Biological properties of a human compact anti-ErbB2 antibody
Biological properties of a human compact anti-ErbB2 antibody
复制标题
DOI：
10.1093/carcin/bgi146
复制
发表时间：
2005-11-01
期刊：
影响因子：
4.7
通讯作者：
D'Alessio, G
中科院分区：
文献类型：
--
作者：
De Lorenzo, C;Cozzolino, R;D'Alessio, G
ErbB2 是许多癌症的预后因素和治疗靶点。与其他 ErbB 受体相比，ErbB2 缺乏可溶性直接配体，但它是 ErbB 家族成员的首选共受体，形成的异二聚体比同二聚体具有更有效和更持久的信号传导活性。我们最近通过融合 Erbicin（一种人类抗 ErbB2 scFv，对 ErbB2 阳性细胞具有选择性细胞毒性）和人类 Fc 结构域，生产了一种新的抗 ErbB2 抗体 Erb-hcAb。这种完全人源抗肿瘤抗体代表了 IgG1 的紧凑版本，具有 scFv 部分对靶细胞的细胞毒性，结合 Fc 部分诱导抗体和补体依赖性细胞毒性的能力。在这里，我们以赫赛汀（一种目前用于临床免疫治疗的抗 ErbB2 人源化单克隆抗体）为参考，描述了 Erb-hcAb 的主要特性。我们发现二价 Erb-hcAb 和赫赛汀都会增加受体磷酸化和下调，而单价 Erbicin 则不会。这些结果与 Erb-hcAb 能够诱导 ErbB2 阳性细胞凋亡并抑制细胞周期进程的发现相关。其强大的体外抗肿瘤作用与在无胸腺小鼠中建立的人 ErbB2 阳性肿瘤异种移植物实验中观察到的体内效果相匹配。最后，Erb-hcAb 显示出的糖基化谱几乎与人 IgG 的糖基化谱重叠。这些发现表明，Erb-hcAb 是一种非常有前途的新药，用于过度表达 ErbB2 受体的癌症的免疫治疗。
ErbB2 is a prognostic factor and target of therapy for many carcinomas. In contrast with the other ErbB receptors, ErbB2 lacks a soluble direct ligand, but it is the preferred co-receptor for the ErbB family members, forming heterodimers with more potent and prolonged signalling activity than that of homodimers. We recently produced a new anti-ErbB2 antibody, Erb-hcAb, by fusion of Erbicin, a human, anti-ErbB2 scFv, selectively cytotoxic to ErbB2-positive cells, and a human Fc domain. This fully human antitumour antibody represents a compact version of an IgG1, with the cytotoxicity of the scFv moiety on target cells, combined with the ability of the Fc moiety to induce both antibody- and complement-dependent cytotoxicity. Here, we describe the main properties of Erb-hcAb, using as a reference Herceptin, an anti-ErbB2 humanized monoclonal currently employed in clinical immunotherapy. We found that both bivalent Erb-hcAb and Herceptin increase receptor phosphorylation and downregulation, whereas monovalent Erbicin does not. These results correlate with the finding that Erb-hcAb is capable of inducing apoptosis and inhibiting cell cycle progression in ErbB2-positive cells. Its powerful in vitro antitumour action matched that observed in vivo in experiments with human ErbB2-positive tumour xenografts established in athymic mice. Finally, Erb-hcAb displays a glycosylation profile virtually superimposable to that of a human IgG. These findings suggest that Erb-hcAb is a very promising new agent for the immunotherapy of carcinomas that overexpress the ErbB2 receptor.