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Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency.
Yang, Yun; Guo, Qingcheng; Xia, Mao; Li, Yantao; Peng, Xiaoyun; Liu, Tao; Tong, Xin; Xu, Jin; Guo, Huaizu; Qian, Weizhu; Hou, Sheng; Dai, Jianxin; Wang, Hao; Liu, Rong; Guo, Yajun.
Afiliação
  • Yang Y; a PLA General Hospital Cancer Center ; PLA School of Medicine ; Beijing , China.
MAbs ; 7(2): 440-50, 2015.
Article em En | MEDLINE | ID: mdl-25679409
Panitumumab, as a commercially available antibody, is an effective anticancer therapeutic against epidermal growth factor receptor (EGFR), although it exerts weak antibody-dependent cell-mediated cytotoxicity (ADCC) activity owing to its IgG2 nature. Here, we firstly engineered panitumumab by grafting its variable region into an IgG1 backbone. The engineered panitumumab (denoted as Pan) retained binding activity identical to the parental antibody while exhibiting stronger ADCC activity in vitro and more potent antitumor effect in vivo. To further enhance the target selectivity of Pan, we generated Pan-P by tethering an epitope-blocking peptide to Pan via a tumor-specific protease selective linker. Pan-P showed almost 40-fold weaker affinity compared with Pan, but functional activity was restored to a similar extent as Pan when Pan-P was selectively activated by urokinase-type plasminogen activator (uPA). More importantly, targeted localization of Pan-P was observed in tumor samples from colorectal cancer (CRC) patients and tumor-bearing nude mice, strongly indicating that specific activation also existed ex vivo and in vivo. Furthermore, Pan-P also exhibited effective in vivo antitumor potency similar to Pan. Taken together, our data evidence the enhanced antitumor potency and excellent target selectivity of Pan-P, suggesting its potential use for minimizing on-target toxicity in anti-EGFR therapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Região Variável de Imunoglobulina / Neoplasias Colorretais / Engenharia de Proteínas / Receptores ErbB / Anticorpos Monoclonais / Anticorpos Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Região Variável de Imunoglobulina / Neoplasias Colorretais / Engenharia de Proteínas / Receptores ErbB / Anticorpos Monoclonais / Anticorpos Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article