The challenges with antibody-based targeting of VEGF

In particular, bevacizumab is approved for the treatment of a variety of cancers including metastatic colorectal cancer, and is also used off-label for treatment of wet age-related macular degeneration (AMD). Furthermore, ranibizumab is approved for use as standard treatment for wet AMD. However, despite the popularity of these drugs, challenges with antibody-based targeting of VEGF remain. A more detailed understanding of the current status of anti-VEGF antibody drugs is needed to overcome unmet medical needs associated with their use.

Introduction

Angiogenesis, which is a physiological process that involves the formation of new blood vessels from pre-existing vessels, occurs during growth and development, as well as during wound healing. Under pathological conditions, angiogenesis is regulated by the complex coordinated actions of upregulated ligands and receptors¹. Angiogenesis is essential not only for tumour progression and metastasis, but also for other angiogenesis-related diseases, including wet AMD, glaucoma and diabetic retinopathy^2-4. The drugs bevacizumab and ranibizumab have been found to be clinically useful for the suppression of pathological angiogenesis⁵.

However, despite the potential effectiveness of anti-VEGF antibody drugs across a significant number of diseases, several unmet medical needs associated with the use of these drugs, including significant adverse side effects, have been reported. This review aims to provide both an overview of the current status of anti-VEGF therapies and a description of the most promising avenues to create next-generation therapeutics that overcome the unmet medical needs of current anti-VEGF treatments.

Bevacizumab therapy for cancer

Tumour angiogenesis is regulated by the balance of various pro-angiogenic and anti-angiogenic factors, leading to the development of abnormal blood vessels that provide oxygen and nutrients to cancerous tumours⁶. Among the known angiogenic factors, VEGF has been identified as the most critical to tumour angiogenesis⁷. Bevacizumab was approved by the US Food and Drug Administration (FDA) in 2004 as the first anti-angiogenic therapeutic antibody for treating patients with metastatic colorectal cancer in combination with chemotherapy⁸. Bevacizumab is a humanised immunoglobulin G (IgG) monoclonal antibody that binds to VEGF with high specificity, thereby blocking VEGF-mediated molecular interactions with the VEGF receptor (VEGFR) and inhibiting the formation of new blood vessels in tumours. Since its initial approval, bevacizumab has been used clinically to treat a variety of cancers, including metastatic non-squamous non-small cell lung cancer, metastatic renal cell carcinoma, epithelial ovarian cancer and glioblastoma^9-12.

Based on statistics, in 2010, the global cancer market was valued at $54 billion, which represents an increase of 5.1% over the previous year of $51.3 billion. Furthermore, the market, which is forecasted to grow at a compound annual growth rate of 6.9% from 2010 to 2016 to reach $81 billion in 2016, is becoming increasingly competitive. Among the top-selling cancer drugs, bevacizumab accounted for the highest sales of $6.2 billion in 2010, which represents a growth of 3.8% compared with the previous year¹³. 

Downside to bevacizumab

There is increasing evidence that bevacizumab is associated with several limitations. Firstly, it has been reported that its therapeutic efficacy is limited for some indications. In Phase III clinical trials, when combined with chemotherapy, bevacizumab extended the median overall survival of patients with metastatic colorectal cancer by 4.7 months when used first line, and by 2.1 months when used as a second-line therapy¹⁴. In contrast, in a clinical study for the treatment of epithelial ovarian cancer, bevacizumab increased progression-free survival by approximately three to four months compared with standard chemotherapeutic agents, but had no impact on median overall survival¹⁵.

Secondly, because VEGFR is also expressed on normal endothelial cells, bevacizumab may adversely affect VEGF-mediated signalling in normal endothelial cells, which in turn may be associated with reported side effects such as bleeding, hypertension, proteinuria, impaired wound healing and gastrointestinal perforation. Finally, due to the redundancy of tumour-secreted angiogenic factors, including placental growth factors, angiopoietin, basic fibroblast growth factor, platelet-derived growth factors, and hepatocyte growth factor, long-term treatment with bevacizumab in cancer patients may also generate a resistant tumour phenotype^16-18. Furthermore, in patients with brain tumours, bevacizumab may provoke a highly infiltrative and invasive phenotype that induces severe necrotic brain lesions^19-21.

Ranibizumab therapy for wet AMD

AMD has been a leading cause of blindness in developed nations over the past several decades. There are two types of AMD, ‘dry’ (non-neovascular) and ‘wet’ (neovascular). Due to a lack of characteristic symptoms, it is difficult to detect AMD progression until the patient reports marked changes in vision. Approximately 10% of patients with AMD have wet AMD, which is associated with over 90% of cases of severe vision loss due to this disease²². Wet AMD is caused by VEGF-dependent abnormal angiogenesis in the central region of the retina that results in severe vision loss due to retinal damage. In 2006, an effective antibody drug ranibizumab, which is the Fab form of bevacizumab, received FDA approval and is currently used as standard treatment for wet AMD²³.

Statistically, the wet AMD market was estimated at approximately $4 billion in 2011, and is expected to reach $8.2 billion by 2016. The wet AMD market is reported to be dominated by ranibizumab, accounting for 94.4% of all wet AMD sales in 2011²⁴.

Bevacizumab has not been approved by the FDA for the treatment of eye diseases, but has been prescribed off-label for wet AMD due to its VEGF-inhibiting properties. In 2011, the FDA also approved aflibercept (Elyea; Regeneron) for this form of AMD. Aflibercept is an Fc fusion protein that consists of extracellular domains of human VEGF receptor 1 (VEGFR1) and VEGFR2 fused with the Fc portion of human immunoglobulin G1. This ‘VEGF-trap’ sequesters all VEGFA isoforms, and has a higher affinity to VEGF than ranibizumab or bevacizumab²⁵. 

Ranibizumab is costly

There are several unmet medical needs among patients with wet AMD. Although ranibizumab is the best-selling antibody drug for wet AMD, it costs approximately $1,950 per dose, which is more expensive than both bevacizumab ($50 per dose) and aflibercept ($1,850 per dose)^24,26. Frequent intravitreal injections of ranibizumab or bevacizumab may lead to adverse side effects, including haemorrhage, eye pain, hypertension, retinal detachment and cataract formation. In addition, several patients with AMD have been found to be resistant to ranibizumab^27,28.

Conclusion

To date, anti-VEGF therapy is an effective strategy for suppressing pathological angiogenesis; however, there are several drawbacks to anti-VEGF antibody treatment. The identification of a novel angiogenic therapeutic target and the development of IgG antibody drugs against this target remain an important open research aim. This novel target protein should meet several requirements, including clinical relevance to angiogenesis-related diseases, as well as exclusive expression in pathological angiogenesis to reduce adverse side effects. Furthermore, the antibody that is developed should be based on the IgG format to increase its half-life in vivo, minimizing the need for frequent injections. Thus, a deeper understanding of basic research and an increase in the speed of development is needed to overcome the problems of existing anti-angiogenic antibody drugs, which will require in-depth cooperation between translational researchers and pharmaceutical companies.

Acknowledgement

The author wishes to acknowledge support from the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIP) (2014M3A9 D9032525).

Biography

SUKMOK LEE is a Principal Investigator of the Laboratory of Molecular Cancer Therapeutics at the Scripps Korea Antibody Institute (SKAI). He obtained a PhD in Biochemistry and Cellular Signalling from Pohang University of Science and Technology (POSTECH), Korea. Prior to joining SKAI in 2010, he joined the National Institute of Health as a postdoc and Seoul National University as Research Associate Professor for participating in more than six years research experience in the field of antibody engineering. Currently, Sukmook and his team have been focused on developing therapeutic antibodies against novel cancer targets, particularly related to tumour angiogenesis and metastasis in collaboration with a wide range of academic and industrial partners.

References

1. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011 Sep 16;146(6):873-87
2. Tortora G, Melisi D, Ciardiello F. Angiogenesis: a target for cancer therapy. Curr Pharm Des. 2004;10(1):11-26
3. Rasmussen A, Sander B. Long-term longitudinal study of patients treated with ranibizumab for neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2014 May;25(3):158-63
4. Sene A, Chin-Yee D, Apte RS. Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye. Trends Mol Med. 2015 Jan;21(1):43-51.
5. Meadows KL, Hurwitz HI. Anti-VEGF therapies in the clinic. Cold Spring Harb Perspect Med. 2012 Oct;2(10)
6. Oklu R, Walker TG, Wicky S, Hesketh R. Angiogenesis and current antiangiogenic strategies for the treatment of cancer. J Vasc Interv Radiol. 2010 Dec;21(12):1791-805; quiz 806
7. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004 Dec;56(4):549-80
8. Hadj Tahar A. Bevacizumab for advanced colorectal cancer. Issues Emerg Health Technol. 2004 Dec(63):1-4
9. Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer – recent advances and future perspectives. Int J Cancer. 2015 Nov 4
10. Summers J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma. Oncologist. 2010;15(1):104-11
11. Schmidt C. Ovarian cancer treatments on the horizon. J Natl Cancer Inst. 2011 Sep 7;103(17):1284-5
12. Omar AI. Tumor treating field therapy in combination with bevacizumab for the treatment of recurrent glioblastoma. J Vis Exp. 2014(92):e51638
13. The cancer market outlook to 2016. Business Insight. 2011. 1-167
14. McCormack PL, Keam SJ. Bevacizumab: a review of its use in metastatic colorectal cancer. Drugs. 2008;68(4):487-506
15. Keating GM. Bevacizumab: a review of its use in advanced cancer. Drugs. 2014 Oct;74(16):1891-925
16. Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010 Jan 20;28(3):453-9
17. Giuliano S, Pages G. Mechanisms of resistance to anti-angiogenesis therapies. Biochimie. 2013 Jun;95(6):1110-9
18. Fan F, Samuel S, Gaur P, Lu J, Dallas NA, Xia L, et al. Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration. Br J Cancer. 2011 Apr 12;104(8):1270-7
19. Lucio-Eterovic AK, Piao Y, de Groot JF. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin Cancer Res. 2009 Jul 15;15(14):4589-99
20. Zhang M, Gulotta B, Thomas A, Kaley T, Karimi S, Gavrilovic I, et al. Large-volume low apparent diffusion coefficient lesions predict poor survival in bevacizumab-treated glioblastoma patients. Neuro Oncol. 2015 Nov 3
21. de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji Y, et al. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol. 2010 Mar;12(3):233-42
22. Yonekawa Y, Miller JW, Kim IK. Age-Related Macular Degeneration: Advances in Management and Diagnosis. J Clin Med. 2015;4(2):343-59
23. Dhoot DS, Kaiser PK. Ranibizumab for age-related macular degeneration. Expert Opin Biol Ther. 2012 Mar;12(3):371-81
24. Syed BA, Evans JB, Bielory L. Wet AMD market. Nat Rev Drug Discov. 2012 Nov;11(11):827
25. Klettner A. [Age-related macular degeneration – biology and treatment]. Med Monatsschr Pharm. 2015 Jul;38(7):258-64; quiz 65-6
26. Steinbrook R. The price of sight–ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1409-12
27. Shin JY, Woo SJ, Ahn J, Park KH. Anti-VEGF-refractory exudative age-related macular degeneration: differential response according to features on optical coherence tomography. Korean J Ophthalmol. 2013 Dec;27(6):425-32
28. Cho M, Barbazetto IA, Freund KB. Refractory neovascular age-related macular degeneration secondary to polypoidal choroidal vasculopathy. Am J Ophthalmol. 2009 Jul;148(1):70-8 e1