# US 6,410,022 B1 · Modulation of cholesteryl ester transfer protein (CETP) activity

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- Number: US 6,410,022 B1
- Document ID: US6410022B1
- Status: Granted
- Kind: B1
- Application number: 08/432,483
- Filed: 1995-05-01
- Granted: 2002-06-25
- Earliest claimed: 1995-05-01
- Assignees: Avant Immunotherapeutics, Inc.
- Inventors: Charles W. Rittershaus
- Web page: https://patentgrep.com/patent/US6410022B1

## CPC

- A61K 39/0012: {Lipids; Lipoproteins}
- A61P 3/06: Antihyperlipidemics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 37/04: Immunostimulants
- C07K 14/47: from mammals
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2039/55572: {Lipopolysaccharides; Lipid A; Monophosphoryl lipid A}
- A61K 2039/6037: {Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

This invention relates to peptides comprising a helper T cell epitope portion and a B cell epitope portion for eliciting an immune response against endogenous cholesteryl ester transfer protein (CETP) activity, to prevent or treat cardiovascular disease, such as atherosclerosis.

## Claims

### Claim 1

An isolated antigenic hybrid peptide comprising a helper T cell epitope portion linked to a B cell epitope portion, wherein said B cell epitope portion comprises six to 26 consecutive amino acids of the carboxyl terminal 26 amino acids of human cholesteryl ester transfer protein (SEQ ID NO:1).

### Claim 2 (depends on 1)

The isolated antigenic hybrid peptide according to claim 1 wherein the helper T cell epitope portion is selected from the group consisting of a helper T cell epitope amino acid sequence of tetanus toxoid, diphtheria toxoid, pertussis vaccine, Bacile Calmette-Guerin (BCG), polio vaccine, measles vaccine, mumps vaccine, rubella vaccine, purified protein derivative of tuberculin, keyhole limpet hemocyanin, and combinations thereof.

### Claim 3 (depends on 1)

The isolated antigenic hybrid peptide according to claim 1, wherein the helper T cell epitope portion comprises a helper T cell epitope from tetanus toxoid or diphtheria toxoid.

### Claim 4

An isolated antigenic hybrid peptide comprising the amino acid sequence of SEQ ID NO:2.

### Claim 5 (depends on 4)

The isolated antigenic hybrid peptide according to claim 4 consisting of the amino acid sequence of SEQ ID NO:2.

### Claim 6 (depends on 4)

The isolated antigenic hybrid peptide according to claim 4, wherein said isolated antigenic hybrid peptide is a dimer of SEQ ID NO:2.

### Claim 7

A vaccine composition comprising an antigenic vaccine hybrid peptide comprising a universal helper T cell epitope linked to a B cell epitope portion comprising six to 26 consecutive amino acids of the carboxyl terminal 26 amino acids of human cholesterol ester transfer protein (SEQ ID NO:1).

### Claim 8 (depends on 7)

The vaccine composition according to claim 7 wherein the helper T cell epitope portion of the antigenic vaccine hybrid peptide is selected from the group consisting of the amino acid sequence of amino acids 830 to 843 of tetanus toxin protein (amino acids 2 to 15 of SEQ ID NO:2) and the amino acid sequence of amino acids 947 to 967 of tetanus toxin protein (SEQ ID NO:3).

### Claim 9 (depends on 7)

The vaccine composition according to claim 7 wherein the T cell epitope portion of the antigenic vaccine hybrid peptide is a universal helper T cell epitope selected from the group consisting of T cell epitope amino acid sequences of tetanus toxoid, diphtheria toxoid, pertussis vaccine, Bacile Calmette-Guerin (BCG), polio vaccine, measles vaccine, mumps vaccine, rubella vaccine, purified protein derivative of tuberculin, keyhole limpet hemocyanin, and combinations thereof.

### Claim 10 (depends on 7)

The vaccine composition according to claim 7 wherein the antigenic vaccine hybrid peptide further comprises an amino terminal cysteine residue.

### Claim 11

A method of elevating the ratio of circulating High Density Lipoprotein to circulating Low Density Lipoprotein, Very Low Density Lipoprotein, or total cholesterol in a human or other animal comprising administering to the human or animal an antigenic vaccine hybrid peptide comprising a universal helper T cell epitope portion and a B cell epitope portion. wherein said B cell epitope portion comprises six to 26 consecutive amino acids of the carboxyl terminal 26 amino acids of human cholesteryl ester transfer protein (SEQ ID NO:1).

### Claim 12 (depends on 11)

The method according to claim 11 wherein the helper T cell epitope portion of the antigenic vaccine hybrid peptide is selected from the group consisting of the amino acid sequence of amino acids 830 to 843 of tetanus toxin protein (amino acids 2 to 15 of SEQ ID NO:2) and the amino acid sequence of amino acids 947 to 967 of tetanus toxin protein (SEQ ID NO: 3).

### Claim 13 (depends on 11)

The method according to claim 11 wherein the antigenic vaccine hybrid peptide further comprises an amino terminal cysteine residue.

### Claim 14

A method of decreasing the level of cholesteryl ester transfer protein activity in a human or other animal comprising administering to the human or animal an antigenic vaccine hybrid peptide comprising a helper T cell epitope portion linked to a B cell epitope portion comprising six to 26 consecutive amino acids of the carboxyl terminal 26 amino acids of human cholesterol ester transfer protein (SEQ ID NO:1).

### Claim 15 (depends on 14)

The method according to claim 14 wherein the antigenic vaccine hybrid peptide is administered in an amount sufficient to elicit production in said human or other animal of anti-cholesterol ester transfer protein antibodies.

### Claim 16

A method of increasing the level of circulating High Density Lipoprotein in a human or other animal comprising administering to the human or animal an antigenic vaccine hybrid peptide comprising a helper T cell epitope portion and a B cell epitope portion, wherein said B cell epitope portion comprises six to 26 consecutive amino acids of the carboxyl terminal 26 amino acids of human cholesterol ester transfer protein (SEQ ID NO:1).

### Claim 17 (depends on 16)

The method according to claim 16, wherein the helper T cell epitope portion is selected from the group consisting of universal helper T cell epitope amino acid sequences of tetanus toxoid, diphtheria toxoid, pertussis vaccine, Bacile Calmette-Guerin (BCG), polio vaccine, measles vaccine, mumps vaccine, rubella vaccine, purified protein derivative of tuberculin, keyhole limpet hemocyanin, and combinations thereof.

### Claim 18

A method of treating atherosclerosis in a human or animal comprising administering to the human or animal an antigenic vaccine hybrid peptide comprising a universal helper T cell epitope portion linked to a B cell epitope portion, wherein said B cell epitope portion comprises six to 26 consecutive amino acids of the carboxyl terminal 26 amino acids of human cholesteryl ester transfer protein.

### Claim 19 (depends on 11, 14, 16)

The method according to any one of claims 11, 14, 16, and 18, wherein said antigenic vaccine hybrid peptide is a dimer.

### Claim 20

A method of making an anti-cholesteryl ester transfer protein (CETP) vaccine comprising a B cell epitope portion and a helper T cell epitope portion to modulate endogenous CETP activity, comprising:
selecting a B cell epitope portion from a region of CETP involved in neutral lipid binding or neutral lipid transfer activity;
selecting a helper T cell epitope portion consisting of a helper T cell epitope; and
linking said B cell epitope portion and said helper T cell epitope portion to form a single immunogenic moiety.

### Claim 21 (depends on 20)

The method according to claim 20 wherein said B cell epitope portion is covalently linked to said helper T cell epitope portion.

### Claim 22 (depends on 21)

The method according to claim 21, wherein said B cell epitope portion is covalently linked to said helper T cell epitope portion via a covalent bond selected from the group consisting of peptide bonds and disulfide bonds.

### Claim 23 (depends on 20)

The method according to claim 20 wherein said B cell epitope portion is linked to said helper T cell epitope portion via a cross-linker molecule.

### Claim 24 (depends on 20)

The method according to claim 20 wherein said B cell epitope portion is linked to said helper T cell epitope portion via a bridge of amino acids.

### Claim 25 (depends on 20)

The method according to claim 20 wherein said B cell epitope portion and said helper T cell epitope portion are linked to a common carrier molecule.

### Claim 26 (depends on 20)

The method according to claim 20 wherein said B cell epitope portion is linked to said helper T cell epitope portion to form a vaccine peptide and further comprising the step of linking said vaccine peptide to a carrier molecule.