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MoA of Avastin

Angiogenesis(The growth of new blood vessels from pre-existing vessels) is the process of new blood vessel formation. It is an important process in the growth of malignant tumours as tumours need to establish their own blood supply to grow beyond 1–2mm in diameter. The predominant regulator of tumour(An abnormal growth of cells, forming a mass of tissue) angiogenesis is VEGF(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour),1,2 which is the only angiogenic factor known to be present throughout the entire tumour life cycle.3,4 This continuous expression, along with the proposed genetic stability of VEGF and endothelial cells (based on preclinical observations),2,5 make direct and continuous targeting of VEGF an important antitumour strategy.3

Avastin is a humanised(The process of making a monoclonal antibody from an animal more similar to a human antibody to reduce the likelihood of toxic effects) MAb with a long half life that specifically inhibits VEGF, thus blocking the angiogenic cascade. Avastin was developed from the murine anti-VEGF MAb A4.6.16 and recognises all major isoforms(Any of two or more functionally similar proteins that have a similar but not an identical amino acid sequence) of human VEGF.

Avastin exerts its anti-angiogenic effects through three key mechanisms.

  • Regression(A characteristic of diseases to show lighter symptoms without completely disappearing. At a later point, symptoms may return ) of tumour vasculature.7,8
  • An anti-permeability(Anti-permeability is the decrease in vessel permeability that results from the blockade of VEGF by anti-VEGF agents) effect in surviving vasculature.9,10
  • Inhibition of new and recurrent vessel growth.11-13

Given the central role of angiogenesis in tumour development, anti-angiogenic agents may be considered a pillar of anticancer therapy, alongside surgery, radiotherapy and chemotherapy (and hormonal therapy).

Precise VEGF inhibition with Avastin: understanding the Avastin MoA

Avastin is a humanised MAb that binds specifically to VEGF, preventing activation of the VEGFR(Characterises the capacity of a blood vessel wall to allow for the flow of small molecules (ions, water, nutrients) or even whole cells (lymphocytes on their way to the site of inflammation) in and out of the vessel).

Avastin inhibits VEGF extracellularly and may, therefore, inhibit angiogenesis without disrupting targets outside the VEGF pathway.1,2

Based on preclinical models and clinical observations, it has been proposed that Avastin exerts continuous antivascular effects throughout tumour development

  • Rapid regression of existing tumour vessels, as shown by significant reductions in microvascular density(A widely applied morphologic measure of vascularisation).5–7
  • An anti-permeability effect in surviving mature vasculature.9,10
  • Ongoing inhibition of both new and recurrent tumour vessel growth.11

Effects of anti-VEGF agents occur rapidly – sometimes after a single infusion – while the long half-life of the monoclonal antibody(An antibody produced by a single clone of cells (specifically, a single clone of hybridoma cells). They are being tested as a possible form of cancer treatment) allows for a sustained anti-VEGF effect.5

Summary

Angiogenesis is a hallmark of cancer throughout the life cycle of the tumour. The predominant pro-angiogenic factor(A substance that causes the growth of new blood vessels) at the centre of the angiogenic pathway is VEGF. The continuous expression of VEGF by the tumour makes it a rational target for cancer therapy. Direct inhibition of VEGF by Avastin allows for greater precision than other means of targeting the VEGF pathway, thereby avoiding unwanted inhibitory effects on non-VEGF-mediated functions. Avastin has three suggested effects on the angiogenic process.

  • Regression of tumour vasculature.
  • An anti-permeability effect in surviving tumour vasculature.
  • Inhibition of new and recurrent vessel growth.

References

  1. Hicklin DJ, Ellis LM. J Clin Oncol 2005;23:1011–27.
  2. Presta LG, Chen H, O'Connor SJ, et al. Cancer Res 1997;57:4593–9.
  3. Jain RK, Duda DG, Clark JW, Loeffler JS. Nat Clin Pract Oncol 2006;3:24–40.
  4. Baka S, Clamp AR, Jayson GC. Expert Opin Ther Targets 2006;10:867–76.
  5. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Proc Natl Acad Sci USA 1996;93:14765–70.
  6. Willett CG, Boucher Y, di Tomaso TE, et al. Nat Med 2004;10:145–7.
  7. Lee CG, Heijn M, di Tomaso TE et al. Cancer Res 2000;60:5565–70.
  8. Gerber HP, Ferrara N. Cancer Res 2005;65:671–80.
  9. Prager GW, Lackner EM, Krauth MT, et al. Mol Oncol. 2010;4(2):150-60.
  10. Ribeiro SC, Vargas FS, Antonangelo L, et al. Respirology. 2009;14(8):1188-93.
  11. Borgström P, Hillan KJ, Sriramarao P, Ferrara N. Cancer Res 1996;56:4032–9.
  12. Borgström P, Bourdon MA, Hillan KJ, Sriramarao P, Ferrara N. Prostate 1998;35:1–10.
  13. Jain RK. Nat Med 2001;7: 987–9.

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