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US 2019/0338037 A1Published application
Method of treating bone metastasis diseases, medicaments therefore, and a method of predicting the clinical outcome of treating bone metastasis diseases
AssigneeMerck Patent GmbH
InventorsJOSEF STRAUB, EIKE STAUB
Life of this patent
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Abstract
A method is used for treating bone metastasis diseases in subjects. The method preferably depends on whether the subject shows certain specific proteins levels in one or more body fluids prior to or during treatment. The treatment includes the administration of at least one pan αv integrin inhibitor to a subject, a medicament for use in said new methods, and a method of predicting the outcome of a treatment with at least one pan αv integrin inhibitor based on the specific protein levels in one or more body fluids of the subject.
Claims28
1:
- A method of treating a bone metastasis disease in a subject, wherein said subject is characterized by:
- a) a high level of one or more proteins in at least one body fluid of said subject, wherein said one or more proteins are selected from the group consisting of:
- DCN (UniProt ID:
- P07585),
- F5 (UniProt ID:
- P12259),
- ICAM3 (UniProt ID:
- P32942),
- PIGR (UniProt ID:
- P01833),
- STK17B (UniProt ID:
- 094768),
- STX1A (UniProt ID:
- Q16623), and
- TEK (UniProt ID:
- Q02763),
- and/or
- b) a low level of one or more proteins in at least one body fluid of said subject, wherein said one or more proteins are selected from the group consisting of:
- ANG (UniProt ID:
- P03950),
- IL1B (UniProt ID:
- P01584),
- LEPR (UniProt ID:
- P48357),
- MAP2K2 (UniProt ID:
- P36507),
- MAPK11 (UniProt ID:
- Q15759),
- RGMB (UniProt ID:
- Q6NW40), and
- TNFRSF17 (UniProt ID:
- Q02223);
- said method comprising:
- administering to said subject at least one pan αv integrin inhibitor.
31 more elements
2:
- The method according to claim 1, wherein said at least one pan αv integrin inhibitor comprises Abituzumab and/or Intetumumab.
3:
- The method according to claim 1, wherein said at least one pan αv integrin inhibitor is Abituzumab and/or Intetumumab.
4:
- The method according to claim 1, wherein the level of said specific protein in at least one body fluid of said subject is
- a) classified as high, if the respective specific protein level in said blood plasma is at least 2% higher than the median threshold determined for the respective specific protein,
- and/or
- b) classified as low, if the respective specific protein level in said blood plasma is at least 2% lower than said median threshold for the respective specific protein.
1 more element
5:
- The method according to claim 1, wherein said median thresholds are determined in a subject population having bone metastasis disease.
6:
- The method according to claim 1, wherein said subject is characterized by a high level of the protein
- STX1A (UniProt ID:
- Q16623)
- and/or a protein having at least 80% sequence homology to said protein.
1 more element
7:
- The method according to claim 1, wherein said subject is characterized by the respective levels of one or more proteins having at least 80% sequence homology to said one or more proteins.
8:
- The method according to claim 1, wherein said body fluid is selected from the group consisting of blood plasma, blood serum and whole blood.
9:
- The method according to claim 1, wherein said high levels and/or low levels of one or more of said proteins are present and/or determined prior to administering said at least one pan αv integrin inhibitor.
10:
- The method according to claim 1, wherein said high levels and/or low levels of one or more of said proteins are present and/or determined during or after administering said at least one pan αv integrin inhibitor.
11:
- The method according to claim 1, wherein the bone metastasis disease is cancer or is derived from cancer.
12:
- The method according to claim 1, wherein the bone metastasis disease is derived from prostate cancer, breast cancer and/or lung cancer.
13:
- The method according to claim 1, wherein said threshold or median threshold for the respective specific protein is determined from the body fluid of a plurality of subjects being part of a diseased subject population suffering from the respective bone metastasis disease.
14:
- The method according to claim 1, wherein said at least one pan αv integrin inhibitor is administered to said subject in an amount of 100 mg to 3000 mg per month.
15:
- The method according to claim 1, wherein said at least one pan αv integrin inhibitor comprises or is Abituzumab, and wherein the Abituzumab is administered to said subject in an amount of 500 to 2000 mg every week, every second week every or every fourth week.
16:
- The method according to claim 1, wherein said at least one pan αv integrin inhibitor comprises or is Abituzumab, and wherein the Abituzumab is administered to said subject in an amount of about 500 mg per week, about 750 mg per week, about 1000 mg per week or about 1500 mg per week.
17:
- The method according to claim 1, wherein said at least one pan αv integrin inhibitor is administered in combination with one or more agents or chemotherapeutic agents,
- a) selected from the group consisting of Leuproreline, Leuproreline acetate, bicalutamide, nilutamide, triptoreline, gosereline, flutamide, cyproterone, busereline and degarelix,
- b) selected from the group consisting of Zoledronic acid, Pamidronic acid, Clodronate disodium, Alendronic acid and Ibandronic acid, and/or
- c) selected from the group consisting of Abiraterone, Abiraterone acetate, Prednisone, Enzalutamide, Radium Ra 223 dichloride, Docetaxel, Sipuleucel-T, Cabazitaxel and Mitoxantrone;
- and/or the pharmaceutically acceptable derivatives and/or salts thereof.
2 more elements
18:
- The method according to claim 1, wherein said at least one pan αv integrin inhibitor is administered in combination with, or additionally in combination with, one or more chemotherapeutic agents, selected from the group consisting of cetuximab, Panitumumab, irinotecan, vinorelbine, capecitabine, leucovorine, oxaliplatin, cisplatin, carboplatin, 5-fluorouracil (5-FU), bevacizumab, aflibercept and regorafenib.
19:
- The method according to claim 1, wherein said at least one pan αv integrin inhibitor is administered in combination with one or more agents or chemotherapeutic agents, selected from the group consisting of
- a) Leuproreline, Leuproreline acetate, bicalutamid, nilutamide, triptoreline, gosereline, flutamide, cyproterone, busereline and degarelix, and/or the pharmaceutically acceptable derivatives and/or salts thereof;
- and/or
- b) Zoledronic acid, Pamidronic acid, Clodronate disodium, Alendronic acid and Ibandronic acid,
- and/or the pharmaceutically acceptable derivatives and/or salts thereof.
2 more elements
20:
- A method to identify a tumor in a subject likely to benefit from treatment with at least one pan αv integrin inhibitor, said method comprising:
- i) determining the levels of one or more proteins, selected from the group consisting of DCN (UniProt ID:
- P07585), F5 (UniProt ID:
- P12259), ICAM3 (UniProt ID:
- P32942), PIGR (UniProt ID:
- P01833), STK17B (UniProt ID:
- 094768), STX1A (UniProt ID:
- Q16623), TEK (UniProt ID:
- Q02763), ANG (UniProt ID:
- P03950), IL1B (UniProt ID:
- P01584), LEPR (UniProt ID:
- P48357), MAP2K2 (UniProt ID:
- P36507), MAPK11 (UniProt ID:
- Q15759), RGMB (UniProt ID:
- Q6NW40), and/or TNFRSF17 (UniProt ID:
- Q02223) in at least one body fluid of said subject, wherein
- a) a high level one or more proteins selected from the group consisting of:
- DCN (UniProt ID:
- P07585),
- F5 (UniProt ID:
- P12259),
- ICAM3 (UniProt ID:
- P32942),
- PIGR (UniProt ID:
- P01833),
- STK17B (UniProt ID:
- 094768),
- STX1A (UniProt ID:
- Q16623), and
- TEK (UniProt ID:
- Q02763),
- and/or
- b) low levels of one or more proteins in at least one body fluid of said subject, wherein said one or more proteins are selected from the group consisting of:
- ANG (UniProt ID:
- P03950),
- IL1B (UniProt ID:
- P01584),
- LEPR (UniProt ID:
- P48357),
- MAP2K2 (UniProt ID:
- P36507),
- MAPK11 (UniProt ID:
- Q15759),
- RGMB (UniProt ID:
- Q6NW40), and
- TNFRSF17 (UniProt ID:
- Q02223);
- identify a tumor likely to benefit from the treatment with at least one pan αv integrin inhibitor.
45 more elements
21:
- A method to identify a tumor in a subject likely to benefit from treatment with at least one pan αv integrin inhibitor, said method comprising:
- determining the level of the protein STX1A (UniProt ID:
- Q16623) and/or a protein having at least 80% sequence homology to STX1A, in one or more body fluids of said subject, wherein a high level thereof identifies a tumor likely to benefit from the treatment with at least one pan αv integrin inhibitor.
22:
- The method according to claim 20, wherein the level of protein in said one or more body fluids is
- a) classified as high, if the respective protein level in said one or more body fluid is at least 2% higher than the median threshold determined for the respective protein,
- and/or
- b) classified as low, if the respective protein level in said blood one or more body fluids is at least 2% lower than said median threshold for the respective protein.
1 more element
23:
- The method according to claim 20, wherein the one or more body fluids comprise a blood plasma or consist of blood plasma.
24:
- The method according to claim 1, wherein the at least one pan αv integrin inhibitor comprises Abituzumab or is Abituzumab.
25:
- A method to identify a subject responsive to treatment with at least one pan αv integrin inhibitor, comprising:
- i) determining the levels of one or more proteins, selected from the group consisting of DCN (UniProt ID:
- P07585), F5 (UniProt ID:
- P12259), ICAM3 (UniProt ID:
- P32942), PIGR (UniProt ID:
- P01833), STK17B (UniProt ID:
- 094768), STX1A (UniProt ID:
- Q16623), TEK (UniProt ID:
- Q02763), ANG (UniProt ID:
- P03950), IL1B (UniProt ID:
- P01584), LEPR (UniProt ID:
- P48357), MAP2K2 (UniProt ID:
- P36507), MAPK11 (UniProt ID:
- Q15759), RGMB (UniProt ID:
- Q6NW40), and/or TNFRSF17 (UniProt ID:
- Q02223)
- in at least one body fluid of said subject, wherein
- a) a high level one or more proteins selected from the group consisting of:
- DCN (UniProt ID:
- P07585),
- F5 (UniProt ID:
- P12259),
- ICAM3 (UniProt ID:
- P32942),
- PIGR (UniProt ID:
- P01833),
- STK17B (UniProt ID:
- 094768),
- STX1A (UniProt ID:
- Q16623), and
- TEK (UniProt ID:
- Q02763),
- and/or
- b) low levels of one ore more proteins in at last one body fluid of said subject, wherein said one or more proteins are selected from the group consisting of:
- ANG (UniProt ID:
- P03950),
- IL1B (UniProt ID:
- P01584),
- LEPR (UniProt ID:
- P48357),
- MAP2K2 (UniProt ID:
- P36507),
- MAPK11 (UniProt ID:
- Q15759),
- RGMB (UniProt ID:
- Q6NW40), and
- TNFRSF17 (UniProt ID:
- Q02223);
- identify a subject responsive to treatment with at least one pan αv integrin inhibitor.
46 more elements
26:
- Pan αv integrin inhibitor for use in the treatment of bone metastases in a subject, wherein said bone metastases are characterized by:
- a) high levels of one or more proteins in at least one body fluid of said subject, wherein said one or more proteins are selected from the group consisting of:
- DCN (UniProt ID:
- P07585),
- F5 (UniProt ID:
- P12259),
- ICAM3 (UniProt ID:
- P32942),
- PIGR (UniProt ID:
- P01833),
- STK17B (UniProt ID:
- 094768),
- STX1A (UniProt ID:
- Q16623), and
- TEK (UniProt ID:
- Q02763),
- and/or
- b) low levels of one or more proteins in at last one body fluid of said subject, wherein said one or more proteins are selected from the group consisting of:
- ANG (UniProt ID:
- P03950),
- IL1B (UniProt ID:
- P01584),
- LEPR (UniProt ID:
- P48357),
- MAP2K2 (UniProt ID:
- P36507),
- MAPK11 (UniProt ID:
- Q15759),
- RGMB (UniProt ID:
- Q6NW40), and
- TNFRSF17 (UniProt ID:
- Q02223).
29 more elements
27:
- Pan αv integrin inhibitor for use in the treatment of bone metastases in a subject, wherein said bone metastases are characterized by a high level of the protein STX1A (UniProt ID:
- Q16623), and/or a protein having at least 80% sequence homology to said protein.
28:
- Pan αv integrin inhibitor for use according to claim 26, wherein
- a) said median thresholds are determined in a subject population having bone metastases,
- b) the at least one Pan αv integrin inhibitor comprises Abituzumab and/or Intetumumab,
- c) the subject is a human subject,
- and/or
- d) the bone metastases are bone metastases from castrate-resisting prostate cancer.
3 more elements