Methods of Treating Disorders Using Anti-Natriuretic Peptide Receptor 1 (NPR1) Antibodies

Abstract

Described herein are methods of using anti-natriuretic peptide receptor 1 (NPR1) antibodies, or antigen-binding fragments thereof, for the treatment or prevention of a disease or disorder in a human, particularly a disorder or disorder associated with natriuretic peptide receptor activity (including, but not limited to, heart failure, e.g., HFrEF, HFmrEF, or HFpEF; or hypertension, e.g., resistant hypertension).

Description

[Technical field]

[0001] Described herein are methods of using anti-NPR1 antibodies or antigen-binding fragments thereof for the treatment of one or more conditions, including cardiovascular diseases such as heart failure (e.g., heart failure with reduced ejection fraction, heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction, heart failure with preserved ejection fraction) and / or hypertension (e.g., arterial hypertension, resistant hypertension). [Background technology]

[0002] The natriuretic peptide (NP) system is an endocrine, autocrine and paracrine system involved in intravascular volume and blood pressure homeostasis. Natriuretic peptide receptor 1 (NPR1; also known as NPRA) is a membrane-bound particulate guanylate cyclase and is the receptor for the natriuretic peptides ANP and BNP. See Kuhn (2003) Circ. Res. p. 700-9; and Boerrigter and Burnett (2004) Expert Opin Investig Drugs p. 643-52. Binding of ANP and BNP to NPR1 stimulates an intracellular cGMP-dependent signaling cascade that mediates the physiological actions of ANP and BNP. ANP and BNP play pivotal roles in the regulation of blood pressure (BP) and intravascular volume. NP acts in the regulation of vascular tone through a direct relaxant effect on vascular smooth muscle cells. Additionally, NPs have been shown to suppress the renin-angiotensin-aldosterone system (RAAS), reduce sympathetic tone, and inhibit the secretion of the vasoconstrictor endothelin-1 (ET-1). See Nishikimi et al. (2006) Cardiovasc. Res. p. 318-28. NPs also regulate intravascular volume through their natriuretic effect in the kidney and mediate direct effects on endothelial permeability in the vasculature. See Curry (2005) J. Clin. Invest. p. 1458-61. Additionally, ANPs have demonstrated direct myocardial antirefractive and antifibrotic properties. Calderone et al(1998)J.Clin.Invest.p.812-8;Patel et al(2005)Am.J.Physiol.Heart Circ.Physiol.p.H777-84;Nishikimi et al.(2006)Cardiovasc.Res.p.318-28;Ichiki et al al. (2014) J. Mol. Cell. Cardiol. p. 199-205; and Theilig and Wu (2015) Am. J. Physiol. Renal Physiol. p. F1047-55.

[0003] Heart failure (HF) is a major public health problem affecting over 20 million patients worldwide (Orso et al., 2014, Expert Opin Pharmacother. 15(13): 1849-1861) and is associated with high morbidity (Ibebuogu et al., 2011, Circulation. Heart failure 4(2): 114-120). Over 6 million patients in the United States alone have heart failure, about half of whom have reduced left ventricular ejection fraction (HFrEF). Recently, sacvatril-valsartan has been shown to provide significant improvement in cardiovascular outcomes with HFrEF and lower than normal ejection fraction (EF). See McMurray et al. (2014) N Engl J Med p. 993-1004 and Solomon et al. (2019) N Engl J Med p. 1609-1620. Treatment with sacbatril-valsartan results in indirect stimulation of NPR1 by increasing circulating levels of ANP and BNP through inhibition of neprilysin, the enzyme responsible for the degradation of NP.

[0004] Specific antibodies against NPR1 are described, for example, in WO 2010 / 065293, WO 2020 / 086406 and WO 2020 / 250159, the contents of each of which are incorporated herein by reference for this purpose. However, there is a need for specific treatments and methods of use to complement or replace existing therapies for disorders or diseases associated with natriuretic peptide receptor 1 (NPR1) activity, such as cardiovascular disease. Such cardiovascular diseases include, but are not limited to, heart failure (e.g., heart failure with reduced ejection fraction, heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction); and / or hypertension (e.g., arterial hypertension, resistant hypertension). Additionally, there is a need for specific treatments and methods of use to complement or replace existing therapies for other disorders or diseases associated with natriuretic peptide receptor 1 (NPR1) activity, including, but not limited to, pre-eclampsia, asthma, glaucoma, cytokine release syndrome and / or renal disorders. Summary of the Invention

[0005] The methods and uses presented herein describe the administration of anti-NPR1 antibodies or antigen-binding fragments thereof that are agonists of NPR1 to supplement or replace existing therapies for disorders or diseases associated with NPR1 activity (e.g., cardiovascular diseases including, but not limited to, heart failure (e.g., heart failure with reduced ejection fraction, heart failure with moderate ejection fraction, or heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction); and / or hypertension (e.g., arterial hypertension or resistant hypertension). The action of the described antibodies or antigen-binding fragments thereof is specific to NPR1, as such antibodies or antigen-binding fragments thereof selectively bind and activate NPR1, but do not bind to NPR3 and / or activate NPR2 in vitro. The described antibodies reproduce the action of ANP (increased plasma cGMP, reduced BP, and increased diuresis) in non-clinical pharmacology studies. The described antibodies can effectively replace ANP in ANP knockout mice, reversing both cardiac hypertrophy and elevated NT-proBNP. The described antibodies also increase plasma cGMP and reduce blood pressure in cynomolgus monkeys. These preclinical data, coupled with human evidence of the potential beneficial effects of ANP and other ANP mimetics on blood pressure and pulmonary wedge pressure, provide a scientific rationale for the use of the methods and antibodies described herein for certain conditions that may be treatable with NPR1 agonists, including, but not limited to, cardiovascular diseases such as heart failure (e.g., heart failure with reduced ejection fraction, heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction); and / or hypertension (e.g., arterial hypertension, resistant hypertension).

[0006] In one aspect, provided herein is a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity in a subject in need thereof, the method comprising administering to the subject about 50 mg to about 700 mg of an anti-NPR1 antibody or antigen-binding fragment thereof.

[0007] In certain embodiments, the disorder or disease associated with natriuretic peptide receptor activity is a cardiovascular disorder.In certain embodiments, the cardiovascular disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, myocardial fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization and myocardial infarction (MI).In some embodiments, the subject has hypertrophic cardiomyopathy, and the hypertrophic cardiomyopathy is ventricular hypertrophy.In certain embodiments, the cardiovascular disorder is heart failure. In some embodiments, the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure. In certain embodiments, the heart failure is heart failure with reduced ejection fraction (HFrEF). In certain embodiments, the heart failure is heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF). In some embodiments, the cardiovascular disorder is hypertension. In certain embodiments, the hypertension is selected from resistant hypertension, hypertensive heart disease, pulmonary hypertension, isolated systolic hypertension, and pulmonary arterial hypertension. In certain embodiments, the hypertension is resistant hypertension.

[0008] In some embodiments, the disorder or disease associated with natriuretic peptide receptor activity is selected from hypertension, pre-eclampsia, asthma, glaucoma, and / or cytokine release syndrome. In certain embodiments, the disorder or disease associated with natriuretic peptide receptor activity is a renal disorder. In certain embodiments, the renal disorder is selected from diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy, and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD).

[0009] In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 ( (HCDR1), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 22 (LCDR3); or (IV) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 19 (LCDR3). In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24; or (b) a heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28 and a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 24; or (b) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 24.In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15 and a light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26; or (b) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30 and a light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain comprising an amino acid sequence of SEQ ID NO: 15 and a light chain comprising an amino acid sequence of SEQ ID NO: 26; or (b) a heavy chain comprising an amino acid sequence of SEQ ID NO: 30 and a light chain comprising an amino acid sequence of SEQ ID NO: 26.

[0010] In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR1), SEQ ID NO:11 (LCDR2) and SEQ ID NO:34 (LCDR3). (CDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:35 (LCDR3); or (IV) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:34 (LCDR3). In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36; or (b) a heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28 and a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 36; or (b) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 36.In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15 and a light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 38; or (b) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30 and a light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 38. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain comprising an amino acid sequence of SEQ ID NO: 15 and a light chain comprising an amino acid sequence of SEQ ID NO: 38; or (b) a heavy chain comprising an amino acid sequence of SEQ ID NO: 30 and a light chain comprising an amino acid sequence of SEQ ID NO: 38.

[0011] In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is therapeutic. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, Fv, and single chain variable fragment (scFv). In some embodiments, about 60 mg, about 120 mg, about 240 mg, about 450 mg, or about 600 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 120 mg or about 240 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 60 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 120 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 240 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 450 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 600 mg of anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In certain embodiments, one or more additional therapeutically active agents are administered to the subject. In certain embodiments, the one or more additional therapeutically active agents are selected from ACE (angiotensin-converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, mineralocorticoid receptor antagonists (MRAs), beta-blockers, diuretics, calcium channel blockers, cardiac glycosides, sodium-glucose cotransporter 2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitors (ARNIs), corticosteroids, leukotriene modifiers, bronchodilators, beta-adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha2-adrenergic receptor agonists, parasympathomimetics, prostaglandin analogs, rho kinase inhibitors, cell therapy, cardiac specific myosin activators, and combinations thereof. In some embodiments, the one or more additional therapeutically active agents are an ACE (angiotensin converting enzyme) inhibitor, an angiotensin receptor blocker (ARB), a beta blocker, a diuretic, or a combination thereof.In some embodiments, the one or more additional therapeutically active agents are ACE (angiotensin-converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), diuretics, or combinations thereof.In some embodiments, the one or more additional therapeutically active agents are enalapril, benazepril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propanolol, metoprolol, metoprolol tartrate, metoprolol succinate, metoprolol tartrate ... Toprolol, thiazide diuretics, loop diuretics, potassium-sparing diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, digitalis glycosides, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, ethacrinic acid, furosemide, torsemide, amiloride, ethacrinic acid, furosemide, torsemide, amiloride, ethacrinic acid, furosemide, torsemide, amiloride, ethylhexyl ether ... Prerenone, Fineron, Spironolactone, Triamterene, Digoxin, Fluticasone, Budesonide, Mometasone, Beclomethasone, Ciclesonide, Fluticasone Furoate, Prednisone, Methylprednisolone, Montelukast, Zafirlukast, Zileuton, Long-acting beta agonists, Short-acting beta agonists, Theophylline, Ipratropium, Salmeterol, Formoterol, Albuterol, Levalbuterol, Timolol, Levobunolol, Methymidine The therapeutic agent is selected from pranolol, carteolol, betaxolol, acetazolamide, dorzolamide, brinzolamide, methazolamide, brimonidine, apraclonidine, cholinergic agents, latanoprost, latanoprost bunod, travoprost, bimatoprost, tafluprost, omecamtiv mecarbil, allogeneic cell therapy Rexel mestrocel-L (REVASCOR®), CardiAMP™ cell therapy, netarsudil, ripasudil, and combinations thereof. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered subcutaneously to the subject.In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks, once per eight weeks, once per nine weeks, once per ten weeks, once per eleven weeks, or once per twelve weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per two weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per three weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per four weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per month. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 5 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 6 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 7 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 8 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 2 months. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 9 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 10 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 11 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 12 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every three months.In one aspect, provided herein is an anti-NPR1 antibody or antigen-binding fragment thereof for use in a method of treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need thereof, the anti-NPR1 antibody or antigen-binding fragment thereof being provided for administration at a dose ranging from about 10 mg to about 700 mg. In one aspect, provided herein is an anti-NPR1 antibody or antigen-binding fragment thereof for use in a method of treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need thereof, the anti-NPR1 antibody or antigen-binding fragment thereof being provided for administration at a dose ranging from about 10 mg to about 700 mg. In one aspect, provided herein is an anti-NPR1 antibody or antigen-binding fragment thereof for use in a method of treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need thereof, the anti-NPR1 antibody or antigen-binding fragment thereof being provided for administration at a dose ranging from about 50 mg to about 700 mg. In one aspect, provided herein is an anti-NPR1 antibody or antigen-binding fragment thereof for use in a method of treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need thereof, the anti-NPR1 antibody or antigen-binding fragment thereof being administered at a dose ranging from about 50 mg to about 700 mg. In some embodiments, the disorder or disease associated with natriuretic peptide receptor activity is a cardiovascular disorder. In certain embodiments, the cardiovascular disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, myocardial fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, and myocardial infarction (MI). In some embodiments, the subject has hypertrophic cardiomyopathy, and the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments, the cardiovascular disorder is heart failure.In certain embodiments, the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure. In certain embodiments, the heart failure is heart failure with reduced ejection fraction (HFrEF). In certain embodiments, the heart failure is heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF). In some embodiments, the cardiovascular disorder is hypertension. In certain embodiments, the hypertension is selected from resistant hypertension, hypertensive heart disease, pulmonary hypertension, isolated systolic hypertension, and pulmonary arterial hypertension. In certain embodiments, the hypertension is resistant hypertension. In some embodiments, the disorder or disease associated with natriuretic peptide receptor activity is selected from hypertension, pre-eclampsia, asthma, glaucoma, and / or cytokine release syndrome. In certain embodiments, the disorder or disease associated with natriuretic peptide receptor activity is a renal disorder, hi certain embodiments, the renal disorder is selected from diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD).In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 ( (HCDR1), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 22 (LCDR3); or (IV) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 19 (LCDR3). In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24; or (b) a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28. and a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15 and a light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26; or (b) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30 and a light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain comprising an amino acid sequence of SEQ ID NO: 15 and a light chain comprising an amino acid sequence of SEQ ID NO: 26; or (b) a heavy chain comprising an amino acid sequence of SEQ ID NO: 30 and a light chain comprising an amino acid sequence of SEQ ID NO: 26.In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR1), SEQ ID NO:11 (LCDR2) and SEQ ID NO:34 (LCDR3). (CDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:35 (LCDR3); or (IV) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:34 (LCDR3). In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36; or (b) a heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28 and a light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises (a) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 36; or (b) a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 36.In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises: (a) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15 and a light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 38; or (b) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30 and a light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 38. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof comprises: (a) a heavy chain comprising an amino acid sequence of SEQ ID NO: 15 and a light chain comprising an amino acid sequence of SEQ ID NO: 38; or (b) a heavy chain comprising an amino acid sequence of SEQ ID NO: 30 and a light chain comprising an amino acid sequence of SEQ ID NO: 38. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is therapeutic. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, Fv, and single chain variable fragment (scFv). In some embodiments, about 60 mg, about 120 mg, about 240 mg, about 450 mg, or about 600 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 120 mg or about 240 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided in a dose of about 60 mg, about 120 mg, about 240 mg, about 450 mg, or about 600 mg. In some embodiments, about 60 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 120 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 240 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 450 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject. In some embodiments, about 600 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject.In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided in a dose of about 120 mg or about 240 mg. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided in a dose of about 120 mg. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided in a dose of about 240 mg. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided in combination with one or more additional therapeutically active agents. In certain embodiments, one or more additional therapeutically active agents have been administered to the subject. In certain embodiments, the one or more additional therapeutically active agents are selected from ACE (angiotensin converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, mineralocorticoid receptor antagonists (MRAs), beta blockers, diuretics, calcium channel blockers, cardiac glycosides, sodium-glucose cotransporter 2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitors (ARNIs), corticosteroids, leukotriene modifiers, bronchodilators, beta-adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha2-adrenergic receptor agonists, parasympathomimetics, prostaglandin analogs, rho kinase inhibitors, cell therapy, cardiac specific myosin activators, and combinations thereof. In some embodiments, the one or more additional therapeutically active agents are ACE (angiotensin converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, diuretics, or combinations thereof. In some embodiments, the one or more additional therapeutically active agents are ACE (angiotensin-converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), diuretics, or combinations thereof.In some embodiments, the one or more additional therapeutically active agents are enalapril, benazepril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propanolol, metoprolol, metoprolol tartrate, metoprolol succinate, metoprolol tartrate ... Toprolol, thiazide diuretics, loop diuretics, potassium-sparing diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, digitalis glycosides, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, ethacrinic acid, furosemide, torsemide, amiloride, ethacrinic acid, furosemide, torsemide, amiloride, ethacrinic acid, furosemide, torsemide, amiloride, ethylhexyl ether ... Prerenone, Fineron, Spironolactone, Triamterene, Digoxin, Fluticasone, Budesonide, Mometasone, Beclomethasone, Ciclesonide, Fluticasone Furoate, Prednisone, Methylprednisolone, Montelukast, Zafirlukast, Zileuton, Long-acting beta agonists, Short-acting beta agonists, Theophylline, Ipratropium, Salmeterol, Formoterol, Albuterol, Levalbuterol, Timolol, Levobunolol, Methymidine The therapeutic agent is selected from pranolol, carteolol, betaxolol, acetazolamide, dorzolamide, brinzolamide, methazolamide, brimonidine, apraclonidine, cholinergic agents, latanoprost, latanoprost bunod, travoprost, bimatoprost, tafluprost, omecamtiv mecarbil, allogeneic cell therapy Rexel mestrocel-L (REVASCOR®), CardiAMP™ cell therapy, netarsudil, ripasudil, and combinations thereof. In certain embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered subcutaneously to the subject.In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks, once per eight weeks, once per nine weeks, once per ten weeks, once per eleven weeks, or once per twelve weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per two weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per three weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per four weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per month. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 5 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 6 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 7 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 8 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every 2 months. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 9 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 10 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 11 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 12 weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every three months. In embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided in a form for subcutaneous administration. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks, once per eight weeks, once per nine weeks, once per ten weeks, once per eleven weeks, or once per twelve weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per week. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per two weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per three weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per four weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per month. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per five weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per six weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per seven weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per eight weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per two months. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per nine weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per ten weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once per eleven weeks. In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every 12 weeks.In some embodiments, the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration about once every three months. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is a graphical representation of a first-in-human (FIH) single ascending dose (SAD) study to investigate safety, tolerability, and pharmacokinetics in healthy participants. [Diagram 2] 1 is a chart containing graphical and baseline characteristics of participants in the FIH SAD study, in which interim analysis data are presented. [Diagram 3] 1 is a chart containing safety and tolerability results for non-Japanese participants in the FIH SAD study, with interim analysis data presented. N=number of participants; nE=number of AEs in a category; nS=number of participants with at least one AE in a category; % is based on number of participants. [Figure 4] 1 is a chart containing safety and tolerability results in Japanese participants in the FIH SAD study, with interim analysis data presented. N=number of participants; nE=number of AEs in a category; nS=number of participants with at least one AE in a category; % is based on number of participants. [Diagram 5] 1 is a graphical representation of serum concentrations of anti-NPR1 antibodies following a single subcutaneous dose of 1 to 240 mg for the non-Japanese cohort and the Japanese 240 mg dose cohort. Tmax was determined to be 4 to 10 days, and the half-life (T1 / 2) at 120 and 240 mg was determined to be 15 to 23 days. [Figure 6] 1 is a graphical representation of plasma cGMP levels (ng / mL) from interim analysis results over time for the non-Japanese cohort following a single subcutaneous dose of 30 mg, 60 mg, 120 mg, and 240 mg of anti-NPR1 antibody compared to placebo results. [Figure 7]Graphical representation of 24-hour ABPM SBP (systolic blood pressure) CFB (mmHG) from interim analysis results over time for the non-Japanese cohort following a single subcutaneous dose of 30 mg, 60 mg, 120 mg, and 240 mg of anti-NPR1 antibody compared to placebo results. [Figure 8] Graphical representation of 24 hour ABPM DBP (diastolic blood pressure) CFB (mmHG) from interim analysis results over time for the non-Japanese cohort following a single subcutaneous dose of 30 mg, 60 mg, 120 mg and 240 mg of anti-NPR1 antibody compared to placebo results. [Figure 9] Graphical representation of 24-hour ABPM heart rate (HR) CFB (beats per minute; bpm) from interim analysis results over time for the non-Japanese cohort following a single subcutaneous dose of 30 mg, 60 mg, 120 mg, and 240 mg of anti-NPR1 antibody compared to placebo results. [Figure 10] FIG. 1 is a graphical representation of cohort 1 of a safety and tolerability study in participants with heart failure with reduced ejection fraction (HFrEF) or heart failure with mildly reduced ejection fraction (HFmrEF). [Figure 11] FIG. 1 is a graphical representation of cohort 2 of the safety and tolerability study in participants with heart failure with reduced ejection fraction (HFrEF) or heart failure with mildly reduced ejection fraction (HFmrEF). [Figure 12] 1 is a graphic representation of the efficacy, safety, tolerability and dose-finding study of anti-NPR-1 antibody in patients with resistant hypertension. ABPM=ambulatory blood pressure monitoring; mean 24-hour SBP=mean ambulatory systolic blood pressure (based on 24-hour ambulatory blood pressure monitoring); msSBP=mean sitting systolic blood pressure (based on office assessment); SC=subcutaneous; WOCBP=women of childbearing potential.

[0013] general definition In order that the methods and uses described herein may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description, as necessary.

[0014] Throughout the description and claims of this specification, the terms "comprise" and "containing" and variations of these words, such as "comprises" and "comprises," mean "including, but not limited to," and do not exclude other components, integers, or steps. Furthermore, the singular includes the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification should be understood as contemplating both the plural and the singular unless the context otherwise requires.

[0015] As used herein, "NPR1" and "NPR1 protein" refer to natriuretic peptide receptor 1. This protein is also known as atrial natriuretic peptide receptor type A (ANP-A, ANPR-A or NPR-A) and guanylate cyclase A (GC-A). In some embodiments, the NPR1 referenced is human NPR1. In some embodiments, the human NPR1 has UniProt accession number P16066 or GenBank accession number EAW53284.1 (SEQ ID NO: 1). In some embodiments, the NPR1 referenced is mouse (Mus musculus) NPR1. In some embodiments, the mouse NPR1 has NCBI reference sequence number NP_032753.5 (SEQ ID NO: 2). In some embodiments, the NPR1 referenced is rat (Rattus norvegicus) NPR1. In some embodiments, the rat NPR1 has NCBI reference sequence number NP_036745.1 (SEQ ID NO: 3). Exemplary NPR1 proteins are shown in Table 1.

[0016] [Table 1]

[0017] [Table 2]

[0018] In various embodiments, the anti-NPR1 antibodies and antigen-binding fragments described herein can bind to and activate NPR1 in the absence of ANP. This activity allows the anti-NPR1 antibodies and antigen-binding fragments described to be used in the treatment of cardiovascular disorders (e.g., hypertension, peripheral vascular disease, heart failure (including, but not limited to, heart failure with reduced ejection fraction (HFrEF), heart failure with moderate or mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction or acute decompensated heart failure), coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina pectoris, hypertrophic cardiomyopathy (e.g., ventricular hypertrophy), diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, and the like, as further described herein. The compositions may be useful in treating undesirable conditions, diseases and disorders including atrial fibrillation, myocardial fibrosis, atrial flutter, adverse vascular remodeling, atherosclerosis, or myocardial infarction (MI), hypertension (e.g., resistant hypertension, hypertensive heart disease, pulmonary hypertension, isolated systolic hypertension, or pulmonary arterial hypertension), pre-eclampsia, asthma, glaucoma, cytokine release syndrome, and / or renal disorders (e.g., diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy, and end stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD)).

[0019] The term "antibody" as used herein refers to a whole antibody or an antigen-binding fragment thereof. A whole antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2 and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and each VL is composed of three CDRs and four FRs arranged in the following order from amino-terminus to carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibody may mediate the binding of the immunoglobulin to various cells of the host tissue or immune system (e.g., effector cells) and factors including the first component (Clq) of the classical complement system. The term "antibody" includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelid antibodies and chimeric antibodies. Antibodies may be of any isotype / class (e.g., IgG, IgE, IgM, IgD, IgA and IgY) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2).

[0020] The term "antigen-binding fragment" refers to a fragment of an intact antibody that retains the ability to specifically bind to a given antigen (e.g., NPR1) and / or provide the function of an intact antibody. Such fragments include Fab fragments, Fab' fragments, monovalent fragments consisting of the VL, VH, CL and CH1 domains; F(ab')2 fragments, bivalent fragments containing two Fab fragments linked by a disulfide bridge at the hinge region; Fd fragments consisting of the VH and CH1 domains; Fv fragments consisting of the VL and VH domains; single-chain Fv fragments (scFv) consisting of the VL and VH domains linked by a linker sequence; and single-domain antibody (dAb) fragments consisting of the VH or VL domain (Ward et al., 1989 Nature 341:544-546).

[0021] The term "single chain antibody", "single chain Fv" or "scFv" refers to a molecule comprising an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) connected by a linker. Such scFv molecules can have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Any suitable linker can be used. A non-limiting set of linkers that can be used in such single chain antibodies are described by Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448, Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56, and Roovers et al. (2001), Cancer Immunol, the contents of each of which are incorporated herein by reference for this purpose. Such single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody. These antibody fragments are obtained using techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies. Without limitation, antigen-binding fragments can be produced by any suitable known method. For example, the various antigen-binding fragments described herein can be produced by enzymatic or chemical modification of intact antibodies, can be synthesized de novo using recombinant DNA methodology (e.g., single-chain Fv), or can be identified using phage display libraries (see, e.g., Pini and Bracci, Curr Protein Pept Sci 2000;1(2):155-69, the contents of which are incorporated herein by reference for this purpose). Antigen-binding fragments are screened for utility (e.g., binding affinity, activity) in the same manner as intact antibodies.

[0022] Antigen-binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136, the contents of which are incorporated herein by reference for this purpose). Antigen-binding portions of antibodies can be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see, e.g., U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies, the contents of which are incorporated herein by reference for this purpose).

[0023] The antigen-binding fragment may be incorporated into a single-chain molecule comprising a pair of tandem Fv segments (VH-CH1-VH-CH1), which, in combination with complementary light chain polypeptides, form a pair of antigen-binding regions (see Zapata et al., 1995 Protein Eng. 8(10):1057-1062; and U.S. Pat. No. 5,641,870, the contents of each of which are incorporated herein by reference for this purpose).

[0024] The terms "individual," "subject," "host," and "patient" are used interchangeably herein and refer to any human subject for whom diagnosis, treatment, or therapy is desired.

[0025] As used herein, "individual in need thereof," "subject in need thereof," and "patient in need thereof" refer to a human selected for treatment or therapy who is in need of such treatment or therapy (e.g., having one or more of the diseases or disorders described herein).

[0026] The term "isolated" is used throughout this specification to mean that an immunoglobulin, antibody or polynucleotide is present in a physical environment that is different from that in which it may naturally occur, as the case may be. For example, a naturally occurring polynucleotide or polypeptide present in an organism is not isolated, but the same polynucleotide or polypeptide separated from some or all of the coexisting materials in an organism is isolated.

[0027] Throughout this specification, complementarity determining regions ("CDRs") are defined according to the Kabat definition, unless otherwise specified that the CDRs are defined according to another definition. The exact amino acid sequence boundaries of a given CDR are set forth in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5 (1996), the contents of each of which are incorporated herein by reference for this purpose. thEd. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme) and ImMunoGenTics (IMGT) numbering (Lefranc, M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al., Dev. Comp. Immunol., 27, 55-77 (2003) ("IMGT" numbering scheme). For example, in the classical format, according to Kabat, the CDR amino acid residues of the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3), and the CDR amino acid residues of the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to Chothia, the CDR amino acids of the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2) and 95-102 (HCDR3), and the amino acid residues of the VL are numbered 26-32 (LCDR1), 50-56 (HCDR2) and 95-102 (HCDR3). Combining the Kabat and Chothia CDR definitions, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) of human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) of human VL. According to MGT, the amino acid residues of the CDRs of VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2) and 93-102 (CDR3), and the amino acid residues of the CDRs of VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2) and 89-97 (CDR3) (numbering according to "Kabat"). According to IMGT, the CDR regions of an antibody can be determined using the program IMGT / DomainGap Align.

[0028] By convention, the CDR regions in the heavy chain are usually referred to as HCDR1, HCDR2 and HCDR3, and in the light chain as LCDR1, LCDR2 and LCDR3, which are numbered consecutively from the amino-terminus to the carboxy-terminus.

[0029] The term "antibody framework" as used herein refers to that part of any variable domain, VL or VH, that serves as a scaffold for the antigen binding loops (CDRs) of this variable domain. Essentially, it is a variable domain without the CDRs.

[0030] The term "constant region" or "constant domain" refers to the carboxy-terminal portions of the light and heavy chains that are not directly involved in binding the antibody to an antigen, but exhibit various effector functions, such as interaction with Fc receptors. The term refers to the portion of the immunoglobulin molecule that has a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, that contains the antigen-binding site. The constant domain contains the CH1, CH2, and CH3 domains of the heavy chain and the CHL domain of the light chain.

[0031] The term "epitope" or "antigenic determinant" refers to a site on an antigen to which an immunoglobulin or antibody specifically binds (e.g., to a specific site on a target molecule). An epitope usually comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 conserved or non-conserved amino acids in a unique spatial conformation. See, for example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, GE Morris, Ed. (1996), the contents of which are incorporated herein by reference for this purpose. In addition, as used herein, an epitope may comprise one or more monosaccharide units of a polysaccharide to which an antibody specifically binds. In certain aspects, an epitope may be a conformational epitope. See, for example, Thompson et al., 2009, J. of Biol. Chem. 51:35621-35631, the contents of which are incorporated herein by reference for this purpose.

[0032] The term "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies produced by a particular cell or cell line, the individual antibodies constituting the population being essentially identical in sequence, except for possible naturally occurring mutations that may be present in minor amounts. A monoclonal antibody preparation exhibits a single binding specificity and affinity for a particular epitope. In contrast, a conventional (polyclonal) antibody preparation usually contains a large number of antibodies directed against or specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. Monoclonal antibodies (mAbs) can be produced by a variety of techniques, including conventional methodologies, such as the standard somatic cell hybridization technique of Kohler and Milstein (Nature 1975;256(5517):495-7), the contents of which are incorporated herein by reference for this purpose. Monoclonal antibodies can also be obtained from other suitable methods, including phage display techniques such as those described in Clackson et al. (Nature 1991;352(6336):624-8) or Marks et al. (J Mol Biol 1991;222(3):581-97), the contents of each of which are incorporated herein by reference for this purpose. The term "monoclonal antibody" also refers to, but is not limited to, antibody sequences derived from a specific species of origin or from one single species of origin. Thus, the meaning of the term "monoclonal antibody" includes chimeric monoclonal antibodies, such as humanized monoclonal antibodies.

[0033] The term "chimeric antibody" as used herein refers to an antibody in which (a) the constant region has been modified, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or modified class, effector function and / or species; or (b) the variable region or a portion thereof has been modified, replaced or exchanged with a variable region or a portion thereof having a different or modified antigen specificity. To create a chimeric antibody, the variable region sequence derived from a non-human donor antibody (e.g., a mouse, rabbit or rat donor antibody) can be linked to a human constant region using methods known in the art (see, for example, U.S. Pat. No. 4,816,567 (Cabilly et al.), the contents of which are incorporated herein by reference for this purpose). For example, a mouse anti-NPR1 antibody can be modified by replacing its constant region with a constant region derived from a human immunoglobulin. Due to the replacement with a human constant region, the chimeric antibody can retain its specificity in recognizing human NPR1, but has reduced immunogenicity in humans compared to the original mouse antibody.

[0034] As used herein, the term "humanized antibody" refers to a format of antibody that contains at least some human sequences and at least some non-human sequences. Usually, the antibody contains human sequences and a small portion of non-human sequences that confer binding specificity to the target antigen. Such antibodies are chimeric antibodies that contain minimal sequences derived from non-human immunoglobulins and retain the reactivity of non-human antibodies, but are less immunogenic in humans. Usually, humanized antibodies are generated by replacing hypervariable region sequences from a human acceptor antibody with hypervariable region sequences from a non-human donor antibody (e.g., a mouse, rabbit or rat donor antibody) that binds to the antigen of interest (e.g., NPR1). In some cases, the framework region sequences of the acceptor antibody may also be replaced with the corresponding sequences of the donor antibody (e.g., via affinity maturation). In addition to the sequences derived from the donor and acceptor antibodies, a humanized antibody may be further modified by substitution of any residues in its framework regions and / or within the replaced non-human residues to refine and optimize antibody specificity, affinity and / or activity as discussed herein. Methods for producing humanized antibodies are known in the art. See, for example, Riechmann et al. (Nature 1988;332(6162):323-7); Jones et al. (Nature 1986;321(6069):522-5); U.S. Patent No. 5,225,539 (Winter); and U.S. Patent Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 (Queen et al.), the contents of each of which are incorporated herein by reference for this purpose.

[0035] The term "human antibody", as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region is also derived from such a human sequence, e.g., a human germline sequence or a variant of a human germline sequence, or an antibody containing a consensus framework sequence derived from human framework sequence analysis, e.g., as described in Knappik, et al., (2000) J Mol Biol; 296:57-86, the contents of which are incorporated herein by reference for this purpose. Human antibodies may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).

[0036] The antibodies or antigen-binding fragments described herein may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0037] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms encompass amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of a corresponding naturally occurring amino acid, as well as naturally occurring and non-naturally occurring amino acid polymers. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses conservatively modified variants thereof.

[0038] The term "conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to nucleic acid sequences, conservatively modified variants refer to nucleic acids that code for identical or essentially identical amino acid sequences, or essentially identical sequences when the nucleic acid does not code for an amino acid sequence. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acids code for any given protein. For example, the codons GCA, GCC, GCG, and GCU all code for the amino acid alanine. Thus, at any position where alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are a type of conservatively modified variant. Every nucleic acid sequence herein that codes for a polypeptide also describes every possible silent variation of the nucleic acid. Those skilled in the art will recognize that each codon in a nucleic acid (except AUG, which is usually the only codon for methionine, and TGG, which is usually the only codon for tryptophan) can be altered to result in a functionally identical molecule. Thus, within each described sequence, each silent variation of the nucleic acid encoding a polypeptide is implied. In polypeptide sequences, "conservatively modified variants" include individual substitutions, deletions, or additions to a polypeptide sequence that result in the replacement of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. The following eight groups contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), valine (V); 6) phenylalanine (F), tyrosine (Y), tryptophan (W); 7) serine (S), threonine (T); and 8) Cysteine ​​(C), Methionine (M).

[0039] The term "identity" or "homology" refers to the relatedness between the sequences of two or more polypeptides, as determined by comparing the sequences. "Identity" also refers to the degree of sequence relatedness between polypeptides, as determined by the number of matches between strings of two or more amino acid residues. The percent "identity" between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap (i.e., the percent identity is equal to the number of identical positions / total number of positions x 100), and must be introduced upon optimal alignment of the two sequences. Sequence comparison and determination of percent identity between two sequences can be achieved using a mathematical algorithm. For sequence comparison, typically, one sequence serves as a reference sequence, which is compared to the test sequence. When using a sequence comparison algorithm, the test sequence and the reference sequence are input into a computer, subsequence coordinates are designated as necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identity of the test sequence relative to the reference sequence based on the program parameters. Additionally or alternatively, the protein sequences described herein can further be used as a "query sequence" to perform a search against public databases, e.g., to identify related sequences. For example, such a search can be performed using the BLAST program of Altschul et al. (J Mol Biol 1990;215(3):403-10), the contents of which are incorporated herein by reference for this purpose.

[0040] Two sequences are "substantially identical" if two sequences have a certain percentage of amino acid residues or nucleotides that are the same (e.g., 60% identity, 65% identity, 70% identity, 75% identity, 80% identity, 85% identity, 90% identity, 95% identity, or 99% identity over a designated region, or if not specified, over the entire sequence), when compared and aligned for maximum correspondence over a comparison window or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Optionally, the identity exists over a region that is at least about 50 nucleotides in length (or 10 amino acids), or over a region that is 100 to 500 or 1000 or more nucleotides in length (or 20, 50, 200 or more amino acids).

[0041] Binding "affinity" refers to the strength of interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" interact with the antigen at multiple sites through weak non-covalent forces. Generally, the greater the interaction, the stronger the affinity. Generally, such determinations can be made using cell-based assays.

[0042] The term "Kassoc" or "Ka", as used herein, is intended to refer to the on-rate of a particular binding molecule-antigen interaction, while the term "Kdis" or "Kd", as used herein, is intended to refer to the off-rate of a particular binding molecule-antigen interaction. D The term "dissociation constant," as used herein, is intended to refer to the equilibrium dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed as a molar concentration (M). D Values ​​can be determined using methods well established in the art. DMethods for determining are by using surface plasmon resonance or solution equilibrium titration (SET), such as with a Biacore® system (see Friguet et al., (1985) J. Immunol. Methods, 77(2):305-319, and Hanel et al., (2005) Anal. Biochem., 339(1):182-184, the contents of each of which are incorporated herein by reference for this purpose).

[0043] As used herein, the terms "specific," "specifically binds," and "binds specifically" refer to the binding reaction between an antibody or antigen-binding fragment (e.g., an anti-NPR1 antibody) and a target antigen (e.g., NPR1) in a heterogeneous population of proteins and other biologics. An antibody can be tested for specificity of binding by comparing binding to an appropriate antigen with binding to an inappropriate antigen or antigen mixture under a given set of conditions. An antibody is considered specific if it binds to an appropriate antigen with at least 2, 5, 7, and preferably 10 or more times higher affinity than to an inappropriate antigen or antigen mixture. A "specific antibody" or "target-specific antibody" is one that binds only to a target antigen (e.g., NPR1) but does not bind (or shows minimal binding to) other antigens. In certain embodiments, an antibody or antigen-binding fragment that specifically binds to a target antigen (e.g., NPR1) has a specificity of 1×10 -6 Less than M, 1×10 -7 Less than M, 1×10 -8 Less than M, 1×10 -9 Less than M, 1×10 -10 Less than M, 1×10 -11 Less than M, 1×10 -12 Less than M or 1×10 -13 K less than M D In certain embodiments, K D In certain embodiments, K D is 600 pM to 1 μM, 1 μM to 100 nM, or 100 mM to 10 nM (inclusive).

[0044] The term "about" in reference to a number x means, for example, x±10%. In certain embodiments, the term "about" in reference to a number x means, for example, x±9%, x±8%, x±7%, x±6%, x±5%, x±4%, x±3%, x±2% or x±1%.

[0045] Antibodies and antigen-binding fragments Described below are certain specific anti-NPR1 antibody sequences for use in the methods and uses described herein. As used herein, the term "anti-NPR1 antibody" or "antibody that binds NPR1" refers to any form of antibody or antigen-binding fragment that specifically binds to NPR1, e.g., 1×10 6 to 10 8 as determined by surface plasmon resonance (SPR) spectroscopy (using Biacore™) or solution equilibrium titration (SET). -8 K under M D This term encompasses monoclonal antibodies (including intact monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, so long as they specifically bind to NPR1.

[0046] The amino acid and nucleic acid sequences of exemplary anti-NPR1 antibodies presented herein are set forth in Table 2. In some embodiments, the antibody has the heavy and light chain CDRs, VH and VL sequences and / or heavy and light chain sequences of any of the antibodies set forth in Table 2. In some embodiments, the anti-NPR1 antibody is a four-chain antibody (also referred to as an intact antibody) comprising two heavy chains and two light chains. In some embodiments, the anti-NPR1 antibody is an antigen-binding fragment of an intact antibody, such as a functional fragment of an intact antibody selected from any of those set forth in Table 2 that retains the ability to bind to NPR1 and / or provide a function of the intact antibody (e.g., activate NPR1 in the absence of ANP). In some embodiments, the anti-NPR1 antibody is an antibody having the CDRs of any of the heavy and light chain variable region pairs set forth in Table 2. In some embodiments, the anti-NPR1 antibody is an antibody having the CDRs of any of the heavy and light chain pairs set forth in Table 2.

[0047] [Table 3]

[0048] [Table 4]

[0049] [Table 5]

[0050] [Table 6]

[0051] [Table 7]

[0052] [Table 8]

[0053]

Table 9

[0054]

Table 10

[0055] For example, N001_DAPA contains: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:19 (LCDR3). or (IV) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 19 (LCDR3). In some embodiments, N001_DAPA may be defined as comprising or having the amino acid sequence of SEQ ID NO: 4 (HCDR1), SEQ ID NO: 5 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3). In some embodiments, N001_DAPA may be defined as comprising or having the amino acid sequence of SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, N001_DAPA may be defined as comprising or having the amino acid sequence of SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3). In some embodiments, N001_DAPA may be defined as comprising or having the amino acid sequence of SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3).In some embodiments, N001_DAPA may be defined as comprising or having a heavy chain variable region that comprises or has the amino acid sequence of SEQ ID NO: 13 and a light chain variable region that comprises or has the amino acid sequence of SEQ ID NO: 24. In some embodiments, N001_DAPA may be defined as comprising or having a heavy chain that comprises or has the amino acid sequence of SEQ ID NO: 15 and a light chain that comprises or has the amino acid sequence of SEQ ID NO:26.

[0056] For example, N001_DAPA contains: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:19 (LCDR3). or (IV) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 19 (LCDR3). In some embodiments, N001_LALA may be defined as comprising or having the amino acid sequence of SEQ ID NO: 4 (HCDR1), SEQ ID NO: 5 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3). In some embodiments, N001_LALA may be defined as comprising or having the amino acid sequence of SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, N001_LALA may be defined as comprising or having the amino acid sequence of SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3). In some embodiments, N001_LALA may be defined as comprising or having the amino acid sequence of SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3).In some embodiments, N001_LALA may be defined as comprising or having a heavy chain variable region that comprises or has the amino acid sequence of SEQ ID NO: 28 and a light chain variable region that comprises or has the amino acid sequence of SEQ ID NO: 24. In some embodiments, N001_LALA may be defined as comprising or having a heavy chain that comprises or has the amino acid sequence of SEQ ID NO: 30 and a light chain that comprises or has the amino acid sequence of SEQ ID NO: 26.

[0057] For example, N002_DAPA contains: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:10 (LCDR3), and SEQ ID NO:11 (LCDR3). or (IV) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:34 (LCDR3). In some embodiments, N002_DAPA may be defined as comprising or having the amino acid sequence of SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3). In some embodiments, N002_DAPA may be defined as comprising or having the amino acid sequence of SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3). In some embodiments, N002_DAPA may be defined as comprising or having the amino acid sequence of SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:35 (LCDR3). In some embodiments, N002_DAPA may be defined as comprising or having the amino acid sequence of SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:34 (LCDR3).In some embodiments, N002_DAPA may be defined as comprising or having a heavy chain variable region that comprises or has the amino acid sequence of SEQ ID NO: 13 and a light chain variable region that comprises or has the amino acid sequence of SEQ ID NO: 36. In some embodiments, N002_DAPA may be defined as comprising or having a heavy chain that comprises or has the amino acid sequence of SEQ ID NO: 15 and a light chain that comprises or has the amino acid sequence of SEQ ID NO: 38.

[0058] For example, N002_LALA is: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:10 (LCDR3), and SEQ ID NO:11 (LCDR3). or (IV) three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:34 (LCDR3). In some embodiments, N002_LALA may be defined as comprising or having the amino acid sequence of SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3). In some embodiments, N002_LALA may be defined as comprising or having the amino acid sequence of SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3). In some embodiments, N002_LALA may be defined as comprising or having the amino acid sequence of SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:35 (LCDR3). In some embodiments, N002_LALA may be defined as comprising or having the amino acid sequence of SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:34 (LCDR3).In some embodiments, N002_LALA may be defined as comprising or having a heavy chain variable region that comprises or has the amino acid sequence of SEQ ID NO: 28 and a light chain variable region that comprises or has the amino acid sequence of SEQ ID NO: 36. In some embodiments, N002_LALA may be defined as comprising or having a heavy chain that comprises or has the amino acid sequence of SEQ ID NO: 30 and a light chain that comprises or has the amino acid sequence of SEQ ID NO: 38.

[0059] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 13, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 24, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In some other embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having the amino acid sequence of SEQ ID NO: 15, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15, and a light chain comprising or having the amino acid sequence of SEQ ID NO: 26, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26.

[0060] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO:28, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28, and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO:24, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:24. In some other embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having the amino acid sequence of SEQ ID NO:30, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30, and a light chain comprising or having the amino acid sequence of SEQ ID NO:26, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:26.

[0061] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 13, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 36, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36. In some other embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having the amino acid sequence of SEQ ID NO: 15, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15, and a light chain comprising or having the amino acid sequence of SEQ ID NO: 38, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 38.

[0062] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO:28, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:28, and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO:36, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:36. In some other embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having the amino acid sequence of SEQ ID NO:30, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:30, and a light chain comprising or having the amino acid sequence of SEQ ID NO:38, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:38.

[0063] Engineered and Modified Antibodies The antibodies described herein for any of the uses or methods described herein can be prepared using an antibody having one or more of the VH and / or VL sequences set forth herein as a starting material to design an engineered antibody, which may have altered properties from the starting antibody. The antibody may be engineered by modifying one or more residues within one or both variable regions (i.e., VH and / or VL), for example within one or more CDR regions and / or within one or more framework regions. Additionally or alternatively, the antibody may be engineered by modifying residues within the constant region, for example to modify the effector function of the antibody.

[0064] One type of variable region engineering that can be performed is antibody binding region / paratope or CDR grafting. Because paratope sequences are involved in most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of a particular naturally occurring antibody by constructing expression vectors that contain CDR / paratope sequences from a particular naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann, L. et al., 1998 Nature 332:323-327; Jones, P. et al., 1986 Nature 321:522-525; Queen, C. et al., 1989 Proc. Natl. Acad. USA 86:10029-10033; U.S. Pat. Nos. 5,225,539 and 5,530,101; 5,585,089; 5,693,762 and 6,180,370, the contents of each of which are incorporated herein by reference for this purpose).

[0065] Thus, another embodiment relates to any of the uses or methods described herein, wherein the isolated anti-NPR1 antibody or antigen-binding fragment thereof, including an antigen-binding portion thereof, comprises a heavy chain variable region comprising the CDR sequences of an antibody or group of antibodies set forth in Table 2. Thus, such antibodies include the V H and V LIt contains the CDR sequences and may further contain different framework sequences from these antibodies.

[0066] Such framework sequences can be obtained from public DNA databases or published references that contain germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes can be found in the human germline sequence database "VBase" (available on the Internet at www.mrc-cpe.cam.ac.uk / vbase), as well as Kabat, EA, et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, IM, et al., 1992 J. Mol. Biol. 227:776-798; and Cox, JP Let al., 1994 Eur. J Immunol. 24:827-836, the contents of each of which are incorporated herein by reference for this purpose.

[0067] Exemplary framework sequences for use in the antibodies or antigen-binding fragments described herein are those that are structurally similar to the framework sequences used by the selected antibodies described herein, e.g., the consensus sequences and / or framework sequences used by the antibodies or antigen-binding fragments described herein. H CDR1, CDR2 and CDR3 sequences and V LThe CDR1, CDR2 and CDR3 sequences can be grafted into framework regions that have the same sequence as found in the germline immunoglobulin gene from which the framework sequences are derived, or the CDR sequences can be grafted into framework regions that contain one or more mutations compared to the germline sequence. For example, it has been found to be beneficial in certain cases to mutate residues in framework regions to maintain or enhance the antigen-binding ability of the antibody (see, for example, U.S. Patent Nos. 5,530,101; 5,585,089; 5,693,762; and 6,180,370, the contents of each of which are incorporated herein by reference for this purpose).

[0068] Another type of variable region engineering is known as "affinity maturation". H and / or V L The amino acid residues in the CDR1, CDR2 and / or CDR3 regions are mutated to improve one or more binding properties (e.g., affinity) of the antibody of interest. Site-directed mutagenesis or PCR-based mutagenesis can be performed to introduce the mutations, and the effect on the binding or other functional properties of the antibody of interest can be evaluated in in vitro or in vivo assays as described herein. Conservative modifications (as discussed above) can also be introduced. Mutations can be amino acid substitutions, additions or deletions. In addition, typically no more than one, two, three, four or five residues in the CDR regions are also modified.

[0069] Grafting of antigen-binding domains onto alternative frameworks or scaffolds A wide variety of antibody / immunoglobulin frameworks or scaffolds can be utilized, so long as the resulting polypeptide contains at least one binding region that specifically binds to NPR1. Such frameworks or scaffolds include the five major idiotypes of human immunoglobulins or fragments thereof (such as those described elsewhere herein), and also include immunoglobulins of other animal species, e.g., with humanized versions. In this regard, single heavy chain antibodies, such as those identified in camelids, are of particular interest. Novel frameworks, scaffolds and fragments continue to be discovered and developed by those skilled in the art.

[0070] In one aspect, the description relates to generating non-immunoglobulin-based antibodies using non-immunoglobulins as scaffolds onto which the CDRs described herein can be grafted. Known or future non-immunoglobulin frameworks and scaffolds can be utilized, so long as they contain a binding region specific for NPR1, such as those described for the antibodies described herein, including but not limited to N001 or N002. Such compounds are known herein as "polypeptides comprising a target-specific binding region." Examples of non-immunoglobulin frameworks are further described in the following sections (Camelidae antibodies and non-antibody scaffolds).

[0071] Camelidae Antibodies Antibody proteins from members of the camel and dromedary (Camelus bactrianus and Camelus dromaderius) family, including New World members such as the Llama species (Lama paccos, Lama glama and Lama vicugna), have been characterized with respect to size, structural complexity and antigenicity to human subjects. Certain IgG antibodies from this family in mammals as found in nature lack light chains and therefore differ structurally from the typical four-chain tetramer structure with two heavy and two light chains for antibodies from other animals (see WO 94 / 04678, the contents of which are incorporated herein by reference for this purpose).

[0072] Regions of camelid antibodies, small single variable domains identified as VHHs, can be obtained by genetic engineering to obtain small proteins with high affinity for targets, resulting in low molecular weight antibody-derived proteins known as "camelid nanobodies". See U.S. Patent No. 5,759,808, the contents of each of which are incorporated herein by reference for this purpose; see also Stijlemans, B. et al., 2004 J Biol Chem 279:1256-1261; Dumoulin, M. et al., 2003 Nature 424:783-788; Pleschberger, M. et al. 2003 Bioconjugate Chem 14:440-448; Cortez-Retamozo, V. et al. 2002 Int J Cancer 89:456-62; and Lauwereys, M. et al. 1998 EMBO J 17:3512-3520. Engineered libraries of camelid antibodies and antibody fragments are commercially available, for example from Ablynx, Ghent, Belgium. As with other antibodies of non-human origin, the amino acid sequences of camelid antibodies can be recombinantly modified to obtain sequences closely similar to human sequences, i.e. the nanobodies can be "humanized". Thus, the naturally low antigenicity of camelid antibodies to humans can be further reduced.

[0073] Camelid nanobodies have a molecular weight approximately ten times smaller than that of a human IgG molecule, and the protein has a physical diameter of only a few nanometers. One significance of the small size is the ability of camelid nanobodies to bind to antigenic sites that are functionally invisible to larger antibody proteins, i.e. camelid nanobodies are useful as reagents and potential therapeutic agents to detect antigens that cannot be detected by conventional immunological techniques. Thus, yet another significance of the small size is that camelid nanobodies can inhibit as a result of binding to specific sites in grooves or narrow clefts of target proteins, and therefore function in a capacity more closely resembling that of conventional low molecular weight drugs than that of conventional antibodies.

[0074] The low molecular weight and small size further result in camelid nanobodies being extremely thermostable, stable to extreme pH and protein digestion, and low antigenicity. Another implication is that camelid nanobodies can easily move from the circulatory system into tissues, and can also cross the blood-brain barrier and treat disorders that affect nervous tissue. Nanobodies can further facilitate the transport of drugs across the blood-brain barrier (see US Patent Application Publication No. 2004 / 0161738, the contents of which are incorporated herein by reference for this purpose). These features, combined with low antigenicity to humans, indicate great therapeutic potential. Furthermore, these molecules can be expressed well in prokaryotic cells such as E. coli and can be expressed as functional fusion proteins by bacteriophages.

[0075] Thus, featured herein is any of the uses or methods described herein, wherein a subject is administered a camelid antibody or nanobody with high affinity for NPR1. In one embodiment, the camelid antibody or nanobody is obtained by grafting the CDR sequences of the heavy or light chain of a human antibody described herein onto a nanobody or single domain antibody framework sequence as described, for example, in WO 94 / 04678, the contents of which are incorporated herein by reference for this purpose.

[0076] Framework or Fc manipulation The engineered antibodies described herein include those in which modifications have been made to framework residues within the VH and / or VL, for example to improve one or more properties of the antibody. Typically, such framework modifications are made to reduce the immunogenicity of the antibody. The antibodies described herein may be modified in one or more ways, including each of the ways described herein.

[0077] For example, one approach is to "backmutate" one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation may contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequence to the germline sequence from which the antibody is derived. To return the framework region sequences to their germline configuration, the somatic mutations can be "backmutated" to the germline sequence, for example, by site-directed mutagenesis or PCR-mediated mutagenesis. Such "backmutated" antibodies and the additional modifications described herein are also intended to be encompassed by the methods and uses described herein.

[0078] Another type of framework modification involves mutating one or more residues within the framework regions or even within one or more CDR regions to remove T cell epitopes, thereby reducing the potential immunogenicity of the antibody. This approach is also referred to as "deimmunization" and is described in more detail in U.S. Patent Application Publication No. 2003 / 0153043, the contents of which are incorporated herein by reference for this purpose.

[0079] In addition to or instead of modifications made in the framework or CDR regions, the antibodies described herein may be engineered to contain modifications in the Fc region that typically alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or antigen-dependent cellular cytotoxicity. Further, the antibodies described herein may be chemically modified (e.g., one or more chemical moieties may be attached to the antibody) or modified to alter its glycosylation and further alter one or more functional properties of the antibody. Each of these embodiments is described in further detail below. The numbering of residues in the Fc region is that of the EU index of Kabat.

[0080] In one embodiment, the hinge region of CH1 is modified such that the number of cysteine ​​residues in the hinge region is altered, e.g., increased or decreased. This approach is further described in U.S. Patent No. 5,677,425, the contents of which are incorporated herein by reference for this purpose. The number of cysteine ​​residues in the hinge region of CH1 is modified, for example, to facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.

[0081] In another embodiment, the antibody's Fc hinge region is mutated to reduce the antibody's biological half-life. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc hinge fragment such that the antibody's binding to Staphylococcus aureus protein A (SpA) is reduced compared to the SpA binding of the native Fc hinge domain. This approach is described in more detail in U.S. Pat. No. 6,165,745, the contents of which are incorporated herein by reference for this purpose.

[0082] In another embodiment, the antibody is modified to increase its biological half-life. Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375, the contents of which are incorporated herein by reference for this purpose. Alternatively, to increase biological half-life, the antibody can be modified in CH1 or CL to contain a salvage receptor binding epitope obtained from two loops of the CH2 domain of the Fc region of IgG, as described in U.S. Pat. No. 5,869,046 and U.S. Pat. No. 6,121,022, the contents of which are incorporated herein by reference for this purpose.

[0083] In yet other embodiments, the Fc region is modified by replacing at least one amino acid residue with a different amino acid residue to modify the effector function of the antibody. For example, one or more amino acids can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand with altered affinity can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260, the contents of each of which are incorporated herein by reference for this purpose.

[0084] To minimize the ADCC activity of an antibody, certain mutations in the Fc region result in an "Fc-silent" antibody that has minimal interaction with effector cells. In general, "IgG Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. The human IgG heavy chain Fc region is generally defined as comprising the amino acid residues from position C226 or P230 to the carboxyl terminus of an IgG antibody. The numbering of residues within the Fc region is that of the EU index of Kabat. The C-terminal lysine (residue K447) of the Fc region can be removed, for example, during production or purification of the antibody.

[0085] Silenced effector functions can be obtained by mutations in the Fc region of the antibody. See, for example, LALA and N297A (Strohl, W., 2009, Curr. Opin. Biotechnol. vol. 20(6): 685-691); and D265A (Baudino et al., 2008, J. Immunol. 181: 6664-69), also see WO 2012065950 to Heusser et al., the contents of each of which are incorporated herein by reference for this purpose. In particular, residues 234 and / or 235 can be optionally mutated to alanine. Thus, in one embodiment, the antibody provided herein has a mutation in the Fc region at one or both of amino acids 234 and 235. Such substitution of both amino acids 234 and 235 results in a reduction of ADCC activity. One example of such a mutation is the LALA mutant, which contains the L234A and L235A mutations in the IgG1 Fc amino acid sequence. Another example of a silent IgG1 antibody is the DAPA (D265A, P329A) mutation (US Pat. No. 6,737,056, the contents of which are incorporated herein by reference for this purpose). Another silent IgG1 antibody contains the N297A mutation, which results in an aglycosylated / non-glycosylated antibody. Fc-silent antibodies produce no or low ADCC activity, which means that the Fc-silent antibody exhibits an ADCC activity that is less than 50% specific cell lysis. No ADCC activity means that the Fc-silent antibody exhibits less than 1% ADCC activity (specific cell lysis).

[0086] In another embodiment, one or more selected amino acid residues may be replaced with a different amino acid residue such that the antibody has altered binding to C1q and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent No. 6,194,551, the contents of which are incorporated herein by reference for this purpose.

[0087] In another embodiment, one or more amino acid residues are altered to modify the ability of the antibody to fix complement, an approach further described in WO 94 / 29351, the contents of which are incorporated herein by reference for this purpose.

[0088] In yet another embodiment, the Fc region is modified by modifying one or more amino acids to increase the ability of the antibody to mediate antibody-dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the antibody for the Fcγ receptor. This approach is further described in WO 00 / 42072, the contents of which are incorporated herein by reference for this purpose. Additionally, the binding sites for FcγRI, FcγRII, FcγRIII and FcRn on human IgG1 have been mapped and variants with improved binding have been described (see Shields, RL et al., 2001 J. Biol. Chen. 276:6591-6604, the contents of which are incorporated herein by reference for this purpose).

[0089] In yet another embodiment, the glycosylation of the antibody is modified. For example, an aglycosylated antibody can be generated (i.e., the antibody lacks glycosylation). The glycosylation can be modified, for example, to increase the affinity of the antibody for an "antigen". Such sugar modifications can be accomplished, for example, by modifying one or more glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions can be made resulting in the absence of one or more variable region framework glycosylation sites, thereby abolishing glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for the antigen. Such approaches are described in further detail in U.S. Pat. Nos. 5,714,350 and 6,350,861, the contents of each of which are incorporated herein by reference for this purpose.

[0090] Additionally or alternatively, antibodies can be made with modified types of glycosylation, e.g., hypofucosylated antibodies with reduced amounts of fucosyl residues or antibodies with structures with increased bisecting GlcNac. Such modified glycosylation patterns have been demonstrated to enhance the ADCC ability of antibodies. Such sugar modifications can be achieved, for example, by expressing the antibody in a host cell with modified glycosylation machinery. Cells with modified glycosylation machinery have been described in the art and can be used as host cells to express the recombinant antibodies described herein, thereby producing antibodies with modified glycosylation. For example, EP 1 176 195 (the contents of which are incorporated herein by reference for this purpose) describes cell lines with a functionally disrupted FUT8 gene encoding a fucosyltransferase, and antibodies expressed in such cell lines exhibit hypofucosylation. WO 03 / 035835 describes a variant CHO cell line, LecI3 cells, that has a reduced ability to attach fucose to sugars linked to Asn(297), which also results in hypofucosylation of antibodies expressed in the host cells (see also Shields, RR et al., 2002 J. Biol. Chem. 277:26733-26740). WO 99 / 54342 describes cell lines engineered to express glycosyltransferases (e.g., β(1,4)-N-acetylglucosaminyltransferase III (GnTIII)) that modify glycoproteins such that antibodies expressed in the engineered cell lines exhibit an increase in bisecting GlcNac structures that result in increased ADCC activity of the antibodies (see also Umana et al., 1999 Nat. Biotech. 17:176-180). The contents of each of the foregoing applications and references are hereby incorporated by reference for this purpose.

[0091] Another modification in the antibodies herein contemplated herein is pegylation. Antibodies can be pegylated, for example, to increase the biological (e.g., serum) half-life of the antibody. To pegylate an antibody, typically, the antibody or a fragment thereof is reacted with polyethylene glycol (PEG), such as a reactive ester of PEG or an aldehyde derivative of PEG, under conditions in which one or more PEG groups are attached to the antibody or antibody fragment. Pegylation can be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or a similar reactive water-soluble polymer). As used herein, the term "polyethylene glycol" is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy-polyethylene glycol or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylation of proteins are known and can be applied to the antibodies described herein. See, for example, EP 0154316 and EP 0401384, the contents of each of which are incorporated herein by reference for this purpose.

[0092] Another modification of the antibodies contemplated is the conjugation or protein fusion of at least the antigen-binding region of the antibodies described herein to a serum protein, such as human serum albumin or a fragment thereof, to increase the half-life of the resulting molecule. Such an approach is described, for example, in EP 0 322 094, the contents of which are incorporated herein by reference for this purpose.

[0093] Another possibility is the fusion of at least the antigen-binding region of the antibody described herein to a protein capable of binding to a serum protein, such as human serum albumin, in order to increase the half-life of the resulting molecule. Such an approach is described, for example, in EP 0 486 525, the contents of which are incorporated herein by reference for this purpose.

[0094] Nucleic acid molecules encoding antibodies Another aspect relates to nucleic acid molecules encoding the antibodies described herein. As used herein, the term "nucleic acid" is used interchangeably with the term "polynucleotide" and refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single-stranded or double-stranded form. This term encompasses synthetic, naturally occurring, and non-naturally occurring nucleic acids that contain known nucleotide analogs or modified backbone residues or linkages, which have similar binding properties as the reference nucleic acid, and are metabolized in a manner similar to the reference nucleotide. Examples of such analogs include, but are not limited to, phosphorothioates, phosphoramidates, methyl phosphonates, chiral methyl phosphonates, 2-O-methyl ribonucleotides, peptide nucleic acids (PNAs). In some embodiments, the nucleic acid may be mRNA.

[0095] Unless otherwise indicated, a particular nucleic acid sequence implicitly encompasses not only the sequence explicitly indicated, but also conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences. In particular, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (see Batzer et al., Nucleic Acids Res 1991;25(19):5081; Ohtsuka et al., J Biol Chem 1985;260(5):2605-8; Rossolini et al., Mol Cell Probes 1994;8(2):91-8, the contents of each of which are incorporated herein by reference for this purpose.

[0096] Provided herein are exemplary full-length heavy and light chain nucleotide sequences of anti-NPR1 antibodies for use in the methods and uses described herein. In some embodiments, the nucleic acid molecules are one or more of those identified in Table 2, such as those encoding anti-NPR1 antibodies or antigen-binding fragments thereof. In some other embodiments, the nucleic acid molecules described herein comprise a nucleotide sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to the nucleotide sequences of those identified in Table 2. When expressed from an appropriate expression vector, the polypeptides encoded by these polynucleotides can bind to NPR1 protein (e.g., human NPR1).

[0097] Also provided herein are polynucleotides encoding at least one CDR region, and usually all three CDR regions, from the heavy and / or light chains of the anti-NPR1 antibodies or antigen-binding fragments described herein. Additionally, provided herein are polynucleotides encoding all or substantially all of the variable region sequences of the heavy and / or light chains of the exemplary anti-NPR1 antibodies or antigen-binding fragments described herein. Due to the degeneracy of the genetic code, a variety of nucleic acid sequences will encode each of the immunoglobulin amino acid sequences.

[0098] In some embodiments, the nucleic acid molecules described herein encode both the variable and constant regions of an antibody. In some embodiments, the nucleic acid molecules described herein comprise nucleotides encoding a full-length heavy chain sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to the heavy chain sequence of one of the antibodies described herein, including those in Table 2. In some embodiments, the nucleic acid molecules described herein comprise nucleotides encoding a full-length light chain sequence that is substantially identical (e.g., at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) to the light chain sequence of one of the antibodies described herein, including those in Table 2.

[0099] The nucleic acid may be present in whole cells, cell lysates, or may be in a partially purified or substantially pure form. A nucleic acid is "isolated" or "made substantially pure" when it is purified away from other cellular components or other contaminants, such as other cellular nucleic acids or proteins, by standard techniques including alkaline / SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis, and others well known in the art. See F. Ausubel, et al., ed. 1987 Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York, the contents of which are incorporated herein by reference for this purpose. The nucleic acids described herein may be, for example, DNA or RNA, and may or may not contain intron sequences. In some embodiments, the nucleic acid is a cDNA molecule. The nucleic acid may be present in a vector, such as a phage display vector, or a recombinant plasmid vector.

[0100] Nucleic acids for the uses and methods described herein can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas (e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as further described herein), cDNAs encoding the light and heavy chains of the antibodies produced by the hybridomas can be obtained by standard PCR amplification or cDNA cloning techniques. For antibodies obtained from an immunoglobulin gene library (e.g., using phage display techniques), nucleic acids encoding the antibodies can be recovered from various phage clones that are members of the library.

[0101] Polynucleotide sequences can be produced by de novo solid-phase DNA synthesis or PCR mutagenesis of existing sequences (e.g., sequences as described herein in Table 2). Direct chemical synthesis of nucleic acids can be accomplished by any known method, such as the phosphotriester method of Narang et al., 1979, Meth. Enzymol. 68:90; the phosphodiester method of Brown et al., Meth. Enzymol. 68:109, 1979; the diethyl phosphoramidite method of Beaucage et al., Tetra. Lett., 22:1859, 1981; and the solid support method of U.S. Pat. No. 4,458,066, the contents of each of which are incorporated herein by reference for this purpose. Introduction of mutations into a polynucleotide sequence by PCR can be performed, for example, as described in PCR Technology: Principles and Applications for DNA Amplification, H.A. Erlich (Ed.), Freeman Press, NY, NY, 1992; PCR Protocols: A Guide to Methods and Applications, Innis et al. (Ed.), Academic Press, San Diego, Calif, 1990; Mattila et al., Nucleic Acids Res. 19:967, 1991; and Eckert et al., PCR Methods and Applications 1:17, 1991.

[0102] Once the DNA fragments encoding the VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, e.g., the variable region genes are converted into full-length antibody chain genes, Fab fragment genes or scFv genes. In these manipulations, the VL- or VH-encoding DNA fragment is operably linked to another DNA molecule or fragment encoding another protein, e.g., an antibody constant region or a flexible linker. The term "operably linked" as used in this context is intended to mean that the two DNA fragments are linked in a functional manner, e.g., such that the amino acid sequences encoded by the two DNA fragments remain in frame or that the protein is expressed under the control of a desired promoter.

[0103] The isolated DNA encoding the VH region can be converted into a full-length heavy chain gene by operably linking the VH-encoding DNA to another DNA molecule encoding a heavy chain constant region (CH1, CH2 and CH3). The sequences of human heavy chain constant region genes are known (see, for example, Kabat, EA, el al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242, the contents of which are incorporated herein by reference for this purpose), and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. In some embodiments, the heavy chain constant region is an IgG1 isotype. For a Fab fragment heavy chain gene, the VH-encoding DNA can be operably linked to another DNA molecule encoding only the heavy chain CH1 constant region.

[0104] The isolated DNA encoding the VL region can be converted to a full-length light chain gene (and a Fab light chain gene) by operably linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL. The sequences of human light chain constant region genes are known (see, for example, Kabat, EA, et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242, the contents of which are incorporated herein by reference for this purpose), and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The light chain constant region can be a kappa or lambda constant region.

[0105] To create an scFv gene, the VH- and VL-encoding DNA fragments are operably linked to another fragment encoding a flexible linker such that the VH and VL sequences can be expressed as a continuous single-chain protein with the VL and VH regions connected by the flexible linker (see, e.g., Bird et al., 1988 Science 242:423-426; Huston et al., 1988 Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., 1990 Nature 348:552-554, the contents of each of which are incorporated herein by reference for this purpose).

[0106] vector A variety of expression vectors can be utilized to express polynucleotides encoding the antibodies or antigen-binding fragments thereof described herein. Both viral-based and non-viral expression vectors can be used to produce antibodies in mammalian host cells. Non-viral vectors and systems include plasmids, episomal vectors and human artificial chromosomes, typically with expression cassettes for expressing proteins or RNA (see, e.g., Harrington et al., Nat Genet. 15:345, 1997, the contents of which are incorporated herein by reference for this purpose). For example, non-viral vectors useful for expressing polynucleotides and polypeptides of the multispecific antibodies or domains thereof described herein in mammalian (e.g., human) cells include pThioHis A, B and C, pcDNA3.1 / His, pEBVHis A, B and C (Invitrogen, San Diego, Calif.), MPS V vectors and numerous other known vectors for expressing other proteins. Useful viral vectors include retroviruses, adenoviruses, adeno-associated viruses, herpes virus-based vectors, SV40-based vectors, papilloma viruses, HBP Epstein-Barr virus, vaccinia virus vectors, and Semliki Forest virus (SFV). See Brent et al., supra; Smith, Annu. Rev. Microbiol. 49:807, 1995; and Rosenfeld et al., Cell 68:143, 1992, the contents of each of which are incorporated herein by reference for this purpose.

[0107] The choice of expression vector depends on the intended host cell in which the vector will be expressed. Expression vectors for mammalian host cells can include expression control sequences such as replication origin, promoter and enhancer (see, for example, Queen, et al., Immunol. Rev. 89:49-68, 1986, the contents of which are incorporated herein by reference for this purpose), and necessary processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites and transcription terminator sequences. These expression vectors usually contain promoters derived from mammalian genes or from mammalian viruses. Suitable promoters can be constitutive promoters, cell type specific promoters, stage specific promoters and / or modifiable or regulatable promoters. Useful promoters include, but are not limited to, the metallothionein promoter, the constitutive adenovirus major late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP polIII promoter, the constitutive MPS V promoter, the tetracycline-inducible CMV promoter (such as the human immediate early CMV promoter), the constitutive CMV promoter, and known promoter-enhancer combinations.

[0108] Cultures of transformed organisms can be grown under non-inducing conditions without biasing the population of coding sequences whose expression products are well tolerated by the host cell. In addition to a promoter, other control elements may be necessary or desirable for efficient expression of the antibodies or fragments thereof described herein. These elements typically include an ATG initiation codon and adjacent ribosome binding sites or other sequences. In addition, the efficiency of expression can be enhanced by incorporating enhancers appropriate for the cell system used (see, for example, Scharf et al., Results Probl. Cell Differ. 20:125, 1994; and Bittner et al., Meth. Enzymol., 153:516, 1987, the contents of each of which are incorporated herein by reference for this purpose). For example, the SV40 enhancer or CMV enhancer can be used to increase expression in mammalian host cells.

[0109] Thus, for any of the uses or methods described herein, provided is a cloning or expression vector comprising one or more of the antibody nucleic acid sequences shown in Table 2. Additionally, for any of the uses or methods described herein, provided is a cloning or expression vector comprising a nucleic acid encoding one or more of the nucleotide sequences shown in Table 2.

[0110] host cell For expression of the light and heavy chains, the expression vector(s) encoding the heavy and light chains can be introduced into a host cell by standard techniques.

[0111] The method for introducing an expression vector containing a polynucleotide sequence of interest varies depending on the type of cell host. For example, calcium chloride transfection is generally used for prokaryotic cells, while calcium phosphate treatment or electroporation can be used for other cell hosts. (See generally Sambrook, et al., supra, the contents of which are incorporated herein by reference for this purpose). Other methods include, for example, electroporation, calcium phosphate treatment, liposome-mediated transformation, injection and microinjection, gene gun method, virosome, immunoliposome, polycationic nucleic acid conjugate, naked DNA, artificial virion, fusion with herpes virus structural protein VP22 (Elliot and O'Hare, Cell 88:223, 1997, the contents of which are incorporated herein by reference for this purpose), drug-enhanced uptake of DNA, and ex vivo transduction.

[0112] It is theoretically possible to express the antibodies described herein in either prokaryotic or eukaryotic host cells. Expression of antibodies in eukaryotic cells, particularly mammalian host cells, is argued because such eukaryotic cells, and particularly mammalian cells, are more likely than prokaryotic cells to assemble and secrete properly folded and immunologically active antibodies. Prokaryotic expression of antibody genes has been reported to be ineffective for producing high yields of active antibodies (Boss, MA and Wood, CR, 1985 Immunology Today 6:12-13, the contents of which are incorporated herein by reference for this purpose).

[0113] For long-term, high-yield production of recombinant proteins, stable expression is often desirable. For example, cell lines stably expressing the antibodies or antigen-binding fragments thereof described herein can be prepared using the expression vectors of the present disclosure, containing a viral origin of replication or endogenous expression elements and a selectable marker gene. After introduction of the vector, the cells can be grown in enriched medium for 1-2 days before switching to selective medium. The purpose of the selectable marker is to confer resistance to selection, allowing the cells to grow by their presence, thereby successfully expressing the introduced sequences in selective medium. Resistant, stably transfected cells can be grown using tissue culture methods appropriate for the cell type. Methods are provided for producing the antibodies or antigen-binding fragments described herein, comprising culturing a host cell containing nucleic acid encoding the antibody or antigen-binding fragment.

[0114] In some embodiments, mammalian host cells are used to express and produce the anti-NPR1 antibodies or antigen-binding fragments described herein for any of the uses and methods described herein. For example, they can be either hybridoma cell lines expressing endogenous immunoglobulin genes or mammalian cell lines carrying exogenous expression vectors. These include any normal mortal or normal or abnormal immortal animal cells or human cells. For example, several suitable host cell lines capable of secreting intact immunoglobulins have been developed, including CHO cell lines, various COS cell lines, HeLa cells, myeloma cell lines, transformed B cells and hybridomas. Exemplary host cells include, but are not limited to, Chinese hamster ovary (CHO) cells, human embryonic kidney (HEK) cells (e.g., HEK293, HEK293T, HEK293F), monkey kidney (COS) cells (e.g., COS-1, COS-7), baby hamster kidney (BHK) cells (e.g., BHK-21), African green monkey kidney cells (e.g., BSC-1), HeLa cells, human hepatocellular carcinoma cells (e.g., Hep G2), myeloma cells (e.g., NS0, 653, SP2 / 0), lymphoma cells, oocytes, and cells derived from transgenic animals (e.g., mammary epithelial cells) or any derivative, immortalized, or transformed cells thereof. In particular, for use with NS0 myeloma cells, another expression system is the GS gene expression system shown in WO 87 / 04462, WO 89 / 01036 and EP 0338841, the contents of each of which are incorporated herein by reference for this purpose. When a recombinant expression vector encoding an antibody nucleic acid is introduced into a mammalian host cell, the antibody is produced by culturing the host cell for a period of time sufficient to allow expression of the antibody within the host cell or secretion of the antibody into the culture medium in which the host cell is grown. The antibody may be recovered from the medium using standard protein purification methods. Such purified antibodies as described herein may be used for any purpose, including, but not limited to, the methods and uses described herein, and / or as part of a pharmaceutical composition as described herein.

[0115] In a further alternative, the host cell can be a yeast or filamentous fungus that has been engineered for a mammalian-like glycosylation pattern and is capable of producing antibodies that lack fucose as a glycosylation pattern (see, e.g., EP 1297172, the contents of which are incorporated herein by reference for this purpose).

[0116] Thus, for any of the uses or methods described herein, there is provided a host cell comprising one or more of the vectors or nucleic acid sequences described herein above.

[0117] Methods of Use and Treatment Therapeutic methods and pharmaceutical compositions for use Provided herein are methods and pharmaceutical compositions for use in treating diseases associated with loss of function of NPR1 by using the anti-NPR1 antibodies or antigen-binding fragments thereof described herein (e.g., an antibody or group of antibodies as defined in Table 2). In some embodiments, the antibody or antigen-binding fragment thereof may be selected from N001 (e.g., N001_DAPA or N001_LALA) and N002 (e.g., N002_DAPA or N002_LALA).

[0118] Provided herein is the use of an anti-NPR1 antibody or antigen-binding fragment thereof described herein (e.g., an antibody or group of antibodies defined in Table 2) and pharmaceutical compositions thereof to treat a disease associated with loss of function of NPR1. In some embodiments, the antibody or antigen-binding fragment thereof may be selected from N001 (e.g., N001_DAPA or N001_LALA) and N002 (e.g., N002_DAPA or N002_LALA).

[0119] Provided herein is an anti-NPR1 antibody or antigen-binding fragment thereof (e.g., an antibody or group of antibodies defined in Table 2) for the manufacture of a medicament for treating a disease associated with loss of function of NPR1. In some embodiments, the antibody or antigen-binding fragment thereof may be selected from N001 (e.g., N001_DAPA or N001_LALA) and N002 (e.g., N002_DAPA or N002_LALA).

[0120] In some embodiments, the antibody or antigen-binding fragment thereof may be selected from N001 (e.g., N001_DAPA or N001_LALA) and N002 (e.g., N002_DAPA or N002_LALA). In some embodiments, the antibody or antigen-binding fragment thereof may be selected from N001_DAPA. In some embodiments, the antibody or antigen-binding fragment thereof may be N001_LALA. In some embodiments, the antibody or antigen-binding fragment thereof may be N002_DAPA. In some embodiments, the antibody or antigen-binding fragment thereof may be N002_LALA.

[0121] In some embodiments, the disease associated with loss of function of NPR1 is a cardiovascular disorder. In some embodiments, the cardiovascular disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, myocardial fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, and myocardial infarction (MI). In some embodiments, the disease associated with loss of function of NPR1 is heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma, or cytokine release syndrome. In some embodiments, the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure. In some embodiments, the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments, the hypertension is selected from resistant hypertension, hypertensive heart disease, pulmonary hypertension, isolated systolic hypertension, and pulmonary arterial hypertension. In some embodiments, the hypertension is selected from resistant hypertension and hypertensive heart disease.

[0122] In some embodiments, the disease associated with loss of function of NPR1 is a renal disorder. In some embodiments, the renal disorder is selected from diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD).

[0123] NPR1-associated disorders also include any other disorders directly or indirectly associated with abnormal NPR1 activity and / or expression. Also provided herein are methods of treating NPR1-associated disorders directly or indirectly associated with abnormal NPR1 activity and / or expression by using the anti-NPR1 antibodies or antigen-binding fragments described herein (e.g., N001_DAPA or N001_LALA, etc., from Table 2).

[0124] In some embodiments, a method of treating an undesirable condition, disease or disorder associated with natriuretic peptide receptor activity in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment described herein. In some embodiments, a use of an antibody or antigen-binding fragment described herein for treating an undesirable condition, disease or disorder associated with natriuretic peptide receptor activity in a subject in need thereof is provided. In some embodiments, an antibody or antigen-binding fragment described herein for use in a method for treating an undesirable condition, disease or disorder associated with natriuretic peptide receptor activity is provided. In some embodiments, an antibody or antigen-binding fragment described herein for use in the manufacture of a medicament for treating an undesirable condition, disease or disorder associated with natriuretic peptide receptor activity is provided.Such conditions, diseases, and disorders include cardiovascular disorders (e.g., hypertension, peripheral vascular disease, heart failure (including, but not limited to, heart failure with reduced ejection fraction (HFrEF), heart failure with moderate or mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction or acute decompensated heart failure), coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina pectoris, hypertrophic cardiomyopathy (e.g., ventricular hypertrophy), diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, myocardial fibrosis, atrial flutter, These conditions include, but are not limited to, adverse vascular remodeling, plaque stabilization or myocardial infarction (MI), hypertension (e.g., resistant hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, resistant hypertension or pulmonary arterial hypertension), pre-eclampsia, asthma, glaucoma, cytokine release syndrome and / or renal disorders (e.g., diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)).

[0125] In some aspects, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, Provided herein are methods comprising administering to a subject about 0 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) comprises administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) comprises administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) comprises administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.In some embodiments, a method of treating a cardiovascular disorder in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, Provided herein are methods that include administering 10 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to a subject. In some embodiments, a method of treating a cardiovascular disorder in a subject in need thereof includes administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, the method of treating a cardiovascular disorder in a subject in need thereof comprises administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, the method of treating a cardiovascular disorder in a subject in need thereof comprises administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., pre-eclampsia, asthma, glaucoma, cytokine release syndrome, or renal disorders such as diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy, and end-stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD)) in a subject in need thereof, comprising administering to a subject at a concentration of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of NPR1. Provided herein are methods that include administering to a subject about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., pre-eclampsia, asthma, glaucoma, cytokine release syndrome or renal disorders such as diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)) comprises administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., pre-eclampsia, asthma, glaucoma, cytokine release syndrome or renal disorders such as diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)) comprises administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., pre-eclampsia, asthma, glaucoma, cytokine release syndrome or renal disorders such as diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)) comprises administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 70 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 80 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 90 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 100 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 110 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral valve. Provided herein is a method for treating stenosis and mitral regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, the method comprising administering about 130 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 140 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 150 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 160 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 170 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 180 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 190 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 200 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.

[0126] In some aspects, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, Provided herein are methods comprising administering to a subject about 0 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) comprises administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) comprises administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) comprises administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.

[0127] In some embodiments, a method of treating a cardiovascular disorder in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, Provided herein are methods that include administering 10 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to a subject. In some embodiments, a method of treating a cardiovascular disorder in a subject in need thereof includes administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, the method of treating a cardiovascular disorder in a subject in need thereof comprises administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, the method of treating a cardiovascular disorder in a subject in need thereof comprises administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.

[0128] In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., pre-eclampsia, asthma, glaucoma, cytokine release syndrome, or renal disorders such as diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy, and end-stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD)) in a subject in need thereof, comprising administering to a subject at a concentration of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of NPR1. Provided herein are methods that include administering to a subject about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., pre-eclampsia, asthma, glaucoma, cytokine release syndrome or renal disorders such as diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)) comprises administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., pre-eclampsia, asthma, glaucoma, cytokine release syndrome or renal disorders such as diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)) comprises administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., pre-eclampsia, asthma, glaucoma, cytokine release syndrome or renal disorders such as diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end stage renal disease (ESRD), endothelial cell dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)) comprises administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.

[0129] In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 70 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 80 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 90 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 100 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.

[0130] In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 110 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 130 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 140 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 150 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 160 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 170 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 180 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 190 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 200 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.

[0131] In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 210 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 220 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 230 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 300 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 350 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 400 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 450 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 500 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 550 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 600 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 650 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, provided herein is a method of treating hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, or myocardial infarction (MI) in a subject in need thereof, comprising administering about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.

[0132] In some embodiments, a method of treating heart failure in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 ... Provided herein are methods comprising administering 10 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to a subject. In some embodiments, provided herein are methods of treating heart failure in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating heart failure in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating heart failure in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, a method of treating heart failure with reduced ejection fraction (HFrEF) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, Provided herein are methods of treating heart failure with reduced ejection fraction (HFrEF) in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein are methods of treating heart failure with reduced ejection fraction (HFrEF) in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating heart failure with reduced ejection fraction (HFrEF) in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating heart failure with reduced ejection fraction (HFrEF) in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, a method of treating heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF) in a subject in need thereof comprises administering at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 50 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about Provided herein are methods comprising administering to a subject about 1 g, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, provided herein is a method of treating heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF) in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF) in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF) in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, a method of treating heart failure with preserved ejection fraction (HFpEF) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about Provided herein are methods that include administering to a subject 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating heart failure following acute myocardial infarction in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, or about 250 mg of the active ingredient, Provided herein are methods comprising administering to a subject about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.In some embodiments, a method of treating acute decompensation in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about Provided herein are methods that include administering to a subject 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.

[0133] In some embodiments, a method of treating hypertension in a subject in need thereof includes administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about Provided herein are methods comprising administering 10 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to a subject. In some embodiments, provided herein are methods of treating hypertension in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension in a subject in need thereof, the method comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating hypertension in a subject in need thereof, the method comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, a method of treating resistant hypertension in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about Provided herein are methods comprising administering to a subject 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, provided herein are methods of treating resistant hypertension in a subject in need thereof, comprising administering to the subject about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, provided herein is a method of treating resistant hypertension in a subject in need thereof, the method comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject. In some embodiments, provided herein is a method of treating resistant hypertension in a subject in need thereof, the method comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject.In some embodiments, a method of treating hypertensive heart disease in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, Provided herein are methods that include administering to a subject about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating pulmonary hypertension in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, Provided herein are methods that include administering to a subject 10 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.In some embodiments, a method of treating pulmonary arterial hypertension in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about Provided herein are methods that include administering to a subject 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. In some embodiments, a method of treating systolic hypertension in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about Provided herein are methods that include administering to a subject 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof.

[0134] In some embodiments, any of the methods or uses described herein comprises administering an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof about once per week, once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0135] In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every week.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every two weeks.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least one of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 210 mg. Provided herein are methods comprising administering about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 3 weeks.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least one of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 210 mg. Provided herein are methods comprising administering about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 4 weeks.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 5 weeks.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 6 weeks.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 7 weeks.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 8 weeks.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 9 weeks. In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, The method comprises administering to a subject about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof, In some embodiments, a method is provided herein for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof, comprising administering at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, or an antigen-binding fragment thereof every 10 weeks. Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 11 weeks.In some embodiments, a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, Provided herein are methods comprising administering about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 12 weeks.

[0136] In certain embodiments, provided herein is a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof using an escalating regimen. In such a regimen, the patient receives an initial dose that is lower than the secondary or subsequent doses. In certain embodiments, the patient may also receive a tertiary dose that is higher than the secondary dose. In certain embodiments, the patient may also receive a quaternary dose that is higher than the tertiary dose. In certain embodiments, the patient may also receive one or more subsequent doses (e.g., quaternary, seventh, eighth, etc.), each higher (e.g., in mg) than the preceding dose. In certain embodiments, the dose escalation reaches and is maintained at a maximum dose level.

[0137] In certain embodiments, provided herein are methods for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. As a non-limiting set of examples, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg may be initially administered, and secondary or subsequent administrations may be administered in the form of, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg, so long as the secondary dose is greater than the initial dose. The amount of the anti-NPR1 antibody or antigen-binding fragment thereof may be about 0 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of the anti-NPR1 antibody or antigen-binding fragment thereof.

[0138] In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered, for example, every week to a patient with a cardiovascular disorder for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks or about 8 weeks. In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered, for example, every two weeks to a patient with a cardiovascular disorder for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks or about 10 weeks. In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered, for example, every two weeks to a patient with a cardiovascular disorder for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks or about 10 weeks. In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered, for example, every three weeks to a patient with a cardiovascular disorder for about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks or about 15 weeks. In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered monthly, for example, for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months or about 8 months to a patient with a cardiovascular disorder.

[0139] In certain embodiments, the duration of each dose may not be equal. For example, an initial dose (e.g., about 30 mg) may be administered on day 1; a secondary dose (e.g., about 60 mg) may be administered on week 2; and a tertiary dose (e.g., about 120 mg) may be administered once every month thereafter (i.e., week 4, week 8, week 12, etc.).

[0140] As a non-limiting example, in certain embodiments, a patient with a cardiovascular disorder can be administered an initial dose of about 30 mg, and the initial dose can be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient can then be administered a secondary dose of about 60 mg, and the secondary dose can be administered one or more times (e.g., 2, 3, 4, or 5 times); or can be maintained at this dose for as long as necessary.

[0141] As a non-limiting example, in certain embodiments, a patient with a cardiovascular disorder may be administered an initial dose of about 30 mg, and the initial dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a secondary dose of about 60 mg, and the secondary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a tertiary dose of about 120 mg, and the tertiary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a quaternary dose of about 240 mg, and the quaternary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times); or may be maintained at this dose for as long as necessary.

[0142] As a non-limiting example, in certain embodiments, a patient with a cardiovascular disorder may be administered an initial dose of about 30 mg, and the initial dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a secondary dose of about 60 mg, and the secondary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a tertiary dose of about 120 mg, and the tertiary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times); or may be maintained at this dose for as long as necessary.

[0143] As a non-limiting example, in certain embodiments, a patient with a cardiovascular disorder can be administered an initial dose of about 60 mg, and the initial dose can be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient can then be administered a secondary dose of about 120 mg, and the secondary dose can be administered one or more times (e.g., 2, 3, 4, or 5 times); or can be maintained at this dose for as long as necessary.

[0144] As a non-limiting example, in certain embodiments, a patient with a cardiovascular disorder may be administered an initial dose of about 60 mg, and the initial dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a secondary dose of about 120 mg, and the secondary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a tertiary dose of about 240 mg, and the tertiary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times); or may be maintained at this dose for as long as necessary.

[0145] As a non-limiting example, in certain embodiments, a patient with a cardiovascular disorder can be administered an initial dose of about 120 mg, and the initial dose can be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient can then be administered a secondary dose of about 240 mg, and the secondary dose can be administered one or more times (e.g., 2, 3, 4, or 5 times); or can be maintained at this dose for as long as necessary.

[0146] As a non-limiting example, in certain embodiments, a patient with a cardiovascular disorder can be administered an initial dose of about 60 mg, and the initial dose can be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient can then be administered a secondary dose of about 240 mg, and the secondary dose can be administered one or more times (e.g., 2, 3, 4, or 5 times); or can be maintained at this dose for as long as necessary.

[0147] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with a cardiovascular disorder at an initial dose of about 30 mg on days 1 and 2; then at secondary doses of about 60 mg every 4 weeks (i.e., at weeks 4, 8, 12, etc.).

[0148] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with a cardiovascular disorder at an initial dose of about 60 mg on days 1 and 2; then at secondary doses of about 120 mg every 4 weeks (i.e., at weeks 4, 8, 12, etc.).

[0149] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with a cardiovascular disorder at an initial dose of about 30 mg on day 1; a secondary dose of about 60 mg can be administered in week 2; and a tertiary dose of about 120 mg every four weeks thereafter (i.e., at weeks 4, 8, 12, etc.).

[0150] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with a cardiovascular disorder at an initial dose of about 60 mg on day 1; then at secondary doses of about 120 mg every four weeks (i.e., at weeks 4, 8, 12, etc.).

[0151] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with a cardiovascular disorder at an initial dose of about 120 mg on day 1; then at secondary doses of about 240 mg every four weeks (i.e., at weeks 4, 8, 12, etc.).

[0152] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with a cardiovascular disorder at an initial dose of about 30 mg on day 1; a secondary dose of about 60 mg can be administered on week 2; a tertiary dose of about 120 mg can be administered on week 4; and a quaternary dose of about 240 mg every four weeks thereafter (i.e., on weeks 8, 12, etc.).

[0153] In certain embodiments, provided herein are methods of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof. As a non-limiting set of examples, initial administration of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg is an example of a method for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., a cardiovascular disorder). and the second or subsequent administrations can be higher, including, for example, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody or antigen-binding fragment thereof. In one embodiment, about 120 mg of an anti-NPR1 antibody is administered in one or more initial doses (e.g., a first or second dose) and about 240 mg of an anti-NPR1 antibody or antigen-binding fragment thereof is administered in a second or subsequent dose (e.g., a second dose, a third dose, or an additional dose).

[0154] In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every week. In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every two weeks.In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 3 weeks. In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 4 weeks.In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 5 weeks. In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 6 weeks.In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 7 weeks. In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 8 weeks.In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about Provided herein are methods comprising administering 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 9 weeks. In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 10 weeks.In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N. Provided herein are methods comprising administering an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof is administered about every 11 weeks. In some embodiments, a method of treating heart failure (e.g., HFrEF) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 12 weeks.

[0155] In some embodiments, provided herein is a method of treating heart failure in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating heart failure in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating heart failure in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0156] In some embodiments, provided herein is a method of treating heart failure with reduced ejection fraction in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating heart failure with reduced ejection fraction in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating heart failure with reduced ejection fraction in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0157] In some embodiments, provided herein is a method of treating heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF) in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF) in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF) in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0158] In certain embodiments, provided herein is a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF))) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof using an escalating regimen. In such a regimen, the patient receives an initial dose that is lower than the secondary or subsequent doses. In certain embodiments, the patient may also receive a tertiary dose that is higher than the secondary dose. In certain embodiments, the patient may also receive a quaternary dose that is higher than the tertiary dose. In certain embodiments, the patient may also receive one or more subsequent doses (e.g., quaternary, seventh, eighth, etc.), each higher (e.g., in mg) than the preceding dose. In certain embodiments, the dose escalation reaches and is maintained at a maximum dose level.

[0159] In certain embodiments, provided herein are methods of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF))) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. As a non-limiting set of examples, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg may be initially administered, and secondary or subsequent administrations may be administered in the form of, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg, so long as the secondary dose is greater than the initial dose. The amount of the anti-NPR1 antibody or antigen-binding fragment thereof may be about 0 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of the anti-NPR1 antibody or antigen-binding fragment thereof.

[0160] In one embodiment, the initial, secondary, tertiary, quaternary, or further doses can be administered weekly for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks, for example, to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)). In one embodiment, the initial, secondary, tertiary, quaternary, or further doses can be administered every two weeks for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, or about 10 weeks, for example, to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)). In one embodiment, the initial, secondary, tertiary, quaternary, or further doses can be administered, for example, every two weeks for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, or about 10 weeks to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)). In one embodiment, the initial, secondary, tertiary, quaternary, or further doses can be administered, for example, every three weeks for about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks, or about 15 weeks to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)). In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered monthly, for example, for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, or about 8 months to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)).

[0161] In certain embodiments, the duration of each dose may not be equal. For example, an initial dose (e.g., about 30 mg) may be administered on day 1; a secondary dose (e.g., about 60 mg) may be administered on week 2; and a tertiary dose (e.g., about 120 mg) may be administered once every month thereafter (i.e., week 4, week 8, week 12, etc.).

[0162] As a non-limiting example, in certain embodiments, a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) may be administered an initial dose of about 30 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses may be administered. Such a patient may then be administered a secondary dose of about 60 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses; or may be maintained at this dose for as long as necessary.

[0163] As a non-limiting example, in certain embodiments, a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) may be administered an initial dose of about 30 mg, and the initial dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a secondary dose of about 60 mg, and the secondary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a tertiary dose of about 120 mg, and the tertiary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a quaternary dose of about 240 mg, and the quaternary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times); or may be maintained at this dose for as long as necessary.

[0164] As a non-limiting example, in certain embodiments, a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) may be administered an initial dose of about 30 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses may be administered. Such a patient may then be administered a secondary dose of about 60 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses may be administered. Such a patient may then be administered a tertiary dose of about 120 mg, and one or more (e.g., 2, 3, 4, or 5) tertiary doses may be administered; or may be maintained at this dose for as long as necessary.

[0165] As a non-limiting example, in certain embodiments, a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) can be administered an initial dose of about 60 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses can be administered. Such a patient can then be administered a secondary dose of about 120 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses can be administered; or can be maintained at this dose for as long as necessary.

[0166] As a non-limiting example, in certain embodiments, a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) may be administered an initial dose of about 60 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses may be administered. Such a patient may then be administered a secondary dose of about 120 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses may be administered. Such a patient may then be administered a tertiary dose of about 240 mg, and one or more (e.g., 2, 3, 4, or 5) tertiary doses may be administered; or may be maintained at this dose for as long as necessary.

[0167] As a non-limiting example, in certain embodiments, a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) can be administered an initial dose of about 120 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses can be administered. Such a patient can then be administered a secondary dose of about 240 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses can be administered; or can be maintained at this dose for as long as necessary.

[0168] As a non-limiting example, in certain embodiments, a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) can be administered an initial dose of about 60 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses can be administered. Such a patient can then be administered a secondary dose of about 240 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses can be administered; or can be maintained at this dose for as long as necessary.

[0169] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) at an initial dose of about 30 mg on days 1 and 2; and then at secondary doses of about 60 mg every four weeks (i.e., at weeks 4, 8, 12, etc.).

[0170] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) at an initial dose of about 60 mg on days 1 and 2; and then at secondary doses of about 120 mg every four weeks (i.e., at weeks 4, 8, 12, etc.).

[0171] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) at an initial dose of about 30 mg on day 1; at a secondary dose of about 60 mg in week 2; and at a tertiary dose of about 120 mg every four weeks thereafter (i.e., at weeks 4, 8, 12, etc.).

[0172] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) at an initial dose of about 60 mg on day 1; and then at secondary doses of about 120 mg every four weeks (i.e., at weeks 4, 8, 12, etc.).

[0173] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) at an initial dose of about 120 mg on day 1; and then at secondary doses of about 240 mg every four weeks (i.e., at weeks 4, 8, 12, etc.).

[0174] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) at an initial dose of about 30 mg on day 1; at a secondary dose of about 60 mg on week 2; at a tertiary dose of about 120 mg on week 4; and at a quaternary dose of about 240 mg every four weeks thereafter (i.e., on weeks 8, 12, etc.).

[0175] In certain embodiments, provided herein are methods of treating heart failure (e.g., heart failure with reduced ejection fraction (HFrEF); or heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF)) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof. As a non-limiting set of examples, initial administration of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg is preferred. and the second or subsequent administrations can be higher, including, for example, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody or antigen-binding fragment thereof. In one embodiment, about 120 mg of an anti-NPR1 antibody is administered in one or more initial doses (e.g., a first or second dose) and about 240 mg of an anti-NPR1 antibody or antigen-binding fragment thereof is administered in a second or subsequent dose (e.g., a second dose, a third dose, or an additional dose).

[0176] In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every week. In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every two weeks.In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 3 weeks. In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 4 weeks.In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 5 weeks. In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 6 weeks.In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 7 weeks. In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 8 weeks.In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 9 weeks. In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering to a subject at least about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 10 weeks.In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, About 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or Provided herein are methods comprising administering an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 11 weeks. In some embodiments, a method of treating hypertension (e.g., rHTN) in a subject in need thereof comprises administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about Provided herein are methods comprising administering 50 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof to a subject, wherein the anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof is administered about every 12 weeks.

[0177] In some embodiments, provided herein is a method of treating hypertension in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating hypertension in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating hypertension in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0178] In some embodiments, provided herein is a method of treating resistant hypertension in a subject in need thereof, comprising administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating resistant hypertension in a subject in need thereof, comprising administering about 120 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks. In some embodiments, provided herein is a method of treating resistant hypertension in a subject in need thereof, comprising administering about 240 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof to the subject, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0179] In certain embodiments, provided herein is a method of treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., hypertension (e.g., resistant hypertension (rHTN))) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof using an escalating regimen. In such a regimen, the patient receives an initial dose that is lower than the secondary or subsequent doses. In certain embodiments, the patient may also receive a tertiary dose that is higher than the secondary dose. In certain embodiments, the patient may also receive a quaternary dose that is higher than the tertiary dose. In certain embodiments, the patient may also receive one or more subsequent doses (e.g., quaternary, seventh, eighth, etc.), each higher (e.g., in mg) than the preceding dose. In certain embodiments, the dose escalation reaches and is maintained at a maximum dose level.

[0180] In certain embodiments, provided herein are methods for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity (e.g., hypertension (e.g., resistant hypertension (rHTN))) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof. As a non-limiting set of examples, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg may be initially administered, and secondary or subsequent administrations may be administered in the form of, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg, so long as the secondary dose is greater than the initial dose. The amount of the anti-NPR1 antibody or antigen-binding fragment thereof may be about 0 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of the anti-NPR1 antibody or antigen-binding fragment thereof.

[0181] In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered, for example, every week for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks or about 8 weeks to a patient with hypertension (e.g., resistant hypertension (rHTN)). In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered, for example, every two weeks for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks or about 10 weeks to a patient with hypertension (e.g., resistant hypertension (rHTN)). In one embodiment, the initial, secondary, tertiary, quaternary or further doses can be administered, for example, every two weeks for about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks or about 10 weeks to a patient with hypertension (e.g., resistant hypertension (rHTN)). In one embodiment, the initial, secondary, tertiary, quaternary, or further doses can be administered, for example, every three weeks for about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks, or about 15 weeks to a patient with hypertension (e.g., resistant hypertension (rHTN)). In one embodiment, the initial, secondary, tertiary, quaternary, or further doses can be administered, for example, every month for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, or about 8 months to a patient with hypertension (e.g., resistant hypertension (rHTN)).

[0182] In certain embodiments, the duration of each dose may not be equal. For example, an initial dose (e.g., about 30 mg) may be administered on day 1; a secondary dose (e.g., about 60 mg) may be administered on week 2; and a tertiary dose (e.g., about 120 mg) may be administered once every month thereafter (i.e., week 4, week 8, week 12, etc.).

[0183] As a non-limiting example, in certain embodiments, a patient with hypertension (e.g., resistant hypertension (rHTN)) can be administered an initial dose of about 30 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses can be administered. Such a patient can then be administered a secondary dose of about 60 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses can be administered; or can be maintained at this dose for as long as necessary.

[0184] As a non-limiting example, in certain embodiments, a patient with hypertension (e.g., resistant hypertension (rHTN)) may be administered an initial dose of about 30 mg, and the initial dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a secondary dose of about 60 mg, and the secondary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a tertiary dose of about 120 mg, and the tertiary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a quaternary dose of about 240 mg, and the quaternary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times); or may be maintained at this dose for as long as necessary.

[0185] As a non-limiting example, in certain embodiments, a patient with hypertension (e.g., resistant hypertension (rHTN)) may be administered an initial dose of about 30 mg, and the initial dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a secondary dose of about 60 mg, and the secondary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a tertiary dose of about 120 mg, and the tertiary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times); or may be maintained at this dose for as long as necessary.

[0186] As a non-limiting example, in certain embodiments, a patient with hypertension (e.g., resistant hypertension (rHTN)) can be administered an initial dose of about 60 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses can be administered. Such a patient can then be administered a secondary dose of about 120 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses can be administered; or can be maintained at this dose for as long as necessary.

[0187] As a non-limiting example, in certain embodiments, a patient with hypertension (e.g., resistant hypertension (rHTN)) may be administered an initial dose of about 60 mg, and the initial dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a secondary dose of about 120 mg, and the secondary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times). Such a patient may then be administered a tertiary dose of about 240 mg, and the tertiary dose may be administered one or more times (e.g., 2, 3, 4, or 5 times); or may be maintained at this dose for as long as necessary.

[0188] As a non-limiting example, in certain embodiments, a patient with hypertension (e.g., resistant hypertension (rHTN)) can be administered an initial dose of about 120 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses can be administered. Such a patient can then be administered a secondary dose of about 240 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses can be administered; or can be maintained at this dose for as long as necessary.

[0189] As a non-limiting example, in certain embodiments, a patient with hypertension (e.g., resistant hypertension (rHTN)) can be administered an initial dose of about 60 mg, and one or more (e.g., 2, 3, 4, or 5) initial doses can be administered. Such a patient can then be administered a secondary dose of about 240 mg, and one or more (e.g., 2, 3, 4, or 5) secondary doses can be administered; or can be maintained at this dose for as long as necessary.

[0190] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with hypertension (e.g., resistant hypertension (rHTN)) at an initial dose of about 30 mg on days 1 and 2; then at secondary doses of about 60 mg every 4 weeks (i.e., at weeks 4, 8, 12, etc.).

[0191] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with hypertension (e.g., resistant hypertension (rHTN)) at an initial dose of about 60 mg on days 1 and 2; then at secondary doses of about 120 mg every 4 weeks (i.e., at weeks 4, 8, 12, etc.).

[0192] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with hypertension (e.g., resistant hypertension (rHTN)) at an initial dose of about 30 mg on day 1; at a secondary dose of about 60 mg in week 2; and at a tertiary dose of about 120 mg every four weeks thereafter (i.e., at weeks 4, 8, 12, etc.).

[0193] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with hypertension (e.g., resistant hypertension (rHTN)) at an initial dose of about 60 mg on day 1; then at secondary doses of about 120 mg every four weeks (i.e., at weeks 4, 8, 12, etc.).

[0194] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with hypertension (e.g., resistant hypertension (rHTN)) at an initial dose of about 120 mg on day 1; then secondary doses of about 240 mg every four weeks (i.e., at weeks 4, 8, 12, etc.).

[0195] In certain embodiments, an anti-NPR1 antibody can be administered to a patient with hypertension (e.g., resistant hypertension (rHTN)) at an initial dose of about 30 mg on day 1; at a secondary dose of about 60 mg on week 2; at a tertiary dose of about 120 mg on week 4; and at a quaternary dose of about 240 mg every four weeks thereafter (i.e., on weeks 8, 12, etc.).

[0196] In certain embodiments, provided herein are methods of treating hypertension (e.g., resistant hypertension (rHTN)) in a subject in need thereof, comprising administering to the subject different amounts of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or antigen-binding fragment thereof. As a non-limiting set of examples, initial administration of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg is an example. and the second or subsequent administrations can be higher, including, for example, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody or antigen-binding fragment thereof. In one embodiment, about 120 mg of an anti-NPR1 antibody is administered in one or more initial doses (e.g., a first or second dose) and about 240 mg of an anti-NPR1 antibody or antigen-binding fragment thereof is administered in a second or subsequent dose (e.g., a second dose, a third dose, or an additional dose).

[0197] Any of the doses, methods or uses described herein may be administered to a patient undergoing one or more additional therapies, including, but not limited to, those described herein. As a non-limiting example, a method of treating a cardiovascular disorder (e.g., heart failure such as HFrEF or hypertension such as resistant hypertension) in a subject in need thereof may include administering about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg Provided herein are methods comprising administering to a subject about 0 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof, wherein the subject is receiving or is being administered one or more additional therapeutically active agents (e.g., an ACE (angiotensin-converting enzyme) inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, a diuretic, or a combination thereof). In some embodiments, a method of treating a cardiovascular disorder in a subject in need thereof comprises administering about 60 mg of an anti-NPR1 antibody (e.g., N001_DAPA or N001_LALA) or an antigen-binding fragment thereof, wherein the subject is receiving or is being administered one or more additional therapeutically active agents (e.g., an ACE (...

Claims

1. A method for treating a disorder or disease associated with natriuretic peptide receptor 1 (NPR1) activity in a subject in need thereof, comprising administering to the subject about 10 mg to about 700 mg of an anti-NPR1 antibody or antigen-binding fragment thereof.

2. The method of claim 1, wherein the disorder or disease associated with natriuretic peptide receptor activity is a cardiovascular disorder.

3. 3. The method of claim 2, wherein the cardiovascular disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, myocardial fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, and myocardial infarction (MI).

4. The method of claim 2 or 3, wherein the cardiovascular disorder is heart failure.

5. 5. The method of claim 4, wherein the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction or acute decompensated heart failure.

6. 6. The method of claim 4 or 5, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF).

7. 4. The method of claim 2 or 3, wherein the cardiovascular disorder is hypertension.

8. 8. The method of claim 7, wherein the hypertension is selected from resistant hypertension, hypertensive heart disease, pulmonary hypertension, isolated systolic hypertension and pulmonary arterial hypertension.

9. 9. The method of claim 7 or 8, wherein the hypertension is resistant hypertension.

10. The anti-NPR1 antibody or antigen-binding fragment thereof comprises: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO: 8 (HCDR1), SEQ ID NO: 9 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 22 (LCDR3); or (IV) SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3) The method according to any one of claims 1 to 9, comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from:

11. The anti-NPR1 antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

24. The method according to any one of claims 1 to 10, comprising:

12. The anti-NPR1 antibody or antigen-binding fragment thereof comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising the amino acid sequence of SEQ ID NO: 26; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 26 The method according to any one of claims 1 to 11, comprising:

13. The anti-NPR1 antibody or antigen-binding fragment thereof comprises: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (III) SEQ ID NO: 8 (HCDR1), SEQ ID NO: 9 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 35 (LCDR3); or (IV) SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 34 (LCDR3) The method according to any one of claims 1 to 9, comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from:

14. The anti-NPR1 antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

36. The method according to any one of claims 1 to 9 and 13, comprising:

15. The anti-NPR1 antibody or antigen-binding fragment thereof comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising the amino acid sequence of SEQ ID NO: 38; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO:

38. The method according to any one of claims 1 to 9, 13 and 14, comprising:

16. The method of any one of claims 1 to 15, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is therapeutic.

17. The antigen-binding fragment may be Fab, Fab', F(ab') ２ 17. The method of any one of claims 1 to 16, wherein the antibody is selected from the group consisting of Fv and single chain variable fragment (scFv).

18. The method of any one of claims 1 to 17, wherein about 60 mg, about 120 mg, about 240 mg, about 450 mg, or about 600 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject.

19. The method of any one of claims 1 to 18, wherein about 120 mg or about 240 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject.

20. The method of any one of claims 1 to 19, wherein one or more additional therapeutically active agents are administered to the subject.

21. 21. The method of any one of claims 1 to 20, wherein the one or more additional therapeutically active agents are selected from ACE (angiotensin converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, beta blockers, diuretics, calcium channel blockers, cardiac glycosides, sodium-glucose cotransporter 2 inhibitors (SGLT2i), angiotensin receptor-neprilysin inhibitors (ARNi), corticosteroids, leukotriene modifiers, bronchodilators, beta-adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha2-adrenergic receptor agonists, parasympathomimetics, prostaglandin analogues, rho-kinase inhibitors, cell therapy, cardiac specific myosin activators and combinations thereof.

22. 22. The method of any one of claims 1 to 21, wherein the one or more additional therapeutically active agents are ACE (angiotensin converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, diuretics or combinations thereof.

23. The one or more additional therapeutically active agents may be enalapril, benazepril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propanolol, metoprolol, metoprolol tartrate, metoprolol succinate, a thiazide diuretic, Loop diuretics, potassium-sparing diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, digitalis glycosides, canagliflozin, dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, fineron , spironolactone, triamterene, digoxin, fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, fluticasone furoate, prednisone, methylprednisolone, montelukast, zafirlukast, zileuton, long-acting beta agonists, short-acting beta agonists, theophylline, ipratropium, salmeterol, formoterol, albuterol, levalbuterol, timolol, levobunolol, metipranolol, carteolol, bevacizumab, cefotaxime ...

23. The method of any one of claims 1 to 22, wherein the therapeutic agent is selected from taxolol, acetazolamide, dorzolamide, brinzolamide, methazolamide, brimonidine, apraclonidine, cholinergic agents, latanoprost, latanoprost bunod, travoprost, bimatoprost, tafluprost, omecamtiv mecarbil, allogeneic cell therapy Revascor mestrocel-L (REVASCOR®), CardiAMP™ cell therapy, netarsudil, ripasudil, and combinations thereof.

24. The method of any one of claims 1 to 23, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered subcutaneously to the subject.

25. The method of any one of claims 1 to 24, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once per week, once per 2 weeks, once per 3 weeks, once per 4 weeks, once per 5 weeks, once per 6 weeks, once per 7 weeks, once per 8 weeks, once per 9 weeks, once per 10 weeks, once per 11 weeks, or once per 12 weeks.

26. The method of any one of claims 1 to 25, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is administered about once every four weeks.

27. An anti-NPR1 antibody or antigen-binding fragment thereof for use in a method for treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need thereof, wherein the anti-NPR1 antibody or antigen-binding fragment thereof is provided for administration at a dose ranging from about 10 mg to about 700 mg.

28. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to claim 27, wherein the disorder or disease associated with natriuretic peptide receptor activity is a cardiovascular disorder.

29. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to claim 28, wherein the cardiovascular disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and mitral regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset atrial fibrillation, recurrent atrial fibrillation, myocardial fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization and myocardial infarction (MI).

30. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to claim 28 or 29, wherein the cardiovascular disorder is heart failure.

31. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to claim 30, wherein the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with moderate ejection fraction or heart failure with mildly reduced ejection fraction, heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction or acute decompensated heart failure.

32. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to claim 30 or 31, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF).

33. 30. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to claim 28 or 29, wherein the cardiovascular disorder is hypertension.

34. 34. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to claim 33, wherein the hypertension is selected from resistant hypertension, hypertensive heart disease, pulmonary hypertension, isolated systolic hypertension and pulmonary arterial hypertension.

35. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to claim 33 or 34, wherein the hypertension is resistant hypertension.

36. (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO: 8 (HCDR1), SEQ ID NO: 9 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 22 (LCDR3); or (IV) SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3) An anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 35, comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from the group consisting of:

37. (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

24.

37. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 36, comprising:

38. (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising the amino acid sequence of SEQ ID NO: 26; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 26 38. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 37, comprising:

39. (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:34 (LCDR3); (III) SEQ ID NO: 8 (HCDR1), SEQ ID NO: 9 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2) and SEQ ID NO: 35 (LCDR3); or (IV) SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 34 (LCDR3) An anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 35, comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) selected from the group consisting of:

40. (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

36.

40. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 35 and 39, comprising:

41. (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising the amino acid sequence of SEQ ID NO: 38; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO:

38.

41. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 35, 39 and 40, comprising:

42. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 41, which is therapeutic.

43. The antigen-binding fragment may be Fab, Fab', F(ab') ２ 43. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 42, which is selected from the group consisting of: Fv and single chain variable fragment (scFv).

44. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 43, wherein about 60 mg, about 120 mg, about 240 mg, about 450 mg or about 600 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject.

45. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 44, wherein about 60 mg, about 120 mg or about 240 mg of the anti-NPR1 antibody or antigen-binding fragment thereof is administered to the subject.

46. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 45, wherein one or more additional therapeutically active agents are administered to the subject.

47. 47. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 46, wherein the one or more additional therapeutically active agents are selected from ACE (angiotensin converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, beta-blockers, diuretics, calcium channel blockers, cardiac glycosides, sodium-glucose cotransporter 2 inhibitors (SGLT2i), angiotensin receptor-neprilysin inhibitors (ARNi), corticosteroids, leukotriene modifiers, bronchodilators, beta-adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha2-adrenergic receptor agonists, parasympathomimetics, prostaglandin analogues, rho-kinase inhibitors, cell therapy, cardiac specific myosin activators and combinations thereof.

48. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 47, wherein the one or more additional therapeutically active agents are ACE (angiotensin converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, diuretics or combinations thereof.

49. The one or more additional therapeutically active agents may be enalapril, benazepril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propanolol, metoprolol, metoprolol tartrate, metoprolol succinate, a thiazide diuretic, a loop diuretic. , potassium-sparing diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, digitalis glycosides, canagliflozin, dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, fineron, spironolactone, triagliflozin Muterene, digoxin, fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, fluticasone furoate, prednisone, methylprednisolone, montelukast, zafirlukast, zileuton, long-acting beta agonists, short-acting beta agonists, theophylline, ipratropium, salmeterol, formoterol, albuterol, levalbuterol, timolol, levobunolol, metipranolol, carteolol, betaxolol, acetazolamide, dorzola 49. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 48, selected from benzodiazepine, brinzolamide, methazolamide, brimonidine, apraclonidine, cholinergic agents, latanoprost, latanoprostene bunod, travoprost, bimatoprost, tafluprost, omecamtiv mecarbil, allogeneic cell therapy Revascor mestrocel-L (REVASCOR®), CardiAMP™ cell therapy, netarsudil, ripasudil and combinations thereof.

50. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 49, which is administered subcutaneously to the subject.

51. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 50, which is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

52. The anti-NPR1 antibody or antigen-binding fragment thereof for use according to any one of claims 27 to 51, administered about once every four weeks.

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