CN113456582B - Liquid preparation of recombinant humanized anti-PD-1 monoclonal antibody - Google Patents
Liquid preparation of recombinant humanized anti-PD-1 monoclonal antibody Download PDFInfo
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- CN113456582B CN113456582B CN202010235536.7A CN202010235536A CN113456582B CN 113456582 B CN113456582 B CN 113456582B CN 202010235536 A CN202010235536 A CN 202010235536A CN 113456582 B CN113456582 B CN 113456582B
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- QPJSIBAOZBVELU-BPNCWPANSA-N Val-Tyr-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N QPJSIBAOZBVELU-BPNCWPANSA-N 0.000 description 1
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
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- 108010081404 acein-2 Proteins 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
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- 210000004027 cell Anatomy 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
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- 230000007012 clinical effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 239000000243 solution Substances 0.000 description 1
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- 125000000185 sucrose group Chemical group 0.000 description 1
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Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a liquid preparation of a recombinant humanized anti-PD-1 monoclonal antibody, which comprises 10mg/ml of an aglycosylated anti-PD-1 monoclonal antibody, 10-20 mM of a buffer, 220-270 mM of a stabilizer, 0.02-0.06% (w/v) of a solubilizer, and a buffer system for regulating the pH to 5.5-6.5. The invention provides a liquid preparation suitable for intravenous administration, which can maintain stability during storage and has low specificity and fragmentation by further optimizing the contents of buffer, stabilizer and solubilizer. After being placed for 24 months at the temperature of 2-8 ℃, the appearance, the concentration and the pH of the preparation, the purity of the antibody and the charge heterosomes are all not obviously changed.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a liquid preparation of a recombinant humanized anti-PD-1 monoclonal antibody.
Background
PD-1 is an immunosuppressive receptor, mainly in activated T cells and B cells, is used as a T cell inhibitory receptor, and can be combined with ligand PD-L1 to inhibit the activity of T lymphocytes and related in-vivo cell immune response, can limit the function of T cell effector in tumor cells, and plays an important role in tumor immune escape. The anti-PD-1 monoclonal antibody can block the Programmed Death (PD) -1 receptor on the surface of activated T cells, can save the exhausted T cells by inhibiting the PD-1 and PD-1 ligand (PD-L1) channels, enhances the anti-tumor immunity, and has good targeting potential in the aspect of treating tumors. In view of this advantage, anti-PD-1 monoclonal antibodies such as opdivo, keytruda and other monoclonal antibodies are developed abroad and marketed in acetonitrile batches, however, the response rate of these antibodies as single drugs is low. The glycosylation modification on the monoclonal antibody used in the invention is knocked out, although the process development is stable, the uniformity is high, and a better clinical effect is expected to be obtained, compared with other anti-PD-1 monoclonal antibodies, the sensitivity of the monoclonal antibody to trypsin and the like is obviously increased due to glycosylation removal, the structural flexibility is enhanced, the tendency of polymer formation is easier under the condition of low pH, and the aggregation and precipitation are easy. In order to prevent denaturation of proteins during storage prior to use, loss of activity or structural integrity due to aggregation is necessary to develop formulation processes for this aglycosylated anti-PD-1 monoclonal antibody.
Patent CN103429264A discloses a lyophilized formulation of an anti-human PD-1 antibody or antigen-binding fragment thereof comprising 25mg/ml anti-human PD-1 antibody or antigen-binding fragment thereof, 10mM histidine buffer pH 5.0-6.0, 70mg/ml sucrose, 0.02mg/ml polysorbate 80.
Patent CN107334728A discloses a solution preparation of an anti-human PD-1 monoclonal antibody, which comprises 100mg/ml of the anti-human PD-1 monoclonal antibody, 20mM of histidine buffer, 250mM of sucrose, 6-8 mg/ml of poloxamer 188,20-100 mg/ml of sulfo Ding Mi cyclodextrin and 2-8 mg/ml of benzyl alcohol.
Patent CN107325180a discloses a monoclonal antibody preparation against human PD-1 suitable for subcutaneous injection, comprising 100mg/ml of the anti-human PD-1 monoclonal antibody, 10mM phosphate buffer, 10mM citrate buffer, 250mM mannitol, 20mM glycine, 8mg/ml tween 20.
Patent CN106390115A discloses a stable preparation of humanized monoclonal antibody, which comprises 25-50 mg/ml, 10-20 mM citric acid buffer solution with pH of 6.0, 150mM mannitol and 50mM sodium chloride, 0.20% polysorbate 80.
CN107198773a discloses a liquid formulation of a recombinant anti-PD-L1 fully human monoclonal antibody, comprising 30mg/ml recombinant anti-PD-L1 fully human monoclonal antibody, 20mM histidine-histidine hydrochloride, 150mM mannitol, 55mM sodium chloride and 0.01wt% polysorbate 80.
CN105793288a discloses an aqueous pharmaceutical formulation of a PDL1 monoclonal antibody, comprising 60mg/ml of an anti-PDL 1 monoclonal antibody, 20mM histidine acetate or sodium acetate buffer, 120mM sucrose, ph5.8.
Most of the patents above improve the stability of antibody preparations by screening auxiliary materials and adding stabilizing agents or additives, and the increase of the auxiliary materials brings about potential safety hazards to clinical medication. In addition, the different PD-1 antibodies differ in structure and in their performance properties, so that the formulation of the prior art is not suitable for aglycosylated anti-PD-1 monoclonal antibodies.
CN110354073A discloses a liquid formulation of an immunosuppressant monoclonal antibody comprising 25mg/ml of an aglycosylated anti-PD-1 monoclonal antibody, 15mM histidine, pH6.0, 270mM sucrose and 0.4mg/ml polysorbate 20. It is relatively stable for 6 months at 2-8 ℃, but the stability under the environment of higher temperature is still to be further improved. There is therefore also a need to provide a more stable liquid formulation of an aglycosylated anti-PD-1 monoclonal antibody.
Disclosure of Invention
Based on the shortcomings of the prior art, the invention aims to provide a stable liquid preparation of a recombinant humanized anti-PD-1 monoclonal antibody.
The technical scheme of the invention is as follows:
A liquid preparation of recombinant humanized anti-PD-1 monoclonal antibody contains 10mg/ml non-glycosylated anti-PD-1 monoclonal antibody, 10-20 mM buffer, 220-270 mM stabilizer, 0.02-0.06% solubilizer, and buffer system for regulating pH to 5.5-6.5.
Preferably, the buffer is histidine hydrochloric acid or citric acid/sodium citrate, more preferably histidine hydrochloric acid.
Preferably, the stabilizer is sucrose or mannitol; sucrose is further preferred.
Preferably, the solubilizing agent is polysorbate 80 or polysorbate 20.
In one embodiment, a liquid formulation of a recombinant humanized anti-PD-1 monoclonal antibody comprises 10mg/ml of an aglycosylated anti-PD-1 monoclonal antibody, 10-20 mM histidine hydrochloride buffer solution, 220-250 mM sucrose, 0.02-0.06% (w/v) polysorbate 80, and the buffer system adjusts the pH to 6.0-6.5.
Preferably, the concentration of the histidine hydrochloride buffer solution is 10mM.
Preferably, the sucrose concentration is 220mM.
Preferably, the polysorbate 80 content is 0.02% (w/v).
Preferably, the pH is 6.0.
In a preferred embodiment, a liquid formulation of a recombinant humanized anti-PD-1 monoclonal antibody comprises the following components:
the invention also provides a preparation method of the recombinant humanized anti-PD-1 monoclonal antibody liquid preparation, which comprises the following steps: weighing a prescribed amount of buffering agent, adding water for injection for dissolution, adjusting pH, carrying out ultrafiltration concentration on the protein stock solution of the non-glycosylated anti-PD-1 monoclonal antibody by using the prepared buffering system, replacing an original buffering system of the non-glycosylated anti-PD-1 monoclonal antibody protein, adding prescribed amounts of sucrose and polysorbate 80, uniformly stirring, adjusting the protein concentration to be 10mg/ml by using the buffering system, carrying out aseptic filtration by using a 0.22 mu m filter membrane, and then filling.
The non-glycosylated anti-PD-1 monoclonal antibody can be prepared by referring to CN106519034A, and the heavy chain and the light chain of the non-glycosylated anti-PD-1 monoclonal antibody have the following sequences:
Heavy chain region
MEWSWVFLFFLSVTTGVHSEVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGMSWVRQTPEKRLEWVATISGGGRDTYYPDSVKGRFTISRDNAKNNLYLQMSSLRSEDTALYYCARQKDTSWFVHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPGK
Light chain region
MSVPTQVLGLLLLWLTDARCEIVLTQSPATLAVSPGERATISCRASESVDDYGISFMNWFQQKPGQPPKLLIYVASNQGSGVPARFSGSGSGTDFTLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
The invention provides a liquid preparation suitable for intravenous administration, which can maintain stability during storage and has lower polymer and fragmentation thereof by further optimizing the contents of buffer, stabilizer and solubilizer. After being placed for 24 months at the temperature of 2-8 ℃, the appearance, the concentration and the pH of the preparation, the purity of the antibody and the charge heterosomes are all not obviously changed. After 6 months acceleration, the appearance, concentration, activity, pH, purity (SEC-HPLC) and charge-coupled agent (CEX-HPLC) of the preparation all showed no significant change.
Detailed Description
The invention is further illustrated by way of examples which are presented as part of a formulation screening assay and are not intended to limit the invention to the examples. The test methods for specific conditions not specified in the following examples were selected according to conventional methods and conditions or according to the commodity specifications. In the examples, stability tests and related biological tests were carried out according to the specifications of the chinese pharmacopoeia. The actual practice in the examples is pharmaceutical grade and is commercially available. The aglycosylated anti-PD-1 monoclonal antibody can be prepared by referring to the method of CN 106519034A.
Example 1
The formula comprises the following components:
The preparation method comprises the following steps:
Weighing a prescribed amount of buffering agent, adding water for injection for dissolution, adjusting pH, carrying out ultrafiltration concentration on the protein stock solution of the non-glycosylated anti-PD-1 monoclonal antibody by using the prepared buffering system, replacing an original buffering system of the non-glycosylated anti-PD-1 monoclonal antibody protein, adding prescribed amounts of sucrose and polysorbate 80, uniformly stirring, adjusting the protein concentration to be 10mg/ml by using the buffering system, carrying out aseptic filtration by using a 0.22 mu m filter membrane, and then filling.
Example 2
The formula comprises the following components:
the preparation is as in example 1.
Example 3
The formula comprises the following components:
the preparation is as in example 1.
Example 4
The formula comprises the following components:
the preparation is as in example 1.
Example 5
The formula comprises the following components:
the preparation is as in example 1.
Example 6
The formula comprises the following components:
The preparation method comprises the following steps:
Weighing a prescribed amount of buffering agent, adding water for injection for dissolution, adjusting pH, carrying out ultrafiltration concentration on the protein stock solution of the non-glycosylated anti-PD-1 monoclonal antibody by using the prepared buffering system, replacing an original buffering system of the non-glycosylated anti-PD-1 monoclonal antibody protein, adding prescribed amount of mannitol and polysorbate 80, uniformly stirring, adjusting the protein concentration to be 10mg/ml by using the buffering system, carrying out aseptic filtration by using a 0.22 mu m filter membrane, and then filling.
Example 7
The formula comprises the following components:
The preparation method comprises the following steps:
Weighing a prescribed amount of buffering agent, adding water for injection for dissolution, adjusting pH, carrying out ultrafiltration concentration on the protein stock solution of the non-glycosylated anti-PD-1 monoclonal antibody by using the prepared buffering system, replacing an original buffering system of the non-glycosylated anti-PD-1 monoclonal antibody protein, adding prescribed amounts of sucrose and polysorbate 80, uniformly stirring, adjusting the protein concentration to be 10mg/ml by using the buffering system, carrying out aseptic filtration by using a 0.22 mu m filter membrane, and then filling.
Example 8
The formula comprises the following components:
The preparation method is the same as in example 1.
Example 9
The formula comprises the following components:
The preparation method is the same as in example 1.
Verification embodiment
Three batches of samples were prepared according to examples 1-9, respectively, and the storage stability was examined using the accelerated stability test and the long-term test.
The long-term test is carried out at the temperature of 2-8 ℃ and is respectively carried out at the end of 0 month, 3 months, 6 months, 12 months and 24 months according to the stability key investigation project; the acceleration test is carried out at 25+/-2 ℃ for 6 months, the temperature of the equipment can be controlled to +/-2 ℃ and the actual temperature is detected, and the samples are taken once at the end of the 0 th month, the 3 rd month and the 6 th month in the test period, and the detection is carried out according to the stability key investigation project. The results are shown in tables 1 and 2.
Table 12 Long-term stability test results at 8 ℃
TABLE 2 accelerated stability test results at 25.+ -. 2 ℃
SEQUENCE LISTING
<110> Lunan pharmaceutical group Co., ltd
<120> Liquid preparation of recombinant humanized anti-PD-1 monoclonal antibody
<130> 2020
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 467
<212> PRT
<213> Artificial sequence
<400> 1
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu
50 55 60
Glu Trp Val Ala Thr Ile Ser Gly Gly Gly Arg Asp Thr Tyr Tyr Pro
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Asn Leu Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu
100 105 110
Tyr Tyr Cys Ala Arg Gln Lys Asp Thr Ser Trp Phe Val His Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 2
<211> 238
<212> PRT
<213> Artificial sequence
<400> 2
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ala
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Asp Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Val Ala Ser Asn Gln Gly Ser
65 70 75 80
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Asn Ile His Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys
100 105 110
Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
Claims (2)
1. A liquid formulation of a recombinant humanized anti-PD-1 monoclonal antibody, comprising the following components in amounts:
The amino acid sequence of the aglycosylated anti-PD-1 monoclonal antibody is as follows:
Heavy chain region
MEWSWVFLFFLSVTTGVHSEVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGMSWVRQTPEKRLEWVATISGGGRDTYYPDSVKGRFTISRDNAKNNLYLQMSSLRSEDTALYYCARQKDTSWFVHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPGK;
Light chain region
MSVPTQVLGLLLLWLTDARCEIVLTQSPATLAVSPGERATISCRASESVDDYGISFMNWFQQKPGQPPKLLIYVASNQGSGVPARFSGSGSGTDFTLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.
2. A method of preparing the liquid formulation of claim 1, comprising the steps of: weighing a prescribed amount of buffering agent, adding water for injection for dissolution, adjusting pH, carrying out ultrafiltration concentration on the protein stock solution of the non-glycosylated anti-PD-1 monoclonal antibody by using the prepared buffering system, replacing an original buffering system of the non-glycosylated anti-PD-1 monoclonal antibody protein, adding prescribed amounts of sucrose and polysorbate 80, uniformly stirring, adjusting the protein concentration to be 10mg/ml by using the buffering system, carrying out aseptic filtration by using a 0.22 mu m filter membrane, and then filling.
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CN202010235536.7A CN113456582B (en) | 2020-03-30 | 2020-03-30 | Liquid preparation of recombinant humanized anti-PD-1 monoclonal antibody |
PCT/CN2020/101516 WO2021196443A1 (en) | 2020-03-30 | 2020-07-11 | Liquid preparation of recombinant humanized anti-pd-1 monoclonal antibody |
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CN202010235536.7A CN113456582B (en) | 2020-03-30 | 2020-03-30 | Liquid preparation of recombinant humanized anti-PD-1 monoclonal antibody |
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CN113456582B true CN113456582B (en) | 2024-06-14 |
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CN114099672B (en) * | 2022-01-28 | 2022-05-06 | 嘉和生物药业有限公司 | Pharmaceutical composition of anti-RANKL humanized monoclonal antibody with enhanced stability |
CN117427157A (en) * | 2023-10-30 | 2024-01-23 | 广州誉衡生物科技有限公司 | Stable preparation of fully human anti-PD-1 monoclonal antibody |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN106519034A (en) * | 2016-12-22 | 2017-03-22 | 安源医药科技(上海)有限公司 | Anti-PD-1 (Programmed Death-1) antibody and application thereof |
CN107198773A (en) * | 2017-06-08 | 2017-09-26 | 上海药明生物技术有限公司 | Recombinate the liquid preparation of anti-PD L1 human monoclonal antibodies |
CN110354073A (en) * | 2018-04-09 | 2019-10-22 | 鲁南制药集团股份有限公司 | A kind of liquid preparation of immunosuppressor monoclonal antibody |
Family Cites Families (5)
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WO2010062896A1 (en) * | 2008-11-28 | 2010-06-03 | Abbott Laboratories | Stable antibody compositions and methods for stabilizing same |
LT2691112T (en) * | 2011-03-31 | 2018-07-25 | Merck Sharp & Dohme Corp. | Stable formulations of antibodies to human programmed death receptor pd-1 and related treatments |
EP3240571A4 (en) * | 2014-12-31 | 2018-06-13 | NovelMed Therapeutics, Inc. | Formulation of aglycosylated therapeutic antibodies |
CN107325180A (en) * | 2016-04-28 | 2017-11-07 | 上海抗体药物国家工程研究中心有限公司 | A kind of monoclonal antibody formulation suitable for hypodermic anti-human PD-1 |
JP2019534863A (en) * | 2016-09-27 | 2019-12-05 | フレゼニウス カービ ドイチュラント ゲーエムベーハー | Liquid pharmaceutical composition |
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2020
- 2020-03-30 CN CN202010235536.7A patent/CN113456582B/en active Active
- 2020-07-11 WO PCT/CN2020/101516 patent/WO2021196443A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106519034A (en) * | 2016-12-22 | 2017-03-22 | 安源医药科技(上海)有限公司 | Anti-PD-1 (Programmed Death-1) antibody and application thereof |
CN107198773A (en) * | 2017-06-08 | 2017-09-26 | 上海药明生物技术有限公司 | Recombinate the liquid preparation of anti-PD L1 human monoclonal antibodies |
CN110354073A (en) * | 2018-04-09 | 2019-10-22 | 鲁南制药集团股份有限公司 | A kind of liquid preparation of immunosuppressor monoclonal antibody |
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CN113456582A (en) | 2021-10-01 |
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