title: Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis.
abstract: Neuropilin-1 (NRP1) receptor, involved in vascular endothelial growth factor (VEGF)-mediated vascular permeability and tumor angiogenesis, is targeted by peptides that bind to its VEGF-binding site. However, these peptides also cross-react with the structurally related receptor, NRP2. Here, we describe an immunoglobulin Fc-fused peptide, Fc-TPP11, which specifically binds to the VEGF-binding site of NRP1 with approximately 2nM affinity, but negligibly to that of NRP2. Fc-TPP11 triggered NRP1-dependent signaling, enhanced vascular permeability via vascular endothelial (VE)-cadherin downregulation, and increased paracellular permeability via E-cadherin downregulation in tumor tissues. Fc-TPP11 also significantly enhanced the tumor penetration of co-injected anti-cancer drug, doxorubicin, leading to the improved in vivo anti-tumor efficacy. Fc-TPP11 was easily adapted to the full-length anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab (Erbitux), cetuximab-TPP11, exhibiting more than 2-fold improved tumor penetration than the parent cetuximab. Fc-TPP11 exhibited a similar whole-body half-life to that of intact Fc in tumor bearing mice. In addition to the tumor-penetrating activity, Fc-TPP11 suppressed VEGF-dependent angiogenesis by blocking VEGF binding to NRP1, thereby inhibiting tumor growth without promoting metastasis in the mouse model. Our results show that NRP1-specific, high-affinity binding of Fc-TPP11, is useful to validate NRP1 signaling, independent of NRP2. Thus, Fc-TPP11 can be used as a tumor penetration-promoting agent with anti-angiogenic activity or directly adapted to mAb-TPP11 format for more potent anti-cancer antibody therapy.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Ye-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Jeomil
authors.initials: J
authors.lastname: Bae
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Tae-Hwan
authors.initials: TH
authors.lastname: Shin
authors.affiliation: Molecular Imaging & Therapy Branch, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Se Hun
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Bio and Brain Engineering & Center of Optics for Health Science, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Moonkyoung
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Department of Bio and Brain Engineering & Center of Optics for Health Science, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Yunho
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Bio and Brain Engineering & Center of Optics for Health Science, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Ji-Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: Molecular Imaging & Therapy Branch, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: Seok-Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea. Electronic address: kimys@ajou.ac.kr.
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D015820:Cadherins / Q000096:biosynthesis; D000068818:Cetuximab / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D039942:Neuropilin-1 / Q000737:chemistry*; D010539:Permeability; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D015820:Cadherins; D007141:Immunoglobulin Fc Fragments; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D004317:Doxorubicin; D000068818:Cetuximab
keywords: Anti-angiogenesis; Antibody therapy; Fc-fusion peptide; Tumor penetration; Tumor targeting, Neuropilin-1