WO2020192693A1 - 抗Her2抗体药物偶联物药物制剂 - Google Patents

抗Her2抗体药物偶联物药物制剂 Download PDF

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WO2020192693A1
WO2020192693A1 PCT/CN2020/081138 CN2020081138W WO2020192693A1 WO 2020192693 A1 WO2020192693 A1 WO 2020192693A1 CN 2020081138 W CN2020081138 W CN 2020081138W WO 2020192693 A1 WO2020192693 A1 WO 2020192693A1
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pharmaceutical preparation
mmol
antibody
aqueous liquid
liquid pharmaceutical
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PCT/CN2020/081138
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English (en)
French (fr)
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徐巧玉
李壮林
姚雪静
鲍倩婧
房健民
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荣昌生物制药(烟台)股份有限公司
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Priority to AU2020239621A priority Critical patent/AU2020239621B2/en
Priority to SG11202104269PA priority patent/SG11202104269PA/en
Priority to FIEP20776430.9T priority patent/FI3811979T3/fi
Priority to PL20776430.9T priority patent/PL3811979T3/pl
Priority to EP23202349.9A priority patent/EP4316521A3/en
Priority to EP20776430.9A priority patent/EP3811979B1/en
Priority to KR1020217012846A priority patent/KR102660249B1/ko
Application filed by 荣昌生物制药(烟台)股份有限公司 filed Critical 荣昌生物制药(烟台)股份有限公司
Priority to CN202080009504.3A priority patent/CN113365665A/zh
Priority to KR1020247013049A priority patent/KR20240063155A/ko
Priority to BR112021002290-2A priority patent/BR112021002290A2/pt
Priority to SI202030340T priority patent/SI3811979T1/sl
Priority to US16/982,974 priority patent/US20210154314A1/en
Priority to CA3094194A priority patent/CA3094194A1/en
Priority to JP2021500575A priority patent/JP7264986B2/ja
Priority to DK20776430.9T priority patent/DK3811979T3/da
Priority to ES20776430T priority patent/ES2967128T3/es
Publication of WO2020192693A1 publication Critical patent/WO2020192693A1/zh
Priority to JP2023065779A priority patent/JP2023085555A/ja
Priority to AU2023282237A priority patent/AU2023282237A1/en

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Definitions

  • the invention relates to an anti-Her2 antibody drug conjugate drug preparation, which belongs to the field of anti-tumor drugs.
  • lymphocyte tumors such as non-Hodgkin’s lymphoma (NHL), chronic lymphocytic tumor (CLL) and so on.
  • NHL non-Hodgkin’s lymphoma
  • CLL chronic lymphocytic tumor
  • ErbB2 also known as Her2/neu, is the second member of the EGFR family. ErbB2 plays a biological role by forming a heterodimer with the other three members of the EGFR family.
  • the neu gene encoding ErbB2 was first isolated from rat neuroblastoma.
  • the homologous gene of the neu gene in human somatic cells, called Her2 is located on the long arm of chromosome 17 (17q21.1).
  • the encoded product ErbB2 is composed of 1255 amino acids and has a molecular weight of about 185kDa, of which 720-987 belong to phenol Active domain of amino acid kinase.
  • ErbB2 can also reduce the expression of cyclin D and c-myc, thereby reducing the expression of cyclin-dependent kinase (cyclin-dependent kinase, cdk) inhibitor p27kipl, cdk2 Its activity is inhibited and leads to cell proliferation.
  • cyclin-dependent kinase cyclin-dependent kinase, cdk
  • ADC biologically targeted drugs-Antibody Drug Conjuate
  • ADC consists of three parts: antibody, cytotoxin, and a connector connecting the two. After coupling the monoclonal antibody to the cytotoxin, the antibody-drug conjugate uses the targeting properties of the monoclonal antibody to specifically recognize the receptor on the surface of the cancer cell, bind to the receptor, and then enter the cell and use the cell The protease inside releases cytotoxic substances to prevent cancer cells from multiplying and kill cancer cells.
  • the prior art generally uses mammalian cell culture to produce expressed antibodies, and the highly purified antibody is coupled to the cytotoxin MMAE through a linker to obtain an antibody drug conjugate (ADC).
  • Antibody drug coupling technology integrates small molecule toxin drugs and biological proteins, and has the advantages of both, becoming a new generation of therapeutic products, which greatly enhances the efficacy of drugs and reduces toxic side effects.
  • US FDA has approved four ADCs for marketing (see Table 2).
  • ADC drugs are prone to degradation such as oxidation, deamidation and fragmentation, and the formation of microparticles and aggregates.
  • the drug coupling itself can reduce the stability and change the physicochemical properties of the antibody.
  • the coupling of DM1 and anti-HER2 antibody trastuzumab leads to the loss of stability of the antibody's CH2 domain (Document 1: Physicochemical Stability of the Antibody-Drug Conjugate Trastuzumab-DM1: Changes due to Modification and Conjugation Processes. Aditya A . Wakankar et al., Bioconjugate Chemistry 2010:21(9), 1588-1595).
  • ADC drugs are generally hydrophobic, and ADC as a whole may be more insoluble than unconjugated antibodies, and therefore become easier to aggregate, forming particles and surface adsorption.
  • each excipient component in the drug formulation must be carefully selected.
  • the excipient ingredients of ADC drugs currently on the market are shown in Table 3. As the types of excipients used in ADC formulations currently on the market are still very limited, and there are many choices of related formulation ingredients, it is necessary to develop a combination of ADC excipients that provide stability during transportation and storage, which involves a large number of The screening of excipient preparation ingredients and the determination of the appropriate concentration require a lot of effort and a long time.
  • each formulation has its own uniqueness. Due to the fragile stability and structural complexity of monoclonal antibody drugs, it is extremely challenging to manufacture and store such drugs. Due to the heterogeneous structure of antibodies, especially the complementarity determining regions (CDR) and Fc glycosylation, the development of different monoclonal antibody preparations needs to be carried out on a case-by-case basis (Document 2: Monoclonal antibodies: formulations of marketed products and recent advances in novel delivery system, Yanan Cui, etc., Drug Development and Industrial Pharmacy, Volume 43, Issue 4, Pages 519-530, 2017). ADC drugs are more unique in their formulation development because they further involve coupling and toxin molecules.
  • the patent application discloses a humanized RC48 antibody drug conjugate, wherein the humanized RC48 antibody is a monoclonal antibody targeting Her2 (preservation number C2013170 deposited in the Chinese Type Culture Collection The antibody secreted by hamster ovary cells (CHO cells) or the antibody derived therefrom) is preserved, and the poison is selected from Monomethyl Auristatin E (MMAE), which belongs to the derivative of dopetoxin peptide.
  • MMAE Monomethyl Auristatin E
  • the purpose of the present invention is to obtain an anti-Her2 monoclonal antibody-MMAE conjugate combination of excipients through a wide range of screening and concentration range research on the available excipients for biological agents, and achieve the following technical effects: -MMAE conjugate can dissolve well before and after freeze-drying, and the insoluble particles and visible foreign matter meet the standards of human injection. At the same time, it keeps the conjugate stable for a long time during the freeze-drying and storage process, and it is not easy to polymerize or degrade after reconstitution. Maintain good biological activity.
  • the present invention provides an aqueous liquid pharmaceutical preparation of an antibody drug conjugate, the preparation comprising the antibody drug conjugate, non-reducing sugars, amino acids, and solubilizers;
  • the non-reducing sugars are selected from mannitol, sucrose, and trehalose Or a combination thereof;
  • the amino acid is selected from histidine, alanine, arginine, glycine, glutamic acid or a combination thereof;
  • the solubilizer is selected from glycerin, Tween80 or a combination thereof.
  • the mannitol concentration is: 100-300mmol/L, preferably 190-300mmol/L, more preferably 200-260mmol/L, most preferably 240-260mmol/L;
  • the sucrose concentration is: 0 -100mmol/L, preferably 40-100mmol/L, more preferably 60-100mmol/L, most preferably 40-60mmol/L.
  • the histidine is histidine hydrochloride, and its concentration is: 0-100 mmol/L, preferably 5-50 mmol/L, more preferably 5-20 mmol/L, most preferably 10 mmol/L;
  • Arginine is arginine hydrochloride, and its concentration is: 0-160 mmol/L, preferably 20-100 mmol/L, more preferably 30-90 mmol/L, most preferably about 35 mmol/L.
  • the glycerin content is: 0-1%, preferably 0.2-0.5% (w/v); the mass percentage of Tween 80 is: 0-0.02% (w/v).
  • the antibody in the antibody-drug conjugate is an anti-HER2 monoclonal antibody; the drug to which the antibody is conjugated is MMAE or MMAF and its biological or DM1, DM4 and its biological.
  • the anti-HER2 antibody drug conjugate is an anti-HER2 monoclonal antibody-vc-MMAE, and the anti-HER2 monoclonal antibody and MMAE are connected by a linker vc, and the structure after the linker and MMAE are connected is:
  • the anti-HER2 monoclonal antibody comprises a heavy chain and a light chain
  • the heavy chain comprises CDR1-3, wherein the amino acid sequence of the CDR1-3 has the amino acid sequence shown in SEQ ID NO: 1, 2 and 3, respectively; and/or
  • the light chain comprises CDR1-3, wherein the amino acid sequence of the CDR1-3 has the amino acid sequence shown in SEQ ID NO: 4, 5, and 6, respectively;
  • the monoclonal antibody is preferably a chimeric antibody or a humanized antibody.
  • concentration of the anti-HER2 monoclonal antibody-vc-MMAE is 5-30 mg/ml.
  • the non-reducing sugar is 240-260mmol/L mannitol and/or 40mmol/L-60mmol/L sucrose
  • the amino acid is 8-12mmol/L histidine hydrochloride
  • the promoting The solvent is 0-0.02% (w/v) Tween 80.
  • the non-reducing sugar is about 260 mmol/L of mannitol and about 40 mmol/L of sucrose
  • the amino acid is about 10 mmol/L of histidine hydrochloride
  • the concentration of the antibody drug conjugate is about 0.02% (w/v) Tween 80.
  • the non-reducing sugar is about 240mmol/L of mannitol and about 60mmol/L of sucrose
  • the amino acid is about 10mmol/L of histidine hydrochloride
  • the concentration of the antibody drug conjugate is about 0.02% (w/v) Tween 80.
  • the pH of the formulation is 4.5-7, preferably 5.6-6.8, more preferably 5.6-6.5, 5.6-6.4, 5.6-6.3, 6.1-6.4, 6.1-6.3.
  • the pH of the formulation is adjusted with NaOH or hydrochloric acid.
  • the freeze-dried pharmaceutical formulation is obtained by freeze-drying the above-mentioned aqueous liquid pharmaceutical formulation.
  • the aqueous liquid pharmaceutical preparation before the lyophilization of the drug contains about 260 mmol/L of mannitol, about 40 mmol/L of sucrose, about 10 mmol/L of histidine hydrochloride, about 0.02% (w/v) of Tween 80, about 10mg/ml anti-HER2 monoclonal antibody-vc-MMAE, pH is 5.6-6.8.
  • the aqueous liquid pharmaceutical preparation before the lyophilization of the drug contains about 240 mmol/L of mannitol, about 60 mmol/L of sucrose, about 10 mmol/L of histidine hydrochloride, 0.02% of Tween 80, and about 10 mg/ml of anti-HER2 Monoclonal antibody-vc-MMAE, pH is 5.6-6.8.
  • non-reducing sugars contained in the aqueous liquid pharmaceutical preparation before the lyophilization of the drug are mannitol and sucrose, the concentrations of which are about 47.36 mg/ml and about 13.69 mg/ml, respectively, and the amino acid is histidine hydrochloride. It is about 2.10 mg/ml, the solubilizer is Tween 80, and its content is about 0.02% (w/v).
  • the non-reducing sugar contained in the aqueous liquid pharmaceutical preparation before the drug is lyophilized is mannitol and sucrose, the concentrations of which are about 43.72 mg/ml and about 20.54 mg/ml, and the amino acid is histidine hydrochloride.
  • the concentration is about 2.10 mg/ml
  • the solubilizer is Tween 80
  • its content is about 0.02% (w/v).
  • the present invention further provides the use of the above-mentioned pharmaceutical preparations in the preparation of drugs for treating diseases caused by abnormal expression of Her2.
  • the diseases caused by abnormal expression are further preferably cancer; the cancer is further preferably Her2 positive cancer; and the Her2 positive cancer is further Preferably breast cancer, ovarian cancer, gastric cancer, urothelial cancer, gastroesophageal cancer, esophageal cancer, endometrial cancer, lung cancer or bladder cancer (see document 3 Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications , Nida Iqbal and Naveed Iqbal, Molecular Biology International, Volume 2014, Article ID 852748; Document 4: CN201810998055.4).
  • HER2 Human Epidermal Growth Factor Receptor 2
  • the present invention further provides a method for preparing an antibody drug conjugate drug formulation, which includes:
  • Figure 1 SDS-PAGE electrophoresis of naked antibodies after purification, in which, 1-2: antibody non-reducing electrophoresis 3-4: antibody reducing electrophoresis, the results of Figure 1 show that the purity of the monoclonal antibody obtained in the experiment meets the requirements of further experiments;
  • Figure 2 ADC 10% SDS-PAGE electrophoresis after coupling, where Na: non-reducing electrophoresis; Nb: non-reducing electrophoresis after antibody is reduced by TCEP; Ra: RC48-vc-MMAE reduction electrophoresis; Rb: reducing electrophoresis after TCEP antibody reduction ;
  • the results in Figure 2 show: the obtained ADC purity after coupling meets the requirements of further experiments;
  • the murine monoclonal antibody mRC48 and the related humanized antibody RC48 were obtained based on the related methods disclosed in the examples of the patent application (CN105008398A or WO2015074528A1), which comprise the constant region of the human IgG1 ⁇ heavy chain and the variable region of the heavy chain RC48-VH, and the human IgG1 ⁇ light chain constant region and light chain variable region RC48-VL, each of the amplified fragments were subcloned into the expression vector pcDNA3.0.
  • the constructed different plasmids were transfected into suspension CHO cells (Invitrogen). Cultivate under standard conditions.
  • the cells are separated out by centrifugation or filtration, and the supernatant is taken.
  • the antibody protein is present in the supernatant.
  • Go to the Protein A affinity chromatography column for the first step of purification the eluted target protein, go to the cation packing chromatography column for the second step of purification, collect the target protein peak, and then go to the third step column with the target protein penetration mode Go to the third step of purification.
  • the purified protein passes the test of various indicators, it is then concentrated by ultrafiltration.
  • the protein concentration reaches about 20-30mg/ml. This is the antibody protein stock solution and can be stored at -80°C for a long time.
  • the CDR sequence of the RC48 antibody is as follows:
  • VH Light chain
  • VL CDR1 DYYIH(SEQ ID NO.1) KASQDVGTAVA(SEQ ID NO.4)
  • CDR2 RVNPDHGDSYYNQKFKD (SEQ ID NO.2)
  • WASIRHT (SEQ ID NO.5)
  • CDR3 ARNYLFDHW (SEQ ID NO.3) HQFATYT(SEQ ID NO.6)
  • TCEP Tris-2-carboxyethyl-phosphine
  • DTPA Diethylene triamine pentacetate acid
  • the antibody can be directly conjugated.
  • Prepare 10mmol/L drugs (vc-MMAE, vc-MMAF, mc-MMAF), dissolve them in DMSO (dimethyl sulfoxide, dimethyl sulfoxide), add slowly according to the molar ratio of drug to sulfhydryl group 1.1:1, stir at 25°C 2h.
  • DMSO dimethyl sulfoxide, dimethyl sulfoxide
  • the reproducibility of the coupling reaction is good, the opened free sulfhydryl group can be coupled completely, and the coupling degree is 3.5-4.5.
  • Example 3 Study on the effect of pH on the dissolution and purity of recombinant humanized anti-Her-2 monoclonal antibody-MMAE conjugate (RC48-vc-MMAE)
  • sucrose, mannitol, glycerol, histidine, arginine, polysorbate 80 (ie Tween 80, Tween 80) and other excipients were initially identified as candidate excipients for further screening. Further carry out the following tests.
  • sucrose, glycerol and polysorbate 80 can all improve the protein condition. So choose to add an appropriate amount of sucrose in the formulation to protect the protein, and add glycerol and polysorbate 80 to promote the solubility of the protein.
  • Pre-freezing temperature -45°C, time 5 hours;
  • One-time drying temperature -26°C, time 40 hours, vacuum degree 10-15Pa;
  • the lyophilized powder appearance inspection eliminates the formula B7-B12, and further excipient screening (formulation B1-B6) is carried out through moisture content inspection, visible foreign matter and insoluble particles inspection, and retention sample stability inspection.
  • the lyophilized powder of each formula was stored at 37, 25 and 4°C, and samples were taken at different times for SDS-PAGE, reverse phase HPLC, ligand binding method, biological activity, moisture content, appearance, pH value, visible foreign matter and Inspection of items such as insoluble particles.
  • the moisture content of formulas B1, B2, B3, B4, B5, and B6 are all less than 3%, which is qualified.
  • Appearance standard means that the agglomerates have shrunk to less than half of the volume before freeze-drying; "-” means that there is atrophy, but the volume of the agglomerates is greater than half of the volume before freeze-drying; "+” means that only the edge part is slightly slightly Atrophy, the volume of the agglomerate is basically the same as before freeze-drying; "++” means no atrophy at all, and the volume of the agglomerate is the same as before freeze-drying.
  • formula B2 and formula B4 have better stability at different temperatures (4°C, 25°C, 37°C), and formula B6 has too many insoluble particles and is eliminated.
  • formula B2 and formula B4 reached an excellent level in terms of appearance inspection of freeze-dried powder, determination of moisture content of freeze-dried powder, inspection of visible foreign matter and insoluble particles after reconstitution of freeze-dried powder, and stability.
  • the anti-Her2 mAb-MMAE conjugate can dissolve well before and after freeze-drying, and the insoluble particles and visible foreign matter meet the standards of human injection, and the coupling
  • the material remains stable for a long time during the process of freeze-drying and storage, especially after being placed for a long time under high temperature conditions of 25°C or 37°C, it still maintains good stability.
  • the ADC preparation is not prone to polymerization or degradation after reconstitution. Maintain good biological activity.

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Abstract

一种包含非还原糖、重组人源化抗Her2单抗-MMAE偶联物和一种表面活性剂的混合物的药物制剂。所述药物制剂具有减少颗粒物、减少聚集体形成、提高偶联物稳定性、改善冻干粉外观等特性。

Description

抗Her2抗体药物偶联物药物制剂 技术领域
本发明涉及一种抗Her2抗体药物偶联物药物制剂，属于抗肿瘤药物领域。
背景技术
肿瘤靶向生物治疗在癌症的治疗研究中受到了越来越多的关注。其中单克隆抗体治疗靶点特异性高、副作用低，但是单独使用，其疗效比较有限。目前抗肿瘤的单抗药物最成功是针对淋巴细胞肿瘤，如非霍奇金淋巴瘤(NHL)，慢性淋巴细胞肿瘤(CLL)等。
ErbB2，又名Her2/neu，是EGFR家族的第二个成员，ErbB2通过与EGFR家族中其它三位成员构成异源二聚体，从而发挥生物学作用。编码ErbB2的neu基因最早从大鼠神经母细胞瘤中分离得到。人类体细胞内neu基因的同源基因，称为Her2，位于17号染色体的长臂(17q21.1)，编码的产物ErbB2由1255个氨基酸组成，分子量约为185kDa，其中720-987位属于酪氨酸激酶活性域。ErbB2除了通过PI3K及MAPK信号通路发挥作用，还可降低细胞周期蛋白(cyclin)D及c-myc的表达，进而降低细胞周期蛋白依赖性激酶(cyclin-dependentkinase，cdk)抑制剂p27kipl的表达，cdk2的活性受抑制而导致细胞的增殖。随着研究的不断扩大和深入，发现HER2在多种肿瘤中表达和过度表达，因此临床上亟需靶向HER2的有效药物来治疗恶性肿瘤，目前已上市的以Her2为靶点的单抗有三种(见表1)。
表1 FDA批准上市的Her2靶点单抗药物
Figure PCTCN2020081138-appb-000001
Figure PCTCN2020081138-appb-000002
基于抗体靶向性特点，出现了新一代的生物靶向药物——抗体药物偶联物(Antibody Drug Conjuate，ADC)，ADC由三部分组成：抗体，细胞毒素与连接两者的连接头。将单克隆抗体与细胞毒素偶联后，抗体药物偶联物利用单克隆抗体的靶向性，特异性地识别癌细胞表面的受体，并与受体结合，然后进入到细胞内部，利用细胞内的蛋白酶释放细胞毒物阻止癌细胞繁殖与杀灭癌细胞。现有技术一般采用哺乳动物细胞培养生产表达抗体，经过高度纯化后的抗体与细胞毒素MMAE通过连接子偶联，获得抗体药物偶联物(Antibody Drug Conjuate,ADC)。抗体药物偶联技术使小分子毒素药物与生物蛋白融为一体，兼具二者之长，成为新一代治疗产品，在极大增强药效的同时减少毒副作用。目前美国FDA批准有四种ADC上市药品(见表2)。
表2 四种ADC上市药品
Figure PCTCN2020081138-appb-000003
Figure PCTCN2020081138-appb-000004
与其他生物大分子药物一样，ADC药物易于降解例如氧化，脱酰胺和片段化以及形成微粒和聚集体。此外，由于药物偶联本身可降低稳定性和改变抗体的物理化学性质。例如，DM1与抗-HER2抗体曲妥单抗的偶联导致抗体的CH2结构域失去稳定性(文献1：Physicochemical Stability of the Antibody-Drug Conjugate Trastuzumab-DM1:Changes due to Modification and Conjugation Processes.Aditya A.Wakankar等,Bioconjugate Chemistry 2010:21(9),1588-1595)。ADC药物通常是疏水的，ADC作为整体可能比未偶联的抗体更加不溶，因此变得更加易于聚集，形成微粒和表面吸附。为提供在运输和贮藏期间稳定的ADC药物，因此必须谨慎选择药物制剂中的各辅料成份。目前已上市的ADC药物的辅料成份见表3。由于目前上市的ADC制剂中所使用的辅料成分种类还非常有限，而相关的制剂成分选择又非常多，因此要开发一种提供在运输和贮藏期间稳定的ADC辅料制剂组合，涉及到对大量的辅料制剂成分筛选及合适浓度的确定工作，需要投入较大的精力和较长的时间。
表3 上市ADC药物辅料成份
Figure PCTCN2020081138-appb-000005
Figure PCTCN2020081138-appb-000006
从上述四种ADC制剂辅料成分中也能看出，每一种制剂均具有其独特性。源于单克隆抗体类药物脆弱的稳定性和结构复杂性，导致制造和储存这类药物具有极大的挑战。由于抗体的异质性结构，特别是互补决定区(CDR)和Fc糖基化，不同单克隆抗体的制剂开发每一项都是需要基于个案开展(文献2：Monoclonal antibodies:formulations of marketed products and recent advances in novel delivery system，Yanan Cui等，Drug  Development and Industrial Pharmacy,第43卷，第4期，第519－530页，2017年)。而ADC药物由于进一步涉及到偶联及毒素分子，因此其制剂开发的独特性更高。
专利申请(CN105008398A或WO2015074528A1)公开了一种人源化RC48抗体药物偶联物，其中人源化RC48抗体为一种靶向Her2的单克隆抗体(保藏编号C2013170保藏于中国典型培养物保藏中心的保藏仓鼠卵巢细胞(CHO细胞)所分泌的抗体或者衍生自其的抗体)，毒物选自Monomethyl AuristatinE(MMAE)，该毒物属于海兔毒素肽的衍生物。接头选择Maleimido-Caproyl-Valine-Citrulline-p-AminoBenzyloxy(mc-VC-PAB)，重组人源化抗Her2单抗-MMAE偶联物中的单抗与MMAE通过半胱氨酸与连接头相连组成。该药物针对Her2阳性肿瘤取得了良好的治疗效果。
前期试验中显示：通过偶联得到的重组人源化抗Her2单抗-MMAE偶联物，经过纯化以后，在常规的缓冲液中溶解度不好，会出现肉眼可见的不溶性微粒，不符合注射液的标准，但是如果要达到临床上的有效治疗剂量，蛋白浓度需要达到5mg/ml以上，因此如何在保证一定担保浓度的前提下解决不溶性颗粒的问题，需要进一步的研究。此外，对蛋白溶液进行真空冷冻干燥时，需要添加冻干保护剂，保护蛋白在冻干过程中不被破坏，同时又要保证冻干粉有良好的外观。为了避免蛋白冻干粉在长期保存过程中发生的缓慢降解，需要添加适当的蛋白稳定剂。如何确定合适的蛋白稳定剂，也需要通过大量的试验进行开发确定。
因此，本发明的目的在于：通过对生物制剂可用辅料进行大范围的筛选和浓度范围研究，得到一种抗Her2单抗-MMAE偶联物的辅料组合，实现以下技术效果：使抗Her2单抗-MMAE偶联物能够在冻干前后溶解良好，不溶性微粒和可见异物符合人用注射液标准，同时使偶联物在冻干和保存过程中长期保持稳定，重建后也不易发生聚合或降解，保持良好的生物活性。
发明内容
本发明提供了一种抗体药物偶联物的含水液体药物制剂，所述制剂包含抗体药物偶联物、非还原糖、氨基酸、促溶剂；所述非还原糖选自甘露醇、蔗糖、海藻糖或其组合；所述氨基酸选自组氨酸、丙氨酸、精氨酸、甘氨酸、谷氨酸或其组合；所述促溶剂选自甘油、Tween80或其组合。
在一些实施方案中，其中所述甘露醇浓度为：100-300mmol/L，优选190-300mmol/L，更优选200-260mmol/L，最优选240-260mmol/L；所述蔗 糖浓度为：0-100mmol/L，优选40-100mmol/L，更优选60-100mmol/L，最优选40-60mmol/L。
在一些实施方案中，所述组氨酸为盐酸组氨酸，其浓度为：0-100mmol/L，优选5-50mmol/L，更优选5-20mmol/L，最优选10mmol/L；所述精氨酸为盐酸精氨酸，其浓度为：0-160mmol/L，优选20-100mmol/L、更优选30-90mmol/L，最优选约35mmol/L。
在一些实施方案中，所述甘油含量为：0-1％，优选0.2-0.5％(w/v)；所述Tween80质量百分比为：0-0.02％(w/v)。
进一步的，所述抗体药物偶联物中所述抗体为抗HER2单克隆抗体；抗体所偶联的药物为MMAE或MMAF及其洐生物或DM1、DM4及其洐生物。
进一步的，所述抗HER2抗体药物偶联物为抗HER2单克隆抗体-vc-MMAE，所述抗HER2单克隆抗体和MMAE通过接头vc连接，其中所述接头与MMAE连接后的结构为：
Figure PCTCN2020081138-appb-000007
进一步的，所述抗HER2单克隆抗体包含重链和轻链，
(i)所述重链包含CDR1-3，其中所述CDR1-3的氨基酸序列分别具有如SEQ ID NO:1、2和3所示的氨基酸序列；和/或
(ii)所述轻链包含CDR1-3，其中所述CDR1-3的氨基酸序列分别具有如SEQ ID NO:4、5和6所示的氨基酸序列；
进一步的，所述单克隆抗体优选为嵌合抗体或人源化抗体。
在一些实施方案中，其中所述抗HER2单克隆抗体-vc-MMAE的浓度为5-30mg/ml。
在一些实施方案中，所述非还原性糖为240-260mmol/L的甘露醇和/或 40mmol/L-60mmol/L蔗糖、所述氨基酸为8-12mmol/L的盐酸组氨酸，所述促溶剂为0-0.02％(w/v)的Tween 80。
在一些实施方案中，其中所述非还原性糖为约260mmol/L的甘露醇和约40mmol/L蔗糖、所述氨基酸为约10mmol/L的盐酸组氨酸，所述抗体药物偶联物的浓度约10mg/ml,所述促溶剂为约0.02％(w/v)的Tween 80。
在一些实施方案中，其中所述非还原性糖为约240mmol/L的甘露醇和约60mmol/L蔗糖、所述氨基酸为约10mmol/L的盐酸组氨酸，所述抗体药物偶联物的浓度约10mg/ml,所述促溶剂为约0.02％(w/v)的Tween 80。
进一步的，所述制剂的pH 4.5－7，优选5.6－6.8、更优选5.6－6.5，5.6-6.4，5.6－6.3，6.1－6.4，6.1－6.3。
所述制剂的pH采用NaOH或盐酸调节。
在一些实施方案中，所述冻干药物制剂通过冷冻干燥上述含水液体药物制剂获得。
进一步的，药物冻干前的含水液体药物制剂含有约260mmol/L的甘露醇、约40mmol/L蔗糖、约10mmol/L的盐酸组氨酸、约0.02％(w/v)的Tween 80、约10mg/ml的抗HER2单克隆抗体-vc-MMAE，pH为5.6－6.8。
进一步的，药物冻干前的含水液体药物制剂含有约240mmol/L的甘露醇、约60mmol/L蔗糖、约10mmol/L的盐酸组氨酸、0.02％的Tween 80，约10mg/ml的抗HER2单克隆抗体-vc-MMAE，pH为5.6－6.8。
进一步的，药物冻干前的含水液体药物制剂含有的所述非还原性糖为甘露醇和蔗糖，其浓度分别约47.36mg/ml和约13.69mg/ml，所述氨基酸为盐酸组氨酸，其浓度为约2.10mg/ml，所述促溶剂为Tween 80，其含量约0.02％(w/v)。
进一步的，药物冻干前的含水液体药物制剂含有的所述非还原性糖为甘露醇和蔗糖，其浓度分别为约43.72mg/ml和约20.54mg/ml、所述氨基酸为盐酸组氨酸，其浓度为约2.10mg/ml，所述促溶剂为Tween 80，其含量为约0.02％(w/v)。
本发明进一步提供了上述药物制剂在制备治疗Her2异常表达导致的疾病药物中的用途，所述异常表达导致的疾病进一步优选为癌症；所述癌症进一步优选为Her2阳性癌症；所述Her2阳性癌症进一步优选为乳腺癌、卵巢癌、胃癌、尿路上皮癌、胃食管癌、食道癌、子宫内膜癌、肺癌或膀胱癌(参 见文献3Human Epidermal Growth Factor Receptor 2(HER2)in Cancers:Overexpression and Therapeutic Implications，Nida Iqbal and Naveed Iqbal，Molecular Biology International，Volume 2014,Article ID 852748；文献4：CN201810998055.4)。
本发明进一步提供了一种制备抗体药物偶联物药物制剂的方法，包括：
(1)制备上述任一项的制剂；
(2)评估该制剂中抗体药物偶联物的稳定性。
附图说明
图1：纯化后裸抗体SDS-PAGE电泳，其中，1-2:抗体非还原电泳3-4:抗体还原电泳，图1的结果表明：实验获得的单抗纯度符合进一步实验的要求；
图2：偶联后ADC 10％SDS-PAGE电泳，其中，Na:非还原电泳；Nb:抗体被TCEP还原后非还原电泳；Ra:RC48-vc-MMAE还原电泳Rb:TCEP抗体还原后还原电泳；图2的结果表明：获得的偶联后ADC纯度符合进一步实验的要求；
具体实施方式
实施例1：抗体纯化
基于专利申请(CN105008398A或WO2015074528A1)实施例公开的相关方法获得了鼠源单克隆抗体mRC48以及相关人源化抗体RC48，其包含人IgG1κ重链恒定区和重链可变区RC48-VH，以及人IgG1κ轻链恒定区和轻链可变区RC48-VL，将上述扩增到的各片段分别亚克隆到表达载体pcDNA3.0上。将构建的不同质粒转染到悬浮CHO细胞(Invitrogen)中。在标准条件下培养，待培养基中的营养物质耗尽、细胞不再进一步生长时放罐，采用离心或过滤的方法将细胞分离出去，取上清液，抗体蛋白存在于上清液中，上Protein A亲和层析柱进行第一步纯化，洗脱下来的目的蛋白，上阳离子填料层析柱进行第二步纯化，收集目的蛋白峰，然后上第三步柱以目的蛋白穿透模式进行第三步纯化，纯化后的蛋白经过各项指标检测合格后，然后进行超滤浓缩，蛋白浓度达到约20-30mg/ml，此即为抗体蛋白原液，可在-80℃长期保存。
其中RC48抗体的CDR序列如下：
表4 RC48抗体的CDR序列
  重链(VH) 轻链(VL)
CDR1 DYYIH(SEQ ID NO.1) KASQDVGTAVA(SEQ ID NO.4)
CDR2 RVNPDHGDSYYNQKFKD(SEQ ID NO.2) WASIRHT(SEQ ID NO.5)
CDR3 ARNYLFDHW(SEQ ID NO.3) HQFATYT(SEQ ID NO.6)
实施例2：抗体和MMAE偶联
人源化抗体RC48与药物分子的偶联
将TCEP(Tris-2-carboxyethyl-phosphine)、DTPA(Diethylene triamine pentacetate acid)母液分别溶于偶联缓冲液中，先用偶联缓冲液稀释，与单克隆抗体按照体积比1：1(v:v＝1：1)混合，TCEP与抗体的终浓度摩尔比1.9：1，DTPA终浓度1mmol/L，于25℃搅拌反应2.5h。TCEP还原可重复性好，还原后自由巯基数可以达到3.5-4.5。
TCEP还原后抗体可直接进行后续偶联。配制10mmol/L药物(vc-MMAE、vc-MMAF、mc-MMAF)溶于DMSO(dimethyl sulfoxide，二甲亚砜)，按照药物与巯基的摩尔比1.1:1缓慢加药，于25℃搅拌反应2h。用DTNB法于412nm检测自由巯基浓度(接近0)，纯化除去残余未反应药物以及DMSO等游离小分子，SDS-PAGE电泳及SEC、HPLC法检测偶联情况。偶联反应可重复性好，打开的自由巯基可以偶联完全，偶联度在3.5-4.5。
实施例3：pH对重组人源化抗Her-2单抗-MMAE偶联物(RC48-vc-MMAE)溶解及纯度作用的研究
实验条件：注射用重组人源化抗Her2单抗-MMAE偶联物蛋白2g超滤透析到0.1mol/L柠檬酸、0.02mol/L三羟甲基氨基甲烷、0.02mol/L磷酸二氢钠、0.15mol/L氯化钠缓冲液中，透析倍数不低于10 4倍，平均分成13份，每份分别用孔径为30kD的离心超滤管浓缩至蛋白浓度10mg/ml，分别用盐酸或氢氧化钠溶液调节pH值至4.2、4.6、5.0、5.4、5.6、5.8、6.0、6.2、6.4、6.6、6.8、7.0、7.4，观察澄清度情况、检测浓 度变化(结果如表1所示)，将样品在超净台内分别用无菌的膜孔径为0.22微米针头滤器过滤至无菌的20ml西林瓶内，每个pH值3支，用灭菌胶塞封口，扎铝盖。置于25℃保存，按照0小时、1天、3天、7天用无菌注射器取样，进行SEC-HPLC纯度检查(结果如表6所示)。
研究发现，在实验条件下改变蛋白的pH对蛋白的溶解情况影响很大，pH5.4以下蛋白沉淀，pH5.6以上，蛋白溶解性良好，pH6.8以下存放3天时蛋白聚合体没有增加，存放7天时稍有增加，pH7.0以上，聚合体随时间的延长而增加，pH越高，聚合体增加的越多(具体结果见表5，表6)。
表5 澄清度与浓度结果
Figure PCTCN2020081138-appb-000008
表6 纯度结果
Figure PCTCN2020081138-appb-000009
实施例4：辅料筛选
通过前期的大量信息分析及试验筛选，初步确定出蔗糖、甘露醇、甘油、组氨酸、精氨酸、聚山梨酯80(即吐温80，Tween80)等辅料作为进一步的筛选候选辅料，并进一步开展如下测试。
表7 注射用RC48-vc-MMAE辅料筛选
Figure PCTCN2020081138-appb-000010
Figure PCTCN2020081138-appb-000011
表8 注射用RC48-vc-MMAE偶联物蛋白澄清度情况
配方编号 0时 1天 3天 7天
A1 ++ ++ ++ ++
A2 - - - -
A3 ++ ++ ++ ++
A4 - - - -
A5 - - - -
A6 - - - -
A7 ++ ++ ++ ++
A8 - - - -
说明：“-”表示白点少于3个，“+”表示白点数介于3-5个，“++”表示白点数大于5个。
表9 注射用RC48-vc-MMAE蛋白纯度情况
配方编号 0时(％) 1天(％) 3天(％) 7天(％)
A1 99.5 99.2 99.0 98.2
A2 99.6 99.1 98.8 98.3
A3 99.5 99.6 99.5 99.5
A4 99.7 99.6 99.6 99.6
A5 99.4 99.1 98.7 98.2
A6 99.5 98.9 98.6 98.3
A7 99.6 99.0 98.6 98.0
A8 99.5 98.9 98.3 98.2
从以上结果可以看出，添加精氨酸对改善蛋白的可见异物情况没有明显的作用。添加蔗糖、甘油与聚山梨酯80均可以改善蛋白的情况。所以选择在制剂配方中添加适量的蔗糖对蛋白进行保护，添加甘油与聚山梨酯80对 蛋白进行促溶。
实施例5：真空冷冻干燥方法
将蛋白原液从-80℃冰箱内取出融化，用“1×制剂缓冲液”准确稀释至蛋白浓度10mg/ml，用无菌、无热源的标准20ml冻干西林瓶分装，每支6ml，进行真空冷冻干燥。
冻干条件：
预冻：温度-45℃，时间5小时；
一次干燥：温度-26℃，时间40小时，真空度10-15Pa；
二次干燥：温度25℃，时间10小时，真空度10-15Pa。
冻干后在真空状态下压胶塞，从冻干机中取出后扎铝盖。
实施例6：配方筛选
根据表10设计的配方进行配方制剂冻干粉的外观及成型稳定性考查。冻干后样品置于4℃、37℃保存，分别在0、1、3、7天观察外观情况，筛选出外观成型较好的制剂配方，结果见表11。
表10 注射用RC48-vc-MMAE制剂缓冲液配方筛选表
Figure PCTCN2020081138-appb-000012
Figure PCTCN2020081138-appb-000013
表11 冻干粉外观检查结果
Figure PCTCN2020081138-appb-000014
说明：1)“--”表示团块萎缩至冻干前体积的一半以下；“-”表示有萎缩，但团块的体积大于冻干前的一半；“+”表示仅仅边缘部分有轻微萎缩，团块体积与冻干前基本相同；“++”表示完全无萎缩，团块体积与冻干前相同。2)冻干粉外观合格标准：颜色均匀，孔隙致密，保持冻干前的体积、形状基本不变，呈块状或海绵状团块结构。由表11可以看出含有甘油的制剂配方，37℃放置一天就出现轻微萎缩，放置七天后外观萎缩、塌陷明显，所以排除甘油作为ADC制剂辅料种类。
实施例7.冻干粉处方确定及稳定性考察
冻干粉外观检查淘汰配方B7-B12，通过水分含量检查、可见异物和不溶性微粒检查及留样稳定性考察进行进一步的辅料筛选(配方B1－B6)。
将各个配方的冻干粉分别置于37、25和4℃保存，在不同的时间取样 进行SDS-PAGE、反相HPLC、配体结合法生物活性、水分含量、外观、pH值、可见异物和不溶性微粒等项目的检查。
表12冻干粉外观检查结果
配方编号 B1 B2 B3 B4 B5 B6
外观 ++ ++ ++ ++ ++ ++
说明：“--”表示团块萎缩至冻干前体积的一半以下；“-”表示有萎缩，但团块的体积大于冻干前的一半；“+”表示仅仅边缘部分有轻微萎缩，团块体积与冻干前基本相同；“++”表示完全无萎缩，团块体积与冻干前相同。
从表12中可以看出，配方B1-B6冻干粉外观均符合要求。
每个配方抽取3支样品，按照规定方法测定水分含量，取平均值，结果如表12。
表12 冻干粉水分含量测定结果
配方编号 B1 B2 B3 B4 B5 B6
含水量(％) 0.658 0.586 0.557 0.606 0.571 0.560
配方B1、B2、B3、B4、B5、B6的水分含量均＜3％，合格。
每个配方随机抽样5支，按照规定方法复溶后检查可见异物，抽取其中的3支，按照规定方法测定不溶性微粒，结果如表13所示。
表13 冻干粉复溶后可见异物和不溶性微粒检查结果
Figure PCTCN2020081138-appb-000015
从以上结果可以看出，可见异物和不溶性微粒检查，配方B1、B3、B5不符合规定，淘汰。
表14 37℃保存1个月稳定性考察结果
Figure PCTCN2020081138-appb-000016
表15 25℃保存3个月稳定性考察结果
Figure PCTCN2020081138-appb-000017
表16 4℃保存6个月稳定性考察结果
Figure PCTCN2020081138-appb-000018
说明：外观标准：“--”表示团块萎缩至冻干前体积的一半以下；“-”表示有萎缩，但团块的体积大于冻干前的一半；“+”表示仅仅边缘部分有轻微萎缩，团块体积与冻干前基本相同；“++”表示完全无萎缩，团块体积与冻干前相同。
根据以上结果可以看出配方B2和配方B4在不同温度(4℃、25℃、37℃)下的稳定性较好，配方B6的不溶性颗粒过多，淘汰。通过上述检测，配方B2和配方B4在冻干粉外观检查、冻干粉水分含量测定、冻干粉复溶后可见异物和不溶性微粒检查以及稳定性方面均达到了优良的水平。
综合以上实验证据可知：非还原性糖、氨基酸、促溶剂大类物质中具体辅料的选择对于最终制剂的影响结果是难以预期的，针对本发明的Her2单克隆抗体药物偶联物，需要通过大量的试验针对各种性能方面的检测，才能最终获得一个良好的制剂组合方案。例如：添加精氨酸对改善蛋白的可见异物情况没有明显的作用。添加蔗糖、甘油与聚山梨酯80均可以改善蛋白凝聚的情况；但甘油的添加，又会使得冻干产品复建后容易出现复建水溶液外观萎缩、塌陷明显。此外，蔗糖浓度过高或甘露糖浓度过低均会导致复建后的不溶物的增多。这些结果均是本领域技术人员在进行相关试验之前难以预料到，且由于ADC制剂涉及多种辅料的组合运用，还涉及长时间的稳定性测试等因素，使得开发一种ADC制剂存在相当的难度。我们通过大量的试验，确定了各方面性能优良的Her2ADC制剂组合，抗Her2单抗-MMAE偶联物能够在冻干前后溶解良好，不溶性微粒和可见异物符合人用注射液标准，同时使偶联物在冻干和保存过程中长期保持稳定，尤其是在25℃或37℃的高温条件下长期放置，仍然保持了良好的稳定性，所述的ADC制剂在重建后也不易发生聚合或降解，保持良好的生物活性。

Claims (19)

  1. 一种抗体药物偶联物的含水液体药物制剂，所述制剂包含抗体药物偶联物、非还原糖、氨基酸、促溶剂；所述非还原糖选自甘露醇、蔗糖、海藻糖或其组合；所述氨基酸选自组氨酸、丙氨酸、精氨酸、甘氨酸、谷氨酸及上述氨基酸盐酸盐或其组合；所述促溶剂选自甘油、Tween80或其组合。
  2. 权利要求1所述的含水液体药物制剂，其中所述甘露醇浓度为：100-300mmol/L，优选190-300mmol/L，更优选200-260mmol/L，最优选240-260mmol/L；所述蔗糖浓度为：0-100mmol/L，优选40-100mmol/L，更优选60-100mmol/L，最优选40-60mmol/L。
  3. 权利要求1或2所述的含水液体药物制剂，其中所述组氨酸为盐酸组氨酸，其浓度为：0-100mmol/L，优选5-50mmol/L，更优选5-20mmol/L，最优选10mmol/L；所述精氨酸为盐酸精氨酸，其浓度为：0-160mmol/L，优选20-100mmol/L、更优选30-90mmol/L，最优选35mmol/L。
  4. 权利要求1-3任一项所述的含水液体药物制剂，其中所述甘油含量为：0-1％，优选0.2-0.5％(w/v)；所述Tween80质量百分比为：0-0.02％(w/v)。
  5. 权利要求1-4中任一项所述的含水液体药物制剂，所述抗体药物偶联物中所述抗体为抗HER2单克隆抗体；抗体所偶联的药物为MMAE或MMAF及其洐生物或DM1、DM4及其洐生物。
  6. 权利要求5所述的含水液体药物制剂，所述抗HER2抗体药物偶联物为抗HER2单克隆抗体-vc-MMAE，所述抗HER2单克隆抗体和MMAE通过接头vc连接，其中所述接头与MMAE连接后的结构为：
    Figure PCTCN2020081138-appb-100001
  7. 权利要求5或6所述的含水液体药物制剂，所述抗HER2单克隆抗体包含重链和轻链，
    (i)所述重链包含CDR1-3，其中所述CDR1-3的氨基酸序列分别具 有如SEQ ID NO:1、2和3所示的氨基酸序列；和/或
    (ii)所述轻链包含CDR1-3，其中所述CDR1-3的氨基酸序列分别具有如SEQ ID NO:4、5和6所示的氨基酸序列；
    所述单克隆抗体优选为嵌合抗体或人源化抗体。
  8. 权利要求1-7任一项所述的含水液体药物制剂，其中所述抗HER2单克隆抗体-vc-MMAE的浓度为5-30mg/ml。
  9. 权利要求8所述的含水液体药物制剂，所述非还原性糖为240-260mmol/L的甘露醇和/或40mmol/L-60mmol/L蔗糖、所述氨基酸为8-12mmol/L的盐酸组氨酸，所述促溶剂为0-0.02％(w/v)的Tween80 。
  10. 权利要求9所述的含水液体药物制剂，其中所述非还原性糖为约260mmol/L的甘露醇和约40mmol/L蔗糖、所述氨基酸为约10mmol/L的盐酸组氨酸，所述抗体药物偶联物的浓度约10mg/ml,所述促溶剂为0.02％(w/v)的Tween 80。
  11. 权利要求10所述的含水液体药物制剂，其中所述非还原性糖为约240mmol/L的甘露醇和约60mmol/L蔗糖、所述氨基酸为约10mmol/L的盐酸组氨酸，所述抗体药物偶联物的浓度约10mg/ml,所述促溶剂为约0.02％(w/v)的Tween 80。
  12. 权利要求1-11任一项所述的含水液体药物制剂，所述制剂的pH 4.5－7，优选5.6－6.8、更优选5.6－6.5，5.6-6.4，5.6－6.3，6.1－6.4，6.1－6.3。
  13. 一种抗体药物偶联物的冻干药物制剂，所述冻干药物制剂通过冷冻干燥权利要求1-12中任一项所述的含水液体药物制剂获得。
  14. 权利要求13所述的冻干药物制剂，其中所述含水液体药物制剂含有约260mmol/L的甘露醇、约40mmol/L蔗糖、约10mmol/L的盐酸组氨酸、约0.02％(w/v)的Tween 80、约10mg/ml的抗HER2单克隆抗体-vc-MMAE，pH为5.6－6.8。
  15. 权利要求13所述的冻干药物制剂，其所述含水液体药物制剂含有约240mmol/L的甘露醇、约60mmol/L蔗糖、约10mmol/L的盐酸组氨酸、约0.02％的Tween 80，约10mg/ml的抗HER2单克隆抗体-vc-MMAE，pH为5.6－6.8。
  16. 权利要求13所述的冻干药物制剂，所述含水液体药物制剂含有的所 述非还原性糖为甘露醇和蔗糖，其浓度分别约47.36mg/ml和约13.69mg/ml，所述氨基酸为盐酸组氨酸，其浓度约2.10mg/ml，所述促溶剂为Tween 80，其含量约0.02％(w/v)。
  17. 权利要求13所述的冻干药物制剂，所述含水液体药物制剂含有的所述非还原性糖为甘露醇和蔗糖，其浓度分别约43.72mg/ml和约20.54mg/ml、所述氨基酸为盐酸组氨酸，其浓度约2.10mg/ml，所述促溶剂为Tween 80，其含量约0.02％(w/v)。
  18. 权利要求1-17中任一项所述的药物制剂在制备治疗Her2异常表达导致的疾病药物中的用途，所述异常表达导致的疾病进一步优选为癌症；所述癌症进一步优选为Her2阳性癌症；所述Her2阳性癌症进一步优选为乳腺癌、卵巢癌、胃癌、尿路上皮癌、胃食管癌、食道癌、子宫内膜癌、肺癌或膀胱癌。
  19. 制备一种抗体药物偶联物药物制剂的方法，包括：
    (1)制备权利要求1-17中任一项的制剂；
    (2)评估该制剂中抗体药物偶联物的稳定性。
PCT/CN2020/081138 2019-03-26 2020-03-25 抗Her2抗体药物偶联物药物制剂 WO2020192693A1 (zh)

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