VEGFR2 targeted antibody fused with MICA stimulates NKG2D mediated immunosurveillance and exhibits potent anti-tumor activity against breast cancer

// Wei Xie 1, * , Fang Liu 1, * , Youfu Wang 1 , Xueyan Ren 1 , Tong Wang 1 , Zhiguo Chen 1 , Mingying Tang 1 , Fumou Sun 1 , Zhaoting Li 1 , Min Wang 1 , Juan Zhang 1 1 State Key Laboratory of Natural Medicines, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China * These authors should be considered as joint first authors Correspondence to: Juan Zhang, e-mail: juancpu@126.com Min Wang, e-mail: minwang@cpu.edu.cn Keywords: antibody fusion protein, VEGFR2, MICA, anti-angiogenesis, immunosurveillance Received: August 25, 2015     Accepted: January 29, 2016     Published: February 19, 2016 ABSTRACT Binding of MHC class I-related chain molecules A and B (MICA/B) to the natural killer (NK) cell receptor NK group 2, member D (NKG2D) is thought critical for activating NK-mediated immunosurveillance. Angiogenesis is important for tumor growth and interfering with angiogenesis using the fully human IgG1 anti-VEGFR2 (vascular endothelial growth factor receptor 2) antibody (mAb04) can be effective in treating malignancy. In an effort to make mAb04 more effective we have generated a novel antibody fusion protein (mAb04-MICA) consisting of mAb04 and MICA. We found that mAb04-MICA maintained the anti-angiogenic and antineoplastic activities of mAb04, and also enhanced immunosurveillance activated by the NKG2D pathway. Moreover, in human breast tumor-bearing nude mice, mAb04-MICA demonstrated superior anti-tumor efficacy compared to combination therapy of mAb04 + Docetaxel or Avastin + Docetaxel, highlighting the immunostimulatory effect of MICA. In conclusion, mAb04-MICA provided new inspiration for anti-tumor treatment and had prospects for clinical application.