CN111246881B

CN111246881B - Use of PD-1 antibodies for treating tumors

Info

Publication number: CN111246881B
Application number: CN201880059067.9A
Authority: CN
Inventors: 张力; 方文峰; 邹建军; 杨清
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Sun Yat Sen University Cancer Center
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Sun Yat Sen University Cancer Center
Priority date: 2017-12-14
Filing date: 2018-12-13
Publication date: 2023-03-10
Anticipated expiration: 2038-12-13
Also published as: WO2019114785A1; TW201927821A; CN111246881A

Abstract

Use of PD-1 antibodies for treating tumors is provided. In particular, there is provided the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of a patient having a tumor that has been treated with an anti-CTLA-4 antibody or antigen-binding fragment thereof.

Description

Use of PD-1 antibodies for treating tumors

Technical Field

The disclosure relates to the use of a PD-1 antibody in the preparation of a medicament for the treatment of a patient with a tumor.

Background

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 a powerful anti-cancer potential, with a broad range of capabilities and fine specificity to respond to a variety of tumor antigens. In addition, the immune system exhibits considerable plasticity and memory components. Successful utilization of all these attributes of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

Cancer immunotherapy has focused on methods to enhance the anti-tumor immune response by adoptive transfer of activated effector cells, immunization against relevant antigens, or providing non-specific immune stimulators such as cytokines. In recent years, the development of specific immune checkpoint pathway inhibitors has begun to become a new immunotherapeutic approach for the treatment of cancer, e.g. the CTLA antibody Ipilimumab for the treatment of advanced melanoma

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

The PD-1 antibody specifically recognizes and combines with the PD-1 on the surface of the lymphocyte, blocks a PD-1/PD-L1 signal channel, further activates the immune killing effect of the T cell on the tumor, mobilizes the immune system of an organism and eliminates the tumor cells in the body. WO2015085847A discloses a novel anti-PD-1 antibody, which is in clinical trials and has shown some anti-tumor effect.

Ipilimumab

Is a humanized IgG1 monoclonalAntibodies that block 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 the overall survival of patients is significantly prolonged compared to Ipilimumab alone, in combination with Nivolumab for the treatment of melanoma (NCT 01844505) (Wolchok et al, 2017). However, such immunomodulatory combinations have been combined and no clinical reports have been reported for administering effective amounts of PD-1 antibody to tumor patients who have not yet been treated with CTLA antibodies.

Disclosure of Invention

The present disclosure provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a patient having a tumor that was 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 amino acid sequence set forth in SEQ ID NO: 4. the amino acid sequence of SEQ ID NO:5 and SEQ ID NO: LCDR1, LCDR2 and LCDR3 as shown in 6; the heavy chain variable region comprises the amino acid sequences shown as SEQ ID NO: 1. the amino acid sequence of SEQ ID NO:2 and SEQ ID NO:3 HCDR1, HCDR2 and HCDR3.

Wherein, the CDR sequences are shown in the following table:

name (R)	Sequence of	Number of
			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, preferably, the humanized antibody light chain variable region sequence is as shown in SEQ ID NO:10 or a variant thereof, said variant preferably having 0-10 amino acid changes in the light chain variable region, more preferably a43S amino acid change; the heavy chain variable region sequence of the humanized antibody is shown as SEQ ID NO:9 or a variant thereof, said variant preferably having 0-10 amino acid changes in the heavy chain variable region, more preferably the amino acid change of G44R.

The sequences of the variable regions of the heavy and light chains of the humanized antibodies of the PD-1 antibodies of the present disclosure are shown below:

heavy chain variable region

Light chain variable region

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

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

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

heavy chain

Light chains

In alternative embodiments, the anti-CTLA-4 antibody or antigen-binding fragment thereof, which is a chimeric, humanized or human monoclonal antibody or portion thereof, cross-competes with Ipilimumab for binding to human CTLA-4.

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

In alternative embodiments, the anti-CTLA-4 antibody is selected from the group consisting of Iplilimumab, tremelimumab, belatacept, and Abatacept.

In alternative embodiments, the tumor is a malignant tumor or a benign tumor; the malignant tumor is selected from malignant epithelial tumor, sarcoma, myeloma, leukemia, lymphoma, melanoma, head and neck tumor, brain tumor, peritoneal cancer, mixed tumor, and children malignant tumor; the malignant epithelial tumor is selected from lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, gastroesophageal adenocarcinoma, esophageal cancer, small intestine cancer, cardia cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, vulva cancer, testicular cancer, prostatic cancer, penis cancer, kidney cancer, bladder cancer, anus cancer, gall bladder cancer, bile duct cancer, teratoma and heart tumor; the head and neck tumor is selected from nasopharyngeal carcinoma, laryngeal carcinoma, thyroid carcinoma, tongue cancer, and oral cancer; the sarcoma is selected from Askin tumor, chondrosarcoma, ewing's sarcoma, malignant vascular endothelioma, malignant nerve sheath tumor, osteosarcoma, and soft tissue sarcoma; the myeloma is selected from isolated myeloma, multiple myeloma, diffuse myeloma, leukemia myeloma, and marrow-type myeloma; the leukemia is selected from acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous 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 lymphoma and Hodgkin lymphoma; the brain tumor is selected from the group consisting of neuroepithelial tissue tumor, cranial nerve and spinal nerve tumor, meningeal tissue tumor; the children malignant tumor is selected from nephroblastoma, neuroblastoma, retinoblastoma and children germ cell tumor.

In another alternative 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 Hormone Receptor (HR) positive breast cancer, human epidermal growth factor receptor-2 (HER 2) positive breast cancer and triple negative breast cancer; the renal cancer is selected from clear renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma; the neuroepithelial tissue tumor is selected from preferably astrocytoma, anaplastic astrocytoma, glioblastoma; the liver cancer is selected from primary liver cancer and secondary liver cancer, and the primary liver cancer is selected from hepatocellular carcinoma, cholangiocellular carcinoma and mixed liver cancer; the colorectal cancer is selected from colon cancer and 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, cholangiocarcinoma, breast cancer, colorectal cancer, gastric cancer, renal cancer, acute myelogenous lymphocytic leukemia, myelodysplastic syndrome, glioma, nasopharyngeal carcinoma, a tumor of unknown primary site.

Further, the dosage of the anti-CTLA-4 antibody or antigen-binding fragment thereof of the present disclosure is 0.1 to 10.0mg/kg, may be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/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, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg.

Further, in a preferred embodiment, the anti-PD-1 antibody or an antigen-binding fragment thereof is administered in a dose of 0.1 to 10.0mg/kg, may be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/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, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg.

The anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered once a week, once a three week, once a four week, or once a month, and the anti-CTLA-4 antibody or antigen-binding fragment thereof is administered once a day, twice a day, three times a day, once a week, once a two week, once a three week, once a four week, or once a month.

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

In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is dosed at 1 to 600mg once every 1 to 4 weeks; the dosage of the anti-CTLA-4 antibody or the antigen-binding fragment thereof is 3-10 mg/kg, and the anti-CTLA-4 antibody or the antigen-binding fragment thereof is taken once every 1-4 weeks.

In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is dosed at 200mg; the dosage of the anti-CTLA-4 antibody or the antigen binding fragment thereof is 3-10 mg/kg.

In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is dosed at 200mg once every 3 weeks; the dosage of the anti-CTLA-4 antibody or the antigen-binding fragment thereof is 3-10 mg/kg, and the anti-CTLA-4 antibody or the antigen-binding fragment thereof is taken once every 3 weeks.

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

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

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

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

In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is dosed at 1mg/kg once every 3 weeks; the dosage of the anti-CTLA-4 antibody or the antigen-binding fragment thereof is 3mg/kg once every 3 weeks.

The route of administration described in the present disclosure may be oral, parenteral, transdermal, including but not limited to intravenous, subcutaneous, intramuscular.

In an alternative embodiment, the PD-1 antibody or CTLA-4 antibody is administered by injection, e.g., subcutaneously or intravenously, prior to which the PD-1 antibody or CTLA-4 antibody is formulated in an injectable form. Particularly preferred injectable forms of the PD-1 antibody or CTLA-4 antibody are injectable solutions or lyophilized powder injections, for example, an injectable form of the PD-1 antibody comprising the PD-1 antibody, a buffer, a stabilizer, and optionally further comprising 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 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 preferably polysorbate 20.

The tumor patients of the present disclosure have also been treated with additional anti-cancer agents, including treatment with additional anti-cancer agents prior to treatment with the anti-CTLA-4 antibody or antigen-binding fragment thereof, or treatment with additional anti-cancer agents after treatment with the anti-CTLA-4 antibody or antigen-binding fragment thereof.

Other anticancer agents described in the present disclosure are compounds useful for the treatment of cancer selected from, but not limited to, alkylating agents such as thiotepa, cyclophosphamide, ifosfamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as bendazol, carbaquinone, meteedopa and uredopa; methylmelamines including altretamine, triethyleneamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethlamelamine; beta-lapachone (beta-lapachone); lapachol (lapachol); colchicine (colchicine); betulinic acid (betulinic acid); <xnotran> (camptothecin) ( (topotecan), CPT-11 ( (irinotecan), (acetylcamptothecin), (scopolectin) 9- ); (bryostatin); (callystatin); CC-1065 ( (adozelesin), (carzelesin); (podophyllotoxin); (podophyllinic acid); (teniposide); (cryptophycin) ( 1 8); (dolastatin); (duocarmycin) ( , KW-2189 CB 1-TM 1); (eleutherobin); (pancratistatin); (sarcodictyin); (spongistatin); , , (chlomaphazine), (estramustine), , (mechlorethamine oxide hydrochloride), , (novembichin), (phenesterine), (prednimustine), (trofosfamide), (uracil mustard); , (carmustine), (chlorozotocin), (fotemustine), (lomustine), </xnotran> Nitrosoureas of pyrimidine (nimustine) and ranimustine (ranirnustine); antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ 1 and calicheamicin ω 1; damicin (dynemicin), including damicin A; esperamicin (esperamicin), epirubicin (epirubicin), esorubicin (esorubicin), idarubicin (idarubicin), marijumycin (marcromycin), mitomycin (mitomycin), (such as mitomycin C), mycophenolic acid (mycophenolic acid), nogomycin (nogalamycin), olivomycin (olivomycin), pelomycin (polyplomycin), nonpalmycin (polypepticin), phleomycin (potomycins), puromycin (puromycin), quinamycins (quemycin), polybixin (streptamycin), puromycin (puromycin), pteromycin (pterocarycin), pterocarpine (6-analogue), pterocarpine (6-6), antimutaline (5), pterocarpine (6-6), pterocarpine (pterocarpine), antimutamide (6), pterocarpine (6-analogue), pterocarcinomycin (6-D), pterocarpine (pterocarcinoxadine), pteridine (analog, such as, carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), deoxyfluorouridine (doxifluridine), enocitabine (enocitabine), floxuridine (floxuridine); androgens such as dimethyltestosterone (calusterone), drostanolone propionate (dromostanolone propionate), epitioandrostanol (epitiostanol), mepiquitane (mepiquitane), testolactone (testolactone); anti-adrenal agents such as aminophenylethylpiperidinone (aminoglutethimide), mitotane (mitotane), trostane (trilostane); folic acid supplements such as florolinic acid (frolicic acid); aceglucomannan lactone (acegultone); aldophosphamide glucoside (aldophosphamide glucoside); aminolevulinic acid (aminolevulinic acid); illiu-la (eniluracil); amfenadine (amsacrine); betalain cloth (bestrabucil); bisantrene; edatrexed (edatraxate); delphamide (defofamine); colchicine (demecolcine); diazaquinone (diazizquone); efletisin (elfornithine); ammonium etiolate (ellitinium acetate); epothilone (epothilone); ethydine (etoglucid); gallium nitrate (gallium nitrate); hydroxyurea (hydroxyurea); lentinan; ronidanine (lonidainine); maytansinoids such as maytansine and ansamitocins; propiguanylhydrazone (mitoguzone); mitoxantrone (mitoxantrone); mopidamol (mopidanmol); nitravirine (nitrine); pentostatin (pentostatin); vannamin (phenamett); doxorubicin (pirarubicin); losoxantrone (losoxantrone); 2-ethyl hydrazide (2-ethyl hydrazide); procarbazine (procarbazine); propyleneimine (razoxane); rhizomycin (rhizoxin); cilostase (sizofuran); spirogermanium (spirogermanium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2',2 "-trichlorotriethylamine; trichothecene toxins (trichothecenes), in particular the T-2 toxin, verracurin a, bacillus a and ancedin (anguidine); urethane (urethan); desacetylvinblastide (vindesine) azocycloxazole (dacarbazine); mannitol mustard (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactotol); bis-bromopropylpiperazine (pipobroman); methylosine (gacytosine); cytarabine (arabine); thiotepa; paclitaxel (taxoids), docetaxel (doxetaxel); crotonam cloth (chlorenbucil); gemcitabine (gemcitabine) 6-thioguanine (6-thioguanine); mercaptopurine (mercaptoprine); methotrexate; platinum analogs such as cisplatin (cissplatin) and carboplatin (carboplatin); vinblastine (vinblastine); platinum; etoposide (VP-16); mitoxantrone (mitoxantrone); vincristine (vincristine); oxaliplatin (oxaliplatin); lucorufen (leucovovin); vinorelbine (vinorelbine); novatron (novantrone); edatrexate (edatrexate); daunomycin; aminopterin; ibandronate (ibandronate); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid (retinoic acid); capecitabine (capecitabine); PARP inhibitors, such as olaparib, talazoparib, veliparib, rucaparib, fluxaparib, CEP-8983 or BGB-290; (ii) an inhibitor of VEGFR-2, such as PAN-90806, foretinib, tafinitib (Tafetinib), canertinib (Kanitinib), apatinib (Apatinib), tanibirumab, anlotinib (Anlotinib), delitinib (Lucitinib), vatalanib, cediranib (Cediranib), sevoranib (Chiaurib), dovirtinib (Dovitinib), donifenib (Donafenib), famitiniib (Famitiniib), sivatinib, teratinib (Telatinib), L-21649, TAS-115, cabovatinib (Cazantinib), thielanib (Thiophenib), fruentinib (Freutinib) at least one of Brivanib (Brivanib), solitinib (sulfotinib), ramucirumab, glesatinib, nintedanib (Nintedanib), puquintinib (Puquitinib), axitinib (Axitinib), EDP317, sorafenib (Sorafenib), martatinib (Metatinib), tivozanib, regorafenib (Regorafenib), midostatin, pezopanib (Pazopanib), HLX-06, altiratinib, ninggoninib (nigoninib), sunitinib (Sunitinib), AL-8326, rebastinib, tizotinib, or a pharmaceutically acceptable salt, acid or derivative thereof.

In an alternative embodiment, the tumor patients of the present disclosure have a relative reduction in target lesion diameter of at least 30%.

In alternative embodiments, the tumor patients of the present disclosure have a relative increase in target lesion diameter of at least 20% or the appearance of one or more new lesions.

In alternative embodiments, the tumor patients of the present disclosure have a relative increase in target lesion diameter of up to 20% or a relative decrease in target lesion diameter of up to 30%.

Further, the tumor patients of the present disclosure are treatment-failed.

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

a. confirming whether the tumor patient has been treated with an anti-CTLA-4 antibody or antigen-binding fragment thereof;

b. administering an effective dose of an anti-PD-1 antibody or antigen-binding fragment thereof to a patient treated with an anti-CTLA-4 antibody or antigen-binding fragment thereof.

Further, the patients have also been treated with other anti-cancer agents.

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

In alternative embodiments, the tumor patient has a relative increase in target lesion diameter of at most 20% or a relative decrease in target lesion diameter of at most 30%.

Preferably, the tumor patient is treatment-failed.

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

the term "humanized antibody" (also referred to as CDR-grafted antibody) as used herein refers to an antibody produced by grafting mouse CDR sequences into a human antibody variable region framework, i.e., a different type of human germline antibody framework sequence. Can overcome the strong antibody variable antibody reaction induced by the chimeric antibody because of carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. Germline DNA Sequences of, for example, 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), and in Kabat, E.A. et al, 1991 Sequences of Proteins of Immunological Interest, 5 th edition. In a preferred embodiment of the disclosure, the CDR sequences of the PD-1 humanized antibody are selected from SEQ ID NO:1,2,3,4,5,6.

The "antigen binding fragment" of the present disclosure refers to Fab fragments, fab 'fragments, F (ab') 2 fragments, and Fv fragments sFv fragments that bind to human PD-1, which have antigen binding activity; an antibody selected from SEQ ID NOs: 1 to SEQ ID NO: 6. The Fv fragment contains the variable regions of the antibody heavy and light chains, but no constant regions, and has the smallest antibody fragment of the entire antigen-binding site. Generally, fv antibodies also comprise a polypeptide linker between the VH and VL domains, and are capable of forming the structure required for antigen binding. Two antibody variable regions can also be joined together with different linkers into a single polypeptide chain, known as single chain antibodies (scFv) or single chain Fv (sFv). The term "binds to PD-1" in the present disclosure means capable of interacting with human PD-1. The term "antigen binding site" of the present disclosure refers to a three-dimensional spatial site that is not antigenically contiguous and is recognized by an antibody or antigen binding fragment of the present disclosure.

The "immunotherapy" as used in the present disclosure refers to immunotherapy that utilizes the immune system to treat diseases, and in the present disclosure, mainly refers to the method of stimulating and enhancing the anti-tumor immune response of the body by increasing the immunogenicity and the sensitivity to killing of effector cells, and using immune cells and effector molecules to transfuse into the body of a host, so as to cooperate with the immune system of the body to kill and inhibit tumor growth.

An "effective amount" as described herein 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 diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

As used herein, "treatment failure" refers to a subject at baseline with measurable tumor lesions, either disease Progression (PD) or intolerance according to RECIST1.1 efficacy assessment criteria.

The term "intolerant" as used herein means that adverse effects caused by the drug are not amenable to further treatment.

Overall Survival (OS) refers to the period from random to death due to any cause. Subjects who survived the last follow-up had OS data loss on the last follow-up time basis. Subjects who were missed their OS were data-loss as the last confirmed survival time before the missed visit. The OS of data erasure is defined as the time from random grouping to erasure.

Objective Response Rate (ORR) refers to the proportion of patients whose tumors have shrunk to a certain extent and are maintained for a certain period of time, including cases of CR and PR. Objective tumor remission was assessed using the criteria for tumor remission assessment (RECIST 1.1 criteria). Subjects must be accompanied by measurable tumor lesions at baseline, and the criteria for efficacy assessment are divided into Complete Remission (CR), partial Remission (PR), stable (SD), progression (PD) according to RECIST1.1 criteria.

Disease Control Rate (DCR) refers to the percentage of confirmed cases of complete remission, partial remission, and stable Disease (> 8 weeks) among patients with evaluable efficacy.

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

Partial Remission (PR): the sum of the target lesion diameters is reduced by at least 30% from baseline levels.

Disease Progression (PD): the diameter and relative increase is at least 20% with respect to the minimum of the sum of all measured target lesion diameters throughout the experimental study (baseline values are referenced if the baseline measurement is minimal); in addition to this, it must be satisfied that the absolute value of the sum of the diameters increases by at least 5mm (the appearance of one or more new lesions is also considered as disease progression).

Disease Stability (SD): the target lesion is reduced to a degree that does not reach PR and increased to a degree that does not reach PD levels, between which the minimum of the sum of the diameters can be used as a reference at the time of study.

The anticancer agents used in the present disclosure can be obtained commercially.

Drawings

FIG. 1: comparison of abdominal wall metastasis volumes before and after PD-1 treatment.

Detailed Description

The disclosure is further described below in conjunction with the following examples, which, however, do not limit the scope of the disclosure.

Example 1:

the nasopharyngeal carcinoma was confirmed by the histology or cytology of the 8 clinical group at stage I.

The administration scheme is as follows:

compound a (Ipilimumab): the dosage is 3mg/kg or 10mg/kg;

compound B (PD-1, prepared according to the method in patent application WO 2017054646A): the dosage is 200mg or 10mg/kg;

and (3) data analysis:

patient 1: after compound A is used for 6 courses of treatment, the disease progresses, the disease is stable after 3 courses of intervening chemotherapy (cisplatin), and after compound B (intravenous drip, once every 2 weeks, and 4 weeks are a period) is used for 2 weeks of treatment, the sum of the diameters of target focuses (left 8 costal soft tissues, spleen 1 and spleen 2) of a patient is reduced by at least 32 percent compared with a baseline level, and the disease is partially relieved;

patient 2: after 4 courses of treatment by the compound A, the disease is stable, and the disease progresses after the experiment is withdrawn due to intolerance, the compound B is given for 6 weeks of treatment (intravenous drip, once every 2 weeks, 4 weeks are a period), the sum of the diameters of target lesions (liver, large rhombus sarcoid and infraspinatus sarcoid) of a patient is reduced by 32 percent compared with the baseline level, and the disease is partially relieved;

patient 3: after 4 courses of treatment with the compound A, the disease progresses, and after 2 weeks of treatment with the compound B (intravenous drip, once every 2 weeks, 4 weeks for one cycle), the sum of the diameters of target lesions (liver, lymph nodes beside abdominal aorta) of a patient is reduced by 38% compared with the baseline level, and the disease is partially relieved;

patient 4: after 4 courses of treatment with compound a, the disease progressed, and after 2 weeks of treatment with compound B (i.v. instillation once every 2 weeks for 4 weeks, one cycle), the sum of the diameters of the target lesions (left cervical lymph node, liver) of the patient decreased 49% from baseline, and the disease partially alleviated;

patient 5: after 4 courses of treatment with compound a, disease progression, 8 courses of intervening chemotherapy (capecitabine), and treatment with compound B (i.v. instillation once every 2 weeks for 4 weeks, one cycle), after 2 cycles of treatment, the sum of the diameters of the target lesions (liver S3, liver S5, peritoneal mass) of the patient was reduced by 62% from baseline, and the disease was partially alleviated, as shown in fig. 1;

patient 6: after 4 courses of treatment with compound a, the disease progressed, after 6 courses of intervening chemotherapy (gemcitabine + vincristine), the disease stabilized, after which time tegafur was administered, and after 2 weeks of treatment with compound B (i.v. instillation once every 2 weeks for 4 weeks for one cycle), the sum of the diameters of the target lesions (left and right middle lobes) of the patient increased 20% from baseline, and the disease progressed;

patient 7: after 4 courses of treatment with compound a, disease progression, after 5 courses of intervening chemotherapy (tegafur), disease progression, and treatment with compound B (i.v. instillation once every 2 weeks for 4 weeks for one cycle), the sum of the diameters of the target lesions (left lung, liver S4 segment, liver S2 segment, right adrenal gland) of the patient increased by 22% from baseline, and disease progression;

patient 8: after 2 weeks of treatment with compound a (2 months) and further compound B (i.v. instillation once every 2 weeks for 4 weeks for one cycle), the patient's target lesion (right lung) was 43% less in diameter than the limiting level and the disease was partially alleviated.

From the above 8 clinical data, the subjects who failed Ipilimumab therapy had very good therapeutic effect after receiving PD-1 therapy, 6 of the 8 subjects achieved PR, and the objective disease remission rate (ORR) was as high as 75%.

Claims

1. Use of an anti-PD-1 antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating a nasopharyngeal cancer patient who has been treated with an anti-CTLA-4 antibody or an antigen-binding fragment thereof, wherein the light chain variable region of the anti-PD-1 antibody or an antigen-binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, respectively, and the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively.

2. The use of claim 1, wherein the anti-PD-1 antibody is a humanized antibody.

3. The use of claim 2, wherein the light chain variable region sequence of the humanized anti-PD-1 antibody is the sequence set forth in SEQ ID No. 10.

4. The use of claim 2, wherein the heavy chain variable region sequence of the humanized anti-PD-1 antibody is the sequence shown in SEQ ID NO 9.

5. The use of claim 2, wherein the humanized antibody has a light chain sequence as set forth in SEQ ID NO 8 and a heavy chain sequence as set forth in SEQ ID NO 7.

6. The use of claim 1, wherein the anti-CTLA-4 antibody is Iplilimumab.

7. The use of any one of claims 1 to 6, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is administered at a dose of 0.1 to 10.0mg/kg.

8. The use of any one of claims 1-6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 0.1 to 10.0mg/kg.

9. The use of any one of claims 1 to 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is at a dose of 1mg/kg and the anti-CTLA-4 antibody or antigen-binding fragment thereof is at a dose of 3mg/kg.

10. The use of any one of claims 1 to 6, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is administered at a dose of 1 to 600mg.

11. The use of any one of claims 1-6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 1 to 600mg.

12. The use of any one of claims 1 to 6, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200mg and the anti-CTLA-4 antibody or antigen-binding fragment thereof is administered at a dose of 3 to 10mg/kg.

13. The use of claim 1, wherein the nasopharyngeal cancer patient has also been treated with an additional anti-cancer agent.

14. The use of any one of claims 1 to 6, 13, wherein the nasopharyngeal cancer patient has failed treatment with the anti-CTLA-4 antibody or antigen-binding fragment thereof.

15. The use of any one of claims 1-6, 13, wherein the nasopharyngeal carcinoma patient has a relative increase in target lesion diameter of at least 20% or the appearance of one or more new lesions.

16. The use of any one of claims 1-6, 13, comprising:

b. administering an effective dose 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.