Delivery of RNA to trigger multiple immune pathways

Patent metadata

Field	Value
Publication number	US-9801897-B2
Application number	US-201113808085-A
Country	US
Kind code	B2
Filing date	Jul 6, 2011
Priority date	Jul 6, 2010
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

RNA encoding an immunogen is co-delivered to non-immune cells at the site of delivery and also to immune cells which infiltrate the site of delivery. The responses of these two cell types to the same delivered RNA lead to two different effects, which interact to produce a strong immune response against the immunogen. The non-immune cells translate the RNA and express the immunogen. Infiltrating immune cells respond to the RNA by expressing type I interferons and pro-inflammatory cytokines which produce a local adjuvant effect which acts on the immunogen-expressing non-immune cells to upregulate major histocompatibility complex expression, thereby increasing presentation of the translated protein to T cells. The effects on the immune and non-immune cells can be achieved by a single delivery of a single RNA e.g. by a single injection.

First claim

The invention claimed is:

1. A method of stimulating an endosomal innate immunity receptor and stimulating a cytoplasmic innate immunity receptor in a vertebrate, comprising administering a composition comprising the following:
(i) an immunogen-encoding self-replicating RNA to the vertebrate such that the RNA is translated to provide expression of the immunogen, wherein all of the nucleotides in the RNA are standard A, C, G and U ribonucleotides other than a 5′ cap, and wherein the RNA comprises genetic elements required for RNA replication and lacks those genetic elements encoding gene products necessary for viral particle assembly; and
(ii) a delivery system substantially free of viral protein.

2. The method of claim 1 , wherein the RNA is administered by injection to skeletal muscle tissue.

3. The method of claim 1 , wherein the RNA is administered by injection.

4. The method of claim 3 , wherein injection is via a needle.

5. The method of claim 1 , wherein the endosomal innate immunity receptor is TLR7.

6. The method of claim 1 , wherein the cytoplasmic innate immunity receptor is a RNA helicase.

7. The method of claim 1 , wherein the delivery systems comprises: (i) liposomes; (ii) non-toxic and biodegradable polymer microparticles; (iii) a submicron cationic oil-in-water emulsion, or (iv) a combination thereof.

8. The method of claim 1 , wherein the RNA is +-stranded.

9. The method of claim 1 , wherein the RNA encodes an immunogen which can elicit an immune response against a bacterium, a virus, a fungus or a parasite.

10. The method of claim 9 , wherein the immnunogen can elicit an immune response in vivo against respiratory syncytial virus glycoprotein F.

11. A method of raising an immune response to an immunogen in a vertebrate, comprising administering a composition comprising the following:
(i) an immunogen-encoding self-replicating (+)-stranded RNA to the vertebrate such that the RNA: (i) stimulates an endosomal innate immunity receptor; (ii) stimulates a cytoplasmic innate immunity receptor; and (iii) is translated to provide expression of the immunogen, wherein all of the nucleotides in the RNA are standard A, C, G and U ribonucleotides other than a 5′ cap, and wherein the RNA comprises genetic elements required for RNA replication and lacks those genetic elements encoding gene products necessary for viral particle assembly; and
(ii) delivery system substantially free of viral protein.

12. The method of claim 11 , wherein the RNA is administered by injection to skeletal muscle tissue.

13. The method of claim 12 , wherein the delivery systems comprises: (i) liposomes; (ii) non-toxic and biodegradable polymer microparticles; (iii) a submicron cationic oil-in-water emulsion, or (iv) a combination thereof.

14. A method of stimulating an endosomal innate immunity receptor and stimulating a cytoplasmic innate immunity receptor in a vertebrate, comprising administering a composition comprising the following:
(i) an immunogen-encoding RNA to the vertebrate such that the RNA is translated to provide expression of the immunogen, wherein all of the nucleotides in the RNA are standard A, C, G and U ribonucleotides other than a 5′ cap, and wherein the RNA comprises genetic elements required for RNA replication and lacks those genetic elements encoding gene products necessary for viral particle assembly; and
(ii) delivery system substantially free of viral protein.

Assignees

• Geall Andrew
• Ramsauer Katrin
• Otten Gillis
• Mandl Christian
• Glaxosmithkline Biologicals Sa

Inventors

• Geall Andrew
• Ramsauer Katrin
• Otten Gillis
• Mandl Christian

Classifications

• A61K39/12

  Viral antigens · CPC title

• C12N2770/36143

  viral genome or elements thereof as genetic vector · CPC title

• A61K2039/55555

  Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers · CPC title

• C12N2760/18522

  New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes · CPC title

• A61K2039/53

  DNA (RNA) vaccination · CPC title