WO2019114785A1 - Use of pd-1 antibody in treating tumor - Google Patents

Abstract

Provided is a use of a PD-1 antibody in treating a tumor. In particular, provided is a use of an anti-PD-1 antibody or an antigen-binding fragment thereof in preparing a drug for treating a tumor patient having received treatment with an anti-CTLA-4 antibody or an antigen-binding fragment thereof.

Description

Use of PD-1 antibody for treating tumors Technical field

The present disclosure relates to the use of a PD-1 antibody for the preparation of a medicament for treating a tumor patient.

Background technique

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 potent anticancer potential, a wide range of capabilities and fine specificity in response to a variety of tumor antigens. In addition, the immune system exhibits considerable plasticity and memory components. Successful use of all of these attributes of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

Cancer immunotherapy has focused on methods for enhancing anti-tumor immune responses by adoptive transfer of activated effector cells, immunization against related antigens, or providing non-specific immunostimulatory agents such as cytokines. In recent years, the development of specific immunological checkpoint pathway inhibitors has begun to become a new immunotherapy for cancer treatment, such as the CTLA antibody Ipilimumab for the treatment of advanced melanoma.

(Hodi et al., 2010), specific binding to programmed death receptor (PD-1) nivolumab or pembrolizumab, and the like.

PD-1 antibody specifically recognizes and binds to PD-1 on the surface of lymphocytes, blocks the PD-1/PD-L1 signaling pathway, and activates the immune killing effect of T cells on tumors, and modulates the immune system of the body to eliminate tumor cells in vivo. WO2015085847A discloses a novel anti-PD-1 antibody, which is in the clinical trial stage and has shown a certain anti-tumor effect.

Ipilimumab

It is a humanized IgGl monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligand, thereby stimulating T cell activation and improving overall survival (OS) in advanced melanoma patients (Hodi et al, 2010). Phase III clinical data showed that the overall survival of patients was significantly longer than that of Ipilimumab alone, in combination with Nivolumab for the treatment of melanoma (NCT01844505) (Wolchok et al., 2017). However, to date, such immunomodulatory therapeutic combinations have been carried out in combination, and no clinical reports have been reported in which an effective amount of PD-1 antibody is administered to a tumor patient who has not been relieved of treatment with a CTLA antibody.

Summary of the invention

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

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, Camrelizumab, 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 the LCDR1, LCDR2 as set forth in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively And LCDR3; the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.

Among them, the CDR sequences described above are shown in the following table:

name	sequence	Numbering
HCDR1	SYMMS	SEQID NO: 1
HCDR2	TISGGGANTYYPDSVKG	SEQID NO: 2
HCDR3	QLYYFDY	SEQID NO: 3
LCDR1	LASQTIGTWLT	SEQID NO: 4
LCDR2	TATSLAD	SEQID NO: 5
LCDR3	QQVYSIPWT	SEQID NO: 6

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

Further, it is preferred that the humanized antibody light chain variable region sequence is the sequence set forth in SEQ ID NO: 10 or a variant thereof, preferably having a 0-10 amino acid change in the light chain variable region, Preferably, the amino acid change of A43S; the humanized antibody heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 9 or a variant thereof, preferably having 0-10 in the heavy chain variable region The amino acid change is more preferably the amino acid change of G44R.

The variable region sequences of the heavy and light chain of the humanized antibody of the PD-1 antibody of the present disclosure are as follows:

Heavy chain variable region

Light chain variable region

Preferably, the humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 8 or a variant thereof; the variant preferably has a 0-10 amino acid change in the light chain variable region, more preferably Amino acid change of A43S; the humanized antibody heavy chain sequence is the sequence set forth in SEQ ID NO: 7 or a variant thereof, preferably having a 0-10 amino acid change in the heavy chain variable region, Amino acid changes of G44R are preferred.

In a preferred embodiment, the light chain sequence of the humanized antibody is the sequence set forth in SEQ ID NO: 8, and the heavy chain sequence is the sequence set forth in SEQ ID NO: 7.

The sequences of the humanized antibody heavy and light chains are as follows:

Heavy chain

Light chain

In an alternative embodiment, the anti-CTLA-4 antibody or antigen-binding fragment thereof competes with Ipilimumab for binding to human CTLA-4, 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 IgGl isotype.

In an alternative embodiment, the anti-CTLA-4 antibody is selected from the group consisting of 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 a malignant epithelial tumor, a sarcoma, a myeloma, a leukemia, a lymphoma, a melanoma, a head and neck tumor, a brain tumor, a peritoneum Cancer, mixed tumor, childhood malignant tumor; the malignant epithelial tumor is selected from the group consisting of lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, gastroesophageal adenocarcinoma, esophageal cancer, small intestine cancer, cardiac cancer, endometrium Cancer, ovarian cancer, fallopian tube cancer, vulvar cancer, testicular cancer, prostate cancer, penile cancer, kidney cancer, bladder cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, teratoma, cardiac tumor; the head and neck tumor is selected from Nasopharyngeal carcinoma, laryngeal cancer, thyroid cancer, tongue cancer, oral cancer; the sarcoma is selected from the group consisting of Askin tumor, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannomas, osteosarcoma, soft tissue sarcoma; The tumor is selected from the group consisting of isolated myeloma, multimodal myeloma, diffuse myeloma, leukemia myeloma, extramedullary myeloma; the leukemia is selected from acute lymphocytic leukemia, chronic lymphocytosis 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, Huo The brain tumor is selected from the group consisting of a neuroepithelial tumor, a cranial nerve and a spinal nerve tumor, and a meningeal tumor; the child malignant tumor is selected from the group consisting of a nephroblastoma, a neuroblastoma, a retinoblastoma, Childhood germ cell tumors.

In another optional embodiment, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer; the breast cancer is selected from the group consisting of hormone receptor (HR) positive breast cancer, human epidermal growth factor receptor Body-2 (HER2)-positive breast cancer, triple-negative breast cancer; the renal cancer is selected from the group consisting of transparent renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting ductal carcinoma; said neuroepithelial neoplasm Selected from a preferred astrocytoma, anaplastic astrocytoma, glioblastoma; the liver cancer is selected from the group consisting of primary liver cancer, secondary liver cancer, and the primary liver cancer is selected from the group consisting of hepatocellular carcinoma and cholangiocarcinoma. Cancer, mixed liver cancer; the colorectal cancer is selected from the group consisting of colon cancer and rectal cancer.

In another alternative embodiment, the tumor is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, prostate cancer, pancreatic cancer, lung cancer, esophageal cancer, liver cancer, cholangiocarcinoma, breast cancer, colorectal cancer , gastric cancer, kidney cancer, acute myeloid lymphocytic leukemia, myelodysplastic syndrome, glioma, nasopharyngeal carcinoma, tumor with unknown origin.

Further, the anti-CTLA-4 antibody or antigen-binding fragment thereof of the present disclosure has a dose of 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, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is in the range of 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, 2.4mg, 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, 8.8mg, 9.0 Mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10.0 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg 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 , 3 50mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 600mg.

Further, in a preferred embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof has a dose of 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, 0.5mg/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, 2.0 mg/kg, 2.2 mg/kg, 2.4 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/kg, 3.6 mg/kg, 3.8 mg/ Kg, 4.0 mg/kg, 4.2 mg/kg, 4.4 mg/kg, 4.6 mg/kg, 4.8 mg/kg, 5.0 mg/kg, 5.2 mg/kg, 5.4 mg/kg, 5.6 mg/kg, 5.8 mg/ 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, 10.0 mg/kg.

Preferably, in another optional embodiment, wherein the PD-1 antibody or antigen-binding fragment thereof has a dose of 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, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8 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, 9.0 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10.0 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 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, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 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, 595 mg, 600 mg.

The anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, and the anti-CTLA-4 antibody or antigen-binding fragment thereof The frequency of administration 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 anti-PD-1 antibody or antigen-binding fragment thereof is administered in an amount of from 1 to 600 mg, and the anti-CTLA-4 antibody or antigen-binding fragment thereof is in a dose of from 3 to 10 mg/kg.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered in an amount of from 1 to 600 mg once every 1-4 weeks; and the anti-CTLA-4 antibody or antigen-binding fragment thereof is administered in an amount of from 3 to 10 mg/kg. Every once every 1-4 weeks.

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

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

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

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

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

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

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

The administration route of the present disclosure may be oral administration, parenteral administration, or transdermal administration, and the parenteral administration includes, but 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, for example subcutaneously or intravenously, and the PD-1 antibody or CTLA-4 antibody is formulated into an injectable form prior to injection. . A particularly preferred injectable form of the PD-1 antibody or CTLA-4 antibody is an injectable or lyophilized powder, such as an injectable form of a PD-1 antibody, comprising a PD-1 antibody, a buffer, a stabilizer, optionally The ground also contains a surfactant. The buffering agent may be selected from one or more of the group consisting 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, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80. Most preferred is polysorbate 20.

The tumor patients described in the present disclosure have also been treated with other anticancer agents, including receiving other anticancer agents prior to treatment with anti-CTLA-4 antibodies or antigen-binding fragments thereof, or receiving anti-CTLA-4 antibodies or antigen-binding fragments thereof. Treated with other anticancer agents after treatment.

Other anticancer agents described in the present disclosure are compounds useful for treating cancer, selected from, but not limited to, alkylating agents such as thiotepa, cyclophosphamide, ifosfamide; alkyl sulfonates such as busulfan , Ying Bing Shu Fan and Pipershufan; aziridines, such as benzodiazepam, carbazone, meturedopa and uredopa; methyl melamines, including altretamine, triethylenemelamine, trietylenephosphoramide, tri-ethyl thiophosphoramide (triethiylenethiophosphoramide) and trimethylolomelamine; beta-lapachone; lapachol; colchicine; betulinic acid; camptothecin (camptothecin) Including synthetic analogues topotecan, CPT-11 (irinotecan, acetylcamptothecin, scopolectin and 9-aminocamptothecin) Bryostatin; calistatin (CCallystatin); CC-1065 (including its adozelesin, carzelesin; podophyllotoxin; oxalic acid (podophyllinic acid); teniposide; Nocturnal cryptophycin (especially Candida cyclic peptide 1 and Nostoccal cyclic peptide 8); dolastatin (dolastatin); doocarmycin (including synthetic analogues, KW-2189 and CB1-TM1) ; eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil, chlomaphazine, female Ashramustine, chloramphenicol, mechlorethamine oxide hydrochloride, melphalan, neomethane, phenesterine, pine Prednimustine, trofosfamide, uracil mustard; nitrourea such as carmustine, chlorozotocin, formoterol (fotemustine), lomustine, rimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (eg, calicheamicin, especially Cachi Γ1 and calicheamicin ω1; dynemicin, including Damisin A Esperamicin; epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, pupa Puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, umbramide ( Ubenimex), zinostatin, zorubicin; anti-cancer metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as guanidine Denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiophene Thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidin Ne), 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine , flooxuridine; androgens, such as kartorone, dromostanolone propionate, epitiostanol, mepitiostane, testosterone ( Testolactone); anti-adrenal agents, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as frolinic acid; vinegar Aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; Bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate Epothilone; ethenyl Cid); gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and amine sartoxin (ansamitocins); mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phennamet; Bibarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; Sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichophyton Trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; deacetylation Vindesine, dacarbazine; mannomustine; mitobronitol; mitolactol; dibromopropyl Pipobroman; gacytosine; arabinoside; thiotepa; taxoids, doxetaxel; chloranbucil; gemcitabine 6-thioguanine; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vinblastine; platinum; Potassium (VP-16); mitoxantrone; vincristine; oxaliplatin; leucovovin; vinorelbine; norvantrol (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, fluzolidine, CEP-8983 Or BGB-290; VEGFR-2 inhibitors, such as PAN-90806, Foretinib, Tafittinib, Kanitinib, Apatinib, Tanibirumab, Anlotinib, Lucitanib, Vatalanib, Cediranib, Chiauranib, Dovitinib, Donafiniib, Famitinib, Sitravatinib, Telatinib, L-21649, TAS-115, Cabozintinib, Thiophenib, Fruquintinib, Brivinib, Sulfatinib, Ramucirumab, Glesatinib, Nintedanib, Puquitinib ), Axitinib, EDP317, Sorafenib, Metatinib, Tivozanib, Regorafenib, Midostaurin, Pazopanib, HLX- 06. At least one of Altiratinib, Ningetinib, Sunitinib, AL-8326, Rebastinib, Teggio or a pharmaceutically acceptable salt, acid or derivative thereof.

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

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

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

Further, the tumor patient of the present disclosure is therapeutically unsuccessful.

The disclosure also provides a method of treating a tumor, the method comprising:

a. Confirm whether the tumor patient has received anti-CTLA-4 antibody or antigen-binding fragment thereof;

b. Administration of an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof to a patient receiving treatment with an anti-CTLA-4 antibody or antigen-binding fragment thereof.

Further, the swollen patient has 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 presence of one or more new lesions.

In an alternative embodiment, the tumor patient has a relative reduction in target lesion diameter of at least 30%.

In an alternative embodiment, the tumor patient has a relative increase in target lesion diameter of at most 20% or a targeted lesion diameter that is relatively reduced by up to 30%.

Preferably, the tumor patient is treatment failure.

Unless otherwise stated, the terms in this disclosure have the following meanings:

The "humanized antibody", also referred to as a CDR-grafted antibody, refers to the transplantation of a mouse CDR sequence into a human antibody variable region framework, ie, a different type. An antibody produced in a human germline antibody framework sequence. It is possible to overcome the strong antibody variable antibody response induced by chimeric antibodies by carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases including germline antibody gene sequences or published references. The germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc. People, 1991Sequences of Proteins of Immunological Interest, found in the 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, 6.

An "antigen-binding fragment" as used in the present disclosure refers to a Fab fragment having antigen-binding activity, a Fab' fragment, an F(ab')2 fragment, and an Fv fragment sFv fragment that binds to human PD-1; comprising the antibody of the present disclosure 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 antibody heavy chain variable region and the light chain variable region, but has no constant region and has the smallest antibody fragment of the entire antigen binding site. In general, Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the desired structure for antigen binding. The two antibody variable regions can also be joined by a different linker into a single polypeptide chain, referred to as a single chain antibody or a single chain Fv (sFv). The term "binding to PD-1" as used herein refers to the ability to interact with human PD-1. The term "antigen binding site" as used in the present disclosure refers to a three-dimensional spatial site that is discrete on an antigen and that is recognized by an antibody or antigen-binding fragment of the present disclosure.

"Immunotherapy" as used in the present disclosure means that immunotherapy is the use of the immune system to treat diseases. In the present disclosure, it mainly refers to stimulating and enhancing the body's anti-tumor immune response by increasing the immunogenicity of tumor cells and sensitivity to effector cell killing. And use immune cells and effector molecules to infuse the host, and cooperate with the body's immune system to kill tumors and inhibit tumor growth.

An "effective amount" as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate the diagnosis. An effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health of the patient, the route and dosage of the method of administration, and the severity of the side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

"Treatment failure" as used in the present disclosure means that the subject is accompanied by a measurable tumor lesion at baseline and is disease progression (PD) or intolerable according to the RECIST 1.1 efficacy assessment criteria.

"Untolerable" as used in the present disclosure means that the adverse reactions caused by the drug cannot continue to be treated.

Total survival (OS) refers to the period from random period to death from any cause. For subjects who survived at the last follow-up, their OS was censored as data at the last follow-up. In the subjects who were lost to follow-up, the OS was counted as data censored by the last confirmed survival time before the loss of follow-up. The data censored OS 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 extent and remains for a certain period of time, including cases of CR and PR. Tumor remission assessment criteria (RECIST 1.1 criteria) were used to assess objective tumor remission. Subjects must be accompanied by measurable tumor lesions at baseline, and the efficacy criteria were divided into complete response (CR), partial response (PR), stable (SD), and progression (PD) according to RECIST 1.1 criteria.

Disease Control Rate (DCR) is the percentage of confirmed complete remission, partial remission, and stable disease (≥8 weeks) in the number of patients with evaluable efficacy.

Complete remission (CR): All target lesions disappeared and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10 mm.

Partial remission (PR): The sum of the target lesion diameters is at least 30% less than the baseline level.

Disease progression (PD): reference to the minimum of the sum of all measured target lesion diameters throughout the experimental study, with a diameter and relative increase of at least 20% (referenced to baseline values if the baseline measurement is minimal); In addition, the absolute value of the diameter and the absolute value must be increased by at least 5 mm (one or more new lesions are also considered to be disease progression).

Stable disease (SD): The extent of target lesion reduction did not reach PR, and the degree of increase did not reach PD level. Between the two, the minimum value of the sum of diameters could be used as a reference.

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

DRAWINGS

Figure 1: Comparison of volume of abdominal wall metastases before and after PD-1 treatment.

Detailed ways

The following examples are provided to further describe the disclosure, but are not intended to limit the scope of the disclosure.

Example 1:

Phase I clinical enrollment of 8 histological or cytological diagnosis of nasopharyngeal carcinoma.

Dosing regimen:

Compound A (Ipilimumab): a dose of 3 mg / kg or 10 mg / kg;

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

data analysis:

Patient 1: After 6 courses of treatment with Compound A, the disease progresses, the disease is stable after 3 courses of intervening chemotherapy (cisplatin), and then compound B (intravenous infusion, once every 2 weeks, 4 weeks for one cycle) After 2 cycles, the sum of the diameters of the target lesions (left 8 rib soft tissue, spleen 1, spleen 2) was at least 32% lower than the baseline level, and the disease was partially relieved;

Patient 2: After 4 courses of treatment with Compound A, the disease was stable, and the disease progressed after withdrawal from the test, and Compound B (intravenous infusion, once every 2 weeks, 4 weeks for one cycle) was given for 6 cycles. The sum of the diameters of the target lesions (liver, rhomboid nodules, subganglia muscle nodules) was 32% lower than the baseline level, and the disease was partially relieved;

Patient 3: After 4 courses of treatment with Compound A, the disease progresses, and then compound B (intravenous infusion, once every 2 weeks, 4 weeks for one cycle) after 2 cycles of treatment, the patient's target lesion (negative liver and abdominal aorta) The sum of the diameters of the lymph nodes was 38% lower than the baseline level, and the disease was partially relieved;

Patient 4: After 4 courses of treatment with Compound A, the disease progresses, and then compound B (intravenous infusion, once every 2 weeks, 4 weeks for one cycle) after 2 cycles of treatment, the target lesion (left neck lymph node, liver) The sum of the diameters is 49% lower than the baseline level and the disease is partially relieved;

Patient 5: After 4 courses of treatment with Compound A, disease progression, intervening chemotherapy (capecitabine) for 8 courses, then compound B (intravenous infusion, once every 2 weeks, 4 weeks for one cycle) After 2 cycles, the sum of the diameters of the target lesions (liver S3, liver S5, peritoneal mass) was 62% lower than the baseline level, and the disease was partially relieved, see Figure 1;

Patient 6: After 4 courses of treatment with Compound A, disease progression, intervening chemotherapy (gemcitabine + vincristine), after 6 courses of treatment, the disease was stable, and then used Teggio, then compound B (intravenous infusion, each 2 weeks, 4 weeks for a cycle) After 2 cycles of treatment, the patient's target lesion (middle left middle lobe, right middle lobe) diameter increased by 20% than the baseline level, disease progression;

Patient 7: After 4 courses of treatment with Compound A, disease progression, intervening chemotherapy (Tiggio) 5 courses, disease progression, and then compound B (intravenous drip, once every 2 weeks, 4 weeks for a cycle) After treatment, the sum of the target lesions (left lung, liver S4 segment, liver S2 segment, right adrenal gland) increased by 22% compared with baseline levels, disease progression;

Patient 8: After treatment with Compound A (February), disease progression, and then compound B (intravenous infusion, once every 2 weeks, 4 weeks for one cycle) after 2 cycles of treatment, the target lesion (right lung) diameter It is 43% lower than the limit level and the disease is partially relieved.

From the above 8 clinical data, subjects who failed treatment with Ipilimumab were very effective in receiving PD-1 treatment. Six of the 8 subjects achieved PR, and the objective response rate (ORR) was as high as 75%. .

Claims (22)

1. Use of an anti-PD-1 antibody or antigen-binding fragment thereof for the preparation of a medicament for treating a tumor patient who has been treated with an anti-CTLA-4 antibody or antigen-binding fragment thereof.
2. The use according to claim 1, 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, Camrelizumab, Pembrolizumab, LZM-009, AK-103 and Nivolumab.
3. The use of claim 1, wherein the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises as set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. The heavy chain variable region of the PD-1 antibody described by LCDR1, LCDR2 and LCDR3 comprises HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
4. The use of claim 3, wherein the anti-PD-1 antibody is a humanized antibody.
5. The use according to claim 4, wherein the light chain variable region sequence of the humanized antibody is the sequence set forth in SEQ ID NO: 10 or a variant thereof, preferably in the light chain variable region Amino acid change of 0-10, more preferably amino acid change of A43S; the heavy chain variable region sequence of the humanized antibody is the sequence shown in SEQ ID NO: 9 or a variant thereof, preferably The heavy chain variable region has an amino acid change of 0-10, more preferably an amino acid change of G44R.
6. The use according to claim 4, wherein the light chain sequence of the humanized antibody is the sequence set forth in SEQ ID NO: 8 or a variant thereof, preferably 0-10 in the light chain variable region. The amino acid change is more preferably an amino acid change of A43S; the heavy chain sequence of the humanized antibody is the sequence shown in SEQ ID NO: 7 or a variant thereof, and the variant is preferably in the heavy chain variable region. The amino acid change of 0-10 is more preferably the amino acid change of G44R.
7. The use according to claim 6, 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.
8. The use according to any one of claims 1 to 7, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof competes with Ipilimumab for binding to human CTLA-4.
9. The use of claim 8, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is a chimeric, humanized or human monoclonal antibody or a portion thereof.
10. The use of claim 8 or 9, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of a human IgGl isotype.
11. The use of claim 8, wherein the anti-CTLA-4 antibody is selected from the group consisting of Ipilimumab, Tremelimumab, Belatacept or Abatacept.
12. The use according to any one of claims 1 to 11, wherein the tumor is nasopharyngeal carcinoma.
13. The use according to any one of claims 1 to 12, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof has a dose of 0.1 to 10.0 mg/kg.
14. The use according to any one of claims 1 to 13, wherein the anti-PD-1 antibody or antigen-binding fragment thereof has a dose of 0.1 to 10.0 mg/kg.
15. The use according to any one of claims 1 to 14, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is at a dose of 1 mg/kg, and the anti-CTLA-4 antibody or antigen-binding fragment thereof is at a dose of 3 mg/kg.
16. The use according to any one of claims 1 to 15, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is in a dose of from 1 to 600 mg.
17. The use according to any one of claims 1 to 16, wherein the anti-PD-1 antibody or antigen-binding fragment thereof has a dose of from 1 to 600 mg.
18. The use according to any one of claims 1 to 17, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered in an amount of 200 mg, and the anti-CTLA-4 antibody or antigen-binding fragment thereof is in a dose of 3 to 10 mg/kg.
19. The use of claim 1 wherein said tumor patient has also received treatment with other anticancer agents.
20. The use of any of claims 1-19, wherein the tumor patient is shown to be therapeutically unsuccessful.
21. The use of any of claims 1-20, wherein the tumor patient has a relative increase in target lesion diameter of at least 20% or the appearance of one or more new lesions.
22. A method of treating a tumor comprising:

    a. Confirm whether the tumor patient has received anti-CTLA-4 antibody or antigen-binding fragment thereof;

    b. Administration of an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof to a patient who has been treated with an anti-CTLA-4 antibody or antigen-binding fragment thereof.

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