RNA aptamers against BAFF-R as cell-type specific delivery agents and methods for their use

Patent metadata

Field	Value
Publication number	US-9695425-B2
Application number	US-201615166793-A
Country	US
Kind code	B2
Filing date	May 27, 2016
Priority date	Apr 13, 2010
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

In one embodiment, a B cell specific aptamer-siRNA chimera is provided. The B cell specific aptamer-siRNA chimera may include an RNA aptamer that binds BAFF-R and an siRNA molecule conjugated to the RNA aptamer via a nucleotide linker. In another embodiment, a B cell specific RNA aptamer is provided. The RNA aptamer may be a molecule that binds to BAFF-R that has the sequence SEQ ID NO:37, SEQ ID NO:38 or SEQ ID NO:39. In some embodiments, the RNA aptamer is conjugated, via a nucleotide linker, to an siRNA molecule that suppresses expression of one or more target oncogenes in one or more B cells. In one aspect, the one or more target oncogenes are selected from Bcl6, Bcl2, STAT3, Cyclin D1, Cyclin E2 and c-myc. In another embodiment, methods for treating a B cell malignancy in a cancer patient are provided. Such methods may include administering a therapeutically effective amount of a therapeutic composition, the therapeutic composition comprising a B cell specific RNA aptamer that binds BAFF-R.

First claim

What is claimed is:

1. A therapeutic composition comprising:
a pharmaceutically acceptable carrier; and
a B cell specific aptamer-siRNA chimera, the B cell specific aptamer-siRNA chimera comprising:
an RNA aptamer comprising an RNA molecule having the sequence SEQ ID NO:9, SEQ ID NO:10 or SEQ ID NO:11 that binds BAFF-R, and
an siRNA molecule conjugated to the RNA aptamer via a nucleotide linker.

2. The therapeutic composition of claim 1 , wherein the aptamer, upon binding BAFF-R, blocks BAFF ligand mediated cell proliferation.

3. The therapeutic composition of claim 1 , wherein the siRNA molecule suppresses expression of a target oncogene when internalized by a B cell.

4. The therapeutic composition of claim 3 , wherein the target oncogene is selected from Bcl6, Bcl2, STAT3, Cyclin D1, Cyclin E2 and c-myc.

5. The therapeutic composition of claim 1 , wherein the siRNA molecule comprises a sense strand SEQ ID NO:7 and an antisense strand SEQ ID NO:8.

6. The therapeutic composition of claim 1 , wherein the siRNA molecule is a bifunctional siRNA molecule which suppresses expression of two target oncogenes when internalized by the B cell.

7. The therapeutic composition of claim 6 , wherein the two target oncogenes are selected from Bcl6, Bcl2, STAT3, Cyclin D1, Cyclin E2 and c-myc.

8. The therapeutic composition of claim 1 , wherein the nucleotide linker is a uracil linker comprising approximately 2-10 uracils.

9. The therapeutic composition of claim 1 , wherein the chimera has
a sense strand selected from SEQ ID NO:37, SEQ ID NO:38 or SEQ ID NO:39, and an antisense strand having the sequence SEQ ID NO:40;
a sense strand selected from SEQ ID NO:41 or SEQ ID NO:42 and an antisense strand having the sequence SEQ ID NO:43;
a sense strand having the sequence SEQ ID NO:46 and an antisense strand having the sequence SEQ ID NO:47; or
a sense strand having the sequence SEQ ID NO:49 and an antisense strand having the sequence SEQ ID NO:48.

10. A therapeutic composition comprising a pharmaceutically acceptable carrier and a B cell specific RNA aptamer, the B cell specific RNA aptamer comprising an RNA molecule that binds to BAFF-R having the sequence SEQ ID NO:9, SEQ ID NO:10 or SEQ ID NO:11.

11. The therapeutic composition of claim 10 , wherein the RNA molecule is conjugated, via a nucleotide linker, to an siRNA molecule that suppresses expression of one or more target oncogenes in one or more B cells.

12. The therapeutic composition of claim 11 , wherein the one or more target oncogenes are selected from Bcl6, Bcl2, STAT3, Cyclin D1, Cyclin E2 and c-myc.

13. The therapeutic composition of claim 10 , further comprising an siRNA molecule conjugated to the RNA aptamer via a nucleotide linker.

14. The therapeutic composition of claim 13 , wherein the siRNA molecule comprises a sense strand SEQ ID NO:7 and an antisense strand SEQ ID NO:8.

15. A therapeutic composition comprising a pharmaceutically acceptable carrier and a B cell specific aptamer-siRNA chimera, the B cell specific aptamer-siRNA chimera comprising:
an RNA aptamer that binds BAFF-R, and
an siRNA molecule comprising a sense strand SEQ ID NO:7 and an antisense strand SEQ ID NO:8 conjugated to the RNA aptamer via a nucleotide linker.

16. The therapeutic composition of claim 15 , wherein the siRNA molecule suppresses expression of a target oncogene when internalized by a B cell.

17. The therapeutic composition of claim 16 , wherein the target oncogene is selected from Bcl6, Bcl2, STAT3, Cyclin D1, Cyclin E2 and c-myc.

Assignees

• Hope City

Inventors

• Rossi John
• Tiemann Katrin
• Zhou Jiehua
• Vallazza Britta

Classifications

• C12N2310/16

  Aptamers · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C12N15/115 Primary

  Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith {; Nucleic acids binding to non-nucleic acids, e.g. aptamers} · CPC title

• C07H21/02

  with ribosyl as saccharide radical · CPC title