WO2014090266A1 - Peptides dérivés de p16ink4a de prophylaxie et de thérapie de tumeurs associées au vph et d'autres tumeurs exprimant le p16ink4a - Google Patents

Peptides dérivés de p16ink4a de prophylaxie et de thérapie de tumeurs associées au vph et d'autres tumeurs exprimant le p16ink4a Download PDF

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WO2014090266A1
WO2014090266A1 PCT/EP2012/005155 EP2012005155W WO2014090266A1 WO 2014090266 A1 WO2014090266 A1 WO 2014090266A1 EP 2012005155 W EP2012005155 W EP 2012005155W WO 2014090266 A1 WO2014090266 A1 WO 2014090266A1
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tumor
cells
vector
ink4a
use according
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PCT/EP2012/005155
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English (en)
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Matthias Kloor
Miriam Reuschenbach
Magnus Von Knebel-Doeberitz
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Ruprecht-Karls-Universität Heidelberg
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Priority to PCT/EP2012/005155 priority Critical patent/WO2014090266A1/fr
Priority to KR1020157015801A priority patent/KR101665410B1/ko
Priority to BR112015013863A priority patent/BR112015013863A2/pt
Priority to CN201280077553.6A priority patent/CN104837497B/zh
Priority to RU2015115137A priority patent/RU2626542C2/ru
Publication of WO2014090266A1 publication Critical patent/WO2014090266A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001148—Regulators of development
    • A61K39/001149—Cell cycle regulated proteins, e.g. cyclin, CDC, CDK or INK-CCR
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4738—Cell cycle regulated proteins, e.g. cyclin, CDC, INK-CCR
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464448—Regulators of development
    • A61K39/464449—Cell cycle regulated proteins, e.g. cyclin, CDC, CDK or INK-CCR
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/464838—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/59—Reproductive system, e.g. uterus, ovaries, cervix or testes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans

Definitions

  • ⁇ 1 derived peptides for prophylaxis and therapy of HPV- associated tumors and other ⁇ 1114 expressing tumors
  • the present invention relates to particular fragments of the cyclin-dependent kinase inhibitor pl6 INK4a and the use of said fragments for immunizing an individual . against pl6 INK a - expressing tumors.
  • the object of the present invention to provide a means for therapy and prophylaxis of HPV-associated tumors and other pl6 INK4a expressing tumors.
  • pl6 INK4a is strongly expressed in virtually all HPV-induced carcinomas and high grade pre-neoplasias, including cervical, vulvar, vaginal, penile, anal and head and neck tumors (Ishikawa et al., 2006; Samama et al., 2006; issaoui et al., 2006; Santos et al., 2006; Roma et al., 2008; Hafkamp et al., 2003). Under physiological conditions pl6 INK4 is only expressed in cells that undergo subsequent senescence and, thus, is barely found expressed in normal tissues (Beausejour et al., 2007).
  • pl6 INK4a is found also overexpressed in various tumors not associated with an HPV infection or in tumors where HPV has been found but a viral carcinogenesis is not proven, including a fraction of melanoma and non-melanoma skin cancers (Nindl et al., 2004; Busch et al., 2010), lung cancers (Leversha et al., 2003; Esposito et al., 2004), esophageal, gastric and colorectal cancers (Ding et al., 2010; Kim et al., 2005) and kidney, bladder, ovarian, endometrial and breast cancers (Ikuerowo et al.
  • T lymphocytes isolated from peripheral blood samples of healthy individuals can be specifically stimulated in vitro with pl6 INK4a derived peptides and that CD4+ and CD8+ T cells from cervical cancer patients show spontaneous reactivity against the same pl6 INK4a peptide and give rise to cytotoxic T cell lines that are able to attack and kill co-cultured HLA-matched pl6 INK a loaded cells and cervical cancer cell lines.
  • fragments of pl6 INK4 are highly immunogenic inducing a very strong immune response against pl6 INK4 .
  • humoral immune responses are detectable against pl6 I K4a .
  • pl6 IN 4 The described expression pattern of pl6 INK4 and the finding of spontaneous immune responses against pl6 INK4 that are not associated with any autoimmune diseases make pl6 IN 4 a promising candidate for immunization of patients with pl6 INK4a expressing cancers.
  • An actively induced strong immune response against pl6 INK4 could specifically destroy HPV-transformed cells and other pl6 INK a -expressing cancer cells.
  • Vaccination of donor T cells with these pl6 INK4 peptides was performed in cell culture experiments. Additional experiments using the pl6 IN 4 peptides revealed spontaneous T cell responses in cervical cancer patients confirming that particular pl6 INK4 peptides are immunogenic also in vivo.
  • pl6 INK4 is strongly expressed in all HPV-associated cancers irrespective of the HPV type and in various other cancer types. Severe side effects of pl6 INK4 immunization are not expected, because pl6 INK4 is barely expressed in normal tissues and no autoimmune phenomena have been observed in individuals with spontaneous immune responses against pl6 INK4 . Finally, immune evasion due to antigen loss is very unlike, because pl6 INK4 expression is intricately linked to the malignant phenotype of the tumor cell.
  • FIG. 1 ELISpot (interferon gamma) results before (A) and after (B) stimulation of donor T cells with the p!6 INK4a peptides
  • the spot count is normalized by subtracting background spot detection in wells without peptides.
  • B the increased spot count in cells stimulated with the peptides pl6lNK4a_37-63, pl6INK4a_51-80 and pl6INK4a_73-104 compared to day 0 becomes clear.
  • CEF CMV, EBV, influenza (flu) peptide mix positive control .
  • FIG. 2 ELISpot (interferon gamma) results in 23 patients (Tx and Fx) and 15 healthy controls (BCx) against the positive control virus mix (CEF) and against the seven 30mer p!6 INK a peptides (Table 1)
  • CD8 T cells from a cervical cancer patient induce lysis of HLA-matched B cells loaded with pl6lNK4a_37-63 (black squares) but not of the same B cells without the pl6 INK4a peptide (open triangles) .
  • Cervical cancer cell lines HeLa pl6 INK4a +, HLA A68, B15, B95, Cw7 Cwl2
  • Caski pl6 INK4a +, HLA A2, A3, B7, B37, Cw5, Cw7 are lysed while no lysis of ME180 and K562 is detected.
  • Figure 4 Proliferation of peripheral blood mononuclear cells from women with cervical dysplasias after stimulation with the seven p!6lNK4a peptides (Table 1)
  • the present invention thus, relates to particular fragments of the cyclin-dependent kinase inhibitor pl6 Inlc4 capable of inducing an immune response against pl6 INK4a .
  • An immune response is defined as a condition fulfilling at least one of the following criteria: 1. The induction of CD8-positive T cells, as detectable by cytotoxicity assays or IFN-gamma secretion or perforin expression or granzyme B expression or other cytokines that may be produced by CD8-positive T cells, measurable as above background by ELISpot or intracellular cytokine staining or cytokine ELISA or equivalent methods. 2.
  • Cytokines may comprise IFN-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, TNF-alpha, TGF-beta or other cytokines that may be produced by CD4-positive T cells.
  • the induction of antibodies as detectable by Western blot, ELISA and equivalent or related methods. 4. The induction of any kind of cellular Immune response not mediated by CD8-positive or CD4-positive T cells as described in 1 and 2.
  • the term "functional equivalent” as used herein relates to, e.g., variants or fragments of (a) which are still capable of inducing an immune response against pl6 INK a , thus, are still useful as an efficient vaccine.
  • the variants are characterized by amino acid deletions, substitutions, and/or additions. Preferably, amino acid differences are due to one or more conservative amino acid substitutions.
  • conservative amino acid substitutions involves replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and lie; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gin, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.
  • genetic engineering can be used to introduce amino acid changes at specific positions of a cloned DNA sequence to identify regions critical for peptide function.
  • site directed mutagenesis or alanine-scanning mutagenesis introduction of single alanine mutations at every residue in the molecule
  • the resulting mutant molecules can then be tested for immunogenicity using the assays of the examples .
  • the variants are characterized by not more than 8 aa, more preferably by not more than 6 aa and, even more preferably, by not more than 4 aa substitutions, deletions and/or additions.
  • the fragment of the original pl6 Ink4a -fragment at least 5 contiguous aa, preferably at least 10 contiguous aa, more preferably at least contiguous 15 aa and even more preferably at least 20 contiguous aa of the particular amino acid sequence are left.
  • Such fragment is still capable of inducing an immune response against pl6 INK4a and, thus, is still useful as an efficient vaccine.
  • the present invention also provides a nucleic acid encoding a fragment of the invention or a vector containing such nucleic acid.
  • the direct injection of genetic material into a living host causes a small amount of its cells to produce the introduced gene products. This inappropriate gene expression within the host has important immunological consequences, resulting in the specific immune activation of the host against the gene delivered antigen.
  • Direct injection of naked plasmid DNA induces strong immune responses to the antigen encoded by the gene vaccine. Once the plasmid DNA construct is injected the host cells take up the foreign DNA, expressing the viral gene and producing pl6 INK4a inside the cell. This form of antigen presentation and processing induces both MHC and class I and class II restricted cellular and humoral immune responses.
  • the DNA vaccines are composed of vectors normally containing two unites: the antigen expression unit composed of promoter/enhancer sequences, followed by antigen (FSP) -encoding and polyadenylation sequences and the production unit composed of sequences necessary for vector amplification and selection.
  • the construction of vectors with vaccine inserts is accomplished using recombinant DNA technology and the person skilled in the art knows vectors that can be used for this approach.
  • the efficiency of DNA immunization can be improved by stabilising DNA against degradation, and increasing the efficiency of delivery of DNA into antigen presenting cells. This has been demonstrated by coating biodegradable cationic microparticles (such as poly (lactide-co-glycolide) formulated with cetyltrimethylammonium bromide) with DNA.
  • biodegradable cationic microparticles such as poly (lactide-co-glycolide) formulated with cetyltrimethylammonium bromide
  • Such DNA-coated microparticles can be as effective at raising C
  • a variety of expression vectors e.g., plasmids or viral vectors, may be utilised -to contain and express nucleic acid sequences encoding a fragment of the present invention.
  • a preferred viral vector is a poxvirus, adenovirus, retrovirus, herpesvirus or adeno-associated virus (AAV) .
  • poxviruses are a vaccinia virus, NYVAG, avipox virus, canarypox virus, ALVAC, ALVAC (2),- fowlpox virus or TROVAC.
  • alphavirus-based vectors have also been used to improve DNA vaccination efficiency.
  • the gene encoding the fragment of the invention is inserted into the alphavirus replicon, replacing structural genes but leaving non-structural replicase genes intact.
  • the Sindbis virus and Semliki Forest virus have been used to build recombinant alphavirus replicons.
  • alphavirus vectors are only transiently expressed. Alphavirus replicons raise an immune response due to the high levels of protein expressed by this vector, replicon-induced cytokine responses, or replicon-induced apoptosis leading to enhanced antigen uptake by dendritic cells.
  • the present invention also provides a pharmaceutical composition containing a fragment, nucleic acid sequence or vector of the present invention in an amount suitable for immunization of an individual and, preferably, one or more common auxiliary agents.
  • a fragment, nucleic acid sequence or vector can be present as such or in combination with carriers. It is favourable for the carriers in the individual not to be immunogenic. Such carriers may be the individual's own proteins or foreign proteins or fragments thereof. Carriers, such as serum albumin, fibrinogen or transferrin or a fragment thereof are preferred.
  • the fragments contain epitopes which are recognized by cytotoxic T cells, e.g. CD8 + T cells or CD4 T cells, and may induce an immune response.
  • Such epitopes of cell cycle regulatory proteins can be determined by methods with which a person skilled in the art is familiar. It can also be advantageous that various fragments are simultaneously present.
  • the present invention also relates to the use of a fragment, nucleic acid sequence or vector of the present invention for the production of a vaccine for preventing or treating a pl6 INK a -expressing pre-neoplasia, neoplasia or carcinoma (including an advanced carcinoma) .
  • these may be HPV-induced, pl6 INK a -expressing anogenital carcinomas, in particular cervical carcinoma, or head and neck cancer and non HPV-induced pl6 INK a -expressing tumors.
  • benign modifications such as papillomas, adenomas, hyperplasias or similar proliferations of epithelial, mesenchymal or hematopoietic proliferations are also to be counted there among.
  • the employed term "individual” comprises an individual of any kind and being able to fall ill with carcinomas. Examples of such individuals are humans and animals as well as cells thereof.
  • the employed term "amount suitable for immunization of an individual” comprises any amount of a fragment of the invention, to which the above explanations apply correspondingly and with which an individual can be immunized.
  • the amount depends on whether immunization is intended as a prophylactic or therapeutic treatment.
  • the individual's age, sex and weight play a role for determining the amount.
  • auxiliary agents comprises any auxiliary agents suitable for a pharmaceutical composition to immunize an individual.
  • auxiliary agents are, e.g., immunization adjuvants, such as GM-CSF or Freund's adjuvant, buffered common salt solutions, water, emulsions, such as oil/water emulsions, wetting agents, sterile solutions, etc.
  • PBMCs Peripheral blood mononuclear cells
  • CIN2/3 high grade cervical dysplasia
  • the BrdU-assay is a colorimetric immunoassay applied for the quantification of cell proliferation based on the measurement of the thymidine analogue 5-bromo-2' -deoxyuridine incorporation during DNA synthesis.
  • PBMCs in IMDM medium supplemented with 10% human serum were seeded in a 96-well-microtiter-plate (flat bottom) at a density of 150.000 cells/50 l/well .
  • Cells in each 4 replicate wells were incubated in the presence of the seven pl6INK4a peptides (Table 1), tetanus toxoid (20 ng/ml, Calbiochem, La Jolla, CA) and mitogen PHA-L (5 ⁇ g/ml, Roche, Mannheim, Germany) as positive controls and no antigen as negative control for 6 days at 37 °C, 5% C02.
  • the remaining cells were dried by using a hair dryer for about 15 minutes and 150 ⁇ /well FixDenat solution were added to the cells and incubated for 30 minutes at room temperature before removing FixDenat by flicking off and tapping carefully.
  • 100 ⁇ /well anti-BrdU-POD working solution were added and incubated for 90 minutes at room temperature, then removed and replaced by 100 ⁇ TMB substrate, which was incubated for 30 minutes at room temperature.
  • the enzyme reaction was stopped by adding 25 ⁇ /well IN H 2 S0 4 and optical density (OD) was measured at 450 nm (reference wavelength 620 nm) . Cut-off for positive reactions was set as three times standard deviation of ODs in the negative control wells without antigen.
  • PBMCs from 3 out of the 13 tested women showed proliferation in response to. the pl6 INK4a peptides, indicating that incubation with the peptides has activated proliferative memory T cell responses. Overall the pattern of response inducing peptides was heterogenic, indicating various T cell epitopes within the pl6 antigen.
  • T cells from 23 patients with invasive cervical cancer and high grade precancerous lesions (CIN2/3) with strong pl6 INK4a overexpression were tested against the seven pl6 INK4a peptides (Table 1) in interferon gamma ELISpot assays.
  • T cells were separated from heparinized blood using Ficoll centrifugation, plastic adherence and antibody coupled magnetic beads (CD11, CD16, CD19, CD36, CD56, Pan T cell isolation Kit, ilteny, Bergisch Gladbach, Germany) .
  • Dendritic cells were generated by culturing plastic adherent cells for 7 days with IL4 and GM-SCF (each 1000 U/ml) and used as antigen presenting cells in the ELIspot. Each 10 5 T cells were tested after a short (2 to 5 days) in vitro presensitization with the respective peptide presented by 2 x 10 4 dendritic cells. When subtracting background (2 times the spots in the negative control well + 2 standard deviations of reactivity against the respective pl6 INK4a peptide) in 7 cervical cancer patients T cells (CD4 or CD8 ) reacting against the ⁇ 16 ⁇ 43_37- ⁇ 63 peptide could be identified ( Figure 2) .
  • pl6 INK a fragments can stimulate healthy donor T cells in vitro to secrete interferon gamma and to identify the most immunogenic pl6 INK4a derived epitopes.
  • T cells isolated from peripheral blood of healthy donors can be stimulated in vitro with these pl6 INK a peptides. If the pl6 INK a peptides are able to induce a specific T cell response in cell culture experiments, the T cells secrete cytokines when challenged with the respective pl6 INK a peptide in so called ELISpot experiments. In ELISpot assays the cytokines (interferon gamma) can be detected by specific antibodies with a subsequent colour reaction.
  • PBMC Peripheral blood mononuclear cells
  • PBMC Peripheral blood mononuclear cells
  • 5 to 10 x 10 7 PBMC were separated into monocytes and T cells by plastic adherence and antibody coupled magnetic beads (CD11, CD16, CD19, CD36, CD56, Pan T cell isolation Kit, Milteny, Bergisch Gladbach, Germany) .
  • the monocytes were cultured over 7 days with GM-CSF and IL-4 (each 1000 U/ml) to generate antigen presenting dendritic cells .
  • 2 x 10 7 T cells were incubated with 2 x 10 6 dendritic cells that were prior pulsed with the pl6 INK a peptides (10 g/ml) for 4 hours to achieve presentation of the antigens.
  • the pl6 INK a peptides (10 g/ml) for 4 hours to achieve presentation of the antigens.
  • a separate stimulation approach was processed for each of the 7 pl6 INK a peptides.
  • the T cells were restimulated with pl6 INK4a peptide pulsed dendritic cells and treated with IL-2 and IL-7 (10 U/ml) every 7 days over a 5 week period.
  • the ⁇ 1 peptide specific T cell response was measured in interferon gamma ELISpot assays before the stimulations (day 0) and after the last stimulation (day 35) .
  • ELISpot assays 96 well nitrocellulose plates (MAHA N4550 Millipore) were coated with anti-interferon gamma antibody 1-DlK (Mabtech, Nacka Strand, Sweden) at a concentration of 0.75ug/well. Each 10 5 T cells were tested with the respective peptide presented by 2 x 10 4 dendritic cells.
  • pl6lNK4a_37-63, pl6INK4a_51-80 and pl6INK4a_73-104 showed an increased interferon gamma secretion in the ELISpot when tested against target cells pulsed with the respective pl6 INK a peptides but not when tested against cells pulsed with the remaining pl6 INK4a peptides
  • T cells The ability of activated T cells to lyze pl6 IN 4a expressing cervical cancer cells was tested by chromium release assays using different cervical cancer cell lines as well as HLA matched B cells loaded with pl6 INK4a peptides as targets.
  • 10 x 6 target cells peptide loaded HLA-matched B cells, B cells without peptide
  • 51 Cr 100 Ci
  • ELIspot assays Specific lysis of target cells by the T cells can be measured by detection of released radioactivity.
  • Bound serum antibodies were detected by HRP-conjugated anti- human IgG antibody (Jackson Iramuno, West Grove, USA and TMB substrate (Sigma Aldrich, St. Louis, USA) . At a cut off of a background normalized optical density of 0.03, 15% (56/374) of the tested sera had antibodies against pl6lNK4a_37-63.
  • pl6(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92, 276.

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Abstract

La présente invention concerne des fragments particuliers de l'inhibiteur de la kinase dépendante de la cycline p16 pouvant augmenter la sécrétion d'IFN-ϒ des lymphocytes T ou d'induire une prolifération de lymphocytes T et l'utilisation desdits fragments pour immuniser un individu contre des carcinomes associés au VPH ou d'autres carcinomes exprimant le p16INK4a, de préférence des carcinomes à l'état déclaré.
PCT/EP2012/005155 2012-12-13 2012-12-13 Peptides dérivés de p16ink4a de prophylaxie et de thérapie de tumeurs associées au vph et d'autres tumeurs exprimant le p16ink4a WO2014090266A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/EP2012/005155 WO2014090266A1 (fr) 2012-12-13 2012-12-13 Peptides dérivés de p16ink4a de prophylaxie et de thérapie de tumeurs associées au vph et d'autres tumeurs exprimant le p16ink4a
KR1020157015801A KR101665410B1 (ko) 2012-12-13 2012-12-13 HPV-관련 종양 및 다른 p16INK4a 발현 종양의 예방 및 치료용 p16INK4a 유래 펩티드
BR112015013863A BR112015013863A2 (pt) 2012-12-13 2012-12-13 peptídeos derivados p16ink4a para profilaxia e terapia de tumores associados a hpv e outros tumores expressando p16
CN201280077553.6A CN104837497B (zh) 2012-12-13 2012-12-13 用于预防和治疗HPV-相关的肿瘤和其它表达p16的肿瘤的p16INK4a衍生肽
RU2015115137A RU2626542C2 (ru) 2012-12-13 2012-12-13 ПЕПТИДЫ, ПОЛУЧЕННЫЕ ИЗ р16INK4a, ДЛЯ ПРОФИЛАКТИКИ И ЛЕЧЕНИЯ ВПЧ-АССОЦИИРОВАННЫХ ОПУХОЛЕЙ И ДРУГИХ ОПУХОЛЕЙ, ЭКСПРЕССИРУЮЩИХ р16INK4а

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PCT/EP2012/005155 WO2014090266A1 (fr) 2012-12-13 2012-12-13 Peptides dérivés de p16ink4a de prophylaxie et de thérapie de tumeurs associées au vph et d'autres tumeurs exprimant le p16ink4a

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2016026919A1 (fr) * 2014-08-20 2016-02-25 Ruprecht-Karls-Universität Heidelberg Vaccins et procédés de fabrication pour le traitement et la prévention de maladies

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* Cited by examiner, † Cited by third party
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CN106046156A (zh) * 2016-06-02 2016-10-26 吉林大学 肿瘤相关基因cdkn2a表位多肽单克隆抗体制备及其应用
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