NZ615915B2 - Compositions and methods for treating, diagnosing and monitoring disease - Google Patents
Compositions and methods for treating, diagnosing and monitoring disease Download PDFInfo
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- NZ615915B2 NZ615915B2 NZ615915A NZ61591512A NZ615915B2 NZ 615915 B2 NZ615915 B2 NZ 615915B2 NZ 615915 A NZ615915 A NZ 615915A NZ 61591512 A NZ61591512 A NZ 61591512A NZ 615915 B2 NZ615915 B2 NZ 615915B2
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
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- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57415—Specifically defined cancers of breast
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
Abstract
Disclosed is the use of a therapeutically effective amount of a composition which inhibits the expression of the TMEM92 gene or which inhibits the function of the TMEM92 protein, in the manufacture of a medicament for the treatment of cancer. Also disclosed is a method for diagnosing cancer in a patient or for identifying a patient at risk of developing cancer, the method comprising: (a) determining an amount of a biomarker in a sample obtained from a patient, the biomarker comprising:- (i) a nucleic acid sequence comprising SEQ ID NO:1, or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1, or a nucleic acid molecule which comprises said nucleic acid sequence; or (ii) an amino acid sequence comprising SEQ ID NO:2, or a functional fragment/variant that has at least about 70% amino acid sequence identity with SEQ ID NO:2, or an amino acid molecule which comprises said amino acid sequence, optionally wherein the biomarker is a cancer biomarker selected from a prostate cancer biomarker, a non-small cell lung cancer biomarker and breast cancer biomarker. patient or for identifying a patient at risk of developing cancer, the method comprising: (a) determining an amount of a biomarker in a sample obtained from a patient, the biomarker comprising:- (i) a nucleic acid sequence comprising SEQ ID NO:1, or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1, or a nucleic acid molecule which comprises said nucleic acid sequence; or (ii) an amino acid sequence comprising SEQ ID NO:2, or a functional fragment/variant that has at least about 70% amino acid sequence identity with SEQ ID NO:2, or an amino acid molecule which comprises said amino acid sequence, optionally wherein the biomarker is a cancer biomarker selected from a prostate cancer biomarker, a non-small cell lung cancer biomarker and breast cancer biomarker.
Description
COMPOSITIONS AND METHODS FOR TREATING, DIAGNOSING AND
RING DISEASE
The present application relates to compositions and methods for treating, diagnosing
and monitoring disease, for example cancer.
Cancer is one of the most prevalent es in the world, affecting millions of people
every year. Many types of cancer are known. For the ty of cancers, effective ents
do not exist or are only effective in a small number of patients.
Accordingly, there is a need to identity new ents for cancer and new methods of
diagnosing cancer.
SUMMARY OF THE INVENTION
TMEM92 (transmembrane protein 92) 3229) is a previously uncharacterised
gene predicted to encode a 159 amino acid (17.2 kDa) protein with a single transmembrane
domain (Figure 1).
Surprisingly, it has been found that whilst TMEM92 is not expressed in many normal
adult tissues, and is expressed at only a very low level in the liver, colon, lung and uterus, it is
strongly expressed in cell lines derived from prostate cancer, non-small cell lung cancer and
breast cancer. As a result of the differential expression of TMEM92, its expression can be
used as a biomarker, for example in relation to cancer.
Furthermore, h the use of a siRNA knock down of TMEM92 in PC3 cells
(derived from a metastatic prostate cancer) and WPMY-l cells (a non-malignant cell line
derived from normal prostate fibroblasts), it has been shown herein that knock down of
TMEM92 in PC3 causes a significant reduction in cell survival as compared to a control
siRNA, whilst TMEM92 knock down in WPMY-l cells does not cause cell death.
CONFIRMATION COPY
ingly, in one aspect of the present invention, there is provided a method for
treating a disease, preferably cancer, the method comprising administering to a patient a
therapeutically effective amount of a composition which ts the expression of the
TMEM92 gene or which inhibits the function of the TMEM92 protein.
Also ed by the present invention is a composition for use in therapy, n
the composition is capable of ting the expression of the TMEM92 gene or is capable of
inhibiting the function of the TMEM92 protein.
Further provided is use of a composition which inhibits the expression of the
TMEM92 gene or which inhibits the function of the TMEM92 protein in therapy.
Additionally provided by the present invention is use of a composition which inhibits
the sion of the TMEM92 gene or which inhibits the function of the TMEM92 protein,
in the manufacture of a medicament for treating a e, preferably cancer.
Preferably, the composition comprises a nucleic acid sequence which is (i)
complementary to the nucleic acid sequence of SEQ ID NO:1 or a fragment or variant thereof;
and/or (ii) hybridizable to the nucleic acid ce of SEQ ID NO:1 or a fragment or variant
thereof.
Preferably, the nucleic acid sequence is an isolated nucleic acid ce.
ably, the composition comprises a nucleic acid molecule sing a nucleic
acid sequence which is (i) complementary to the nucleic acid sequence of SEQ ID NO:1 or a
fragment or variant thereof; and/or (ii) hybridizable to the nucleic acid sequence of SEQ ID
N02] or a fragment or variant thereof.
Preferably, the nucleic acid molecule comprises double stranded RNA.
Preferably, the nucleic acid molecule comprises small interfering RNA (siRNA).
WO 31301
As such, it is preferred that, in one embodiment of the invention, the nucleic acid
sequence which is (i) complementary to the c acid sequence of SEQ ID NO:1 or a
fragment or variant f; and/or (ii) izable to the nucleic acid ce of SEQ ID
N011 or a fragment or variant thereof, is capable of disrupting, e.g. downregulating,
expression of the TMEM92 gene.
Preferably, the nucleic acid molecule further comprises vector nucleic acid sequences.
Preferably, the nucleic acid molecule further comprises nucleic acid sequences
ng a heterologous ptide.
Preferably, the nucleic acid molecule comprises a TMEM92~responsive promoter. As
such, the nucleic acid molecule may preferably selectively drive gene expression in cells that
express TMEM92. Such genes preferably include those that encode pro-drug activators or
allow the replication of a lytic virus.
Preferably, the composition comprises a host cell which contains the c acid
molecule.
The host cell may be a mammalian host cell or a non—mammalian host cell.
Preferably, the nucleic acid sequence, which is (i) complementary to the nucleic acid
sequence of SEQ ID N021 or a fragment or variant thereof; and/or (ii) hybridizable to the
nucleic acid sequence of SEQ ID NO:1 or a fragment or t thereof, is incorporated into a
, for example a DNA plasmid. As such, in some embodiments of the present invention,
the composition comprises a vector, for example a DNA plasmid, comprising a nucleic acid
sequence which is (i) complementary to the nucleic acid sequence of SEQ ID N02] or a
fragment or variant thereof; and/or (ii) hybridizable to the nucleic acid sequence of SEQ ID
NO:1 or a fragment or variant thereof.
Preferably, the composition comprises an dy or fragment thereof which is
capable of binding to the TMEM92 protein.
W0 2012/131301
ably, the antibody specifically binds the TMEM92 protein.
Preferably, the antibody is conjugated to a detectable marker, for example a
fluorescent marker or tag. Preferably, the antibody is a monoclonal antibody. Preferably, the
antibody is conjugated to a growth inhibitory agent. Preferably, the antibody is conjugated to
a cytotoxic agent, for example a toxin (e.g. an immunotoxin), antibiotic, lytic enzyme or
radioactive isotOpe.
Preferably, the composition comprises an nist of TMEM92 protein function, for
example a small molecule antagonist.
Preferably, the composition is a pharmaceutical composition.
ably, the therapy is the treatment of cancer.
Preferably, the disease is cancer.
Preferably, cancer is selected from te cancer, non-small cell lung cancer and
breast cancer.
ing to r aspect of the present invention, there is provided a biomarker
comprising:—
(i) a nucleic acid sequence comprising SEQ ID NO:1, or a fragment or variant thereof,
or a nucleic acid molecule which comprises said nucleic acid sequence; or
(ii) an amino acid sequence comprising SEQ ID N02, or a fragment or variant
thereof, or an amino acid molecule which ses said amino acid sequence.
In this t, SEQ ID NO:1 corresponds to the nucleic acid sequence of the single
transmembrane domain TMEM92 gene (GenBank reference number 229) and SEQ
ID N022 corresponds to the TMEM92 protein encoded thereby (NCBI accession number
EAW94628, gi119615034).
ably, the biomarker is a cancer biomarker, for example selected from a prostate
cancer biomarker, non-small cell lung cancer biomarker and breast cancer biomarker.
Preferably, the cancer is selected from prostate cancer, non-small cell lung cancer and
breast cancer.
Preferably, the fragments or variants thereof comprise:-
(i) a c acid sequence that has at least about 50%, or at least about 60%, or at
least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least
about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least
about 98%, or at least about 99% nucleic acid sequence identity with SEQ ID NO: 1, a nucleic
acid sequence that is hybridizable thereto under stringent conditions, and/or a nucleic acid
sequence that is complementary o;
(ii) an amino acid sequence that has at least about 50%, or at least about 60%, or at
least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least
about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least
about 98%, or at least about 99% amino acid sequence identity with SEQ ID N02, or
(iii) an amino acid ce encoded by a nucleic acid sequence of (i).
Put r way, in accordance with part (iii) above, it is preferred that the fragments
or ts thereof comprise:-
(A) an amino acid ce encoded by a nucleic acid sequence, wherein said nucleic
acid sequence has at least about 50%, or at least about 60%, or at least about 70%, or at least
about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least
about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least
about 99% nucleic acid sequence identity with SEQ ID NO: 1;
(B) an amino acid sequence encoded by a nucleic acid sequence, wherein said nucleic
acid sequence is hybridizable under stringent conditions to a nucleic acid sequence that has at
least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least
about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least
about 96%, or at least about 97%, or at least about 98%, or at least about 99% nucleic acid
sequence identity with SEQ ID NO: 1; or
(C) an amino acid sequence encoded by a nucleic acid ce, wherein said nucleic
acid sequence is complementary to a nucleic acid ce that has at least about 50%, or at
least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least
about 85%, or at least about 90%, or at least about 95%, or at least about 96%, or at least
about 97%, or at least about 98%, or at least about 99% nucleic acid sequence identity with
SEQ ID N021.
Preferably, the fragments thereof comprise (i) at least four, preferably at least five,
preferably at least six, preferably at least seven, preferably at least eight consecutive amino
acids from SEQ ID N022 or (ii) a fragment of the nucleic acid sequence of SEQ ID N021
which s at least four, preferably at least five, preferably at least six, preferably at least
seven, preferably at least eight consecutive amino acids from SEQ ID N022. Longer
fragments are also preferred, for example at least about 10, 15, 20, 25, 30, 50, 75, 100, 125,
and up to at least about 150 amino acids of SEQ ID N022 or corresponding coding fragments
of SEQ ID N0:l. Fragments may also include truncated peptides that have x amino acids
deleted from the N-terminus and/or C-terminus. In such truncations, x
may be 1 or more (i.e.
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more), but preferably less
than 125 amino acids of SEQ ID N02 or corresponding coding fragments of SEQ ID N021.
Preferably, the fragments or variants thereof are functional fragments or variants
thereof.
According to another aspect of the t invention, there is provided a method for
diagnosing disease, for example cancer, in a patient or for identifying a patient at risk of
developing disease, for example cancer, the method comprising:
(a) determining an amount of the ker in a sample obtained from a patient;
(b) ing the amount of the determined biomarker in the sample from the patient
to the amount of the biomarker in a normal control;
wherein a ence in the amount of the biomarker in the sample from the patient
compared to the amount of the biomarker in the normal control is associated with the presence
of disease or is associated with a risk of developing disease, ally wherein the disease is
cancer, for example ed from prostate cancer, non-small cell lung cancer and breast
cancer.
In preferred embodiments of the ion, the amount of the biomarker in the normal
control is undetectable.
According to another aspect of the present invention, there is provided a method for
diagnosing e, for example cancer, in a patient or for identifying a patient at risk of
developing disease, for example cancer, the method comprising:
determining an amount of the biomarker in a sample obtained from a patient, wherein
the presence of the biomarker is associated with the presence of disease or is associated with a
risk of developing disease, optionally wherein the e is cancer, for example selected from
prostate cancer, non-small cell lung cancer and breast cancer.
According to another aspect of the present ion, there is provided a method for
ring the ssion of disease, for example cancer, in a patient, the method
comprising:
(a) ining an amount of the biomarker in a sample obtained from a patient;
(b) comparing the amount of the determined biomarker in the sample from the t
to the amount of the biomarker in a normal control; and
(c) repeating steps (a) and (b) at two or more time intervals,
wherein an increase in the amount of the biomarker from the patient over time is
associated with an increase in the progression of disease and a se in the amount of the
biomarker from the patient over time is associated with a decrease in the progression of
disease, optionally wherein the disease is cancer, for example selected from prostate cancer,
non-small cell lung cancer and breast cancer.
Accordingly, the methods of the present invention can be used to detect the onset,
progression, stabilisation, amelioration and/or remission of disease.
Preferably, the control may be from the same patient from a previous sample, to thus
r onset or ssion. However, it is also preferred that the control may be normalised
for a tion, particularly a healthy or normal population, where there is no disease. In
other words, the control may consist of the level of a biomarker found in a normal control
sample from a normal subject.
Accordingly, in one example of the t invention, there is provided a method of
diagnosing or monitoring the progression of disease, for example cancer, comprising
detecting and/or quantifying the biomarker in a biological fluid obtained from a patient,
optionally wherein the disease is cancer, for example ed from prostate cancer, all
cell lung cancer and breast cancer.
As discussed above, it is preferred that at least two detection and/or quantification
steps are provided, spaced apart ally.
ably, the steps are spaced apart by a few days, weeks, years or months, to
determine whether the levels of the biomarker have changed, thus indicating whether there
has been a change in the progression of the disease, enabling isons to be made
n a level of the biomarker in samples taken on two or more occasions, as an increase in
the level of the biomarker over time is indicative of the onset or progression of disease,
whereas a se in the level of the biomarker may indicate amelioration and/or remission
of disease.
Preferably, the difference in the level of the biomarker is statistically significant,
determined by using a "t-test" providing confidence intervals of ably at least about 80%,
preferably at least about 85%, preferably at least about 90%, preferably at least about 95%,
preferably at least about 99%, preferably at least about 99.5%, preferably at least about
99.95%, preferably at least about 99.99%.
The biomarkers and s of the invention are particularly useful in detecting early
stage cancer and are more sensitive than known methods for detecting early stage cancer.
Thus, the biomarkers and methods of the invention are particularly useful for continuing
cancer when a patient has tested negative for cancer using conventional s.
Prognosis and choice of treatment are dependent upon the stage of the cancer and the
patient's general state of health.
Different types of prostate cancer are known. The most common starts in the prostate
gland cells and is known as prostate adenocarcinoma. However, other forms of prostate
cancer exist, such as, sarcomas, small cell carcinomas, and transitional cell carcinomas. The
methods of the invention may be used to detect the onset of any of these types of cancer,
although the detection of adenocarcinoma is preferred.
The progression of cancer is usually monitored by a g process. This indicates
how well developed the cancer is and if it has spread. The score runs from one to four, with
the prognosis becoming progressively worse at each stage.
In relation to prostate cancer, the stages are as follows:-
Stage 1: ant cells are confined to the prostate; they have not spread to the
lymph nodes or other organs; Gleason scores are between two to four, and less than five
percent of the prostate is composed of tumor growth.
Stage 2: Gleason scores are five or higher, or over five percent of the gland shows
abnormal growth; the cancer is still restricted to the prostate.
Stage 3: Malignant cells have spread to the seminal vesicles, but not to the lymph
nodes or other organs.
Stage 4: The lymph nodes, pelvic tissue or more distant organs are affected.
In relation to non-small cell lung cancer, the stages are as follows:-
Stage 1: The cancer is localized within the lung and has not spread to any lymph
nodes. Stage 1 is divided into stage 1A (tumours 3 cm or less in size), and stage IB (tumours
greater than 3 cm).
Stage 2: The cancer has spread to nearby lymph nodes, or has not spread to lymph
nodes but is large, in a n region of the main bronchus, or in a on where it invades
the lung lining. Stage 2 is divided into stage 2A (a tumour 3 cm or less in size with spread to
lymph nodes), or stage ZB (tumours 3 cm or greater in size with spread to lymph nodes, or
present in locations such as a region of the main us or ng the lung lining or chest
wall).
Stage 3: The cancer has spread to tissue near the lungs. Stage 3 is divided in stage 3A
(large tumours with spread to nearby lymph nodes, or any size tumour that has spread to
lymph nodes further away from the tumour), and stage 3B (any size tumour that has spread to
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t lymph nodes, a tumour that has invaded other structures in the chest such as the heart
or esophagus, or a tumour with a malignant pleural effusion).
Stage 4: The cancer has spread to another part of the body. This can include spread to
another lobe of the lung.
In relation to breast cancer, the stages are as follows:-
Stage 1: The tumour measures less than 2cm. The lymph nodes in the armpit are not
affected and there are no signs that the cancer has spread elsewhere in the body.
Stage 2: The tumour measures between 2 and 5cm, or the lymph nodes in the armpit
are affected, or both. However, there are no signs that the cancer has spread further.
Stage 3: The tumour is larger than 5cm and may be attached to surrounding structures
such as the muscle or skin. The lymph nodes are usually affected, but there are no signs that
the cancer has spread beyond the breast or the lymph glands in the armpit.
Stage 4: The tumour is of any size, but the lymph nodes are usually affected and the
cancer has spread to other parts of the body. This is secondary or metastatic breast cancer.
ably, the methods of the ion detect the onset of cancer prior to, or during
stage one or stage two, more preferably stage one.
It will be appreciated that the term “early stage” as used herein can be said to refer to
stage 1 and/or stage 2, as discussed above.
With regard to the term “late stage” as used herein, it will be iated that this term
can be said to refer to stage 3 and/or stage 4.
It will be appreciated that the "early stage" and "late stage" nature of the cancer
disease states can be determined by a physician. It is also envisaged that they may be
associated with non-metastatic and metastatic states, respectively.
In one aspect, there are provided methods according to the present invention for
detecting early stage cancer, n an increase between the control and the sample obtained
from the patient is tive of early stage cancer. Preferably, the increase is at least about
100%, preferably at least about 125%, ably at least about 150%, preferably at least
about 200%, preferably at least about 250%, preferably at least about 300%, preferably at
least about 500%.
Also provided are methods according to the present invention for ing late stage
cancer wherein an increase n the control and the sample obtained from the patient is
indicative of late stage cancer. Preferably, the inerease is at least about 100%, preferably at
least about 125%, preferably at least about 150%, preferably at least about 200%, preferably
at least about 250%, preferably at least about 300%, preferably at least about 500%,
preferably at least about 750%, preferably at least about 1000%.
Further provided are s according to the present invention for monitoring a
change in stage of cancer, wherein an increase, relative to an r stage sample or control is
tive of progression of the cancer from an earlier stage to later stage of disease, for
example from from stage 1 to stage 2, from stage 2 to stage 3, from stage 3 to stage 4, from
early stage to late stage, or from stages in between, for example from stage 2A to stage 2B in
accordance with cancer specific stages described above. Preferably, the se is at least
about 100%, preferably at least about 125%, preferably at least about 150%, preferably at
least about 200%, preferably at least about 250%, preferably at least about 300%, preferably
at least about 500%, preferably at least about 750%, ably at least about 1000%.
It is preferred that the biomarker is indicative of the presence of disease, for example
cancer or the risk of developing disease, for example cancer when present at a level of at least
about 2~fold, preferably at least about 3-fold, preferably at least about 4-fold, preferably at
least about 5-fold, preferably at least about 10-fold, preferably at least about 20~fold,
preferably at least about 30-fold, preferably at least about d, preferably at least about
50—fold, preferably at least about 75-fold, preferably at least about lOO-fold that of a normal
control.
Preferably, in the methods of the present invention, it is possible to guish
between different types of cancer by reference to (i) different levels of increase in expression
of the biomarker compared to that of a normal control, and/or (ii) different levels of
expression of the biomarker.
For e, as shown in Figure 4, the level of expression for PC3 (prostate cancer)
was r than that for A549 (non—small cell lung cancer) which was greater than that for
MDA—MB-23l t cancer).
Also provided by the present invention is a method for monitoring the efficacy of a
treatment for disease, for example cancer, comprising detecting and/or quantifying the
presence of the biomarker in a biological sample obtained from a patient, optionally wherein
the cancer is selected from prostate cancer, non-small cell lung cancer and breast cancer.
Preferably, in the methods of the present ion, detection and/or quantification of
the biomarker is by one or more of MALDI-TOF, SELDI, via interaction with a ligand or
ligands, 1-D or 2-D gel-based analysis s, Liquid Chromatography, combined liquid
tography and Mass spectrometry techniques including ICAT(R) or iTRAQ(R), thin-
layer chromatography, NMR spectroscopy, sandwich immunoassays, enzyme linked
immunosorbent assays (ELISAs), radioimmunoassays (RAI), enzyme immunoassays (EIA),
lateral flow/immunochromatographic strip tests, Western Blotting, immunoprecipitation, and
particle-based immunoassays including using gold, silver, or latex particles, ic
particles or Q-dots and histochemistry on tissue sections.
Preferably, detection and/or quantification of the biomarker is performed on a
microtitre plate, strip format, array or on a chip.
Preferably, detection and/or quantification of the biomarker is by an ELISA
comprising dies specific for the biomarker, preferably linked to a reporter.
Preferably, detection and/or quantification of the biomarker is by a biosensor.
Preferably, the sample comprises biological fluid or tissue obtained from the patient.
Preferably, the biological fluid or tissue comprises urine, cells collected from urine,
circulating tumour cells, biopsy samples, semen, fluid from a lung lavage, nipple aSpirate,
ar fluid, , blood or saliva.
In preferred embodiments relating to prostate , the sample comprises urine,
semen, blood, cells collected from urine, circulating tumour cells and/or prostate biopsy
samples obtained from a patient. In some embodiments, the sample comprises biological fluid
or tissue obtained from the prostate of a patient.
In preferred embodiments ng to non-small cell lung cancer, the sample comprises
sputum, fluid from a lung lavage, blood, circulating tumour cells and/or lung biopsy samples
obtained from a patient. In some ments, the sample comprises biological fluid or tissue
obtained from the lung of a patient.
In red embodiments relating to breast , the sample comprises nipple
aspirate (from a saline wash into nipple), blood, ating tumour cells, and/or breast tissue
biopsy samples. In some embodiments, the sample comprises biological fluid or tissue
obtained from the breast of a patient.
Accordingly, it will be appreciated that, in some embodiments, the site in the body of
the patient from where the sample has been ed may correspond to a particular type of
disease, for example cancer.
It is also preferred that the biological fluid is substantially or completely free of
whole/intact cells. Preferably the biological fluid is free of platelets and cell debris (such as
that produced upon the lysis of cells). Preferably the biological fluid is free of both
yotic and eukaryotic cells.
Such samples can be obtained by any number of means known in the art, such as will
be apparent to the skilled person. For instance, urine samples are easily attainable, whilst
blood or serum samples can be obtained parenterally by using a needle and syringe, for
instance. Cell free or substantially cell free samples can be obtained by subjecting the sample
to various techniques known to those of skill in the art which include, but are not limited to,
centrifugation and ion.
Although it is generally red that no invasive techniques are used to obtain the
sample, it still may be preferable to obtain samples such as tissue homogenates, tissue
sections and biopsy specimens.
Another aspect of the present invention relates to a method for treating a patient with a
disease, preferably cancer, the method comprising stering to a patient a therapeutically
effective amount of a biomarker of the present invention, optionally, wherein the cancer is
ed from prostate cancer, non-small cell lung cancer and breast cancer.
Another aspect of the present invention relates to a method for g disease, for
example cancer in a t, the method comprising administering to a patient an antibody or
fragment thereof that binds to a biomarker of the present invention, Optionally wherein the
cancer is selected from prostate cancer, non-small cell lung cancer and breast cancer.
Preferably, the antibody is conjugated to a detectable marker, for example a
fluorescent marker or tag. Preferably, the antibody is a monoclonal antibody. Preferably, the
antibody is conjugated to a growth inhibitory agent. ably, the dy is conjugated to
a cytotoxic agent, for example a toxin (e.g. an immunotoxin), antibiotic, lytic enzyme or
radioactive isotope.
Reference herein to the composition is also intended to relate to the composition per
se. Accordingly, another aspect of the present invention s to a composition comprising
(A) a biomarker of the present invention;
(B) a nucleic acid sequence which is (i) complementary to the nucleic acid sequence of
SEQ ID N011 or a fragment or variant thereof; and/or (ii) hybridizable to the nucleic acid
ce of SEQ ID NO:1 or a fragment or variant thereof;
(C) a nucleic acid molecule comprising a nucleic acid sequence which is (i)
complementary to the nucleic acid sequence of SEQ ID N011 or a fragment or variant thereof;
and/or (ii) hybridizable to the c acid sequence of SEQ ID NO:1 or a fragment or variant
(D) a host cell which contains the nucleic acid molecule;
(E) a vector, for example a DNA plasmid, comprising a nucleic acid sequence which is
(i) complementary to the nucleic acid ce of SEQ ID N011 or a fragment or variant
PCT/G32012/000285
thereof; and/or (ii) hybridizable to the nucleic acid sequence of SEQ ID NO:1 or a fragment
or variant thereof;
(F) an antibody or fragment f which is capable of binding to the TMEM92
protein;
(G) an antibody or fragment thereof which is capable of binding to a biomarker of the
present invention; and/or
(H) an antagonist of TMEM92 n function, for example a small molecule
antagonist.
Preferably, the composition is a pharmaceutical composition.
Also provided by the present invention is a vaccine comprising a composition of the
present invention, for example a biomarker of the present invention or an antibody or
fragment thereof that binds to a biomarker of the t invention.
In this respect, TMEM92 is present on the outside of the cell membrane and is
therefore an ideal target in relation to a vaccine.
Preferably the e is a cancer e, for example selected from a prostate cancer
vaccine, a non-small cell lung cancer vaccine and a breast cancer vaccine.
Another aspect of the t invention relates to use of the biomarker, detectable in a
body fluid, as a biomarker for disease, for example cancer, optionally wherein the cancer is
selected from te cancer, non-small cell lung cancer and breast cancer.
Preferably, said use is in a method selected from the group consisting of: clinical
screening, methods of sis assessment, monitoring the results of therapy, method to
identify patients most likely to respond to a particular eutic treatment, and drug
screening and development.
Another aspect of the t invention relates to use of a composition or biomarker of
the t invention in the manufacture of a medicament for the treatment of disease, for
2012/000285
example cancer, optionally wherein the cancer is selected from prostate cancer, non-small cell
lung cancer and breast cancer.
Also provided is a composition or biomarker of the present invention for use in
y or diagnosis, for example in relation to , optionally wherein the cancer is
selected from prostate cancer, all cell lung cancer and breast cancer.
Another aspect of the present invention relates to an antibody or fragment thereof that
binds to a biomarker of the present ion for use in a method of imaging disease, for
example cancer in a patient, ally n the cancer is selected from prostate cancer,
non~small cell lung cancer and breast cancer.
Preferably, the antibodies or fragments thereof described herein specifically bind to a
biomarker of the present invention.
In preferred ments, the methods and compositions of the invention are for
treatment or sis of disease at an early stage, for example, before symptoms of the
disease appear.
In some embodiments, the methods and compositions of the invention are for
treatment or diagnosis of disease at a clinical stage
According to another aspect of the present invention, there is provided a kit for use in
the methods or uses described above, wherein the kit ses a ligand, for example an
antibody or fragment thereof as described herein, capable of binding or specifically
recognising the biomarker, detectable in a body fluid and reporter means.
Preferably, the kit is an array or chip.
Preferably, the kit comprises a microtitre plate, test strip, array or chip.
Preferably, the kit comprises ctions for use in accordance with the methods, uses
and/or compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Example embodiments of the present invention will now be described with reference
to the accompanying figures.
Figure 1 shows a schematic representation of the extracellular and cytoplasmic
domains of TMEM92;
Figure 2 shows the nucleic acid sequence of TMEM92 (SEQ ID NO:1);
Figure 3 shows the amino acid sequence ofTMEM92 (SEQ ID N02);
Figure 4 shows expression 92 in the cancer derived cell lines PC3, A549 and
MDA—MB-23 1, together with normal adult tissues. Expression is shown relative to the
GAPDH gene (ratio x 10,000);
Figure 5 shows siRNA knock down of TMEM92 in PC3 and WPMY-l cells. “Con
siR” = control (non-specific) siRNA, “TMEM92 siR” = TMEM92 specific siRNA. **p<0.01
for cell survival in TMEM92 siRNA treated PC3 v WPMY-l cells; and
Figure 6 shows expression data for three other TMEMs.
Figure 7 shows TMEM92 protein is present in PC3 cells but not WMPY-l cells.
Fluorescent copy using an anti-TMEM92 dy ). (A) PC3 cells (nuclear,
cytoplasmic and membrane staining evident), (B) WPMY-l cells (no staining). The nuclei are
stained with DAPI . Scale bar: 50pm.
Figure 8 shows TMEM92 protein in PC3 cells. Fluorescent microscopy using an anti-
TMEM92 antibody (green). (A) Cells made permeable by re to ent. The nucleus
is stained with DAPI (blue). (B) Non-permeable cell to show surface expression of TMEM~
92. Scale bar: 5pm.
The invention relates to methods and compositions for treating disease, for example
cancer and to biomarkers, ably, wherein the cancer is selected from prostate cancer,
non-small cell lung cancer and breast cancer.
TMEM92 is a novel cell surface protein that is differentially expressed in cancer as
opposed to normal tissue. The data provided herein shows that it could be used as a marker of
cancer, for example in tissue sections or when present in certain bodily fluids, and as a target
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in cancer, for example by using an dy that recognises it or by blocking its activity
through, for example, a small le drug.
Within this specification, the term “abou ” means plus or minus 20%, more ably
plus or minus 10%, even more preferably plus or minus 5%, most preferably plus or minus
As used herein, the term "therapeutically effective " means the amount of a
composition which is required to reduce the severity of and/or ameliorate at least one
condition or symptom which results from the disease in question.
Within this specification embodiments have been described in a way which enables a
clear and concise specification to be n, but it is intended and will be appreciated that
embodiments may be sly combined or separated without parting from the invention.
For clinical use, a compound according to the present invention or prodrug form
thereof is ated into a pharmaceutical formulation which is formulated to be compatible
with its intended route of administration, for example for oral, rectal, parenteral or other
modes of administration. Pharmaceutical formulations are y prepared by mixing the
active substance with a conventional pharmaceutically acceptable diluent or carrier. As used
herein the language "pharmaceutically acceptable carrier" is intended to include any and all
solvents, dispersion media, coatings, antibacterial and ngal agents, isotonic and
absorption delaying agents, and the like, compatible with pharmaceutical administration.
Examples of pharrnaceutically acceptable diluents or carrier are water, gelatin, gum arabicum,
lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen
ate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. The use of
such media and agents for pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the active compound, use
thereof in the compositions is contemplated.
Such ations may also n other pharmacologically active agents, and
conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents,
buffers, and the like.
The formulations can be further prepared by known methods such as granulation,
compression, ncapsulation, spray coating, etc. The formulations may be prepared by
conventional methods in the dosage form of tablets, capsules, granules, powders, syrups,
suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving
or suspending the active substance in water or other suitable vehicles. Tablets and granules
may be coated in a conventional manner.
ons or suspensions used for parenteral, intraderrnal, or subcutaneous application
can include the following components: a e diluent such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other tic
solvents; antibacterial agents such as benzyl l or methyl parabens; antioxidants such as
ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid;
s such as acetates, citrates or phosphates and agents for the adjustment of tonicity such
as sodium de or dextrose. pH can be adjusted with acids or bases, such as hydrochloric
acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
Pharmaceutical compositions le for injectable use include sterile aqueous
solutions (where water soluble) or dispersions and sterile powders for the externporaneous
ation of sterile injectable solutions or dispersion. For intravenous administration,
suitable carriers include physiological saline, bacteriostatic water, Cremephor ELTM (BASF,
Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be
sterile and should be fluid to the extent that easy syringability exists. It must be stable under
the conditions of manufacture and e and must be preserved against the contaminating
action of microorganisms such as bacteria and fungi. The carrier can be a solvent or
dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol,
propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
The proper fluidity can be maintained, for example, by the use of a coating such as lecithin,
by the nance of the required particle size in the case of dispersion and by the use of
tants. tion of the action of rganisms can be achieved by various
antibacterial and antifungal , for example, parabens, ‘chlorobutanol, phenol, ascorbic
acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents,
for example, sugars, polyalcohols such as manitol, sorbitol, sodium de in the
composition. Prolonged tion of the injectable compositions can be brought about by
including in the composition an agent which delays absorption, for example, aluminum mono
stearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound
(e.g., a compound according to an embodiment of the invention) in the required amount in an
appropriate solvent with one or a combination of ingredients ated above, as required,
followed by filtered sterilization. Generally, dispersions are prepared by incorporating the
active compound into a sterile vehicle which ns a basic dispersion medium and the
required other ingredients from those enumerated above. In the case of sterile powders for the
preparation of sterile able solutions, the preferred methods of ation are vacuum
drying and freeze-drying which yields a powder of the active ingredient plus any additional
desired ient from a previously sterile-filtered solution thereof.
Oral compositions generally include an inert diluent or an edible carrier. They can be
enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic
administration, the active compound can be incorporated with excipients and used in the form
of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier
for use as a ash, wherein the compound in the fluid carrier is applied orally and
swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or
adjuvant materials can be included as part of the composition. The tablets, pills, capsules,
troches and the like can contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth or n; an ent
such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch;
a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide;
a sweetening agent such as e or saccharin; or a flavoring agent such as mint,
methyl salicylate, or orange ng.
For administration by inhalation, the compounds are delivered in the form of an
aerosol spray from pressured container or dispenser which ns a suitable propellant, e.g.,
a gas such as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means. For
transmucosal or ermal administration, penetrants appropriate to the r to be
permeated are used in the formulation. Such penetrants are lly known in the art, and
e, for example, for transmucosal administration, detergents, bile salts, and fusidic acid
derivatives. Transmucosal administration can be accomplished h the use of nasal sprays
into
or suppositories. For transdermal administration, the active compounds are formulated
ointments, salves, gels, or creams as generally known in the art.
The nds can also be prepared in the form of suppositories (e.g., with
conventional suppository bases such as cocoa butter and other glycerides) or retention enemas
for rectal delivery.
Preferably, the active compounds are prepared with carriers that will protect the
compound against rapid elimination from the body, such as a controlled release formulation,
including implants and microencapsulated delivery systems. Biodegradable, biocompatible
polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations
will be apparent to those skilled in the art. The materials can also be obtained commercially
from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including
liposomes targeted to infected cells with monoclonal antibodies to Viral antigens) can also be
used as ceutically acceptable carriers. These can be prepared ing to methods
known to those d in the art.
It is especially advantageous to formulate oral or parenteral compositions in dosage
unit form for ease of administration and uniformity of . Dosage unit form as used
herein refers to ally discrete units suited as unitary dosages for the subject to be treated;
each unit ning a predetermined quantity of active compound calculated to produce the
d therapeutic effect in association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention are dictated by and directly dependent
on the unique characteristics of the active compound and the particular therapeutic effect to be
achieved, and the limitations inherent in the art of compounding such an active compound for
the treatment of individuals.
Toxicity and therapeutic efficacy of such compounds can be determined by rd
pharmaceutical ures in cell cultures or experimental animals, e.g., for determining the
LDSO (the dose lethal to 50% of the population) and the EDSO (the dose therapeutically
effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the
therapeutic index and it can be sed as the ratio LDSO/EDSO. Compounds which exhibit
large therapeutic indices are preferred. While compounds that exhibit toxic side effects may
be used, care should be taken to design a delivery system that targets such compounds to the
site of affected tissue in order to ze potential damage to uninfected cells and, thereby,
reduce side effects.
The data obtained from the cell culture assays and animal studies can be used in
formulating a range of dosage for use in humans. The dosage of such compounds lies
preferably within a range of circulating concentrations that include the EDSO with little or no
toxicity. The dosage may vary within this range ing upon the dosage form employed
and the route of administration utilized. For any compound used in the method of the
invention, the eutically effective dose can be estimated initially from cell culture assays.
A dose may be formulated in animal models to achieve a circulating plasma concentration
range that es the ICSO (i.e., the concentration of the test compound which achieves a
half-maximal inhibition of symptoms) as determined in cell culture. Such information can be
used to more accurately ine useful doses in humans. Levels in plasma may be
ed, for example, by high performance liquid chromatography.
The pharmaceutical compositions can be included in a container, pack, or dispenser
together with instructions for stration.
Within this specification, “identity,” as it is known in the art, is a relationship between
two or more polypeptide sequences or two or more cleotide sequences, as determined
by comparing the sequences. In the art, “identity” also means the degree of sequence
relatedness between polypeptide or polynucleotide sequences, as the case may be, as
determined by the match between strings of such sequences. Percentage identity can be
readily calculated by known methods, ing but not limited to those described in
Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York,
1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press,
New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H.
G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von
Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, ov, M. and
Devereux, J ., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman, D.,
SIAM J. Applied Math., 48: 1073 (1988), all of which are incorporated herein by reference in
their entirety. Preferred methods to ine identity are designed to give the largest match
between the sequences tested. Methods to determine identity are codified in publicly available
computer programs. Preferred computer m methods to determine percentage identity
between two sequences include, but are not d to, the GCG m package (Devereux,
J., et al., c Acids Research 12(1): 387 , which is incorporated herein by reference
in its entirety), BLASTP, BLASTN, and FASTA (Atschul, S. F. et al., J. Molec. Biol. 215:
403-410 (1990), which is incorporated herein by reference in its entirety). The BLAST X
m is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et
al., NCBI NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol. 215: 403-410
(1990), which is incorporated herein by reference in its entirety). As an illustration, by a
polynucleotide having a nucleotide sequence having at least, for example, 95% “identity” to a
reference nucleotide sequence of “SEQ ID NO: A” it is intended that the nucleotide sequence
of the cleotide is identical to the reference sequence except that the cleotide
sequence may include up to five point mutations per each 100 nucleotides of the reference
nucleotide sequence of “SEQ ID NO: A.” In other words, to obtain a polynucleotide having a
tide sequence at least 95% cal to a reference nucleotide sequence, up to 5% of the
nucleotides in the reference sequence may be d or substituted with another nucleotide,
or a number of tides up to 5% of the total nucleotides in the reference ce may be
inserted into the reference sequence. These mutations of the reference sequence may occur at
the 5’ or 3’ terminal positions of the reference nucleotide sequence or anywhere between
those terminal positions, interspersed either individually among nucleotides in the reference
sequence or in one or more contiguous groups within the reference sequence. ously, by
a polypeptide having an amino acid sequence having at least, for example, 95% identity to a
reference amino acid sequence of “SEQ ID NO:B” is intended that the amino acid sequence
of the polypeptide is identical to the reference sequence except that the polypeptide sequence
may include up to five amino acid alterations per each 100 amino acids of the reference amino
acid of “SEQ ID NO: B.” In other words, to obtain a polypeptide having an amino acid
sequence at least 95% identical to a reference amino acid sequence, up to 5% of the amino
acid es in the reference sequence may be deleted or substituted with another amino acid,
or a number of amino acids up to 5% of the total amino acid residues in the reference
sequence may be inserted into the reference sequence. These alterations of the reference
acid
sequence may occur at the amino or carboxy terminal positions of the reference amino
sequence or anywhere between those terminal positions, interspersed either individually
among residues in the reference sequence or in one or more contiguous groups within
reference sequence.
As used herein, the term "hybridizes under stringent conditions" is ed to
describe conditions for ization and washing under which nucleotide ces
encoding a receptor at least 50% gous to each other typically remain hybridized to
each other. The conditions can be such that sequences at least about 65%, at least about 70%,
or at least about 75% or more homologous to each other typically remain hybridized to each
other. Such stringent conditions are known to those skilled in the art and can be found in
Current Protocols in Molecular Biology, John Wiley & Sons, N. Y. (1989), 6. 3.1-6.3.6,
which is incorporated herein by reference in its entirety. One example of stringent
hybridization conditions are hybridization in 6X sodium chloride/sodium citrate (SSC) at
about 45°C, followed by one or more washes in 0.2 X SSC, 0.1% SDS at 50—65°C. In one
ment, an isolated receptor c acid molecule that hybridizes under stringent
conditions to the ce of SEQ ID N021 corresponds to a naturally-occurring nucleic acid
le. As used , a "naturally-occurring" nucleic acid molecule refers to an RNA or
DNA molecule having a nucleotide sequence that occurs in nature (e. g., encodes a l
protein).
Within this specification, ”antibody or antibody fragment” refers to an antibody (for
example IgG, lgM, IgA, lgD or IgE) or fragment (such as a Fab, F(ab‘)2, Fv, disulphide
linked Fv, scFv, closed conformation multispecific antibody, disulphide-linked scFv, y)
whether derived from any species naturally producing an antibody, or created by recombinant
DNA technology; whether ed from serum, B- cells, hybridomas, transfectomas, yeast or
bacteria.
Within this specification, the term “treatment” means treatment of an existing disease
and/or pr0phylactic treatment in order to prevent incidence of a disease. As such, the methods
2012/000285
of the invention can be used far the treatment, prevention, inhibition of progression or delay
in the onset of disease.
The term rker" is used throughout the art and means a ctive biological or
biologically-derived indicator of a process, event or condition. In other words, a biomarker is
indicative of a certain biological state, such as the presence of cancerous tissue. In some
cases, different forms of biomarkers can be tive of certain disease states but, without
being bound by theory, it is thought that merely the presence of elevated levels of the
kers of the present invention in body fluids or tissues is indicative of cancer. Although
it is not currently envisaged that different glycoforrns, for ce, of the TMEM92 peptide,
are secreted, these are nevertheless encompassed by the present invention. For instance,
different glycoforms, such as altered glycoform structure or sugar content, may yet be
determined for TMEM92, but these are encompassed and may even also be indicative of the
progress of cancer. Truncations, mutations, or deletions of, or ligations to, the TMEM92
peptide, or fragment thereof, are also envisaged.
As discussed above, it has singly been found that there is a significant increase
in expression of the TMEM92 gene in cancer d samples compared to normal samples.
In many instances, whilst there is expression in cancer derived samples, there is no expression
at all in corresponding normal samples. The biomarkers of the present invention can therefore
be said to be cancer specific biomarkers.
The results obtained for TMEM92 e 4) are especially surprising when compared
with the results obtained with other TMEM genes (Figure 6).
It is another advantage of the present invention that an accurate diagnosis can be
provided without resorting to unpleasant and ially harmful invasive procedures, which
may also be inaccurate. Furthermore, the present invention is particularly sensitive. ably
the methods of the present invention may detect the onset of cancer prior to any other
detection method and prior to the onset of the overt symptoms of cancer. Thus, the cancer
may be treated at an early stage when it is more susceptible to such treatment and less likely
to have entered the metastatic stage.
The biomarkers of the present invention can be used in methods of sis, for
instance clinical screening, and in s of prognosis assessment, monitoring the results of
therapy, identifying patients most likely to respond to a ular therapeutic treatment, drug
screening and development. Furthermore, the biomarkers of the present invention and uses
thereof are valuable for identification of new drug treatments and for discovery of new targets
for drug treatment.
The term "diagnosis" encompasses identification, confirmation, and or characterisation
of the presence or absence of disease, for example cancer, together with the developmental
stage thereof, such as early stage or late stage, or benign or metastatic cancer.
EXAMPLES
TMEM92 3229) is a previously uncharacterised gene predicted to encode a 159
amino acid (17.2 kDa) protein with a single transmembrane domain (Figure 1). Our data
shows that it is not expressed in many normal adult tissues, and is expressed at only a very
low level in the liver, colon, lung and uterus (Figure 4). However, it is strongly expressed in
the cancer d cell lines PC3 (prostate cancer), A549 (non-small cell lung cancer), and
MDA-MB—231 (breast cancer).
This ential expression indicates that TMEM92 could be a potential target in
cancer. To explore this possibility further, we used a siRNA knock down of TMEM92 in PC3
cells (derived from a metastatic prostate cancer), and WPMY—l cells (a non-malignant cell
line derived from normal prostate fibroblasts). The siRNA used had the following ce:
Forward: 5’ GCUUCAGGCCUGAAGAAUA 3’ (SEQ ID N023), and
Reverse: 5’ UAUUCUUCAGGCCUGAAGC 3’ (SEQ ID NO:4).
Knock down of TMEM92 in PC3 caused a significant ion in cell survival as
compared to a control siRNA (Figure 5), whilst TMEM92 knock down in WPMY-l cells
does not cause cell death.
These results indicate that TMEM92 could be a useful eutic target in cancer, for
example through (i) knock down of the TMEM92 gene by siRNA, as described above, (ii)
antibody g to TMEM92 protein to block its function and/or target cells for immune
mediated killing, and (iii) a small molecule antagonist of TMEM92 function.
In addition, the differential expression of TMEM92 indicates that it could be useful as a
biomarker for cancer.
TMEM92 has not previously been shown to be present on cancer cells. In on, the
ability to kill cancer cells by ng TMEM92 makes it a very important target.
Despite there being many diagnostic and therapeutic approaches to cancer, none are
perfect and many are of limited value. Diagnostic tests often give false positive or negative
results, and therapeutics may become ineffective due to innate or developed resistance of
cancer cells. The high expression of TMEM92 in cancer together with its role in cancer cell
survival (shown by knock down studies to be required for cancer cell survival) te that it
could make a useful contribution to both diagnostics and targeting.
The results obtained for TMEM92 were repeated for three other TMEMS. The
expression data obtained (Figure 6) for the three other TMEMs shows that these TMEMs are
expressed more highly in normal adult tissues than in , this being the exact te of
the results obtained for TMEM92. ingly, this provides further evidence of the
surprising nature of the results presented herein for TMEM92.
As shown in s 7 and 8, prostate cancer cells express high levels of TMEM92
protein, in contrast to WPMY-l, a non-malignant cell line derived from normal prostate
epithelial cells (Fig 7). TMEM92 is present in the nucleus, cytoplasm and membrane (Fig 8),
and is ed by cells into the culture medium. Furthermore, TMEM92 protein can be
detected in the urine of men with prostate cancer but is not present in aged matched controls,
ting that it could be used as a biomarker for this disease.
It should be understood that various changes and modifications to the presently
preferred embodiments described herein will be apparent to those skilled in the art. Such
changes and modifications can be made without departing from the spirit and scope of the
present invention and without shing its attendant advantages. It is therefore intended
that such changes and modifications are covered by the appended claims.
Claims (14)
1. Use of a therapeutically effective amount of a composition which inhibits the expression of the TMEM92 gene or which inhibits the function of the TMEM92 protein, in the cture of a ment for the treatment of cancer.
2. A use according to claim 1, wherein the composition comprises a nucleic acid sequence which is (i) complementary to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; and/or (ii) hybridizable to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1.
3. A use according to claim 1 or 2, wherein the composition comprises a nucleic acid molecule sing a nucleic acid sequence which is (i) complementary to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; and/or (ii) hybridizable to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1.
4. A use according to claim 3, wherein the nucleic acid molecule comprises double stranded RNA, optionally, n the nucleic acid molecule comprises small ering RNA (siRNA).
5. A use according to any preceding claim, wherein the ition comprises an antibody which is e of g to the TMEM92 protein.
6. A use according to claim 5, wherein the antibody is conjugated to a detectable marker and/or a growth inhibitory agent, optionally, wherein the antibody is conjugated to a cytotoxic agent, antibiotic, lytic enzyme or radioactive isotope.
7. A use according to any preceding claim, wherein the composition ses an antagonist of TMEM92 n function.
8 A use according to any preceding claim, wherein the cancer is selected from prostate cancer, non-small cell lung cancer and breast .
9. A method for diagnosing cancer in a patient or for identifying a patient at risk of developing cancer, the method sing: (a) determining an amount of a biomarker in a sample obtained from a patient, the biomarker comprising:- (i) a nucleic acid sequence comprising SEQ ID NO:1, or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1, or a nucleic acid molecule which ses said c acid sequence; or (ii) an amino acid sequence comprising SEQ ID NO:2, or a functional fragment/variant that has at least about 70% amino acid sequence identity with SEQ ID NO:2, or an amino acid molecule which comprises said amino acid sequence, optionally wherein the biomarker is a cancer biomarker selected from a prostate cancer biomarker, a non-small cell lung cancer biomarker and breast cancer biomarker. (b) comparing the amount of the determined biomarker in the sample from the patient to the amount of the ker in a normal control; wherein a difference in the amount of the biomarker in the sample from the patient compared to the amount of the biomarker in the normal control is associated with the presence of cancer, or is associated with a risk of developing cancer, optionally wherein the cancer is selected from prostate cancer, all cell lung cancer and breast .
10. A method for diagnosing cancer in a patient or for identifying a patient at risk of developing cancer, the method comprising: determining an amount of a biomarker in a sample obtained from a patient, wherein the presence of the biomarker is associated with the presence of cancer or is associated with a risk of ping cancer, optionally n the cancer is selected from prostate cancer, ll cell lung cancer and breast cancer, the biomarker comprising:- (i) a nucleic acid sequence comprising SEQ ID NO:1, or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1, or a nucleic acid molecule which comprises said c acid sequence; or (ii) an amino acid sequence comprising SEQ ID NO:2, or a functional fragment/variant that has at least about 70% amino acid sequence identity with SEQ ID NO:2, or an amino acid molecule which comprises said amino acid sequence, optionally wherein the biomarker is a cancer biomarker selected from a prostate cancer biomarker, a non-small cell lung cancer biomarker and breast cancer biomarker.
11. A method for monitoring the progression of cancer in a patient, the method sing: (a) determining an amount of a ker in a sample obtained from a patient, the biomarker comprising:- (i) a nucleic acid sequence sing SEQ ID NO:1, or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1, or a nucleic acid molecule which comprises said nucleic acid sequence; or (ii) an amino acid sequence comprising SEQ ID NO:2, or a functional fragment/variant that has at least about 70% amino acid sequence ty with SEQ ID NO:2, or an amino acid molecule which comprises said amino acid sequence, optionally wherein the biomarker is a cancer biomarker selected from a prostate cancer biomarker, a non-small cell lung cancer biomarker and breast cancer biomarker. (b) comparing the amount of the determined biomarker in the sample from the patient to the amount of the ker in a normal control; and (c) repeating steps (a) and (b) at two or more time intervals, wherein an increase in the amount of the biomarker from the patient over time is associated with an increase in the ssion of cancer and a decrease in the amount of the biomarker from the patient over time is associated with a decrease in the progression of cancer, optionally wherein the cancer is selected from prostate , non-small cell lung cancer and breast cancer.
12. A method for monitoring the efficacy of a treatment for cancer, comprising (a) detecting and/or fying the presence of a ker in a biological sample obtained from a patient after treatment has commenced, the biomarker comprising:- (i) a nucleic acid sequence sing SEQ ID NO:1, or a onal fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1, or a nucleic acid molecule which comprises said nucleic acid sequence; or (ii) an amino acid sequence comprising SEQ ID NO:2, or a functional fragment/variant that has at least about 70% amino acid sequence identity with SEQ ID NO:2, or an amino acid molecule which comprises said amino acid sequence, optionally n the biomarker is a cancer biomarker selected from a prostate cancer biomarker, a non-small cell lung cancer biomarker and breast cancer biomarker; and (b) comparing the amount of the determined biomarker in the sameple from the patient to the amount of the biomarker in a control sample taken from the patient prior to treatment;, optionally wherein the cancer is selected from prostate cancer, non-small cell lung cancer and breast cancer.
13. Use of a therapeutically effective amount of a biomarker in the cture of a medicament for the treatment of cancer, the biomarker comprising:- (i) a nucleic acid sequence comprising SEQ ID NO:1, or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1, or a nucleic acid le which comprises said c acid sequence; or (ii) an amino acid sequence comprising SEQ ID NO:2, or a functional fragment/variant that has at least about 70% amino acid sequence identity with SEQ ID NO:2, or an amino acid molecule which comprises said amino acid sequence, optionally wherein the ker is a cancer ker selected from a prostate cancer biomarker, a non-small cell lung cancer biomarker and breast cancer ker. optionally, wherein the cancer is selected from prostate cancer, non-small cell lung cancer and breast cancer.
14. Use of a composition comprising:- (A) a biomarker, the biomarker sing:- (i) a nucleic acid sequence sing SEQ ID NO:1, or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1, or a nucleic acid molecule which comprises said nucleic acid sequence; or (ii) an amino acid sequence comprising SEQ ID NO:2, or a functional fragment/variant that has at least about 70% amino acid sequence identity with SEQ ID NO:2, or an amino acid molecule which comprises said amino acid sequence, ally wherein the biomarker is a cancer biomarker ed from a prostate cancer biomarker, a non-small cell lung cancer biomarker and breast cancer biomarker; (B) a nucleic acid sequence which is (i) complementary to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid ce identity with SEQ ID NO:1; and/or (ii) hybridizable in stringent conditions to the nucleic acid sequence of SEQ ID NO:1 or a onal fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; (C) a nucleic acid molecule comprising a nucleic acid sequence which is (i) complementary to the c acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; and/or (ii) hybridizable in stringent ions to the c acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; (D) a host cell which contains a nucleic acid le comprising a nucleic acid sequence which is (i) complementary to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment t that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; and/or (ii) hybridizable in stringent conditions to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment t that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; (E) a vector, for example a DNA plasmid, comprising a nucleic acid sequence which is (i) complementary to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; and/or (ii) hybridizable in stringent conditions to the nucleic acid sequence of SEQ ID NO:1 or a functional fragment/variant that has at least about 70% nucleic acid sequence identity with SEQ ID NO:1; and/or (F) an antagonist of TMEM92 protein function, for example a small molecule antagonist; optionally wherein the ition is a pharmaceutical composition, in the manufacture of a medicament for therapy or diagnosis of cancer. ellular domain (aa 1-58)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GB1105129.9 | 2011-03-28 | ||
GBGB1105129.9A GB201105129D0 (en) | 2011-03-28 | 2011-03-28 | Compositions and methods for treating, diagnosing and monitoring disease |
PCT/GB2012/000285 WO2012131301A1 (en) | 2011-03-28 | 2012-03-28 | Compositions and methods for treating, diagnosing and monitoring disease |
Publications (2)
Publication Number | Publication Date |
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NZ615915A NZ615915A (en) | 2015-08-28 |
NZ615915B2 true NZ615915B2 (en) | 2015-12-01 |
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