# US 11,306,148 B2 · Anti-NPR1 antibodies and uses thereof

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- Number: US 11,306,148 B2
- Document ID: US11306148B2
- Status: Granted
- Kind: B2
- Application number: 16/657,000
- Filed: 2019-10-18
- Published: 2020-04-23
- Granted: 2022-04-19
- Earliest claimed: 2018-10-23
- Assignees: Regeneron Pharmaceuticals, Inc.
- Applicants: Regeneron Pharmaceuticals, Inc.
- Inventors: Michael Dunn; Jia Su; Jason Mastaitis; Jesper Gromada; Lori Morton
- Web page: https://patentgrep.com/patent/US11306148B2

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2869: {against hormone receptors (for antibodies against neuromediator receptors C07K16/286)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 2039/505: {comprising antibodies}
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A61P 9/12: Antihypertensives
- C07K 14/72: for hormones {(for neuromediators C07K14/70571)}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/32: specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides monoclonal antibodies that bind to the natriuretic peptide receptor 1 (NPR1) protein, and methods of use thereof. In various embodiments of the invention, the antibodies are fully human antibodies that bind to NPR1. In some embodiments, the antibodies of the invention are useful for activating NPR1 activity, thus providing a means of treating or preventing a disease, disorder or condition associated with NPR1 in humans.

## Claims

### Claim 1

An isolated antibody or antigen-binding fragment thereof that binds specifically to natriuretic peptide receptor 1 (NPR1) protein, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising an amino acid sequence of SEQ ID NO:2; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising an amino acid sequence of SEQ ID NO:10.

### Claim 2 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1 comprising a HCVR having an amino acid sequence of SEQ ID NO: 2.

### Claim 3 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1 comprising a LCVR having an amino acid sequence of SEQ ID NO: 10.

### Claim 4 (depends on 1)

The antibody or antigen-binding fragment thereof of claim 1 comprising:
(a) a HCDR1 having an amino acid sequence of SEQ ID NO: 4;
(b) a HCDR2 having an amino acid sequence of SEQ ID NOs: 6;
(c) a HCDR3 having an amino acid sequence of SEQ ID NOs: 8;
(d) a LCDR1 having an amino acid sequence of SEQ ID NO: 12;
(e) a LCDR2 having an amino acid sequence of SEQ ID NO: 14; and
(f) a LCDR3 having an amino acid sequence of SEQ ID NO: 16.

### Claim 5 (depends on 4)

The antibody or antigen-binding fragment thereof of claim 4 comprising a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 2/10.

### Claim 6 (depends on 1)

The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof interacts with one or more amino acids contained within the extracellular domain of NPR1 (amino acids 29-347 of SEQ ID NO: 194), as determined by hydrogen/deuterium exchange, and wherein the antibody or antigen-binding fragment thereof: (i) binds to cells expressing human NPR1 in the presence or absence of atrial natriuretic peptide (ANP); and/or (ii) activates NPR1.

### Claim 7 (depends on 6)

The isolated antibody or antigen-binding fragment thereof of claim 6, wherein the antibody or antigen-binding fragment thereof interacts with an amino acid sequence selected from the group consisting of (a) amino acids 29 to 45 of SEQ ID NO: 194, and (b) amino acids 336 to 347 of SEQ ID No: 194.

### Claim 8 (depends on 6)

The isolated antibody or antigen-binding fragment thereof of claim 6, wherein the antibody or antigen-binding fragment thereof interacts with an amino acid sequence selected from the group consisting of (a) amino acids 29 to 45 of SEQ ID NO: 194, and (b) amino acids 331 to 347 of SEQ ID No: 194, in the presence of ANP.

### Claim 9 (depends on 6)

The antibody or antigen-binding fragment thereof of claim 6, wherein the antibody is a fully human monoclonal antibody.

### Claim 10 (depends on 6)

The antibody or antigen-binding fragment thereof of claim 6, wherein the antibody has one or more properties selected from the group consisting of: (a) is a fully human monoclonal antibody; (b) binds to monomeric human NPR1 in the absence of ANP and/or brain natriuretic peptide (BNP) at 25° C. and at 37° C. with a dissociation constant (KD) of less than 690 nM, as measured in a surface plasmon resonance assay; (c) binds to dimeric human NPR1 in the absence of ANP or BNP at 25° C. and at 37° C. with a KD of less than 42 nM, as measured in a surface plasmon resonance assay; (d) binds to human NPR1 complexed to ANP at 25° C. and 37° C. with a KD of less than 80 nM, as measured in a surface plasmon resonance assay; (e) binds to human NPR1 complexed to BNP at 25° C. and 37° C. with a KD of less than 20 nM, as measured in a surface plasmon resonance assay; (f) binds to monomeric monkey NPR1 in the absence of ANP and/or BNP at 25° C. and 37° C. with a KD of less than 365 nM, as measured in a surface plasmon resonance assay; (g) binds to dimeric monkey NPR1 in the absence of ANP or BNP at 25° C. and at 37° C. with a KD of less than 30 nM, as measured in a surface plasmon resonance assay; (h) binds to monkey NPR1 complexed to ANP at 25° C. and 37° C. with a KD of less than 10 nM, as measured in a surface plasmon resonance assay; (i) binds to monkey NPR1 complexed to BNP at 25° C. and 37° C. with a KD of less than 10 nM, as measured in a surface plasmon resonance assay; (j) does not bind to mouse NPR1; (k) binds to cells expressing human NPR1 (without ANP) or NPR1-complexed to ANP with a EC50 less than 5 nM; (l) activates NPR1 with a EC50 of less than 385 nM, as measured in a calcium flux cell-based bioassay; (m) reduces the systemic blood pressure when administered to normotensive and hypertensive mice, wherein the reduction in systemic and mean arterial blood pressures lasts for up to 28 days upon administration of a single dose; and (n) improves glucose tolerance when administered to diet-induced obese mice.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof that binds to natriuretic peptide receptor 1 (NPR1) protein according to claim 1 and a pharmaceutically acceptable carrier or diluent.