# US 5,871,747 A · Antigen-carrying microparticles and their use in the indication of humoral or cellular responses

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- Number: US 5,871,747 A
- Document ID: US5871747A
- Status: Granted
- Kind: A
- Application number: 08/397,286
- Filed: 1995-04-28
- Granted: 1999-02-16
- Earliest claimed: 1992-09-11
- Assignees: Institut Pasteur
- Inventors: Christine Gengoux-Sedlik; Claude LeClerc
- Web page: https://patentgrep.com/patent/US5871747A

## CPC

- C07K 17/08: the carrier being a synthetic polymer
- A61K 9/167: {with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface (with further drug-free outer coating A61K9/5073)}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 39/385: Haptens or antigens, bound to carriers
- A61K 47/6935: {the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol}
- A61P 37/04: Immunostimulants
- A61K 2039/60: {characteristics by the carrier linked to the antigen}
- A61K 2039/6093: {Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine}
- 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
- Y10S 530/811: Peptides or proteins is immobilized on, or in, an inorganic carrier
- Y10S 530/815: Carrier is a synthetic polymer
- Y10S 977/773: Nanoparticle, i.e. structure having three dimensions of 100 nm or less
- Y10S 977/906: Drug delivery
- Y10S 977/915: Therapeutic or pharmaceutical composition
- Y10S 977/918: Immunological
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

The invention concerns the use, in the induction of an immune response, of a synthetic microparticle polymer carrying on the surface one or more covalently bonded proteins capable of carrying one or more epitopes, the densities of the protein(s) on the surface of the microparticles, and their molecular weights, being adjusted so as to direct the immune response to the induction of a humoral and cellular response or to the induction of a largely cellular response. Said microparticles have an average diameter of approximately 0.25 to 1.5 .mu.m.

## Claims

### Claim 1

A method of inducing an immune response in warm-blooded animals comprising administering to warm-blooded animals an immune response inducing amount of synthetic biocompatible microparticles having an average diameter between about 0.25 .mu.m and 1.5 .mu.m and carrying on their surface at least one covalently bonded protein, each carrying at least one epitope to induce an humoral or cellular immune response, the density of the protein(s) on the microparticle surfaces being adjusted to comprise between 10.sup.4 to 5.10.sup.5 molecules per .mu.m.sup.2 and to direct the said immune response towards the induction of cellular and/or humoral response.

### Claim 2 (depends on 1)

The method of claim 1 of inducing an immune response in warm-blooded animals comprising administering to warm-blooded animals an immune inducing amount of synthetic microparticles having an average diameter between about 0.25 .mu.m and 1.5 .mu.m and carrying on their surface at least one covalently bonded protein, each carrying at least one epitope to induce an immune response, the density being comprised between 10.sup.4 to 5.10.sup.4 molecules per .mu.m.sup.2 and the molecular weight of the protein(s) on the microparticle surfaces being adjusted to direct a T cell immune response.

### Claim 3 (depends on 1)

The method of claim 1, for the induction of cellular and/or humoral responses, characterized in that the microparticles have a density for each of the proteins carrying an epitope of a minimum of 10.sup.5 molecules/.mu.m.sup.2 and preferentially 5.10.sup.5 molecules/.mu.m.sup.2.

### Claim 4 (depends on 1)

The method of claim 1, for the induction of a mainly cellular response, characterized in that the microparticles have a density for each of the proteins carrying an epitope of between 10.sup.4 and 5.10.sup.4 molecules/.mu.m.sup.2.

### Claim 5 (depends on 1)

The method of claim 1, for the induction of a mainly cellular response, characterized in that the microparticles carry on their surface proteins having molecular weights greater than 50 kD.

### Claim 6 (depends on 1)

The method of claim 1, characterized in that the microparticles have an average diameter of between about 0.25 .mu.m and about 1.5 .mu.m, and preferentially of 1 .mu.m.

### Claim 7 (depends on 1)

The method of claim 1, characterized in that the bond is formed by reaction between the NH.sub.2 and/or CO groups of the proteins and the material making up the microparticle.

### Claim 8 (depends on 1)

The method of claim 1, characterized in that the bond between the proteins and the material making up the microparticle is covalent and formed with or without a bridging reagent.

### Claim 9 (depends on 8)

The method of claim 8, characterized in that the bridging reagent is glutaraldehyde or carbodiimide.

### Claim 10 (depends on 1)

The method of claim 1, characterized in that said microparticles are biocompatible polymers.

### Claim 11 (depends on 10)

The method of claim 10, characterized in that said polymer is polyacrolein or polystyrene or lactic acid polymers or copolymers of lactic and glycolic acids.

### Claim 12 (depends on 1)

The method of claim 1, characterized in that the microparticles carry on their surface molecules able to activate the immune system.

### Claim 13

Process for the production of microparticles whose immune response is either mainly humoral or mainly cellular, said process being characterized in that at least one protein carrying one or more epitopes or peptides containing T or B epitopes alone or a combination of the two are covalently fixed to synthetic polymer microparticles, the density of the protein fixed to the surface being varied according to the humoral or cellular response required.

### Claim 14 (depends on 1, 13)

Process according to claim 13, characterized in that microparticles as defined in claim 1 are used.

### Claim 15

Synthetic biocompatible microparticles having an average diameter between about 0.25 .mu.m and 1.5 .mu.m and carrying on their surface at least one covalently bonded protein, each carrying at least one epitope to induce an humoral or cellular immune response, the density of the protein(s) on the microparticle surfaces being adjusted to comprise between 10.sup.4 to 5.10.sup.5 molecules per .mu.m.sup.2 and to direct the said immune response towards the induction of cellular and/or humoral response.

### Claim 16 (depends on 15)

Microparticles of claim 15 wherein the protein is selected from the group consisting of hemoglobin, ovalbumin and lysozyme.

### Claim 17 (depends on 15)

Microparticles of claim 15, having an average diameter of 1 .mu.m.

### Claim 18 (depends on 15)

Microparticles of claim 15, characterized in that the bond is formed by reaction between the NH.sub.2 and/or CO groups of the proteins and the material making up the microparticle.

### Claim 19 (depends on 15)

Microparticles of claim 15 wherein the bond between the proteins and the polymer microparticle is formed by use of a bridging reagent.

### Claim 20 (depends on 19)

Microparticle according to claim 19, characterized in that the bridging reagent is glutaraldehyde, or carbodiimide.

### Claim 21 (depends on 15)

Microparticle according to one of claim 15, characterized in that it is composed of a biocompatible polymer.

### Claim 22 (depends on 21)

Microparticle according to claim 21, characterized in that said polymer is poly(acrolein) or polystyrene, a lactic acid polymer or a copolymer of lactic and glycolic acids.

### Claim 23 (depends on 17)

Microparticle according to claim 17, characterized in that it carries on its surface molecules able to activate the immune system.

### Claim 24 (depends on 17)

Microparticle according to claim 17, characterized in that said protein comprises the B epitope from the pre-S.sub.2 region of the HBs antigen of the viral hepatitis virus.

### Claim 25 (depends on 17)

Microparticle according to claim 17, characterized in that said protein comprises the B epitope of the VP1 protein of the poliomyelitis virus.

### Claim 26 (depends on 17)

Microparticle according to claim 17, characterized in that said protein comprises the B epitope of the gp120 protein of the HIV-1 virus.

### Claim 27 (depends on 17)

Pharmaceutical composition characterized in that it comprises microparticles according to claim 17, in combination with pharmaceutically compatible diluents or adjuvants.