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Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and
Ruei-Min Lu1, Chiung-Yi Chiu1, I-Ju Liu1
1Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Abstract:
Vascular endothelial growth factor receptor 2 (VEGFR2) 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. 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 leukemia-xenografted 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.
Insights
A new antibody, anti-VEGFR2-AF, effectively targets vascular endothelial growth factor receptor 2 (VEGFR2) in prostate cancer and leukemia models. This novel antibody shows promise for cancer therapy by inhibiting tumor growth and metastasis.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Vascular endothelial growth factor receptor 2 (VEGFR2) is crucial for tumor angiogenesis and is expressed on tumor cells.
- Current anti-VEGFR2 antibody (Ab) therapeutics are not approved for prostate cancer or leukemia.
- Novel anti-VEGFR2 Abs are needed to improve cancer treatment outcomes.
Purpose of the Study:
- To develop and characterize a novel fully human anti-VEGFR2 Ab, anti-VEGFR2-AF.
- To evaluate the efficacy of anti-VEGFR2-AF in preclinical models of prostate cancer and leukemia.
- To investigate the potential of anti-VEGFR2-AF as a standalone therapy and in combination with chemotherapy.
Main Methods:
- Utilized a human Ab library and affinity maturation to generate anti-VEGFR2-AF.
- Assessed VEGFR2 binding activity and inhibition of VEGF-A interaction.
- Evaluated in vitro functions including inhibition of capillary formation and induction of cytotoxicity.
- Tested in vivo efficacy in PC-3 prostate cancer and HL-60 leukemia xenograft mouse models.
- Compared anti-VEGFR2-AF efficacy with ramucirumab and docetaxel.
Main Results:
- Anti-VEGFR2-AF demonstrated high binding affinity to VEGFR2, disrupting VEGF-A signaling.
- The antibody inhibited angiogenesis and exhibited cytotoxic effects in vitro.
- In vivo, anti-VEGFR2-AF significantly repressed prostate cancer growth and angiogenesis, comparable to ramucirumab.
- Combination therapy with anti-VEGFR2-AF and docetaxel enhanced prostate cancer treatment efficacy.
- Anti-VEGFR2-AF showed superior efficacy to ramucirumab in leukemia models, prolonging survival and reducing metastasis.
Conclusions:
- Anti-VEGFR2-AF is a potent therapeutic candidate targeting VEGFR2 in cancer.
- The antibody possesses both anti-angiogenic and direct anti-tumor activities.
- Anti-VEGFR2-AF holds significant potential for treating prostate cancer and leukemia, including in combination therapies.
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