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CN108079292A - A kind of purposes of anti-PD-1 antibody in the drug for preparing treatment liver cancer - Google Patents

A kind of purposes of anti-PD-1 antibody in the drug for preparing treatment liver cancer Download PDF

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Publication number
CN108079292A
CN108079292A CN201711173943.4A CN201711173943A CN108079292A CN 108079292 A CN108079292 A CN 108079292A CN 201711173943 A CN201711173943 A CN 201711173943A CN 108079292 A CN108079292 A CN 108079292A
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China
Prior art keywords
ser
sequence
seq
antibody
thr
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CN201711173943.4A
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Chinese (zh)
Inventor
蒋杰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Rich Biological Medicine Co Ltd
Jiangsu Hengrui Medicine Co Ltd
Suzhou Suncadia Biopharmaceuticals Co Ltd
Original Assignee
Suzhou Rich Biological Medicine Co Ltd
Jiangsu Hengrui Medicine Co Ltd
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Publication of CN108079292A publication Critical patent/CN108079292A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The present invention relates to a kind of purposes of anti-1 antibody of PD in the drug for preparing treatment liver cancer.

Description

A kind of purposes of anti-PD-1 antibody in the drug for preparing treatment liver cancer
Technical field
The present invention relates to a kind of purposes of anti-PD-1 antibody in the drug for preparing treatment liver cancer.
Background technology
Primary carcinoma of liver (Primary Hepatocellular Carcinoma) is global common malignant tumour, in State is High Phc Incidence Area, and number of the infected accounts for the 55% of the whole world, and death toll accounts for 50%；Lung is only second in tumour associated death Cancer occupies the 2nd.Hepatocellular carcinoma (Hepatocellular Carcinoma, HCC) is most common type in primary carcinoma of liver, HCC occurs on the basis of hepatitis cirrhosis mostly, occurs in about 10~20 years after original hepatic lesion.Most of liver cancer is in morning Phase is asymptomatic, and most of patients has reached Locally Advanced when making a definite diagnosis or DISTANT METASTASES IN occurs.Advanced liver cancer there is no standard at present Therapy, clinical treatment is faced with stern challenge.3 to 6 are generally in the time-to-live of Chinese late period HCC patient Month, in worldwide from the point of view of it is most long be also no more than 1 year, this lacks efficient system treatment with these patients much relations. HCC resists common chemotherapy, and therapy generally comprises operation (hepatectomy, liver transfer operation and palliative treatment are performed the operation), non- It operative treatment (local treatment, artery chemoembolization, chemotherapy, radiotherapy, biological therapy and molecular targeted therapy) and other controls Treatment method (including participating in clinical research).
In December, 2007, Sorafenib became the drug for being used to treat HCC of the first approval of U.S. FDA, but at present due to valency Lattice are expensive, limit the use in China patient.In addition, a variety of multi-kinase inhibitors being developed with Sorafenib head It meets setbacks for many times in the research of enemy relatively：The Sutent of Pfizer and Sorafenib late liver cancer head to head compared with III Clinical trial phase is forced to terminate in advance in April, 2010.The multi-kinase inhibitor ABT-869 of Abbott Laboratories compared with Sorafenib also without Advantage.The epidermal growth factor recipient tyrosine kinase inhibitor Erlotinib (Tarceva) of Roche Holding Ag is compared with Sorafenib Failure has equally been met in terms of additional benefit is increased.Brivanib be targeting vegf receptor and basic fibroblast growth because The tyrosine kinase inhibitor of sub- receptor, the advanced liver cancer for excision, Locally Advanced or the DISTANT METASTASES IN of cannot undergoing surgery in treatment In the experiment of II phase of patient clinical, June, Progression free survival rate reached 18.2%, and the middle position Progression free survival time is 2.7 months, middle position life October time is deposited, side effect is weaker, mainly tired, hypertension and diarrhea, but non-bad in III phase compared with Sorafenib Failure is met in the clinical test of effect property, overall survival is simultaneously unsatisfactory.
The identification of PD-1 antibody specificities and bind lymphocytes surface PD-1 block PD-1/PD-L1 signal paths, and then It activates T cell to act on the immunologic cytotoxicity of tumour, transfers body immune system and remove interior tumor cell.
WO201508584 discloses a kind of new anti-PD-1 antibody, and PD-1 antibody is in domestic third stage at present, pacifies Full property is good, it has been shown that certain antitumor action.But it is only considered that in WO201508584 in breast cancer, lung cancer, stomach The expression of high PD-L1 is detected in the specific tumour such as cancer, intestinal cancer, kidney, melanoma, may provided by PD-1 antibody Treatment, but fail to study whether PD-1 antibody has therapeutic effect for liver cancer.
The content of the invention
The present invention provides a kind of purposes of anti-PD-1 antibody in the drug for preparing treatment liver cancer.It is preferred that the liver cancer is Hepatocellular carcinoma, the more preferable liver cancer is advanced hepatocellular carcinoma.
In especially preferred embodiment of present invention, the patient of the liver cancer is system chemotherapy (single medicine or drug combination Systemic chemotherapy) and/or targeted therapy failure or not tolerable patients with hepatocellular carcinoma, wherein the targeted therapy it is preferable to use Sorafenib or Ah pa treat for Buddhist nun.Wherein, the system chemotherapy of the liver cancer patient can be using one or more chemotherapeutics The chemotherapy that object carries out, such as anthracene ring antitumor medicinal (it is soft to include but not limited to Doxorubicin, epirubicin, idarubicin, pyrrole Than star, Mycocet), platinum class (cis-platinum, carboplatin, Nedaplatin, oxaliplatin), metabolic antagonist (such as methotrexate (MTX), 5 FU 5 fluorouracil, Tegafur, gemcitabine, capecitabine etc.), folinic acid or its salt, such as Calciumlevofolinate.Preferred a variety ofization It is to carry out chemotherapy using FOLFOX (oxaliplatin, 5 FU 5 fluorouracil, folinic acid) scheme to treat the system chemotherapy regimen that drug carries out.
Wherein, treatment failure refers to recur after progression of disease or treatment end in therapeutic process.
Wherein, chemotherapy is not tolerable refers to the haematics toxicity for occurring >=IV grade over the course for the treatment of or >=III grade of non-blood The damage of the main organs such as liquid toxicity or >=II grade of the heart, liver, kidney.
Wherein, Sorafenib is not tolerable refers to taking sufficient supportive treatment by local standard, and in pause medication At least 7 days and after reducing a dosage level medication, the drug correlation adverse events of 2 grades of CTCAE still continued or recur； Sufficient supportive treatment is taken by mechanism standard or after suspending medication at least 7 days and reducing a dosage level medication, The drug correlation adverse events of CTCAE >=3 grade still continue or recur.
PD-1 antibody is that the light chain variable region of known, preferably described PD-1 antibody is included respectively such as SEQ ID NO:4、 SEQ ID NO:5 and SEQ ID NO:LCDR1, LCDR2 and LCDR3 shown in 6.
The heavy chain variable region of the PD-1 antibody is included respectively such as SEQ ID NO:1、SEQ ID NO:2 and SEQ ID NO:HCDR1, HCDR2 and HCDR3 shown in 3.
Wherein, foregoing 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.
Preferred humanized antibody light chain's variable region sequences are such as SEQ ID NO:Sequence or its change shown in 10 Body；The amino acid that the variant preferably has 0-10 in light chain variable region changes；The amino acid variation of more preferably A43S.It is described Humanised antibody heavy chain's variable region sequences are such as SEQ ID NO:Sequence or its variant shown in 9；The variant is preferably in heavy chain The amino acid that there is 0-10 in variable region changes；The amino acid variation of more preferably G44R.
Foregoing humanized antibody is heavy, the variable region sequences of light chain are as follows：
Heavy chain variable region
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFT ISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS
SEQID NO：9 light chain variable regions
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO：10 preferred humanized antibody light chain's sequences are such as SEQ ID NO:Sequence or its variant shown in 8； The amino acid that the variant preferably has 0-10 in light chain variable region changes；The amino acid variation of more preferably A43S.
Humanised antibody heavy chain's sequence is such as SEQ ID NO:Sequence or its variant shown in 7；The variant is preferred Change in the amino acid that heavy chain variable region has 0-10；The amino acid variation of more preferably G44R.
Particularly preferred humanized antibody light chain's sequence is such as SEQ ID NO:Sequence shown in 8, sequence of heavy chain For such as SEQ ID NO:Sequence shown in 7.
Foregoing humanized antibody 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
Specifically, in administration, wherein the dosage of the dosage PD-1 antibody of the PD-1 antibody is 1-10mg/kg, it is excellent Selected from 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, more It is preferred that 1mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 10mg/kg.Dosage rate can be weekly, two Mondays It is secondary, once in three weeks, once a month.
Specifically, in administration, wherein the PD-1 antibody or its antigen-binding fragment dosage are selected from 50-600mg, it is excellent Selected from 50mg, 60mg, 70mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 600mg, more preferably from 60mg, 100mg, 200mg, 400mg, 600mg.Administration The frequency can be weekly, two weeks once, once in three weeks, once a month.
In the present invention, the PD-1 antibody can be administered alone, and can also combine other chemotherapeutics or targeted therapy Administered in combination is preferably administered alone.
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：One PD-1 antibody is in the past by random, flat in advanced hepatocellular carcinoma (HCC) patient for the treatment of Row control, multicenter II/III phase clinical researches
First, research purpose
PD-1 antibody is evaluated in the past by the validity and security in advanced hepatocellular carcinoma (HCC) patient for the treatment of 2nd, test medicine and medication
Test medicine：
SEQ ID NO in its heavy, light chain sequence of the PD-1 antibody such as present invention：7 and SEQ ID NO：8.Manufacturer：On Hai Hengrui medicine limited company, is prepared into freeze dried powder form.
Medication：
First stage：A groups：PD-1 antibody, 3mg/kg, intravenous injection are administered once for every two weeks, and 42 days are a cycle；B Group：PD-1 antibody, 3mg/kg, intravenous injection, once every three weeks, 42 days are a cycle；
Second stage：Test group：PD-1 antibody, 3mg/kg, intravenous injection, is administered once for every two weeks or every three weeks are administered Once+optimal supportive treatment, 42 days are a cycle.Note：According to the first stage
3rd, inclusion criteria
(1) the HCC patient in the late period made a definite diagnosis through Histopathology or cytolgical examination, is not suitable for operation or part is controlled It treats, and at least one measurable lesion.(2) system chemotherapy (systemic chemotherapy of single medicine or drug combination) and/or Sorafenib Targeted therapy failure or not tolerable HCC patient.(3) ECOG PS score before entering group：0-1 points.
4th, clinical trial results
Enter 210 subjects of group altogether, the security events observed meet advanced hepatocellular carcinoma patients' feature, do not see Examine new security signal.Wherein 110 patients carried out tumor evaluation after treatment at least once, and 17 conditions of patients parts are delayed Solution, 34 patient diseases are stablized, and 59 patient diseases are in progress.Disease control rate (DCR) is 46.4%, objective remission rate (ORR) it is 15.5%.Clinical test results show that PD1 antibody shows good tumor killing effect.
Sequence table
<110>Suzhou Sheng Diya biological medicines Co., Ltd
Hengrui Medicine Co., Ltd., Jiangsu Prov.
<120>A kind of purposes of anti-PD-1 antibody in the drug for preparing treatment liver cancer
<150> CN201611035790.2
<151> 2016-11-23
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213>Mouse source (Mus musculus)
<400> 1
Ser Tyr Met Met Ser
1 5
<210> 2
<211> 17
<212> PRT
<213>Mouse source (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>Mouse source (Mus musculus)
<400> 3
Gln Leu Tyr Tyr Phe Asp Tyr
1 5
<210> 4
<211> 11
<212> PRT
<213>Mouse source (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>Mouse source (Mus musculus)
<400> 5
Thr Ala Thr Ser Leu Ala Asp
1 5
<210> 6
<211> 9
<212> PRT
<213>Mouse source (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 (11)

1. a kind of purposes of anti-PD-1 antibody in the drug for preparing treatment liver cancer.
2. purposes according to claim 1, wherein the liver cancer is hepatocellular carcinoma.
3. purposes according to claim 1, wherein the liver cancer is advanced hepatocellular carcinoma.
4. purposes according to claim 1, wherein the patient of the liver cancer be system chemotherapy and/or targeted therapy failure or Not tolerable patients with hepatocellular carcinoma, wherein it is preferable to use Sorafenib treatments for the targeted therapy.
5. purposes according to claim 1, wherein the light chain variable region of the PD-1 antibody is included respectively such as SEQ ID NO:4、SEQ ID NO:5 and SEQ ID NO:LCDR1, LCDR2 and LCDR3 shown in 6；Heavy chain variable region is included respectively such as SEQ ID NO:1、SEQ ID NO:2 and SEQ ID NO:HCDR1, HCDR2 and HCDR3 shown in 3.
6. purposes according to claim 5, wherein the PD-1 antibody is humanized antibody.
7. the purposes described in claim 6, wherein the light-chain variable sequence of the humanized antibody is such as SEQID NO:10 institutes The sequence shown or its variant；The amino acid that the variant preferably has 0-10 in light chain variable region changes；More preferably A43S's Amino acid changes.Weight chain variabl area sequence is such as SEQ ID NO:Sequence or its variant shown in 9；The variant is preferably in heavy chain The amino acid that there is 0-10 in variable region changes；The amino acid variation of more preferably G44R.
8. purposes according to claim 6, wherein humanized antibody light chain's sequence is such as SEQ IDNO:Shown in 8 Sequence or its variant；The amino acid that the variant preferably has 0-10 in light chain variable region changes；The more preferably amino of A43S Acid variation；Sequence of heavy chain is such as SEQ ID NO:Sequence or its variant shown in 7；The variant preferably has 0- in heavy chain variable region 10 amino acid variation；The amino acid variation of more preferably G44R.
9. purposes according to claim 6, wherein humanized antibody light chain's sequence is such as SEQ IDNO:Shown in 8 Sequence, sequence of heavy chain is such as SEQ ID NO:Sequence shown in 7.
10. claim 1-9 any one of them purposes, wherein the PD-1 antibody or its antigen-binding fragment dosage is selected from 50-600mg, preferably 60mg, 100mg, 200mg, 400mg, 600mg, most preferably 200mg.
11. according to claim 1-9 any one of them purposes, wherein the dosage of the PD-1 antibody is 1-10mg/kg, It is preferred that 1-5mg/kg, most preferably 3mg/kg.
CN201711173943.4A 2016-11-23 2017-11-22 A kind of purposes of anti-PD-1 antibody in the drug for preparing treatment liver cancer Pending CN108079292A (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110812485A (en) * 2018-08-10 2020-02-21 江苏恒瑞医药股份有限公司 Application of anti-PD-1 antibody in preparation of medicine for treating tumor in combination with chemotherapy
WO2020093993A1 (en) * 2018-11-06 2020-05-14 江苏恒瑞医药股份有限公司 Use of anti-pd-1 antibody in combination with famitinib in preparation of drug for treating tumors
CN111423510A (en) * 2019-01-10 2020-07-17 迈威(上海)生物科技有限公司 Recombinant anti-human PD-1 antibody and application thereof
WO2021203769A1 (en) * 2020-04-10 2021-10-14 江苏恒瑞医药股份有限公司 Use of anti-pd-1 antibody in preparation of drugs for treating acral lentiginous melanoma
CN114437204A (en) * 2020-10-30 2022-05-06 苏州盛迪亚生物医药有限公司 Method for purifying antibody or Fc fusion protein
RU2783846C1 (en) * 2018-11-06 2022-11-21 Цзянсу Хэнжуй Медсин Ко., Лтд. Application of an antibody to pd-1 in combination with famitinib for producing a medicinal product for treating tumours
CN116407629A (en) * 2022-12-28 2023-07-11 广州誉衡生物科技有限公司 anti-PD-1 antibody and application thereof in preparation of medicines for treating liver cancer patients
WO2024188333A1 (en) * 2023-03-15 2024-09-19 山东第一医科大学附属肿瘤医院(山东省肿瘤防治研究院、山东省肿瘤医院) Method for treating diseases by using reparixin alone or in combination with anti-pd-1 antibody

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104144700A (en) * 2011-10-14 2014-11-12 特瓦制药澳大利亚私人有限公司 ANTIBODIES TO CD1d
CN105026428A (en) * 2013-12-12 2015-11-04 上海恒瑞医药有限公司 PD-1 antibody, antigen-binding fragment thereof, and medical application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104144700A (en) * 2011-10-14 2014-11-12 特瓦制药澳大利亚私人有限公司 ANTIBODIES TO CD1d
CN105026428A (en) * 2013-12-12 2015-11-04 上海恒瑞医药有限公司 PD-1 antibody, antigen-binding fragment thereof, and medical application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EL-KHOUEIRY，A.B. ET AL: "Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma(HCC)：CA209-040", 《J.CLIN.ONCOL.》 *
MASAFUMI IKEDA ET AL: "Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and Future", 《DISEASES》 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110812485A (en) * 2018-08-10 2020-02-21 江苏恒瑞医药股份有限公司 Application of anti-PD-1 antibody in preparation of medicine for treating tumor in combination with chemotherapy
WO2020093993A1 (en) * 2018-11-06 2020-05-14 江苏恒瑞医药股份有限公司 Use of anti-pd-1 antibody in combination with famitinib in preparation of drug for treating tumors
JP2022512822A (en) * 2018-11-06 2022-02-07 ジエンス ヘンルイ メデイシンカンパニー リミテッド Use of anti-PD-1 antibody in combination with famitinib in the preparation of drugs to treat tumors
RU2783846C1 (en) * 2018-11-06 2022-11-21 Цзянсу Хэнжуй Медсин Ко., Лтд. Application of an antibody to pd-1 in combination with famitinib for producing a medicinal product for treating tumours
TWI822897B (en) * 2018-11-06 2023-11-21 大陸商江蘇恆瑞醫藥股份有限公司 Use of anti-pd-1 antibody in combination with famitinib for preparation of medicament for treating tumor diseases
CN111423510A (en) * 2019-01-10 2020-07-17 迈威(上海)生物科技有限公司 Recombinant anti-human PD-1 antibody and application thereof
CN111423510B (en) * 2019-01-10 2024-02-06 迈威(上海)生物科技股份有限公司 Recombinant anti-human PD-1 antibody and application thereof
WO2021203769A1 (en) * 2020-04-10 2021-10-14 江苏恒瑞医药股份有限公司 Use of anti-pd-1 antibody in preparation of drugs for treating acral lentiginous melanoma
CN114437204A (en) * 2020-10-30 2022-05-06 苏州盛迪亚生物医药有限公司 Method for purifying antibody or Fc fusion protein
CN116407629A (en) * 2022-12-28 2023-07-11 广州誉衡生物科技有限公司 anti-PD-1 antibody and application thereof in preparation of medicines for treating liver cancer patients
WO2024188333A1 (en) * 2023-03-15 2024-09-19 山东第一医科大学附属肿瘤医院(山东省肿瘤防治研究院、山东省肿瘤医院) Method for treating diseases by using reparixin alone or in combination with anti-pd-1 antibody

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