A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity
A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity
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DOI：
10.4161/mabs.3.3.15188
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发表时间：
2011-05-01
期刊：
影响因子：
5.3
通讯作者：
Glaser, Scott M.
中科院分区：
文献类型：
--
作者：
Dong, Jianying;Sereno, Arlene;Glaser, Scott M.
表皮生长因子受体（EGFR）和I型胰岛素样生长因子受体（IGF-1R）是两种已知的细胞表面受体酪氨酸激酶，共同促进肿瘤进展和耐药。联合阻断EGFR和IGF-1R在临床前模型中显示出更好的抗肿瘤活性。在这里，我们报告了一种稳定的igg样双特异性抗体（BsAb）的特性，该抗体双靶向EGFR和IGF-1R，用于癌症治疗。BsAb分子（EI-04）是由针对IGF-1R的稳定工程单链可变片段（scFv）构建的，该片段连接在针对EGFR的IgG的羧基端，具有良好的生物物理特性，可用于生物制药开发。生物化学上，EI-04以亚纳摩尔亲和力结合人EGFR和IGF-1R，同时共结合这两个受体，并以与亲本单克隆抗体（mab）相似的效力阻断它们各自配体的结合。在肿瘤细胞中，EI-04有效抑制EGFR和IGF-1R的磷酸化，同时阻断下游AKT和ERK的激活，对肿瘤细胞生长和细胞周期进展的抑制作用比单抗更大。EI-04可能是由于其四价双特异性格式，与共表达EGFR和IGF-1R的BxPC3肿瘤细胞表现出高亲和力结合，因此与单抗组合相比，其抑制igf驱动的细胞生长的效力更高。重要的是，在两种异种移植模型中，EI-04在体内的抗肿瘤效果优于亲本单抗，甚至优于BxPC3模型中的单抗联合。我们的数据支持EI-04作为治疗EGFR和IGF-1R通路反应性肿瘤的优越癌症治疗药物的临床研究。
The epidermal growth factor receptor (EGFR) and the type I insulin-like growth factor receptor (IGF-1R) are two cell surface receptor tyrosine kinases known to cooperate to promote tumor progression and drug resistance. Combined blockade of EGFR and IGF-1R has shown improved anti-tumor activity in preclinical models. Here, we report the characterization of a stable IgG-like bispecific antibody (BsAb) dual-targeting EGFR and IGF-1R that was developed for cancer therapy. The BsAb molecule (EI-04), constructed with a stability-engineered single chain variable fragment (scFv) against IGF-1R attached to the carboxyl-terminus of an IgG against EGFR, displays favorable biophysical properties for biopharmaceutical development. Biochemically, EI-04 bound to human EGFR and IGF-1R with sub-nanomolar affinity, co-engaged the two receptors simultaneously, and blocked the binding of their respective ligands with similar potency compared to the parental monoclonal antibodies (mAbs). In tumor cells, EI-04 effectively inhibited EGFR and IGF-1R phosphorylation, and concurrently blocked downstream AKT and ERK activation, resulting in greater inhibition of tumor cell growth and cell cycle progression than the single mAbs. EI-04, likely due to its tetravalent bispecific format, exhibited high avidity binding to BxPC3 tumor cells co-expressing EGFR and IGF-1R, and consequently improved potency at inhibiting IGF-driven cell growth over the mAb combination. Importantly, EI-04 demonstrated enhanced in vivo anti-tumor efficacy over the parentall mAbs in two xenograft models, and even over the mAb combination in the BxPC3 model. Our data support the clinical investigation of EI-04 as a superior cancer therapeutic in treating EGFR and IGF-1R pathway responsive tumors.