TW201922793A

TW201922793A - Uses of PD-1 antibody combined with VEGFR inhibitor for treating small cell lung cancer

Info

Publication number: TW201922793A
Application number: TW107140576A
Authority: TW
Inventors: 高陽; 康曉燕
Original assignee: 大陸商江蘇恆瑞醫藥股份有限公司; 大陸商蘇州盛迪亞生物醫藥有限公司
Priority date: 2017-11-16
Filing date: 2018-11-15
Publication date: 2019-06-16
Also published as: CN111065411A; CN111065411B; WO2019096194A1

Abstract

The present invention relates to uses of PD-1 antibody combined with VEGFR inhibitor for treating small cell lung cancer. Specifically, the present invention relates to uses of anti-PD-1 antibody combined with VEGFR inhibitor in the preparation of drugs for treating small cell lung cancer.

Description

PD-1抗體和VEGFR抑制劑聯合治療小細胞肺癌的用途 Application of PD-1 antibody and VEGFR inhibitor in the treatment of small cell lung cancer

本發明涉及一種抗PD-1抗體和VEGFR抑制劑聯合在製備治療小細胞肺癌的藥物中的用途。 The invention relates to the use of a combination of an anti-PD-1 antibody and a VEGFR inhibitor in the preparation of a medicament for treating small cell lung cancer.

小細胞肺癌(Samll Cell Lung Cancer，SCLC)起源於支氣管，沿支氣管壁黏膜向腔內浸潤生長，SCLC占肺癌的15%-20%。SCLC在臨床通常分期為侷限期和廣泛期，侷限期病變局限於同側胸腔，病變能被一個可以耐受的放射野包全，包括同側縱隔淋巳結、同側鎖骨上淋巴結，不包括血行播散；廣泛期病變超越侷限期範圍，包括血行播散。SCLC在臨床上以化療和放療為主要治療手段。 Small cell lung cancer (SCLC) originates from the bronchus and infiltrates into the cavity along the bronchial wall mucosa. SCLC accounts for 15% -20% of lung cancer. SCLC clinical staging is usually limited and extensive. The localized lesions are limited to the ipsilateral thoracic cavity. The lesions can be covered by a tolerable radiation field, including ipsilateral mediastinal lymphadenopathy and ipsilateral supraclavicular lymph nodes, excluding Hematogenous dissemination; extensive-stage lesions are beyond the limited period, including hematogenous dissemination. SCLC uses chemotherapy and radiotherapy as the main treatment methods in clinical.

PD-1抗體特異性識別並結合淋巴細胞表面PD-1，阻斷PD-1/PD-L1信號通路，進而激活T細胞對腫瘤的免疫殺傷作用，調動機體免疫系統而清除體內腫瘤細胞。WO2015085847A公開了一種新的抗PD-1抗體，目前正處於臨床試驗階段，已經顯示出一定的抗腫瘤作用。 The PD-1 antibody specifically recognizes and binds to PD-1 on the surface of lymphocytes, blocks the PD-1 / PD-L1 signaling pathway, and then activates the immune killing effect of T cells on tumors, modulates the body's immune system and clears tumor cells in the body. WO2015085847A discloses a new anti-PD-1 antibody, which is currently in the clinical trial stage and has shown a certain antitumor effect.

WO2005000232A公開的小分子酪胺酸激酶抑制劑阿帕替尼(Apatinib)具備高度選擇性競爭細胞內VEGFR-2的ATP結合位點，阻斷下游信號轉導，抑制腫瘤新生血管的生成，最終達到治療腫瘤的目的，阿帕替尼的結構式如式(I)所示。 The small molecule tyrosine kinase inhibitor Apatinib disclosed in WO2005000232A has a highly selective competition for the ATP binding site of VEGFR-2 in cells, blocks downstream signal transduction, and inhibits tumor neovascularization. For the purpose of treating tumors, the structural formula of apatinib is shown in formula (I).

CN101676267A公開了阿帕替尼的一系列鹽，例如甲磺酸鹽、鹽酸鹽、馬來酸鹽等。CN101675930A公開的臨床前的動物實驗也顯示阿帕替尼聯用細胞毒類藥物如奧沙利鉑、5-Fu、多西他賽、阿黴素，能明顯增加其療效。 CN101676267A discloses a series of salts of apatinib, such as mesylate, hydrochloride, maleate and the like. The preclinical animal experiments disclosed by CN101675930A also show that apatinib combined with cytotoxic drugs such as oxaliplatin, 5-Fu, docetaxel, and doxorubicin can significantly increase its efficacy.

目前尚無PD-1抗體和VEGFR抑制劑聯用獲批上市，但有多個PD-1抗體(其他公司的)與VEGFR抑制劑(如舒尼替尼，索拉菲尼等)正處於臨床II/III期，適應症分別為惡性肝癌(索拉菲尼與PD-1抗體聯用)和轉移性腎細胞癌(舒尼替尼與PD-1抗體聯用)，初步結果顯示兩種藥物聯用效果均優於單藥。CN105960415A公開了一種PD-1抗體與阿昔替尼聯用治療腎細胞癌的用途，WO2015088847A公開了一種PD-1抗體與帕唑帕尼聯用治療腎細胞癌的用途WO2016141218A公開了一種PD-1抗體與樂伐替尼聯用治療甲狀腺癌、肝細胞癌、非小細胞肺癌、腎細胞癌、子宮內膜癌、惡性膠質瘤和黑色素瘤等的用途。但是這些VEGFR抑制劑，包括樂伐替尼、索拉菲尼、舒尼替尼、阿昔替尼以及帕唑帕尼與阿帕替尼的作用機制有所不同，阿帕替尼對VEGFR-2具有最強的抑制作用，但對於其它激酶則抑制作用較差或完全不具有抑制作用，即阿帕替尼對於VEGFR-2具有高度的選擇性，因此其治療的疾病也與前述藥物有所不同，其與PD-1聯合能否產生協同作用，從而提高療效值得進一步研究；另外，根據目前PD-1單獨給藥臨床研究顯示(Phase I study of the anti-PD-1 antibody SHR-1210 in patients with advanced solid tumors.(2017)：e15572-e15572)，PD-1抗體在單獨應用治療時，毛細血管瘤發生率高達79.3%，不良反應無疑給腫瘤患者的精神健康和生存質量造成了負擔，因此降低其用藥時的不良反應非常重要。 Currently, no PD-1 antibody and VEGFR inhibitor combination have been approved for marketing, but there are multiple PD-1 antibodies (of other companies) and VEGFR inhibitors (such as sunitinib, sorafenib, etc.) are in clinical Phase II / III, the indications are malignant liver cancer (sorafenib combined with PD-1 antibody) and metastatic renal cell carcinoma (sunitinib combined with PD-1 antibody). Preliminary results show two drugs The combined effect is better than single drug. CN105960415A discloses the use of a PD-1 antibody combined with axitinib to treat renal cell carcinoma, and WO2015088847A discloses the use of a PD-1 antibody combined with pazopanib to treat renal cell carcinoma. WO2016141218A discloses a PD-1 Combination of antibodies with lovatinib Application for treating thyroid cancer, hepatocellular carcinoma, non-small cell lung cancer, renal cell carcinoma, endometrial cancer, malignant glioma and melanoma. However, these VEGFR inhibitors, including lovatinib, sorafenib, sunitinib, axitinib, and pazopanib have different mechanisms of action with apatinib. Apatinib affects VEGFR- 2 has the strongest inhibitory effect, but has poor or no inhibitory effect on other kinases, that is, apatinib is highly selective for VEGFR-2, so the disease it treats is also different from the aforementioned drugs, Whether its combination with PD-1 can produce a synergistic effect and thus improve the efficacy is worthy of further research; in addition, according to current clinical studies of PD-1 alone (Phase I study of the anti-PD-1 antibody SHR-1210 in patients with advanced solid tumors. (2017): e15572-e15572), when PD-1 antibody is used alone, the incidence of capillary hemangioma is as high as 79.3%. Adverse reactions will undoubtedly burden the mental health and quality of life of cancer patients, thus reducing The adverse reactions during its administration are very important.

本發明提供一種VEGFR抑制劑和抗PD-1抗體或其抗原結合片段聯合在製備治療小細胞肺癌患者的藥物中的用途。 The invention provides a combined use of a VEGFR inhibitor and an anti-PD-1 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating a patient with small cell lung cancer.

本發明還提供一種抗PD-1抗體或其抗原結合片段在製備治療小細胞肺癌患者的藥物中的用途。 The invention also provides an application of an anti-PD-1 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating patients with small cell lung cancer.

在本發明一個較佳的實施方案中，其中該VEGFR抑制劑是VEGFR-2抑制劑。 In a preferred embodiment of the invention, the VEGFR inhibitor is a VEGFR-2 inhibitor.

在本發明一個較佳的實施方案中，其中該VEGFR-2 抑制劑選自：PAN-90806、佛瑞替尼(Foretinib)、他菲替尼(Tafetinib)、康尼替尼(Kanitinib)、阿帕替尼(Apatinib)、坦尼布盧單抗(Tanibirumab)、安羅替尼(Anlotinib)、德立替尼(Lucitanib)、瓦他拉尼布(Vatalanib)、西地尼布(Cediranib)、西奧羅尼(Chiauranib)、多韋替尼(Dovitinib)、多納非尼(Donafenib)、法米替尼(Famitinib)、西他伐替尼(Sitravatinib)、特拉替尼(Telatinib)、L-21649、TAS-115、卡博替尼(Cabozantinib)、噻爾非尼(Thiophenib)、呋喹替尼(Fruquintinib)、布立尼布(Brivanib)、索凡替尼(Sulfatinib)、雷莫盧單抗(Ramucirumab)、葛雷沙尼布(Glesatinib)、尼達尼布(Nintedanib)、普喹替尼(Puquitinib)、阿西替尼(Axitinib)、EDP317、索拉非尼(Sorafenib)、麥他替尼(Metatinib)、替沃札尼布(Tivozanib)、瑞戈非尼(Regorafenib)、Midostaurin、培唑帕尼(Pazopanib)、HLX-06、艾爾提拉尼布(Altiratinib)、寧格替尼(Ningetinib)、舒尼替尼(Sunitinib)、AL-8326、瑞貝斯尼布(Rebastinib)或以上藥物的可藥用鹽。 In a preferred embodiment of the present invention, wherein the VEGFR-2 Inhibitors are selected from the group consisting of: PAN-90806, Foretinib, Tafetinib, Kanitinib, Apatinib, Tanibirumab , Anlotinib, Lucitanib, Vatalanib, Cediranib, Chiauranib, Dovitinib, Dovidin Donafenib, Famitinib, Sitravatinib, Telatinib, L-21649, TAS-115, Cabozantinib, Thiel Thiophenib, Fluquintinib, Brivanib, Sulfatinib, Ramucirumab, Glesatinib, Nida Nibedanib, Puquitinib, Axitinib, EDP317, Sorafenib, Metatinib, Tivozanib, Swiss Regorafenib, Midostaurin, Pazopanib, HLX-06, Altiratinib, Ningetinib, Sunitinib, AL-8326 , Bass Technip (Rebastinib) above or a pharmaceutical acceptable salt thereof may be.

在本發明一個較佳的實施方案中，其中該阿帕替尼可藥用鹽選自甲磺酸鹽、馬來酸鹽、酒石酸鹽、琥珀酸鹽、醋酸鹽、二氟醋酸鹽、富馬酸鹽、檸檬酸鹽、枸櫞酸鹽、苯磺酸鹽、苯甲酸鹽、萘磺酸鹽、乳酸鹽、蘋果酸鹽、鹽酸鹽、氫溴酸鹽、硫酸鹽、以及磷酸鹽。 In a preferred embodiment of the present invention, the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, and fumarate. Acid salt, citrate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate.

在本發明一個較佳的實施方案中，其中該抗PD-1抗體或其抗原結合片段選自：AMP-224、GLS-010、IBI-308、 REGN-2810、PDR-001、BGB-A317、加利妥昔單抗(Pidilizumab)、PF-06801591、傑諾單抗(Genolimzumab)、CA-170、MEDI-0680、JS-001、TSR-042、卡瑞利珠單抗(Camrelizumab)、派姆單抗(Pembrolizumab)、LZM-009、AK-103和納武單抗(Nivolumab)。 In a preferred embodiment of the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Galiduximab (Pidilizumab), PF-06801591, Genolizumab, CA-170, MEDI-0680, JS-001, TSR-042 Carrelizumab, Pembrolizumab, LZM-009, AK-103, and Nivolumab.

在本發明一個較佳的實施方案中，其中該抗PD-1抗體或其抗原結合片段的輕鏈可變區包含分別如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3；重鏈可變區包含分別如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3。其中，前面所述的各CDR序列如下表所示： In a preferred embodiment of the present invention, the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively. The LCDR1, LCDR2, and LCDR3 are shown; the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively. The CDR sequences described above are shown in the following table:

較佳地，該PD-1抗體為人源化抗體。 Preferably, the PD-1 antibody is a humanized antibody.

較佳的人源化抗體輕鏈可變區序列為如SEQ ID NO：10所示的序列或其變體；該變體較佳在輕鏈可變區有0至10的胺基酸變化；更佳為A43S的胺基酸變化。該人源化抗體重鏈可變區序列為如SEQ ID NO：9所示的序列或其變體；該變體較佳在重鏈可變區有0至10的胺基酸變化；更佳為G44R的胺基酸變化。 A preferred humanized antibody light chain variable region sequence is the sequence shown in SEQ ID NO: 10 or a variant thereof; the variant preferably has a 0 to 10 amino acid change in the light chain variable region; More preferred is the amino acid change of A43S. The humanized antibody heavy chain variable region sequence is the sequence shown in SEQ ID NO: 9 or Variant; this variant preferably has an amino acid change of 0 to 10 in the heavy chain variable region; more preferably the amino acid change of G44R.

前述的人源化抗體重、輕鏈的可變區序列如下所示：重鏈可變區 SEQID NO：9 The sequences of the variable regions of the heavy and light chains of the aforementioned humanized antibodies are as follows: SEQID NO: 9

輕鏈可變區 SEQID NO：10 Light chain variable region SEQID NO: 10

較佳的人源化抗體輕鏈序列為如SEQ ID NO：8所示的序列或其變體；該變體較佳在輕鏈可變區有0至10的胺基酸變化；更佳為A43S的胺基酸變化。該人源化抗體重鏈序列為如SEQ ID NO：7所示的序列或其變體；該變體較佳在重鏈可變區有0至10的胺基酸變化；更佳為G44R的胺基酸變化。 A preferred humanized antibody light chain sequence is the sequence shown in SEQ ID NO: 8 or a variant thereof; the variant preferably has a 0 to 10 amino acid change in the light chain variable region; more preferably A43S amino acid changes. The humanized antibody heavy chain sequence is the sequence shown in SEQ ID NO: 7 or a variant thereof; the variant preferably has an amino acid change of 0 to 10 in the heavy chain variable region; more preferably G44R Amino acid changes.

在本發明一個較佳的實施方案中，人源化抗體輕鏈序列為如SEQ ID NO：8所示的序列，重鏈序列為如SEQ ID NO：7所示的序列。 In a preferred embodiment of the present invention, the humanized antibody light chain sequence is the sequence shown in SEQ ID NO: 8, and the heavy chain sequence is the sequence shown in SEQ ID NO: 7.

前述的人源化抗體重、輕鏈的序列如下所示：重鏈 SEQID NO：7 The sequences of the heavy and light chains of the aforementioned humanized antibodies are as follows: SEQID NO: 7

輕鏈 SEQID NO：8 Light chain SEQID NO: 8

在本發明一個較佳的實施方案中，其中該小細胞肺癌為廣泛期小細胞肺癌。 In a preferred embodiment of the present invention, the small cell lung cancer is a general stage small cell lung cancer.

在本發明一個較佳的實施方案中，其中該患者接受過鉑類藥物治療。例如接受鉑類藥物治療失敗或者不可耐受的患者。 In a preferred embodiment of the invention, the patient has received Platinum drugs. For example, patients who have failed or tolerated platinum therapy.

在本發明一個較佳的實施方案中，其中鉑類藥物治療選自：依託泊苷/順鉑聯合化療、依託泊苷/卡鉑聯合化療、依託泊苷/順鉑聯合化療和放療、依託泊苷/卡鉑聯合化療和放療。 In a preferred embodiment of the present invention, the platinum drug treatment is selected from the group consisting of etoposide / cisplatin combined chemotherapy, etoposide / carboplatin combined chemotherapy, etoposide / cisplatin combined chemotherapy and radiotherapy, etoposide Glycoside / carboplatin combined with chemotherapy and radiotherapy.

在本發明一個較佳的實施方案中，其中該PD-1抗體或其抗原結合片段劑量選自1-10mg/kg，較佳選自1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg，更佳選自1mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、10mg/kg。 In a preferred embodiment of the present invention, the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 1-10 mg / kg, preferably from 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg. , 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, more preferably selected from 1mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 10mg / kg.

在本發明一個較佳的實施方案中，其中該PD-1抗體或其抗原結合片段劑量選自50-600mg，較佳選自50mg、60mg、70mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、375mg、400mg、425mg、450mg、475mg、500mg、600mg，更佳選自60mg、100mg、200mg、400mg、600mg。 In a preferred embodiment of the present invention, the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 50-600 mg, preferably from 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg , 225mg, 250mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 600mg, more preferably selected from 60mg, 100mg, 200mg, 400mg, 600mg.

在本發明一個較佳的實施方案中，其中該VEGFR抑制劑劑量選自0.01-500mg，較佳自0.1mg、0.25mg、0.5mg、0.75mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、30mg、45mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、400mg、500mg，更佳選自0.25mg、0.5mg、1mg、2mg、3mg、4mg、10mg、15mg、20mg、30mg、45mg、50mg、60mg、75mg、100mg。 In a preferred embodiment of the present invention, the dose of the VEGFR inhibitor is selected from 0.01-500 mg, preferably from 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg , 200mg, 225mg, 250mg, 275mg, 300mg, 400mg, 500mg, more preferred From 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100mg.

在本發明一個較佳的實施方案中，其中該PD-1抗體或其抗原結合片段的給藥頻次為一日一次、一日二次、一日三次、一週一次、二週一次、三週一次、一月一次，該VEGFR抑制劑的給藥頻次為一日一次、一日二次、一日三次、一週一次、二週一次、三週一次、一月一次。 In a preferred embodiment of the present invention, the frequency of administration of the PD-1 antibody or antigen-binding fragment thereof is once a day, twice a day, three times a day, once a week, once every two weeks, and once every three weeks. Once a month, the VEGFR inhibitor is administered once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, and once a month.

本發明所述聯合的給藥途徑選自經口給藥、胃腸外給藥、經皮給藥，該胃腸外給藥包括但不限於靜脈注射、皮下注射、肌肉注射。 The combined administration route of the present invention is selected from oral administration, parenteral administration, and transdermal administration. The parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

在本發明一個較佳的實施方案中，在給藥時，其中該PD-1抗體的用量是60至600mg，靜脈輸注，每一至三週一次；VEGFR抑制劑的用量是250mg至500mg，口服，每一到兩日一次。 In a preferred embodiment of the present invention, when administered, the amount of the PD-1 antibody is 60 to 600 mg, intravenously, once every three to three weeks; the amount of the VEGFR inhibitor is 250 mg to 500 mg, orally, Once every two days.

在本發明一個較佳的實施方案中，在給藥時，其中該PD-1抗體的用量是60至600mg，靜脈輸注，每一至三週一次；VEGFR抑制劑的用量是250mg至500mg，口服，給藥5天停藥2天。 In a preferred embodiment of the present invention, when administered, the amount of the PD-1 antibody is 60 to 600 mg, intravenously, once every three to three weeks; the amount of the VEGFR inhibitor is 250 mg to 500 mg, orally, The drug was discontinued for 2 days after 5 days of administration.

在本發明一個較佳的實施方案中，在給藥時，其中該PD-1抗體的用量是60至600mg，靜脈輸注，每一至三週一次；VEGFR抑制劑的用量是250mg至500mg，口服，給藥7天停藥7天。 In a preferred embodiment of the present invention, when administered, the amount of the PD-1 antibody is 60 to 600 mg, intravenously, once every three to three weeks; the amount of the VEGFR inhibitor is 250 mg to 500 mg, orally, The drug was discontinued for 7 days after 7 days of administration.

在本發明一個較佳的實施方案中，在給藥時，其中該PD-1抗體的用量是200mg，靜脈輸注，每兩週一次；VEGFR 抑制劑的用量是375mg，口服，每日一次。 In a preferred embodiment of the present invention, at the time of administration, the amount of the PD-1 antibody is 200 mg, intravenous infusion, once every two weeks; VEGFR The dose of inhibitor is 375mg, taken orally once daily.

在本發明一個較佳的實施方案中，在給藥時，其中該PD-1抗體的用量是200mg，靜脈輸注，每兩週一次；VEGFR抑制劑的用量是375mg，口服，給藥5天停藥2天。 In a preferred embodiment of the present invention, at the time of administration, the amount of the PD-1 antibody is 200 mg, which is administered intravenously, every two weeks; the amount of the VEGFR inhibitor is 375 mg, which is administered orally and stopped for 5 days. Medicine for 2 days.

在本發明一個較佳的實施方案中，在給藥時，其中該PD-1抗體的用量是200mg，靜脈輸注，每兩週一次；VEGFR抑制劑的用量是375mg，口服，給藥7天停藥7天。 In a preferred embodiment of the present invention, at the time of administration, the amount of the PD-1 antibody is 200 mg, which is administered intravenously every two weeks; the amount of the VEGFR inhibitor is 375 mg, which is administered orally and stopped for 7 days. Medicine for 7 days.

在本發明一個較佳的實施方案中，該PD-1抗體以注射的方式給藥，例如皮下或靜脈注射，注射前需將PD-1抗體配製成可注射的形式。特別佳的PD-1抗體的可注射形式是注射液或凍乾粉針，其包含PD-1抗體、緩衝劑、穩定劑，視需要地還含有表面活性劑。緩衝劑可選自醋酸鹽、檸檬酸鹽、琥珀酸鹽、以及磷酸鹽中的一種或幾種。穩定劑可選自糖或胺基酸，較佳為二糖，例如蔗糖、乳糖、海藻糖、麥芽糖。表面活性劑選自聚氧乙烯氫化蓖麻油、甘油脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯，較佳該聚氧乙烯山梨醇酐脂肪酸酯為聚山梨酯20、40、60或80，最佳為聚山梨酯20。最佳的PD-1抗體的可注射形式包含PD-1抗體、醋酸鹽緩衝劑、海藻糖和聚山梨酯20。 In a preferred embodiment of the present invention, the PD-1 antibody is administered by injection, such as subcutaneously or intravenously, and the PD-1 antibody needs to be formulated into an injectable form before injection. A particularly preferred injectable form of the PD-1 antibody is an injection solution or a lyophilized powder needle, which contains the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffer may be selected from one or more of acetate, citrate, succinate, and phosphate. The stabilizer may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, maltose. The surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, and polyoxyethylene sorbitan fatty acid ester. Preferably, the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60, or 80. , The best is polysorbate 20. Optimal injectable forms of PD-1 antibodies include PD-1 antibodies, acetate buffers, trehalose, and polysorbate 20.

本發明提供上述抗PD-1抗體聯合上述VEGFR作為減少藥物不良反應的藥物，較佳的，該藥物不良反應選自由抗PD-1抗體引起或由VEGFR抑制劑引起。 The present invention provides the above-mentioned anti-PD-1 antibody in combination with the above-mentioned VEGFR as a drug for reducing adverse drug reactions. Preferably, the adverse drug reaction is selected from the group consisting of an anti-PD-1 antibody or a VEGFR inhibitor.

在本發明一個較佳的實施方案中，當PD-1抗體與VEGFR抑制劑聯合使用時，可減少由抗PD-1抗體和/或免疫介導的藥物不良反應；較佳的，該不良反應選自血管相關不良反應。 In a preferred embodiment of the present invention, when a PD-1 antibody is used in combination with a VEGFR inhibitor, the anti-PD-1 antibody and / or immunity can be reduced. Epidemic-mediated adverse drug reactions; preferably, the adverse reaction is selected from vascular-related adverse reactions.

本發明提供了一種治療腫瘤/癌症的辦法，包括向患者施用上述抗PD-1抗體或其抗原結合片段和上述VEGFR抑制劑。 The present invention provides a method for treating tumors / cancers, which comprises administering to a patient the above-mentioned anti-PD-1 antibody or antigen-binding fragment thereof and the above-mentioned VEGFR inhibitor.

本發明還提供了一種藥物套組或者藥物包裝盒，其中含有上述抗PD-1抗體或其抗原結合片段和上述VEGFR抑制劑。 The present invention also provides a medicine kit or a medicine packaging box, which contains the above-mentioned anti-PD-1 antibody or antigen-binding fragment thereof and the above-mentioned VEGFR inhibitor.

發明詳述Detailed description of the invention

一、術語 I. Terminology

為了更容易理解本發明，以下具體定義了某些技術和科學術語。除顯而易見在本文件中的它處另有明確定義，否則本文使用的所有其它技術和科學術語都具有本發明所屬領域的一般技術人員通常理解的含義。 To make the present invention easier to understand, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

術語“人源化抗體(humanized antibody)”，也稱為CDR移植抗體(CDR-grafted antibody)，是指將小鼠的CDR序列移植到人的抗體可變區框架，即不同類型的人種系抗體構架序列中產生的抗體。可以克服嵌合抗體由於攜帶大量小鼠蛋白成分，從而誘導的強烈的抗體可變抗體反應。此類構架序列可以從包括種系抗體基因序列的公共DNA數據庫或公開的參考文獻獲得。如人重鏈和輕鏈可變區基因的種系DNA序列可以在“VBase”人種系序列數據庫(在因特網www.mrccpe.com.ac.uk/vbase可獲得)，以及在Kabat，E.A.等人，1991 Sequences of Proteins of Immunological Interest，第5版中找到。在本發明一個較佳的實施方案中，所述的PD-1人源化抗體的CDR序列選自SEQ ID NO：1，2，3，4，5，6。 The term "humanized antibody", also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into the human antibody variable region framework, that is, different types of human germline Antibodies produced in antibody framework sequences. It can overcome the strong antibody variable antibody response induced by the chimeric antibody because it carries a large amount of mouse protein components. Such framework sequences can be obtained from a public DNA database including germline antibody gene sequences or published references. For example, germline DNA sequences of human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk/vbase), and in Kabat, EA, etc. Human, 1991 Sequences of Proteins of Immunological Interest, found in version 5. In a preferred embodiment of the present invention, the CDR sequence of the PD-1 humanized antibody is selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.

術語“抗原結合片段”，指具有抗原結合活性的Fab片段，Fab‘片段，F(ab’)2片段，以及與人PD-1結合的Fv片段sFv片段；包含本發明所述抗體的選自SEQ ID NO：1至SEQ ID NO：6中的一個或多個CDR區。Fv片段含有抗體重鏈可變區和輕鏈可變區，但沒有恒定區，並具有全部抗原結合位點的最小抗體片段。一般地，Fv抗體還包含在VH和VL結構域之間的多肽接頭，且能夠形成抗原結合所需的結構。也可以用不同的連接物將兩個抗體可變區連接成一條多肽鏈，稱為單鏈抗體(single chain antibody)或單鏈Fv(sFv)。本發明的術語“與PD-1結合”，指能與人PD-1相互作用。本發明的術語“抗原結合位點”指抗原上不連續的，由本發明抗體或抗原結合片段識別的三維空間位點。 The term "antigen-binding fragment" refers to Fab fragments, Fab 'fragments, F (ab') 2 fragments, and Fv fragments sFv fragments that bind to human PD-1; One or more CDR regions of SEQ ID NO: 1 to SEQ ID NO: 6. The Fv fragment contains the variable region of the heavy chain and light chain of the antibody, but has no constant region and has the smallest antibody fragment with all antigen-binding sites. Generally, Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structure required for antigen binding. The variable regions of two antibodies can also be linked into a polypeptide chain with different linkers, which is called a single chain antibody (single chain antibody) or a single chain Fv (sFv). The term "binding to PD-1" in the present invention refers to the ability to interact with human PD-1. The term "antigen-binding site" of the present invention refers to a three-dimensional spatial site on the antigen that is discontinuous and is recognized by the antibody or antigen-binding fragment of the present invention.

術語“免疫療法”指免疫療法是利用免疫系統來治療疾病，在本發明中主要指藉由提高腫瘤細胞的免疫原性和對效應細胞殺傷的敏感性，激發和增強機體抗腫瘤免疫應答，並應用免疫細胞和效應分子輸注宿主體內，協同機體免疫系統殺傷腫瘤、抑制腫瘤生長。 The term "immunotherapy" refers to the use of the immune system to treat diseases. In the present invention, it mainly refers to stimulating and enhancing the body's anti-tumor immune response by increasing the immunogenicity of tumor cells and the sensitivity to killing of effector cells, and Immune cells and effector molecules are infused into the host to cooperate with the body's immune system to kill tumors and inhibit tumor growth.

本發明關於“聯合”是一種給藥方式，是指在一定時間期限內給予至少一種劑量的阿帕替尼和至少一種劑量的PD-1抗體或其抗原結合片段，其中兩種物質都顯示藥理學作用。所述的時間期限可以是一個給藥週期內，較佳4週內，3週內，2週內，1週內，或24小時以內，更佳12小時以內。可以同時或依次給予阿帕替尼和PD-1抗體或其抗原結合片段。這種期限包括這樣的治療，其中藉由相同給藥途徑或不同給藥途徑給予阿帕替尼和PD-1抗體或其抗原結合片段。本發明所述聯合的給藥方式選自同時給藥、獨立地配製並共給藥或獨立地配製並相繼給藥。 The "combination" of the present invention is a method of administration, which means that at least one dose of apatinib and at least one dose of PD-1 antibody or antigen-binding fragment thereof are administered within a certain period of time, both of which show pharmacology learn effect. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. Apatinib and PD-1 antibodies or antigen-binding fragments thereof can be administered simultaneously or sequentially. This term includes treatments in which apatinib and PD-1 antibodies or antigen-binding fragments thereof are administered by the same route or different routes of administration. The combined mode of administration of the present invention is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.

本發明中所述“治療失敗”是指受試者在基線時伴有可測量的腫瘤病灶，根據RECIST 1.1療效評定標準為疾病進展(PD)、毒性不可耐受或研究者判斷受試者不能繼續臨床獲益。 The “treatment failure” in the present invention refers to a subject with a measurable tumor lesion at baseline. According to the RECIST 1.1 curative effect evaluation criteria, the disease progression (PD), intolerable toxicity, or the investigator's judgment Continue clinical benefit.

本發明中所述“毒性不可耐受”是指因藥物引起的不良反應不能繼續接受治療。 The "tolerance of toxicity" in the present invention means that an adverse reaction caused by a drug cannot continue to be treated.

無進展生存期(PFS)：從隨機開始到首次記錄腫瘤客觀進展日期或到任何原因導致死亡的時間，以先出現者為准。 Progression-free survival (PFS): The time from the start of randomization to the date when the objective tumor progression is first recorded or until any cause of death, whichever occurs first.

總生存期(OS)指從隨機日期至任何原因導致死亡的日期。末次隨訪時仍存活的受試者，其OS以末次隨訪時間計為數據刪失。失訪的受試者，其OS以失訪前末次證實存活時間計為數據刪失。數據刪失的OS定義為從隨機日期到刪失日期。 Overall survival (OS) refers to the date from a random date to the death of any cause. For subjects who were alive at the last follow-up, their OS was calculated as data censored based on the time of the last follow-up. Lost follow-up subjects had their OS as data censored based on the last confirmed survival time before loss of follow-up. The data censored OS is defined as from random date to censored date.

客觀緩解率(ORR)：定義為最佳總體緩解(BoR)，CR和PR的受試者在各治療組至少用藥一次的受試者人數中所占比例。BOR的定義為隨機日期開始至客觀記錄的進展日期或後續抗腫瘤治療日期(以先發生者為准)之間的最佳緩解指標，對於沒有記錄進展或後續抗腫瘤治療的受試者，將根據所有的緩解評定結果確定BOR。 Objective response rate (ORR): defined as the best overall response (BoR), the proportion of CR and PR subjects among the number of subjects who received at least one dose in each treatment group. BOR is defined as the best from the date of randomization to the date of objectively recorded progression or the date of subsequent antitumor treatment, whichever occurs first Remission indicators. For subjects who have not documented progress or subsequent antitumor therapy, BOR will be determined based on all remission assessment results.

緩解持續時間(DoR)：首次PR或者CR至首次PD或者死亡的時間。 Duration of Remission (DoR): Time from first PR or CR to first PD or death.

疾病控制率(DCR)：CR、PR和SD的受試者在各治療組至少用藥一次的受試者人數中所占比例。DCR從隨機日期開始至客觀記錄的進展日期或後續抗腫瘤治療日期(以先發生者為准)之間的最佳緩解指標，對於沒有記錄進展或後續抗腫瘤治療的受試者，將根據所有的緩解評定結果確定DCR。 Disease control rate (DCR): The proportion of subjects who received CR, PR, and SD at least once in each treatment group. DCR is the best response index from the date of randomization to the objectively recorded progression date or the date of subsequent anti-tumor treatment (whichever occurs first). For subjects without recorded progress or subsequent anti-tumor treatment, The results of the response assessment determine the DCR.

療效評定標準根據RECIST 1.1標準分為完全緩解(CR)、部分緩解(PR)、穩定(SD)、進展(PD)。 Efficacy evaluation criteria were divided into complete response (CR), partial response (PR), stable (SD), and progress (PD) according to the RECIST 1.1 standard.

靶病灶評估： Target lesion assessment:

完全緩解(CR)：所有靶病灶消失，全部病理淋巴結(包括靶結節和非靶結節)短直徑必須減少至<10mm。 Complete remission (CR): All target lesions disappear, and the short diameter of all pathological lymph nodes (including target and non-target nodules) must be reduced to <10mm.

部分緩解(PR)：靶病灶直徑之和比基線水平減少至少30%。 Partial response (PR): The sum of the diameters of the target lesions is reduced by at least 30% from the baseline level.

疾病進展(PD)：以整個實驗研究過程中所有測量的靶病灶直徑之和的最小值為參照，直徑和相對增加至少20%(如果基線測量值最小就以基線值為參照)；除此之外，必須滿足直徑和的絕對值增加至少5mm(出現一個或多個新病灶也視為疾病進展)。 Disease progression (PD): The minimum value of the sum of the diameters of all target lesions measured during the entire experimental study is used as a reference, and the relative increase in diameter is at least 20% (if the baseline measurement is the smallest, the baseline value is used as the reference); In addition, the absolute value of the diameter sum must be increased by at least 5 mm (the appearance of one or more new lesions is also considered as disease progression).

疾病穩定(SD)：靶病灶減小的程度沒達到PR，增加的程度也沒達到PD水平，介於兩者之間，研究時可以直徑之和的最小值作為參考。 Stable disease (SD): The extent of reduction of target lesions did not reach PR, and the extent of increase did not reach PD levels, somewhere in between. The minimum value of the sum is used as a reference.

以下結合實施例用於進一步描述本發明，但這些實施例並非限制本發明的範圍。 The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

實施例1：抗PD-1抗體聯合甲磺酸阿帕替尼治療廣泛期小細胞肺癌的Ⅱ期臨床研究Example 1: Phase II clinical study of anti-PD-1 antibody combined with apatinib mesylate in the treatment of extensive small cell lung cancer

1、受試抗體和化合物 1.Test antibodies and compounds

PD-1抗體其重、輕鏈的序列如本發明中SEQ ID NO：7和SEQ ID NO：8。200mg/支，配成20mg/m1備用。 The sequences of the heavy and light chains of the PD-1 antibody are as shown in SEQ ID NO: 7 and SEQ ID NO: 8. 200 mg / branch in the present invention, and 20 mg / m1 is prepared for use.

市售甲磺酸阿帕替尼片。 Apatinib mesylate tablets are commercially available.

2、入組標準：(1)廣泛期小細胞肺癌；(2)接受過一線鉑類為基礎的針對廣泛期小細胞肺癌治療，且客觀影像學進展；(3)具有可測量的病灶；(4)ECOG評分0-1分。 2. Enrollment criteria: (1) extensive stage small cell lung cancer; (2) received first-line platinum-based treatment for extensive stage small cell lung cancer, and objective imaging advances; (3) have measurable lesions; ( 4) ECOG score is 0-1.

3、給藥方法：經篩選合格的18例受試者按1：1：1隨機分配至以下三組： 3. Method of administration: Eighteen subjects who passed the screening were randomly assigned to the following three groups according to 1: 1: 1:

A組：PD-1抗體200mg，靜脈輸注，每兩週一次+阿帕替尼375mg，口服，每日一次 Group A: PD-1 antibody 200mg, intravenous infusion, once every two weeks + apatinib 375mg, orally, once daily

B組：PD-1抗體200mg，靜脈輸注，每兩週一次+阿帕替尼375mg，口服(給藥5天停藥2天) Group B: 200 mg of PD-1 antibody, intravenous infusion, once every two weeks + apatinib 375 mg, orally (five days off and two days off)

C組：PD-1抗體200mg，靜脈輸注，每兩週一次+阿帕替尼375mg，口服(給藥7天停藥7天) Group C: PD-1 antibody 200mg, intravenous infusion, once every two weeks + apatinib 375mg, orally (7 days after dosing and 7 days off)

數據分析： data analysis:

從上述臨床數據來看，每日一次、日服劑量375mg阿帕替尼聯合PD-1抗體針對廣泛期小細胞肺癌的疾病客觀緩解率(ORR)高達83.3%，疾病控制率(DCR)為83.3%，已經顯示出優異的治療廣泛期小細胞肺癌的作用。 From the above clinical data, the daily objective and daily dose of 375mg of apatinib combined with PD-1 antibody against extensive stage small cell lung cancer is 83.3%, and the disease control rate (DCR) is 83.3 %, Has shown an excellent effect on the treatment of extensive stage small cell lung cancer.

<110> 江蘇恆瑞醫藥股份有限公司蘇州盛迪亞生物醫藥有限公司 <110> Jiangsu Hengrui Pharmaceutical Co., Ltd. Suzhou Shengdia Biological Medicine Co., Ltd.

<120> PD-1抗體和VEGFR抑制劑聯合治療小细胞肺癌的用途 <120> Use of PD-1 antibody and VEGFR inhibitor in the treatment of small cell lung cancer

<160> 10 <160> 10

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<213> 鼠源(Mus musculus) <213> Mus musculus

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<211> 214 <211> 214

<212> PRT <212> PRT

<213> 人工序列(Artificial Sequence) <213> Artificial Sequence

<220> <220>

<221> 肽 <221> Peptide

<222> (1)..(214) <222> (1) .. (214)

<223> 輕鏈序列 <223> Light chain sequence

<400> 8 <400> 8

<210> 9 <210> 9

<211> 116 <211> 116

<212> PRT <212> PRT

<213> 人工序列(Artificial Sequence) <213> Artificial Sequence

<220> <220>

<221> 肽 <221> Peptide

<222> (1)..(116) <222> (1) .. (116)

<223> 重鏈可變區 <223> Variable region of heavy chain

<400> 9 <400> 9

<210> 10 <210> 10

<211> 107 <211> 107

<212> PRT <212> PRT

<213> 人工序列(Artificial Sequence) <213> Artificial Sequence

<220> <220>

<221> 肽 <221> Peptide

<222> (1)..(10) <222> (1) .. (10)

<223> 輕鏈可變區 <223> Light chain variable region

<400> 10 <400> 10

Claims

一種VEGFR抑制劑和抗PD-1抗體或其抗原結合片段的用途，其聯合在製備治療小細胞肺癌患者的藥物。 A use of a VEGFR inhibitor and an anti-PD-1 antibody or an antigen-binding fragment thereof, which is used in combination to prepare a medicine for treating small cell lung cancer patients.

如申請專利範圍第1項所述的用途，其中，該VEGFR抑制劑是VEGFR-2抑制劑。 The use according to item 1 of the scope of patent application, wherein the VEGFR inhibitor is a VEGFR-2 inhibitor.

如申請專利範圍第2項所述的用途，其中，該VEGFR-2抑制劑選自：PAN-90806、佛瑞替尼(Foretinib)、他菲替尼(Tafetinib)、康尼替尼(Kanitinib)、阿帕替尼(Apatinib)、坦尼布盧單抗(Tanibirumab)、安羅替尼(Anlotinib)、德立替尼(Lucitanib)、瓦他拉尼布(Vatalanib)、西地尼布(Cediranib)、西奧羅尼(Chiauranib)、多韋替尼(Dovitinib)、多納非尼(Donafenib)、法米替尼(Famitinib)、西他伐替尼(Sitravatinib)、特拉替尼(Telatinib)、L-21649、TAS-115、卡博替尼(Cabozantinib)、噻爾非尼(Thiophenib)、呋喹替尼(Fruquintinib)、布立尼布(Brivanib)、索凡替尼(Sulfatinib)、雷莫盧單抗(Ramucirumab)、葛雷沙尼布(Glesatinib)、尼達尼布(Nintedanib)、普喹替尼(Puquitinib)、阿西替尼(Axitinib)、EDP317、索拉非尼(Sorafenib)、麥他替尼(Metatinib)、替沃札尼布(Tivozanib)、瑞戈非尼(Regorafenib)、米朵妥林(Midostaurin)、培唑帕尼(Pazopanib)、HLX-06、艾爾提拉尼布(Altiratinib)、寧格替尼(Ningetinib)、舒尼替尼(Sunitinib)、AL-8326、瑞貝斯尼布(Rebastinib)或以上藥物的可藥用鹽。 The use according to item 2 of the patent application scope, wherein the VEGFR-2 inhibitor is selected from the group consisting of: PAN-90806, Foretinib, Tafetinib, Kanitinib , Apatinib, Tanibirumab, Anlotinib, Lucitanib, Vatalanib, Cediranib , Chiauranib, Dovitinib, Donafenib, Famitinib, Sitravatinib, Telatinib, L-21649, TAS-115, Cabozantinib, Thiophenib, Fluquintinib, Brivanib, Sulfatinib, Remo Lumucirumab, Glesatinib, Nintedanib, Puquitinib, Axitinib, EDP317, Sorafenib, Metatinib, Tivozanib, Regorafenib, Midostaurin, Pazopanib, HLX-06, El Tiranib Cloth (A ltiratinib), Ningetinib, Sunitinib, AL-8326, Rebastinib or more Pharmaceutically acceptable salt.

如申請專利範圍第3項所述的用途，其中，該阿帕替尼可藥用鹽選自甲磺酸鹽、馬來酸鹽、酒石酸鹽、琥珀酸鹽、醋酸鹽、二氟醋酸鹽、富馬酸鹽、檸檬酸鹽、枸櫞酸鹽、苯磺酸鹽、苯甲酸鹽、萘磺酸鹽、乳酸鹽、蘋果酸鹽、鹽酸鹽、氫溴酸鹽、硫酸鹽以及磷酸鹽。 The use according to item 3 of the scope of patent application, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, Fumarate, citrate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate .

如申請專利範圍第1項所述的用途，其中，該抗PD-1抗體或其抗原結合片段選自：AMP-224、GLS-010、IBI-308、REGN-2810、PDR-001、BGB-A317、加利妥昔單抗(Pidilizumab)、PF-06801591、傑諾單抗(Genolimzumab)、CA-170、MEDI-0680、JS-001、TSR-042、卡瑞利珠單抗(Camrelizumab)、派姆單抗₍Pembrolizumab)、LZM-009、AK-103和納武單抗(Nivolumab)。 The use according to item 1 of the patent application scope, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB- A317, Galiduximab (Pidilizumab), PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Carrelizumab, Camrelizumab, Paim monoclonal antibody _{(Pembrolizumab), LZM-009,} AK-103 and sodium Wu monoclonal antibody (Nivolumab).

如申請專利範圍第1項所述的用途，其中，該抗PD-1抗體或其抗原結合片段的輕鏈可變區包含分別如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3的PD-1抗體的重鏈可變區包含分別如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3。 The use according to item 1 of the scope of patent application, wherein the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: The heavy chain variable regions of the PD-1 antibodies of LCDR1, LCDR2, and LCDR3 shown in FIG. 6 include HCDR1, HCDR2, and HCDR3 shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively.

如申請專利範圍第6項所述的用途，其中，該抗PD-1抗體為人源化抗體。 The use according to item 6 of the scope of patent application, wherein the anti-PD-1 antibody is a humanized antibody.

如申請專利範圍第7項所述的用途，其中，該人源化抗體的輕鏈可變區序列為如SEQ ID NO：10所示的序列或其變體；重鏈可變區序列為如SEQ ID NO：9所示的序列或其變體。 The use according to item 7 of the scope of patent application, wherein the light chain variable region sequence of the humanized antibody is the sequence shown in SEQ ID NO: 10 Or a variant thereof; the sequence of the heavy chain variable region is the sequence shown in SEQ ID NO: 9 or a variant thereof.

如申請專利範圍第8項所述的用途，其中，該人源化抗體的輕鏈可變區的變體在輕鏈可變區有0至10的胺基酸變化。 The use according to item 8 of the scope of patent application, wherein the variant of the light chain variable region of the humanized antibody has a 0 to 10 amino acid change in the light chain variable region.

如申請專利範圍第9項所述的用途，其中，該人源化抗體的輕鏈可變區的變體在輕鏈可變區為A43S的氨基酸變化。 The use according to item 9 of the scope of patent application, wherein the variant of the light chain variable region of the humanized antibody is an amino acid change of A43S in the light chain variable region.

如申請專利範圍第8項所述的用途，其中，該人源化抗體的重鏈可變區在重鏈可變區有0至10的胺基酸變化。 The use according to item 8 of the scope of patent application, wherein the heavy chain variable region of the humanized antibody has a 0 to 10 amino acid change in the heavy chain variable region.

如申請專利範圍第11項所述的用途，其中，該人源化抗體的重鏈可變區的變體為G44R的胺基酸變化。 The use according to item 11 of the scope of patent application, wherein the variant of the heavy chain variable region of the humanized antibody is an amino acid change of G44R.

如申請專利範圍第8項所述的用途，其中，該人源化抗體輕鏈序列為如SEQ ID NO：8所示的序列或其變體；重鏈序列為如SEQ ID NO：7所示的序列或其變體。 The use according to item 8 of the scope of patent application, wherein the light chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 8 or a variant thereof; the heavy chain sequence is shown in SEQ ID NO: 7 Sequence or a variant thereof.

如申請專利範圍第13項所述的用途，其中，該人源化抗體的輕鏈可變區的變體在輕鏈可變區有0-至10的胺基酸變化。 The use according to item 13 of the scope of patent application, wherein the variant of the light chain variable region of the humanized antibody has a 0 to 10 amino acid change in the light chain variable region.

如申請專利範圍第14項所述的用途，其中，該人源化抗體的輕鏈可變區的變體在輕鏈可變區為A43S的氨基酸變化。 The use according to item 14 of the scope of patent application, wherein the variant of the light chain variable region of the humanized antibody is an amino acid change of A43S in the light chain variable region.

如申請專利範圍第13項所述的用途，其中，該人源化抗體的重鏈可變區在重鏈可變區有0至10的胺基酸變化。 The use according to item 13 of the scope of patent application, wherein the heavy chain variable region of the humanized antibody has 0 to 10 amino acid changes in the heavy chain variable region Into.

如申請專利範圍第16項所述的用途，其中，該人源化抗體的重鏈可變區的變體為G44R的胺基酸變化。 The use according to item 16 of the scope of patent application, wherein the variant of the heavy chain variable region of the humanized antibody is an amino acid change of G44R.

如申請專利範圍第13項所述的用途，其中，該人源化抗體輕鏈序列為如SEQ ID NO：8所示的序列，重鏈序列為如SEQ ID NO：7所示的序列。 The use according to item 13 of the scope of patent application, wherein the light chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 8, and the heavy chain sequence is the sequence shown in SEQ ID NO: 7.

如申請專利範圍第1項所述的用途，其中，該小細胞肺癌為廣泛期小細胞肺癌。 The use according to item 1 of the scope of patent application, wherein the small cell lung cancer is a wide-phase small cell lung cancer.

如申請專利範圍第1項所述的用途，其中，該患者接受過鉑類藥物治療。 The use according to item 1 of the scope of patent application, wherein the patient has been treated with a platinum drug.

如申請專利範圍第20項所述的用途，其中，該鉑類藥物治療選自：依託泊苷/順鉑聯合化療、依託泊苷/卡鉑聯合化療、依託泊苷/順鉑聯合化療和放療、依託泊苷/卡鉑聯合化療和放療。 The use according to item 20 of the scope of patent application, wherein the platinum drug treatment is selected from the group consisting of etoposide / cisplatin combined chemotherapy, etoposide / carboplatin combined chemotherapy, etoposide / cisplatin combined chemotherapy, and radiotherapy , Etoposide / carboplatin combined with chemotherapy and radiotherapy.

如申請專利範圍第1至21項中任一項所述的用途，其中，該PD-1抗體或其抗原結合片段劑量選自1至10mg/kg。 The use according to any one of claims 1 to 21 of the patent application range, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 1 to 10 mg / kg.

如申請專利範圍第22項所述的用途，其中，該PD-1抗體或其抗原結合片段劑量選自1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg。 The use according to item 22 of the scope of patent application, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, and 6 mg / kg. , 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg.

如申請專利範圍第23項所述的用途，其中，該PD-1抗體或其抗原結合片段劑量選自1mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、10mg/kg。 The use according to item 23 of the scope of patent application, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 1 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg .

如申請專利範圍第1至21項中任一項所述的用途，其中，該PD-1抗體或其抗原結合片段劑量選自50至600mg。 The use according to any one of claims 1 to 21, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 50 to 600 mg.

如申請專利範圍第25項所述的用途，其中，該PD-1抗體或其抗原結合片段劑量選自50mg、60mg、70mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、375mg、400mg、425mg、450mg、475mg、500mg、600mg。 The use according to item 25 of the scope of patent application, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 375 mg , 400mg, 425mg, 450mg, 475mg, 500mg, 600mg.

如申請專利範圍第26項所述的用途，其中，該PD-1抗體或其抗原結合片段劑量選自60mg、100mg、200mg、400mg、600mg。 The use according to item 26 of the scope of patent application, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from 60 mg, 100 mg, 200 mg, 400 mg, and 600 mg.

如申請專利範圍第1至21項中任一項所述的用途，其中，該VEGFR抑制劑劑量選自0.01至500mg。 The use according to any one of claims 1 to 21, wherein the dose of the VEGFR inhibitor is selected from 0.01 to 500 mg.

如申請專利範圍第28項所述的用途，其中，該VEGFR抑制劑劑量選自0.1mg、0.25mg、0.5mg、0.75mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、30mg、45mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、400mg、500mg。 The use according to item 28 of the scope of patent application, wherein the dose of the VEGFR inhibitor is selected from the group consisting of 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg , 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 400mg, 500mg.

如申請專利範圍第29項所述的用途，其中，該VEGFR抑制劑劑量選自0.25mg、0.5mg、1mg、2mg、3mg、4mg、10mg、15mg、20mg、30mg、45mg、50mg、60mg、75mg、100mg。 The use according to item 29 of the scope of patent application, wherein the dose of the VEGFR inhibitor is selected from 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 10 mg, 15 mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg , 100mg.

一種降低抗PD-1抗體或VEGFR抑制劑導致的不良反應的方法，包括向患者聯合施用如申請專利範圍第1至30項中任一項所述的VEGFR抑制劑和抗PD-1抗體或其抗原結合片段。 A method for reducing adverse reactions caused by an anti-PD-1 antibody or a VEGFR inhibitor, comprising administering to a patient a combination of a VEGFR inhibitor according to any one of claims 1 to 30 and an anti-PD-1 antibody or an anti-PD-1 antibody Antigen-binding fragment.

一種藥物包裝盒，其含有如申請專利範圍第1至30項中任一項所述的VEGFR抑制劑和抗PD-1抗體或其抗原結合片段。 A pharmaceutical packaging box containing the VEGFR inhibitor according to any one of claims 1 to 30 and an anti-PD-1 antibody or an antigen-binding fragment thereof.