Technology Networks
`WhatIs Angiogenesis?
`
`Article Published: July 6, 2022 | Sarah Whelan
`
`iy
`
`2.
`
`2.
`
`Induction of VEGF signaling
`
`Formation oftip cells
`
`Stalk cell development
`
`4.
`
`Vessel outgrowth Vascular endothelial cf
`
`growth factor
`
`Endothelial cell
`
`RS
`C~ Pericyte
`
`°e
`ree Blood cells
`
`Angiogenesis is the formation of new bloodvessels, an essential process that
`
`facilitates tissue growth and woundhealing in living things. However, diseaseslike
`
`cancer can take advantage of angiogenesis and useit to grow andspread.In this
`
`article, we will describe the different types of angiogenesis, how it goes out of
`
`control in cancer and how wecan usedrugsto inhibit angiogenesis and reduce
`
`tumor growth.
`
`Angiogenesis definition
`
`Angiogenesis is defined as the process by which new blood vessels are formed
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2135
`Page 1
`
`
`WhatIs Angiogenesis?
`
`Article Published: July 6, 2022 | Sarah Whelan
`
`iy
`
`2.
`
`2.
`
`Induction of VEGF signaling
`
`Formation oftip cells
`
`Stalk cell development
`
`4.
`
`Vessel outgrowth Vascular endothelial cf
`
`growth factor
`
`Endothelial cell
`
`RS
`C~ Pericyte
`
`°e
`ree Blood cells
`
`Angiogenesis is the formation of new bloodvessels, an essential process that
`
`facilitates tissue growth and woundhealing in living things. However, diseaseslike
`
`cancer can take advantage of angiogenesis and useit to grow andspread.In this
`
`article, we will describe the different types of angiogenesis, how it goes out of
`
`control in cancer and how wecan usedrugsto inhibit angiogenesis and reduce
`
`tumor growth.
`
`Angiogenesis definition
`
`Angiogenesis is defined as the process by which new blood vessels are formed
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2135
`Page 1
`
`
`
`from existing ones. The term angiogenesis comes from the words “angio” meaning
`blood vessels and “genesis” meaning creation.
`
`
`
`Angiogenesis begins during embryo development, when the growth of new blood
`vessels is essential for the development of new cells and tissues. The new veins,
`arteries and capillaries are needed to supply cells with oxygenated blood and
`nutrients and take away deoxygenated blood and waste products. In adult
`organisms, the endothelial cells that line the inside of blood vessels (the lumen) are
`largely dormant. However, specific signals can reactivate these cells and induce
`angiogenesis when their environment is low in oxygen (hypoxic), after injury or in
`placenta formation during pregnancy.
`
`
`
`Angiogenesis was first described in 1794, with the observation that pronounced
`metabolic activity is dependent on the extent of the vascular system.1 More recent
`research investigating how angiogenesis works in cancer began in 1971 with the
`hypothesis that the growth of cancerous tumors is dependent on angiogenesis.2
`
`Regulation of angiogenesis
`
`Angiogenesis is a tightly regulated process. Strict control is necessary to make sure
`that new vasculature is only formed when and where it is needed, and organisms
`have several “off” and “on” switches to facilitate this.
`
`
`
`If these signals controlling angiogenesis are unbalanced, this can result in the
`abnormal formation of blood vessels, which can play a role in the pathogenesis of
`many diseases. Increased angiogenesis can lead to diseases such as cancer,
`arthritis, retinopathy and atherosclerosis.3 On the other hand, impaired
`angiogenesis can lead to heart and limb ischemia and delayed wound healing.4
`
`
`
`Therefore, it is important to maintain this balance between pro-angiogenic and
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2135 Page 2
`
`
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`anti-angiogenic signals, which is known as the “angiogenic switch”. This steady
`equilibrium is maintained through the activity of cellular signaling pathways,
`particularly through the activation of growth factor receptors.
`
`
`
`Pro-angiogenic factors include5:
`
`•
`•
`•
`•
`
`VEGFR – vascular endothelial growth factor receptor
`EGFR – endothelial growth factor receptor
`PDGFR – platelet-derived growth factor receptor
`TIE2 – angiopoietin-1 receptor
`
`
`
`Anti-angiogenic factors and endogenous angiogenesis inhibitors include6:
`
`•
`•
`•
`
`Angiostatin
`Endostatin
`Thrombospondin
`
`Types of angiogenesis
`
`Angiogenesis is split into two main types: sprouting angiogenesis and
`intussusceptive angiogenesis. These occur both in adult organisms and in utero,
`taking place in nearly all organs and tissues.
`
`
`
`Sprouting angiogenesis
`
`First discovered almost 200 years ago, sprouting angiogenesis is the more well
`understood of the two types. During sprouting angiogenesis, new blood vessels
`sprout from pre-existing ones following a gradient of growth factor signals
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2135 Page 3
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`produced by endothelial cells.1,7 It is initiated and driven by the secretion of pro-
`angiogenic growth factors such as VEGF.
`
`Figure 1: The stages of sprouting angiogenesis.
`
`
`
`The main stages of sprouting angiogenesis are:
`
`
`Induction of VEGF signaling – Cells near blood vessels produce VEGF, which 1.
`forms a gradient of high to low intensity.
`
`Formation of tip cells – The endothelial cell exposed to the strongest VEGF 2.
`signals becomes a “tip” cell. Tip cells have thin cellular processes called
`filopodia, which secrete enzymes designed to degrade the extracellular
`matrix and guide the extension of the developing vessel across the VEGF
`signal gradient.
`
`Stalk cell development – The tip cell stimulates NOTCH signaling in adjacent 3.
`cells, transforming them into “stalk” cells as the tip cell follows the VEGF
`gradient.
`
`Vessel outgrowth – Stalk cells proliferate and drive the outgrowth of the new 4.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2135 Page 4
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`vessel.
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`Anastomosis and perfusion – As stalk cells proliferate, opposing tip cells are 5.
`guided together, fusing the new vessels in a process called anastomosis. A
`continuous lumen is created that allows blood to flow between the pre-
`existing vessels.
`
`Maturation and stabilization – Finally, recruitment of pericytes and 6.
`deposition of extracellular matrix along the walls of the vessel result in
`maturation and stabilization.
`
`
`
`Intussusceptive angiogenesis
`
`Figure 2: The stages of intussusceptive (splitting) angiogenesis.
`
`
`Intussusceptive angiogenesis was first discovered in 1986 and is less well
`understood than sprouting angiogenesis.7 Also known as “splitting” angiogenesis,
`pre-existing vessels are effectively split in two. Small hollow pillars form within the
`pre-existing vessel, eventually expanding to create two parallel capillaries. This is
`thought to be quicker and more efficient than sprouting angiogenesis, initially only
`requiring the reorganization of existing endothelial cells and not the growth or
`proliferation of new cells.1
`
`
`
`Intussusceptive angiogenesis occurs throughout life, taking place in the eye,
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2135 Page 5
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`intestine, kidney, ovary and uterus. It is also particularly important in embryo
`development; a situation where fast growth is needed without being too
`energetically demanding.
`
`Angiogenesis in cancer
`
`Cancer and angiogenesis were first linked in 1971 with the observation that
`malignant tumors have extensive vascular networks while benign tumors do not.2
`
`
`
`Sustained angiogenesis is one of the fundamental hallmarks of cancer.8 Tumor
`cells gain the ability to flip the “angiogenic switch”, resulting in an overabundance
`of pro-angiogenic signals and a lack of endogenous anti-angiogenic signals. This
`promotes their growth and spread to other parts of the body in a process known
`as metastasis. During metastasis, blood vessels carry tumor cells to establish
`themselves in distant sites, typically in the liver, lungs and skeletal system.9
`
`
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`In this way, angiogenesis and cancer go hand-in-hand, as tumors cannot grow
`more than 2–3 mm3 in diameter without support from the growth of additional
`blood vessels. To do this, tumors use both sprouting and intussusceptive
`angiogenesis to secure extra blood supply and provide themselves with oxygen
`and nutrients.7
`
`
`
`Without an adequate blood supply, rapidly growing tumor cells suffer from a lack
`of oxygen and become hypoxic. Hypoxia is a key part of angiogenesis in tumors as
`it upregulates many pro-angiogenic signals, often through hypoxia-inducible
`factors (HIFs). HIFs are transcription factors that activate and upregulate the
`transcription of various genes in response to low oxygen availability. HIFs bind to
`areas of DNA within target genes known as hypoxia response elements (HREs).
`Once bound, HIFs activate the transcription of genes such as VEGF, thereby
`increasing angiogenesis.10
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2135 Page 6
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`Angiogenesis inhibitors
`
`Several angiogenesis inhibitors, also known as anti-angiogenics, have been
`developed and approved by regulatory authorities such as the U.S. Food and Drug
`Administration (FDA) to treat cancer. These prevent tumors from growing new
`blood vessels, cutting off the incredibly resource-hungry cancer cells from much-
`needed nutrients and oxygen. In this way, angiogenesis inhibitors “starve” tumors
`with the goal of preventing them from growing and metastasizing, or even helping
`to shrink them.
`
`
`
`Anti-angiogenic drugs have been approved for several cancers such as kidney,
`colorectal and lung cancer. However, the success of angiogenesis inhibitors has
`been limited as they are often effective only for short periods before the cancer
`cells become resistant. Resistance is common and is often acquired through tumor
`cells activating alternative cellular pathways that induce blood vessel growth.11
`
`
`
`Anti-angiogenic therapy is given either as a pill or through a vein (intravenously).
`These inhibitors can be used on their own (i.e., as monotherapy) or in combination
`with other treatments such as chemotherapy or radiotherapy. Using angiogenesis
`inhibitors as a combination therapy can help increase the efficacy of the drug(s)
`they are paired with and reduce the likelihood of developing drug resistance.9
`
`
`
`Examples of angiogenesis inhibitors and their targets are summarized in the table
`below, along with examples of some of the cancer types they are approved to treat
`(this is not an exhaustive list).11,12
`
`
`
`However, there are many possible side effects of anti-angiogenics.12 This is
`because angiogenesis is still needed to create new blood vessels in non-cancerous,
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2135 Page 7
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`Drug name
`
`Axitinib (Inlyta)
`
`Target(s)
`
`Approved cancer type(s)
`
`VEGFR, PDGFR
`
`Kidney
`
`Bevacizumab (Avastin)
`
`VEGF-A
`
`Cervical, colorectal,
`glioblastoma, kidney,
`liver, non-squamous
`small-cell lung cancer
`(NSCLC)
`
`Cabozantinib (Cometriq, Cabometyx) VEGFR
`
`Kidney, liver, thyroid
`
`Lenvatinib (Lenvima)
`
`VEGFR1–3, PDGFR Endometrial, kidney, liver,
`thyroid
`
`Ramucirumab (Cyramza)
`
`VEGFR2
`
`Regorafenib (Stivarga)
`
`VEGFR1–3, TIE2
`
`Colorectal, liver, NSCLC,
`stomach
`
`Colorectal,
`gastrointestinal, liver
`
`Sorafenib (Nexavar)
`
`VEGFR, PDGFR
`
`Kidney, liver, thyroid
`
`Sunitinib (Sutent)
`
`VEGFR, PDGFR
`
`GI, kidney, pancreatic
`neuroendocrine
`
`healthy tissue.
`
`
`
`Relatively common side effects include:
`
`•
`•
`
`High blood pressure (hypertension)
`Dry, itchy, rash-prone skin
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2135 Page 8
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`
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`•
`•
`•
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`Diarrhea
`Fatigue
`Impaired wound healing
`
`
`
`More serious side effects can also occur with anti-angiogenesis inhibitors, such as
`bleeding, blood clots and holes in the intestine (bowel perforations) – although
`these are very rare.
`
`
`
`References:
`
`1.
`Adair TH, Montani JP. Overview of Angiogenesis. Morgan & Claypool Life
`Sciences; 2010. Accessed June 17, 2022.
`https://www.ncbi.nlm.nih.gov/books/NBK53238/?utm source=363436&utm
`medium=pdf&utm campaign=pdf lead conversion?utm source=363436&ut
`m medium=pdf&utm campaign=pdf lead conversion?utm source=363436&
`utm medium=pdf&utm campaign=pdf lead conversion?utm source=363436
`&utm medium=pdf&utm campaign=pdf lead conversion
`
`Folkman J. Tumor Angiogenesis: Therapeutic Implications. N. Engl. J. Med. 2.
`1971;285(21):1182-1186. doi: 10.1056/NEJM197111182852108
`
`Fallah A, Sadeghinia A, Kahroba H, et al. Therapeutic targeting of angiogenesis 3.
`molecular pathways in angiogenesis-dependent diseases. Biomed.
`Pharmacother. 2019;110:775-785. doi: 10.1016/j.biopha.2018.12.022
`Moriya J, Minamino T. Angiogenesis, cancer, and vascular aging. Front.
`4.
`Cardiovasc. Med. 2017;4. doi: 10.3389/fcvm.2017.00065
`
`Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, 5.
`consequences, challenges and opportunities. Cell Mol. Life Sci.
`2020;77(9):1745-1770. doi: 10.1007/s00018-019-03351-7
`
`Folkman J. Endogenous angiogenesis inhibitors. APMIS. 2004;112(7-8):496-6.
`507. doi: 10.1111/j.1600-0463.2004.apm11207-0809.x
`
`Udan RS, Culver JC, Dickinson ME. Understanding vascular development. 7.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2135 Page 9
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`
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`Wiley Interdiscip. Rev. Dev. Biol. 2013;2(3):327-346. doi: 10.1002/wdev.91
`
`8. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell.
`
`2011;144(5):646-674. doi: 10.1016/j.cell.2011.02.013
`
`9. Riihimaki M, Thomsen H, Sundquist K, Sundquist J, HemminkiK. Clinical
`
`landscape of cancer metastases. Cancer Med. 2018;7(11):5534-5542. doi:
`
`10.1002/cam4.1697
`
`10. Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and
`
`clinical translation. /. Clin. Invest. 2022;132(11). doi: 10.1172//Cl159839
`
`11. Haibe Y, Kreidieh M, El Hajj H, et a/. Resistance mechanismsto anti-angiogenic
`
`therapies in cancer. Front. Oncol. 2020;10. doi: 10.3389/fonc.2020.00221
`
`12. Angiogenesis and Angiogenesis Inhibitors to Treat Cancer. Cancer.Net.
`
`Published November 1, 2018. Accessed June 23, 2022.
`
`https://www.cancer.net/navigating-cancer-care/how-cancer-
`
`treated/personalized-and-targeted-therapies/angiogenesis-and-angiogenesis-
`
`inhibitors-treat-
`
`cancer?utm source=363436&utm medium=pdf&utm campaign=pdf lead co
`
`nversion?utm source=363436&utm medium=pdf&utm campaign=pdf lead c
`
`onversion?utm source=363436&utm medium=pdf&utm campaign=pdf lead
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`_conversion
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`
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`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2135
`Page 10
`
`
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