# US 2020/0399362 A1 · Combination therapy for cardiovascular diseases

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- Number: US 2020/0399362 A1
- Document ID: US20200399362A1
- Status: Published application
- Kind: A1
- Application number: 16/978,660
- Filed: 2019-03-08
- Published: 2020-12-24
- Earliest claimed: 2018-03-09
- Assignees: The Brigham and Women's Hospital, Inc.
- Applicants: The Brigham and Women's Hospital, Inc.
- Inventors: Paul M. Ridker
- Web page: https://patentgrep.com/patent/US20200399362A1

## CPC

- C07K 16/245: {IL-1}
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61K 31/4418: having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/00: Drugs for disorders of the cardiovascular system
- C07K 16/40: against enzymes
- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- C12N 15/1138: {against receptors or cell surface proteins}
- A61K 2039/505: {comprising antibodies}
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Provided herein are methods of treating or reducing the risk of a cardiovascular disease using a lipid lowering agent (e.g., statin and/or PCSK9 inhibitor) and an anti-inflammatory agent (e.g., a pro-inflammatory cytokine inhibitor). Further provided herein are methods of predicting the recurrence rate of a subject who has received or is undergoing therapy for a cardiovascular disease with a lipid lowering agent on the basis of the C-reactive protein (CRP) level in the subject. In some embodiments, the recurrence rate can be reduced using an anti-inflammatory agent.

## Claims

### Claim 1

A method of treating a cardiovascular disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a lipid lowering agent and an anti-inflammatory agent.

### Claim 2 (depends on 1)

The method of claim 1, wherein the anti-inflammatory agent is a proinflammatory cytokine inhibitor.

### Claim 3 (depends on 1, 2)

The method of claim 1 or claim 2, wherein the anti-inflammatory agent comprises an IL-1 inhibitor, an IL-1 receptor (IL-1R) inhibitor, an IL-6 inhibitor, an IL-6 receptor (IL-6R) inhibitor, a NLRP3 inhibitor, a TNF inhibitor, an IL-8 inhibitor, an IL-18 inhibitor, an inhibitor of natural killer cells, or combinations thereof.

### Claim 4 (depends on 1, 2, 3)

The method of any one of claims 1-3, wherein the anti-inflammatory agent is a nucleic acid, an aptamer, an antibody or antibody fragment, an inhibitory peptide, or a small molecule.

### Claim 5 (depends on 3, 4)

The method of claim 3 or claim 4, wherein the anti-inflammatory agent comprises an IL-1 inhibitor.

### Claim 6 (depends on 5)

The method of claim 5, wherein the IL-1 inhibitor is an IL-1α inhibitor.

### Claim 7 (depends on 6)

The method of claim 6, wherein the IL-1α inhibitor is an anti-sense oligonucleotide against IL-1α, MABp1, or sIL-1RI.

### Claim 8 (depends on 5)

The method of claim 5, wherein the IL-1 inhibitor is an IL-1β inhibitor.

### Claim 9 (depends on 8)

The method of claim 8, wherein the IL-1β inhibitor is an anti-sense oligonucleotide against IL-1β, canakinumab, gevokizumab, diacerein, LY2189102, CYT013, sIL-1RII, VX-740, or VX-765.

### Claim 10 (depends on 5)

The method of claim 5, wherein the IL-1 inhibitor is suramin sodium, methotrexate-methyl-d3, methotrexate-methyl-d3 dimethyl ester, or diacerein.

### Claim 11 (depends on 3, 4, 5, 6, 7, 8, 9, 10)

The method of claim any one of claims 3-10, wherein the anti-inflammatory agent comprises an IL-1R inhibitor.

### Claim 12 (depends on 11)

The method of claim 11, wherein the IL-1R inhibitor is an IL-1R antagonist.

### Claim 13

The method of claim A11 or claim A12, wherein the IL-1R inhibitor is an anti-sense oligonucleotide against IL-1R, anakinra, Rilonacept, MEDI-8968, sIL-1RI, EBI-005, interleukin-1 receptor antagonist (IL-1RA), or AMG108.

### Claim 14 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The method of any one of claims 3-13, wherein the anti-inflammatory agent comprises an IL-6 inhibitor.

### Claim 15 (depends on 14)

The method of claim 14, wherein the IL-6 inhibitor is an anti-sense oligonucleotide against IL-6, siltuximab, sirukumab, clazakizumab, olokizumab, elsilimomab, IG61, BE-8, CNT0328 PGE1 and its derivatives, PGI2 and its derivatives, or cyclophosphamide.

### Claim 16 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The method of any one of claims 3-15, wherein the anti-inflammatory agent comprises an IL-6R inhibitor.

### Claim 17 (depends on 16)

The method of claim 16, wherein the IL-6R inhibitor is an IL-6R antagonist.

### Claim 18 (depends on 16, 17)

The method of claim 16 or claim 17, wherein the IL-6R inhibitor is an anti-sense oligonucleotide against IL-6R, tocilizumab, sarilumab, PM1, AUK12-20, AUK64-7, AUK146-15, MRA, or AB-227-NA.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

The method of any one of claims 1-18, wherein the anti-inflammatory agent comprises a NLRP3 inhibitor.

### Claim 20 (depends on 19)

The method of claim 19, wherein the NLPR3 inhibitors is an anti-sense oligonucleotide against NLPR3, colchicine, MCC950, CY-09, ketone metabolite beta-hydroxubutyrate (BHB), a type I interferon, resveratrol, arglabin, CB2R, Glybenclamide, Isoliquiritigenin, Z-VAD-FMK, or microRNA-223.

### Claim 21 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

The method of any one of claims 3-20, wherein the anti-inflammatory agent comprises a TNF inhibitor.

### Claim 22 (depends on 21)

The method of claim 21, wherein the TNF inhibitor is an anti-sense oligonucleotide against TNF, infliximab, adalimumab, certolizumab pegol, golimumab, etanercept (Enbrel), thalidomide, lenalidomide, pomalidomide, a xanthine derivative, bupropion, 5-HT2A agonist, or a hallucinogen.

### Claim 23 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 3-22, wherein the anti-inflammatory agent comprises an IL-8 inhibitor.

### Claim 24 (depends on 23)

The method of claim 23, wherein the IL-8 inhibitor is an anti-sense oligonucleotide against IL8, HuMab-10F8, Reparixin, Curcumin, Antileukinate, Macrolide, or a trifluoroacetate salt.

### Claim 25 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The method of any one of claims 3-24, wherein the anti-inflammatory agent comprises an IL-18 inhibitor.

### Claim 26 (depends on 25)

The method of claim 25, wherein the IL-18 inhibitor is an anti-sense oligonucleotide against IL-18, IL-18 binding protein, IL-18 antibody, NSC201631, NSC61610, or NSC80734.

### Claim 27 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The method of any one of claims 3-26, wherein the anti-inflammatory agent comprises an inhibitor of natural killer cells.

### Claim 28 (depends on 27)

The method of claim 27, wherein the inhibitor of natural killer cells is an antibody targeting natural killer cells.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The method of any one of claims 1-28, wherein the anti-inflammatory agent comprises methotrexate.

### Claim 30 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The method of any one of claims 1-29, wherein the anti-inflammatory agent comprises arhalofenate.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

The method of any one of claims 1-30, wherein the lipid lowering agent comprises a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

The method of any one of claims 1-30, wherein the PCSK9 inhibitor is a natural PCSK9 inhibitor, a PCSK9 antibody, an antisense nucleic acid, a peptide inhibitor, a PCSK9 vaccine, or a small molecule inhibitor.

### Claim 33 (depends on 32)

The method of claim 32, wherein the natural PCSK9 inhibitor is berberine, annexin A2, or adnectin.

### Claim 34 (depends on 32)

The method of claim 32, wherein the small molecule inhibitor is PF-06446846, anacetrapib, or K-312.

### Claim 35 (depends on 32)

The method of claim 32, wherein the PCSK9 antibody is alirocumab, evolocumab, 1D05-IgG2, RG-7652, LY3015014, or bococizumab.

### Claim 36 (depends on 32)

The method of claim 32, wherein the antisense nucleic acid is an RNAi molecule.

### Claim 37 (depends on 36)

The method of claim 36, wherein the RNAi molecule is inclisiran or ALN-PCS.

### Claim 38 (depends on 32)

The method of claim 32, wherein the peptide inhibitor is a peptide that mimics an EGFa domain of low-density lipoprotein receptor (LDL-R).

### Claim 39 (depends on 32)

The method of claim 32, wherein the PCSK9 vaccine comprises an antigenic PCSK9 peptide.

### Claim 40 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)

The method of any one of claims 1-39, wherein the lipid lowering agent comprises a HMG-CoA reductase inhibitor.

### Claim 41 (depends on 40)

The method of claim 40, wherein the HMG-CoA reductase inhibitor is a statin.

### Claim 42 (depends on 41)

The method of claim 41, wherein the statin is simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, or pitivastatin.

### Claim 43 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)

The method of any one of claims 1-42, wherein the lipid lowering agent is a fibric acid derivative (fibrate), a bile acid sequestrant, a resin, a nicotinic acid agent, a cholesterol absorption inhibitor, acyl-coenzyme A, a cholesterol acyl transferase (ACAT) inhibitor, a cholesteryl ester transfer protein (CETP) inhibitor, a LDL receptor antagonist, a farnesoid X receptor (FXR) antagonist, a sterol regulatory binding protein cleavage activating protein (SCAP) activator, a microsomal triglyceride transfer protein (MTP) inhibitor, a squalene synthase inhibitor, or a peroxisome proliferation activated receptor (PPAR) agonist.

### Claim 44 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The method of any one of claims 1-43, wherein the lipid lowering agent and the anti-inflammatory agent are administered together.

### Claim 45 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The method of any one of claims 1-43, wherein the lipid lowering agent and the anti-inflammatory agent are administered separately.

### Claim 46 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)

The method of any one of claims 1-45, wherein the lipid lowering agent and/or the anti-inflammatory agent is administered intranasally, intravenously, intramuscularly, subcutaneously, or orally.

### Claim 47 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46)

The method of any one claims 1-46, wherein the level or activity of a proinflammatory cytokine in the subject is reduced.

### Claim 48 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The method of any one of claims 1-47, wherein the level or activity of C-reactive protein (CRP) in the subject is reduced.

### Claim 49 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48)

The method of any one of claims 1-48, wherein the level or activity of non-high-density lipoprotein (HDL)-cholesterol in the subject is reduced.

### Claim 50 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49)

The method of any one of claims 1-49, wherein the level or activity of LDL-cholesterol in the subject is reduced.

### Claim 51 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)

The method of any one of claims 1-50, wherein the level or activity of total cholesterol in the subject is reduced.

### Claim 52 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51)

The method of any one of claims 1-51, wherein the level or activity of apolipoprotein B (ApoB) in the subject is reduced.

### Claim 53 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52)

The method of any one of claims 1-52, wherein the level or activity of triglycerides in the subject is reduced.

### Claim 54 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53)

The method of any one of claims 1-53, wherein the ratio of total cholesterol to HDL-cholesterol in the subject is reduced.

### Claim 55 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)

The method of any one of claims 1-54, wherein the occurrence of non-fatal myocardial infarction is reduced.

### Claim 56 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)

The method of any one of claims 1-54, wherein the occurrence of non-fatal stroke is reduced.

### Claim 57 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)

The method of any one of claims 1-54, wherein the rate of cardiovascular mortality is reduced.

### Claim 58 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57)

The method of any one of claims 1-57, wherein the cardiovascular disease is myocardial infarction, stroke, acute coronary syndrome, myocardial ischemia, chronic stable angina pectoris, unstable angina pectoris, cardiovascular death, coronary re-stenosis, coronary stent re-stenosis, coronary stent re-thrombosis, recurrent cardiovascular events, revascularization, angioplasty, transient ischemic attack, pulmonary embolism, vascular occlusion, or venous thrombosis.

### Claim 59

A method of reducing a recurrence rate of a cardiovascular disease in a subject who has received or is undergoing therapy with a lipid lowering agent, the method comprising administering to the subject an effective amount of an anti-inflammatory agent.

### Claim 60

A method of predicting a recurrence rate of a cardiovascular disease in a subject who has received or is undergoing therapy with the lipid lowering agent, the method comprising measuring a level of C-reactive protein (CRP) in the subject and determining that the subject is likely to have recurrence of the cardiovascular disease if the CRP level is above a pre-determined value.

### Claim 61 (depends on 60)

The method of claim 60, wherein the pre-determined value is 3 mg/L.

### Claim 62 (depends on 60)

The method of claim 60, wherein the pre-determined value is 2 mg/L.

### Claim 63 (depends on 60)

The method of claim 60, wherein the pre-determined value is 1 mg/L.

### Claim 64

A method of treating a cardiovascular disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody comprising a first antigen-binding domain that binds a proinflammatory cytokine and a second antigen-binding domain that binds a proprotein convertase subtilisin/kexin type 9 (PCSK9).

### Claim 65 (depends on 64)

The method of claim 64, wherein the proinflammatory cytokine is IL-1, IL-1 receptor (IL-1R), IL-6, IL-6 receptor (IL-6R), NLRP3, TNF, IL-8, or IL-18.

### Claim 66 (depends on 65)

The method of claim 65, wherein the first antigen-binding domain binds to IL-1.

### Claim 67 (depends on 66)

The method of claim 66, wherein the first antigen-binding domain binds to IL-1α.

### Claim 68 (depends on 66)

The method of claim 66, wherein the first antigen-binding domain is derived from MABp1.

### Claim 69 (depends on 66)

The method of claim 66, wherein the first antigen-binding domain binds to IL-13.

### Claim 70 (depends on 69)

The method of claim 69, wherein the first antigen-binding domain is derived from canakinumab, diacerein, gevokizumab, or LY2189102.

### Claim 71 (depends on 65)

The method of claim 65, wherein the first antigen-binding domain binds to IL-1R.

### Claim 72 (depends on 71)

The method of claim 71, wherein the first antigen-binding domain is derived from MEDI-8968 or AMG108.

### Claim 73 (depends on 65)

The method of claim 65, wherein the first antigen-binding domain binds to IL-6.

### Claim 74 (depends on 73)

The method of claim 73, wherein the first antigen-binding domain is derived from siltuximab, sirukumab, clazakizumab, olokizumab, or elsilimomab.

### Claim 75 (depends on 65)

The method of claim 65, wherein the first antigen-binding domain binds to IL-6R.

### Claim 76 (depends on 75)

The method of claim 75, wherein the first antigen-binding domain is derived from tocilizumab, sarilumab, PM1, AUK12-20, AUK64-7, AUK146-15, or AB-227-NA.

### Claim 77 (depends on 65)

The method of claim 65, wherein the first antigen-binding domain binds to NLRP3.

### Claim 78 (depends on 77)

The method of claim 77, wherein the first antigen-binding domain is derived from an anti-NLRP3 antibody.

### Claim 79 (depends on 65)

The method of claim 65, wherein the first antigen-binding domain binds to TNF.

### Claim 80 (depends on 79)

The method of claim 79, wherein the first antigen-binding domain is derived from infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept (Enbrel).

### Claim 81 (depends on 65)

The method of claim 65, wherein the first antigen-binding domain binds to IL-8.

### Claim 82 (depends on 81)

The method of claim 81, wherein the first antigen-binding domain is derived from HuMab-10F8.

### Claim 83 (depends on 65)

The method of claim 65, wherein the first antigen-binding domain binds to IL-18.

### Claim 84 (depends on 83)

The method of claim 83, wherein the first antigen-binding domain is derived from an IL-18 antibody.

### Claim 85 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84)

The method of any one of claims 64-84, wherein the second antigen-binding domain is derived from alirocumab, evolocumab, 1D05-IgG2, RG-7652, LY3015014, or bococizumab.

### Claim 86 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85)

The method of any one of claims 64-85, wherein the bispecific antibody comprises a common Fc region.

### Claim 87 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86)

The method of any one of claims 64-86, wherein the bispecific antibody is a monoclonal bispecific antibody.

### Claim 88 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87)

The method of any one of claims 64-87, further comprising administering to the subject a therapeutically effective amount of a HMG-CoA reductase inhibitor.

### Claim 89 (depends on 88)

The method of claim 88, wherein the HMG-CoA reductase inhibitor is a statin.

### Claim 90 (depends on 89)

The method of claim 89, wherein the statin is simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, or pitivastatin.

### Claim 91 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89)

The method of any one of claims 64-89, wherein the bispecific antibody is administered intravenously, intramuscularly, subcutaneously, or orally.

### Claim 92 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91)

The method of any one claims 64-91, wherein the level or activity of a proinflammatory cytokine in the subject is reduced.

### Claim 93 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92)

The method of any one of claims 64-92, wherein the level or activity of C-reactive protein (CRP) in the subject is reduced.

### Claim 94 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93)

The method of any one of claims 64-93, wherein the level or activity of non-high-density lipoprotein (HDL)-cholesterol in the subject is reduced.

### Claim 95 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94)

The method of any one of claims 64-94, wherein the level or activity of LDL-cholesterol in the subject is reduced.

### Claim 96 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95)

The method of any one of claims 64-95, wherein the level or activity of total cholesterol in the subject is reduced.

### Claim 97 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96)

The method of any one of claims 64-96, wherein the level or activity of apolipoprotein B (ApoB) in the subject is reduced.

### Claim 98 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97)

The method of any one of claims 64-97, wherein the level or activity of triglycerides in the subject is reduced.

### Claim 99 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98)

The method of any one of claims 64-98, wherein the ratio of total cholesterol to HDL-cholesterol in the subject is reduced.

### Claim 100 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99)

The method of any one of claims 64-99, wherein the occurrence of non-fatal myocardial infarction is reduced.

### Claim 101 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99)

The method of any one of claims 64-99, wherein the occurrence of non-fatal stroke is reduced.

### Claim 102 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101)

The method of any one of claims 64-101, wherein the rate of cardiovascular mortality is reduced.

### Claim 103

A method of treating a cardiovascular disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody comprising a first antigen-binding domain that binds IL-1 and a second antigen-binding domain that binds a proprotein convertase subtilisin/kexin type 9 (PCSK9).

### Claim 104 (depends on 103)

The method of claim 103, wherein the first antigen-binding domain binds to IL-1α.

### Claim 105 (depends on 104)

The method of claim 104, wherein the first antigen-binding domain is derived from MABp1.

### Claim 106 (depends on 103)

The method of claim 103, wherein the first antigen-binding domain binds to IL-1β.

### Claim 107 (depends on 106)

The method of claim 106, wherein the first antigen-binding domain is derived from canakinumab, diacerein, gevokizumab, or LY2189102.

### Claim 108 (depends on 103, 104, 105, 106, 107)

The method of any one of claims 103-107, wherein the second antigen-binding domain is derived from alirocumab, evolocumab, 1D05-IgG2, RG-7652, LY3015014, or bococizumab.