title: Enhancement of the tumor penetration of monoclonal antibody by fusion of a neuropilin-targeting peptide improves the antitumor efficacy.
abstract: 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.
authors.affiliation: Corresponding Author: Yong-Sung Kim, Ajou University, 206 Worldcup-ro, Suwon, 443-749, Korea. kimys@ajou.ac.kr.
authors.forename: Tae-Hwan
authors.initials: TH
authors.lastname: Shin
authors.forename: Eun-Sil
authors.initials: ES
authors.lastname: Sung
authors.forename: Ye-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Ki-Su
authors.initials: KS
authors.lastname: Kim
authors.forename: Se-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Seok-Ki
authors.initials: SK
authors.lastname: Kim
authors.forename: Young-Don
authors.initials: YD
authors.lastname: Lee
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000235:genetics*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D015703:Antigens, CD / Q000187:drug effects / Q000235:genetics; D015820:Cadherins / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000235:genetics*; D000068818:Cetuximab; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D039921:Neuropilins / Q000008:administration & dosage / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics*; D000068878:Trastuzumab; D000099152:Cadherin 5
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015820:Cadherins; D057846:Cell-Penetrating Peptides; D000068818:Cetuximab; D039921:Neuropilins; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab; D000099152:Cadherin 5