Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis

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• 作者：Ye-Jin Kim^a ; ¹ ; Jeomil Bae^a ; ¹ ; Tae-Hwan Shin^a ; Se Hun Kang^b ; Moonkyoung Jeong^c ; Yunho Han^c ; Ji-Ho Park^c ; Seok-Ki Kim^b ; Yong-Sung Kim^a ; ^{kimys@ajou.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Antibody therapy ; Tumor penetration ; Tumor targeting ; Neuropilin-1 ; Fc-fusion peptide ; Anti-angiogenesis
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：28 October 2015
• 年：2015
• 卷：216
• 期：Complete
• 页码：56-68
• 全文大小：2484 K

文摘

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 2 nM 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.