A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor

被引：54

作者：

Emanuel, Stuart L. ^{[2
]}

Engle, Linda J. ^{[1
]}

Chao, Ginger ^{[1
]}

Zhu, Rong-Rong ^{[1
]}

Cao, Carolyn ^{[2
]}

Lin, Zheng ^{[2
]}

Yamniuk, Aaron ^{[2
]}

Hosbach, Jennifer ^{[2
]}

Brown, Jennifer ^{[2
]}

Fitzpatrick, Elizabeth ^{[2
]}

Gokemeijer, Jochem ^{[1
]}

Morin, Paul ^{[2
]}

Morse, Brent ^{[1
]}

Carvajal, Irvith M. ^{[1
]}

Fabrizio, David ^{[1
]}

Wright, Martin C. ^{[1
]}

Das Gupta, Ruchira ^{[1
]}

Gosselin, Michael ^{[1
]}

Cataldo, Daniel ^{[2
]}

Ryseck, Rolf P. ^{[2
]}

Doyle, Michael L. ^{[2
]}

Wong, Tai W. ^{[2
]}

Camphausen, Raymond T. ^{[1
]}

Cload, Sharon T. ^{[1
]}

Marsh, H. Nicholas ^{[1
]}

Gottardis, Marco M. ^{[2
]}

Furfine, Eric S. ^{[1
]}

机构：

[1] Adnexus, Waltham, MA USA

[2] Bristol Myers Squibb Co, Oncol Drug Discovery, Princeton, NJ USA

来源：

MABS | 2011年 / 3卷 / 01期

关键词：

Adnectin; biologics; EGFR; IGF-IR; bispecific; COLON-CARCINOMA CELLS; CANCER-THERAPY; MONOCLONAL-ANTIBODY; III-DOMAIN; BINDING; HETERODIMERIZATION; PROTEIN; IGG; NIMOTUZUMAB; ACTIVATION;

D O I：

10.4161/mabs.3.1.14168

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Engineered domains of human fibronectin (Adnectins (TM)) were used to generate a bispecific Adnectin targeting epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR), two transmembrane receptors that mediate proliferative and survival cell signaling in cancer. Single-domain Adnectins that specifically bind EGFR or IGF-IR were generated using mRNA display with a library containing as many as 10(13) Adnectin variants. mRNA display was also used to optimize lead Adnectin affinities, resulting in clones that inhibited EGFR phosphorylation at 7 to 38 nM compared to 2.6 mu M for the parental clone. Individual optimized Adnectins specific for blocking either EGFR or IGF-IR signaling were engineered into a single protein (El-Tandem Adnectin). The El-Tandems inhibited phosphorylation of EGFR and IGF-IR, induced receptor degradation and inhibited down-stream cell signaling and proliferation of human cancer cell lines (A431, H292, BxPC3 and RH41) with IC50 values ranging from 0.1 to 113 nM. Although Adnectins bound to EGFR at a site distinct from those of anti-EGFR antibodies cetuximab, panitumumab and nimotuzumab, like the antibodies, the anti-EGFR Adnectins blocked the binding of EGF to EGFR. PEGylated El-Tandem inhibited the growth of both EGFR and IGF-IR driven human tumor xenografts, induced degradation of EGFR and reduced EGFR phosphorylation in tumors. These results demonstrate efficient engineering of bispecific Adnectins with high potency and desired specificity. The bispecificity may improve biological activity compared to monospecific biologics as tumor growth is driven by multiple growth factors. Our results illustrate a technological advancement for constructing multi-specific biologics in cancer therapy.

引用

页码：38 / 48

页数：11

共 49 条

[1]

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status [J].