Patent application EP16164235A (EP), filed 2016-04-07
Publication number: EP3228630A1
Title: COMBINATION OF AN APELIN ANTAGONIST AND AN ANGIOGENESIS INHIBITOR FOR THE TREATMENT OF CANCER
Abstract: The field of the present invention is the field of anti-angiogenic cancer therapy. Efforts are needed to reduce or overcome resistance of cancer to anti-angiogenic therapies, such as therapies based on the receptor tyrosine kinase (RTK) inhibitor sunitinib. It is hence an object of the present invention to provide an agent that can be combined with an anti-angiogenic therapy in order to reduce or overcome resistance to the anti-angiogenic therapy. The present invention thus relates to a pharmaceutical composition or set comprising an apelin antagonist and/or apelin receptor antagonist, and an angiogenesis inhibitor. The angiogenesis inhibitor is an RTK inhibitor, preferably sunitinib. The apelin antagonist can be an anti-apelin antibody. The apelin receptor antagonist can be an apelin peptide analogue or an anti-apelin-receptor antibody. Furthermore, methods of cancer treatment, especially breast or lung cancer treatment, based on an apelin antagonist and/or apelin receptor antagonist, and an angiogenesis inhibitor are disclosed.
IPC codes: A61K  38/    17            A I
A61K  39/    00            A I
C07K  14/   515            A I
C07K  16/    28            A I
Claims: number: 1
text: A pharmaceutical composition comprising an apelin antagonist and/or an apelin receptor antagonist, and further comprising an angiogenesis inhibitor, wherein the angiogenesis inhibitor is selected from the group of receptor tyrosine kinase (RTK) inhibitors.
number: 2
text: A set comprising a first pharmaceutical composition, comprising an apelin antagonist and/or an apelin receptor antagonist, and a second pharmaceutical composition, comprising an angiogenesis inhibitor, wherein the angiogenesis inhibitor is selected from the group of RTK inhibitors.
number: 3
text: The composition or set according to claim 1 or 2, wherein the angiogenesis inhibitor is selected from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib.
number: 4
text: The composition or set according to claim 3, wherein the angiogenesis inhibitor is sunitinib.
number: 5
text: The composition or set according to any one of claims 1 to 4, wherein the apelin antagonist is selected from the group of anti-apelin antibodies, and/or
wherein the apelin receptor antagonist is selected from apelin analogues, preferably a peptide with the sequence QRPRLSHKGPMPA (SEQ ID NO: 14) or N-α-acetyl-nona-D-arginine amide (SEQ ID NO: 22) or cyclo(1-6)CRPRLC-KH-cyclo(9-14)CRPRLC (SEQ ID NO: 23), and anti-apelin-receptor antibodies.
number: 6
text: An apelin antagonist and/or apelin receptor antagonist for use in the prevention or treatment of cancer in a patient, wherein the apelin antagonist and/or apelin receptor antagonist is administered to the patient, and
wherein an angiogenesis inhibitor, preferably selected from the group of RTK inhibitors, is administered to the patient, in a composition together with the apelin antagonist and/or apelin receptor antagonist, in combination with the apelin antagonist and/or apelin receptor antagonist, before the apelin antagonist and/or apelin receptor antagonist is administered, or after the apelin antagonist and/or apelin receptor antagonist has been administered;
preferably wherein the angiogenesis inhibitor is selected from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib; especially sunitinib.
number: 7
text: An apelin antagonist and/or apelin receptor antagonist for use in the treatment of a cancer patient who has resistance or is at risk of developing resistance to anti-angiogenic therapy, preferably anti-angiogenic therapy with an angiogenesis inhibitor selected from the group of RTK inhibitors;
preferably wherein the angiogenesis inhibitor is selected from the group of sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, regorafenib, vandetanib, tivozanib, cediranib, nintedanib and vatalanib.
number: 8
text: The apelin antagonist and/or apelin receptor antagonist for use according to claim 6 or 7, wherein the angiogenesis inhibitor is sunitinib.
number: 9
text: The apelin antagonist and/or apelin receptor antagonist for use according to any one of claims 6 to 8, wherein the cancer is selected from breast cancer and lung cancer.
number: 10
text: The apelin antagonist and/or apelin receptor antagonist for use according to any one of claims 6 to 9, wherein the cancer is HER-2-positive, estrogen-receptor-positive, p53-negative, KRaspositive or combinations thereof.
number: 11
text: The apelin antagonist and/or apelin receptor antagonist for use according to any one of claims 6 to 10, wherein the cancer over-expresses epithelial-mesenchymal transition (EMT) markers, preferably selected from the group of Snail, fibronectin, and TGF-beta, and/or
wherein the cancer over-expresses invasiveness-related genes, preferably selected from the group of Met, IL1b, COL1A1 and COL1A2 and/or
wherein the cancer over-expresses apelin and/or apelin receptor.
number: 12
text: The apelin antagonist and/or apelin receptor antagonist for use according to any one of claims 6 to 11, wherein a further chemotherapeutic agent, and/or radiotherapy for the latter three of the following cases, is administered to the patient, in a composition together with the apelin antagonist and/or apelin receptor antagonist, in combination with the apelin antagonist and/or apelin receptor antagonist, before the apelin antagonist and/or apelin receptor antagonist is administered, or after the apelin antagonist and/or apelin receptor antagonist has been administered,
wherein the further chemotherapeutic agent is selected from the group of alkylating agents, platin-based chemotherapeutic agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic antibiotics,
preferably wherein the further chemotherapeutic agent is selected from the group of 5-fluorouracil, cisplatin, carboplatin, cyclophosphamide, doxorubicin, epirubicin, gemcitabine, taxanes such as paclitaxel or docetaxel, methotrexate, pemetrexed, vinorelbine and etoposide, in particular etoposide.
number: 13
text: The apelin antagonist and/or apelin receptor antagonist for use according to any one of claims 6 to 12, wherein a Src tyrosine kinase inhibitor is also administered to the patient, in a composition together with the apelin antagonist and/or apelin receptor antagonist, in combination with the apelin antagonist and/or apelin receptor antagonist, before the apelin antagonist and/or apelin receptor antagonist is administered or after the apelin antagonist and/or apelin receptor antagonist has been administered,
preferably wherein the Src tyrosine kinase inhibitor is selected from bosutinib, dasatinib, ponatinib, vandetanib, saracatinib and AZD0424, especially dasatinib.
number: 14
text: The apelin antagonist and/or apelin receptor antagonist for use according to any one of claims 6 to 13, wherein the patient has an apelin level, preferably a plasma or serum apelin level, higher than a control, and/or the cancer has an apelin or apelin receptor level higher than a control;
preferably wherein the apelin level is measured after the patient has undergone cancer treatment with an angiogenesis inhibitor, preferably selected from the group of RTK inhibitors, especially sunitinib.
number: 15
text: The apelin antagonist and/or apelin receptor antagonist for use according to any one of claims 6 to 14, for tumour blood vessel normalisation.
Office action: search_report, dated 2017-10-11
Rejection reasons: novelty_epc_54
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severity: novelty_destroying
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severity: background
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severity: background
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severity: background
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severity: background
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severity: background
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ref_type: npl
severity: background
Final disposition: pending (2017-10-11)