Method and medicament for treating cancer unresponsive to PD-1 / PD-l1 signaling inhibitor

Abstract

To provide a medicament for treating cancer in individuals.SOLUTION: The present invention relates to a medicament for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual, comprising a PD-1 / PD-L1 signaling inhibitor, for use in combination with a VEGF signaling inhibitor.SELECTED DRAWING: Figure 2A

Description

[Technical Field]

[0001] The present invention relates to a medicament, a method of treatment, a kit, and a use for treating cancer in an individual, characterized in that a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor are administered in combination, as well as a VEGF signaling inhibitor, a PD-1 / PD-L1 signaling inhibitor, and a combination thereof. More specifically, the present invention relates to a medicament, a method of treatment, a kit, and a use for treating cancer unresponsive to a PD-1 / PD-L1 signaling inhibitor in an individual, characterized in that a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor are administered in combination, as well as a VEGF signaling inhibitor, a PD-1 / PD-L1 signaling inhibitor, and a combination thereof. [Background technology]

[0002] The programmed cell death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1 and PD-L2, respectively) play important roles in immune regulation. PD-1, expressed on activated T cells, is activated by PD-L1 (also known as B7-H1) and PD-L2, expressed by stromal cells, tumor cells, or both. Amplification of PD-1 signaling causes T cells to lose their ability to replicate and attack cancer cells, ultimately leading to cell death. Administration of signaling inhibitors of these proteins, such as anti-PD-1 or anti-PD-L1 antibodies, reactivates T cells and restores cytotoxic immune function.

[0003] Human vascular endothelial growth factor (VEGF / VEGF-A) is involved in normal and abnormal angiogenesis and the restriction of angiogenesis associated with tumors and intraocular disorders. VEGF is a homodimeric glycoprotein isolated from multiple sources. In endothelial cells, VEGF exhibits proliferation-promoting activity. VEGF plays an important regulatory role in the formation of new blood vessels during embryonic angiogenesis and in adult angiogenesis. As of October 2018, three angiogenesis inhibitors (VEGF inhibitors) have been approved for manufacturing and marketing in Japan. The three products are bevacizumab (trade name: Avastin), ramucirumab (trade name: Cyramza), and aflibercept (trade name: Zaltrap).

[0004] Nivolumab (trade name: Opdivo) and pembrolizumab (trade name: Keytruda) are commercially available anti-PD-1 antibodies, while atezolizumab (trade name: Tecentriq) and avelumab (trade name: Bavencio), and durvalumab (trade name: Imfinzi) are commercially available anti-PD-L1 antibodies.

[0005] As of October 2018, the anti-CTLA4 antibody ipilimumab (Yervoy) is the only agent approved for combination with these PD-1 / PD-L1 signaling inhibitors, which are otherwise administered as single agents.

[0006] However, there is a need for more effective treatments that utilize the synergistic effect of combining anticancer drugs with immunotherapy (Non-Patent Document 1). Combinations of PD-1 / PD-L1 signaling inhibitors and VEGF signaling inhibitors have also been developed (Patent Documents 1 to 5). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 2012-511329 [Patent Document 2] Japanese Patent Application Publication No. 2017-506227 [Patent Document 3] Japanese Patent Application Publication No. 2018-522887 [Patent Document 4] Japanese Patent Application Laid-Open No. 2018-529375 [Patent Document 5] Japanese Patent Application Publication No. 2018-522850 [Non-patent literature]

[0008] [Non-Patent Document 1] Cancer J.2018 Jul / Aug;24(4):193-204. Summary of the Invention

[0009] The present invention provides medicaments, treatment methods, kits, and uses for treating cancer, as well as VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, and combinations thereof. More specifically, the present invention provides medicaments, treatment methods, kits, and uses, as well as VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, and combinations thereof for treating cancers unresponsive to PD-1 / PD-L1 signaling inhibitors in individuals.

[0010] Through extensive research, the present inventors have found that a combination of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor is more effective in treating cancer than the separate use of either a VEGF signaling inhibitor or a PD-1 / PD-L1 signaling inhibitor, i.e., provides a synergistic effect. In particular, the present inventors have found that a combination of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor is effective in treating cancers that are unresponsive to PD-1 / PD-L1 signaling inhibitors, and have completed the present invention.

[0011] The medicament according to the present invention is a medicament for treating cancer in an individual, comprising a PD-1 / PD-L1 signaling inhibitor for use in combination with a VEGF signaling inhibitor.

[0012] The medicament according to the present invention is a medicament for treating cancer in an individual, comprising a VEGF signaling inhibitor for use in combination with a PD-1 / PD-L1 signaling inhibitor.

[0013] The medicament according to the present invention is a medicament for treating cancer in an individual, comprising a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor.

[0014] The medicament according to the present invention is a medicament for treating cancer in an individual, in which a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor are administered in combination.

[0015] Any one of the above-mentioned medicaments according to the present invention is a medicament in which a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor are administered simultaneously, separately, or sequentially.

[0016] Any one of the above medicaments according to the present invention is a medicament wherein the VEGF signalling inhibitor is a VEGF antagonist or a VEGFR antagonist.

[0017] Any one of the above-mentioned medicaments according to the present invention is a medicament in which the VEGF signaling inhibitor is an anti-VEGF antibody or an anti-VEGFR antibody.

[0018] Any one of the above-mentioned medicaments according to the present invention is a medicament in which the anti-VEGF antibody or anti-VEGFR antibody is bevacizumab, ramucirumab, or aflibercept beta.

[0019] Any one of the above-mentioned medicaments according to the present invention is a medicament in which the PD-1 / PD-L1 signaling inhibitor is a PD-1 antagonist or a PD-L1 antagonist.

[0020] Any one of the above-mentioned medicaments according to the present invention is a medicament wherein the PD-1 / PD-L1 signaling inhibitor is AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011).

[0021] Any one of the above-mentioned medicaments according to the present invention is a medicament in which the PD-1 / PD-L1 signaling inhibitor is an anti-PD-L1 antibody.

[0022] Any one of the above-mentioned medicaments according to the present invention may be a medicament for treating cancer selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial cancer, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid tumors, virus-negative solid tumors, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumors, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma, and endometrial cancer.

[0023] The medicament according to the present invention is a medicament for treating cancer comprising a PD-1 / PD-L1 signaling inhibitor for use in combination with a VEGF signaling inhibitor, wherein the medicament improves the response rate in a group comprising individuals in need of cancer treatment and to whom the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor are administered simultaneously, separately or sequentially, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor in combination.

[0024] The medicament according to the present invention is a medicament for treating cancer comprising a VEGF signaling inhibitor for use in combination with a PD-1 / PD-L1 signaling inhibitor, which improves the response rate in a group comprising individuals in need of cancer treatment and who are administered a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor simultaneously, separately or sequentially, compared to when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0025] The medicament according to the present invention is a medicament for treating cancer, comprising a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor, which improves the response rate in a group including individuals in need of cancer treatment and to whom a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor are administered simultaneously, separately, or sequentially, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor, or when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0026] A kit according to the present invention is a kit for treating cancer in an individual, comprising a PD-1 / PD-L1 signaling inhibitor for use in combination with a VEGF signaling inhibitor.

[0027] A kit according to the present invention is a kit for treating cancer in an individual, comprising a VEGF signaling inhibitor for use in combination with a PD-1 / PD-L1 signaling inhibitor.

[0028] The kit according to the present invention is a kit for treating cancer in an individual, comprising a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor.

[0029] The kit according to the present invention is a kit for treating cancer, in which a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor are administered in combination.

[0030] Any one of the above kits according to the present invention is a kit in which the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor are administered simultaneously, separately, or sequentially.

[0031] Any one of the above kits according to the present invention is a kit in which the VEGF signaling inhibitor is a VEGF antagonist or a VEGFR antagonist.

[0032] Any one of the above kits according to the present invention is a kit in which the VEGF signaling inhibitor is an anti-VEGF antibody or an anti-VEGFR antibody.

[0033] Any one of the above kits according to the present invention is a kit in which the anti-VEGF antibody or anti-VEGFR antibody is bevacizumab, ramucirumab, or aflibercept beta.

[0034] Any one of the above kits according to the present invention is a kit in which the PD-1 / PD-L1 signaling inhibitor is a PD-1 antagonist or a PD-L1 antagonist.

[0035] Any one of the above kits according to the present invention is a kit in which the PD-1 / PD-L1 signaling inhibitor is AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011).

[0036] Any one of the above kits according to the present invention is a kit in which the PD-1 / PD-L1 signaling inhibitor is an anti-PD-L1 antibody.

[0037] Any one of the above kits according to the present invention may be a kit in which the cancer is selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial carcinoma, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid tumors, virus-negative solid tumors, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumors, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma, and endometrial cancer.

[0038] A kit according to the present invention is a kit for treating cancer comprising a PD-1 / PD-L1 signaling inhibitor for use in combination with a VEGF signaling inhibitor, wherein the kit improves the response rate in a group of individuals in need of cancer treatment and to which the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor are administered simultaneously, separately or sequentially, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor.

[0039] A kit according to the present invention is for treating cancer, comprising a VEGF signaling inhibitor for use in combination with a PD-1 / PD-L1 signaling inhibitor, wherein the kit improves the response rate in a group of individuals in need of cancer treatment who are administered the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor simultaneously, separately or sequentially, compared to when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0040] A kit according to the present invention is a kit for treating cancer comprising a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor, wherein the kit improves the response rate in a group including individuals in need of cancer treatment and to which the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor are administered simultaneously, separately, or sequentially, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor, or when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0041] The treatment method according to the present invention is a method for treating cancer, comprising the step of administering to an individual one or more of the medicament and kit of the present invention in each embodiment described herein, as well as a VEGF signaling inhibitor, a PD-1 / PD-L1 signaling inhibitor, and a combination thereof.

[0042] The use according to the present invention is the use of a PD-1 / PD-L1 signaling inhibitor and / or a VEGF signaling inhibitor for the manufacture of a medicament or kit of the present invention.

[0043] The VEGF signaling inhibitor according to the present invention is a VEGF signaling inhibitor for use in cancer treatment, and is administered to an individual in need thereof in combination with a PD-1 / PD-L1 signaling inhibitor.

[0044] The PD-1 / PD-L1 signaling inhibitor according to the present invention is a PD-1 / PD-L1 signaling inhibitor used for cancer treatment, and is administered to an individual in need thereof in combination with a VEGF signaling inhibitor.

[0045] The combination according to the present invention is a combination of a VEGF signaling inhibitor with a PD-1 / PD-L1 signaling inhibitor for use in the treatment of cancer. [Effects of the Invention]

[0046] The medicament, treatment method, kit, and use, as well as the VEGF signaling inhibitor, the PD-1 / PD-L1 signaling inhibitor, and their combination according to the present invention, can treat cancer in an individual more effectively than when the VEGF signaling inhibitor or the PD-1 / PD-L1 signaling inhibitor is used separately. More specifically, the present invention can treat cancer unresponsive to a PD-1 / PD-L1 signaling inhibitor in an individual more effectively than when the VEGF signaling inhibitor or the PD-1 / PD-L1 signaling inhibitor is used separately. [Brief explanation of the drawings]

[0047] [Figure 1] Figure 1 shows baseline (untreated) intratumoral expression of PD-L1 protein (A) and CD8 protein (B) in mouse tumor tissue bearing OV2944-HM-1 cancer (HM-1) and mouse tumor tissue bearing Colon38 cancer (Colon38). Six mice were treated in the OV2944-HM-1 cancer-bearing group. One mouse (a preliminary experiment performed on multiple individuals) was treated in the Colon38 cancer-bearing group. [Figure 2] Figure 2 shows the change in tumor volume of the mouse ovarian cancer cell line OV2944-HM-1 (A) or the mouse colorectal cancer cell line Clone 38 (B) in mice treated with monotherapy (5 mg / kg anti-PD-L1 antibody (clone 6E11) twice weekly or 10 mg / kg anti-VEGF antibody (clone B20-4.1.1) once weekly), the combination of anti-PD-L1 antibody and anti-VEGF antibody, or a control antibody (control) at the same dose. Fifteen (A) or eight (B) mice were treated in each group. The mean and SD bars for tumor volume for each group are plotted. [Figure 3]Figure 3 shows the percentage of CD8+ T cells (A) and the percentage of granzyme B-positive CD8+ T cells (B) among all live cells in the tumors of OV2944-HM-1 tumor-bearing mice on day 8 after the start of treatment in each treatment group, as set up in Figure 2A. For each group, 14 to 15 mice (A) and 15 mice (B) were treated. The mean cell percentages and SD bars for each group are plotted. Also shown are tissue sections in which intratumoral CD8 protein was detected by immunohistochemistry (C) and its expression was quantified (D) in OV2944-HM-1 tumor-bearing mice on day 8 after the start of treatment in each treatment group, as set up in Figure 2A. For each group, 14 to 15 mice (C, D) were treated. The mean tumor volume and SD bars for each group are plotted. [Figure 4] Figure 4A shows the change in tumor volume over time in OV2944-HM-1 tumor-bearing mice treated with an anti-CD8a antibody (white (+ anti-CD8α antibody)) or without the antibody (black) in the respective control groups, anti-VEGF antibody monotherapy groups, and anti-PD-L1 and anti-VEGF antibody combination groups (combination). Fourteen mice were treated in each group. The mean tumor volume and SD bars for each group are plotted. Figure 4B shows the tumor volume in OV2944-HM-1 tumor-bearing mice on day 22 after the start of treatment in each group (+) treated with an anti-PD-L1 antibody, anti-VEGF antibody, anti-CD8α antibody, or the respective control antibody (-). Fourteen mice were treated in each group. The mean tumor volume and SD bars for each group are plotted. [Figure 5] Figure 5A shows CXCL9 protein expression per mg of protein in tumor tissue from OV2944-HM-1 tumor-bearing mice on day 8 after the start of treatment in each treatment group, as set up in Figure 2A. Fourteen to fifteen mice were treated in each group. The mean cell percentage and SD bars are plotted for each group. Figure 5B shows the percentage of CD8+ T cells among all surviving cells in tumors from OV2944-HM-1 tumor-bearing mice on day 8 after the start of treatment in each group treated with anti-PD-L1 antibody, anti-VEGF antibody, anti-CXCR3 antibody, or the respective control antibodies (-). Sixteen mice were treated in each group. The mean cell percentage and SD bars are plotted for each group. [Figure 6] Figure 6 shows the protein expression of MHC class I molecules, expressed as mean fluorescence intensity (MFI), in tumor tissues of OV2944-HM-1 tumor-bearing mice 8 days after the start of treatment, for each treatment group set up as in Figure 2A. Fifteen mice were treated for each group. The mean and SD bars for the cell percentages for each group are plotted. [Figure 7] Figure 7 shows tissue sections (A) and quantification of MVD (B) in tumor tissues from OV2944-HM-1 tumor-bearing mice on day 8 of treatment in each treatment group, as set up in Figure 2A. Seven mice were treated in each group. The mean and SD bars for the cell percentages in each group are plotted. DETAILED DESCRIPTION OF THE INVENTION

[0048] Hereinafter, the embodiments of the present invention will be described in detail with reference to examples. Unless otherwise specified in the embodiments and examples, the methods described in J. Sambrook, E.F. Fritsch, and T. Maniatis (eds.), Molecular cloning, a laboratory manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2001), and F.M. Usubel, R. Brent, R.E. Kingston, D.D. Moore, J.G. Seidman, J.A. Smith, and K. Struhl (eds.), Current Protocols in Molecular Biology, John Wiley & Sons Ltd., or modified and altered methods thereof, will be used. Furthermore, when using a commercially available reagent kit or measuring device, the accompanying protocol will be used unless otherwise specified.

[0049] Furthermore, the objects, features, advantages, and concepts of the present invention will be apparent to those skilled in the art from the description in this specification, and those skilled in the art can easily reproduce the present invention based on the description in this specification. The embodiments and specific examples of the present invention described below show preferred embodiments of the present invention. They are provided for the purpose of illustration or explanation, and do not limit the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made based on the description in this specification within the purpose and scope of the present invention disclosed herein.

[0050] ==Medicine according to the present invention== The pharmaceutical composition according to the present invention is for treating cancer in an individual, and comprises a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor administered in combination. In the pharmaceutical composition, the cancer is preferably resistant to the PD-1 / PD-L1 signaling inhibitor.

[0051] The medicament according to the present invention is a medicament for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual. In one embodiment, the medicament comprises a PD-1 / PD-L1 signaling inhibitor. The medicament is preferably for use in combination with a VEGF signaling inhibitor.

[0052] The medicament according to the present invention is a medicament for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual. In one embodiment, the medicament comprises a VEGF signaling inhibitor. The medicament is preferably for use in combination with a PD-1 / PD-L1 signaling inhibitor.

[0053] The medicament according to the present invention is a medicament for treating a cancer in which resistance to a PD-1 / PD-L1 signaling inhibitor has developed in an individual. In one embodiment, the medicament comprises a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor.

[0054] In any one of the above-mentioned medicaments according to the present invention, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In addition, in any one of the above-mentioned medicaments according to the present invention, the cancer may have inherent resistance, acquired resistance, or relapsed cancer.

[0055] The medicament according to the present invention is for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the medicament comprises a PD-1 / PD-L1 signaling inhibitor. The medicament is preferably for use in combination with a VEGF signaling inhibitor. In the medicament, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the medicament improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor in combination.

[0056] The medicament according to the present invention is for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the medicament comprises a VEGF signaling inhibitor. The medicament is preferably for use in combination with a PD-1 / PD-L1 signaling inhibitor. In the medicament, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the medicament improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor in combination.

[0057] The medicament according to the present invention is a medicament for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the medicament comprises a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor. In the medicament, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the medicament improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor or when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0058] With regard to the medicament according to the present invention characterized by an improved response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, in one embodiment, the group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor may include individuals who have not been tested for the presence or absence of resistance through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. Alternatively, in another embodiment of the medicament, the group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor may include individuals who have been tested for the presence or absence of resistance and determined to be resistant through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. In yet another embodiment, the resistance may be resistance caused by a conventional treatment including a PD-1 / PD-L1 signaling inhibitor.

[0059] In any one of the above medicaments according to the invention, the VEGF signalling inhibitor may be a VEGF antagonist or a VEGFR antagonist.

[0060] In any one of the above medicaments according to the present invention, the VEGF signaling inhibitor may be an anti-VEGF antibody or an anti-VEGFR antibody. In the medicament, the anti-VEGF antibody or the anti-VEGFR antibody is preferably bevacizumab, ramucirumab, or aflibercept beta.

[0061] In any one of the above medicaments according to the present invention, the PD-1 / PD-L1 signaling inhibitor may be a PD-1 antagonist or a PD-L1 antagonist. In the medicament, the PD-1 antagonist may be AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011). In the pharmaceutical, the PD-1 antagonist is preferably an anti-PD-1 antibody, more preferably nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011), and more preferably nivolumab or pembrolizumab. Furthermore, in the pharmaceutical, the PD-L1 antagonist can be an anti-PD-L1 antibody. In the pharmaceutical, the PD-L1 antagonist can be durvalumab, atezolizumab, avelumab (MSB0010718C), BMS-936559, MPDL3280A, or MEDI4736, and preferably durvalumab, atezolizumab, or avelumab.

[0062] Any one of the above-mentioned medicaments according to the present invention may be a medicament for treating cancer selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial cancer, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid tumors, virus-negative solid tumors, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumors, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma, and endometrial cancer.

[0063] ==Kit according to the present invention== The kit according to the present invention comprises a VEGF signaling inhibitor and / or a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the kit is for treating cancer in an individual. In the kit, the cancer is preferably a cancer resistant to a PD-1 / PD-L1 signaling inhibitor.

[0064] A kit according to the present invention is a kit for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual. In one embodiment, the kit comprises a PD-1 / PD-L1 signaling inhibitor. The kit is preferably for use in combination with a VEGF signaling inhibitor.

[0065] The kit according to the present invention is for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual. In one embodiment, the kit comprises a VEGF signaling inhibitor. The kit is preferably for use in combination with a PD-1 / PD-L1 signaling inhibitor.

[0066] The kit according to the present invention is for treating a cancer in which resistance to a PD-1 / PD-L1 signaling inhibitor has developed in an individual. In one embodiment, the kit comprises a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor.

[0067] In any one of the above kits according to the present invention, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. Additionally, in any one of the above kits according to the present invention, the cancer may be an intrinsic resistant cancer, an acquired resistant cancer, or a relapsed cancer.

[0068] A kit according to the present invention is a kit for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the kit comprises a PD-1 / PD-L1 signaling inhibitor. The kit is preferably a kit for use in combination with a VEGF signaling inhibitor. In the kit, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the kit improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to administration of the PD-1 / PD-L1 signaling inhibitor without the VEGF signaling inhibitor in combination.

[0069] A kit according to the present invention is a kit for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the kit comprises a VEGF signaling inhibitor. The kit is preferably a kit for use in combination with a PD-1 / PD-L1 signaling inhibitor. In the kit, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the kit improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0070] A kit according to the present invention is a kit for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the kit comprises a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor. In the kit, the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the kit improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor or when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0071] With regard to the above-described kit according to the present invention characterized by an improved response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, in one embodiment, the group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor may include individuals who have not been tested for the presence or absence of resistance through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. Alternatively, in another embodiment of the kit, the group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor may include individuals who have been tested for the presence or absence of resistance and determined to be resistant through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. In yet another embodiment, the resistance may be resistance caused by a conventional treatment including a PD-1 / PD-L1 signaling inhibitor.

[0072] In any one of the above kits according to the invention, the VEGF signaling inhibitor may be a VEGF antagonist or a VEGFR antagonist.

[0073] In any one of the above kits according to the present invention, the VEGF signaling inhibitor may be an anti-VEGF antibody or an anti-VEGFR antibody. Preferably, in the kit, the anti-VEGF antibody or anti-VEGFR antibody is bevacizumab, ramucirumab, or aflibercept beta.

[0074] In any one of the above kits according to the present invention, the PD-1 / PD-L1 signaling inhibitor may be a PD-1 antagonist or a PD-L1 antagonist. In the kit, the PD-1 antagonist may be AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011). In the kit, the PD-1 antagonist is preferably an anti-PD-1 antibody, more preferably nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011), and more preferably nivolumab or pembrolizumab. Furthermore, in the kit, the PD-L1 antagonist can be an anti-PD-L1 antibody. In the kit, the PD-L1 antagonist can be durvalumab, atezolizumab, avelumab, BMS-936559, MSB0010718C, MPDL3280A, or MEDI4736, and preferably durvalumab, atezolizumab, or avelumab.

[0075] Any one of the above kits according to the present invention may be a kit in which the cancer is selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial carcinoma, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid tumors, virus-negative solid tumors, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumors, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma, and endometrial cancer.

[0076] ==Treatment Method According to the Present Invention== The method of treatment according to the present invention is a method for treating cancer in an individual.

[0077] In one embodiment, a treatment method according to the present invention comprises administering to an individual a PD-1 / PD-L1 signaling inhibitor, preferably in combination with a VEGF signaling inhibitor.

[0078] In one embodiment, a treatment method according to the present invention comprises administering to an individual a VEGF signaling inhibitor, preferably in combination with a PD-1 / PD-L1 signaling inhibitor.

[0079] In one embodiment, a treatment method according to the present invention comprises administering to an individual a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor.

[0080] In any one of the above treatment methods according to the present invention, the cancer is preferably a cancer that is resistant to a PD-1 / PD-L1 signaling inhibitor.

[0081] In any one of the above treatment methods according to the present invention, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In addition, in any one of the above treatment methods according to the present invention, the cancer may be an intrinsic resistant cancer, an acquired resistant cancer, or a relapsed cancer.

[0082] A treatment method according to the present invention is a treatment method for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the treatment method comprises the step of administering a PD-1 / PD-L1 signaling inhibitor. In the treatment method, the PD-1 / PD-L1 signaling inhibitor is preferably administered in combination with a VEGF signaling inhibitor. In the treatment method, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the treatment method improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor in combination.

[0083] A treatment method according to the present invention is a treatment method for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the treatment method comprises the step of administering a VEGF signaling inhibitor. In the treatment method, the PD-1 / PD-L1 signaling inhibitor is preferably administered in combination with a VEGF signaling inhibitor. In the treatment method, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the treatment method improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor in combination.

[0084] A treatment method according to the present invention is a treatment method for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the treatment method comprises the step of administering a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor. In the treatment method, the VEGF signaling inhibitor is preferably administered in combination with a PD-1 / PD-L1 signaling inhibitor. In the treatment method, the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the treatment method improves the response rate in a group including individuals in need of treatment for a cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor or when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0085] With regard to the above-described treatment method according to the present invention for improving the response rate in a group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors, in one embodiment, the group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors may include individuals who have not been tested for the presence or absence of resistance through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. Alternatively, in another embodiment of the treatment method, the group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors may include individuals who have been tested for the presence or absence of resistance and determined to be resistant through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. In yet another embodiment, the resistance may be resistance caused by a conventional treatment including a PD-1 / PD-L1 signaling inhibitor.

[0086] In any one of the above methods of treatment according to the present invention, the VEGF signaling inhibitor may be a VEGF antagonist or a VEGFR antagonist.

[0087] In any one of the above treatment methods according to the present invention, the VEGF signaling inhibitor may be an anti-VEGF antibody or an anti-VEGFR antibody. In the treatment method, the anti-VEGF antibody or the anti-VEGFR antibody is preferably bevacizumab, ramucirumab, or aflibercept beta.

[0088] In any one of the above treatment methods according to the present invention, the PD-1 / PD-L1 signaling inhibitor can be a PD-1 antagonist or a PD-L1 antagonist. In the treatment method, the PD-1 antagonist can be AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011). In this treatment, the PD-1 antagonist is preferably an anti-PD-1 antibody, more preferably nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011), and more preferably nivolumab or pembrolizumab. Furthermore, in this treatment, the PD-L1 antagonist can be an anti-PD-L1 antibody. In this treatment, the PD-L1 antagonist can be durvalumab, atezolizumab, avelumab, BMS-936559, MSB0010718C, MPDL3280A, or MEDI4736, and preferably durvalumab, atezolizumab, or avelumab.

[0089] In any one of the above treatment methods according to the present invention, the cancer may be selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial carcinoma, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid tumors, virus-negative solid tumors, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumors, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma, and endometrial cancer.

[0090] ==Use According to the Invention== The use according to the present invention is the use of a PD-1 / PD-L1 signaling inhibitor and / or a VEGF signaling inhibitor for the manufacture of a medicament or kit of the present invention.

[0091] In the use according to the present invention, the medicament or kit is a medicament or kit for treating cancer in an individual. In the use, the cancer is preferably a cancer resistant to a PD-1 / PD-L1 signaling inhibitor.

[0092] In the use according to the present invention, the medicament or kit is for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual. In one embodiment of the use, the medicament or kit comprises, in one embodiment, a PD-1 / PD-L1 signaling inhibitor. The medicament or kit is preferably for use in combination with a VEGF signaling inhibitor.

[0093] In the use according to the present invention, the medicament or kit is for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual. In one embodiment, the medicament or kit comprises a VEGF signaling inhibitor. The medicament or kit is preferably a medicament or kit for use in combination with a PD-1 / PD-L1 signaling inhibitor.

[0094] In the use according to the present invention, the medicament or kit is for treating a cancer having acquired resistance to a PD-1 / PD-L1 signaling inhibitor in an individual. In one embodiment, the medicament or kit comprises a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor.

[0095] In any one of the above uses according to the present invention, the medicament or kit may be a kit-medicine in which the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor are administered simultaneously, separately, or sequentially. In addition, in any one of the above uses according to the present invention, the cancer may be an intrinsic-resistant cancer, an acquired-resistant cancer, or a relapsed cancer.

[0096] In the use according to the present invention, the medicament or kit is for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the medicament or kit comprises a PD-1 / PD-L1 signaling inhibitor. The medicament or kit is preferably for use in combination with a VEGF signaling inhibitor. In the medicament or kit, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the medicament or kit improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor.

[0097] In the use according to the present invention, the medicament or kit is for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the medicament or kit comprises a VEGF signaling inhibitor. The medicament or kit is preferably for use in combination with a PD-1 / PD-L1 signaling inhibitor. In the medicament or kit, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the medicament or kit improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0098] In the use according to the present invention, the medicament or kit is for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the medicament or kit comprises a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor. In the medicament or kit, the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the medicament or kit improves the response rate in a group including individuals in need of treatment for cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor or when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0099] With regard to the above-described uses according to the present invention characterized by an improved response rate in a group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors, in one embodiment, the group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors may include individuals who have not been tested for the presence or absence of resistance through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. Alternatively, in another embodiment of the medicament or kit, the group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors may include individuals who have been tested for the presence or absence of resistance and determined to be resistant through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. In yet another embodiment, the resistance may be resistance caused by a conventional treatment including a PD-1 / PD-L1 signaling inhibitor.

[0100] In any one of the uses according to the invention, the VEGF signalling inhibitor may be a VEGF antagonist or a VEGFR antagonist.

[0101] In any one of the uses according to the present invention, the VEGF signaling inhibitor may be an anti-VEGF antibody or an anti-VEGFR antibody. In the use, the anti-VEGF antibody or anti-VEGFR antibody is preferably bevacizumab, ramucirumab, or aflibercept beta.

[0102] In any one of the above uses according to the present invention, the PD-1 / PD-L1 signaling inhibitor may be a PD-1 antagonist or a PD-L1 antagonist. In the use, the PD-1 antagonist may be AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011). In use, the PD-1 antagonist is preferably an anti-PD-1 antibody, more preferably nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011), and more preferably nivolumab or pembrolizumab. Furthermore, in use, the PD-L1 antagonist can be an anti-PD-L1 antibody. In use, the PD-L1 antagonist can be durvalumab, atezolizumab, avelumab, BMS-936559, MSB0010718C, MPDL3280A, or MEDI4736, and preferably durvalumab, atezolizumab, or avelumab.

[0103] Any one of the above-mentioned medicaments according to the present invention may be a medicament for treating cancer selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial cancer, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid tumors, virus-negative solid tumors, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumors, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma, and endometrial cancer.

[0104] VEGF Signaling Inhibitor, PD-1 / PD-L1 Signaling Inhibitor, or Combination Thereof for Use in Cancer Treatment According to the Present Invention The VEGF signaling inhibitor according to the present invention is a VEGF signaling inhibitor used for cancer treatment. The VEGF signaling inhibitor is preferably administered to an individual in need thereof in combination with a PD-1 / PD-L1 signaling inhibitor. The VEGF signaling inhibitor is preferably a VEGF signaling inhibitor for use in treating cancer resistant to PD-1 / PD-L1 signaling inhibitors.

[0105] The PD-1 / PD-L1 signaling inhibitor according to the present invention is a PD-1 / PD-L1 signaling inhibitor used in the treatment of cancer. The PD-1 / PD-L1 signaling inhibitor is preferably administered to an individual in need thereof in combination with a VEGF signaling inhibitor. The PD-1 / PD-L1 signaling inhibitor is preferably a PD-1 / PD-L1 signaling inhibitor used in the treatment of cancer resistant to PD-1 / PD-L1 signaling inhibitors.

[0106] The combination of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor according to the present invention is for use in the treatment of cancer, preferably cancer resistant to PD-1 / PD-L1 signaling inhibitors.

[0107] With respect to any one of the above-mentioned VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, or combinations according to the present invention, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In addition, in any one of the above-mentioned VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, or combinations according to the present invention, the cancer may be an intrinsic-resistant cancer, an acquired-resistant cancer, or a relapsed cancer.

[0108] The VEGF signaling inhibitor, PD-1 / PD-L1 signaling inhibitor, or combination thereof according to the present invention is a VEGF signaling inhibitor, PD-1 / PD-L1 signaling inhibitor, or combination thereof for treating cancer resistant to PD-1 / PD-L1 signaling inhibitors. In one embodiment, the VEGF signaling inhibitor is preferably used in combination with a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the PD-1 / PD-L1 signaling inhibitor is preferably used in combination with a VEGF signaling inhibitor. In the present invention, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the PD-1 / PD-L1 signaling inhibitor or combination thereof improves the response rate in a group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor.

[0109] The VEGF signaling inhibitor, PD-1 / PD-L1 signaling inhibitor, or combination thereof according to the present invention is a VEGF signaling inhibitor, PD-1 / PD-L1 signaling inhibitor, or combination thereof for treating cancer resistant to PD-1 / PD-L1 signaling inhibitors. In one embodiment, the VEGF signaling inhibitor is preferably used in combination with a PD-1 / PD-L1 signaling inhibitor. In one embodiment, the PD-1 / PD-L1 signaling inhibitor is preferably used in combination with a VEGF signaling inhibitor. In the present invention, the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the VEGF signaling inhibitor or the combination thereof improves the response rate in a group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors, compared to when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0110] A combination according to the present invention is a combination of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor for treating cancer resistant to PD-1 / PD-L1 signaling inhibitors. In one embodiment, the combination comprises a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor. In the combination, the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor may be administered simultaneously, separately, or sequentially. In one embodiment, the combination improves the response rate in a group including individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors, compared to administering the PD-1 / PD-L1 signaling inhibitor without the VEGF signaling inhibitor or the VEGF signaling inhibitor without the PD-1 / PD-L1 signaling inhibitor.

[0111] With respect to the above-mentioned VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, or combinations according to the present invention, the present invention is characterized by an improved response rate in a group comprising individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors. In one embodiment, the group comprising individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors may include individuals who have not been tested for the presence or absence of resistance through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. Alternatively, in another embodiment of the present invention, the group comprising individuals in need of treatment for cancer resistant to PD-1 / PD-L1 signaling inhibitors may include individuals who have been tested for the presence or absence of resistance and determined to be resistant through diagnosis before administration of a PD-1 / PD-L1 signaling inhibitor. In yet another embodiment, the resistance may be resistance caused by a conventional treatment including a PD-1 / PD-L1 signaling inhibitor.

[0112] With respect to any one of the above VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, or combinations according to the present invention, the VEGF signaling inhibitor may be a VEGF antagonist or a VEGFR antagonist.

[0113] With respect to any one of the above-mentioned VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, or combinations thereof according to the present invention, the VEGF signaling inhibitor may be an anti-VEGF antibody or an anti-VEGFR antibody. In the pharmaceutical, the anti-VEGF antibody or anti-VEGFR antibody is preferably bevacizumab, ramucirumab, or aflibercept beta.

[0114] With respect to any one of the above-mentioned VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, or combinations according to the present invention, the PD-1 / PD-L1 signaling inhibitor can be a PD-1 antagonist or a PD-L1 antagonist. In the present invention, the PD-1 antagonist can be AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011). In the present invention, the PD-1 antagonist is preferably an anti-PD-1 antibody, more preferably nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011), and more preferably nivolumab or pembrolizumab. Furthermore, in the present invention, the PD-L1 antagonist may be an anti-PD-L1 antibody. In the present invention, the PD-L1 antagonist may be durvalumab, atezolizumab, avelumab, BMS-936559, MSB0010718C, MPDL3280A, or MEDI4736, and preferably durvalumab, atezolizumab, or avelumab.

[0115] With regard to any one of the above VEGF signaling inhibitors PD-1 / PD-L1 inhibitors, or combinations according to the present invention, the cancer may be selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial carcinoma, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid tumors, virus-negative solid tumors, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumors, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma, and endometrial cancer.

[0116] One embodiment of the present invention is a medicament for treating cancer in an individual, in which a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor are administered in combination.

[0117] One embodiment of the present invention is a medicament comprising a PD-1 / PD-L1 signaling inhibitor, which is administered to an individual in need thereof in combination with a VEGF signaling inhibitor to treat cancer.

[0118] One embodiment of the present invention is a medicament comprising a VEGF signaling inhibitor, which is administered to an individual in need thereof in combination with a PD-1 / PD-L1 signaling inhibitor for the treatment of cancer.

[0119] One embodiment of the present invention is a medicament comprising a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor, which is administered to an individual in need thereof to treat cancer.

[0120] One embodiment of the present invention is a medicament comprising a PD-1 / PD-L1 signaling inhibitor or a VEGF signaling inhibitor, which improves the response rate in a group comprising individuals in need of cancer treatment compared to a control group. In this embodiment, the medicament comprises a PD-1 / PD-L1 signaling inhibitor and can be for use in combination with a VEGF signaling inhibitor, in which case the medicament improves the response rate in this group compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor. In another embodiment, the medicament comprises a VEGF signaling inhibitor and can be for use in combination with a PD-1 / PD-L1 signaling inhibitor, in which case the medicament improves the response rate in this group compared to when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0121] One embodiment of the present invention is a kit for treating cancer comprising a VEGF signaling inhibitor and / or a PD-1 / PD-L1 signaling inhibitor.

[0122] The medicament and kit of the present invention can be used in combination with, in addition to a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor, other additional medicaments for the treatment of cancer, or known therapies such as radiation therapy or surgery.

[0123] The medicaments and kits of the present invention include embodiments in which the active ingredients, a PD-1 / PD-L1 signaling inhibitor and / or a VEGF signaling inhibitor, are formulated in a single preparation (combined preparation), or embodiments in which the active ingredients include two or more separately formulated preparations.

[0124] The treatment method according to the present invention is a method for treating cancer in an individual in need thereof, comprising the step of administering to the individual one or more of the medicament and kit of the present invention, and a VEGF signaling inhibitor, a PD-1 / PD-L1 signaling inhibitor, and combinations thereof, in each of the embodiments described herein.

[0125] The treatment methods of the present invention may include a step of treatment with another medicament, agent, kit, etc. for treating cancer other than the medicaments and kits of the present invention, as well as VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, and combinations thereof, specifically described herein, or a step of administering a known therapy such as radiation therapy or surgery. The other medicament may include one or more chemotherapeutic agents.

[0126] The use of the present invention is the use of a PD-1 / PD-L1 signaling inhibitor and / or a VEGF signaling inhibitor for the manufacture of a medicament or kit of the present invention. The use of the present invention may include the use of another agent for treating cancer, or a known treatment such as radiation therapy or surgery, in addition to a PD-1 / PD-L1 signaling inhibitor and / or a VEGF signaling inhibitor. The other agent may include one or more chemotherapeutic agents.

[0127] The VEGF signaling inhibitor of the present invention is a VEGF signaling inhibitor used for cancer treatment. The VEGF signaling inhibitor is preferably administered to an individual in need thereof in combination with a PD-1 / PD-L1 signaling inhibitor. The VEGF signaling inhibitor of the present invention can be used in combination with other additional medicines, drugs, kits, etc. for treating cancer, or known treatments such as radiation therapy or surgery, other than the PD-1 / PD-L1 signaling inhibitor.

[0128] The PD-1 / PD-L1 signaling inhibitor of the present invention is a PD-1 / PD-L1 signaling inhibitor used in cancer treatment. The PD-1 / PD-L1 signaling inhibitor is preferably administered to an individual in need thereof in combination with a VEGF signaling inhibitor. The PD-1 / PD-L1 signaling inhibitor of the present invention can be used in combination with other additional medicines, drugs, or kits for treating cancer, or with known therapies such as radiation therapy or surgery, other than a VEGF signaling inhibitor.

[0129] The combination of the present invention is a combination of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor for use in treating cancer. The combination of the present invention can be used in combination with another additional drug, agent, kit, etc. for treating cancer, in addition to the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor, or in combination with known therapies such as radiation therapy or surgery.

[0130] A PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor administered in combination to an individual with cancer provide a greater effect, i.e., a synergistic effect, compared to the individual and separate use of a VEGF signaling inhibitor or a PD-1 / PD-L1 signaling inhibitor. Therefore, in the medicaments, treatment methods, kits, and uses of the present invention, as well as the VEGF signaling inhibitor, the PD-1 / PD-L1 signaling inhibitor, and combinations thereof (hereinafter also referred to as "medicaments, etc. of the present invention" or "medicaments, etc. according to the present invention"), an embodiment in which a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor are administered in combination is preferred.

[0131] Here, in the pharmaceuticals, kits, treatment methods, uses, VEGF signaling inhibitors, PD-1 / PD-L1 signaling inhibitors, and combinations of the present invention, chemotherapeutic agents that can be administered in combination with the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor are, for example, known or new anticancer substances for the cancer being treated. More specifically, examples include erlotinib, capecitabine, calcium levofolinate, calcium folate, carboplatin, cyclophosphamide, cisplatin, docetaxel, nedaplatin, paclitaxel, pirarubicin, fluorouracil (5-FU), bleomycin, mitomycin C, tegafur-uracil preparations, tegafur-gimeracil-oteracil potassium preparations, tegafur, aclarubicin, amrubicin, ifosfamide, irinotecan hydrochloride hydrate, topotecan, etoposide, crizotinib, gemcitabine, and the like. These include, but are not limited to, fluticasone hydrochloride, cytarabine, doxorubicin, nimustine, temozolomide, topotecan hydrochloride, pemetrexed sodium hydrate, everolimus, epirubicin, exemestane, goserelin, tamoxifen, dexamethasone, doxifluridine, toremifene, vinorelbine, pirarubicin, prednisolone, methotrexate, lapatinib, mepitiostane, mitoxantrone, medroxyprogesterone, leuprorelin, letrozole, octreotide, vindesine, and teceleukin.

[0132] The type of chemotherapeutic agent that can be administered in combination with a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor can be appropriately selected by those skilled in the art depending on the type of cancer to be treated, the therapeutic effect, the patient's condition and tolerability, and the type of VEGF signaling inhibitor and PD-1 / PD-L1 signaling inhibitor. However, when bevacizumab is used as the VEGF signaling inhibitor and atezolizumab is used as the PD-1 / PD-L1 signaling inhibitor, the chemotherapeutic agent is preferably carboplatin, docetaxel, paclitaxel, etoposide, capecitabine, oxaliplatin, fluorouracil, calcium levofolinate, calcium folate, irinotecan hydrochloride hydrate, gemcitabine hydrochloride, cisplatin, temozolomide, or nogitecan hydrochloride, or a combination thereof, and more preferably carboplatin and / or paclitaxel.

[0133] When a PD-1 / PD-L1 signaling inhibitor or a VEGF signaling inhibitor is administered separately to a cancer, effective anticancer effects are achieved if the cancer is responsive to each of these drugs. Furthermore, as shown in the Examples, administering a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor in combination to a cancer responsive to each of these drugs is recognized to have a significantly stronger anticancer effect, i.e., a synergistic effect, than the anticancer effects achieved by administering a PD-1 / PD-L1 signaling inhibitor or a VEGF signaling inhibitor individually. Therefore, according to the pharmaceuticals and the like of the present invention, cancer treatment using a combination of a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor is more effective than the individual use of a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor separately. Therefore, in the pharmaceuticals and kits of the present invention, as well as the VEGF signaling inhibitor, PD-1 / PD-L1 signaling inhibitor, and their combinations, cancer is preferably treated with a combination of a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor.

[0134] Furthermore, when a cancer is unresponsive to a PD-1 / PD-L1 signaling inhibitor, treatment with the PD-1 / PD-L1 signaling inhibitor has significantly lower, or no or almost no observable anti-cancer effect, compared to cancers that are responsive to the PD-1 / PD-L1 signaling inhibitor. However, it has been shown that the combined use of a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor against cancers unresponsive to the PD-1 / PD-L1 signaling inhibitor has a significantly higher anti-cancer effect than when the PD-1 / PD-L1 signaling inhibitor is not used in combination with the VEGF signaling inhibitor. The effect obtained by this combination is naturally significantly higher than when the PD-1 / PD-L1 signaling inhibitor is not used in combination with the VEGF signaling inhibitor. Thus, the pharmaceutical composition of the present invention is particularly effective in treating cancers that are unresponsive to PD-1 / PD-L1 signaling inhibitors and are difficult to treat.

[0135] As described above, the pharmaceutical composition of the present invention, when used in combination with a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor, exhibits a significantly higher anti-cancer effect, i.e., a synergistic effect, regardless of whether the patient is responsive or unresponsive to the PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor or the VEGF signaling inhibitor is used individually or separately.

[0136] Thus, in a group including individuals in need of cancer treatment, treatment of cancer with a pharmaceutical agent of the present invention that combines a PD-1 / PD-L1 signaling inhibitor with a VEGF signaling inhibitor will result in a greater anti-cancer effect in each individual in the group compared to a control group that is not so treated. Here, the control group is a group including individuals in need of cancer treatment, and may be a group that is not administered with either a PD-1 / PD-L1 signaling inhibitor or a VEGF signaling inhibitor, a group that is administered with a PD-1 / PD-L1 signaling inhibitor without a VEGF signaling inhibitor, or a group that is administered with a VEGF signaling inhibitor without a PD-1 / PD-L1 signaling inhibitor.

[0137] For example, when the medicament of the present invention is a medicament comprising a PD-1 / PD-L1 signaling inhibitor for use in combination with a VEGF signaling inhibitor, a higher anti-cancer effect is achieved in each individual of a group that is a collective comprising individuals in need of cancer treatment, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without the VEGF signaling inhibitor.For example, when the medicament of the present invention is a medicament comprising a VEGF signaling inhibitor for use in combination with a PD-1 / PD-L1 signaling inhibitor, a higher anti-cancer effect is achieved in each individual of a group that is a collective comprising individuals in need of cancer treatment, compared to when the VEGF signaling inhibitor is administered without the PD-1 / PD-L1 signaling inhibitor.

[0138] As already explained, the medicaments and the like of the present invention are effective against cancers unresponsive to PD-1 / PD-L1 signaling inhibitors when treated with a combination of a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor. As a result, the effectiveness of the medicaments and the like of the present invention is particularly pronounced when the "group" (a collection including individuals in need of cancer treatment) is a collection of individuals with cancers unresponsive to PD-1 / PD-L1 signaling inhibitors. When the medicaments and the like of the present invention are administered to a group including individuals with cancers unresponsive to PD-1 / PD-L1 signaling inhibitors, the proportion of individuals demonstrating anti-cancer activity can be increased, i.e., the response rate can be improved, compared to when a PD-1 / PD-L1 signaling inhibitor or a VEGF signaling inhibitor is administered separately. Furthermore, the unresponsiveness is not particularly limited as long as it is unresponsiveness or resistance to a PD-1 / PD-L1 signaling inhibitor, and may include acquired resistance, intrinsic resistance, or unresponsiveness in recurrent cancer. In one embodiment, the group including individuals in need of cancer treatment includes individuals determined to be resistant. In another embodiment, the group comprising individuals in need of cancer treatment includes individuals who have been determined to have acquired resistance to conventional treatments. In this embodiment, for example, the medicament can be a medicament comprising a PD-1 / PD-L1 signaling inhibitor for use in combination with a VEGF signaling inhibitor, or a medicament comprising a VEGF signaling inhibitor for use in combination with a PD-1 / PD-L1 signaling inhibitor.

[0139] In one embodiment, the group including individuals in need of cancer treatment may be a group including individuals whose cancer unresponsiveness to a PD-1 / PD-L1 signaling inhibitor has not been determined prior to treatment with a combination of a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor. In one embodiment, the presence or absence of cancer unresponsiveness to a PD-1 / PD-L1 signaling inhibitor can be determined for at least some of the individuals in the group including individuals in need of cancer treatment prior to treatment with a combination of a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor. The unresponsiveness may be unresponsiveness or resistance to a PD-1 / PD-L1 signaling inhibitor, and may also be inherent resistance. As described above, when a cancer is unresponsive to a PD-1 / PD-L1 signaling inhibitor, the efficacy of the medicament or the like of the present invention is particularly pronounced, thereby improving the response rate in a group including individuals in need of cancer treatment.

[0140] The method for determining whether a cancer is resistant to a PD-1 / PD-L1 signaling inhibitor is not limited as long as it is possible to make the determination. However, for example, the determination can be made based on the presence or absence of a marker by detecting a marker, such as a gene, protein, or histological feature, that is specifically expressed in such resistant cancer in cancer tissue collected before treatment. Those skilled in the art can arbitrarily select a genetic or histological method for the determination from known methods.

[0141] Here, the cancer that can be treated by the medicament of the present invention is not limited as long as the medicament of the present invention is effective.However, for example, cancer can be selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, stomach cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial carcinoma, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid cancer, virus-negative solid cancer, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumor, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma and endometrial cancer.

[0142] The pharmaceutical composition of the present invention, when used in combination with a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor, exhibits a significantly higher anti-cancer effect, regardless of whether the patient is responsive or unresponsive to the PD-1 / PD-L1 signaling inhibitor, compared to the use of the PD-1 / PD-L1 signaling inhibitor or the VEGF signaling inhibitor individually. However, the present invention is particularly effective in treating cancers that are unresponsive to PD-1 / PD-L1 signaling inhibitors and are difficult to treat, and is therefore particularly effective in treating difficult-to-treat cancers, such as individuals that are resistant or unresponsive to conventional treatments, cancers that are unsuitable for continuation of conventional treatments, or cancers that do not show a desired level of responsiveness to conventional treatments (e.g., due to unresponsiveness and / or toxicity), i.e., cancers with inherent resistance to PD-1 / PD-L1 signaling inhibitors, cancers with acquired resistance acquired from conventional treatments with PD-1 / PD-L1 signaling inhibitors or the like, or cancers that have relapsed after conventional treatments with PD-1 / PD-L1 signaling inhibitors or the like. In particular, the pharmaceutical compositions of the present invention are particularly effective against cancers that are difficult to treat due to their unresponsiveness to PD-1 / PD-L1 signaling inhibitors. Even in cancers that are unresponsive to PD-1 / PD-L1 signaling inhibitors, i.e., cancers with inherent resistance to PD-1 / PD-L1 signaling inhibitors, cancers with acquired resistance due to existing conventional treatments, or recurrent cancers, the combination of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor exhibits a highly effective, i.e., synergistic, effect compared to the separate administration of a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor, significantly improving the efficacy of cancer treatment. Furthermore, the pharmaceutical compositions of the present invention are useful, for example, for the treatment of surgically unresectable, progressive, and / or recurrent cancers. The pharmaceutical compositions of the present invention can preferably be used to treat progressive or recurrent cancers that do not require curative resection, unresectable progressive or recurrent cancers, or inoperable or recurrent cancers.

[0143] Here, "resistance," "unresponsiveness," and "tolerance" are synonymous terms and refer to a state in which a cell or individual lacks responsiveness (also referred to as sensitivity) and / or has a reduced ability to show a significant response (e.g., partial response and / or complete response). For example, a cancer resistant to a PD-1 / PD-L1 signaling inhibitor is a cancer that shows no response or no significant response, such as a partial or complete response, to treatment using a PD-1 / PD-L1 signaling inhibitor. When a drug is administered to a "resistant" or "unresponsive" cancer, not only will the desired effect not be achieved, but in some cases the cancer may progress further or become more malignant. "Resistance" or "unresponsiveness" may also be "intrinsic resistance" or "acquired resistance."

[0144] As used herein, the term "intrinsic resistance" refers to the inherent unresponsiveness of cells or individuals to drugs. When cells or individuals have inherent resistance to a drug, the drug does not function or functions poorly compared to when there is no resistance (i.e., when there is sensitivity or responsiveness). Regardless of the drug treatment, no drug achieves a 100% response rate, and there are always non-responders to whom the drug does not work. The response rates of drugs for asthma, cancer, depression, diabetes, peptic ulcers, hyperlipidemia, etc. are generally said to be several tens of percent.

[0145] Here, "acquired resistance" refers to the unresponsiveness that develops after exposure to a drug, even though cells or individuals originally had responsiveness (or sensitivity) to the drug. Due to acquired resistance, the drug that initially worked does not work or works poorly during administration compared to the absence of resistance (i.e., the presence of responsiveness). In particular, acquired resistance in the pharmaceuticals of the present invention may be resistance that develops after conventional treatment. For example, antiangiogenic therapeutic agents are commonly used to treat many cancers, including liver cancer. However, even if a drug is effective in the early stages of treatment, repeated treatment may result in resistance. For example, a cancer resistant to a PD-1 / PD-L1 signaling inhibitor is a cancer that no longer regresses or even progresses in the presence of a PD-1 / PD-L1 signaling inhibitor.

[0146] As used herein, "recurrence" refers to the reappearance or regrowth of cancer after it has been cured or reduced by treatment. Even when treatment appears successful, "recurrence" occurs when a cancer reappears that is too small to be seen due to incomplete surgical resection, or when a cancer that was reduced by chemotherapy (anticancer therapy) or radiation therapy grows again. In "recurrence," the same cancer may appear near or in the same location as the treated cancer, but it may also appear in an organ or member separate from the treated cancer. The appearance of the same cancer in an organ or member separate from the treated cancer is specifically called "metastasis." Cancer cells enter the bloodstream and lymphatic system and travel via the blood or lymphatic system to another organ or member, where they grow. Cancer often metastasizes to areas with abundant blood flow, such as lymph nodes, lungs, liver, brain, and bones. In the case of cancer that recurs, the individual with cancer has undergone conventional treatment, such as chemotherapy or radiation therapy. Therefore, cancer that recurs may be cancer with acquired resistance to conventional treatment.

[0147] The unresponsiveness and / or responsiveness to treatment can be evaluated using methods known in the art, and are not limited as long as the desired evaluation can be performed. For example, the unresponsiveness and / or responsiveness can be evaluated by in vivo or in vitro assays regarding the proliferation of disease-derived cells toward treatment (e.g., treatment with a drug). The acquisition of unresponsiveness, the maintenance of responsiveness, and / or the increase of unresponsive individuals can be evaluated by in vivo or in vitro assays regarding the proliferation of disease-derived cells. In one embodiment, the unresponsiveness can be evaluated by IC 50 Or EC 50 The change can be expressed by a change in the level of response or a decrease in proliferation of disease-derived cells. In one embodiment, the change is greater than any one of about 50%, 100%, and / or 200%. In addition, the change in unresponsiveness and / or responsiveness can be assessed in vivo, for example, by assessing response to treatment, duration of response, and / or progression-free survival, e.g., partial response and complete response. The change in unresponsiveness and / or responsiveness can also be based on a change in response to treatment, duration of response, and / or progression-free survival, e.g., the number of partial responses and / or complete responses, in a population of individuals.

[0148] In one embodiment of the present invention, the cancer to be treated with the medicament of the present invention may be a cancer that has progressed when, during, or after receiving conventional treatment. For example, the cancer may be a cancer that has progressed after receiving conventional treatment. For example, the cancer has progressed about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after the start of conventional treatment. In another embodiment, for example, the cancer has progressed about 3, 6, 9, or 12 months after the start of conventional treatment. In one embodiment of the present invention, the cancer is resistant or unresponsive to conventional treatment. In another embodiment, the cancer is pancreatic cancer, i.e., the cancer is initially responsive to conventional treatment but either recurs at the primary lesion or metastatic cancer develops at any one of about 6, 7, 8, 9, 10, 11, 12, 24, or 36 months after cessation of conventional treatment.

[0149] In the present invention, conventional treatment comprises administration of a PD-1 / PD-L1 signaling inhibitor. In another embodiment, conventional treatment is monotherapy with a PD-1 antagonist or a PD-L1 antagonist. In another embodiment, conventional treatment is monotherapy with a PD-1 antagonist or a PD-L1 antagonist. In another embodiment, conventional treatment comprises administration of a PD-1 / PD-L1 signaling inhibitor and a chemotherapeutic agent. In another embodiment, conventional treatment comprises administration of a PD-1 antagonist and a chemotherapeutic agent. In another embodiment, conventional treatment comprises administration of a PD-L1 antagonist and a chemotherapeutic agent. In another embodiment, conventional treatment comprises administration of a PD-1 antagonist and a taxane. In another embodiment, conventional treatment comprises administration of a PD-L1 antagonist and a taxane. In another embodiment, conventional treatment comprises administration of a PD-L1 antagonist and Nab-paclitaxel. In another embodiment, the conventional treatment comprises administration of a PD-L1 antagonist and 5-FU. In another embodiment, the conventional treatment comprises administration of a PD-L1 antagonist and a topoisomerase inhibitor. The conventional treatment comprises administration of a PD-L1 antagonist and a topoisomerase inhibitor. In another embodiment, the conventional treatment comprises administration of a PD-L1 antagonist and irinotecan hydrochloride hydrate or topotecan. In another embodiment, the conventional treatment comprises administration of a PD-L1 antagonist, erlotinib, capecitabine, and / or 5-FU. In another embodiment, the conventional treatment comprises administration of a PD-1 antagonist and an anti-CTLA4 antibody. In another embodiment, the conventional treatment comprises administration of a PD-L1 antagonist and an anti-CTLA4 antibody. In another embodiment, the conventional treatment comprises administration of an anti-CTLA4 antibody. In another embodiment, the conventional treatment is neoadjuvant therapy with a PD-L1 antagonist.

[0150] In one embodiment of the present invention, the taxane is paclitaxel. In another embodiment, the albumin is human serum albumin. In another embodiment, the nanoparticles comprise paclitaxel coated with albumin. In another embodiment, the average particle size of the nanoparticles in the nanoparticle composition is about 200 nm or less (less than about 200 nm). In another embodiment, the composition comprises a nanoparticle formulation of paclitaxel stabilized with albumin (Nab-paclitaxel (used interchangeably with the term "ABRAXANE®")). In another embodiment, the composition is Nab-paclitaxel (ABRAXANE®).

[0151] As used herein, the "combined use" of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor or their "use together" includes simultaneous administration using separate formulations or a single pharmaceutical formulation, and administration in any order, preferably within a period during which both (or all) active agents simultaneously exhibit biological activity. The order, frequency, and duration of administration of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor can be determined by one skilled in the art as needed. Either a VEGF signaling inhibitor or a PD-1 / PD-L1 signaling inhibitor may be administered before or after the other, or they may be administered simultaneously. In another embodiment, another drug or pharmaceutical agent other than a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor may be used simultaneously with a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor, or before or after each inhibitor. In another embodiment, radiation therapy or surgery may be administered simultaneously with a VEGF signaling inhibitor and a PD- / PD-L1 signaling inhibitor, or before or after each inhibitor.

[0152] Herein, "treatment," "treating," or "treating" (also referred to as "therapy," "applying therapy," or "applying therapy") refers to the alleviation, mitigation, or pacification of a specific disease or symptom, including protection against future onset (prophylaxis) and inhibition of progression of the disease or symptom. Desirable therapeutic effects of treatment include alleviation of symptoms, reduction of direct or indirect pathological consequences of the disease, slowing the rate of progression of symptoms, amelioration or alleviation of the disease state, and improved prognosis. "Treatment" or "therapy" is not necessarily limited to "treatment" or "therapy" that achieves complete recovery or results in a cure of the disease or symptom, nor is it limited to obtaining a desired therapeutic effect, i.e., effective "treatment" or "cure." For example, cancer treatment (or treatment against cancer) refers to administering medication, surgery, radiation therapy, etc. to a subject having or diagnosed with cancer, with the intent of achieving at least one desired therapeutic effect, such as reducing the number of cancer cells, reducing tumor size, reducing the proportion of cancer cells that invade peripheral organs, or reducing tumor metastasis or tumor growth rate. In one embodiment of the present invention, cancer treatment refers to treatment with the medicament, kit, or treatment method of the present invention.

[0153] The therapeutic effect, i.e., effectiveness, of cancer treatment can be evaluated by the method or standard shown herein, or by one or more known methods or standards (WA Weber, J. Nucl. Med. 50:1S-10S 2009).For example, in terms of tumor growth inhibition, T / C of 42% or less is the minimum level of anti-tumor activity according to the standards of the National Cancer Institute (NCI).T / C of less than 10% is considered to be a high level of anti-tumor activity, and T / C (%) = median tumor volume of treated person / median tumor volume of control × 100.

[0154] In one embodiment, the therapeutic effect of a treatment against cancer, i.e., the effectiveness of the anti-cancer effect, can be evaluated by one or more known criteria for the condition of the patient, affected organ, or affected cell, etc. Examples of criteria include partial response (PR), complete response (CR), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), pathological complete response (pCR), and clinical complete response (cCR).

[0155] ORR refers to the percentage of people who experience a reduction in the size or volume of their cancer over a minimum period of time. Furthermore, ORR can be expressed as the sum of the complete response rate and partial response rate. DCR refers to the percentage of patients whose disease does not progress and can be expressed as the sum of the complete response rate, partial response rate, and stable disease rate (SD). PFS, also known as "time to tumor progression," refers to the length of time during and after treatment that a patient survives without cancer progression, including the period during which the patient experiences CR or PR and the period during which the patient experiences SD. DFS is the length of time during and after treatment that a patient survives without recurrence or other disease. OS is the period of time a subject survives, starting from the date of treatment initiation. Prolonging OS due to treatment is, for example, extending the point estimate of median survival from the date of study in a group of treated patients compared to a group of untreated patients.

[0156] In one embodiment, the response to treatment with the medicament, kit or treatment method of the present invention is any one of PR, CR, PFS, DFS, ORR, DCR or OS as assessed using the response criteria in Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

[0157] In one embodiment, the effectiveness of a cancer treatment can be evaluated using a specific efficacy assessment marker: The serum CA19-9 (carbohydrate antigen 19-9) level in an individual administered a composition comprising nanoparticles containing a PD-1 / PD-L1 signaling inhibitor and albumin is reduced by at least about 50% (e.g., at least one of about 60%, 70%, 80%, 90%, 95%, etc.) compared to the serum CA19-9 level before treatment.

[0158] Not all embodiments of the present invention will be effective in achieving the desired therapeutic effect in all subjects, but any one of the embodiments of the present invention should achieve the desired therapeutic effect in a statistically significant number of subjects as determined by any statistical test known in the art, such as Student's t-test, chi-squared test, Mann-Whitney U test, Kruskal-Wallis test (H test), Jonkheel-Terpstra test, and Wilcoxon test.

[0159] A treatment can be determined to be effective or have anti-cancer effects if the effectiveness is recognized by at least one of the criteria set forth herein or known criteria for evaluating therapeutic effects against cancer. Preferably, the effectiveness is related to the extension of a patient's survival time or the improvement of general symptoms, such as pain relief. However, a treatment can also be determined to be effective if it has a therapeutic effect, such as the shrinkage or temporary disappearance of cancer. Furthermore, "more effective," "higher efficacy," "high therapeutic effect," or "increased therapeutic effect," etc., compared to a comparison subject, means a higher efficacy by comparison with at least one of the criteria set forth herein or known criteria.

[0160] The PD-1 / PD-L1 signaling inhibitor may be any agent that can inhibit the function or activity of PD-1 or PD-L1 by direct or indirect effects, and may be a PD-1 antagonist or a PD-L1 antagonist. The PD-1 / PD-L1 signaling inhibitor may be an inhibitor that inhibits the function or activity of PD-1, or may be a PD-L1 inhibitor that inhibits the function or activity of PD-L1.

[0161] A PD-1 antagonist can be any molecule that can neutralize, block, inhibit, suppress, reduce, or interfere with the function or activity of PD-1 or PD-L1. For example, a PD-1 antagonist can be an anti-PD-1 antibody or its antigen-binding fragment, or a PD-L1 molecule or its derivative that binds to PD-1 and inhibits the binding of PD-1 and PD-L1. Examples of PD-1 antagonists include antibodies, antibody fragments, binding polypeptides, peptides, and non-peptide molecules. More specifically, examples of PD-1 antagonists include AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, and pidilizumab (CT-011). The PD-1 antagonist is preferably an anti-PD-1 antibody or an antigen-binding fragment thereof, and more preferably a PD-1 neutralizing antibody or an antigen-binding fragment thereof.

[0162] The anti-PD-1 antibody is an antibody that binds to PD-1, preferably an antibody that binds to PD-1 and inhibits its function, more preferably an antibody that inhibits the binding of PD-1 or B7.1 to PD-L1 and inhibits its function, and more preferably an antibody that inhibits signal transduction induced by the binding of PD-1 or B7.1 to PD-L1, such as a neutralizing antibody.

[0163] Inhibiting PD-1 function refers to relieving the suppression of T cell activation induced as a result of PD-1 or B7.1 binding to PD-L1, and PD-1 activity is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to activity in a control. PD-1 activity can be determined by any standard method in the art, including those described herein.

[0164] Examples of PD-1 antagonists that can be used include nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, and pidilizumab (CT-011), but it is preferable to use nivolumab or pembrolizumab.

[0165] Taking into consideration the desired function, the anti-PD-1 antibody may be any antibody that has the same antigen-binding characteristics as nivolumab, AMP-514, pembrolizumab, REGN2810, PDR001, BGB-A317, or pidilizumab. For example, the anti-PD-1 antibody may be an antibody or antigen-binding fragment thereof that contains hypervariable regions (CDRs) that each have the same amino acid sequence as the amino acid sequence of each CDR in the heavy and light chains of nivolumab, AMP-514, pembrolizumab, REGN2810, PDR001, BGB-A317, or pidilizumab. Alternatively, taking into consideration the desired function, the anti-PD-1 antibody may be an antibody or antigen-binding fragment thereof comprising an amino acid sequence of a heavy chain variable (HV) region or a light chain variable (LV) region that has the same amino acid sequence as the amino acid sequence of the HV region or LV region of nivolumab, AMP-514, pembrolizumab, REGN2810, PDR001, BGB-A317, or pidilizumab.

[0166] In one embodiment, the anti-PD-1 antibody may be an antibody or antigen-binding fragment thereof comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of nivolumab, AMP-514, pembrolizumab, REGN2810, PDR001, BGB-A317, or pidilizumab, respectively. In one embodiment, the anti-PD-1 antibody may be an antibody or antigen-binding fragment thereof comprising CDRs each comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of each CDR in the heavy and light chain, respectively, of nivolumab, AMP-514, pembrolizumab, REGN2810, PDR001, BGB-A317, or pidilizumab, respectively. In one embodiment, the anti-PD-1 antibody may be an antibody or antigen-binding fragment thereof comprising HV and LV regions that comprise amino acid sequences having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequences of the HV and LV regions, respectively, of nivolumab, AMP-514, pembrolizumab, REGN2810, PDR001, BGB-A317, or pidilizumab.

[0167] A PD-L1 antagonist can be any molecule that can neutralize, block, inhibit, suppress, reduce, or interfere with the function or activity of PD-L1 or PD-1. For example, a PD-L1 antagonist can be an anti-PD-L1 antibody or its antigen-binding fragment, or a PD-1 molecule or derivative thereof that inhibits the binding of PD-1 and PD-L1 by binding to PD-L1. Examples include antibodies, antibody fragments, binding polypeptides, peptides, and non-peptide molecules. The PD-L1 antagonist is preferably an anti-PD-L1 antibody or its antigen-binding fragment, and more preferably a PD-L1 neutralizing antibody or its antigen-binding fragment.

[0168] The anti-PD-L1 antibody is an antibody that binds to PD-L1, preferably an antibody that binds to PD-L1 and inhibits its function, more preferably an antibody that inhibits the binding of PD-1 or B7.1 to PD-L1 and inhibits its function, and more preferably an antibody that inhibits signal transduction induced by the binding of PD-1 or B7.1 to PD-L1, such as a neutralizing antibody.

[0169] Inhibiting PD-L1 function refers to relieving the suppression of T cell activation induced as a result of PD-1 or B7.1 binding to PD-L1, and PD-L1 activity is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to activity in a control. PD-L1 activity can be determined by any standard method in the art, including those described herein.

[0170] Examples of anti-PD-L1 antibodies that can be used include atezolizumab, avelumab (MSB0010718C), durvalumab, BMS-936559, MPDL3280A, MEDI4736, KN035, CX-072, LY3300054, and FAZ053. However, atezolizumab, avelumab, durvalumab, BMS-936559, MPDL3280A, or MEDI4736 are preferred, and atezolizumab, avelumab, or durvalumab are even more preferred.

[0171] Considering the desired function, the anti-PD-L1 antibody can be any antibody that has the same antigen-binding characteristics as atezolizumab, avelumab, durvalumab, BMS-936559, MPDL3280A, MEDI4736, KN035, CX-072, LY3300054, or FAZ053. For example, anti-PD-L1 antibodies include antibodies comprising CDR sequences having the same amino acid sequences as the amino acid sequences (SEQ ID NOs: 5 to 10) of the hypervariable regions (HCDR1 to 3, LCDR1 to 3) of the heavy chain (SEQ ID NO: 1) and light chain (SEQ ID NO: 2) of atezolizumab, antibodies comprising CDR sequences having the same amino acid sequences as the amino acid sequences (SEQ ID NOs: 15 to 20) of the hypervariable regions (HCDR1 to 3, LCDR1 to 3) of the heavy chain (SEQ ID NO: 11) and light chain (SEQ ID NO: 12) of avelumab, antibodies comprising CDR sequences having the same amino acid sequences as the amino acid sequences (SEQ ID NOs: 15 to 20) of the hypervariable regions (HCDR1 to 3, LCDR1 to 3) of the heavy chain (SEQ ID NO: 21) and light chain (SEQ ID NO: 22) of durvalumab, and antibodies comprising CDR sequences having the same amino acid sequences as the amino acid sequences of the hypervariable regions (HCDR1 to 3, LCDR1 to 3) of the heavy chain (SEQ ID NO: 21) and light chain (SEQ ID NO: 22) of durvalumab. the antibody may be an antibody comprising CDR sequences having the same amino acid sequences as the amino acid sequences (SEQ ID NOs: 27 to 29) of the hypervariable regions (HCDR1 to 3) of the heavy chain (SEQ ID NO: 25) of CX-072; an antibody comprising CDR sequences having the same amino acid sequences as the amino acid sequences of the hypervariable regions (HCDR1 to 3, LCDR1 to 3) of the heavy chain (SEQ ID NO: 30) and light chain (SEQ ID NO: 31) of CX-072; or an antibody comprising CDR sequences having the same amino acid sequences as the amino acid sequences (SEQ ID NOs: 38 to 43) of the hypervariable regions (HCDR1 to 3, LCDR1 to 3) of the heavy chain (SEQ ID NO: 34) and light chain (SEQ ID NO: 35) of LY3300054, or an antigen-binding fragment thereof. Alternatively, the anti-PD-L1 antibody may be an antibody or antigen-binding fragment that comprises hypervariable regions (CDRs), each with an amino acid sequence identical to the amino acid sequence of each CDR of the heavy and light chains of BMS-936559, MPDL3280A, MEDI4736, or FAZ053, respectively. Alternatively, taking into consideration the desired function, the anti-PD-L1 antibody may be an antibody or antigen-binding fragment thereof comprising a heavy chain variable (VH) region and / or a light chain variable (VL) region having the same amino acid sequence as the VH region of atezolizumab (SEQ ID NO: 3) and / or VL region (SEQ ID NO: 4), the VH region of avelumab (SEQ ID NO: 13) and / or VL region (SEQ ID NO: 14), the VH region of durvalumab (SEQ ID NO: 23) and / or VL region (SEQ ID NO: 24), the VH region of KN035 (SEQ ID NO: 26), the VH region of CX-072 (SEQ ID NO: 32) and / or VL region (SEQ ID NO: 33), or the VH region of LY3300054 (SEQ ID NO: 36) and / or VL region (SEQ ID NO: 37). Alternatively, it may be an antibody or antigen-binding fragment thereof comprising a heavy chain variable (VH) region and / or a light chain variable (VL) region having the same amino acid sequence as the amino acid sequence of the VH region and / or VL region of BMS-936559, MPDL3280A, MEDI4736, or FAZ053, respectively.

[0172] In one embodiment, the anti-PD-L1 antibody may be an antibody or antigen-binding fragment thereof that comprises amino acids with at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of atezolizumab, avelumab, durvalumab, BMS-936559, MPDL3280A, MEDI4736, KN035, CX-072, LY3300054, or FAZ053, respectively. In one embodiment, the anti-PD-L1 antibody may be an antibody or antigen-binding fragment thereof comprising CDRs each comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of each CDR in the heavy and light chains of atezolizumab, avelumab, durvalumab, BMS-936559, MPDL3280A, MEDI4736, KN035, CX-072, LY3300054, or FAZ053, respectively. In one embodiment, the anti-PD-L1 antibody may be an antibody or antigen-binding fragment thereof comprising a VH region and a VL region comprising amino acid sequences that have at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequences of the VH region and VL region, respectively, in atezolizumab, avelumab, durvalumab, BMS-936559, MPDL3280A, MEDI4736, KN035, CX-072, LY3300054, or FAZ053.

[0173] The VEGF signaling inhibitor can be any agent that can inhibit the function or activity of VEGF signaling by direct or indirect effects, and can be a VEGF antagonist or a VEGFR antagonist. The VEGF signaling inhibitor can be a VEGF inhibitor that inhibits the function or activity of VEGF, or a VEGF receptor (VEGFR) inhibitor that inhibits the function of VEGFR.

[0174] A VEGF antagonist can be any molecule that can neutralize, block, inhibit, suppress, reduce, or interfere with the function or activity of VEGF or VEGF receptor (VEGFR), and can be an anti-VEGF antibody or an anti-VEGF receptor (VEGFR) antibody or an antigen-binding fragment thereof. In addition, it can be, for example, a VEGF molecule or a derivative thereof that inhibits the binding of VEGF and VEGFR by binding to VEGFR. Examples of VEGF antagonists can include antibodies, antibody fragments, binding polypeptides, peptides, and non-peptide molecules. The VEGF antagonist is preferably an anti-VEGF antibody or an anti-VEGFR antibody, or an antigen-binding fragment thereof, and more preferably a VEGF-neutralizing antibody or a VEGFR-neutralizing antibody, or an antigen-binding fragment thereof.

[0175] VEGF neutralizing antibodies and VEGFR neutralizing antibodies are antibodies that reduce or eliminate the function or activity of VEGF and VEGFR, respectively, and neutralize their function or activity. However, because VEGF and VEGFR have a ligand-receptor relationship, both VEGF neutralizing antibodies and VEGFR neutralizing antibodies can be anti-VEGF antibodies or anti-VEGFR antibodies that bind to VEGF or VEGFR and inhibit the binding of VEGF and VEGFR.

[0176] Inhibiting VEGF or VEGFR function reduces VEGF or VEGFR activity by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to activity in a control. VEGF or VEGFR activity can be determined by any standard method in the art, including those described herein.

[0177] As the anti-VEGF antibody or anti-VEGFR antibody, bevacizumab, ramucirumab, or aflibercept beta can be preferably used.

[0178] Considering the desired function, the anti-VEGF or anti-VEGFR antibody may be any antibody that has the same antigen-binding specificity as bevacizumab, ramucirumab, or aflibercept beta. For example, it may be an antibody containing CDR sequences with the same amino acid sequences as the amino acid sequences (SEQ ID NOS: 48-53) of the hypervariable regions (HCDRs 1-3, FCDRs 1-3) of the heavy chain (SEQ ID NOS: 44) and light chain (SEQ ID NOS: 45) of bevacizumab, or an antibody containing CDR sequences with the same amino acid sequences as the amino acid sequences (SEQ ID NOS: 58-63) of the hypervariable regions (HCDRs 1-3, LCDRs 1-3) of the heavy chain (SEQ ID NOS: 54) and light chain (SEQ ID NOS: 55) of ramucirumab, or an antigen-binding fragment thereof. Alternatively, it may be an antibody or antigen-binding fragment thereof containing CDRs with the same amino acid sequences as the amino acid sequences of the hypervariable regions (CDRs) of the heavy and light chains of aflibercept beta. Alternatively, taking into consideration the desired function, the anti-VEGF antibody or anti-VEGFR antibody may be an antibody or antigen-binding fragment thereof comprising a heavy chain variable (VH) region and / or a light chain variable (VL) region having the same amino acid sequence as the VH region (SEQ ID NO: 46) and / or the VL region (SEQ ID NO: 47) of bevacizumab or the VH region (SEQ ID NO: 56) and / or the VL region (SEQ ID NO: 57) of ramucirumab. Alternatively, the anti-VEGF antibody or anti-VEGFR antibody may be an antibody or antigen-binding fragment thereof comprising a heavy chain variable (VH) region and / or a light chain variable (VL) region having the same amino acid sequence as the VH region and / or the VL region of aflibercept beta.

[0179] In one embodiment, the anti-VEGF antibody or anti-VEGFR antibody may be an antibody or antigen-binding fragment thereof comprising amino acids having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of bevacizumab, ramucirumab, or aflibercept beta, respectively. In one embodiment, the anti-VEGF antibody or anti-VEGFR antibody may be an antibody or antigen-binding fragment thereof comprising CDRs each comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequence of each CDR in the heavy chain and light chain, respectively, of bevacizumab, ramucirumab, or aflibercept beta, respectively. In one embodiment, the anti-VEGF antibody or anti-VEGFR antibody may be an antibody or antigen-binding fragment thereof comprising a heavy chain variable (VH) region and a light chain variable (VL) region comprising amino acid sequences having at least 80%, 85%, 90%, 95%, 98%, or 99% sequence identity to the amino acid sequences of the VH and VL regions, respectively, in bevacizumab, ramucirumab, or aflibercept beta.

[0180] In the medicament, treatment method, kit and use, as well as the VEGF signaling inhibitor, the PD-1 / PD-L1 signaling inhibitor and combinations thereof of the present invention, embodiments of the combination of the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor include, but are not limited to, the following:

[0181] combination of bevacizumab and AMP-224, combination of bevacizumab and BMS-936559, combination of bevacizumab and MEDI4736, combination of bevacizumab and MSB0010718C, combination of bevacizumab and MPDL3280A, combination of bevacizumab and nivolumab, combination of bevacizumab and AMP-514, combination of bevacizumab and pembrolizumab (MK-3475), combination of bevacizumab and REGN2810, combination of bevacizumab and PDR001, combination of bevacizumab and BGB-A317, or combination of bevacizumab and pidilizumab (CT-011).

[0182] combination of ramucirumab and AMP-224, combination of ramucirumab and BMS-936559, combination of ramucirumab and MEDI4736, combination of ramucirumab and MSB0010718C, combination of ramucirumab and MPDL3280A, combination of ramucirumab and nivolumab, combination of ramucirumab and AMP-514, combination of ramucirumab and pembrolizumab (MK-3475), combination of ramucirumab and REGN2810, combination of ramucirumab and PDR001, combination of ramucirumab and BGB-A317, or combination of ramucirumab and pidilizumab (CT-011).

[0183] The combination of aflibercept beta and AMP-224, the combination of aflibercept beta and BMS-936559, the combination of aflibercept beta and MEDI4736, the combination of aflibercept beta and MSB0010718C, the combination of aflibercept beta and MPDL3280A, the combination of aflibercept beta and nivolumab, the combination of aflibercept beta and AMP-514, the combination of aflibercept beta and pembrolizumab (MK-3475), the combination of aflibercept beta and REGN2810, the combination of aflibercept beta and PDR001, the combination of aflibercept beta and BGB-A317, or the combination of aflibercept beta and pidilizumab (CT-011).

[0184] combination of bevacizumab and atezolizumab, combination of bevacizumab and avelumab (MSB0010718C), combination of bevacizumab and durvalumab, combination of bevacizumab and BMS-936559, combination of bevacizumab and MPDL3280A, combination of bevacizumab and MEDI4736, combination of bevacizumab and KN035, combination of bevacizumab and CX-072, combination of bevacizumab and LY3300054, or combination of bevacizumab and FAZ053.

[0185] Ramucirumab in combination with atezolizumab, ramucirumab in combination with avelumab (MSB0010718C), ramucirumab in combination with durvalumab, ramucirumab in combination with BMS-936559, ramucirumab in combination with MPDL3280A, ramucirumab in combination with MEDI4736, ramucirumab in combination with KN035, ramucirumab in combination with CX-072, ramucirumab in combination with LY3300054, or ramucirumab in combination with FAZ053.

[0186] Aflibercept beta in combination with atezolizumab, aflibercept beta in combination with avelumab (MSB0010718C), aflibercept beta in combination with durvalumab, aflibercept beta in combination with BMS-936559, aflibercept beta in combination with MPDL3280A, aflibercept beta in combination with MEDI4736, aflibercept beta in combination with KN035, aflibercept beta in combination with CX-072, aflibercept beta in combination with LY3300054, or aflibercept beta in combination with FAZ053.

[0187] The antibody can be obtained as a polyclonal or monoclonal antibody using known techniques. The antibody origin is not limited, but the antibody is preferably of mammalian origin, more preferably of human origin. Monoclonal antibodies of mammalian origin include those produced by hybridomas and those produced by hosts transformed with expression vectors containing antibody genes using genetic engineering techniques. The antibody can be a chimeric antibody, a humanized antibody, or a human antibody, or an antibody derived from a library or antibody fragment thereof.

[0188] The antibody may be a conjugated antibody linked to various molecules such as polyethylene glycol (PEG), radioactive substances, or toxins. Such conjugated antibodies can be obtained by chemically modifying the antibody. In addition, methods for modifying antibodies have already been established in the field. The term "antibody" as used herein also includes these conjugated antibodies.

[0189] Antibodies include not only bivalent antibodies such as IgG, but also monovalent or multivalent antibodies such as IgM. The multivalent antibodies of the present invention include multivalent antibodies having completely identical antigen-binding sites, or multivalent antibodies having partially or completely different antigen-binding sites.

[0190] Additionally, the antibody may be a bispecific antibody, which refers to an antibody having variable regions that recognize different epitopes within the same antibody molecule, although the epitopes may be located on different molecules or on the same molecule.

[0191] Methods for producing bispecific antibodies are known. For example, bispecific antibodies can be produced by linking two types of antibodies that recognize different antigens. The linked antibodies may be half molecules of an antibody having an H chain and an F chain, or a quarter molecule of an antibody consisting of only an H chain. Alternatively, fused cells that produce bispecific antibodies can be produced by fusing hybridomas that produce different monoclonal antibodies. Furthermore, bispecific antibodies can be produced using genetic engineering techniques.

[0192] The antibody may be a low-molecular-weight antibody. Low-molecular-weight antibodies include antibody fragments lacking a portion of a full-length antibody. Partial deletions of the antibody molecule are acceptable as long as the antibody molecule binds to Arid5A. The antibody fragments of the present invention preferably comprise either or both of the heavy chain variable region (VH) and the light chain variable region (VL). The amino acid sequence of the VH or VL may include additions, deletions, and / or substitutions. Furthermore, the molecule may lack portions of either or both of the VH and VL, as long as they bind to PD-L1. Such antibody fragments may be chimeric or humanized antibody fragments. Specific examples of antibody fragments include Fab, Fab', F(ab')2, and Fv. Specific examples of low-molecular-weight antibodies include Fab, Fab', F(ab')2, Fv, scFv, diabody, and sc(Fv)2.

[0193] The formulation can be made into tablets, granules, powders, capsules, emulsions, suspensions, or syrups or injections, such as sterile solutions or liquid suspensions, according to conventional methods.When these active ingredients are formulated separately into two or more formulations, the individual formulations can be administered simultaneously, or separately or sequentially at set time intervals.Two or more formulations can also be administered at different frequencies per day.The medicament according to the present invention can be administered orally or parenterally, systemically or locally.When these active ingredients are formulated separately into two or more formulations, the individual formulations can also be administered by different routes.

[0194] When the medicament according to the present invention is prepared as multiple different formulations that are likely to be administered simultaneously or at specific intervals, documentation such as the package insert or sales pamphlet of the commercially available medicine may indicate the respective combinations. In addition, it is possible to prepare a kit containing the respective formulations described above.

[0195] The formulations can be prepared for storage by mixing the desired active ingredient in the form of a lyophilized formulation or aqueous solution with any pharmaceutically acceptable carriers, excipients, or stabilizers.

[0196] Examples of pharmaceutically acceptable materials include sterilized water, physiological saline, stabilizers, excipients, buffers, preservatives, surfactants, chelating agents (such as EDTA), binders, and the like.

[0197] The surfactant may be a nonionic surfactant. Representative examples include sorbitan fatty acid esters such as sorbitan monocaprylate, sorbitan monolaurate, and sorbitan monopalmitate; and glycerin fatty acid esters such as glycerin monocaprylate, glycerin monomyristate, and glycerin monostearate, each having an HLB of 6 to 18.

[0198] The surfactant may be an anionic surfactant. Typical examples of surfactants include C surfactants such as sodium acetyl sulfate, sodium lauryl sulfate, and sodium oleyl sulfate. 10~18 Alkyl sulfates with alkyl groups; C such as polyoxyethylene sodium lauryl sulfate 10~18 Polyoxyethylene alkyl ether sulfates having an alkyl group and an average number of moles of ethylene oxide added of 2 to 4; C such as sodium lauryl sulfosuccinate 8~18 Alkyl sulfosuccinates with alkyl groups; natural surfactants, such as lecithin and glycerophospholipids; sphingophospholipids such as sphingomyelin; and C 12 ~ 18 Mention may be made of sucrose fatty acid esters with fatty acids.

[0199] Examples of buffers may include phosphate, citrate buffer, acetic acid, malic acid, tartaric acid, succinic acid, lactic acid, potassium phosphate, gluconic acid, caprylic acid, deoxycholic acid, salicylic acid, triethanolamine, fumaric acid, other organic acids, etc., or carbonate buffer, Tris buffer, histidine buffer, imidazole buffer, etc.

[0200] Furthermore, solution formulations can be prepared by dissolving in an aqueous buffer known in the field of solution formulations. The concentration of the buffer is generally 1 to 500 mM, preferably 5 to 100 mM, and more preferably 10 to 20 mM.

[0201] Examples of carbohydrates or sugars, such as polysaccharides and monosaccharides, include dextran, glucose, fructose, lactose, xylose, mannose, maltose, sucrose, trehalose, raffinose, and the like.

[0202] Examples of sugar alcohols include mannitol, sorbitol, and inositol.

[0203] When the formulation is an aqueous solution, examples thereof include saline and tonic solutions containing glucose or other adjuvants such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, which can be used in combination with a suitable solubilizer such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, PEG), or nonionic surfactant (polysorbate 80, HCO-50).

[0204] If desired, the composition may further contain a diluent, a solubilizing agent, a pH adjuster, an analgesic, a sulfur-containing reducing agent, an antioxidant, and the like.

[0205] In one embodiment, in addition to administering the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor via conventional routes, administration by gene therapy may be included. For example, the use of an anti-VEGF antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody in gene therapy can be carried out using known methods.

[0206] The dose and administration schedule of the pharmaceutical agent of the present invention will vary depending on the subject to be administered, the subject's age and weight, disease symptoms, administration method, and the types of VEGF signaling inhibitor and PD-1 / PD-L1 signaling inhibitor used, and can be determined empirically by one skilled in the art according to the manufacturer's instructions.

[0207] In the pharmaceutical compositions of the present invention, the VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor are preferably administered in combination, and may be administered simultaneously, separately, or sequentially. The VEGF signaling inhibitor and the PD-1 / PD-L1 signaling inhibitor can be administered simultaneously as individual formulations, separately, or sequentially at a set time interval. Two or more formulations may be administered at different frequencies within a day, or at different frequencies separated by a set number of days. Each formulation may be administered to a single subject according to a separate administration schedule, as described below.

[0208] The VEGF signaling inhibitor can be administered to a human subject, for example, by intravenous infusion, at a dose of about 1 mg / kg to about 50 mg / kg or about 4 mg / kg to about 15 mg / kg per administration. More specifically, the dose can be about 4 mg / kg (body weight), about 5 mg / kg (body weight), about 8 mg / kg (body weight), about 7.5 mg / kg (body weight), about 10 mg / kg (body weight), or about 15 mg / kg (body weight). These doses can be administered, for example, at intervals of about one week or more, about two weeks or more, or about three weeks or more. The duration of each administration is preferably about 30 to 90 minutes, but is not limited thereto as long as it is safe.

[0209] As mentioned above, specific examples of VEGF signaling inhibitors include anti-VEGF antibodies bevacizumab, ramucirumab, aflibercept beta, etc. As mentioned above, the dose and dosing schedule of the VEGF signaling inhibitor can be determined by those skilled in the art according to the embodiment. However, for example, in the case of bevacizumab, it can be administered to a human subject at a dose of about 5 mg / kg (body weight) or about 10 mg / kg (body weight) per administration at a dosing interval of about 2 weeks or more than 2 weeks, about 7.5 mg / kg (body weight) per administration at a dosing interval of about 3 weeks or more than 3 weeks, or about 15 mg / kg (body weight) per administration at a dosing interval of about 3 weeks or more than 3 weeks. In the case of ramucirumab, it can be administered to a human subject at a dose of about 8 mg / kg (body weight) per administration at a dosing interval of about 2 weeks, or about 10 mg / kg (body weight) per administration at a dosing interval of about 3 weeks. In the case of aflibercept beta, administration can be at about 4 mg / kg (body weight) per dose with dosing intervals of about 2 weeks.

[0210] Furthermore, the PD-1 / PD-L1 signaling inhibitor can be administered to a human subject, for example, by intravenous infusion, at a dose of about 0.1 mg to about 30,000 mg per administration. More specifically, the dose can be about 1 mg to about 10 mg, about 80 mg to about 240 mg, about 840 mg to about 1,000 mg, or about 1,200 mg per administration. More specifically, the dose can be about 10 mg, about 80 mg, about 240 mg, about 840 mg, or about 1,200 mg per administration. Alternatively, the dose can be about 1.0 mg / kg (body weight) or more, about 2.0 mg / kg (body weight) or more, about 2.5 mg / kg (body weight) or more, about 10 mg / kg (body weight) or more, or about 20 mg / kg (body weight) or more, to about 100 mg / kg (body weight) per administration. More specifically, the dosage can be about 2 mg / kg (body weight), about 10 mg / kg (body weight), about 15 mg / kg (body weight), or about 20 mg / kg (body weight) per administration. In addition, these doses can be administered, for example, at intervals of about 2 weeks or more than about 2 weeks, or at intervals of about 3 weeks or more than about 3 weeks. The duration of each administration is preferably about 30 to 90 minutes, but is not limited thereto as long as it can be administered safely.

[0211] As described above, the dose and dosing schedule of the PD-1 / PD-L1 signaling inhibitor can be determined by those skilled in the art according to the embodiment. However, for example, in the case of atezolizumab, it can be administered to a human subject at a dose of about 1,200 mg per administration at dosing intervals of about one week or more, preferably at dosing intervals of about two to four weeks, and more preferably at dosing intervals of about three weeks. Alternatively, in the case of atezolizumab, it can be administered at a dose of about 840 mg per administration at dosing intervals of about one week or more, preferably at dosing intervals of about two weeks. In the case of avelumab, it can be administered at a dose of about 10 mg / kg (body weight) per administration at dosing intervals of about three weeks. In the case of durvalumab, it can be administered at a dose of about 10 mg / kg (body weight) per administration at dosing intervals of about two weeks. In the case of nivolumab, it can be administered at a dose of about 240 mg per administration at dosing intervals of about two weeks, or at a dose of about 80 mg per administration at dosing intervals of about three weeks. For pembrolizumab, dosing can be at about 2 mg / kg (body weight) per dose at about 3 week intervals between doses, or about 200 mg per dose at about 3 week intervals between doses.

[0212] In the pharmaceutical composition of the present invention, a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor are administered in combination. However, for example, when bevacizumab is used as the VEGF signaling inhibitor and atezolizumab is used as the PD-1 / PD-L1 signaling inhibitor, the following dosing schedule can be used: atezolizumab is administered intravenously, followed by intravenous administration of bevacizumab at least about 5 minutes later. Alternatively, if the subject feels unwell after intravenous administration of atezolizumab, a period of about 60 minutes ± 15 minutes follows, followed by intravenous administration of bevacizumab.

[0213] With regard to the administration of a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor, those skilled in the art can appropriately adjust the administration time, dosage interval, number of doses, and administration period depending on the therapeutic effect, patient condition, tolerability, etc.

[0214] In the pharmaceutical compositions of the present invention, a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor may be administered in combination, and one or more chemotherapeutic agents may also be administered in combination. For example, when bevacizumab is used as the VEGF signaling inhibitor and atezolizumab is used as the PD-1 / PD-L1 signaling inhibitor, the chemotherapeutic agents are preferably carboplatin, docetaxel, paclitaxel, etoposide, capecitabine, oxaliplatin, fluorouracil, calcium levofolinate, calcium folate, irinotecan hydrochloride hydrate, gemcitabine hydrochloride, cisplatin, temozolomide, or nogitecan hydrochloride, or a combination thereof, with carboplatin and / or paclitaxel being more preferred. In this case, a person skilled in the art can appropriately adjust the administration time, dosing interval, number of doses, and administration period of the VEGF signaling inhibitor, PD-1 / PD-L1 signaling inhibitor, and one or more chemotherapeutic agents depending on the therapeutic effect, patient symptoms, tolerability, etc. For example, in a human subject, administration can be performed at about 5 mg / kg (body weight), about 10 mg / kg (body weight), about 7.5 mg / kg (body weight), or about 15 mg / kg (body weight) per administration for bevacizumab, and about 1,200 mg or 840 mg per administration for atezolizumab. Further, in a combination of bevacizumab and atezolizumab, for example, carboplatin can be administered at about AUC6 per administration, and docetaxel can be administered at about 75 mg / m per administration. 2 and paclitaxel may be administered at about 200 mg / m per dose. 2 (iv), wherein Nab-paclitaxel is administered at about 100 mg / m per dose. 2 (iv) and / or etoposide may be administered at about 100 mg / m per dose. 2 The administration may be at an AUC of about 6 per dose for carboplatin and about 200 mg / m per dose for paclitaxel. 2(iv) The drugs may be administered simultaneously, separately, or sequentially, each at a dosing interval of about 1 to 4 weeks. For example, bevacizumab may be administered at about 5 mg / kg (body weight) per administration at about 2-week dosing intervals, about 10 mg / kg (body weight) per administration at about 2-week dosing intervals, about 7.5 mg / kg (body weight) per administration at about 3-week dosing intervals, or about 15 mg / kg (body weight) per administration at about 3-week dosing intervals. For example, atezolizumab can be administered at about 1,200 mg per dose at about three-week intervals, or 840 mg per dose at about two-week intervals.

[0215] Additionally, when "about" is used to modify a numerically defined parameter (e.g., the dosage or length of treatment of a drug used in a combination therapy described herein), it means that the parameter varies within a 10% range above or below the numerical value given for the parameter. For example, "about 5 mg" means "4.5 mg to 5.5 mg."

[0216] Incorporation by Reference All publications, patents, and patent applications mentioned herein are herein incorporated by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including definitions herein, will control. [Example]

[0217] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples.

[0218] ==Creating a Mouse Model== OV2944-HM-1 cells and Colon38 cells were cultured in a cell culture flask in an incubator (set at 37°C and 5% CO2). For OV2944-HM-1 cells, cells were harvested and cultured at 1 × 10 7The cells were resuspended at 1 × 10 cells / mL and inoculated subcutaneously into the right groin of B6C3L1 mice (CLEA Japan, Inc.). 6 cells / mouse). For Colon38 cells, cells were harvested and diluted to 2 × 10 7 The cells were resuspended at 1 × 10 cells / mL, mixed with an equal volume of Matrigel (Nippon Becton, Dickinson and Company), and inoculated subcutaneously into the right groin of C57BL / 6 mice (Charles River Laboratories Japan). 6 After palpable tumors were established, animals were randomized into test groups so that each group had a similar mean tumor volume at the start of the study.

[0219] ==Immunohistochemistry For immunohistochemistry, anti-mouse CD8α monoclonal antibody (clone KT15, GeneTex) was used to detect CD8 protein, anti-mouse B7-H1 / PD-L1 polyclonal antibody (R&D Systems) was used to detect PD-L1 protein, and anti-mouse granzyme B antibody (clone GB11) was used to detect granzyme B. [Example 1]

[0220] Characterization of isogenic mouse models using the murine ovarian cancer cell line OV2944-HM-1 and murine colorectal cancer cell line Colon38 and antitumor activity of a combination of anti-PD-L1 and anti-VEGF antibodies

[0221] ==Treatment method== The treatment was initiated on the day of randomization. Patients received 5 mg / kg of an anti-mouse PD-L1 antibody (clone 6E11, WO 2015 / 095418) intraperitoneally twice weekly, and 10 mg / kg of an anti-mouse VEGF antibody (clone B20-4.1.1) intraperitoneally once weekly. Mouse IgG was administered at the same dose as the control for each antibody.

[0222] ==Intratumoral PD-L1 and CD8 protein expression== Paraffin sections were prepared from tumors excised from OV2944-HM-1 tumor-bearing mice and Colon38 tumor-bearing mice on the day of randomization (non-treatment), and the expression of PD-L1 and CD8 proteins in the tumor tissue was detected using immunohistochemistry. Tumor tissue from OV2944-HM-1 tumor-bearing mice (HM-1) showed lower expression levels of PD-L1 and CD8 proteins compared with tumor tissue from Colon38 tumor-bearing mice (Colon38) and exhibited an immune desert phenotype (Figure 1).

[0223] ==Tumor Volume== Tumor volumes were measured using calipers on days 1, 4, 8, 11, 15, 19, 23, and 25 after the start of treatment, and statistical analysis was performed using the tumor volumes measured on the final day of the study. When using OV2944-HM-1 cells, no significant difference was observed in the anti-PD-L1 antibody alone group compared to the control group, but a significant decrease was observed in the anti-VEGF antibody alone group. The combination group (combination) showed a significant decrease in tumor volume compared to the individual monotherapy groups (Figure 2A). When using Colon38 cells, both the anti-PD-L1 antibody alone and the anti-VEGF antibody alone groups showed a significant decrease in tumor volume compared to the control group. The combination group (combination) showed a significant decrease in tumor volume compared to the individual monotherapy groups (Figure 2B).

[0224] Specifically, tumors in OV2944-HM-1 tumor-bearing mice were unresponsive to anti-PD-L1 antibodies, a PD-1 / PD-L1 signaling inhibitor, but the combination of anti-PD-L1 antibodies with anti-VEGF antibodies, a VEGF signaling inhibitor, significantly inhibited tumor growth compared to the control group (mouse IgG), the anti-VEGF antibody alone group, and the anti-PD-L1 antibody alone group. These results demonstrate that the combination of anti-PD-L1 antibodies and anti-VEGF antibodies exerts a stronger antitumor effect than either antibody alone, regardless of the presence or absence of resistance or sensitivity to anti-PD-L1 antibodies alone. [Example 2]

[0225] Effect on intratumoral CD8+ T cells and its contribution to the antitumor effect of the combination of anti-PD-L1 and anti-VEGF antibodies in OV2944-HM-1 tumor-bearing mice

[0226] ==Treatment method== The day of randomization was the day drug administration began. OV2944-HM-1 tumor-bearing mice received intraperitoneal administration of 5 mg / kg of 6E11 antibody twice weekly and 10 mg / kg of B20-4.1.1 once weekly. Also, OV2944-HM-1 tumor-bearing mice received intraperitoneal administration of 100 μg / mouse of anti-mouse CD8 antibody (clone 116-13.1) twice weekly starting 11 days before randomization. Mouse IgG was administered at the same dose as the control for each antibody.

[0227] ==CD8+ T cells and granzyme B+ CD8+ T cells== Tumors were excised from the mice on day 8 after the start of administration, and cells were dispersed using gentleMACS®. Octo Dissociator was used to quantify granzyme B-positive T cells and CD8-positive T cells in the tumor tissue by flow cytometry using anti-mouse granzyme B antibody (clone GB11)-Alexa647 (BD Biosciences) and anti-mouse CD8α antibody (clone 53-6.3)-BV650 (BD Biosciences). In addition, paraffin sections of tumors removed 8 days after the start of administration were prepared for IHC score measurement of CD8 protein, and CD8-positive T cells in tumor tissues of each treatment group were detected using anti-mouse CD8α antibody (clone KT15) (GeneTex).

[0228] ==Tumor Volume== On days 1, 3, 8, 11, 15, 18 and 22 after the start of administration, the tumor volume was measured using a vernier caliper.

[0229] The percentage of CD8+ T cells relative to total viable cells was not significantly different between the anti-PD-L1 antibody alone and the anti-VEGF antibody alone groups, but was significantly higher in the combined anti-PD-L1 and anti-VEGF antibody groups compared to the control group (Figure 3A).The percentage of granzyme B+CD8+ T cells relative to total viable cells was also not significantly different between the anti-PD-L1 antibody alone and the anti-VEGF antibody alone groups, but was significantly higher in the combined anti-PD-L1 and anti-VEGF antibody groups compared to the control group (Figure 3B).

[0230] The IHC score for CD8 protein (graph created by setting the following: absent (-), very slight (±), slight (+), moderate (++), marked (+++), then converted to a score ("-" = 0, "±" = 1, "+" = 2, "++" = 3, "+++" = 4)) on day 8 after the start of treatment was significantly higher in mice that received the combination of 6E11 and B20-4.1.1 compared to the control group and the group that received anti-VEGF antibody alone (Figure 3C, D).

[0231] These results demonstrate that the administration of the anti-PD-L1 antibody 6E11 alone did not affect the number of intratumoral CD8+ T cells. Furthermore, granzyme B-positive CD8+ T cells represent activated CD8+ T cells. Thus, even in cancers in which the sole administration of anti-PD-L1 antibodies, which are PD-1 / PD-L1 signaling inhibitors, does not affect activated CD8+ T cells in the tumor, the combined use of anti-PD-L1 antibodies and anti-VEGF antibodies was shown to have the effect of significantly increasing activated CD8+ T cells infiltrating into the tumor compared to the control group and the group administered anti-VEGF antibodies alone.

[0232] Regarding tumor volume, no significant difference was observed between the control group and the group treated with anti-VEGF antibody alone, regardless of whether or not anti-CD8α antibody was administered. On the other hand, administration of anti-CD8α antibody in the combination group (combination) (combination + anti-CD8α antibody) significantly increased tumor volume to the same level as the group treated with anti-VEGF antibody alone (Figure 4A). Figure 4B shows a comparison of tumor volume 22 days after the start of treatment in each group. The group treated with the combination of anti-PD-L1 and anti-VEGF antibodies (both anti-PD-L1 and anti-VEGF antibodies marked "+") showed a significant reduction in tumor volume compared to the control group (all marked "-") or the group treated with anti-VEGF antibody alone (anti-VEGF antibody only marked "+"). This indicates a significantly greater antitumor effect. The group treated with the combination of anti-PD-L1 and anti-VEGF antibodies (all marked "+") and anti-CD8α antibody also showed an increase in tumor volume comparable to that of the group treated with anti-VEGF antibody alone. This offset the increased antitumor effect induced by the combination.

[0233] These results indicate that intratumoral CD8+ T cells mediate the enhanced antitumor effect induced by the combination of anti-PD-L1 and anti-VEGF antibodies. [Example 3]

[0234] The effect of combined anti-PD-L1 and anti-VEGF antibodies on intratumoral CXCL9 protein expression and its contribution to the increase of intratumoral CD8+ T cells in OV2944-HM-1 tumor-bearing mice

[0235] ==Treatment method== The randomization date was the day drug administration began. 5 mg / kg of 6E11 antibody was administered intraperitoneally twice weekly to OV2944-HM-1 tumor-bearing mice, and 10 mg / kg of B20-4.1.1 was administered intraperitoneally once weekly to OV2944-HM-1 tumor-bearing mice. Anti-mouse CXCR3 antibody (clone CXCR3-173) was administered intraperitoneally twice weekly to OV2944-HM-1 tumor-bearing mice at 100 μg / mouse. Mouse IgG was administered at the same dose as the control for each antibody.

[0236] ==CXCL9 Protein Expression== On day 8 after the start of administration, tumors were excised from the mice, and the expression level of CXCL9 protein in the tumor tissue was quantified by ELISA using Quantikine ELISA (Mouse CSCL9 / MIG) (R&D Systems). Regarding CXCL9 protein expression levels, no significant differences were observed between the anti-PD-L1 antibody monotherapy group and the anti-VEGF antibody monotherapy group compared with the control group. CXCL9 protein expression levels were significantly higher in the anti-PD-L1 antibody and anti-VEGF antibody combination group compared with the control group or the anti-VEGF antibody monotherapy group (Figure 5A). Furthermore, the percentage of CD8+ T cells among total viable cells was significantly lower in the group receiving anti-CXCR3 antibody in addition to anti-PD-L1 and anti-VEGF antibodies (all "+") compared with the group receiving anti-PD-L1 and anti-VEGF antibodies in combination, and was similar to that in the control group (Figure 5B). This indicates that anti-CXCR3 antibody-induced blockade of the CXCR3 axis in CD8+ T cells offset the increased antitumor effect observed with the combination of anti-PD-L1 and anti-VEGF antibodies.

[0237] In Example 2, it was shown that the increase in intratumoral CD8-positive T cells observed in the group treated with the anti-PD-L1 antibody and anti-VEGF antibody in combination contributed to the enhanced anti-tumor effect. CXCL9 is a T cell chemotactic factor that acts via binding to CXCR3, a receptor expressed on T cells. This Example (Figure 5) demonstrated that the increase in intratumoral CXCL9 protein concentration observed in the group treated with the anti-PD-L1 antibody and anti-VEGF antibody contributes to enhanced tumor infiltration by CD8+ T cells via the CXCR3 axis. Considering the results of Examples 2 and 3 together, the strong enhancement of the antitumor effect by the combination of an anti-PD-L1 antibody and an anti-VEGF antibody shown in Figures 2 and 4 is thought to be due to an increase in intratumoral CD8+ T cells induced by the increase in intratumoral CXCL9 protein concentration. [Example 4]

[0238] Effect of anti-PD-L1 antibody and anti-VEGF antibody combination on MHC class I molecules in tumor cells in OV2944-HM-1 tumor-bearing mice

[0239] ==Treatment method== The randomization date was the day drug administration began. 5 mg / kg of 6E11 antibody was administered intraperitoneally twice weekly to OV2944-HM-1 tumor-bearing mice, and 10 mg / kg of B20-4.1.1 was administered intraperitoneally once weekly to OV2944-HM-1 tumor-bearing mice. Mouse IgG was administered at the same dose as the control for each antibody.

[0240] ==MHC class I molecules== Eight days after the start of administration, tumors were excised from the mice, and the cells were dispersed using a gentleMACS (registered trademark) Octo Dissociator. The protein expression levels of MHC class I molecules on the tumor cells were quantified by flow cytometry using anti-mouse H-2Kk (C3H) antibody-FITC (BioLegend). Compared with other treatment groups, the group treated with anti-PD-L1 antibody and anti-VEGF antibody showed a significant increase in protein expression of MHC class I molecules (Figure 6).

[0241] MHC class I molecules present antigens to CD8-positive T cells and play an important role in the elimination of cancer cells. These results suggest that the combined use of anti-PD-L1 and anti-VEGF antibodies enhances the presentation of tumor-specific antigens to CD8-positive T cells. [Example 5]

[0242] Effect of combined anti-PD-L1 and anti-VEGF antibodies on intratumoral microvascular density in OV2944-HM-1 tumor-bearing mice

[0243] ==Treatment method== The randomization date was the day drug administration began. 5 mg / kg of 6E11 antibody was administered intraperitoneally twice weekly to OV2944-HM-1 tumor-bearing mice, and 10 mg / kg of B20-4.1.1 was administered intraperitoneally once weekly to OV2944-HM-1 tumor-bearing mice. Mouse IgG was administered at the same dose as the control for each antibody.

[0244] ==Intratumoral microvascular density== Tumors excised from mice on day 8 after the start of treatment were measured for intratumoral microvascular density (MVD). CD31 protein was detected in tumor tissue by immunohistochemistry using a rat anti-mouse CD31 monoclonal antibody (clone MEC 13.3) (Becton Dickinson and Company) and Rat HRP-Polymer, 1-Step (Mouse adsorbed) (Biocare Medical). MVD was calculated from the ratio of the CD31-positive area to the total observed area (3–6 live tissue areas per section). Regarding MVD, microvascular density was not significantly different in the anti-PD-FL1 antibody monotherapy group compared with the control group. Meanwhile, microvascular density was significantly lower in the anti-PD-L1 antibody plus anti-VEGF antibody (combination) group and the anti-VEGF antibody monotherapy group compared with the control group or the anti-PD-L1 antibody monotherapy group (Figure 7).

[0245] Intratumoral microvascular density is involved in cancer progression. These results suggest that even in cancers resistant to anti-PD-L1 antibodies, which are PD-1 / PD-L1 signaling inhibitors, the combination of anti-PD-L1 antibodies and anti-VEGF antibodies, or the administration of anti-VEGF antibodies, can significantly reduce intratumoral microvascular density, thereby having an anti-tumor effect.

[0246] Based on this Example and Examples 1 to 4, it was found that the combined use of an anti-PD-L1 antibody, which is a PD-1 / PD-L1 signaling inhibitor, and an anti-VEGF antibody, which is a VEGF signaling inhibitor, can effectively inhibit PD-L1 低 In a PD-L1 signaling inhibitor-refractory mouse model with tumor and immune desert-like phenotypes, increased intratumoral CXCL9 and subsequent enhanced CD8+ T cell infiltration into the tumor were shown to exert strong antitumor effects. [Industrial Applicability]

[0247] The present invention is useful in the treatment of cancer. (Sequence Listing) SEQUENCE LISTING <110> Genentech, Inc. <120> METHOD AND MEDICAMENT FOR TREATING CANCER UNRESPONSIVE TO PD-1 / PD-L1 SIGNALING INHIBITOR <130> IW195054 <160> 63 <170> PatentIn version 3.5 <210> 1 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab HC <400> 1 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser 20 25 30 Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 2 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab LC <400> 2 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 3 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab VH <400> 3 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser 20 25 30 Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 4 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab VL <400> 4 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 5 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab HCDR1 <400> 5 Gly Phe Thr Phe Ser Asp Ser Trp Ile His 1 5 10 <210> 6 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab HCDR2 <400> 6 Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 1 5 10 15 Lys Gly <210> 7 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab HCDR3 <400> 7 Arg His Trp Pro Gly Gly Phe Asp Tyr 1 5 <210> 8 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab LCDR1 <400> 8 Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala 1 5 10 <210> 9 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab LCDR2 <400> 9 Dear Ala Dear Phe Leu Tyr Dear 1 5 <210> 10 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Atezolizumab LCDR3 <400> 10 Gln Gln Tyr Leu Tyr His Pro Ala Thr 1 5 <210> 11 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> Avelumab HC <400> 11 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 12 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Avelumab LC <400> 12 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 13 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Avelumab VH <400> 13 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 14 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> Avelumab VL <400> 14 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110 <210> 15 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Avelumab HCDR1 <400> 15 Ser Tyr Ile Met Met 1 5 <210> 16 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Avelumab HCDR2 <400> 16 Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val Lys 1 5 10 15 Gly <210> 17 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Avelumab HCDR3 <400> 17 Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr 1 5 10 <210> 18 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Avelumab LCDR1 <400> 18 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <210> 19 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Avelumab LCDR2 <400> 19 Asp Val Ser Asn Arg Pro Ser 1 5 <210> 20 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Avelumab LCDR3 <400> 20 Ser Ser Tyr Thr Ser Ser Ser Thr Arg Val 1 5 10 <210> 21 <211> 451 <212> PRT <213> Artificial Sequence <220> <223> Durvalumab HC <400> 21 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 22 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> Durvalumab LC <400> 22 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 23 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Durvalumab VH <400> 23 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 24 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Durvalumab VL <400> 24 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 25 <211> 360 <212> PRT <213> Artificial Sequence <220> <223> KN035 HC <400> 25 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Lys Met Ser Ser Arg Arg 20 25 30 Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val 35 40 45 Ala Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val Thr Ser Ser 100 105 110 Gly Ala Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 130 135 140 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 145 150 155 160 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 165 170 175 Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 180 185 190 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 195 200 205 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 210 215 220 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 225 230 235 240 Leu Pro Ala Gly Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 245 250 255 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 260 265 270 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 275 280 285 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 290 295 300 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 305 310 315 320 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 325 330 335 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 340 345 350 Ser Leu Ser Leu Ser Pro Gly Lys 355 360 <210> 26 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> KN035 VH <400> 26 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Lys Met Ser Ser Arg Arg 20 25 30 Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val 35 40 45 Ala Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val Thr Ser Ser 100 105 110 <210> 27 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> KN035 HCDR1 <400> 27 Gly Lys Met Ser Ser Arg Arg Cys Met Ala 1 5 10 <210> 28 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> KN035 HCDR2 <400> 28 Lys Leu Leu Thr Thr Ser Gly Ser Thr Tyr Leu Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 29 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> KN035 HCDR3 <400> 29 Asp Ser Phe Glu Asp Pro Thr Cys Thr Leu Val Thr Ser Ser Gly Ala 1 5 10 15 Phe Gln Tyr <210> 30 <211> 442 <212> PRT <213> Artificial Sequence <220> <223> CX-072 HC <400> 30 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Trp Arg Asn Gly Ile Val Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Trp Ser Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 340 345 350 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 <210> 31 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> CX-072 LC <400> 31 Gln Gly Gln Ser Gly Ser Gly Ile Ala Leu Cys Pro Ser His Phe Cys 1 5 10 15 Gln Leu Pro Gln Thr Gly Gly Gly Ser Ser Gly Gly Ser Gly Gly Ser 20 25 30 Gly Gly Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asn His Gly 35 40 45 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 50 55 60 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser 65 70 75 80 Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 85 90 95 Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe 100 105 110 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 115 120 125 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Asn Gly Tyr 130 135 140 Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val 145 150 155 160 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 165 170 175 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 180 185 190 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 195 200 205 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 210 215 220 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 225 230 235 240 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 245 250 255 Lys Ser Phe Asn Arg Gly Glu Cys 260 <210> 32 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> CX-072 VH <400> 32 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Trp Arg Asn Gly Ile Val Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Trp Ser Ala Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 33 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> CX-072 VL <400> 33 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Asn Gly Tyr Pro Ser 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 34 <211> 453 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 HC <400> 34 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Pro Asp Tyr Ser Pro Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 210 215 220 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala 225 230 235 240 Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 305 310 315 320 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ser 325 330 335 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 355 360 365 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445 Leu Ser Pro Gly Lys 450 <210> 35 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 LC <400> 35 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Ser Val Phe Gly Gly Gly Ile Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Ala Glu Cys Ser 210 215 <210> 36 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 VH <400> 36 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Pro Asp Tyr Ser Pro Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 37 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 VL <400> 37 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Ser Val Phe Gly Gly Gly Ile Lys Leu Thr Val Leu 100 105 110 <210> 38 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 HCDR1 <400> 38 Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser 1 5 10 <210> 39 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 HCDR2 <400> 39 Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 40 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 HCDR3 <400> 40 Ala Arg Ser Pro Asp Tyr Ser Pro Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 41 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 LCDR1 <400> 41 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn 1 5 10 <210> 42 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 LCDR2 <400> 42 Tyr Gly Asn Ser Asn Arg Pro Ser 1 5 <210> 43 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LY3300054 LCDR3 <400> 43 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser Val 1 5 10 <210> 44 <211> 453 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab HC <400> 44 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205 Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220 Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 225 230 235 240 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 275 280 285 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser 290 295 300 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 305 310 315 320 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 325 330 335 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 340 345 350 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 355 360 365 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445 Leu Ser Pro Gly Lys 450 <210> 45 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab LC <400> 45 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 46 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab VH <400> 46 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 47 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab VL <400> 47 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 48 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab HCDR1 <400> 48 Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn 1 5 10 <210> 49 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab HCDR2 <400> 49 Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys 1 5 10 15 Arg <210> 50 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab HCDR3 <400> 50 Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val 1 5 10 <210> 51 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab LCDR1 <400> 51 Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 52 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab LCDR2 <400> 52 Phe Thr Ser Ser Leu His Ser 1 5 <210> 53 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Bevacizumab LCDR3 <400> 53 Gln Gln Tyr Ser Thr Val Pro Trp Thr 1 5 <210> 54 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab HC <400> 54 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Leu Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 55 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab LC <400> 55 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Ile Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asp Asn Trp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Asp Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ala Lys Ala Phe Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 56 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab VH <400> 56 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Thr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 <210> 57 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab VL <400> 57 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Ile Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asp Asn Trp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Asp Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ala Lys Ala Phe Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105 <210> 58 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab HCDR1 <400> 58 Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ser Met Asn Trp Val 1 5 10 15 <210> 59 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab HCDR2 <400> 59 Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 60 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab HCDR3 <400> 60 Val Thr Asp Ala Phe Asp Ile 1 5 <210> 61 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab LCDR1 <400> 61 Arg Ala Ser Gln Gly Ile Asp Asn Trp Leu Gly Trp 1 5 10 <210> 62 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab LCDR2 <400> 62 Asp Ala Ser Asn Leu Asp Thr 1 5 <210> 63 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Ramucirumab LCDR3 <400> 63 Gln Gln Ala Lys Ala Phe Pro Pro Thr 1 5

Claims

1. A medicament for treating a cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual, comprising a PD-1 / PD-L1 signaling inhibitor for use in combination with a VEGF signaling inhibitor.

2. A medicament for treating a cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual, comprising a VEGF signaling inhibitor for use in combination with a PD-1 / PD-L1 signaling inhibitor.

3. A medicament for treating a cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual, comprising a VEGF signaling inhibitor and a PD-1 / PD-L1 signaling inhibitor.

4. A medicament for treating cancer resistant to a PD-1 / PD-L1 signaling inhibitor in an individual, wherein a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor are administered in combination.

5. The pharmaceutical agent according to any one of claims 1 to 4, wherein the PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor are administered simultaneously, separately, or sequentially.

6. The pharmaceutical agent according to any one of claims 1 to 5, wherein the VEGF signaling inhibitor is a VEGF antagonist or a VEGFR antagonist.

7. The pharmaceutical agent according to any one of claims 1 to 6, wherein the VEGF signaling inhibitor is an anti-VEGF antibody or an anti-VEGFR antibody.

8. The pharmaceutical composition of claim 7 , wherein the anti-VEGF antibody or the anti-VEGFR antibody is bevacizumab, ramucirumab, or aflibercept beta.

9. The pharmaceutical agent according to any one of claims 1 to 8, wherein the PD-1 / PD-L1 signaling inhibitor is a PD-1 antagonist or a PD-L1 antagonist.

10. The pharmaceutical agent according to any one of claims 1 to 9, wherein the PD-1 / PD-L1 signaling inhibitor is AMP-224, BMS-936559, MEDI4736, MSB0010718C, MPDL3280A, nivolumab, AMP-514, pembrolizumab (MK-3475), REGN2810, PDR001, BGB-A317, or pidilizumab (CT-011).

11. The pharmaceutical according to any one of claims 1 to 9, wherein the PD-1 / PD-L1 signaling inhibitor is an anti-PD-L1 antibody.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the cancer is selected from the group consisting of breast cancer, liver cancer, lung cancer including small cell lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, biliary tract cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, esophageal cancer, prostate cancer, malignant melanoma, head and neck cancer, malignant pleural mesothelioma, glioblastoma, urothelial carcinoma, soft tissue sarcoma, malignant lymphoma, multiple myeloma, virus-positive solid cancer, virus-negative solid cancer, leukemia, squamous cell carcinoma, Merkel cell carcinoma, pediatric malignant solid tumor, glioma, thyroid cancer, non-small cell lung cancer, Hodgkin's lymphoma, and uterine cancer.

13. A medicament for treating a cancer resistant to a PD-1 / PD-L1 signaling inhibitor, comprising a PD-1 / PD-L1 signaling inhibitor, said medicament for use in combination with a VEGF signaling inhibitor; The PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor are administered simultaneously, separately, or sequentially, and improve the response rate in a group including individuals in need of treatment for a cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without being combined with the VEGF signaling inhibitor.

14. A pharmaceutical agent for treating a cancer resistant to a PD-1 / PD-L1 signaling inhibitor, comprising a PD-1 / PD-L1 signaling inhibitor and a VEGF signaling inhibitor, The PD-1 / PD-L1 signaling inhibitor and the VEGF signaling inhibitor are administered simultaneously, separately, or sequentially, and improve the response rate in a group including individuals in need of treatment for a cancer resistant to a PD-1 / PD-L1 signaling inhibitor, compared to when the PD-1 / PD-L1 signaling inhibitor is administered without combination with the VEGF signaling inhibitor, or when the VEGF signaling inhibitor is administered without combination with the PD-1 / PD-L1 signaling inhibitor.

15. The pharmaceutical agent according to claim 13 or 14, wherein the group comprising individuals in need of treatment for cancer resistant to the PD-1 / PD-L1 signaling inhibitor comprises individuals who have not been tested for the presence or absence of resistance through diagnosis prior to administration of the PD-1 / PD-L1 signaling inhibitor.

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