Stabilized aptamers to platelet derived growth factor and their use as oncology therapeutics

• US 8,853,376 B2
• Filed: 09/16/2011
• Issued: 10/07/2014
• Est. Priority Date: 11/21/2002
• Status: Expired due to Fees

• Current Assignee: Archemix LLC
• Original Assignee: Archemix LLC
• Inventors: McCauley, Dilara, Diener, John L., Wilson, Charles, McCauley, Thomas Greene
• Primary Examiner(s): SCHNIZER, RICHARD A
• Application Number:
  US13/235,222
• Publication Number:
  US 20120171304A1
• Time in Patent Office: 1,117 Days
• Field of Search: None
• US Class Current: 536/23.1
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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 2310/16 Aptamers
• CPC Class Codes: C12N 2310/335 Modified T or U
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/353 linked to the nucleic acid via an atom other than carbon
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/31 Combination therapy

Abstract

Materials and methods are provided for producing and using aptamers useful as oncology therapeutics capable of binding to PDGF, PDGF isoforms, PDGF receptor, VEGF, and VEGF receptor or any combination thereof with great affinity and specificity. The compositions of the present invention are particularly useful in solid tumor therapy and can be used alone or in combination with known cytotoxic agents for the treatment of solid tumors. Also disclosed are aptamers having one or more CpG motifs embedded therein or appended thereto.

Claims

1. An unpegylated or pegylated aptamer or pharmaceutically acceptable salt thereof that binds to PDGF and comprises 5′

-(SEQ ID NO;

     69)-PEG-(SEQ ID NO;

     40)-PEG-(SEQ ID NO;

     70)-3T-3′

, wherein PEG is a polyethylene glycol spacer and 3T is an inverted deoxythymidine.

2. The aptamer or pharmaceutically acceptable salt of the aptamer of claim 1, wherein the aptamer or pharmaceutically acceptable salt of the aptamer is pegylated.

3. The aptamer or pharmaceutically acceptable salt of the aptamer of claim 2, wherein the aptamer or pharmaceutically acceptable salt of the aptamer is pegylated with a 40 kDa PEG moiety.

4. The aptamer or pharmaceutically acceptable salt of the aptamer of claim 3, wherein the 40 kDa PEG moiety is branched.

5. The aptamer or pharmaceutically acceptable salt of the aptamer of claim 4, wherein the aptamer or pharmaceutically acceptable salt of the aptamer comprises the following structure at its 5′

end;

6. The aptamer or pharmaceutically acceptable salt of the aptamer of claim 5, wherein the polyethylene glycol spacer is a PEG-6 spacer.

7. A composition comprising a therapeutically effective amount of the aptamer of claim 1, 2, 3, 4, 5, or 6, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. The composition of claim 7, further comprising a VEGF/VEGFR antagonist.

9. The composition of claim 7, further comprising an aptamer that binds to VEGF.