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Enhancement of the tumor penetration of monoclonal antibody by fusion of a neuropilin-targeting peptide improves the antitumor efficacy.
Shin, Tae-Hwan; Sung, Eun-Sil; Kim, Ye-Jin; Kim, Ki-Su; Kim, Se-Ho; Kim, Seok-Ki; Lee, Young-Don; Kim, Yong-Sung.
Afiliação
  • Shin TH; Corresponding Author: Yong-Sung Kim, Ajou University, 206 Worldcup-ro, Suwon, 443-749, Korea. kimys@ajou.ac.kr.
Mol Cancer Ther ; 13(3): 651-61, 2014 Mar.
Article em En | MEDLINE | ID: mdl-24435448
The limited localization and penetration of monoclonal antibodies (mAb) into solid tumors restricts their antitumor efficacy. Here, we describe a solid tumor-targeting antibody with enhanced tumor penetration activity. We designed a 22-residue peptide (A22p), which was extracted from the C-terminal basic region of semaphorin 3A (Sema3A) but modified to have higher affinity with neuropilin receptors (NRP), and genetically fused it to the C-terminus of Fc of human immunoglobulin G1 via a 15-residue (G4S)3 linker, generating Fc-A22p, for the bivalent binding to NRPs. In contrast to Fc or the monovalent A22p peptide alone, Fc-A22p homed to tumor vessels and induced vascular permeability through VE-cadherin downregulation and penetrated tumor tissues by interacting with NRPs in mice bearing human tumor xenografts. We extended the Fc-A22p platform by generating mAb-A22p antibodies of two clinically approved solid tumor-targeting mAbs, the anti-EGF receptor mAb cetuximab (erbitux), and the anti-Her2 mAb trastuzumab (herceptin). The mAb-A22p antibodies retained the intrinsic antigen binding, natural Fc-like biophysical properties, and productivity in mammalian cell cultures, comparable with those of the parent mAbs. In mouse xenograft tumor models, the mAb-A22p antibodies more efficiently homed to tumor vessels and spread into the extravascular tumor parenchyma, which significantly enhanced antitumor efficacy compared with the parent mAbs. Our results suggest that mAb-A22p is a superior format for solid tumor-targeting antibodies due to its enhanced tumor tissue penetration and greater antitumor efficacy compared with conventional mAbs.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Recombinantes de Fusão / Neuropilinas / Peptídeos Penetradores de Células / Anticorpos Monoclonais Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Recombinantes de Fusão / Neuropilinas / Peptídeos Penetradores de Células / Anticorpos Monoclonais Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article