TW201927821A - Uses of PD-1 antibody for treating tumor - Google Patents

Abstract

The disclosure relates to uses of PD-1 antibody for treating tumor. Specifically, the disclosure relates to uses of PD-1 antibody, antigen-binding fragments in the preparation of drugs for treating tumor patients who have been previously treated with anti-CTLA-4 antibody, antigen-binding fragments thereof.

Description

Use of PD-1 antibodies for treating tumors

The present disclosure relates to the use of a PD-1 antibody in the manufacture of a medicament for treating tumor patients.

Cancer has many genetic and epigenetic changes that produce new antigens that can be recognized by the immune system. The adaptive immune system, including T and B lymphocytes, has strong anti-cancer potential, has extensive capabilities and fine specificity to respond to various tumor antigens. In addition, the immune system exhibits considerable plasticity and memory components. Successfully utilizing all these attributes of the adaptive immune system will make immunotherapy unique among all cancer treatment models.

Cancer immunotherapy has focused on methods to enhance the anti-tumor immune response by adoptive transfer of activated effector cells, immunization against related antigens or by providing non-specific immunostimulants such as cytokines. In recent years, the development of specific immune checkpoint pathway inhibitors has begun to become a new type of immunotherapy for cancer treatment, such as the CTLA antibody Ipilimumab (YERVOY ^® ) (Hodi et al.) For the treatment of advanced melanoma. , 2010), specifically binds to PD-1 nivolumab or pembrolizumab.

PD-1 antibody specifically recognizes and binds PD-1 on the surface of lymphocytes, blocking The PD-1 / PD-L1 signaling pathway activates the immune-killing effects of T cells on tumors and modulates the body's immune system to clear tumor cells in the body. WO2015085847A discloses a new anti-PD-1 antibody, which is in the clinical trial stage and has shown a certain antitumor effect.

Ipilimumab (YERVOY ^® ) is a humanized IgG1 monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligand, thereby stimulating T cell activation and improving overall survival (OS) in patients with advanced melanoma (Hodi et al. , 2010). Phase III clinical data indicate that patients with melanoma (NCT01844505) in combination with Nivolumab alone have significantly improved overall survival compared to Ipilimumab alone (Wolchok et al., 2017). However, to date, this combination of immunomodulatory therapies has been performed in combination, and there have been no clinical reports of giving effective amounts of PD-1 antibody therapy to tumor patients who have not been relieved after receiving CTLA antibody therapy.

The present disclosure provides the use of an anti-PD-1 antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating a tumor patient who has been treated with an anti-CTLA-4 antibody or an antigen-binding fragment thereof.

Wherein, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF- 06801591, Genolizumab, CA-170, MEDI-0680, JS-001, TSR-042, Carrelizumab, Pembrolizumab, LZM-009 , AK-103, and Nivolumab.

In some embodiments, the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises LCDR1, LCDR2, and SEQR NO: 4, respectively LCDR3; the variable region of the heavy chain 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:

Preferably, the PD-1 antibody is a humanized antibody.

Further, the preferred humanized antibody light chain variable region sequence is the sequence shown in SEQ ID NO: 10 or a variant thereof, and the variant preferably has a 0 to 10 amino acid change in the light chain variable region. The amino acid change of A43S is more preferable; the sequence of the variable region of the heavy chain of the humanized antibody is the sequence shown in SEQ ID NO: 9 or a variant thereof, and the variant preferably has the variable region of the heavy chain An amino acid change of 0 to 10, more preferably an amino acid change of G44R.

The sequence of the variable region of the heavy and light chains of the humanized antibody of the PD-1 antibody described in the present disclosure is as follows:

Heavy chain variable region SEQID NO: 9

Light chain variable region SEQID NO: 10

Preferably, the 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 variable region of the light chain, more Preferably the amino acid change of A43S; the humanized antibody heavy chain sequence is the sequence shown in SEQ ID NO: 7 or a variant thereof, and the variant preferably has an amine of 0 to 10 in the heavy chain variable region The amino acid change is more preferably the amino acid change of G44R.

In a preferred embodiment, 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.

The sequences of the heavy and light chains of this humanized antibody are shown below:

Heavy chain SEQID NO: 7

Light chain SEQID NO: 8

In an alternative embodiment, the anti-CTLA-4 antibody or antigen-binding fragment thereof cross-competes with ipilimumab to bind human CTLA-4, and the anti-CTLA-4 antibody or antigen-binding fragment thereof is chimeric, humanized, or Human monoclonal antibodies or parts thereof.

Further, the anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of a human IgG1 isotype.

In an alternative embodiment, the anti-CTLA-4 antibody is selected from ipilimumab, Tremelimumab, Belatacept, or Abatacept.

In an alternative embodiment, the tumor is a malignant tumor or a benign tumor; the malignant tumor is selected from the group consisting of malignant epithelial tumor, sarcoma, myeloma, leukemia, lymphoma, melanoma, head and neck tumor, brain tumor, peritoneal cancer, mixed Tumor, childhood malignant tumor; the malignant epithelial tumor is selected from lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, gastric cancer, gastroesophageal adenocarcinoma, esophageal cancer, small intestine cancer, cardiac cancer, endometrial cancer, ovarian cancer , Fallopian tube cancer, vulvar cancer, testicular cancer, prostate cancer, penile cancer, kidney cancer, bladder cancer, anal cancer, gallbladder cancer, bile duct cancer, teratoma, heart tumor; the head and neck tumor is selected from nasopharyngeal cancer, laryngeal cancer , Thyroid cancer, tongue cancer, oral cancer; the sarcoma is selected from Askin tumor, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, soft tissue sarcoma; the myeloma is selected from solitary myeloma, Multiple myeloma, diffuse myeloma, leukemia myeloma, extramedullary myeloma; the leukemia is selected from acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute Myeloid leukemia, chronic myelogenous leukemia, hairy cell leukemia, T-cell lymphocytic leukemia, large granular lymphocytic leukemia, adult T-cell leukemia; the lymphoma is selected from non-Hodgkin's lymphoma, Hodgkin's lymphoma The brain tumor is selected from the group consisting of neuroepithelial tissue tumors, cranial nerve and spinal nerve tumors, and meningeal tissue tumors; the child malignant tumor is selected from nephroblastoma, neuroblastoma, retinoblastoma, and child germ cell tumor.

In another optional embodiment, the lung cancer is selected from the group consisting of non-small cell lung cancer and small cell lung cancer; the breast cancer is selected from hormone receptor (HR) positive breast cancer, human epidermal growth factor receptor- 2 (HER2) positive breast cancer, triple negative breast cancer; the renal cancer is selected from the group consisting of clear renal cell carcinoma, papillary renal cell carcinoma, Colorectal renal cell carcinoma, collecting duct cancer; The neuroepithelial tissue tumor is preferably selected from astrocytoma, anaplastic astrocytoma, and glioblastoma; the liver cancer is selected from primary liver cancer, secondary Liver cancer, the primary liver cancer is selected from hepatocellular carcinoma, bile duct cell carcinoma, mixed liver cancer; the colorectal cancer is selected from colon cancer, rectal cancer.

In another alternative embodiment, the tumor is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, prostate cancer, pancreatic cancer, lung cancer, esophageal cancer, liver cancer, bile duct cancer, breast cancer, colorectal cancer, Gastric cancer, kidney cancer, acute myeloid lymphocytic leukemia, myelodysplastic syndrome, glioma, nasopharyngeal carcinoma, and tumors of unknown primary site.

Further, the dose of the anti-CTLA-4 antibody or the antigen-binding fragment thereof described in the present disclosure is 0.1 to 10.0 mg / kg, and may be 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg. / kg, 0.6mg / kg, 0.7mg / kg, 0.8mg / kg, 0.9mg / kg, 1.0mg / kg, 1.2mg / kg, 1.4mg / kg, 1.6mg / kg, 1.8mg / kg, 2.0mg / kg, 2.2mg / kg, 2.4mg / kg, 2.6mg / kg, 2.8mg / kg, 3.0mg / kg, 3.2mg / kg, 3.4mg / kg, 3.6mg / kg, 3.8mg / kg, 4.0mg / kg, 4.2mg / kg, 4.4mg / kg, 4.6mg / kg, 4.8mg / kg, 5.0mg / kg, 5.2mg / kg, 5.4mg / kg, 5.6mg / kg, 5.8mg / kg, 6.0mg / kg, 6.2mg / kg, 6.4mg / kg, 6.6mg / kg, 6.8mg / kg, 7.0mg / kg, 7.2mg / kg, 7.4mg / kg, 7.6mg / kg, 7.8mg / kg, 8.0mg / kg, 8.2mg / kg, 8.4mg / kg, 8.6mg / kg, 8.8mg / kg, 9.0mg / kg, 9.2mg / kg, 9.4mg / kg, 9.6mg / kg, 9.8mg / kg, 10.0mg / kg.

In an alternative embodiment, the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 1 to 600 mg, and may be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2 mg, 2.4 mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg , 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8 mg, 10.0mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg , 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg , 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg , 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg.

Further, in a preferred embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 0.1 to 10.0 mg / kg, and may be 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg. kg, 0.5mg / kg, 0.6mg / kg, 0.7mg / kg, 0.8mg / kg, 0.9mg / kg, 1.0mg / kg, 1.2mg / kg, 1.4mg / kg, 1.6mg / kg, 1.8mg / kg, 2.0mg / kg, 2.2mg / kg, 2.4mg / kg, 2.6mg / kg, 2.8mg / kg, 3.0mg / kg, 3.2mg / kg, 3.4mg / kg, 3.6mg / kg, 3.8mg / kg, 4.0mg / kg, 4.2mg / kg, 4.4mg / kg, 4.6mg / kg, 4.8mg / kg, 5.0mg / kg, 5.2mg / kg, 5.4mg / kg, 5.6mg / kg, 5.8mg / kg, 6.0mg / kg, 6.2mg / kg, 6.4mg / kg, 6.6mg / kg, 6.8mg / kg, 7.0mg / kg, 7.2mg / kg, 7.4mg / kg, 7.6mg / kg, 7.8mg / kg, 8.0mg / kg, 8.2mg / kg, 8.4mg / kg, 8.6 mg / kg, 8.8 mg / kg, 9.0 mg / kg, 9.2 mg / kg, 9.4 mg / kg, 9.6 mg / kg, 9.8 mg / kg, 10.0 mg / kg.

Preferably, in another optional embodiment, the dose of the PD-1 antibody or antigen-binding fragment thereof is 1 to 600 mg, and may be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg , 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8 mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg.

The frequency of administration of the anti-PD-1 antibody or antigen-binding fragment thereof is once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. The frequency of the drug is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once every four weeks or once a month.

Further, in an alternative embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 to 600 mg, and the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3 to 10 mg / kg.

In an alternative embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 to 600 mg, once every 1 to 4 weeks; the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3 to 10 mg / kg, each Once every 1 to 4 weeks.

In an alternative embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg; the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3 to 10 mg / kg.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof The dose is 200 mg, once every 3 weeks; the dose of the anti-CTLA-4 antibody or its antigen-binding fragment is 3 to 10 mg / kg, once every 3 weeks.

In an alternative embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, once every 2 weeks; the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3 to 10 mg / kg, once every 3 weeks.

In an alternative embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 to 10.0 mg / kg every 1 to 4 weeks; the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 1 to 10.0 mg / kg every 1 to 4 weeks.

In an alternative embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 10.0 mg / kg every 2 weeks; the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3 to 10 mg / kg, each Once every 1 to 4 weeks.

In an alternative embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 mg / kg, and the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3 mg / kg.

In an alternative embodiment, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 mg / kg once every 3 weeks; the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3 mg / kg once every 3 weeks .

The administration route described in the present disclosure may be oral administration, parenteral administration, or transdermal administration. The parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

In an alternative embodiment, the PD-1 antibody or CTLA-4 antibody is administered by injection, such as subcutaneously or intravenously, and the PD-1 antibody or CTLA-4 antibody needs to be formulated into an injectable form before injection. . Particularly preferred The injectable form of the PD-1 antibody or CTLA-4 antibody is an injection solution or a lyophilized powder injection, such as an injectable form of the PD-1 antibody, which contains a PD-1 antibody, a buffer, a stabilizer, and optionally also contains 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.

Patients with tumors described in this disclosure have also been treated with other anticancer agents, including prior to treatment with anti-CTLA-4 antibodies or antigen-binding fragments thereof, or with anti-CTLA-4 antibodies or antigen-binding fragments thereof. After treatment with other anticancer agents.

The other anticancer agents described in the present disclosure are compounds that can be used to treat cancer, and are selected from, but not limited to, alkylating agents such as tiotepa, cyclophosphamide, ifosfamide; alkyl sulfonates, such as white Diazepam, Inprosyl Sufate and Supor Sulfate; aziridines, such as benzodopa, carbachoquinone, meturedopa, and uredopa; methylmelamines, including hexamethyl Altretamine, triethylenemelamine, tritylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; β-la Beta-lapachone; lapachol; colchicine; betulinic acid; camptothecin (including the synthetic analog topotecan, CPT-11 (irinotecan, acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callis Callystatin; CC-1065 (including its adozelesin, carzelesin; podophyllotoxin; podophyllinic acid; teniposide ); Candida cyclic peptides (especially Candida cyclic peptide 1 and Candida cyclic peptide 8); sea rabbit toxin (dolastatin); duocarmycin (including synthetic analogs, KW-2189 and CB1- TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil and chlomaphazine , Estramustine, dichloromethanediethylamine, mechloroethamine oxide hydrochloride, melphalan, novelmichin, cholesterol phenacetine, phenesterine, Prednimustine, trofosfamide, uracil mustard; Carbamides, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and laninstein (ranimnustine); antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ 1 and calicheamicin ω 1; dynemicin, including damicin A; Esperamicin; epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, ( (Such as mitomycin C), mycophenolic acid, Nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodobisin (rodorubicin), streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin ); Anticancer metabolites, such as methotrexate and 5-fluorouracil (5-FU); folate analogs, such as denopterin, methotrexate, pteropterin ), Trimetrexate; triazine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs , Such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxy Doxifluridine, enocitabine, floxuridine; androgens, such as dioxin Testosterone (calusterone), dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenal agents, such as aminoacetophenone (aminoglutethimide), mitotane, trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside); aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; Defofamine; Demecolcine; diaziquone; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate nitrate); hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocins; propylamidine (mitoguazone); mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; Losoxantrone; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofuran; spirox Germanium (spirogermaniuim); tenuazonic acid; triaziquone; 2,2 ', 2 "-trichlorotriethylamine; trichothecenes Especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; go Vindesine dacarbazine; mannitol nitrogen mustard (mannomustine); dibromomannitol (mitobronitol); dibromo dulcitol (mitolactol); dibromopropylpyrazine (pipobroman) Gacytosine; arabinoside; thiotepas; taxoids; doxetaxel; chloranbucil; gemcitabine 6-thioguanine (6-thioguanine); mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16 ); Mitoxantrone (mitoxantrone); Vincristine; oxaliplatin; leucovovin; vinorelbine; novantrone; edatrexate; daunorubicin Aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid ); Capecitabine; PARP inhibitors, such as olaparib, talazoparib, Veliparib, Rucaparib, fluazoparib, CEP-8983 or BGB-290; VEGFR-2 inhibitors such as PAN-90806, Foretinib, Tafetinib, Kanitinib, Apatinib , Tanibirumab, Anlotinib, Lucitanib, Vatalanib, Cediranib, Chiauranib, Dodo Dovitinib, Donafenib, Famitinib, Sitravatinib, Telatinib, L-21649, TAS-115, Carbo Cabozantinib, Thiophenib, Fluquintinib, Brivanib, Sulfatinib, Ramucirumab, Graceatinib (Glesatinib), Nintedanib, Puquitinib, Axitinib, EDP317, Sorafenib, Metatinib, Tevozani (Tivozanib), Regorafenib, Midostaurin, Pazopanib, HLX-06, Altiratinib, Ningetinib, Shu At least one of Sunitinib, AL-8326, Rebastinib, Tigio or It is a pharmaceutically acceptable salt, acid or derivative.

In an alternative embodiment, the target lesion diameter of a tumor patient described in the present disclosure is relatively reduced by at least 30%.

In alternative embodiments, the target lesion diameter of a tumor patient described in the present disclosure is relatively increased by at least 20% or one or more new lesions appear.

In an alternative embodiment, the target lesion diameter of a tumor patient described in the present disclosure is relatively increased by up to 20% or the target lesion diameter is relatively decreased by up to 30%.

Further, the tumor patient described in the present disclosure is a treatment failure.

The present disclosure also provides a method for treating a tumor, the method comprising: a. Confirming whether a tumor patient has been treated with an anti-CTLA-4 antibody or an antigen-binding fragment thereof; b. Administering an anti-CTLA-4 antibody or an antigen-binding fragment thereof that has been received The treated patient has an effective dose of an anti-PD-1 antibody or antigen-binding fragment thereof.

Further, the patient had also been treated with other anticancer agents.

In an alternative embodiment, the tumor patient has a relative increase in target lesion diameter of at least 20% or the appearance of one or more new lesions.

In alternative embodiments, the target lesion diameter of the tumor patient is relatively reduced by at least 30%.

In alternative embodiments, the target patient's diameter is relatively increased by up to 20% or the diameter of the targeted lesion is relatively decreased by up to 30%.

Preferably, the tumor patient is a treatment failure.

If not interpreted to the contrary, the terms in this disclosure have the following meanings: "humanized antibodies" as described in this disclosure, It is also called CDR-grafted antibody, which refers to the antibody generated by transplanting mouse CDR sequences into the human antibody variable region framework, that is, different types of human germline 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, 5th edition. In a preferred embodiment of the present disclosure, 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.

The “antigen-binding fragment” described in the present disclosure 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 selected from the group consisting 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 disclosure refers to the ability to interact with human PD-1. The term "antigen-binding site" in the present disclosure refers to a three-dimensional discontinuity in the antigen that is recognized by the antibodies or antigen-binding fragments of the present disclosure. Spatial loci.

The term "immunotherapy" as used in this disclosure refers to the use of the immune system to treat diseases. In this disclosure, it mainly refers to stimulating and enhancing the body's anti-tumor immunity by increasing the immunogenicity of tumor cells and the sensitivity to effector cell killing. In response, and infused into the host with immune cells and effector molecules, it cooperates with the body's immune system to kill tumors and inhibit tumor growth.

An "effective amount" as described herein includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's general health, the route and dosage of administration, and the severity of the side effects. An effective amount may be the maximum dose or dosage regimen to avoid significant side effects or toxic effects.

The “treatment failure” described in the present disclosure refers to a subject with a measurable tumor lesion at baseline, which is disease progression (PD) or intolerable according to the RECIST 1.1 efficacy evaluation criteria.

"Intolerable" as described in this disclosure means that an adverse reaction caused by a drug cannot continue to be treated.

Overall survival (OS) refers to the period from randomization to death for any reason. 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 OS of data censoring is defined as the time from random grouping to censoring.

Objective response rate (ORR) refers to the proportion of patients whose tumor shrinks to a certain level and stays for a certain period of time, including CR And PR cases. The tumor remission assessment standard (RECIST 1.1 standard) was used to evaluate the objective tumor remission. Subjects must be accompanied by measurable tumor lesions at baseline. The efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable (SD), and progressive (PD) according to RECIST 1.1.

Disease Control Rate (DCR) refers to confirmed complete, partial, and stable disease ( (8 weeks) The percentage of cases among evaluable patients.

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.

Partial response (PR): The sum of the diameters of the target lesions is reduced by at least 30% from the baseline level.

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).

Stable disease (SD): The target lesions did not decrease to PR, and the increase did not reach PD. Between the two, the minimum value of the sum of diameters can be used as a reference during the study.

The anticancer agents used in the present disclosure are commercially available.

Figure 1 compares the volume of abdominal wall metastases before and after PD-1 treatment.

The following examples are used to further describe the present disclosure, but these implementations The examples do not limit the scope of this disclosure.

Example 1:

Eight patients with stage I clinical diagnosis were diagnosed with nasopharyngeal carcinoma by histology or cytology.

Dosing plan:

Compound A (Ipilimumab): a dose of 3 mg / kg or 10 mg / kg; Compound B (PD-1, prepared according to the method in patent application WO2017054646A): a dose of 200 mg or 10 mg / kg;

data analysis:

Patient 1: The disease progressed after 6 courses of compound A treatment, and the disease was stable after 3 courses of intervening chemotherapy (cisplatin). Compound B (intravenous infusion, once every 2 weeks, 4 weeks as a cycle) was given. After 2 cycles, the sum of the diameter of the target lesions (left 8 costal soft tissue, spleen 1, spleen 2) of the patient was reduced by at least 32% from the baseline level, and the disease was partially relieved; Patient 2: After 4 courses of Compound A treatment, the disease was stable After withdrawing from the experiment due to intolerance, the compound B (intravenous infusion, once every 2 weeks, 4 weeks as a cycle) was given for 6 cycles, and the patient's target lesions (liver, large muscle nodule, Okanata The total diameter of the muscle nodules is 32% lower than the baseline level, and the disease is partially relieved. Patient 3: After 4 courses of Compound A treatment, the disease progresses, and then Compound B (intravenous infusion, every 2 weeks, 4 weeks as a cycle) ) After 2 cycles of treatment, the sum of the diameter of the target lesions (liver, para-aortic lymph nodes) of the patient was reduced by 38% from the baseline level, and the disease was partially relieved; Patient 4: After 4 courses of Compound A treatment, the disease progressed, and then Compound B (intravenous infusion, every 2 weeks) Times, for a period of 4 weeks) After 2 cycles of treatment, the sum of the diameter of the target lesions (left neck lymph nodes, liver) of the patient was reduced by 49% from the baseline level, and the disease was partially alleviated. Patient 5: After 4 courses of Compound A treatment, the disease progressed and intervening chemotherapy (card After 8 cycles of treatment, and then given Compound B (intravenous infusion, every 2 weeks, 4 weeks as a cycle) after 2 cycles of treatment, the patient's target lesions (liver S3, liver S5, peritoneal mass) diameter The sum is 62% lower than the baseline level, and the disease is partially relieved, as shown in Figure 1. Patient 6: The disease progresses after 4 courses of Compound A treatment, and the disease is stable after 6 courses of intervening chemotherapy (gemcitabine + vincristine). After that, I used tegio, and then gave compound B (intravenous infusion, every 2 weeks, 4 weeks as a cycle) after 2 cycles of treatment, the sum of the diameter of the patient's target lesion (left middle lobe, right middle lobe) 20% increase from baseline, disease progression; patient 7: disease progression after 4 courses of compound A treatment, disease progression after 5 courses of intervening chemotherapy (tigio), compound B (intravenous infusion, each Once every 2 weeks and 4 weeks as a cycle) After treatment, the patient's target The sum of the diameters of the foci (left lung, liver S4, liver S2, right adrenal gland) increased by 22% from the baseline level, and the disease progressed. Patient 8: After treatment with compound A (February), the disease progressed, and then compound B ( Intravenous infusion, once every 2 weeks, 4 weeks as a cycle) After 2 cycles of treatment, the diameter of the target lesion (right lung) of the patient was reduced by 43% from the limit level, and the disease was partially relieved.

From the above 8 clinical data, the subjects who failed the treatment with ipilimumab received subsequent PD-1 therapy with very good results, 6 of the 8 subjects The cases achieved PR, and the objective response rate (ORR) was as high as 75%.

<110> Jiangsu Hengrui Pharmaceutical Co., Ltd. Cancer Hospital Affiliated to Sun Yat-sen University

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Claims (30)

Use of an anti-PD-1 antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating a tumor patient who has been treated with an anti-CTLA-4 antibody or an antigen-binding fragment thereof. 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, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Carrelizumab , Pembrolizumab, LZM-009, AK-103, and Nivolumab. 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: LCDR1, LCDR2, and LCDR3 shown in FIG. 6, and the heavy chain variable region of the PD-1 antibody includes HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively. The use according to item 3 of the scope of patent application, wherein the anti-PD-1 antibody is a humanized antibody. The use according to item 4 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 heavy chain of the humanized antibody The variable region sequence is the sequence shown in SEQ ID NO: 9 or a variant thereof. The use according to item 5 of the scope of patent application, wherein the sequence of the light chain variable region of the humanized antibody is a 0 to 10 amino acid change in the light chain variable region. The use according to item 6 of the scope of patent application, wherein the light chain variable region sequence of the humanized antibody has an amino acid change of A43S in the light chain variable region. The use according to item 5 of the scope of patent application, wherein the sequence of the heavy chain variable region of the humanized antibody is a 0 to 10 amino acid change in the heavy chain variable region. The use according to item 8 of the scope of the patent application, wherein the sequence of the heavy chain variable region of the humanized antibody is a G44R amino acid change in the heavy chain variable region. The use according to item 4 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 of the humanized antibody is as The sequence shown in SEQ ID NO: 7 or a variant thereof. The use according to item 10 of the scope of patent application, wherein the sequence of the light chain variable region of the humanized antibody is a 0 to 10 amino acid change in the light chain variable region. The use according to item 11 of the scope of patent application, wherein the sequence of the light chain variable region of the humanized antibody is an amino acid change of A43S in the light chain variable region. The use according to item 10 of the scope of patent application, wherein the heavy chain variable region sequence of the humanized antibody is an amine having 0 to 10 in the heavy chain variable region Basic acid changes. The use according to item 13 of the scope of patent application, wherein the sequence of the heavy chain variable region of the humanized antibody is a G44R amino acid change in the heavy chain variable region. The use according to any one of claims 10 to 14, in which 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 shows the sequence. The use according to any one of claims 1 to 15, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof cross-competes with Ipilimumab to bind human CTLA-4. The use according to item 16 of the scope of patent application, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is a chimeric, humanized or human monoclonal antibody or a part thereof. The use as described in claim 16 or claim 17, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of a human IgG1 isotype. The use according to item 16 of the scope of patent application, wherein the anti-CTLA-4 antibody is selected from the group consisting of Ipilimumab, Tremelimumab, Belatacept or Abashi (Abatacept). The use according to any one of claims 1 to 19, wherein the tumor is nasopharyngeal carcinoma. The use according to any one of claims 1 to 20, wherein the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 0.1 to 10.0mg / kg. The use according to any one of claims 1 to 21 of the application, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 0.1 to 10.0 mg / kg. The use according to any one of claims 1 to 22 of the application, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 mg / kg, and the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3mg / kg. The use according to any one of claims 1 to 23 of the patent application scope, wherein the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 1 to 600 mg. The use according to any one of claims 1 to 24 of the scope of patent application, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 to 600 mg. The use according to any one of claims 1 to 25, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, and the dose of the anti-CTLA-4 antibody or antigen-binding fragment thereof is 3 to 10 mg. / kg. The use according to item 1 of the scope of patent application, wherein the tumor patient has also been treated with other anticancer agents. The use according to any one of claims 1 to 27 of the scope of patent application, wherein the tumor patient has failed treatment. The use as described in claims 1 to 28 of the scope of the patent application, wherein the target lesion diameter of the tumor patient is relatively increased by at least 20% or one or more new lesions appear. A method of treating a tumor, comprising: a. Confirming whether a tumor patient has been treated with an anti-CTLA-4 antibody or antigen-binding fragment thereof; b. Administering an effective dose of anti-CTLA-4 antibody or an antigen-binding fragment to a patient who has been treated PD-1 antibodies or antigen-binding fragments thereof.