针对 I 型胰岛素样生长因子受体的稳定 IgG 样双特异性抗体表现出增强的配体阻断和抗肿瘤活性。
Stable IgG-like bispecific antibodies directed toward the type I insulin-like growth factor receptor demonstrate enhanced ligand blockade and anti-tumor activity.
机构信息
Biogen Idec, San Diego, California 92122, USA.
出版信息
J Biol Chem. 2011 Feb 11;286(6):4703-17. doi: 10.1074/jbc.M110.184317. Epub 2010 Dec 1.
Bispecific antibodies (BsAbs) target multiple epitopes on the same molecular target or different targets. Although interest in BsAbs has persisted for decades, production of stable and active BsAbs has hindered their clinical evaluation. Here, we describe the production and characterization of tetravalent IgG-like BsAbs that combine the activities of allosteric and competitive inhibitors of the type-I insulin-like growth factor receptor (IGF-1R). The BsAbs, which were engineered for thermal stability, express well, demonstrate favorable biophysical properties, and recognize both epitopes on IGF-1R. Only one BsAb with a unique geometry, denoted BIIB4-5scFv, was capable of engaging all four of its binding arms simultaneously. All the BsAbs (especially BIIB4-5scFv) demonstrated enhanced ligand blocking over the single monoclonal antibodies (mAbs), particularly at high ligand concentrations. The pharmacokinetic profiles of two IgG-like BsAbs were tested in nude mice and shown to be comparable with that of the parental mAbs. The BsAbs, especially BIIB4-5scFv, demonstrated an improved ability to reduce the growth of multiple tumor cell lines and to inhibit ligand-induced IGF-1R signaling in tumor cells over the parental mAbs. BIIB4-5scFv also led to superior tumor growth inhibition over its parental mAbs in vivo. In summary, BsAbs that bridge multiple inhibitory mechanisms against a single target may generally represent a more effective strategy for intervention in oncology or other indications compared with traditional mAb therapy.
双特异性抗体 (BsAbs) 靶向同一分子靶标或不同靶标上的多个表位。尽管人们对 BsAbs 的兴趣已经持续了几十年,但稳定和有效的 BsAbs 的生产一直阻碍着它们的临床评估。在这里,我们描述了四价 IgG 样 BsAbs 的生产和表征,这些 BsAbs 结合了 I 型胰岛素样生长因子受体 (IGF-1R) 的变构和竞争性抑制剂的活性。这些 BsAbs 经过工程设计以提高热稳定性,表达良好,表现出良好的物理化学特性,并识别 IGF-1R 上的两个表位。只有一种具有独特几何形状的 BsAb,称为 BIIB4-5scFv,能够同时结合其所有四个结合臂。所有的 BsAbs(尤其是 BIIB4-5scFv)都表现出比单克隆抗体 (mAb) 更强的配体阻断作用,尤其是在高配体浓度下。两种 IgG 样 BsAbs 的药代动力学特征在裸鼠中进行了测试,并显示与亲本 mAb 相当。与亲本 mAb 相比,BsAbs,特别是 BIIB4-5scFv,在多种肿瘤细胞系中的生长抑制能力和抑制配体诱导的 IGF-1R 信号转导方面均表现出增强的能力。BIIB4-5scFv 在体内也表现出比其亲本 mAb 更好的肿瘤生长抑制作用。总之,与传统的 mAb 治疗相比,针对单一靶标桥接多种抑制机制的 BsAbs 可能代表了一种更有效的干预肿瘤学或其他适应症的策略。