肿瘤细胞治疗研究
英文原题：Full-length recombinant antibodies from Escherichia coli: production, characterization, effector function (Fc) engineering, and clinical evaluation.
尽管在大肠杆菌中生产的几种抗体片段和抗体片段融合蛋白已被证明是安全有效的治疗药物，但产量低和易形成包涵体仍然是限制其广泛应用的主要障碍。
尽管已有几种在大肠杆菌（E. coli）中生产的抗体片段和抗体片段融合蛋白被批准用于治疗多种人类疾病，但在大肠杆菌中生产的全长单克隆抗体或双特异性抗体尚未获得批准。过去十年间，在大肠杆菌细胞质和周质中以及无细胞表达系统中表达全长抗体方面取得了实质性进展。大肠杆菌生产的无糖基化抗体与其哺乳动物细胞生产的对应物在生物化学和生物物理学特性方面，包括抗原结合、体外和体内血清稳定性、药代动力学以及体内血清半衰期，已被证明具有等效性。尽管缺乏N-连接聚糖，对无糖基化抗体Fc结构域的广泛工程化改造使其能够招募多种效应功能。本综述总结了大肠杆菌生产的无糖基化治疗性抗体作为单克隆抗体、双特异性抗体和抗体-药物偶联物在自身免疫、肿瘤学和免疫肿瘤学领域的最新研究、临床前进展和临床开发。缩略语：ADA 抗药抗体；ADCC 抗体依赖性细胞介导的细胞毒性；ADCP 抗体依赖性细胞吞噬作用；ADC 抗体-药物偶联物；aFc 无糖基化 Fc；AMD 年龄相关性黄斑变性；aTTP 获得性血栓性血小板减少性紫癜；BCMA B 细胞成熟抗原；BLA 生物制品许可申请；BsAb 双特异性抗体；C1q 补体蛋白 C1q；CDC 补体依赖性细胞毒性；CDCC 补体依赖性细胞介导的细胞毒性；CDCP 补体依赖性细胞吞噬作用；CEX 阳离子交换色谱；CFPS 无细胞蛋白表达；CHO 中国仓鼠卵巢；CH1-3 重链恒定区 1-3；CL 轻链恒定区；DLBCL 弥漫性大 B 细胞淋巴瘤；DAR 药物抗体比；DC 树突状细胞；dsFv 二硫键稳定 Fv；EU 欧盟；EGFR 表皮生长因子受体；E.大肠杆菌Escherichia coli；EpCAM上皮细胞黏附分子；Fab抗原结合片段；FACS荧光激活细胞分选；Fc可结晶片段；FcRn新生儿Fc受体；Fc Rs Fcγ受体；FDA美国食品药品监督管理局；FL-IgG全长免疫球蛋白；Fv可变区片段；FolR a叶酸受体α；gFc糖基化Fc；GM-CSF粒细胞-巨噬细胞集落刺激因子；GPx7人过氧化物酶7；HCL毛细胞白血病；HIV人类免疫缺陷病毒；HER2人表皮生长因子受体2；HGF肝细胞生长因子；HIC疏水相互作用色谱；HLA人类白细胞抗原；IBs包涵体；IgG1-4免疫球蛋白1-4；IP腹腔注射；ITC等温滴定量热法；ITP免疫性血小板减少症；IV静脉注射；kDa千道尔顿；KiH杵臼结构；mAb单克隆抗体；MAC膜攻击复合物；mCRC转移性结直肠癌；MM多发性骨髓瘤；MOA作用机制；MS质谱法；MUC1黏蛋白1；MG重症肌无力；NB纳米抗体；NK自然杀伤；nsAA非标准氨基酸；NSCLC非小细胞肺癌；P. aeruginosa铜绿假单胞菌；PD-1程序性细胞死亡1；PD-L1程序性细胞死亡配体1；PDI蛋白二硫键异构酶；PECS周质表达流式筛选；PK药代动力学；P.pastoris 毕赤酵母；PTM 翻译后修饰；Rg 回转半径；RA 类风湿关节炎；RT-PCR 逆转录聚合酶链反应；SAXS 小角X射线散射；scFv 单链Fv；SCLC 小细胞肺癌；SDS-PAGE 十二烷基硫酸钠-聚丙烯酰胺凝胶电泳；SEC 尺寸排阻色谱；SEED 链交换工程化结构域；sRNA 小调节RNA；SRP 信号识别颗粒；T1/2 半衰期；Tagg 聚集温度；TCR T细胞受体；TDB T细胞依赖性双特异性；TF 组织因子；TIR 翻译起始区；Tm 熔解温度；TNBC 三阴
Although several antibody fragments and antibody fragment-fusion proteins produced in Escherichia coli ( E. coli ) are approved as therapeutics for various human diseases, a full-length monoclonal or a bispecific antibody produced in E. coli has not yet been approved. The past decade witnessed substantial progress in expression of full-length antibodies in the E. coli cytoplasm and periplasm, as well as in cell-free expression systems. The equivalency of E. coli -produced aglycosylated antibodies and their mammalian cell-produced counterparts, with respect to biochemical and biophysical properties, including antigen binding, in vitro and in vivo serum stability, pharmacokinetics, and in vivo serum half-life, has been demonstrated. Extensive engineering of the Fc domain of aglycosylated antibodies enables recruitment of various effector functions, despite the lack of N -linked glycans. This review summarizes recent research, preclinical advancements, and clinical development of E. coli -produced aglycosylated therapeutic antibodies as monoclonal, bispecific, and antibody-drug conjugates for use in autoimmune, oncology, and immuno-oncology areas. Abbreviations: ADA Anti-drug antibody; ADCC Antibody-dependent cellular cytotoxicity; ADCP Antibody-dependent cellular phagocytosis; ADC Antibody-drug conjugate; aFc Aglycosylated Fc; AMD Age-related macular degeneration aTTP Acquired thrombotic thrombocytopenic purpura; BCMA B-cell maturation antigen; BLA Biologics license application; BsAb Bispecific antibody; C1q Complement protein C1q; CDC Complement-dependent cytotoxicity; CDCC Complement-dependent cellular cytotoxicity; CDCP Complement-dependent cellular phagocytosis; CEX Cation exchange chromatography; CFPS Cell-free protein expression; CHO Chinese Hamster Ovary; CH1-3 Constant heavy chain 1-3; CL Constant light chain; DLBCL Diffuse large B-cell lymphoma; DAR Drug antibody ratio; DC Dendritic cell; dsFv Disulfide-stabilized Fv; EU European Union; EGFR Epidermal growth factor receptor; E. coli Escherichia coli; EpCAM Epithelial cell adhesion molecule; Fab Fragment antigen binding; FACS Fluorescence activated cell sorting; Fc Fragment crystallizable; FcRn Neonatal Fc receptor; Fc Rs Fc gamma receptors; FDA Food and Drug Administration; FL-IgG Full-length immunoglobulin; Fv Fragment variable; FolR a Folate receptor alpha; gFc Glycosylated Fc; GM-CSF Granulocyte macrophage-colony stimulating factor; GPx7 Human peroxidase 7; HCL Hairy cell leukemia; HIV Human immunodeficiency virusl; HER2 Human epidermal growth factor receptor 2; HGF Hepatocyte growth factor; HIC Hydrophobic interaction chromatography; HLA Human leukocyte antigen; IBs Inclusion bodies; IgG1-4 Immunoglobulin 1-4; IP Intraperitoneal; ITC Isothermal titration calorimetry; ITP Immune thrombocytopenia; IV Intravenous; kDa Kilodalton; KiH Knob-into-Hole; mAb Monoclonal antibody; MAC Membrane-attack complex; mCRC Metastatic colorectal cancer; MM Multipl myeloma; MOA Mechanism of action; MS Mass spectrometry; MUC1 Mucin 1; MG Myasthenia gravis; NB Nanobody; NK Natural killer; nsAA Nonstandard amino acid; NSCLC Non-small cell lung cancer; P. aeruginosa Pseudomonas aeruginosa; PD-1 Programmed cell death 1; PD-L1 Programmed cell death-ligand 1; PDI Protein disulfide isomerase; PECS Periplasmic expression cytometric screening; PK Pharmacokinetics; P. pastoris Pichia pastoris; PTM Post-translational modification; Rg Radius of gyration; RA Rheumatoid arthritis; RT-PCR Reverse transcription polymerase chain reaction; SAXS Small angle X-ray scattering; scF Single chain Fv; SCLC Small cell lung cancer; SDS-PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SEC Size exclusion chromatography; SEED Strand-exchange engineered domain; sRNA Small regulatory RNA; SRP Signal recognition particle; T1/2 Half-life; Tagg Aggregation temperature; TCR T cell receptor; TDB T cell-dependent bispecific; TF Tissue factor; TIR Translation initiation region; Tm Melting temperature; TNBC Trip
MEMBER ACCOUNT
登录成功会直接打开下一页。
