TARGETED SYNTHETIC NANOCARRIERS WITH PH SENSITIVE RELEASE OF IMMUNOMODULATORY AGENTS

• US 20110020388A1
• Filed: 05/26/2010
• Published: 01/27/2011
• Est. Priority Date: 05/27/2009
• Status: Abandoned Application

• Current Assignee: Selecta Biosciences, Inc.
• Original Assignee: Selecta Biosciences, Inc.
• Inventors: Zepp, Charles, Fu, Fen-Ni, Keegan, Mark J., Gao, Yun, Baldwin, Sam, Lipford, Grayson B., Johnston, Lloyd
• Application Number:
  US12/788,260
• Publication Number:
  US 20110020388A1
• Time in Patent Office: Days
• US Class Current: 424/193.1
• CPC Class Codes: A61K 2039/55511 Organic adjuvants
• CPC Class Codes: A61K 2039/55544 Bacterial toxins
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/6093 Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
• CPC Class Codes: A61K 2039/62 characterised by the link between antigen and carrier
• CPC Class Codes: A61K 2039/627 characterised by the linker
• CPC Class Codes: A61K 39/0013 Therapeutic immunisation against small organic molecules, e.g. cocaine, nicotine
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• 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: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 473/34 : attached in position 6, e.g. adenine
• CPC Class Codes: C08G 63/06 : derived from hydroxycarboxylic acids
• CPC Class Codes: C08G 63/08 : Lactones or lactides
• CPC Class Codes: C08G 63/912 : derived from hydroxycarboxylic acids
• CPC Class Codes: C08G 64/42 : Chemical after-treatment
• CPC Class Codes: C08J 2367/04 : Polyesters derived from hydroxy carboxylic acids, e.g. lactones C08J2367/06 takes precedence
• CPC Class Codes: C08J 3/24 : Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K

Abstract

This invention relates to compositions, and related methods, of synthetic nanocarriers that target sites of action in cells, such as antigen presenting cells (APCs), and comprise immunomodulatory agents that dissociate from the synthetic nanocarriers in a pH sensitive manner. Also disclosed are compositions and methods relating to synthetic nanocarriers that encapsulate labile immunomodulatory agents that dissociate from the synthetic nanocarriers in a pH sensitive manner.

Claims

1. A composition comprising:

synthetic nanocarriers that comprise an immunomodulatory agent coupled to the synthetic nanocarrier;

wherein the immunomodulatory agent dissociates from the synthetic nanocarrier according to the following relationship;

IArel(4.5)₂₄%/IArel(7.4)₂₄%≧

1.2;

wherein IArel(4.5)₂₄% is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours divided by the sum of the weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours plus a weight of immunomodulatory agent retained in the synthetic nanocarrier upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours, expressed as weight percent, and taken as an average across a sample of the synthetic nanocarriers; and

wherein IArel(7.4)₂₄% is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours divided by the sum of the weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours plus a weight of immunomodulatory agent retained in the synthetic nanocarrier upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours, expressed as weight percent, and taken as an average across a sample of the synthetic nanocarriers.

2. The composition of claim 1, wherein the immunomodulatory agent is coupled to the synthetic nanocarrier via an immunomodulatory agent coupling moiety.

3. The composition of claim 1, wherein the immunomodulatory agent is encapsulated within the synthetic nanocarrier.

4. The composition of claim 3, wherein the immunomodulatory agent comprises a labile immunomodulatory agent.

5. The composition of claim 4, wherein the labile immunomodulatory agent comprises an imidazoquinoline, an adenine derivative, or an oligonucleotide that comprises 5′

-CG-3′

, wherein C is unmethylated and wherein the oligonucleotide comprises a backbone comprising one or more unstabilized internucleotide linkages.

6. The composition of claim 5, wherein the imidazoquinoline comprises an imidazoquinoline amine, an imidazopyridine amine, a 6,7-fused cycloalkylimidazopyridine amine, an imidazoquinoline amine, imiquimod, or resiquimod.

7. The composition of claim 5, wherein the oligonucleotide'"'"'s backbone comprises no stabilizing chemical modifications that function to stabilize the backbone under physiological conditions.

8. The composition of claim 7, wherein the oligonucleotide'"'"'s backbone comprises a backbone that is not modified to incorporate phosphorothioate stabilizing chemical modifications.

9. The composition of claim 1, wherein the immunomodulatory agent is an adjuvant.

10. The composition of claim 9, wherein the adjuvant comprises a Toll-like receptor (TLR) agonist.

11. The composition of claim 10, wherein the TLR agonist is a TLR 3 agonist, TLR 7 agonist, TLR 8 agonist, TLR 7/8 agonist, or a TLR 9 agonist.

12. The composition of claim 10, wherein the TLR agonist is an immunostimulatory nucleic acid.

13. The composition of claim 12, wherein the immunostimulatory nucleic acid is an immunostimulatory DNA or immunostimulatory RNA.

14. The composition of claim 12, wherein the immunostimulatory nucleic acid is a CpG-containing immunostimulatory nucleic acid that comprises one or more stabilizing chemical modifications that function to stabilize the backbone under physiological conditions.

15. The composition of claim 9, wherein the adjuvant comprises a universal T-cell antigen.

16. The composition of claim 1, wherein the synthetic nanocarriers further comprise a B cell antigen and/or a T cell antigen.

17. The composition of claim 1, wherein the synthetic nanocarriers further comprise an antigen presenting cell (APC) targeting feature.

18. The composition of claim 1, wherein the synthetic nanocarriers comprise one or more biodegradable polymers.

19. The composition of claim 18, wherein the immunomodulatory agent is coupled to the one or more biodegradable polymers via the immunomodulatory agent coupling moiety.

20. The composition of claim 18, wherein the biodegradable polymer comprises poly(lactide), poly(glycolide), or poly(lactide-co-glycolide).

21. The composition of claim 18, wherein the biodegradable polymers have a weight average molecular weight ranging from 800 Daltons to 10,000 Daltons, as determined using gel permeation chromatography.

22. The composition of claim 2, wherein the immunomodulatory agent coupling moiety comprises an amide bond.

23. The composition of claim 2, wherein the immunomodulatory agent coupling moiety comprises an ester bond.

24. The composition of claim 1, wherein the synthetic nanocarriers comprise lipid-based nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles, peptide or protein-based particles, nanoparticles that comprise a combination of nanomaterials, spheroidal nanoparticles, cubic nanoparticles, pyramidal nanoparticles, oblong nanoparticles, cylindrical nanoparticles, or toroidal nanoparticles.

56. A composition comprising a vaccine comprising the composition claim 1.

57. A method comprising:

administering the composition of claim 1 to a subject.

25. A composition comprising:

synthetic nanocarriers that comprise an immunomodulatory agent coupled to the synthetic nanocarrier;

wherein the immunomodulatory agent dissociates from the synthetic nanocarrier according to the following relationship;

IA(4.5)₂₄/IA(4.5)₆≧

1.2;

wherein IA(4.5)₂₄ is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours taken as an average across a sample of the synthetic nanocarriers; and

wherein IA(4.5)₆ is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 6 hours taken as an average across a sample of the synthetic nanocarriers.

26-30. -30. (canceled)

31. A composition comprising:

synthetic nanocarriers that comprise an immunomodulatory agent coupled to the synthetic nanocarrier;

wherein the immunomodulatory agent dissociates from the synthetic nanocarrier according to the following relationship;

6≦

IA(4.5)₂₄/IA(4.5)₆≧

1.2;

wherein IA(4.5)₂₄ is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours taken as an average across a sample of the synthetic nanocarriers; and

wherein IA(4.5)₆ is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 6 hours taken as an average across a sample of the synthetic nanocarriers.

32-55. -55. (canceled)

58-59. -59. (canceled)