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WO2020138486A1 - Traitement par double inhibition de la voie du vegf-a/vegfr2 et composition pharmaceutique associée - Google Patents

Traitement par double inhibition de la voie du vegf-a/vegfr2 et composition pharmaceutique associée Download PDF

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Publication number
WO2020138486A1
WO2020138486A1 PCT/JP2019/051593 JP2019051593W WO2020138486A1 WO 2020138486 A1 WO2020138486 A1 WO 2020138486A1 JP 2019051593 W JP2019051593 W JP 2019051593W WO 2020138486 A1 WO2020138486 A1 WO 2020138486A1
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Prior art keywords
vegf
antibody
drug
vegfr2
antibody drug
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PCT/JP2019/051593
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Japanese (ja)
Inventor
哲夫 馬島
尊 若槻
啓之 清宮
研成 山口
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Japanese Foundation for Cancer Research
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Japanese Foundation for Cancer Research
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • 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

Definitions

  • the present invention combines anti-VEGFR2 (vascular endothermic factor receptor 2 and vascular endothelial growth factor receptor 2) antibodies with anti-VEGF-A (vascular endothel growth factor-A) neutralizing antibody treatment method.
  • anti-VEGFR2 vascular endothermic factor receptor 2 and vascular endothelial growth factor receptor 2
  • anti-VEGF-A vascular endothel growth factor-A neutralizing antibody treatment method.
  • VEGF Vascular endothelial growth factor
  • VEGFR Vascular endothelial growth factor
  • VEGFR which is a VEGF receptor
  • VEGFR2 is a type of receptor tyrosine kinase, and there are three types of proteins, VEGFR1 to VEGFR3.
  • VEGFR2 has a weaker binding ability to a ligand than VEGFR1, but has a strong tyrosine kinase activity, and has a large contribution to intracellular signal transduction as a whole, and is considered to be greatly involved in the process of angiogenesis.
  • VEGFR2 is capable of binding to VEGF-A, C, D and E and is one of the three VEGFRs that is said to be most closely associated with tumor angiogenesis induced by VEGF. ..
  • Ramucirumab specifically binds to VEGFR2, thereby inhibiting the binding with the ligands VEGF-A, VEGF-C, and VEGF-D, and inhibiting the activation of VEGFR2 and its downstream signal transduction system. As a result, it inhibits the proliferation and migration of vascular endothelial cells, inhibits the formation of tumor blood vessels, and exerts an antitumor effect.
  • ramucirumab is used as a second-line treatment for advanced gastric cancer.
  • Systemic chemotherapy has been performed for patients with unresectable advanced gastric cancer, but the prognosis is unsatisfactory, with an average of around one year.
  • Ramucirumab was found to have significantly prolonged overall survival in the second-line treatment of advanced gastric cancer, was approved for gastric cancer in Japan in June 2015, and has been widely used for colon cancer and lung cancer since then.
  • Ramucirumab a human anti-VEGFR2 antibody
  • Ramucirumab showed a significant prolongation of overall survival in combination with paclitaxel in the RAINBOW trial, which is a global phase III trial targeting second-line treatment of gastric cancer, and has become the standard treatment.
  • MOS median overall survival, median overall survival: 9.6 months vs 7.4 months
  • Non-Patent Document 1 Non-Patent Document 1
  • its therapeutic effect was not sufficient, and a subset analysis of Japanese in the previous RAINBOW trial showed that the response rate of the combination therapy with ramucirumab/paclitaxel was about 40%, and the median survival time was around 11.4 months.
  • Ramucirumab has many side effects with few side effects, but there are some patients who are not so effective. For patients with little therapeutic benefit, if it is possible to predict the therapeutic effect before the start of treatment with ramucirumab or at the early stage of the treatment, without unnecessary treatment for patients who are not expected to have the therapeutic effect, Alternative treatments can be given. Also, from the viewpoint of proper use of pharmaceuticals, it would be of great benefit to develop an appropriate biomarker for predicting the therapeutic effect that makes this possible. Furthermore, understanding the mechanism of resistance to ramucirumab will lead to the development of new therapeutic strategies. Therefore, the present inventors analyzed biomarkers that correlate with the therapeutic effect of ramucirumab.
  • FIG. 1 shows VEGF-A levels in plasma of patients 8 days after the start of ramucirumab in patients treated with ramucirumab alone and co-administered with paclitaxel in other cases.
  • PFS gression Free Survival, progression-free
  • the plasma VEGF-A concentration was divided into two groups, a high value group and a low value group, based on the optimal cutoff value (424 pg/ml), and PFS and OS were analyzed.
  • the VEGF-A high value group showed a significant prognosis. Was defective (FIG. 1(B)). Since a negative correlation between VEGF-A concentration in plasma and PFS or OS is not observed in paclitaxel administration, it is considered to be a phenomenon characteristic of ramucirumab administration. The following phenomena are observed by the administration of ramucirumab. (1) Plasma VEGF-A is markedly increased early after administration, and a negative correlation is observed between the VEGF-A value and the survival period.
  • VEGF-A vascular endothelial growth
  • Non-patent Document 8 VEGF-A has also been reported to suppress tumor immunity through the proliferation/infiltration of regulatory T cells (Non-patent Document 8), which may adversely affect the mechanism via immunosuppression. There is.
  • the efficacy of anti-VEGFR2 antibody administration represented by ramucirumab can be determined by the blood VEGF-A concentration at the early stage of the treatment.
  • An object of the present invention is to provide a therapeutic agent and a therapeutic method that exert an effect on a patient group whose efficacy is not recognized by administration of ramucirumab. It is another object of the present invention to provide a therapeutic agent and a therapeutic method that eliminate the adverse effects of excessive VEGF-A produced by administration of anti-VEGFR2 antibody on the treatment.
  • the present invention relates to a novel therapeutic method and therapeutic agent for improving the therapeutic effect on patients who are not therapeutically effective by administering anti-VEGFR2 antibody including ramucirumab.
  • a concomitant drug which is used in combination with an anti-VEGFR2 antibody drug in a disease in which angiogenesis is an exacerbation, and which comprises an anti-VEGF antibody as an active ingredient.
  • the concomitant drug according to (1), wherein the anti-VEGF antibody is an anti-VEGF-A antibody.
  • the concomitant drug according to (1) or (2), wherein the disease is a tumor.
  • the concomitant drug according to (3), wherein the tumor is gastric cancer, colon cancer, or non-small cell lung cancer.
  • the concomitant drug according to any one of (1) to (4) which is used simultaneously or separately with the anti-VEGFR2 antibody drug.
  • a kit for testing a patient who responds effectively by using an anti-VEGFR2 antibody drug and an anti-VEGF antibody drug in combination which comprises a reagent for measuring the VEGF-A concentration in a patient sample kit.
  • Blood VEGF concentration is measured before and after administration of anti-VEGFR2 antibody drug, and when a significant increase in blood VEGF concentration is observed after administration of anti-VEGFR2 antibody drug, anti-VEGFR2 antibody drug.
  • FIG. 1 A diagram showing the relationship between VEGF-A concentration in patient plasma and PFS (left) and OS (right) on day 8 after administration of ramucirumab.
  • B PFS (left) and OS (right) of plasma VEGF-A high value group and low value group on day 8 of administration of ramucirumab.
  • A A diagram showing a DC101 antibody administration schedule that is a mouse surrogate antibody for ramucirumab.
  • B Changes in mouse VEGF-A in plasma after administration of DC101 antibody.
  • FIG. 1 A photograph showing a state 14 days after the start of antibody administration of a tumor transplanted in a mouse upon administration of each antibody. The histological observation of the kidney image
  • A An example in which an infarcted site is observed in each group is shown.
  • B shows an example in which there is no infarct site in each group.
  • the histological findings of the kidney photographed by PAS staining and an objective lens of 40 times are shown.
  • a therapeutic effect can be obtained even in a patient group where anti-VEGFR antibody alone does not produce an effect.
  • bevacizumab is used as an anti-VEGF-A antibody in clinical use
  • aflibercept which is a biopharmaceutical capable of binding to VEGF-A, B, and PlGF
  • ramucirumab is used as an anti-VEGFR2 antibody.
  • the anti-VEGFR antibody drug and the anti-VEGF antibody drug to be developed in the future are not limited thereto.
  • a drug containing an antibody fragment such as ranibizumab, which is a Fab fragment against VEGF-A, as an active ingredient can be used.
  • a drug containing a bispecific antibody targeting both VEGFR2 and VEGF-A as an active ingredient may be used.
  • the diseases targeted by the therapeutic agents and treatment methods shown in this Example are diseases in which angiogenesis is involved in the onset and exacerbation of the disease.
  • Tumors are examples of such diseases, and typical examples thereof include gastric cancer, colon cancer, and non-small cell lung cancer, which are known to be effective by administration of ramucirumab.
  • the timing of administration of the therapeutic agents may be the same, or it is possible to administer the therapeutic agents individually on different schedules in consideration of the half-life of each therapeutic agent.
  • each antibody may be administered in combination on the first day (D1) and again after 2 weeks (D15).
  • the dose may be a dose that has been confirmed to be effective for each antibody.
  • 8 mg/kg for ramucirumab and 5 mg/kg for bevacizumab may be administered at D1 and D15.
  • the dose and administration schedule may be determined for each antibody based on the results of future clinical studies.
  • Ramucirumab is the standard treatment in combination with paclitaxel, but it is not administered in combination with other antibody drugs.
  • An anti-VEGFR antibody drug alone does not show any effect as an antibody drug, but a group of patients who show an effect by co-administration with an anti-VEGF antibody drug is treated with anti-VEGFR antibody and blood VEGF-A Is a group of patients with an increase in Therefore, in addition to the combined administration of ramucirumab and paclitaxel, which is currently the standard treatment, the combined administration of bevacizumab may be performed.
  • the blood VEGF-A concentration is measured early, and if the value is high, the anti-VEGF antibody drug is used as a concomitant drug, and if the value is low, the antibody drug is The anti-VEGFR antibody drug alone may be administered for treatment.
  • the blood VEGF-A concentration is measured here on the 8th day, but it may be measured early after the start of administration of the anti-VEGFR2 antibody, and the samples on the 4th to 10th days may be measured. Further, blood, plasma, or serum can be used as the sample. In the case of blood, plasma, or serum, it is possible not only to obtain a sample from a patient and perform an examination even for unresectable advanced/recurrent cancer, but also to reduce the physical burden on the patient.
  • the present inventors believe that the excess VEGF-A increased after administration of ramucirumab adversely affects the subsequent survival period, and that neutralizing this excess VEGF-A may improve the therapeutic effect. It was however, as described above, the treatment method that suppresses the activation of VEGFR by the kinase inhibitor sorafenib and inhibits the binding of VEGF to VEGFR by bevacizumab is a treatment method that suppresses both the ligand and the receptor. , Although some effects have been obtained, the combination therapy has been abandoned due to the increased toxicity. Furthermore, there is no case where treatment is performed by simultaneously inhibiting the ligand and the receptor with an antibody drug.
  • a human gastric cancer cell line was transplanted into a nude mouse, and a model mouse showing a similar reaction to an anti-VEGFR antibody as a human gastric cancer patient was constructed.
  • VEGF-A secretion per 10,000 cells in the culture supernatant was calculated. As shown in FIG. 2, since VEGF-A secreted from MKN45 cells was the highest among the analyzed cells, it was decided to construct a mouse model using MKN45 cells.
  • Nude mouse, CAnN. 2,000,000 human gastric cancer cell lines MKN45 or MKN74 were subcutaneously transplanted into Cg-Foxn1nu/CrlCrlj (6 weeks old, female, obtained from Charles River Japan, Inc.), and the tumor size was determined 14 days after the transplantation. It measured and was divided into groups at random. The tumor volume at the time of grouping was 80 to 150 mm 3 .
  • Ramucirumab mouse surrogate antibody DC101 Bio X Cell
  • MKN45 cells are cells whose tumor regression effect has already been examined by the DC101 antibody.
  • DC101 antibody was intraperitoneally administered at 5, 10 and 20 mg/kg twice a week for 2 weeks (FIG. 3(A)). Blood was collected 14 days after the administration to measure human and mouse VEGF-A in plasma. For the measurement, a human VEGF-A measurement kit and a mouse VEGF-A measurement kit (both manufactured by R&D) were used. It has been previously confirmed that the human VEGF-A measurement kit detects only human VEGF-A and the mouse VEGF-A measurement kit detects only mouse VEGF-A. As a result, induction of mouse VEGF-A was confirmed when the DC101 antibody was administered at a dose of 10 or 20 mg/kg (FIG. 3(B)). On the other hand, no increase in human VEGF-A was observed (Fig. 3(C)).
  • the notation “tumor(+)” indicates a mouse transplanted with MKN45 or MKN74, which is a gastric cancer cell line.
  • the notation “tumor( ⁇ )” indicates the result of analysis of the effect of the DC101 antibody in a mouse not transplanted with a cancer cell line as a control.
  • mouse PlGF was significantly increased by DC101 administration, and weak induction was observed for mouse VEGF-C and mouse VEGF-D. This result was similar to the result of plasma of patients administered ramucirumab (Patent Document 1, Non-Patent Document 3). Further, with respect to any of the cytokines, the induction was of mouse origin, and not of human origin.
  • mice constructed by subcutaneously transplanting MKN45 cells into nude mice the behavior of vascular growth factor produced after administration of the DC101 antibody is very similar to that of ramucirumab administered to patients. , Considered a good model.
  • nude mice were subcutaneously transplanted with MKN45 cells, and 14 days later, the tumor size was measured, and 80 to 150 mm 3 tumors were grouped.
  • bevacizumab Since bevacizumab has relatively few serious side effects, it is considered that toxicity is slight even when used in combination. In fact, no significant weight loss was observed even in the mouse model, and no serious side effects were observed.
  • VEGF is constantly produced from podocytes in the kidney, and it has been revealed that it binds to VEGFR2 of endothelial cells and maintains the morphology and function of endothelial cells by the paracrine action, and filtration of glomerular blood vessels.
  • Non-Patent Document 9 The importance of VEGF in the constant maintenance of barriers has been shown (Non-Patent Document 9). Therefore, glomerular abnormalities and other renal disorders may occur as side effects.
  • liver damage since it is generally highly likely that liver damage will occur as a side effect of the drug, pathological analysis of the kidney and liver was performed.
  • a group Abnormalities of kidneys and liver tissues of individual animals of non-administration group (A group), DC101 administration group (B group), DC101 and mVEGF antibody combination administration group (C group), mVEGF antibody administration group (D group) I examined if there were any findings.
  • the kidney was subjected to HE staining and PAS staining, and the liver was subjected to HE staining by a conventional method, and microscopic observation was performed (FIGS. 6 to 8).
  • the results of abnormal findings are shown in Table 1. Mild infarcts were observed in the kidneys in all groups. In group C to which the antibody was co-administered, only mild atrophic tubules were observed.
  • FIG. 6(A) shows an infarct focus of an individual in which an infarct site was observed in each group
  • FIG. 6(B) shows a histological image of an individual in which the infarction site was not observed.
  • atrophic tubules and interstitial fibrosis were localized (wedge-shaped) in the infarct lesion, and tubule casts were also observed.
  • the fibrosis site was less noticeable in A12 than in other cases, and the fibrosis site was observed in D29 in a wider area than in other cases.
  • FIG. 7 shows an image of an individual with an observed infarction. No changes in glomeruli or renal tubules were observed in any of the cases.
  • anti-VEGF-A antibody It is considered that the ligand-receptor dual inhibition therapy, which uses both and anti-VEGFR2 antibody in combination, to simultaneously suppress ligand and receptor is a highly safe treatment method.
  • both the antibody drugs targeting the VEGF ligand and the receptor have an action of suppressing angiogenesis via VEGF-VEGFR2 which is a target pathway.
  • both antibody drugs show contradictory effects in the actions mediated by receptors other than VEGFR2. That is, when an anti-VEGF antibody is used, the ligand itself is suppressed by the antibody, so that it cannot act on receptors other than VEGFR2. As a result, responses mediated by receptors other than VEGFR2 are also suppressed.
  • the anti-VEGFR2 antibody when used, the ligand VEGF-A is present and the level of VEGF-A derived from the host in the blood is increased, so that the response mediated by receptors other than VEGFR2 is enhanced. It is thought to be done. Therefore, when each of the antibodies is used alone, it is considered that there is a phenomenon in which the effects of the antibody drug are diminished due to these contradictory side reactions, or side effects occur, which have a negative effect on the therapeutic effect. It is considered that by using both antibody drugs in combination, such side reaction can be canceled, the target pathway VEGF-VEGFR2 pathway can be reliably suppressed, and the tumor can be regressed.
  • the treatment method using the anti-VEGFR2 antibody and the anti-VEGF-A neutralizing antibody in combination is the VEGF-A in the blood early after the administration of the anti-VEGFR antibody. Shows a response to a group of patients with markedly increased or a group of high values when the VEGF-A value is divided into two groups by the optimum cutoff.
  • dual inhibition therapy of the VEGF-A/VEGFR2 pathway is not considered to have serious side effects, the combined administration from the beginning without studying the increase in VEGF-A level in patients due to anti-VEGFR antibody administration. You can go.
  • the ligand-receptor dual blockade therapy in which a ligand and a receptor are simultaneously suppressed by an antibody drug to obtain a therapeutic effect, is not a therapeutic method that has been attempted until now, but a completely new therapeutic method. Is.

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Abstract

L'invention concerne un nouveau traitement de blocage à la fois des ligands et des récepteurs associés avec des anticorps. Plus particulièrement, l'administration d'un médicament à base d'anticorps anti-VEGFR2 ainsi qu'un médicament à base d'anticorps anti-VEGF en tant que médicaments concomitants est également efficace contre des tumeurs qui ne répondent pas à des anticorps anti-VEGFR2 seuls.
PCT/JP2019/051593 2018-12-28 2019-12-27 Traitement par double inhibition de la voie du vegf-a/vegfr2 et composition pharmaceutique associée Ceased WO2020138486A1 (fr)

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JP2018247198A JP7299700B2 (ja) 2018-12-28 2018-12-28 ＶＥＧＦ－Ａ／ＶＥＧＦＲ２経路のｄｕａｌ ｉｎｈｉｂｉｔｉｏｎ療法、及びこれに使用する医薬組成物

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010538972A (ja) * 2007-08-20 2010-12-16 ブリストル−マイヤーズ スクイブ カンパニー 転移性癌の処置のためのｖｅｇｆｒ−２阻害剤の使用
WO2018124153A1 (fr) * 2016-12-28 2018-07-05 公益財団法人がん研究会 Biomarqueur pour la prédiction de l'effet thérapeutique d'un médicament à base d'anticorps anti-vegfr-2, procédé de criblage et kit de criblage

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010538972A (ja) * 2007-08-20 2010-12-16 ブリストル−マイヤーズ スクイブ カンパニー 転移性癌の処置のためのｖｅｇｆｒ−２阻害剤の使用
WO2018124153A1 (fr) * 2016-12-28 2018-07-05 公益財団法人がん研究会 Biomarqueur pour la prédiction de l'effet thérapeutique d'un médicament à base d'anticorps anti-vegfr-2, procédé de criblage et kit de criblage

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