IP Library › Granted Patent US 12,365,739
Granted Patent B2
US 12,365,739 · App. 17/702,890 · Granted Jul 22, 2025

Monoclonal antibodies to angiotensin-(1-12), compositions including the same, and methods of use thereof

Inventors: Carlos M. Ferrario (Wilmington, NC); Sarfaraz Ahmad (Winston-Salem, NC); Jasmina Varagic (Winston-Salem, NC)
Assignee: Wake Forest University Health Sciences
C07K16/2869A61K2039/505C07K2317/565C07K2317/76
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Quick Facts
Patent No.
US 12,365,739
App. No.
17/702,890
Granted
Jul 22, 2025
Kind
B2
Abstract

The present invention relates to monoclonal antibodies to angiotensin-(1-12) as well as compositions comprising the same and methods of using the same.

Claims (12)

1. A monoclonal antibody or a fragment thereof, wherein the monoclonal antibody or the fragment thereof binds to human angiotensin-(1-12) and comprises a light chain variable region having SEQ ID NO:3 (LC CDR1), SEQ ID NO:4 (LC CDR2) and SEQ ID NO:5 (LC CDR3) and comprises a heavy chain variable region having SEQ ID NO:6 (HC CDR1), SEQ ID NO:7 (HC CDR2), and SEQ ID NO:8 (HC CDR3).

2. The monoclonal antibody or the fragment thereof of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence having at least about 70% sequence identity to SEQ ID NO:10.

3. The monoclonal antibody or the fragment thereof of claim 1 , wherein the light chain variable region comprises an amino acid sequence having at least about 70% sequence identity to SEQ ID NO:11.

4. The monoclonal antibody or the fragment thereof of claim 1 , wherein the monoclonal antibody or the fragment thereof is configured for intracellular delivery.

5. The monoclonal antibody or the fragment thereof of claim 4 , wherein the monoclonal antibody or the fragment thereof is configured for intracellular delivery as a liposomal formulation.

6. The monoclonal antibody or the fragment thereof of claim 1 , wherein the monoclonal antibody or the fragment thereof reduces, inhibits, or blocks one or more angiotensin II pathological mechanisms and/or actions.

7. A pharmaceutical composition comprising the monoclonal antibody or the fragment thereof of claim 1 and a pharmaceutically acceptable carrier.

8. A method of reducing or inhibiting pressor activity of angiotensin-(1-12) in a subject, the method comprising administering a therapeutically effective amount of the monoclonal antibody or the fragment thereof of claim 1 to a subject,

thereby reducing or inhibiting pressor activity of angiotensin-(1-12) in the subject.

9. A method of treating hypertension in a subject, the method comprising administering to the subject a therapeutically effective amount of the monoclonal antibody or the fragment thereof of claim 1 , thereby treating the hypertension in the subject.

10. The monoclonal antibody or the fragment thereof of claim 1 , wherein the light chain variable region comprises SEQ ID NO:2.

11. The monoclonal antibody or the fragment thereof of claim 1 , wherein the heavy chain variable region comprises SEQ ID NO:1.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2022
From: FERRARIO, CARLOS M.; AHMAD, SARFARAZ; VARAGIC, JASMINA
To: WAKE FOREST UNIVERSITY HEALTH SCIENCES
Reel/Frame 059603/0418 →
Continuity (2)
Provisional Application 63165381 · Mar 24, 2021
Related Publication 20220306756A1 · Sep 29, 2022
References Cited (80)
US 4474893A · Reading · 1984 [cited by applicant]
US 4676980A · Segal et al. · 1987 [cited by applicant]
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 7186809B2 · Pluenneke · 2007 [cited by examiner]
US 10035853B2 · Arathoon · 2018 [cited by examiner]
Ahmad et al. “Angiotensin-(1-12): A Chymase-Mediated Cellular Angiotensin II Substrate” Current Hypertension Reports, 16(5):429 (2014). [cited by applicant]
Ahmad et al. “Chymase Mediates Angiotensin-(1-12) Metabolism in Normal Human Hearts” Journal of the American Society of Hypertension, 7(2):128-136 (2013). [cited by applicant]
Ahmad et al. “Chymase-Dependent Generation of Angiotensin II from Angiotensin-(1-12) in Human Atrial Tissue” PLoS One, 6(12):e28501 (2011). [cited by applicant]
Ahmad et al. “Mast cell peptidases (carboxypeptidase a and chymase)-mediated hydrolysis of human angiotensin-(1-12) substrate” Biochemical and Biophysical Research Communications, 518(4):651-656 (2019). [cited by applicant]
Ahmad et al. “Primacy of cardiac chymase over angiotensin converting enzyme as an angiotensin-(1-12) metabolizing enzyme” Biochemical and Biophysical Research Communications, 478(2):559-564 (2016). [cited by applicant]
Ali et al. “The Management of Hypertension in 2018: What Should the Targets Be?” Current Hypertension Reports, 21(41):1-4 (2019). [cited by applicant]
Arnold et al. “Angiotensin-(1-12) requires angiotensin converting enzyme and AT1 receptors for cardiovascular actions within the solitary tract nucleus” American Journal of Physiology—Heart and Circulatory Physiology, 2… [cited by applicant]
Balyasnikova et al. “Monoclonal Antibodies 1G12 and 6A12 to the N-Domain of Human Angiotensin-Converting Enzyme: Fine Epitope Mapping and Antibody-Based Detection of ACE Inhibitors in Human Blood” Journal of Proteome Re… [cited by applicant]
Carey et al. “Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association” Hypertension, 72:e53-e90 (2018). [cited by applicant]
Celerier et al. “Angiotensinogen and Its Cleaved Derivatives Inhibit Angiogenesis” Hypertension, 39(2):224-228 (2002). [cited by applicant]
Chen et al. “Effectiveness and Safety of a Therapeutic Vaccine Against Angiotensin II Receptor Type 1 in Hypertensive Animals” Hypertension, 61(2):408-416 (2013). [cited by applicant]
Cole et al. “Human monoclonal antibodies” Molecular and Cellular Biology, 62:109-120 (1984). [cited by applicant]
Corvol et al. “Inhibition of angiogenesis: A new function for angiotensinogen and des(angiotensin i)angiotensinogen” Current Hypertension Reports, 5:149-154 (2003). [cited by applicant]
Cote et al. “Generation of human monoclonal antibodies reactive with cellular antigens” Proceedings of the National Academy of Sciences USA, 80(7):2026-2030 (1983). [cited by applicant]
De Mello et al. “Intracellular angiotensin-(1-12) changes the electrical properties of intact cardiac muscle” Molecular and Cellular Biochemistry, 422:31-40 (2016). [cited by applicant]
Ding et al. “Vaccination against type 1 angiotensin receptor prevents streptozotocin-induced diabetic nephropathy” Journal of Molecular Medicine (Berlin, Germany), 94(2):207-218 (2016). [cited by applicant]
Dusing, Rainer “Mega clinical trials which have shaped the RAS intervention clinical practice” Therapeutic Advances in Cardiovascular Disease, 10:133-150 (2016). [cited by applicant]
Dzau et al. “Antibodies as specific renin inhibitors: Studies with polyclonal and monoclonal antibodies and fab fragments” Clinical and Experimental Hypertension, Part A, 5:1207-1220 (1983). [cited by applicant]
Ferrario et al. “Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts” Frontiers in Cardiovascular Medicine, 6:163 (2019). [cited by applicant]
Ferrario et al. “Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene” American Journal of Physiology—Heart and Circulatory Physiology, 310:H995-H1002 (2016). [cited by applicant]
Ferrario et al. “Differential regulation of angiotensin-(1-12) in plasma and cardiac tissue in response to bilateral nephrectomy” American Journal of Physiology—Heart and Circulatory Physiology, 296:H1184-H1192 (2009). [cited by applicant]
Ferrario et al. “Intracrine angiotensin II functions originate from noncanonical pathways in the human heart” American Journal of Physiology—Heart and Circulatory Physiology, 311:H404-H414 (2016). [cited by applicant]
Ferrario, Carlos M. “New Physiological Concepts of the Renin-Angiotensin System From the Investigation of Precursors and Products of Angiotensin I Metabolism” Hypertension, 55(2):445-452 (2010). [cited by applicant]
Ganten et al. “Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes” Proceedings of the National Academy of Sciences USA, 89:7806-7810 (1992). [cited by applicant]
Garay-Gutierrez et al. “Vaccines against components of the renin-angiotensin system” Heart Failure Reviews, pp. 1-16 (2020). [cited by applicant]
Huang et al. “Dose-related reductions in blood pressure with a rna interference (rnai) therapeutic targeting angiotensinogen in hypertensive patients” Circulation, vol. 142, Abstract 14387 (2020). [cited by applicant]
Huse et al. “Generation of a Large Combinatorial Library of the Immunoglobulin Repertoire in Phage Lambda” Science, 254(4935):1275-1281 (1989). [cited by applicant]
Isa et al. “Angiotensin-(1-12) contributes to renin-independent angiotensin II activity in brain” Conference Abstracts—62nd High Blood Pressure Research Conference, Abstract p. 126 (2018). [cited by applicant]
Isa et al. “Chronic immunoneutralization of brain angiotensin-(1-12) lowers blood pressure in transgenic (mren2)27 hypertensive rats” American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 29… [cited by applicant]
Iyer et al. “Contribution of angiotensin-(1-7) to blood pressure regulation in salt-depleted hypertensive rats” Hypertension, 36(3)::417-422 (2000). [cited by applicant]
Iyer et al. “Vasodepressor actions of angiotensin-(1-7) unmasked during combined treatment with lisinopril and losartan” Hypertension, 31:699-705 (1998). [cited by applicant]
Kang et al. “Antibody redesign by chain shuffling from random combinatorial immunoglobulin libraries” Proceedings of the National Academy of Sciences USA, 88:11120-11123 (1991). [cited by applicant]
Kennedy et al. “Anti-Idiotypic Antibody Vaccine for Type B Viral Hepatitis in Chimpanzees” Science, 232(4747):220-223 (1986). [cited by applicant]
Kohler et al. “Continuous cultures of fused cells secreting antibody of predefined specificity” Nature, 265:495-497 (1975). [cited by applicant]
Kozbor et al. “Specific immunoglobulin production and enhanced tumorigenicity following ascites growth of human hybridomas” Journal of Immunological Methods, 81:31-42 (1985). [cited by applicant]
Kurashiki et al. “Prevention of progression of aortic aneurysm by peptide vaccine against ang ii (angiotensin ii) in a rat model” Hypertension, 76:1879-1888 (2020). [cited by applicant]
Lee et al. “Antenatal betamethasone increases vascular reactivity to endothelin-1 by upregulation of cd38/cadpr signaling” Journal of Developmental Origins of Health and Disease, 5:56-62 (2014). [cited by applicant]
Li et al. “Critical role of the chymase/angiotensin-(1-12) axis in modulating cardiomyocyte contractility” International Journal of Cardiology, 264:137-144 (2018). [cited by applicant]
Li et al. “Reversal of angiotensin-(1-12)-caused positive modulation on left ventricular contractile performance in heart failure: Assessment by pressure-vol. analysis” International Journal of Cardiology, 301:135-141 (… [cited by applicant]
Lin et al. “Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor” Journal of Pharmacology and Experimental Therapeutic… [cited by applicant]
Lobo et al. “Antibody Pharmacokinetics and Pharmacodynamics” Journal of Pharmaceutical Science, 93(11):2645-2668 (2004). [cited by applicant]
Lu et al. “Angiotensinogen Exerts Effects Independent of Angiotensin II” Arteriosclerosis, Thrombosis, and Vascular Biology, 36:256-265 (2016). [cited by applicant]
Lu et al. “Development of therapeutic antibodies for the treatment of diseases” Journal of Biomedical Science, 27:1 (2020). [cited by applicant]
Lu et al. “Structure and functions of angiotensinogen” Hypertension Research, 39:492-500 (2016). [cited by applicant]
Mak TW, Saunders ME. 7—exploiting antigen-antibody interaction. In: Mak TW, Saunders ME, eds. The immune response. Burlington: Academic Press; 2006:147-177. [cited by applicant]
McNamara et al. “Monoclonal Idiotope Vaccine Against [cited by applicant]
Moniwa et al. “Primacy of angiotensin converting enzyme in angiotensin-(1-12) metabolism” American Journal of Physiology—Heart and Circulatory Physiology, 305:H644-H650 (2013). [cited by applicant]
Morimoto et al. “Elevated Blood Pressure in Transgenic Mice With Brain-Specific Expression of Human Angiotensinogen Driven by the Glial Fibrillary Acidic Protein Promoter” Circulation Research, 89(4):365-372 (2001). [cited by applicant]
Morrison et al. “Chimeric human antibody molecules: Mouse antigen-binding domains with human constant region domains” Proceedings of the National Academy of Sciences USA, 81:6851-6855 (1984). [cited by applicant]
Mullick et al. “Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury” Hypertension, 70(3):566-576 (2017). [cited by applicant]
Nagata et al. “Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system” Biochemical and Biophysical Research Communications, 350(4):1026-1031 (2006). [cited by applicant]
Neuberger et al. “Recombinant antibodies possessing novel effector functions” Nature, 312:604-608 (1984). [cited by applicant]
Orlandi et al. “Cloning immunoglobulin variable domains for expression by the polymerase chain reaction” Proceedings of the National Academy of Sciences USA, 86(10):3833-3837 (1989). [cited by applicant]
Ovacik et al. “Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development” Clinical and Translational Science, 11(6):540-552 (2018). [cited by applicant]
Percie Du Sert et al. “The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research” PLoS Biology, 18:e3000410 (2020). [cited by applicant]
Prosser et al. “Cardiac chymase converts rat proAngiotensin-12 (PA12) to angiotensin II: Effects of PA12 upon cardiac haemodynamics” Cardiovascular Research, 82:40-50 (2009). [cited by applicant]
Prosser et al. “Regional vascular response to ProAngiotensin-12 (PA12) through the rat arterial system” Peptides, 31(8):1540-1545 (2010). [cited by applicant]
Ravichandran et al. “Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in pkd2” American Journal of Physiology—Renal Physiology, 308(4):F349-F357 (2015). [cited by applicant]
Reddy et al. “Circulating angiotensin peptides levels in acute respiratory distress syndrome correlate with clinical outcomes: A pilot study” PLoS One, 14(3):e0213096 (2019). [cited by applicant]
Reilly et al. “Characterization of the functional antagonism and antihypertensive activity displayed by a monoclonal antibody to angiotensin II” Journal of Pharmacology and Experimental Therapeutics, 244:160-165 (1988). [cited by applicant]
Reyes et al. “Angiotensin-(1-12)/chymase axis modulates cardiomyocyte I-type calcium currents in rats expressing human angiotensinogen” International Journal of Cardiology, 297:104-110 (2019). [cited by applicant]
Reyes et al. “Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease” Current Hypertension Reports, 19:16 (2017). [cited by applicant]
Sun et al. “Potential Cure for Hypertension? The Effect of Crispr Genome Editing” Circulation, 142, Abstract 15555 (2020). [cited by applicant]
Takeda et al. “Construction of chimaeric processed immunoglobulin genes containing mouse variable and human constant region sequences” Nature, 314:452-454 (1985). [cited by applicant]
Trask et al. “Angiotensin-(1-12) is an alternate substrate for angiotensin peptide production in the heart” American Journal of Physiology—Heart and Circulatory Physiology, 294(5):H2242-H2247 (2008). [cited by applicant]
Uijl et al. “Strong and Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen” Hypertension, 73(6):1249-1257 (2019). [cited by applicant]
Walker et al. “Interaction of human IgG chimeric antibodies with the human FcRI and FcRII receptors: requirements for antibody-mediated host cell-target cell interaction” Molecular Immunology, 26:403-411 (1989). [cited by applicant]
Walker et al. “Pharmacokinetic comparison of a diverse panel of non-targeting human antibodies as matched IgG1 and IgG2 isotypes in rodents and non-human primates” PLoS One, 14:e0217061 (2019). [cited by applicant]
Winter et al. “Man-made antibodies” Nature, 349:293-299 (1991). [cited by applicant]
Wu et al. “Antisense oligonucleotides targeting angiotensinogen: insights from animal studies” Bioscience Reports, 39:1-10 (2019). [cited by applicant]
Wu et al. “Cys18-Cys137 Disulfide Bond in Mouse Angiotensinogen Does Not Affect AngII-Dependent Functions In Vivo” Hypertension, 65(4):800-805 (2015). [cited by applicant]
Wu et al. “Effects of Renin-Angiotensin Inhibition on ACE2 and TMPRSS2 Expression: Insights into COVID-19” bioRxiv, pp. 1-4 (2020). [cited by applicant]
Wu et al. “Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients” Critical Care, 24:290 (2020). [cited by applicant]
Yan et al. “Structural basis for the specificity of renin-mediated angiotensinogen cleavage” Journal of Biological Chemistry, 294(7):2353-2364 (2019). [cited by applicant]
Ye et al. “Angiotensinogen and Megalin Interactions Contribute to Atherosclerosis—Brief Report” Arteriosclerosis, Thrombosis, and Vascular Biology, 39(2):150-155 (2019). [cited by applicant]