): 45-53 Khan, M. F. et al., Transl.Oncol 5 (2012): 85-91 Kibbe, A. H., Handbook of Pharmaceutical Excipients rd (2000) Kikkawa, Y. et al., Exp.Ce|| Res 328 (2014): 197-206 Kikkawa, Y. et al., J Biol Chem 288 (2013): 30990-31001 Kikkawa, Y. et al., Exp.Cel| Res 314 (2008): 2579-2590 Kim, B. K. et al., J Dermatol.Sci. 79 (2015a): 137-147 Kim, B. R. et al., Cell Signal. 26 (2014): 1765-1773 Kim, T. D. et al., J Clin Invest 126 : 706-720 Kim, T. H. et al., J Korean Med Sci. 30 (2015b): 155-161 Kim, Y. D. et al., lnt.J Mol.Med. 29 (2012): 656-662 Kim, Y. H. et al., Ann.Surg.Oncol 18 (2011): 347 King, M. L. et al., ne 34 (2015): 3452-3462 Kinoshita, T. et al., lnt.|mmunol. 18 (2006): 1701-1706 Kinoshita, T. et al., J Biol Chem 280 (2005): 21720-21725 Kirkova, M. et al., col.Rep. 61 : 1163-1172 Klatka, J. et al., Eur.Aroh.Otorhinolaryngol. 270 (2013): 2683-2693 Klauke, K. et al., Nat Cell Biol 15 (2013): 353-362 K|eeff, J. et al., Nat Rev Dis.Primers. 2 (2016): 16022 Knudsen, K. A. et al., J Cell Biochem. 95 (2005): 488-496 Ko, A. et al., BMB.Rep. 49 (2016): 598-606 Kocak, H. et al., Cell Death.Dis. 4 (2013): e586 Kohrt, D. et al., Cell Cycle 13 (2014): 62-71 Kontos, C. K. et al., Clin Chem Lab Med 54 (2016): 315-324 Koonrungsesomboon, N. et al., Cancer iol. 39 (2015): 487-496 Korr, D. et al., Cell Signal. 18 (2006): 910-920 Kountourakis, P. et al., Thromb.Haemost. 101 (2009): 6 Krepischi, A. C. et al., Mol.Cytogenet. 9 (2016): 20 Krieg, A. M., Nat Rev.Drug Discov. 5 (2006): 4 Kruhlak, M. et al., Nature 447 (2007): 730-734 Kuball, J. et al., Blood 109 (2007): 2331-2338 Kuga, T. et al., J Cell Sci. 126 (2013): 4721-4731 Kuga, T. et al., Sci.Rep. 6 (2016): 26557 Kumar—Sinha, C. et al., Genome Med 7 (2015): 129 Kumari, A. et al., BMC.Res Notes 9 (2016): 92 Kuner, R. et al., J Mol.Med (Berl) 91 (2013): 237-248 Kuo, C. T. et al., Cancer Lett. 378 : 104-110 Kuppers, R. et al., J Clin Invest 111 (2003): 529-537 Kuraishi, Y., Yakugaku Zasshi 134 (2014): 1125-1142 Kurscheid, S. et al., Genome Biol 16 (2015): 16 Kwon, O. S. et al., rget. 6 (2015): 41916-41928 La, Vecchia C., Eur.J Cancer Prev. 10 (2001): 125-129 Lally, K. M. et al., |nt.J Cancer 93 : 841-847 Lapin, V. et al., Oncogenesis. 3 : e133 Latini, F. R. et al., Blood Cells Mol.Dis. 50 (2013): 161-165 son, K. et al., |nt.J Cancer 136 (2015a): 1390-1401 Lawrenson, K. et al., Nat . 6 (2015b): 8234 Lazaro-lbanez, E. et al., BMC.Cancer 17 (2017): 92 Lederer, M. et al., Semin.Cancer Biol 29 (2014): 3-12 Lee, E. et al., BMB.Rep. 46 (2013): 594-599 Lee, 0. H. et al., Mol.Cel| Proteomics. 10 (2011): M110 Leong, S. R. et al., Mol.Pharm. 12 (2015): 1717-1729 Leung, F. et al., Cancer Epidemiol.Biomarkers Prev. 25 (2016): 1333-1340 Li, B. et a|., Cell Biochem.Biophys. 70 (2014a): 1363-1368 Li, B. et a|., Oncotarget. (2016a) Li, H. et a|., Gynecol.Oncol 84 (2002): 216-221 Li, L. et a|., Cytokine 89 (2017): 173-178 Li, L. et a|., Zhongguo Shi Yan.Xue.Ye.Xue.Za Zhi. 24 (2016b): 326-331 Li, M. et a|., Oncotarget. 7 (2016c): 51503-51514 Li, M. et a|., Clin Cancer Res 11 (2005): 1809-1814 Li, Q. et a|., J Gastroentero|.Hepato|. 29 (2014b): 835-842 Li, W. M. et a|., J Surg.Oncol ) Li, Z. et a|., Cancer Res 76 (2016e): 619-629 Liang, X. et a|., Oncotarget. 7 : 52217 Liddy, N. et a|., Nat Med. 18 (2012): 980-987 Lilja-Maula, L. et a|., J Comp Pathol. 150 : 399-407 Lim, J. Y. et a|., World J Gastroenterol. 19 (2013): 7078-7088 Lin, J. et a|., Clin Cancer Res 10 (2004): 5708-5716 Lin, L. et a|., Oncol Lett. 6 (2013a): 740-744 Lin, Q. et a|., J Cancer Res Clin Oncol 135 (2009): 1675-1684 Lin, Z. et a|., Diagn.Pathol. 8 (2013b): 133 Linn, D. E. et a|., PLoS.One. 10 (2015): e0120628 Linz, K. et a|., J Pharmacol.Exp.Ther. 349 : 535-548 Liu, D. B. et a|., World J Gastroenterol. 11 : 1562-1566 Liu, M. et a|., Cell Mo|.Neurobio|. 34 (2014a): 913-923 Liu, Q. et a|., J Biol Chem 286 (2011): 29951-29963 Liu, R. et a|., Cancer Biol Ther. 16 (2015a): 317-324 Liu, W. et a|., M0|.C|in Oncol 2 (2014b): 219-225 Liu, X. et a|., .Pharmacother. 88 (2017): 595-602 Liu, X. et a|., |nt.|mmunopharmaco|. 25 (2015b): 416-424 Liu, Y. et a|., |nt.J Gynecol.Cancer 23 (2013): 304-311 Ljunggren, H. G. et a|., J Exp.Med. 162 (1985): 1745-1759 Llaurado, M. et a|., |nt.J Cancer 130 ): 1532-1543 Llaurado, M. et a|., Mo|.Cancer Res 10 (2012b): 914-924 Longenecker, B. M. et a|., Ann ad.Sci. 690 (1993): 276-291 Lopez, R. et a|., |nt.J Gynecol.Cancer 16 (2006): 1289-1296 Lopez-Romero, R. et al., Rev Med |nst.Mex.Seguro.Soc. 53 Suppl 2 (2015): S188- Lorincz, A. T., Acta Cytol. 60 (2016): 501-512 Lose, F. et a|., Biol Chem 393 (2012): 403-412 Low, G. M. et a|., Oral Oncol 61 : 27-30 Lukas, T. J. et a|., Proc.Nat|.Acad.Sci.U.S.A 78 (1981): 2791-2795 Lunardi, A. et al., Cancer Discov 5 (2015): 550-563 Lundblad, R. L., Chemical Reagents for Protein Modification 3rd (2004) Luo, H. et a|., |nt.J Clin Exp.Med 7 (2014): 1244-1254 Luo, P. et a|., Oncol Rep. (2017) Luostari, K. et a|., PLoS.One. 9 (2014): e102519 Lv, G. Q. et a|., Biochem.Ce|| Biol 92 (2014): 379-389 Lv, L. et a|., Cancer Lett. 357 (2015a): 105-113 Lv, X. et a|., J Exp.C|in Cancer Res 34 (2015b): 133 Ma, K. et a|., Clin Epigenetics. 8 (2016a): 43 Ma, Y. et a|., s.BioeIectron. 85 (2016b): 641-648 Ma, Z. et a|., |nt.J Clin Exp.PathoI. 8 (2015): 5071-5079 n, J. A. et a|., PLoS.One. 11 (2016): e0156109 Mahajan, A., Hum.Pathol. 51 (2016): 64-74 Maine, E. A. et al., Oncotarget. 7 : 14708-14726 Maines-Bandiera, S. et al., |nt.J Gynecol.Cancer 20 (2010): 16-22 Mamane, Y. et al., J Interferon ne Res 22 (2002): 135-143 Mantia-Smaldone, G. M. et al., Hum.Vaccin.lmmunother. 8 (2012): 1179-1191 Manzella, L. et al., Curr.Cancer Drug Targets. 16 (2016): 5 Mao, L. et al., Cancer Res 71 (2011): 4314-4324 Marcinkiewicz, K. M. et al., Exp.Cell Res 320 (2014a): 128-143 kiewicz, K. M. et al., J Cell Physiol 229 (2014b): 1405-1416 Marlow, L. A. et al., J Cell Sci. 125 (2012): 4253-4263 Maruta, S. et al., APMIS 117 (2009): 791-796 Marzese, D. M. et al., Hum.Mol.Genet. 23 : 226-238 Masamoto, I. et al., Leuk.Lymphoma 57 (2016): 685-691 Mason, J. M. et al., Nucleic Acids Res. 43 (2015): 3180-3196 Mawrin, C. et al., J Neurooncol. 99 (2010): 379-391 McCormack, E. et al., Cancer l.lmmunother. 62 : 773-785 Medina-Aguilar, R. et al., Data Brief. 11 (2017): 169-182 Mehta, A. et al., Breast 23 (2014): 2-9 Melin, B., Curr.Opin.Oncol 23 (2011): 643-647 Menezes, J. et al., Leukemia 28 (2014): 823-829 Mercer, K. E. et al., Adv.Exp.Med Biol 815 (2015): 185-195 Mercer, K. E. et al., Cancer Prev.Res (Phila) 7 (2014): 675-685 Mesquita, D. et al., Oncotarget. 6 : 5217-5236 Meziere, C. et al., J |mmunol 159 (1997): 3230-3237 Michaelidou, K. et al., Breast Cancer Res Treat. 152 (2015): 323-336 Millan, J. L. et a|., Crit Rev C|in Lab Sci. 32 (1995): 1-39 Mitsuhashi, K. et a|., |nt.J l. 100 (2014): 88-95 Miyazaki, M. et a|., ty. 28 (2008): 231-245 Miyoshi, Y. et a|., Med.Mol.Morphol. 43 (2010): 193-196 Mizuno, K. et a|., |nt.J Oncol 48 (2016): 450-460 Moon, H. J. et a|., Bioorg.Chem 57 (2014): 1 Moore, K. N. et a|., J Clin Oncol (2016): JCO2016699538 Morgan, R. A. et a|., Science 314 (2006): 9 Moroy, T. et a|., Semin.lmmunol. 23 (2011): 379-387 Mortara, L. et a|., C|in Cancer Res. 12 (2006): 3435-3443 Moskvina, L. V. et a|., Arkh.Pato|. 72 (2010): 58-61 Moussa, O. et al., J Cell Biochem. 108 (2009): 1389-1398 Mumberg, D. et a|., Proc.Nat|.Acad.Sci.U.S.A 96 (1999): 8633-8638 Nabeshima, K. et a|., Diagn.CytopathoI. 44 : 774-780 Nalla, A. K. et a|., Mol.Carcinog 55 (2016): 1761-1771 Nawaz, I. et a|., Oncotarget. 6 (2015): 31493-31507 Nishida, C. R. et a|., MoI.Pharmacol. 78 (2010): 2 Niskakoski, A. et a|., Epigenetics. 9 (2014): 1577-1587 Noah, T. K. et a|., Gastroenterology 144 (2013): 1012-1023 Notaridou, M. et a|., |nt.J Cancer 128 (2011): 2063-2074 Notaro, S. et al., BMC.Cancer 16 (2016): 589 Noubissi, F. K. et a|., J Invest Dermatol. 134 : 1718-1724 Obiezu, C. V. et a|., Cancer Lett. 224 (2005): 1-22 Oh, S. et a|., m.Biophys.Acta 1826 (2012): 1-12 Ohno, S. et a|., Anticancer Res 28 (2008): 2493-2497 Okada, K. et a|., Cancer Sci. 95 (2004): 949-954 Okamoto, O. K. et a|., Biochim.Biophys.Acta 1769 (2007): 437-442 OIiveira-Costa, J. P. et a|., Oncotarget. 6 (2015): 20902-20920 Orsini, G. et a|., PathoI.Onco| Res 20 : 6 Orwat, D. E. et a|., Arch.Patho|.Lab Med 136 (2012): 333-338 aard, Pedersen L. et a|., Eur.J Immunol. 31 : 2986-2996 Ottaviani, S. et a|., Cancer |mmunol.lmmunother. 55 (2006): 867-872 Otte, M. et a|., Cancer Res 61 (2001): 6682-6687 Oue, N. et a|., Cancer Sci. 106 (2015): 951-958 czyk, M. et a|., Med Pr 67 (2016): 255-266 Pagnotta, S. M. et a|., PLoS.One. 8 (2013): e72638 Pai, V. P. et a|., Breast Cancer Res 11 (2009): R81 Pal, M. et a|., J Biol Chem 288 (2013): 12222-12231 Palacios, J. et a|., Pathobiology 75 : 85-94 Paliouras, M. et a|., Breast Cancer Res Treat. 102 (2007): 7-18 Paliouras, M. et a|., Mo|.Onco| 1 (2008a): 413-424 Paliouras, M. et a|., Tumour.BioI 29 (2008b): 63-75 Palma, M. et a|., BMC.C|in Pathol. 12 (2012): 2 Papachristopoulou, G. et a|., Tumour.BioI 34 (2013): 369-378 Papadakis, A. I. et a|., Cell Res 25 (2015): 445-458 Papadopoulou-Boutis, A. et a|., Cancer Detect.Prev. 8 (1985): 141-150 Paredes, J. et a|., Breast Cancer Res 9 (2007): 214 Paredes, J. et a|., Biochim.Biophys.Acta 1826 (2012): 297-311 Parris, T. Z. et a|., ncer 14 (2014): 324 Parris, T. Z. et a|., C|in Cancer Res 16 (2010): 3860-3874 Pathiraja, T. N. et al., ansl.Med 6 (2014): 229ra41 Patrick, A. N. et al., Nat Struct.MoI.Biol 20 (2013): 447-453 Pattani, K. M. et al., ne. 7 (2012): e45534 s, M. C. et al., Cell Signal. 27 (2015): 2579-2588 Pelkonen, M. et al., ncer 15 (2015): 431 Peng, H. X. et al., Biomed.Res Int. 2015 (2015): 326981 Pereira, B. et al., Nucleic Acids Res 41 (2013): 3986-3999 Perez, C. A. et al., Expert.Rev Anticancer Ther. 11 (2011): 1599-1605 Petersen, G. M., Semin.Oncol 43 (2016): 3 Petrau, C. et al., J Cancer 5 (2014): 761-764 Pich, C. et al., Br.J Cancer 114 (2016a): 63-70 Pich, C. et al., PLoS.One. 11 ): e0148095 Pickard, M. R. et aI., Breast Cancer Res 11 (2009): R60 Pineda, C. T. et al., Cell 160 (2015): 715-728 Piura, B. et al., Harefuah 144 (2005): 261-5, 303, 302 Planaguma, J. et al., Hum.Pathol. 42 (2011): 57-67 Planque, C. et al., Biol Chem 389 (2008a): 781-786 Planque, C. et al., Clin Chem 56 (2010): 987-997 Planque, C. et aI., Clin Cancer Res 14 (2008b): 1355-1362 ski, M. et al., Eur.J Immunol 25 (1995): 1783-1787 Pollack, S. M. et al., PLoS.One. 7 (2012): e32165 Pollard, C. et al., Expert.Rev Mo|.Med 12 (2010): e10 Ponte, J. F. et al., Neoplasia. 18 (2016): 775-784 Ponzoni, M. et al., Ann.Onco| 25 (2014): 316-322 Popov, N. et al., Epigenetics. 5 : 685-690 Porta, C. et a|., Virology 202 (1994): 949-955 Power, P. F. et a|., J Orthop.Res 31 (2013): 493-501 Prasad, M. L. et a|., Head Neck 26 (2004): 1053-1057 Pu, X. et a|., C|in co|.Ther. 96 : 609-615 Pyle-Chenault, R. A. et a|., .BioI 26 (2005): 245-257 Qin, Y. et a|., Chin Med.J (Eng|.) 127 (2014): 1666-1671 Rabien, A. et a|., Tumour.BioI 29 (2008): 1-8 Raeisossadati, R. et a|., Tumour.BioI 35 : 5299-5305 Rahmatpanah, F. B. et a|., Leukemia 20 (2006): 862 Rajapakse, S. et a|., Zoolog.Sci. 24 (2007): 774-780 Rammensee, H. et a|., Immunogenetics 50 (1999): 9 Ramos-Solano, M. et a|., Exp.Ce|| Res 335 (2015): 39-50 Rapoport, A. P. et a|., Nat Med 21 (2015): 914-921 Rasmussen, S. L. et a|., Colorectal Dis. 18 (2016): 549-561 RasteIIi, F. et a|., Tumori 96 (2010): 875-888 Rauscher, G. H. et a|., BMC.Cancer 15 (2015): 816 Ravenni, N. et a|., MAbs. 6 (2014): 86-94 Reck, M., Ann.Onco| 23 Suppl 8 (2012): viii28-viii34 RefSeq, The NCBI handbook [Internet], r 18, (2002), http://www.ncbi.nlm.nih.gov/books/NBK21091/ Resende, C. et a|., Helicobacter. 16 Suppl 1 (2011): 38-44 Reyes, C. et a|., Appl.|mmunohistochem.Mol.MorphoI. 21 (2013): 283-286 Reyniers, L. et a|., J Neurochem. 131 (2014): 239-250 Ribeiro, A. S. et a|., Front Oncol 4 (2014): 371 ts, C. J. et a|., PLoS.One. 9 (2014): e85621 Riedel, S. S. et a|., J C|in Invest 126 (2016): 1438-1450
Claims (18)
1. A peptide sing an amino acid sequence ed from the group consisting of SEQ ID No 35, SEQ ID Nos. 1 to 34, SEQ ID Nos. 37 to 128, SEQ ID Nos. 130 to 417, and SEQ ID No. 419 to 772, and variant sequences thereof which are at least 88% homologous to SEQ ID No 35, SEQ ID Nos. 1 to 34, SEQ ID Nos. 37 to 128, SEQ ID Nos. 130 to 417, and SEQ ID No. 419 to 772, and wherein said t binds to molecule(s) of the major histocompatibility complex (MHC) and/or induces T cells cross-reacting with said variant peptide; and a ceutical acceptable salt thereof, wherein said peptide is not a full-length polypeptide.
2. The peptide according to claim 1, wherein said peptide has the ability to bind to an MHC class-I or –II molecule, and wherein said peptide, when bound to said MHC, is capable of being recognized by CD4 and/or CD8 T cells.
3. The peptide or variant thereof according to claim 1 or 2, wherein the amino acid ce thereof comprises a continuous h of amino acids according to any one of SEQ ID No 35, SEQ ID Nos. 1 to 34, SEQ ID Nos. 37 to 128, SEQ ID Nos. 130 to 417, and SEQ ID No. 419 to 772.
4. The peptide or variant thereof according to any of claims 1 to 3, n said peptide or variant f has an overall length of from 8 to 100, preferably from 8 to 30, and more preferred from 8 to 16 amino acids, and most preferred wherein the peptide consists or consists essentially of an amino acid sequence according to any of SEQ ID No 35, SEQ ID Nos. 1 to 34, SEQ ID Nos. 37 to 128, SEQ ID Nos. 130 to 417, and SEQ ID No. 419 to 772.
5. The peptide or variant thereof according to any of Claims 1 to 4, wherein said peptide is modified and/or includes non-peptide bonds.
6. The peptide or variant thereof according to any of Claims 1 to 5, wherein said peptide is part of a fusion protein, in particular comprising N-terminal amino acids of the HLA-DR n-associated invariant chain (Ii).
7. An antibody, in particular a soluble or membrane-bound antibody, preferably a monoclonal antibody or fragment thereof, that specifically recognizes the peptide or variant thereof according to any of claims 1 to 5, ably the peptide or variant thereof according to any of claims 1 to 5 when bound to an MHC molecule.
8. A T-cell receptor, preferably soluble or membrane-bound, or a fragment thereof, that is reactive with an HLA ligand, wherein said ligand is the peptide or variant thereof according to any of claims 1 to 5, preferably the peptide or variant thereof according to any of claims 1 to 5 when bound to an MHC molecule.
9. The T-cell receptor according to claim 8, wherein said ligand amino acid ce is at least 88% identical to any one of SEQ ID No 35, SEQ ID Nos. 1 to 34, SEQ ID Nos. 37 to 128, SEQ ID Nos. 130 to 417, and SEQ ID No. 419 to 772, or wherein said ligand amino acid sequence consists of any one of SEQ ID No 35, SEQ ID Nos. 1 to 34, SEQ ID Nos. 37 to 128, SEQ ID Nos. 130 to 417, and SEQ ID No. 419 to
10. The T-cell receptor according to claim 8 or 9, wherein said T-cell receptor is provided as a e molecule and optionally carries a further or function such as an immune stimulating domain or toxin.
11. An aptamer that specifically recognizes the peptide or t thereof according to any of claims 1 to 5, preferably the peptide or variant thereof according to any of claims 1 to 5 that is bound to an MHC molecule.
12. A nucleic acid, encoding for a e or variant thereof according to any one of claims 1 to 5, an dy or fragment thereof according to claim 7, a T-cell receptor or fragment thereof according to claim 8 or 9, optionally linked to a heterologous promoter ce, or an expression vector expressing said nucleic acid.
13. A recombinant host cell comprising the peptide according to any one of claims 1 to 6, the dy or fragment thereof according to claim 7, the T-cell receptor or fragment f according to claim 8 or 9 or the nucleic acid or the expression vector according to claim 12, wherein said host cell preferably is selected from an antigen presenting cell, such as a dendritic cell, a T cell or an NK cell.
14. An in vitro method for ing activated T lymphocytes, the method comprising contacting in vitro T cells with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said T cells in an antigen specific manner, wherein said antigen is a peptide according to any one of claims 1 to 4.
15. An activated T lymphocyte, ed by the method according to claim 14, that selectively recognizes a cell which ts a polypeptide comprising an amino acid sequence given in any one of claims 1 to 4.
16. A pharmaceutical ition sing at least one active ingredient selected from the group consisting of the e according to any one of claims 1 to 6, the antibody or fragment thereof according to claim 7, the T-cell receptor or fragment thereof according to claim 8 or 9, the r according to claim 11, the nucleic acid or the expression vector according to claim 12, the host cell according to claim 13, or the activated T lymphocyte according to claim 15, or a conjugated or labelled active ient, and a pharmaceutically acceptable carrier, and optionally, pharmaceutically acceptable excipients and/or stabilizers.
17. A method for producing the peptide or variant thereof according to any of claims 1 to 6, the antibody or fragment thereof according to claim 7, or the T-cell or or fragment thereof according to claim 8 or 9, the method comprising culturing the host cell according to claim 13, and isolating the peptide or variant thereof, the antibody or fragment thereof or the T cell receptor or nt thereof from said host cell and/or its culture medium.
18. The the peptide according to any one of claims 1 to 6, the antibody or fragment thereof according to claim 7, the T-cell receptor or fragment thereof according to claim 8 or 9, the aptamer according to claim 11, the nucleic acid or the expression
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