# US 11,028,448 B2 · Methods of identifying risk of vascular endothelial growth factor (VEGF) pathway inhibitor-induced hypertension

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- Number: US 11,028,448 B2
- Document ID: US11028448B2
- Status: Granted
- Kind: B2
- Application number: 16/932,002
- Filed: 2020-07-17
- Published: 2021-03-25
- Granted: 2021-06-08
- Earliest claimed: 2019-09-20
- Assignees: The University of North Carolina at Chapel Hill; Duke University
- Applicants: The University of North Carolina at Chapel Hill; Duke University
- Inventors: Federico Innocenti; Julia Quintanilha; Danyu Lin; Kouros Owzar; Jin Wang
- Web page: https://patentgrep.com/patent/US11028448B2

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/112: Disease subtyping, staging or classification
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

The disclosure relates to methods of identifying subjects at risk of developing bevacizumab-induced toxicities such as proteinuria and/or hypertension involving measuring nucleic acid or gene mutations in a sample obtained from the subject.

## Claims

### Claim 1

A method for reducing the risk of vascular endothelial growth factor (VEGF) pathway inhibitor-induced hypertension in a subject in need of treatment with a VEGF pathway inhibitor, the method comprising:
(i) identifying the subject as having a single nucleotide polymorphism (SNP) at rs6770663, wherein the base identified at rs6770663 is a guanine; and
(ii) administering one or more antihypertensive agents to the subject identified as having a guanine at rs6770663.

### Claim 2 (depends on 1)

The method of claim 1, wherein the SNP lowers expression of KCNAB1 relative to wildtype.

### Claim 3 (depends on 1)

The method of claim 1, wherein the anti-hypertensive agent is selected from the group consisting of diuretics, beta blockers, alpha and beta blockers, calcium channel blockers, Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARBs), adrenergic receptor antagonists, vasodilators, renin inhibitors, aldosterone receptor antagonists, alpha-2 adrenergic receptor agonists, central alpha-2 agonists and other centrally acting drugs, and endothelin receptor blockers.

### Claim 4 (depends on 1)

The method of claim 1, wherein the subject was receiving a first antihypertensive agent prior to administration of the VEGF-pathway inhibitor, and wherein administering one or more antihypertensive agents comprises adding a second antihypertensive agent to the subject's treatment regimen, increasing the dose of the first antihypertensive agent, switching the subject to a different antihypertensive agent relative to the first antihypertensive agent, and/or switching the subject to an antihypertensive agent that is in a different class of therapeutic agent relative to the first antihyertensive agent.

### Claim 5 (depends on 1)

The method of claim 1, wherein the subject is administered the antihypertensive agent prior to or concurrently with the VEGF pathway inhibitor.

### Claim 6 (depends on 1)

The method of claim 1, wherein the VEGF-pathway inhibitor is selected from the group consisting of bevacizumab, bevacizumab-awwb, bevacizumab-bvzr, ranibizumab, aflibercept, ziv-aflibercept, lenalidomide, lenvatinib, ramucirumab, cabozantinib, pazopanib, sunitinib malate, regorafenib, axitinib, tipiracil and trifluridine, ponatinib, vandetanib, sorafenib, everolimus, thalidomide, temsirolimus, interferon alfa, interferon alfa-2B, interferon alfa-N3, peginterferon alfa-2B, peginterferon alfa-2A, rhEndostatin, cediranib, semaxanib, pomalidomide, alitretinoin, imiquimod, sinecatechins, vismodegib, sonidegib, pegaptanib sodium, dexamethasone intravitreal implant, fluocinolone acetonide, conbercept, brolucizumab-dbll, selpercatinib, nintedanib, apatinib, and motesanib.