WO2015084808A4 - Identification of predictive biomarkers associated with wnt pathway inhibitors - Google Patents

Identification of predictive biomarkers associated with wnt pathway inhibitors Download PDF

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Publication number
WO2015084808A4
WO2015084808A4 PCT/US2014/068097 US2014068097W WO2015084808A4 WO 2015084808 A4 WO2015084808 A4 WO 2015084808A4 US 2014068097 W US2014068097 W US 2014068097W WO 2015084808 A4 WO2015084808 A4 WO 2015084808A4
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Prior art keywords
seq
heavy chain
light chain
antibody
pathway inhibitor
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PCT/US2014/068097
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French (fr)
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WO2015084808A1 (en
Inventor
Ann M. Kapoun
Chun Zhang
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Oncomed Pharmaceuticals, Inc.
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Application filed by Oncomed Pharmaceuticals, Inc. filed Critical Oncomed Pharmaceuticals, Inc.
Priority to EP14867583.8A priority Critical patent/EP3077546A4/en
Priority to CN201480065718.7A priority patent/CN105829547A/en
Priority to CA2931975A priority patent/CA2931975A1/en
Priority to JP2016535646A priority patent/JP2017501137A/en
Priority to US15/101,242 priority patent/US20160304968A1/en
Priority to AU2014357354A priority patent/AU2014357354A1/en
Priority to MX2016007066A priority patent/MX2016007066A/en
Publication of WO2015084808A1 publication Critical patent/WO2015084808A1/en
Publication of WO2015084808A4 publication Critical patent/WO2015084808A4/en
Priority to HK16111927.7A priority patent/HK1223657A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

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  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

The present invention provides biomarkers for identifying tumors likely to respond to treatment with Wnt pathway inhibitors. Also provided are methods for identifying tumors and/or patients that are likely to be responsive or non-responsive to treatment with a Wnt pathway inhibitor. Methods for treating a patient with cancer are provided, wherein the cancer is predicted to respond to a Wnt pathway inhibitor.

Claims

AMENDED CLAIMS received by the International Bureau on 29 June 2015 (29.06.2015)What is claimed is:
1. A method of treating breast cancer in a patient, comprising:
(a) identifying if the patient is likely to respond to treatment with a Wnt pathway inhibitor, wherein the Wnt pathway inhibitor is an antibody that specifically binds human FZDl, FZD2, FZD5, FZD7. and FZD8, comprising a heavy chain CDRl comprising GFTFSHYTLS (SEQ ID NO: 1), a heavy chain CDR2 comprising
VISGDGSYTYYADSVKG (SEQ ID NO:2). a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO: 3). a light chain CDR l comprising SG^IGSFYVH (SEQ ID NO:4 ). a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSI . (SEQ ID NO:6):
wherein the identification comprises:
(i) obtaining a sample of the patient's breast cancer;
(ii) measuring the expression level of each biomarker of a biomarker signature in the sample, wherein the signature comprises the biomarkers FBXW2, CCND2. RMOU, CTBP2. Wl F l , and DKK I ; and
(iii) identi lying the patient who is likely to respond to treatment based upon the expression level of the biomarkers: and
(b) administering an effective amount of the; Wrrt pathway inhibitor to the patient who is likely to response to treatment.
2. A method of identifying a human breast tumor that is likely to be responsive or non- responsive to treatment with a Wnt pathway inhibitor, wherein the Wnt pathway inhibitor is an antibody that specifically binds human FZD 1 , FZD2. FZD5, FZD7, and FZD8, comprising a heavy Chain CDR l comprising GFTFSHYTLS (SEQ ID NO: 1 ), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), a light chain CDR 1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO: 5). and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6);
wherein the method comprises:
(a) obtaining a sample of the breast tumor;
(b) measuring the expression level of each biomarker of a biomarker signature in the sample, wherein the signature comprises the biomarkers FBXW2. CCND2. RI IOU, CTBP2, WIF1 , and DKK I ; and
(c) identifying the tumor as likely to be responsive or non-responsive to treatment based upon I he expression level of the biomarkers.
3. A method of classifying a human breast tumor as likely to be responsive or non-responsive to treatment with a Writ pathway inhibitor, wherein the Wnt pathway inhibitor is an antibody that specifically binds human FZD1, FZD2, FZD5, FZD7, and FZD8, comprising a heavy chain CDR1 comprising GFTFSHYTLS (SEQ ID NO: l), a heavy chain CDR2 comprising VISGDGSYTYYADSVKG (SEQ ID NO:2), a heavy chain CDR3 comprising NITKYVI AN (SEQ ID NO:3), a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO: 5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6)
wherein the method comprises:
(a) obtaining a sample of the breast tumor;
(b) measuring the expression level of each biomarker of a biomarker signature in the sample, wherein the signature comprises the biomarkers FBXW2, CCND2, RHOU, (TBP2, W.. l , and DKK l : and
(c) classifying the tumor as likely to be responsive or non-responsive to treatment based upon the expression of the biomarkers.
4. A method of determining the responsiveness of a human breast tumor to treatment with a Wnt pathway inhibitor, wherein the Wnt pathway inhibitor is an antibody that specifically binds human 1 ZD 1 , FZD2, FZD5. FZD7, and FZD8. comprising a heavy chain CDR 1 comprising GFTFSHYTLS (SEQ ID NO: I ). a heavy chain CDR2 comprising
VISGDGSYTYYADSVKG (SEQ ID NO:2), a heavy chain CDR3 comprising N1TKYVFAN (SEQ ID NO :3), a light chain CDR1 comprising SGDNIGSFYVH (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6): ;
wherein the method comprises:
(a) obtaining a sample of the breast tumor;
(b) measuring the expression lev el of each biomarker of a biomarker signature in the sample, wherein the signature comprises the biomarkers FBXW2, CCND2, RHOU, CTBP2, WIF 1 , and DKK I ; and
(e) determining the responsiveness of the tumor to treatment based upon the expression of the biomarkers.
5. A method of identifying a patient with breast cancer who is likely to respond to treatment with a Wnt pathway inhibitor, wherein the Wnt pathway inhibitor is an antibody that specifically binds human FZD 1 , FZD2, FZD5, FZD7, and FZD8, comprising a heavy chain CDR1 comprising GFTFSHYTLS (SEQ TD NO: 1 ), a heavy chain CDR2 comprising
VISGDGSYTY YADSVKG (SEQ ID NO:2), a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO:3), a light chain CDR 1 comprising SGDNIGSFYVH. (SEQ ID NO: 4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6);
wherein the method comprises:
(a) obtaining a sample of the patient ' s breast tumor;
(b) measuring the expression level of each biomarker of a biomarker signature in the sample, wherein the signature comprises the biomarkers I BXW2, CCN D2, RHOU, CTBP2. WIF 1 , and DKKl ; and
(c) identifying the patient who is likely to respond to treatment based upon the
expression level of the biomarkers .
6. A method of selecting a patient with breast cancer for treatment with a Wnt pathway
inhibitor, wherein the Wnt pathway inhibitor is an antibody that Specifically binds human FZD 1. I ZD2, FZD5, FZD7. and FZD8, comprising a heavy chain CDR 1 comprising GITFSHYTLS (SEQ ID NO: 1 ). a heavy chain CDR2 comprising
VISGDGSYTY VADSVKG (SEQ ID NO:2). a heavy chain CDR3 comprising NFIKYVFAN (SEQ ID NO: 3), a light chain CDR1 comprising SGDNIGSFY VI I (SEQ ID NO:4), a light chain CDR2 comprising DKSNRPSG (SEQ ID NO:5 ), and a light chain CDR3 comprising QSYANTLSL (SEQ ID NO:6);
wherein the method comprises:
(a) obtain ing a samp le of the patient' s breast
(b) measuring the expression level of each biomarker of a biomarker signature in the sample, wherein the biomarker signature comprises the biomarkers F BXW2.
CCND2, RH OU, CTBP2, Wil l , and DKK l : and
(c) selecting the patient for treatment based upon the expression level of the biomarkers.
7. The method of any one of claims 1 -6. wherein the expression of each biomarker is measured by a PCR-based assay, a qPCR assay, a microarray, or RNA sequencing.
8. The method of any one of claims 1 -6, wherein the expression levels of FBXW2, CCND2, RHOU, CTBP2, WIF1 , and DKK l are measured using polynucleotides selected from the group consisting of SEQ I D NOs:62-79.
9. The method of claim 8, wherein the expression levels of FBXW2, CCND2, RH OU, CTBP2, WIF 1 , and DKKl are measured using:
(a) a forwrid primer of SEQ ID NO:62, a reverse primer of SEQ ID NO:63, and a probe comprisin g SEQ ID NO:64; (b) a forward primer of SEQ ID NO:65, a reverse primer of SEQ ID NO:66, and a probe comprising SEQ ID NO:67;
(c) a forward primer of SEQ ID NO:68, a reverse primer of SEQ ID NO:69, and a probe comprising SEQ ID NO: 70;
(d) a forward primer Of SEQ ID NO:71, a reverse primer of SEQ ID NO: 72. and a probe comprising SEQ ID NO:73;
(e) a forward primer of SEQ ID NO:74, a reverse primer of SEQ ID NO:75, and a probe comprising SEQ ID NO: 76; and
(f) a forward primer of SEQ ID NO:77, a reverse primer of SEQ ID NO: 78. and a probe comprising SEQ I D NO: 79.
10. The method of any one of claims 1-9, wherein the Wnt pathway inhibitor is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 7 and a light chain variable region comprising Sf'Q ID NO:8.
1 1. The method of any one of claims 1-9. wherein the W nt pathway inhibitor is an antibody comprising a heavy chain variable region ai d a light chain variable region encoded by the plasmid deposited w ith ATCC as ΡΤA-9541 .
12. The method of any one of claims 1 - 1 1 , wherein the antibody is a monoclonal antibody, a recombinant antibody, a chimeric antibody, a bispeeifie antibodv , a humanized antibody, a human antibody, or an antibody fragment comprising an antigen-binding site.
13. The method of any one of claims 1 -9. wherein the Wnt pathway inhibitor is antibody OMP- 1 8R5.
14. The raethod Of any one of claims 1-13, wherein the breast tumor or breast cancer is a HHR2 negative breast tumor.
15. The method of any one Of claims 1 - 13, wherein the breast tumor or breast cancer is a triple negative breast cancer (TNBC) tumor.
16. The method of any one of claims 1 -15, wherein the treatment with the Wnt pathway inhibitor is in combination with one or more additional therapeutic agents.
17. The method of claim 16, wherein the additional therapeutic agent is a chemotherapeutic agen t
18. The method of claim 16, wherein the additional therapeutic agent is paclitaxel.
19. The method of claim 16, wherein the additional therapeutic agent is nab-bound paclitaxel
(ABRAXANE).
20. The method of any one of claims 1-19, wherein the sample is a tissue sample or a tumor biopsy.
21. The method of arty one of claims 1 -20, wherein: the sample is a formal in-fixed paraffin
embedded: (FFPE) sample .
22. A kit for detecting FBXW2, CCND2, RHOU, CTBP2. WIFl, and DKKl in a breast tumor or breast cancer sample, wherein the kit comprises polynucleotides selected from the group consisting of SEQ ID NOs:62-79.
The kit of claim 22, which comprises:
(a) a forward piSmer of SEQ ID NO: 62, a reverse primer of SEQ ID NO:63. and a probe comprising SEQ ID NO:64:
(b) a forward primer of SEQ ID \0:65, a reverse primer of SF.Q ID NO:66, and a probe comprising SEQ ID NO:67:
(c) a forward primer of SEQ ID NO: 68, a reverse primer of SEQ ID NO: 69. and a probe comprising SEQ ID NO:70;
(d) a forward primer of SF.Q ID NO: 71 , a reverse primer of SEQ ID NO: 72. and a probe comprising SEQ ID NO:73;
(e) a forward primer of SEQ ID NO: 74, a reverse primer of SFQ ID NO:75. and a probe comprising SEQ: ID NO:76; and
(f) a forward primer of SEQ ID NO:77, a reverse primer of SEQ ID NO:78. and a probe comprising SEQ ID NO:79.
PCT/US2014/068097 2013-12-02 2014-12-02 Identification of predictive biomarkers associated with wnt pathway inhibitors WO2015084808A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP14867583.8A EP3077546A4 (en) 2013-12-02 2014-12-02 Identification of predictive biomarkers associated with wnt pathway inhibitors
CN201480065718.7A CN105829547A (en) 2013-12-02 2014-12-02 Identification of predictive biomarkers associated with Wnt pathway inhibitors
CA2931975A CA2931975A1 (en) 2013-12-02 2014-12-02 Identification of predictive biomarkers associated with wnt pathway inhibitors
JP2016535646A JP2017501137A (en) 2013-12-02 2014-12-02 Identification of predictive biomarkers associated with WNT pathway inhibitors
US15/101,242 US20160304968A1 (en) 2013-12-02 2014-12-02 Identification of Predictive Biomarkers Associated With WNT Pathway Inhibitors
AU2014357354A AU2014357354A1 (en) 2013-12-02 2014-12-02 Identification of predictive biomarkers associated with Wnt pathway inhibitors
MX2016007066A MX2016007066A (en) 2013-12-02 2014-12-02 Identification of predictive biomarkers associated with wnt pathway inhibitors.
HK16111927.7A HK1223657A1 (en) 2013-12-02 2016-10-17 Identification of predictive biomarkers associated with wnt pathway inhibitors wnt

Applications Claiming Priority (4)

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US201361910663P 2013-12-02 2013-12-02
US61/910,663 2013-12-02
US201461975339P 2014-04-04 2014-04-04
US61/975,339 2014-04-04

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WO2015084808A4 true WO2015084808A4 (en) 2015-08-13

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AU (1) AU2014357354A1 (en)
CA (1) CA2931975A1 (en)
HK (1) HK1223657A1 (en)
MX (1) MX2016007066A (en)
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EP3077546A4 (en) 2017-04-26
HK1223657A1 (en) 2017-08-04
WO2015084808A1 (en) 2015-06-11
MX2016007066A (en) 2016-09-08
AU2014357354A1 (en) 2016-06-09
CA2931975A1 (en) 2015-06-11
JP2017501137A (en) 2017-01-12
EP3077546A1 (en) 2016-10-12
TW201610168A (en) 2016-03-16

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