Oligonucleotide mimetics

• US 20060246123A1
• Filed: 03/12/2004
• Published: 11/02/2006
• Est. Priority Date: 03/12/2003
• Status: Abandoned Application

• Current Assignee: Duke University
• Original Assignee: Duke University
• Inventors: Santulli-Marotto, Sandra L., Sullenger, Bruce A., Rusconi, Christopher P., Gilboa, Eli
• Application Number:
  US10/548,532
• Publication Number:
  US 20060246123A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: 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
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/1048 SELEX
• CPC Class Codes: C12N 15/115 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 Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/3521 Methyl

Abstract

The present invention relates, in general, to a method of using aptamers to modulate the immune system and, in method of inhibiting CTLR-4 function and to aptamers suitable for use in such a method.

Claims

1. A method of regulating immune function in a mammal comprising administering to said mammal an amount of an aptamer that binds CTLA-4, CD40, 4-1BB, OX40 or TGFβ

receptor sufficient to effect said regulation.

2. The method according to claim 1 wherein said mammal is a cancer patient.

3. The method according to claim 2 wherein said patient is a human.

4. The method according to claim 2 wherein said patient is undergoing antigen specific immunotherapy.

5. The method according to claim 4 wherein administration of said aptamer potentiates said immunotherapy.

6. The method according to claim 1 wherein said aptamer binds CTLA-4.

7. The method according to claim 6 wherein said aptamer does not bind CD28.

8. The method according to claim 6 wherein said aptamer is specific for a conserved epitope of interspecies homologues of CTLA-4.

9. The method according to claim 6 wherein said aptamer is Del 60.

10. The method according to claim 1 wherein said aptamer is resistant to nuclease degradation.

11. The method according to claim 10 wherein said aptamer comprises a modified nucleotide selected from the group consisting of a 2′

-amino, 2′

-fluoro or 2′

-O-alkyl nucleotide.

12. The method according to claim 11 wherein said aptamer bears a 3′

cap.

13. The method according to claim 1 wherein said aptamer comprises a polyethylene glycol moiety.

14. The method according to claim 1 wherein said aptamer is bound to a liposome.

15. The method according to claim 1 wherein said aptamer is present as a multimer.

16. A method of identifying an a CTLA-4 aptamer comprising:

i) preparing a candidate mixture of nucleic acids,

ii) contacting said mixture with CTLA-4, wherein nucleic acids present in said mixture having an increased affinity for CTLA-4 relative to the candidate mixture can be partitioned from the remainder of the candidate mixture, and

iii) partitioning said nucleic acids having an increased affinity for CTLA-4 from the remainder of said candidate mixture.

17. The method according to claim 16 further comprising, between steps (i) and (ii), contacting said candidate mixture with CD28 and partitioning out of said candidate mixture nucleic acids having an increased affinity for CD28 relative to the candidate mixture.

18. A method of identifying an aptamer that inhibits CTLA-4 function comprising assessing T cell proliferation in the presence and absence of said aptamer, enhancement of T cell proliferation in the presence of said aptamer indicating inhibition of CTLA-4 function.

19. An aptamer that binds CTLA-4.

20. The aptamer according to claim 19 wherein said aptamer is Del 60 or M9-14 del 55.

21. A composition comprising the aptamer of claim 19 and a carrier.