CN110507820A - A kind of purposes of the antibody combined radiotherapy of anti-PD-1 in the drug of preparation treatment tumor patient - Google Patents

Abstract

A kind of purposes of the anti-antibody combined radiotherapy of PD-1 involved in present disclosure in the drug of preparation treatment tumor patient.Specifically, providing anti-PD-1 antibody or its antigen-binding fragment and radiotherapy is combined in medicinal usage of the preparation treatment with the patient such as non-small cell lung cancer, hepatocellular carcinoma, advanced melanoma, metastatic renal cell cancer or Huppert's disease.The disease control rate of the program is up to 71.43%.

Description

A kind of antibody combined radiotherapy of anti-PD-1 is in the drug of preparation treatment tumor patient Purposes

Technical field

A kind of purposes of the antibody combined radiotherapy of PD-1 involved in present disclosure in the drug of preparation treatment tumor patient.

Background technique

Radiotherapy is to discharge neoantigen into immune system by inducing immunogenic cell death, to influence to exempt from Epidemic disease response improves the starting and activation of effector T cell.Surface molecular on the further exciting irradiation cancer cell of radiotherapy, which is expressed, to be increased Add, the cell killing for making it be easier to be mediated by cytotoxic T cell.Finally, radiotherapy can promote cytokine release, attract T thin Born of the same parents are close to radiation exposed tumour.The inflow of improvement effector T cell and raising T cell may all exempt from the lethal effect of cancer cell Epidemic disease system offers neoantigen.

Immunotherapy of tumors concentrates on the adoptive transfer of the effector cell by activation, for the immune of related antigen or mentions In the method for enhancing anti tumor immune response for non-specific immunostimulating agents such as cell factor.Develop specific immunity inspection Point approach restrainer has begun the immunotherapy method for becoming a kind of new treating cancer, such as treating advanced stage melanomas The CTLA antibody I pilimumab of tumor(Hodi et al., 2010) specifically binds programmed death receptor (PD- 1) nivolumab or pembrolizumab.WO2015085847A also discloses a kind of new anti-PD-1 antibody, is in clinic Experimental stage, it has been shown that certain antitumor action.

After operation, radiation and chemotherapy, immunotherapy becomes the fourth-largest strut means for the treatment of cancer, causes to grind The persons of studying carefully pay attention to extensively.As immunotherapy of tumors makes a breakthrough, researchers start to notice the two combination, compare Radiotherapy or immunization therapy is used alone, may result in more effective antitumor reaction.

Cancer center, the University of Pennsylvania is studies have shown that utilize radiotherapy and targeting CTLA4 and PD-1 signal path Two kinds of immunotherapies treat metastasis melanin tumor, can cause optimum response in patients, enhance immune system to tumour Attack.

Clinical research (NCT01689974) discovery ipilimumab combination radiotherapy in the treatment can unclamp the brake to immune system Vehicle enables T cell to infiltrate and attacks tumour cell.22 metastasis melanin tumor patients first receive the body to single tumour Portion's stereotactic radiotherapy (SBRT) divides after 3-5 days and gives within 4 courses for the treatment of every three weeks an ipilimumab treatment.As a result 18% patient obtains part without the tumour of radiotherapy and alleviates, and 18% patient disease is stablized, and the middle position of patient gets nowhere life It deposits the phase and Overall survival is respectively 3.8 months and 10.7 months, the overall survival of this group of patient is 35%, and is only received The overall survival that ipilimumab treats patient is 20%.

Campbell et al. (Transl Lung Cancer Res 2017；6 (2): 220-229) statistics carries out at present The clinical test that immunotherapy combined radiotherapy treats non-small cell lung cancer is 15 existing, as pembrolizumab combines low segmentation Radiotherapy in the treatment metastasis melanin tumor or non-small cell lung cancer (NCT02303990), MPDL3280A joint stereo directional radiative are controlled Treat (SBRT) treatment non-small cell lung cancer (NCT02400814), etc..

The immunotherapy field that these achievements allow scientists pair to apply with chemotherapy combined radiotherapy produces significant interest.

Summary of the invention

A kind of anti-PD-1 antibody or its antigen-binding fragment are provided in present disclosure and radiotherapy is combined in preparation treatment Purposes in the drug of tumor patient.

PD-1 antibody be it is known, the light chain variable region of the preferably described PD-1 antibody include respectively as SEQ ID NO:4, LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:5 and SEQ ID NO:6.

The heavy chain variable region of the PD-1 antibody includes respectively such as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID HCDR1, HCDR2 and HCDR3 shown in NO:3.

Wherein, mentioned-above each CDR sequence is as shown in the table:

Title	Sequence	Number
			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 humanized antibody.

Further, it is preferable to which humanized antibody light chain's variable region sequences are the sequence as shown in SEQ ID NO:10 or its change Body, the variant preferably have the amino acid of 0-10 to change in light chain variable region, the amino acid variation of more preferably A43S；The people Source antibody heavy chain variable region sequence be the sequence as shown in SEQ ID NO:9 or its variant, the variant preferably heavy chain can Becoming area has the amino acid of 0-10 to change, the amino acid variation of more preferably G44R.

Humanized antibody above-mentioned is heavy, the sequence of light chain is as follows:

Heavy chain variable region

EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFT ISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS

SEQID NO:9

Light chain variable region

DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK

SEQID NO:10

Preferably, humanized antibody light chain's sequence is the sequence as shown in SEQ ID NO:8 or its variant；The change Body preferably has the amino acid of 0-10 to change in light chain variable region, the amino acid variation of more preferably A43S；The humanized antibody Sequence of heavy chain is the sequence as shown in SEQ ID NO:7 or its variant, and the variant preferably has the ammonia of 0-10 in heavy chain variable region The variation of base acid, the amino acid variation of more preferably G44R.

In another embodiment, the sequence of light chain of the humanized antibody is the sequence as shown in SEQ ID NO:8, weight Chain-ordering is the sequence as shown in SEQ ID NO:7.

The humanized antibody weight, the sequence of light chain are as follows:

Heavy chain

EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFT ISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

SEQID NO:7

Light chain

DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQID NO:8

Combining anti-PD-1 antibody or its antigen-binding fragment and radiotherapy described in present disclosure has collaboration drug action.

Purposes described in present disclosure, wherein the anti-PD-1 antibody or its antigen-binding fragment dosage is 0.1~ 10.0mg/kg can 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。

It, can be with wherein the PD-1 antibody or its antigen-binding fragment dosage are 1~600mg in optional embodiment For 1.0mg, 1.2mg, 1.4mg, 1.6mg, 1.8mg, 2.0mg, 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、8.8mg、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、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、 585mg, 590mg, 595mg, 600mg, preferably 50~600mg, most preferably 200mg.

Anti- PD-1 antibody or its antigen-binding fragment described in present disclosure administration frequency be once a day, once two days, three It once, once four days, once five days, once six days, weekly, two weeks it is primary, once in three weeks, surrounding is primary or January one It is secondary.

In optional embodiment, anti-PD-1 antibody described in present disclosure or its antigen-binding fragment dosage be 50~ 600mg/2-3 weeks primary, and more preferably 200mg/2-3 weeks primary.

In optional embodiment, tumour described in present disclosure includes but is not limited to entity tumor, haematological tumours (example Such as, leukaemia, lymthoma, myeloma (such as Huppert's disease) and metastasis (metastases).

In some optional embodiments, entity tumor includes but is not limited to malignant tumour, and e.g., sarcoma and cancer are e.g., various The gland cancer of tract such as influences lung, breast, ovary, lymph, stomach and intestine (such as colon), anus, genitals and urogenital tract (such as kidney, urethra, bladder cells, prostate), pharynx, CNS (such as brain, nerve or spongiocyte), neck, skin are (for example, melanocyte Tumor) and pancreas and gland cancer, such as colon cancer, kidney, clear-cell carcinoma, liver cancer, non-small cell lung cancer, the cancer of small intestine and esophagus Cancer.Tumour can be early stage, mid-term, advanced stage or metastatic tumo(u)r.

In other embodiments, selected from lung cancer, (e.g., non-small cell lung cancer (NSCLC), NSCLC include the tumour Squamous carcinoma, gland cancer (such as large cell carcinoma) and bronchovesicular cancer), melanoma (such as advanced melanoma), kidney (such as clear-cell carcinoma), liver Cancer, myeloma (such as Huppert's disease).

On the other hand, in optional embodiment, tumour described in present disclosure is few transfer.

In some embodiments, tumour described in present disclosure is few transfer non-small cell lung cancer.

Radiotherapy described in present disclosure includes but is not limited to spiral-fault radiotherapy (tomotherapy), stereoscopic localized photograph It penetrates, proton therapy.

In some embodiments, radiotherapy described in present disclosure includes but is not limited to the radiotherapy of intensity adjustment (IMRT), hypofractionation method (hypofractionation radiotherapy) or the radiotherapy of hypoxemia guidance.

In some embodiments, the radiotherapy be selected from hypofractionation method, can be effectively reduced anti-PD-1 antibody or Dosage is administered alone in its antigen-binding fragment, reduces adverse reaction caused by anti-PD-1 antibody or its antigen-binding fragment.

In some embodiments, hypofractionation method in present disclosure: total radiotherapy number 5-10 times (including 5,6,7,8,9, 10 times), each widow transfer stove BED should be not less than 72Gy.

In some embodiments, hypofractionation method in present disclosure: total radiotherapy number 5-10 times (including 5,6,7,8,9, 10 times), once a day, each widow transfer stove BED should be not less than 72Gy.

In some embodiments, hypofractionation method in present disclosure: total radiotherapy number 5-10 times (including 5,6,7,8,9, 10 times), secondary on every Fridays (stopping 2 days within such as continuous 5 days), each widow transfer stove BED should be not less than 72Gy.

In some embodiments, hypofractionation method in present disclosure: total radiotherapy number 5 times, once a day, each few turn 72Gy should be not less than by moving stove BED.

In some embodiments, hypofractionation method in present disclosure: total radiotherapy number 10 times, secondary on every Fridays (such as continuous 5 It is stopped 2 days), each widow transfer stove BED should be not less than 72Gy.

In optional embodiment, anti-PD-1 antibody or its antigen-binding fragment described in present disclosure and radiotherapy joint Mode be synchronous therapeutic, i.e., anti-PD-1 antibody or its antigen-binding fragment it is synchronous with radiotherapy progress.

In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment and radiotherapy are administered in combination, from And anti-tumor activity is enhanced, and improve the therapeutic effect of tumor disease.

Further, in optional embodiment, the tumor patient once received oncotherapy, the oncotherapy choosing From one of chemotherapy, immunization therapy, surgical operation, radiotherapy or vaccine or a variety of.

In some embodiments, the target lesion diameter of the tumor patient relatively reduces at least 30%.

In some embodiments, the target lesion diameter relative increase of the tumor patient at least 20% or occurs one Or multiple new lesions.

In some embodiments, the target lesion diameter relative increase of the tumor patient at most 20% or targeting lesion Diameter relatively reduces at most 30%.

Further, the tumor patient is treatment failure.

Chemotherapy described in present disclosure refers to that application is treated for treating the compound of tumour, the compound of the treatment tumour Selected from but not limited to alkylating agent, such as thiotepa, cyclophosphamide, ifosfamide；Alkyl sulfonates, such as busulfan, Ying Bingshu All and piposulfan；Aziridines, such as benzene azoles DOPA, carbaxilquinone, meturedopa and uredopa；Methyl melamine class, including Altretamine, triethylenemelamine, trietylenephosphoramide, three stretch ethylenebis dithiocarbamate phosphamide (triethiylenethiophosphoramide) and front three melamine (trimethylolomelamine)；β-lapachone (beta-lapachone)；Camptothecine (camptothecin) (including synthetic analogues topotecan (topotecan), CPT- 11 (irenotecan (irinotecan), acetyl group camptothecine (acetylcamptothecin), the general Lay of scott are stung (scopolectin) and 9- amido camptothecine)；Bryostatin (bryostatin)；This tower of Cali stings (callystatin)；CC- 1065 (including its Adozelesin (adozelesin), Carzelesin (carzelesin)；Nitrogen mustards, such as Chlorambucil, naphthalene nitrogen Mustard (chlomaphazine), estramustine (estramustine)；Anticancer metabolin, such as methotrexate and 5 FU 5 fluorouracil (5- fluorouracil)(5-FU)；Folacin, such as Dai Nationality's promise spy purine (denopterin), methotrexate, pteropterin (pteropterin), Trimetrexate (trimetrexate)；Male sex hormone, such as clausterone (calusterone), epithio Male alcohol (epitiostanol), Testolactone (testolactone)；Anti- adrenal gland agent, such as amido glutethimide (aminoglutethimide)；Difluoromethyl bird amino acid (difluoromethylornithine) (DMFO)；Retinoid class, Such as retinoic acid (retinoic acid)；Capecitabine (capecitabine)；PARP inhibitor, such as olaparib, fluorine azoles Pa Li；VEGFR-2 inhibitor, such as Foretinib, his phenanthrene replace at least one of Buddhist nun (Tafetinib) or its officinal salt, acid Or derivative.

Further, in optional embodiment, the anti-PD-1 antibody or its antigen-binding fragment 1~600mg of dosage, The radiotherapy: total radiotherapy number 5-10 times (including 5,6,7,8,9,10 times), each widow transfer stove BED should be not less than 72Gy。

In optional embodiment, the anti-PD-1 antibody or its antigen-binding fragment dosage 1~600mg, every 1~4 week Once；The radiotherapy: total radiotherapy number 5-10 times (including 5,6,7,8,9,10 times), once a day, each few turn 72Gy should be not less than by moving stove BED.

In optional embodiment, the anti-PD-1 antibody or its antigen-binding fragment dosage 1~600mg, every 1~4 week Once；The radiotherapy: total radiotherapy number 5-10 times (including 5,6,7,8,9,10 times), it is secondary on every Fridays (5 days such as continuous Not 2 days), each widow transfer stove BED should be not less than 72Gy.

Administration route described in present disclosure can be oral administration, parenteral, percutaneous dosing, the parenteral It is including but not limited to injected intravenously, is subcutaneously injected, intramuscular injection.

In optional embodiment, the PD-1 antibody is administered in a manner of injecting, such as subcutaneous or intravenous injection, injection The preceding form that PD-1 antibody need to be configured to injectable.The injectable forms of particularly preferred PD-1 antibody are injection or freeze-drying Powder needle, such as the injectable forms of PD-1 antibody, it includes PD-1 antibody, buffer, stabilizers, optionally also living containing surface Property agent.Buffer can be selected from one or more of acetate, citrate, succinate and phosphate.Stabilizer is optional From sugar or amino acid, preferably disaccharides, such as sucrose, lactose, trehalose, maltose.Surfactant is selected from polyethylene glycol hydrogenated Castor oil, fatty acid glyceride, polyoxyethylene sorbitan carboxylic ester, the preferably described polyoxyethylene sorbitan carboxylic ester For polysorbate 20,40,60 or 80, most preferably polysorbate 20.

A kind of method for treating tumour is additionally provided in present disclosure, this method comprises: synchronous effective to tumor patient application The anti-PD-1 antibody of dosage or its antigen-binding fragment and radiotherapy.

Further, the swollen patient also once received oncotherapy.

In optional embodiment, the target lesion diameter relative increase of the tumor patient at least 20% or occurs one Or multiple new lesions.

In optional embodiment, the target lesion diameter of the tumor patient relatively reduces at least 30%.

In optional embodiment, the target lesion diameter relative increase of the tumor patient at most 20% or targeting lesion Diameter relatively reduces at most 30%.

Preferably, the tumor patient is treatment failure.

Scheme described in present disclosure, the described joint it is optional also include other components, the other components include but It is not limited to other antineoplastics etc..

Present disclosure additionally provide it is a kind of reduce it is bad caused by anti-PD-1 antibody or its antigen-binding fragment, radiotherapy The method of reaction, including the anti-PD-1 antibody or its antigen-binding fragment and radiotherapy to tumor patient application effective dose.

In some embodiments, the method for reducing adverse reaction includes: synchronous to tumor patient application effective dose Anti- PD-1 antibody or its antigen-binding fragment and radiotherapy.

A kind of reduction PD-1 antibody is additionally provided in present disclosure or dosage is administered alone in its antigen-binding fragment, radiotherapy Method, including the synchronous anti-PD-1 antibody to tumor patient application effective dose or its antigen-binding fragment and radiotherapy.

In some embodiments, reducing the method that dosage is administered alone includes: synchronous to tumor patient application effective agent The anti-PD-1 antibody or its antigen-binding fragment and radiotherapy of amount.

Term:

" humanized antibody (humanized antibody) ", also referred to as CDR grafted antibody (CDR- described in present disclosure Grafted antibody), refer to the antibody variable region frame that the CDR sequence of mouse is transplanted to people, i.e., different types of people The antibody generated in germline antibodies frame sequence.Chimeric antibody can be overcome due to carrying a large amount of murine protein ingredients, to lure The strong antibody variable antibody response led.Such frame sequence can be from the public DNA number including germline antibody gene sequences It is obtained according to library or disclosed bibliography.As people's heavy chain and the germline DNA sequence dna of light-chain variable region gene can be in " VBase " people Germline sequences database (can get) in internet www.mrccpe.com.ac.uk/vbase, and in Kabat, E.A. etc. People, 1991Sequences of Proteins of Immunological Interest are found in the 5th edition.In present disclosure In one preferred embodiment, the CDR sequence of the PD-1 humanized antibody is selected from SEQ ID NO:1, and 2,3,4,5,6.

" antigen-binding fragment " described in present disclosure refers to the Fab segment with antigen-binding activity, Fab ' segment, F (ab ') 2 segment, and the Fv segment sFv segment in conjunction with people PD-1；SEQ ID is selected from comprising antibody described in present disclosure One or more CDR regions in NO:1 to SEQ ID NO:6.Fv segment contains antibody heavy chain variable region and light chain variable region, but There is no constant region, and there is the minimum antibody fragment of whole antigen binding sites.Generally, Fv antibody is also included in VH and VL knot Peptide linker between structure domain, and structure needed for being capable of forming antigen binding.It can also be anti-by two with different attachments Body variable region connects into a polypeptide chain, referred to as single-chain antibody (single chain antibody) or scFv (sFv).This Term " in conjunction with PD-1 " in disclosure, referring to can interact with people PD-1.Term " antigen binding site " in present disclosure refers to Three-dimensional space site discontinuous on antigen, being identified by antibody in present disclosure or antigen-binding fragment.

" immunotherapy " described in present disclosure refers to that immunotherapy is to treat disease using immune system, in present disclosure in The sensibility by the immunogenicity and pairing effect cell killing that improve tumour cell is referred mainly to, excitation and enhancing body are antitumor Immune response, and in application immunocyte and effector molecule infusion host, collaboration body immune system killing tumour inhibits swollen Tumor growth.

" widow's transfer (oligometastatic and oligoprogressive) " is Hellman etc. described in present disclosure What people put forward, rear Niibe et al. further has modified the concept of few transfer, refers to malignant tumour at a distance in one organ There are one to five transfer stoves, long term survival can be obtained by local treatment.

" effective quantity " described in present disclosure includes to be enough to improve or the amount of the symptom of preventive medicine illness or illness.Effective quantity Still mean that the amount for being enough to allow or promoting diagnosis.It can be according to following factor for the effective quantity of particular patient or veterinary science subject And change: as illness to be treated, the general health of patient, the method and approach of administration and dosage and side effect are serious Property.Effective quantity can be the maximum dose or dosage regimen for avoiding significant side effect or toxic effect.

Radiotherapy and the mode of immunization therapy are selected from alternating treatment, sequential therapy, synchronous therapeutic in present disclosure.It is described " synchronous therapeutic " refer to immunization therapy and radiotherapy treat start when with regard to carrying out simultaneously, such as in the same of chemotherapy a cycle When give radiotherapy；" alternating treatment " refers to that radiotherapy carries out in any chemotherapy twice in 6 courses for the treatment of, such as completes 2 Start radiotherapy after period chemotherapy, continues to give chemotherapy after Radiation treatment plans；" sequential therapy " refers to that radiotherapy is placed on chemotherapy It is carried out after period whole, after 6 courses for the treatment of of chemotherapy, then carries out radiotherapy.

" treatment failure " described in present disclosure refers to subject in baseline with measurable tumor focus, RECIST 1.1 efficacy assessment standards are progression of disease (PD) or intolerable.

" intolerable " described in present disclosure refers to because drug-induced adverse reaction cannot continue to receive treatment.

Overall survival (OS), which refers to, leads to the dead phase from random phase to any reason.What is still survived when last follow-up is tested Person, OS are calculated as data with last follow up time and delete mistake.Subject lost to follow-up, OS are confirmed in terms of the time-to-live by preceding last lost to follow-up Mistake is deleted for data.The OS that data delete mistake is defined as from being grouped into the time for deleting mistake at random.

Objective remission rate (Objective response rate, ORR) refers to that tumor regression reaches certain and keeps certain The ratio of the patient of time contains the case of CR and PR.It is commented using Tumor response evaluation criteria (1.1 standard of RECIST) Determine tumour Objective responses.Subject must be with measurable tumor focus, efficacy assessment standard RECIST 1.1 in baseline Standard is divided into complete incidence graph (CR), part alleviates (PR), stablizes (SD), progress (PD).

Disease control rate (Disease Control Rate, DCR) refers to that confirmed complete incidence graph, part alleviates and disease Stablize percentage of (>=8 weeks) case load in evaluable curative effect patient.

Complete incidence graph (CR): all target lesion disappear, and whole pathology lymph nodes (including target tubercle and non-target tubercle) are short straight Diameter must be reduced to < 10mm.

Alleviate (PR) in part: the sum of target lesion diameter reduces at least 30% than baseline level.

Progression of disease (PD): being ginseng with the minimum value of the sum of the target lesion diameter of all measurements in entire process of experimental According to diameter and relative increase at least 20% (using baseline value as reference if baseline measures minimum)；In addition to this, it is necessary to full The absolute value increase at least 5mm (one or more new lesions occur and be also considered as progression of disease) of sufficient diameter sum.

Stable disease (SD): the degree that target lesion reduces does not reach PR, and increased degree does not reach PD level yet, between two It, can be using the minimum value of the sum of diameter as reference when research between person.

Anticancer agent used can be obtained through commercial channels in present disclosure.

Specific embodiment

With reference to embodiments for further describing present disclosure, but these embodiments are not to limit the range of present disclosure.

Inclusion criteria:

The IV phase widow for 1 to 5 place's DISTANT METASTASES IN stove that enrolled 12 subject's histologies or cytology are made a definite diagnosis shifts NSCLC Patient, these patients are previously by containing the double medicine chemotherapy of platinum class, (a. is replaced because of drug toxicity reason for the past chemotherapy regimen number >=1 Platinum medicine is calculated as a scheme；B. adjuvant chemotherapy of patients is not counted in the past chemotherapy regimen in > 6 months from treatment end to recurrence Number), treatment failure or there is the patient recurred.

Dosage regimen:

Compound A (PD-1 is prepared according to the method in patent application WO2017054646A): intravenous injection is administered, dosage 200mg is administered once for 2 weeks, and every 4 weeks are 1 period.

Radiotherapy: treatment should use energy >=6MV x-ray, give low point according to the position of few transfer stove, size decision The target area of radiotherapy is cut, total radiotherapy number 5-10 times (including 5,6,7,8,9,10 times), each widow transfer stove BED should be not less than 72Gy。

Conclusion: in 7 evaluable data, 1 patient is that (PR) is alleviated in part, and 4 patients are stable disease (SD), 2 Patient is progression of disease (PD), and evaluable objective remission rate (Objective response rate, ORR) is 14.3%, disease Sick control rate (Disease Control Rate, DCR) is 71.43%.Safety: have occurred 3 it is related with compound A possibility Adverse events (SAE), SAE incidence be 33.3% (3/9), wherein 3 grades of SAE incidences relevant to drug be 11.1% (1/9)。

Sequence table

<110>Hengrui Medicine Co., Ltd., Jiangsu Prov.

Suzhou Sheng Diya biological medicine Co., Ltd

<120>purposes of a kind of antibody combined radiotherapy of anti-PD-1 in the drug of preparation treatment tumor patient

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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 8

<211> 214

<212> PRT

<213>artificial sequence (Artificial Sequence)

<220>

<221> PEPTIDE

<222> (1)..(214)

<223>sequence of light chain

<400> 8

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp

20 25 30

Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 9

<211> 116

<212> PRT

<213>artificial sequence (Artificial Sequence)

<220>

<221> PEPTIDE

<222> (1)..(116)

<223>heavy chain variable region

<400> 9

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val

100 105 110

Thr Val Ser Ser

115

<210> 10

<211> 107

<212> PRT

<213>artificial sequence (Artificial Sequence)

<220>

<221> PEPTIDE

<222> (1)..(10)

<223>light chain variable region

<400> 10

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp

20 25 30

Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

Claims (15)

1. anti-PD-1 antibody or its antigen-binding fragment and radiotherapy combine the use in the drug of preparation treatment tumor patient On the way.

2. purposes described in claim 1, wherein the light chain variable region of the PD-1 antibody includes respectively such as SEQ ID NO: 4, the heavy chain variable region of PD-1 antibody described in LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:5 and SEQ ID NO:6 Include HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 respectively.

3. purposes as claimed in claim 2, wherein the PD-1 antibody is humanized antibody.

4. purposes as claimed in claim 3, wherein the light-chain variable sequence of the humanized antibody is such as SEQ ID NO:10 Shown in sequence or its variant, the variant preferably light chain variable region have 0-10 amino acid change, more preferably A43S's Amino acid variation；The weight chain variabl area sequence of the humanized antibody is the sequence as shown in SEQ ID NO:9 or its variant, institute State variant preferably has the amino acid of 0-10 to change in heavy chain variable region, the amino acid variation of more preferably G44R.

5. purposes as claimed in claim 3, wherein the sequence of light chain of the humanized antibody is the sequence as shown in SEQ ID NO:8 Column or its variant, the variant preferably have the amino acid of 0-10 to change in light chain variable region, and the amino acid of more preferably A43S becomes Change；The sequence of heavy chain of the humanized antibody is the sequence as shown in SEQ ID NO:7 or its variant, and the variant is preferably in weight Chain variable region has the amino acid of 0-10 to change, the amino acid variation of more preferably G44R.

6. purposes described in claim 5, wherein humanized antibody light chain's sequence is the sequence as shown in SEQ ID NO:8 Column, sequence of heavy chain are the sequence as shown in SEQ ID NO:7.

7. purposes described in claim 1, wherein the tumour be selected from lung cancer, melanoma, breast cancer, liver cancer, gastric cancer, intestinal cancer, Kidney preferably is selected from non-small cell lung cancer, hepatocellular carcinoma, advanced melanoma, metastatic renal cell cancer or Huppert's disease.

8. the described in any item purposes of claim 1-7, wherein the radiotherapy is selected from low segmentation therapy.

9. the described in any item purposes of claim 1-8, wherein the tumour is few transfer, preferably few transfer non-small cell Lung cancer.

10. the described in any item purposes of claim 1-9, wherein the tumor patient once received oncotherapy.

11. purposes described in any one of claim 10, wherein the oncotherapy is controlled selected from chemotherapy, immunization therapy, surgical operation, radiation One for the treatment of or vaccine are a variety of.

12. the described in any item purposes of claim 1-11, wherein the tumor patient is treatment failure.

13. the described in any item purposes of claim 1-12, wherein the anti-PD-1 antibody or its antigen-binding fragment dosage are 0.1~10.0mg/kg.

14. the described in any item purposes of claim 1-13, wherein the anti-PD-1 antibody or its antigen-binding fragment and radiation Therapy is synchronous to be carried out.

15. a kind of method for treating tumour, including synchronous anti-PD-1 antibody or its antigen to tumor patient application effective dose Binding fragment and radiotherapy.