Natsume Akito, Niwa Rinpei, Satoh Mitsuo
Antibody Research Laboratories, Research Division, Kyowa Hakko Kirin Co. Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo, Japan.
Drug Des Devel Ther. 2009 Sep 21;3:7-16.
As platforms for therapeutic agents, monoclonal antibodies (MAbs) have already been approved, and several MAbs have demonstrated clinical effectiveness in a variety of malignancies. However, several issues have also been emerging in antibody therapy, such as high cost and insufficient drug action. Recently, to improve MAb activity in humans, effector functions have been subjects of focus, especially antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Extensive efforts have been made to enhance these effector functions of MAbs, and successful approaches have been reported by us and others, wherein the binding activity of MAbs to FcgammaRIIIa or C1q is increased by introducing amino acid mutations into heavy chain constant regions or through glyco-modification of Fc-linked oligosaccharides. In addition, one of the next approaches to optimizing therapeutic antibodies would be to combine multiple enhancing modifications into a single antibody platform to overcome the diverse mechanisms of clinical resistance of tumor cells. For this aim, we have recently developed a successful combination composed of ADCC-enhancing modification by the fucose depletion from Fc-linked oligosaccharides and CDC-enhancing modification by IgG1 and IgG3 isotype shuffling in heavy chains, which could be of great value for the development of third-generation antibody therapeutics.
作为治疗药物的平台，单克隆抗体（MAb）已获批准，并且几种单克隆抗体已在多种恶性肿瘤中显示出临床疗效。然而，抗体治疗中也出现了一些问题，例如成本高昂和药物作用不足。最近，为了提高单克隆抗体在人体内的活性，效应功能成为了研究重点，尤其是抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。人们已做出大量努力来增强单克隆抗体的这些效应功能，我们和其他人也报道了成功的方法，即在重链恒定区引入氨基酸突变或通过对Fc连接的寡糖进行糖基修饰来提高单克隆抗体与FcγRIIIa或C1q的结合活性。此外，优化治疗性抗体的下一个方法之一是将多种增强修饰组合到一个抗体平台中，以克服肿瘤细胞临床耐药的多种机制。为了实现这一目标，我们最近成功开发了一种组合方法，该方法由通过去除Fc连接寡糖中的岩藻糖来增强ADCC的修饰和通过重链中IgG1和IgG3同种型改组来增强CDC的修饰组成，这对于第三代抗体疗法的开发可能具有重要价值。
