WO2018138257A1 - Nouveaux peptides et combinaison de peptides à utiliser en immunothérapie contre le cancer de l'ovaire et d'autres cancers - Google Patents

Nouveaux peptides et combinaison de peptides à utiliser en immunothérapie contre le cancer de l'ovaire et d'autres cancers Download PDF

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WO2018138257A1
WO2018138257A1 PCT/EP2018/051952 EP2018051952W WO2018138257A1 WO 2018138257 A1 WO2018138257 A1 WO 2018138257A1 EP 2018051952 W EP2018051952 W EP 2018051952W WO 2018138257 A1 WO2018138257 A1 WO 2018138257A1
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peptide
cancer
cell
peptides
seq
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PCT/EP2018/051952
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English (en)
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Heiko Schuster
Janet PEPER
Kevin RÖHLE
Philipp Wagner
Hans-Georg Rammensee
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Immatics Biotechnologies Gmbh
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Priority to BR112019015237A priority Critical patent/BR112019015237A2/pt
Priority to MA47367A priority patent/MA47367B1/fr
Priority to KR1020197022277A priority patent/KR20190112271A/ko
Priority to MX2019008843A priority patent/MX2019008843A/es
Application filed by Immatics Biotechnologies Gmbh filed Critical Immatics Biotechnologies Gmbh
Priority to LTEPPCT/EP2018/051952T priority patent/LT3573647T/lt
Priority to ES18702642T priority patent/ES2946584T3/es
Priority to IL299051A priority patent/IL299051A/en
Priority to RS20230396A priority patent/RS64217B1/sr
Priority to CR20210128A priority patent/CR20210128A/es
Priority to EP18702642.2A priority patent/EP3573647B1/fr
Priority to AU2018212584A priority patent/AU2018212584B2/en
Priority to SG11201906198PA priority patent/SG11201906198PA/en
Priority to SI201830920T priority patent/SI3573647T1/sl
Priority to CA3048108A priority patent/CA3048108A1/fr
Priority to CR20210129A priority patent/CR20210129A/es
Priority to CR20190388A priority patent/CR20190388A/es
Priority to CN201880008006.XA priority patent/CN110198734A/zh
Priority to JP2019539937A priority patent/JP7337695B2/ja
Priority to CR20210130A priority patent/CR20210130A/es
Priority to EA201991444A priority patent/EA201991444A1/ru
Priority to EP22151693.3A priority patent/EP4035675A3/fr
Priority to HRP20230512TT priority patent/HRP20230512T8/hr
Priority to NZ754139A priority patent/NZ754139A/en
Publication of WO2018138257A1 publication Critical patent/WO2018138257A1/fr
Priority to PH12019501377A priority patent/PH12019501377A1/en
Priority to CONC2019/0008008A priority patent/CO2019008008A2/es
Priority to IL268278A priority patent/IL268278B2/en
Priority to AU2021201347A priority patent/AU2021201347A1/en
Priority to AU2021201346A priority patent/AU2021201346A1/en
Priority to AU2021201348A priority patent/AU2021201348A1/en
Priority to AU2021201350A priority patent/AU2021201350B9/en
Priority to AU2021201349A priority patent/AU2021201349A1/en
Priority to JP2023135232A priority patent/JP2023179415A/ja

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Definitions

  • Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers are novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers
  • the present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods.
  • the present invention relates to the immunotherapy of cancer.
  • the present invention furthermore relates to tumor- associated T-cell peptide epitopes, 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.
  • MHC major histocompatibility complex
  • the present invention relates to several novel peptide sequences and their variants derived from HLA class I and HLA class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses, or as targets for the development of pharmaceutically / immunologically active compounds and cells.
  • 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 occurred 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 Europe, 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.
  • ovarian carcinomas are also the most lethal gynecological malignancies. 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 together account for more than 95% of cases. Much less common are malignant germ cell tumors (dysgerminomas, yolk sac tumors, and immature teratomas) (3% of ovarian 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 ovulation, typically by pregnancy or oral contraceptives. These tumors are generally considered to originate from the cells covering the ovarian surface or the pelvic peritoneum. Malignant transformation of this mesothelium has been explained by the "incessant ovulation" theory (La, 2001 ).
  • Surgical resection 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 chemotherapy is not indicated.
  • stage IA very low grade ovarian cancers
  • the first line chemotherapy comprises a combination of carboplatin with paclitaxel, which can be supplemented with bevacizumab.
  • the standard treatment for platinum-resistant ovarian cancers consists of a monotherapy with one of the following chemotherapeutics: pegylated liposomal doxorubicin, topotecane, gemcitabine or paclitaxel (S3-Leitline maligne Ovarialtumore, 2013).
  • Immunotherapy appears to be a promising strategy to ameliorate the treatment of ovarian cancer patients, as the presence of pro-inflammatory tumor infiltrating lymphocytes, especially CD8-positive T cells, correlates with good prognosis and T cells specific for tumor-associated antigens can be isolated from cancer tissue.
  • Cytokine therapy with interleukin-2, interferon-alpha, interferon-gamma or granulocyte- macrophage colony stimulating factor aims at boosting the patient's own anti-tumor immune response and these treatments have already shown promising results in small study cohorts.
  • Monoclonal antibodies that specifically recognize tumor-associated proteins are thought 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.
  • the anti-MUC1 antibody HMFG1 failed to clearly enhance survival in a phase III study.
  • An alternative approach uses monoclonal antibodies to target and block growth factor and survival receptors on tumor cells.
  • trastuzumab anti-HER2/neu antibody
  • MOv18 and MORAb-003 anti-folate receptor alpha antibodies
  • bevacizumab anti-VEGF antibody
  • Adoptive transfer of immune cells achieved heterogeneous results 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.
  • 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 correlate with clinical effects. Transfer of natural killer cells caused significant toxicities in a phase II study.
  • Intrinsic anti-tumor immunity as well as immunotherapy are hampered by an immunosuppressive tumor microenvironment.
  • immunomodulatory drugs like cyclophosphamide, anti-CD25 antibodies and pegylated liposomal doxorubicin are tested in combination with immunotherapy.
  • Most reliable data are currently available for ipilimumab, an anti-CTLA4 antibody, which enhances T cell activity. Ipilimumab was shown to exert significant anti-tumor effects in ovarian cancer patients (Mantia-Smaldone et al., 2012).
  • TAAs tumor associated antigens
  • Cancer-testis antigens The first TAAs ever identified that can be recognized by T cells belong to this class, which was originally called cancer-testis (CT) antigens because of the expression of its members in histologically different human tumors and, among normal tissues, only in spermatocytes/spermatogonia of testis and, occasionally, in placenta. Since the cells of testis do not express class I and II HLA molecules, these antigens cannot be recognized by T cells in normal tissues and can therefore be considered as immunologically tumor-specific.
  • CT antigens are the MAGE family members and NY-ESO-1 .
  • TAAs Differentiation antigens: These TAAs are shared between tumors and the normal tissue from which the tumor arose. Most of the known differentiation antigens 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 different types of tumors as well as in many normal tissues, generally with lower expression levels.
  • TAAs Her-2/neu, survivin, telomerase, or WT1.
  • Tumor-specific antigens arise from mutations of normal genes (such as ⁇ -catenin, CDK4, etc.). Some of these molecular changes are associated with neoplastic transformation and/or progression. Tumor-specific antigens are generally able to induce strong immune responses without bearing the risk for autoimmune reactions against normal tissues. On the other hand, these TAAs are in most cases only relevant to the exact tumor on which they were identified and are usually not shared between many individual tumors. Tumor-specificity (or -association) of a peptide may also arise if the peptide originates from a tumor- (-associated) exon in case of proteins with tumor-specific (-associated) isoforms.
  • TAAs arising from abnormal post-translational modifications may arise from proteins which are neither specific nor overexpressed in tumors but nevertheless become tumor associated by posttranslational processes primarily active in tumors. Examples for this class arise from altered glycosylation patterns leading to novel epitopes in tumors as for MUC1 or events like protein splicing during degradation which may or may not be tumor specific.
  • Oncoviral proteins are viral proteins that may play a critical role in the oncogenic process and, because they are foreign (not of human origin), they can evoke a T-cell response. Examples of such proteins are the human papilloma type 16 virus proteins, E6 and E7, which are expressed in cervical carcinoma.
  • 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).
  • MHC major histocompatibility complex
  • the antigens that are recognized by the tumor specific T lymphocytes, that is, the epitopes thereof, can be molecules derived from all protein classes, such as enzymes, receptors, transcription factors, etc. which are expressed and, as compared to unaltered cells of the same origin, usually up-regulated in cells of the respective tumor.
  • MHC class I 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 beta-2-microglobulin, MHC class II molecules of an alpha and a beta chain. Their three-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 ribosomal products (DRIPs) and larger peptides. However, peptides derived from endosomal compartments or exogenous sources are also frequently found on MHC class I molecules. This non-classical way of class I presentation is referred to as cross- presentation in the literature (Brossart and Bevan, 1997; Rock et al., 1990). MHC class II molecules can be found predominantly on professional antigen presenting cells (APCs), and primarily present peptides of exogenous or transmembrane proteins that are taken up by APCs e.g. during endocytosis, and are subsequently processed.
  • APCs professional antigen presenting cells
  • TCR T-cell receptor
  • CD4-positive-helper-T cells bearing the appropriate TCR. It is well known that the TCR, the peptide and the MHC are thereby present in a stoichiometric amount of 1 :1 :1.
  • CD4-positive helper T cells play an important role in inducing and sustaining effective responses by CD8-positive cytotoxic T cells.
  • TAA tumor associated antigens
  • T helper cells support a cytotoxic T cell- (CTL-) friendly cytokine milieu (Mortara et al., 2006) and attract effector cells, e.g. CTLs, natural killer (NK) cells, macrophages, and granulocytes (Hwang et al., 2007).
  • CTL- cytotoxic T cell- friendly cytokine milieu
  • NK natural killer cells
  • macrophages macrophages
  • granulocytes Hwang et al., 2007.
  • MHC class II molecules 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.
  • APC professional antigen-presenting cells
  • monocytes e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells.
  • monocytes e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells.
  • Elongated (longer) peptides of the invention can act as MHC class II active epitopes.
  • 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 T-helper cell response of the TH1 type support effector functions of CD8- positive killer T cells, which include cytotoxic functions directed against tumor cells displaying tumor-associated peptide/MHC complexes on their cell surfaces. In this way tumor-associated T-helper cell peptide epitopes, alone or in combination with other tumor-associated peptides, can serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses.
  • CD4-positive T cells are sufficient for inhibiting manifestation of tumors via inhibition of angiogenesis by secretion of interferon-gamma (IFNy) (Beatty and Paterson, 2001 ; Mumberg et al., 1999). There is evidence for CD4 T cells as direct anti-tumor effectors (Braumuller et al., 2013; Tran et al., 2014).
  • IFNy interferon-gamma
  • HLA class II molecules Since the constitutive expression of HLA class II molecules is usually limited to immune cells, the possibility of isolating class II peptides directly from primary tumors was previously not considered possible. However, Dengjel et al. were successful in identifying a number of MHC Class II epitopes directly from tumors (WO 2007/028574, EP 1 760 088 B1 ).
  • CD8 and CD4 dependent 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.
  • MHC-class-l- binding peptides are usually 8-12 amino acid residues in length and usually contain two conserved residues ("anchors") in their sequence that interact with the corresponding binding groove of the MHC-molecule. In this way, each MHC allele has a "binding motif" determining which peptides can bind specifically to the binding groove.
  • peptides In the MHC class I dependent immune reaction, peptides 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).
  • TCR T cell receptors
  • the antigen should be expressed mainly by tumor cells and not, or in comparably small amounts, by normal healthy tissues.
  • the peptide should be over-presented by tumor cells as compared to normal healthy tissues. It is furthermore desirable that the respective antigen is not only present in a type of tumor, but also in high concentrations (i.e. copy numbers of the respective peptide per cell).
  • Tumor- specific and tumor-associated antigens are often derived from proteins directly involved in transformation of a normal cell to a tumor cell due to their function, e.g. in cell cycle control or suppression of apoptosis.
  • 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 vaccination approach (Singh-Jasuja et al., 2004). It is essential that epitopes are present in the amino acid sequence of the antigen, in order to ensure that such a peptide ("immunogenic peptide"), being derived from a tumor associated antigen, leads to an in vitro or in vivo T-cell-response.
  • any peptide able to bind an MHC molecule may function as a T-cell epitope.
  • a prerequisite for the induction of an in vitro or in vivo T-cell-response is the presence of a T cell having a corresponding TCR and the absence of immunological tolerance for this particular epitope. 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 usually 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 between tumors and normal tissues.
  • the identification of genes over-expressed in tumor tissues or human tumor cell lines, or selectively expressed in such tissues or cell lines, does not provide precise information as to the use of the antigens being transcribed from these genes in an immune therapy. This is because only an individual subpopulation of epitopes of these antigens are suitable for such an application since a T cell with a corresponding TCR has to be present and the immunological tolerance for this particular epitope needs to be absent or minimal. In a very preferred embodiment of the invention it is therefore important to select only those over- or selectively presented peptides against which a functional and/or a proliferating T cell can be found.
  • a functional T cell is defined as a T cell, which upon stimulation with a specific antigen can be clonally expanded and is able to execute effector functions ("effector T cell").
  • the immunogenicity of the underlying peptides is secondary. In these cases, the presentation is the determining factor.
  • the present invention 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% identical) 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 invention further relates to a peptide of the present invention 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 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 thereof has an overall length of between 8 and 100, preferably between 8 and 30, and most preferred of between 8 and 14 amino acids.
  • peptides with SEQ ID NO: 1 to SEQ ID NO: 9 bind to HLA-A * 02
  • peptides with SEQ ID NO: 10 to SEQ ID NO: 19 bind to HLA-A *
  • 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 * 01
  • 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 4.
  • 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: 1 1 1 bind to HLA-A * 03
  • peptides with SEQ ID NO: 1 12 to SEQ ID NO: 1 16 bind to HLA-A * 01
  • peptides with SEQ ID NO: 1 17 to SEQ ID NO: 149 bind to HLA-B * 07
  • peptides with SEQ ID NO: 150 to SEQ ID NO: 172 bind to HLA-B * 08
  • peptides with SEQ ID NO: 173 to SEQ ID NO: 215 bind to HLA-B 4.
  • 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 * 03
  • peptides with SEQ ID NO: 288 to SEQ ID NO: 292 bind to HLA-A * 01
  • peptides with SEQ ID NO: 293 to SEQ ID NO: 392 bind to HLA-B * 07
  • 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.
  • 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 * 02
  • peptide with SEQ ID NO: 774 binds to HLA-A * 24.
  • 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
  • PCDHB5 PCDHB15
  • PCDHB9 PCDHB8
  • PCDHB7 PCDHB4
  • PCDHGB7 PCDHGB6, Q9NRJ7, Q9UN66,
  • PCDHGB2 PCDHGB1 , Q9Y5E1 , Q9Y5E2,
  • PCDHGA10 PCDHGA9, Q9Y5E5, Q9Y5E6,
  • PCDHGA5 PCDHGA4, Q9Y5E9, Q9Y5F0,
  • PCDHGA1 PCDHGB8P, Q9Y5F3, Q9Y5F8,
  • PCDHB15 PCDHB14, Q9Y5F9, Q9Y5G0,
  • PCDHB13 PCDHB12, Q9Y5G1 , Q9Y5G2,
  • PCDHB1 1 PCDHB10, Q9Y5G3, Q9Y5G4,
  • PCDHB9 PCDHB8, Q9Y5G5, Q9Y5G6,
  • PCDHB7 PCDHB6, Q9Y5G7, Q9Y5G8,
  • PCDHB4 PCDHB3, Q9Y5G9, Q9Y5H0,
  • PCDHB2 PCDHB16, Q9Y5H1 , Q9Y5H2,
  • CT45A5 CT45A6,
  • TCEA1 P2 TCEA1 .
  • TCEA1 P2 TCEA1 .
  • CTAGE4 CTAGE10P
  • TCEA1 P2 TCEA1 .
  • PCDHB5 PCDHB18, Q96TA0, Q9NRJ7,
  • PCDHB17 PCDHB15, Q9UN66, Q9UN67,
  • PCDHB14 PCDHB1 1 , Q9Y5E1 , Q9Y5E3,
  • PCDHB8 PCDHB6, Q9Y5E6, Q9Y5E7,
  • PCDHB4 PCDHB3, Q9Y5E8, Q9Y5E9,
  • Table 4 HLA Class I peptides according to the present invention.

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Abstract

La présente invention concerne des peptides, des protéines, des acides nucléiques et des cellules destinées à être utilisés dans des procédés immunothérapeutiques. En particulier, la présente invention concerne l'immunothérapie du cancer. La présente invention concerne, en outre, des épitopes peptidiques des lymphocytes T associés à une tumeur, seuls ou en combinaison avec d'autres peptides associés à une tumeur, qui peuvent, par exemple, servir de principes pharmaceutiques actifs pour des compositions vaccinales qui stimulent les réponses immunitaires antitumorales, ou pour stimuler des lymphocytes T ex vivo et les transférer aux patients. Des peptides liés aux molécules du complexe majeur d'histocompatibilité (CMH), ou des peptides en tant que tels, peuvent également être des cibles d'anticorps, des récepteurs des lymphocytes T solubles et d'autres molécules de liaison.
PCT/EP2018/051952 2017-01-27 2018-01-26 Nouveaux peptides et combinaison de peptides à utiliser en immunothérapie contre le cancer de l'ovaire et d'autres cancers WO2018138257A1 (fr)

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