Satoh Mitsuo, Iida Shigeru, Shitara Kenya
Kyowa Hakko Kogyo Co. Ltd, Tokyo Research Laboratories, 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan.
Expert Opin Biol Ther. 2006 Nov;6(11):1161-73. doi: 10.1517/14712598.6.11.1161.
Most of the existing therapeutic antibodies that have been licensed and developed as medical agents are of the human IgG1 isotype, the molecular weight of which is approximately 150 kDa. Human IgG1 is a glycoprotein bearing two N-linked biantennary complex-type oligosaccharides bound to the antibody constant region (Fc), in which the majority of the oligosaccharides are core fucosylated, and it exercises the effector functions of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity through the interaction of the Fc with either leukocyte receptors (FcgammaRs) or complement. Recently, therapeutic antibodies have been shown to improve overall survival as well as time to disease progression in a variety of human malignancies, such as breast, colon and haematological cancers, and genetic analysis of FcgammaR polymorphisms of cancer patients has demonstrated that ADCC is a major antineoplasm mechanism responsible for clinical efficacy. However, the ADCC of existing licensed therapeutic antibodies has been found to be strongly inhibited by serum due to nonnpecific IgG competing for binding of the therapeutics to FcgammaRIIIa on natural killer cells, which leads to the requirement of a significant amount of drug and very high costs associated with such therapies. Moreover, enhanced ADCC of non-fucosylated forms of therapeutic antibodies through improved FcgammaRIIIa binding is shown to be inhibited by the fucosylated counterparts. In fact, non-fucosylated therapeutic antibodies, not including the fucosylated forms, exhibit the strongest and most saturable in vitro and ex vivo ADCC among such antibody variants with improved FcgammaRIIIa binding as those bearing naturally occurring oligosaccharide heterogeneities and artificial amino acid mutations, even in the presence of plasma IgG. Robust stable production of completely non-fucosylated therapeutic antibodies in a fixed quality has been achieved by the generation of a unique host cell line, in which the endogenous alpha-1,6-fucosyltransferase (FUT8) gene is knocked out. Thus, the application of non-fucosylated antibodies is expected to be a promising approach as next-generation therapeutic antibodies with improved efficacy, even when administrated at low doses in humans in vivo. Clinical trials using non-fucosylated antibody therapeutics are underway at present.
大多数已获许可并作为药物开发的现有治疗性抗体属于人IgG1同种型，其分子量约为150 kDa。人IgG1是一种糖蛋白，带有两个与抗体恒定区（Fc）结合的N-连接双天线复合型寡糖，其中大多数寡糖是核心岩藻糖基化的，并且它通过Fc与白细胞受体（FcγRs）或补体的相互作用发挥抗体依赖性细胞毒性（ADCC）和补体依赖性细胞毒性的效应功能。最近，治疗性抗体已被证明可改善多种人类恶性肿瘤（如乳腺癌、结肠癌和血液系统癌症）的总生存期以及疾病进展时间，并且对癌症患者FcγR多态性的基因分析表明，ADCC是负责临床疗效的主要抗肿瘤机制。然而，已发现现有获许可治疗性抗体的ADCC会被血清强烈抑制，这是由于非特异性IgG竞争治疗药物与自然杀伤细胞上的FcγRIIIa的结合，这导致需要大量药物以及与此类疗法相关的非常高的成本。此外，通过改善FcγRIIIa结合增强非岩藻糖基化形式治疗性抗体的ADCC会被岩藻糖基化对应物抑制。事实上，在具有改善的FcγRIIIa结合的此类抗体变体（如具有天然存在的寡糖异质性和人工氨基酸突变的变体）中，不包括岩藻糖基化形式的非岩藻糖基化治疗性抗体在体外和体内均表现出最强且最饱和的ADCC，即使存在血浆IgG。通过产生一种独特的宿主细胞系，其中内源性α-1,6-岩藻糖基转移酶（FUT8）基因被敲除，已实现了完全非岩藻糖基化治疗性抗体的稳健稳定生产，且质量固定。因此，即使在人体内以低剂量给药，非岩藻糖基化抗体的应用有望成为一种有前景的方法，作为具有更高疗效的下一代治疗性抗体。目前正在进行使用非岩藻糖基化抗体疗法的临床试验。
