Immunomodulatory agent-polymeric compounds

• US 9,884,112 B2
• Filed: 03/13/2015
• Issued: 02/06/2018
• Est. Priority Date: 05/27/2009
• Status: Expired due to Fees

• Current Assignee: Selecta Biosciences, Inc.
• Original Assignee: Selecta Biosciences, Inc.
• Inventors: Zepp, Charles, Lipford, Grayson B., Gao, Yun, Johnston, Lloyd, Fu, Fen-ni, Keegan, Mark J., Baldwin, Sam
• Primary Examiner(s): JONES JR., ROBERT STOCKTON
• Application Number:
  US14/658,040
• Publication Number:
  US 20150328300A1
• Time in Patent Office: 1,061 Days
• 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 compounds and methods, of conjugates of immunomodulatory agents and polymers or unit(s) thereof. The conjugates may be contained within synthetic nanocarriers, and the immunomodulatory agents may be released from the synthetic nanocarriers in a pH sensitive manner.

Claims

1. A compound that comprises a structure as in formula (IV):

3. The compound of claim 1, wherein R₁ is H, R₂ is isobutyl, Y is C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

4. The compound of claim 1, wherein R₁ is ethoxymethyl, R₂ is hydroxyisobutyl, Y=C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

5. The compound of claim 1, wherein R₁ is ethoxymethyl, R₂ is methanesulfonamidoisobutyl, Y=C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

6. The compound of claim 1, wherein R₁ is OH, R₂ is benzyl, Y=N, R₃ is absent, and R₄ is butoxy.

7. The compound of claim 1, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is butylamino.

8. The compound of claim 1, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is butoxy.

9. The compound of claim 1, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is benzylamino.

10. The compound of claim 1, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is pentyl.

11. A composition comprising the compound of claim 1.

2. A method for making a compound that comprises a structure as in formula (IV):

12. The method of claim 2, wherein R₁ is H, R₂ is isobutyl, Y is C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

13. The method of claim 2, wherein R₁ is ethoxymethyl, R₂ is hydroxyisobutyl, Y=C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

14. The method of claim 2, wherein R₁ is ethoxymethyl, R₂ is methanesulfonamidoisobutyl, Y=C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

15. The method of claim 2, wherein R₁ is OH, R₂ is benzyl, Y=N, R₃ is absent, and R₄ is butoxy.

16. The method of claim 2, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is butylamino.

17. The method of claim 2, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is butoxy.

18. The method of claim 2, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is benzylamino.

19. The method of claim 2, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is pentyl.

20. A compound that comprises a structure as in formula (VI):

21. The compound of claim 20, wherein the polymer is selected from the group consisting of polyketaldiols, poly(ethylene)glycol, polycaprolactone diol, diblock polylactide-co-poly(ethylene)glycol, diblock polylactide/polyglycolide-co-poly(ethylene)glycol, diblock polyglycolide-co-poly(ethylene)glycol, poly(propylene) glycol, poly(hexamethylene carbonate)diol, and poly(tetrahydrofuran).

22. The compound of claim 20, wherein the polymer has a weight average molecular weight ranging from 800 Daltons to 10,000 Daltons, as determined using gel permeation chromatography.

23. The compound of claim 20, wherein the polymer does not comprise polyketal or unit thereof.

24. The compound of claim 20, wherein R₁ is H, R₂ is isobutyl, Y is C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

25. The compound of claim 20, wherein R₁ is ethoxymethyl, R₂ is hydroxyisobutyl, Y=C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

26. The compound of claim 20, wherein R₁ is ethoxymethyl, R₂ is methanesulfonamidoisobutyl, Y=C, and R₃ and R₄ are combined to form a benzene ring with the carbon atoms of the pyridine ring to which they are connected.

27. The compound of claim 20, wherein Y=N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is butoxy.

28. The compound of claim 20, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is butylamino.

29. The compound of claim 20, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is benzylamino.

30. The compound of claim 20, wherein Y is N, R₁ is OH, R₂ is benzyl, R₃ is absent, and R₄ is pentyl.

31. A composition comprising the compound of claim 20.

32. A synthetic nanocarrier that comprises the compound of claim 20.

33. A composition comprising the synthetic nanocarrier of claim 32.

34. A composition comprising a vaccine comprising the compound of claim 20.

35. A composition comprising a vaccine comprising the synthetic nanocarrier of claim 32.

36. A method comprising:

administering the compound of claim 20 to a subject.