全长重组抗体：生产、表征、效应功能（Fc）工程和临床评估。
Full-length recombinant antibodies from : production, characterization, effector function (Fc) engineering, and clinical evaluation.
机构信息
Senior Research Fellow, Absci, Vancouver, WA, USA.
出版信息
MAbs. 2022 Jan-Dec;14(1):2111748. doi: 10.1080/19420862.2022.2111748.
Although several antibody fragments and antibody fragment-fusion proteins produced in () are approved as therapeutics for various human diseases, a full-length monoclonal or a bispecific antibody produced in has not yet been approved. The past decade witnessed substantial progress in expression of full-length antibodies in the cytoplasm and periplasm, as well as in cell-free expression systems. The equivalency of -produced aglycosylated antibodies and their mammalian cell-produced counterparts, with respect to biochemical and biophysical properties, including antigen binding, and serum stability, pharmacokinetics, and 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 -linked glycans. This review summarizes recent research, preclinical advancements, and clinical development of -produced aglycosylated therapeutic antibodies as monoclonal, bispecific, and antibody-drug conjugates for use in autoimmune, oncology, and immuno-oncology areas. 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; FcɣRs Fc gamma receptors; FDA Food and Drug Administration; FL-IgG Full-length immunoglobulin; Fv Fragment variable; FolRαa 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 Triple-negative breast cancer; TNF Tumor necrosis factor; TPO Thrombopoietin; VEGF Vascular endothelial growth factor; vH Variable heavy chain; vL Variable light chain; vWF von Willebrand factor; WT Wild type.
尽管已有几种在 中产生的抗体片段和抗体片段融合蛋白被批准用于治疗各种人类疾病，但尚未批准在 中产生的全长单克隆抗体或双特异性抗体。在过去的十年中，在 细胞质和周质以及无细胞表达系统中表达全长抗体取得了实质性进展。已经证明，在生化和生物物理特性方面，包括抗原结合、 和血清稳定性、药代动力学以及血清半衰期，在 中产生的糖基化抗体与其在哺乳动物细胞中产生的对应物相当。尽管缺乏 -连接的聚糖，但对糖基化抗体的 Fc 结构域进行广泛的工程改造可以招募各种效应功能。本综述总结了最近在自身免疫、肿瘤学和免疫肿瘤学领域中使用的在 中产生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的研究、临床前进展和临床开发。ADA 抗药物抗体；ADCC 抗体依赖性细胞毒性；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 补体依赖性细胞毒性；CDCP 补体依赖性细胞吞噬作用；CEX 阳离子交换层析；CFPS 无细胞蛋白表达；CHO 中国仓鼠卵巢；CH1-3 恒定重链 1-3；CL 恒定轻链；DLBCL 弥漫性大 B 细胞淋巴瘤；DAR 药物抗体比；DC 树突细胞；dsFv 二硫键稳定的 Fv；EU 欧盟；EGFR 表皮生长因子受体；E. coli 大肠杆菌；EpCAM 上皮细胞黏附分子；Fab 片段抗原结合；FACS 荧光激活细胞分选；Fc 片段可结晶；FcRn 新生儿 Fc 受体；FcɣRs Fc 伽玛受体；FDA 食品和药物管理局；FL-IgG 全长免疫球蛋白；Fv 片段可变；FolRαa 叶酸受体 alpha；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 人类表皮生长因子受体 2；HGF 肝细胞生长因子；HIC 疏水相互作用层析；HLA 人类白细胞抗原；IBs 包涵体；IgG1-4 免疫球蛋白 1-4；IP 腹腔内；ITC 等温热滴定法；ITP 免疫性血小板减少症；IV 静脉内；kDa 千道尔顿；KiH 旋钮入孔；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；MUC1 粘蛋白 1；MG 重症肌无力；NB 纳米抗体；NK 自然杀伤细胞；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 蛋白质二硫键异构酶；PECS 周质表达细胞筛选；PK 药代动力学；P. pastoris 巴斯德毕赤酵母；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；scF 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 尺寸排阻层析；SEED 链交换工程结构域；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 熔点；TNBC 三阴性乳腺癌；TNF 肿瘤坏死因子；TPO 血小板生成素；VEGF 血管内皮生长因子；vH 可变重链；vL 可变轻链；vWF 血管性血友病因子；WT 野生型。
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