Methods and compositions for enhancing cd4+ regulatory t cells

a technology of regulatory t cells and immunosuppressants, applied in the direction of drug compositions, immunological disorders, metabolism disorders, etc., can solve the problems of overall systemic downregulation of the immune system, decrease of undesired immune responses, etc., and achieve the effect of enhancing the number or percentage (or ratio)

Pending Publication Date: 2014-11-13
SELECTA BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0004]In one aspect, a method comprising enhancing the number or percentage (or ratio) of CD4+ regulatory T cells, such as those specific to a therapeutic macromolecule, by administering to a subject synthetic nanocarriers attached to immunosuppressants, and therapeutic macromolecules, wherein the therapeutic macromolecules are not co-formulated with the synthetic nanocarriers attached to immunosuppessants prior to administration, is provided.
[0019]In another aspect, a use of any one of the compositions or kits provided herein for the manufacture of a medicament for enhancing the number or percentage (or ratio) of CD4+ regulatory T cells, such as therapeutic macromolecule-specific CD4+ regulatory T cells, in a subject is provided. In one embodiment, the composition or kit comprises an immunosuppressant and a therapeutic macromolecule, wherein the immunosuppressant and therapeutic macromolecule are not co-formulated. In another embodiment of any one of the uses provided herein, the immunosuppressant is attached to synthetic nanocarriers.
[0021]In another aspect, a method of manufacturing a medicament intended for enhancing the number or percentage (or ratio) of CD4+ regulatory T cells, such as therapeutic macromolecule-specific CD4+ regulatory T cells, is provided. In one embodiment, the medicament comprises an immunosuppressant and a therapeutic macromolecule, wherein the immunosuppressant and therapeutic macromolecule are not co-formulated. In another embodiment of any one of the methods of manufacturing provided herein, the immunosuppressant is attached to synthetic nanocarriers.

Problems solved by technology

As previously mentioned, current conventional immunosuppressants are broad-acting and generally result in an overall systemic downregulation of the immune system.
Accordingly, such methods and compositions can result in a decrease in undesired immune responses associated with administration of therapeutic macromolecules and / or can be beneficial for subjects in need of treatment with therapeutic macromolecules.

Method used

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  • Methods and compositions for enhancing cd4+ regulatory t cells
  • Methods and compositions for enhancing cd4+ regulatory t cells
  • Methods and compositions for enhancing cd4+ regulatory t cells

Examples

Experimental program
Comparison scheme
Effect test

example 1

Polymeric Nanocarrier Containing Polymer-Rapamycin Conjugate (Prophetic)

Preparation of PLGA-Rapamycin Conjugate

[0186]PLGA polymer with acid end group (7525 DLG1A, acid number 0.46 mmol / g, Lakeshore Biomaterials; 5 g, 2.3 mmol, 1.0 eq) is dissolved in 30 mL of dichloromethane (DCM). N,N-Dicyclohexylcarbodimide (1.2 eq, 2.8 mmol, 0.57 g) is added followed by rapamycin (1.0 eq, 2.3 mmol, 2.1 g) and 4-dimethylaminopyridine (DMAP) (2.0 eq, 4.6 mmol, 0.56 g). The mixture is stirred at rt for 2 days. The mixture is then filtered to remove insoluble dicyclohexylurea. The filtrate is concentrated to ca. 10 mL in volume and added to 100 mL of isopropyl alcohol (IPA) to precipitate out the PLGA-rapamycin conjugate. The IPA layer is removed and the polymer is then washed with 50 mL of IPA and 50 mL of methyl t-butyl ether (MTBE). The polymer is then dried under vacuum at 35 C for 2 days to give PLGA-rapamycin as a white solid (ca. 6.5 g).

[0187]Nanocarrier containing PLGA-rapamycin is prepared a...

example 2

Preparation of Gold Nanocarriers (AuNCs) Containing Rapamycin (Prophetic)

Preparation of HS-PEG-Rapamycin

[0191]A solution of PEG acid disulfide (1.0 eq), rapamycin (2.0-2.5 eq), DCC (2.5 eq) and DMAP (3.0 eq) in dry DMF is stirred at rt overnight. The insoluble dicyclohexylurea is removed by filtration and the filtrate is added to isopropyl alcohol (IPA) to precipitate out the PEG-disulfide-di-rapamycin ester and washed with IPA and dried. The polymer is then treated with tris(2-carboxyethyl)phosphine hydrochloride in DMF to reduce the PEG disulfide to thiol PEG rapamycin ester (HS-PEG-rapamycin). The resulting polymer is recovered by precipitation from IPA and dried as previously described and analyzed by H NMR and GPC.

[0192]Formation of Gold NCs (AuNCs):

[0193]An aq. solution of 500 mL of 1 mM HAuC14 is heated to reflux for 10 min with vigorous stirring in a 1 L round-bottom flask equipped with a condenser. A solution of 50 mL of 40 mM of trisodium citrate is then rapidly added to t...

example 3

Mesoporous Silica Nanoparticles with Attached Ibuprofen (Prophetic)

[0196]Mesoporous SiO2 nanoparticle cores are created through a sol-gel process. Hexadecyltrimethyl-ammonium bromide (CTAB) (0.5 g) is dissolved in deionized water (500 mL), and then 2 M aqueous NaOH solution (3.5 mL) is added to the CTAB solution. The solution is stirred for 30 min, and then Tetraethoxysilane (TEOS) (2.5 mL) is added to the solution. The resulting gel is stirred for 3 h at a temperature of 80° C. The white precipitate which forms is captured by filtration, followed by washing with deionized water and drying at room temperature. The remaining surfactant is then extracted from the particles by suspension in an ethanolic solution of HCl overnight. The particles are washed with ethanol, centrifuged, and redispersed under ultrasonication. This wash procedure is repeated two additional times.

[0197]The SiO2 nanoparticles are then functionalized with amino groups using (3-aminopropyl)-triethoxysilane (APTMS)...

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Abstract

Disclosed are methods and related compositions for administering immunosuppressants and therapeutic macromolecules for enhancing CD4+ regulatory T cells.

Description

RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119 of U.S. provisional applications 61 / 819,517, filed May 3, 2013; 61 / 881,851, filed Sep. 24, 2013; 61 / 881,913, filed Sep. 24, 2013; 61 / 881,921, filed Sep. 24, 2013; 61 / 907,177, filed Nov. 21, 2013; 61 / 948,313, filed Mar. 5, 2014; and 61 / 948,384, filed Mar. 5, 2014, the entire contents of each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to administering immunosuppressants and therapeutic macromolecules for enhancing CD4+ regulatory T cells, such as those specific to the therapeutic macromolecules. The methods and compositions provided herein allow for a shift to tolerogenic immune response development, in particular CD4+ regulatory T cell production or development. Accordingly, the methods and compositions provided can be used to generate tolerogenic immune responses in a subject in which the administration of a therapeutic macromolecule may result in ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/436A61K31/192A61K38/17A61K31/4709A61K38/48A61K38/50A61K47/48A61K38/13
CPCA61K31/436A61K47/48215A61K31/192A61K38/13A61K31/4709A61K38/482A61K38/50A61K38/1767A61K47/482C12Y305/01001A61K9/0019A61K9/127A61K9/5115A61K9/5153C07K16/18C07K16/241C07K16/40A61K2039/505A61K38/47A61K9/5192A61K47/6923A61K47/6929A61K47/6935A61K47/6937A61K38/19A61K38/21A61K38/37A61K38/43A61P19/02A61P29/00A61P3/00A61P35/00A61P37/00A61P37/06A61P37/08A61P43/00A61K2300/00A61K39/39533A61K45/06A61K39/3955A61K38/1761A61K2039/575A61K38/195A61K9/51A61K2039/622A61K47/34A61K2039/545A61K38/18A61K39/0003A61K2039/577A61K38/20A61K47/60A61K38/22A61K47/593A61K2039/55511A61K38/38A61K47/6921
Inventor KISHIMOTO, TAKASHI KEIMALDONADO, ROBERTO A.
Owner SELECTA BIOSCI
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