EP1496923A1 - Cancer immunotherapy - Google Patents
Cancer immunotherapyInfo
- Publication number
- EP1496923A1 EP1496923A1 EP02723576A EP02723576A EP1496923A1 EP 1496923 A1 EP1496923 A1 EP 1496923A1 EP 02723576 A EP02723576 A EP 02723576A EP 02723576 A EP02723576 A EP 02723576A EP 1496923 A1 EP1496923 A1 EP 1496923A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- subject
- immune response
- composition
- protein
- response against
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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Definitions
- the invention relates generally to the fields of biology, immunology, medicine, and oncology. More particularly, the invention relates to the use of the interleukin 13 (IL-13) receptor subunit alpha 2 (IL-13R ⁇ 2) as an immune system modulator and target for vaccines for the treatment and prevention of cancer.
- IL-13 interleukin 13
- IL-13R ⁇ 2 interleukin 13 receptor subunit alpha 2
- TAA tumor-associated antigens
- TSA tumor-specific antigens
- melanoma associated antigens include prostate specific antigen (PSA), E6 and E7, carcinoembryonic antigen (CEA), p53, and gangliosides (e.g., GM2). More recent studies have shown that certain TAAs and TSAs are particularly effective at stimulating specific immune responses.
- MAGE- 1 (Melanoma Antigen 1) as a T-cell activating TSA.
- MAGE- 1 Melanoma Antigen 1
- MART-1 MART-1
- glycoprotein 100 gplOO
- tyrosinase BAGE
- GAGE GAGE
- the SEREX technique involves screening a cDNA expression library of an autologous tumor by exposing the library to antibodies contained in a patient's sera.
- Several active cancer antigens have been identified using this technique. See, Old, L. J. and T. C. Chen, J. Exp. Med., 187: 1163-1167, 1998.
- SEREX analysis showed that patients produce a high titer of IgG antibodies against cancer antigens- a finding that indicated that indicated that helper T cells (e.g., CD4+ T cells) and B cells cooperate in stimulating an immune response against the cancer.
- helper T cells e.g., CD4+ T cells
- CTAs cancer/testis antigens
- CTAs share several common features including (a) among normal organs, almost exclusive expression in the testis, (b) expression in a wide variety of tumors, (c) presence of multiple members in each identified family, and (d) localization of their genes to the X chromosome (with the notable exception of SCP 1). Chen et al., J. Biol. Chem., 273: 17618-17625, 1998. Based on the foregoing criteria, several previously identified TAAs or TSAs (e.g., MAGE, BAGE and GAGE) were re-discovered as CTAs.
- TAAs or TSAs e.g., MAGE, BAGE and GAGE
- CTAs unlike many non-CTA antigens, most of these previously identified CTAs as well as newly identified CTAs (e.g., SSX2, NY-ESO-1, SCP1 and CT7) have unequivocally been shown to stimulate an immune response in a subject.
- CTAs e.g., SSX2, NY-ESO-1, SCP1 and CT7
- the invention relates to the discovery that IL-13R ⁇ 2 is a cancer/testis antigen. This discovery is important because, in contrast to most other cancer-associated agents, most of the cancer/testis antigens so far tested as active immunotherapy agents against cancer have proven very effective in stimulating anti-cancer immune responses in subjects. Thus, the present discovery provides methods and compositions for preventing and/or treating cancers that express IL-13R ⁇ 2.
- the invention relates to the treatment and/or prevention of high-grade gliomas (HGG) in a subject as HGG cells have been shown to express high levels of IL- 13R ⁇ 2 on their surfaces.
- Human HGG are rapidly progressing heterogeneous brain tumors of astroglial origin.
- the present invention is especially important because no effective modalities for treating HGG are yet accepted for clinical use.
- IL-13R ⁇ 2 a new IL-13 binding protein, termed IL-13R ⁇ 2 was cloned. This protein was shown to have affinity for IL-13 but not IL-4.
- this characteristic relates to the more restrictive receptor for IL-13 expressed on HGG.
- IL-13R ⁇ 2 serves as a selective target for HGG and other cancers that express IL-13R ⁇ 2 because, as described in more detail below, with the exception of testis, normal human tissue expresses little or no IL-13R ⁇ 2.
- this receptor (sometimes termed the "shared” receptor because it binds both IL-13 and IL-4) differs functionally from IL-13R ⁇ 2 (believed to be the "restrictive" receptor) in that the shared receptor binds both IL-13 and IL-4, while the restrictive receptor binds only IL-13.
- IL-13R ⁇ 2 is strongly expressed only in testis. This finding along with the showing that (a) IL-13R ⁇ 2 is preferentially over-expressed on HGG but not normal central nervous system (CNS) tissue and (b) that the IL-13R ⁇ 2 gene is localized to chromosome X, indicates that IL-13R ⁇ 2 is a CTA. Because other CTAs, such as MAGE and BAGE, have proven to stimulate a strong immune response against cancer cells (see Mintz and Debinski in Crit. Rev. Oncogen 11:77-95; 2000), the present invention provides methods and compositions useful for generating or increasing an anti-cancer immune response in a subject.
- IL-13R ⁇ 2 has the following distinct advantages over other cancer-related antigens. Firstly, IL-13R ⁇ 2 is a cell-surface receptor, affording it exposure to the humoral arm of the immune system. Secondly, IL-13R ⁇ 2 is expressed on the vast majority of HGGs tested, indicating its critical role in HGG progression and its potential as a target for immunotherapy. Thirdly, the physiological distribution of IL- 13R ⁇ 2 is limited to cancer cells and the testes, limiting the potential for autoimmune side affects that are observed when the target is also expressed in healthy tissue. Furthermore, autoimmune side affects are unlikely because the testes are an immune-privileged organ that expresses little MHC class I molecules. Fourthly, hIL-13Roc2 is an ideal target for anti-cancer immunotherapy because of its size (380 amino acids in full length IL-13R 2 and 343 amino acids in the extracellular domain), providing the immune system with multiple epitopes to recognize and target.
- the invention features a method for stimulating a immune response against IL-13R ⁇ 2 in a subject having or at risk for developing a disease having cells expressing IL-13R ⁇ 2.
- the method includes the steps of: (a) formulating an anti-cancer vaccine outside of the subject, the vaccine including an agent that can stimulate an immune response against IL-13R ⁇ 2 when administered to an animal; and (b) administering the vaccine to the subject in an amount sufficient to stimulate an immune response against IL- 13 R ⁇ 2 in the subject.
- the invention features a composition for stimulating an immune response against IL-13R ⁇ 2 when administered to an animal.
- the composition includes: (a) an isolated agent that can stimulate an immune response against IL-13R ⁇ 2 when administered to an animal; and (b) a pharmaceutically acceptable carrier.
- the agent that can stimulate an immune response against IL-13R ⁇ 2 can include a peptide including at least seven contiguous amino acids of SEQ ID NO: 1.
- the agent can be a protein including the amino acid sequence of SEQ ID NO:l.
- the agent can also take the form of a nucleic acid that encodes a peptide including at least seven contiguous amino acids of SEQ ID NO: 1.
- Such a nucleic acid can be used as a naked DNA or in an expression vector construct including the nucleic acid.
- the agent that can stimulate an immune response against IL-13R ⁇ 2 can also be a cell.
- This cell can be one that expresses a peptide including at least seven contiguous amino acids of SEQ ID NO: 1 , or one into which a purified nucleic acid that encodes a peptide including at least seven contiguous amino acids of SEQ ID NO:l has been introduced.
- the vaccines and compositions within the invention can further include an adjuvant such as an aluminum salt; an oil-in-water emulsion; a composition including saponin; a composition including a bacterial protein; or a cytokine.
- an adjuvant such as an aluminum salt; an oil-in-water emulsion; a composition including saponin; a composition including a bacterial protein; or a cytokine.
- the method of the invention can further include a step of providing a subject (e.g., a human being) having or at risk for developing a cancer having cells expressing IL-13R ⁇ 2 (e.g., glioma cells). Also in the method, the step of administering the vaccine to the subject in an amount sufficient to stimulate an immune response against IL-13R ⁇ 2 in the subject can include administering the vaccine in at least a first dose and a second dose, wherein the first dose is administered to the subject at least 24 hours before the second dose is administered to the subject.
- a subject e.g., a human being
- IL-13R ⁇ 2 e.g., glioma cells
- nucleic acid means a chain of two or more nucleo tides.
- RNA ribonucleic acid
- DNA deoxyribonucleic acid
- An "isolated" nucleic acid is one that has been substantially separated or purified away from other nucleic acid sequences in the cell of the organism in which the nucleic acid naturally occurs, i.e., other chromosomal and extrachromosomal DNA and RNA, e.g., by conventional nucleic acid purification methods.
- nucleic acid molecule or polypeptide When referring to a nucleic acid molecule or polypeptide, the term “native” refers to a naturally-occurring (e.g., a "wild-type") nucleic acid or polypeptide.
- a “homolog” of an IL- 13R ⁇ 2 gene is a gene sequence encoding an IL-13R ⁇ 2 polypeptide isolated from a species other than Homo sapiens.
- naked nucleic acid is meant an isolated nucleic acid not incorporated in an expression vector.
- IL-13R0-2 gene or "IL-13R ⁇ 2 polynucleotide” is meant a native IL- 13R ⁇ 2 encoding nucleic acid sequence (e.g., the IL-13R ⁇ 2 cDNA sequence shown as SEQ ID NO: 2 (Fig. 2)), genomic sequences from which IL-13R ⁇ 2 cDNA can be transcribed, and/or allelic variants and homologs of the foregoing.
- protein means any peptide-linked chain of amino acids, regardless of length or post-translational modification, e.g., glycosylation or phosphorylation.
- peptide is used herein to refer to amino acid chains less than about 25 amino acid residues in length, while the terms “protein” and “polypeptide” are used to refer to larger amino acid chains.
- isolated means proteins or peptides that are isolated from other cellular proteins or are made synthetically. The term thus encompasses both purified and recombinant polypeptides.
- recombinant protein or “recombinant peptide” refers to a protein or peptide that is produced by recombinant nucleic acid techniques, wherein generally, a nucleic acid encoding the peptide or protein is inserted into a suitable expression vector which is in turn used to transform a host cell such that, when cultured under appropriate conditions, the cell produces the peptide or protein.
- IL-13R ⁇ 2 protein "IL-13R ⁇ 2 polypeptide,” or simply “IL-13R ⁇ 2” is meant an expression product of an IL-13R ⁇ 2 gene such as the protein of SEQ ID NO:l (Fig. 1); or a protein that shares at least 65% (but preferably 75, 80, 85, 90 , 95, 96, 97 ,98, or 99%) amino acid sequence identity with SEQ ID NO: 1 and cross-reacts with antibodies that specifically bind the protein of SEQ ID NO: 1.
- sequence identity means the percentage of identical subunits at corresponding positions in two sequences when the two sequences are aligned to maximize subunit matching, i.e., taking into account gaps and insertions.
- sequence identity means the percentage of identical subunits at corresponding positions in two sequences when the two sequences are aligned to maximize subunit matching, i.e., taking into account gaps and insertions.
- the length of the compared sequences is at least 60 nucleotides, more preferably at least 75 nucleotides, and most preferably 100 nucleotides.
- Sequence identity is typically measured using sequence analysis software (e.g., Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, WI 53705).
- a first nucleic-acid sequence is "operably" linked with a second nucleic-acid sequence when the first nucleic-acid sequence is placed in a functional relationship with the second nucleic-acid sequence.
- a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence.
- operably linked DNA sequences are contiguous and, where necessary to join two protein coding regions, in reading frame.
- the term "vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
- a vector capable of directing the expression of a gene to which it is operatively linked is referred to herein as an "expression vector.”
- promoter means a nucleic acid sequence that regulates expression of a selected nucleic acid sequence operably linked to the promoter, and which effects expression of the selected nucleic acid sequence in cells.
- tissue specific promoters i.e. promoters, which effect expression of the selected nucleic acid sequence only in specific cells (e.g. cells of a specific tissue).
- the term also covers so-called “leaky” promoters, which regulate expression of a selected nucleic acid primarily in one tissue, but cause expression in other tissues as well.
- the term also encompasses both non-tissue specific promoters and promoters that are constitutively active and inducible.
- lymphocyte e.g., a B cell or T cell
- the stimulation of an immune response against a specific antigen can be measured as an increase in antibody titer against that antigen or the activation of one or more lymphocytes having a surface receptor specific for the antigen.
- Activation of lymphocytes can be determined by conventional assays, e.g., the induction of mitosis, secretion of cytokines, modulation of cell surface molecule expression, secretion of immunoglobulin (B cells), and increased killing of target cells (cytotoxic T cells).
- bind means that one molecule recognizes and adheres to a particular second molecule in a sample, but does not substantially recognize or adhere to other structurally unrelated molecules in the sample.
- a first molecule that "specifically binds" a second molecule has a binding affinity greater than about 10 5 to 10° liters/mole for that second molecule.
- antibody any antigen-binding peptide derived from an immunoglobulin.
- the term includes polyclonal antisera, monoclonal antibodies, fragments of immunoglobulins produced by enzymatic digestion (e.g., Fab fragments) or genetic engineering (e.g., sFv fragments).
- Fig. 1 is the amino acid sequence of the native H. sapiens IL-13R ⁇ 2 protein.
- Fig. 2 is the nucleic acid sequence of a cDNA corresponding to a native mRNA encoding the native H. sapiens IL-13R ⁇ 2 protein.
- Fig. 3 is a schematic representation of two types of IL-13 receptors: the shared with IL-4 physiological, heterodimeric IL-13/4R, and an IL-4-independent monomeric, HGG- associated IL-13R.
- A 140-kDa IL-4R -chain.
- B 45-kDa IL-13R l -chain;
- a and B constitute the elements of the heterodimeric high affinity IL-13/4R.
- C a 42-kDa monomer of IL-13R ⁇ 2.
- Fig. 4 is a Northern blot analysis of human IL-13Rcc2 transcripts (closed figure) in series of CNS (panels I and II) and peripheral tissues (panels III and IV). The migration position of mRNA is shown in kilobases. Films were exposed for 2 weeks.
- Fig. 5 is a Northern blot analysis of human IL-13R ⁇ 2 transcripts (closed figure) in series of CNS (panels I and II) and peripheral tissues (panels III and IV). The migration position of mRNA is shown in kilobases. Films were exposed for 2 weeks except for membranes shown in panels III and IV, which were exposed for 3 days.
- Fig. 6 is a Northern blot analysis of human 140-kDa IL-4R ⁇ -chain transcripts (closed figure) in series of CNS (panels I and II) and peripheral tissues (panel IV). The migration position of mRNA is shown in kilobases. Films were exposed for 2 weeks.
- Fig. 7 is a Northern blot analysis of human ⁇ -actin transcripts in CNS (panels I and II) and peripheral tissues (panel IV). The migration position of mRNA is shown in kilobases. Films were exposed for 1-3 hours.
- Fig. 8 is a Northern blot analysis of transcripts of different IL-13 receptors in malignant glioma cells (G-48, A- 172 MG, U-373 MG, and U-251 MG), normal human umbilical vein endothelial cells (HUVEC) and in surgical specimens of GBM and normal human brain.
- the migration position of mRNA is shown in kilobases. Films were exposed for 2 weeks, except for actin (1 hr).
- Fig. 9 is two graphs showing the effectiveness of an hIL-13R ⁇ 2 recombinant protein vaccine (A) and a nucleic acid vaccine (B) in preventing tumor formation in an animal model.
- the invention encompasses compositions and methods relating to stimulating an immune response against IL-13R ⁇ 2 in a subject having or being at risk for developing a cancer or other disease having cells expressing IL-13R ⁇ 2.
- the below described preferred embodiments illustrate adaptations of these compositions and methods. Nonetheless, from the description of these embodiments, other aspects of the invention can be made and/or practiced based on the description provided below.
- IL-13R ⁇ 2 is a receptor for the lymphokine IL-13.
- IL-13 has been identified as a homologue of IL-4 that is secreted by both B and T cells. Minty et al., Nature, 36: 248-251, 1993; McKenzie et al., Proc. Natl. Acad. Sci. USA, 90: 3735-3739, 1993.
- IL-13 receptor termed the shared IL-13/IL-4 receptor, which is a heterodimer that includes an IL-13 binding subcomponent named IL- 13R ⁇ l (Interleukin 13 receptor alpha one). Hilton et al., Proc. Natl. Acad. Sci.
- the shared receptor also includes a protein referred to as pi 40 (or IL-4R ⁇ ), the subcomponent responsible for IL-4 binding. Idzerda et al., J. Exp. Med., 171: 861-873, 1990; Hilton et al., Proc. Natl. Acad. Sci.
- Exposing cells to IL-13 results in responses very similar to those responses that occur after exposure to IL-4. Zurawski, G., and J.E. de Vries, Stem Cells. 12: 169-174, 1994. Examples of cellular responses resulting from both IL-13 and IL-4 exposure include enhanced expression of CD72 , IgM, and MHC class II antigen, as well as induced CD23 expression and IgE heavy-chain gene production in B lymphocytes. Id.
- IL-13R ⁇ l was not the only IL-13 binding site that existed on cells. In previous studies, it was demonstrated that many cancers, most notably HGG, are capable of binding IL-13.
- IL-13R ⁇ 2 is a transmembrane receptor, it is exposed to the extracellular environment independently of MHC presentation.
- cytotoxic agents or antibodies can be directly targeted to cancer cells bearing IL-13R ⁇ 2 on their surface.
- This discovery that IL-13R ⁇ 2 is a CTA associated with HGG is significant because no other HGG-associated antigens of this prevalence are known that could serve as a basis for a rational design of anti-glioma vaccines.
- the invention provides vaccines that can stimulate an immune response against IL- 13R ⁇ 2 in a subject when administered to the subject.
- Vaccines within the invention include an antigenic agent which can take the form of any substance that can evoke or increase an immune response against IL-13R ⁇ 2 when introduced into a subject.
- Typical immune responses include (a) the production of, or increase in titer of, antibodies that specifically bind IL-13R ⁇ 2 and (b) the activation of T lymphocytes (e.g., to kill a target cell or provide help in the activation of antibody production in B lymphocytes).
- a number of different antigenic agents have been shown to be effective in stimulating an immune response against a protein antigen, including, for example, protein- and peptide-based vaccines, tumor-cell vaccines, dendritic cell/gene therapy vaccines and DNA/viral vaccines. See, e.g., Greten, T.F. and E.M. Jaffee, J. Clin. Oncol., 17: 1047-1060, 1999.
- various substances such as adjuvants and excipients/carriers can be included in the vaccine compositions of the invention to non-specifically enhance the antigen-specific immune response stimulated by the antigenic agent and to facilitate delivery of the other components of the vaccine to a subject.
- Protein Peptide Based Vaccines Protein Peptide Based Vaccines
- the antigenic agent for use in the vaccines of the invention can take the form of the native IL-13R ⁇ 2 (SEQ ID NO:l) or a peptide fragment of IL-13R 2.
- Vaccines made with the whole protein antigen are advantageous because they have the capability of stimulating an immune response against all of the potential antigenic sites expressed by the protein.
- Vaccines made with peptide antigens e.g., 7-15 or 8-12 contiguous amino acids of the whole protein
- Peptide-based vaccines are sometimes advantageous over whole protein-based vaccines where it is desired to more specifically target the stimulated immune response, e.g., to avoid undesired cross reactions.
- Cell-based vaccines are provided in the invention to stimulate an immune response against IL-13Rcc2.
- cancer cells isolated from a patient have been harbored in vitro and transfected with DNA encoding for immune stimulants, such as cytokines, MHC molecules or co-stimulatory molecules.
- immune stimulants such as cytokines, MHC molecules or co-stimulatory molecules.
- the transfected cancer cells were then re-injected to the patient in order to activate the immune system in order to generate an anti-cancer response.
- polyclonal or monoclonal antibodies can be tested for specific IL- 13R ⁇ 2 recognition by Western blot or immunoprecipitation analysis by standard methods, for example, as described in Ausubel et al., supra.
- Antibodies that specifically recognize and bind to IL-13R ⁇ 2 are useful in the invention.
- such antibodies can be used in an immunoassay to monitor the level of IL-13R ⁇ 2 in a sample (e.g., to determine the amount of cellular expression or subcellular location of IL-13R ⁇ 2, or the presence and amount of soluble forms of IL-13R ⁇ 2 in a liquid sample).
- Single chain antibodies can be adapted to produce single chain antibodies against a IL-13R ⁇ 2 protein, or a fragment thereof.
- Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide.
- compositions and methods of the invention can be utilized with any suitable subject, e.g., an animal such as a mammal (e.g., human beings, dogs, cats, goats, sheep, cows, horses, etc.).
- a mammal e.g., human beings, dogs, cats, goats, sheep, cows, horses, etc.
- a human patient suffering or at risk for developing a cancer or other disease that has cells that overexpress IL-13R ⁇ 2 e.g., a brain cancer such as HGG
- a brain cancer such as HGG
- the invention also provides polyvalent vaccines that incorporate one or more of the foregoing compositions that can stimulate an immune response against IL-13R ⁇ 2 in a subject.
- Two general types of polyvalent vaccines are within the invention.
- a vaccine that contains more than one agent that can stimulate an immune response against IL-13R ⁇ 2 e.g., a composition that contains 2, 3, 4, 5, 6 , 7, 8, or more different peptides listed in Table 1 below.
- a vaccine that contains both (a) an agent that can stimulate and immune response against IL-13R ⁇ 2 and (b) a different agent that can stimulate an immune response against a molecule other than IL-13R ⁇ 2 e.g., another TSA or TAA.
- the vaccine compositions of the present invention can be used in a method for stimulating an immune response against IL-13R ⁇ 2 in a subject.
- an vaccine compositon of the invention can be administered to a subject by any method that stimulates the aforesaid immune response.
- the exact method selected is determined by the particular vaccine composition to administered.
- the injection can be in situ (i.e., to a particular tissue or location on a tissue, e.g., into a tumor or lymph node), intramuscular, intravenous, intraperitoneal, or by another parenteral route.
- the vaccine may be administered by subcutaneous or intradermal injection. In some cases other routes can be used, e.g. intravenous injection, intraperitoneal injection, or in situ injection into target tissue.
- Naked nucleic acid vaccines or expression vector vaccines may be administered by intramuscular injection.
- Cell-based vaccines can be introduced into an animal by any suitable method, e.g., subcutaneous injection.
- the vaccines of the invention can also be administered by a non-parenteral route, e.g, by oral, buccal, urethral, vaginal, or rectal administration.
- the vaccine compositions of the invention are preferably administered to a subject in an amount sufficient to stimulate an immune response against IL-13R ⁇ 2 in the subject, and not cause an overly toxic effect.
- a therapeutically effective amount can be determined as described below.
- the vaccines of the invention can be administered to a subject using various different vaccination schedules.
- a nucleic acid vaccine might be administered to a subject only once, while a protein/peptide- based vaccine might be administered to the subject on multiple occasions (1, 2, 3, 4, 5 or more times).
- a first dose of a vaccine compositions of the invention may be administered to a subject at least 24 hours before a second (booster) dose is administered to the subject.
- CHO cells Normal Chinese hamster ovary (CHO) cells were transfected with a pcDNA 3.1 plasmid (Invitrogen) containing the full length open reading frame of IL-13R ⁇ 2 and positive clones were selected with geneticin. The expression of IL-13R ⁇ 2 in these clones was tested for their ability to bind 125 I-labeled IL-13. Selected clones were shown to bind labeled IL-13 independently of IL-4. In addition, labeled IL-13 was displaced by IL-13.E13K, a mutant of IL-13 shown to have a greater affinity for the IL-13 binding protein on HGG than for the shared IL-13/IL-4 receptor found in a plethora of tissues under a physiological state.
- these IL-13R ⁇ transfected CHO cells were exposed to an IL-13.E13K- PE38QQR cytotoxin, a fusion protein showing potent dose dependent cytotoxicity on HGG cells.
- the clones expressing the receptor were killed in direct proportion to their affinity for IL-13, but not CHO cells alone or CHO cells transfected with an empty plasmid. In neutralization experiments, an excess of IL-13 prevented the cytotoxic effect of IL-13.
- El 3K- PE38QQR Therefore the only way the toxin, PE38QQR, could have entered and killed the cells was through receptor-mediated endocytosis, a process directed through the IL-13 portion of the cytotoxin.
- IL-13R ⁇ 2 was demonstrated to share properties ascribed to more restrictive, IL-4 independent, IL-13 binding sites found on HGGs in situ and in vitro.
- RNA was extracted from the cells using the acid-guanidium isothiocyanate-phenol-chloroform method. Poly(A)+ RNA was further isolated using the Mini-oligo(dT) Cellulose Spin Column Kit (5 prime-3 prime Inc., Boulder, CO).
- RNA-blotted membranes were also purchased from Clontech (Palo Alto, CA). Two Multiple Tissue Expression (MTETM) Blots (cat # 7770-1 and 7775-1; www.clontech.com/mtn index.html) were analyzed to determine the tissue distribution of the IL-13 binding proteins.
- MTETM Multiple Tissue Expression
- Membranes were pre-hybridized overnight at 42° C in a solution consisting of 50% formamide, 5x SSC, 50 mM sodium phosphate, 5x Denhardt's, 50 ⁇ g/ml sheared salmon sperm DNA, and 1% SDS. Membranes were subsequently hybridized overnight at 42° C in the same solution with the addition of full length cDNA probes labeled by random priming (Life Technologies, Rockville, MD) with 32 P-dCTP using l-2x 10 6 cpm/ml. Following hybridization, the membranes were washed with 2x SSC/0.2% SDS at 42° C for 20 minutes followed by two washes with lx SSC/0.1% SDS at 42° C for 20 minutes each.
- IL-13R l a component of a heterodimeric form of IL-13 receptor that is shared with IL-4, IL-13/4 receptor was examined in a variety of normal human tissues (Fig. 5) by either dot- blot analyses (not shown) or blots of electrophoretically separated transcripts (Fig. 5, panels I- IV).
- IL-13Rocl was expressed in a variety of the organs, including CNS tissue from medulla, spinal cord, substantia nigra, thalamus, and corpus callosum.
- mRNA Size fractionated mRNAs confirmed the many positive signals seen in dot blots with the strongest signals observed in ovary, heart, liver and lung (Fig. 5, panels III and IV, respectively).
- liver showed two hybridized species of mRNA: one of 4.5 kb and the other of 2.0 kb, as an example of a normal organ with doublet of positive signals of different sizes.
- discrete regions of normal human brain did produce clear-cut positive hybridization signals for IL-13R ⁇ l (Fig. 5, panels I and II).
- many vital peripheral organs exhibited hybridization bands corresponding to the mRNA of 4.5-4.65 kb (Fig. 5, panels III and IV).
- IL-4R ⁇ Gene expression analysis of IL-4R ⁇ in normal tissues.
- IL- 4R ⁇ is another component of a heterodimeric form of IL-13 receptor that is shared with IL-4, i.e., the shared IL-13/4 receptor.
- All Northern blot analysis membranes used in this study demonstrated enriched content of the IL-4R ⁇ transcripts in a variety of tissues (Fig. 6, panels I, II, and IV). The presence of the transcripts within the CNS was most evident, as it was for IL-13R ⁇ l, in medulla, spinal cord, substantia nigra and thalamus (Fig.
- ⁇ -actin Control hybridization of ⁇ -actin. All membranes used for Northern blot analysis of IL-13 receptors transcripts were also hybridized with a cDNA probe for a house-keeping gene, ⁇ -actin (Fig. 7; dot blots and panel III not shown). The intensity of the signals for ⁇ - actin was usually in accordance with the amount of mRNA present on the membranes, as estimated by the manufacturer.
- IL-13 receptors Gene expression of IL-13 receptors in cells. Gene expression of the two IL-13 receptors was also examined in malignant and normal cells (Fig. 8). Transcripts for IL- 13R ⁇ 2, IL-13R ⁇ l, IL-4R ⁇ and ⁇ -actin were examined in serial hybridization assays. Isolated explant cells of HGG (G-48) as well as human malignant glioma established cell lines (A- 172 MG, U-373 MG, and U-251 MG) demonstrated intense signals for IL-13Rcc2 (Fig. 8).
- transcripts for the elements of the shared IL-13/4 receptor, IL-13R ⁇ l and IL- 4R ⁇ were found at lower levels when compared with that for IL-13R ⁇ 2 (Fig. 8).
- two species of different sizes of the transcripts for both IL-13R ⁇ 2 and IL-13R l were seen in cells (Fig. 8).
- human umbilical vein endothelial cells (HUVEC) showed the presence of transcripts for IL-13R l and IL-4R ⁇ , but not those for IL- 13R ⁇ 2 (Fig. 8).
- Table I presents a list of IL-13R ⁇ 2 peptides that might be used to stimulate an immune response against IL-13R ⁇ 2 in a subject.
- the listed peptides were obtained using a computer program provided by the Ludwig Institute For Cancer Research (Lausanne, Switzerland) on the Internet at http://www-ludwig.unil.ch.SEREX.html. This program provided the best (at high stingency) fit of predicted immunogenic peptides that bind specific classes of MHC molecules (i.e., the various alleles of human MHC Class I indicated in Table I).
- the peptides indicated with the "*" are those that should bind under high stringency.
- mice vaccinated with recombinant IL- 13R ⁇ 2 manifested a strong specific antibody response against IL-13Roc2 as demonstrated by enzyme-linked immunosorbent assay ( ⁇ LISA).
- mice/group mice vaccinate mice via gene gun (10 mice/group) (Vaccine 18:2937-2944; 2000). Mice were immunized every two weeks for a total of 3 times. Three weeks after the last immunization, mice were injected subcutaneously with 5 x 10 6 G-26-IL-13R ⁇ 2(+) murine glioma cells. Tumors appeared 16 days after tumor cell injection only in mice vaccinated with pcDNA 3.1 vector alone but no tumors were visible in mice vaccinated with pcDNA 3.1/R ⁇ 2 ( Figure IB). Other Embodiments
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- 2002-03-22 AU AU2002254348A patent/AU2002254348B2/en not_active Ceased
- 2002-03-22 WO PCT/US2002/008983 patent/WO2003092717A1/en active Application Filing
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Patent Citations (1)
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WO2001058479A1 (en) * | 2000-02-08 | 2001-08-16 | The Penn State Research Foundation | Immunotherapy using interleukin 13 receptor subunit alpha 2 |
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CA2480008C (en) | 2015-10-06 |
EP1496923A4 (en) | 2005-10-19 |
AU2002254348B2 (en) | 2007-12-06 |
WO2003092717A1 (en) | 2003-11-13 |
JP2005526842A (en) | 2005-09-08 |
AU2002254348A1 (en) | 2003-11-17 |
CA2480008A1 (en) | 2003-11-13 |
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