Small sized EGFR1 and HER2 specific bifunctional antibody for targeted cancer therapy.
Small sized EGFR1 and HER2 specific bifunctional antibody for targeted cancer therapy.
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用于癌症靶向治疗的小尺寸 EGFR1 和 HER2 特异性双功能抗体
作者：
Ding L;Tian C;Feng S;Fida G;Zhang C;Ma Y;Ai G;Achilefu S;Gu Y
使用微型抗体靶向肿瘤是一种新颖且有吸引力的治疗方法，因为这些生物分子表现出低免疫原性、快速清除和高靶向特异性。然而，现有的大多数小尺寸抗体没有表现出显著的抗肿瘤作用，这限制了它们在靶向癌症免疫治疗中的应用。为了克服通过组合疗法靶向多种生物标志物的困难，我们设计了一种新的双功能抗体，称为MaAbNA（由纳米抗体和多价抗体部分组成的多价抗体），能够靶向EGFR 1和HER 2，其在各种肿瘤类型中广泛过表达。在大肠杆菌中表达的小尺寸（29 kDa）MaAbNA由一个抗EGFR 1纳米抗体和两个抗HER 2纳米抗体组成，并且对EGFR 1（~4.1 nM）和HER 2（~4.7 nM）具有高亲和力（KD）。为了增强其抗肿瘤活性，使用PEG 2000接头将MaAbNA与阿霉素（ADM）缀合，形成新的复合抗癌药物，MaAbNA-PEG 2000-ADMJaAbNA对过表达EGFR 1和HER 2的肿瘤细胞表现出高抑制作用，但对低水平表达EGFR 1和HER 2的细胞表现出最小的细胞毒性。此外，MaAbNA-PEG 2000-ADM显示出比单独的ADM或MaAbNA增加的杀肿瘤作用，以及显示出比EGFR 1（西妥昔单抗）和HER 2（赫赛汀）抗体药物更大的抗肿瘤功效。通过qPCR和蛋白质印迹分析评估MaAbNA调节下游癌基因c-jun、c-fos、c-myc以及AEG-1表达的治疗潜力的能力。MaAbNA及其衍生物MaAbNA-PEG 2000-ADM的抗肿瘤功效在体内得到验证，突出了MaAbNA作为高度肿瘤特异性的双分子成像探针和靶向癌症治疗剂的潜力。
Targeting tumors using miniature antibodies is a novel and attractive therapeutic approach, as these biomolecules exhibit low immunogenicity, rapid clearance, and high targeting specificity. However, most of the small-sized antibodies in existence do not exhibit marked anti-tumor effects, which limit their use in targeted cancer immunotherapy. To overcome this difficulty in targeting multiple biomarkers by combination therapies, we designed a new bifunctional antibody, named MaAbNA (multivalent antibody comprised of nanobody and affibody moieties), capable of targeting EGFR1 and HER2, which are widely overexpressed in a variety of tumor types. The small-sized (29 kDa) MaAbNA, which was expressed in E.coli, consists of one anti-EGFR1 nanobody and two anti-HER2 affibodies, and possesses high affinity (KD) for EGFR1 (~4.1 nM) and HER2 (~4.7 nM). In order to enhance its anti-tumor activity, MaAbNA was conjugated with adriamycin (ADM) using a PEG2000 linker, forming a new complex anticancer drug, MaAbNA-PEG2000-ADM. MaAbNA exhibited high inhibitory effects on tumor cells over-expressing both EGFR1 and HER2, but displayed minimal cytotoxicity in cells expressing low levels of EGFR1 and HER2. Moreover, MaAbNA-PEG2000-ADM displayed increased tumoricidal effects than ADM or MaAbNA alone, as well exhibited greater antitumor efficacy than EGFR1 (Cetuximab) and HER2 (Herceptin) antibody drugs. The ability of MaAbNA to regulate expression of downstream oncogenes c-jun, c-fos, c-myc, as well as AEG-1 for therapeutic potential was evaluated by qPCR and western-blot analyses. The antitumor efficacy of MaAbNA and its derivative MaAbNA-PEG2000-ADM were validated in vivo, highlighting the potential for use of MaAbNA as a highly tumor-specific dual molecular imaging probe and targeted cancer therapeutic.
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