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

被引：73

作者：

Dong, Jianying ^{[1
]}

Sereno, Arlene ^{[1
]}

Aivazian, Dikran ^{[1
]}

Langley, Emma ^{[1
]}

Miller, Brian R. ^{[1
]}

Snyder, William B. ^{[1
]}

Chan, Eric ^{[1
]}

Cantele, Matt ^{[1
]}

Morena, Ronald ^{[1
]}

Joseph, Ingrid B. J. K. ^{[1
]}

Boccia, Antonio ^{[1
]}

Virata, Cyrus ^{[1
]}

Gamez, James ^{[1
]}

Yco, Grace ^{[1
]}

Favis, Michael ^{[1
]}

Wu, Xiufeng ^{[1
]}

Graff, Christilyn P. ^{[1
]}

Wang, Qin ^{[1
]}

Rohde, Ellen ^{[1
]}

Rennard, Rachel ^{[1
]}

Berquist, Lisa ^{[1
]}

Huang, Flora ^{[1
]}

Zhang, Ying ^{[1
]}

Gao, Sharon X. ^{[1
]}

Ho, Steffan N. ^{[1
]}

Demarest, Stephen J. ^{[1
]}

Reff, Mitchell E. ^{[1
]}

Hariharan, Kandasamy ^{[1
]}

Glaser, Scott M. ^{[1
]}

机构：

[1] Biogen Idec Inc, San Diego, CA USA

来源：

MABS | 2011年 / 3卷 / 03期

关键词：

EGFR; IGF-1R; bispecific antibody; stability; anti-tumor; cancer therapy; MONOCLONAL-ANTIBODY; ACQUIRED-RESISTANCE; CLINICAL-OUTCOMES; CANCER-THERAPY; TUMOR-GROWTH; INHIBITORS; EGFR; GEFITINIB; CELLS; PHARMACOKINETICS;

D O I：

10.4161/mabs.3.3.15188

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：273 / 288

页数：16

共 58 条

[1] Signalling by the type 1 insulin-like growth factor receptor: Interplay with the epidermal growth factor receptor [J].