WO2021259963A1 - Immunisation contre wnt4 pour le traitement et la prophylaxie du cancer du sein - Google Patents

Immunisation contre wnt4 pour le traitement et la prophylaxie du cancer du sein Download PDF

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WO2021259963A1
WO2021259963A1 PCT/EP2021/067056 EP2021067056W WO2021259963A1 WO 2021259963 A1 WO2021259963 A1 WO 2021259963A1 EP 2021067056 W EP2021067056 W EP 2021067056W WO 2021259963 A1 WO2021259963 A1 WO 2021259963A1
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pharmaceutical composition
protein
cell
wnt4
amino acid
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PCT/EP2021/067056
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English (en)
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Herman Jan Tijmen Coelingh Bennink
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Pandora Endocrine Innovation B.V.
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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
    • 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
    • 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
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/812—Breast

Definitions

  • the present invention relates to the fields of medicine, oncology, immunology, developmental biology and biopharmacy. More specifically, the invention relates to methods for treatment and prophylaxis of breast cancer, which method comprises the passive and/or active immunization against the Wnt 4 protein, using antigen sources providing at least an immunogenic portion of a Wnt 4 protein. Such antigen sources may be used in vaccines and pharmaceutical compositions for therapeutic and prophylactic treatment of primary and/or recurring breast cancer and metastases thereof.
  • the lifetime absolute risk of women in the USA to develop breast cancer (BC) is 1 in 8 (12.4%) over an 80-year lifespan [1]
  • the lifetime risk of acquiring breast cancer is about 1 in 1 ,000 (0.1%) [2], which means that the risk in women is 125 times higher.
  • Lifetime risk for women is similar in Europe, and even reported as 1 in 7 (14.3%) in the United Kingdom (UK) for women born after 1960, with a yearly incidence of new cases of about 480 per 100,000 for women, and about 10 per 100,000 for men [3] Geographical differences exist.
  • the lifetime risk of BC is lower with about 1 in 38 (2.6%) for women, but the huge difference with males remains with an incidence of about 1 in 2,000 (0.05%) in Japanese males [4]
  • estrogens are considered to be responsible for causing BC. This perception is supported by the fact that estrogens are known to stimulate the growth of existing estrogen-receptor positive (ER+) BC indeed clinically as well as in preclinical in vitro and in vivo models [5] However, high dose estrogen (HDE) is also an effective treatment of BC more than 5 years after menopause or after the occurrence of resistance to endocrine anti-estrogen treatment [6]. This contradictory knowledge is known as the “estrogen paradox” [5,7] Essential for HDE efficacy is an extended period of estrogen deprivation before the tumor is subjected to estrogen treatment (the “gap hypothesis”) [8,9] The stimulatory or inhibitory effect of estrogens on the growth of BC tumors must be distinguished from the question whether or not estrogens cause BC de novo [10] While estrogen metabolites are held responsible for causing BC, which may be true in in vitro and in vivo preclinical models [11], no evidence is available that women with BC have increased levels of such potentially carcinogenic
  • estrogen related risk factors such as breast density, estradiol (E2) levels, age at menopause, age at first life birth, age at menarche, body weight, obesity, menopausal hormone therapy and combined oral contraceptive use.
  • non-estrogen related risk factors are a family history of BC and lifestyle related risks such as diet, alcohol use and exercise [14] Most factors are not relevant for males, but also for men, high E2 levels are related to a greater risk of developing breast cancer [15] Except for an early first pregnancy before the age of 20, which reduces the BC life time risk by about 50% in comparison to nulliparous women, all these factors affect the BC risk to a relatively small extent which is incomparable to the big gender difference. An exception is the presence of germline mutations, especially the BRCA1 or BRCA2 gene, which increases the BC risk with a factor of about 10 to a lifetime risk of 45-85% in women and 1 % in men [16-18]
  • the invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising an immunogen for inducing an immune response against a Wnt4 protein or an antibody or fragment thereof that specifically binds to the Wnt4 protein for use in the treatment of breast cancer and/or metastases thereof.
  • the treatment can be prophylactic i.e. before the onset of breast cancer or the treatment can be therapeutic to cure or delay existing breast cancer of metastases thereof.
  • the term "and/or” indicates that one or more ofthe stated cases may occur, alone or in combination with at least one of the stated cases, up to with all of the stated cases.
  • At least a particular value means that particular value or more.
  • at least 2 is understood to be the same as “2 or more” i.e. , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, ... ,etc.
  • the word “about” or “approximately” when used in association with a numerical value preferably means that the value may be the given value (of 10) more or less 0.1% of the value.
  • an effective amount is meant the amount of an agent required to ameliorate the symptoms of a disease relative to an untreated patient.
  • the effective amount of active agent(s) used to practice the present invention for therapeutic treatment of a cancer varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • a drug which, in the context of the current disclosure, is "effective against" a disease or condition indicates that administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in at least one disease sign or symptom, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.
  • an antibody means an isolated or recombinant binding agent that comprises the necessary variable region sequences to specifically bind an antigen. Therefore, an antibody is any form of antibody or fragment thereof that exhibits the desired biological activity, e.g., binding the specific target antigen.
  • Antibodies can derive from multiple species. For example, antibodies include rodent (such as mouse and rat), rabbit, sheep, camel, and human antibodies. Antibodies can also include chimeric antibodies, which join variable regions from one species to constant regions from another species. Likewise, antibodies can be humanized, that is constructed by recombinant DNA technology to produce immunoglobulins which have human framework regions from one species combined with complementarity determining regions (CDRs) from a another species' immunoglobulin.
  • CDRs complementarity determining regions
  • the antibody can be monoclonal or polyclonal. Antibodies can be divided into isotypes (IgA, IgG, IgM, IgD, IgE, lgG1 , lgG2, lgG3, lgG4, lgA1, lgA2, lgM1 , lgM2).
  • the term "antibody” refers to an intact antibody, or a fragment of an antibody that competes with the intact antibody for antigen binding.
  • antibody fragments are produced by recombinant DNA techniques.
  • antibody fragments are produced by enzymatic or chemical cleavage of intact antibodies.
  • antibody fragment is a compound having qualitative biological activity in common with a full-length antibody.
  • a functional fragment of an anti-Wnt4 antibody is one that can bind to Wnt4.
  • Exemplary antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, and scFv.
  • Exemplary antibody fragments also include, but are not limited to, domain antibodies, nanobodies, minibodies ((scFv-CH.sub.3).sub.2), maxibodies ((scFv-CH.sub.2--CH.sub.3).sub.2), diabodies (noncovalent dimer of scFv).
  • a substance as a medicament as described in this document can also be interpreted as the use of said substance in the manufacture of a medicament.
  • a substance is used for treatment or as a medicament, it can also be used for the manufacture of a medicament for treatment.
  • Products for use as a medicament described herein can be used in methods of treatments, wherein such methods of treatment comprise the administration of the product for use.
  • the Mayer-Rokitansky-Kiister-Hauser (MRKH) syndrome or Miillerian agenesis is a congenital malformation characterized by failure of the Miillerian ducts to develop in an XX phenotype female, resulting in absence of the upper two-third of the vagina, the uterus, and the oviducts, all normally derived from the paramesonephric Miillerian ducts [19] Women with the MRKH syndrome have functioning ovaries, i.e. they ovulate and produce normal ovarian steroids, including progesterone (P4).
  • P4 progesterone
  • Wnt4 is a member of the Wnt family of secreted molecules that were originally identified as mammalian homologues of the Drosophila wingless gene.
  • the Wnt4 gene on chromosome 1 and the encoded Wnt4 glycoprotein ligand are signaling molecules shown to influence the sex-determination cascade known to antagonize the testis-determining factor and play a concerted role in both the control of female development and the prevention of testes formation.
  • the Wnt4 gene, its nuclear receptor and the Wnt4 protein are associated with abnormal proliferation in breast tissue and have a special role in mammary development and in the origin and stimulation of breast cancer.
  • Wnt4 is also required for normal antral follicle development and regulation of granulosa cell function including steroidogenesis [23]
  • Wnt4 has an essential function in mammary gland development downstream of P4 signaling [24]
  • SRY Sex-determining Region Y
  • Wnt4 activity is downregulated by the Sex-determining Region Y (SRY) gene on the Y- chromosome causing regression of the Miillerian ducts and development of the mesonephric Wolffian ducts, resulting in the formation of epididymis, vas deferens and seminal vesicles [25]
  • SRY Sex-determining Region Y
  • the invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising an immunogen for inducing an immune response against a Wnt4 protein or an antibody or fragment thereof that specifically binds to the Wnt4 protein, for use in a method for therapeutic and/or prophylactic treatment of breast cancer and/or metastases thereof in a female mammal.
  • breast cancer refers to both primary and/or recurring breast cancers as well as metastases thereof that may have settled anywhere in the body.
  • the invention concerns prophylactic treatment of breast cancer i.e. preventing the occurrence of breast cancer and/or metastases thereof in a female mammal.
  • Breast cancers can be divided into at least five distinct molecular subtypes based on gene expression, cellular morphology, and response to treatment.
  • Breast cancers can first be divided into two broad groups, estrogen-receptor (ER)-positive and ER-negative. These two groups can further be subdivided into additional distinct biologically and clinically significant subgroups.
  • ER-positive tumors express estrogen-receptor, ER-responsive genes, and other proteins of luminal epithelial cells.
  • luminal tumors which can further be classified into luminal A and luminal B tumors, depending on the characteristic gene expression patterns.
  • ER-negative tumors can be further classified into three groups: HER-2 positive, basal-like tumors, and normal breast-like tumors.
  • HER-2 positive tumors express high levels of genes located in the HER2 amplicon on chromosome 17 at location 17q21 , including HER-2 and growth factor receptor-bound protein 7 (GRB7). They also have a high level of nuclear factor (NF)-kappaB activation and express a high level of the transcription factor GATA4 but lack expression of ER and GATA3.
  • the normal breast-like tumors resemble normal breast tissue samples with relatively high expression of many genes characteristic of adipose cells and other nonepithelial cell types, and low levels of expression of luminal epithelial cell genes.
  • Basal-like breast cancers are defined by the lack of expression of the hormone receptors estrogen (ER) and progesterone (PR), and the human epidermal growth factor receptor- 2 (HER2).
  • triple negative breast cancer is meant estrogen-receptor (ER) negative, progesterone- receptor (PR) negative, and HER2 negative breast cancer. Triple negative breast cancers do not express ER, PR, or HER2.
  • the highest Wnt activity is found in basal-like BC, triple-negative BC, and more specific in subsets of BC cancer stem cells.
  • immunogen or “immunogenic agent” or “antigen” are used interchangeably to describe a molecule capable of inducing an immunological response against itself on administration to a recipient, either alone, in conjunction with an adjuvant, or presented on a display vehicle.
  • the phrase "immune response” or its equivalent “immunological response” refers to the development of a humoral (antibody mediated), cellular (mediated by antigen-specific T cells or their secretion products) or both humoral and cellular response directed against a protein in a recipient patient.
  • a response can be an active response induced by administration of immunogen or a passive response induced by administration of antibody, antibody containing material, or primed T-cells.
  • the invention relates to a method for therapeutic and/or prophylactic treatment of breast cancer and/or metastases thereof in a female mammal by active immunization.
  • the method of active immunization preferably comprises administering a source of an immunogenic polypeptide capable of eliciting a cellular immune response against Wnt4 and/or a humoral immune response against Wnt4.
  • the immunogenic polypeptide comprises a contiguous amino acid sequence selected from the amino acid sequence of an Wnt4 protein, which contiguous amino acid sequence preferably comprises at least one of a B cell epitope class I MHC- and a class II MHC- restricted T cell epitope.
  • the immunogenic (poly)peptide comprises a B-cell epitope.
  • the B-cell epitope or epitopes may be of any chemical nature, including without limitation peptides, carbohydrates, lipids, glycopeptides and glycolipids.
  • the epitopes are peptides derived from one or more of the antigens described herein or known in the art.
  • the epitope may be identical to a naturally occurring epitope, or may be a modified form of a naturally occurring epitope.
  • B-cell epitopes are recognized by B-cells and by antibodies.
  • B-cell epitopes are typically at least five amino acids, more often at least six amino acids, still more often at least seven or eight amino acids in length, and may be continuous (“linear”) or discontinuous (“conformational”); the latter being formed, for example, by the folding of a protein to bring non-contiguous parts of the primary amino acid sequence into physical proximity. Conformational epitopes may be recognizable as linear epitopes, such as when they are synthetically prepared as such. Typically, linear B-cell epitopes vary from 5-20 amino acids in length. B-cell epitopes may also be carbohydrate epitopes.
  • the antigen of the compositions described herein may either consist of or comprise a B-cell epitope capable of inducing a humoral immune response.
  • the immunogen of the compositions described herein may consist of or comprise one or more B-cell epitopes associated with an infectious disease.
  • the immunogen may consist of or comprise a B-cell epitope derived from a virus, such as for example influenza virus, Zika virus or respiratory syncytial virus.
  • the B-cell epitope may be an epitope derived from the hemagglutinin glycoprotein of the H5N1 influenza virus.
  • the B-cell epitope may be an epitope derived from the ectodomain of the small hydrophobic protein (SHe) of a respiratory syncytial virus.
  • SHe small hydrophobic protein
  • the antigen of the compositions described herein may consist of or comprise a B-cell epitope derived from a bacterium, such as for example Bordetella pertussis or Bacillus anthracis.
  • the B-cell epitope may be an epitope of the pertussis toxoid protein produced by Bordetella pertussis.
  • the B-cell epitope may be an epitope of the anthrax recombinant protective antigen (rPA) or the anthrax mutant recombinant protective antigen (mrPA).
  • the antigen of the compositions described herein may consist of or comprise a B-cell epitope derived from aprotozoan, such as from the genus Plasmodium.
  • the composition may comprise a mixture of B-cell epitopes as antigens for inducing a humoral immune response.
  • the B-cell epitopes may be linked to form a single molecule (e.g. one polypeptide) or be presented as separate molecules (e.g. separate polypeptides).
  • the immunogenic polypeptide comprises a contiguous amino acid sequence selected from the amino acid sequence of the Wnt4 protein (i.e. SEQ ID NO:1 or the amino acid sequence of GenBank accession number AL031281 .6) which contiguous amino acid sequence preferably comprises at least one of B-cell epitope, a class I MHC- and a class II MHC-restricted T cell epitope. More preferably, the contiguous amino acid sequence comprises at least one of a class I MHC- and a class II MHC-restricted T cell epitope with a low percentile rank (see Moutaftsi et al., Nat Biotechnol.
  • a class I MHC-restricted T cell epitope with a low percentile rank preferably is an epitope with a percentile rank that is not higher than 1.00, 0.80, 0.40, 0.30, 0.20, 0.15, 0.10 or 0.05 (see e.g. Tables 2 and 5).
  • a class II MHC-restricted T cell epitope with a low percentile rank preferably is an epitope with a percentile rank that is not higher than 2.50, 2.40, 2.05, 2.00, 1 .80, 1 .60, 1 .40, 1 .20, 1.10, 1 .00, 0.90, 0.70, 0.60, 0.50, 0.40, 0.20. 0.15, 0.10, 0.05 or 0.02.
  • the contiguous amino acid sequence from an Wnt4 protein as comprised within the immunogenic polypeptide preferably comprises an immunologically active (sequence) fragment of the Wnt4 protein.
  • immunologically active fragments thereof will generally be understood in the art to refer to a fragment of a Wnt4 protein antigen comprising at least an epitope, which means that the immunogenic polypeptide at least comprises 4, 5, 6, 7 or 8 contiguous amino acids from the sequence of the Wnt4 protein antigen.
  • the fragment comprises at least an MHC class I or MHC class II binding peptide presented by such MHC molecule to the immune system.
  • An ‘immunologically active fragment’ comprises at least 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16 or 17 contiguous amino acids from the sequence of the Wnt4 protein antigen or homologue or analogue thereof. While the majority of the MHC binding peptides are of a length of 9 amino acids, longer peptides can be accommodated by the bulging of their central portion (Guo et al., 1992, Nature; 360(6402):364-366; Speir et al., 2001 , Immunity; 14(1):81— 92), resulting in binding peptides of length 8 to 15 (Schumacher et al., 1991 , Nature; 350(6320):703-706).
  • the fragment comprises both a Cytotoxic T Lymphocyte (CTL) and a Helper T Lymphocyte (HTL) epitope.
  • CTL Cytotoxic T Lymphocyte
  • HTL Helper T Lymphocyte
  • the fragment is a peptide that requires processing by an antigen presenting cell (APC), i.e. the fragment has a length of at least about 18 amino acids, which 18 amino acids are not necessarily a contiguous sequence from the Wnt4 protein antigen.
  • APC antigen presenting cell
  • the length of a contiguous amino acid sequence from Wnt4 protein as comprised within the immunogenic polypeptide or the length of the immunogenic polypeptide itself therefore preferably is at least 18, 19, 20, 21 , 22, 25, 27, 30, 33 or 35 amino acids and preferably no more than 100, 80, 60, 50, 45, 40, 35, 33 or 30 amino acids.
  • the length of a contiguous amino acid sequence from an Wnt4 protein as comprised within the immunogenic polypeptide, or the length of the immunogenic polypeptide itself is 19 - 50 or 19 - 45, more preferably 25 - 40 amino acids, even more preferably 25 - 35 and most preferably 25 - 30 amino acids. From the view point of manufacturability an immunogenic polypeptide with a length of around 25 amino acids is optimal, while still long enough to contain multiple epitopes and force presentation via Antigen Presenting Cells.
  • the immunogenic polypeptide comprises a peptide comprising a contiguous amino acid sequence of 5 - 25 amino acids that comprises a B cell epitope.
  • this B-cell epitope is specific for Wnt4, i.e. selected from a region that does not comprise conserved amino acid sequences of the other Wnt proteins.
  • homologues thereof refer to polypeptides which differ from the naturally occurring polypeptide by minor modifications, but which maintain the basic polypeptide and side chain structure of the naturally occurring form.
  • changes include, but are not limited to: changes in one or a few amino acid side chains; changes in one or a few amino acids, including deletions (e.g., a truncated version of the peptide) insertions and/or substitutions; changes in stereochemistry of one or a few atoms; and/or minor derivatizations, including but not limited to: methylation, glycosylation, phosphorylation, acetylation, myristoylation, prenylation, palmitation, amidation and/or addition of glycosylphosphatidyl inositol.
  • a homologue or analogue has either enhanced or substantially similar functionality as the naturally occurring polypeptide.
  • a naturally occurring polypeptide and a homologue thereof share at least a certain percentage of sequence identity.
  • GAP uses the Needleman and Wunsch global alignment algorithm to align two sequences over their entire length, maximizing the number of matches and minimizes the number of gaps.
  • the default scoring matrix is Blosum62 (Henikoff & Henikoff, 1992, PNAS 89, 915-919).
  • Sequence alignments and scores for percentage sequence identity may be determined using computer programs, such as the GCG Wisconsin Package, Version 10.3, available from Accelrys Inc., 9685 Scranton Road, San Diego, CA 92121- 3752, USA. Alternatively percent similarity or identity may be determined by searching against databases such as FASTA, BLAST, etc.
  • a homologue herein is understood to comprise an immunogenic polypeptide having at least 70 %, preferably at least 80 %, more preferably at least 90 %, still more preferably at least 95 %, still more preferably at least 98 % and most preferably at least 99% amino acid sequence identity with the naturally occurring Wnt4 polypeptide mentioned above and is still capable of eliciting at least the immune response obtainable thereby.
  • a homologue or analogue may herein comprise substitutions, insertions, deletions, additional N- or C- terminal amino acids, and/or additional chemical moieties, such as carbohydrates, to increase stability, solubility and immunogenicity.
  • an immunogenic polypeptide comprising an amino acid sequence that is a homologue of a wild-type Wnt4 protein, but differs therefrom as a result of tumor-specific mutations (which can be patient-specific or shared) that result in altered amino acid sequences, i.e. so-called neoantigens.
  • epitope refers to a portion of an antigen, typically defined by a short peptide, which is capable of eliciting a cellular or humoral immune response when presented in a physiologically relevant context in vivo.
  • a "T cell epitope” refers to a short peptide or portion thereof that binds to an MHC molecule and is recognized by certain T cells when presented in certain MHC molecules.
  • a T cell epitope is capable of inducing a cell mediated immune response via direct or indirect presentation in heterodimeric membrane MHC molecules.
  • the peptide of the invention preferably comprises at least one MHC class I presented epitope and preferably also at least one MHC class II presented epitope.
  • Each of these epitopes are presentable and will bind to the corresponding specific MHC molecule present on the cells after having been processed as described herein.
  • Each MHC restricted epitope may therefore also be named an MHC binding and/or presentable epitope.
  • a specific proteasomal cleavage site generating the C-terminus of such epitope is present exactly after the epitope’s amino acid sequence in order to be liberated from the immunogenic polypeptide and presented on the MHC class I molecule.
  • Length requirements are much less strict for MHC class II presented epitopes, therefore a need for precise enzymatic generation of the class II binding peptide is less absolute.
  • MHC molecules preferentially bind particular amino acid residues known as “anchor” residues (K. Falk et al., Nature 351 :290-96 (1991)). This characterization permits class I and II MHC binding motifs to be recognized within any known peptide sequence (see e.g. Tables 2, 5 and 3).
  • MHC restricted epitope is synonymous with T cell epitope.
  • class I MHC restricted epitope refers to peptide sequences recognized by cytotoxic T lymphocytes (also called CD8+ cells, TCD8 or CTLs) in association with class I MHC.
  • class II MHC restricted epitope refers to a peptide recognized by helper T cells (also called CD4+ cells, TCD4 or HTLs) in association with class II MHC.
  • helper T cells also called CD4+ cells, TCD4 or HTLs
  • a “B cell epitope” is the portion of an antigen that is capable of binding to an antigen binding site of an immunoglobulin and therefore capable of stimulating a humoral response without presentation by an MHC molecule.
  • the polypeptide useful in the present invention comprises at least one T cell epitope.
  • the use of polypeptides that also comprise a B cell epitope is however not excluded from the present invention.
  • the present immunogenic polypeptides may also include multiple T cell epitopes and, optionally a B cell epitope. When multiple epitopes are present in a peptide, the epitopes may be oriented in tandem or in a nested or overlapping configuration wherein at least one amino acid residue may be shared by two or more epitopes.
  • the immunogenic polypeptide of the invention preferably includes one or more MHC class I restricted epitopes.
  • an antigen comprising a single MHC restricted epitope will be useful only for treating a (small) subset of patients who express the MHC allele product that is capable of binding that specific peptide. It has been calculated that, in humans, vaccines containing CTL epitopes restricted by HLA-A1 , -A2, -A3, -A24 and -B7 would offer coverage to approximately 80 % of individuals of most ethnic backgrounds.
  • the present method comprises the administration of a composition comprising one or more different polypeptides comprising one, more preferably two, most preferably three MHC class I binding native Wnt4 epitopes selected from HLA-A1 , HLA-A2, HLA-A3, HLA-A24 and HLA-B7 restricted epitopes; or homologues thereof.
  • the immunogenic polypeptide of the invention preferably includes one or more MHC class II restricted epitopes.
  • the most frequently found MHC class II allele products in humans include HLA-DR1 , -DR3, -DR4 and -DR7.
  • the method comprises the administration of a composition comprising one or more different polypeptides, said one or more different polypeptides comprising one, more preferably two and most preferably three MHC class II binding native Wnt4, epitopes selected from HLA-DR1 , HLA- DR3, HLA-DR4 and HLA-DR7 restricted epitopes; or homologues thereof.
  • the method of the invention comprises the administration of a composition comprising one or more polypeptides, said one or more polypeptides comprising one or more MHC class I restricted epitopes and one or more MCH class II restricted epitopes or homologues thereof.
  • said composition comprises an effective amount of one or more different polypeptides that together include essentially all of the MHC class I and MHC class II binding epitopes comprised in Wnt4, glycoproteins; or homologues of said one or more polypeptides.
  • the present method comprises the administration of a composition comprising one or more different immunogenic polypeptides.
  • said one or more different polypeptides together comprise at least 50 %, more preferably at least 70 %, still more preferably at least 80 %, still more preferably at least 90 % and most preferably at least 95 % of the MHC class I and MHC class II restricted epitopes comprised in Wnt4 or homologues of said one or more polypeptides.
  • the pharmaceutical composition of the invention comprises a T cell comprising a T cell receptor that binds an MHC-peptide complex, wherein the peptide is a peptide from the amino acid sequence of the Wnt4 protein.
  • a T cell can e.g. be obtained in a method comprising contacting a T-cell with an antigen presenting cell expressing a polynucleotide encoding an immunogenic polypeptide of the invention and/or contacting a T-cell with an antigen presenting cell loaded with an immunogenic polypeptide of the invention; and, optionally, culturing said T-cell.
  • the antigen presenting cell preferably is a dendritic cell (DC).
  • the T-cell is preferably a CD8+ cytotoxic T-cell or a CD4+ T-helper cell.
  • Introducing a polynucleotide encoding the immunogenic polypeptide into the APC or DC may be performed using any method known to the person skilled in the art, preferably a polynucleotide according to the invention is introduced into the APC or DC using transfection.
  • the polynucleotide encoding the immunogenic polypeptide is provided with proper control sequences, or be comprised in a proper expression vector.
  • Contacting a T-cell with an immunogenic polypeptide of the invention can be performed by any method known to the person skilled in the art.
  • the immunogenic polypeptide or an epitope comprised in the immunogenic polypeptide is presented to the CD8+ cytotoxic T-cell or CD4+ T-helper cell by an MHC class I or an MHC class II molecule on the surface of an APC, preferably a DC.
  • an MHC class I or an MHC class II molecule on the surface of an APC, preferably a DC.
  • the person skilled in the art knows how to load an APC or DC with a peptide. Culturing said T-cell may be performed using any method known by the person skilled in the art. Maintaining a T-cell under conditions to keep the cell alive is herein also to be construed to be culturing.
  • the T-cell according to this aspect of the invention is contacted with an immunogenic polypeptide according to the invention as defined in the first aspect of the invention.
  • the invention also relates to a composition comprising an (activated) T-cell according to the invention, as well as to methods of the inventions for therapeutic and/or prophylactic treatment of breast cancer and/or metastases, comprising administering to the subject a therapeutically effective amount of an (activated) tumor specific T- cell described herein.
  • silico prediction software such as NETMHCPAN 3.0 can be used to predict potential HLA-A2 restricted T-cell epitopes from hWnt4.
  • the administering comprises administering from about 106 to 1012, from about 108 to 1011 or from about 109 to 1010 of the (activated) tumor specific T-cells.
  • the T-cell or composition therewith is preferably administered via intravenous, intraperitoneal, intratumoral, intradermal, or subcutaneous administration.
  • the T-cell or composition therewith is administered into an anatomic site that drains into a lymph node basin.
  • the administration is into multiple lymph node basins.
  • the pharmaceutical composition for a use according to the invention comprises a source of the immunogenic polypeptide.
  • the source of the immunogenic polypeptide can be a proteinaceous source, a nucleic acid, an antigen presenting cell or a combination thereof.
  • the proteinaceous source can e.g. be a composition comprising one or more peptides, polypeptides or proteins that act as immunogen.
  • the source of the immunogenic polypeptide of the invention to be administered comprises a nucleic acid molecule encoding the immunogenic polypeptide.
  • the source or composition comprising the nucleic acid molecule encoding the immunogenic polypeptide can comprise one or more different nucleic acid molecule encoding any one of the immunogenic polypeptides, polypeptide fragments, and/or peptides as herein defined above.
  • the nucleic acid molecule can encode a larger part of a native Wnt4.
  • the nucleic acid molecule can e.g.
  • a polypeptide comprises at least 50, 70, 80, 90, 95 or 100% of the complete amino acid backbone of a Wnt4, preferably a human Wnt4, more preferably of hWnt4(23-351) or a homologue of said polypeptide.
  • the nucleic acid molecule encodes a contiguous stretch of at least 50, 70, 80, 90, 95 99% or 100%of the complete amino acid backbone.
  • nucleic acid molecule encodes more than one (T-cell epitope containing) immunologically active fragments of contiguous amino sequences from an Wnt4 as defined hereinabove, whereby in the encoded amino acids sequences, the different immunologically active fragments can be separated by spacer or linker sequences as beads on a string.
  • the nucleic acid molecule encoding the immunogenic polypeptide of the invention can be a DNA molecule, preferably a genetic construct wherein the nucleotide sequence coding for the immunogenic polypeptide (cDNA) is operably linked to appropriate expression regulatory sequence that ensure functional expression of the immunogenic polypeptide in the target cells in the human subject, e.g. including at least a strong (e.g. viral) promoter.
  • cDNA nucleotide sequence coding for the immunogenic polypeptide
  • Genetic constructs for use as DNA vaccines including e.g. plasmids or viral vectors, are inter alia described in WO2014/165291 , WO2016/123285 and WO2017/136758.
  • the nucleic acid molecule encoding the immunogenic polypeptide of the invention can be an RNA molecule, e.g. an mRNA, ssRNA, dsRNA or combinations thereof.
  • the RNA molecule can e.g. be formulated in a particle comprising the molecule. Suitable embodiments for RNA-based vaccines are e.g. described in WO2013/087083.
  • the source of the immunogenic polypeptide of the invention can further be a live cell that expresses and/or presents the immunogenic polypeptide.
  • the cell can be an autologous or allogeneic immune cell, e.g. a dendritic cell derived from the subject to treated, or the cell can be a microbial cell, more preferably a bacterium such as e.g. a live-attenuated Listeria monocytogenes.
  • the expressed immunogenic polypeptide preferably is an immunogenic polypeptide as defined hereinabove.
  • the immunogenic polypeptide can be expressed as part of a fusion protein, wherein preferably the immunogenic polypeptide is fused to a protein that is endogenous to the organism, e.g.
  • the source of the immunogenic polypeptide of the invention is an autologous or allogeneic dendritic cell (DC) that presents at least one MHC restricted epitope of the immunogenic polypeptide in an HLA molecule on its surfaces.
  • DC autologous or allogeneic dendritic cell
  • Such dendritic cells can e.g. be prepared ex vivo by contacting and/or loading DCs from the patient’s blood, e.g.
  • DCs isolated from mononuclear cells from the patient/subject, with a composition comprising the immunogenic polypeptide of the inventions are isolated from mononuclear cells from the patient/subject, with a composition comprising the immunogenic polypeptide of the inventions.
  • the immunogenic polypeptide contacted with mononuclear cells or DCs preferably is an immunogenic polypeptide as defined hereinabove.
  • a pharmaceutical to facilitate harvesting of DC can be used, such as ProgenipoietinTM (Monsanto, St. Louis, Mo.) or GM-CSF/IL-4.
  • the DCs are reinfused into the patient.
  • a composition is provided comprising peptide-pulsed DC which present the pulsed peptide epitopes in HLA molecules on their surfaces.
  • allogenic DCs can be used that are derived from a precursor human dendritic cell line and designed to deliver tumor associated antigens, such as e.g. described in W02009/019320, WO2014/090795 and WO2014/006058.
  • Methods of inducing an immune response employing ex vivo peptide-pulsed DC are well known to the skilled person.
  • the aforementioned immunogenic polypeptides of the invention may also be fused with a carrier molecule.
  • the carrier protein is selected from the group consisting of detoxified Exotoxin A of P. aeruginosa (EPA), E.
  • coli flagellin FLC
  • CRM197 maltose binding protein
  • MBP maltose binding protein
  • Diphtheria toxoid Tetanus toxoid
  • detoxified hemolysin A of S. aureus clumping factor A
  • clumping factor B E. coli heat labile enterotoxin
  • detoxified variants of E. coli heat labile enterotoxin Cockayne syndrome
  • CTB Cholera toxin B subunit
  • cholera toxin detoxified variants of cholera toxin
  • E. coli Sat protein the passenger domain of E. coli Sat protein
  • Streptococcus pneumoniae Pneumolysin Streptococcus pneumoniae Pneumolysin
  • KLH Keyhole limpet hemocyanin
  • the pharmaceutical composition for a use according the invention is for the treatment and/or prophylactic treatment of a human female.
  • the female mammal is a human female and the Wnt4 protein is a human Wnt4 protein.
  • the human Wnt4 protein comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence of an allelic variant thereof having at least 95 % sequence identity with SEQ ID NO: 1.
  • the human Wnt4 protein comprises an amino acid sequence with at least 95 % sequence identity with the amino acid sequence of the mature Wnt4 protein, comprises positions 23-351 of SEQ ID NO: 1.
  • a further aspect of the invention relates to a method for therapeutic and/or prophylactic treatment of breast cancer and metastases thereof in a subject by administering an antibody or fragment thereof that specifically binds to an epitope of human Wnt4 protein.
  • the antibody is a humanized or human monoclonal antibody. More preferably, the antibody or fragment thereof specifically binds to an epitope of human Wnt4 or human Wnt4(23-351).
  • an antibody "which binds" an antigen of interest e.g. a tumor-associated hWnt4 protein antigen or epitope thereof, is one that binds the antigen with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell or tissue expressing the antigen, and does not significantly cross-react with other proteins.
  • the extent of binding of the antibody to a "non-target" protein will be less than about 10% of the binding of the antibody to its particular target protein as determined by fluorescence activated cell sorting (FACS) analysis or radioimmunoassay (RIA).
  • the term “specific binding” or “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction.
  • Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity.
  • specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labelled target. In this case, specific binding is indicated if the binding of the labelled target to a probe is competitively inhibited by excess unlabeled target.
  • telomere binding or “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a Kd for the target (which may be determined as described below) of at least about 10-4 M, alternatively at least about 10-5 M, alternatively at least about 10-6 M, alternatively at least about 10-7 M, alternatively at least about 10-8 M, alternatively at least about 10-9 M, alternatively at least about 10-10 M, alternatively at least about 10-11 M, alternatively at least about 10-12 M, or greater.
  • the term "specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.
  • a “Kd” or “Kd value” can be measured by using surface plasmon resonance assays using a BIAcoreTM-2000 or a BIAcoreTM- 3000 (BIAcore, Inc., Piscataway, NJ) at 25°C with immobilized antigen CM5 chips at ⁇ 10 - 50 response units (RU). Briefly, carboxymethylated dextran biosensor chips (CM5, BIAcore Inc.) are activated with N-ethyl-N’-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier’s instructions.
  • CM5 carboxymethylated dextran biosensor chips
  • EDC N-ethyl-N’-(3-dimethylaminopropyl)-carbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • Antigen is diluted with 10mM sodium acetate, pH 4.8, into 5 pg/ml (-0.2 pM) before injection at a flow rate of 5pl/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of the antibody or Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% Tween 20 (PBST) at 25°C at a flow rate of approximately 25pl/min.
  • PBST Tween 20
  • association rates (kon) and dissociation rates (koff) are calculated using a simple one-to-one Langmuir binding model (BIAcore Evaluation Software version 3.2) by simultaneous fitting the association and dissociation sensorgram.
  • the equilibrium dissociation constant (Kd) is calculated as the ratio koff/kon. See, e.g., Chen, Y., et al., (1999) J. Mol Biol 293:865-881.
  • an "on-rate” or “rate of association” or “association rate” or “kon” according to this invention can also be determined with the same surface plasmon resonance technique described above using a BIAcoreTM-2000 or a BIAcoreTM-3000 (BIAcore, Inc., Piscataway, NJ) as described above.
  • One embodiment of the invention concerns a method of treating method for therapeutic and/or prophylactic treatment of breast cancer and/or metastases thereof, the method comprising administering to said subject a composition comprising an anti-Wnt4 antibody, preferably an anti- hWnt4 or anti-hWnt4(23-351) antibody, wherein the antibody induces killing of breast cancer cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC) or apoptosis.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • CDC complement dependent cytotoxicity
  • apoptosis As is generally understood by those of average skill in the art these antibody effector functions may be mediated by the Fc portion of the antibody, e.g.
  • Fc effector domain(s) by binding of an Fc effector domain(s) to an Fc receptor on an immune cell with phagocytic or lytic activity or by binding of an Fc effector domain(s) to components of the complement system.
  • the effect(s) mediated by the Fc-binding cells or complement components eventually result in inhibition and/or depletion of target cells, i.e.Wnt4- expressing cells.
  • Human IgG isotypes lgG1 , lgG2, lgG3 and lgG4 exhibit differential capacity for effector functions.
  • ADCC may be mediated by lgG1 and lgG3
  • ADCP may be mediated by lgG1 , lgG2, lgG3 and lgG4
  • CDC may be mediated by lgG1 and lgG3.
  • the anti-hWnt4 or anti-hWnt4(23-351) antibody preferably is an lgG1 , lgG2, lgG3 or lgG4 antibody.
  • the antibody for a use according to the invention is a humanized version of the anti-Wnt4 mouse monoclonal antibody ab169592 (Abeam) or B- 6 (sc376279; Santa Cruz Biotechnology).
  • Humanization of non-human (e.g., rodent) antibodies is described in Jones et al. , Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also the following review articles and references cited therein: Vaswani and Hamilton, Ann. Allergy, Asthma and Immunol., 1 :105-115 (1998); Harris, Biochem.
  • anti-Wnt4 monoclonal antibodies useful in the present invention may be prepared by the hybridoma methodology first described by Kohler et al., Nature, 256:495 (1975), e.g. using full length human Wnt4 protein as immunogen, as described by www.abcam.com (see product datasheet Anti-Wnt4 antibody ab169592).
  • anti-Wnt4 monoclonal antibodies may be made using recombinant DNA methods in bacterial, eukaryotic animal or plant cells (see, e.g., U.S. Patent No. 4,816,567).
  • the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991). .
  • the anti-Wnt4 antibody may be provided in suitable pharmaceutical compositions comprising the anti-Wnt4 antibody and a pharmaceutically acceptable carrier.
  • suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in e.g. Remington: The Science and Practice of Pharmacy, 21st Edition, Troy, D. B. ed., Lipincott Williams and Wilkins, Philadelphia, Pa. 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, see especially pp. 958-989.
  • the pharmaceutical composition of the invention is administered to a human female prior to menarche. In certain embodiments the pharmaceutical composition of the invention is administered post-menarche. In certain embodiments the pharmaceutical composition of the invention is administered to a human female before menopause. In certain embodiments, the pharmaceutical composition of the invention is administered to a human female between the ages of 11-55. In certain embodiments, the pharmaceutical composition of the invention is for the prophylactic treatment of breast cancer.
  • prophylactic treatment or “preventive treatment” relate to any treatment that is intended to prevent a disease from occurring in an individual. The terms “prophylactic treatment” or “preventive treatment” are used herein interchangeably. In one embodiment, the pharmaceutical composition of the invention is for the prophylactic treatment of breast cancer of a human female prior to menarche.
  • the pharmaceutical composition of the invention is administered concurrently with HPV vaccination.
  • the pharmaceutical composition of the invention is for the prophylactic treatment of breast cancer in a human female at risk to develop breast cancer.
  • being at risk is meant a subject that is identified as having a higher than normal chance of developing a disease, in particular cancer, compared to the general population.
  • a subject who has had, or who currently has, a disease, in particular cancer is a subject who has an increased risk for developing a disease, as such a subject may continue to develop a disease.
  • Subjects who currently have, or who have had, a cancer also have an increased risk for cancer metastases.
  • the human female is at risk to develop breast cancer due to a BRCA1 or BRCA2 mutation.
  • the pharmaceutical composition for a use according to the invention is for use in the therapeutic treatment of breast cancer.
  • “Therapeutic treatment” is herein defined as curing, alleviating or delaying the progression of breast cancer and or metastases thereof.
  • the present method preferably comprises administration of the present immunogenic polypeptides and compositions comprising them via the parenteral or oral route, preferably the parenteral route.
  • Preferred routes of administration include, but are not limited to, intratumoral, intramuscular, intranasal, intraperitoneal, intradermal, subcutaneous, intravenous, intra-arterial, intraocular and oral as well as topically, transdermal, by inhalation or suppository or to mucosal tissue such as by lavage to vaginal, rectal, urethral, buccal and sublingual tissue.
  • Preferred routes of administration include intramuscular, intraperitoneal, intradermal and subcutaneous injection.
  • administration is into an anatomic site that drains into a lymph node basin.
  • the administration is into multiple lymph node basins.
  • Example 1 WNT-4 expression in MRKH patients.
  • Biopsies from breast tissue are taken from four women diagnosed with MRKH and from control women during the mid-luteal phase of the menstrual cycle to ensure that progesterone levels are at their peak. In parallel to the biopsy, blood samples from these women are taken for analysis of the hormonal levels at the time of the biopsies.
  • the genomic and transcriptomic material is isolated from the breast biopsies using DNA and RNA isolation and purification techniques that are known in the art.
  • the isolated genomic and transcriptomic material is subjected to next generation sequencing (NGS) using a library of oligonucleotide probes to enable a genome wide DNA mutation analysis and RNA sequencing of the sample. Wnt-4 expression is observed to be reduced or absent in the four MRKH patients used in this study.
  • NGS next generation sequencing
  • Prunskaite-Hyyrylainen, R. et al. Wnt4 coordinates directional cell migration and extension of the Mullerian duct essential for ontogenesis of the female reproductive tract.

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Abstract

La présente invention concerne un procédé de prévention ou de traitement du cancer du sein et/ou de métastases de celui-ci chez un mammifère femelle. Spécifiquement, le procédé comprend l'administration d'une composition pharmaceutique comprenant un immunogène pour induire une réponse immunitaire contre une protéine Wnt4 ou un anticorps ou un fragment de celle-ci qui se lie spécifiquement à la protéine Wnt4.
PCT/EP2021/067056 2020-06-23 2021-06-23 Immunisation contre wnt4 pour le traitement et la prophylaxie du cancer du sein WO2021259963A1 (fr)

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
WO2009019320A2 (fr) 2008-05-19 2009-02-12 Dcprime B.V. Procédé d'induction et d'accélération de cellules
WO2013087083A1 (fr) 2011-12-15 2013-06-20 Biontech Ag Particules comprenant un arn simple brin et un arn double brin à des fins d'immunomodulation
WO2014006058A1 (fr) 2012-07-02 2014-01-09 Dcprime B.V. Procédé de chargement de cellules dendritiques par des antigènes de classe i
WO2014090795A1 (fr) 2012-12-11 2014-06-19 Dcprime B.V. Vaccins thérapeutiques contre le cancer dérivés d'une nouvelle lignée de cellules dendritiques
WO2014165291A1 (fr) 2013-03-12 2014-10-09 The Trustees Of The University Of Pennsylvania Vaccins améliorés pour le papilloma virus humain et leurs procédés d'utilisation
WO2015164121A1 (fr) 2014-04-24 2015-10-29 Advaxis, Inc. Souches de listeria utilisées comme vaccin recombinant et procédé de production
WO2016123285A1 (fr) 2015-01-29 2016-08-04 The Trustees Of The University Of Pennsylvania Associations d'inhibiteurs de point de contrôle immunitaires et de vaccins, et leur utilisation en immunothérapie
WO2017136758A1 (fr) 2016-02-05 2017-08-10 Inovio Pharmaceuticals, Inc. Vaccins anticancéreux et méthodes de traitement les utilisant
WO2017173321A1 (fr) 2016-03-31 2017-10-05 Neon Therapeutics, Inc. Néoantigènes et leurs procédés d'utilisation
CN110082536A (zh) * 2019-04-17 2019-08-02 广州医科大学附属肿瘤医院 一种乳腺癌细胞标志物细胞因子群及其应用
CN110129451A (zh) * 2019-06-18 2019-08-16 河南大学 一种胃肠道恶性肿瘤标志物及其应用

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
WO2009019320A2 (fr) 2008-05-19 2009-02-12 Dcprime B.V. Procédé d'induction et d'accélération de cellules
WO2013087083A1 (fr) 2011-12-15 2013-06-20 Biontech Ag Particules comprenant un arn simple brin et un arn double brin à des fins d'immunomodulation
WO2014006058A1 (fr) 2012-07-02 2014-01-09 Dcprime B.V. Procédé de chargement de cellules dendritiques par des antigènes de classe i
WO2014090795A1 (fr) 2012-12-11 2014-06-19 Dcprime B.V. Vaccins thérapeutiques contre le cancer dérivés d'une nouvelle lignée de cellules dendritiques
WO2014165291A1 (fr) 2013-03-12 2014-10-09 The Trustees Of The University Of Pennsylvania Vaccins améliorés pour le papilloma virus humain et leurs procédés d'utilisation
WO2015164121A1 (fr) 2014-04-24 2015-10-29 Advaxis, Inc. Souches de listeria utilisées comme vaccin recombinant et procédé de production
WO2016123285A1 (fr) 2015-01-29 2016-08-04 The Trustees Of The University Of Pennsylvania Associations d'inhibiteurs de point de contrôle immunitaires et de vaccins, et leur utilisation en immunothérapie
WO2017136758A1 (fr) 2016-02-05 2017-08-10 Inovio Pharmaceuticals, Inc. Vaccins anticancéreux et méthodes de traitement les utilisant
WO2017173321A1 (fr) 2016-03-31 2017-10-05 Neon Therapeutics, Inc. Néoantigènes et leurs procédés d'utilisation
CN110082536A (zh) * 2019-04-17 2019-08-02 广州医科大学附属肿瘤医院 一种乳腺癌细胞标志物细胞因子群及其应用
CN110129451A (zh) * 2019-06-18 2019-08-16 河南大学 一种胃肠道恶性肿瘤标志物及其应用

Non-Patent Citations (43)

* Cited by examiner, † Cited by third party
Title
"Breast cancer rates vary substantially in the US", AM J PHARMACY BENEFITS, 2017, Retrieved from the Internet <URL:https://www.ajpb.com/news/breast-cancer-rates-vary-substantially-in-the-us-japan>
"GenBank", Database accession no. AL031281.6
"Remington: The Science and Practice of Pharmacy", 2006, LIPINCOTT WILLIAMS AND WILKINS, article "Pharmaceutical Manufacturing", pages: 691 - 1092
BOYER, A. ET AL.: "WNT4 is required for normal ovarian follicle development and female fertility", FASEB J, vol. 24, 2010, pages 3010 - 3025
BREAST CANCER RISK FACTORS, 26 June 2019 (2019-06-26), Retrieved from the Internet <URL:https://www.breastcancer.org/risk/factors>
BRINTON, L. A. ET AL.: "Prediagnostic Sex Steroid Hormones in Relation to Male Breast Cancer Risk", J CLIN ONCOL, vol. 33, 2015, pages 2041 - 2050
BRISKEN, C. ET AL.: "Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling", GENES DEV, vol. 14, 2000, pages 650 - 654
CHEN, Y. ET AL., J. MOL BIOL, vol. 293, 1999, pages 865 - 881
COELINGH BENNINK, H. J. T.VERHOEVEN, C.DUTMAN, A. E.THIJSSEN, J.: "The use of high-dose estrogens for the treatment of breast cancer", MATURITAS, vol. 95, 2017, pages 11 - 23, XP029820925, DOI: 10.1016/j.maturitas.2016.10.010
ELLIS, M. J. ET AL.: "Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study", JAMA, vol. 302, 2009, pages 774 - 780
GENETICS, 26 June 2019 (2019-06-26), Retrieved from the Internet <URL:https://www.breastcancer.org/risk/factors/genetics>
GUO ET AL., NATURE, vol. 360, no. 6402, 1992, pages 364 - 366
HARRIS, BIOCHEM. SOC. TRANSACTIONS, vol. 23, 1995, pages 1035 - 1038
HENIKOFFHENIKOFF, PNAS, vol. 89, 1992, pages 915 - 919
HURLEGROSS, CURR. OP. BIOTECH., vol. 5, 1994, pages 428 - 433
JONES ET AL., NATURE, vol. 321, 1986, pages 522 - 525
JORDAN, V. C.: "The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer", ENDOCR RELAT CANCER, vol. 22, 2015, pages R1 - 31
JORDAN, V. C.FORD, L. G.: "Paradoxical clinical effect of estrogen on breast cancer risk: a ''new'' biology of estrogen-induced apoptosis", CANCER PREV RES (PHILA, vol. 4, 2011, pages 633 - 637
KASHIMADA, K.KOOPMAN, P.: "Sry: the master switch in mammalian sex determination", DEVELOPMENT, vol. 137, 2010, pages 3921 - 3930, XP055224818, DOI: 10.1242/dev.048983
KOHLER ET AL., NATURE, vol. 256, 1975, pages 495
KOTTURI ET AL., J VIROL., vol. 81, no. 10, May 2007 (2007-05-01), pages 4928 - 40
KUCHENBAECKER, K. B. ET AL.: "Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers", JAMA, vol. 317, 2017, pages 2402 - 2416
LEDIG, S.WIEACKER, P.: "Clinical and genetic aspects of Mayer-Rokitansky-Kuster-Hauser syndrome", MED GENET, vol. 30, 2018, pages 3 - 11, XP036448842, DOI: 10.1007/s11825-018-0173-7
MACMAHON, B. ET AL.: "Age at first birth and breast cancer risk", BULL WORLD HEALTH ORGAN, vol. 43, 1970, pages 209 - 221
MARKS ET AL., J. MOL. BIOL., vol. 222, 1991, pages 581 - 597
MOUTAFTSI ET AL., NAT BIOTECHNOL., vol. 24, no. 7, July 2006 (2006-07-01), pages 817 - 9
NELSON ET AL., REV IMMUNOGENET, vol. 1, no. 1, 1999, pages 47 - 59
PRESTA, CURR. OP. STRUCT. BIOL., vol. 2, 1992, pages 593 - 596
PRUNSKAITE-HYYRYLAINEN, R. ET AL.: "Wnt4 coordinates directional cell migration and extension of the Mullerian duct essential for ontogenesis of the female reproductive tract", HUM MOL GENET, vol. 25, 2016, pages 1059 - 1073
RAMMENSEE, IMMUNOGENETICS, vol. 41, no. 4, 1995, pages 178 - 228
RANGEL MARIA CRISTINA ET AL: "Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer", BREAST CANCER RESEARCH AND TREATMENT, SPRINGER , NY, US, vol. 156, no. 2, 11 March 2016 (2016-03-11), pages 211 - 226, XP035653632, ISSN: 0167-6806, [retrieved on 20160311], DOI: 10.1007/S10549-016-3746-7 *
RIECHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 329
SAMAVAT, H.KURZER, M. S.: "Estrogen metabolism and breast cancer", CANCER LETT, vol. 356, 2015, pages 231 - 243, XP029098169, DOI: 10.1016/j.canlet.2014.04.018
SAMPSON, J. N. ET AL.: "Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women", CANCER RES, vol. 77, 2017, pages 918 - 925
SANTEN, R. J.ALLRED, D. C.: "The estrogen paradox", NAT CLIN PRACT ENDOCRINOL METAB, vol. 3, 2007, pages 496 - 497
SANTEN, R. J.YUE, W.WANG, J. P.: "Estrogen metabolites and breast cancer", STEROIDS, vol. 99, 2015, pages 61 - 66, XP029187087, DOI: 10.1016/j.steroids.2014.08.003
SCHUMACHER ET AL., NATURE, vol. 352, no. 6320, 1991, pages 624 - 628
SPEIR ET AL., IMMUNITY, vol. 14, no. 1, 2001, pages 81 - 92
SULTAN, C.BIASON-LAUBER, A.PHILIBERT, P.: "Mayer-Rokitansky-Kuster-Hauser syndrome: recent clinical and genetic findings", GYNECOL ENDOCRINOL, vol. 25, 2009, pages 8 - 11
VASWANIHAMILTON, ANN. ALLERGY, ASTHMA AND IMMUNOL., vol. 1, 1998, pages 105 - 115
VOUYOVITCH, C. M. ET AL.: "WNT4 mediates the autocrine effects of growth hormone in mammary carcinoma cells", ENDOCR RELAT CANCER, vol. 23, 2016, pages 571 - 585
YAGER, J. D.DAVIDSON, N. E.: "Estrogen carcinogenesis in breast cancer", N ENGL J MED, vol. 354, 2006, pages 270 - 282
YASSAI ET AL., J IMMUNOL, vol. 168, no. 3, 2002, pages 1281 - 1285

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