# US 12,180,270 B2 · Anti-ANGPTL 3/8 complex antibodies and methods of using the same

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- Number: US 12,180,270 B2
- Document ID: US12180270B2
- Status: Granted
- Kind: B2
- Application number: 17/559,808
- Filed: 2021-12-22
- Published: 2022-04-14
- Granted: 2024-12-31
- Earliest claimed: 2018-12-21
- Assignees: Eli Lilly and Company
- Applicants: Eli Lilly and Company
- Inventors: Qing Chai; Jonathan Wesley Day; Robert John Konrad; Yuewei Qian; Oliver Schroeder; Robert William Siegel
- Web page: https://patentgrep.com/patent/US12180270B2

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61B 5/02125: {of pulse wave propagation time}
- A61B 5/02438: {with portable devices, e.g. worn by the patient}
- A61B 5/02444: {Details of sensor (A61B5/02427 takes precedence)}
- A61B 5/05: Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves (measuring movement of the entire body or parts thereof A61B5/11; detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof A61B5/24)
- A61B 5/681: {Wristwatch-type devices}
- A61B 5/6843: {Monitoring or controlling sensor contact pressure}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- 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)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

Angiopoietin-like protein (ANGPTL)3/8 complexes and antibodies are disclosed, where the antibodies bind to and thereby neutralize ANGPTL3/8 complexes. Pharmaceutical compositions also are disclosed that include one or more anti-ANGPTL3/8 complex antibodies herein in a pharmaceutically acceptable carrier. Methods of making and using the same also are disclosed, especially for increase lipoprotein lipase activity and lowering triglycerides. In this manner, the compounds and compositions may be used in treating lipid metabolism-related and glucose metabolism-related diseases and disorders.

## Claims

### Claim 1

An antibody that binds human ANGPTL3/8 complex comprising a light chain (LC) and a heavy chain (HC),
wherein the LC comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:5, 21, 22, 23, 24, and 25, and
wherein the HC comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 10.

### Claim 2 (depends on 1)

The antibody of claim 1, wherein the antibody binds and neutralizes human ANGPTL3/8 complex in a standard lipoprotein lipase activity assay with an EC50 of 3.0 nM or less.

### Claim 3 (depends on 1)

The antibody of claim 1, wherein the antibody binds to human ANGPTL3/8 complex with a dissociation constant of less than or equal to 1×10−6 M.

### Claim 4 (depends on 1)

The antibody of claim 1, wherein the antibody binds to human ANGPTL3/8 complex and does not bind to human ANGPTL3 alone or human ANGPTL8 alone, up to an antigen concentration of 100 nM as measured by an ELISA assay.

### Claim 5 (depends on 1)

The antibody of claim 1, wherein the antibody lowers triglycerides in vivo by at least 50% as compared to IgG control at a dose of 10 mg/kg at a time point 14 days after dosing.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising the antibody of claim 1 and an acceptable carrier, diluent or excipient.

### Claim 7 (depends on 1)

A method of lowering triglycerides, the method comprising the step of:
administering to a patient in need thereof an effective amount of the antibody of claim 1.

### Claim 8

An antibody produced by: (i) cultivating a mammalian cell comprising a cDNA molecule, wherein the cDNA molecule encodes a polypeptide comprising the amino acid sequence of one of SEQ ID NOs:5, 21, 22, 23, 24, and 25, and the cDNA molecule encodes a heavy chain for the antibody comprising a HCVR comprising the amino acid sequence of SEQ ID NO: 10, and the mammalian cell is cultivated under such conditions that the encoded polypeptides are expressed; and (ii) recovering the antibody.

### Claim 9

An antibody produced by: (i) cultivating a mammalian cell comprising at least two cDNA molecules, wherein a first cDNA molecule encodes a light chain for the antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:5, 21, 22, 23, 24 and 25 and a second cDNA molecule encodes a heavy chain for the antibody comprising a HCVR comprising the amino acid sequence of SEQ ID NO: 10, and the mammalian cell is cultivated under such conditions that the antibody is expressed; and (ii) recovering the antibody.

### Claim 10

A mammalian cell comprising a DNA molecule, wherein the DNA molecule comprises a polynucleotide sequence encoding a polypeptide comprising the amino acid sequence of one of SEQ ID NOs:5, 21, 22, 23, 24, and 25, and the DNA molecule comprises a polynucleotide sequence encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 10, wherein the cell is capable of expressing the encoded polypeptides.

### Claim 11

A mammalian cell comprising a first DNA molecule and a second DNA molecule, wherein the first DNA molecule comprises a polynucleotide sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:5, 21, 22, 23, 24 or 25, and wherein the second DNA molecule comprises a polynucleotide sequence encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 10, wherein the cell is capable of expressing the polypeptides.

### Claim 12

A method of lowering triglycerides in a patient having atherosclerotic cardiovascular disease or hypertriglyceridemia, the method comprising the step of:
administering to the patient in need thereof an effective amount of an antibody that binds human ANGPTL3/8 complex comprising light chain determining regions LCDR1, LCDR2, and LCDR3 and heavy chain determining regions HCDR1, HCDR2, and HCDR3, wherein LCDR1 has an amino acid sequence RSSQSLLDSDDGNTYLD (SEQ ID NO: 11), LCDR2 has an amino acid sequence YMLSYRAS (SEQ ID NO: 12), LCDR3 has an amino acid sequence MQRIEFPLT (SEQ ID NO: 13), HCDR1 has an amino acid sequence TFSGFSLSISGVGVG (SEQ ID NO: 14), HCDR2 has an amino acid sequence LIYRNDDKRYSPSLKS (SEQ ID NO: 15), and HCDR3 has an amino acid sequence ARTYSSGWYGNWFDP (SEQ ID NO: 16).

### Claim 13 (depends on 12)

The method of claim 12, wherein the antibody comprises a light chain variable region (LCVR), and wherein the LCVR has an amino acid sequence of SEQ ID NO: 9.

### Claim 14 (depends on 12)

The method of claim 12, wherein the antibody comprises a HCVR, and wherein the HCVR has an amino acid sequence of SEQ ID NO: 10.

### Claim 15 (depends on 12)

The method of claim 12, wherein the antibody comprises a LCVR and a HCVR, and wherein the LCVR has an amino acid sequence of SEQ ID NO: 9 and the HCVR has an amino acid sequence of SEQ ID NO: 10.

### Claim 16 (depends on 12)

The method of claim 12, wherein the antibody comprises a HC, and wherein the HC comprises an amino acid sequence of SEQ ID NO: 6.