Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and prostate cancer

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed in tumorassociated endothelial cells, where it modulates tumor-promoting angiogenesis, and it is also found on the surface of tumor cells. Currently, there are no Ab therapeutics targeting VEGFR2 approved for the treatment of prostate cancer or leukemia.Therefore, development of novel efficacious anti-VEGFR2 Abs will benefit cancer patients. We used the Institute of Cellular and Organismic Biology human Ab library and affinity maturation to develop a fully human Ab, anti-VEGFR2-AF, which shows excellent VEGFR2 binding activity. Anti-VEGFR2-AF bound Ig-like domain 3 of VEGFR2 extracellular region to disrupt the interaction between VEGF-A and VEGFR2, neutralizing downstream signaling of the receptor. Moreover, anti-VEGFR2-AF inhibited capillary structure formation and exerted Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity in vitro. We found that VEGFR2 is expressed in PC-3 human prostate cancer cell line and associated with malignancy and metastasis of human prostate cancer. In a PC-3 xenograft mouse model, treatment with anti-VEGFR2-AF repressed tumor growth and angiogenesis as effectively and safely as US FDA-approved anti-VEGFR2 therapeutic, ramucirumab. We also report for the first time that addition of anti-VEGFR2 Ab can enhance the efficacy of docetaxel in the treatment of a prostate cancer mouse model. In HL-60 human leukemiaxenografted mice, anti-VEGFR2-AF showed better efficacy than ramucirumab with prolonged survival and reduced metastasis of leukemia cells to ovaries and lymph nodes. Our findings suggest that anti-VEGFR2-AF has strong potential as a cancer therapy that could directly target VEGFR2-expressing tumor cells in addition to its anti-angiogenic action.

Exosomes in Angiogenesis and Anti-angiogenic Therapy in Cancers

“…Further possible treatment options, including direct targeting of VEGFR-2-expression, indirect inhibition of angiogenesis, and targeting the interplay between tumor or stromal cells and angiogenesis, have been evaluated. Lu et al suggested that anti-VEGFR-2-AF is a prospective therapeutic Ab for prostate cancer treatment that inhibits angiogenesis, through vascular endothelial cells, and tumorigenesis at the same time by VEGFR-2-expressing tumor cells [ 118 ]. The therapeutic efficacy of anti-VEGFR-2-AF is currently under study in preclinical trials using solid and liquid xenograft mouse models [ 118 ].…”

“…Lu et al suggested that anti-VEGFR-2-AF is a prospective therapeutic Ab for prostate cancer treatment that inhibits angiogenesis, through vascular endothelial cells, and tumorigenesis at the same time by VEGFR-2-expressing tumor cells [118]. The therapeutic efficacy of anti-VEGFR-2-AF is currently under study in preclinical trials using solid and liquid xenograft mouse models [118].…”

Expression and prognostic significance of vascular endothelial growth factor‐A (VEGF‐A) and its receptor in canine prostate cancer

“…This finding will aid in future investigations on the development of reliable and effective antiangiogenic therapeutic options for canine PC, similar to the scenario already delineated in human PC. In human PC, the mechanism of angiogenesis 29–31 as well as the association between tumor hypoxia and vasculogenesis have been widely studied 31 . Therefore, different therapeutic strategies have been developed to target the angiogenic markers, including the anti‐VEGFR‐2 monoclonal antibodies 29 and oncolytic vaccines expressing anti‐VEGF antibodies 32 …”

“…In human PC, the mechanism of angiogenesis 29–31 as well as the association between tumor hypoxia and vasculogenesis have been widely studied 31 . Therefore, different therapeutic strategies have been developed to target the angiogenic markers, including the anti‐VEGFR‐2 monoclonal antibodies 29 and oncolytic vaccines expressing anti‐VEGF antibodies 32 …”

Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism

“…Therefore, development of an excellent anticancer agents are very much essential, especially ones with potent biological activities, enzyme inhibitory activities and low/no toxicity [2][3][4][5] (Figure 1). Regarding enzyme inhibitory activities: (i) cyclin-dependent kinases (CDKs) are considered as a vital feature, inciting various key transitions in the cell cycle for cancer cells, in addition to instructing apoptosis, transcription and exocytosis; (ii) the epidermal growth factor receptor (EGFR) [6] kinase enzyme promote overexpression, and overexpression of certain proteins may play a role in various cancer development [7][8][9][10][11][12][13][14][15]; (iii) the vascular endothelial growth factor receptor 2 (VEGFR-2) [16,17] is highly expressed in tumor-associated endothelial cells, where it modulates tumor-promoting angiogenesis, and it is also found on the surface of tumor cells [18]; (iv) FMS-like tyrosine kinase-3 (FLT-3) is a protein found in humans and is encoded by the FLT-3 gene [19][20][21]. Mutations of the FLT-3 receptor can lead to the development of leukemia, a cancer of bone marrow hematopoietic progenitors [22][23][24][25].…”