CN109806393A - The purposes of anti-PD-1 antibody, pemetrexed and platinum medicine combination therapy non-small cell lung cancer - Google Patents
The purposes of anti-PD-1 antibody, pemetrexed and platinum medicine combination therapy non-small cell lung cancer Download PDFInfo
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- CN109806393A CN109806393A CN201811362630.8A CN201811362630A CN109806393A CN 109806393 A CN109806393 A CN 109806393A CN 201811362630 A CN201811362630 A CN 201811362630A CN 109806393 A CN109806393 A CN 109806393A
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Abstract
The present invention relates to the purposes of a kind of antibody combined pemetrexed of anti-PD-1 and platinum medicine in the drug of preparation treatment non-small cell lung cancer.Specifically, the purposes the present invention relates to a kind of antibody combined pemetrexed of anti-PD-1 and carboplatin in the drug of preparation treatment non-small cell lung cancer, the antibody combined pemetrexed of anti-PD-1 and carboplatin show good antitumor curative effect compared to pemetrexed and carboplatin.
Description
Technical field
Anti- PD-1 antibody or its antigen-binding fragment, pemetrexed and platinum medicine, which are combined, treats non-small cell lung in preparation
Purposes in the drug of cancer.
Background technique
Worldwide, lung cancer has become the main reason for cancer mortality.In China, whether cancer incidence or
The death rate, lung cancer all occupy first place.It is controlled although in the past the several generations cytotoxic drug and targeting for being proposed update in 20 years
Treat, but Patients with Advanced Lung Cancer, particularly without it is known driving mutated gene survival of patients prognosis it is still very poor, advanced stage or turn
Shifting property lung cancer is still that one kind has the unsatisfied fatal disease of a large amount of medical demands.
Non-small cell lung cancer (NSCLC) accounts for about the 85% of all lung cancer, during when about 75% NSCLC Finding case has been in
In advanced stage, survival rate is very low within 5 years.Select suitable systemic treatment mode still in clinic advanced stage or metastatic NSCLC patient
It is upper to there is very big demand.NSCLC can be divided into squamous cell carcinoma and non-squamous cell carcinoma again.Non- squamous cell carcinoma include gland cancer,
Large cell carcinoma and other sub-types of cells cancers.Non- squamous cell carcinoma patients according still further to whether there is or not driving mutated gene (EGFR mutation or
ALK gene is reset) further classification.For the advanced NSCLC patients of EGFR/ALK gene wild type, generally use with platinum class medicine
The double medicine systemic treatment schemes of platiniferous based on object.It is granted for treating advanced stage/drug the packet of Metastatic Nsclc
Include platinum medicine (such as cis-platinum, carboplatin), taxone (such as the taxol that combines of taxol, albumin and mostly western
He matches), vinorelbine, vincaleukoblastinum, Etoposide, pemetrexed, gemcitabine etc..It can get using the combination of these drugs
30% to 40% 1 year survival rate, better than single medicine.
PD-1 inhibitor is the new class immunotherapy of tumors drug currently to attract attention, has the transnational pharmacy of more families public at present
Take charge of research and development be directed to PD-1/PD-L1 signal path monoclonal antibody, anti-PD-1 antibody provided by the invention,
WO2017054646A discloses the sequence and preparation method of the antibody, which has been in third stage, and safety is good
Good, the clinical study results registered have shown that it with certain antitumor action ([J] .Journal of
Clinical Oncology 35(2017):e15572-e15572)。
The clinical research that existing PD-1 combined chemotherapy drug is used to treat non-small cell lung cancer at present is being carried out, tentatively
It confirms clinical Benefit and safety, but needs clinical trial and further confirm, and advanced optimize combined treatment
To further improve clinical Benefit and safety, thus therapy field there is still a need for it is further explore suitable anti-PD-1 antibody with
Chemotherapy drugs in combination treats non-small cell lung cancer.
Summary of the invention
The present invention provides a kind of antibody combined pemetrexed of anti-PD-1 and platinum medicine is added to treat non-small cell lung cancer in preparation
Drug in purposes, wherein the light chain variable region of the PD-1 antibody or its antigen-binding fragment includes respectively such as SEQ ID
LCDR1, LCDR2 and LCDR3 shown in NO:4, SEQ ID NO:5 and SEQ ID NO:6；Heavy chain variable region includes respectively such as SEQ
HCDR1, HCDR2 and HCDR3 shown in ID NO:1, SEQ ID NO:2 and SEQ ID NO:3；The wherein platinum medicine choosing
From: carboplatin, cis-platinum, oxaliplatin, Nedaplatin (Nedaplatin), Lobaplatin (lobaplatin), Satraplatin (satraplatin),
Cycloplatin (cycloplatin), Miboplatin (Miboplatin), Enloplatin, Iproplatin, Dicycloplatin, preferably block
Platinum and cis-platinum.
The present invention provides a kind of medicine that the antibody combined pemetrexed of anti-PD-1 adds carboplatin to treat non-small cell lung cancer in preparation
Purposes in object, wherein the light chain variable region of the PD-1 antibody or its antigen-binding fragment include respectively as SEQ ID NO:4,
LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:5 and SEQ ID NO:6；Heavy chain variable region includes respectively such as SEQ ID
HCDR1, HCDR2 and HCDR3 shown in NO:1, SEQ ID NO:2 and SEQ ID NO:3.
The present invention also provides a kind of anti-PD-1 antibody to prepare the purposes in the drug for treating non-small cell lung cancer, wherein institute
The light chain variable region for stating PD-1 antibody or its antigen-binding fragment includes respectively such as SEQ ID NO:4, SEQ ID NO:5 and SEQ
LCDR1, LCDR2 and LCDR3 shown in ID NO:6；Heavy chain variable region include respectively such as SEQ ID NO:1, SEQ ID NO:2 and
HCDR1, HCDR2 and HCDR3 shown in SEQ ID 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 anti-PD-1 antibody or its antigen-binding fragment are anti-PD-1 humanized antibody.
Preferably, humanized antibody light chain's variable region sequences are the sequence as shown in SEQ ID NO:10 or its variant；Institute
The variant stated preferably has the amino acid of 0-10 to change in light chain variable region；The amino acid of more preferably A43S changes.The source of people
Changing antibody heavy chain variable region sequence is the sequence as shown in SEQ ID NO:9 or its variant；The variant is preferably in weight chain variable
Area has the amino acid of 0-10 to change；The amino acid of more preferably G44R changes.
Humanized antibody above-mentioned is heavy, the variable region sequences of light chain are 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 variant
It is preferred that thering is the amino acid of 0-10 to change in light chain variable region；The amino acid of more preferably A43S changes.The humanized antibody weight
Chain-ordering is the sequence as shown in SEQ ID NO:7 or its variant；The variant preferably has the amino of 0-10 in heavy chain variable region
Acid variation；The amino acid of more preferably G44R changes.
In a preferred embodiment of the present invention, humanized antibody light chain's sequence is as shown in SEQ ID NO:8
Sequence, sequence of heavy chain are the sequence as shown in SEQ ID NO:7.
Humanized antibody above-mentioned is heavy, the sequence of light chain is as follows:
Heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFT
ISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVK
DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP
PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW
ESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQID NO:7
Light chain
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGT
DFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV
QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO:8
In a preferred embodiment of the present invention, the non-small cell lung cancer is that advanced stage or the non-squamous carcinoma of metastatic are non-small
Cell lung cancer.
In a preferred embodiment of the present invention, the non-small cell lung cancer is selected from EGFR/ALK gene wild type evening
Phase or the non-squamous carcinoma non-small cell lung cancer of metastatic.
In a preferred embodiment of the present invention, the anti-PD-1 antibody or its antigen-binding fragment dosage are selected from
1-10mg/kg preferably is selected from 1mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 10mg/kg, most preferably 3mg/kg.
In a preferred embodiment of the present invention, the anti-PD-1 antibody or its antigen-binding fragment dosage are selected from
50-600mg preferably is selected from 60mg, 100mg, 200mg, 400mg, 600mg, most preferably 200mg.
In a preferred embodiment of the present invention, the pemetrexed dosage is selected from 200-700mg/m2, it preferably is selected from
200mg/m2、300mg/m2、400mg/m2、500mg/m2、600mg/m2、700mg/m2, most preferably 500mg/m2。
In a preferred embodiment of the present invention, the carboplatin dosage is with area under the curve (AUC) calculating, choosing
From 1-10mg/ml/min, preferably be selected from 3mg/ml/min, 4mg/ml/min, 5mg/ml/min, 6mg/ml/min, 7mg/ml/min,
8mg/ml/min, most preferably 5mg/ml/min.
In a preferred embodiment of the present invention, the carboplatin dose is selected from 200-400mg/m2, every three to surrounding
It is administered once, preferably is selected from 200mg/m2、300mg/m2、400mg/m2。
In a preferred embodiment of the present invention, the carboplatin dose is selected from 50mg/m2, it is administered once each day.
In the present invention, wherein the dosage rate of the anti-PD-1 antibody or its antigen-binding fragment be weekly,
Two weeks once, once in three weeks, once a month, preferably once in three weeks.
In the present invention, wherein the dosage rate of the pemetrexed be weekly, two weeks once, once in three weeks, one
The moon is primary, preferably once in three weeks.
In the present invention, wherein the dosage rate of the carboplatin be weekly, two weeks once, once in three weeks, January one
It is secondary, preferably once in three weeks.
In the present invention, anti-PD-1 antibody or its antigen-binding fragment, pemetrexed and carboplatin joint are used for non-small cell
The treatment of lung cancer, the administration order of three are first to give anti-PD-1 antibody, then give pemetrexed, finally give carboplatin.
In a preferred embodiment in accordance with this invention, the dosage rate of anti-PD-1 antibody or its antigen-binding fragment is
Once in three weeks, the dosage rate of pemetrexed be once in three weeks, the dosage rate of carboplatin be once in three weeks, administering drug combinations sequence:
Drug therapy was given in order within each period the 1st day, first give anti-PD-1 antibody intravenous drip, then give pemetrexed vein drop
Note, then give carboplatin intravenous drip.
In the present invention, anti-PD-1 antibody or its antigen-binding fragment, pemetrexed and carboplatin joint are used for non-small cell
The treatment of lung cancer, three can be administered in the same dosage period, can also be administered in different dosage periods.The treatment cycle
It can be 1 week, 2 weeks, 3 weeks (21 days), 3-4 weeks (21-28 days), 4 weeks (28 days), the preferred therapeutic period is 3 weeks.
In the present invention, after continuing the 4-6 period using anti-PD-1 antibody, pemetrexed and carboplatin, Ke Yixuan
It selects and uses anti-PD-1 antibody and pemetrexed maintenance therapy.
In the present invention, anti-PD-1 antibody or its antigen-binding fragment can also be double with other platiniferous based on platinum medicine
Medicine chemotherapy regimen is used in combination.Such as PD-1 antibody+pemetrexed+cis-platinum, PD-1 antibody+taxol+carboplatin, PD-1 antibody+
Taxol+cis-platinum, PD-1 antibody+gemcitabine+cis-platinum, PD-1 antibody+docetaxel+cis-platinum, PD-1+ vinorelbine+cis-platinum.
In a preferred embodiment of the present invention, the anti-PD-1 antibody or its antigen-binding fragment are in a manner of injecting
Administration, such as subcutaneous or intravenous injection, need that PD-1 antibody or its antigen-binding fragment will be resisted to be configured to the shape of injectable before injection
Formula.The injectable forms of particularly preferred anti-PD-1 antibody or its antigen-binding fragment are injection or freeze-dried powder, it includes
Anti- PD-1 antibody or its antigen-binding fragment, buffer, stabilizer, optionally also contain surfactant.Buffer can be selected from
One or more of acetate, citrate, succinate and phosphate.Stabilizer can be selected from sugar or amino acid, preferably
Disaccharides, such as sucrose, lactose, trehalose, maltose.Surfactant is selected from Crodaret, glycerine fatty acid
Ester, polyoxyethylene sorbitan carboxylic ester, the preferably described polyoxyethylene sorbitan carboxylic ester be polysorbate 20,40,
60 or 80, most preferably polysorbate 20.The injectable forms of highly preferred anti-PD-1 antibody or its antigen-binding fragment include
Anti- PD-1 antibody or its antigen-binding fragment, acetate buffer, trehalose and polysorbate 20.
In the present invention, so-called " joint " is a kind of administration mode comprising three kinds of drugs are successive, or are administered simultaneously each
Kind of situation, it is so-called herein refer to " simultaneously " give anti-PD-1 antibody in same dosage period or its antigen-binding fragment, training U.S. are bent
Plug and carboplatin, such as give three kinds of drugs within 1 week, in 2 weeks, in 3 weeks, in 4 weeks.So-called " successively " administration, then be included in not
With anti-PD-1 antibody or its antigen-binding fragment, pemetrexed and carboplatin are given in dosage period respectively.These administration modes,
Belong to administering drug combinations of the present invention.
United administration route of the present invention is selected from oral administration, parenteral, percutaneous dosing, described parenterally to give
Medicine includes but is not limited to be injected intravenously, be subcutaneously injected, intramuscular injection.
A effective amount of anti-PD-1 antibody above-mentioned is applied the present invention also provides a kind of methods for the treatment of, including to patient
Or its antigen-binding fragment, pemetrexed and carboplatin.
The present invention also provides a kind of medicine sleeve group or a kind of medicine package boxes, wherein containing above-mentioned a effective amount of
Anti- PD-1 antibody or its antigen-binding fragment, pemetrexed and carboplatin.
The present invention also provides a kind of pharmaceutical compositions, include a effective amount of anti-PD-1 antibody above-mentioned or its antigen binding
Segment, pemetrexed and carboplatin and one or more pharmaceutical excipients, diluent or carrier.
Detailed description of the invention
One, term
In order to be easier to understand the present invention, certain technical and scientific terms are defined in detail below.Except obviously at this
It is separately explicitly defined at it in file, otherwise all other technical and scientific term used herein all has belonging to the present invention
The normally understood meaning of the those skilled in the art in field.
Term " humanized antibody (humanized antibody) ", also referred to as CDR grafted antibody (CDR-grafted
Antibody), refer to the antibody variable region frame that the CDR sequence of mouse is transplanted to people, i.e., different types of human germline antibody
The antibody generated in frame sequence.Chimeric antibody can be overcome due to carrying a large amount of murine protein ingredients, so that induction is strong
Antibody variable antibody response.Such frame sequence can be from public DNA database or public affairs including germline antibody gene sequences
The bibliography opened obtains.As people's heavy chain and the germline DNA sequence dna of light-chain variable region gene can be in " VBase " human germ line sequences
Database (can get) in internet www.mrccpe.com.ac.uk/vbase, and in Kabat, E.A. et al.,
1991Sequences of Proteins of Immunological Interest is found in the 5th edition.At the present invention one
In preferred embodiment, the CDR sequence of the PD-1 humanized antibody mouse is selected from SEQ ID NO:1, and 2,3,4,5,6.
Term " antigen-binding fragment ", refers to the Fab segment with antigen-binding activity, Fab ' segment, 2 segment of F (ab '),
And the Fv segment sFv segment in conjunction with people PD-1；SEQID NO:1 to SEQ ID is selected from comprising antibody of the present invention
One or more CDR regions in NO:6.Fv segment contains antibody heavy chain variable region and light chain variable region, but does not have constant region, and
Minimum antibody fragment with whole antigen binding sites.Generally, Fv antibody also includes more between VH and VL structural domain
Peptide linker, and structure needed for being capable of forming antigen binding.Two antibody variable regions can also be connected with different attachments
At a polypeptide chain, referred to as single-chain antibody (single chain antibody) or scFv (sFv).Term of the invention " with
PD-1 combination ", referring to can interact with people PD-1.Term " antigen binding site " of the invention refer to it is discontinuous on antigen, by
The three-dimensional space site of antibody or antigen-binding fragment identification of the present invention.
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.
Embodiment 1
1, Subject antibodies and compound
SEQ ID NO:7 and SEQ ID NO:8 in its heavy, light chain sequence of anti-PD-1 antibody such as present invention.200mg/ branch,
It is spare to be made into 20mg/ml.
Pemetrexed is purchased from Jiangsu Hao Sen medicine company Group Co., Ltd, and carboplatin is purchased from Qilu Pharmaceutical Co., Ltd..
2, enrolled subject's standard
(1) histology or cytodiagnosis are advanced stage or the non-squamous carcinoma non-small cell lung cancer (NSCLC) of metastatic.
(2) do not received for advanced stage/metastatic NSCLC whole body system drug therapy.
(3) EGFR mutation and ALK dystopy are feminine gender.
(4) ECOG scores 0-1 points.
3, medication
Anti- PD-1 antibody: every three weeks are a dosage period, give within each cycle first day patient 200mg anti-PD-1 antibody,
Intravenous drip, the time about 20-60 minutes.Allow to postpone to be administered, delay time longest 12 weeks, be calculated from last administration time,
Otherwise stopped treatment.
Injection pemetrexed: every three weeks are a dosage period, give patient 500mg/m within each cycle first day2Pei Mei
Qu Sai, intravenous drip, the time was at 10 minutes or more.Allow to postpone to be administered, delay time longest 9 weeks, from last administration time
It calculates, otherwise stopped treatment.
Carboplatin for injection: every three weeks are a dosage period, give within each cycle first day 5 carboplatin of patient AUC, vein drop
Note, the time was at 30 minutes or more.Allow to postpone to be administered, delay time longest 9 weeks, be calculated from last administration time, otherwise eventually
Only treat.
Administering drug combinations sequence: giving drug therapy in each period the 1st day in order, first gives anti-PD-1 antibody vein drop
Note after being spaced at least 30min, then gives pemetrexed intravenous drip, after being spaced at least 30min, then gives carboplatin intravenous drip.
Administration time window can be ± 3 days, but are administered in preceding 72h every time, and subject must complete to include every clinical inspection needed to comment
Estimate the tolerance for continuing medication.
Test group: anti-PD-1 antibody+pemetrexed+carboplatin sustainable 4-6 period may be selected to carry out later
Anti- PD-1 antibody+pemetrexed maintenance therapy.
Control group: pemetrexed+carboplatin sustainable 4-6 period may be selected to carry out pemetrexed list later
Medicine maintenance therapy.
4, clinical test results
End on November 14th, 2017, enter 121 patients of group altogether, wherein 66 patients swelled after carrying out treatment at least once
Tumor assessment.Wherein 14 conditions of patients parts of test group are alleviated, and 21 patient diseases are stablized, and 2 patient diseases are in progress.Disease
Sick control rate (DCR) is 94.6%, and objective remission rate (ORR) is 37.8%.10 conditions of patients parts of control group are alleviated, and 21
Patient disease is stablized, and 5 patient diseases are in progress.Disease control rate (DCR) is 86.1%, and objective remission rate (ORR) is
27.8%.Preliminary analysis objective remission rate the result shows that, the double medicine chemotherapy regimens of the anti-antibody combined platiniferous of PD-1 are double compared to platiniferous
Medicine chemotherapy regimen shows good antitumor curative effect.With the increase of patient in group's data, the ORR of test group has larger mention
It rises.Test group and two groups of adverse events incidences of control group are substantially suitable.
Sequence table
<110>Hengrui Medicine Co., Ltd., Jiangsu Prov.
Suzhou Sheng Diya biological medicine Co., Ltd
<120>purposes of anti-PD-1 antibody, pemetrexed and platinum medicine combination therapy non-small cell lung cancer
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213>source of mouse (Mus musculus)
<400> 1
Ser Tyr Met Met Ser
1 5
<210> 2
<211> 17
<212> PRT
<213>source of mouse (Mus musculus)
<400> 2
Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 3
<211> 7
<212> PRT
<213>source of mouse (Mus musculus)
<400> 3
Gln Leu Tyr Tyr Phe Asp Tyr
1 5
<210> 4
<211> 11
<212> PRT
<213>source of mouse (Mus musculus)
<400> 4
Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Thr
1 5 10
<210> 5
<211> 7
<212> PRT
<213>source of mouse (Mus musculus)
<400> 5
Thr Ala Thr Ser Leu Ala Asp
1 5
<210> 6
<211> 9
<212> PRT
<213>source of mouse (Mus musculus)
<400> 6
Gln Gln Val Tyr Ser Ile Pro Trp Thr
1 5
<210> 7
<211> 443
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> PEPTIDE
<222> (1)..(443)
<223>sequence of heavy chain
<400> 7
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 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 (16)
1. the purposes of the antibody combined pemetrexed of anti-PD-1 and platinum medicine in the drug of preparation treatment non-small cell lung cancer,
It is characterized in that, the light chain variable region of the anti-PD-1 antibody or its antigen-binding fragment includes respectively such as SEQ ID NO:4, SEQ
LCDR1, LCDR2 and LCDR3 shown in ID NO:5 and SEQ ID NO:6；Heavy chain variable region include respectively as SEQ ID NO:1,
HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO:2 and SEQ ID NO:3.
2. purposes according to claim 1, which is characterized in that the anti-PD-1 antibody or its antigen-binding fragment are selected from and resist
PD-1 humanized antibody.
3. purposes as claimed in claim 2, 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 has the amino acid of 0-10 to change in light chain variable region；More preferably A43S
Amino acid variation.Weight chain variabl area sequence is the sequence as shown in SEQ ID NO:9 or its variant；The variant is preferably in weight
Chain variable region has the amino acid of 0-10 to change；The amino acid of more preferably G44R changes.
4. purposes according to claim 3, which is characterized in that the anti-PD-1 humanized antibody light chain sequence is such as SEQ
Sequence shown in ID NO:8 or its variant；The variant preferably has the amino acid of 0-10 to change in light chain variable region；More preferably
Change for the amino acid of A43S.Sequence of heavy chain is the sequence as shown in SEQ ID NO:7 or its variant；The variant is preferably in weight
Chain variable region has the amino acid of 0-10 to change；The amino acid of more preferably G44R changes.
5. purposes according to claim 4, which is characterized in that the anti-PD-1 humanized antibody light chain sequence is such as
Sequence shown in SEQ ID NO:8, sequence of heavy chain are the sequence as shown in SEQ ID NO:7.
6. purposes according to claim 1, which is characterized in that the platinum medicine is selected from: carboplatin, cis-platinum, oxaliplatin,
Nedaplatin (Nedaplatin), Lobaplatin (lobaplatin), Satraplatin (satraplatin), Cycloplatin (cycloplatin), Miboplatin
(Miboplatin), Enloplatin, Iproplatin, Dicycloplatin, most preferably carboplatin and cis-platinum.
7. purposes according to claim 1-6, which is characterized in that the non-small cell lung cancer is advanced stage or transfer
The non-squamous carcinoma non-small cell lung cancer of property.
8. purposes according to claim 7, which is characterized in that it is wild that the non-small cell lung cancer is selected from EGFR/ALK gene
Type advanced stage or the non-squamous carcinoma non-small cell lung cancer of metastatic.
9. purposes according to claim 1-8, which is characterized in that the anti-PD-1 antibody or its antigen binding
Segment dosage is selected from 1-10mg/kg, preferably is selected from 1mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 10mg/kg, most preferably
3mg/kg。
10. purposes according to claim 1-8, which is characterized in that the anti-PD-1 antibody or its antigen knot
It closes segment dosage and is selected from 50-600mg, preferably be selected from 60mg, 100mg, 200mg, 400mg, 600mg, most preferably 200mg.
11. purposes according to claim 1-8, which is characterized in that the pemetrexed dosage is selected from 200-
700mg/m2, it preferably is selected from 200mg/m2、300mg/m2、400mg/m2、500mg/m2、600mg/m2、700mg/m2, most preferably
500mg/m2。
12. purposes according to claim 1-8, which is characterized in that the carboplatin dosage with curve below
Product (AUC) calculates, and is selected from 1-10mg/ml/min, preferably is selected from 3mg/ml/min, 4mg/ml/min, 5mg/ml/min, 6mg/ml/
Min, 7mg/ml/min, 8mg/ml/min, most preferably 5mg/ml/min.
13. purposes according to claim 1-8, which is characterized in that the carboplatin dose is selected from 200-400mg/
m2, every three to surrounding are administered once, and preferably are selected from 200mg/m2、300mg/m2、400mg/m2, every three to surrounding are administered once.
14. purposes according to claim 1-8, which is characterized in that the carboplatin dose is selected from 50mg/m2, each
Day is administered once.
15. a kind of medicine package box, which is characterized in that include a effective amount of anti-described in claim 1-14 any one
PD-1 antibody or its antigen-binding fragment, pemetrexed and carboplatin.
16. a kind of pharmaceutical composition, which is characterized in that include a effective amount of anti-described in claim 1-14 any one
PD-1 antibody or its antigen-binding fragment, pemetrexed and carboplatin and one or more pharmaceutical excipients, diluent or
Carrier.
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